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Full text of "A century of the United States pharmacopoeia, 1820-1920. I. The galenical oleoresins"

THE LIBRARY 

OF 

THE UNIVERSITY 

OF CALIFORNIA 

PRESENTED BY 

PROF. CHARLES A. KOFOID AND 

MRS. PRUDENCE W. KOFOID 




Digitized by the Internet Archive 

in 2007 with funding from 

IVIicrosoft Corporation 



http://www.archive.org/details/centuryofunitedsOOdumerich 



BULLETIN OF THE UNIVERSITY OF WISCONSIN 

Serial No. 980. Geaeral Seriet No. 764 



A CENTURY OF THE UNITED STATES 
"^ PHARMACOPOEIA, 1820-1920 



I— THE GALENICAL OLEORESINS 

BY 
ANDREW G. DUMEZ 



THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF< PHILOSOPHY 

UNIVERSITY OF WISCONSIN 

1917 



Repriated from vol. xix o( th« 
Transaction* of the Witconiin 
Academy of Scieneei, Am 
and Letters. 



PHARMACEUTICAL PUBLICATIONS OF THE 
UNIVERSITY OF WISCONSIN 



Monographs 

Price 

Nellie Wakeman, Plant pigments 0.35 

A. G. Du Mez, The galenical oleoresins 0. 50 

H. A. Langenhan, The arsenical liquors (In preparation) 

BULLETIXS 

A. F. Sievers, On the addition of organic acids to unsaturated hy- 
drocarbons 0.20 

Nellie Wakeman, The Monardas, a phytochemical study 0.20 

E. Kremers, The classification of carbon compounds . 40 

H. A. Langenhan, The alkaloldal content of stramonium leaves. . 0.25 
E. R. Miller, A chemical study of the oils of several species of 
Eupatorium; and A study of the chemical and physical prop- 
erties of Wisconsin wormwood oil 0.2.") 

E. R. Miller, The chemistry of the oil of Achillea millefolium, a 

study in economic drug culture 0.25 

Grri)i:s 

E. V. Ljmn, Laboratory guide to pharmaceutical technique 0.25 

Nellie Wakeman, Guide to chemistry 40. Plant chemistry for 

pharmacy students 0.20 

E. Kremers, A bibliographic guide for students of the history of 

pharmacy 0.25 

Station Reports 

Report of the Director of the Pharmaceutical Experiment Station for 

the fiscal year July 1, 1913, to June 30, 1914. 
Report of the Director of the Pharmaceutical Experiment Station for 

the fiscal years July 1, 1914, to June 30, 1916. 
Report of the Pharmaceutical Experiment Station for the fiscal vears, 

July 1, 1916, to June .30, 1918. 

Stattox CTi'cn.M's 
1.) General announcement. 
2.) The volatile oil of Pi/, nantri^ m nhi hnncoUthnn l^ursli, hv E. R. 

Miller. 
:•-.) Medicinal plants and designs, by Bernice Oehler. 
4. ) The volatile oil of Monarda fistiilosa L., by E. R. Miller. 
5.) N. F. petroxolins and parallel preparations, bv H. A. Langenhan 

and G. J. Noel. 
6.) Preliminary report of the Conference on the Help Situation in 

Wisconsin, by its chairman. 
7.) Water-soluble volatile products from peppermint, by E. R. Miller. 
S.) The application of the principles of breeding to drug planls, i)nr- 

ticnlarly DaUira, by C. M. Woodworth. (In press.) 



BULLETIN OF THE UNIVERSITY OF WISCONSIN 

SERIAL NO. 980. GENERAL SERIES NO. 764 



C^ei^ 



A CENTURY OF THE UNITED STATES 
PHARMACOPOEIA, 1820-1920 



I_THE GALENICAL OLEORESINS 

BY 
ANDREW G. DU MEZ 



THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILOSOPHY 

UNIVERSITY OF WISCONSIN 

1917 



Reprinted from vol. xii of the 
Transactions of the Wisconsin 
Academy of Sciences, Arti 
and Letters. 



Ri<^0 






CONTENTS 



CONTENTS 



PART I— GENERAL 



Page 

Historical Introduction 7 

Definition l"? 

Drugs used 14 

Solvents used 15 

Methods of preparation 20 

Apparatus employed 27 

Yield 46 

Chemistry 46 

Physical and chemical proper- 
ties 47 

Physical properties 47 

Color 47 

Odor 48 

Taste 48 



Page 

Consistence 48 

Solubility 4» 

Specific gravity ■• . . 49 

Refractive index 50 

Chemical properties 51 

Loss in weight on heating. . 51 

Ash content 53 

Acid number 54 

Saponification vailue 54 

Iodine value (....... 55 

Special tests 55 

Qualitative tests 56 

Quantitative tests 5ft 

Adulterations 5S 



PART II — INDIVIDUAL OLEORESINS 



Page 

Oleoresin of aspidium 59 

Synonyms 59 

History 61 

Drugs used, its collection, pres- 
ervation, etc 62 

IT. S. P. text and comments 

thereon 67 

Yield ./ 74 

Chemistry of the oleoresin and 
of the drug from which 

prepared 79 

Constituents of therapeutic 

importance 86 

Physical properties 86 

Color 86 

Odor 87 

Taste . . . .1 87 

Consistence 87 

Solubility 87 

Specific gravity i 88 

Refractive index 90 

Chemical properties 92 

Loss in weight on heating . . 9S 

Ash content 93 

Acid number 94 

Saponification value 95 

Iodine vailue 97 

Other properties 98 



Page 

Special qualitative tests 9* 

Tests for filicin 99 

Austrian Pharmacopoeia. . 99 

Netherlands Pharmacopoeia 99' 

Hungarian Pharmacopoeia 99^ 

Tests for starch 100 

German Pharmacopoeia. . . 100' 
Test for oleoresin of Dryop- 

teris spinulosa 101 

Hausmann's method 101 

Test for castor oil 101 

Test for copper 101 

Special quantitative tests .... 101 
Methods for the determina- 
tion of filix acid 102^ 

Method of Kremel 102 

Method of Bocchi 10^ 

Method of Kraft 102 

Method of Fromme (orig- 
inal) 103 

Method of Fromme (im- 
proved) . .1 103 

Method of Stoeder '. 103 

Comparison of above 

methods 104 

Methods for the determin- 
ation of crude filicin . . . 104 
Method of Rulle 105 



CONTENTS 



Page 
Method of Daccomo and 

Scoccianti 105 

Method of Schmidt 105 

Method of Fromme 105 

Influence of different alka- 
llies on yield of crude 

filicin 106 

Crude filicin content of 

laboratory properations. 107 
Crude filicin content of 

commercial samples . . . 108 

Physiological tests 109 

Method of Yagi 109 

Adulterations . . . 110 

Oleoresin of capsicum Ill 

Synonyms Ill 

History , 111 

Drugs used, its collection, 

preservation, etc . Ill 

U. S. P. text and comments 

thereon 112 

Yield . ., 117 

Chemistry of the oleoresin 
and of the drug from 

which prepared 121 

Constituents of therapeutic 

importance 124 

Physical properties 124 

CoHor , 124 

Odor 124 

Taste > 124 

Consistence 124 

Solubility 125 

Specific gravity 125 

Refractive index . 126 

Chemical properties 127 

Loss in weight on heating 127 

Ash content 127 

Acid number i 128 

Saponification value 129 

Iodine value 130 

Special quantitative tests. . . 131 

Physiological test 131 

Adulterations ,. . . 132 

Oleoresin of cubeb 132 

Synonyms 132 

History 132 

Drug used, its collection, 

preservation, etc 134 

U. S. P. text and comments 

thereon 134 

Yield 139 

Chemistry of the oleoresin 
• and of the drug from 

which prepared 143 

Constituents of therapeutic 

k importance 147 



Page 

Physical properties 147 

Coilor 147 

Odor 147 

Taste 148 

Consistence 148 

Solubility 148 

Specific gravity 148 

Refractive ihdex 149 

Chemical properties 150 

Loss in weight on heating 150 

Ash content 151 

Acid number 151 

Saponification value 152 

Iodine value 153 

Other properties 154 

Special qualitative tests .... 154 

Method of Dietrich 155 

Method of Gluecksmann. . 156 

Austrian Pharmacopoeia. . 156 

French Pharmacopoeia ... 156 

Swiss Pharmacopoeia .... 156 

Hungarian Pharmacopoeia 156 

German Pharmacopoeia . . 157 

Special quantitative tests ... 157 
Kremel's method for the 
determination of cube- 

bic acid 157 

Adulterations 157 

Oleoresin of ginger 158 

Synonyms 158 

History 158 

Drug used, its collection, 

preservation, etc 158 

U. S. P. text and comments 

thereon 160 

Yield 163 

Chemistry of the oileoresin 
and of the drug from 

which prepared 167 

Constituents of therapeutic 

importance 170 

Physical properties 171 

Color 171 

Odor 171 

Taste 171 

Consistence I7i 

Solubility 171 

Specific gravity 172 

Refractive index 172 

Chemical properties 173 

Loss in weight on heating 173 

Ash content 174 

Acid number 175 

Saponification value 175 

Iodine value 176 

Special qualitative tests .... 177 
Tests for oleoresin of cap- 
sicum , 177 



CONTENTS 



Page 
Method of Garnet and 

Grier 178 

Method of La Wall 178 

Method of Nelson . . 178 

Special quantitative tests . . 179 
Methods for the estimation 

of the g-ing-erol content 179 

Method of Garnet and Grier 179 

Physioilogical tests 180 

Adulterations 181 

Oleoresin of lupulin 181 

Synonyms 181 

History 181 

Drug used, its collection 

preservation, etc. 182 

U. S. P. text and comments 

thereon 183 

Yield 186 

Chemistry of the oleoresin 
and of the drug from 

which prepared ....... 187 

Constituents of therapeutic 

importance 190 

Physical properties 191 

Color 191 

Odor 191 

Taste 191 

Consistence 191 

Solubility 191 

Specific gravity 192 

Refractive index 192 

Chemical properties 193 

Loss in vsreight on heating 193 

Ash content 194 

Acid number 195 

Saponification value 195 

Iodine value 196 

Adulterations 197 

Oleoresin of parsley fruit . . . . 197 

Synonyms 197 

History 198 

Drug used, its coQlection, 

preservation, etc. 198 

U. S. P. text and comments 

thereon 199 

Yield 201 

Chemistry of the oleoresin 

and of the drug from 

which prepared . 202 

Constituents of therapeutic 

importance 204 



Page 

Physical properties "SOS 

Color 205 

Odor 205 

Taste 205 

Consistence 205 

Solubility 205 

Specific gravity 205 

Refractive index 206 

Chemical properties 207 

Loss in weight on heating 207 

Ash content 207 

Acid number 208 

Saponification value 208 

Iodine value 209 

Adulterations 210 

Oleoresin of pepper !210 

Synonyms 210 

History 210 

Drug used, its collection, 

preservation, etc 211 

U. S. P. text and comments 

thereon 212 

Yield 216 

Chemistry of the oleoresin 
and of the drug from 

which prepared 218 

Constituents of therapeutic 

importance 222 

PhysicaJl properties 222 

Color 2122 

Odor 222 

Taste 222 

Consistence 222 

Solubility 222 

Specific gravity 2122 

Refractive index 223 

Chemical properties 224 

Loss in weight on heating 224 

Ash content 225 

Acid number 226 

Saponification value 226 

Iodine value 227 

Special quanitative tests ... 228 
Method for the estimation 

of the piperine content 228 

Advilterations 229 

I 

BIBLIOGRAPHY 29 

INDEX TO BIBLIOGRAPHY 284 



Abbreviations Used for the Titles of PHARMACOPOEiAe and 
Treatises on Pharmacy. 

AUg. P. — Strump, Allgemeine PJiarmakopoe. 

Argent. P. — Argentine Pharmacopoeia — Farmacopcea Na- 
cianal Argentina. 

Aust. P. — Austrian Pharmacopceia — PJiarmacopoea Austriaca. 

Bad. P. — Baden Pharmacopoeia — Pharmacopoea Badensis. 

Belg. P. — Belgian Pharmacopoeia — Pliarmacopcea Belgica. 

Bern. P. — Bernese Pharmacopoeia — Pharmacopoea Bernensis. 

B. P. — BritisJi Phdrmacoposa. 

B. P. C. — BritisJi Pharmaceutical Codex. 

Comp. to the U. S. P. — Companion to the United States Phar- 
macopoeia. 

Dan. P. — Danish Pharmacopoeia — Pharmacopoea Danica. 

Dan. Mil. P. — Danish Military Pharmacopoeia. 

Diet, of Pharm. Sc. — Schweringer, Dictionary of Pharmaceu- 
tical Science. 

Fin. P. — Finnish Pharmacopoeia — Pharmacopoea Fennica. 

Fr. P. — French Pharmacopoeia — Pharmacopoee Francaise. 

G. P. — German Pharmacopoeia — Pharmacopoea Germanica. 

Geiger's P. — Geiger's Pharmacopoe. 

Han. P. — Hannoverian Pharmacopoeia — Pharmahopbe fiir das 
Koenigreich Hannover. 

Hess. P. — Hessian Pharmacopoeia — Pharmakopde fiir das 
Kurfuerstenthum Hessen. 

Hung. P. — Hungarian Pharmacopoeia — Pharmacopoea Hun- 
garica. 

Xtal. P. — Italian Pharmacopoeia — Farmacopoea TJfficiale del 
Regno d' It alia. 

Jap. P. — Japanese Pharmacouoeia — The Pharmacopoeia of 
Japan. 

King's Am. Disp. — King's American Dispensatory, 

Mex. P. — Mexican Pharmacopoeia — Pharmacopoea Mexicana. 

Nat. Stand. Disp. — National Standard Dispensatory. 

Neth. P. — Netherlands Pharmacopoeia — Pharmacopoea Neder- 
landica — Nederlandische Apotheek. 

Nor. P. — Norwegian Pharmacopoeia — Pharmacopoea Nor- 
vegica. 



6 ABBREVIATIONS 

Port. P. — Portuguese Pharmacopoeia — Pharmacopcra Portu- 

gueza. 
Pruss. P. — Prussian Pharmacopoeia — PJiarmacopoea Bonis- 

sica. 
Roum, P. — Roumanian Pharmacopoeia — PJiarmacopoea Ro- 

mana. 
Russ. P. — Russian Pharmacopoeia — PJiarmacopoea Russica. 
Schlesw. Holt. P. — Schleswig-Holstein Pharmacopoeia — PJiar- 

maJcopoe fur ScJileswig und Holstein, 
Sp. P. — Spanish Pharmacopoeia — Farmacopoea Oficial Es- 

panola. 
Swed. P. — Swedish Pharmacopoeia — PJiarmacopoea Suecica. 
Swiss P. — Swiss Pharmacopoeia — PJiarmacopoea Helvetica. 
U. S. Disp. — United States Dispensatory, 
U. S. P. — United States PJmrmacopceia. 
Univ. P. — Hirsch, Universal-PJiarmacopoe. 
Ver. P. der Lond., Edinb. und Dub . Med. Coll. — Yereinigte 

PJiarmacopceen der Londoner, EdinhurgJier, und Duhliner 

Medicines Collegien. 



PART I — GENERAL 



Historical Introduction 

The type of galenical preparation now known as an oleoresin 
has been official in the United States Pharmacopoeia since 1850, 
the oleoresins of cubeb and pepper being the first members of 
this class of preparations to receive recognition, however, under 
the title of fluid extract. 

The suggestion for the name oleoresin appears to have come 
from Buchner though first applied as the name of a galenical 
by Peschier. The latter, in 1825, had prepared an ethereal 
extract of male fern which he designated Huile de Fougere Male. 
To this name, Buchner objected, suggesting the title Extractum 
resinosum. In reporting Peschier 's work, however, Buchner 
•speaks of the constituents of the ethereal extract as the oelharzige 
BestandtJieile of male fern, and later in his account, he refers to 
the finished preparation as the oelJiarziges Extract, i, e. an 
oleoresinous extract. It would appear, therefore, that when 
Peschier, in his second account (1828), speaks of an oleoresine, 
our English oleoresin, he evidently took his suggestion from 
Buchner 's use of the German attribute, oelJiarzig. 

The suggestion of Buchner, that the above mentioned pre- 
paration of male fern be called an extract, appears to have met 
with general favor throughout Europe as is indicated by its title 
in the various European pharmacopoeias, past and present. 
Likewise, such other members of this class of preparations as 
have received recognition in the European countries are to be 
found in the respective pharmacopoeias of these countries under 
the heading, extracta. In the United States, a latinized form 
of Peschier 's title, oleoresine, has been adopted and these pre- 
parations are officially known as oleorsinae. 

The following table of titles will give a fair idea of the early 
development of the synonymy of these preparations : 



DU MEZ— THE GALENICAL OLEORESINS. 



Table I. Early titles of oleoresins 

1825. Huile de Fougere Male — PescMer. 

1826. Extractum Filicis maris resinosum — Buchner. 

1827. Extractum oleo-resinosum Filicis — Brandes. 
Oleum Filicis Maris — Van Dyk. 

Oleo-Besina Filicis, PescMer — Ver. P. d. Lond., Edinb. and Dub. 
Med. Coll. 

1828. Oleoresine de Fougere Male — Peschier. 
Extrait oleoresineux de Cuhehe — Dublanc. 

1829. Extractum Filicis aethereum — App. to Pruss. P. 
Aetherisches FamJcrautextract — App. to Pruss. P. 

1832. Extractum Filicis oleo-resinosum — Jourdan, Univ. P. 

1834. Fiperoide du Gingemhre — Beral. 

1841. Extractum Eadicis Filicis Maris aethereum — Bad. P. 

Aetherisches FarrnTcrautwurzel Extract — Bad. P. 

Extractum Cuheharum aethereum — Bad. P. 

Aetherisches Cuhehen Extract — Bad. P. 
1845. Extractum Filicis Maris aethereum — Geiger's P. 

Farrnwurzelextract — Geiger 's P. 

Extrait eth^re de Cutehe — Geiger 's P. 

Oleoresinous Extract of Cuhehs — Bell 

Ethereal Extract of Cuheis — Procter. 
1849. Oleoresinous Ethereal Extracts — Procter. 
1852. Extractum Filicis Maris aethereum — Swiss P. 

Extrait oleo-r^sineux de Fougere — Swiss P. 

Huile de Fougere de Peschier — Swiss P. 
1854. Extractum Stipitum Aspidii — Nor. P. 
1857. Oleo-Besineux de Cultehe — Garot and Schaeuffele. 
1859. Oleoresina (ae) — Procter. 
1863. Oleoresina Capsici — U. S. P. 

Oleoresina Cuhehae — U. S. P. 

Oleoresina Lupulinae — U. S. P. 

Oleoresina Piperis — U. S. P. 

Oleoresina Zingiberis — U. S. P. 

As becomes apparent from the preceding table, oleoresins be- 
came a recognized class of galenical preparations with their in- 
troduction into the United States PJiarmacopma of 1860. The 
name, as applied to a class of galenicals, appears to have been sug- 
gested by Procter in 1846. Although this term thereby ac- 
quired a dual meaning,^) it was not only shorter, but in other 
respects more convenient than extracta aetherea, previously in 
use in some of the European pharmacopoeias. The disadvan-. 



^As a class of natural plant products and as a class of galenicals. 



HISTORICAL. INTRODUCTION. Q 

tage accruing from the substitution of oleoresina for extracta 
uetherea lay in the fact that as a sub-class they were removed 
from the other sub-classes of extracts : e. g., the extracta (solida)^ 
extracta fluida, etc. With the substitution of acetone for ether 
as an extracting medium, in the eighth revision of the United 
States Pharmacopoeia, it is possibly fortunate that the designa- 
tion extracta aetherea never gained a footing in this country. 

The preparation of this particular class of galenicals was de- 
pendent upon the use of ether. Although, a number of chem- 
ists before the eighteenth century had obtained some ether as an 
ingredient of a mixture resulting from the action of sulphuric 
acid upon alcohol, it appears that the first commercial ether 
was prepared in 1730 by Frobenius,^) who, however, kept his 
process a secret. The use of the distillation residues for the 
preparation of more ether, known to Frobenius, was emphasized 
by several German chemists, and caused a considerable reduc- 
tion in the price of this article. Thus Cadet, in 1774, pointed 
out that he could sell an ounce of ether at 40 sous,^) whereas 
Baume had sold it at 12 livres. But even with this reduction 
in price, ether does not appear to have been a common phar- 
maceutical commodity at that time. Thus, e. g., Hermbstaedt^) 
in 1792, mentions ether and enumerates its properties evidently 
for the reason that it is of pharmaceutical interest primarily be- 
cause it is an ingredient of Liquor anodynus mineralis Hoff- 
manni. However, it should be remarked that Baume mentioned 
it in 1762 as a solvent in the preparation of resin of Jalap,*) and 
in 1790,^) he described its use in the preparation of ethereal, 
tinctures. 

The first positive reference concerning the use of ether as a 
solvent in the preparation of a galenical of the type of our pres- 
ent oleoresins, that appears in the literature, is to be found in 
Peschier's report (in 1825) on the preparation of the Huile de 
Fougere Male, the present oleoresin of aspidium. As a result 
of the almost immediate popularity of this preparation, other 
pharmacists were induced to experiment with ether in attempting 
duplicate or modify Peschier's process. However, none of the 



^Kopp. Geschicht. d. Chem,, vol. 4, p. 302. 

2 Ibid. 

3 Grundriss d. exp. Pharm., part 2, p. 161. 
♦Elements de Pharm. (1872), p. 284. 
•Ibid. (1790), p. 262. 



IQ DU MEZ— THE GALENICAL. OLEORESINS 

early workers attempted to employ it in the extraction of other 
plant drugs, and it was not until 1834, when Beral again called 
attention to the use of ether as a solvent in his preparation of 
Piperoide du Gingemhre, our present oleoresin of ginger, that 
its value in the extraction of oleoresinous drugs appears to have 
been recognized. From then on, however, its use seems to have 
widened rapidly as the French Pharmacopoeia of 1839 contained 
no less than nineteen ethereal tinctures. The increase in the 
number of oleoresins was not as rapid as might be expected in 
view of the statement concerning the ethereal tinctures. Only 
two other members of this class of preparations made their ap- 
appearance before 1850, namely, the Extractum Cxihehariim 
aethereum and the Extractum Seminis Cinae aefhereum. 

Some idea of the rate at which the Extracta aetJierae, our pres- 
ent oleoresins, came into existence and were given official recog- 
nition will become evident from the following : 

In the Prussian Pharmacopoeia of 1829, but one such prepara> 
tion was official, namely, 

Extractum Filicis aethereum. 



The Baden Pharmacopoeia of 1841 contained three prepara- 
tions of this class, viz: 

1.) Extractum Badicis Filicis Maris aethereum. 
2.) Extractum Cuheharum aethereum. 
3.) Extractum Seminis Cinae aethereum. 



The Danish Pharmacopoeia of 1850 contained two prepara- 
tions of this class, viz: 

1.) Extractum Cuheharum aethereum. 
2.) Extractum Filicis Maris aethereum. 



The third edition of the United States Pharmacopoeia, which 
appeared in 1851, included two fluid extracts prepared with 
ether as a menstrum, viz: 

1.) Extractum Culehae fluidum. 
2.) Extractum Piper is fluidum. 



HISTORICAL INTRODUCTION. 



11 



The Belgian Pharmacopoeia of 1854 recognized no less than 
seven ethereal extracts, viz: 

1) Extrait etJiere de Fougere 

2) Extrait 4there de Cantharides 

3) Extrait ^there de Croton 

4) Extrait ^there de Culjehe 

5) Extrait 4therS de d'Aunee 

6) Extrait etMre de Bois garu 

7) Extrait etMre de Semen-contra 

It will be seen from the above array of ethereal extracts of- 
ficial in European pharmacopoeias that the introduction of 
oleoresins into the fifth edition of the United States Pharmaco- 
poeia, which appeared in 1863, was well prepared. 

Procter is commonly given credit for having introduced oleore- 
sins into American materia medica. That he was instrumental 
in bringing them to the attention of the representatives of the 
regular medical school, and that he obtained a place for them 
in the United States PJiarmacopoeia, possibly no one has reason 
to doubt. A review of the early American literature on this 
subject not only reveals this fact, but it also brings out the fact 
that Procter appears to have been ignorant in large part of the 
use of this class of preparations in Europe,^) for nowhere does 
he mention it. It is note-worthy that it was a medical prac- 
titioner (Goddard) who first drew Procter's attention (1846), 
not to a typical representative of this class, but to the prepara- 
tion of Dublanc which was a representative of the extracta oleo- 
resina made by a very cumbersome process, now long discarded 
as being as unscientific as it is impractical. In the same year, 
the English pharmacist, Bell, had his attention drawn to this 
same preparation by Vore, thus showing that valuable prepara- 
tions not advertised were ignored, while a quasi scientific pre- 
paration heralded about apparently attracted general attention. 

To what extent the Eclectic school of medical practioners 
contributed to the popularization of this class of galenicals be- 
fore 1860 cannot be definitely stated from the scanty informa- 



1 That Proctor did know of Mohr's work on this class of preparations 
becomes apparent when the fact is recalled that he adapted Redwood's 
translation of Mohr's Pharmaceutische Technik to American pharmacy under 
the title of Mohr, Redwood & Procter's Pharmacy in 1849, and that he bad 
previously reviewed Redwood's translation in the Am. Jour, of Pharm. 



22 DU MBZ— THE GALENICAL. OLEORESINS. 

tion at hand. However, it is interesting to note that the 
American Dispensatory of 1854, gives the formula of Robinson 
for preparing the ethereal oil of xanthoxylum, the present 
Eclectic oleoresin of xanthoxylum. The same is directed to be 
prepared by extracting the bark with ether and subsequently 
removing the ether by evaporation — a process similar to the one 
now employed in preparing the official oleoresins. Of but 
slightly lesser interest is the advertisement of Wm. S. Merrel 
which appeared in the Eclectic Medical JournM in 1855. Under 
the heading, Class II. — Soft resinoids and oleo-resins, etc., the 
following preparations were listed: 

Apocynin (from Dogsbane). 

Ascelepedin (from Pleurisy Boot), 

Aletrin (from Star Koot). ; 

^upurpurin (from Queen of the Meadow). I 

Iridin^ (from Blue Flag). 

Ptelein, or Oil of Ptelea (from Water Ash). 

Oil of Lohelia (from Lobelia Seed). 

Oil of Xanthoxylum (from Prickley Ash). 

Oil of Capsicum (from African Cayenne). i 

Oil of Stillingia .^p^ 

Oil of Male Fern 



In view of the fact that these preparations were already being 
manufactured and advertised commercially in 1855, there can be 
but little doubt that the Pharmacopoeial Revision Committee of 
1860 must have been aware of their existence and have been in- 
fluenced to some extent thereby. 

Definition 

Oleoresins, as a class of galencials, are extracts prepared, as 
a rule, with the aid of a highly selective solvent. Ether is the 
solvent usually employed for this purpose at the present time, 
whereas, acetone was directed to be used in the eighth revised 
edition of the United States PJiarmacopma. Other solvents of 
this nature, namely: petroleum ether, benzene, chloroform, car- 
bon tetrachloride, et cetera, have been used, but have not been 
ofQcially recognized. The oleoresin of cubeb is an exception 



- Prof. John King is said to have prepared and used Irisin ( identical with 
Iridin) in 1844. Letter from J. U. Lloyd to Edward Kremers (1906). 



DEFINITION 13 

to the rule as alcohol is the menstruum directed to be used 
in its preparation. 

These preparations derive their name from the fact that 
the drugs from which they were originally prepared con- 
tained appreciable amounts of fatty or volatile oil and resin, 
substances, for which ether and acetone were recognized to 
be good solvents. They do not by any means necessarily cor- 
respond to the so-called natural oleoresins, which consist for 
the main part of volatile oil and resin; but, in some cases, 
are products relatively poor in one or both of these constit- 
uents. Thus, for example, the oleoresin of capsicum contains 
little or no volatile oil and only a small amount of resin, 
while the oleoresin of parsely is practically free from resin. 
Furthermore, these preparations are not always liquid as is gen- 
erally stated. The oleoresin of lupulin, for instance, is of the 
consistence of a soft extract when prepared according to phar- 
macopoeial directions, and tends to become firmer with age 
owing to the transformation of the so-called soft into hard resin. 
The manner in which the oleoresins have been defined in the 
various text books and treatises on pharmacy is brought out by 
the following examples, which are representative of the periods 
corresponding to the different decennial revisions of the United 
States PJiarmacopoeia: 

"Oleoresinae — Their peculiarity is that they consist of principles which 
when extracted by means of ether, retain a liquid or semi-liquid state 
upon the evaporation of the menstruum, and at the same time have the 
property of self-preservation, differing in this respect from the fluid ex- 
tracts which require the presence of alcohol to prevent decomposition. 
They consist chiefly, as their name implies, of oil, whether fixed or volatile, 
holding resin and sometimes other active matter in solution.*' V. S. Disp. 
(1870), p. 1315. 

" Oleoresinae, Oleoresins — Mixtures of volatile oils with resins prepared 
by exhausting certain drugs containing both together, the menstruum be- 
ing usually ether which extracts both. The menstruum or solvent is evap- 
orated off, and the usually semi-liquid extract which remains constitutes 
the oleo-resin.*' Oldberg and Wall, C&mp. to the Z7. S. P. (1884), p. 721. 

**The oleoresins are official liquid preparations, consisting principally 
of natural oils and resins extracted from vegetable substances by per- 
colation with ethylic ether. The oleoresins were formerly classed with 
the fluid extracts, but they differ essentially from the latter: 

1. They do not bear any uniform relation to the drug as fluid ex- 
tracts do, of gramme to cubic centimeter, — the yield of oleoresin obtained 



14 DU MEZ— THE GALENICAL, OLEORESINS 

from the drug varying according to the proportion of oil and resin naturally 
present : 

2. The menstruum used, ethylic ether, extracts principles which are 
often insoluble in alcohol or diluted alcohol, and vice versa. Oleoresin of 
Cubeb, for instance, is not identical with Fluid Extract of Cubeb: 

3. They are without exception the most concentrated liquid prepara- 
tions of the drugs that are produced.^' Kemington, Pract. of Pharm. 
(1894), p. 433. 

''Oleoresins are those substances obtained from vegetable medicines by 
means of ether (sometimes alcohol, etc.,) which consist principally of a 
fixed or volatile oil and a resin. In some cases the resin will be held in 
solution by the oil, while in other cases, it will be precipitated upon stand- 
ing and will require agitation to diffuse and suspend it in the oil. A 
third case occurs in which the oil and resin form a more or less perman- 
ent mixture, having the consistency of a very soft extract." King's Am. 
Disp. (1900), p. 1330. 

"Oleoresins are ethereal extracts of an oleoresinous nature, obtained 
from vegetable drugs by percolation with ether." Coblenz's EandbooJc of 
Pharm. (1902), p. 290. 

' ' Oleoresins, Oleoresinae (Oleoresins, L. oleum, oil and resina, resin) — 
Natural solutions of resin in volatile oils, extracted by ether, acetone or 
alcohol." Culbreth, Mat. Med. (1906), p. 20. 

"The pharmaceutical oleoresins are liquid preparations of drugs con- 
taining volatile oil and resin, obtained by percolation of such drug with 
acetone, ether, or alcohol, and subsequent distillation of the solvent from 
the dissolved oleoresins." Arny, Prin. of Pharm. (1909), p. 259. 

"Solutions of this class represent the medicinal virtues of the drugs 
from which they are made, in a more concentrated form than is possible 
•in any other. They possess the power of self-preservation, and in this 
respect are superior to fluidextracts. Oleoresins consist chiefly of fixed 
or volatile oils associated with resin and other constituents; those of- 
ficially recognized, with one" exception, are all prepared, " et cetera. 
Caspari, Treat, on Pharm. (1916). p. 354. 



Drugs Used, Their Collection, Preservation, Etc. 

Since the oleoresins are characterized chiefly by their content 
of oil and resin (see definition above), it is evident that they 
may be prepared from many of the numerous vegetable drugs) 
'of which these substances constitute an appreciable part. The 
number of such drugs, however, which has actually been used 
for this purpose, is comparatively small as is shown in the 
table which follows. The table also reveals the fact that nearly 
all of these drugs are derived from phenogamous plants and 
that they consist, as a rule, of those organs in which oils and 
resins are usually present in the greatest abundance. 



SOLVENTS USED 15 

Tablk 2 — Drufis from which oleoresias have been prepared. 

Phenogams 

Alkanet (root) Cypripedium (rhizome) Pepo (seed) 

Anacardium (fruit) Eucalyptus (leaf) Pepper (fruit) 

Annatto (seed) Galan^al (rhizome) Pomegranate (root) 

Asarum (root) Ginger (rhizome) Ptelea (bark) 

Capsicum (fruit) Helenium (flower) Pyrelhrum (root) 

Cardamon (seed) Iris (rhizome) Sabal (fruit) 

Chenopodium (fruit) Kousso (flower) Santonica (unexp. flower) 

Clove (unexp. flower) Lobelia (seed) Savine (leaf) 

Conium (leaf) Lupulin (strobile) Senecio (root & herb) 

Croton (seed) Matico(leaf) Spiraea (herb) 

Cubeb (fruit) Mezereum (bark) Taxus (leaves) 

Parsley (fruit) Xanthoxylum (bark) 

Cryptogams 
Aspidium (rhizome) Ergot (sclerotium of Claviceps purpurea) 

Of the total immber of drugs enumerated above, seven have 
been utilized in the preparation of the oleoresins official in the 
United States Pharmacopoeia, namely : 

Aspidium Ginger Paisley 

Capsicum Lupulin Pepper 

Cubeb 

With respect to the collection (harvesting) of the foregoing 
and their preparation for use, there is little of a general nature 
to be said as the plants from which these drugs are obtained 
differ so widely in their habits. This subject will, therefore, 
not be given consideration here, but will be discussed in Part II 
under tlic treatment of the individual preparations. 

Solvents Used. 

At the present time, ether is the .solvent directed to be em- 
ployed in the preparation of the official oleoresins with the ex- 
ception of the oleoresin of cubeb which is prepared with alcohol. 
It will be recalled that the first of this class of preparations to 
make its appearance, namely, the Huile de Fougere ofPeschier, 
was also prepared with ether. In fact, ether appears to have 
been the only solvent^) given consideration in this connection 
by the early European investigators. 

* One animal drug, cantharides, has been utilized for the preparation of 
an ethereal extract. This preparation, which was official in the Belgian 
Pharmacopoeia of 1854, cannot properly be classed with the oleoresins since 
it contained no resin — the animal organism being free from constituents of 
this nature. 

2 Buchner in 1826 experimented with alcohol in preparing the Extractum 
Filicis resinosum, while Brandes, in 1827, made use of a menstrum con- 
taining both alcohol and ether, namely the Liquor anodynus, for the same 
purpose. • Later, 1828, Dublanc and Oberdoerffer employed alcohol In th« 
preparation of the oleoresinous extract of cubeb. 



1g DU MEZ— THE GALENICAL* OLJE30RESINS. 

With the introduction of the oleoresins into the United States 
PJiarmacopma of 1860, and their extensive use in this country,, 
a number of American pharmacists were lead to the conducting- 
of experiments, which had for their main object the discovery of 
a solvent less expensive and less dangerous to handle than ether. 
We must, however, note that prior to this time (1860) an at- 
tempt was made by Berjot, a Frenchman, to use carbon disul- 
phide for the purpose of preparing the Extrait olea-resineux de 
Cuhehe. Garot and Schaeuffele, in 1857, in a paper on Berjot 's 
preparation showed that nothing was gained by its use, as two 
and one-half times as much carbon disulphide as ether was re-' 
quired to extract the drug. Furthermore, the removal of the 
last traces of this solvent was a matter of considerable difficulty. 

The solvent which first appears to have suggested itself to 
American investigators was benzin as is indicated in the publi- 
cations of Procter, Maish, Trimble and others. The first ac- 
count of its use in this connection appeared in 1866, when 
Procter published his results on the preparation of the oleoresin 
of cubeb. The following table shows the relative value of alco- 
hol, benzin and ether for the extraction of cubeb as found by 
Procter. 

Table 3. — Yield of oleoresin of cubeb. 



Quantity of drugr 


Menstruum 


Total Yield 


grains 

1000 


Alcohol ... . 


grains 
250 


1000 




170 


1000 


Ether 


'£19 









While Procter could find no objection to the use of alcohol as 
a solvent in the preparation of this oleoresin, he advised against 
the use of benzin as he stated that it did not extract the cubebin 
completely. 

Simultaneously with the above publication of Procter, there 
appeared an account of a general method for preparing the 
oleoresins by Rittenhouse. The latter also worked with benzin, 
but employed it as a ''follow up" solvent after percolation had 
been partially completed with ether. He also experimented 
with glycerin and fusel oil, employing them in a similar manner. 

In 1872 Maish published a review of the experiments of A. H. 



SOLVENTS USED 



17 



Bolton and M. Koth. The latter of these two men conducted 
an investigation on the extraction of ginger and cubebs with 
benzin, the former also included capsicum in his series of ex- 
periments. These workers found that ether still extracted 
some non-volatile matter after the drugs had presumably been 
exhausted with benzin. Further, that, while the benzin oleore- 
sins were all soluble in ether, the ethereal uleoresins of cubeb 
and ginger were only partially soluble in benzin, thus confirming 
Procter 's work in 1866 on the oleoresin of cubeb. 

Henry Trimble was the next investigator^) to experiment to 
any considerable extent with benzin as a solvent. In his re- 
port to the Pennsylvania Pharmaceutical Association, in 1888, 
on commercial oleoresins, he stated that while benzin was in his 
opinion preferable to concentrated ether for the extraction of 
capsicum, it would not answer for the other official oleoresins. 
Following h a table showing the comparative extractive powers 
of ether and benzin as compiled by Trimble : 

Table 4 — Itelatixe extractive power of benzin and ether. 



Drugr 



Aspidium 
Capsicum, 
Cubeb . . . . 
Lupulin.. 
Pepper — 
Ginger — 



Yield witli 
etiier 



Percent. 

6.51 

19.5 

21.26 

60.59 

8 79 

3.97 



Yield with 
benzin 



Percent 
5.? 

18.1-3 

16.65 
7.04 

2.80 
2.48 



Results similar to the above with respect to the oleoresins of 
ginger were reported by Samuel J. Riegel in 1891. 

About this time George M. Beringer became interested in the 
preparation of the oleoresins, and in 1892, he published an ac- 
count of his researches, in which he had employed not only 
ether and benzin as extracting menstrua, but also the heretofore 
little used solvent, acetone. With respect to benzin, he ar- 
rived at the same conclusions as did Trimble, viz: that its use 



1 In 1877, L. Wolff in an article entitled: The use of Petroleum Benzine! 
in Pharmacy, stated that benzin extracted none of the pungent resin from 
ginger, no cubebic acid from cubeb, no piperin from pepper and no san- 
tonin or resin from wormseed. 



18 



DU MEZ— THE GALENICAL. 0KE30RESINS 



is not permissable in the preparation of the official oleoresins^), 
except, perhaps in the case of capsicum, and then only under 
certain restrictions, namely: that percolation be terminated 
after 2 cubic centimeters of percolate are obtained for every 
gram of the drug, as upon further percolation, the oleoresin be- 
comes almost solid owing to the large increase of palmitin ex- 
tracted. In his experiments with acetone^) he found that, as 
with ether, the first portion of the percolate contained nearly 
all the medicinal ingredients of the drug. He, however, 
continued percolation until the drug was exhausted. The 
marc was then removed from the percolator, dried and re- 
percolated with stronger ether; but except in the case of 
capsicum no further extractive matter was obtained. The 
oleoresins were stated to be of excellent quality and the 
yield and properties were nearly the same as when ether 
was used. ■ He especially recommended the use of acetone in 
preparing the oleoresin of ginger, as he claimed that it was in 
every way equal to the preparation made with ether. Follow- 
ing is a table showing Beringer's results with acetone as com- 
pared with ether and benzin : 

Table 5 — Relative extractive values of acetone, ether and benzin. 





Yield to acetone 


Yield to ether 


Yield to benzin 


Drug 


U.S. P. 
method 


Complete 
exhaus- 
tion 


U. S. P. 
method 


Complete 
exhaus- 
tion 


U.S. P. 
metliod 


Complete 
exhaus- 
tion 




Percent. 


Percent. 

18.00 
25.00 
25.00 
24.10 
21.75 
5.57 
71.00 
24.00'^ 
5.93to9.97 3 


Per cent. 


Percent. 


Per cent. 
16.18 
21.00' 


Per cent. 


Capsicum 


18.00' 


17.32 




25 00 


Cubeb 




Cubeb 












Cubeb 


















1... 




Lupulin 







70.80 






Parsley 






22.30 








5.00 to 6.70 

















' Two cubic centimeters of percolate were collected tor each grram of druer. 
'^Represents total extract from which 3 per cent, of wax precipitated, leaving 
21.00 percent, of oleoresin. 

3 Represents total extract whicii yielded 5.93 per cent, of oleoresin. 



^ Pile (1867) confirms this statement in so far as it concerns the oleoresin 
of g-inger. He states that neither benzin nor ether completely extract ginger, 
but that alcohol is the best solvent for this purpose. 

2 The acetone used by Beringer was procured from manufacturers of 
chloroform as the product obtained from the distillation of wood was found 
to consist largely of methyl alcohol and even higher boiling fraction.*?. 



' SOLVENTS USED 19 

From a comparison of the above data with those obtained by 
Trimble (See table 4), it would appear that acetone is equally 
as serviceable as ether in the preparation of the official oleo- 
resins. Such appears, also, to have been the opinion of the Re- 
vision Committee of the United States Pharmacopoeia of 1900, 
as the edition, which became official in 1905, directed that acetone 
be employed in the manufacture of those oleoresins which were 
formerly required to be prepared with ether.^ That this change 
was unsatisfactory is evidenced by the numerous comments 
on the subject occurring in the literature, and by the fact that 
ether is again directed to be used for this purpose in the ninth 
revised edition of the United States Fliarmacopoeia. 

To those unacquainted with the situation, the above action of 
the Revision Committee of 1910, might be taken to indicate that 
the matter of the proper solvent to be employed in the manu- 
facture of these preparations has been definitely settled and the 
superiority of ether in this respect firmly established. A close 
inspection of the preceding reports, along with other informa- 
tion of a similar nature occuring in the literature, would,, how- 
ever, appear to point out, that, as in the case of the oleoresin of 
cubeb, other solvents might be advantageously employed in the 
preparation of certain of these individuals. In this connection 
the use of benzin,^) or better, petroleum ether,^) in the prepara- 
tion of the oleoresins of capsicum and parsley fruit might be 
mentioned, or the employment of acetone in the preparation of 
the oleoresin of ginger..*) As further evidence of the possibil- 
ities along this line, attention is also called to the experiments 
of WoUenweber (1906) on the extraction of aspidium with ben- 
zene, and to the mention of chloroform^) and carbon tetra- 
chloride^) as solvents for the preparation of the oleoresins m 
general. 

The manner in which these solvents have been employed in 



^ The most important factor in determining this change was probably the 
difference in cost of the two solvents at the time (1900), acetone being the 
cheaper. This statement is confirmed in a measure by the fact that now, 
since the price of ether has been reduced, owing to its preparation from 
denatured alcohol, it is again the solvent officially recognized. 

2 See preceding reports by Trimble, Beringer and others. 

^Hyers (1895) also made use of petroleum ether in extracting cubeb. 

*Idris (1898) stated that he found acetone, b. p. 65" C, to be the most 
suitable solvent for extracting ginger. 

«Dorvault, L'Officine (1898), p. 591. 

"Lucas, Practical Pharmacy (1908), p. 149. 



20 I>U MEZ— THE GAUSNICAX. OLEORESINS. 

the preparation of the various oleoresins will be discussed in 
a general way under methods of preparation and in detail under 
individual oleoresins. 

Methods of Preparation 

The methods of preparing the oleoresins as outlined in the 
present edition of the United States PJiarmacopoeia may be 
stated in the following general way: extract the drug com- 
pletely^) by percolation, expose the percolate in a warm place 
until the solvent has completely evaporated and separate the 
remaining liquid portion from any deposited material. This is 
essentially the method of procedure given in most of the late 
editions of the foreign pharmacopoeias as well, notable excep- 
tions being the German and Japanese. In the two latter, the 
drug is directed to be exhausted by maceration instead of per- 
colation. In detail, the methods described in the United States 
Pharmacopoeia, as well as the foreign pharmacopoeias, differ 
somewhat Avith the particular oleoresin as will be brought out to 
some extent in the following discussion and more minutely 
under the separate treatment of each individual. It is perhaps 
needless to state that these methods are not of recent invention 
but have been gradually evolved from the numerous experiments 
conducted both in this country and abroad. 

The first of these experiments dates back to the year 1825, 
when Peschier prepared the Huile de Fougere Male, our pres- 
ent oleoresin of aspidium. In his description of the method of 
preparation, he directs that the male fern rhizomes be extracted 
with successive portions of ether, the decanted ethereal solu- 
tions mixed and evaporated at a gentle heat, and the remaining 
oily residue collected and preserved as the finished product. 
This is essentially the method which appeared in the early 
European pharmacopoeias as is shown in the following typical 
example taken from the Prussian Pharmacopoeia of 1830 : 

Agitate one ounce of powdered male fern root with successive portions 
of eight ounces of ether until the ether decants clear. Then mix the 
several portions and strain. Distill down to one-fourth of the volume 
and evaporate the remainder on a water bath to a thin yellowish-brown 

extract. 



1 Percolation, in the extraction of capsicum is directed to be discontinued 
when eight hundred mills of percolate have been obtained. 



METHODS OF PREPARATION 21 

An inspection of the above method brings out the fact that 
the decanted menstruum was directed to be clarified by the 
process of straining. Not only was a great deal of the solvent 
lost by evaporation in this procedure, but a very considerable 
amount remained adhering to the marc. While some of the 
latter was, in actual practice, removed by pressing the drug 
on the strainer with the hands, Mohr^) in commenting on the 
method stated that, inasmuch as three-fourths of the ether were 
■often lost in these operations, it was useless to recover the re- 
mainder by evaporation. To overcome this loss to some extent, 
he suggested making these preparations in the winter when the 
low temperature would be less favorable for the volatilization of 
the solvent. As ether, at this time and for many years later, 
was a comparatively expensive solvent, it will become apparent 
that a change in the method was to be desired. 

The first decided departure^ from the above method of pro- 
cedure, which appears to have been given official recognition, is 
to be noticed in the Baden Pharmacopoeia of 1841. The method 
briefly stated is as follows : 

Mix the powdered male fern root with a sufficient quantity of ether to 
thoroughly moisten it. Then extract it in a EeaVsche Presse so connected 
with a receiving flask that none of the menstruum will be lost by evap- 
oration. 

A few years later, in 1846, there appeared a method in the 
Swedish Pharmacopceia which likewise included the process of 
displacement, viz: 

Macerate the male fern root, cut in small pieces, with ether and extract 
in a displacement apparatus.^ Then distill the ethereal solution to one- 
fourth of its volume and evaporate the remainder on a water bath to the 
consistence of a thin extract. 

Even with the use of a pressure percolator, so much ether 
was still lost through spontaneous evaporation and through ab- 



* Mohr, Redwood and Procter's Pharmacy (1849), p. 263. 

2 Geiger, in 1827, employed the Real'sche Presse in the preparation of the 
Oleum Filicis Maris, our present oleoresin of aspidium. 

' The apparatus employed for this purpose was most probably the Filtre- 
presse of Count Real or the Luft-presse of Dr. Romershausen, as both of 
these so-called presses were in general use at that time. In fact, both are 
mentioned in connection with the preparation of the extracta by the Prus- 
sian Pharmacopoeia as early as 1834. 



22 DU MEZ— THE GALENICAL OLEORESINS 

sorption by the bag/) that, in operating with small quantities 
of the drug, the recovery of the remainder was scarcely worth 
the trouble. The recognition of these defects by Mohr lead 
him to construct (in 1847) a special form of apparatus for con- 
tinuous extraction with volatile solvents. However, while 
Mohr 's apparatus was a success from an economical standpoint,, 
there is no evidence to show that it was ever employed to any 
extent by the American pharmacist, although, Procter, the 
American editor of Kedwood's translation of Mohr's treatise 
on pharmacy, advocated its use in this connection in 1849. 

About this time (1846) Procter caused the American pharma- 
cists to become interested in this class of preparations by call- 
ing attention to his improvement upon Soubeiran's method (as 
suggested by Dublanc)^) for preparing the Extrait oleo-resineux 
de CuhehCf a preparation similar to our present oleoresin of 
cubeb. The following is the method as devised by Procter. 

"Take cubebs, in powder, one pound avoirdupois, and sulphuric ether 
a sufficient quantity, which is two and one-half to three pounds; intro- 
duce the powder into a displacer, insert the lower end into a bottle that 
fits it, add the ether carefully, and cover the top of the filter with a 
piece of wet bladder through which several pin holes have been made.' The 
flow should be very gradual and if too rapid, the filter should be partially 
closed with a cork. By attention to this point, much less ether will be 
required. The ethereal tincture should be introduced into a large retort^ 
heated by a water bath, and the receiver well refrigerated. The dis- 
tillation should not be hurried toward the last. When five-sixths of the 
ether have passed, it should be separated for use, and the evaporation be 
continued in the retort, observing to keep the temperature below 120®F, 
so as not to volatilize the volatile oil.'* 

A few years later (1850), this method (in essential detail) 
was given recognition by the United States Pharmacopma in 
connection with the preparation of the fluid extracts of cubeb 
and pepper, later known as the oleoresins of cubeb and pepper, 
respectively. For the purpose of better bringing out this 



» Mohr, Redwood and Procter's Pharmacy (1845), p. 263. 

^Although Dublanc described a method for preparing the oleoreslnous 
extract of cubeb, similar to that of Soubeiran, in 1828, neither method is 
given consideration here as both differed to such an extent from the usual 
procedure that they had little or no influence on the development of the 
present process. 

«From the above description, it appears that the form of displacer used 
by Procter was the one described in Mohr, Redwood and Procter's Phar- 
macy, (1849), p. 270. 



METHODS OF PREPARATION 23 

similarity, the following general statement of the pharmaeopoeial 
methods is also given : 

Take of the Drug, in powder, a poundj 

Ether a sufficient quantity. 

Put the drug into a percolator, and having packed it carefully, pour 
the ether gradually upon it until two pints of filtered liquid are ob- 
tained, then distill off by means of a water-bath, at a gentle heat, a pint 
and a half of the ether, and expose the residue in a shallow vessel, until 
the whole of the ether has evaporated. 

The methods in general as they were given in the United 
States Pharmacopoeia of 1860 differ from the above only in the 
quantity of drug and menstruum directed to be taken. Thus, 
twelve troy ounces of drug were directed to be subjected to per- 
colation with ether until twenty-four fluidounces of filtered 
liquid were obtained, "when eighteen fluidounces of the ether 
were to be removed by distillation. In the preparation of the 
oleoresin of ginger, however, the following method of procedure 
was given: 

"Take of Ginger, in fine powder, twelve troyounces; 

"Stronger ether twelve fluidounces; 

"Alcohol a sufficient quantity. 

"Put the ginger into a cylindrical percolator, press it firmly, and pour 
upon it the stronger ether. When this has been absorbed by the powder, 
add alcohol until twelve fluidounces of filtered liquid have passed. Ee- 
cover from this, by distillation on a water-bath, nine fluid-ounces of ether, 
and expose the residue in a capsule until the volatile part has evaporated.'^ 

That the Pharmaeopoeial Eevision Committee was informed 
of the work of Beral in this connection appears to be clearly 
evident, as it was he, who first suggested this procedure (1834), 
also, in the preparation of the oleoresin of ginger, then known 
as the Piperoide du Gingemhre. 

In 1866, Kittenhouse, commenting on the methods in gen- 
eral, which were given in the United States Pharmacopoeia of 
1860, stated that about thirty-six fluid ounces of ether were re- 
quired to extract the drug when proceeding as officially directed. 
He, however, conceived the idea of reducing the amount of ether 
by a procedure similar to that employed in extracting the gin- 
ger rhizomes. Alcohol did not appeal to him as the proper 
* 'follow up" solvent for this purpose and he, therefore, con- 
ducted a series of experiments, in which he made use of benzin. 



24 



DU MEZ — THE GALENICAL. OLEORESINS. 



glycerin and fusel oil. 
finally devised by him : 



The following is the working formula 



''Take any convenient quantity of the drug; for each ounce thus em- 
ployed, iy2 fluid ounces of ether, and 1 fluid ounce or q. s. of benzin. 
Pack the drug in a suitable apparatus, add the ether, and when it has ceased 
to pass, pour on the benzin in the proportion of one fluid ounce for eacli 
ounce of the drug employed or until as much percolate has been obtained 
as equals the amount of ether employed. Eeeover the ether by distilla- 
tion in the usual manner." 

The process of Rittenhouse does not appear to have received 
much attention as there is no subsequent mention of it to be 
found in the literature. 

During the meantime Procter continued his work on the oleo- 
resins and in the same year (1866), he pointed out that prac- 
tically all of the oleoresinous material was to be found in the first 
portions of the percolate, and that a considerable quantity of 
menstruum could be saved by discontinuing the operation be- 
fore the drug was completely exhausted. The following table 
compiled by Procter clearly brings out this point: 



Table 6 — Yield of oleoresin of cubeb to ether, alcohol and benzin . 



Quantity 
of cubeb 


Solvent 


Quantity 

of 1st 
percolate 


Yield of 
oleoresin 


Quantity 

of 2nrt 
percolate 


Yield of 
oleoresin 


Total 
yield 


grains 
1000 


Ether 

Alcohol 

Benzin 


grains 
1000 


grains 
205 
240 
140 


grains 
1000 

2000 


grains 
14 
30 
25 


grains 
219 
250 
170 



The effect of Procter's work is noticed in the 1870 and 1880 
editions of the United States PJiarmacopma. Thus, the Phar- 
macopoeia of 1870 directed that twenty instead of twenty-four 
fluidounces (as formerly required) of percolate be collected for 
every twelve troyounces of drug, while the Pharmacopoeia of 
1880 required that only 150 parts of percolate be obtained for 
every 100 parts of drug taken. It should also be noted, that 
in the 1880 edition, the method of preparing the oleoresin of 
ginger was made to conform with that given for the other oleo- 
resins. 



METHODS OF PREPARATION 25 

The United States Pharmacopoeia of 1890, directed, that, in 
the preparation of all of the official oleoresins, the drug be com- 
pletely exhausted by percolation with ether. The following 
directions for the preparation of the oleoresin of cubeb are 
typical of the methods given : 

* * Cubeb, in No. 30 powder, 500 Gm. ; ether a sufficient quantity. 

* ' Put the cubeb into a cylindrical glass percolator provided with a stop- 
cock, and arranged with a cover and receptacle suitable for volatile liquids. 
Press the drug firmly and percolate slowly with ether, added in suc- 
sive portions, until the drug is exhausted. Eecover the greater part 
of the ether, etc." 

The next edition of the United States Pharmacopoeia (1900) 
contained a number of changes with respect to the methods of 
preparing this class of galenicals. Two new solvents were in- 
troduced, namely, acetone and alcohol ; the method of procedure 
was modified in the case of the oleoresin of capsicum, and an 
ordinary percolator was directed to be used in the preparation 
of the oleoresin of cubeb. The following is a general state- 
ment of the manner in which the oleoresins of aspidium, ginger, 
lupulin and pepper were directed to be extracted. 

Introduce the powdered drug (degree of fineness specified) into a cylin- 
drical glass percolator, provided with a stop-cock, and arranged with a cover 
and receptacle suitable for volatile liquids. Pack the powder firmly, and 
percolate slowly with acetone, added in successive portions, until the drug 
is exhausted. 

The method of extracting the cubeb was stated as follows : 

Introduce the powdered cubeb (degree of fineness specified) into a 
cylindrical glass percolator, pack the powder firmly, and percolate slowly 
with alcohol, added in successive portions, until the cubeb is exhausted. 

The method described for the extraction of capsicum was 
similar in all respects to the first of the methods given above, 
except that percolation was directed to be discontinued when 
eight hundred cubic centimeters of percolate had been obtained. 

The above changes, except in the case of the oleoresin of 
cubeb^) must be attributed to the work of Beringer, an account 
of which was published in 1892. Not only did he advocate 
the use of acetone in these preparations, but he also pointed out 



^ It will be recalled that Procter in 1866 suggested the use of alcohol in 
preparing the oleoresin of cubeb. See table 3, page 922. 



26 r>U MEIZ— THE GALENICAL OLEORESINS 

the advantage of discontinuing percolation short of exhaustion 
in the case of capsicum. 

The ninth revised edition of the United States PJiarmacopoeia 
shows but one change in the method of preparing the oleoresins, 
viz: ether is directed to be used in those cases where acetone was 
employed in the preceding edition. 

From the foregoing discussion, it becomes apparent that the 
United States PJiarmacopoeia, even to the present edition, has 
consistently adhered to the process of simple percolation in ex- 
tracting the oleoresinous drugs. This condition not only ap- 
pears strange, in view of the fact that modern methods of 
operating with the volatile solvents, such as ether, make use of 
some form of continuous extraction apparatus; but is thought 
to show a lack of progress as well. Maish, in 1900, suggested 
the use of Soxhlet's apparatus for this purpose and pointed out 
its advantage, especially when operating with small quantities 
of drug. Reference is also made in this connection to similar 
forms of apparatus in most of the present day text-books on 
pharmacy. 

With reference to the preparation of the oleoresins on a com- 
mercial scale, there is good reason to doubt the employment of 
any of the heretofore mentioned methods. The method most 
likely in use at the present time is one similar to that offi- 
cial in the British PJiarmacopoeia of 1867. The latter, briefly 
stated, is as follows: 

Exhaust the powdered drug by percolation with alcohol, and distill the 
percolate until a soft extract is obtained. Treat this extract with suc- 
cessive portions of ether, mix the ethereal solutions and again distill off 
the solvent, when the residue will constitute the oleoresin. 

The advantage of this method lies in the fact that it requires 
the handling of comparatively small amounts of ether, and 
thereby lessens the danger incurred in working witK large quan- 
tities of this highly inflammable solvent. The disadvantage is 
that alcohol may not extract all of the eother-soluble material 
from the drug. 

In the preceding survey, only the official oleoresins and their 
methods of preparation have been considered. There is, how- 
ever, a number of preparations which have been classed as 
oleoresin, in Parrish's Treatise on Pharmacy, and King's 
American Dispensatory, although, they have never received of- 



APPARATUS EMPLOYED 



27 



licial recognition. They are the so-called Eclectic oleoresins 
^nd are in general directed to be prepared in the following man- 
ner : 

Extract the drug by percolation with alcohol or ether and precipitate the 
oil and resin by pouring the alcoholic or ethereal tincture into water. Lastly, 
separate the product from the water by filtration. 

Among the preparations which have been made in this way 
are the following: oleoresin of iris (iridin), oleoresin of 
xanthoxylum, oleoresin of cardamon (oil of cardamon), oleo- 
resin of ergot, (oil of ergot) and oleoresin of parsley,^) (oil of 
parsley). 

In this connection, it should be pointed out that the fore- 
going are liquid preparations and do not constitute the so-called 
resinoids, which are solids, although prepared in a similar way. 

Apparatus Employed. 

Under the two preceding headlines, the preparation of the 
oleoresins has been discussed from the standpoint of the solvent 
employed in extracting the drug, and with respect to the method 
of procedure. There, is however, still another factor of inter- 
est which deserves consideration in this connection, namely: 
the form of apparatus made use of. 

It will be recalled that the first of this class of preparations 
to make its appearance, the oleoresin of aspidium, as originally 
prepared, required the use of nothing but a macerating jar, 
a cloth strainer and some sort of container, in which the colated 
liquid could be collected and exposed to the air to permit the 
evaporation of the solvent. Likewise, these were the utensils 
generally employed in the experimental stages of the prepara- 
tion of the other members of this class which became known at 
an early date. As soon, however, as the oleoresins became 
recognized as regular pharmaceutical commodities, the method 
of preparation as outlined above was found to be impractical 
owing to the complete loss of the solvent by evaporation. In 
adapting the same to commercial use, steps were, therefore, 
taken to recover as much of the latter as possible. For this 
purpose, some form of distilling apparatus was employed, pre- 



*This preparation should not be confused with the oleoresin of parsley 
as official in the present edition of the United States PharmacopoBia. 



28 



DU MEZ— THE GAUENICAL. OL.EORESINS. 



sumably, the retort and condenser. Even with this modifica- 
tion, however, a large part of the solvent was still lost in the 
operation of straining. 

About this time (1820 to 1840), the extraction of drugs by 
the process of downward displacement was attracting consider- 
able attention, and, as the pharmacist saw in this procedure a 
means of eliminating the operation of straining, it is not at all 
surprising that it should have received early application in the 
preparation of the oleoresins. In explanation of the method of 
procedure as followed at the time, it should be stated that it was 
in reality a process of percolation under pressure, and, as such, 
required the use of a special form of apparatus. Two such 
forms were already available at the time when the oleoresins 
became a subject for investigation, namely : the Filtre-Presse of 
Keal and the Luft-Presse of Romershausen. In fact, Geiger 
made use of the former in the preparation of the oleoresin of 
male fern as early as 1827. While these forms of pressure 
percolators eliminated the process of straining, their use, never- 
theless, appears to have been disadvantageous in certain other 
respects. For instance, the method of operation was rather 
cumbersome, and a considerable amount of solvent was absorbed 
by the cloth bag containing the powdered drug, thus rendering 
the apparatus of little value in working with small quantities 
of the latter. 

As a result of the early work with the pressure percolators, 
experimentation along this line was stimulated and it was soon 
shown that drugs could be completely extracted by simple per- 
colation under ordinary atmospheric pressures. The first evi- 
dence of the use of a simple percolator in the preparation of 
the oleoresins appears in Beral's account of his preparation of 
the Piperoide du Gingembre in 1834. Fifteen years later 
(1849), Procter, in an article on the oleoresinous ethereal ex- 
tracts, mentioned two forms of simple percolators, a conical 
percolator made of tin, and Gilbertson's displacement apparatus 
constructed of glass. Both of these were similar in essential 
detail to the percolators in general use at the present time. In 
fact, the United States Pharmacopoeia still directs that these pre- 
parations be made by simple percolation, a modified form of 
Gilbertson's displacement apparatus being specified for use in 
this connection. This condition seems strange, indeed, in view 
of the fact that modern methods of operating with volatile 



APPARATUS EMPLOYED 



29 



solvents, such as ether, make use of some form of continuous ex- 
traction apparatus. 

Such an apparatus was invented by Mohr in 1847 and its 
advantages in the preparation of the oleoresins pointed out by 
him at this time, and later, by Procter. An apparatus operat- 
ing on similar principles was described by Parrish in 1884 in his 
Treatise on Pharmacy. More recently Maish (1900) has sug- 
gested the use of the Soxhlet apparatus for the preparation of 
small quantities of oleoresins, while a number of other forms of 
continuous extraction apparatus have been mentioned in this 
connection in the various periodicals and text-books on phar- 
macy. 

The different forms of apparatus, which have been mentioned 
at various times in connection with the preparations of the oleo- 
resins, and the methods of operating with the same are described 
in detail in the following chronological list: 
Cadet, C. L. 

Filtre-presse de M. Real. 

Jour, de Pharm., 2, pp. 165 and 192; Repert. der Pharm. 2, 

p. 356. 




Fig. 1.) The body of the extraction apparatus A is made of 
tin, the top of which, being screwed on, can be remaved. It is 



30 



DU MEZ— THE GALENICAL OLEORESINS 



supported on a tripod. At D and D are two false bottoms be- 
tween which the material to be extracted is packed. Into the 
cpver of the apparatus, the pipe B, which may be 50 to 60 feet 
high, is fitted. The communication between B and A may be 
stopped by means of the stop cock C. The dish E under the 
tripod receives the percolate. 

Fig. 2.) The second figure is a modification of the first do- 
ing away with the long tube. The solvent is admitted to the 
space X by pouring it into the funnel E. The percolate is 
collected in the container G. The pressure is secured by filling 
the cast iron container A with mercury. After the apparatus 
C is charged with drug and solvent, the stop-cock H is closed 
and the pipe B also filled with mercury which then forces the 
menstruum through the firmly packed drug. 



Buchner, J. A. 

Beschreibung und Abbildung der von 
hausen erfundenen Luft-presse. 
Repert. der Pharm., 6, p. 316. 



Herrn Dr. 



1819 

Romers- 



'^. i^JPAarma^i^ ^ 




APPARATUS EMPLOYED 



31 



TaiM 




.£U 



The two twin cylinders B and C are mounted on the support A 
and are provided with covers 1 and 10. On the support, the 
diaphragm 3 is placed, covered with a straining cloth which is 
held in position by the diaphragm 4 which in turn is fastened 
by the clamp 5. A third diaphragm 6 is used to covef the sub- 
stance to be extracted. The two cylinders are united by the 
tube 7 provided with a stop-cock. The lower part of B is also 
provided with a stop-cock at S in order to allow the percolate to 
flow out at 9. The lower section of C is converted into an air 
tight compartment by the cover 11, which is provided with an 
opening and stopper at 12. The parts indicated by 13, 14, 15, 
16, and 17 belong to the suction pump necessary to create a va- 
cuum. The suction pump is outside the cylinder and the per- 
colate is not allowed to collect underneath the percolator B, but 
is at once pumped in the reservoir C. 

Beindorff 1826 

Mag. f. d. Pharm., 9, p. 185. [Geiger, Hanbuch d. Pharm. 
(1830), p. 142]. 

The cuts represent Beindorff 's modification of the Eeal 
and Romershausen extraction apparatus. It will be noticed 
that the apparatus in figure 6 is so mounted that it can be tipped 



32 



DU MEZ— THE GALENICAL OLEORESINS. 



at a convenient angle for filling and emptying. In figure 7, a 
more compact form of the apparatus is shown. In the latter, 
the long tube is replaced by an air pump. 




These forms of pressure percolators were mentioned in con- 
nection with the preparation of the oleoresins by Mohr (1854) 
in his Commentary on the Prussian PJiarmacopoeia. 



APPARATUS EMPLOYED 



Simonin 

Journ. de Pharm. et de Chim., 20, p. 128. 



33 

1834 




It is thought that one of the above represents the form of per- 
colator made use of by Beral (1834) in his preparation of the 
Piperoide due Gingemhre. 



34 



DU MEZ— THE GALENICAL OLEORESINS 



Mohr 1847 

Neuer Extractions Apparat fuer Weingeist und Aether. 
Arch, der Pharm., 100, p. 305. [Am. Journ. Pharm., 21, 
p. 117]. 

Fig- 78. Fig. 79. 




J e I 

•iii 




The apparatus consists of a two-necked Woulf 's bottle, figure 
78 p, into the central mouth of which the metallic vessel R, figure 
79, is fitted by means of a cork. The vessel R consists of a me- 
tallic cylinder a having a perforated strainer k near the bottom 
and terminating with a funnel neck, to admit of its being fitted 
into the Woulf 's bottle. This cylinder is surrounded by a 
second cylinder &, the space between them being intended to 
contain either hot or cold water. In the top of the inner cylin- 
der a, a slightly conical vessel c is made to fit air tight, as shown 
in the drawing. This vessel c is intended to be used as a con- 
densing apparatus, and for this purpose it is filled with cold 
water. From the second or lateral opening of the Woulf 's bot- 
tle, a glass or tin .tube d, figure 78, is carried to the upper part of 
the cylinder a, where it is inserted as shown in figure 80. The 
cold water in the vessel c is renewed through the pipe e which 
conducts it to the bottom, while the warm water runs off from 
the top through the pipe /, figure 79. Hot or cold water is re- 
newed to the space between the two cylinders R. by the tube 
funnel hy figure 78, and the water from this space overfiows inta 
g and is carried off together with that from /. The tube h is 
inserted through a perforated cork at i so that by turning the 



APPARATUS EMPLOYED 35 

tube downwards, the water from the space between the cylin- 
ders can be run off. 

1849 



Mohr, Redwood and Procter 's Pharmacy, p. 270. 




This consists of a conical vessel A with a water joint rim at 
the top into which the cover fits. A tube D is ground to fit into 
the opening in the bottom, and over the end of this tube is 
placed a conical tube C, the lower end of which has several 
notches cut in it, so that the liquid can pass under when placed 
as shown in the drawing. The lower extremity of the vessel 
A is ground to fit into the mouth of the receiver B. 

The above apparatus was mentioned by Procter, in 1849, in 
his article on "the preparation of the oleoresinous ethereal ex- 
tracts. ' ' 

1849 



Mohr, Eedwood and Procter's Pharmacy, p. 272. 

A is an ordinary tin displacer, except that the rim c is soldered 
around the mouth, in such a manner as to form a water joint 
when the rim of the cover d is placed in it; a is a perforated 
diaphragm, e a tin tube open below and above. The latter is 
soldered to the lower diaphragm, through which it passes, while 
the upper diaphragm slips over it loosely. In using the dis- 



36 I^U MEZ— THE GALENICAL OLEORESINS 

placer, the ingredients are introduced around the tube to a 
suitable height, the upper diaphragm put in its place, and 
menstruum poured on, the joint half filled with water and the lid 
inserted. The atmosphere of the bottle B communicates with 
that of A through the tube e. 




This form of percolator was mentioned by Procter (1849) in. 
his article on "The oleoresinous ethereal extracts." 



1849 



Mohr, Eedwood and Procter's Pharnmcy, p. 270. 



Figure A is a glass adapter, which is selected of suitable size. 
The lower extremity of this is partially stopped with a cork cut 
as represented in F. A layer of coarsely pounded glass is put 
over the cork, and above this a layer of clean sand, thus form- 
ing a strainer for arresting the passage of the solid particles of 
material to be acted upon. The end of the adapter is fitted, 
by means of a perforated cork, into the mouth of the bottle. A 
glass tube, one end of which is drawn to a capillary opening, 
is also fixed in the cork as shown at C so as to allow the air to 
escape out of the bottle as the liquid drops in. A piece of blad- 
der may be tied over the mouth of the vessel at A to prevent 
the evaporation of the solvent, but a few pin holes must be made 
in the bladder to admit of the ingress of air as the liquid passes 
into the receiver below. 



APPARATUS EMPLOYED 



37 




The above form of percolator was mentioned by Procter 
(1849) in his article entitled The Preparation of the Oleoresin- 
ous Ethereal Extracts. 



1873 

Utensilien zur Bereitung der aetherischen nnd weingeistig- 
aetherischen Extracte. 

Hager's Commentar zur Pharmakopoea Germanica, 1, p. 620. 

This consists of a cylinder hh fitted into a cork / which is in- 
serted into the neck of a flask or bottle g, aa is a cover which 
serves as a condenser. In the lower end of the cylinder && is 
a tin sieve plate ss in the center of which is a tin tube rr en- 
closed in a glass tube vv. The glass tube is held firmly in place 
by a cork at each end pp. The condenser aa has a conical 
shaped bottom N around the interior of which run two cor- 
rugated rings zz of tin. The space a, Fig. B, contains cold 
water which enters from the openings cc and flows out through 



38 



DU MEZ— THE GALENICAL OLEORESINS 



the tubes ee. As soon as the menstruum drops through color- 
less, the top aa is taken off and D put on in its place. It is 
also a condenser. The water flows in at a and off through &. 
The conical bottom K is so arranged that the condensed solvent 




drops from off the receiver i and is carried off into a flask 
through the outlet e. The space between vv and aa is filled 
with either hot or cold water. 



1873 

Utensilien zur Bereitung der aetherischen und weingeistig- 

aetherischen Extracte. 

Hagers Commentar zur Pharmakopoea Germanica, 1, p. 622. 

A displacement tube D with a wide mouth at its upper end is 
closed with a cork through which runs a thistle tube T. The 
lower end is pushed through a cork which fits tightly in a re- 
ceiving bottle R. The small glass tube I is for the purpose 
of letting the air escape from the receiver R. 



APPARATUS EMPLOYED 



^9 




1884 



Parish's Treatise on Pharmacy, p. 755 




A percolator of tinned copper is surrounded by a jacket of 
the same material ; the receiver is a copper vessel with two necks 
into one of which the percolator is secured, the other is connected 
with a pipe leading to the closed head of the percolator which is 
also jacketed ; on the other side of the head is a perforated plate 



40 



DU MEZ— THE GALENICAL OLEORESINS 



of tinned copper, which distribute^ the ether over the surface of 
the drug when it has been volatilized by placing the receiver 
in hot water. After the exhaustion of the drug, the receiver is 
removed, the lower orifice of the percolator closed, and the head 
well refrigerated; a stream of hot water is then passed into the 
jacket around the percolator, by which means the contained 
ether may be recovered. 



1886 



Kemington's Practice of Pharmacy 1886, p. 366. 



The apparatus consists of a cylindrical percolator fitted into 
the mouth of a receiving bottle with the aid of a cork. The 
upper part of the percolator being closed and a small opening 
left in the cork to allow the escape of air from the receiving 
bottle. 





A continuous extraction apparatus can be made of this per- 
colator by enclosing the upper part in a suitable case and pass- 
ing cold water between, arranging the apparatus like a Liebig's 
condenser. A glass tube is connected with the top of the perco- 
lator and the mouth of the bottle by rubber tube connections, 



APPARATUS EMPLOYED 



41 



and if the receiving bottle be placed in a water bath and the water 
gently heated, the ether will evaporate from the percolate, the 
vapors rising in the tube and condensing in the upper part of 
the percolator. 



Lewin R. 

Ein neuer Extractions Apparat, 

Arch, der Pharm., 215, p. 74. [Proc. A. Ph., 35, p. 12.] 



1887 




This apparatus is adapted for 1) continuous extraction with 
hot menstrua, 2) continuous extraction with cooled menstrua, 
3) recovery of the menstrua from the finished extract by direct 
distillation. 

It is composed of three easily separable principle parts: C, 
the tinned copper still, B, the copper percolator, which is pro- 
vided with three movable sieve bottoms for the reception of 

1) For continuous extraction with hot solvents, the vapors 
pass from the still C, in the tube 1, and enter through the tri- 



42 DU MEZ— THE GALENICAL OLEORESINS 

faucet I, when in position a, through tube 4, into the percolator, 
the substance to be extracted. A is the condenser. 
B, penetrate the substance to be extracted, and condense. The 
percolate passes into the receiver and from this flows through 
the tri-faucet III in its position a, through the tube 7, again 
into the still, to repeat this course as long as it may be desir- 
able. To prevent pressure in the apparatus, the tube 2, is 
removed during this operation, and the tri-faucet II is placed 
in position a. This admits the vapor into the cooling worm, A, 
which thus forms a safety valve. 

2) For the continuous extraction with cooled solvents, the 
vapors pass from the still C, into tube 1, and enter through the 
tri-faucet I, in its position h, through tube 2, into the cooling 
worm A, from this as a liquid through the tri-faucet II, in its 
position a, into the percolator, and so through the substance to 
be extracted into the still as before. 

3) For the recovery of the solvent from the extract by direct 
distillation, the vapors pass from the still C, through tube 1, 
through the tri-faucet I, in its position h, through tube 2, into 
the cooler, A, through the tri-faucet II in its position h, into the 
exit tube 3, which latter may be lengthened at pleasure. 

Portions of the percolator may be removed from the receiver 
at pleasure through the tri-faucet III, in its position c, by the 
tubes 2 and 3. All of the tubes are connected or disconnected 
by good screw joints. 

Flueckiger, F. A. 1889 

Ein zweckmaessiger Extraktionsapparat. 
Arch. d. Pharm., 227, p. 162. [Proc. Am. Pharm. Assoc, 37, 
p. 338]. 

The extraction tube A is provided at C with a diaphragm 
from the center of which a small tube or neck extends into the 
funnel D. The tube B F attached to the side, passes into 
a tubulure G, which is provided with an ordinary cork K 
by means of which communication through the tube B F, 
between the upper, and the lower portions of the apparatus 
may be cut off or established. Thus causing the condensed 
liquid to return through the drug when the communication is 
closed or allowing the liquid to be distilled off when it is open. 



APPARATUS EMPLOYED 



43 



Caspar! in his Treatise on Pharmacy (1916) describes the use 
of this apparatus in connection with the preparation of the oleo- 



resms. 



1890 

Szombazi Soxhlet's Extraction Apparatus. 

Dingier 's pol. Journ., 256, p. 461. [Zeitschrift f Anal. Chem., 

19, p. 365.] 




Maish (1900) first suggested the use of this apparatus in the 
preparation of the oleoresins. 



44 



DU MEZ — THE GALENICAL OLEORESINS 



Alpers, William C. 1896 

Oleoresinae. 
Merck's Rep., 5, p. 593. [Proc. Am. Pharm. Assoc, 45, p. 435.] 




The apparatus consists of a cylindrical percolator a. The 
upper end of the percolator is closed with a large cork b through 
which two holes have been bored — the one for receiving a bent 
glass tube c, the other for a small glass funnel d. The lower 
narrow end of the percolator is closed by a cork e through which 
a straight connecting glass cock / passes into another perforated 
cork g that closes the receiving bottle h. This cork contains 
a second perforation with a small bent glass tube i. The glass 
tubes and i are joined by means of a small piece of rubber 
tubing at k. 



1902 



Coblentz's Handbook of Phannacy, p. 290. 



(^ 




B 



A is a percolator with a stop cock C. It is inserted into a 
receiver B. The receiver B and percolator A are connected 



APPARATUS EMPLOYED 



45 



with a tube as shown in the figure for the purpose of equalizing 
the pressure as the apparatus is closed throughout. 



1908 



Brandel and Kremers, Percolation, p. 52. 




A is an ordinary conical percolator of such a size that it will 
not be more than two-thirds filled with the drug to be extracted. 
B is a round-bottom flask, containing a twice perforated stop- 
per, through one hole of which a glass tube connects the flask 
to the percolator. Through the second hole is inserted the 
glass tube C which also passes through the cork stopper in the 
top of the percolator. The end of the condenser D is also in- 
serted through this cork. All cork connections should be tightly 
sealed with gelatine. 

The above is the form of apparatus which was used in the 
laboratory in the preparation of the oleoresins when 500 grams 
or more of the drug were extracted. 



46 DU MEZ— THE GALENICAL OLEORESINS 



Yield 

The yield of oleoresin is a variable quantity depending, first 
of all, upon the oleoresin content of the particular drug from 
which it is prepared. Thus, the oleoresin content of ginger 
is only about one-half that of the aspidium and one-fourth that 
of cubeb. Not, only, however, does the oleoresin content vary 
with the different drugs, but the drug, when of the same genus 
and species, may show a variation due to a number of in- 
fluences, such as the climate in which grown, time of harvest- 
ing, conditions under which stored, et cetera. As an illustra- 
tion of these influences, aspidium may be taken. The maxi- 
tnum yield of oleoresin, in this case, is obtained from the freshly 
^dried Russian rhizomes collected in the month of September.^) 
^Or, the case of ginger may be cited. In this instance, the 
African rhizomes harvested at maturity (usually in Feb- 
:ruary)^) give the largest amount of oleoresin. This character- 
istic will be taken up in detail under the treatment of the 
'^individual oleoresins. The other important factors in deter- 
mining the amount of oleoresin obtained, in general, are two 
in number, viz: the solvent employed in extracting the drug, 
and the method employed in operating with the same. Both 
of these factors have been dealt with in a general way under 
the two preceding headings. They will also be discussed more 
fully in connection with the individual preparations. 

Chemistry 

The Chemistry of the oleoresins per se has apparently re- 
ceived but little attention, except in the case of the 
oleoresin of aspidium. The latter has been the subject 
of numerous investigations and its chemistry is now under- 
stood fairly well. Some work has also been done toward de- 
termining the composition of the oleoresins of cubeb and 
lupulin, but our present knowledge of the chemistry of these 
preparations is still very indefinite. 

A very considerable amount of work has been done toward 
clearing up the chemistry of the drugs from which the oleo- 
resins are prepared, and it is from this source that we are 



1 See tables of yield under the oleoresins of aspidium and ginger, re- 
spectively. 



PHYSICAL PROPERTIES 47 

obliged to obtain what information we have concerning the 
composition of most of these preparations. It is for this rea- 
son that the chemistry of the drugs from which the oleoresins 
are prepared is given consideration in this monograph. See 
^'Chemistry of the drug and its oleoresin" under the treatment 
of each individual oleoresin. 

Physical and Chemical Properties 

The determination of the physical and chemical properties 
of the galenical oleoresins in general does not appear to have 
been undertaken systematically in the past. While there are 
numerous references in the literature concerning color, odor, 
taste and consistence, there is no mention, except in connection 
with the oleoresins of* aspidium and cubeb, of the properties 
which we should naturally expect to find under a description 
of a class of preparations of this nature, viz: specific gravity, 
refractive index, acid number, saponification value, et cetera. 
This condition is surprising in view of the work which has 
been done along this line in connection with the natural pro- 
ducts of the same name. That cognizance is, however, being 
taken of the subject at the present time is evidenced in the 
comparatively recent work which has been done abroad on the 
oleoresin of aspidium. In the latter case, the methods usually 
employed in fixing the standards of similar natural products 
were applied, and with considerable success. A brief general dis- 
cussion of these properties as well as other characteristics, which 
have been mentioned in this connection, follows. 

Physical Properties 
Color: 

The color is a characteristic property of the individual mem- 
bers of this class of preparations. Considered with respect 
to a single member, it serves in some cases as a measure whereby 
the quality of the product may be roughly determined. Thus, 
a brown color in the oleoresin of aspidium indicates an inferior 
preparation, in the making of which old deteriorated rhizomes 
have been used, whereas, a deep green color is said to indicate 
adulteration with salts of copper. Likewise, a brown color 
in the oleoresin of cubeb warrants the opinion that ripe in- 
stead of unripe fruits have entered into its preparation. How- 



48 DU MEZ — THE GALENICAL OLEORESINS 

ever, as the color of the individual preparations, when properly 
made, varies to a considerable extent, and as the description of 
exact shades is a difficult matter, this property as described in 
the literature is naturally somewhat indefinite. This subject 
will receive further consideration of the treatment of the in- 
dividual oleoresins. 

Odor: 

The oleoresins without exception possess distinct odors re- 
sembling in an intensified degree those of the drugs from which 
they are prepared. In general, this property offers a ready 
means of identifying these preparations. In specific instances,, 
it may also serve as an indication of the quality of the product. 
For example, a rancid odor in the case of the oleoresin of as- 
pidium is evidence of the use of old deteriorated rhizomes in 
its preparation or of undue exposure to the air while kept in 
storage. For similar reasons, the oleoresin of lupulin may 
have a disagreeable cheesy odor. Furthermore, unevaporated 
solvent, even when present in comparatively small amounts, 
may be most easily detected by this means. This property will be 
discussed in greater detail under the individual oleoresins. 

Taste: 

The taste of the individual oleoresins, like the odor, is a 
property acquired in an intensified degree from the drugs from 
which they are prepared. Likewise, this property also serves 
as an acid in the identification of these preparations. In addi- 
tion, however, it has been made the basis of a quantitative 
physiological test (^) for the determination of the quality of 
the oleoresins of capsicum and ginger. For a further discus- 
sion of this property, see the individual oleoresins. 

Consistence : 

The U. S. P. oleoresins, with the exception of the one pre- 
pared from lupulin, are liquids. The degree of fluidity, how- 
ever, varies with the individual under consideration, with the 
temperature and with certain other conditions, which will be dis- 
cussed in detail under the separate treatment of each indi- 
vidual. The oleoresin of lupulin is usually of the consistence 
of a very soft extract. 



* See under the oleoresins of capsicum and ginger respectively. 



PHYSICAL PROPERTIES 



49 



SoluhUity: 

The solubility of the different oleoresins naturally depends 
to a large extent on the solvent which was employed in their 
preparation. It does not, however, follow from this statement 
that, because an oleoresin was prepared with ether, it will al- 
ways be completely soluble in the same. Some of these prep- 
arations on standing undergo chemical changes with a result- 
ing change in solubility. For example, the oleoresin of aspi- 
dium forms a deposit on ageing, and the deposited material is 
practically insoluble in ether. As a rule, the oleoresins, when 
prepared with ether, form clear or slightly cloudy solutions 
with absolute alcohol, acetone and chloroform, whereas, they 
are only partially soluble in petroleum ether and carbon tetra- 
chloride. 

In the case of certain members of this class of preparations, 
this property has been of considerable value in detecting adul- 
terations or in the identification of the solvent which was em- 
ployed in their manufacture. For specific instances of the 
application in this connection, see under the oleoresins of aspi- 
dium and ginger. 

Specific gravity: 

The value of determining the specific gravity as an aid to 
standardizing the oleoresins appears to have been first noted by 
Procter. In 1866, he published data showing how this constant, 
in the case of the oleoresin of cubeb, varied with the solvent 
employed in its preparation, and further pointed out that a low 
specific gravity observed in the commercial product was, in one 
instance at least, an indication of the incomplete removal of 
the solvent, ether. Procter 's observations were as follows : 



Table 7. — The specific gravity of the oleoresin of cubeb. 



Drug 


Solvent 


Specific gravity 


Remarks 


Cubeb 


Alcohol 

Ether 

Benzin 

Ether 


at 76° P. 
0,9850 
0.9675 
0.9325 
0.9000 


Prepared by Procter. 

Commercial sample containing ether» 



This work, however, appears to have received but little atten- 
tion as there is no further mention of the determination of this 



.50 DU MEZ— THE GALENICAL OLEORESINS 

constant in this connection in the literature until 1903. In that 
year, the English firm of Southall Brothers and Barclay pub- 
lished a statement in their Laboratory Reports, in which a stan- 
dard range for the specific gravity of the oleoresin of aspidium 
was given. Interest in the matter again seems to have waned 
and it was not until 1911, when Parry showed that the last 
named preparation was being extensively adulterated with castor 
oil, that the necessity for standardizing this preparation be- 
came apparent. The subject was then taken up in earnest, 
however, and in 1913, no less than four articles on the deter- 
mination of the physical and chemical constants of the oleo- 
resin of aspidium made their appearance. In each of these, 
the determination of the specific gravity was given some con- 
sideration. 

From the foregoing brief resume of the literature on this sub- 
ject, it becomes apparent that the determination of the ^ecific 
gravity as a factor in evaluating the oleoresins has received 
consideration in connection with but two of the official prepara- 
tions. Furthermore, that practical use has been made of this 
constant only in the case of the oleoresin of aspidium. The 
results obtained with respect to these two preparations, how- 
ever, are deemed to be of sufficient importance to warrant the 
determination of this constant in the case of the other members 
of this class of preparations. 

The manner in which this constant was determined by the 
above mentioned investigators does not become apparent from 
their work as reported in the literature. It is thought, how- 
ever, that an ordinary glass pycnometer and chemical balance 
were employed for this purpose. In the determinations made 
in the laboratory, a 10 cubic centimeter pycnometer was used, 
except in the case of the oleoresin of lupulin which was usually 
too thick to handle in this manner. For the determination of 
the specific gravity of the latter, a Nicholson's hydrometer was 
employed. All determinations were made at 25° C. 

The results as obtained in the laboratory and those reported 
elsewhere will be discussed in detail under the treatment of the 
individual oleoresins. 

Refractive index: 

The determination of the refractive index has received con- 
sideration only in connection with the standardization of the 



CHEMICAL. PROPERTIES 5J 

oleoresin of aspidium. In this case, it has proven to be of par- 
ticular value in detecting adulteration with castor oil as was 
first pointed out by Parry in 1911. Subsequent work by other 
investigators has not only confirmed Parry's observations, but 
has shown that in some instances a low refractive index may be 
an indication of a low filicin content due to natural causes^) 
as well. 

Since most of the other official oleoresins are sufficiently trans- 
parent to permit of the direct determination of this constant, 
it was thought that such determination might likewise prove to 
be of some aid in standardizing these preparations. That such 
an opinion has proven to be correct will be shown in connection 
with the discussion of this topic under the individual cases. 

For the determination of this constant in the laboratory, the 
Abbe refractometer was employed, all observations being made 
at 25° C. In those cases (the oleoresins of ginger and lupulin) 
where the color was too intense to permit of a direct determina- 
tion being made, the oleoresin was dissolved in an equal volume 
of castor oil and the refractive index computed from the follow- 
ing formula : 

njj (b) == 2nj^^ (a + b) — n^ (a) 

a = refractive index of castor oil. 
b= '' '' '' oleoresin. 

Chemical Properties 
Loss on Hearting : 

The oleoresins without exception lose weight on drying. This 
loss is usually referred to in the literature as the moisture con- 
tent. It has been determined by heating the preparation at 
100 to 105° C. for a definite period of time, or until of con- 
stant weight. The fallacy of designating the loss of weight 
thus obtained as the moisture content becomes evident when we 
take into consideration the fact that these preparations con- 
tain volatile substances other than water, which would also be 
removed by heating to a temperature of 100° C. Indeed, the oily 



^ The male fern rhizomes have been shown to vary in fllicin content due 
to the climatic conditions under which they were grown, time of harvesting, 
€t cetera. See under "Drug used, its collection, preservation, etc." 



52 DU MEZ— THE GALENICAL OLEORESINS 

nature of these preparations exclude the presence of any great 
quantity of moisture. This statement has been borne out by 
laboratory experiments. Attempts to determine the moisture 
by means of the xylene^) method failed to reveal the presence 
of a measurable amount of water in any of the samples examined. 
The loss in weight is, therefore, due, ordinarily, to the removal 
of volatile oil and in exceptional cases to the removal of un- 
evaporated solvent. Such being the case, the determination of 
this constant serves as a means of measuring the amount of 
volatile oil naturally occurring in these preparations and as a 
means of detecting the presence of unevaporated solvent. 

The amount of weight lost by the oleoresins when deter- 
mined as stated above varies greatly with the individual 
members comprising this class of preparations. The oleoresin 
of cubeb which contains a comparatively large amount 
of volatile oil naturally sustains a comparatively great 
loss, while the oleoresin of capsicum which contains 
a small amount of volatile matter shows but a slight loss. 
There is noted a further variation in the case of each individual 
due to a variation in the amount of volatile matter naturally 
occurring in the drug from which the oleoresin was obtained, 
or to a variation in the conditions under which the individual 
was prepared. As an illustration, the oleoresin of cubeb may 
be cited. The volatile oil content of cubeb is stated to be 10 to 
18 per cent. A much greater variation is, therefore, to be ex- 
pected in the oleoresin which represents only the alcohol soluble 
portion of the drug. With respect to the conditions under 
which the oleoresin of cubeb is prepared, observations in the 
laboratory have shown that the preparation will contain a larger 
amount of volatile oil when the solvent is allowed to evaporate 
spontaneously at room temperature, than when the same is re- 
moved by evaporation on a water bath. In most cases, the 
variation, due to the difference in solvent used in extracting 
the oleoresins, appears to be so slight as to be almost negligible. 
In the case of the oleoresin of pepper, however, there is a very no- 
ticeable difference. This is very likely due to the nature of the 
preparation, its viscosity making it difficult to remove the last 
traces of the less volatile solvents without the application of 
heat. 



1 U. S. Dept. Agric, Forest Service, Circ. 134. 



CHEMICAL. PROPERTIES 53 

In the determinations of this nature made in the laboratory, 
a, weighed amount of the oleoresin (about 2 grams) was heated 
in an electric oven at 100° C. for 3 hours, cooled in a desiccator 
and weighed, the difference in the two weights being taken as 
the loss. 

A more detailed consideration of this subject will be found 
under the treatment of the individual oleoresins. 

Ash Content: 

The determination of the ash content of the oleoresins is 
of special value in identifying the solvents which have been used 
in their preparation. Such determinations, made in this 
laboratory, also by the firm of Dieterich^) in Helfenberg, have 
shown that, while there is as a rule comparatively little dif- 
ference in the ash content of these preparations, when prepared 
with the same solvent, there is a marked variation in the case 
of each individual when different solvents are employed. The 
oleoresin of lupulin is an exception to this rule. Its ash con- 
tent varies to a considerable extent even when prepared with 
the same solvent. 

In addition to the above, the qualitative examination of the 
ash of commercial samples has revealed the fact that nearly all 
of them contain copper, due in most cases to the action of the 
free fatty acids on the utensils employed in their preparation* 
In some instances, the presence of the metal must be attributed 
to the addition of copper salts for the purpose of imparting 
the desired green color to preparations of inferior quality. See 
under the adulteration of the oleoresins of aspidium and cubeb, 
respectively. 

The ash content of the oleoresins examined in the laboratory 
was determined as directed by the last edition of the United 
States Pharmacopoeia under ''Determination of Ash or Non- 
volatile Matter,'* p. 589. 

Copper, when present, was identified by the blue color of the 
solution formed when the ash was dissolved in a few drops of 
hydrochloric acid, diluted with water, and ammonium hy- 
droxide solution added. 



^ The firm of Dieterich has for a number of years determined the ash 
content of the oleoresins of aspidium and cubeb. A tabulation of the re- 
sults as obtained by this firm will be found under the separate treatment 
of these oleoresins. 



54 I^U MEZ— THE GALENICAL OLEORESINS 

For a more detailed discussion of this subject, see under in- 
dividual oleoresins. 

Acid Number: 

Kremel in 1887 determined the acid numbers of the oleo- 
resins of aspidium and cubeb. Inasmuch, however, as he made- 
but one determination in each case, no conclusions can be drawn 
from his work. Similar determinations made in this laboratory 
on all of the official oleoresins show that this property varies, 
greatly depending on the particular individual under considera- 
tion. Furthermore, that no general statement can be made aa 
to -its value in fixing the standards of these preparations, but 
that it is of importance when considered in connection with 
individual cases as will be brought out later. 

For the manner in which this constant was determined in 
the laboratory, see the United States Pharmdcopoeia, ninth re- 
vision, (1916), p. 591. 

Saponification Value : 

The saponification values of the official oleoresins, as deter- 
mined in this laboratory and elsewhere,^) indicate that this 
property may be an important factor in fixing standards for 
these preparations. The results obtained by Parry, Harrison 
;and Self, and others show that in the case of the oleoresin of 
aspidium, the saponification value varies directly as the filicin 
content, and is, therefore, useful as a check on the determina- 
tion of the latter. Considered in connection with such of these 
preparations as contain easily oxidizable substances, an abnor- 
mally high saponification value is very likely caused by an in- 
crease in the acid content due to the action of the oxygen of the 
air, and is thus an indication of an old product^) or of improper 
care in storing. As an example, the oleoresin of lupulin may 
be cited. In this case, a high saponification value signifies an 
old preparation or one that has been prepared from deteriorated 
drug.^) These factors, together with the influence of the solvent 
employed and the method of preparation on this property, will 



* Saponification values have only been determined in the past in the case 
of the oleoresin of aspidium and in one instance in the case of the oleoresin 
of cubeb. 

2 See oleoresin of aspidium. 

2 See oleoresin of lupulin. 



SPECIAL TESTS 55. 

be considered in greater detail under the treatment of the in- 
dividual members. 

The manner in which this constant was determined in the 
laboratory is described on p. 590 of the United States Phar- 
macopma, ninth revision. 

Iodine value: 

The determination of the iodine value as an aid to the 
standardization of the oleoresins appears to have been first em- 
ployed by the firm of Dieterich in Helfenberg in 1904, however^ 
only in the case of the oleoresin of aspidium. It has since re- 
ceived further practical application, in connection with the same 
preparation, by the English firm of Evans Sons, Lescher and 
Webb, while a number of similar determinations have been made 
by the author. The results^) obtained with respect to this 
preparation show that the iodine value varies directly as the 
filicin content, and, therefore, serves as another check on the 
determination of the latter constituent. 

With respect to the other official oleoresins, it may be stated 
that, as a general rule, the iodine value is high in the case of 
those preparations which contain a large amount of unsaturated 
constituents of ether fatty or volatile oil.^) Further than this,, 
it may be influenced largely by the nature of the other consti- 
tuents of these preparations and will be considered in detail in 
connection with the treatment of each individual. 

For the method employed in the laboratory in the determina- 
tion of this constant, see the United States Pha/rnmcopwia, ninth 
revision, p. 590. 

Special Tests 

While the different official oleoresins can, as a rule, be identi- 
fied without difficulty, the use of various adulterants in their 
preparation, through ignorance in some cases, or with willful 
intent on the part of unscrupulous manufacturers, has made 
it necessary to guard against this practice by making use of 
certain qualitative and quantitative tests. As will be brought 
out later, such tests have been applied principally to the pre- 
parations official in foreign countries, namely: the oleoresins 



* See under oleoresin of aspidium. 
^ See under oleoresin of cubeb. 



56 DU MEZ— THE GALENICAL. OLEORESINS 

of aspidium and cubeb. No tests of this, or, as a matter of fact, 
of any kind have been included in the United States Phar- 
macopoeia. It is thought, however, that if interest in these prep- 
arations could be awakened in this country, the need of sim- 
ilar precautions with respect to all of the official oleoresins would 
become apparent. 

Qualitative Tests: 

Inasmuch as the common physical properties, such as odor, 
taste and appearance, are very characteristic of the oleoresins, 
it is hardly necessary to resort to other means for their identi- 
fication. It appears, however, that the use of the so-called 
false cubebs in the preparation of the oleoresin of cubeb has 
made necessary a more certain method of identification. Such 
a method, based on the red color produced when concentrated 
sulphuric acid is added to the oleoresin prepared from the gen- 
uine fruit,^) has, therefore, been given in most of the late Eur- 
opean pharmacopoeias. Likewise, the use of other species of 
fern in the preparation of the oleoresin of aspidium caused a 
qualitative test for this preparation to be included in the late 
editions of the Austrian, Hungarian and Netherlands phar- 
macopoeias. For the details of these methods, see qualitative 
tests under the respective oleoresins. 

Quantitative Tests: 

On the whole, very little has been done in the past toward 
developing quantitative methods for the evaluation of the oleo- 
resins. This condition is perhaps due, for the main part, to an 
imperfect knowledge of the chemistry of most of these prepara- 
tions, as well as to the lack of exact information concerning the 
constituents of therapeutic value. In the case of the oleoresin 
of aspidium, however, the therapeutic value of the preparation 
has been shown to depend upon a number of acid constituents, 
the quantity present varying through natural and artificial causes. 
As a result, various methods^) for the determination of the total 
acid content have been devised and are in use at the present 
time, a modification of the original method of Fromme being 
officially recognized in the late edition of the British and Swiss 



^ Dekker states that the so-called false cubebs give a yellow color with 
concentrated sulphuric acid. Pharm. Ztgr. (1912), 84, p. 845. 
2 See under oleoresin of aspidium. 



SPECIAL, TESTS 57 

pharmacopoeias. The only other work of this nature appears 
to have been done quite recently (1914) by the H. K. Mulford 
Co. in the standardization of the oleoresins of capsicum and 
ginger. This firm has devised a physiological method for this 
purpose based on the extreme pungency of these preparations, 
the highest dilutions in which these preparations (on the aver- 
age) are still perceptable to the taste being taken as standards. 

Experiments conducted in the laboratory in preparation for 
this monograph have shown, not only that there is an oppor- 
tunity for improving on some of the above mentioned methods, 
but that there is need for the development of quantitative meth- 
ods which may be applied to the other individuals of this class 
as well. With respect to the forepart of this statement, it Is 
thought that a gravimetric method for the estimation of the 
pungent priniciples (gingerol) in ginger would be an improve- 
ment over the physiological method of the Mulford Co. as per- 
sonal idiosyncrasy would thus be eliminated. Trials with the 
method of Garnett and Grier^) (for the estimation of gingerol 
in ginger) adapted to the oleoresin appear to indicate the cor- 
rectness of this opinion. In the case of the oleoresin of capsi- 
cum, however, the physiological method apparently offers the 
only practical course at the present time, in view of the fact 
that the active constituent, capsaicin, is present in such minute 
quantities that an accurate gravimetric determination would be 
a difficult matter. 

In considering the application of new methods, the work done 
in this laboratory on the oleoresin of pepper may be cited. 
Since the therapeutical value of this preparation is apparently 
due to its piperine content, a method for the quantitative de- 
termination of this constituent appeared to be desirable. With 
this object in view, the nitrogen present was determined by the 
Kjeldahl method and the piperine content computed therefrom. 
Some very interesting results were obtained.^) As to further 
possibilities along this line the determination of the apiol con- 
tent of the oleoresin of parsley, or the estimation of the quantity 
of total acid resins present in the oleoresin of cubeb may be- 
mentioned. 



* See under oleoresin of ginger. 
2 See under oleoresin of pepper. 



53 DU MEZ— THE GALENICAL OLEORESINS 



Adulterations 

The examination of commercial samples of the oleoresins has 
shown that they are all adulterated at times. With respect to 
most of these preparations, adulteration is thought to be acci- 
dental, 6. g. the presence of copper in nearly all samples due to 
the use of copper utensils in the manufacture of the same, or 
the use of ripe instead of unripe fruits in the preparation of 
the oleoresin of cubeb. In some cases, however, adulteration 
has been practiced with willful intention to defraud, as for 
example, the addition of fatty oils to the oleoresins of aspidium 
and cubeb. Other instances of this kind will be given con- 
sideration under the treatment of the individual oleoresins. 



PART II— INDIVIDUAL OLEORESINS 
OLBORESIN OP ASPIDIUM 

Synonyms 

Aceite de Helecho Macho, Sp. P. 1905. 

Aetheres pafran-Kivonat, Hung. P. 1880. 

Aetherhaltiges FarrenTcraut extract y Aust. P. 1844. 

Aetherisches Farrnkrautextract, Pruss. P. 1830. ; 

Aetherisches Farrnkrautwurzel Extract, Bad. P. 1841. 

AlvejuurieTcstrakti, Finn. P. 1914. , 

Balsamo de Helecho, Dorvault, L'Officine, Sp. Trans. 1879. 

Balsamum Filicis, Pareira, Mat. Med. 1854. 

Baum^ de Fougere, Dorvault, L' Officme, 1898. 

Braegne-Extract, Dan. Mil. P. 844. 

Bregnerod Extract, Nor. P. 1870. 

Bregnerodelcstralct, Nor. P. 1895. 

BregnerotekstraM, Nor. P. 1913. 

Estratto di Felce Maschio, Swiss. P. 1907. 

Estrato di Felce Maschio Etereo, Ital. P. 1902. 

Ethereal Extract of Male Fern, Journals. 

Extract of Male Fern, Jap. P. 1907. 

Extract van Mannetjes-Varen, Nethl. P. 1871. ■ * 

Extracto de Feto Macho, Port. P. 1876. 

Extracto de Feto Macho Ethereo, Port. P. 1876. 

Extracto Etereo Helecho, Sp. P. 1884. 

Extracto Ethereo de Helecho M<acho, Sp. P. 1905. 

Extracto oleo-resinoso de Helecho, Dorvault, L'Officine, Sp. Trans. 1879. 

Extractu de Filice Mascule, Roum. P. 1874. 

Extractu di Felce Machio, Swiss. P. 1865. 

Extractum Aethereum Filicis, Sp. P. 1884. 

Extractum Aethericum Filicis, Fr. P. 1866. 

Extractum Aethericum Filicis Maris, Fr. P. 1866. 

Extractum Aspidii, Nor. P. 1854. 

Extractum di Felce Machio Etereo, Port. P. 1876. 

Extractum Filicis, G. P. 1900. 

Extractum Filicis aethereum, Pruss. P. 1861. 

Extractum Filicis liquidum, B. P. 1914. 

Extractum Filicis Maris aethereum, Ital. P. 1902. 

Extractum Filicis oleoso-resinosum, Jourdan, Univ. P. 1832. 

Extractum Badicis Filicis Maris athereum. Bad. P. 1841. 



go DU MEZ— THE GALENICAL OLEORESINS 

Extractum Stipitum Aspidii, Nor. P. 1854. 

Extrait de Fougere, Belg. P. 1906. 

Extrait de Fougere Male, F. P. 1908. 

Extrait Ethcre de Fougere, Belg. P. 1854. 

Extrait EtMre de Fougere Male, Fr. P. 1866. 

Extrait oleo-resineux de Fougere, Bern. P. 1852. 

Extrait oleo-resineux de Fougere Male, Fr. P. 1908. 

Farnextrakt, Ger. P. 1900. 

Farrenkr<iutextralct, Bern. P. 1852. 

Farrnwurzel Extract, Swiss. P. 1865. 

Filicis Extractum, Belg. P. 1906. 

Filixextrakt, Journals. 

Huile de Fougere Male, Belg. P. 1854. 

Huile de Fougere de Peschier, Bern. P. 1852. 

Liquid Extract of Fern Root, Br. P. 1864. 

Liquid Extract of Male Fern, Br. P. 1885. 

Oil of Filix mas, Parrish, Treat, on Pharm. 1867. 

Oil of Male Fern, Journals. 

Oleoresin of Fern, U. S. P. 1870. 

Oleoresin of Male Fern, U. S. P. 1910. 

Oleoresina Aspidii, U. S. P. 1910. 

Oleo-resina de Helecho, Dorvault, L'Officine, Sp. Trans. 1879. 

Oleoresina Filicis, U. S. P. 1860. 

Oleo-Besina Filicis, Peschier, Ver. P. der Lond., Edinb., and Dub. Med. 

Coll. 1827. 
OUo-r^sine de Fougere, Dorvault, L'Officine, 1898. 
Oleum Filicis, Hung. P. 1861. 
Oleum Filicis Maris, Sp. P. 1905. 
Oleum Filicis Maris aethereum, Swiss. P. 1865. 
Oleum Filicis Peschieri, Pareira, Mat. Med. 1854. 
Oleum Filicis pingue resinosum Geiger's P. 1835 
Oleum Badicis filicis, Strump. Allg. P. 18661. 
Orbunksrot Extrakt, Swed. P. 1901. 
Pafran-Kivonat, Hung. P. 1871. 
Varenextract, Neth. P. 1905. 
Wurmfarnextrakt, Swiss. P. 1893. 
Wurmfarnoel, U. S. Disp. 1907. 



OL.EORESIN OF ASPIDIUM Q\ 



History 



The oleoresin of aspidium, or Huile de Fougere Male as it 
was originally known, was first prepared by Peschier in 1825.^ 
The advantages of Peschier 's preparation over the forms in 
which male fern was being administered at the time were quickly 
noted and it received almost immediate recognition throughout 
Europe. The rapidity with which it was taken up by the 
medical profession is evidenced in the fact that it was mentioned 
in the Vereinigte Pharmacopoeen der Londoner, Edingurgher 
und Duhliner Medicm<e Collegien, a German translation of the 
pharmacopoeias of London, Edinburgh and Dublin, which ap- 
peared in 1827, and, that two years later (1829), it became of- 
ficial in the Prussian Pharmacopoeia. Its introduction into 
other European pharmacopoeias followed, as a general rule, in 
the chronological order of their appearance or revision, whereas, 
it was the last of this class of preparations to be admitted to the 
United States PhQrmacoposia previous to the ninth revision, 
having been recognized for the first time in the edition of 1870. 
At the present time, it is the only preparation of this kind 
which is official in all of the national pharmacopoeias. How- 
ever, it is only in the United States where it is officially recog- 
nized under the title oleoresin, it being classed as an extract 
in all of the foreign pharmacopoeias. For a better apprecia- 
tion of this fact, see the preceding table of synonyms. 

A better idea of the popularity of this preparation and the 
rate at which it came into prominence will be obtained from 
the following table in which are chronologically enumerated the 
names of the pharmacopoeias of the countries, states and muni- 
cipalities where it first received official recognition, also, the 
dates of appearance of the succeeding editions in which it occurs. 

Prussian Pharmacopoeia — 1829, 1846, 1862. 
Pharmacopoeia of Baden — 1841. 
Austrian Pharmacopoeia — 1844, 1869, 1889, 1906. 
Pharmacopoeia of Schleswig-Holstein — 1844. 



1 Gebhardt in 1821, and Morin in 1824, in their analyses of male fern, 
extracted the rhizomes with ether and obtained what they termed a thick, 
green, fatty oil. This was, of course, the Huile de Fougere of Peschier. 
Neitlier of these investiefators, however, pointed out its value as a galenical 
preparation, although, the latter stated that he considered it to be the ther- 
apeutically active principle of the rhizomes. 



g2 DU MEZ— THE GALENICAL OLEORESINS 

Swedish Pharmacopoeia— 1846, 1869, 1879, 1888, 1901, 1908. 
Pharmacopoeia of Berne — 1852. 
Belgian Pharmacopoeia — 1854, 1885, 1906. 
. Norwegian Pharmacopoeia — 1854, 1870, 1879, 1895, 1913. 
Pharmacopoeia of Hannover — 1861. 

Pharmacopoeia of Hessia — 1862. \^ i 

British Pharmacopoeia — 1864, 1867, 1885, 1898, 1814. 
Swiss Pharmacopoeia— 1865, 1872, 1893, 1907. 
French Pharmacopoeia — 1866, 1884, 1908. 
Austrian Pharmacopoeia— 1869, 1889, 1906. 
Hungarian Pharmacopoeia — 1871, 1888, 1909. 
Netherlands Pharmacopoeia — 1871, 1889, 1909. 
German Pharmacopoeia — 1873, 1882, 1890, 1900, 1910. 
United States Pharmacopoeia — 1870, 1880, 1890, 1900, 1910. 
Eoumanian Pharmacopoeia — 1874. 
Portuguese Pharmacopoeia — 1876. 
Spanish Pharmacopoeia — 1884. 
Italian Pharmacopoeia — 1892, 1902, 1909. 
Danish Pharmacopoeia — 1893, 1907. 
Japanese Pharmacopoeia — 1907. 
Eussian Pharmacopoeia — 1910. 
Finnish Pharmacopoeia — 1914. 



Drug Used, Its Collection, Preservation, Etc. 

The rhizomes directed by all of the present day pharma- 
copoeias to be used in the preparation of the oleoresin of as- 
pidium are those of the male fern^ now referred by botanists. 
to the genus Dryopteris as Dryopteris Filix-mas (Linne) Schott. 
As male fern, especially in the older works on pharmacy, has been 
referred to genera other than Dryopteris, the following table of 
botanical synonyms is given : 



^ The rhizomes of ferns other than those which have been offlcially recog- 
nized are said to yield oleoresins which are active in the expulsion of the 
tapeworm. 

Kuersten states that the rhizomes of Aspidium athamanticum Kunse yield 
a preparation which is as active as that obtained from male fern. Arch, 
d. Pharm. (1891), 229, p. 258. 

Lauren reports the use of an extract in Finland prepared from Aspidium- 
spinulosum Sw. which he states is very active as a teniafuge. Finska 
Laegaresaellck. Handl. (1897), p. 9; Pharm. Centralh, (1897), 39, p. 775. 

Rosendahl suggests that the rhizomes of Dropteris dilata replace those 
of Dryopteris Filix-mas in the preparation of the oflflcial oleoresin as he has 
found them to be four times as active as the latter in the expulsion of 
Bothryocephalus latus. Hygienic Lab. Bull. No. 87, p. 250. 



OLEORESIN OF ASFIDIUM 03 

Aspidium Filix-mas Swartz. 
Aspidium Mildeanum Goeppert. 
Lastrea Filix-mas Presl. 
Nephrodium Filix-mas Michaux 
PolypodiAim Filix-mas Linne. 
Folystichum Filix-mas Eoth. 
Tectarea Filix-mas Cavan. 
Polypodium-nemorale Salisbury, 
Folystichum Durum et induratum Schur. 
Folystichum ahhreviatum De Candolle. 

In addition to the rhizomes of Dryopteris Filix-mas (Linne) 
Schott, the United States Pharmacopwia also permits the use of 
the rhizomes of Dryopteris marginalis, Linne formerly referred 
to the genus Aspidium as Aspidium marginale Schwartz. It 
should be noted in this connection that the official recognition 
of Dryopteris marginalis Linne appears to have been based on 
the somewhat doubtful statements of but three persons made 
back in the seventies. These men, Pa^tterson,^ Cressler,^ and 
Kennedy,^ respectively, reported that they had prepared oleo- 
resins from the rhizomes of this fern. Two of them, Cressler 
and Kennedy, also stated that their preparations were found to 
be active in the expulsion of tape worm, while Patterson merely 
reported that his preparation resembled the German oleoresin 
of male fern in appearance and taste. There does not appear 
to be any evidence in the literature to show that an oleoresin 

f authentically prepared from this rhizome was ever given a trial 
by a reputable physician. Furthermore, there is no evidence 
to the effect that the rhizome is ever used in preparing the 

I oleoresin at the present time, a statement which has also been 
made by Rusby.* 

The definition of Aspidium as given in the ninth revision of 

ithe United States Pharmacopoeia is as follows: ''The rhizome 
and stipes of Dryopteris Filix-mas (Linne) Schott, or of 
Dryopteris marginalis (Linne) Asa Gray (Fam. Polypodiaceae) , 
collected in the autumn, freed from the roots and dead portions 
of rhizomes and stipes and dried at a temperature not exceed- 
ing 70° C. Preserve aspidium in tightly closed containers and 
protect from light. ' ' 



*Am. Journ. Fharm. (1875), 47, p. 292. 

^ Cressler states that he prepared an oleoresin from what he thought to 
be male fern, but which later proved to be Aspidium marginale. Ibid., 
(1878), 5, p. 290. 

•Ibid. (1879), 51, p. 382. 

<Drugg. Circ. (1910), 54, p. 6l6. 



'64 



DU MEZ— THE GALENICAL OLEORESINS 



With further reference to the species of drug specified by the 
Pharmacopoeia, it should be stated that the male fern of com- 
merce, obtained from Europe, is frequently contaminated with 
the rhizomes of other species of fern, principally those of 
Dryopteris spinulosa Kunze. Pendorff (1903), who examined 20 
samples of the commercial drug, reported that 12 of them con- 
tained over 50 per cent, of rhizomes of this species. 

The pharmacopoeial directions concerning the collection of the 
rhizomes in autumn are in keeping with specifications given in 
most of the foreign pharmacopoeias^ and are based on the re- 
sults of extensive investigations carried out in continental 
Europe and England. Analyses of the drug harvested at dif- 
ferent periods of the year have shown autumn to be the sea- 
son in which the therapeutically active constituents are pres- 
ent in greatest amount. Thus, the firm of Caesar and Loretz, 
in their Berichte for 1898, state that the amount of active con- 
stituents present does not begin to approach the maximum until 
the month of August and that it again begins to diminish in 
October. They, therefore, conclude that the rhizomes should 
be harvested only in the months of August, September and 
October. Similar conclusions were drawn by Ed. Schmidt^ 
from a series of observations made in France in 1903. The fol- 
lowing table compiled by the latter shows the variation in crude 
filicin content of the ethereal extracts (oleoresins) prepared 
from the rhizomes harvested during six consecutive months of 
the year. 



Table 8. — Variation of crude filicin content due to season. 





Crude filicin content of oleoresins prepared from 
rliizomes gathered in the — 


Time of harvesting 


Forest near 
Paris 


Jura 

Mts. 


Vosges 
Mts. 


Vosg-es Mts. 
Peeled Rhiz. 


May 


Per cent 

9.70 
10.80 
10.86 
11.64 
13.78 
11.80 


Per cent 

12.78 
13.86 
14.60 
17.80 
19.60 
18.68 


Per cent 

13.76 
15.65 
17.70 
19.70 
20.76 
19.80 


Per cent 




12.75 


July 


14.85 


Ausrust 


15.60 




17.76 


October 


16.70 

















*The Spanish Pharmacopoeia (1905) directs that the rhizomes be collected 
at the end of spring: or in the autumn. 

^ TMse pour Vobtention du Diplome de Docteur de I'Universitc de Paris 
•(1903), p. 116. 



OLEORESIN OF ASFIDIUM 65 

The table not only shows a variation in the crude filicin 
content due to season, but also points out the fact that there is 
a very considerable variation due to the locality^ in which the 
rhizomes are grown. This factor, while evidently overlooked 
by the United States Pharmacopceial Revision Committee, ap- 
pears to be of considerable importance in influencing the qual- 
ity of the oleoresin. Further proof of this is to (be found in 
the reports of Van Aubel,^ Madsen,^ Matzdorff,^ and Caesar 
and Loretz/ 

Further inspection of the pharmacopoeia! definition shows 
that the official drug is intended to be represented by the whole 
rhizome and stipe deprived only of the roots and dead portions, 
which is also in conformity with the description generally found 
in foreign pharmacopoeias. This is a wise provision in that the 
rhizomes not only contain less of the active constituents when 
peeled^ but deteriorate much more rapidly. On the other hand, 
compliance with this specification would appear to be a difficult 
problem for the pharmacist as practically all of the drug on the 
American market is peeled. The latter statement is based on 
the examination of a number of samples in the laboratory^ and 
on the reports of pharmaceutical manufacturers^ and others^. 

In the drying of the rhizomes, the United States Pharmaco- 
pccia specifies that the temperature shall not exceed 70 °C. 
This temperature is thought to be too high, as filmaron, the 
most active constituent therapeutically, melts at 60° C and is 
very prone to undergo decomposition.^ The directions as given 



^ A variation due principally to soil and climate. 

'Van Aubel (1896) states that the rhizomes growing in Wolmnr on the 
flhores of the Aa and those growing in the Jura and Vosges mountains yield 
fl,n oleoresin which is more active therapeutically than that prepared from 
the rhizomes growing in Italy. 

^ Madsen (1897) and Matzdorff (1901) report the oleoresin prepared from 
Russian rhizomes to be the most active. 

• Caesar and Loretz attribute the uniform activity of the oleoresin pre- 
pared by them to the fact that they obtain their supply of rhizomes from 
the same locality each year. 

• See preceding table by Schmidt. 

• Of the sixteen samples of male fern rhizomes purchased from various 
«ources in the United States and examined in the laboratory all but three 
were in the peeled condition. 

^ Letters received from a number of pharmaceutical manufacturers in this 
country indicate that the drug as usually received from Europe is peeled. 

'Plaut (1914) states that though the U. 8. Pharmacooepia requires the 
use of unpeeled aspidium., none such is to be found on the market. 

"Kraft (1902). 



gg DU MEZ— THE GALENICAL. OLEORESINS 

in the Belgian Pharmacopoeia (1906), ''dry at a temperature 
below 40°C," or the Norwegian Pharmacopoeia (1914), ''dry 
at a temperature not exceeding 60 °C," appear to be more 
rational. 

In connection with the pharmacopoeial provision concerning 
the preservation of the drug, attention is called to the fact that 
the late edition of the German Pharmacopoeia (1910) requires- 
that the dried rhizomes be kept over freshly calcined lime. 
Such a procedure was shown by Hager, as early as 1871, to- 
render the oleoresin prepared therefrom less liable to form a 
deposit. 

The fact that the United States Fliarmacopma does not 
specify a time limit for the consumption of the drug is unfor- 
tunate in view of the rapidity with which it is known to de- 
teriorate.^ So important is this factor, that the French Phar- 
macopoeia (1908) directs that only the recently collected and 
freshly dried rhizomes be employed and the other European 
pharmacopoeias commonly specify that they be renewed an- 
nually. That there is need of similar restrictions in this 
country will become evident from the following table showing 
the results obtained in the examination of fourteen samples 
of commercial rhizomes. Six of these samples were purchased 
from importers and drug millers in the United States during 
the winter and spring of 1909 and 1910, respectively. . The other 
specimens were received in January of 1913 and represent 
samples obtained from abroad as well as in this country. In 
each case, the rhizomes were sorted, those showing a green frac- 
ture having been separated from those showing an internal 
brown color. 



1 Peschier as early as 1825 noted that the therapeutic activity of the 
rhizomes diminished on ageing and recommended that they should be con- 
sumed within a period of less than two years after harvesting. 

Caesar and Loretz state that they prepare the year's supply of oleoresin 
immediately after harvesting and drying the rhizomes to insure the maxi- 
mum activity of the preparation. 



OLEORESIN OF ASPIDIUM 



67 



Table 9. — Percentage of green rhizomes in samples of male fern purcliased 
from drug millers and jobbers. 



Sample No. 


Date of purchase 


Source 


Content of 

grreen 
rhizomes 




December, 1909 

Aoril 1910 ! '. '. 


United States 


Per cent. 
6.5 


2 


18.0 


m 


O.Qi 


O... 


li 4. 


8.0 


? * 




4; 


0.0 




•1 It 


" " 


53.7 


2 »•.«• 


January, 1913 


44 44 


0.0 


r, 




1. 44 


9.2 


9'"* 


.» 


Eng'land 


0.0 


<« 

u....... 


ti n 




0.0 




•> t> 


Germany 


X.'i 


in 

X6. 


» (> 




8.5 




li ii 


France 


0.0 




.1 >k 




0.0 











1 Composed entirely of Osmunda rhizomes. 

It will be noticed that even the rhizomes purchased in Ger- 
many were not in good condition. As these rhizomes were ob- 
tained in January, they should have shown an internal green 
coloration had they consisted of the fresh stock harvested in 
the preceding autumn. From this, it appears that the German 
supply for exportation, at least, is not renewed yearly as it 
should be, but is allowed to accumulate and deteriorate. 

TJ. S. P. Text and Comments Thereon. 

Oleoresin of aspidium was admitted to the United States 
Pharmacopoeia in 1870 and has been official in all subsequent 
editions. 



1870 

Oleoresina Filicis 
Oleoresin of Fern 



Take of Male Fern,* in fine powder,^ 
twelve troy ounces; Ether* a suf- 
ficient quantity. 
Put the male fern into a cylindri- 
cal glass percolator, provided with a 
stop-cock, and arranged with cover 
and receptacle suitable for volatile 
liquids," press it firmly, and gradually 



pour ether upon it, until twenty-four 
fluidounces of liquid have slowly 
passed.' Recover' the greater part of 
the ether by distillation on a water- 
bath, and expose the residue, in a 
capsule, until the remaining ether has 
evaporated.' Lastly, keep the oleo- 
resin in a well-stopped bottle.' 



68 DU MEZ— THE GALENICAL OLEORESINS 

1880 

Oleoresina Aspidii ■,' 

Oleoresin of Aspidium 

[Oleoresina Filicis, Pharm., 1870] 

Aspidium,* in No. 60 powder/ one ether by distillation on a water-bath, 

hundred parts 100. and expose the residue, in a capsule, 

Stronger Ether,* a sufficient quantity, until the remaining ether has evap- 

Put the aspidium into a cylindrical orated,* 

glass percolator, provided with a Keep the oleoresin in a well stopped 

cover and receptacle suitable for vola- bottle*. 

tile liquids,* press it firmly, and Note. Oleoresin of aspidium us- 

gradually pour stronger ether upon it, ually deposits, on standing, a granu- 

until one hundred and fifty (150) lar crystalline substance.** This should 

parts of liquid have slowly passed.' be thoroughly mixed with the liquid 

Recover' the greater part of the portion, before use." 



r 1890 

Oleoresina Aspidii 

Oleoresin of Aspidium 

Aspidium,* recently' reduced to No. 60 of the ether from the percolate 

powder,* five hundred grams by distillation on a water-bath, and, 

500 Gm. having transferred the residue to a 

Ether* a sufficient quantity. capsule, allow the remaining ether to 

Put the aspidium into a cylindrical evaporate spontaneously.' 
glass percolator, provided with a stop- Keep the oleoresin in a well-stop- 
cock, and arranged with cover and pered bottle.' 

receptacle suitable for volatile liquids." NOTE. Oleoresin of Aspidium 

Press the drug firmly, and percolate usually deposits, on standing, a gran- 

slowly with ether, added in succes- ular-crystalline substance.** This 

■sive portions, until the drug is ex- should be thoroughly mixed with the 

hausted.* Eecover the greater part liquid portion before use.** 



OLBORESIN OF ASPIDIUM 



69 



1900 

Oleoresina Aspidii 
Oleoresin of Aspidium 



Aspidium,* recently ' reduced to No. 
40 powder/ five hundred grammes 

500 Gra. 

Acetone,* a sufficient quantity. 

Introduce the Aspidium into a cy- 
lindrical glass percolator, provided 
with a stop-cock, and arranged with a 
cover and a receptacle suitable for 
volatile liquids." Pack the powder 
firmly and percolate slowly with ace- 
tone, added in successive portions, 
until the Aspidium is exhausted.' 
Eecover^ the greater part of the ace- 
tone from the percolate by distilla- 



tion on a water-bath, and, having 
transferred the residue to a dish, al- 
low the remaining acetone to evap- 
orate spontaneously in a warm place." 
Keep the oleoresin in a well-stoppered 
bottle." 

NOTE. Oleoresin of aspidium us- 
ually deposits, on standing, a granu- 
lar crystalline substance." This 
should be thoroughly mixed with the 
liquid portion before use." 

Average dose 2 Gm. 

(30 grains). 



1910 

Oleoresina Aspidii 
Oleoresin of Aspidium 
Oleores. Aspid. — Oleoresin of Male Fern 



Aspidium,^ recently' reduced to 
No. 40 powder,' five hundred 

grammes 500 Gm. 

Ether,* a sufficient quantity. 

Place the aspidium in a cylindrical 
glass percolator, provided with a 
stop-cock, and arranged with a cover 
and a receptacle suitable for volatile 
liquids.'' Pack the powder firmly, and 
percolate slowly with ether, added in 
successive portions, until the drug is 
exhausted." Eecover ' the greater 
part of the ether from the percolate 
by distilling on a water bath, and, 



having transferred the residue to a 
dish, allow the remaining ether to 
evaporate spontaneously in a warm 
place.* Keep the oleoresin in a well- 
stoppered bottle.' 

NOTE. — Oleoresin of Aspidium, on 
standing, usually deposits a granular 
crystalline substance." This should 
be thoroughly mixed with the liquid 
portion before use." 

Average Dose — Caution ! Single 
dose, once a day. Metric, 2 Gm. — 
Apothecaries, 30 grains. 



rjQ DU MEZ— THE GALENICAL. OLEORESINS 

1.) The Pharmacopoeia of 1870 recognized but one species 
of fern (Aspidium Filix-mas) as the source of the official drug, 
hence, the directions : * ' Take of Male Fern, etc. ' ' In the sub- 
sequent editions, Aspidium marginale was also recognized as a 
cource of supply. In these editions, the drug is, therefore, 
referred to by the generic name, Aspidium. The species from 
which the official drug is obtained are now referred by botanists 
to the genus Dryopteris. See page 969 under "Drug used, its 
collection, preservation, etc." 

2.) Owing to the fact that the drug deteriorates rapidly 
when in the powdered condition, the last three editions of the 
Pharmacopoeia have specified that the rhizomes be preserved 
whole and that they may be reduced to a powder shortly before 
using. For factors causing the deterioration of the drug, see 
under "Drug used, its collection, preservation, etc.'' 

3.) In the last two editions of the Pharmacopoeia, it is di- 
rected that the drug be employed in the form of a moderately 
coarse powder (No. 40). In the previous editions, a fine pow- 
der (No. 60) was specified. The coarser powder posesses dis- 
tinct advantage in that it is better adapted to percolation and 
can be produced with a greater degree of uniformity. 

4.) It will be observed that the pharmacopoeias of 1870, 1880 
and 1890 directed that the drug be extracted with ether; that 
acetone was the menstruum specified in the Pharmacopoeia of 
1900; and that ether is again directed to be used for this pur- 
pose by the present Pharmacopoeia. 

These changes appear to have been made for economic rea- 
sons as is evidenced in the following statement by Beringer 
(1916) : "In the Eighth Revision, acetone was directed in place 
of ether, because at that time the former was cheaper. As it 
is now permissable to use denatured alcohol in the manufacture 
of ether, that solvent is made so cheaply that it is again advan- 
tageous to use it in place of acetone. ' ' If the comparative cost 
of the two solvents was the factor which induced the Revision 
Committee to make the last change, it is indeed fortunate that 
ether was the cheaper inasmuch as it has proven to be the more 
desirable from a scientific standpoint as well. 

Acetone, although the official menstruum for the preparation 
of this oleoresin for more than a decade, does not appear to 
have been employed for this purpose to any considerable ex- 



OLEORESIN OF ASPIDIUM 71 

tent by the manufacturer. This statement is based upon the 
examination of a number of commercial samples purchased at 
various times during the past ten years. While the reason for 
the above condition does not become apparent from the litera- 
ture, it is thought that it is to be attributed to the fact that 
acetone yields a product of inferior quality, rather than to the 
relatively low cost of ether. In support of this supposition, at- 
tention is called to the statement of Dunn (1909), who reports 
that it is necessary to purify the oleoresin made with acetone 
hy dissolving the same in ether, also, to the observations made in 
the laboratory. 

Experiments conducted in the laboratory have shown that 
the oleoresin, when prepared with acetone, is brown in color and 
always contains considerable deposited matter. While the greater 
bulk of the deposited material has the appearance of extractive 
matter and is very likely of no consequence from a therapeutical 
standpoint, portions of it answer to the descriptions of filixnigrin 
and filix acid, decomposition products of the therapeutically 
active constituents. The latter observation is in keeping with 
that of Kraft (1902), who found that filmaron, the most im- 
portant of the therapeutically active constituents, decomposes 
in acetone solution yielding the above mentioned decomposition 
products. It was also noted that the amount of deposited 
material increases much more rapidly in the preparations made 
with acetone than in those in which ether was used as the men- 
struum for extracting the drug. 

As previously stated, ether has proven to be the more sat- 
isfactory solvent for scientific as well as economic reasons. In 
fact it has been found to be superior to any of the solvents 
which have been experimented with in this connection, namely: 
benzin, benzene, chloroform and carbon disulphide. See Part I, 
page 921, under *' Solvents." At the present time, it is the sol- 
vent universally employed in the manufacture of the oleoresin, 
which is in itself a good reason for its adoption by the Pharma- 
copoeia. Furthermore, the product obtained with ether is 
perfectly homogenous and forms a deposit only after long 
standing, the constituents of therapeutic value evidently under- 
going no decomposition in ethereal solution. However, the 
quality of the preparation, even when ether is employed in ex- 
tracting the drug, is influenced to a certain extent by the purity 
of the solvent. 

©2— S. A. L. 



72 I5U MEZ— THE GALENICAL. OLEORESINS 

Alcohol and water appear to be the impurities which tend 
to exert a deleterious influence upon the finished product. Thus, 
Daccomo and Scoccianti (1896) observed that ether containing- 
a considerable amount of alcohol did not completely extract the 
therapeutically active constituents from the drug and that the 
oleoresin obtained was more prone to form a .deposit than when 
ether of a greater degree of purity was used. See also page 984 
ander ''Yield of oleoresin." Similar effects were observed 
by the firm of Caesar and Loretz (1899.) The presence of 
water is so great a factor in promoting decomposition 
(hydrolysis?) that the German Pharmacopoeia (1910) directs 
that the rhizomes be preserved over freshly burned lime, a 
procedure which was recommended by Hager as early as 1871. 
Further evidence of the undesirability of the presence of water 
is to be found in the Norwegian (1913) and Finnish (1914) 
pharmacopoeias, which direct that the ethereal tincture be dried 
with anhydrous sodium sulphate or fused calcium chloride pre- 
vious to the removal of the solvent by distillation. 

5.) For a description of the various forms of percolators 
designed for extraction with volatile solvents, see Part I under 
''Apparatus used." 

6.) All editions of the Pharmacopoeia, including the present,, 
direct that the drug be extracted by the process of simple per- 
colation even though the advantages of a continuous extraction 
apparatus in the handling of a volatile solvent like ether have 
been repeatedly pointed out. See Part 1 under "Solvents" 
and under "Apparatus used." 

Of special interest in this connection is the work of Matzdorif 
(1901), the results of which show that the therapeutically ac- 
tive constituents are not completely extracted by simple perco- 
lation as ordinarily carried out, but that complete extraction 
is effected in a comparatively short time with the use of a Soxh- 
let's apparatus. 

7.) In connection with the recovery of the solvent by dis- 
tillation, attention is again directed to the deleterious effect of 
the presence of moisture and to the manner in which the same 
is directed to be removed by the Norwegian and Finnish phar- 
macopoeias. See above. 

Attention is also invited to the pharmacopoeial directions re- 
garding distillation, namely that it be conducted on a water 



OLEORESIN OF ASFIDIUM 73 

bath. Inasmuch as Kraft (1902) states that filmaron melts 
at 60°C and undergoes decomposition at higher temperatures, 
it is thought that the pharmacopoeial directions should contain 
a. warning against exceeding this temperature during distilla- 
tion. 

8.) The removal of a part of the solvent by spontaneous 
evaporation as directed by the Pharmacopoeia tends to operate 
against obtaining a uniform product as the time required to 
accomplish the same varies mth the temperature. If evapora- 
tion is allowed to proceed at a low temperature (winter tem- 
perature), the preparation will be exposed to the action of the 
air for a very considerable length of time and partial oxida- 
tion of some of the constituents will very likely result. 

The complete removal of the solvent can be accomplished 
much more rapidly by heating the preparation on a water bath, 
and without injury, if the temperature is kept below 60° C. By 
such a procedure, the above conditions are eliminated and a more 
uniform product will be obtained. 

9.) The oleoresin should be kept in well-stoppered bottles 
as it becomes rancid on prolonged exposure to the air due to 
the hydrolysis and partial oxidation of the glycerides composing 
the fatty oil. 

10.) For a discussion of the nature of the deposit which 
forms in the oleoresin on standing, see pages 992 and 1004 under 
■''Constituents of therapeutic importance," and under ''Other 
properties. ' ' 

11.) As to the propriety of the pharmacopoeial directions 
concerning the mixing of the deposit with the liquid portion 
before dispensing, there is some doubt. The question, however, 
is one which should be decided by the pharmacologist rather 
than the pharmacist and will, therefore, not be considered here. 

The use of an alkali, ammonia as suggested by Beringer 
(1892), for the purpose of facilitating the admixture of the pre- 
cipitate with the liquid portion should be condemned as a dan- 
gerous practice. The danger lies in the fact that the slightly 
soluble toxic constituents are converted into soluble compounds 
by union with the alkali and are thereby rendered readily ab- 
sorbable. 

Of further interest in this connection is the procedure recom- 
mended by Seifert (1881) and Kraemer (1884) for avoiding 



74 DU MEZ— THE GALENICAL. OLEORESINS 

the formation of a deposit, namely: that the ethereal tincture 
be kept on hand and that the oleoresin be prepared therefrom 
just previous to dispensing. 

Yield 

The yield of oleoresin, when ether is the solvent employed 
in extracting the drug, is commonly stated to be 10 to 15 per 
cent, in the various dispensatories and American text-books on 
pharmacy. As a matter of fact, the amount of oleoresin actually 
obtained is about 7 to 10 per cent. (See the tables which fol- 
low.) When petroleum ether or benzene is used, the yield m 
slightly lower, as a rule, whereas, it is much higher (about 18 
per cent.) when acetone is employed. These statements refer 
to the yield as found for the air dried drug. When the latter 
is dried at a temperature of 100 to 110° C, the percentage of 
oleoresin obtained will naturally be somewhat higher as is shown 
in the table immediately following. 



OLEORESIN OP ASPIDIUM 



75 



Table 10. — Yield of oleoresin as reported in the literature. 





Observer 


Yield of oleoresin to 




Date 


< 


1 


1 


CO 

J 


Remarks 


1826 


von Esenbeck . 

Van Dyk 

Zeller 


Perct. 


Per ct. 


Perct. 
5.63 
7.30 


Perct. 


Rhizomes harvested in 


1827 


37.5 
32.0 






August. 
Rhizomes harvested in 


1828 


Meylink 




6.04 




September. 




Winkler 

Haendess 


15.6 






Rhizomes harvested in 


1829 




8.85 

8.33 

12.87 

7.80 

8.20 
8.50 

10.30 

12.40 

11.50 

14.00 

6.51- 
5.60 

6.20 

5.70 

6.00 

8.50 
8.00 

11.00 
13.00 
6.00 
6.50 
5.70 

9.87 
7.26 
8.90 
5.90 

6.12 

8.92 

9.96 

9.50 

9.88 





February. 


1844 










1851 


Bock 








Peeled rhizomes dried at 


1852 


von der Marck 








100° c. 
Portion of rhizomes having 










borne fronds the previous 
year. 
Portion of rhizome bearing 










fronds. 
Portion of rhizome to de- 


1876 






r Petrol. 
1 Etlier 

1 '-' 

1 9.1 

I 


velop fronds the next year. 
Rhizomes harvested in 




Kremel 

Trimble 






April. Dried at 110° C. 
Rhizomes harvested in July 








Dried at 110° C. 
Rhizomes harvested in Oc- 


1887 


29.0 




tober. Dried at 110° C. 


1888 


J Benzin 

1 5.9 




1891 


Nagrelwoort (i) 






Rhizomes harvested in 










July. 1889. 
Rhizomes harvested in 










September, 1889. 
Rhizomes harvested in 










October, 1889 
Rhizomes harvested in 










December. 








Rhizomes harvested in 











February, 1890.^^ 








" " •' 










Rhizomes harvested in 










April. 1890. 












1892 




18.0 


j Benzin 
1 16.18 


" 




Sherrard 




Whole Rhizomes. 




Bellingrodt . . . 


















Peeled 












1898 






Rhizomes from "Rheinische 










Tiefebene (Calcar)." 
Rhizomes from "'Rheinische 










Tiefebene (Dinslaken)." 
Rhizomes from "Voreifel 










(Aachen.)" 
Rhizomes from "Hocheifel 










(Gerolstein.)" 
Rhizomes from "Taunus 










(Braubach.)" 
Rhizomes from Wester- 










wald auf Thonschiefer 
(Daaden.)" ^—^ 



' Ed. Schmidt, Th&se pour I'Obtention 
Paris, 1903, p. 78. 



du DiplOme du Docteur I'UnlverslW 



76 



DU MEZ— THE GALENICAL. OLEORESINS 



Table 10.— Continued. 



Date 



1902 
1903 



1905 



1906 



1906 



Observer 



Bellingrodt— 
Con. 



Hausmann 



Buttin 

Schmidt. E.(») 



Dietrich 



Roder 



Wollenweber. 



Yield of oleoresin to 



Perct. 



Perct. 



Perct. 
9.95 

8.90 
8.50 
10.00 
8.00 
9.30 
8.00 
6.60 

9.60 

9.10 

6.40 

6.90 

9.80 

9.30 

7.00 



9.94 to 
10.60 

Up to 
11.20 

9.22 to 
10.1 



10.30 
10.00 






Per ct. 



Benzene 
! 9.81 



10.10 



Petrol. 
Ether 



9.5 



Remarks 



Rhizomes from "Wester- 

wald auf Basalt boden 

(Daaden.)' 
Rhizomes from "Hansruclc 

(Simmern) ' 
Rhizomes from "St.Gallen, 

Switzerland." 
Rhizomes from "Bludenz 

(Vorarlberg)." 
Rhizomes from "Appenzell, 

Switzerland." 
Rhizomes from "Bierber- 

wier, Tyrol." 
Rhizomes harvested in 

spring:. 
Whole rhizomes from near 

Paris harvested in Sep- 
tember. 
Whole rhizomes from the 

Vosges JVIts. harvested in 

September. 
Whole rhizomes from the 

Jura Mts. harvested in 

September. 
Peeled rhizomes from the 

Vosges Mts. harvestsd in 

September. 
Whole rhizomes from near 

Paris harvested in Oc- 
tober. 
Whole rhizomes from the 

Vosg-es Mts. harvested in 

October. 
Whole rhizomes from the 

Jura Mts. harvested in 

October. 
Peeled rliizomes from the 

Vosges Mts. harvested in 

October. 
From air dried rhizomes. 

From rliizomes dried at 
100° C. 

Yield obtained when the 
product was heated at 
95° C for 2 hours, cooled 
in a desiccator & weighed . 

Air dried rhizomes extract- 
ed in a Soxh let's appar- 
atus. 

Exiccated rhizomes ex- 
tracted in a Soxhlet's 
apparatus. 



Air dried rhizomes extract- 
ed in a Soxhlet's appar- 
atus. 

Exiccated rhizomes ex- 
tracted in a Soxhlet's 
apparatus, 



1. c, p. 110. 



OLBORESIN OF ASPIDIUM 



77 



Table 10. —Continued. 





Observer 


Yield of oleoresin to 




Date 


< 


1 
§ 
< 


Si 


Other 
solvents 


Remarks 


1908 


Vanderkleed(i) 
Vanderkleed . . 


Perct. 


Perct. 


Per ct. 


Per ct. 

r Solvent? 

6.68 
\ 10.003 
1 17.90 
I 10.33 


Reported as yield of oleo- 


















resin. 


1999 










1911 


Rosendahl. ... 






10.00 

12.50 

11.50 

9.50 
11.60 
8.80 
7.90 
8.30 
7.70 
9.70 
8.60 

7.50 

7.00 

10.90 

9.40 to 

9.70 


Rhizomes harvested in 




Harrison & Self 
Riedel 










May. 
Rhizomes harvested in 








August. 


1913 








October. 
Rhizomes from "Harz." 




















i» .< 










H t( 










.1 41 .4 










" *' "Bayem" 




















(k (( .1. 










( "Schwarz- 
" "! wald, Wuert- 










f em berg." 
i "Mo&el, 
" *' ■{ Rhein- 










rPreussen." 


914 








" 




Vanderkleed . . 






i Solvent ? 
\ 6.85 to 
\ 10.12 


Average yield of oleoresin 
is reported as 8. 23 per cent. 















^ The high yield (1.79 per cent.) obtained in this instance is suggestive of 
the use of acetone as the menstruum for exhausting the drug. It may, how- 
ever, have been due to the extensive adulteration of the latter with the- 
rhizomes of Dryopteris spinuloaa. Rosendahl (1911) obtained 17.0 per cent., 
of oleoresin from the rhizomes of this species by extraction with ether. 

Table 11. — Yield of oleoresin obtained in the laboratory. 





Observer 


Yield of oleoresin to 




Date 


Alco- 
hol 


Ace- 
tone 


Ether 


Benzin 


Remarks 


1909 


DuMez & Baker 


Per ct. 


Per ct. 
18.27 


Per ct. 
9.3 

9.7 

8.70 


Per ct. 


Represents the yield 
using a Soxhlet's ex- 
traction apparatus. 

Represents the yield 
using a Soxhlet's ex- 
traction apparatus. 

Represents the yield 
using a Soxhlet's ex- 
traction apparatus. 




DuMez&Beedle.... 







1910 


DuMez &Netzel 


43.33(1) 


16.10 


7.5 



(i)The alcoholic extract was obtained by simple percolation. 



78 



DU MEZ— THE GALENICAL OLEORESINS 



An examination of the first of the foregoing tables reveals 
the fact that the yield is influenced to a very considerable extent 
by the condition of the drug from which the oleoresin is pre- 
pared. Thus, for instance, the amount obtained is less when the 
powdered whole rhizomes are used than when peeled rhizomes 
are employed. This is to be expected in view of the fact that 
the outer layers contain little that is soluble in the solvent 
(ether) usually made use of. It will also be noticed that na- 
tural causes, such as, locality in which the rhizomes are grown, 
and time of harvesting are important factors in this connec- 
tion. These influences will be brought out more clearly on an 
inspection of the following table which shows the results of this 
nature obtained by Ed. Schmidt. 

Table 12. — Effect of locality in which the rhizomes are gr0wn and the time 
of harvesting on the yield of oleoresin. 



Time of harvesting 



May 

June 

July 

Autrust 

Peptembet 
October . . . 



Peeled rhizomes from- 



Forest 
near Paris 



Per cent. 

4.00 
4.80 
5.60 
6.20 
6.60 
6.90 



Vosges 

Mts. 



Per cent. 

7.00 
7.60 
8.70 

g.oo 

9.60 
9.80 



Jura Mts. 



Per cent. 

6.40 
7.00 
8.00 
8.40 
9.10 
9.30 



Whole 

rhizomes 

from— 



Vosges 
Mts. 



Per cent. 



4.90 
5.70 
6.00 
6.40 
7.00 



In addition to the comments already made with regard to the 
influence of the solvent on the yield, the observations of Dac- 
como and Sccocianti (1896) are of importance in this connec- 
tion. These investigators found that the amount of oleoresin 
obtained, when ether was employed for extracting the drug, de- 
pended to some extent on the purity of the former. Thus, 
ether, specific gravity 0.720 gave 10 per cent, of oleoresin, 
whereas, ether, specific gravity 0.756 yielded 17 per cent. It 
was further pointed out, however, that the greater yield was 
not desirable as in this case the preparation did not contain 
all of the therapeutically active constituents and in addition 
was more prone to form a deposit on standing. 



OLEORESIN OF ASPIDIUM 79 

Chemistry of the Drug aTid Oleoresin. 

Tabulation of Constituents, 

A survey of the voluminous literature^ pertaining to the 
chemistry of the mak fern rhizome shows the constituents of 
pharmaceutical interest to be as follows: volatile oil, fatty oil, 
iilix acid, albaspidin, flavaspidic acid, aspidinol, flavaspidinin 
(phloraspin), filmaron, filixnigrin, chlorophyll, filix tannic acid, 
wax, sugar, starch and inorganic constituents. Of these sub- 
stances, the following have been identified in the oleoresin ob- 
tained by extracting the drug with ether: 

Volatile oil =* 0.40 to 0.45 per cent 

Fatty oiP 70.00 to 75.00 " '* 

Filix acid* 5.75 to 12.48 " '' 

Albaspidin'^ Av. 0.05 " '' 

Flavaspidic acid » " 2.50 " " 

Aspidinol » " 0.10 '' '* 

Flavaspidinin" ** O.IO " ** * 

Filmaron* " 5.00 " '' 



^ The following have reported more or less complete analyses of the male 
fern rhizome or of the ethereal extract : Gebhardt, cited by Geiger, Mag. f. 
Pharm. (1824), 7, p. 38; Morin, Journ. de Pharm, et de Chim. (1824), 10, 
p. 223; Buchner, Rep. f. d. Pharm. (1827), 27, p. 337; Batso, TrommsdorfE's 
n. Journ. d. Pharm. (1827), 14, p. 294; Peschier, Ibid. (1828), 17, p. 9; 
Luck, Jahrb. f, prakt. Pharm. (1851), 14, p. 129 ; Bock, Arch. d. Pharm. 
(1851), 115, p. 257; Kruse, Ibid (1876), 209, p. 24; Daccomo, Annali di 
Chim et Farmak. (1887), 87, p. 69; Boehm, Arch. f. Exp. Path. u. Pharmak. 
(1896), 38, p. 35; Kraft, Schweiz. Wochenschr. f. Chem. u. Pharm. (1902), 
40, p. 322. 

' The percentage of volatile oil as given above has been computed on the 
basis of an average yield of 10 pr cent, of oleoresin. 

3 The quantity of fatty oil present in the oleoresin has been shown to vary 
•with the strength of the ether employed in extracting the drug and with 
the degree to which the latter has been exhausted. These factors, however, 
are not sufficient to explain the large variation in oil content as found by 
various investigators. The variation is more probably due to the different 
methods employed in its estimation. Thus, Bock reports the presence of 
42 per cent of fatty oil, Arch. d. Pharm. (1851), 115, p. 266; Kremel esti- 
mates it at 40 to 45 per cent, Pharm. Post d. Pharm. (1887), 20, p. 525; 
IVollenweber at 70 to 75 per cent. Arch. d. Pharm. (1906), 244. p. 467. 

* There is a very considerable difference in the filix acid content of the 
oleoresin as reported in the literature. This is due, principally, to the nat- 
ural variation in the filix acid content of the drug and to the different 
methods employed in its estimation. The limits as given above are those 
obtained by the method of Fromme and represent the percentage occuring 
In the oleoresin prepared from the better rhizomes. Under these conditions, 
Madsen found 5.8 to 12.1 per cent. Arch. f. Pharm. og. Chem. (1897), 54, 
p. 269; Gehe & Co., 5.78 to 11.32 per cent, Handels-Ber. (1897), p. 60; 
Bellingrodt, 5.75 to 10.75 per cent, Apoth. Ztg. (1898), 13, p. 869; Caesar 
and Loretz, 8.65 to 12.48 per cent, Geschaefts-Ber. (1901), p. 68. 



gQ DU MEZ— THE GALENICAL OLEORESINS 

Filixnigrin = " " 6.00 " " 

Chlorophyll • ' ' " 

Wax ' '' " 

Ash '' 3.50 to 5.00 '' " 

Occurrence and Description of Individual Constituents. 

Volatile oil.^ The volatile oil as described by Ehrenberg is 
a clear yellow liquid having a specific gravity of 0.85 to 0.86 
at 15° C, and is stated by him to be composed principally of 
fatty acid esters of hexyl and octyl alcohol, the acids ranging 
from propionic to caproic. 

The quantity of essential oil present in the rhizomes is stated 
to vary with the seasons of the year, 0.04 to 0.045 per cent, being 
contained therein at the time of the year when the drug is- 
usually collected.^ 

Fatty oil}^ The fatty oil as obtained from the male fern 
rhizomes by extraction with ether and subsequent purification 
is stated by Katz^^ to be composed of the glyceryl esters of oleic^ 
palmitic, cerotic and butyric acids.^^ 

Filix acid^^ (Filiciny* Filix acid (CggHggOig) crystalizes 



» Kraft, Schweiz. Wochenschr. f. Chem. u. Pharm. (1902), 40. p. 323. 

•Bock, Arch. d. Pharm. (1851), 115, p. 266. 

T Kraft, 1. c, 

* The volatile oil as described above is that obtained from the rhizomes 
by steam distillation and in all probabilities differs somewhat from the same 
as it exists in the galenical oleoresin. 

» Ehrenberg reports the presence of volatile oil as follows : rhizomes 
gathered in April, 0.008 per cent; in June .025 per cent; in September, Octo- 
ber and November, 0.04 and 0.045 per cent. Arch. d. Pharm. (1893), 231, 
p. 345. 

10 The fatty oil of male fern was probably first isolated by Luck. In 
1851, he reported that the oily portion (filixoline) of the ethereal extract 
was a glyceride yielding filomysilsaeure and filixoUnsaeure upon saponifi- 
cation. Jahrb. f. prakt. Pharm. (1851), 22. p. 130. 

From Luck's description it is considered that these acids were in all 
probability butyric and oleic, respectively. 

"Arch. d. Pharm. (1898), 236, p. 655. 

" Butyric and oleic acids have also been identified by Farup in the fatty 
oil obtained from Aspidium Spinulosum. In addition a phytosterol, lino- 
linic, and probably isolinolinic acid are stated to have been detected. Arch, 
d. Pharm. (1904), 242, p. 17. 

"The term filixsaeure was first used by Luck to designate this constituent, 
Filix acid is the translation given above rather than the usual English 
form, filidc acid, to avoid confusion with the fiUcinsaeure of Boehm, a re- 
duction product of the former, Ann .d. Chem. (1899), 307, p. 249, or the 
Acidum fiUceum of Batso, a supposedly volatile acid which the latter isolated 
from the ethereal extract. Tromsdorff's n. Journ. d. Pharm. (1827), 14, 
p. 249. 

" Filicin is the term introduced by Poulsson to designate the crystalline 
form of filix acid as he was of the opinion that it also existed in the amor- 



OLEORESIN OF ASPIDIUM 



81 



in small yellow plates melting at 184 to 185° C. It is difficulty 
soluble in water, alcohol, and ether, quite readily soluble in 
ethyl acetate. According to Boehm,^^ its constitution^^ is prob- 
ably represented by the following structural formula : 




H0C|^ jIoh: 

H,C,COcL ]iC 

COH 




Filix acid has been found to be present in the male fern 
rhizome^^ in quantities varying from 0.268 to 2.159 per cent^ 
the variation in content depending principally upon the loca- 
tion in which the rhizomes are grown and on the time of har- 
vesting.^^ 



phous state. Arch. f. Exp. Path. u. Pharm. (1895), p. 357. The term is now 
usually employed to designate the mixture of acid substances obtained in 
the quantitative evaluation of the oleoresin. It should not be confused 
with the Filicina of Batso, supposedly an alkaloid isolated from the ethereal 
extract. 1. c. 

"Ann. d. Chem. (1901), 318, p. 256. 

!• The following investigators have contributed work on the constitution 
of fllix acid: Luck, Ann. d, Chem. (1845), 54, p 119; Jahrb. f. prakt. 
Pharm. (1851), 22, p. 129; Grabowski, Ann. d. Chem. (1867), 143, p. 279; 
Daccomo, Ber. d. deutsch. Chem. Gesell. (1888), 21, p. 2962; Gaz. Chim. 
Ital. (1895), 24, 1, p. 511 ; Ibid. (1896), 26, 2, p. 441 ; Paterno, Ber. d. deutsch. 
Chem. Gesell. (1889), 22, p. 463; SchifC, Ann. d. Chem. (1889), 253, p. 236; 
Poulsson, Arch. f. Exp. Path. u. Pharm. (1895), 35, p. 97; Boehm, Ibid. 
(1897), 38. p. 35; Ann. d. Chem. (1898, 302, p. 171. 

" Fllix acid has also been isolated by Hausmann from Athyrium Filix 
femma Roth. Arch. d. Pharm. (1899), 237. p. 556, and has been identified 
by Bowman in Aspidium rigidum Swartz. Am. J. Pharm. (1881), 53, p. 389.' 

"MatzdorfC, Apoth. Ztg. (1901), 16, p. 274. 



«2 



DU MEZ— THE GAKENICAL OL.EORBSINS 



Alhaspidin}^ Albaspidin crystallizes in fine colorless needles 
melting at 147 to 148° C. It is readily soluble in ether, chloro- 
form and benzol, difficultly soluble in alcohol, acetone and 
^glacial acetic acid. Its constitution is stated to be represented 
by one of the three following formulae :^^ 



ac cHi 




HOC 



H3C CH, 

X 



H3C CH, 



CO 



oc 




H,C.C0CI^ /^ V 



COH 
COCQH, 



COH CH, 



COH 




COH 



CH, 



Flavaspidic acid. Flavaspidic acid (C24H28O8) was first 
isolated from the ethereal extract by Boehm. It is stated to 
€xist in two forms (a and j8) which differ in their melting points, 
the a-fiavaspidic acid melting at 92° C and the ^-modification at 
156 °C. The a-acid on heating is converted into the j8-acid 



^» Albaspidin should not be confused with aspidin. Hausmann has shown 
the latter to be a constituent of Dryopteris spinulosa O. Kuntze, but that 
it Is not present in Dryopteris filix mas Schott. Arch. d. Fharm. (1899), 
237, p. 544. 

*> Boehm, Arch. f. Exp. Path. u. Pharm. (1897), 38, p. 35; Ann. d. Chem. 
<1901), 318, p. 268. 



OLEORESIN OF ASPIDIUM 



83 



which may be crystallized from hot benzol or glacial acetic acid. 
The ^-form is converted into the a-modification on crystallizing 
the former from alcohol. The a-acid is thought to be the enol-, 
the /8-acid the keto-form. The structure is shown in the fol- 
lowing formulae :^^ 

c"» cocn^5 

c 



H,C,CO 




COH 



CCH, 



HjCCOG 



CH, 
o(-F)ava5pidicAdd 




y3 f^ffavaspidkAdH 



COHJ 



Flavaspidic acid has been isolated from the male fern rhi- 
zome in quantities varying from 0.10 to 0.15 per cent.^^ 

Aspidinol. Aspidinol (CiaHigO^) crystallizes in small yel- 
lowish-white needles melting at 156 to 161 °C. It is difficultly 
soluble in petroleum ether and benzol, readily soluble in ether, 
alcohol, chloroform, carbon disulphide and acetone. The fol- 
lowing two formulae have been suggested by Boehm as repre- 
senting the structure of this compound :^^ 





CH. 






CH^ 






A 






p. 




HOCf 


^^ 


\C0CH. 


HOC 




Voj 


HC^ 


V 


^COCC.M> 


H,CX^OC 


V 


JcH 



COH COH 

Flavaspidinin.^* Flavaspidinin closely resembles flavaspidic 



« Boehm, Ann. d. Chem. (1901), 318, p. 253"; Ibid. (1903, 329, p. 310. 

2* In addition to establishing the presence of flavaspidic acid in the male 
fern rhizome, Hausmann has also isolated this compound from Athyrium 
JF'ilix femina Roth, and Aspidium apinulosum Swartz. Arch. d. Pharm. (1899), 
237, p. 556. 

28 Arch. f. Exp. Path. u. Pharm. (1893), 33, p. 35; Ann. d. Chem. (1901), 
■318, p. 245; Ibid. (1903), 329. p. 286. 

« Kraft. Schweiz. Wochenschr. f. Chem. u. Pharm. (1902), 40, p. 323. 

The "phloraspin" (C^^H^O^) of Boehm is probably identical with flavas- 

-pidinin. The pale yellow crystals obtained from the alcoholic solution melt 

at 211 "C, and are stated to be almost insoluble in ether, petroleum ether, 

benzene and carbon disulphide, but more readily soluble In acetone, chloro- 

torm, hot absolute alcohol, ethyl acetate, glacial acetic acid and boiling 

xylene. Ann. d. Chem. (1903), 329, p. 338. 



84 



DU MEZ— THE GALENICAL. OLBORESINS 



acid. It crystallizes from ethyl acetate in nearly colorless 
prisms melting at 199° C. It is soluble in methyl alcohol, dif- 
ficultly soluble in ether, carbon disulphide and alcohol, readily 
soluble in warm benzene, chloroform, ethyl acetate, acetone and 
amyl alcohol. 

Filmaron,^^ Filmaron (C^THggOis) is a light yellow, amor- 
phous powder melting at about 60° C. It is insoluble in water,, 
difficultly soluble in alcohol, methyl alcohol and petroleum ether^ 
readily soluble in acetone, chloroform, ether, ethyl, acetate,- 
benzene, carbon disulphide, carbon tetrachloride, amyl alcohol 
and glacial acetic acid. In acetone solution, at ordinary tem- 
peratures' or upon warming with alcohol, it gradually decom- 
poses into filix acid and filixnigrin. The following structural 
formula has been suggested by Kraft: 




COH 



Filixnigrin.^^ Filixnigrin is the term used by Kraft to desig- 
nate the mixture of brown to black amorphous decomposition, 
products of the foregoing constituents. These decomposition 
products differ from the mother substances in that they are in- 
soluble in petroleum ether. They have been isolated from the- 
etheral extract. To what extent they occur in the plant, if at 
all, has not been determined. 

Chlorophyll. The green coloring matter of the male fern 
rhizome and of the oleoresin prepared therefrom is generally^ 
conceded by the various investigators to be chlorophyll, al- 



» Kraft, 1. c. 
»« Kraft, I. c. 



OLBORESIN OF ASFIDIUM 85 

though, no attempt appears to have been made to determine its 
composition. Work upon the pigments present in a closely 
related species of fern, Aspidium Filix femina Roth, has re- 
•sulted in the isolation of carrotin (CigHggO) and three aspi- 
■diophylls, CaogHg^^OgaN, C24oH32o03iN2 and C2ioH34e048N2o " 

The amount of chlorophyll present in the rhizome varies 
with its age and with the season of the year.^^ 

Wax. The wax occurring in the male fern rhizome has not 
been studied from a chemical standpoint, although its presence 
in the ethereal extract was observed at a very early date.^^ 

Filix Tannic Acid.^^ ' Filix tannic acid (C41H48NO24) is a 
^glucoside breaking down upon hydrolysis into hexose and a 
Tiiixture of reddish-brown compounds.^^ It is readily soluble 
in water and dilute alcohol. 

Filix tannic acid usually constitutes about 7 per cent, of 
the rhizome, as much as 7.8 per cent, having been isolated there- 
from.^^ 

Ash. Analyses^^ of the male fern rhizome have shown the 
ash to contain the basic elements, K, Na, Ca,. Mg, Al and Fe 
combined with the acid radicles CI', SO4'', PO/", SiOg'' and 



"'EhaLTd, Ann. Inst. Pasteur (1899), 13, p. 456. The more recent work 
of Willstaetter and his pupils on the chlorophylls isolated from more than 
200 different plants belonging to numerous families indicates that mag- 
Tiesium is a constant consituent of the molecule, which is considered by 
them to be a methyl phytyl ester of the tricarboxylic acid, chlorophyllin, 
'C3iH29N^Mg(COOH)3. Viewed in this light, the above formulae for the 
aspidiophylls are erroneous in that they contain no magnesium and express 
molecular weights which are much too high. Ann. d. Chem. (1908), 358, 
p. 267; Ibid. (1910), 378, p. 1. 

2» Kruse has observed that the rhizomes collected in April and October 
:have a more intense green color than those gathered in July. Arch. d. 
Pharm. (1876), 209, p. 24. 

»Batso, Trommsdorff's n. Journ. d. Pharm. (1827), 14, p. 294; Peschier 
Ibid. (1828), 17, p. 5 and Bock, Arch. d. Pharm. (ISBi), 115, p. 266, report 
the presence of a stearin-like substance in the ethereal extract. 

Caesar and Loretz have observed that rhizomes rich in wax yield an 
-ethereal extract which is not fluid at the ordinary temperature. GecJiaefts 
Ber. (1897), p. 62. 

30 In the light of our present knowledge concerning the chemistry of male 
fern, fllix tannic acid Is not considered to be a constituent of the oleoresin 
when prepared with ether. As its presence in the latter has been reported 
1)y early investigators, the above description has been included here. See 
-analysis by Bock, Arch. d. Pharm. 1851, 115, p. 266. 

"Malin, Ann. d. Chem. (1867), 115, p. 276; Wollenweber, Arch. d. Pharm. 
<1906), 244, p. 480. 

3' Wollenweber, 1. c. 

»3Bock, Arch. d. Pharm. (1851), 115, p. 257; Spies, Jahresb. d. Pharm. 
<1860), 20, p. 15. 



gg DU MEZ— THE GALENICAL OLEORESINS 

CO3''. Hell and Company^* report the presence of 0.0144 per 
cent, of copper. Sp'ies, however, was unable to detect the presence 
of either copper or manganese. 

The ash content of the dried rhizomes varies, about 2.0 to 
3.0 per cent being the usual amount obtained.^^ 

Constituents of Therapeutic Importance 

The value of the oleoresin of aspidium as a teniafuge has 
at various times been attributed to either its filix acid^ or vola- 
tile oiP content. Comparatively recent pharmacological in-^ 
vestigation, ^ however, has shown that the property of expell- 
ing the tape worm is not due to a single constituent, but is 
shared by a number of the acid-like components, namely: filix 
acid, flavaspidic acid, albaspidin, aspidinol, flavaspidinin and 
filmaron. Of these substances, filmaron is the most active and 
is stated by Jacquet* and others to be the constituent of most 
importance therapeutically. 

The diminution in the therapeutic activity of the oleoresin 
on ageing has been found to be due to the breaking down of 
some of these constituents into compounds which are inert or 
less active as teniafuges. Of the decomposition products tested 
by Straub, phloroglucin, filicin acid and butyric acid were 
found to be non-toxic when administered to frogs.^ Filix acid 
on the other hand was found to be toxic. Its value as a 
teniafuge is, however, doubtful.* 

Physical Properties 

Color: The color of the oleoresin varies to a considerable 
extent depending principally on the condition of the drug from 
which it is prepared. It is described by various writers as 
being yellowish-green, green, dark green or greenish-brown. 



34Pharm. Post (1894), 27, p. 168; Journ. de Pharm. et de Chim., 139, 
p. 493. 

^ Bock gives the ash content of the air dried rhizomes as 2.13 per cent., 
Kruse as 1.90 to 2.2 and Spies as 2.74. For the exsicated rhizomes, the latter 
obtained 3.19 per cent. 

iPoulsson, Arch. f. Exp. Path. u. Pharmak. (1891), 29, p. 9. 

a Robert, Therap. Monatsch. (1893), p. 136. 

8 Straub, Arch. f. Exp. Path. u. Pharmak. (1902), 48, pp. 1-47. 

* Therap. Monatsh. (1904), 18, p. 391. 

»Z. c. 

•Boehm, Arch. f. Exp. Path. u. Pharmak. (1897), 38, p. 35. 



OLEORESIN OF ASPIDIUM 8T 

When prepared from the freshly dried and powdered rhizomes 
gathered in the autumn/ it usually has an olive-green color 
when spread out in a thin layer on a white porcelain surface. 
A brownish-green color is an indication of the use of old de- 
teriorated drug^ in its preparation, whereas, a deep green color 
suggests adulteration with salts of copper or chlorophyll.^ 

The nature of the solvent employed in extracting the drug is 
also stated to have an influence on the color of the prepara- 
tion, the use of ether (specific gravity 0.720) yielding an oleo- 
resin of a green color, whereas, the color is brownish-green 
when ether (specific gravity 0.728) is employed.* 

Odor: The odor of the oleoresin is peculiar, like that of 
male fern. 

Taste: The preparation has a bitter, nauseous, subacrid 
taste. 

Consistence: The oleoresin when freshly prepared is homo- 
geneous and is of about the same degree of fiuidity as castor 
oil. It is variously stated as being of the consistence of syrup,, 
fresh honey or an oily extract. 

Solubility: The oleore'sin when prepared with ether forms 
clear or slightly cloudy solutions with acetone, ether, chloro- 
form and carbon disulphide.^ It is partially soluble in carbon: 
tetrachloride, benzene, methyl alcohol, ethyl alcohol (95 per 
cent.), glacial acetic acid and petroleum ether. The degree to 
which it is soluble in the last three solvents mentioned ha» 
been made the basis of tests for the detection of adulteration 
with castor oil. 

According to Hill (1913), not less than 8 volumes of the 
oleoresin should be soluble in 10 volumes of petroleum ether, 
a lesser degree of solubility indicating adulteration. Jehn and 



* The oleoresin prepared from rhizomes gathered in October is stated by 
Kruse (1876) to have a more intense green color than that prepared fronn 
rhizomes gathered in July. 

Caesar and Loretz in their Berichte for 1913 state the condition of the 
season in which the rhizomes are harvested has an influence on their color, 
which becomes evident in the oleoresin, e. g. the oleoresin, when prepared 
from the rhizomes gathered in a dry season, is often very dark green in color. 

'Buchner (1826) found that when the drug was kept in an open container 
for more than a year a brown instead of a green colored oleoresin was ob- 
tained. 

^Wepen and Lueders (1892), Beckurts and Peters (1893) and others. 

* Bellingrodt. (1898). 

•This statement holds good only for the freshly prepared oleoresin ancJ 
does not apply when the same contains deposited material. 



88 



DU MEZ— THE GALENICAL OLEORESINS 



Crato^ state that the presence of castor oil is indicated when 
more than 50 per cent, of the oleoresin is soluble in 95 per cent, 
alcohol. Solubility tests made in the laboratory with glacial 
acetic acid have shown that not over 10 per cent, by volume 
of the oleoresin is soluble in the latter, a greater degree of 
solubility indicating adulteration with castor oil. 

Specific gravity: Observations made in the laboratory show 
that the specific gravity should be above 1.000 when determined 
at 25 °C. This is in keeping with the findings of Parry (1911) 
and Hill (1913), respectively, even though their determinations 
were made at 15° C. It is also the standard given in the latei 
edition of the British Pharmacopoeia. A specific gravity of 
less than 1.000 usually indicates adulteration with castor oil 
or a preparation naturally low in filicin content. It may, how- 
ever, be due to the addition of chlorophyll as pointed out by 
Hill, or to the presence of unevaporated solvent. These de- 
tails, together with the effect produced by the use of different 
solvents in the extraction of the drug are brought out in the 
following tables: 



Table IJi. — Specific gravities of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Specific 
gravity 


1 


1910... 
1916... 


DuMez&Netzel 




At25''C 
1 166 


2 


Acetone 


1 052 


3 


•• '♦ 


Ether 


1 012 


4 


.4 l( • • 


Petrol ether 


995 


1 


DuMez 




1 048 


2 




Ether 


1 000 


1 


•• :::::::::::::::::::::: 


Acetone 


1.009 (2) 
0.997 (») 


2 


Ether 











^ Kommentar zum Arzneibuch ftier das deutsche Reich (1901), p. 258. 

2 Same as 2 and 3 after having stood in the laboratory for 6 years. Both 
contained a heavy deposit which was not mixed with the liquid portion when 
the specific gravity was redetermined.. 



OLEORESIN OF ASPimUM 



89 



Table 14. — Specific gravities of commercial samples. 



Sample 
No. 


Date 


Observer 


Source 


Specific 
g-ravity 


1 


1911 
1912 

1913 
1913 

1913 

1915 
1916 


Parry 


Notffiven 


At 15° C 
0.973 (1) 


2 




0.973 (1) 


3 


" 


" 


0.974 (') 


4 


" 


" 


0.975 (1) 


5 


" 


'• 


0.975 (») 


6 


•' 


>i 


0.988 (') 


1 

2 


Southall Bros. & Barclay. 
Bohrisch 


" 


0.9745 (") 
0.0800 (i> 


3 

4 


" 


1.0148 
1.0200 


5 


• ' 


1.0205 


6 


" 


1.0231 


1 




Temp. ( ?) 
0.9836(3) 


2 






0.9842 (*> 


3 


" 


" 


0.9888 (») 


4 


" 


»' 


1.0109 


1 


DuMez 


Manila. P.I 


At 25° C 
0.977 (') 


2 




0.985 (i> 


3 


" 


United States .............. 


0.9889 (i> 


4 


'* 


1.001 


5 


" 


Germany 


1.003 


6 


<■' 


1.003 (») 


7 


„ 


UUnited States 


1.008 {") 


8 




1.008 


1 


Harrison & Self 


Germany 


At 15° C 
0.987 (♦> 


2 


V 




0.997 


3 


«» 


1.015 


4 


»• 


" 


1.020 


5 


'« 


«• 


1.029 


6 


" 


" 


1.029 


1 


Hill 


Europe 


0.9829 (3> 


2 




0.9850 


3 


'» 


»' 


0.9921 


4 


" 


1. 


0.9944 


5 


" 


" 


0.9980 c^y 


6 


»» 


'» 


0.9980 (1) 


7 


" 




0.9985 (1) 


8 


" 




1.000 


9 


«• 


•' 


1.000 


10 


'« 


»' 


2.0006 (»> 


11 


" 


" 


1.0036 


12 


" 


»« 


1.0045 


13 


" 


•' 


1.0065 


14 


»• 


" 


1.0075 


15 . . . . 


" 


Rngrland 


1.0090 


16 


.4 




1.0109 


17 


1« 




1 0179 


18 


•' 


J. 0190 


19 


•' 


•' 


1.0227 


20 


" 


England 


1.0233 


21 


" 


Europe 


1.0235 


22 


•» 




1.0240 


23 


" 


•' 


1.0249 


1 


Southall Bros. & Barclay. 
DuMez 


Not srlven 


1.025 


2 




1.025 


1 


" 


9985 


2 


" 


1.0110 


8 


»« 


1.021 


4 


" 


1.023 


5 


»» 


1.030 


1 


Sauibb & Sons 


At25°C 
0.9808 O 


2 




Lilly &Co 


0.9947 (') 


3 . 


" 


Parlte Davis & Co 


1 0103 


4 


" 


Steams & Co 


1 0379 (') 









^ Adulterated with castor oil. 

* Contained added chorophyll. 
' Low in crude fllicin content. 

* Referred to as suspicious. 

* Contained ether. 



90 



DU MEZ— THE GALENICAL OLEORESINS 



Refractive index: A refractive index of not less than 1.490 
at 40° C is required for this oleoresin by the late edition of the 
British Pharmacopoeia. This is in accordance with the observa- 
tions of Hill (1913). The statement by Parry (1911), that 
the refractive index should not be below 1.500 when deter- 
mined at 20 °C is confirmed by the results which were obtained 
by Harrison and Self (1913), and is more in conformity with 
the observations made in this laboratory at 25 °C. When the 
oleoresin is properly prepared, ether being the menstruum used, 
the refractive index appears to vary directly as the crude filicin 
content. A low refractive index, therefore, indicates a pre- 
paration naturally low in filicin content. With respeet to the 
commercial oleoresins, however, a low refractive index may also 
result from adulteration with castor oil or chlorophyll, or may 
be due to the presence of unevaporated solvent as is shown in 
the tables which follow: 

Table 15.— Refractive indices of laboratory preparations. 



Sample 
No. 



Date 



Observer 



Solvent 



Refractive 
index 



1913 



DuMez 

Harrison & Self. 



1916 



DuMez. 



Ether 


At 25° G 
1.500 




At20°C 
1 4995 




1 5018 




1 5036 


" 


1.5088 
1.5088 
1.5102 
1 5120 




1.5122 




1.5126 




1 5145 




1.5157 


Acetone 


1 500^ 


Ether 


1.498' 







1 These figures represent the refractive indices of oleoresins which had 
stood in the laboratory for six years. 



OLEORESIN OF ASPIDIUM 



91 



Table 16 — Refractive indices of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Refractive 
index 


1 


1011 

1912 
1913 

1915 
1916 


Evans Sons.Lescher &Webb 
Parry 


Not stated 


At 15° C 
1.484(3) 


2 




1.485 (») 


3 

4 


.. 


1.501 
1.501 


1 


.. 


At 20° C 
1.484(1) 


2 




" 


1 484(1) 


3 







1.487 (') 


4 




»• 


1 488 (') 


5 


" 


'• 


1.4885 ( ) 


6 




•» 


1 493(1) 


1-16 


Evans Sons,Le8cher&Webb 
Sou thai! Bros. & Barclay . 

DuMez 


,4 


At 15° C 
1.507 to 




«• 


1.509 


1 


.. 


At 20° C 
1.4830(1) 


2 


•' 


1.4840 (1) 


3 




1.5040 


4 


" 


1.5055 


5 


»• 


1.5065 


€ 


»• 


1.5210(?) 


1 


England .... . 


At 25° C 
1 484(1) 


2 






1 485 (1) 


3 


" 


Manila, P. I . 


1.489 


4 


'• 


United States 


1 490 


5 


•' 




1.490 


^ 






1.492 


7 


■* 


England 


1.493 


8 


'• 


Germany 


1 494 


1 


Harrison & Self 




At 20° C 
1.4910 (») 


2 






1 4944 


3 


" * * 


• ' 


1.4984 


4 


•• 


'« 


1.5055 


5 


.. •••• 


" 


1.5080 


f 


'• 


•• 


1 5084 


1 


Hill 


Europe 


At 40° C 
1,4823 (1) 


2 






1.4869(1) 


3 




'• 


1 4874(1) 


4 


»* 


" 


1.4880 


5 




'« 


1.4909 


6 




" 


1.4915 (') 


7 




«« 


1.4920 


8 




England 


1.4922 


9 




Europe 


1.4925 


10 






1.4935 


11 




•• 


1.4940 


12 




•« 


1.4945 


13 




England 


1.4960 


14 






1.4965 


15 






1.4980 


16 






1.4985 


17 




»• 


1.4988 


18 




" 


1 4990 


19 




'» 


1.5006 


20 


• • 


" 


1.5025 


21 




" 


1.5036 


1 7 


Evans SonsXescher &Webb 

Southall Bros. & Barclay . 
Southall Bros. & Barclay . 

DuMez 


Not stated 


At 15° C 
1 500 to 1.510 


8 




1.495 (•) 


9 


•• 


1.497(3) 
1.499 (S) 
At 2,5» C 
1.4975 


10 

1 


" 


2 


" 


1.5115 


1 


'• 


1.4976 


2 


•• 


1.4983 


3 


•« 


1.5000 


4 


•• 


1.5001 


5 


«» 


1.5020 


1 


Stearns & Co 


At 25° C 
1.4953 (*) 


2 




Lilly&Co 


1.4988 (*) 


3 


•' 


Squibb & Sons 


1.4993 (*) 


4 


" 


Parke, Davis & Co 


1.4998 



1 Samples adulterated with castor oil. 

» Samples contained added chlorophyll. 

* Samples are referred to as being suspicious. 



92 



DU MBZ— THE GALENICAL. OL.EORESINS 



Chemical Properties. 

Loss in weight on heating: Hill (1913) stated that the oleo- 
resin when heated at 100 °C should not lose more than 6 per 
cent, of its weight, a greater loss indicating the presence of 
unevaporated solvent. The statement is confirmed by other 
data of this nature reported in the literature as well as by 
the results obtained in the laboratory as is shown in the tables 
which follow: 

Table 17 — Laboratory preparations — Loss in weight on heating. 



Sample 
No. 


Date 


Observer 


Solvent 


Per cent 

of loss on 

heating: 


1 


1887 
1904 
1916 


Kremel 


Alcohol. 


At 100^ C 
17 40 


2 




Ether 


70 


] 


Dieterich 




4 51 


1 . 


DuMez 


Acetone 


At lio" 
2 51C 


2 




Ether 


2 37 











OLEORESIN OF ASPIDIUM 



93 



Table 18 — . Commercial oleoresins — Loss in weight on heating. 



Sample 
No. 


Date 


Observer 


Source 


Per cent. 

of loss on 

heatinff 


1 


1891 
1893 

1894 

1895 
1896 
1897 

1901 
1903 

1904 

1905 

1913 

•• 

1914 
1916 


Dieterich 


Germany 


At 1()0° C 
2.70 


1 






1.15 


2 


" 




1.60 


3 


•' 




1.75 


1 


'• 




1.90 


2 


•♦ 


2 32 


^ 


'• 




3 65 


1 


4» 




1.75 ■ 


1 


" 




1.62 


1 


" 




4.52 


2 


•• 




4 72 


1 


" * * 




5.23 


1 


•« 




5 52 


2 


.. " 




7.38 


1 


t< 




2.96 


2 


.' 




3.09 


1 


•• 




5.06 


2 


" 




7.51 




Hill 


Europe 


2 43 


2 






2.44 


3 


'• 


Eng'land 


2.57 


4 


•• 


Europe 


2.69 


^ 


" 




3.55 


R 


•• 


•« 


3.63 


7 


«' 


»» 


3 65 


}j 


It 


'• 


4.23 


9 




»• 


4 40 


10 




.. • 


4.57 


11 




'♦ 


4.64 


12 




»» 


4.84 


13 


•• 


England 


5 03 


14 


.. • 




5.22 


15 


•» 




6.500 


16 




•' 


6.52 (>) 


17 


»• 


•« 


6 60(1) 


18 


" 


'• 


6.68(1) 


1 


Unke 


Brtickner. Lampe & C5o 

Caesar & Loretz 


At l(X)tol05°C 
3.20 


2 .. . 




3.25 


3 


•• 


Merck&Co 


6.85 


1 


DuMez 


Parke, Davis & Co 


At 110° C 
1.75 


2 




Stearns & Co 


2.03 


3 


•• 


Lilly& Co 


6.01 


4 


41 • ••• • 


Squibb & Sons 


7.18(1) 











(') Unevaporated solvent (ether) was present. 



AsJi Content: The results of this nature reported in the lit- 
erature, as well as those obtaiined in the laboratory, indicate 
that the ash content of the oleoresin, when prepared with ether, 
seldom exceeds 0.50 per cent, which is the standard given in the 
Belgian and Spanish pharmacopoeias. With respect to the 
^commercial samples examined in the laboratory, the high ash 
content obtained was due to the presence of copper, evidently 
a result of the use of copper utensils in the manufacture of these 
preparations. The results of the determinations made in the 



94 



DU MEZ— THH GALENICAL OLEORESINS 



laboratory and those reported in the literature are given in the 
tables which follow : 



Table 19. — A»li contents of laboratory preparations. 



Sample 
No. 


Date 


Observer 


Solvent 


Per cent 
of ash. 


1 


1904 
1916 


Dieterich 


Ether 


36 


1 


DuMez : 




0.26 


2 






31 











Table 20 — Ash contents of commercial oleoresins. 



Sample 

No. 


Date 


Observer 


Source 


Per cent 
of ash 


Fereign con- 
stituents 


1 


1891 
1893 

1894 

1895 
1896 
1897 

1901 
1903 

1904 
1905 
1914 

1916 


Dieterich 



\\ 

;; ::::■.::: 

Llnke ............ 


Germany 


0.40 

0.45 

0.50 

0.50 

0.42 

0.50 

0.55 

0.50 

0.45 

0.43 

0.52 

0.32 

0.27 

0.30 

0.39 

0.36 

0.83 

0.26 

0.46 

0.34 

0.41 

0.52 

0.52 

0.58 

0.54(1) 

0.80 

0.82 




1 






2 


«' 




3 






1 






2 . ... 






3 






1 






1 






1 






2 






1 






1 . .. 






2 






3 .... 






1 






2 


" 




1 


" 




2 


»• 




1 


Brueckner, Lampe & Co . . 
Caesar & Loretz. . .... 


Copper 


2 






3 .... 


" 


Riedel 


•' 


4 


Merck&Co 

Lilly «& Co 




1 


DuMez 


Copper 


2 




Squibb & Sons 




8 


" 


Parke, Davis & Co 


•' 


4 


•' 


Stearns & Co 


»' 











(*) Contained unevaporated solvent — ether. 

Acid number: The acid numbers 82.2 and 82.7 were ob- 
tained for the oleoresins prepared in the laboratory. Inas- 
much, however, as these preparations were made six years 
previous to the time when the determinations were made, it is 
thought that the value of this constant would be somewhat 
lower for the oleoresin when freshly prepared. This state- 
ment is based on the assumption that the acidity of the prep- 
aration will increase on standing due to the partial hydrolysis- 
of the glycerides of the fatty acids and to the breaking down 
of the complex substances constituting the so-called crude filioin. 



OLEORESIN OF ASPIDIUM 



95 



In the case of the commercial samples, the acid numbers were 
found to vary as a rule in the same direction as the filicin 
content. It would appear, therefore, that the value obtained 
for this constant might serve as a check on the latter determina- 
tion. The results obtained in the determination of the acid 
numbers of the preparations examined in the laboratory and 
those reported by Kremel follow: 





Table 21.— Acid numbers of laboratory preparations. 


Sample 
No. 


Date 


Observer 


Solvent 


Acid 
number 


1 


1887 
1916 


Kr^mel 


Alcohol 


23 






Ether 


50 to 70 


1 


DuMez 




82.7(1) 


2 




Acetone.. 


82 2(1) 











(1) These preparations were 6 years old when the acid number was de- 
termined. 



Table 22 Acid numbers of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Acid 
Number 


1 


1916 


Du Mez 


Ptearns & Co 


50 2 


2 




Squibb & Sons 


65.90 


n 


•• 


Lilly&Co 


72 9 


4 


• » 


Parkp. Davis Ar Cn 


87.8 









(*) Contained ether. 



Saponification value: Determinations made by Parry in 1911 
lead him to state that the saponification value of this prepara- 
tion should not be lower than 230, corresponding to a crude 
filicin content of not less than 22 per cent. The values obtained 
for this constant in the laboratory and those reported by Har- 
rison and Self agree, as a rule with this statement, when the 
minimum filicin content is taken as 20 per cent. A value of 
less than 230 in the case of commercial samples has been shown 
to be due in general to adulteration with castor oil. In a few 
instances, however, it is to be attributed to the presence of 
unevap orated solvent, or to a low filicin content due to the use 
of a poor quality of drug in the manufacture of the oleoresin. 



96 



DU MEZ— THE GALENICAL OLEORESINS 



The relatively high values obtained in the laboratory for the 
old preparations low in filicin content (16.0 and 16.27 per cent, 
respectively) is very likely due to the effect caused by the 
hydrolysis of the constituents of high molecular weight with 
the formation of acids of comparatively low molecular weight.^ 
The saponification values found for the preparations examined 
in the laboratory as well as those reported in the literature are 
given in the tables which follow: 



Table 23 — Saponification values of laboratory preparations. 



Sample 
No. 


Date 


Observer 


Solvent 


Saponifica- 
tion value 




1887 
1911 
1913 

1916 




Ether 


116 to 165 


1-20 


Parry 




van to 250 




DuMez 




208.8 






Ether 


229 3 




Harrison & Self 




225.0 








227.0 




•' 


" 


236.5 




" 




248.0 




" 


248.9 




•• 




251 5 




" 


" 


252.0 




" 




254.5 




'» 


•• 


255 


10 


•• 




259.0 


11 


" 


>> " * * 


259 




DuMez 




245.2 (^) 


2 




Ether 


246 4 (0 











(*) Old preparations low in filicin content 



»See under "Chemistry of the drug and oleroesin/ 



OLEORESIN OF ASPIDIUM 



97 



Table 24 — Saponification values of commercial oleoresins. 



Sample 
No. 


Date. 


Observer. 


Source. 


Saponifica- 
tion value 


1 


1904 
1911 

1912 
1913 

1915 
1916 


Dieterich 




204.4 


2. 






234 2 


1 


Evans Sons, Lescher & 
Webb 








195.2 (1) 
220 4 


2 




5 


'« 




248.8 


1 


Parry 


" 


197.0 (» 


2 






200 (0 


3 


" 


'• 


207.0 (0 
208.0 (0 
210.0 (" 


4 


" 


;; 


5 


«' 


6 


" 


" 


221.0 (1) 

195.1 (0 
204.6 (1) 
235.4 


1 


Southall Bros. & Barclay. 
DuMez 


*' 


2 


\\ • 


3 


4 


«» 


241.0 


5 


•' 


256.3 


6 




258 2 


1 


England 


195.7 (0 
200.3 (3) 
202 4 0) 


2 ... 




Manila,P.I 


3 


" 


4 


>. 


United States 


206.7 (2) 
208.7 (I) 


5 


" 


England 


% 




Germany 


214.6 (3) 
225.5 


7.. 






% 


-i 


United States 


240 5 


1 


Harrison & Self 




205.0 (3) 
213.0 


2 .. .. 






3 


.i •••• 


" 


218 


4 . 


»' 


*» 


223 


5 





'« 


225.0 


6 


" 


" 


237.0 


1 


Southall Bros. & Barclay. 
DuMez 


Not given 


225.1 


2 




263.1 




" 


206.5 


3 


'• 


236.0 


3 


" 


250.0 


4 


253.1 


5 


•<■ 


254 6 


1 


Stearns <fe Co 


190.0 (2) 


2 




Lilly & Co 


211.4 (") 


3. 


" 


Sauibb & Sons 


233 2 («) 


4 


" 


Parke, Davis & Co 


249.1 











1 Adulterated with castor oil. 

2 Lovsr in crude fllicin content. 
2 Referred to as suspicious. 

* Contained ether. 



Iodine value: Observations made in the laboratory indicate 
that the oleoresin should have an iodine value of not less than 
99, corresponding to at least 20 per cent, of crude filicin. Pre- 
parations giving a lower value than this were found to be low 
in crude filicin content due to adulteration with castor oil or 
to the presence of unevaporated solvent. On the other hand, 
it was observed that a high iodine value does not always signify 
a high filicin content, e. g. iodine values of 106.3 and 108.1 
were obtained for preparations containing only 16.0 and 16.27 
per cent, of crude filicin, respectively. As the latter were 



98 



DU MEZ— THE GALENICAL OLEORESINS 



old and contained deposited material equal to nearly one-half 
of their bulk, the high iodine values obtained for the super- 
natent liquid portions were very likely due to the concentra- 
tion of the compounds of a lesser degree of saturation (glycer- 
ides of the unsaturated fatty acids) as a result of the decom- 
position and deposition of the more highly saturated com- 
pounds (crude filicin). The results obtained in the determina- 
tion of this constant are shown in the following tables : 

Table 25. — Iodine values of laboratory 'preparations. 



Sample 
No. 


Date 


Observer 


Solvent 


Iodine valu» 


1 


1911 
1913 
1913 
1916 
1916 


Evans Sons, Lescher & Webb 

DuMez 


Ether 


101 8 


1 


Acetone , 


95 3 


2 




Ether 


99.8 


1 


" 


Acetone . 


106 3 (1) 


2 




Ether 


108.1 (I) 











These preparations were six years old when examined. 

Table 26. — Iodine values of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Iodine 
value 


I 


1804 
1911 

1913 
1916 


Dieterich 




100.6 


2 






84.2 


1 


Evans Sons, Lescher & Webb 
DuMez 


Not given 


89.2vO 


z .... 




92. 3(') 


3 




95.9 


4 


t. .1 


99.1 


\ 


England 


85.8('> 


2 




Manila.?. I 

England 


87.2 (») 


3 


». 


89.4 (1) 


4 


*» 


United States 


94.4 


5 


it 


Germany 


97.1 


g 


" 




98.3 (') 


7 


" 


Germany 


100.2 


8 


'' 


United States 


101.5 


1 


n 


Squibb & Sons 


95. 3(') • 


2 


»' 


Stearns & Co 


97.7 C') 


3 .... 


'« 


Lillv& Co 


98.2(») 


4 


" 


Parlie, Davis «fe Co 


103.2 











1 Adulterated with castor oil. 

2 Low in crude fllicin content. 
' Contained ether. 



Other Properties 

The oleoresin, when freshly prepared, is homogeneous, but 
upon standing, a deposit is formed therein as a result of the 
breaking down of some of its constituents. The precipitated 



OL.EORESIN OF ASPIDIUM 99 

material has been identified by Boehm^ as crystalline filix acid 
and a wax-like substance. Kraft,^ in a later investigation, con- 
firmed the findings of Boehm insofar as they concerned the 
presence of filix acid. The wax-like material, however, he 
found to be composed of a number of substances, decomposi- 
tion products of the therapeutically active constituents, which 
he designated as filixnigrin. As the deposit has been found to 
be active^ in the expulsion of tapeworm, although in a much 
lesser degree than the oleoresin proper, the United States PJiar- 
macopocia directs that it be mixed with the liquid portion be- 
fore dispensing. 

Special Qualitative Tests 

A number of the European pharmacopoeias prescribe tests 
for the determination of the quality of this preparation. These 
tests are of two kinds, namely, those which have for their object 
the establishment of the presence of the constituents of thera- 
peutic value, i. e. the substances of an acid character known 
collectively as crude filicin, and those which serve to identify 
starch when present. The former are based on the fact that 
the above mentioned constituents of an acid character may be 
precipitated directly by means of certain solvents, or from 
alkaline solutions by means of acids. The following are the 
official tests of this nature : 

Tests for Filicin. 

Austrian Pharmacopoeia (1906) : Upon adding an excess of petroleum 
ether to the oleoresin dissolved in a small quantity of ethyl ether, a white 
precipitate should be produced. 

' Netherlands Pharmacopceia (1905) : If 0.025 gram of the oleoresin dis- 
solved in 2 cubic centimeters of ether be shaken with 5 cubic centimeters 
of a saturated barium hydroxide solution and 5 cubic centimeters of water, 
the aqueous portion, when separated and filtered, should give a floccu- 
lent precipitate on being acidified with hydrochloric acid. 

Hungarian Pharmacopoeia (1909) : If 0.25 gram of the extract be dis- 
solved in 2 cubic centimeters of ether and shaken with 10 cubic centi- 
meters of lime water, the aqueous portion filtered and acidified with hydro- 
chloric acid, a copious white precipitate should be formed. 



^Arch. f. exp. Path. u. Pharmak. (1897), 38, p. 85. 
'Kraft (1902). 

'Renter, Pharm. Ztg. (1891), 36. p. 245; Straub, Arch. f. exp Path u 
Pharmak. (1902), 48, p. 1. v. . . 



100 ^U MEZ— THE GALENICAL OLEORBSINS 

The application of these tests in the laboratory has shown 
that they are of practically no value as an indication of the 
quality of the oleoresin, as preparations very low in crude 
filicin content give comparatively heavy precipitates when 
treated as described above. Furthermore, they do not serve 
as a means of identification as oleoresins prepared from the 
rhizomes of certain other species of fem^ behave in a similar 
manner when subjected to these conditions. 



Tests for Starch 

A test for the presence of starch has been included in those 
pharmacopoeias in which the oleoresin is directed to be pre- 
pared by the process of maceration, namely, the German and 
Japanese. In these instances, it serves as a means of distin- 
guishing between preparations which have been filtered as of- 
ficially directed and those which have been merely strained 
through cloth as is often the case. A similar test is also found 
in the pharmacopoeias of those countries (Hungary, Spain and 
Switzerland) in which this preparation is frequently made by 
maceration, although the official process is that of percolation. 
The test as officially recognized in the different countries is 
identical with that described in the German Pharmacopoeia. 
It is as follows: 

The oleoresin, when diluted by shaking with glycerin, should not 
show the presence of starch grains under the microscope. 

Experience in the application of this test to the preparations 
examined in the laboratory has shown that it is unsatisfac- 
tory when carried out as described above. The fault lies in 
the fact that the glycerin cannot be thoroughly mixed with 
the oleoresin by shaking. If mixing is effected by trituration 
in a mortar, the results are better, although there is consider- 
able danger in rupturing the starch grains by this procedure. 

In addition to the foregoing, special tests have been pro- 
posed for the detection of adulterants when present. They 
are as follows: 



*Bee under "Drug used. Its collection, preservation, etc' 



OLEORESIN OF ASPIDIUM IQl 



Tests for the Presence of the Oleoresin of Dryopteris Spinulosa. 

Hausmann found that the male fern of commerce frequently- 
contained large quantities of the rhizomes of Dryopteris spinv^ 
losa Kunze. He therefore devised a test for the detection of the 
use of the latter in the preparation of the oleoresin. It is based 
on the fact that the rhizomes of Dryopteris spinulosa Kunze 
contain aspidin, whereas those of the official species, Dryopteris 
Filixmas Schott do not. 

Eausmann's Method (1899): Dissolve a small amount of crude filicin* 
in as small a quantity of absolute ether as possible and set the solution 
aside in a desiccator. If aspidin is present, the thick solution will form 
a crystalline brine in a few hours, when the needle-like crystals of the 
former can easily be identified under the microscope. If aspidin is not 
present, the solution undergoes no change even on long standing except 
to deposit a granular substance. 

Tests for the Presence of Castor OH 

The tests for the presence of castor oil are based on the 
solubility of the oleoresin in various solvents and are discussed 
under the heading, ** Solubility. ' ' 

Tests for the Presence of Salts of Copper 

The tests for the presence of salts of copper involve an ex- 
amination of the ash of the oleoresin and are discussed under 
the general treatment of the subject, **Ash content/' 

Special Quantitative Tests. 

A great deal of work has been done with reference to the 
evaluation of this preparation, and as a result, a number of 
methods for the quantitative estimation of the constituents of 
therapeutic importance has been devised. The chemical meth- 
ods may be conveniently divided into two groups, the one includ- 
ing those methods which have for their object the quantitative 
determination of the filix acid; and the other comprising the 
methods in which the quantity of the total constituents of an 
acid character is determined. 



*See under "Special quantitative methods". 



2Q2 DU MEZ— THE GALENICAL. OLEORESINS ■ ■ - " 

Methods for the Determination of Filix Acid. 

As the oleoresin was originally thought to owe its teniafuge 
properties to its filix acid content, the determination of this 
constituent naturally received consideration first. The nature 
of the methods devised for its estimation and their subsequent 
development is illustrated in the descriptions which follow : 

Method of Kremel (1887) : Place a weighed quantity (about 10 grains) 
of the oleoresin in a flask and macerate it successively with several portions 
of petroleum ether when the greater part will be dissolved leaving the 
filix acid as an insoluble residue. Collect the latter on a fiilter and wash 
with more petroleum ether. Then dissolve it while on the filter in hot 
alcohol, remove the latter by evaporation and again wash with petroleum 
ether to remove the last traces of fat. Finally dry and weigh. 

Method of Bocchi (1896) : * Dissolve 1 to 2 grams of the oleoresin in a 
small quantity of ether, place the solution in a separatory funnel and 
shake it with successive portions of lime water until the shakings become 
colorless and remain clear on the addition of acetic or hydrochloric acids. 
Filter the united lime water solutions into a separatory funnel and acidify 
with hydrochloric acid when a dirty yellow precipitate will form. Dis- 
solve the latter by shaking with carbon disulphide added in successive 
portions, unite the shakings, filter and remove the solvent by evaporation 
on a water bath. Dry and weigh the residue which is pure fili;x acid. 

Method of Kraft (1896): Add a solution composed of 2 grams of 
potassium carbonate, 40 grams of water and 60 grams of alcohol (95 per 
cent.) to 5 grams of the oleoresin in a suitable flask and shake for 15 
minutes. Filter 83 grams of this liquid into a separatory tunnel, add 9 
grams of dilute hydrochloric acid, 50 grams of ether and 35 grams of 
water and shake vigorously. After the mixture has separated draw off 
the lower hydro-alcoholie liquid and repeat the shaking, using 35 grams 
more of water. Separate the latter and run the remaining ethereal so- 
lution into a tared Erlenmeyer flask of 100 cubic centimeters capacity. 
Distill off the greater part of the ether and evaporate the remainder down 
to about 2 grams. Dissolve the dried mass in 1.5 grams of amyl alcohol 
and precipitate the filix acid by the addition of 30 cubic centimeters of 
methyl alcohol (5 cubic centimeters added at once and the remainder drop 
by drop.) Allow the precipitate and supernatant liquid to stand over 
night in a cool place, then collect the former on a tared filter and wash 
it with 15 cubic centimeters of methyl alcohol (use 3 portions of 5 cubic 
centimeters.) Finally, dry the precipitate at a temperature between 60° 
and 70 "C and weigh. The weight obtained will represent the filix acid 
contained in 4 grams of the oleoresin. 



^The procedure as outlined above really grives the amount of total acid 
substances (crude filicin) present, but is described here as it was proposed 
by its originator as a method for the determination of the filix acid content 



OLEORESIN OF ASPIDIUM ^Q3 

Original Method of Fromme (1896): Dissolve 1.5 to 2 grams of the 
«leoresin in 2 grams of ether, and thoroughly mix the solution in a porce- 
lain dish (diameter 8 to 10 centimeters) with 3 grams of calcined mag- 
nesia (or 8 grams of burned lime.) Allow the ether to evaporate com- 
pletely and triturate the remaining dry pulverent mass with water, added 
gradually until a thin brine is formed. Set the mixture aside until the 
magnesia has settled, then decant the supernatant aqueous portion on a 
•dry filter. Continue to repeat this operation, using fresh portions of 
water, until the filtrate no longer gives a precipitate when acidified with 
hydrochloric acid. Place the combined filtrates (usual weight 200 to 250 
grams) in a separatory funnel, acidify with hydrochloric acid and shake 
out the precipitate with carbon disulphide added in successive portions 
(20, 10 and 10 cubic centimeters.) Filter the united carbon disulphide 
shakings into a round-bottom flask of 100 cubic centimeters capacity ^nd 
evaporate to dryness on a water bath. Dissolve the crude filix acid ob- 
tained in this manner in 10 drops of amyl alcohol, using a gentle heat 
if necessary, then add 10 cubic centimeters of methyl alcohol (added drop 
by drop at the beginning and later rapidly.) Set the liquid containing 
the crystals aside in a cool place for 12 hours, then collect the latter on a 
tared filter, and, after washing with several 5 cubic eentimener portions 
of methyl alcohol, dry at a temperature between 60° and 70 °C and weigh. 

Improved Method of Fromme (1897): Place 5 grams of the oleoresin, 
30 grams of ether and 100 grams of a solution of barium hydroxide (1 per 
cent.) in a 200 cubic centimeter flask and shake for 5 minutes. Then run 
the mixture into a separatory funnel, and, after allowing it to stand for 10 
to 15 minutes, run off into another separatory funnel 86 grams (cor- 
responding to 4 grams of the oleoresin) of the lower aqueous layer. 
Acidify by the addition of hydrochloric acid (25 to 30 drops) and shake 
out with ether (in 25, 15, 10 and 10 cubic centimeter portions.) Filter 
the combined ether washings into a 100 cubic centimeter flask and evapor- 
ate to dryness on a water bath. Dissolve the residue in 1 cubic centimeter 
of amyl alcohol by heating over a free flame and precipitate the pure filix 
acid with 30 cubic centimeters of methyl alcohol (added drop by drop 
until a permanent precipitate is produced, and the remainder at once.) 
After the liquid has stood quietly in a cool place for 10 to 12 hours, 
collect the precipitate on a tared filter, wash with methyl alcohol (two 5 
cubic centimeter portions,) press the filter between porous plates, dry at 
an initial temperature of 40 °C and finally at 80 °C, and weigh. 

Stoder's Method (1901): Dissolve 5 grams of the oleoresin in 20 cubic 
centimeters of ether, add 100 cubic centimeters of a freshly prepared so- 
lution of barium hydroxide (2 per cent.) and shake the mixture fre- 
quently during 1 hour. After allowing the mixture to stand quietly for 
a short time, separate the lower aqueous layer by filtration. Collect 
86 cubic centimeters of this portion (corresponding to 4 grams of the 
oleoresin) in a separatory funnel and acidify with 10 cubic centimeters of 
dilute hydrochloric acid. Shake out the resulting precipitate with three 
portions of ether (40, 30 and 20 cubic centimeters) added successively, 
unite the shakings and remove the solvent by distillation. Dissolve the 



104 



DU MEZ— THE GALENICAL OLEORESINS 



residue in 1 cubic centimeter of amyl alcohol, and, after the solution has 
stood in a cool place for 48 hours, add 15 cubic centimeters of methyl 
alcohol. After standing for 24 hours more, collect the precipitated filii 
acid on a filter, wash with 5 cubic centimeters of methyl alcohol, dry on 
a water bath and weigh. 

It will be noticed that the preceding methods, with the ex- 
ception of the one devised by Kremel, are very similar in gen- 
eral outline, practically the only difference being found in the 
procedure by which the crude filix acid is directed to be purified. 
This difference is of special importance, however, as the weight 
of the product finally obtained will naturally vary with the de- 
gree to which purification has been effected, and this in turn 
will cause the computed percentage to vary, as is shown in the 
following table : 

Table 'il .— Variation in filix, acid content due to the difference in the meth 
ods employed in its determination. 





Observer 


Per cent, of filix acid by the metliod of 


Date 


Bocchi 


Kraft 


Fromme 
(Original) 


Fromme 
(Improved) 


1887 


Gehe & Co 

Madsen 


13.24 to S0.35 




3.28 to 11.32 

13.07 

6.58 

6.00 




1897 




12.10 


1897 








5.85 


1898 


Plzak 




6.48 


5.20 











The above table shows further that the filix acid is obtained 
in the state of greatest purity when the improved method of 
Fromme is employed. And this method was usually given 
preference in the valuation of the oleoresin until it was dis- 
covered that the teniafuge properties were not due to the filix 
acid, alone, but were to be attributed in part to the presence of 
a number of other substances as well, compounds resembling 
acids to a certain extent in their chemical behavior. 



Methods for tJie determination of the Crude Filicin. 

With the above mentioned advance in our knowledge con- 
cerning the therapeutic constituents of this preparation, the 
methods for the determination of the filix acid lost their value 
and have since been superceded by those which have for their 



OLEORESIN OP ASFIDIUM 105 

object the determination of the quantity of total active constit- 
uents (crude filicin) present. The methods which have been 
proposed for this purpose are as follows: 

Method of Bulle (1867) :"■ Add a liberal amount of water to a weighed 
portion of the oleoresin contained in a suitable flask and heat on a water 
bath at 40° to 50 °C. Add sufficient ammonia water to produce a strong 
odor of the same after vigorously shaking. Allow the mixture to stand 
in cold water for 3 or 4 hours and add 1/5 to i/4 of its volume of a sat- 
urated solution of salt, then filter. Wash the flask and filter with the 
salt solution, diluted with 6 parts water, until the filtrate no longer gives 
a precipitate with hydrochloric acid. Add dilute hydrochloric acid to the 
filtrate until precipitation is complete, collect the precipitate on a filter, 
wash and dry over sulphuric acid until of constant weight. 

Method of Daccomo and Sccocianti (1896) : ^ Dissolve 1 to 3 grams of 
the oleoresin in a small quantity of ether and shake the solution for % 
hour with an equal volume of an aqueous copper acetate solution. Allow 
the mixture to stand and separate, decant the ethereal liquid and collect 
the precipitate on a tared filter. Wash it successively with water, alco- 
hol and ether, then heat at 100°C until of constant weight. When dry 
111.55 parts of the precipitate represent 100 parts, of filix acid. 

Method of Schmidt (1903) : ^ Place 5 grams of the oleoresin in a mortar 
and convert it to a coarse powder by triturating it with a sufficient quantity 
of calcined magnesia. Then add 250 cubic centimeters of water and thor- 
oughly mix. After the magnesia has settled, decant the aqueous portion 
on a filter. Repeat this operation twice using 150 cubic centimeters of 
water each time. Transfer the combined filtrate to a separatory funnel 
and add hydrochloric acid in sufficient quantity to produce complete pre- 
cipitation. Shake out the precipitate with ether, specific gravity 0.720 to 
0.722, added in successive portions (100, 50 and 30 cubic centimeters.) 
After filtering the ethereal shakings, remove the solvent by distillation 
and dry the residue at 100*C. 

Method of Fromme (1905) : * Dissolve 5 grams of the extract in 30 
grams of ether, add 100 grams of a saturated solution (3 per cent.) of 
barium hydroxide, and shake the mixture vigorously during several minutes. 
Transfer to a separator, and run 86 grams (4 grams of the extract) of the 
lower equeous layer into a flask of 200 cubic centimeters capacity. Add 
2 grams of hydrochloric acid (25 per cent.) and shake out with 3 portions 
of ether, 25, 15, and 10 cubic centimeters. Separate the ether, and filter 
each portion successively through the same plain double filter into an 



1 Cited by Doesterbehn (1898). 

2 This procedure was proposed as a method for the estimation of the 
illix acid. As its nature and the results obtained In its application show that 
it is in reality a method for determining the total constituents of an acid 
•character, It has been included here. 

•The method proposed by Goris and VoisIn (1913) is almost identical 
with the above, the only difference being- that 2 to 3 grams of the oleoresin 
are taken instead of 5 grams as directed by Schmidt, 

*This is the method (but slightly modified) which is official in the British, 
Finnish and Swiss pharmacopceias. 



106 



DU MEZ— THE GALENICAL OLEORESINS 



Erlenmeyer flask of 200 cubic centimeters capacity which has been pre- 
viously weighed. Wash the filter with 10 cubic centimeters more of ether^ 
and finally distill off the ether and dry the residue at 100 °C. Weigh after 
allowing it to stand in a desiccator for half an hour. The weight multi- 
plied by 25 will give the percentage of crude filicin in the sample. 



The striking similarity in the above methods is quite ap- 
parent and needs no special mention. Attention, however, is 
invited to the principal point of difference, namely, the reagent 
employed for the purpose of rendering the constituents to be 
determined soluble in water. In the methods under considera- 
tion, ammonia water, magnesium oxide and barium hydroxide 
have been made use of. As the amount of crude filicin ob- 
tained has been shown to depend to a considerable extent upon 
which one of these reagents is employed, the difference in the 
results reported in the literature in this connection is readily 
accounted for. The importance of this factor is clearly brought 
out in the following data obtained by Hill : 

Table 28 — Influence of different alkalies on the percentage of crude 
filicin obtained. 



Alkali 


K2CO3 


1 per cent 
KOH 


6 per cent. 
KOH 


Mfir(OH)2) 


Ca(0H)2 


Ba(0H)2 


Per cent, of crude 
filicin 


37.6 


37.9 


38.8 


1S,6 


20.0 


21.6 







These results would appear to indicate that potassium hy- 
droxide is the most efficient reagent for effecting a soluble com- 
bination of the constituents comprising the so-called crude 
filicin. The data, however, are misleading in that the strong- 
alkali combines with other material therapeutically inert, and 
thereby causes the results to be high. While there is no in- 
formation of a physiological nature at hand to substantiate the 
statement that barium hydroxide is the best reagent for this 
purpose, it is nevertheless, thought to be the most satisfactory 
from a chemical stand point at least. The method of Fromme^ 
in which the latter is directed to be used, was, therefore, em- 
ployed in the evaluation of the oleoresins examined in the 
laboratory. The results obtained in these analyses, together 
with those reported by other workers are given in the table 
which follows: 



OLEORESIN OF ASPIDIUM: 



107 



Table 29. — Crude filicin content of laboratory samples of the oleoresin 
determined hy Fromme's method. 



Sample 
No. 


Date 


Observer 


Solvent 


Crude 
filicin 


1 


1898 

1899 
1913 

1914 
1916 


Bellincrnflt 


EtbPT- 


Percent. 
18.20 


2 




. 






18.96 


3 


• 




19 82 


4 






20.38 


5 


' 




20.87 


6 


* 


t 


21.76 


7 


' 




21.85 


8 ^. 




• 


24 32 


1 


Caesa 

Bohn 
DuMe 

Harri 

Linke 
DuMe 






31.44» 


2 






27. 48^^ 


1 


sch 




18.22 


1 


»z 


Ac 
Etl 

Ac( 
Etl 


Btone 


13.79 


2 






20.37 


1 


son & Self 




19.30 


2 




* 


19.70 


3.... . 




21.50 


S::::::::: 


" 


' 


21.90 


3 


" 




24.10 


6 


•' 




24.20 


7 


»» 




24 50 


8 


" 




24.70 


9 


•' 




26.50 


10.... 






27.70 


11 


»' 




28.0 


1 






19.30 


2 


z." 




16. 00^ 


2 




ler 


16.27 ' 











1 Ether, specific gravity 0.720. 

=» Ether, specific gravity 0.728. 

' Oleoresins which were prepared in 1910 and had deteriorated. Exam- 
ined shortly after being prepared, the ethereal oleoresin showed a crude 
filicin content of 26.35 per cent. 

From the foregoing, it is apparent that the crued filicin 
content is influenced^ by the age of the oleoresin as well as by 
the solvent which has been employed in its preparation. In the 
case of acetone, the low results obtained are not due to the in- 
complete extraction of the constituents to be determined, as 
might be inferred, but rather to the relatively large amount of 
total extractive matter obtained. It will be noticed that when 
the oleoresin is fresh and ether is the solvent which has been 
used in its preparation, the crude filicin content is usually 
above 20 per cent. This is in accordance with the require- 
ments of the British Pharmacopoeia and is thought to be a more 
reasonable standard than that adpoted by the Swiss, or the 
Finnish pharmacopoeias. The former requires a filicin content 
of 26 to 28 per cent, while the latter specifies a minimum con- 
tent of 26 per cent. This statement is further supported by 
the results obtained in the examination of commercial samples 
as is shown in the following compilation of such data : 



*For the effect of the condition of the rhizomes used on the crude filicin 
content, see under "Drui^ used, its collection, preservation, etc.'/ 



108 



DU MEZ — THE GALENICAL OLEORESINS 



Table 30. — Crude filicin content of commercial samples of the oleoresin 
determined by Fromme's method. 



Sample 
No. 


Date: 




Observer 


Source 


Crude fllicin 


1 


1901 

1903 
1911 

1912 
1913 

1913 


C. 


lesar & Loretz 


Prepared by the firm 

England 


Per cent. 
21.40 


2 

3 




26.15 
27.37 


4 

5 




28.17 
30.00 


6 




30.12 


7 

8 




30.80 
30.92 


1 




27.08 


2 


4i 4» 


28.22 


3 




28.78 


4 


14 (> 


29.39 


5 

6 




30.05 
36 60 


1 


Evans Snns. T^ftsr>her & 


26.30 


2 


Webb. ^^ 




28.00 




P 
E 


irry 


" 


8.40 (1) 


2 






8.60 (1) 


3 


" 


" 


8.80 (1) 


4 


" 


44 


9,00 (1) 


5 


" 


" 


9.20 (1) 


6 


" 


'4 


10.80 (1) 


Ito 16.. 


vans Sons. T^fisr'.her & 




22.90 to 26.30 


1 "... 

2 


Webb. 
South all Bros. & Barclay 


:; 


6.09 0) 
7.16 (0 


3 

4 





26.04 
28.76 


1 


B 
D 

E 


ohrlsch 


Germany 


14.85 


2 






15.42 


3 


" 


16.00 


4 


uMez 


" 


24.00 


1 


Enjrland 


8.79 


2 




United States 


14.36 


3 


4' 


Germany 

England . . . 


16.55 


4 


44 


17.51 (») 


5 


" 




20.32 


6 


44 


United States 


20.77 


Ito 7 

8 

9 


vans Sons, Lescher & 
Webb. 


Not given 


21.3 to 25.30 

15.60 0) 
19.60 (0 


10.... 


" 


4. 4. 


19.70 (0 




G 
H 

H 


oris & Voisin 


Germany 


13.61 to 19.00 








7.13 to 24.00 






France 


20 60 to 22.13 


1 




13.70 


2.. 






19.10 


3 

4 


'• " 


" 


21.20 
24.80 


5 


44 44 


44 


25.80 


6 


44 4. 


44 


28.10 (IS 
11.60 },{ 
13.20 )A 
14.10 ^ ^ 


1 


ill 




2 








3 




" 


4 




Not given 


18.10 


5 






18.92 


6 




4. 44 


19.30 


7.. 




(4 44 


20.22 


8 




44 


20.67 


9 




44 44 


21.57 


10 




44 44 


21.60 


11 




44 


22.00 


12 




[', i. 


22.65 


13 




23.10 











OLEORESIN OF ASPIDIUM 



109 



Table 30. —Continued. 



Sample 
No. 







14 


1913 


15 




16 


" 


17 


'* 


18 


" 


19 


" 


20 


" 


21 


" 


22 


" 


23 


*' 


1 


1914 


2 

3 




1 


"mh" 


2 




3 


'• 


4 


" 


5 


•' 




1916 


2 




3 


" 


4 


" 



Date 



Observer 



Hill. 



Linke 

Southall Bros. & Barclay 



DuMez . 



Source 



Not given. 



Merck & Co 

Brueckner, Lampe & Co. 

Caeser & Loretz 

Notgiven 



Stearns & Co 

Lilly & Co 

Squibb & Sons 

Parke, Davis & Co. 



Crude fllicin 



Percent. 

23,72 
23.75 
24.50 
24.55 
25.15 
25.27 
27.10 
27.82 
28.10 
29.75 
20.40 
21.67 
27.22 
20.40 
21.60 
24.20 
24.60 
27.70 
7.79 (2) 
17.57 
19.04 
22.66 



1 These samples were adulterated with castor oil. 

'Apparently an oleoresin from some species of fern other than Dry- 

opteris Mix-mas. 

In addition to the information gtiven in table No. 29, table 
No. 30 reveals the fact that a low filicin content in the com- 
mercial oleoresins is frequently due to adulteration with castor 
oil. 



Physiological Tests. 

In view of the difference in toxicity of the various constit- 
uents of the oleoresin with respect to the tapeworm, a physio- 
logical method for the evaluation of this preparation would ap- 
pear to be desirable. The method proposed for this purpose 
by Yagi indicates the possibilities along this line. However, 
as there is no available information regarding its application, 
aside from that given by the originator, no statement can be 
made concerning its practical value. A description of the 
method for conducting the test follows : 

Method of Yagi (1914): After thoroughly drying in a desiccator, ac- 
curately weigh 1 gram of the oleoresin and dissolve it in 25 cubic centi- 
meters of ether. Bring the therapeutically active constituents into 
aqueous solution by shaking the ethereal liquid with a saturated solution 
of magnesium hydroxide, using 50 cubic centimeters of the latter for every 



110 



DU MEZ— THE GALENICAL OLEORESINS 



cubic centimeter of the former. Filter and divide the filtrate into several parts. 
Prepare solutions of different dilution from these parts - by adding a 
measured amount of water to each. Then immerse 5 earthworms in each 
of these solutions and note the maximum dilution in which all 5 are killed. 
For computing the relative value of the preparation compare these re- 
sults with those obtained when using a standard solution prepared by dis- 
solving a weighed amount of filix acid, filmaron or albaspidin in water in 
the same manner as described above for the oleoresin. In the case of these 
standard solutions the limit of toxicity is given as follows: filmaron, 3 
parts in 1,000,000; filix acid 4 parts in 1,000,000; albaspidin 1 part ia 
100,000. 

Adulterations 

The efforts which have been made in recent years to stand- 
ardize this preparation have resulted in the discovery that the 
commercial article is very frequently adulterated, the latter 
being accomplished in a variety of ways. 

The method usually resorted to by unscrupulous manufac- 
turers in order to increase their profits consists of diluting the 
finished product with some comparatively cheap material. 
Castor oiP has generally been used for this purpose. In some 
cases, the oleoresin is prepared from deteriorated brown rhi- 
zomes and made to assume the green color of the official pre- 
paration by the addition of chlorophyll or salts of copper.^ 

Adulteration, however, is not limited to the addition of for- 
eign materials to the finished product, but may take place in 
the drug from which the oleoresin is prepared. The forms in 
which the drug may be contaminated are conveniently classed 
under three heads, viz.: (a) the substitution of old deteriorated 
rhizomes for the fresh material, (b) the admixture of chaff 
and dead stipe bases with the rhizomes, and (c) the admixture 
of rhizomes of unofficial species of fern with those of the 
official species. For a discussion of these conditions, see under 
^'Drug used, its collection, preservation, etc." 



^ Parry (1911) ; Evans Sons, Lescher and Webb (1911) ; and others, 
^Weppen and Lueders (1892); Beckurts and Peters (1893); PendorfiC 

(1913) ; and others. 
A trace of copper is usually* present in the commercial product as a result 

of the use of copper utensils in the manufacture of the preparation. (See 

under "Ash"). 



OLEORESIN OF CAPSICUM HI 

OLEORBSIN OF CAPSICUM 

Sy7ionyms 

Aetherische SpunishpfefferextraTct, Nat. Disp. 1884. 

Capsicum,'' Chem. & Drugg. (1913), 82, p. 470. 

Capsicol, Vierteljahrschr. f. prakt. Pharm. (1873), 22, p. 507. 

Ethereal Extract of Capsicum, Am. Journ. Pharm. (1849), 21, p, 134. 

Extractum Capsici aethereum, Hirch, Univ. P. Ii90'2, No. 1905. 

Oleoresin of Bed Pepper, Stevens, Pharm. and Disp. (1909), p. 255. 

Oleoresina Capsici, U. S. P. 1910. 

Oleoresine de Capsique, U. S. Disp. 1907. 

SpanishpfefferextraTct, Nat. Disp. 1884. 

Spanishpfefer-Oelharz, Nat. Disp. 1884. 

History 

The oleoresin of capsicum appears to have been first prepared 
by Procter in 1849, and it was through his efforts that it was 
introduced into the United States Pharmacopma of 1860. Up 
to the present time, no such preparation appears in any of the 
foreign pharmacopoeias. A similar preparation known as capsi- 
ein has, however, been in use in Europe since 1873.^ 

Drug Used, Its Collection, Preservation, Etc. 

The drug directed to be used by the present edition of the 
United States PJiarmacopoeia is ''the dried ripe fruits of Capsi- 
cum fructescens Linne^ (Fam. Solanaceae), without the presence 
or admixture of more than 2 per cent, of stents, calyxes or other 
foreign matter." The preceding editions of the Pharmacopoeia 
since 1880 have specified the use of the species known as Capsi- 
cum fastigiatum Blume. The change is evidently due to the 
fact that the leading commercial varieties of Cayenne pepper 
are at the present time being received from Africa and Japan and 



^For other uses of the term capsicin, see under "Chemistry of capsicum 
and its oleoresin." 

=* Buchheim states that capsicin (the ethereal extract of capsicum) was 
being prepared and sold by Merck of Darmstadt in 1873. Vierteljahrschr. 
f. prakt. Pharm. (1873), 22, p. 507. 

Capsicin, as found on the market in England, is stated to be indefinite in 
that it may be an alcoholic, a chloroformic, an ethereal or an acetone prep- 
aration. Chem. and Drugg. (1913), 82, p. 470. 

3 This is also the species recognized by the French Pharmacopoeia. In the 
other European pharmacopoeias, in which this drug occurs, it is usually the 
the larger fruited variety, Capsicum annum, which is designated. 



112 ^^ MEZ— THE GALENICAL. OL.EORESINS 

belong to the first mentioned species* which has also been 
known as Capsicum haccatum Veil. 

The fruit is plucked when ripe, exposed to the sun until dried, 
and then usually packed in suitable shape for market. It should 
be preserved in the whole condition in a cool place,^ and prefer- 
ably in a closed container as it is prone to become rancid owing 
to the large amount of fatty oil which it contains. 

U. S. P. Texts and Comments Thereon. 

The oleoresin has been official in the United States Phar- 
macopoeia for the past half century having been recognized for 
the first time in the edition of 1860. 

1860 

Oleoresina Capsici 
Oleoresin of Capsicum 
Take of Capsicum,* in fine powder,' distillation on a water-bath, eighteen 
twelve troy-ounces; fluid-ounces of ether," and expose the 

Ether ' a sufficient quantity. residue, in a capsule, until the re- 

Put the capsicum into a cylindrical maining ether kas evaporated. "^ 
percolator,* press it firmly, and grad- Lastly, remove, by straining, the fatty 
ually pour ether upon it until twenty- matter which separates on standing,* 
four fluid ounces of filtered liquid and keep the Oleoresin in a well-stop- 
have passed.' Eecover from this, by pered bottle." 

1870 

Oleoresina Capsici 
Oleoresin of Capsicum 

Take of Capsicum,* in fine powder,^ ounces of liquid have slowly passed.* 
twelve troyounces; Eecover the greater part of the ether 
Ether ^ a sufficient quantity. by distillation on a water -bath,' and 
Put the capsicum into a cylindrical expose the residue in a capsule, until 
percolator, provided with a stop-cock, the remaining ether has evaporated.'^ 
and arranged with cover and recep- Lastly, remove, by straining, the fatty 
taele suitable for volatile liquids,* matter which separates on standing,* 
press it firmly, and gradually pour and keep the Oleoresin in a well-stop- 
ether upon it, until twenty-four fluid pered bottle.*". 



*Tolman and Mitchell, Bull. 163, Bur. of Chem. (1913), p. 9. 
'Brown, Bull. 150, Kentucky Agric. Exp. Sta. (1910), p. 131. 



OLEORESIN OF CAPSICUM 113 

1880 

Oleoresina Capsici 

Oleoresin of Capsicum 

Capsicum/ in No. 60 powder/ one residue, in a capsule, until the remain- 

Hundred parts 100 ing ether has evaporated/ Lastly, 

Stronger Ether,^ a sufficient quantity, pour off the liquid portion," transfer 
Put the capsicum into a cylindrical the remainder to a strainer, and, when 
percolator, provided with a cover and the separated fatty matter (which is 
receptacle suitable for volatile liquidflj* to be rejected) has been completely 
press it firmly, and gradually pour drained, mix all the liquid portions to- 
stronger ether upon it, until one hun- gether." 

dred and fifty (150) parts of liquid Keep the oleoresin in a well stop- 
have slowly passed.** Kecover the ped bottle." 

greater part of the ether by distilla- Preparation. Emplastrum Capsici. 
tion on a water-bath," and expose the 



1890 

Oleoresina Capsici 

Oleoresin of Capsicum 

Capsicum,* in No. 60 powder,^ five a water-bath," and, having transferred 
hundred grammes 500 Gm. the residue to a capsule, allow the re- 
Ether,^ a sufficient quantity. maining ether to evaporate spontan- 
Put the capsicum into a cylindrical eously.^ Then pour off the liquid por- 
glass percolator, provided with a stop- tion, transfer the remainder to a 
cock, and arranged with cover s^nd strainer, and, when the separated fatty 
receptacle suitable for volatile liquids,* matter (which is to be rejected) has 
Press the drug firmly, and percolate been completely drained, mix the li- 
slowly with ether, added in successive quid portions together.' 
portions, until the drug is exhausted.' Keep the oleoresin in a well-stop- 
Eecover the greater part of the ether pered bottle.", 
from the percolate by distillation on Preparation: Emplastrum Capsici. 



114 



DU MEZ— THE GALENICAL. OLEORESINS 



1900 



Oleoresina Capsici 
Oleoresin of Capsicum 



Capsicum/ in No. 40 powder,' -five 

hundred grammes 500 Gm. 

Acetone/ a sufficient quantity. 

Introduce the capsicum into a cylin- 
drical glass percolator, provided with 
a stop-cock, and arranged with a 
cover and a receptacle suitable for 
volatile liquids.* Pack the powder 
firmly, and percolate slowly with ace- 
tone, added in successive portions, 
until eight hundred cubic centimeters 
of percolate have been obtained." 
Recover the greater part of the ace- 
tone from the percolate by distilla- 



tion on a water-bath,* and, having 
transferred the residue to a dish, al- 
low the remaining acetone to evapor- 
ate spontaneously in a w^arm place.' 
Then pour off the liquid portion,* 
transfer the remainder to a glass fun- 
nel provided with a pledget of cotton, 
and when the separated fatty matter 
(which is to be rejected) has been 
completely drained, mix the liquid 
portions together.* Keep the oleo- 
resin in a well-stoppered bottle.^** 

Average dose. — 0.030 Gm. z=z 30 
milligrammes (^ grain). 



1910 
Oleoresina Capsici 
Oleoresin of Capsicum 
Oleores. Capsic. 



Capsicum,^ in No. 40 powder* ^ive 

hundred grammes 500 Gm. 

Ether,' a sufficient quantity. 

Place the capsicum in a cylindrical 
glass percolator, provided with a stop- 
cock, and arranged with a cover and 
a receptacle suitable for volatile li- 
quids.* Pack the powder firmly and 
percolate slowly with ether, added in 
successive portions, until the perco- 
late measures eight hundred mils.^ 
Eecover the greater part of the ether 
from the percolate by distillation on 
a water-bath,« and, having transferred 



the residue to a dish, allow the re- 
maining ether to evaporate spontan- 
eously in a warm place.^ Then pour 
off the liquid portion,' transfer the 
remainder to a glass funnel provided 
with a pledget of cotton, and, when 
the separated fatty matter (which is 
to be rejected) has been completely 
drained, mix the liquid portions to- 
gether." Keep the oleoresin in a well- 
stoppered bottle." 

Preparation — Eplastrum Capsici. 

Average Dose. — Metric, 0.03 Gm. — 
Apothecaries, % grain. 



OLEORESIN OF CAPSICUM 115 

1) For a description of the drug, see pag 1017 under ''Drug 
used, its collection, preservation, etc." 

2) The editions of the Pharmacopoeia previous to that of 1900 
directed that the drug be reduced to a fine powder (No. 60) 
for percolation. As a No. 40 powder has been found to be 
equally satisfactory for this purpose, the last two editions 
of the PharmacopcBia have specified the use of the coarser 
powder. 

3) Ether is the solvent which is directed to be used in the ex- 
traction of the drug at the present time. Previous editions of 
the Pharmacopoeia, with the exception of that 1900, also, speci- 
fied the use of ether for this purpose. The use of acetone as di- 
rected by the Pharmacopoeia of 1900 was unsatisfactory as the 
large amount of extractive matter obtained caused the residue 
which remained upon the evaporation of the solvent to assume a 
semi-solid gelatinous form, and thus increased the difficulty 
of separating the liquid portion. 

Among the other solvents which have received considera- 
tion in this connection, benzin is worthy of mention. The re- 
ports of Maisch, Trimble and Beringer, respectively, (see 
part I, pages 923 and 924) indicate that it is a good solvent for 
the oleoresinous constituents of capsicum and that the pro- 
duct obtained is equal in quality to that yielded by ether. 
Experiments conducted in the laboratory confirm these ob- 
servations. The solvent used in the laboratory, however, was 
petroleum ether, boiling temp, 45 to 50° C, as the composition 
of ordinary commercial benzin varies to a considerable extent. 

4) The Pharmacopoeia of 1860 directed that the extraction 
of the drug be carried out in an ordinary glass percolator. As 
a considerable amount of solvent was lost under these condi- 
tions, the subsequent editions of the Pharmacopoeia have 
specified that a form of percolator adapted to the use of vola- 
tile liquids be employed for this purpose. For a description 
of such forms, see Part I, under *' Apparatus used.'' 

5.) Of interest in connection with the preparation of this 
oleoresin is the fact that the pharmacopoeial directions con- 
cerning the amount of percolate to be collected have been 
changed no less than three times. The first change appeared 
in the Pharmacopoeia of 1880, and was apparently instituted 
for economic reasons as the amount of percolate directed to 



116 DU MEZ— THE GALENICAL. OLEOKBSINS 

be collected was reduced from approximately 2 cubic centi- 
meters for each gram of drug used (24 fluid ounces for 12 troy 
ounces of drug) to 1.5 cubic centimeters. In the succeeding 
edition of the Pharmacopoeia (edition of 1890), the second 
change was made, the directions being to continue percolation 
until the drug is exhausted. The third change occurs in the 
Pharmacopoeia of 1900, which directs that 1.6 cubic centi- 
meters of percolate be collected for each gram of drug taken. 

The reason for making the second change does not become 
apparent from the information at hand. The third change^ 
however, appears to have been instituted primarily for the 
purpose of reducing the amount of solid fats (mainly pal- 
mitin and stearin) extracted in order that the separation of 
the liquid portion constituting the oleoresin might be ac- 
complished more easily. 

In commenting further upon these changes, it is stated that, 
in the preparation of the oleoresin in the laboratory, no 
greater difficulty was experienced in the separation of the 
liquid portion when the amount of sold fats present was large 
than when the quantity present was relatively small. From 
this standpoint, therefore, the last change does not appear to 
have been warranted. For economic reasons, however, the 
change was desirable since at least twice as much ether was 
required for the complete exhaustion of the drug as is ordin- 
arily used when proceeding according to the directions given 
in the last edition of the Pharmacopoeia. 

It is thought that the present pharmacopoeial method could 
be still further improved through the use of some form of con- 
tinuous extraction apparatus for exhausting the drug. Not 
only would this procedure result in the saving of a large 
amount of solvent, but the time required to complete the 
preparation of the oleoresin would be considerably shortened. 

6) The Pharmacopoeia of 1860 directed that only % of the 
menstruum contained in the percolate be recovered by distil- 
lation on a water bath. In all of the subsequent editions the 
directions are to recover the greater part of the solvent, no 
specific amount being mentioned. In this connection, it may 
be stated that the preparation will not be injured even if all 
of the solvent is recovered under the above conditions. In 
case this is done, however, it is necessary to use ether in re- 



OLEORESIN OF CAPSICUM ll7 

moving the thick liquid from the flask so that no particular 
advantage is gained by such a procedure. 

7) In all editions of the Pharmacopoeia in which this prepara- 
tion is official, it is directed that the last traces of solvent be 
allowed to evaporate spontaneously at room temperature. 
Since the complete removal of the solvent can be accomp- 
lished much more rapidly by heating the ethereal liquid on a 
water bath, and without injury to the finished product, it is 
thought that such a procedure would be a desirable improve- 
ment over the present pharmacopoeial method. 

8-9) The liquid portion constituting the oleoresin is directed 
to be separated from the solid fats, which precipitate up- 
on the removal of the solvent, by decantation, and straining 
through a pledget of cotton. Experience has shown that this 
may be accomplished much more rapidly and satisfactorily by 
the aid of a force filter. By this procedure a more complete 
separation can be effected without washing the residue on the 
filter with a portion of the solvent as has been suggested by 
some and thus, the necessity of further exposure of the prep- 
aration to the air is done away with. 

With further reference to the removal of the solid fats, at- 
tention is called to the fact that the degree to which this is ac- 
complished depends upon the temperature at which the oper- 
ation is carried out. The preparation when made during the 
summer may be perfectly homogeneous at the time, but deposit 
fat during the winter. In order to secure a more uniform 
product, it is therefore, thought that the Pharmacopoeia 
should direct that the mixture be chilled to a definite tempera- 
ture previous to the separation of the liquid portion. 

10) The oleoresin should be kept in well-stoppered bottles for 
the same reasons as are given in the comments on the oleoresin 
of aspidium. See page 979. 

Yield 

The average yield of oleoresin is usually about 15 to 18 per 
cent, when ether is the solvent employed in exhausting the 
drug. It is about the same when alcohol, acetone, petroleum 
ether, carbon disulphide or chloroform are used. In this con- 
nection, attention is called to the fact that the total amount of 



118 DU MEZ— THE GALENICAL OLEORESINS 

extract obtained and the oleoresin are not identical, the latter 
consisting only of the oily, liquid portion of the former. Thus, 
it will be observed, upon examining the tables which follow, that 
the total amount of extract obtained with acetone may amount 
to 25 per cent, of the drug operated upon, whereas, the yield 
of oleoresin is only about 18 per cent. The factor which ap- 
pears to influence the yield to the greatest extent is the tem- 
perature at which the preparation is completed. This is due 
to the fact that the oleoresin is saturated with solid fats 
(principally palmitin) and, that these will be precipitated to 
a greater or lesser degree depending on the temperature at 
which the preparation is finally strained. The finished pro- 
duct will, therefore, contain a relatively small amount of these 
fats, and the yield will be correspondingly low when made dur- 
ing the cold winter months, whereas, the opposite will be the 
case when the oleoresin is prepared in the hot months of sum- 
mer. The following tables show the yield of oleoresin, as re- 
ported in the literature, likewise, that obtained in the labora- 
tory: 



OLEORESIN 0F .CAPSICUM 



119 



Table 31. — Yield of oleoresin as reported in the literature. 





Observer 


Yield of oleoresin to 




Date 


Alco- 
hol 


Ace- 
tone 


Ether 


Other 
solvents 


Remarks 


1853 


Bakes 


Perct 
25.00 


Per ct 


Per ct 


Percent. 




888 


Trimble 




19.50 
17.32 

15.50 
17.40 
18.30 
18.40 
19.00 

15.81 
16.85 
21.31 
16.19 

15.67 
15.34 


j Benzin 
1 18.15 
21.00 

25.00 




1892 






18.00 
25.00 


Yield of oleoresin when pre- 


1892 


Sherrard, 


28.00 


paied b.v the U. S. P. method. 
Total yield of extract on com- 
plete exhaustion of the drug. 




Alpers 






























1896 








Oleoresin from which deposited 


1898 


Wlnton, Ogden & 
Mitchell 








fat had been removed. 
Total ether extract from "Chilli 




Southall B10S.& 
Barclay 








Colorado." 
Total ether extract from Natal 










capsicum. 
Total ether extract from Ne- 










paul capsicum. 
Total ether extract from Zan- 


1903 








zibar capsicum. 
Capsicum minimum total .yield 




Vanderkleed 








to ether, sp. gv. Q.717. 
Capsicum annum total yield to 


1905 






j 9olvent(?) 
19.40 to 23 90 

J Benzin 
» 18.60 
\ Petrol 
< Ether 
\ 16.40 
\ Carbon 
X disulDhlde 
1 16.70 
j Chloroform 
( 17.50 


ether.sp.gr. 0.717. 
Reported as yield of oleoresin. 


1905 


Gerrard 


fAIco- 
Jhol 
1 (905t) 
126.40 




18.20 


The average yield of 8 
samples is given as 18.13 per 
cent. 

1 




Patch 


i Represents yield of total ex- 
1 tractive matter. 




















J 


1907 


16.20 to 
26.50 

15.0 to 
25.20 






Total alcoholic extract. Re- 


1908 










sults obtained in the exam- 
ination of 10 samples of cap- 
sicum. 
Total alcoholic extract. 


1908 


Vanderkleed 






jSolvent(?) 
1 11.59 to 18.35 

14.34 to 17.95 

j Benzene 
1 14.00to 15.40 


Reported as yield of oleoresin : 


1909 










Represents the yield from 3 
samples of capsicum. 


1910 


Southall Bros. & 
Barclay 








Results obtained In the ex- 
traction of 5 samples of cap- 
sicum. 


1910 


Eldred 






11.00 to 
26.00 


Ueported as yield of ether 


i9ia 


Vanderkleed 






J Solvent(?) 
\ 15.10 to 22.27 


soluble oleoresin. The aver- 
erage yield obtained from 48 
samples of capsicum Is given 
as 18.00 per cent. 

Reported as yield of oleoresin. 
Results obtained In extract- 
ing 7 samples of capsicum 













120 



DU MEZ— THE GALENICAL. OLEORESINS 



Table 31. — Yield of oleoresin as reported in the literature — Continued. 





Observer 


Yield of oleoresin to 




Date 


Alco- 
hol 


Ace- 
tone 


Ether 


Other 
solvents 


Remarks 


1911 


Vanderkleed— 
Continued. 

Johnson and 
Jolinson 


Per ct. 


Per ct. 


Per ct. 


Percent. 

\ Solvent (?) 
\ 14.70 
\ 17.93 


1 Reported as .yield of oleo- 
resin. 










1912 






16.00 to 
19.00 


J 
Reported as yield of ether ex- 


1912 


Vanderkleed 







J Solvent(?) 
(14.41 to 16.70 


tract. 

Reporte<l as yield of oleoresin. 
Total alcoholic extract. Re- 


1913 


Patch 


19.00 to 
24.00 




.!!!!!!. 


1913 


Vanderkleed 






J Solvent (?) 
I 13.10 to 18.10 

Solvent(?) 
11.00 
11.30 
13.10 
14.80 
15.26 
I 15.80 


sults obtained in extracting 
4 samples of capsicum. 

Reported as yield of oleoresin. 


1913 


Englehardt 








Seven samples of capsicum 
were extracted. 

1 




Rippetoe 









1 










\ Reported as yield of oleoresin. 
































1914 


17.02 to 
24.46 

31.90 to 
35.30 




16.49 to 

17.88 


Total yield of extract. 


1914 


Riedel 




Total yield of extract. 


1914 


Vanderkleed 






J Solvent(?) 
( 13.00 to 18. 00 

j SolventC?) 
113.85 to 20. 84 


Reported as yield of oleoresin . 


1915 


Vanderkleed 









The average yield from 15 
samples is given as 10.00 per 
cent. 












The average yield of 6 
samples is given as 16.65 per 
cent. 



Table 32 — Yield of oleoresin obtained in the laboratory. 





Observer 


Yield of oleoresin to— 




Date 


Alco- 
hol 


Ace- 
tone 


Ether 


Other 
solvents 


Remarks . 


1910.. 
1916.. 


DuMez & Netzel. 
DuMez 


Per ct. 
25.12 

29.90 
16.40 


Per ct. 

20.25 

22.48 
17.50 


Per ct. 
18.33 

19.98 
16.14 


Per cent. 

J Benzine 
116.50 

fPetrol. 
J Ether. 
118.82 


ct. 






tl6.18 


Represents oleoresin separated 






from deposited fat and other 
extractive matter. 



OLEORESIN OF CAPSICUM 121 

Chemistry of the Drug and Oleoresin. 

Tabulation of Constituents. 

The reported analyses^ of the various varieties of red peppers 
show the constituents of pharmaceutical interest to be as fol- 
lows: fixed oil, volatile oil, fatty acids, capsaicin, capsicine, 
resin, mudilage, starch, coloring matter and inorganic sub- 
stances. Most of these substances have been identified in the 
oleoresin prepared by extracting the fruits with ether. They 
are the following: 



Fatty Oil 


Capsaicin 


Coloring Matter 


Fatty Acids 


Capsicine 


Ash 


Volatile Oil 


Eesin 





Occurrence and Description of Individual Constituents. 

Fatty Oil. Work on the oil of capsicum has practically been 
limited to that obtained from the variety official in most of the 
continental pharmacopoeias, namely: Capsicum annum L. The 
properties of the oil of Capsicum fastigiatum Bl. as observed by 
Goetz appears to indicate that it is very likely identical with 
the former.^ The oil as obtained from the seeds of Capsicum 
annum BU is a yellowish brown, mobile liquid, specific gravity 
15.5°C 0.91095; iodine value (Huebls) 119.5; saponification 
value (Koettsdorffer) 187.2. It is composed of the glyceryl 
esters of oleic, palmitic and stearic acids. 

The oil of capsicum is located in the seeds and is variously 
stated to comprise from 20* to 24.06^ per cent, of these organs 
in Capsicum annum. The yield as computed by Goetz for the 
entire fruit of Capsicum fastigiatum is 8.4 per cent.. The yield 
in the case of Capsicum fructescens does not appear to have been 
determined. 



* Taylor, Am. Journ. Fharm. (1857), 29, p. 303; Buchheim, Vierteljahrschr. 
f. prakt. Pharm. (1872), 4, p. 507; Free. A. Ph. A. (1873), 22, p. 106; 
Strohmer, Chem. Centralb. (1884), 55, p. 557; Pabst, Arch. d. Pharm. (1892), 
230, p. 108 ; Tolman and Mitchell, Bull. No. 163, Bur. of Chem., Dep. of Agr. 
(1913), p. 9. 

* Goetz obtained 15.7 per cent of a yellowish-brown fixed oil from the 
seeds of Capsicum fastigiatum BL, specific gravity at 25", 0.919. Goetz, un- 
published results. 

3 Buchheim, I. c; Pabst, I. c; von Bitto, Landwirt. Versuchs-Stat. (1896). 
46, p. 310; Meyer-Essen, Chemiker Ztg. (1903), 27, p. 958. 

* Meyer-Essen, I. c. 
■von Bitto, I. c. 



122 



DU MEZ— THE GAUENICAL. OL.EOKESINS 



Fatty Acids.^ The free fatty acids present have been iden- 
tified as oleic, palmitic and stearic, palmitic acid predominating 
in the fruits of Capsicum annum. The proportions of these 
acids as they occur in the fruit of Capsicum fastigiatum or C. 
fructescens have apparently not been determined to date. 

Volatile Oil. The presence of a volatile oil was first noted in 
the fruits of Capsicum annum by Taylor."^ Pabst isolated a 
small amount of a volatile liquid having the odor of parsley 
from the same. Inasmuch as the oleoresin, when prepared 
from Capsicum fructescens has a distinct odor, it is quite prob- 
able that a similar volatile oil is also present in the fruit of 
this variety. 

Capsaicin^ Capsaicin is the sharp tasting constituent of the 
fruits of the various varieties of red pepper. It crystallizes 
from petroleum ether in colorless plates melting at 60.5° C 
(Morbitz), 63 to 63.5°C (Micko), 64.5°C (Nelson) .^« The sub- 
stance is stated to be soluble in water (1:30,000), petroleum 
ether (1:3,633), ether, alcohol, carbon disulphide and chloro- 
form. According to Morbitz, its composition is represented 
by the formula C35H54N3O4. Micko^^ does not agree with the 
latter and has proposed the formula ,CH30.Ci7H24NO.OH, as 
also representing the structure in part. . 

Capsaicin is stated by Morbitz to be present in the fruit of 
Capsicum fastigiatum to the extent of 0.05 to 0.07 per cent. 



« Buchheim, Pabst, von Bitto, I. c. 

U. c. 

» The term capsicin was first used to designate the sharp tasting- principle 
principle in red peppers. Bucholz, Taschenb. f. Scheidkuenst. u. Apoth. 
(1816), 37, p. 1; Landerer, Vierteljahresschr. f. prakt. Pharm. (1854), i, 
p. 34. The name was also applied to the ethereal extract of capsicum as 
marketed by Merck and Co. See note by Buchheim, Vierteljahrschr. f. prakt. 
Pharm. (1873), 22, p. 507. Later it was used to indicate a coniine-like 
alkaloid isolated from the fruit of Capsicum fastigiatum by Thresh. Pharm. 
Journ. (1876), 35, p. 941. 

In 1873, Buchheim gave the name Capsicol to a dark red oily liquid (our 
present oleoresin) which he considered to be the pungent principle. 

Capsaicin is the term which was Introduced by Thresh to denote the sharp 
tasting substance isolated by him from the fruits of Capsicum fastigiatum. 
Pharm. Journ. (1876), 36, p. 21. It is the name now generally employed to 
indicate this substance, although, Morbita (I. c.) subsequently proposed the 
name Capsicutin. 

A more recent investigator, Gabriel de la Puerta, has given the name 
"capsic acid" to the irritant principle isolated ffom pimenta. Ann. de la 
Soc. Espanola de fls. y. quim. (1905), No. 23; Am. Drugg. & Pharm. Rec. 
(1906), 48, p. 40. 

"Chem. News (1911, 103, p. 111. 

"Chem. Centralbl. (1899), 70, p. 293. 



OLEORESIN OF CAPSICUM 123 

The amount present in Capsicum fructescens has not been re- 
ported. 

Capsicine. According to Felletar^^ and Thresh," capsicine 
is present in the fruits of Capsicum annum and C. fastigiatum. 
The latter describes it as an alkaloid possessing an odor simi- 
lar to that of coniine. The hydrochloride is stated to have been 
isolated in the crystalline form and to be precipitated from 
aqueous solution by the usual alkaloidal reagents. Pabst^* 
states that the base is not a normal constituent of the fruits 
of Capsicum anniwi, but that it is formed when the latter are 
stored or by the action of various reagents. 

Resin. Kesin is mentioned by several investigators^^ as a 
constituent of the fruits of the red peppers. Apparently noth- 
ing has been done toward determining its composition or proper- 
ties. 

Coloring Matter. The red color of the capsicum fruit as 
well as that of the ethereal extract appears to have attracted 
the attention of all investigators, although, Pabst, is the only 
observer who attempted to identify the substance. He concluded, 
from saponification experiments, that it was a cholesterin ester 
of a fatty acid.^^ 

AsTi. According to von Bitto,^^ the ash of cap^cum is com- 
posed of the basic elements, K, Na, Mg, Ca, Fe, Al and Mn 
combined with the acid radicles CI', SiOg", SO/', PO/", NO3' 
and CO3''. 

The ash content of red pepper varies with the variety of the 
fruit.^^ That of the commercial drug is also influenced by 
the presence of sand. The ash of Capsicum fructescens (sand 
free) amounts to about 4.90 per cent of the dried fruit.^* 



^2 Vierteljahrschr. f. prakt. Pharm. (1868), 17, p. 360; Buchner's Hepert 
f. d. Pharm. (1828), 27, p. 35; Froc. A. Ph. A., (1871), 19, p. 289. 

"Pharm. Journ. (1876), 35, p. 941. 

"Z. c. 

"Strohmer, Pabst, Tolman and Mitchell, I. c. 

" Pabst, I. c. 

"Landw. Versuchsstat. (1893), 42, p. 369. 

" Tolman and Mitchell give the ash content of sand free Capsicum annum 
as 6.69 to 7.54 per cent. Bull. 163, Bur, of Chem., Dept of Agr., Washington, 
1913. 

"McKeown gives the ash content of Capsicum fastigiatum as 4.50 to 4.95 
per cent. Am. Drugg. (1886), 14, p. 128. 

Tolman and Mitchell report the sand free ash content of Capsicum fruc- 
tescens (African) as 4.49 to 5.44 per cent, that of the fruits of the same 
variety coming from Japan as 4.60 to 5.35 per cent, I. c. 



124 ^^ MEZ— THE GALENICAL OLEORESINS 



Constituents of Therapeutic Importance 

The early investigators assigned the intensely irritating- 
properties of the oleoresin of capsicum to various substances 
supposed to be contained therein. Bracconot^ and Buchheim^ 
thought it due to the oily constituents, Felletar^ attributed the 
action to a liquid organic base, and Pabst* to a resin intimately 
mixed with the red pigment. The irritating principle is now 
known to be the crystalline con^ituent, capsaicin.^ The latter 
has not been isolated in sufficient quantities to permit of an. 
extensive investigation of its physiological properties. It is^ 
however, known to act as a rubefacient when applied exter- 
nally, and to be extremely pungent to the taste, its sharpnesa 
being perceptible in aqueous solution, 1 part to 11 million, 
parts of water.* 

Physical Properties 

Color: The color of the oleoresin, when the latter i» 
spread out in a thin layer on a white porcelain surface, is a 
characteristic light brownish-red. The descriptions of th© 
color given in pharmaceutical literature vary to a considerable 
extent (light reddish-brown to dark brown) owing very likely to 
a difference in the conditions under whieh the observations were 
made. 

Odor: The odor of the preparation is rather faint, but char- 
acteristic, resembling that of the red peppers. 

Taste: It is extremely pungent and should be tasted with 
caution. The taste is usually described as being hot and fiery; 
or burning. 

Consistence: The consistence of the oleoresin varies with the 
amount of solid fats (palmitin and stearin) present,*^ and with 

*Ann. Chlm. Phys. (1817), 6, p. 122. 

» Vierteljahresschr. f. prakt. Pharm. (1873), 22, p. 507. 

^Ihid. (1868), 17, p. 360. 

*Arch. d. Pharm. (1892), 230, p. 108. 

"Micko, Zeitschr. f. Unters. Nahr.-u. Genussm. (1898), 12, p. 215. 

•Morbitz, Pharm. Zeitschr. f. Russland, (1897), p. 372. 

' See under "Methods of preparation". : 



OLEORESIN OF CAPSICUM 



125 



the temperature. At ordinary temperatures the degree of 
fluidity is usually such that it can be readily poured. It should 
be homogeneous and not contain a deposit of fat. 

Solubility: The oleoresin, when prepared with ether, is 
soluble in acetone, ether, chloroform, carbon tetrachloride, car- 
bon disulphide, petroleum ether, oil of turpentine^ and solu- 
tions of the caustic alkalies. It should not be soluble to any 
great extent in 90 per cent, alcohol, solubility therein indicating 
that alcohol was the menstruum used in the preparation of the 
oleoresin. 

Specific gravity: The specific gravity of the oleoresin de- 
termined at 25 °C was found to be 0.925 to 0.932 when ether was 
the solvent employed in extracting the drug. When alcohol 
or acetone were employed for this purpose, the results were 
almost the same, whereas petroleum ether yielded a product 
of low specific gravity. The low specific gravity observed in the 
one case, where acetone was used in the preparation of the oleo- 
resin, was not due to the nature of the solvent, but to the 
more complete removal of the solid fats. The variation in the 
amounts of the latter retained in the finished product is thought 
to be the chief factor infiuencing the specific gravity of this 
preparation. In the case of the commercial samples, how- 
ever, the presence of unevap orated solvent must also be taken 
into consideration as is shown in the tables which follow: 

Table S^Specific gravities of oleoretins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Specific 
gravity 


1 


1910 
1916 


DuMez & Netzel 


Alcohol 


At25°C 
0.932 


2 






0.933 


3 


>( «« 


Ether 


0.932 


4 


4. .. 


Benzine 


0,925 


1 


DuMez 


Alcohol 


0.926 


2 




Acetone 


0.919 


■3 


" 


Ether 


0.925 


4 


" 


Petrol, ether 


0.914 











King's American Dispensatory (1900), p. 1331. 



126 



DU MEZ— THB GALENICAL OLiEORESINS 



Table 34 — Specific gravities of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Specific 
gravity 


1 


1916 


DuMez 


Squibb «& Sons 


At 25° C 
0.9101 


2 




Lilly «& Co 


0.919 


3 


»i 


Sharp & Doiitne 


0.928 




* 







1 taine d ether 

Refractive index: Determinations made in the laboratory 
show that the oleoresin should have a refractive index of about 
1.47 when observed at 25° C. A refractive index lower than 
this was found to be due to the presence of unevaporated solvent. 
The solvent employed in extracting the drug or the variation 
in solid fat content appears to have very little influence, if 
any, on this constant. The results obtained in the laboratory 
in the examination of the oleoresin follow: 

Table ^6— Refractive indices of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Refractive 
index 




1910 
1916 


DuMez & Netzel 


Alcohol 


At 25° C 
1 463 


2 




1 477 




'4 


Ether 


1 474 


4 


" 


Petrol, ether 


1 47.5 




DuMez 


Alcohol 


1 473 


2 






1.473 




»* 


Ether 


1 474 




»» 


Petrol, ether 


1 472 









Table 36 — Refractive indices of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Refractive 
index 


1 


1916 


DuMez 


Lilly & Co 


At 25° C 
1 472 


2 






1.473 


3 


'< 


Sauibb & Sons 


1 467' 











* Contained ether. 



OLEORESIN OF CAPSICUM 



127 



Chemical Properties. 

Loss in weight on heating: Determinations made in the 
laboratory show that the oleoresin loses but little in weight on 
heating at 110 °C, a loss of but 0.42 to 2.13 per cent, having 
been observed for the preparation when free from solvent. The 
laboratory preparations as a rule showed a smaller loss than 
the commercial samples, which is very likely due to a difference 
in the temperature conditions under which the preparations 
were made. The results obtained in the determinations made 
in the laboratory are given in the following tables : 

Table ^1 —Laboratory preparations — loss in iceight on heating 



Sample 
No. 


Date 


Observer 


Solvent 


Per cent, of 
loss on 
heating 


1 


1916 


DuMez 


Alcohol 


At 110° € 
0.42 


2 


•• 




Acetone 


52 


3 




Ether 


0.88 


4 


. : 


Petrol, ether 


0.68 


5 


" 




Alcohol 


5.15' 


6 .... 




Acetone 


74 


7 


4( • 


Ether 


2 09 


8 


" 


Benzine 


1 01 









Contained alcohol. 



Table 38. — Commercial oleoresins — loss in weigJit on heating. 



Sample 
No. 


Date 


Observer 


Source 


Per cent of 
loss on 
heating 


1 


1916 


DuMez 


Sharp & Dohme . 


At 110° C 
1 93 


2 




Lill.v& Co 

Squibb & Sons.. . 


2.13 


3 


" 


4 09 > 











* Contained ether. 



Ash Content: The determinations made in the laboratory 
show that the ash content of the oleoresin varies with the solvent 
employed in its preparation. When acetone was the solvent 
used, the amount of ash obtained did not exceed 0.26 per cent, 
whereas, the amount was only 0.09 to 0.12 per cent, when the 
oleoresin was prepared with ether. The variable results ob- 
tained in the examination of the commercial samples appear to 



128 



DU MEZ— THE GALENICAL. OLEORESINS 



indicate the use of different solvents in their preparation. The 
comparatively high value (0.40 per cent.) obtained in one case, 
however, may have been due to the copper present. The ash 
content of the samples examined in the laboratory is given in 
the tables which follow: 



Table 39 — AsJi contents of oleorsins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Per cent, 
of ash 


1 


1916 


DuMez 


Alcohol 


0.39 


2 




Acetone 


0.26 


3 




Ether 

Petrol, ether 


0.09 


4 


»» 


09 


5 


;; 




0.39 


6 


Acetone 


0.24 


7 


" 


Ether 


0.12 


8 






0.10 











Tabe 40 — Ash contents of commercial oleoresins 



Sample 
No. 


Date 


Observer 


.Source 


Per cent, of 
ash 


Foreign 
constituents 


J 


1916 


DuMez 


Sauibb & Sons 


0.091 
0.40 
0.30 




2 




Sharp & Dohme 

Lilly & Co 


Copper 


3 


" 













^ Contained ether. 



Acid number: The acid numbers, when acetone, ether, or 
petroleum ether were used in the preparation of the oleoresin, 
were found to be 106.6, 103.8 and 105 respectively. When 
alcohol was employed for this purpose, the value obtained for 
this constant was considerably lower, being 93.5. With respect 
to the commercial samples examined, the acid number was in 
all cases found to be much lower. This is thought to be due, 
in two instances, to a low free acid content (principally pal- 
mitic acid) of the drug from which the oleoresins were pre- 
pared, or to the more complete removal of these acids in the 
separation of the deposited material. In the third case, it 
was caused, in part, at least, by the presence of unevaporated 
solvent. The acid numbers obtained for the preparations ex- 
amined in the laboratory are as of Hows: 



OLBORESIN OF CAPSICUM 



129 



Table 41- Acid numbers of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Acid 
number 


1 

2 

3 

4 


1916 


T)iiMp7 




93.5 




Acetone 


106.6 


ii 


Ether 


103.8 


.4 


Petrol. Ether 


105.0 









Table 42 — Acid numbers of commercial oleoresins. 



1 Contained ether. 



Sample 
No. 


Date 


Observer 


Source 


Acid , 
number 


1 

2 

3 


1916 


DuMez 


Sauibb & Sons 


30.81 




Sharp &Dohme 


60.3 


it 


Lilly & Co 


82.7 









Saponification value: The saponification values obtained for 
the oleoresins prepared in the laboratory were above 200, as a 
rule, regardless of the nature of the solvent used in extracting 
the drug. The comparatively slight variations observed were 
very likely due to the difference in the degree to which the 
solid fats (principally palmitin) had been removed. This also 
accounts for the comparatively low values obtained for the 
commercial preparations. The exceptionally low value ob- 
tained for the sample from Squibb and Sons is to be attributed 
to the presence of unevaporated solvent. The values obtained 
for the preparations examined in the laboratory are given in. 
the tables which follow: 



Table 43 — Saponification values of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Saponifica.- 
tion value 




1916 


DuMez . 


Alcohol 


203 5 






Acetone 


209.2 






Ether 


207 4 






Petrol, ether 


208.6 






Alcohol 


196 7 






Acetone 


202,8 


•J 




Ether 


206,9 






Benzin 


198 7 











130 



DU MEZ— THE GALENICAL OLEORESINS 



Table 44 — Saponification values of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Saponifica- 
tion value 


1 


1916 


DuMez 


Squibb & Sons 


193.4' 
196 9 


2 






3 


«■ 


Lilly & Co 


198 3 











* Contained ether. 

Iodine value: An iodine value of 122 to 123.9 was obtained 
for the oleoresins prepared in the laboratory using ether as the 
•extracting menstruum. Results very near the same were ob- 
tained when acetone or petroleum ether were the solvents used, 
whereas, the preparation when made with alcohol gave a lower 
value, 109.3 to 105.7. The principal cause^ for the variation 
in this constant (aside from the effect which the quality of the 
drug or the solvent may have thereon) as observed in the case 
of some of the laboratory preparations, as well as the commercial 
samples, is thought to be the difference in the degree to which 
the saturated fats (principally palmitin) have been removed. 
In the case of one of the commercial samples, however, the 
low iodine value is to be attributed to the presence of unevap- 
orated solvent. The results obtained in the determinations 
made in the laboratory together with those reported by Kebler 
for the total ether extract are given in the tables which follow: 



Table 45 — Iodine values of laboratory preparations. 



Sample 
No. 


Date 


Observer 


Solvent 


Iodine 
value 


\ 


1913 
1916 


Keblera 


Ether 


107. 


2 






\2%A 


3 


»• 


•« 


\2^ 2 


4 


•' 


•' 


127.3 


5 


«' 


»« 


132 


6 


" 


" 


137.3 


7 


" 




138 


8-24 


•' 


" 


110.0 to 14-5.7 
11.5.7 


1 


DuMez 


Alcohol 


2 




Acetone 


125.2 


8 


" 


Ether 


122.0 


4 


'• 


Petrol. Ether 


123.7 


1 


«♦ 


Alcohol 


109 3 


2 


'• 


Acetone 


118.0 


3 


♦» 


Ether 


102 9 


4 . ... 


»« 


Benzin 


116 9 











<a) Kebler's results represent the iodine value of the total ether extract. 



*Lowenstein and Dunn have shown that heating at 110° C. to remove 
volatile matter from the total ether extract causes a lowering in the iodine 
value due to absorption of oxygen by the unsaturated fats. Journ. Indust. 
And Eng. Chem. (1910), 2, p. 48. 



OLEORESIN OF CAPSICUM 



lai 



Table 46. — Iodine values of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Iodine 
value 


1 


1916 


DaMez 


Squibb & Sons 

Sharp & Dohme 


109.2 (1) 


2 




116.2 


3. 


" 


Lilly & Co 


121.7 











Contained ether. 



Special Quantitative Tests. 

PJiysiological Test. 

As the active constituent is present in the oleoresin in such 
minute quantities that a gravimetric method for Its estimation 
is not practical at the present time, a physiological method would 
appear to be the best means to employ in the standardization 
of this preparation. Such a method is reported to be in use 
for this purpose by the H. K. Mulford Company. Aside, how- 
ever, from the fact that the test is based on the ability to de- 
tect the pungency of the oleoresin in extremely dilute solutions, 
and that the firm takes as its standard a preparation which is 
still pungent to the taste in a maximum dilution of 1 to 150,000, 
there is no exact information available to show in what man- 
ner the same is actually carried out. It is thought, however,, 
that a procedure similar to that developed in this laboratory 
some years ago (1910) is made use of. The following is a 
description of this method. 

Accurately weigh about 1 drop of the oleoresin contained in a small 
flask, add 5 cubic centimeters of normal potassium hydroxide solution and 
heat on a water bath for a short time to saponify the fats. Transfer 
the saponified material to a 100 cubic centimeter flask, using several por- 
tions of water for this purpose, and finally dilute up to the mark with 
more water. With the aid of a pipette, measure off 5 cubic centimeters 
of this solution and run it into a graduated cylinder (glass stoppered) of 
1,000 cubic centimeters capacity. Dilute this with water added in por- 
tions of 100 cubic centimeters, tasting the solution after each addition. 
Note the highest dilution in which the pungent taste is still distinctly per- 
ceptible and compare this with the results obtained using a standard 
preparation. 

As all of the samples prepared in this laboratory were found 
to be distinctly pungent to the taste in dilutions of 1 to 250,000, 



232 ^U MEZ— THE GALENICAL OLEORESINS 

it is thought that the standard employed by the H. K. Mulford 
Company is rather low. In view of these observations, it would 
appear that a standard of 1 in 200,000 would be more desirable. 

Adulterations 

A trace of copper was found in most of the commercial 
samples examined. See under "Ash content.'' 

OLEORBSIN OF CUBEB 
Synonyms 

Aetherisches Cvibebenextrdkt, Bern. P. 1852. 

Aether-szeszes Tcuheba hivonat, Hung. P. 1888. 

Cubehen Extrdkt, Nethl. P. 1902. 

Estratto di Cubehe, Swiss P. 1907. 

Estratto di Pepe Cubehe, Swiss P. 1865. 

Estratto di Pepe Cubebe Etereo, Ital. P. 1902. 

Ethereal Extract of Cubeb, Am. Journ. Pharm. (1846), 18, p. 167. 

Extract van Staartpeper, Nethl. P. 1871. 

Exiractu de Cubebe, Eoum. P. 1874. 

Extractum Cubebae Fluidum, U. S. P. 1850. 

Extractum Cubebarum, Aust. P. 1906. 

Extractum, Cubebarum aethereum, Swiss P. 1865. 

Extractum Cubebarum aethereo-spirituosuw, Hung. P. 1888. 

Extractum Cubebarum oleoso-resinosum, Strump, AUg. P. 1861. 

Ecitractum Kubebae oleo-resinosum, Pruss. P. 1829. 

Extrait de Cubebe, Fr. P. 1884. 

Extrait ether^ de Cubebe, Bern. P. 1852. 

Extrait oUo-s^sineux Cubebe, Fr. P. 1884. ; 

Fluid Extract of Cubebs, U. S. P. 1850. 

Kubebe Extract, Dan. P. 1869. 

KubebenextraM, G. P. 1872. 

KubeberextraTct, Dan. 1893. 

Kubeba Kivonat, Hung. P. 1875. 

Oelig-Harziges KubebenextraTct, Strump, Allg. P. 1861. 

Oleo-Resin of Cubebs, B. P. 1885. 

Oleo-Besina Cubebae, B. P. 1885. 

Oleoresina Cubebae, U. S. P. 1910. 

OUoresine de Cubebe, U. S. Disp. 1907. 

Oleoresinous Extract of Cubeb, Pareira, Mat. Med. 1854. 

History 

The oleoresin of cubeb, prepared by extracting the drug with 
ether and then removing the latter by distillation, was first 



OLEORESIN OF CUBEB 133 

brought to the attention of the European pharmacist by Haus- 
mann in 1838. Ten years previous (1828), however, Dublanc 
in France and simultaneously Oberdoerffer in Germany had 
made known a similar preparation obtained by a rather long 
and tedious process involving the distillation of the drug with 
steam and subsequent extraction of the marc with alcohol. The 
latter became official in the Prussian Pharmacopoeia of 1829 
and in the Pharmacopoeia of Schleswig-Holstein in 1846, while 
the former first received official recognition in the Baden Phar- 
macopoeia of 1841. 

Through the efforts of Procter, a preparation similar to that 
made by Hausmann was introduced into the United States 
Pharmacopoeia of 1850 under the title Extr actum Cuhehae 
Fluidum. In the edition of 1860, this title was changed to 
•Oleoresina Cuhehae. The preparation official in the United 
States at present is the oleoresin obtained by extracting the 
cubeb with alcohol, whereas, that which is given recognition 
in the late European pharmacopoeias is the product obtained 
by exhausting the drug with a mixture of alcohol and ether. 

The pharmacopoeias of the countries, states and municipali- 
ities in which this preparation has been officially recognized, to- 
gether with the dates of appearance of the various editions in 
which it received such recognition, are enumerated below. 

Prussian Pharmacopoeia — 1829, 1833, 1868. 
Pharmacopoeia of Baden — 1841. 
Pharmacopoeia of Schleswig-Holstein — 1844. 
Pharmacopoeia of Berne — 1852. 
Belgian' Pharmacopoeia — 1854, 1855. 

Qnited States Pharmacopoeia — 1850, 1860, 1870, 1880, 1890, 1900, 1910. 
Pharmacopoeia of Hannover — 1861. 
Pharmacopoeia of Hessen — 1862. 
Swiss Pharmacopoeia — 1865, 1872, 1893, 1907. 
Austrian Pharmacopoeia — 1869, 1889, 1906. 
Danish' Pharmacopoeia — 1869, 1893. 
Hungarian Pharmacopoeia — 1871, 1888, 1909. 
Netherlands Pharmacopoeia — 1871, 1902. 
■German Pharmacopoeia — 1873, 1882, 1890, 1900, 1910. 
Roumanian Pharmacopoeia — 1874. 
French Pharmacopoeia — 1884, 1908. 

British' Pharmacopoeia — 1885. ~ 

Italian Pharmacopoeia — 1902,1909. 
Japanese Pharmacopoeia — 1907. 



* Not official In the recent editions. 



234 I^U MEZ— THE GALENICAL. OLEORESINS 

Drug Used, Its Collection, Preservation, Etc. 

The drug recognized by the ninth revised edition of the 
United States Pharmacopoeia is 'Hhe dried, unripe fruits of 
Piper Cuheha Linne filius (Fam. Piperaceae), without the pres- 
ence or admixture of more than 5 per cent of stems or other 
foreign matter." Other botanical synonyms for the same fre- 
quently met with in the literature are : Cuheha Cuheha (Linne 
filius) Lyons; and Cuheha officinalis Mique. 

The fruit is supposedly gathered when full grown, but before 
ripe, and is immediately packed for exportation. That some 
of the fruit for sale on the American market is not collected 
until after ripening would appear to be the case from the color 
of some of the oleoresins prepared by the author, a condition 
which has also been noted by the others.^ In addition, it should 
also be noted that the so-called false cuhehs^ are sometimes sub- 
stituted for the official drug. 

As cubeb gradually deteriorates with age,^ and in the 
powdered condition becomes rapidly weaker owing to the loss 
of volatile oil, it should be stored whole, in closed containers, 
and powdered only as it is used. 

U. S. P. Text and Comments Thereon. 

The oleoresin has been official in the last seven editions of the 
Pharmacopoeia, having been recognized for the first time in the 
edition of 1850 under the title Extractum Cuhehae Fluidum. 

1850 
Extractum Cubebae Fluidum 
Fluid Extract of Cubebs 
Take of Cubebs,* in powder,'^ a pound; then distill off, by means of a water- 
Ether ^ a sufficient quantity. bath, at a gentle heat, a pint and a 
Put the Cubebs into a percolator,* half of the ether," and expose the 
and, having packed it carefully, pour residue, in a shallow vessel, until the 
Ether gradually upon it until two whole of the ether has evaporated.^ 
pints of filtered liquor are obtained;" 



1 Emanuel (1894) stated that when he reported to the jobber that he had 
obtained a brown colored oleoresin from the cubeb purchased, the latter 
replied that, while the United States Pharmacopceia specified the unripe fruit, 
this was rarely found on the market. 

2 The botanical origin of this fruit is not knoM'n. Culbreth, Materia Medica 
and Pharmacology (1903), p. 138, 

8 The volatile oil, in part, is converted into the so-called cubeb camphor, 
especially when stored in a damp place. Schmidt, Ber. d. deutsch chem, 
Ges. (1877), 10, p. 188. 



OLEORESIN OF CTJBBB 



135 



1860 

Oleoresina Cubebae 
Oleoresin of Cubeb 
Extractum Cubebae Fluidum, PJiarm., 1850 
Take of Cubeb/ in fine powder," liquid have passed.^ Eecover from 
twelve troyounces; this, by distillation on a water-bath, 

Ether * a sufficient quantity. eighteen fluid-ounces of ether,* and 

Put the Cubeb into a cylindrical expose the residue, in a capsule, until 
percolator,* press it moderately, and the remaining ether has evaporated.' 
gradually pour Ether upon it until Lastly keep the oleoresin in a well- 
twenty-four fluid-ounces of filtered stopped bottle." 



1870 
Oleoresina Cubebae 



Oleoresin 
Take of Cubeb,^ in fine powder,^' 

twelve troy-ounces; 
Ether ' a sufficient quantity. 

Put the Cubeb into a cylindrical 
percolator, provided with a stop-cock, 
and arranged with a cover and recep- 
tacle suitable for volatile liquids,* 
press it moderately, and gradually 
pour ether upon it, until twenty-four 
fluidounces of liquid have slowly pass- 



of Cubeb 

ed.^ Eecover the greater part of the 
ether by distillation on a water-bath,* 
and expose the residue, in a capsule, 
until the remaining ether has evapor- 
ated.'' When, after standing in a close 
vessel, the liquid has deposited a waxy 
and crystalline matter, decant the 
oleoresin * and keep it in a well-stop- 
ped bottle.* 



1880 

Oleoresina Cubebae 
Oleoresin of Cubeb 



Cubeb,^ in No. 60 powder,' one hun- 
dred parts 100 

Stronger Ether,' a sufficient quantity. 
Put the Cubeb into a cylindrical 
percolator, provided with a cover and 
receptacle suitable for volatile li- 
quids,* press it firmly, and gradually 
pour stronger ether upon it, until one 
hundred and fifty (150) parts of 
liquid have slowly passed." Eecover 
the greater part of the ether by dis- 



tillation on a water-bath," and ex- 
pose the residue, in a capsule, until 
the remaining ether has evaporated.' 
Transfer the remainder to a close ves- 
sel, and let it stand until it ceases to 
deposit a waxy and crystalline mat- 
ter. Lastly, pour off the oleoresin." 

Keep the oleoresin in a well-stop- 
ped bottle." 

Preparation: Trochisci Cubebae. 



136 



DU MEZ— THE GALENICAL. OLEOKEJSINS 



*^\ 



1890 

Oleoresina Cubebae 
Oleoresin of Cubeb 



Cubeb/ in No. 30 powder,' -five hun- 
dred grammes 500 Gm. 

Ether,^ a sufficient quantity. 

Put the Cubeb into a cylindrical 
glass percolator, provided with a 
stop-cock, and arranged with a cover 
and receptacle suitable for volatile 
liquids.* Press the drug firmly, and 
percolate slowly with ether, added in 
successive portions, until the drug is 
exhausted.' Eecover the greater part 
of the ether from the percolate by 



distillation on a water-bath," and, hav- 
ing transferred the residue to a cap- 
sule, allow the remaining ether to 
evaporate spontaneously.'^ 

Keep the product in a well-stop- 
pered bottle." 

NOTE. Oleoresin of Cubeb de- 
posits, after standing for some time, 
a waxy and crystalline matter, which 
should be rejected, only the liquid 
portion being used.' 

Preparation: Trochisci Cubebae. 



1900 



Oleoresina Cubebae 
Oleoresin of Cubeb 



Cubeb,* in No. 30 powder,' five hun- 
dred grammes 500 Gm. 

Alcohol,' a sufficient quantity. 

Introduce the cubeb into a cylindri- 
cal glass percolator,* pack the powder 
firmly, and percolate slowly with al- 
cohol, added in successive portions, 
until the cubeb is exhausted." Re- 
cover the greater part of the alcohol 
from the percolate by distillation on 
a water-bath," and, having transferred 
the residue to a dish, allow the re- 



maining alcohol to evaporate, with 
constant stirring, in a warm place.^ 
Keep the oleoresin in a well-stoppered 
bottle." 

NOTE. Oleoresin of cubeb de- 
posits, after standing for some time, 
a waxy and crystalline matter, which 
should be rejected, the liquid portion 
only being used.* 

Average dose. — 0.500 Gm. = 500 
milligrammes (7^ grains.) 



OLEORBSIN OF CUBES 1^7 

1910 

Oleoresina Cubebae 
Oleoresin of Cubeb 
Oleores. Cubeb 

Cubeb/ in No. 30 powder,^ iive hun- alcohol to evaporate, in a warm place, 

dred grammes 500 Gm. stirring frequently/ Keep the oleo- 

Alcohol,^ a sufficient quantity. resin in a well stoppered bottle.' 

Place the cubeb in a cylindrical ' NOTE — Oleoresin of Cubeb, after 

glass percolator,* pack the powder standing for some time, deposits a 

firmly, and percolate slowly with alco- waxy and crystalline precipitate, 

hoi, added in successive portions, until which should be rejected, the liquid, 

the drug is exhausted." Eecover the portion only being used.* 

greater part of the alcohol from the Preparation — Trochisci Cubebae. 

percolate by distillation on a water- Average Dose — Metric, 0.5 Gm. — 

bath,* and,, having transferred the Apothecaries, 8 grains, 
residue to a dish, allow the remaining 

1) For a description of the drug, see page 1040 under ''Drug 
used, its collection, preservation, etc." 

2) The last three editions of the Pharmacopoeia have specified 
that the drug used be reduced to a No. 30 powder for perco- 
lation. Previous editions, with the exception of that of 1850, 
directed that a fine powder (No. 60) be used for this purpose. 
In the Pharmacopoeia of 1850, the degree of fineness was not 
specified. The coarser powder corresponds more nearly in its 
composition to that of the whole fruit than does the fine pow- 
der, owing to the fact that a relatively large amount of vola- 
tile oil is lost in the preparation of the latter. 

3) Previous to the edition of 1900, the Pharmacopoeia speci- 
fied the use of ether for extracting the drug, whereas, the last 
two editions have directed that alcohol be employed for this 
purpose. The fact, that the latter yields a product differing 
but slightly in its physical properties from the oleoresin ob- 
tained with ether, was pointed out by Procter in 1866, and 
later confirmed by other investigators. Since the alcoholic 
preparation appears to be equally as efficient from a therapeu- 
tic standpoint, as well, the change from ether to alcohol ap- 
pears to be justified. The use of a menstruum consisting of 
equal parts of alcohol and ether, as specified in some of the 
foreign pharmacopoeias, the Austrian, German and Japanese, 



238 DU MEZ— THE GALENICAL. OLEORESINS 

does not appear to offer any special advantage either from a 
pharmaceutic or therapeutic standpoint. 

4) In the Pharmacopoeias of 1870, 1880 and 1890,t he drug 
was directed to be extracted in a percolator specially adapted 
to the use of volatile solvents. See Part I under "Apparatus 
used." With the change in menstruum (ether to alcohol), a 
special form of percolator was no longer necessary, and the 
Pharmacopoeia now directs that an ordinary cylindrical, glass 
percolator be used. 

5) In the earlier editions of the Pharmacopoeia (1850 to 1880 
inclusive), it was directed that percolation be discontinued short 
of the complete exhaustion of the drug, the object evidently 
having been to economize in the use of the relatively expen- 
sive solvent, ether. With the reduction in the price of the 
latter, however, the economic factor diminished in importance 
and as a result the Pharmacopoeia of 1890 directed that perco- 
lation be allowed to proceed until the drug was exhausted. 
This is also the procedure given in the more recent editions of 
.the Pharmacopoeia, in which alcohol has replaced ether as the 
extracting menstruum. 

In this connection, it is desired to point out that, whereas 
percolation, when ether is the menstruum used, should be con- 
tinued to complete exhaustion of the drug in order that the 
extraction of the total amount of therapeutically active con- 
stituents may be assured, this procedure does not appear to be 
necessary when alcohol is the solvent employed. While this 
statement is not in conformity with the present pharma- 
copoeial directions governing the extraction of the drug and is 
not supported by direct experimental evidence, it is thought 
to be justified in view of the (ftfference in the solubility of the 
therapeutically active resins in the above mentioned men- 
strua. The indifferent resin is but slightly soluble in ether. 
It will, therefore, be extracted but slowly by this solvent and 
will be present in the percolate even to the last portions. Al- 
cohol, on the other hand, dissolves both, the acid and indiffer- 
ent resins readily. These substances should therefore be con- 
tained in tota in the first portions of the percolate. In this 
case, it would therefore appear that the continuation of the 
process of extraction to the complete exhaustion of the drug 



OLEORBSIN OF CUBEB 139 

only serves to load the percolate with undesirable extractive 
matter such as cubebin. 

6-7) The various editions of the Pharmacopoeia, since 1870, 
have directed that the greater part of the solvent be removed 
from the percolate by distillation on a water bath, and that 
the remainder be allowed to evaporate spontaneously. 

Experience in the laboratory has shown that it is impos- 
sible to obtain a uniform product, when operating according 
to the above directions, unless identical conditions are main- 
tained in each case. This is due to the fact that a compara- 
tively slight variation in the procedure, with respect to the 
quantity of the solvent removed by distillation or to the tem- 
perature at w^hich spontaneous evaporation is allowed to pro- 
ceed produces a variation in the volatile oil content of the finished 
product, which in turn affects its physical and chemical proper- 
ties. It is thought, therefore, that the amount of solvent to be 
removed by distillation, as well as the temperature at which 
the last portions are to be removed, should be definitely stated 
by the Pharmacopoeia in order that a more uniform product 
may be obtained. 

8) For a statement concerning the nature of the precipitate 
which forms in the oleoresin upon standing, see page 1060 un- 
der '* Other properties." 

Since the greater part of the precipitate is composed of ma- 
terial which is of no therapeutic value, it should be removed 
before dispensing the preparation as directed by the Pharma- 
copoeia. 

9) The oleoresin should be kept in well stoppered bottles ow- 
ing to the fact that it loses volatile oil and undergoes other 
changes on exposure to the air. See cubeb camphor, page 
1050. 



Yield 

The amount of oleoresin obtained varies to a considerable 
extent, 10 to 30 per cent, having been obtained when alcohol, 
acetone or ether were employed as menstrua for the extraction 
of the drug. When petroleum ether is the solvent made use of, 
the yield is much lower, 4 to 18 per cent, having been reported 
in this case. Aside from the effect of the solvent, the principal 



2^40 I^U MEZ— THE GALENICAL OLEORESINS 

factors influencing the yield appear to be the variation in the- 
volatile oil content of the drug from which the oleoresin is pre- 
pared and the conditions under which the preparation of the 
latter has been accomplished. As the volatile oil content of 
the cubeb fruit is stated to vary from 10 to 18 per cent., a var- 
iation of even greater magnitude is to be expected in the amount 
of oleoresin obtained. While this is true when a vacuum pan is 
employed in the evaporation of the solvent, the difference is 
not so great when the pharmacopoeial directions are followed 
as the loss in volatile oil in this case is relatively greater when 
the fruits contain a large amount of this constituent than when 
only a small amount is present. The difference is still further 
decreased when the solvent is evaporated on a water bath under 
ordinary atmospheric pressures. The following tables show 
the yield of oleoresin obtained with the use of various solvents r 



OLEORBSIN OF CTJBEB 



141 



Table 47 — Yield of oleoresin as reported in the literature. 





Observer 


Yield of oleoresin to— 




Date 


Alco- 
hol 


Ace- 
tone 


Ethei 


Other 
solvents 


Remarks 


1846 


Bell .. . 


Per 
cent 


Per 
cent 


Per 

cent 

15.0 to 

20.0 

21.90 


Per cent. 




1868 


Procter 


27.00 




Benzin 

16.50 

Benzin 

5.00 




1867 


Pile 


Yield to ben/in, .sp. gr. 86" 
Baum6. 


1868 


TTfivdpnrplpVi 






23.75 


1877 


Griffin 






Gasolin 
16,50 

Benzin 
16.65 




1887 


Kremel 


30.00 





22.00 
21.26 




1888 


Trimble 




1892 


Rprincpr 




21.75 
24.10 
25.00 






Sherrard, 









3 The cubebs were completely 








exhausted. 


1892 


16.40 
18.80 
21.06 
21.90 
23.00 
24.70 
24.80 
24.80 

22.45 








Hyers 


























































/ 












1895 


14.48 


18.48 


i Petrol. 
\ Ether. 
\ 13.47 
j Solvent(?) 
(18.85 to 26.88 

22.08 

22.60 

21.13 

22.80 
j Solvent(?'> 
1 13. 69 to 23.60 

3 Solvent (?) 
(16.49 to 24.34 
f Petrol 
Ether 
3.88 
4.30 
j 4.45 
1 14.00 
16.03 
16.. 54 
16.90 
I 18.08 
3 Sol vent (?) 
1l8.42to 24.40 

3 Solvent (?) 
( 22.14 
Petrol 
< Ether 
4.66 to 8.78 




1907 


Blome 


Reported as yield of oleoresin 


1907 


Evans Sons, 
Lescher & Webb 

Vanderkleed .... 








Results obtained in the ex- 
traction of 5 samples of 
cubeb. 






■ 


























1908 








Reported as yield of oleoresin. 


1909 










Results obtained in the ex- 
traction of 4 samples of 
cubebs. 

Reported as j'ield of oleoresin. 


1910 


Southall Bros., 
& Barclay 








On subsPQuent extraction with 




Vanderkleed .... 








alcohol 3.40 to 5.66 per cent. 










of extractive matter was ob- 










tained. 










































1910 








Reported as yield of oleoresin. 


1911 


Vanderkleed .... 








Results obtained in the ex- 
traction of 6 samples of 
cubebs. 

Reported as yield of oleoresin. 


1911 


Southall Bros. 
& Barclay 








The average yield of 5 samples 












of cubebs is griven as 6.95. 



142 



DU MEZ— THE GALENICAL OLEORESINS 



Table 47 — Yield of oleoresin as reported in the literature — Continued. 





Observer 


Yield of oleoresin to— 




Date 


Alco- 
hol 


Ace- 
tone 


Ether 


Other 
solvents 


Remarks 


1912 


Vanderkleed . . . . 


Per 

cent 


Per 

cent 


Per 
cent 


Per cent. 

J Solvent (?) 
117.36 to 24.49 

' Solvent (?) 
he. 00 to 22.00 
j Solvpnt(?) 
/ 21.18 

Alcohol and 
■( ether 

11.10 to 14.70 


Reported as yield of oleoresin 


1913 


Dohme & Engel- 
hardt 








Results obtained in the ex- 
traction of 5 samples of 
cubebs. 

Reported as yield of oleoresin. 


1913 


Vanderkleed . . . . 










1914 


Riedel 










1914 




8.87 to 
11.04 




7.68 to 
9.80 


Results obtained in the ex- 


1914 


Scoville 


J Solvent (?) 
(18.1010 22.00 
J Solvent(?) 
113.90 to 19.80 


traction of 6 samples of 
cubebs. Reported as an- 
hydrous extracts. 

Reported as yield of oleoresin. 


1914 


Vanderkleed .... 









Reported as yield of oleoresin. 












Results obtained in the ex- 
traction of 6 samples of 
cubebs. 



Table 48 — Yield of oleoresin as obtained in the laboratory. 





Observer 


Yield of oleoresin to— 




Date 


Alco- 
hol 


Ace- 
tone 


Ether 


Other 
solvents 


Remarks 


1910 
1916 


DuMez & Netzel. 
DuMez 


Per 
cent 
27.09 

16.34 


Per 

cent 
26.07 

16.76. 


Per 
cent 
23.47 

15.28 


Percent. 
j Benzin 
1 18.75 

( Petrol 
\ Ether 
1 13.04 


Represents the yield using a 
Soxhlet's extraction app., ex- 
cept in the case of alcohol. 

Represents the vield usingr s 






Soxhlet's extraction app.. ex- 
cept in the case of alcohol. 



OLEORBSIN OF CUBEB 143 

Chemistry of the Drug and Oleoresin, 

Tabulation of Constituents. 

We are indebted principally to Bernatzik^ Schmidt^ and 
Schulze^ for definite information concerning the constituents 
of the cubeb fruit. According to these investigators, the con- 
stituents of importance from a pharmaceutical standpoint are 
as follows: volatile oil, fatty oil, fat, cubebin, cubebic acid, 
indifferent resin, coloring matter, starch, gum and inorganic 
substances. Inasmuch as an attempt to determine the compo- 
sition of the oleoresin does not appear to have been made since 
the identification of the above enumerated constitutents, a 
definite statement concerning its exact composition can not be 
given.* However, a knowledge of the physical properties of 
the constituents of the fruit warrants the statement that the 
following are present in the oleoresin when prepared with alco- 
hol or ether : 

Volatile oil Cubebin Coloring matter 

Fatty oil Cubebic acid (Acid resin) Ash 

Fat Eesin (Indifferent resin) 

Occurrence and Description of Individual Constituents 

Volatile Oil.^ The volatile oil of cubeb is a colorless or pale 
green, thick fluid possessing a burning, spicy, but not a bitter 
taste. Its specific gravity varies (0.915 to 0.937 at 15°C) de- 
pending on the age of the oil after distillation or the length 
of time that the fruits have been stored before obtaining the 
oil. It is strongly refractive and is laevogyrate, — 39.45° to 



iBuchner's n. Repert. f. d. Pharm. (1865), 14, p. 97. 

a Arch. d. Pharm. (1870), 191, p. 23. 

»Jhid. (1873, 202, p. 388. 

The following are among the early Investigators who have reported analy- 
ses of the fruit: Trommsdorff, Trommsdorff's n. Joum. der Pharm. (1811), 
20, p. 69; Vauquelin, Journ. de Chim. Med. (1820), 21, p. 103; Taschenb. f. 
Scheidekuenst. (1822), p. 185; Monheim, Buchner's Repert. d. Pharm. (1833), 
44, p. 199. 

*Vieth in an article on the relation between the chemical composition and 
therapeutic activity of various balsams states that Kubebenextrakt consists 
of terpenes (25 per cent.) resin acids (10 per cent.) and resins (25 per 
cent.) Verh. d. Ges. deutsch. Naturf. u. Aerzte (1905), 2, p. 364. 

•The above description is for the volatile oil obtained from the fruits by 
steam distillation and corresponds to the properties as observed by Schmidt, 
Arch. d. Pharm. (1870), 191, p. 18. 



244 DU MEZ— THE GALENICAL OLEORESINS 

— 40.16°. Alcohol, ether, carbon disulphide, petroleum ether, 
chloroform and fatty oils dissolve it readily. 

The investigation of the composition of this oil has been 
undertaken by a number of workers.^ Oglialoro^ noted the 
presence of a small amount of a 1-terpene (pinene or camphene). 
Wallach^ isolated dipentene and cadinene. The presence of the 
latter has been confirmed by others.^ Cubeb camphor^'' has also 
been obtained from certain samples of the oil. It is a sesqui- 
terpene hydrate (C15H24H2O) which forms when the fruits are 
stored in a damp place or when the oil is exposed to a moist 
atmosphere. It separates out in the form of rhombic octahe- 
drons when the oil is cooled at a low temperature ( - 12 to 
-14° C) for some time. 

The yield of the oil is stated by Schimmel & Co.^^ to be from 
10 to 18 per cent. A yield as low as 0.4 per cent, has been re- 
ported.^^ Schmidt obtained 14.215 per cent, from fresh cubebs 
and 13.041 per cent, from stored cubebs.^^ 

Fatty Oil. Schmidt^* describes the fatty oil as a thick, dark 
green liquid congealing at 0°C. It is stated to be slowly but 
completely soluble in cold alcohol, more soluble in hot alcohol, 
readily soluble in ether, chloroform, carbon disulphide and fatty 
oils. 

The yield as reported by the above investigator is 1.175 per 
cent, for fresh cubebs and 1.096 per cent, for fruits which have 
been stored for some time. 



"The earliest work on the constituents of the oil is that of Soubeiran and 
Capitaine, Ann. d. Chem. (1840), 34, p. 31. 
'Gaz. Chim. Ital. (1875), 5, p. 497. 
•Ann. d. Chem. (1887), 238, p. 78. 

»Schaer and Wyss, Arch, d. Pharm. (1875), 206, p. 216; Umney, Pharm. 
Journ. (1895), 25, p. 951. 

"Blanchet and Sell, Ann. d. Chem. (1833), 6, p. 294; Winckler, Buchner's 
Repert. f. d. Pharm. (1833), 45, p. 397; Bernatzik, Buchner's n. Repert. f. 
d. Pharm. (1865), 14, p. 97; Schmidt, Ber. d. deutsch. chem. Ges. (1877), 
10, p. 188. 

"Schimmel & Co., Ber. (1897), p. 14. 

"Busse reports the yield of volatile oil as obtained by various investi- 
gators as follows : 

Baumfe 5.3 per cent. 

Schoenwald 7.03 per cent. 

OberdoerfPer 12.5 per cent. 

Hager 0.4 per cent. 

Busse 15. per cent. 

Arch. d. Pharm. (1844), 89, p. 30. 

"Ibid. (1870), 191, p. 18. 

**Ihid., p. 34. ; . ', 



OLEORESIN OF CUBEB 145 

Fat. Schmidt^^ obtained 0.511 per cent, of a semi-solid fat 
from fresh cubebs, 0.408 per cent, from old cubebs. It is stated 
to be of ointment-like consistence, melting at 30 to 32° C. Hot 
alcohol, ether, carbon disulphide, chloroform, benzene and 
petroleum ether dissolve it readily. It is reported to be insoluble 
in cold alcohol. 

Cuhehin}^ Cubebin crystallizes from alcohol in white, odor- 
less needles melting at 125 to 126°C (Schmidt), ^^ 132°C 
(Mameli).^^ The alcoholic solution has a bitter taste. It is 
only slightly soluble in cold alcohol, quite soluble in hot alcohol, 
readily soluble in ether, chloroform, carbon disulphide, glacial 
acetic acid, fatty and volatile oils. The chloroformic solution 
is laevogyrate. Concentrated sulphuric acid dissolves it with a 
purple violet color, a reaction which is used as test for the 
identity of the cubeb fruit and the oleoresin prepared therefrom. 

Cubebin was thought by Heldt^^ to be an oxidation product 
of the sesquiterpene constituent of the volatile oil, 2 C15H24 -f 18 
P = C30H30O9 + 9 H2O. Later work on the determination of 
its structure, however, has shown this theory to be untenable. 
The following structural formulas have been brought forward to 
represent its composition. 





CCHiCHCK&Tf 


HC|^ 


A^.„ 


"< 


^\ 




'\X. 


F.nn«lirt|it«t«tt"" 



« Ibid. 

"Monheim, Buchner's Repert. f. d. Pharm. (1833), 44, p. 199; Cassola, 
Journ. d. Chim. Med. (1834), 10, p. 685; Soubeiran and Capitaine, Journ. 
de Pharm. et de Chim. (1839), 25, p. 355; Ann. d. Chem. (1840), 34, p. 323; 
Steer, Buchner's Repert. f. d. Pharm. (1838), 11, p. 88; Ibid. (1840), 20, p. 
119; Schuck, Buchner's n. Repert. f. d. Pharm. (1852), 1, p. 213; En&el- 
hardt, Ibid. (1854), 3, p. 1; Bernatzik, Ibid. (1865), 14, p. 97; Schmidt, 
Arch. d. Pharm. (1870), 191, p. 1; Weidel, W^ien. Akad. Ber. (1878), 74, 
p. 377. 

" I. c. 

"Chem. Ztg. (1908), 32, p. 46. 

"Arch, der Pharm. (1870), 191, p. 23. 

*>Monatsch. f. Chem. (1888), 9> p. 323. 





146 ^U MEZ— THE GALENICAL OLEORESINS 

CH 
CH HC ^ 

C-(Qa(OH)J-C 

CH 

(21) 
Fonnula of Mameli 

Cubebin occurs in the fruit to the extent of about 2.5 per 
cent.^^ 

Ciihehic Acid. (Acid Resin) Cubebic acid, C13H14O71 
(Schmidt) ,f C28H30O7H2O (Schulze),-* was first described by 
Bernatzik. It is a white, resinous mass melting at 56 °C 
(Schmidt), 45° C (Schulze) and becoming brown on exposure 
to the air. It shows only a weak acid reaction. Alcohol, ether, 
ammonia and the caustic alkalies dissolve it readily. 

There is a considerable variation in the cubebic acid content 
of the fruit as reported in the literature. Schmidt^^ obtained 
0.96 per cent, from fresh cubebs and 1.16 per cent, from the 
fruit which had been stored. Bernatzik reports the presence 
of 3.458 per cent.^^ 

Resin. The so-called indifferent resin, CisHj^Os (Schmidt)^'' 
is a yellowish-brown, pulverulent mass readily soluble in alcohol 
and the caustic alkalies, but only slightly soluble in ether, chloro- 
form and carbon disulphide. 

The indifferent resin occurs in the fruit to the extent of about 
3 per cent, on the average.^® 

Coloring Matter, Schmidt^^ isolated a brown amorphous sub- 
stance to which he attributes the brown color. This substance 
is stated to be soluble in dilute alcohol and solutions of the alka- 



ML C. 

"Monheim obtained 4.5 per cent, of a resin resembling piperine which he 
designated cuheMn. Buchner's Repert. f. d. Pharm. (1833), 44. p. 199. 

Schmidt reports the presence of 2.484 per cent, in fresh cubebs and 2.576 
per cent, in cubebs kept in storage for some time. I. c. 

MZ. c. 

"Arch. d. Pharm. (1873), 202. p. 388. 

»I. c. 

"Buchner's n. Repert. f. d. Pharm. (1865), 14, p. 97. 

«l. .c 

» Schmidt observed the presence of 2.258 per cent .of indifferent resin in 
the fresh fruits, 2.968 per cent, in stored fruits, I. c. 

Bernatzik obtained 3.515 per cent, of this resin, I. c. 

»l. c. 



OLEORESIN OF CTJBEB 147 

lies. The green color of the fatty oil as observed by the same 
investigator is stated to be due to chlorophyll. 

Asli. According to E. Schmidt, ^^ the ash of the cubeb fruit is 
composed of the basic elements, K, Ca, Mg, and Fe in combina- 
tion with the acid radicles CI', SO/', PO/", CO3" and SiOa'', 
also free SiOs- 

Cubeb fruits yield about 5.5 to 6.0 per cent, of ash.^^ 

Constituents of Therapeutic Importance. 

The value of the oleoresin of cubeb as a therapeutic agent is 
very probably due to its resin content. In addition to its 
diuretic action, the acid resin is said to render the urine feebly 
antiseptic and to act as an astringent.^ Cubebin has been shown 
to be physiologically inactive passing through the intestines 
unabsorbed.- The volatile oil is stated to act merely as a car- 
minative^ and its presence is even considered by some to be un- 
desirable* owing to its irritating action. 

Physical Properties 

Ash. According to E. Schmidt,^^ the ash of the cubeb fruit is 
directed by the United States Plmrmacopoeia has a grass-green 
color when spread out in a thin layer on a white porcelain sur- 
face. The commercial product, however, is often brownish-green 
or brown in color due to the use of the ripe fruit^ in its manu- 
facture. In such cases, the desired green color is sometimes im- 
parted to the preparation by the addition of copper salts.* 

Odor: The oleoresin has a strong aromatic odor like that of 
the crushed cubeb fruit. In fact, the odor is so strongly aro- 
matic that unevaporated solvent (alcohol), even when present 
in considerable amounts, cannot be detected by the sense of 
smell. 



so Arch. d. Pharm. (1870), 191, p. 11. 

"Schmidt obtained only 3.36 per cent of ash, I. c. 

Warnecke reports the yield of ash as 5.45 per cent. Pharm. Ztg. (1886), 
31, p. 536. 

LaWall and Bradshaw give the ash content of two samples of cubeb as 
5.70 and 6.10 per cent., respectively. Proc. A. Ph. A. (1910), 58, p. 751. 

^Vieth, Med. Klin. (1905), p. 1276. 

•HefCter, Arch. f. Exp. Path. u. Pharm. (1895), 35, p. 871. 

« Heydenreich, Am. Journ. Pharm. (1868), 40, p. 42. 

*Bematzik, Buchner's neues Repert. (1865), 14, p. 97. 
» See under "Drug used, its collection, preservation, etc." 

•B6dall (1894). 



148 



DU MEZ— THE GALENICAL OLEORESINS 



Taste: The taste is bitter and somewhat spicy, like that of 
cubeb, only more pronounced. 

Consistence: The oleoresin is, as a rule, a rather thin liquid 
when compared with the other members of this class of prepara- 
tions. Its consistence, however, varies to a considerable extent 
owing to a difference in the volatile oil content.^ Some of the 
preparations examined in the laboratory were so thick that they 
could only be poured with difficulty. 

Solubility: The official preparation forms clear or slightly 
cloudy solutions with alcohol, acetone, ether, chloroform, carbon 
disulphide, and glacial acetic acid. It is almost completely 
soluble in petroleum ether. The solubility of the European 
product, which is usually prepared with a mixture consisting 
of equal parts of alcohol and ether, is about the same. 

Specific gravity: The oleoresins prepared in the laboratory 
in 1916 showed a specific gravity of 0.99 + at 25° C regardless of 
whether the solvent employed in extracting the drug was alcohol, 
acetone or ether. The uniformity is attributed to the fact that 
particular pains were taken to evaporate the solvent under the 
same conditions in each case, thereby insuring approximately 
the same volatile oil content for each of the finished prep- 
arations. The variation in specific gravity due to a difference 
in volatile oil content is shown in the data given for the first 
four of the laboratory preparations. The commercial samples 
examined also show a variation due to this influence, except, in 
the case of the low specific gravity observed by Procter, which 
was stated to be due to the presence of unevaporated solvent 
(ether). Tables illustrating these points follow: 

Table 49 — Specific gravities of laboratory preparations. 



Sample 
No. 


Date 


Observer 


Solvent 


Specific 
gravity 


1 


1866 

1910 
1916 


Procter 


Alcohol 


At 76° F 
0.985 


2 


Ether 


0.967 


3 


«' 


Benzin 


932 


1 


DuMez & Netzel 


Alcohol 


At 25° C 
980 


2 




Acetone 


0.994 


3 


♦> 


Ether 


985 


1 


DuMez 


Alcohol 


1.049 (1) 
0.994 


2 






3 


•• 


Acetone 

Ether ... 


999 


4 


•» 


998 


5 


'• 


Petrol, ether 


963 











*A thick preparation containing only 4.71 per cent, of volatile matter. 



See under "Chemistry of the drug and the oleoresin". 



OLEORBSIN OF CUBEB 



149 



Table 50SpeciJlc gravities of commercial olcoresins. 



Sample 
No. 


Date 


Observer 


Source 


Specific 
gravity 


1 . 


1866 
1916 






At 76° F. 
0.900 (»> 


1 


DuMez 


Lillv & Co 


At Z'y° C. 
0.968 


2 


Squibb & Sons 


0.969 


3 


»» 


Parke, Davis & Co 

Sharp & Dohme 

Stearns & Co 


0.971 


4 


•' 


0.975 


5 


•» ' 


1.017 











^ Contained ether. 

Refractive index: The results obtained in the laboratory in- 
dicate that the refractive index of the oleoresin should be about 
1.499 when determined at 25 °C. The solvent employed in ex- 
tracting the drug appears to have little influence on this con- 
stant, except in case petroleum ether is used, when it is slightly 
lower. The effect due to variation in volatile oil content is but 
slight as is shown in the tables which follow: 

Table 51. — Refractive indices of oleoresins 'pre'pared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Refractive 
index 


1 


1910 
1916 


DuMez & Netzel 


Alcohol 

A cetone 


At25°C 
1.495 


2 




1.499 


3 


" 


Ether 


1.499 


1 


DuMez 


Alcohol 


1 .502 (>> 


2 


Alcohol 


1 500 


3 


" 


Acetone ,... 


'.500 


4 


!!!!.!!!!!!!!!!!!!!! 


Ether 


1.499 


5 


Petrol ether 


1.495 









(*) Low in volatile oil content. 



Table 52 — Refractive indices of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Refractive 
index 


1 


1916 


DuMez 


Lilly & Co 


At 25° C 
1.498 


2 






1.499 


3 


" 


Parice. Davis «& Co 


1 499 


4 


" 


1.499 


5 


" 


Stearns & Co 


1 501 











150 



DU MEZ— THE GALENICAL. OLEORESINS 



Chemical Properties. 

Loss in weight on heating: An examination of the tables 
which follow shows that the oleoresin usually loses between 
20 and 40 per cent, on heating at 100 to 110° C, the variation 
being due to the difference in the volatile oil content. The 
relatively small loss in weight observed in the case of four of 
the laboratory preparations is to be attributed to the removal 
of a part, or the whole, of the more volatile constituents of the 
essential oil in the process of evaporating the solvent. The com- 
paratively great loss noted for two of the commercial samples is 
thought to have been due to the presence of unevaporated 
solvent. The results obtained in the determinations made in 
the laboratory as well as those reported in the literature are 
given in the tables which follow : 

Table 53. — Laboratory preparations — loss in weight on heating. 



Sample 
No. 


Date 


Observer 


Solvent 


Per cent of 
loss on drying 


1 


1887 
1916 


Kremel 


Alcohol 


At 100° C 
20.40 


1 


DuMez 


Alcohol 


At 110° C 
23.06 


■2 


Acet/Oiie 


24 10 


3 


" 


Ether 


25.88 


4 


*' ::. ..::.■;:::::: :::: 


Petrol ether 


25 . 24 


5 




11.99 


4 


Xcerone 


9-96 


7 


" 


Ether 


8.81 


8 




Alcohol 


4.71 









Table 54 — Commercial oleoresins — loss in weight on heating. 



Sample 
No. 


Date 

1893 
1.S94 
1895 
1905 

1916 


Observer 


Source 


Per cent of 
loss on 
drying' 


1 


Dieterich 




At 100° C 
32.70 


1 






31 OJ 


1 


i» 


20 90 


I 


«' 


55.91(1) 


I 


DuMez 


Sharp & Dohme 


At 110° C 
30 72 


2 






31.68 


3 




Parke. Davis & Co 


37 03 


4 




Lilly & Co 


44.21 (1) 


5 




Squibb & Sons 


61.96 (') 











* Probably contained unevaporated solvent (alcohol). 



OLEORESIN OF CUBES 



151 



Ash content: The ash content of the oleoresin varies with 
the solvent employed in its preparation as is shown in the first 
of the tables which follow. The highest values were obtained 
for the official product, in the preparation of which alcohol 
was the solvent used. The camparatively low ash content ob- 
tained for the commercial samples examined, while suggesting 
the use of some other solvent in the manufacture of these 
preparations, is thought to have been due to the greater amount 
of volatile matter (essential oil) present. Although copper 
was detected in the ash of all of the commercial products, the 
quantities present were too small to effect the value of this 
constant to any considerable extent. The following tables 
give the ash content of the oleoresin as reported in the litera- 
ture and as determined in the laboratory: 

Tablb 55. — Ash contents of oleorexins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Per cent of 
ash 


1 


1916 


DuMez 


Alcohol 

Acet»jne 

Ether 


45 






0.20 




" 


0.13 




•' 




0.07 




•• 


Alcohol 


48 


^ 


'• 


22 




" 


Fther 


15 


8 


'• 


Alcohol 


51 









Table 5G — Ash contents of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Percent, 
of ash 


Forelgrn crm- 
stituents 




1893 
1894 
1895 
1897 
1905 
1916 


Dieterich . . . 
Du Mez ....... 




50 

0.52 

0.47 

0.10 

0.87 

21 (') 

0.40 

35 

0.''9 (1) 

0:37 












•' 






•» 




1 


•' 






Squibb & Sons 


Copper 


2 


Sharpe & Dohme 






" 




Lilly & Co 


'• 




Stearns&Co 


>> 







* Unevaporated solvent (alcohol) probably present. 



Acid number: The acid numbers of the oleoresins prepared 
in the laboratory varied from 21.8 to 26.7, depending on the 
nature of the solvent employed in their preparation. The num- 



152 



DU MEZ— THE GALENICAL OLEORESINS 



/ 



ber, 26.7, obtained in the case of the preparation made with 
alcohol agrees very well with that (26.2) obtained by Kremel 
for the oleoresin when prepared in a like manner. The low acid 
numbers obtained for the commercial samples are explained 
by the presence of relatively large amounts of volatile matter 
(generally essential oil, but unevaporated solvent in two cases) 
in these preparations, which has the effect of reducing the con- 
centration of the free acids. The values obtained for this 
constant follow: 

Table 57. — Acid numbers of laboratory preparations. 



Sample 
No. 


Date 


Observer 


Solvent 


Acid number 


1 


1887 
1916 


Kremel 




26.2 


2 




Ether 


31.2 


1 


DuMez . 


Alcohol 


26 7 


2 






22.8 


3 


" 


Ether 


22 2 


4 






21.8 











Table 58 Acid numbers of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Acid number 


1. 


1916 


DuMez 


Lilly «& Co 


12.8(1) 


2 




SQuibb & Sons 


13.4(1) 


3.!..!.... 


" 


Stearns & Co 


14.4 


4 


" 


Parke, Davis &Co 

Sharp & Dohme 

— 


15.4 


5 


" 


18.7 







(>) Probably contained unevaporated solvent (alcohol), 



Saponification value: The saponification values obtained for 
the oleoresins prepared in the laboratory showed a slight 
variation due to the nature of the solvent used in extracting 
the drug as is shown in the first of the tables which follow. As 
a rule, however, the difference in the volatile oil content of the 
oleoresin, due to a variation in the conditions under which it 
has been prepared, is thought to be the principal factor in- 
fluencing the value of this constant, as is also brought out in the 
first table. In the examination of commercial samples, the 
presence of unevaporated solvent must be taken into considera- 



OLEOKBSIN OF CTJBEB 



153 



tion in this connection. The results obtained in the determina- 
tion of this constant in the laboratory follow: 

Table 59 — Saponification values of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Saponifica- 
tion value 


1 


1916 
1' 


DuMez 


Alcohol 

Acetone 


65.9 


2 




63.7 


3 


4« 


Ether 


63.4 


4 




Petrol, ether 


67.0 




" 


Alcohol 


63.9 


2 




57.9 


3 


t» 


Ether 


59.5 


1 






105.9 (0 











1 This preparation contained a relatively email amount of volatile matter (principally 
essential oil). See page 1056 under "Loss in Weight on Drying". 



Table 60. — Saponification values of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Saponifica- 
tion value 


1 


1916 


DuMez 


Lillv& Co 


48.5 (0 


2 




Parice. Davis & Co 

SQuibb & Sons 


53.3 


3. . 


" 


49.3 {}) 


4 


i> • •• 




55.0 


5 


•» 


Stearns & Co 


65.9 











i}) Unevaporated solvent (alcohol) probably present. 



Iodine value: Further observations are necessary before a 
definite statement can be made as to what the iodine value of 
this preparation should be. Determinations made in the labora- 
tory appear to indicate that it is influenced largely by the 
volatile oil content as those preparations which lost the greatest 
amount on drying usually gave the highest values for this con- 
stant. Apparent exceptions to this rule are to be found in 
the samples obtained from Lilly & Company and Squibb & 
Sons, respectively. In these cases, unevaporated solvent 
(alcohol) is thought to have been present, although, it could 
not be detected by the odor. The following tables show the 
values obtained for the preparations examined in the laboratory. 



154 



DU MEZ— THE GALENICAL OLEORESINS 



Table 61 — Iodine values of oleoresins prepared in tlie laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Iodine 
value 




1916 


DuMez 


Alcohol 


126 








131.6 






Ether 


138.5 






Petrol, ether 

Alcohol 


141.8 






130.0 








113.2 






Ether 


115.6 


J 


Alcohol 


92.0 











Table 62 — Iodine values of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Iodine value 


J 


1916 


DuMez 


Squibb & Sons 


130.61 


2 


Lilly & Co 


136.71 


3 


•» 


Parke, Davis & Co 

Sharp & Dohme 


146.9 


4 


" 


147.3 


5 


»• 


Stearns & Co 


147.6 











^ Unevaporated solvent probably present. 

Ofher Properties. 

The oleoresin, upon long standing, forms a white deposit 
consisting of cubebin, indifferent resin, cubebic acid and thick- 
ened oil. As the greater part (80 per cent.)^ of this precipitated 
material consists of the therapeutically inert ciibebin,^ the 
United States PJiarniacopceia directs that it be removed before 
dispensing the preparation. 



Special Qualitative Tests. 

The methods which have been devised for the indentification 
of this oleoresin or as a test for its quality are based on the 
fact that characteristic color changes are produced when it is 
acted upon by certain acids. Sulphuric, sulphomolybdic^ and 



1 Schmidt (1870). 

^ See under "Constituents of therapeutic importance", 

' Dieterich, in 1897, pointed out that sulphomolybdic acid might be used 
in place of sulphuric acid. The resulting color, however, was stated to be 
a cherry-red instead of a blood-red. 



OLEORBSIN OF CUBEB 155* 

hydrochloric^ acids have been made use of in this connection, 
the first mentioned being the reagent most generally employed. 
Attention was first called to the value of sulphuric acid in 
the identification of this preparation by Kremel in 1887. He,. 
however, reported nothing definite, merely stating that a car- 
mine-red color was produced when the ''strong'* acid and 
oleoresin were mixed. It was not until ten years later (1897), 
when the firm of Dieterich in Helfenberg published their method- 
of procedure, that this test assumed a definite form. The test 
as carried out by this firm is typical of those in use at the 
present time and is as follows: 

Upon mixing 0.01 gram of the oleoresin with 3 to 5 drops of concen- 
trated sulphuric acid, the mixture should assume an intense blood-red color." 

The fact that certain constituents of the cubeb fruit, namely,, 
cubebin, the acid resin (cubebic acid) and the indifferent resin, 
formed red colored mixtures with sulphuric acid was noted by 
Schmidt in 1870. These observations have been confirmed in 
this laboratory in so far as they pertain to the production of a 
red color. It was further noted, however, that the shade of 
red varies with the particular constituent under consideration, 
the cubebin giving rise to a mixture which is brownish-red in 
•color, whereas, the color is bright red (carmine-red) in the case 
of the acid or indifferent resin. As all of the above mentioned 
constituents are normally present in the oleoresin, the particular 
shade of red (blood-red) obtained in this test must be due to- 
the blending of the colors produced by the action of the acid' 
on the several constituents, and cannot be caused by the action 
of the acid on the cubebin, alone, as is usually reported in the 
literature. 

As the shade of red obtained will naturally vary with the 
relative quantities of the several constituents present, this test 
not only serves as a means of identification, but is also of value 
in determining roughly the quality of the preparation as well.* 
Thus, a bright red color obtained by the action of the acid may 



1 Test of Gluecksmann. See the following pages. 

2 The so-called false cubebs give a dirty brown color when triturated with 
concentrated sulphuric acid, hence, we may expect the oleoresin prepared 
therefrom to form a mixture of a similar color. See Pharm Ztg. (1912)^ 
84, p. 845. 

* B^dall (1894) observed that the oleoresins possessing a green color gave 
a more intense red with sulphuric aeid that those which were brown in color. 



156 DU MEZ— THE GALENICAL. OLEORESINS 

be taken as an indication of the presence of relatively large 
amounts of the therapeutically active resins, while a dark shade 
of red implies that the cubebin content is exceptionally large 
or that the resins are present in comparatively small amounts. 

The test of Gluecksmann (1912) in which hydrochloric acid 
is the reagent made use of, appears to be based on the presence 
of cubebin.^ It is carried out as follows: 

Dissolve a small quantity (a trace) of the oleoresin in concentrated 
acetic acid and dilute with the latter until the solution shows scarcely any 
color. Heat to boiling and add 5 drops of a 35 per cent, solution of 
hydrochloric acid to a 5 cubic centimeter portion. A faint yellowish-brown 
color should appear immediately. Upon standing quietly, the color should 
change in 2 to 4 hours to a brownish-violet, and then to a violet blue, 
after which it should gradually disappear. 

While the foregoing may prove to be a test of considerable 
worth in the identification of the oleoresin, the length of time 
required for its completion would appear to be a drawback to 
its general application. 

The tests of this nature prescribed by the various phar- 
macopoeias all involve the use of sulphuric acid. As will be- 
come apparent in the following description of these methods, 
the color specified differs to a considerable extent. This may 
"be due, as already pointed out, to a variation in the relative 
quantities of the reacting constituents, or, as has been further 
observed in the laboratory, to the strength of the acid employed. 
A very slight dilution with water will cause the color to change 
from red to purple. The following are the tests prescribed 
by the different pharmacopoeias: 

Austrian Pharmacopoeia (1906) : The oleoresin should give a red color 
on being triturated with concentrated sulphuric acid. 

French Pharmacopoeia (1908) : The oleoresin should give a purple-red 
-color with concentrated sulphuric acid. 

Swiss Pharmacopoeia (1907) : If 0.01 to 0.02 grams of the oleoresin 
are mixed with a few drops of concentrated sulphuric acid, an intense 
brownish-red color should be produced. Upon diluting with a little water, 
The color should change to a rose and upon further dilution, it should 
disappear. 

Hungarian Pharmacopoeia (1909) : A drop of concentrated sulphuric 



* This assumption is made in view of the fact that the closely related 
•compounds, coniferyl alcohol and syringenin, give similar color reactions 
'With hydrochloric acid. See Euler, Die Pflanzenchemie (1908), Vol. I, p. 87. 



OLEORESIN OF CUBES 157 

acid added to a drop of the oleoresin spread out in a thin layer on a white 
porcelain surface should produce a blood -red mixture. 

German Pharmacopoeia (1910) : If 1 cubic centimeter of a mixture of 
4 parts of concentrated sulphuric acid and 1 part of water is poured over 
1 drop of the oleoresin, a red color should be produced. Upon diluting 
the mixture with water the color should disappear. 

Special Quantitative Tests. 

Apparently but one attempt has been made to develope a 
method for the quantitative determination of the constituents 
of therapeutic importance in this preparation, the same having" 
been made by Kremel in 1887. As no work of this nature was 
done on the oleoresin in the laboratory, and, as there is no 
further information on this subject in the literature, a state- 
ment cannot be made as to the value of this method. However,, 
as a suggestion of what might be accomplished in this direction, 
a description of the method is included here. It is as follows : 

KremeVs Method for the Estimation of Cuhehic Acid (1887) : Dissolve 
3 to 5 grams of the oleoresin in 4 times the quantity of alcohol (90 per 
cent.), filter the solution and add alternately to the filtrate an alcoholic 
solution of calcium chloride and ammonia water until a distinct cloudi- 
ness appears. Set the liquid aside for a day or two to allow the cal- 
cium salt of cubebic acid to crystallize. Then, collect the precipitate 
on a filter, wash successively with alcohol (90 per cent.) and ether, dry 
at lOO'C and weigh. Compute the weight of the cubebic acid using the 
formula, C H O Ca, for the calcium salt. 

According to the results obtained by Kremel, the oleoresin 
prepared with ether shsowed a cubebic acid content of 2.35 per 
cent., while the same when prepared with alcohol gave 5.75 per 
cent, of cubebic acid. 

Adulterations, 

Willful adulteration of this preparation does not appear to 
be practiced very extensively, although, the occassional use of 
fixed oils^ or salts of copper^ for this purpose has been reported 



' Schneider and Suess, Handkommentar zum Arzneibuch fuer das deutsche 
Reich (1902), p. 376. 

»B6dall (1894). 

A trace of copper is usually present in the commercial preparations as a 
result of the use of copper utensils in their manufacture. (See under 
"Ash".) 



^58 ^U MEZ— THE GALENICAL. OLEORESINS 

in the literature. On the other hand, accidental adulteration 
■effected through the use of ripe instead of unripe fruits in the 
preparation of the oleoresin is thought to be quite general. 
«(See under ''Drug used, its collection, preservation, etc.") 

OLEORESIN OF GINGER 
Synonyms 

Aetherisches Ingwerextrdkt, Nat. Stand. Disp. 1884. 

Ethereal Extract of Ginger, King's Am. Disp., (1900), p. 1336. 

Extractum Zingiheris aetJiereum, Hirsh, Univ. P. 1902, No. 1320. 

Extractum Zingiberis aethereum, King's Am. Disp. (1900), P. 1336. 

Gingerin, Chem. and Drugg. (1913), 82, p. 470. 

Gingerine, Am. Journ. Pharm. (1898), 70 p. 466. 

Oleoresina Zingiberis, U. S. P. 1910. 

jQl^oresine de Gingemhre, U. S. Disp. 1907. 

Piperoide du Gingerribre, B§ral, 1834. 

.Piperoid of Ginger, U. S. Disp. 1865. 

Zingiberin, U. S. Disp. 1907. 

History 

The oleoresin of ginger was prepared in 1834 by Beral, a 
^Frenchman, but was apparently first brought to the notice of 
American pharmacists by Proctor in 1849. It was intro- 
duced into the United States PJiarmacopma in 1860 and is still 
official at the present time. While the oleoresin has never 
been officially recognized abroad, a similar preparation is said 
ito be used extensively in England under the name of gingerin.^ 

Drug Used, Its Collection, Preservation, Etc. 

For this drug, the present pharmacopoeial definition is as 
follows: "The dried rhizomes oi Zingiber officinale Jioscoe 
(Fam. Zingiber aceae,) the outer cortical layers of which are 
often either partially or completely removed. Preserve it in 
tightly-closed containers, adding a few drops of chloroform or 
carbon tetrachloride, from time to time, to prevent attacks by 
insects.'^ The official drug has also been described in the 
literature under the following botanical synonyms: Amomum 
Zingiber Linne, and Zingiber Zingiber (Linne) Rusby. 



* Gingerin is stated to be the extract obtained upon evaporating off the 
•alcohol from the tincture of. ginger. Chem. & Drugg, (1913), 82, p. 470. 



OLEORESIN OF GINGER 159 

The rhizomes as they are found on the market occur in a 
variety of forms characteristic of the source from which they 
are obtained. In view of this fact, the Pharmacopoeia recog- 
nizes six different commercial varieties, namely : Jamaica ginger, 
African ginger, Calcutta ginger, Calicut ginger, Cochin 
ginger and Japanese ginger. These commercial forms differ 
to a considerable extent, not only through natural causes, but 
also through a difference in the conditions under which they are 
harvested and prepared for the market. 

As a rule the rhizomes are dug after the stems have withered, 
January or February, when one or more years old. Experience 
has shown the oleoresin content to be the greatest at this period 
of the year.^ They are then washed in boiling water to pre- 
vent germination, dried rapidly in the sun, and as such con- 
stitute, what is known as black, coated, or unscraped ginger. 
In other cases, after treatment with boiling water, a part or 
the whole of the epidermis is removed, the rhizomes dried, and 
bleached with sulphur fumes, chlorinated lime, milk of lime or 
gypsum. This constitutes the so-called, white, uncoated, 
scraped, race or hard ginger. ^ 

In commenting on the relative values of these various forms 
of ginger in the preparation of the oleoresin, it should be stated, 
first of all, that the yield of oleoresin is influenced to the largest 
extent by habitat, African ginger giving the maximum yield.® 
Secondly, the extent to which the rhizomes have been decorticated 
is an important factor, as the outer corky layer contains none 
of the oleoresinous material. These factors will be more fully 
discussed under yield. To what degree, if at all, the process 
of so-called bleaching effects the yield or quality of oleoresin 
does not become apparent from the literature. It is thought, 
however, that a heavy coating of gypsum, for instance, would 
tend to considerably reduce the percentage of oleoresin ob- 
tainable. 



* Hooper, Fharm. Joum. (1912), 89, p. 391. 

' Culbreth, Mat. Med. and Pharmacol. (1917), p. 130. 

» See reference under "Yield of oleoresin". 



160 



DU MEZ— THE GALENICAL. OL.EORESINS 



V. S. P. Text and Comments Thereon. 

The oleoresin of ginger first became official in the Pharmaco- 
poeia of 1860. It has remained official throughout all of the? 
subsequent editions. 

1860 

Oleoresina Zingiberis 

Oleoresin of Ginger 

Take of ginger/ in fine powder,* alcohol until twelve fluidounces ^ of 
twelve troyounces; filtered liquid have passed. Eecover 
Stronger Ether ^ twelve fluidounces; from this, by distillation on a water- 
Alcohol* a sufficient quantity. bath, nine fluidounces of ether,' and 
Put the ginger into a cylindrical expose the residue, in a capsule, until 
percolator," press it firmly, and pour the volatile part has evaporated.* 
upon it the stronger ether." When this Lastly keep the oleoresin in a well- 
has been absorbed by the powder, add stopped bottle." 



1870 



Oleoresina 

Oleoresin 

Take of ginger,* in fine powder,* 

twelve troyounces; 
Stronger Ether' twelve fluidounces; 
Alcohol* a sufficient quantity. 

Put the ginger into a cylindrical 
percolator, provided with a stop-cock, 
and arranged with a cover and recep- 
tacle suitable for volatile liquids,' press 
it firmly, and pour upon it the 



Zingiberis 
of Gringer 

stronger ether.* When this has been, 
absorbed by the powder, add alcohol 
until twelve fluidounces of liquid have 
slowly passed.' Eecover from thia the 
greater part of the ether by distilla- 
tion on a water-bath,' and expose the 
residue, in a capsule, until the volatile 
part has evaporated.* Lastly, keep 
the oleoresin in a well-stopped bottle.*" 



1880 



Oleoresina 

Oleoresin 

Ginger,* in No. 60 powder,* one hun- 
dred (100) parts 100 

Stronger Ether,' a sufficient quantity. 
Put the ginger into a cylindrical 
percolator, provided with a cover and 
receptacle suitable for volatile liquids," 
press it firmly, and gradually pour 
stronger ether upon it, until one hun- 
dred and fifty (150) parts of the 



Zingiberis 
of Ginger 

liquid have slowly passed, or until the 
Ginger is exhausted.' Eecover the 
greater part of the ether by distilla- 
tion on a water-bath,' and expose the 
residue, in a capsule, until the remain- 
ing ether has evaporated.' 

Keep the oleoresin in a well-stopped 
bottle." 



OLEORBSIN OF GINGER 
1890 

Oleoresina Zingiberis 
Oleoresin of Ginger 

Ginger/ in No. 60 powder,^ five hun- portions, until the drug is exhausted.* 

dred grammes 500 Gm. Eeeover the greater part of the ether 

Ether,^ a sufficient quantity. from the percolate by distillation on 
Put the ginger into a cylindrical a water-bath,» and, having transferred 
glass percolator, provided with a stop- the residue to a capsule, allow the re- 
cock, and arranged with cover and maining ether to evaporate spontaa- 
receptacle suitable for volatile liquids." eously." 

Press the drug firmly, and percolate Keep the oleoresin in a well-stop- 

slowly with ether, added in successive pered bottle.^" 

1900 >; 

Oleoresina Zingiberis ' 

Oleoresin of Ginger 

Ginger,* in No. 60 powder,' five hun- is exhausted.^ Eeeover the greater 

dred grammes 500 Gm. part of the acetone from the percolate 

Acetone,^ a sufficient quantity. by distillation on a water-bath,« and, 

Introduce the ginger into a cylindri- having transferred the residue to a 
cal glass percolator, provided with a dish, allow the remaining acetone to* 
stop-cock, and arranged with a cover evaporate spontaneously in a warmi 
and a receptacle suitable for volatile place.* Keep the oleoresin in a well- 
liquids." Pack the powder firmly, and stoppered bottle." 
percolate slowly with acetone, added Average dose. — 0.030 Gm. = 3(r 
in successive portions, until the ginger milligrammes (% grain.) 

1910 

Oleoresina Zingiberis 

Oleoresin of Ginger 

Oleores. Zingib. 

Ginger,* in No. 60 powder,'' five hun- hausted.' Eeeover the greater part 

dred grammes 500 Gm. of the ether from the percolate bj 

Ether,' a sufficient quantity. distillation, on a water-bath,* and, 
Place the ginger in a cylindrical having transferred the residue to a 
glass percolator, provided with a stop- dish, allow the remaining ether to 
cock and arranged with cover and a evaporate spontaneously in a warm 
receptacle suitable for volatile liquids." place.* Keep the oleoresin in a well- 
Pack the powder firmly, and perco- stopped bottle.** 

late slowly with, ether, added in sue- Average dose. — Metric, 0.03 Gm.^ 

eessive portions, until the drug is ex- Apothecaries, % grain. 



162 ^^ MEZ— THE GALENICAL. OL.EORESINS 

1) For a description of the different commercial varieties of 
the official drug, see page 1065 under ''Drug used, its collection, 
preservation, etc." 

2) As starch, in the shape of fine granules, constitutes about 
20 per cent, of the ginger rhizome, the latter can only be ob- 
tained in the form of a uniformly fine powder by reducing 
the other tissues to a corresponding degree of fineness. It is for 
this reason and for' the purpose of insuring the complete 
breaking up of all of the small resin cells that the Pharma- 
•copoeia directs that the drug be reduced to a No. 60 powder. 

3-4) Ether is the solvent which appears to be best adapted to 
the preparation of this oleoresin in that it completely extracts 
the pungent principles from the drug and yields a product 
containing a minimum amount of undesirable extractive mat- 
ter. According to Garnett and Grier (1909) acetone, which 
"was directed to be used by the Pharmacopoeia of 1900, does 
not completely exhaust ginger, even when a Soxlet's appara- 
tus is used. It is, therefore, fortunate that the present Phar- 
macopoeia again specifies that ether be used for this purpose. 

In the earlier editions of the Pharmacopoeia (editions of 
1860 and 1870), alcohol was directed to be used as a "follow 
lip" solvent to replace the ether with which percolation was 
begun. This procedure was abandoned in 1880 for reasons 
which will be discussed later. 

5) Since 1870, the Pharmacopoeia has directed that percola- 
tion be carried out in a special form of percolater adapted to 
the use of volatile liquids. For a description of such forms, 
see Part I under ''Apparatus used." 

6-7) The method of extracting the drug as outlined in the 
earlier editions of the Pharmacopoeia, the editions of 1860 and 
1870, was essentially the same as suggested by Beral in 1834. 
See Part I, page 929. From' a practical standpoint, this method 
possessed distinct advantages, especially at the time when it 
was adopted, in that a considerable saving in the cost of the 
preparation of the oleoresin was effected through the use of 
alcohol as a "follow up" solvent for replacing the relatively 
expensive ether. The method, however, was not entirely sat- 
isfactory as the finished product contained a considerable 
amount of undesirable extractive matter owing to the greater 
•solvent properties of the alcohol. Another disadvantage lay 



OLEORESIN OF GINGER 153 

in the fact that a relatively large amount of volatile oil was 
lost in the removal of the solvent. 

The present edition of the Pharmacopoeia directs that the 
drug be completely exhausted by simple percolation with 
ether. Here, as in the case of the oleoresin of capsicum, the 
extraction of the drug with the aid of some form of continu- 
ous extraction apparatus would effect a considerable saving 
in solvent and without injury to the finished product. 

8-9) With respect to the removal of the solvent from the per- 
colate, the present edition of the Pharmacopoeia directs that 
this be accomplished in greater part by distillation on a water 
bath and that the remainder be allowed to evaporate spon- 
taneously in a warm place, a procedure similar to that de- 
scribed in the earlier editions. For reasons, identical with 
those given in the comments on the oleoresin of cubeb (see 
page 1045), it is thought that the pharmacopoeial directions 
should include specific statements with reference to the 
amount of solvent to be recovered by distillation and the tem- 
perature at which the remainder is to be removed in order to 
insure greater uniformity in the product obtained. 

10) Upon exposure to the air, a portion of the volatile oil con- 
tained in the oleoresin is altered (resinified) or lost through 
evaporation. The preparation should, therefore, be kept in 
well-stoppered bottles. 



Yield 

With respect to the solvents, alcohol (95 per cent.), acetone 
and ether, the yield of oleoresin, in the case of ginger, varies in 
magnitude in the order in which the solvents are mentioned. 
For these menstrua, a minimum yield of 2.57 per cent has been 
reported while the maximum yield has been stated to be as high 
as 11.1 per cent. . When petroleum ether is the solvent used, 
the yield is much lower, being only about one-half that obtained 
in the preceding cases. In this connection, the source of the 
rhizomes is a factor of first importance. Thus, it has been 
found that Jamaica ginger usually gives the smallest yield and 
African ginger the highest, while Cochin ginger occupies an 
intermediate position in this respect. These facts will be 
brought out more clearly in the tables which follow. 



-^Q^ DU MEZ— THE GALENICAL. OLEORESINS 

The yield of oleoresin is further influenced by the degree to 
which the rhizomes have been deprived of the outer corky layer, 
and, in the case of bleaching, to the manner in which the latter 
was accomplished. "With respect to this statement, the yield, 
in the case of the unbleached ginger, will be the greatest when 
decortication is complete. When the rhizomes have been 
bleached, in addition to being partially or wholly decorticated, 
the influence of the latter, may be diminished, in part at least, 
by the process employed in accomplishing the f onner. Thus, if 
gypsum or lime have been used for this purpose, the weight of 
the insoluble material in the rhizomes will be considerably in- 
creased, which will have the effect of reducing the percentage 
yield of oleoresin. These points are also brought out in the 
tables which follow. 



OLEORESIN OF GINGER 



165 



Table 63. — Yield of oleoreain as reported in the literature. 



Date 
1834 


Observer 


Yield of oleoresin to— 




Alco- 
hol 


Ace- 
tone 


Ether 


Other 
solvents 


Remarks 


B6ral 


Per ct. 


Per ct. 


Per ct. 

5.20 
3.29 
4.96 
8.06 
3.58 


Per cent. 




1879 










.Tamaica ginger. 
Cochin *' 




.Tones 


















1886 


3.38 
fAlco- 
1 hoi 
|( sp. 
1 gr. 
1 0.82) 
\ 5.00 
1 4.80 
1 
6.65 
6 57 
6.17 
I 7.00 








1888 


Siggnis 




Jamaica ginger, unbleached. 
'* *' , bleached 




Trimble 
















(limed) 
East Indian ginger. 


















African ginger. 










18S8 




3.97 


i Benzin 
1 2.48 
3 Benzin 
1 2.50 




1891 


Rlegel 


5.00 
8.00 




Jamaica ginger, unbleached. 
East Indian ginger, epidermis 




Sherrard 




8.00 

3.85 
4.72 
5.20 
5.40 


1892 




removed. 




Beringer 






























1892 




5.57 






1893 


Dyer and Gilbard 
Davis 




3.00 to 
5.20 

4.30 to 
4.84 

5.75 to 
6.27 

5.50 
5.00 
4.33 
6.33 

2.57 to 
6.41 

2.97 to 
4.60 




Upon subsequent extraction 


1895 








with alcohol 0.80 to 1.50 per 
cent, of material was ob- 
tained. 
Jamaica ginger. 












African " 


1896 






I Methyl 
\ alcohol 
\ 6.50 




1S97 


Glass and Thresh 






.Jamaica ginger. 




r Alco- 
hol 
(90 
per 

cent.) 

3.94to 

5.61 

3.41to 
,5.67 

4.91to 

6.74 

5.4110 

6.51 

5.14to 

6.61 

5.14to 
16.47 







Cochin 






African 


IdOl 




Jamaica ginger, whole. 




Ballard 




•Jamaica ginger, ground. 







Cochin ginger, whole. 










Cochin ginger, ground. 










African ginger, whole. 










African ginger, ground. 


1903 




3.75 
6.33 

fEth'r 

(Sp. 

gr. 

-! 0.717) 
1 4.76 
1 6 04 
111.09 




Tahiti ginger. 




Southall Bros, 
& Barclay 








Ivory Coast ginger. 


1903 


r Alco- 
hol 
(90 

J per 

Icent) 
4 35 
4.57 

I 9.93 






Jamaica ginger. 






Cochin 






African 











166 I^U MEZ— THE GALENICAL OLEORESINS 

Table 63. — Yield of oleoresin as reported in the literature — Continued. 





Observer 


Yield of oleoresin to— 




Date 


Alco- 
hol 


Ace- 
tone 


Ether 


Other 
solvents 


Remarks 


1908 


Vanderkleed .... 


Per ct. 


Per ct. 


Per ct. 


Per cent 

I Solvent (?) 
\ 5.58 
/ 9.55 
j Solvent(?) 
1 3.14 to 6.91 

8.20 
9.03 


Reported as yield of oleoresin. 


1909 


Vanderkleed .... 








Represents tlie yield from 16 


1909 


Vanderkleed .... 








samples of Jamaica ginger. 
Reported as oleoresin. 




Vanderkleed .... 










1909 


Patch 


3.70 to 
6.20 








1910 


Vanderkleed .... 






r Solvent(?) 
5.63 
6.31 
10.12 

3.40 to 6.60 

j 7.12 to 9.48 

1 3.44 to 6.64 

1 6.85 to 11.10 

I 


\ Jamaica ginger. Reported as 
( yield of oleoresin. 




Vanderkleed 
















African ginger. Reported as 


1911 








yield of oleoresin. 
Jamaica ginger. Reported as 




Vanderkleed.... 








yield of oleoresin. 
African ginger, Repoi'ted as 


1912 








yield of oleoresin. 




Patch 








yield of oleoresin. 
African ginger. Reported as 


1912 


3.30 to 
6.00 
6.40 

8.30 

4.23 






yield of oleoresin. 
Jamaica ginger. 


1912 


Hooper 








Young rhizomes harvested in 




Patch 








December. 
Rhizomes harvested in Feb- 


1913 








ruary . 
Average yield of 9 samples of 


1913 


Vanderkleed 






j SolventC?) 
1 3.10 to 5.75 

S Solvent(?) 
1 6.85 to 9.92 

J SolventC?) 
1 2.81 to 5.24 


ginger. 
Reported as yield of oleoresin. 


1913 


Vanderkleed . . . . 








Results obtained in extract- 
ing 37 samples of Jamaica 
ginger. 

Results obtained in extracting 


1913 


Engelhard t 








17 samples of African ginger. 
Results obtained in extracting 


1914 


Rlppetoe 


4.98 
5.50 
6.20 
6.23 





2.79 
4 97 
5.31 
5.45 


8 samples of Jamaica ginger. 
Jamaica ginger. 




Vanderkleed . . . . 










African ginger. 








1914 


S Solvent(?) 
1 5.06 

9.00 

3.93 
7.99 
8.90 


Average yield of 3 samples of 




Vanderkleed 








Jamaica ginger. 
Average yield of 3 samples of 


1915 








African ginger. 
Yield of Jamaica ginger. 












" African ginger. 
























OLEORESIN OF GINGER 



167 



Table 6L — Yield of oleoredn as obtained in the laboratory. 



Yield of oleoresin 




Date 


Observer 


Alco- 
hol 


Ace- 
tone 


Ether 


Other 
solvents 


Remarks 


1909 


DuMez & Arnold 

DuMez & Netzel. 
DuMez 


Per ct. 
6.60 

6.33 
6.28 


Per ct. 

5.62 
5.49 


Per ct. 
5.30 

5.00 
4.92 


Per cent 


Represents yield using a Soxh- 
lei's extraction app.^ except- 


1910 
1916 


Henzin 

2.57 

Petrol, ether 
3.15 


in the case of alcohol. (^) 

Represents yield usinj? a Soxh- 
let's extraction app. . except 
in the case of alcohol. 

Represents yield using a Soxh-^ 
let's extraction app., except 
in the case of alcohol. 



1 Jamaica ginger was the variety of the drug used in all cases. When 
alcohol was the solvent employed, the process of extraction was that of 
simple percolation. 



Chemistry of the Drug and Oleoresin. 

Tabulation of Constituents, 

The chemistry of the constituents of ginger is still incomplete 
in many details, although, it has been the subject of a number of 
investigations.^ In the light of our present knowledge, the fol- 
lowing may be said to comprise the constituents ol importance 
to the pharmacist: volatile oil, gingerol, resins, fat, wax, gum, 
sugar, starch and inorganic matter. Thresh^ has identified the 
following in the oleoresin prepared by extracting the rhizomes 
with ether : 



Volatile Oil 
Gingerol 



Eesin 
Fat 



Wax 

Ash 



Occurrence and Description of Individual Constituents. 

Volatile Oil.^ The volatile oil or so-called essence of ginger 
is described by Thresh* as being a pale straw colored limpid 



»Morin, Journ. de Pharm. et de Chim. (1823), 9, p. 25$; Thresh, Pharm. 
Journ. (1879), 39, p. 171; Jones, Chem. & Drugg. (1886), 28, p. 413; Gane, 
Pharm. Journ. (1892), 51, p. 802; Balland, Journ. Pharm. Chim. (1903), 18, 
p. 248; Reich, Zeitschr. Unters. Nahr. u. Genussm. (1907), 14, p. 549. 

M. c. 

"The description of the volatile oil as given above is for the product ob- 
tained from the rhizomes by steam distillation. The oil as it exists in the 
oleoresin prepared from the rhizomes by extraction with a solvent will un- 
doubtedly differ somewhat. 

*Pharm. Journ. (1881), 41, p. 198; Tear-Book of Pharm. (1881). 18. p. 39S. 



168 ^^ MEZ— THE GALENICAL OLEORESINS 

fluid with a somewhat camphoraceous odor and an aromatic, but 
not a pungent taste. It is laevogyrate (-25 to 50°) and has a 
specific gravity of 0.875 to 0.886. It is soluble in strong alcohol, 
petroleum ether, carbon disulphide, benzene, turpentine and 
glacial acetic acid. The principal constituent of the oil, a 
sesquiterpene, gingerene or zingiberene, (C15H24) was first 
definitely described by von Soden and Rojahn^ in 1900. Accord- 
ing to Semmler and Becker,^ it is a monocyclic butadiene having 
the -following structure : 



CH CH. 


H,C 


f y Y 


H.C 


k A" A"' 


¥ I 




CH, 



The former investigators also identified d-camphene and phellan- 
drene^ in the lower boiling fractions. In addition to these hy- 
drocarbons, Schimmel & Company® have reported the presence 
of citral, cineol, borneol and probably geraniol, and Dodge^ the 
presence of an aldehyde of the probable formula, n-CglligCHO. 
The volatile oil has been found to be present in the rhizomes 
in varying quantities depending on their age before harvesting, 
the methods of curing and their geographical source.^*' Ac- 



•Pharm. Ztgr. (1900), 45. p. 414. 

•Ber. d. deutsch. chem. Gesell. (1913), 46, p. 1814. 

T Schimmel & Co. Semi-Ann. Rep. (1905), II, p. 38. 

' Phellandrene and d-caniphene were identified in the oil by Bertram and 
Walbaum in 1894. Journ. f. prakt. Chem. (1894), 49, p. 18. 

•Chem. Abs. (1912), 6, 3, p. 2976; Orlg. Com. 8th Intern. Congr. Appl. 
Chem, 6 p. 77. 

*» Gane reports the presence of volatile oil in ginger as follows : Jamaica 
0.64 per cent., Cochin 1.35 per cent., African 1.615 per cent, Fijian 1.45 per 
cent. Pharm. Journ. (1892), 51, p. 802. 

Thresh obtained 0.75 per cent, of oil from Jamaica ginger, 1.35 per cent, 
from Cochin and 1.61 per cent, from African. Pharm. Journ. (1879), 39, 
p.l. 191. 

Haensel states that he obtained only 1.072 per cent, of volatile oil from. 
Jamaica ginger, whereas other sorts yielded from 2 to 3 per cent. Pharm. 
Ztg. (1903), 48, p. 58. 

Bennet found 0.20 to 0.90 per cent, of oil in Jamaica ginger, Pharm. Journ. 
(1901), 66, p. 522. 

Reich gives the following as the volatile oil content of various sorts of 



OLEORESIN OF GINGER 169 

cording to Cripps and Brown a ''good ginger" will yield from 
2.24 to 3.48 per cent.^^ 

Gingerol. Gingerol or zingiberoP^ is the constituent or mix- 
ture of constituents to which ginger is said to owe its pungency. 
It is a colorless, odorless, viscid fluid possessing an extreme 
pungency. Its exact composition has not been determined, the 
most recent investigations indicating that it is a mixture of 
phenols.^^ It is readily soluble in strong alcohol, carbon disul- 
phide, benzol and oil of turpentine, but only slightly soluble in 
petroleum ether. 

Gingerol is present in the rhizomes in amounts varying from 
0.6 to 1.82 per cent.^* 

Resins. The resins of ginger have been isolated and described ; 
by Thresh.^ ^ This investigator recognizes four individuals with 
respect to their physical properties and their behavior toward 
acids and alkalies, viz : a neutral resin, an a-resin, a jS-resin and 
a y-resin. 

The neutral resin is stated to be a black, pitch-like substance; 
soluble in ether, alcohol, benzene and oil of turpentine, but in- 
soluble in petroleum ether and carbon disulphide. 

The a-resin is a soft, but brittle substance soluble in ether> 
and alcohol, but insoluble in the remainder of the above men- 
tioned solvents. 

The /8-resin is also soft and brittle, but is soluble in all of the 
above solvents. 

The y-resin is firmer in consistence and is soluble in ether, 
alcohol and petroleum ether. 

The total resin content of the rhizomes varies to a considerable • 



ginger: Cochin 1.38 per cent., Japan 1.38 per cent, Bengal 1.6 per cent», 
African 2.54 per cent. Zeitschr. Unters. Nahr. u. Genussm. (1907), 1^, 
p. 549. 

"Analyst (1909), 34, p. 519. 

"The term gingerol was first used by Thresh in 1884 to designate the 
pungent principle of ginger. Year-Book of Pharm. (1884), 21, p. 516. 

Zingiberol is evidently a modification of the above, the idea being to bring 
the nomenclature in closer conformity with the name of the botanical source — 
Zingiheris officinale Roscoe. 

"Garnet and Grier, Year-Book of Fharm. (1907), 44, p. 441, 

" Thresh obtained gingerol in the following quantities : Jamaica ginger 
0.66 per cent.. Cochin 0.60 per cent., African 1.45 per cent. Pharm. Joum. 
(1879), 39, p. 193. 

Gane reports the presence of the following percentages: Jamaica 0.84 per^ 
cent., Cochin 0.60 per cent., African 1.45 per cent., Fijian 1.82 per cent. 
Pharm. Joum. (1892), 51, p. 802. 

"Pharm. Journ. (1879), 39, p. 193. 



X70 ^U MEZ— THE GALENICAL OLEORESINS 

extent and appears to depend principally on their geographical 
source. The minimum yield (1.18 per cent.) has been obtained 
from Jamaica ginger, the maximum yield (4.47 per cent.) from 
the Fijian rhizome.^^ 

Fat and Wax. Little or no work has been done toward de- 
termining the composition of the fat or wax in ginger. The 
two substances, combined, are stated to constitute 0.70 to 1.225 
per cent, of the rhizome.^'^. 

Ash. The qualitative examination of the ash of ginger has 
been undertaken by Thresh,^^ who reports the presence of the 
basic elements : K, Ca, Mg, Mn,^^ and Fe combined with H2CO3 
and H3PO4. The ash of African ginger is stated to contain the 
largest amount of manganese. 

The ash content^^ of the whole rhizome appears to be in- 
fluenced but little by the locality from which obtained, 3.0 to5.5 
per cent, being conservative limits for the usual commercial var- 
ieties. Peeling^^ appears to decrease the amount of ash while 
bleaching^- (liming) increases it. 

Constituents of Therapeutic Importance. 

The physiological action of the oleoresin of ginger was at one 
time thought to be due to the resin content, but the work of 
Thresh^ has shown the pungency to be the property of the 
phenolic constituents known collectively as gingerol. The car- 



" Thresh reports the total resin content of g-inger as follows : Jamaica 1.18 
per cent, Cochin 1.815 per cent., African 3.775 per cent., Pliarm. Journ, 
(1879), 39, p. 173. 

Gane noted the presence of the following percentages : Jamaica g-inger 1.76 
per cent.. Cochin 1.815 per cent., African 3.775 per cent., Fijian 4.475 per 
c^nt. Pharm. Journ. (1892), 51, p. 802. 

" The combined fat and wax present in g-inger is stated by Thresh to be 
as follows: Jamaica 0.70 per cent., Cochin 1.205 per cent., African 1.225 per 
■cent. I. c. 

Gane found the following amounts: Jamaica ginger 0.92 per cent., Cochin 
1.20 per cent., African 1.225 per cent., Bengal 0.86 per cent., L. C. 

"Pharm. Journ. (1879), 29 pp. 174 and 193. 

"See also Flueckiger, Ihid. (1872), 32, p. 208. 

*> C. Richardson. Bull. 13, Dept Agr. Washing-ton, 1887; Gane, Pharm. 
Journ. (1892), 51, p. 802; Liverseeg-e, Vierteljahresschr. Nahrungs-u. Genussm. 
(1896), 11, p. 353; Glass, Pharm. Journ. (1897), 58, p. 245; Bennet, Ibid. 
(1901, 66. p. 522. 

»Winton, Ogden and Mitchell obtained 3.66 to 4.06 per cent, of ash for un- 
peeled and unbleached Cochin ginger, 3.36 per cent, for the same when peeled 
and bleached. Rep. Conn. Agr. Exp. Sta. (1898), p. 202; (1899), p. 102. 

22 Davis reports 5.20 per cent, of ash for unbleached Jamaica ginger, 6. 55 
per cent, for the bleached. Fharm. Journ. (1895), 54, p. 472. 

» Tear-Book of Pharm. (1884), 21, p. 516. 



OLEORESIN OF GINGER 



171 



minative action of the preparation must also be attributed in 
part to the volatile oil contained therein. 

Physical Properties. 

Color: The oleoresins examined in the laboratory were ob- 
served to be rather dark brown in color when spread out in thin 
layers on a white porcelain surface. This property, however, 
is reported to vary somewhat with the variety and condition of 
the ginger used in making the preparation. When African 
ginger is employed, the oleoresin is stated to be dark brown in 
color, whereas, uncoated Jamaica ginger is said to yield a 
preparation comparatively light in color.^ 

Odor: The oleoresin, when prepared according to the official 
process, has the full aroma of ginger, the quality of which is 
stated to be influenced largely by the variety of ginger used.^ 

Taste: The preparation has the sharp pungency and flavor 
of ginger. This property, like the odor, is stated to vary with 
the variety of ginger used, Jamaica ginger yielding the product 
with the best flavor.^ 

Consistence: The oleoresin is a thick liquid, being of about 
the consistence of molasses, as a rule, but varying somewhat 
with the variety of the ginger used in its preparation. The 
fluidity is said to be the greatest when prepared from Jamaica 
ginger and the least when made from the African variety.'* 

Solubility: The oleoresin is soluble in absolute alcohol, ace- 
tone, ether, chloroform, and glacial acetic acid. It is partially 
soluble in petroleum ether, the extent of its solubility depend- 
ing on the solvent used in its preparation as is shown in the fol- 
lowing table: 

Table 65 — Solubility of the oleoresin in petroleum ether. 



9ol<rent used in preparing the oleoresin. 


Alcohol 


Acetone 


Ether 


Per cent, of oleoresin soluble in petrol, ether.. 


45.55 


49.59 


69.44 



iParrish. Treatise on Pharmacy, (1867), p. 233. 
"Idris (1898). 
'Idris (1898). 
*Idris (1898). 



172 



DU MEZ— THE GALENICAL, OLEORESINS 



As will be noticed this difference in solubility is quite pro- 
nounced and it should, therefore, serve as a ready means of 
identifying the solvent used in the manufacture of the prepara- 
tion. 

Specific gravity: At 25° C a specific gravity of 1.020 to 1.036 
was found for this oleoresin when acetone or ether were em- 
ployed in its preparation. This constant was observed to be 
slightly higher when alcohol was used as a menstruum and con- 
siderably lower (less than 1.000) when petroleum ether was em- 
ployed. In the case of the commercial samples examined, a low 
specific gravity is to be attributed to the presence of unevapor- 
ated solvent in one instance, and in the other, it is thought to be 
due to an abnormally darge volatile oil content. The data ob- 
tained in the examination of laboratory and commercial samples 
are given in the tables which follow. 

Table 66 — Specific gravities of oleoresins prepared in the laboratory, 



Sample 
No. 


Date 


Observer 


Solvent 


Specific 
gravity* 


1 


1916 


DuMez 


Alcohol 


At 25° C 
1.041 


2 




Acetone . . .. 


1 030 


3 




1 033 


4 


•« 





1.036 


5 


•• 


Ether . 


1 020 


6 




Petrol, ether 


990 











Table ©7 — Specific gravities of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Specific 
gravity 




1916 


DuMez. 


Squibb & Sons. 


At 25° C 
997 1 


2 






1.014 


3 


•' 


Lilly & Co.. 


1 024 











1 Contained ether. 



Refractive index: A refractive index of about 1.517 at 25 °C 
was observed for the preparations made in the laboratory with 
acetone or ether. When alcohol was employed in extracting the 
drug, the resulting product was found to have a slightly higher 
refractive index, while petroleum ether yielded an oleoresin in 



OLEORESIN OF GINGER 



173 



which this constant was observed to be considerably lower. The 
low refractive index found for two of the commercial samples 
was very likely due to the fact that they contained twice as 
much volatile matter (principally essential oil) as the laboratory 
preparations. The effect of this influence, together with that 
produced by the presence of unevaporated solvent, is brought 
out in the following: tables: 



Table 68. — Refractive indices of the oleoresins prepared in laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Refractive 
index 


1, 


1916 


DuMez 


Alcohol 

Acetone 


At 25° C 
1 520 


2 


1.517 


3 




1.517 


4 




Ether...!..!!..'.!...!..!!. 


1.518 


5 


.4 / 


1.517 


6 




Petrol, ether 


1 501 









Table 69 Refractive indices of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Refractive 
index 


1 


1916 


DuMez 




At 25° 
1,501' 


3 




Sharp & Dohme 


1.505 


2 


■ ■ 


Lilly & Co 


1.512 












* Contained ether. 



Chemical Properties. 

Loss in weight on heating: The oleoresins prepared in the 
laboratory lost, as a rule, between 11 and 13 per cent, of their 
weight on heating at 110° C, whereas the loss in the case of the 
commercial samples was about twice as great. "While this dif- 
ference may have been due to the employment of different 
methods in the making of these preparations (a vacuum pan 
having probably been used in the r-emoval of the solvent in the 
case of the commercial products), it is more likely the re- 
sult of the presence of a greater amount of volatile oil in the 
drugs from which the latter were prepared. The loss in weight 



174 



DU MEZ— THE GALENICAL OLEORESINS 



as found for the preparations examined in the laboratory is given 
in the tables which follow. 

Table 70 — Laboratory preparations — loss in weight on heating. 



Sample 
No. 


Date. 


Observer. 


Solvent. 


Per ct. of loss 
on heating. 


1 


1916 


DuMez 




At 110° C 
12.82 


2 




Acetone 


11.92 


5 


•• 




7.34 


6 . 


•« 


Ether ...... ....V.....V.V... 


11.54 


3 


" 


11.08 


4 . . .. 


'» 


Petrol, ether 


11.50 











Table 80. — Commercial samples — loss in weight on heating. 



Sample 
No. 


Date 


Observer 


Source 


Per cent of 
loss on 
heating 


1. 


1916 


DuMez 


Lilly & Co 


At 110° C 
18.90 


2 




Squibb & Sons 


21.391 


3 





Sh arp & Dohme 


22.97 









* The presence of ether could be detected by the odor. 

Ash content: The ash content of the oleoresin prepared with 
acetone was found to be 0.28 per cent., whereas, that of the 
preparation made with ether was only 0.14 per cent. The values 
obtained for the commercial samples examined also showed this 
variation due to the nature of the solvent. Copper, although 
•detected in two of these preparations (commercial oleoresins), 
was present in such small quantities that the results were not 
affected materially thereby. The following tables show the 
results obtained in the ash determinations made in the laboratory. 



Table 81. — Ash contents of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Per cent of 
ash 


1 


1916 


DuMez 


Alcohol 

Acetone 


0.42 


2 




0.30 


3 




0.26 


i 


•' 


Ether 


0.28 


5 


•« 


14 


6 


•• 


Petrol, ether 


0.06 











OLEORESIN OF GINGER 



175 



Table 82.— Ash contents of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Per cent of 
ash 


Foreign 
constituents 




1916 


DuMez 


Squibb & Sons 


0.15 » 

0.26 

0.27 




2 

3, 


Lilly & Co 


Copper 


Sharp & Dohme 











1 Contained ether. 

Acid nuynher: The acid numbers obtained for the oleo- 
resins prepared in the laboratory were found to be fairly 
uniform regardless of the solvent employed in extracting the 
drug, except in the case of petroleum ether, when the value 
found was low, namely, 11.2. The values obtained for the com- 
mercial samples examined were almost identical with those ob- 
tained for the laboratory preparations, even though the former 
in all cases contained about twice as much volatile matter (gen- 
erally essential oil, in one case, unevaporated solvent in addi- 
tion) as the latter. The values obtained for this constant in the 
laboratory are given in the tables which follow. 

Table 83 — Acid numbers of oleoresins prepared in the laboratory- 



Sample 

,.5?°.- 


Date 


Observer 


Solvent 


Acid 
number 


1 


1916 


DuMez 


Alcohol 


13 9 


2 




Acetone 


14 5 


3 






13 8 


4 


• ' 




13 5 


5 




Ether 


13 7 


6 


" 


Petrol, ether 


11 2 











Table 84 — Acid numbers of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Acid 
number 


1 


1916 


DuMez 


Lilly &Co 


13 3 


2::::::::: 




Squibb & Sons... 


13 8 > 


S 


»» 


Sharp & Dohme 


14 











1 Contained ether. 



Saponification value: Saponification values of 103.4 to 
110.4 were obtained for the oleoresin when prepared with 



176 



DU MEZ— THE GALENICAL OLEORESINS 



acetone. For the preparation in which ether was employed as 
a menstruum in extracting the drug, a saponification value of 
102.9 was obtained. The comparatively low values obtained for 
the commercial samples examined are to be accounted for by 
the fact that in all cases, they contained nearly twice as much 
volatile matter (presumably essential oil) as the laboratory 
preparations. The values found for this constant are given in 
the tables which follow. 



Table 85 — Saponification values of oleoresins prepared in the laboratory. 



Sample 
, No. 


Date 


Observer 


Solvent 


Saponifica- 
tion value 


1 


1916 


DuMez 


Alcohol 


119 4 


2 






103.4 
110 4 


3 


«» 




4, 


" 


• •• • 


105.7 


« 


»» 


Ether 


102 9 


5 


•' 


Petrol, ether 


78.1 











Table 86 — Saponification values of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Saponifica- 
tion value 


1 


1916 


DuMez 


Sharp & Dohme 


94.1 


2.. .. 




SQuibi)& Sons 


98.41 


3 


" 


Lillv& Co 


89.9 









* Contained a trace of ether. 



Iodine value: Iodine values of 122.4 to 124.1 were ob- 
tained for the oleoresin when prepared with acetone. The 
preparations made with alcohol or ether gave values very 
near the same, whereas, the value of this constant was some- 
what higher (126.9) when petroleum ether was the solvent em- 
ployed. With respect to the commercial samples, the values 
found were lower in all cases. In one instance, this was due 
to the presence of unevaporated solvent, while, in the other cases 
it is to be attributed to the relatively large amount of volatile 
matter (essential oil) present. The iodine values found for the 
preparations examined in the laboratory follow. 



OLEORESIN OF GINGER 



177 



Table 87. — Iodine values of oUoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Iodine value 


1 


1916 






122.3 


2 




Acetone 


122 4 


3 


»' 




111.5 1 


4 


" 


" 


124.1 


5 


Ether 


121.1 


6 


" 


Petrol, ether .. 


126.9 









Tlie drug in this instance was extracted by simple percolation. 
TabLiE 88. — Iodine values of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Iodine value 


1 


1916 


DuMez 


?quibb&9ons 


104. 2> 


2 




Lilly & Co 


109.9 


3 


" 


Sharp & Dohme 


112 









* Contained ether. 

Special Qualitative Tests. 

Most of the qualitative methods which have been mentioned in 
connection with the standardization of this preparation are of 
the nature of tests for the detection of adulterations. The oleo- 
resin of capsicum^ is the adulterant which appears to have re- 
ceived special attention, several methods for detecting its pres- 
ence having been reported. 



Tests for the Presence of the Oleoresin of Capsicum 

La Wall, in 1910, pointed out the necessity of a test for the 
presence of the oleoresin of capsicum as he had observed that 
many of the commercial samples of the oleoresin of ginger used 
in the preparation of ginger ale extracts were adulterated with 
this substance. At the same time, he also described a method 
whereby this form of adulteration might be detected. His 
method is almost identical with that of Garnett and Grier pub- 
lished in 1907, both being based on the destruction of the 



1 While the oleoresin of capsicum per se may occassionally be added to the 
finished product, it Is thought that the adulteration is usually accomplished 
^y mixing capsicum with the ginger previous to the extraction of the oleoresin. 



178 I^U MEZ— THE GALENICAL OLEORESINS 

pungent principles ( ginger ol) of the oleoresin of ginger with 
alkalies, whereby the pungent principle (capsiciri) of the oleo- 
resin of capsicum remains unaltered. As it was subsequently 
found that the pungent principles of the former were not com- 
pletely destroyed by this treatment, Nelson proposed a modi- 
fication of the above methods, in which he makes use of 
manganese dioxide for completing the disintegration of these 
constituents. Full descriptions of these methods follow : 

Method of Garnett and Grier (1907) : Digest 1 gram of the oleoresin 
for 15 minutes on a water bath with a small quantity of caustic alkali 
dissolved in alcohol. Evaporate the solution to remove the alcohol and 
make the residue faintly acid with hydrochloric acid. Transfer the liquid 
to a test tube and shake it with 5 cubic centimeters of ether which have 
previously been used to rinse the dish. Allow the mixture to stand quietly 
and then taste the separated ethereal layer. If sharply pungent, adultera- 
tion with capsicum is indicated. 

Method of La Wall (1910) : Add 10 cubic centimeters of half -normal 
alcoholic potassium hydroxide solution to 1 gram of the oleoresin contained 
in a shallow porcelain dish and evaporate to dryness on a water bath. Dis- 
solve the residue in 50 cubic centimeters of water and transfer the solution 
to a separatory funnel. Add 20 cubic centimeters of ether and shake vigor- 
ously. After allowing the mixture to stand until the ether has separated, 
run the latter off on a watch glass and expose it until the solvent has all 
evaporated. The residue should have a warm camphoraceous taste. A 
sharp pungent taste indicates adulteration with capsicum. 

Method of Nelson (1902) :' Add 10 cubic centimeters of double-normal 
alcoholic potassium hydroxide solution to one gram of the oleoresin contained 
in a porcelain dish and evaporate on a steam bath. Add about 0.1 gram 
of powdered manganese dioxide and 5 to 10 cubic centimeters of water, 
and continue heating for about 20 minutes, or until all of the volatile oil 
has been expelled. Cool, acidify with dilute sulphuric acid and extract 
at once with petroleum ether. Evaporate the petroleum ether solution in a 
small crucible, keeping the residue within as small an area as possible. When 
all of the solvent has evaporated, apply the tongue to the residue, being 
careful to keep the material on the tip. If capsicum is present, the char- 
acteristic burning sensation will soon be felt. 

The latter is the method which was employed in making the 
test in the laboratory. In no case, however, was capsicum de- 
tected in the samples examined. 



« Journ. Indust. and Eng. Chem. (1910), 2, p. 419. 



OLEORESIN OF GINGER 



119 



Special Quantitative Tests. 

While tlie matter of determining the quality of the unadulter- 
ated product has apparently received but little attention, two 
distinct methods have, nevertheless, been made use of in its 
evaluation. They are the methods of Garnett and Grier for the 
determination of the gingerol content, and the physiological test 
employed by the H. K. Mulford Company. 

Methods for the Estimation of the Gingerol Content. 

The only method of an analytical nature which has been sug- 
gested for the quantitative evaluation of this oleoresin is based 
on the fact that the pungent principles, gingerol, are more 
readily soluble in 60 per cent alcohol, than in petroleum ether, 
A description of the manner in which this assay is carried out 
follows. 

Method of Garnett and Grier (1909): Dissolve the gingerol by boiling 
about 1 gram of the oleoresin with several portions of petroleum ether^ 
filter the solutions thus obtained and remove the solvent bj evaporation 
on a water bath. Dissolve the residue in alcohol (60 per cent.) added in 
three separate portions, shake the united alcoholic solutions with a small 
amount of petroleum ether to remove traces of fat and remove the alcohol 
from the hydro-alcoholic portion by evaporation. Shake the residual liquid 
with 3 portions of ether added successively, filter the combined shakinga 
into a tared flask, remove the ether by evaporation on a water bath, dry 
at 100°C and weigh. In the final shaking out, carbon disulphide or chloro- 
form may be used in place of the ether. 



The use of this method in the laboratory has shown that it 
gives fairly constant results, and, as it is easily carried out, it 
should prove to be of practical value. The results obtained in 
the examination of oleoresin s prepared in the laboratory and 
those obtained from commercial sources are given in the fol- 
lowing tables : 

Table 89 — Gingerol content of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Gingerol 
content 


1 


1916 


DuMez 


Alcohol 


Percent. 
27 2 


2 




Acetx)ne 


23.2 


3 


" 


Ether 


27.5 


4 


" 


Petrol ether . 


43 9 











ISO 



DU MEZ— THE GALENICAL OLEORESINS 



Table 90 — Oingerol content of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Gingerol 
content 


1 


1916 


DuMez 


Li lly «Sz; Co 


Per cent. 
19.5 


12 




Sharp & Dobme 


24.0 


Z 


" 


flQuibt) & Sons 


28.2 











The first of the preceding tables shows that the gingerol con- 
tent varies with the solvent employed in the preparation of the 
oleoresin. Further, that this variation is not in inverse ratio 
to the yield of oleoresin obtained as might be expected, but is 
•exceptionally low in the case of acetone due to the fact that it is 
a difficult matter to completely exhaust the drug when the lat- 
ter is the solvent used. 

The low gingerol content of two of the commercial samples as 
shown in the second table, points to the use of acetone in their 
preparation. A similar effect might, however, be produced when 
ether or alcohol are employed if the ginger used is of poor 
quality (low in gingerol content,) or if percolation is termin- 
ated before complete exhaustion of the drug has taken place. 
The oleoresin obtained from Squibb and Sons is stated to have 
been prepared with ether, which statement is confirmed by the 
result obtained in the determination of the gingerol content as 
is also shown in the second table. 



Physiological Tests. 

The H. K. Mulford Company reports the use of a physiologi- 
-cal test for determining the quality of this oleoresin. As an 
arbitrary standard, the firm has taken a preparation which is 
pungent to the taste in a maximum dilution of 1 to 20,000'. 
While there is no information, at hand to indicate what solvent 
was employed as the diluent, experience in the laboratory has 
shown that dilute alcohol (50 per cent.) may be used for this 
purpose. After vigorously shaking the oleoresin with alco- 
"hol, the resulting solution should preferably be filtered before 
applying to the tongue. AlUiough no extensive series of ex- 
periments were made with this test in the laboratory, the results 
obtained would appear to indicate that the above standard is 
rather low as the pungency in the preparations examined was 



OLEORESIN OF LUPIILIN lg% 

easily perceptible in dilutions of 1 to 30,000. In view of the 
fact that personal idiosyncrasy must be a factor in applying this- 
test, the use of the previously described method for the estima- 
tion of the gingerol content is thought to be more preferable for 
use in this connection. 

Adulterations 

There is no evidence to show that the oleoresin as prepared 
for pharmaceutical use is adulterated. La Wall,^ however, states 
that the commercial article used in the manufacture of 
ginger ale frequently contains oleoresin of capsicum. 

A trace of copper was found in most of the commercial 
samples examined. See under **Ash content." 

Oleoresin of Lupulin 
Synonyms 

Aetherisches Lwpulinextrdkt, Nat. Disp. 1879. 

Extractum Lupulini, Hirsh, Univ. P. 1902, No. 1222. 

Extractum Lupulini aethereum, Nat. Disp. 1879. 

Oleoresina Lupulinae, U. S. P. 1860. 

Oleoresina Lupulini, U. S. P. 1880. 

Oleoresine de Lupuline, U. S. Disp. 1907. 

Ethereal Extract of Lupulin, King's Am. Disp. (1900), p. 1333. 

History 

The first mention of the oleoresin of lupulin which could be 
f ound in pharmaceutical literature appeared in Procter 's article, 
'^ Formulae for fluid extracts in reference to their more general 
adoption in the next Pharmacopoeia," published in 1859.. 
Procter's oleoresin was in reality an ethereal extract, ether hav- 
ing been the menstruum employed in exhausting the drug. In 
this connection, it is interesting to note that the extract prepared 
with the use of alcohol had previously been brought to the 
notice of the American pharmacist by Livermore in 1853, while 
the attention of the European pharmacist had been directed ta 
the same by Planche as early as 1823. The oleoresin was first 
admitted to the United States Pharmacopoeia in 1860, in which 
it remained official for more than half a century, having been 



1 La Wall (1910). 



282 ^U MEZ— THE GALENICAL. OLEORESINS 

omitted from the present revised edition. It has never re- 
<jeived recognition by any of the foreign pharmacopoeias. 

Drug Used, Its Collection, Preservation, Etc. 

Lupulin has not been included in the late edition of the United 
States Plfiarmacopoeia, In the preceding edition, it was defined 
as ^'the glandular trichomes separated from the fruit of Humvr 
lus LupiUus Linne (Fam. Moraceae).^' 

The drug, as it occurs on the market, is of varying degrees of 
purity due, principally, to the method of obtaining it While 
some of it is probably obtained by picking the scales from 
the fruits and then shaking or rubbing the glands through a 
fine sieve, the bulk of the commercial article consists of the 
-sweepings gathered up from the floors of the hop bins.^ Such 
being the case, it is only natural to expect contamination with 
sand and other earthy materials. The impurities, in part, are 
usually removed by washing with water when the sand settles 
to the bottom and the lupulin is skimmed off and dried. 

The glands, on storing, especially if exposed to the air, 
undergo a change, becoming dark brown in color and developing 
& rancid odor. Rabak- and Russell,^ respectively, have shown 
one of the changes to be a conversion of the so-called soft resin 
into the hard. The development of the disagreeable odor has 
been attributed to the formation of valeric acid* resulting from 
the oxidation of one or more of the constituents. In view of the 
foregoing, the British Pliarmacopma directs that the drug be 
renewed annually and rejected as soon as it becomes dark in 
■color or developes a cheesy odor. 

In this connection, it should also be stated that hops are often 
sulphured previous to storing. To what extent, if any, this 
treatment affects the quality of the lupulin obtained therefrom 
«-nd later the oleoresin, does not appear to have been determined. 



^ Flueckiger, Pharmakognoise des Pflanzenreichs (1891), p. 255. 
«Bull. No. 271. U. S. Dept. of Agric. (1913), p. 13. 
'Bull. No. 282. U. S. Dept of Agric. (1915), p. 9. 
-•Bungener. Pharm. Journ. (1884), 43, p. 1008. 



OLBORESIN OF LUPULIN 



183 



Z7. S. P. Text and Comments Thereon. 

The oleoresin, which was official in the United States PJiar- 
macopma from 1860 to 1900, has been omitted from the last 
edition (edition of 1910). 

1864 

Oleoresina Lupulinae 
Oleoresin of Lupulin 
Take of Lupulin* twelve troyounces; distillation on a water-bath, eighteen 
Ether* a sufficient quantity. fluidounces of ether,' and expose the 

Put the lupulin into a narrow eylin- residue, in a capsule, until the remain- 
drieal percolator, press it firmly, and ing ether has evaporated." Lastly, 
gradually pour ether upon it until keep the oleoresin in a wide-moutiied 
thirty fluidounces of filtered liquid bottle, well stopped.^ 
have passed.* Eecover from this, by 



1870 

Oleoresina Lupulinae 
Oleoresin of Lapulin 



Take of Lupulin * twelve troyounces ; 
Ether' a sufficient quantity. 

Put the lupulin into a narrow cylin- 
drical percolator, provided with a 
fltop-cock, and arranged with cover 
and receptacle suitable for volatile 
liquids,^ press it firmly, and gradually 
pour ether upon it, until twenty fluid- 



ounces of liquid have slowly passed.* 
Eecover the greater part of the ether 
by distillation on a water-bath,"^ and 
expose the residue in a capsule, until 
the remaining ether has evaporated.' 
Lastly, keep the oleoresin in a wide- 
mouthed bottle, well stopped.' 



1880 

Oleoresina Lupulini 

Oleoresin of Lupulin 

[Oleoresina Lupulinae, Pharm., 1870] 

Lupulin,* one hundred 'parts ....100. parts of liquid have 
Stronger Ether*, a sufficient quantity. 
Put the lupulin into a narrow cylin- 
drical percolator, provided with a 
«over and receptacle suitable for 
volatile liquids,' press it firmly, and 
gradually pour stronger ether upon ped, wide-mouthed bottle.' 
it, until one hundred and fifty (150) 



slowly passed.* 
Recover the greater part of the ether 
by distillation on a water-bath,' and 
expose the residue, in a capsule, until 
the remaining ether has evaporated.* 
Keep the oleoresin in a well-stop- 



23^ DU MEZ— THE GALENICAL OLEORESINS 



1890 

Oleoresina Lupulini 

Oleoresin of Lupulin 

Lupulin/ one hundred grammes the drug is exhausted.* Recover the 

100 Gm. greater part of the ether from the 

Ether,^ a sufficient quantity. percolate by distillation on a water- 
Put the lupulin into a cylindrical bath/ and, having transferred the 
glass percolator, provided with a residue to a capsule, allow the re- 
stop-cock, and arranged with a cover maining ether to evaporate spontan- 
and receptacle suitable for volatile eously.* 

liquids.^ Press the drug very lightly, Keep the product in a well-stop- 

and percolate slowly with ether, pered bottle,' 
added in successive portions, until 

1900 

Oleoresina Lupulini 

Oleoresin of Lupulin 

JjupuVm,^ five hundred grammes Recover the greater part of the ace- 

500 Gm. tone from the percolate by distilla- 

Acetone,' a sufficient quantity. tion on a water-bath,"* and, having 

Introduce the lupulin into a cylin- transferred the residue to a dish, al- 

drical glass percolator, provided with low the remaining acetone to evap- 

a stop-cock, and arranged with a orate spontaneously in a warm place.* 

cover and a receptacle suitable for Keep the oleoresin in a well-stoppered 

volatile liquids.^ Press the powder bottle.' 

very lightly, and percolate slowly Average dose. — 0.200 = Gm. 200 

with acetone, added in successive por- milligrammes (3 grains), 
tions, until the lupulin is exhausted.* 



1) For description of the drug, see page 1088 under ''Drug 
used, its collection, preservation, etc." 

2) The solvents which have been used for the purpose of ex- 
tracting lupulin are ether, acetone and alcohol. Of these, the 
first two have been recognized at different times by the 
Pharmacopoeia, acetone being the solvent which was directed 
to be used by the edition of 1900, whereas ether was specified 
in previous editions. 

With respect to the relative values of the above, from a 
therapeutical standpoint, a statement cannot be made owing 
to the lack of specific information on the subject. From a 
pharmaceutical standpoint, however, ether and acetone, re- 



OLEORESIN OF LUPULIN ^85 

spectively possess an advantage over alcohol in that they ex- 
tract less inert material and yield products which are softer 
in consistence and conform more closely in their general 
properties to the other members of this class of preparations. 
The products obtained, even when using acetone or ether, are, 
however, more of the nature of an extract than an oleoresin. 
A better solvent for use in this connection would appear to 
be petroleum ether. While, it has apparently never received 
consideration for this purpose, it appears to be particularly 
well adapted to the same in that it completely extracts the 
valuable constituents of the drug (see soft resins, page 1095) 
with but little of the inert material and yields a product of 
such consistence that it can be poured. 

3) For a description of the various forms of percolation con- 
forming to the pharmacopoeial specifications for use in this 
connection, see Part I under ''Apparatus used." 

4) The various editions of the Pharmacopoeia in which this 
preparation has been official have directed that the material 
composing the oleoresin be extracted from the drug by simple 
percolation. In the earlier editions, percolation was directed 
to be continued until a certain definite amount of percolate 
was obtained, whereas, the pharmacopoeias of 1890 and 1900 
required that the operation be continued until' the drug was 
exhausted. In either case, the quantity of solvent required is 
considerably greater than that which is necessary to com- 
pletely exhaust the drug when some form of continuous ex- 
tractor is used. Since the quality of the finished product is 
the same in both cases, it is thought that the later method of 
extraction is to be preferred. 

5-6) Owing to the fact that certain constituents of the oleo- 
resin are prone to undergo changes when the latter is exposed 
to' the air (see page 1088 under ''Drug used, its collection, pres- 
ervation, etc.''), the pharmacopoeial directions, that the last 
portions be allowed to evaporate spontaneously, are unfortu- 
nate. It is thought that a better procedure would be to evap- 
orate the solvent completely at the temperature of the water 
bath, thereby considerably shortening the time of exposure. 

8) For the reasons just mentioned, the finished product 
should be kept in well-stoppered bottles. 



186 



DU MEZ— THE GALENICAL OLEORESINS 



Yield 



The yield of oleoresin to ether is usually given in the text- 
books and treatises on pharmacy as 50 to 60 per cent., while a 
yield of 32.49 to 70.8 per cent, has been reported in the journals. 
The irregularity in the quality of the lupulin as ordinarily found 
on the market very likely accounts for this variation. The 
drug, when of good quality should give a yield of at least 60 
per cent. The following tables show the variation in the yield 
as reported in the literature, also, the results obtained in the 
laboratory. 

Table 91 — Yield of oleoresin as reported in the literature. 





Observer 


Yield of oleoresin to— 




Date 


Alco- 
hol 


Ace- 
tone 


Ether 


Other 
solvents 


Remarks 


1853 


Livermore 

Trimble 


Per ct. 
66.00 


Per ct. 


Per ct. 


Per ct. 




1888 




60.59 

70. fO 
86.50 
52.00 
65.00 

56.00 
54.00 
60.10 
66.70 
34.00 to 
65.80 

47.00 
50 00 
5:^.00 
57.70 
58.90 
62.10 
60.0+ 

44.94 to 
65.60 

63.96 to 
77.82 

Below 
60.00 

32.49 
55.18 
57.06 
44.20 
54.70 
55.00 
55.30 
.55.50 
57.10 
58.60 
68.20 
69.20 


J Benzin 
( 7.04 




1892 






71.00 




1892 


Sherrard 








1907 


Van der Harst .. 












Dohme and En- 










1908 










1909 


Parson . , 












Bernegau 




















1909 








Results obtained In the ex- 


1909 


Dohme & En- 
gelhardt 








traction of 10 samples ofilu- 
pulin. 




Berneg'au 




















1911 




■ 








Francis 

















1911 








Seven of 8 samples yielded 


1913 


Gane 

Patf'h 









more than 60 per cent, of ex- 
tractive to ether. • rS 
Results ol)tained in the ex- 


1913 




traction of .4 samples of lu- 
pulin. 
Results obtained in the ex- 


1913 


Engrelhardt 








traction of 53 samples of lu- 
pulin. 
Eiffht of 12 samples of lupulin 


1914 


Rippetoe 








extracted srave below 60 per 
cent, of ether soluble matter. 






















1915 
















































































: 







. :!_:=» 



OLEORESIN OF LUPULIN 



18T 



Table 92 — Yield of oleoresin as obtained in the laboratory. 





Observer 




Yield of oleoresin to— 




Date 


Alco- 
hol 


Ace- 
tone 


Ether 


Benzin 


Remarks 


1910 


DuMez& Netzel. 


Per ct. 
78.13 


Per ct. 
68.42 


Per ct. 
66.71 


Per cent 
14.46 


Represents the yiel* 
obtained using' a 
Soxhlet's extraction- 
app , except in the 
case of alcohol. 



Chemistry of the Drug and Oleoresin 

Tabulation of Constituents 

The chemistry of lupulin^ per se has received comparatively 
little attention, although, a very considerable knowledge con- 
cerning its constituents has been gained through the work of 
the brewing chemists and others^ on hops. The isolation of the 



II 



1 The following have reported more or less complete analyses of lupulin : 
Ives, Silliman's Am. Journ. of Science (1820), 2. p. 303; Payen, Pelletan and' 
Chevalier, Journ. de Pharm. et de Chim. (1822), 8, p. 209; Personne, Ihid. 
(1854), 59, p. 329; Chapman, The Hop and its Constituents. The Brew- 
ing Review, London, (1905). 

' Power, Tutin and Rogerson, who have completed one of the most recent 
as well as extensive pieces of work on the constituents of the hop, have- 
isolated the following substances : 
I Volatile oil 

Alcoholic Extract soluble in water: 
1. Choline (C.H^^O^N.) 

1-Asparagine (C^HgOjNj.) 
Potassium nitrate 
Tannin 

Sugar forming a d-phenylhydrazone, m, p. 208. 
Amorphous bitter material. 
Volatile base having a coniine-like odor. 
Alcoholic extract insoluble in water: 

1. Hentriacontane (Cg^Hg^.) 

2. Ceryl alcohol (C^-H^gO.) 

3. Phytosterol (C^.H.gO.) 

4. A phytosterolin, phytosterol glucoside (Cg^HjgOg.) 

5. Volatile fatty acids: formic, acetic, butyric, valeric, /3-isopro^ 
pylacrylic (CgH,„OJ, and nonoic. 

6. Saturated and unsaturated non-volatile acids: palmitic, ste- 
aric, cerotic, an isomeride of arachidic (C2oH^02), cluytinlc 
and linolic. 

A new bitter crystalline phenolic substance, humulol 

(C,,H,,0,) 
A new tasteless crystalline phenolic substance, xanthonumoF 

(Cj3H,,0„.) 
Journ. Chem. Soc. (1913), 103, p. 1267. 



Ill 



7. 



8. 



288 ^U MEZ— THE GALENICAL OLEORESINS 

following constituents of pharmaceutical interests has been re- 
ported: Volatile oil, resin, wax, alkaloids and inorganic sub- 
stances. Chapman^ gives the composition of the ethereal ex- 
tract as follows: 

o-resin 18.06 per cent. 

jS-resin 67.74 " " 

Wax 0.28 " " 

Other constituents (fat, oil, 7-resin, etc.) 13.64 " " 

Ash 0.27 " " 

Occurrence and Description of Individual Constituents. 

Volatile Oil^ The volatile oil obtained by distillation with 
steam is a pale yellow, or colorless, mobile liquid possessing a 
fragrant and characteristic odor, and a slightly burning taste. 
It is almost insoluble in water, to which, however, it imparts its 
odor, and only slightly soluble in dilute alcohol. It is soluble 
in ether, petroleum ether, chloroform and the other volatile oil 
solvents. The specific gravity at 20° C is 0.8357 to 0.8776, and 
the specific rotatory power, [alo^*^, is 0.20 to 0.58.^ 

According to Chapman,^ the oil is composed of the terpene, 
myrcene, (CioHjg), 40 to 50 per cent; inactive linalool, a fraction 
of 1 per cent ; linalyl isononoate, a fraction of 1 per cent ; the 
sesquiterpene, humulene^ (C15H24), about 40 per cent; and 
probably some ether of geraniol with a small amount of a diter- 
pene. Rabak,^ who has more recently completed an . investiga- 
tion of the constituents of the oil, states that, in addition to 
myrcene and humulene, the oil contains the heptoic, octoic and 
nonoic acid esters of myrcenol with traces of free fatty acids and 
probably some free alcohols. 

As much as 2 per cent of volatile oil has been obtained from 
lupulin by steam distillation.^ 

Resin. The chemical constitution of the so-called "hop 
resins ' ' is still an unsolved problem, the literature being replete 



^ Ihid, p. 81. The hop and its constituents. The Brewing Review, Lon- 
don (1905). 

*The following references are to the earlier literature on the volatile oil: 
Payen, Felletan and Chevalier and Personne, 1. c. ; Wag'ner, Journ. f. prakt. 
Chem. (1853), 58, p. 351; Ossipon, Ibid. (1886), 142, p. 238. 

" Chapman, I. c. 

« Ibid. 

' E. Deussen. who has determined the constitution of humulene, finds it to 
%e 1-caryophyllene. Journ. f. prakt. Chem. (1911), 83, p. 483. 

8 Journ. Agric. Research (1914), 2, p. 115. 

•Payen, Pelletan and Chevalier, I. c. See also Semmler, Z. c. 



OLEORESIN OF L.UFULIN 189 

with vague and contradictory statements.^" Foi practical pur- 
poses, the classification of Hayduck^^ appears to be the most 
useful. This investigator distinguishes three resins, which he 
designates a, (3 and y, according to their solubility in petroleum 
ether and their behavior toward a solution of lead acetate. The 
a- and /3- resins are soluble in petroleum ether, and are further 
known as the "soft resins," being of a soft consistence at the 
ordinary temperature. The y-resin is insoluble in petroleum 
ether, but soluble in ether or alcohol. It is also known as the 
''hard resin." 

The soft resins are supposed to contain the valuable bitter 
substances present in hops. From these resins, Lintner and 
SchnelP" isolated two crystalline bitter substances of an acid 
nature. One of these, C15H24O4, they proposed naming 
**humulon;"^^ the other, they have designated ''lupulic acid."^* 

According to Chapman, the total resins constitute more than 
55 per cent, of the lupulin.^^ 

Wax. According to Lermer^^ the wax is insoluble in 90 per 
cent alcohol and can be obtained by treating the ethereal extract 
with this solvent. He identified it as myricyl palmitate. As 
Power, Tutin and Rogerson^'' report the presence of ceryl alco- 
hol and cerotic acid in hops, it is quite probable that ceryl 
cerotate is also a constituent of the wax. 

Alkaloids. Choline^* (C5H15O0N) is the only base occurring 
in lupulin, the identity of which has been established. There 
is, however, considerable evidence of the presence of a volatile 



^oThe theory advanced by Seyffert (Zeitschr. ges. Brauw. (1896), 19, p. 1 
namely, that the hop resins are mixtures of substances in a progressive stajt© 
of change is probably correct. Confirmation of this theory is to be found 
in the work of Russell who states that a portion of the "soft resin'" is con- 
verted into the "hard resin" upon keeping the hops in storage. U. S. Dept. 
Agric, Bull. No. 282 (1915), p. 9. 

11 Wochenschr. f. Brau. (1887), 4, p. 397; Ihid. (1888), 5, p. 937. 

"Zeitschr. ges. Brauw. (1904), 27, p. 666. 

" "Humulon" is very likely identical with the "hop-bitter acid" of H. feun- 
gener, (Bull. Soc. Chim. (1886), 45, p. 487), and the "a-lupullc acid" of 
Barth. Zeitschr. ges. Brauw. (1900), 23, pp. 509, 587. 664, 672 and 694. 

" "Lupulic acid" corresponds to the ")8-lupulic acid" of Barth, I. c. 

^l. c. 

«Dingler's Folytech. Journ. (1863), 169, p. 54. 

"Z. c. 

" Grless and Harrow have shown that hops contain not over 0.02 per cent, 
of choline. Ber. der deutsch. chem. Ges. (1885), 18, p. 717. 



|[90 ^U MEZ— THE GALENICAL OLEORESINS 

alkaloid possessing a coniine-like odor. Griessmayer/® who 
first noted its presence, gave it the name ''lupuline." 

In 1885, Williamson^*^ reported the isolation of a crystalline 
alkaloid from wild American hops. He gave it the name 
*'hopeine," and assigned to it the formula, C18H20NO4. HoO. 
Ladenburg,^^ who examined a sample of the material thought 
it to be a mixture of morphine and a more soluble base.^^ As 
further work^^ along this line has failed to confirm the findings 
of Williamson, the presence of a crystalline alkaloid must be 
considered doubtful. 

AsJi, Analyses of the ash of lupulin have apparently not 
^been reported to date. However, Wehmer^ states that Ca, CI 
and SiOa are present in the ash from all parts of the hop plant, 
and, as Na, Mg, Fe, Al, and H3PO4 were identified in the ash 
of the oleoresins examined in the laboratory, it is quite probable 
that the constituents of lupulin ash are identical with those 
present in the ash of hops.^ 

There is a great variation in the quantity of ash obtained 
from commercial samples of lupulin owing to contamination 
with sand and other earthy matter. Barth^ gives the yield of 
ash as 9.5 to 24.4 per cent, while Flueckiger* states that a good 
sample of lupulin should give about 7.0 per cent. Accord- 
ing to Keller,^ lupulin, washed free from all earthy matter, 
yielded only 2.37 per cent, of ash. 

Constituents of Therapeutic Importance, 

There appears to be considerable doubt at the present time 
as to the value of the oleoresin of lupulin as a therapeutic 
agent. The presence of the soluble bitter principles is said to 



"Dingrler's Polytech. Journ. (1874), 212, p. 67. See also Power, Tutin and 
Rogerson, Z. c. 

»Pharm. Ztg. (1885), 30 p. 620. 

»Ber. der deutsch. Chem. Ges. (1886), 19, p. 783. 

*■ Williamson, in a second publication, agrees with the findings of Laden- 
burg and assigns the name hopeine to the more soluble base. Chem. Zeit 
(1886), 10, p. 491. 

*• GreshofE could not obtain a crystalline alkaloid from lupulin. Dingler's 
Polytech. Journ. (1887), 266, p. 316. 

iWehmer, Die Pflanzenstoffe. Jena (1911). p. 100. 

•Richardson, in an examination of hop ash, identified the elements, Na, K. 
Ca, Mg. Al and Fe, and the acids, HgPO^, HjCOj and H^SiO,. Wochenschr. 
Brau. (1898), 15, p. 160. 

•Zeitschr. ges. Brauw. (1900), 23. p. 509. 

•Flueckiger, Pharmakofjnosie des Pflanzenreiches. Berlin (1891), p. 257. 

•Fharm. Ztg. (1889), 34, p. 533. 



OLEORESIN OF LUPULIN 191 

impart to it the properties of a simple bitter.^ The somewhat 
-general belief that the oleoresin is a mild sedative does not ap- 
pear to be well founded and is probably based on the doubtful 
report that hops ^contain an alkaloid (hopeine) resembling 
morphine in physiological action.^ 

Physical Properties 

Color: When spread out in a thin layer on a white porce- 
lain surface, the color of the oleoresin was observed to be a 
dark brown resembling very much that of the oleoresin of gin- 
ger. 

Odor: The preparation when made with acetone or ether 
has the peculiar odor of lupulin. The odor of the commercial 
product, however, is often quite different. In some cases it is 
disagreeable and resembles valeric acid,^ while in other cases 
it is pleasant and suggests the presence of the ethyl esters of 
the lower fatty acids.* 

Taste : The taste is bitter and somewhat aromatic resembling 
that of lupulin. 

Consistence: The oleoresin, when prepared according to the 
directions of the United States Pliarmacopoeia of 1900 is of the 
consistence of a very soft extract. On standing in partially 
filled containers, it becomes firmer as a result of the conversion 
of a part of the soft resin into hard resin. 

Solubility: The official preparation is freely soluble in alco- 
hol (95 per cent.), acetone, ether, chloroform and glacial acetic 
acid. It is partially soluble in petroleum ether, the extent of 
its solubility depending on the age of the oleoresin (if stored 
in partially filled containers) or on the age of the drug from 
which the latter is prepared.^ It is also slightly soluble in 
hot water to which it imparts a bitter taste. 



» Potter, Mat. Med., Pharm. & Therap. (1903), p. 339. 

«Pharm. Ztg. (1885), 30, p. 620. 

•This is due to the use of old deteriorated drug in the preparation of the 
oleoresin or to the storing of the latter under improper conditions. See under 
"Drug used, its collection, preparation, etc." 

♦The agreeable fruity odor sometimes noticed is thought to be due to the 
presence of ethyl esters of the lower fatty acids formed as a result of the 
extraction of old deterloratd drug with alcohol. 

• On aging under ordinary conditions, the soft resin present in the drug or 
oleoresin is converted, in part, into hard resin. As only the former Is soluble 
in petroleum ether, old oleoreslns, or those prepared from old drug, are 
usually less soluble in this solvent than the preparations freshly made from 
unaltered drug. See under "Drug used, its collection, preservation, etc." 



192 



DU MEZ— THE GALENICAL. OLEORESINS 



Specific gravity: The oleoresin has the highest specific 
gravity of any of the preparations of this class, specific grav- 
ities of 1.065 and 1.067 having been observed for the same when 
made with ether and acetone, respectively. Alcohol yields a pro- 
duct of somewhat greater density, whereas the use of petroleum 
ether gives an oleoresin of low specific gravity. The important 
factors influencing the specific gravity of this oleoresin, aside 
from the effect produced by the use of different solvents in its 
preparation, are thought to be the condition of the drug^ when 
extracted and the presence of unevaporated solvent in the 
finished product. The results obtained in the examination of 
laboratory and commercial samples are given in the following 
tables. 



Table 93 — Specific gravities of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Specific 
gravity 


1 


1910 


DuMez & Netzel 


Alcohol 


At 25° C 
1 089 


2 




Acetone 


1.067 


3 


Ether 


1 065 


4 


Benzin 


1.037 









Table 94 — Specific gravities of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Specific 
gravity 


1 


1916 


DuMez 


Sharp & Dohme 


At 25° C 
1.065 


2 




Squibb & Sons 


1 .083 1 


3 


T.illv JtrCn 


1.086 




,j 





* The preparation had a slight odor of ether. 

Refractive index: The refractive index of the oleoresin, when 
prepared with acetone, was found to be 1.516 at 25° C, which 
agrees fairly well with that obtained for the sample from Sharp 
and Dohme. The low refractive index observed for the sample 
from Lilly and Co. is thought to be due to the presence of un- 



* See under the caption "Chemistry of the drug and oleoresin". 



OLEORESIN OF LUPULIN 



193 



evaporated solvent (probably alcohol). The results obtained 
in the determinations made in the laboratory are given in the 
tables which follow: 

Table 95 — Refractive index of the oleoresin prepared in the 
laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Refractive 
index 




1916 


DuMez 


Acetone 


At 25° C 
1.5163 











Table 96 — Refractive indices of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Refractive 
index 


1 


1916 


DuMe/ 


Lilly «fe Co 


At 25° C 
1.496 


2 






1.519 











Chemical Properties. ^^ 

Loss in weiglit on heating: A loss in weight of 9.59 to 15.63 
per cent, was observed for the laboratory preparations when 
heated at 110° C. Except in the case of the oleoresin which 
contained nnevaporated solvent (alcohol), the loss did not ex- 
ceed 10.32 per cent. Results of a similar magnitude were ob- 
tained for the commercial samples examined as is shown in the 
tables which follow. 



Table 97 — Laboratory preparations — loss in weight on heating. 



Sample 
No. 


Date 


Observer 


Solvent 


Per cent, of 
of loss on 
heating 


1 


1916 


DuMez 


Alcohol 


At 110° C 

15. 63^ 

9.59 

10.32 

10.08 


2 






3 


" 


Ether 


4 


" 











^ Contained unevaporated solvent. 



194 



DU MEZ— THE GALENICAL OLEORESINS 



Table 98 — Commercial oleoresins — loss in weight on heating. 



Sample 

No. 


Date 


Observer 


Source 


Per cent, 
of loss on 
heating 


1 


1916 


DuMez 


Sharp & Dohme 

Squibb & Sous 


At 110° C 
7 22 


2 




9 46 


s 


" 


Lilly «fe Co 


20 68 











* Contained ether. 

'Probably contained unevaporated solvent (alcohol). 



Ash content: The ash contents, in the case of the oleoresins 
prepared in the laboratory, were found to be 0.93, 1.46 and 1.82, 
depending on whether ether, acetone or alcohol was employed 
in their preparation. A somewhat similar variation in the 
amount of ash obtained for the commercial samples examined 
is, therefore, taken to be an indication of the indiscriminate use 
of the above mentioned solvents in their manufacture, instead 
of acetone as was directed to be employed by the 1900 edition 
of the United States Pyiarmacopoeia. The slightly higher values 
obtained for the commercial samples may have been due to the 
copper, which was found to be present in considerable amounts. 
The results obtained in the ash determinations made in the lab- 
oratory follow: 

Table 99 — Ash contents of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Per cent, 
of ash 


1 


1916 


IVuMez 


Alcohol 


1 62 


2 




Acetone 


1.46 


8 


»' 


Ether 


0.93 


}:.!...:.. 


ti 


Petrol, ether 


0.08 












Table 100 — Ash contents of commercial oleoresins. 



Sample 
No. 


Date 


Ob- 
server 


Source 


Percent, 
of ash 


Forelg-n con- 
stituents 


1 


1916 


DuMez. 


Squibb & Sons 


0.871 
1.53' 
1.71 


Copper 


2 


Lilly & Co 


3 


Sharp & Dohme 


1. 









» Contained ether, 

'Probably contained unevaporated solvent (alcohol), 



OLEORESIN OF LUPULIN 



195 



Acid nuynher: The acid numbers given in the first of the 
tables which follow are those obtained for preparations which, 
had stood in the laboratory for six years previous to being 
examined. As the acidity of the oleoresin very likely in- 
creases on ageing, when kept under ordinary conditions, due to 
the oxidation of some of its constituents, it is thought that a 
somewhat lower value is to be expected for this constant in the 
case of the freshly made preparation. The relatively low 
value found for the oleoresin prepared with alcohol was due to 
the presence of unevaporated solvent, w^hich not only acts as a 
diluent, but also combines to some extent with the acids present 
forming esters, the latter imparting a fruity odor to the 
preparation. Viewed in the light of the foregoing statements, 
the acid numbers obtained for the commercial samples indicate 
that two of them were very probably old preparations and that 
the third (the sample obtained from Lilly & Co.) contained 
unevaporated solvent (alcohol). The results obtained in the 
determination of this constant in the laboratory follow. 

Table 101 — Acid numbers of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Acid 
number 


J 


1916 


DuMez 


Alcohol 


62.9 > 


2 




Acetone 


84 1 


3 


., 


Ether 

Benzin 


80.1 


4 


79 7 











* Contained unevaporated solvent. 

Table 102 — Acid numbers of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Acid 
number 


1 


1916 


DuMez 


Lillv& Co 


61.7 


2 




85.5 


3 


" 


.*Quibb&Sons 


78 4' 











* Contained ether. 



Saponification value: Saponification values ranging from 
223.4 to 239.6 were obtained for the oleoresins prepared in the 
laboratory, the variation being due, very likely, to the nature of 
the solvent employed in extracting the drug. The values found 



196 



DU MEZ— THE GALENICAL OLEORESINS 



for the commercial preparations were somewhat lower, due, in 
two eases, to the presence of unevaporated solvent. In the third 
instance, the low saponification value obtained was very probably 
due to a difference in the quality of the lupulin from which the 
oleoresin was extracted. The results obtained in the examina- 
tion of laboratory and commercial preparations follow. 



Table 103 — Saponification values of oleoresins prepared in the 
laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Saponifica- 
tion value 


1 


1916 


DuMez 




223.4 > 


2 




Acetone . 


239 6 


3 


'« 


Ether 


230 8 


4 


•» 


Benzin 


227 4 











1 Contained ether. 



Table 104 — Saponification values of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Saponifica- 
tion value 


1 


1916 


DuMez 


Lilly & Co 


158. 8* 


2 






220.0 


3 


•• 


Squibb & Sons 


223.3" 











2 Probably contained unevaporated solvent (alcohol). 
* Contained ether. 



Iodine value: The oleoresin, when prepared with acetone, 
ether, or benzin, was found to have an iodine value varying 
from 94.7 to 96.2. When alcohol was the solvent employed 
in its preparation, the value obtained was considerably lower, 
namely, 82.05. A comparison of thse values with those found 
for the commercial samples indicates that alcohol is sometimes 
used in their preparation. The extrernely low value obtained 
for the oleoresin of Lilly & Co. is to be attributed to the pres- 
ence of unevaporated solvent (alcohol) as well as to the effect 
produced by its use as a menstruum. The iodine values ob- 
tained for the preparations examined in the laboratory are 
given in tihe tables which follow. 



OLEORESIN OF PARSLEY FRUIT 



197 



Table 105 — Iodine values of oleoresins prepared in the laboratory. 



9 ana pie 
No. 


Date 


Observer 


Solvent 


Iodine, 
value 


1... 


1916 


DuAIez . 


Alcohol 


82.05' 


2 




Acetone 


96.2 


3 


•' 


Ether 


94.7 


4 


" 


Benzin., 


95.7 











Alcohol was present. 



Table 106 — Iodine values of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Iodine 
value 


J 


1916 


DuMe/ 


Lilly <fe Co 

Sh!\rp & Dohme 


68.71 


2 




92.9 


3 


" 




91. S'' 











> Alcohol was probably present. 
' The odor of ether was noticeable. 



Adulterations, 

Adulteration effected through the use of old deteriorated drug 
in the iiiaimfacture of this preparation has been noted. See 
under ''Drug used, its collection, preservation, etc." 

The presence of copper was detected in all of the commercial 
samples examined. See under "Ash content." 



OLEORESIN OF PARSLEY FRUIT 

Synonyms 

Aetherisches PetersilieextraTct. Culbreth, Mat. Med. (1917), p. 42S. 

Green Apiol,"- Brit. Pharm. Cod. 1907. 

Oil of Parsley, Parrish. Treat, on Phar. (1867), p. 757. 

Oleoresina Petroselini, U. S. P. 1910. 

Oleoresine de Persil, Culbreth, Mat. Med. (1917), p. 428. 

Liquid Apiol, Brit. Phann. Cod. 1907. 



* "Green apiol" is stated to be an alcoholic extract of the parsley fruit ; 
"yellow apiol." the product obtained on treating- this extract with animal 
charcoal, or upon saponifying the same with lead oxide ; and "white apiol" 
the volatile oil obtained on distilling the extract with steam. Brit, and 
Col. Drugg. (1910), 58, p. 235. 

The compound, Cj^Hj^O^, spoken of in chemical literature as apiol is known 
commercially as crystalline apiol. Brit. Fharm. Cod. (1907), p. 112. 



198 I^U MEZ— THE GALENICAL OLEORESINS 

History. 

The oleoresin of parsley appears to have come into existence 
through the attempts which were made to discover a simple 
method for the preparation of the so-called ''apiol" of Homolle 
and Joret,^ which was first brought to the attention of the phar- 
macist in 1855. The first mention of the oleoresin, insofar as 
could be determined with the information at hand, is to be 
found in Parrish's Treatise on Pharmacy published in 1867. 
Since that time, the preparation, or one of a similar nature, has 
been on the market under the name of "green apiol" or ''liquid 
apiol,'' but was never given official recognition until the ap- 
pearance of the present edition of the United States PJiar- 
macopoeia. 

Drug Used, Its Collection, Preservation, Etc. 

In the present edition of the United States Pharmacopoeia, 
parsley fruit is defined as follows: ''The dried ripe fruit of 
Petroselinum sativum Hoffman (Fam. Umhelliferae), without 
the presence or admixture of more than 5 per cent, of foreign 
seeds or other matter. Preserve Parsley Fruit carefully in 
tightly-closed containers protected from light." The plant 
from which the fruit is obtained has also been known under the 
following botanical synonyms: Carum Petroselinum Benth. 
and Hook., and Apium Petroselinum Linne. 

Parsley is an annual herb commonly cultivated in the gar- 
dens of Europe and America. The fruit ripens in the fall, 
when it is gathered, dried and preserved for domestic use or 
shipped to market. The fruit as found in the market shows 
no marked difference in appearance regardless of its source. 
However, it is known to differ in its chemical composition. Thus, 
the fruits grown in Germany contain apiol as the principal 
constituent of therapeutic importance, whereas, those grown 
in France contain mj-risticin.^ The volatile oil content also 
appears to vary with the source as Flueckiger^ states that the 



^ The "apiol" of Homolle and Joret is stated to be the product which re- 
mains unsaponified when the ether or chloroform soluble portion of the alco- 
holic extract of parsley fruit is heated with litharge. Journ. de Pharm. et 
de Chim. (1855), 28, p. 212. 

2 See under "Chemistry of parsley fruit". 
* Pharmakognosie des Pflanzenreichs (1891), p. 938. 



OLEORESIN OF PARSLEY FRUIT 199 

fruits grown in Norway have an exceptionally strong odor. 
Both of the foregoing variations in the composition of the drug 
would naturally be imparted in an increased degree to the 
oleoresins prepared therefrom. As the chemistry of the 
American fruit does not appear to have been studied, its value 
in this connection cannot be said to be definitely established. 
There is good reason, however, to believe that the oleoresins 
made in this country, in part at least, are prepared from home 
grown fruits.^ 

The large amount of fixed and volatile oils present in these 
fruits requires that they be preserved in tightly closed con- 
tainers protected from the light. 

Z7. S. P. Text and Comments Thereon, 

The oleoresin was given official recognition for the first time 
by being admitted to the late edition of the United States Phar- 
macopoeia (edition of 1910). 

1910 

Oleoresina Petroselini 
Oleoresin of Parsley Fruit 
Oleores. Petrosel. — Liquid Apiol 
Parsley Fruit,* in No. 60 powder,' tillation on a water-bath,* and, hav 
five hundred grammes ....500 Gm. ing transferred the residue to a dish. 
Ether,' a sufflcient quantity. remove the remaining ether by spon 

Place the parsley fruit in a cylin- taneous evaporation in a warm place 
drical glass percolator provided with a stirring frequently.' Allow the oleo 
stop-cock and arranged with a cover resin to stand without agitation for 
and a receptacle suitable for volatile four or five days, decant the clear 
liquids.* Pack the powder firmly, liquid portion from any solid residue,' 
and percolate slowly with ether, and preserve it in well-stoppered bot- 
added in successive portions until the ties.' 

drug is exhausted." Eecover the Average Dose. — Metric, 0.5 mil — 
greater portion of the ether by dis- Apothecaries, 8 minims. 

1) For a description of the drug, see page 1104 under *'Drug 
used, its collection, preservation, etc.'' 

2) The Pharmacopoeia directs that the fruit be reduced to a 



^ Joseph K. Janks in his book on spices states thati parsley is being grown in thli 
country. Jos. K. Janks, Spices, New York (1915), p. 69. 

Oulbreth on page 428 of the 1917 edition of his work on Materia Medica also refen 
to the cultivation of parsley in the United States. 



2Q(^ DU MEZ— THE GALENICAL OLEORESINS 

No. 60 power for percolation. Owing to the large fatty oil 
content, this degree of fineness is difficult to attain, and, as 
experiments conducted in the laboratory indicate that a No. 
40 powder is equally satisfactory for this purpose, it appears 
that a change to this effect in the pharmacopooeial directions 
is desirable. 

3) Ether is the solvent directed by the Pharmacopoeia to be 
used for the extraction of the substances constituting the oleo- 
resin. Observations made in the laboratory indicate that 
other solvents may also be employed for this purpose without 
in any way detracting from the value of the finished product. 
Thus, acetone and petroleum ether were found to yield pro- 
ducts almost identical with that obtained by the use of ether. 
The latter is to be preferred to benzin as suggested by Bering- 
er (1892) since its composition is more constant. Alcohol 
which is used commercially in the preparation of some of the 
so-called liquid apiols dissolves a considerable amount of col- 
oring matter and other inert substances and, therefore, yields 
a product of inferior quality. 

4) For a description of the various forms of percolators which 
have been designed to meet the specifications of the Pharma- 
copoeia, see Part I under "Apparatus used". 

5) The pharmacopoeial directions governing the extraction of 
the oleoresinous material are to slowly percolate the drug with 
ether, added in successive portions, until complete exhaustion 
has been effected. Here again, the use of some form of contin- 
uous extraction apparatus would appear to be an improve- 
ment over the present method. 

6-7) For comments on this step in the pharmacopoeial method 
of preparation, see under comments on the oleoresin of cubeb. 

8) Upon the complete removal of the solvent from the perco- 
late, the residual oily liquid deposits a small amount of waxy 
matter which the Pharmacopoeia directs shall be removed by 
decantation. When either is the solvent used in extracting 
the drug, this deposit amounts to less than 1 per cent of the 
oleoresin, while the percentage is somewhat greater, about 1.5 
per cent when acetone is used. The deposit resulting when 
benzin was the solvent employed was found by Beringer to be 
equal to about 3 per cent. 

9) The oleoresin should be kept in well-stoppered bottles as 



OLEORESIN OF PARSLEY FRUIT 



201 



it loses volatile oil upon exposure to the air, and as the glycer- 
ides are prone to undergo partial decomposition due to the ac- 
tion of the moisture and oxygen. 



Yield. 

The information at hand is not sufficient to permit of a state- 
ment being made as to what the average yield of oleoresin 
should be in this case. The results obtained in the laboratory 
and those reported by Beringer show that it is at least 24 per 
cent., when ether or acetone are the solvents employed in ex- 
tracting the drug, whereas those reported by Vanderkleed 
would appear to indicate that the yield is much lower. The 
available information of this nature is given in the following 
tables : 

Table 107 — Yield of oleoresin as reported in the literature. 





Observer 


Yield of Oleoresin to— 




Date 


Alco- 
hol 


Ace- 
tone 


Ether 


Other Solvents 


Remarks 


1892.. 


Beringer 


Per 
cent. 


Per 
cent. 

24.0 


Per 
cent. 


Per cent. 

Benzin 
19.3 

Solvent (?) 
11.40 

13.04 
14.70 


The total yield of 


1913 


Vanderkleed . . . 




extractive mat- 
ter to benzin is 
given as 22.3 per 
cent, which in- 
cludes 3 percent, 
of deposited wax. 

Reported as yield 












of oleoresin. 




" 























Table 108 — Yield of oleoresin as obtained in the laboratory. 





Observer 


Yield of oleoresin to— 




Date 


Alco- 
hol 


Ace- 
tone 


Ether 


Other 
• sol- 
vents 


Remarks 


1916 


DuMez 


Per ct. 


Perct. 

28.89 


Perct, 
29.17 


Perct. 


Represents the yield using a 








Soxhlet's Extraction App. 



2Q2 DU MEZ— THE GALENICAL. OLEORESINS 

Chemistry of the Drug and Oleoresin. 
Enumeration of Constituents. 

The following are the known constituents of parsley fruit which 
may be considered of pharmaceutical interest ; volatile oil, fatty 
oil, apiin, and inorganic substances. While analyses of the 
oleoresin have not been reported, the first two named constitu- 
ents of the fruit, together with a small amount of inorganic 
matter, very likely represent this preparation when made by 
extracting the drug with ether, as apiin is stated to be insoluble 
in this solvent. 

Occurrence and Description of Individual Constituents. 

Volatile Oil} The volatile oil of parsley fruit is described as a 
colorless or yellowish, thick liquid having a specific gravity of 
1.03 to 1.10 at 15 °C. The angle of rotation in a 100 milli- 
meter tube is given as -5° to -10°. It is soluble in alcohol, ether, 
chloroform and petroleum ether. On cooling or shaking with 
water, it precipitates apiol.^ 

The composition of the oil varies with the locality in which 
the fruit is grown. The principal constituent of the oil dis- 
tilled from the fruit grown in Germany is apiol. Myristicin 
is present only in very small quantities.' It is stated that the 
apiol content is often so great that the oil is a semi-solid at or- 
dinary temperatures. In the French oil, myristicin predom- 
inates, while apiol, together with allyltetramethoxybenzene, is 
present in small amount.* The constitution of these compounds 
is represented by the following formulas: 



*The following- list comprises the more important references to the earlier 
literature on the volatile oil: Bley, TrommsdorfC's neues Joum. (1827), 14, 
p. 134; Bolle, Arch, der Pharm. (1829), 29, p. 168; Blanchet and Sell, Ann. 
der Chem. (1833), 6, p. 301; Loewig and W^eidmann, Ibid. (1839), 32, p. 
283; von Gerichten, Ber. der. deutsch. chem. Ges. (1876), 9, pp. 258 and 
1477. 

aSchimmel & Co., Ber. (1906), p. 95. 

"Thorns, Ber. der deutsch. chem. Ges. (1903), 36, p. 3451; Ihid (1908), 
41, p. 2753; Chevalier, Bull. sci. pharmacologique (1910), 17, p. 128; Chem. 
Abs. (1911). 5, p. 1490. 

*Ibid. Also, Bignami and Testoni, Gaz. Chim. ital. (1900), 30, p. 240. 



OLEORESIN OF PARSLEY FRUIT 



203 




Apiol is a crystalline solid possessing in a strong degree the 
odor of parsley. Its melting point is 30 °C and the boiling 
point 294° C* Eykman^ gives the specific gravity at 14° C as 
1.176, and the refractive index [n]D as 1.538. It is soluble in 
alcohol, ether, chloroform and oils. It also dissolves in con- 
centrated sulphuric acid, the solutron formed being blood-red 
in color. 

Myristicin is a liquid possessing but little odor. It does not 
solidify even when cooled to a comparatively low temperature. 
Semmler^^ gives the specific gravity as 1.141 at 25° C. Its 
solubility is similar to that of apiol. 

In addition to the foregoing, Thoms^^ reports the presence 
of the following in both, the German and French oils : 1-pinene, 
phenols and palmitic acid. 

Semmler^^ reports the volatile oil content of parsley fruit 
to be 2 to 6 per cent. 

Fatty X)il}^ The fatty oil of parsley fruit is a greenish yellow 
mobile liquid. It is soluble in a mixture of alcohol and ether, 
in ether, chloroform and carbon disulphide. A sample from 
Schimmel & Co., examined by von Gerichten and Koehler,^* 



'Eykman, Ber. der. deutsch. chem. Ges. (1890), 23, p. 862; Thorns, IMd. 
1903, 36, p. 174. 

•Thorns. Chem. Ztg. (1903). 27, p. 938. 

T Thorns. Ber. der. deutsch. chem. Ges. (1908), 41, p. 2761. 

•Ciamician and Silber, IJyid. (1888), 21, p. 1632. 

•I. c. 

»»Semmler, Die aetherische Oele (1907). 4. p. 168. 

^ Arbeiten axis d. Pharm. Inst., Univ. Berlin (1909), 6, p. 190. 

" Semmler, Die aetherische Oele (1907), 4. p. 173. 

" Grimme obtained 16.7 per cent, of a red-brown oil having the following 
properties: specific gravity at 15° C, 0.9243 ; refractive index at 35" C, 1.4778 ; 
saponification value, 176.5 ; iodine value, 109.6 ; acid value, 3.4 ; unsaponifl- 
able matter, 2.18 per cent. He was unable to obtain a test for the presence 
of phytosterin in the unsaponifiable residue. Pharm, Centralh. (1911), 52, 
p. 663. 

"Ber. der. deutsch. chem. Ges. (1909), 42. p. 1638. 



204 ^U MEZ— THE GALENICAL OLEORESINS 

showed the following properties: specific gravity at 15°C, 0.972; 
refractive index at 40°C, 1.4624; saponification value, 190.9; 
iodine value, 80.07. 

The saponifiable portion of the oil was found to be com- 
posed of the glyceryl esters of oleic, palmitic, stearic and 
petroselinic acids. The latter is stated to be isomeric with 
oleic acid. From the unsaponifiable residue, Matthes and 
Heintz^^ isolated a hydrocarbon, C20H40, to which they gave the 
name petrosilan; also, myricyl alcohol and a mixture giving a 
test for phytosterin. 

The average fatty oil content of the fruit is probably about 
20 per cent.^^ 

Apiin.^'^ Apiin (C27H30O1G) is a glucoside. Its melting 
point is stated to be 228 °C. On hydrolysis, it yields a sugar 
and apigenin (trioxyflavon) C15H10O5. It is soluble in hot 
alcohol or water, insoluble in ether, and therefore, it is not 
likely to be present in the oleoresin. 

Ash. Available information concerning the constituents of 
the ash of parsley fruit is limited to the anaylsis of Rump,^* 
who reports the presence of the basic elements, K Ca, Mg and 
Fe in combination with the acids, HCl, H2SO4, H3PO4, H2CO3 
and H2Si03, also, some free SiOo. 

The ash content^® of parsley fruit is about 6.50 to 7.00 per 
cent. Commercial samples sometimes show a higher percentage 
of ash due to contamination with foreign matter.-^ 

Constituents of Therapeutic Importance. 

The oleoresin of parsley fruit is said to be used chiefly as an 
emmenagogue. Such being the case, its therapeutical value 
is undoubtedly due to the volatile oil which it contains as both 
apioP and myristicin,- constituents of the essential oil, have 



i^Ber. der. pharm. Ges. (1909), 19, p. 325. 

1^ Rump, obtained 22 per cent, of fatty oil. Buchner's Repert. f. d. Fharm. 
(1836), 6, p. 6. Grimme gives the yield as 16.7 per cent. 1. c. 

"von Gerichten, Ber. der deutsoh. chem. Ges. (1876), 9, p. 1121. 

"Buchner's Repert. f. d. Pharm. (1836), 56. p. 26. 

1® Rump gives the ash content as 6.5 per cent. Ibid. Warnecke reports 
the percentage of ash as 7.04. Pharm. Ztg. (1886), 31. p. 53 6. 

*• La Wall and Bradshaw report two commercial samples of parsley fruit 
yielding 6.61 and 9.10 per cent, of ash, respectively. Proc. A. Ph. A. (1910), 
58, p. 752. 

^Heffter, Arch. f. exp. Path. u. Pharmak. (1895), 35, p. 365. Chevalier 
Bull. Sci. pharmacologique, 17, pp. 128-131. 

2Juerss, Schimmel & Co., Ber, (1904), p. 159. 



OLEORESIN OF PARSLEY FRUIT 



205 



been shown to be severe intestinal irritants. The activity of 
the volatile oil may be further accounted for by the presence 
of terpenes as these compounds are also known to be irritants.* 

PJiysical Properties 

Color: When spread out in a thin layer on a while porcelain 
surface, the oleoresin was observed to be greenish-yellow in 
color. The so-called fluid apiols of commerce, preparations 
made with alcohol, are of a comparatively deep green color. 

Odar: The oleoresin has the agreeable aromatic odor of 
parsley. 

Taste: The taste is spicy like that of the drug from which 
it is prepared. 

Consistence: The oleoresin is a rather thin liquid, being of 
about the consistence of olive oil. 

Solubility: The official preparation is soluble in acetone, 
ether, chloroform, carbon disulphide and petroleum ether. It 
is almost insoluble in alcohol or water. 

Specific gravity: The specific gravities of the oleoresins pre- 
pared in the laboratory were found to be 0.937 and 0.940 at 25° C. 
In the making of these preparations ether and acetone, respec- 
tively, were employed as menstrua for extracting the drug. The 
specific gravity of the only commercial sample, conforming in its 
general properties to the official product, was observed to be 
about the same, i. e. 0.943. In the case of the other commercial 
products, the greater density is thought to be due to the use of 
alcohol in their preparation.^ The results for the determina- 
tions made in the laboratory follow. 

Table 109 — Specific gravities of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


specific 
gravity 


I 


1916 


Du Me7 


Acetone 


At25° C 
0.940 


2 




Ether 


0.937 





















sKehrer, Arch. f. Gyn. (1910), 90. p. 169. 

^ This statement is also based on the dark green color of the preparations 
and the fact that alcohol is the solvent mentiond in the literature in con- 
nection with the preparation of the so-called fluid apiols. See under "His- 
tory" of the oleoresin. 



206 



DU MEZ— THE GALENICAL OLEORESINS 



Table 110 — Specific gravities of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Specific 
erravity 


1 


1916 


DuMez 


Sharp & Dohme 


At 25° C 
0.943 


2 




SQuibb & Sons 


0.984' 


3 


" 


Merck& Co 


1.0082 











^Apiol, fluid, — Squibb. 

2 Apiol, fluid, green, — Merck. 



Refractive index: Observations made in the laboratory in- 
dicate that the oleoresin should have a refractive index of 
about 1.477 at 25° C, when ether or acetone are employed in the 
extraction of the drug. A result almost identical with the 
preceding was obtained for the only commercial sample ex- 
amined. The refractive indices observed in the case of the 
so-called liquid apiols were somewhat higher, due very likely 
to the use of alcohol in their preparation. The data given in 
the following tables illustrate these points. 

Table 111 — Refractive indices of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Refractlre 
index 


1 


1916 


DuMez 


Acetone 


At 25° C 

1 477 


2 




Ether 


1.477 











Table 112 — Refractive indices of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Refractive 
index 


1 


1916 


DuMez 


Sharp & Dohme 


At 25° C 
1.475 


2 




Sauibb & Sons 


1 486' 


3 


♦• 


Merck & Co 


1 1488* 











1 Apiol, Fluid— Squibb. 

* Apiol, Fluid, Green, — Merck. 



OLEORESIN OF PARSLEY FRUIT 



207 



Ckemical Properties. 

Loss in weight on heating: The oleoresins prepared in the 
laboratory, using ether and acetone as menstrua for exhausting 
the drug, lost 7.87 and 7.92 per cent, of their weight, respec- 
tively, on heating at 110°C. In the case of the only com- 
mercial sample examined, the loss was about one-half as 
great due very likely to a smaller amount of volatile matter 
(essential oil) being contained in the drug from which the lat- 
ter was prepared. The results obtained are given in the 
tables which follow. 



Table 113 — Laboratory preparations — loss in weight on heating. 



Sample 
No. 



Date 



1916 



Observer 



DuMez 



Solvent 



Acetone 
Ether... 



Percent, of 
loss on 
heatlncr 



At 100° C 
7.92 
7.87 



Table 114 — Commercial oleoresins — loss in weight on heating. 



Sample 
No. 


Date 


Observer 


Source 


Per cent, of 
loss on 
heating 


1 


1916 


DuMez 


Sharp & Dohme 


At 110° C 
8.35 











Asli content: The results obtained in the determination of 
the ash content of the oleoresins examined in the laboratory are 
given in the tables which follow. Aside from the fact that the 
amount of ash obtained varied with the solvent used in the 
making of the preparations, the only items of importance 
brought out by these results are that ether was evidently em- 
ployed in the manufacture of the commercial product and that 
the latter contained copper. 

Table 115 — Ash contents of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Per cent, 
of ash 


1 


1916 


DuMez 




0.18 
0.09 


2 




F.thAT 







208 



DU MEZ— THE GALENICAL, OLEORESINS 



Table 116 — Ash contents of commercial oleoresins. 



Sample 
NO. 


Date 


Observer 


Source 


Percent, 
of ash 


Foreign con- 
stituents 


1 


1916 


DuMez 


Sharp & Dohme 


0.09 


Copper 





Acid number: The acid numbers obtained for the oleoresins 
prepared with acetone and ether were found to be 9.3 and 9.2, 
respectively, indicating that the difference in the nature of the 
two solvents has but little influence on the value of this con- 
stant. The high value found for the sample obtained from 
Sharp & Dohme is thought to be due to the hydrolysis of some 
of the glycerides, and, therefore, to indicate an old preparation, 
or one that has been prepared from old deteriorated drug. The 
acid numbers obtained for the oleoresins examined, also those 
found for the so-called liquid apiols, are given in the tables 
which follow. 

Table 117 — Acid numbers of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Acid 
number 


1 


1916 


DuMez 


Acetone 


9 3 


2 




Ether 


9.2 











Table 118 — Acid numbers of commercial preparations. 



Sample 
No. 


Date: 


Observer 


Source 


Acid 
number 


I 


1916 


DuMez 


Merck & Co 


12.11 


2 




Sharp & Dohme 


50.5 


3 


n 


Squibb & Sons 


58.5' 











^Apiol, Fluid, Green. 



Saponification value: The saponification values of the oleo- 
resins prepared in the laboratory, using ether and acetone as 
menstrua for extracting the drug, were found to be 158.5 and 
165.6, respectively. The high value (181.6) obtained for Sharp 



OLEORESIN OF PARSLEY FRUIT 



209 



& Dohme's preparation is thought to be due to the presence of a 
relatively large amount of the glyceride of petroselinic acid, 
which is stated by von Gerichten to have a saponification value 
of 191.2. See under ''Chemistry of the drug and oleoresin." 
Tables showing the saponification values of the preparations 
examined in the laboratory follow. For comparison with the 
foregoing data, the values obtained for the so-called liquid 
apiols have also been included in these tables. 

Table 119 — Saponification values of oleoresins prepared in the 

laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Saponi6ca- 
tion value 


1 


1916 


DuMez 


Acetone 


165 6 


2 




Ether 


158.5 











Table 120 — Saponification values of commercial preparations. 



Sample 

No. 


Date 


Observer 


Source 


Saponifica- 
tion value 


I 


1916 


DuMez 


Mpfck &Co 


108.51 


S::::::::: 




Sauibb & Sons 


126.7''' 


45 


" 


Sharp & Dohme 


181.6 











^ Apiol, Fluid, Green, — Merck. 
2Apiol, Fluid,— Squibb. 



Iodine value: The iodine values as found for the oleoresins 
prepared in the laboratory are given in the first of the tables 
which follow. It will be observed that there is a considerable 
difference in these values due to the nature of the solvent em- 
ployed in extracting the drug. The low iodine value observed 
for the preparation made by Sharp & Dohme is to be attributed 
to the partial oxidation of the unsaturated glycerides. For 
comparison, the iodine values of two samples of so-called 
^'liquid apiols "( preparations made with alcohol) have been 
included in the tables which follow. 



210 



DU MEZ— THE GALENICAL OLBORESINS 



Table 121 — Iodine values of oleoresins prepared in the laJ)oratoru, 



Sample 
No. 


Date 


Observer 


Solrent 


Iodine value 


1 


1916 


DuMez 


Acetone 


132.5 


2 




Ether 


12?. 9 









Table 122 — Iodine values of commercial preparations. 



Sample 
No. 


Date 


Observer 


Source 


Iodine value 


1 


1916 


DuMez 


Sharp & Dohme 


110.6 


2 




Sfiuibb & Sons 


123.3 1 


3 


'» 


Merck & Co 


130.2 « 











1 Labeled "Apiol-Fluid." 

2 Labeled Apiol, Fluid, Green. 

Adulterations. 

A trace of copper was found to be present in the commercial 
samples examined. See under "Ash content.'' 

OLEORESIN OF PEPPER 

Synonyms 

Aetherisches Pfefferextralct, Nat. Disp. 1884. 

Ethereal Extract of Black Pepper, King's Am. Disp. 1900. 

Extractum Piperis, Hirsh, Univ. P. 1902, No. 1244. 

Extr actum Piperis Fluidum, U. S. P. 1850. 

Fluid Extract of BlacTc Pepper, U. S. P. 1850. 

Oil of BlacTc Pepper, King's Am. Disp. 1900. 

Oleoresina Piperis, U. S. P. 1900. 

OUoresine de Poivre noir, U. S. Disp. 1907. 



History. 

The oleoresin of pepper appears to have been first obtained 
as a by-product^ in the preparation of piperine. Thus, Dr. 
Meli in France as early as 1825, reported having obtained the 
so-called ''oil of black pepper'' as a residue on separating the 
piperine from the alcoholic extract of the drug. The first 
notice of its use as a therapeutic agent apparently came from 

>Jourdan, Univ. P, (1832), p. 84f 



OLEORESIN OF PEPPER 211 

America as Carpenter, in 1829, in an article on Peruvian bark, 
refers to its use by Dr. Chapman of Philadelphia in connec- 
tion with the administration of quinine. The oleoresin prepared 
with ether became official in the United States Pharmacopoeia 
in 1850 under the title Extractum Piperis Fluidum. In the 
1860 edition, the name was changed to Oleoresina Piperis, under 
which title, it is still official at the present time. Neither this 
preparation nor one of a similar nature has ever been given of- 
ficial recognition abroad. 

Drug Used, Its Collection, Preservation, Etc. 

According to the present edition of the United States PJiar- 
macopoeia, the drug recognized is ''the dried, unripe fruit of 
Piper nigrum Linne (Fam. Piperaceae), without the presence 
or admixture of more than two per cent of stems or other for- 
eign matter. ' ' It has also occassionally been referred to under 
the botanical synonyms. Piper trioicum Roxb. 

As becomes apparent from the foregoing, only the unripe 
fruits should be used. As the fruit reaches maturity, the 
chlorophyll content diminishes and it becomes less pungent.* 
A variation in the chlorophyll would naturally effect the prop- 
erties of the oleoresin prepared therefrom, while a difference 
in piperine content would have no significance in this connec- 
tion as only a small portion of the total piperine (to which pep- 
per owes its pungency)^ remains in solution in the oleoresin, 
the greater part being precipitated upon the ermoval of the sol- 
vent. 

Pepper, as it occurs on the market, consists of a number of 
commercial varieties, viz: Malabar, Cochin, Penang, Singapore, 
Siam and others.^ The quality of these varieties is ordinarily 
governed by weight, the Malabar being the heaviest. The 
Penang, however, is stated to be the most pungent. The man- 
ner in which either of these qualities effect the oleoresin does 
not appear to have been determined. While the Pharmacopoeia 
makes no provisions for the preservation of this drug, its volatile 
oil content necessitates the use of closed containers. 



iFlueckiger, Pharmakognosie des Pflanzenreiches (1891), p. 913. 
'Kayser, Chem. Centralb. (1888), 59, p. 261. 
■Jos. K. Janks, Spices, New York, (1915), p. 10. 



-212 I^U MEZ— THE GALENICAL, OLEORESINS 



JJ. S. p. Text and Comments Thereon. 

The oleoresin of pepper has been official in the United States 
Pharmacopoeia since 1850, when it was recognized under the 
title of Extractum Piperis Fluidum. 



1850 

Extractum Piperis Fluidum 

Fluid Extract of Black Pepper 

Take of Black Pepper/ in powder,^ heat, apint and a half of ether," and 

a pounds expose the residue in a shallow ves- 

Ether,^ a sufficient quantity. sel, until the whole of the ether has 

Put the powder into a percolator,* evaporated,^ and the deposition of 

and pour ether gradually upon it until piperin in crystals, has ceased. Lastly, 

two pints of filtered liquor are ob- separate the piperin by expression 

tained." From this distill off, by through a cloth,* and keep the liquid 

means of a water-bath, at a gentle portion. 



1860 
Oleoresina Piperis 
Oleoresin of Black Pepper 
Extractum Piperis Fluidum, Pharm., 1850 

Take of Black Pepper,^ in fine pow- eighteen fluidounces of ether,* and 
der,2 twelve troyounces; expose the residue, in a capsule, until 
Ether,' a sufficient quantity. the remaining ether has evaporated,^ 
Put the Black Pepper into a cylin- and the deposition of piperin in cry- 
drical percolator,* press it firmly, and stals has ceased. Lastly, separate 
gradually pour ether upon it until the oleoresin from the piperin by ex- 
twenty-four fluidounces of filtered pression through a muslin strainer,' 
liquid have passed." Recover from and keep it in a well-stopped bottle.' 
this, by distillation on a water-bath. 



OLEORESIN OF PEPPER 



2ia 



1870 

Oleoresina Piperis 
Oleoresin of Black Pepper 



Take of Black Pepper/ in fine pow- 
der,' twelve troy ounces; 

Ether,^ a suificient quantity. 

Put the Black Pepper into a cylin- 



Recover the greater part of the ether 
by distillation on a water-bath,* and 
expose the residue, in a capsule, until 
the remaining ether has evaporated,' 



drical percolator provided with a and the deposition of piperin in crys- 

stop-cock, and arranged with cover tals has ceased. Lastly, separate the 

and receptacle suitable for volatile oleoresin from the piperin by expres- 

liquids,* press it firmly, and gradually sion through a muslin strainer,* and 

pour ether upon it, until twenty fluid keep it in a well-stopped bottle.' 
ounces of liquid have slowly passed.' 

1880 

Oleoresina Piperis 
Oleoresin of Pepper 
Pepper,^ in No. 60 powder,' one hun- greater part of the ether by distilla- 

dred parts 100 tion on a water-bath,* and expose the 

Stronger Ether,' a sufficient quantity, residue, in a capsule, until the re- 
Put the pepper into a cylindrical maining ether has evaporated,' and 
percolator, provided with a cover and the deposition of piperine, in crystals, 
receptacle suitable for volatile liquids,* has ceased. Lastly, separate the 
press it firmly, and gradually pour oleoresin from the piperine by ex- 
stronger ether upon it, until one hun- pression through a muslin strainer.' 
dred and fifty (150) parts of liquid Keep the oleoresin in a well-stopped 
have slowly passed.' Recover the bottle.' 



1890 

Oleoresina Piperis 
Oleoresin of Pepper 

Pepper,^ in No. 60 powder,' five hun- from the percolate by distillation on a 

dred grammes 500 Gm. water-bath,* and, having transferred 

Ether,^ a sufficient quantity. the residue to a capsule, set this aside 

Put the pepper into a cylindrical until the remaining ether has evapor- 

glass percolator, provided with a stop- ated,^ and the deposition of crystals of 

cock, and arranged with a cover and piperine has ceased. Lastly, sepa- 

receptaele for volatile liquids.'* Press rate the oleoresin from the piperin by 

the drug firmly, and percolate slowly expression through a muslin strainer.' 

with ether, added in successive por- Keep the oleoresin in a well-stop- 

tions, until the drug is exhausted." pered bottle.' 
Recover the greater part of the ether 



214 E>U MEZ— THE GALENICAL OLEORESINS 

1900 

Oleoresina Piperis 
Oleoresin of Pepper 

Pepper/ in No. 40 powder/ -five hun- distillation on a water-bath,' and, 

dred grammes 500. Gm. having transferred the residue to a 

Acetone/ a sufficient quantity. dish, set this aside in a warm place, 

Introduce the pepper into a cylin- until the remaining acetone has evap- 

drical glass percolator, provided with orated,'' and the deposition of crystals 

a stop-cock, and arranged with a cover of piperin has ceased. Lastly, sepa- 

and a receptacle for volatile liquids.* rate the oleoresin from the piperin by 

Pack the powder firmly, and percolate straining through purified cotton.' 

slowly with acetone, added in succes- Keep the oleoresin in a well-stoppered 

sive portions, until the pepper is ex- bottle.* 

hausted." Kecover the greater part Average dose. — 0.030 Gm. :=30 mil- 

of the acetone from the percolate by ligrammes (^ grain). 



1910 
Oleoresina Piperis 
Oleoresin of Pepper 
Olcores. Piper. 

Pepper,* in No. 40 powder,* -five hun- tillation on a water-bath,* and, hav- 

dred grammes 500. Gm. ing transferred the residue to a dish, 

Ether,^ a sufficient quantity. set this aside in a warm place until 

Place the pepper in a cylindrical the remaining ether has evaporated,' 

glass percolator, provided with a stop- and the deposition of piperine has 

cock, and arranged with a cover and ceased. Lastly, separate the oleo- 

s. receptacle for volatile liquids.* resin from the piperine by straining 

Pack the powder firmly, and perco- through purified cotton.' Keep the 

late slowly with ether, added in sue- oleoresin in a well-stopped bottle.' 

cessive portions until the drug is ex- Average Dose. — Metric, 0.03 Gm. — 

hausted.' Kecover the greater part of Apothecaries, ^2 grain, 
the ether from the percolate by dis- 

1) For a description of the official drug, see page 1117 under 
^'Drug used, its collection, preservation, etc." 

2) The last two editions of the Pharmacopoeia have specified 
that the drug be in the form of a No. 40 powder for percolation. 
Previous editions, with the exception of that of 1850, in which 
the degree of .fineness was not stated, required that a fine 



OLEORESIN OF PEPPER 215 

powder (No. 60) be used for this purpose. The coarser 
powder possesses the advantages of being more readily pro- 
duced and of being better adapted to the rapid exhaustion of 
the drug. 

3) The solvents which have been experimented- with in the 
preparation of this oleoresin are alcohol, ether, acetone, ben- 
zin and petroleum ether. Of these, ether has proven to be the 
most satisfactory and is the solvent specified for this purpose 
by the present Pharmacopoeia. Acetone, which was directed 
to be used by the Pharmacopoeia of 1900, like alcohol, is un- 
satisfactory as the large amount of extractive matter obtained 
interferes with the separation of the piperine. Benzin or pe- 
troleum ether, on the other hand, dissolves piperine but 
slightly and, therefore, yield a product low in piperine con- 
tent. See tables on page 1134. 

4) For a description of percolators adapted to the use of 
volatile liquids, as specified for use in this connection by the 
Pharmacopoeia, see Part I under ''Apparatus used." 

5) With respect to the manner of exhausting the drug, it is 
thought that the process of continuous extraction would be a 
distinct improvement over the present pharmacopoeial method. 
The reasons for this statement have already been given in 
the comments of the preceding oleoresins and need not be re- 
peated here. 

6-7) As this oleoresin does not appear to undergo any notice- 
able changes upon exposure to the air, except to lose a small 
amount of volatile oil, the conditions under which the solvent 
is removed from the percolate are not as important as in the 
case of the other oleoresins. The time necessary to complete 
the preparation, however, can be considerably shortened if 
the operation is completed at the temperature of the water 
bath, for which reason, this procedure is thought to be justi- 
fied. 

8) The Pharmacopoeia directs that the mixture obtained on 
evaporating the solvent from the percolate be allowed to stand 
until the deposition of the piperine is complete and that the 
latter then be separated from the liquid portion by straining 
through purified cotton. The object to be attained in allow- 
ing the piperine to deposit is not understood as it has been 
found in actual practice that the liquid portion. does not sep- 



21 g DU MEZ— THE GALENICAL, OLEORESINS 

arate as a rule, but that the whole sets to form a semi-solid 
mass owing to the large amount of piperine present. The 
means by which the separation of the piperine was accomp- 
lished in the laboratory appears to be more rational and is as 
follows: the mixture was heated on the water bath until the 
portion constituting the oleoresin was quite fluid when it was 
filtered through cotton with the aid of a suction pump. The 
piperine which deposited from the filtered oleoresin on cool- 
ing was finally separated by decantation. 

9) As the oleoresin loses volatile oil on exposure to the air,, 
it should be kept in well-stoppered bottles. 

Yield. 

The yield of oleoresin to acetone or ether is about 4.5 to 6.5 
per cent. With petroleum ether, a yield of 3.2 per cent, was ob- 
tained in the laboratory. Aside from the effect which the solvent 
has upon the amount of the oleoresin obtained, the temperature at 
which the piperin is separated is a factor to be considered. The 
higher the temperature at which this is accomplished, the greater 
the amount of piperine remaining in solution and the greater 
the yield of finished product, and visa versa. 

In the tables which follow, the yield of total extract is fre- 
quently reported as oleoresin. These reports should not be 
confused with those pertaining to the official preparation, which 
consists of the liquid portion only, the precipitated piperine 
and other insoluble material having been removed. Data of 
this kind have been included here for the sake of comparison 
with results of a like nature obtained in the laboratory and in 
order to point out the erroneousness of such reports. 



OLEORESIN OF PEPPER 



217 



Table 123 — Yield of oleoresin as reported in the literature. 





Observer 




Yield of oleoresin to- 




Date 


Alco- 
hol 


Ace- 
tone 


Ether 


Other solvents 




1888 


Trimble 


Per ct. 


Per ct. 


Perct. 

8.79 


Per cent. 

J Benzin 

1 2.80 J 


Represents total 


1892 


Bei iii^er 




9.97 
5.93 


yield of extract- 
tive matter. 




Sherrard 





5.00 to 
6.70 

8.84 

9.64 

5.50 

8.70 

10 15 

10.04 
10.87 
12.88 




Yield of oleoresin. 




.....1 


Reported as yield 




Ballard 






... . f 


of" oleoresin (' ) 


1903 












Patch 






, . ) 


liidies. Total ex- 
tract. 
Pepper from Gua- 








deloupe. Total 
extiacL. 


1913 






coa.stof Daliomey. 
Total extract. 




Enifelhardt 






I 


Represents total 








::::::: ::::::::::i 

» Solvent (?)... . 

1 9.20 ] 
10.60 1 
11.00 f 
12.50 J 


yield of extract. 


,. 


















Reported as yield 

































(1) Undoubtedly represents total extract. 



Table 124 — Yield of oleoresin as obtained in the laboratory. 





Observer 


Yield of oleore.sin to— 




Date 


Alco- 
hol 


\ce- 
tone 


Ether 


Pptrol. 
ether. 


Remarks 


1916 


Du Mez 


Per ct. 
11.10 

5.32 


Per ct. 
lO.fiS 

5.09 


Per nt. 
10.42 

4.44 


Perct. 
7.14 

3.20 


Repre-ents. total ex- 
tract. 

Rei resents the por- 
tion (iecaiitod and 
waslied from the de- 
posited piperine. 











21g DU MEZ— THE GALENICAL. OLEORESINS 

Chemistry of the Drug and Oleoresin. 

Tabulation of Constituents. 

The chemistry of black pepper has been the subject of a 
number of investigations^ conducted during the past century. 
As a result of these investigations, the presence of the follow- 
ing substances of pharmaceutical interest has been established: 
volatile oil, piperine, resin, starch, coloring matter and inor- 
ganic constituents. In addition to the foregoing, the presence 
of fatty oil, piperidine and methyl pyrroline has been reported. 
The following are stated by Kayser and others^ to be present 
in the oleoresin when prepared with ether: 



Eesin 


Volatile Oil 


Coloring Matter 


Fatty Oil 


Ash 


Piperine 



Occurrence of Description of Individual Constituents. 

Volatile Oil:^ According to the report of Schimmel and 
Company,* the volatile oil of pepper is a colorless or yellowish- 
green liquid, having a phellandrene-like odor. At 15°C, the 
specific gravity is given as 0.88 to 0.905 and the angle of ro- 
tation in a 100 millimeter tube as -5° 2' to -[-2° 27'. It is 
stated to be soluble in 15 parts of alcohol (90 per cent). 

Early attempts to determine the composition of the oil were 
made by Dumas,^ and Soubeiran and Capitaine.® In 1887, 
Eberhardt^ isolated a 1-terpene which he failed, however, to 



* Among those who have reported more or less complete analyses of pepper 
the following may be mentioned: Pelletier, Ann. de Chim. et de Phys. (1821), 
16, p. 337; Luca, Tschenb. f. Scheidekiinstl. u. Apoth. (1822), 43, p. 81; H. 
ROttger, Arch. f. Hygiene (1886), 4, p. 183; Richardson, U. S. Dept. of 
Agric. Bull. No. 13, (1887), p. 206; Johnstone, Chem. News (1888), 58, p. 
235; Kayser, Chem. Centralb. (1888). 59, p.261 ; V^eigle, Apoth. Ztg. (1893), 
8, p. 468; Hebebrand, Zeitschr. Unters. Nahr. u. Genussm. (1896), p. 345; 
Winton, Ogden and Mitchell, Ann. Rep. Conn. Exp. Sta. (1898), p. 198; 
Balland, Journ. de Pharm. et de Chim. (1903), 157, p. 296. 

2 Kayser, Weigle, Balland, I. c. 

3 The description of the oil as here given is for that obtained from the 
fruit by distillation with steam. 

* Schimmel & Co., Semi-Ann. Rep., Oct. 1893, p. 34. 

»Ann. d. Chem. (1835), 15, p. 159; Journ. f. prakt. Chem. (1835), 4, p. 434. 
"Journ. de Pharm. et de Chim. (1840), 26, p; 83. 
'Arch, der Pharm. (1887), 225, p. 515. 



OLEORESIN OF PEPPER 219^ 

identify. Schimmel and Company* have reported the presence 
of phellandrene and cadinene. 

From 0.70 to 2.2 per cent, of volatile oil has been obtained 
from the fruits by steam distillation.® 

Piperine}^ Piperine (C17H19NO3) was first isolated by 
Oersted in 1819.^^ It is a weak base crystallizing from alcohol 
in colorless, shining, four sided prisms, the melting point of 
which is 128 to 129 °C. It is slightly soluble in boiling water, 
readily soluble in alcohol, ether, chloroform, benzene and volatile 
oils, slightly soluble in petroleum ether. When acted upon by 
solutions of the alkalies, it is hydrolyzed breaking down into 
piperidine and piperic acid. Its constitution is represented* 
by the following structural formula :^^ 

H. H, 



-O 



N COCH:CH CH:CH. 




^ C H H 

H, H, H H 

The quantity of piperine present in the fruit of black pepper 
as obtained on the market varies to a considerable extent. This 
variation is very probably due in greater part to natural causes, 
such as the age of the fruit before harvesting, climatic condi- 
tions under which grown, et cetera}^ The yield is variously 
stated as being from 4.05 to 13.02 per cent.^* 



*i. c. 

»A yield of 0.7 to 1.69 per cent, of volatile oil is reported by C. H. Rich- 
ardson I. c. W. Johnstone obtained 0.98 to 1.87 per cent. Analyst (1889), 
14, p. 41. G. Teyxeira and B. Ferrucio give the yield as 1.4 per cent. Bull. 
Chim. Fharm. (1900), 38. p. 534; Chem. Centralb. (1900), 71, p. 736. Schim- 
mel & Co. (1. c.) report the yield as 1.3 to 2.2 per cent. 

wRochleder, Ann. d. Chem. (1845), 54, p. 255; Babo and Keller, Journ. f. 
prakt. Chem. (1857), 72, p. 53; Rugheimer, Ber. d. deutsch. chem. Ges. 
(1882), 15. p. 1390. 

"Schweitz. Med. Journ. (1819), 29, p. 80; Buchner, Repert. f. die Pharm.. 
(1820). 10, p. 127. 

"Ladenburg- and Scholtz, Ber. d. deutsch. chem. Ges. (1894), 27, p. 2958. 

" Caseneuve and Caillot report the piperine content to be as follows : 
Sumatra. 8.10 per cent; Singapore, 9.15 per cent; Fenang, 5.24 per cent. Z. c.. 
G. Graff gives the following percentages of ether soluble nitrogenous matter 
as piperine: Java, 5.85 to 9.5 per cent.; Lampong, 5.13 to 7.09 p^r cent.; 
Penang, 9.12 to 9.42 per cent; Saigon, 6.16 per cent.; Singapore, 11.08 per 
cent. Zeitschr. f. offentl. Chem. (1908), 14, p. 425. 

"W. Johnstone obtained 5.21 to 13.03 per cent of piperine from nine 
samples of black pepper, I. c. 

C. Heisch gives the yield as 4.05 to 9.38 per cent. Analyst (1886), 11. 
p. 186. 

F. Stevenson reports the presence of 7.14 per cent, or piperine. Ihid. 12^ 
p. 144. 



220 ^U MEZ— THE GALENICAL OLEORESINS 

Resin. The presence of 1.25 to 2.08 per cent, of resin in 
black pepper has been reported.^^ Buchheim/® the only in- 
vestigator who appears to have attempted to isolate the same 
in sufficient purity to determine its composition, states that it 
Is a condensation product of piperidine with an acid, to which 
lie gives the name Chavicinsaure. He assigns the name Chavicin 
to this compound, and describes it as a yellowish-brown mass 
■soluble in alcohol, ether, petroleum ether and the other com- 
mon solvents. 

Coloring Matter. The green coloring matter in pepper is 
■stated to be chlorophyll.^^ The brown coloring matter observed 
in the ethereal or alcoholic extracts has not been identified. 

Fatty Oil}^ The presence of a fatty oil in black pepper must 
be considered doubtful at the present time. Hirsch^^ states that 
•a microscopical examination of the fruit revealed the presence 
of a fatty oil in the endosperm. Kayser,^° Weigle,^^ and others 
mention fatty oil as one of the constituents. None of these 
investigators, however, appear to have isolated the oil in a pure 
state or to have described it in detail. Ditzler,^^ who made this 
matter the subject of a special investigation, concluded that 
glycerides were absent. Likewise, Gerock^^ could obtain no 
fat from white pepper. 

Piperidine. "^^ Piperidine has been named as a constituent of 
black pepper by Johnstone,^^ who found the average content 
of nine samples to be 0.56 per cent. Kayser^® disputes the find- 
ings of Johnstone and states that the base obtained by distilla- 
tion is ammonia. 



^' Teyxeira and Ferruoio grive the resin content as 1.25 per cent., F. 
Stevenson as 1.44 per cent. I. c. 

F. Blyth reports the presence of 1.7 to 2.08 per cent. Foods. Their Com- 
position and Analysis (1903). p. 496. 

"Buchner's n. Repert. f. Pharm. (1876), 25 p. 335; Pharm. Journ. 1876, 
36. p. 315. 

"Arthur Meyer, Das Chlorophyllkorn, Leipzig (1883), p. 2. 

"In the literature on food chemistry, the non-volatile ether extract is 
Aisuolly spoken of as fat or fatty oil. See "Wanton, Ogden and Mitchell, 1. c. 

^® Flueckiger, Pharmako gnosis des Pflanzenreiches (1891), p. 914. 

^' I. c. 

217. c. 

«Arch. d. Pharm. (1886), 224, p. 103. 

2J Ihid. 

2* As piperidine is one of the products obtained when piperine ia hydrolysed, 
It is quite probable that it is not a normal constituent of the fruit but is 
'formed when the powdered material is subjected to distillation. 

2* I. c. 

2« I. c. 



OLEORESIN OF PEPPER 



221 



Piperidine is a colorless limpid liquid having a specific 
gravity of 0.8591 at 25 °C, and boiling at 106.3 °C." It m 
stated to have an odor resembling both, that of ammonia and 
pepper. It is a powerful base behaving generally like am- 
monia in its action on the metallic bases. It is soluble in all 
proportions in alcohol or water. It has the following struc- 
tural formula.^®. 




Methyl-Pyrroline. Pictet and Court-*^ report the occurrence^ 
of 0.01 per cent of methyl-pyrroline in black pepper obtained 
from Singapore. The exact constitution has not been deter- 
mined, but the authors are of the opinion that it is a C-methyl 
pyrroline represented by one of the following formulas: 




Ash. The basic elements, K, Na, Mg, Ca, Fe and Mn, com- 
bined with the acids, HCl, H3PO4, H2SO4, HgSiOg are the com- 
ponents of the ash of black pepper as determined by Rottger**' 
and others.^^ 

The average ash content of black pepper is stated by Blyth^^ 



2^Ferkin, Chem. Soc. Journ. (1889), 55, p. 699. 

28Hofmann, Ber. der. deutsch. chem. Ges. (1879), 12, p. 985; Koenigs, 
Ibid., p. 2341; Ladenburg, Ibid. (1885), 18, pp. 2956 and 3100. 

*» Pictet states that he was able to isolate pyrrolidine and N-methyl pyrro- 
line from various leaves by steam distillation after treatment with sodiuno 
carbonate. He is of the opinion that the methyl pyrrolines undergo re- 
arrangement forming pyridine and quinoline rings, thus giving rise to the- 
more complex alkaloids. Arch. Sci. Phys. Nat. (1905), 19, p. 329; Ber. d- 
deutsch. chem. Ges. (1907), 40, p. 3771. 

"Arch. Hyg. (1886), 4, p. 183. „ 

»Blyth, Chem. News (1874), 30, p. 170. 

«2 Ibid. 



,"222 DU MEZ— THE GALENICAL, OLEORESINS 

to be 4.845 per cent. As high as 8.99 per cent, has been re- 
ported.^^. 

Constituents of Therapeutic Importance 

The oleoresin of pepper is said to be used chiefly in the South, 
where it is administered with quinine in the treatment of ''in- 
termittent fever." Its value in this connection is accounted 
for by the presence of piperine which has been shown to be an 
:active antiperiodic.^ Piperdine and methyl pyrroline, if pres- 
ent, would impart similar properties,^ while the composition of 
the contained volatile oil w^ould indicate a carminative action. 

PJiysical Properties 

Color: The color of the oleoresin, when the latter was spread 
out in a thin layer on a white porcelain surface, was observed 
to be a greenish-brown, closely resembling that of the oleoresin 
of cubeb when prepared from the ripe fruits. The so-called oil 
of black pepper, sometimes sold as a substitute for the official 
oleoresin, is stated to be considerably darker in color due to the 
removal of the greater part of the volatile oil. 

Odor: The odor, while slight, resembles that of ground 
pepper. 

Taste: The taste is sharp and spicy, the sharpness becom- 
ing more noticeable after the oleoresin has been retained in the 
mouth for a short time. 

Consistence: The oleoresin is a thick, sticky liquid which 
•can only be poured with difficulty. The fluidity is greatly in- 
creased by heating the preparation on a water bath. 

Solubility: The oleoresin is completely soluble in alcohol, 
ether, acetone, chloroform, carbon disulphide and glacial acetic 
acid. It is only partially soluble in petroleum ether and is 
insoluble in water. 

Specific gravity: The specific gravity of the oleoresin is 
fairly constant, only, when similar conditions with respect to 



"Heish reports the ash content of 8 samples of black pepper to be from 
4.35 to 8.99 per cent. Analyst (1886), 11, p. 186. Others who have reported 
on the ash content of pepper are Bergman, Zeitschr. f. Analyt. Chem. (1882), 
^1, p. 535, and von Raumer, Zeitschr. angew. Chem. (1893), p. 453. 

^Wood, Therapeutics, Principles and Practice, (1908), p. 482. 

^Tunnicllffe and Rosenheim, Centralbl. f. Physiol. (1902), 16, p. 93. 



OLEORESIN OF PEPPER 



223 



temperature have been observed during the separation of the 
precipitated piperine. A comparatively slight difference in tem- 
perature causes a considerable variation in the amount of the 
latter constituent retained in solution, which results in a cor- 
responding variation in the specific gravity of the finished pro- 
duct. This effect is further ncviced in connection with the 
menstruum employed in extracting the drug, e. g. petroleum 
ether which is a poor solvent for piperine yields an oleoresin 
relatively low in specific gravity. With respect to the com- 
mercial samples examined, a low specific gravity was, in one in- 
stance, found to be due to the presence of unevaporated solvent. 
The tables which follow show the specific gravity of the samples 
examined in the laboratory. 

Table 125 — Specific gravities of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Specific 
gravity 


1 


1916 


DuMez 


Alcohol 


At 25° C 
1.069 


2 






1.083 


3 


•♦ 


Ether 


1.056 


4 


•• 


Petrol, ether 


981 










Table 126 — Specific gravities of commercial oleoresins. 


Sample 
No. 


Date 


Observer 


Source 


Specific 
gravity 


1 


1916 


DuMez 


Squibb & Sons 


At 25° C 
0.985' 


2 




Sharp & Dohme 


1.061 











The odor of ether was very noticeable. 



Refractive index: The refractive index of this preparation 
as observed in the laboratory was not constant, varying from 
1.521 to 1.696. From an inspection of the first of the tables 
which follow, it would appear that this variation was a result 
of the influence of the solvent employed in extracting the drug. 
While the solvent undoubtedly exerts an influence in this con- 
nection, it does so indirectly, that is, through its effect on the 
piperine content.^ The latter, however, is also influenced by 



* See discussions under "Piperine content" and "Yield of oleoresin, 
spectively. 



224 



DU MEZ— THE GALENICAL OLEORESINS 



the temperature at which the preparation is finished — the tem- 
perature at which the liquid oily portion, which constitutes the 
official oleoresin, is separated from the deposited material, in- 
cluding the excess of piperine. In the case of commercial 
samples, the piperine content and, therefore, the refractive in- 
dex may also be affected by the presence of unevaporated 
solvent. The results obtained in the laboratory in the deter- 
mination of this property are given in the tables which follow. 

Table 127 — Refractive indices of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Refractive 
index 


1 


1916 


DuMez 


Alcohol 


At 25° C 
1 =559 


2 .. . 




Acetone . 


1 696 


3 


" 


Ether 


1 562 


4 


" 


Petrol, ether 


1 521 









Table 128 — Refractive indices of commercial oleoresins. 



Sample 
No, 


Date 


Observer 


Source 


Refractive 
index 


1 


1916 


DuMez 


Squibb & Sons 

Sharp & Dohme 


At 25° C 
1.501(a) 
1 560 


2 . . 











(a) Contained ether. 



Chemical Properties. 

Loss in iveiglit 071 Jieating: A loss in weight varying fromi 
9.49 to 11.52 per cent, was obtained for the laboratory prepara- 
tions, when heated at 110° C, showing that the nature of the 
solvent employed in extracting the drug has but little influence 
on this property. With respect to the commercial samples ex- 
amined, the loss was much greater, being as high as 32.64 per 
cent, in one case. The comparatively great loss in the latter 
instance was due to the presence of unevaporated solvent 
(ether.) The results obtained in the determination of this 
constant in the laboratory follow. 



OLEORESIN OF PEPPER 



225 



Table 129 — Laboratory preparations — loss in weight on heating. 



Sample 
No. 


Date 


Observer 


Solvent 


Per cent, of 
loss on 
heatingr 


1 


1916 


DuMez ,.. 


Alcohol 


At 110° C 
10.34 


2 




Acetone 

Ether 

Petrol, ether 


11.52 


3 


'« 


10.91 


4 


ti 


9.49 









Table 130 — Commercial oleoresins—loss in weight on heating-.. 



Sample 
No. 


Date 


Observer 


Source 


Per cent, of] 
loss on 
heatin«r 


1 


1916 


DuMez 




At llO^C 
17.52 


2 




Sauibb & Sons 


32.64» 











^ Unevaporated solvent (ether) was present. 

Ash content: The ash determinations made on the oleoresinsi 
prepared in the laboratory show that the solvent employed ini 
their preparation is the chief factor influencing the results ob- 
tained. The official product, in the making of which ether was: 
the solvent used, yielded 0.11 per cent, of ash, which was about, 
the percentage yield obtained for one of the commercial samples; 
examined. The other commercial oleoresin gave 0.29 per cent, 
of ash indicating the use of acetone in its preparation. Both 
samples contained copper, apparently, however, in quantities 
too small to noticeably affect the weight of the ash. The re- 
sults of the determinations made in the laboratory follow:. 



Table 131 — Ash contents of oleoresins prepared in the laJ>oratorvi 



Sample 
No. 


Date 


Observer 


Solvent 


Per cent of 

asli 


J 


1916 


DuMez 


Alcohol 


O.fS 
0.32 
O.ll 
0.05 


2 




Acetone 


8 


•' 


Ether ..'.'..'.'.*.* 


4 


•» 


Petrol, ether 









226 



DU MEZ— THE GALENICAL OLEORESINS 



Table 132 — Ash content of commercial oleoresins. 



Sample 

No. 


Date 


Observer 


Source 


Per eent. of 

ash 


Foreign 
constituents 


1 


1916 


DuMez 


Squibb & Sons... 
Sharp & Dohme.. 


0.12 (a) 
0.29 


Copper 


2 











* Contained ether. 

Acid number: The acid number of the oleoresin when pre- 
pared with alcohol, acetone or ether was found to be about 19. 
In the case of the two commercial samples examined, however, 
the values obtained differed to a considerable extent, being 19.2 
in one instance and 27.5 in the other. As the preparation 
represented by the first number contained considerable unevap- 
orated solvent, this difference can be accounted for in part. The 
high values obtained for the commercial samples are thought to 
be due to their relatively low piperine content or to a partial 
decomposition of the resin. The values obtained for this con- 
stant in the laboratory follow. 



Table 133 — Acid numbers of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Acid 
number 


J 


1916 


DuMez 


Alcohol . . 


19.2 


2 






19.0 


3 


»• 


Ether 


18 9 


4 


•t 


Pfitrnl.-fithfir 


15.1 









Table 134 — Acid numbers of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Acid 
number 


1 


1916 


DuMez 


Sauibb & Sons 


19.2 (a) 


2 




Sharp & Dohme 


27 5 











(a) Contained ether. 



Saponification value: As will be observed in an inspection 
of the first of the tables which follow, the saponification value 
of the oleoresin varies with the solvent employed in its prepara- 
tion. This appears to be due principally to the effect which 
the nature of the solvent has upon the piperine content of the 



OLEORESIN OF PEPPER 



227 



finished product, e.. g. the piperine content of the preparation 
made with acetone was found to be 54.36 per cent and the 
saponification value 88.6, while the oleoresin when prepared with 
petroleum ether, contained only 15.06 per cent, of piperine and 
gave a saponification value of 109.5. Other influences, besides 
the nature of the solvent, affecting the piperine content may 
likewise produce a variation in the saponification value, e. g. 
the temperature at which the preparation is made and the 
presence of unevaporated solvent in the finished product. The 
latter may also have a direct infiuence. The saponification 
values as found for the oleoresins examined in the laboratory 
are given in the following tables. 



Table 135 — Saponification values of oleoresins prepared in the 
laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


SaDonlflca- 
tion value 


1 


1916 


DuMez 


Alcohol 


63 7 


2 






74 9 


3 


•« 


Ether 


83 5 


4 


•• 


Petrol, ether 


86 8 











Table 136 — Saponification values of commercial oleoresins. 



Sample 
No. 


Date 


Observer 


Source 


Saponifica- 
tion value 


1 


1916 


DuMez 


Sharp & Dohme 


66.3 


2 




Saulbb & Sons 


73 7(a) 









(a) Contained ether. 



Iodine value: Iodine values ranging from 88.6 to 95.4 were 
obtained for this oleoresin when acetone, alcohol or ether were 
the solvents employed in its preparation. This variation is 
due to the difference in the piperine content of these oleo- 
resins as a result of operating under different conditions of 
temperature when preparing the same, as well as to the nature 
of the solvent. In addition to these influences, the presence 
of unevaporated solvent must also be taken into consideration 
in the case of the commercial samples, as is indicated by the 
values given in the following tables. 



228 ^U MEZ— THE GALENICAL OLEORESINS 

Table 137 — Iodine values of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Iodine value 


1 


1916 


DuMez 


Alcohol 

Act'tone 


90.0 


2 




88.6 


3 


.» * ■ 


Eiher 

Petrol. -elher 


95.4 


4 


'• 


109.5 









Table 138 — Iodine values of commercial oleoresins. 



Sample 
No. 



Date 



1916 



Observer 



DuMez. 



Scource 



Sharp & Dohme. 
Stiuibb & Sons... 



Iodine value 



83.7 
89.9 (a) 



(a) Contained ether. 



Special Quantitative Tests. 

At the present time, there does not appear to be a method in 
use for the evaluation of this oleoresin. As its therapeutic 
properties are due, in greater part at least, to its piperine con- 
tent,^ a quantitative method for the estimation ot this con- 
stituent appears to offer the best means of determining its 
quality. 

Method for the Estimation of the Pipeline Content. 

In the laboratory, the amount of piperine present was com- 
puted from the nitrogen content of the oleoresin, the latter 
being determined by the Gunning-Arnold^ method. The re- 
sults obtained are given in the following tables: 



Table 139 — Piperine content of oleoresins prepared in the laboratory. 



Sample 
No. 


Date 


Observer 


Solvent 


Piperine 
content 


1 


1916 


DuMez 


Alcohol 


Per cent. 
47.0 


2 




Acetone 


54.3 


8 


«» 


Ether 


51.3 


4 


•« 


Fetrol, ether 


15 1 











1 See under "Constituents of therapeutic importance.' 
'Bull. No. 107. Bur. of Chem. (1912), p. 162. 



BIBLIOGRAPHY 



229 



Table 140 — Piperine content of commercial samples. 



Sample 
No. 


Date 


Observer 


Source 


Piperine 
content 


1 


1916 


DuMez 


Sharp & Dohme 


Per cent. 
27.3 


2 




Squibb & Sons 


33.8 











The laboratory samples were prepared and tested during 
the warm months of summer, which accounts for the high 
piperine content. A very considerable amount of the latter 
precipitated out during the colder months which followed. It 
is, therefore, thought that the results obtained in the case of 
the commercial products are the more typical. 

Adulterations. 

Copper was found to be present in all of the commercial 
samples examined. See under ''Ash content.'* 

Bibliography. 
Planche 1823 

Von den pharmaceutischen Zubereitungen des Lupulins. 

Mag. f. Pharm., 1, p. 183. [Trommsdorff's n. Journ. d. 
Pharm., 7, p. 345.] 

A method for preparing the alcoholic tincture of lupulin is given. It is 
further stated that an extract similar in all respects to the resin said to 
have been isolated by Ives results when the alcohol is removed from the 
tincture by evaporation. 



Geiger, Ph. L. 1824 

Versuche fiber die chemische Zusammensetzung der Wurzel 

des maennlichen Parrenkrauts, Polypodium (Aspidium, NepJi- 

r odium) Filix Mas. 

Mag. f. Pharm., 7, p. 38. 

The article is a review of Morin's analysis of the rhizome of male fern 
with a note pointing out that Morin was not the first investigator to make 
such an analysis, but that Gebhardt had already published an analysis of 
the same in 1821 in an inaugural dissertation delivered at Kiel. Gebhardt 
is stated to have used ether for extracting the "oil." 



230 I^U MEZ— THE GALENICAL. OLEORESINS 

Morin 1824 

Sur la composition chimique de la racine de fougere male, 

Polypodium filix mas Linn. 

Journ. de Pharm. et de Chim., 10, p. 223. [Mag. f. Pharm., 

7, p. 38.] 

In making a chemical examination of the male fern rhizomes, the author 
used the method of selective solvents. Upon extracting with ether, as the 
first solvent, and subsequently evaporating of the ether, a thick green fatty 
oil was obtained. The author considers this fatty substance the active 
principle. 

Meli 1825 

Nene Erfahrungen und Beobachtungen ueber die Art, das 

Alkaloid und das seharfe Oel des Pfeffers zu gewinnen. 

Trommsdorff's n. J. d. Pharm., 11, p. 174. [Bull, de scien. 

math., phys. et chim., 1825, p. 191.] 

It is stated that more than an ounce and a half of piperine and about 
four ounces of a sharp tasting oil were obtained from three pounds of 
black pepper by extraction with alcohol. 

Peschier, Ch. 1825 

Oel des maennlichen Farrenkrauts (Aspidium Filix Mas), 

ein sehr vorzuegliches und sicheres Mittel gegen den Bandwurm. 
Biblioth. univers., Nov. 1825, p. 205. [Mag. f. Pharm., 13, 

p. 188.] 

The so called oil, Euile de Fougere Mdle, is directed to be prepared by 
extracting the powdered male fern rhizomes with ether and subsequently re- 
moving the ether by warming gently. 

Buchner, A. 1826 

Extractum Filicis maris resinosum. 

Repert f. d. Pharm., 23, p. 433. 
The preparation of this extract by means of alcohol instead of ether 
is recommended. The product thus obtained is spoken of as an Extractum 
resinosum. The Kuile de Fougere of Peschier is spoken of as the harz- 
haltiges Oel. A chemical analysis of the extrpiCt is also given. 

von Esenbeck, Nees 1826 

Farrnkrautwurzelextrakt. 

Arch. d. Pharm., 19, p. 153. 
The extract is reported to have been prepared by the process of macera- 
tion, ether being the solvent employed. Four ounces of rhizomes gathered 
in August gave 108 grains of extract. 



BIBLIOGRAPHY 



231 



1827 

Verhandlungen des pharmaceutischen Vereins in Wuertem- 
berg. Eepert. f. d. Pharm., 26, p. 441. 

Zeller is stated to have prepared the Extractum radicis Filicis maris 
resinosum according to the method suggested by Buchnerj extraction with 
alcohol. The extract obtained in this manner from rhizomes gathered 
in September amounted to 30 per cent, of the air dried drug. 

Batso, Y. 1827 

Dissertatio inaugur. chemica de Aspidio filice mare 
Quam cons, et auctor. praes et direct, etc., pro summis in scient. 
et arte chemica honor, et doct. laurrite cappess. in miivers. 
vindobon. publ. erudit, disq. snbmittit Valentinus Batso, N. H. 
Debreczino Bibariensis p. 37, 8. Vindobonae, typis Antonii 
Pichler. 1826. [Trommsdorff's n. Journ. d. Pharm., 14, 2, p. 
249.] 

In addition to oil, resin and fatty wax, the author finds a free acid and 
an alkaloid in the ethereal extract of male fern. He calls the acid Acidum 
filiceum and the alkaloid Filicina. He attributes the activity of the extract 
to these two substances. 

Brandes, R. * 1827 

Ueber das Extractum oleo-resinosum Filicis. 
Arch d. Pharm., 21, p. 253. 

The physical properties of the extracts obtained by extracting male 
fern rhizome with ether and with Liquor anodynus, respectively, are de- 
scribed. 

Buchner, A. 1827 

Zur medicinischen und chemischen Geschichte der Filix mas. 
Repert. f. d. Pharm., 27, p. 337. 

The author speaks of the ethereal extract of male fern as the Extractum 
oleoso-resinosum Filicis maris. It is stated to contain a volatile oil, a 
green fatty oil, a fatty wax, a brown resin and a volatile acid (probably 
acetic acid.) 

Van Dyk 1827 

Ueber das Oleum Filicis maris. 
Arch. d. Pharm., 22, p. 141. 

Two ounces of powdered male fern rhizome gave 70 grains of ethereal 
extract, while 8 ounces of the rhizome yielded 3 ounces of extractive matter 



232 DU MEZ— THE GALENICAL OLEORESINS 

to alcohol. The extract prepared with ether is stated to be dark olive- 
;green in color and of the consistence of honey, that prepared with alcohol 
.•greenish-brown in color and much thicker. 

Oeiger, Ph. L. 1827 

Analytische Versuche mit der Wurzel des maennlichen 
Parrenkrauts und Darstellung des Gels (01. Filicis Maris) 
^us derselben. 

Mag. f. Pharm., 17, p. 78. 
The ethereal extract when prepared from green rhizome, by extraction 
with ether in a Bealsche Presse is said to be a yellowish-green oily sub- 
stance. 

An analysis of this extract showed the presence of 30 per cent, of resin- 
ous material soluble in alcohol, 50 per cent, of a fixed oil and a considerable 
amount of volatile substances. 

TiUoy 1827 

Bereitungsart des Oels des maennlichen Farrenkrauts. 
Journ. de Chim. med., 3, p. 154. [Geiger's Mag. f. Pharm., 

18, p. 157.] 

The so-called oil of male fern is directed to be prepared by extracting 
the rhizome with alcohol. The alcoholic liquor thus obtained is treated 
with lead subacetate, filtered, and the solvent removed by distillation. 
The resulting oil is further purified by dissolving in ether and evaporating. 

Dublanc, H. 1828 

Extrait oleoresineux de Cubebe. 
Journ. de Pharm. et de Chim., 14, p. 41. 

The author's method for preparing the oleoresinous extract consists 
in distilling off the volatile oil with water, exhausting the dried marc with 
alcohol, evaporating off the alcohol, and mixing the residue so obtained 
with the volatile oil. 

Meylink 1828 

Ueber das Extractum oleo resinosum Filicis. 
Arch. d. Pharm., 25, p. 243. 

Two ounces of the powdered male fern rhizome are reported to have 
yielded 58 grains of a dark green, oily extract to ether. 

Oberdoerffer 1826 

Ueber die Darstellung des Cubeben Extracts. 
Arch. d. Apoth. Ver., 24, p. 178. 

In the method of preparation, the oil is first obtained by steam distilla- 
tion, the marc remaining in the still, after drying, is then extracted with 



BIBLIOGRAPHY 233 

alcohol. The residue remaining after removing the alcohol by evapora* 
tion is mixed with the volatile oil, this mixture constituting the so-called 
extract. 

Peschier, Ch. 1828 

Ueber mehrere schon frueher erschienene Analysen der 

Farrenkrautwurzel (Aspidium filix mas L.) und neber die 

Gewinnnng seines harzigen Oels. 

Trommsdorff's n. Journ. d. Pharm., 17, p. 5. 

The vermifuge properties of male fern are said to be due to its ol6o- 
resine (oelliars) content. This the author prepares by extracting the 
drug with ether and subsequently evaporating the solvent, (p. 8.) It is 
further stated that this oleosesine remains perfectly homogenous after 
months if prepared from freshly gathered rhizomes, but deposits a white 
granular substance when old rhizomes are used (p. 9.) 

According to the author's analysis the oleoresine consists of a volatile 
aromatic oil, a fatty oil, resin, stearin, green and red coloring materials, 
acetic and gallic acids. 

Winkler, F. L. 1828 

Einige Worte ueber die Bereitung des 01. Filic. Maris. 
Geiger's Mag. f. Pharm., 22, p. 48. 

The ''oil" extracted with ether is said to be a mixture of oil, resin 
and oxidized tannin. Twelve ounces of rhizomes gathered in February 
yielded 15 drachms of extract. Two drachms of this extract yielded 43 
grains of fatty oil. 

Allard 1829 

• Note sur rhuile de fougere. 
Journ. de Pharm. et de Chim., 21, p. 292. 

The powdered rhizome of the male fern is directed to be extracted with 
alcohol and the alcoholic extract after evaporating off the solvent, washed 
with water. The extract is then further purified by solution in ether and 
subsequent evaporation. 

Carpenter, G. W. 1829 

Observations and Experiments on Peruvian Bark. 
Silliman's Am. Journ., 16, p. 28. [Buchner's Repert f. d. 

Pharm., 34, p. 446.] . 

In the discussion of the therapeutic uses of the various constituents of 
Peruvian bark, it is stated that Dr. Chapman of Philadelphia prescribed 
piperin and oil of pepper in combination with quinine. The oil of pep- 
per is said to be the more active therapeutically, one drop of oil being 
equivalent to three grains of piperin (p. 39.) 



234f 



DU MEZ— THE GALENICAL OLEORESINS 



Haendess 1^29 

Ueber 01. filicis maris. 
Arch. d. Pharm., 28, p. 212. 

Four ounces of powdered male fern rhizomes gave 170 grains of ethereal 
extract. Upon treating this ethereal extract with alcohol, 20 grains were 
dissolved leaving a residue of 150 grains. The extract first obtained was 
of a brownish color, after treating with alcohol it assumed a beautiful 
green color. 

Voget 1829 

Notiz ueber 01. filicis maris. 
Arch. d. Pharm., 30, p. 104. 

According to the author's method of preparing the Oleum filicis maris, 
the powdered male fern rhizome is first extracted with water. After dry- 
ing the drug is then extracted with ether. Twenty-eight grains of a 
brownish-green extract were obtained from 9 drachms of the marc. 

Schuppmann 1830 

Extractum resinosum Seminis Cynae. 
Buchner's Repert. f. d. Pharm., 35, p. 430. 

The extract is directed to be prepared by macerating 4 ounces of the 
coarsly powdered seed with 16 ounces of ether for 3 or 4 days, decanting 
the liquid portion and evaporating to remove the solvent. 

Beral 1834 

Du principe du gingembre, et formules de plusieurs com- 
poses pharmaceutiques dont il est la base medicamenteuse. 
Journ. de Chim. med., Pharm. et Tox., 10, p. 289. 

The product obtained by extracting ginger with ether is designated 
Fiperoide du Gingemhre. It is directed to be prepared by extracting in a 
percolator 4 ounces of ginger with 6 ounces of ether, the rate of flow being 
so regulated that the operation will consume not less than 2 hours. It is 
stated that 5 scruples of piperoide were obtained in this manner, and that 
€ scruples can be obtained if the residual ether is forced out by subse- 
quent percolation with alcohol (40°). The piperoide is 'reported to be 
soluble in ether, anhydrous alcohol and oils. 

• 1838 



Extrait Oleo-Resineaux de Cubebe, 

Journ. de Chim. med., Pharm. et Tox., 14, p. 366. 

It is stated that Hausman prepared the oleoresinous extract of cubebs 
by macerating the powdered drug with ether (625 grams of ether to 250 
grams of drug), then decanting and evaporating the ethereal solution to 
remove the solvent. 



BIBLIOGRAPHY 235 

Hornung 1844 

Pharmaceutisch-Chemische Mittheilungen. 
Arch. d. Pharm., 89, p. 34. 

Three ounces of fresh, powdered rhizomes of male fern, treated with 
3 ouncs of ether in a Verdraengungsapparat, are reported to have yielded 
2 drachms of extract. 

Luck, E. 1845 

Ueber einige Bestandtheile der Eadicis Filicis. 
Ann. d. Chem., 54, p. 119. 

Upon standing, the ethereal extract deposits a granular substance which 
can be obtained quite pure by pouring off the supernatant oily layer and 
washing the deposit rapidly with ether. The washed precipitate, dis- 
solved in ether, crystallizes, upon evaporation, in rhombic leaflets, m. p. 
160°C, insoluble in alcohol or water. The crystals were not obtained in a 
suflScient degree of purity to determine their chemical constitution. 

Procter, Wm., Jr. 1846 

On the Ethereal Extract of Cubebs. 
Am. Journ. Pharm., 18, p. 167. [Pharm. Jonm., 6, p. 319.] 

At Dr. Goddard 's request, Procter prepared a * ' true oleoresin ' ' of cubebs 
by extracting the drug with ether. This method is regarded by him as a 
great improvement over the method of Soubeiran. 

Bell 1846 

Oleoresinous Extract of Cubebs. 
Pharm. Journ., 6, p. 319. 

The report includes a reprint of Procter's paper on the ethereal ex- 
tract of cubebs and remarks by Ure, at whose request the preparation was 
made and by whom it is stated to have been used with success. A yield of 
15 to 20 per cent, of oleoresin was obtained. 

Procter, Wm., Jr. 1849 

Remarks on oleoresinous ethereal extracts, their preparation 

and the advantages they offer to the medical practitioner. 
Am. Journ. Pharm., 21, p. 114. 

A method for the preparation of the following ethereal extracts is given: 
capsicum, chenopodium, semen contra, ginger, cardamom and pellitory. 
(p. 116.) Several forms of apparatus, including a tin percolator, Mohr's 
apparatus for extracting with ether and Gilbertson's diplacement appara- 
tus are also described as being useful in this connection. 



?36 



DU MEZ — THE GALENICAL OLEORESINS 



Bock, H. 1851 

Analyse der Wurzel nnd des Wedels von Filix mas. 
Arch. d. Pharm., 115, p. 257. [Am. Jonrn. Pharm., 24, 

p. 61.] 

The powdered rhizomes were extracted with ether, specific gravity 0.720. 
By this means, 2000 grains of the powder are reported to have yielded 257.4 
grains of an oily extract which was found to be composed of volatile oil, 
tannic acid, resin, fatty oil stearin and chlorophyll. 

The author recommends preparing the oleoresin from fresh rhizomes as 
he states that the greater part of the volatile oil is lost upon drying and 
the fatty oil tends to become rancid. 

Lncke, E. 1851 

Ueber einige Bestandtheile der Wurzel von Aspidium 

Filix mas. 

Jahrb. f. prakt. Pharm., 22, p. 130. [Arch. d. Pharm., 119, 

p. 178 ; Journ. de Pharm. et de Chim., 54, p. 476.] 

A crystalline substance resembling the Filicin obtained by Trommsdorff 
eight years previous was isolated from the ethereal extract. The author 
calls it Filixsaeure and assigns it the formula C20H15O9 It is further stated 
that extracts prepared with ether contain no tannic acid or sugar, but 
filix acid, pteritannic acid and fatty oil are present. Upon being saponi- 
fied, the oil yielded Filixolinsaeure (C42H40O4 + H O) and Filosmylsaeure. 



Von der Marck, W. 1852 

Ueber Verfaelschnng der Radicis Filicis maris. 
Arch. d. Pharm., 120, p. 87. 

The botanical characteristics of other than the official species are 
enumerated and the manner in which they differ from those of male fern 
pointed out. 

With respect to the male fern rhizomes, the author gives the following 
information: rhizomes gathered in September are the most active as they 
contain the greatest amount of oil. In the preparation of the extract, only 
that portion of the rhizome having borne fronds in the year collected, 
should be taken. The following results were obtained using different 
parts of the rhizome: 

1.) Extract from portion of rhizome which had borne fronds the 
previous year. Yield 7.8% of a brownish-green extract. 

2.) Extract from portion bearing fronds during year collected. Yield 
8.2% of a beautiful green extract. 

3») Extract from portion which will develop fronds the coming year. 
Yield, 8.5% of a beautiful green extract. 



BIBLIOGRAPHY 237 

Schuck, F. 1852 

Ueber Cubebin 

Buchner's n. Repert. f. d. Pharm., 1, p. 213. [Jahresb. d. 
Pharm., 12, p. 34.] 

Cubebin is stated to be slowly deposited from the ethereal extract of 
cubeb upon standing. The extract prepared from 17 ounces of cubeb 
gave 15 grains of cubebin. 

Bakes, W. C. 1853 

Extract of Capsicum. 
Am. Journ. Pharm., 25, p. 513. 

The extract was prepared at the request of a physician. Dilute alcohol 
was employed for exhausting the drug. Eight ounces of Capsicum yielded 
two ounces of extract. 

It is stated that a simple ointment which acts as a rubiafacient in 20 
minutes may be prepared by mixing one drachm of this extract with 1 
ounce of simple cerate. 

Livermore 1853 

Extract of Lupulin. 

Am. Journ. Pharm., 25, p. 294. 
The extract is directed to be prepared by maceration, using alcohol as 
the solvent. Sixty-six per cent, of extractive matter was obtained by this 
treatment. 

Garot and Schaeuffele 1857 

Rapport sur le produit oleo-resineux de cubebe obtenu a 

Taide du sulfure de carbone. 

Journ. de Phai-m. et de Chim., 65, p. 368. 

The article is on the experimental preparation of the oleoresin of cubebs 
with carbon disulphide. This solvent is proven to be worthless for this 
purpose on account of the large amount necessary for extracting the drug 
and on account of the difficulty in removing it by evaporation. 

Landerer, X. 

Ueber Cubebinum. 

Arch. d. Pharm., 139, p. 302. 

The so-called cubebin was obtained in the preparation of Extractum 
Cubebarum oleoso-resinosum, for which a mixture of ether and alcohol was 
used. Upon standing in a cool place, needle-like crystals adhering in 
groups were noticed. These crystals were soluble in warm alcohol and 
gave a carmine red color with sulphuric acid. 



238 



DU MEZ— THE GALENICAL OLEORESINS 



Procter, Wm., Jr. 1859 

Formulae for the fluid extracts in reference to their more 

general adoption in the next pharmacopoeia. 

Proc. A. Ph. A., 8, p. 265. [Am. Journ. Pharm., 31, p. 548.] 

It is suggested that the preparations made by extracting drugs with 
ether be designated as Oleoresinae in the next pharmacopoeia. Methods for 
preparing the following oleoresins are described: " Oleoresina Cardamom^ 
Oleoresina CaropJiylli, Oleoresina Cuhelae, Oleoresina Filicis maris, Oleo- 
resina LupuUnae, Oleoresina Piperis Nigri, Oleoresina Pyrethri, Oleoresina 
Satinae, Oleoresina xanthoxyli and Oleoresina Zingiieris.'* 

Girtle 1863 

Extractum Cubebarum oleoresinosum. 
Pharm. Centralh., 3, p. 608. [Canstatt's Jahresber., 23, p. 

178.] 

The preparation is an aqueous-alcoholic-ethereal extract with which the 
volatile oil, previously obtained by distillation, has been incorporated. It 
is said to represent the therapeutic properties of the entire drug. It is 
also stated that this preparation is not identical with the Extr. Cub. oleoso- 
resinosum of Landerer (1857.) 

Parrish, E. 1864 

On Capsicum. 
Proc. A. Ph. A., 12, p. 262. [Jahresb. 1 Pharm. 1, p. 68.] 

In discussing the constituents of capsicum, Parrish refers to the 
ethereal extract as the oleoresin. 



Bernatzik, W. 1865 

Chemische Untersuchung der Cubeben mit besonderer 

Beruecksichtigung der Wirkungsweise ihrer wesentlichen 

Bestandtheile. 

Buchner's Repert. f. d. Pharm., 14, p. 97. [Arch. 

Pharm., 179, p. 123.] 

The article is a comprehensive discussion of the constituents of cubebs 
and their physiological and therapeutic action. 

Based on the results of clinical experiments, it was concluded that the 
desired therapeutic principle is the resinous constituent and that the 
volatile oil, cubeb camphor and cubebin are practically of no therapeutic 
value. A method for preparing the Extractum Cubeharum resinosum, in 
^vhich cubebs freed from the volatile oil are extracted with alcohol, is 
given (p. 139.) 



BIBLIOGRAPHY 239 



1866 



Procter, Wm., Jr. 

Note on Oleoresina Cubebae. 

Am. Journ. Pharm., 38, p. 210. [Pharm. Journ., 25, p. 620.] 
The author reports the results obtained in the extraction of cubebs with 
ether, alcohol and benzine. The yield of oleoresin obtained was as fol- 
lows: ether, 21.9 per cent., alcohol, 27 per cent, benzine, 16.5 per cent, 
(p. 212). The use of benzine in the preparation of this oleoresin is 
not recommended as it does not extract the cubebin completely. 

Rittenhouse, H. N. 1866 

On Substitutes for Ether and Alcohol in the Preparation 

of the Official Oleoresins. 

Proc. A. Ph. A., 14, p. 208. [Am. Journ. Pharm., 38, p. 24.] 

The feasibility of displacing the ether remaining in the exhausted drug 
with benzine, glycerine or water is discussed. From experiments conducted 
along this line, it was concluded that benzine would be the most preferable 
for this purpose. A working formula in which benzine is used to this 
end is described. Cubebs and ginger were the drugs employed in the 
experiments. 

Paul, C. 1867 

Sur I'extrait oleoresineux de cubebe. 
Journ. de Pharm., et de Chim., 84, p. 197. 

The extract is directed to be prepared by treating the powdered drug 
successively with water, alcohol and ether. The extract so prepared iSi 
said to contain all of the medicinal principles of the original drug. 

Pile • 1867 

On the preparation of Oleoresins with benzine. 
Proc. A. Ph. A., 15, p. 94. 

One pound of cubebs percolated with 2 pounds of light benzine, specific 
gravity 86°, Beaume, is stated to have yielded a trifle over 5 per cent, of 
oleoresin of a pale ash color. 

It is further stated that neither benzine nor ether completely exhaust 
ginger, but that alcohol is a much better solvent for this purpose. 

Heydenreich, F. V. 1868 

On Cubebin and the Diuretic Principle of Cubebs. 
Am. Journ. Pharm., 40, p. 42. 

Eighty ounces of cubebs yielded, when extracted with ether, 19 ounces 
of oleoresin or nearly 24 per cent. 

The results obtained in the administration of cubebin, the volatile oil 
and the soft resin are given. 



240 ^^ MEZ— THE GALENICAL OLEORESINS 

Rump, C. ' 1869 

Extractum Lupulini aethereum. 
Arch. d. Pharm., 189, p. 232. [Jahresb. d. Pharm., 4, p. 39.] 

The extract of lupulin is directed to be prepared hj macerating the 
fresh drug with ether, decanting and evaporating the ethereal solution to 
the consistence of a thin syrup. 

Squibb, E. 1869 

Keport of the Committee on the Pharmacopoeia. 
Proc. A. Ph. A., 17, p. 298. 

The process of repercolation is stated to be well adopted to the prep- 
aration of the oleoresins and that it materially lessens their cost. 

Lefort, M. J. 1870 

Memoire sur les extraits sulfocarboniques, et sur leur emploi 

dans la preparation des huiles medicinales. 
Journ. de Pharm., 90, pp. 102-110. 

In considering the methods of medicating oils, the author proposes pre- 
paring the extract of the leaves of Conium maculatum by exhausting the 
drug with carbon disulphide and subsequently removing the solvent by 
evaporation. 

Hager, 1871 

Zur Bereitung des Extractum Filicis aethereum. 
Pharm. Centralh., 12, p. 457. [Am. Journ. Pharm., 44, p. 

104.] 

It is stated that, if the rhizomes are dried over burned lime previous 
to extraction, and anhydrous ether (Sp. gr. below 0.723) used as the ex- 
tracting solvent, the oleoresin does not deposit on standing but remains 
perfectly clear. 

Maiseh, J. M. 1872 

On the use of Petroleum-Benzine in Making Oleoresins. 
Am. Journ. Pharm. 44, p. 208. [Pharm. Journ., 31, p. 968; 

Proc. A. Ph. A., 21, p. 138; Year-Book of Pharm., 10, p. 328.] 

Petroleum benzine, sp. gr. 0.700, is stated to have been used to advantage 
in the preparation of the oleoresins of capsicum, cubeb and ginger, but. 
the author regards the use of this solvent in the place of ether as inad- 
missable until it has been proven that the proximate principles not ex- 
tracted by th(B benzine are medicinally inert. 



BIBLIOGRAPHY 241 

Buchheim 1873 

Fructus Capsici. 

Vierteljahresschr, f. prakt. Pharm., 22, p. 507. 
[Proc. A. Ph. A., 22, p. 106.] 

The capsicin sold by the firm of E. Merck is stated to be the ethereal 
extract of the capsicum fruit. 

Kemington, J. P. 1873 

On the Use of Petroleum Benzin for Extracting Oleo- 

resinous Drugs. 

Proc. A. Ph. A., 21, p. 592. 

It is stated that benzin does not extract all of the diuretic principles 
from buchu and that its use for extracting the oleoresinous drugs is limited 
on account of its inflammability and great volatility. 

Patterson, J. 1875 

Aspidium marginale, Wildenow. 
Am. Journ. Pharm., 47, p. 292. 

The ethereal extract compared very favorably in appearance, taste and 
color with the best German oleoresin of male fern which could be obtained 
upon the market. An acid resembling the filicic acid of Luck was isolated 
therefrom. 

Kruse 1876 

Versuch einer vergleichenden Analyse der in den Monaten 

April, Juli und October 1874, in der Umgegend Wolmars gesam- 

melten Radicis filics maris. 

Arch. d. Pharm., 209, p. 24. 

The results obtained in the analyses of rhizomes gathered during the 
months of April, July and October are tabulated. The rhizomes gathered 
in April and October were found to have a more intensive green color and 
stronger odor than those gathered in July. The rhizomes gathered in 
April and July yielded a yellow colored extract while those gathered in 
October gave a beautiful green colored product. 

Griffin, L. F. 1877 

Preparations of Cubebs. 
Am. Journ. Pharm., 49, p. 552. 

The author found that cubebs yielded 16.5 per cent, of oil and resin to 
gasoline, while the wax and cubebin were not extracted. He, therefore, 
concludes that gasoline is adapted to the making of a good oleoresin of 
cubebs. 



242 DU MEZ— THE GALENICAL OLEORESINS 

Wolfe, L. 1877 

On the use of Petroleum Benzin in Pharmacy. 
Am. Journ. Pharm., 49, p. 1. 

It is stated that benzin does not extract any of the pungent resins from 
ginger, no cubebic acid from cubebs, no piperin from pepper, and no 
santonin or resin from wormseed. 

Cressler, C. H. ' 1878 

On Aspidium marginale, Swartz. 
Am. Journ. Pharm., 50, p. 290. 

The author prepared an oleoresin from what he thought was male fern, 
but later proved to be Aspidium marginale. According to his report, it 
proved effective in expelling tapeworm. 

Rohn, E. 1878 

Recovering Ether in the Preparation of the Ethereal 

Extracts. 

Schweiz. Worchenschr. f . Chem. u. Pharm., — , p. — [Year- 

Book Pharm., 16, p. 250.] 

The author recommends mixing the exhausted drug with water and 
then heating the mixture over a direct flame up to 60° C, when the ether 
remaining in the marc distills over. In this manner three kilos of ether 
are stated to have been recovered from eight to ten kilos of male fern used 
in the preparation of the extract. 

Kennedy, . 1879 

Aspidium marginale. 
Am. Journ. Pharm., 51, p. 382. 

Favorable results in the expulsion of taenia by the administration of 
oleoresin of Aspidium marginale a'*© reported. 

Thresh 1879 

Proximate Analysis of the Rhizome (Dried and Decorti- 
cated) of Zingiber Officinalis and Comparative Examination of 
Typical Specimens of Commercial Gingers. 
Pharm. Journ., 39, pp. 171 and 191. 

The yield of ether extract is given as follows: Jamaica ginger, 3.29 per 
sent., Cochin, 4.965 per cent., African, 8.065 per cent. It is further stated 
that twice as much ether is required to exhaust the African ginger as it 
is necessary in the case of the other sorts (p. 191.) 



BIBLIOGRAPHY 24$ 

Bowman, J. ' 1881 

Aspidium rigidum. 
Am. JoTirn. Pharm., 53, p. 389. [Pharm. Journ. 12, p. 263.] 

A crystalline substance thought to be identical with the Filixsaeure of 
Luck was obtained from the ethereal extract of Aspidium rigidum. 

Seifert, 0. * 1881 

Einiges ueber Bandwurmkuren. 

Wien. Med. Wochenschr., 31, p. 1364. [Centralb. f. klin, 
Med. 3, p. 1884.] 

The author contends that the extract should be prepared from the 
peeled fresh drug gathered in May or October as drying causes the loss of 
a greater part of the volatile oil. The ether should not be evaporated 
until just before the extract is to be dispensed. 

Maisch, J. M. 1883 

Comparison of Galenical Preparations of the United States 

and German Pharmacopoeias. 

Am. Journ. Pharm., 55, p. 398. 

In the preparation of oleoresin of cubebs, the German Pharmacopceia 
directs that a mixture of equal parts of ether and alcohol be used as a 
menstruum^ while the Z7. S. Pharmacopoeia directs that ether alone be used. 
In the preparation of oleoresin of aspidium, the solvents are the same 
(ether) but the German Pharmacopoeia directs that the oleoresin be pre- 
pared by maceration instead of percolation as in the Z7. S. Piiarma^opodia, 

Kramer 1884 

Extractum filicis maris. 
Pharm. Centralh., 25, p. 578. 

The fresh rhizomes gathered in May or October, are directed to be ex- 
tracted with, ether containing a little alcohol. The tincture thus obtained 
is to be preserved in a cool place and the oleoresin prepared therefrom 
immediately before dispensing. 

Berenger-Feraud 1886 

Valeur taenifuge de la fougere de Normandy. 
Journ. de Pharm. et de Chim., 14, p. 321. [Arch. d. Pharm., 

224, p. 134.] 

The author states that the rhizomes gathered in Normandy have scarcely 
any action while those gathered in the Vosges or Jura mountainB are very 
active as taeniafuges. 



^44 ^U MEZ— THE GALENICAL OLEORESINS 

Jones, E. W. 1886 

Amount of Starch in Ginger. 
Chem. & Drugg., 28, p. 413. [Arch. d. Pharm., 224, p. 769.] 

The yield of ethereal extract is given as 3.58 per cent., of alcoholic extract 
:-as 3.38 per cent. 



1887 



Extractum Cubebarum aethereum. 

Gehe & Co. Handels -Ber. Sept., 1887, p. 50. 

It is stated that, upon long standing, the extract of cubebs deposits a 
crystalline substance. The firm, therefore, cannot guarantee that the 
•extract will remain clear. 

Kremel, A. 1887 

Notizen zur Pruefung der Arzneimittel. 

Pharm. Post, 20, p. 521. [Archiv. d. Pharm., 225, p. 880.J 

Methods for the identification and evaluation of the ethereal extract 

of cubebs are presented. The chemical constants of both the alcoholic 

and ethereal extracts are tabulated (p. 522.) Analytical data on the 

alcoholic and ethereal extract of male fern are also given (p. 523.) 

Lippincott, C. P. 1887 

What Are the uses of Benzine and the Lighter Petroleum 
Products in Pharmacy? 

Proc. Penn. Pharm. Assoc, 10, p. 156. 
The six official oleoresins were prepared using "benzole" as the ex- 
iiausting menstruum. 

Keefer, C. D. 1888 

Aspidium marginale, Willdenow. 
Am. Journ. Pharm., 60, p. 230. 

The author states that the ethereal extract of the rhizomes of Aspidium 
marginale contains 0.61 per cent, of resin, and chlorophyll. Filicic acid 
could not be identified. 

:Siggnis, F. M. 1888 

Comparative value of commercial gingers. 
Am. Journ. Pharm., 60, p. 278. 
The following percentages of resin were obtained on extracting ginger 
<with alcohol, sp. gr. 0.820. 

Jamaica, unbleached 5.0 per cent. 

Jamaica, bleached 4.8 

East Indian 6,65 

East Indian 6.57 

African 6.17 

African 7.00 



BIBLIOGRAPHY 245» 

Trimble, H. 1888 

The Comparative Extractive Powers of Ether and Benzin. 
Proe. Penn. Pharm. Assoc., 11, p. 60. 

The following percentages of oleoresin were obtained on extraction 
with ether: aspidiiim, 6,51 per cent; capsicum, 19.5 per cent; cubebs,. 
21.26 per cent; lupulin, 60.59 per cent; pepper, 7.89 per cent, and ginger, 
3.07 per cent. The same drugs yielded to benzin 5.9, 18.5, 16.65, 7.04, 2.8- 
and 2.48 per cent., respectively. 

Greenwalt, W. G. 1889 

Oleoresin of Male Fern. 
Am. Journ. Pharm., 61, p. 169. [Proc. A. Ph. A., 37, p.- 

379.] 

The sediment deposited by the ethereal oil of male fern was found by^ 
actual test to be as active as the supernatant oil; experiment is thus said 
to help out the statement (U. S. P. 1880) that the granular deposit should' 
be thoroughly mixed with the liquid portion before being used. 

Minner, L. A. 1890 

Oleum Peponis. 
Am. Jour. Pharm., 62, p. 274. [Proc. A. Ph. A., 38, p. 323.] 

The pumpkin seeds comminuted with pumice stone are directed to be 
extracted with ether. Such a preparation is stated to have proved to be- 
an effective taenifuge, whereas Oleum Peponis was ineffective. 

Dieterich 1891 

Extracta. 
Helfenberger Ann., 1891, p. 29. 

One sample of extract of male fern examined showed a ** moisture con- 
tent" of 2.7 per cent, and gave 0.40 per cent, of ash. 

Kuersten, R. 1891 

Ueber Rhizoma Pannae, Aspidium athamanticum Kunze. 
Arch. d. Pharm., 229, p. 258. 

The author found no filix acid in the ethereal extract, but a substance 
Tannasaeure having the formula C11H14O4. A fatty and volatile oil were 
also isolated. The extract was found to be as active as the extract of 
male fern in the expulsion of tape worm. 



246 ^U MEZ— THE GALENICAL OLEORESINS 

Poulsson, E. 1891 

Ueber den giftigen und bandwurmtreibenden Bestand- 

theil des aetherischen Filixextractes. 

Arch. f. exper. Path. u. Pharm., 29, p. 1. 

Filix acid is stated to occur in two forms, amorphous and crystalline. 
"The first is reported to be therapeutically active, the latter is not. The 
-crystalline acid is thought to be an anhydride or lactone of the amorphous 
acid. The author gives the name Filicin to the crystalline acid. 

Rayman 1891 

Wirkung des Extr actum Filicis aether eum. 
Pharm. Post, 24, p. 933. 

It is stated that the extract of male fern is not well borne when taken 
internally if the ether has not been completely removed. 

Renter, Ludwig 1891 

Ueber die Beziehungen des Filixsaeuregehaltes zur Wirk- 
ung des Extractum Filicis aethereum. 

Pharm. Ztg., 36, p. 245. [Pharm. Post, 24, p. 511; Am. 
Journ. Pharm., 63, p. 288.] 

It is stated that, in 14 out of 15 cases, prompt action was obtained using 
an extract which showed no deposit of filix acid and which left no residue 
of filix acid after treating with petroleum ether. On the other hand 
tcxtracts which were rich in a deposit of filix acid also showed prompt action. 

Professor Robert is cited as stating that the Russian extract is about 
ten times as active as the German extract and twenty times as active 
as the French extract. 

Riegel, S. J. 1891 

Ginger and its Oleoresin. 

Am. Journ. Pharm., 63, p. 531. [Year-Book of Pharm., 29, 
p. 168.] 

Unbleached Jamaica ginger and East Indian ginger (having epidermis 
removed) yielded 5 and 8 per cent., respectively, of oleoresin to alcohol. 
"The unbleached Jamaica ginger gave 2.5 per cent, of extractive matter 
to bens in and the East Indian ginger gave 8 per cent of oleoresin to ether. 
All of the foregoing oleoresins were found to be completely soluble in 
alcohol and chloroform. 



1892 



Extractum Alcannae aethereum. 

Gehe & Co., Handels-Ber. Apr. 1892, p. 46. 

The ether extract of alkanet root is stated to be completely soluble in 
•oil which is said not to be true of all commercial alkanet extracts. 



BIBLIOGRAPHY 247 

Beringer, G. M. 1892 

Oleoresins. 

Am. Journ. Pharm., 64, p. 145. [Proc. A. Ph. A., 40, p. 
474; Pharm. Centralh., 33, p. 314; Jahresb. d. Pharm., 27, 

p. 589.] 

The author presents experimental data to show that acetone might be 
used to advantage in the preparation of the official oleoresins. He es- 
pecially recommends the use of this solvent in the preparation of the 
oleoresin of ginger. The yield of oleoresin, using acetone as the extract- 
ing solvent for the various drugs, is reported to be as follows: aspidium, 
18 per cent; capsicum, 18 per cent. (25 per cent, when the drug was com- 
pletely exhausted); cubebs, 21.75 to 25 per cent; lupulin, 71 per cent; 
pepper, 5.93 per cent; ginger, 5.57 per cent; and parsley seed 24 per cent. 

Dieterich 1892 

Extracta spissa et sicca. 
Helfenberger Ann., 1892, p. 44. 

Three lots of extract of male fern gave 1.50, 2.10 and 1.50 per cent., 
respectively, of * ' moisture ' ' and showed an ash content of 0.55, 0.55 and 
0.55 per cent., respectively. 

Kobert " 1892 

Ueber die wirksamen Bestandtheile im Ehizoma Filicis 

maris. 

Pharm. Post, 25, p. 1325. [Apoth. -Ztg., 8, p. 77; Chem. 

Centralb., 64, p. 269 ; Arch. d. Pharm., 231 ; p. 350, Pharm. Ztg., 

38, p. 64.] 

The author states that the volatile oil of male fern is therapeutically 
active and that Poulsson 's statement based on the work of Carlbohm, 
Liebig and Eulle, that the activity is due to filix acid alone is erroneous. 
He cites as an example the activity of Aspidium athamanticum Kun^e, which 
contains no traces of filix acid but contains the volatile oil. 

Sherrad, C. C. 1892 

Value of Oleoresinous Drugs. 
Chem. and Drugg., 40, p. 523. [Year-Book Pharm., 29, p. 

157.] 

The yield of oleoresin obtained using ether as a menstrum is reported 
to be as follows: 

Capsicum, 4 samples, 15.5, 17.4, 18.3 and 18.4 per cent; cubebs, 9 samples, 
16.4, 18.8, 21.06, 21.9, 23, 24.7, 24.8, and 24.8 per cent; ginger, 4 samples, 
3.85, 4.72, 5.2, and 5.4 per cent; lupulin, 1 sample, 66.5 per cent; crude 
whole male fern rhizomes, 2 samples, 9.27 and 9.87 per cent; peeled male 
fern rhizomes, 3 samples, 7.1, 7.26 and 8.9 per cent. 



248 DU MEZ— THE GALENICAL. OLEORESINS 

Weppen and Lueders 1892 

Ueber Extractum Filicis. 

Apoth.-Ztg., 7, p. 514. [Pharm. Ztg., 38, 922; Pharm. 
Post, 25, p. 1173.] 

It is stated that the extract prepared according to the D. A. Ill should 
have a yellowish-green color but not a deep green color. Preparations 
having a deep green color probably have chlorophyll or copper salts added 
to them. Copper can best be detected by dissolving the ash in hydro- 
chloric acid and making the usual tests for the metal. 

Two samples (commercial) of a deep green color were found to contaia 
0.056 and 0.044 per cent, of copper, respectively. 

1893 



Extractum Filicis aethereum. 

Gehe & Co., Handels-Ber., Apr., 1893, p. 43. 

The condition of the season in which the rhizomes are harvested i» 
stated to have a marked effect on the color of the extract. Sometimes- 
the genuine extract is very dark green in color, especially in dry seasons. 

Beckurts and Peters. 1893 

Extractum Filicis. 
Apoth.-Ztg., 8, p. 549. 

Upon examination, two beautiful green samples of the commercial ex- 
tract were found to contain 0.135 and 0.044 per cent, of copper, respectively^ 
evidently added for the purpose of coloring the product. An extract pre- 
pared by the author was yellowish green in color and contained no copper. 
A warning is issued against the use of copper utensils in the preparation 
of the extract. 

Dieterich 1893 

Extracta spissa et sicca. 
Helfenberger Ann., 1893, p. 38. 

One sample of extract of cubeb showed a '* moisture '^ content of 32.7" 
per cent, and gave 0.50 per cent of ash (p. 39). 

Three samples of extract of male fern contained 1.15, 1.60 and 1.75 per 
cent, of ''moisture" and gave 0.50, 0.50 and 0.50 per cent, of ash,, 
respectively (p. 39). 

Dyer and Gibbard 1893 

Determination between Genuine and Exhausted Ginger. 
Analyst, 18, p. 197. [Proc. A. Ph. A., 42, p. 936.] 

The ether extract of genuine ginger is stated to be 3.0 to 5.2 per cent. 
After exhausting with ether, alcohol was found to yield 0.8 to 1.5 per cent, 
additional extractive matter. 



BIBLIOGRAPHY 249 

Bedall 1894 

Extractum Cubebarum Aethereum. 
Pharm. Ztg., 39, p. 49. 

The author states that the extracts having a green color give a more 

intensive reaction for cubebin than those having a brownish color. This 

does not apply when the green color is due to the presence of salts of 
copper. 

Dieterich 1894 

Extracta spissa et sicca. 
Helfenberger Ann., 1894, p. 72. 

Three samples of extract of male fern were found to contain 3.65, 2.32 
and 1.90 per cent., respectively, of "moisture.'^ The same samples gave 0.55, 
0.42 and 0.50 per cent., respectively, of ash. 

Emmanuel, L. 1894 

Do Drugs Supplied by the Jobber Comply with Pharmaco- 

poeial Requisition. If Not, Who is Responsible, The Jobber or 

the Retailer? 

Am. Journ., Pharm. 56, p. 358. 

A sample of powdered cubebs obtained from an Eastern firm yielded 18 
per cent, of a brown oleoresin. This was reported to the seller who re- 
plied: ''the TJ. S. Pharmacopoeia specifies the unripe fruit, but this is 
jparely found in the market, the regular article of commerce being the ripe 
fruit which contains less chlorophyll." p. 360. 

Hell & Co. 

Zur Kritik liber Extract-Vorschriften und ueber fabrik- 
maessig dargestellte Extracte. 

Pharm. Post, 27, pp. 168-171. [Journ. de Pharm. et de 
Chim., 139, p. 493.] 

Copper is stated to be a natural constituent of the male fern rhizome. 
Duplicate analyses of a sample of the rhizomes carefully powdered in an 
iron mortar, and incinerated in a porcelain dish showed 0.0144 and 0.0148 
per cent, of copper, respectively. An ethereal extract prepared in the 
company's laboratory showed 0.0S3 per cent, of the metal and a com- 
mercial sample of the extract gave 1.96 per cent. Likewise, a commer- 
cial sample of extract of cubeb was found to contain 0.40 per cent, of 
copper. 



250 DU MEZ — THE GALENICAL OLEORESINS 

Poulsson, E. 1894 

Beitraege zur Toxicologie der Farnkrauter. 
Pharm. Post, 27, p. 238. 

Two new acid substances C34HS8O14 and C84H40O14 are reported to have 
been isolated from the rhizomes of Polystichum spinulosum. They were 
found to be toxic. 



1895 



Extractum Orleanae aethereum. 

Gehe & Co., Handels-Ber. Apr., 1895, p. 53. 



It is stated that good * ' bixinreiche " orlean species are rare. The ex- 
tract is said to be used for coloring " Genussmitteln. ' ' 



1895 



Extractum Cubebarum aethereum liquidium. 
Gehe & Co., Handels-Ber., Apr., 1895, p. 53. 

A note concerning the precipitation of resin. 



Bourquelot, Em. 1895 

Keactions d'identite de quelquess medicaments galenique» 

officinaux. 

Journ. de Pharm. et de Chim., 140, p. 361. 

The Extrait de Cubele of the French Codex is semi-liquid, that of the 
German and Austrian pharmacopoeias of the consistence of fresh honey* 
To identify the oleoresin, a small quantity is placed in a white porcelain 
dish and a few drops of concentrated sulphuric acid are added. The gen- 
uine oleoresin gives a purple-red color immediately. 

Davis, K. G. 1895 

Ginger. 

Am. Journ. Pharm. 67, p. 597.» [Proc. A. Ph. A., 44, p. 538.] 

The yield of oleoresin obtained from "ginger by the official process wa» 
found to be as follows: 

Jamaica ginger, whole rhizome, bleached, 4.53 to 4.62 per cent; Jamaica 
ginger, whole rhizome, unbleached, 2.82 to 4.41 per cent; Jamaica ginger, 
powdered unbleached, 4.48 per cent; Eaces ginger, powered, bleached,. 
4.09 to 5.40 per cent; Eaces ginger, w^hole rhizome, bleached, 4.02 to 5.75 
per cent; African ginger, whole rhizome, 5.75 per cent; African ginger^ 
powdered, 6.27 per cent. 



BIBLIOGRAPHY 251 

Dieterich l^^^ 

Extracta spissa et sicca. 
Helfenberger Ann., 1895, p. 17. 

One sample of extract of cubebs contained 20.90 per cent, of "mois- 
ture" and showed an ash content of 0.47 per cent. (p. 17). 

A sample of extract of male fern showed a "moisture" content of 1.75- 
per cent, and gave 0.50 per cent, of ash (p. 18.) 

Hyers, P. 1895 

Fluid Extract of Cnbeb. 

Am. Jonrn. Pharm., 67, p. 519. 

The following percentages of oleoresin are reported to have been yielded 
by cubebs to different solvents: ether, 22.45 per cent; alcohol, 14.48 per- 
cent; acetone, 18.48 per cent; petroleum ether, 13.47 per cent. 



1896 



Extractnm Filicis Ph. G. III. 

Caesar and Loretz, Geschaefts-Ber., Sept. 1896, p. 46. 

The firm attributes the uniform activity of their extract of male fern tO' 
the fact that the rhizomes are obtained from the same locality each year, 
that they are collected in the autumn and, after carefully garbling, are 
immediately made into extract. 

Fromme's method for estimating the filix acid content of the extract is^ 
given. 

Alpers, W. C. 1896 

Oleoresin Capsicum. 
Merck's Eep. 5, p. 593. 

The author states that he obtained a yield of 19 per cent, of oleoresia 
after removing the fat by Alteration instead of 5 per cent, as usually given 
in the text-books. 



Bocchi, I. 1896 

Methoden zur Feststellung der Identitaet und der Guete 

des aetherischen Filixextraktes. 

Boll. Chim. farm., 1896, p. 449. [Apoth-Ztg., 11, pp. 597 

and 837; Pharm. Ztg., 41, p. 596.] 

Keactions for the identification of filix acid, and a method for the eval- 
uation of the extract of male fern are given. 



252 ^^ MEZ— THE GALENICAL OLEORESINS 

Daccomo and Scoccianti 1896 

Die Bestimmung des Gehaltes an Filixsaenre im kaeuflichen 

Extr actum Filicis. 

Boll. Chim. farm., 5, p. 129. [Pharm., Ztg., 39, p. 280; 

Jahresb. d. Pharm., 31, p. 583; Apoth.-Ztg., 11, p. 174; Proc. 

A. Ph. A.., 44, p. 433.] 

The filix acid content of a number of samples of extract of male fern 
(self prepared and commercial) was found to vary from 11.86 to 42.53 
per cent., when assayed according to the method devised by the authors. 
The average yield of extract obtained is given as 10 per cent. 

The quantity and quality of the extract is stated to be influenced by 
the locality in which the rhizomes are grown, the moisture content of the 
drug when extracted, and the solvent. Ether, specific gravity, 0.720, is 
stated to be the most suitable menstruum for this purpose. Ether, specific 
gravity, 0.756, yielded 17 per cent, of a brownish colored extract of a 
tarry consistence. The presence of alcohol is said to retard the complete 
extraction of the filix acid. 

Dieterich 1896 

Extracta spissa et sicca. 
Helfenberger Ann., 1896, p. 33. 

One sample of extract of male fern contained 1.62 per cent, of "mois- 
ture" and gave 0.45 per cent, of ash. 

Kraft, P. 1896 

Ueber die Wertbestimmung von Extractum Filicis und 

eine neue Bestimmungsmethode der Filixsaeure. 

Schweiz. Wochenschr. f. Chem. u. Pharm., 34, p. 217. 

[Zeitschr, d. Allg. Oesterr, Apoth. Ver. 34, p. 798; Zeitschr. 1 

Anal. Chem., 39, p. 531.] 

It is stated that the method of Daccomo and Scoccianti for the evalua- 
tion of the extract of male fern does not give the filix acid content but 
the total acid content. Extracts examined by the author's method gave 
from 0.4 to 10.0 per cent, of filix acid. 

A new constituent which the author calls Filixwachs was isolated from 
the extract. 

Liverseege 1896 

The Effect of Solvents on the Analytical Character of 

Ginger. 

Pharm. Journ., 57, p. 112. [Apoth.-Ztg., 11, p. 639.] 
The ethereal extract of ginger is stated to amount to 5.5 per cent. 

The yield to methyl alcohol is given as 6.5 per cent. 



BIBLIOGRAPHY 253 

1897 

Extractum Filicis, Ph. G. III. 

Caesar and Loretz, Geschaefts-Ber., Sept. 1897, p. 62. 
[Pharm. Centralh., 38, p. 34.] 

Investigations carried on by the firm showed that the best time for 
harvesting the rhizomes of male fern is from the middle of September 
to the end of October. Ehizomes collected in the spring yielded an ex- 
tract low in filix acid content. 

The consistence of the abstract is said to be dependent upon variations 
in the rhizomes, thus rhizomes rich in wax give an extract which is not 
fluid at ordinary temperatures. 

Fromme 's improved method for estimating the filix acid is given. 

1897 



Extractum Filicis aethereum, P G.. III. 
Gehe & Co., Handels-Ber., Apr. 1897, p. 60. 

The results obtained in the assay of male fern extracts by the methods 
of Daccomo and Scoccianti, Bocchi, and Fromme are tabulated. 

Boehm, R. " • 1897 

Beitraege zur Kenntniss der Filixsaeuregruppe. 
Archiv. f. exp. Path. u. Pharm., 38, p. 35. 

In addition to the volatile oil, fixed oil and filix acid, Boehm isolated 
four acid substances from the extract of male fern, viz: aspidin (C23H32OT), 
flavaspidic acid (CasHsgOg), albaspidin (CjzHjgO,) and aspidinol (CijHuO*). 

Candussio 1897 

Ueber die Bereitung des Extractum Filicis aethereum. 
Pharm. Post, 30, p. 7. 
The author is impressed with the low cost of the commercial extract of 
male fern as compared with the cost when prepared by the apothecary him- 
self. The examination of a number of samples from the best German 
houses showed a low filix acid content when estimated according to the 
method of Daccomo and Scoccianti. They were all of a beautiful green 
color, however. 

Dieterich 1897 

Extracta spissa et sicca. 

Helfenberger Ann., 1897, p. 244. [Apoth.-Ztg., 13, p. 788; 
Pharm. Centralh., 39, p. 775.] 

Two samples of extract of male fern, D. A. Ill, lost 4.5 and 4.72 per 
cent., respectively, on drying at 100*0; and gave 0.43 and 0.52 per cent, 
of ash, respectively. 

Dieterich contends that a standard, which does not take into consideratioB 



"254 ^U MEZ— THE GALENICAL OLEORESINS 

the volatile oil as well as the filix acid, is worthless, as the former is also 
active as a taenifuge. Old extracts which are inactive show the normal 
Amount of filix acid. The diminution in activity is said to be due to the 
loss of the volatile oil by resinification and evaporation (p. 248.) 

Dietericli 1897 

Extractum Filicis aetherum, D. A. III. 
Extractum Cubebarum aethereum. 
Erstes Dezennium d. Helfenberger Ann., 1886-1895, p. 322. 

Eighteen samples of extract of male fern examined during 10 years 
showed a loss upon drying at lOO'C of from 0.60 to 9.73 per cent. The 
same samples showed an ash content varying from 0.40 to 0.63 per cent. 

Four samples of ethereal extract of cubeb showed a loss upon drying 
at 100°C of 20.13 to 32.7 per cent., and gave 0.10 to 0.52 per cent, of ash. 

Glass and Thresh 1897 

Commercial Gingers and Essence of Ginger. 
Pharm. Journ., 58, p. 245. [Am. Journ. Pharm., 69, p. 320.] 

Jamaica ginger was found to yield 6.0 per cent of extractive matter 
to ether; Cochin, 4.33 per cent; African, 6.33 per cent. 

Iiauren, W. 1897 

Extractum Filicis spinulosae. 

Finska Laekaresaellsk. Handl., 1897, p. 9. [Pharm. Cen- 
tralh., 39, p. 975.] 

The ethereal extract prepared from the rhizomes of Aspidmm spinulosum 
is stated to be as active a taeniafuge as that prepared from Aspidium filix 
mas. 



Madsen, H. P. . 1897 

Meddelelser fra Vesterbro Apotheke Laboratorium. 
Arch. f. Pharm. og Chem., 54, p. 269. [Jahresb. d. Pharm., 

32, p. 591; Apoth.-Ztg., 12, p. 461.] 

Extracts of male fern from Denmark, Germany, Bohemia, central Eus- 
sia and Livonia were tested quantitatively for filix acid according to 
Fromme's method. Those from Bohemia and central Russia gave from 
0.71 to 0.97 per cent, of filix acid; two samples from Germany gave 5.58 
and 9.58 per cent., respectively; an extract from Wolmar in Livonia gave 
13.07 per cent; the extracts from Denmark, with two exceptions (6.07 and 
8.25 per cent.), gave below 2 per cent. (p. 277.) 



BIBLIOGRAPHY 255 
1898 

Extr actum Filicis aetherum. 

Gehe & Co., Handels-Ber., 1898, p. 68. [Pharm. Centralh., 
39, p. 298.] 

In the analyses of 11 extracts obtained during different years, 6 were 
found to contain aspidin, 0.2 to 3.0 per cent., but no filix acid; 4 samples 
contained filix acid but no aspidin; 1 sample showed a trace of aspidin 
and a small quantity of filix acid. 



1898 



Zur Arzneiform lind Werthbestimmung des Filixextracts. 
Pharm. Centralh., 39, p. 873. 

The dilution of the extract of male fern with castor oil to a definite 
filix acid content is discussed. 



1898 



Extractum Filicis, Ph. G. III. 

Caesar and Loretz, Geschaefts-Ber., Sept. 1898, p. 72. 

A continuation of the firm's investigations concerning the influence of 
time of harvesting upon the quality of the male fern rhizomes has shown 
that they do not contain the maximum amount of active constituents until 
the month of August. They, therefore, conclude that the rhizomes should 
only be harvested in the months of August, September and October. 

It is further reported that analyses of the extracts recently prepared 
show that the present year's (1898) crop of rhizomes is, on the whole, lower 
in crude filicin content than that of the preceding year (1897.) 

Bellingrodt, Fr. 1898 

Ueber Rhizoma und Extractum Filicis. 
Apoth.-Ztg., 13, p. 869. 

The crude, and purified filicin content of 8 different extracts of male 
fern prepared by the author from rhizomes obtained from different sources 
are given. Similar data in the examination of 9 commercial extracts are 
also reported. 

Dieterich, K. 1898 

Zur Wertbestimmung und Arzneiform des Filixextraktes. 
Apoth.-Ztg., 13, p. 788. 

The addition of castor oil to the extract of male fern in sufficient quantity 
to bring the filix acid content to a definite standard is recommended. 



256 I^U MEZ— THE GALENICAL, OLEORESINS 

Duesterbehn, F. 1898 

Rhizoma und Extractum Filicis in therapeutiwher, chem- 

ischer und toxicologischer Beziehung. 

Apoth.-Ztg., 13, pp. 713, 720, 729 and 734. 

The article is principally a review of the literature on the extract of 
male fern and its constituents. 

Lefils 1898 

Zur Herstellung von Filixextract. 

Pharm. Centralh., 39, p. 901. [Zeitschr. d. oest. Apotk 
Ver., 37, p. 167; Pharm. Ztg., 43, p. 939.] 

The author advises the mixing of the powdered rhizomes with castor oil 
before preparing the extract as he is of the opinion that this procedure 
will retard the evaporation of the volatil oil and the precipitation of the 
crystalline filix acid. 

Idris, T. H. 1898 

Notes on Extract of Ginger. 
Am. Journ. Pharm., 70, p. 466. 

The alcoholic extract of ginger known as gingerine does not contain all 
of the aromatic principles of the rhizome, as most of the essential oil is 
lost on removing the alcohol upon evaporation. Acetone boiling at SS^C 
was found to be the most suitable solvent for extracting ginger. The 
acetone extract is a dark brown substance of treacly consistence, intensely 
pungent and at the same time possessing the full aroma of ginger, the 
quality of which largely depends on the variety of ginger used. 

Miehle, Feodor 1898 

Eine empf ehlenswerte Form der Verordung von Extractum 

Filicis. 

Apoth.-Ztg., 13, 777. [Pharm. Centralh., 39, p. 873,] 

The author recommends diluting the extract with castor oil in order to 
make a standard preparation containing a definite amount of filix acid. 
He advises the introduction of such a preparation into the D. A. lY, 
under the name Extractum Filicis oleatum. 

Plzak, F. 1898 

Extractum Filicis. 
Pharm. Centralh., 39, p. 687. [Jahresb. d. Pharm., 33, 

p. 547.] 

The author found 6.48 per cent of filix acid in the extract of male fern 
by the Kraft method, 6.0 per cent, by Fromme 's old method and 5.2 per cent* 
by Fromme 's improved method. 



PIPLIOGRAPHY 257 

Wintan, Ogden and Mitchell 1898 

Capsicum. 

Rep. of Conn. Agr. Exp. Sta. (1898), p. 200. 
The amount of extractive matter obtained with ether from different 
samples of red peppers is given as follows: Chilli Colorado, 15.81 per 
cent; peppers from Natal, 16.85 per cent; from Nepaul, 21.31 per cent; 
and from Zanzibar, 16.19 per cent. 

• 1899 



Recently Introduced Remedies. 

Am. Drugg. & Pharm. Rec, 34, p. 129. 
It is stated that the extract of Filix Spinulosa is an ethereal extract of 
the rhizome of Aspidium spinulosum and that it has been recommended as 
a substitute for the preparation made from Aspidium Filix-mas. 

1899 



Extractum Filicis, Ph. G. III. 

Caesar and Loretz, Geschaefts-Ber., Sept. 1899, p. 73. 
A table showing the crude filicin and filix acid content of extracts pre- 
pared from 15 of the better samples of male fern rhizomes obtained from 
different sources in Germany is given. 

Eesults showing the difference in extractive power of ether, ap. gr. 0.720 
and ether, sp. gr. 0.728 are also given, 

Hausmann, A. 1899 

Ueber Extractum Filicis aethereum. 
Arch. d. Pharm., 237, p. 544. 

The examination of 21 commercial extracts of male fern obtained from 
various sources showed that aspidin was a constituent of 4 of them. As 
aspidin is said to be found only in Aspidium spinulosum, the author infers 
that the rhizomes of this species have been used to adulterate the official 
drug. 

A method for the detection of aspidin is given. 

1900 



Extractum Filicis. 

Caesar and Loretz, -Geschaefts-Ber., Sept. 1900, p. 77. 

A table showing the crude and purified filicin content of 12 samples 
of extract of male fern is given 

Attention is also called to the greater tendency of the extract, prepared 
with ether, specific gravity 0.728, to deposit than that prepared with 
ether, specific gravity 0.720. The deposited material is reported to have 
been identified by Boehm as filix acid and a wax-like substance. 



258 ^^ MEZ— THE GALENICAL OLEORESINS 

1900 

Extractum Filicis aethereum. 

Gehe & Co., Handels-Ber., Apr. 1900, p. 63. 

The constituents of the extracts of Aspidium filix mas, A. filix femina 
and A. spinulosum are discussed. 

Maish, H. C. C. 1900 

Oleoresins. Economical preparation. 

P. C. P., Alumni Report, March, 1900, p. 49. [Proc. A. Ph. 

A., 48, p. 495.] 
Maish advises the use of the Soxhlet extraction apparatus for pre- 
paring the oleoresins on a small scale. 

Patch, E. L. 1900 

Answere to queries issued by the Scientific Section of the 
American Pharmaceutical Association. 
Proc. A. Ph. A., 48, p. 199. 
The commercial oleoresins frequently show the presence of acetone, p. 205. 



1901 



Extractum Filicis. 

Caesar and Loretz, Geschaefts-Ber., Sept. 1901, p. 68. 
The crude and purified filicin contents of 8 batches of extract of male fern 
prepared during the year are presented in tabular form. 

Bennet 1901 

Report on Commercial Ginger. 
Pharm. Journ., 66, p. 522. 
The yield of extractive matter obtained on exhausting ginger with ether 
and alcohol is given as follows: 

Per cent, of ether extract: 

Jamaica ginger (whole), 2.57 to 6.41. 

*' '* (ground), 2.97 to 4.6. 

Per cent, of alcoholic extract after ether: 
Jamaica ginger (whole), 3.09 to 5.16. 
" ** (ground), 3.01 to 4.16. 

Per cent, of alcoholic extract. 
Jamaica ginger (whole), 3.94 to 5.61. 

*' '* (ground), 3.41 to 5.67. ^ 

Cochin ** (whole), 4.91 to 6.74. " ' 

*' ** (ground), 5.41 to 6.51. 

African ** (whole), 5.41 to 6.61. 

" *' (ground), 5.14 to 6.47. ^ 



BIBLIOGRAPHY 259 

Dieterich 1901 

Extracta spissa et sicca. 

Helfenberger Ann., 1901, p. 170. 
One sample of extract of male fern, D. A. IV, gave 5.23 per cent, of 
*' moisture" and 0.32 per cent, of ash (p. 171). 

Matzdorfe, M. 1901 

Wertbestimmnng des Khizoma Filicis. 
Apoth.-Ztg., 16, pp. 233, 256 and 273. 
The various constituents of the extract of male fern are discussed with 
respect to their therapeutic activity. Of these filix acid is thought to 
be the most important. Tables showing the crude filicin and filix acid 
content of ethereal fluid extracts prepared by ordinary percolation and 
by extraction with a Soxhlet's apparatus are given. 

Stoeder 1901 

Bestimmung der Filixsaenre in Extr actum Filicis. 
Pharm. Ztg., 46, p. 541. 
A method very similar in all respects to that of Fromme for the esti- 
mation of the filix acid in the extract of male fern is described. 



1902 



Oleoresin of Insect Powder. i,^ 

Southall Bros. & Barclay, Lab., Bep., 10, p. 20. 

This oleoresin is said to be extracted from the powdered drug and is 
offered for sale, in the crude form, as an extract, or precipitated, in the 
form of a coarse powder. 

It is said to be useful as a basis for nursery hair lotions, dusting pow- 
ders and similar articles. 



1902 



Extractum Filicis. 

Caesar and Loretz, Geschaefts-Ber., Sept. 1902, p. 73. 
It is stated that the crude filicin contains the amorphous acid recently 
shown by Kraft to be the active principle of male fern extract. The 
estimation of the crude filicin will, therefore, be continued by the firm. 

Buttin, L. 1902 

Extract de Fougere male. 

Schweiz. Wochenschr. f. Chem. u. Pharm., 40, p. 234. 
A short review of the early work on the constituents of the extract of 
male fern is given. 
The variation in the constituents of the rhizomes dne to the locality in 



2^0 ^^ MEZ— THE GALENICAL OLEORESINS 

which they are grown, the time of the year when harvested, storing, etc., 
and the effect of the same upon the activity of the extract is emphasized. 

Eight per cent of extract is reported as having been obtained from 
rhizomes harvested in the spring. 

Kraft, F. 1902 

Untersuchung des Extractum Filicis. 
Schweiz. Wochenschr. f. Chem. u. Pharm., 40, p. 322. 
[Chem. Centralb., 73, 2, p. 53; Pharm. Ztg., 48, p. 275.] 

Two new substances were isolated by the author from the ethereal ex- 
tract of male fern, flavaspidin and an amorphous acid. The amorphous acid is 
reported to be the active principle and to be present to the extent of 5 per 
cent, in a good extract. 

1903 



Table showing suggested standards, ranges of specific 
gravity, etc., for galencial preparations. 

Southall Bros., & Barclay, Lab. Rep., 11, p. 23. 

The standard range for the specific gravity of Extractum Filicis Uquidum 
is given as 1.000 to 1.019 at IS.S^C p. 24.) 



1903 



Extractum Filicis. 

Caesar and Loretz, Geschaefts-Ber., Sept. 1903, p. 77. 
It is reported that extracts prepared from the male fern rhizomes har- 
vested during the previous year, when assayed according to the method of 
Kraft, yielded 27.08 to 36.6 per cent, of crude filicin. 



1903 



Ginger. 

Southall Bros. & Barclay, Lab. Rep., 11, p. 13. 

The following table shows the proportion of oleoresin found in three 
varieties of commercial ginger. 

Jamaica Cochin African 

Per cent. sol. in alcohol (90 per cent.) 4.35 4.57 9.93 

Per cent. sol. in ether, Sp. gr. 0.717 4.76 6.04 11.09 



1903 



Capsicum. 

Southall Bros. & Barclay, Lab. Rep., 11, p. 13. 

A sample of Capsicum minimum yielded ,5.67 per cent, of material soluble 
in ether, Sp. gr. 0.717, and a sample of Capsicum annum yielded 15.34 
per cent, to the same solvent. 



BIBLIOGRAPHY 261 

Ballard 1903 

Sur quelques condiments des colonies francaise (Anise 
etoile, Cannelle, Cardamome, Curcurma, Gingembre, Girofle. 
Journ. de Pharm. et de Chim., 157, pp. 248 and 296. 
Ginger from the Ivory Coast is reported to have yielded 6.33 per cent. 
of ether extract, that from Tahiti, 3.75 per cent, p. 248. 

Black pepper yielded the following percentages of extractive matter 
to ether: 10.15, 8.70 and 5.50. 

Beythien 1903 

Capsicum. 
Zeitschr. Unters. Nahr. u Genussm., 5, p. 858. [Pharm. 

Ztg., 47, p. 549; Proc. A. Ph. A., 51, p. 747.] 

The examination of a number of commercial samples of powdered capsi- 

sicum showed the following: 

Yield of extract to ether (total) 12.54 to 19.70 per cent. 

" << << <' " (av.) 14.94 ** ** 

" '' " '< alcohol (total) 26.55 to 35.71 '* " 

" " " '< '* (av.) 28.94 " " 

Dieterich 1903 

Extracta spissa et sicca. 
Helfenberger Ann., 1903, p. 240. 

Three samples of extract of male fern examined showed a *' moisture" 
content of from 5.52 to 7.38 per cent,, and gave from 0.27 to 0.39 per 
cent, of ash (p. 241.) 

Penndorff, O. 1905 

Untersuchungen ueber die Beschaffenheit kaeuflicher Filix- 
Ehizoma und Extrakte. 
Apoth.-Ztg., 18, p. 150. 
The author states that the rhizomes turn brown on aging due to the 
breaking down of the filix-tannic acid into filix-red and sugar. 

An examination of 20 samples of commercial rhizomes showed that 
12 of them or over 50 per cent, contained rhizomes of Aspidium spinulosum, 
1 sample consisted of 90 per cent, of {his species. 

Twenty samples of commercial extracts were examined with the fol- 
lowing results: 

4 samples — Starch present in small quantities. 
1 sample — Aspidin present. 
20 samples — 6,65 to 18.31 per cent, crude filicin. 
20 samples — 1.06 to 7.48 per cent, filix acid. 
20 samples — 0.40 to 3.00 per cent, filix acid in solution. 
20 samples — 0.40 to 6.05 per cent, filix acid deposited. 
7 samples — copper, more or less. 



252 E>U MEZ— THE GALENICAL OLEORESINS 

1904 



Extractum Filicis. 

Caesar and Loretz, Geschaefts-Ber., Sept. 1904, p. 77. 

It is stated that for years the firm has placed upon the market under 
their name an extract of male fern containing not less than 29 per cent. 
of crude filicin. 

Dieterich 1904 

Ueber Extractum Filicis, D. A. IV. 
Helfenberger Ann., 1904, p. 182. 

The results obtained in the examination of 3 samples of the extract of 
male fern are tabulated. The results include the per cent, of ' ' moisture ' ' 
and ash, and the iodine and saponification values. 



1905 



Extractum Filicis. 

Caesar and Loretz, Geschaefts-Ber., Sept. 1905, p. 7. 

It is stated that, although the year's crop of male fern is poor, the firm 

guarantees a crude filicin content of 28 per cent, for their extract, (p. 71.) 

Promme's method for estimating the crude filicin content is given (p. 85.) 

1905 



Ueber die wirksamen Bestandtheile des Famwurzel- 
extrakts. Pharm. Ztg., 50, p. 651. 

The work of Boehm, also thai of Kraft, is commented on, special ref- 
erence being made to Filmaron isolated from the extract by the latter. 



1905 



The Newer Remedies. 

Am. Drugg. & Pharm. Rec, 46, p. 135. 



Capsolin which is recommended as a substitute for mustard papers, is 
said to consist of a mixture of oleoresin of capsicum, the oils of turpentine, 
cajuput and croton, with an ointment base. It is manufactured and 
marketed by Parke, Davis & Co., Detroit. 



1905 



The New U. S. P., Changes in Composition and Strength. 
Drug Topics, 20, p. 210. [Am. Journ. Pharm., 78, p. 412.] 

The new edition of the U. S, P. specifies acetone as the solvent for 
making all of the oleoresins with the exception of oleoresin of cubebs, which 



BIBLIOGRAPHY 263 

is prepared with alcohol. It is stated that manufacturers have long since 
seen the folly of employing an expensive solvent like ether, and the 
adoption of acetone for this purpose is a recognition of commercial phar- 
maceutical advances, (p. 214.) 

Dieterich 1905 

Extracta spissa et sicca. 
Helfenberger Ann., 1905, p. 159. 

A sample of the ethereal extract of cubeb, D. A. IV, showed a "mois- 
ture" content of 55.91 per cent, and an ash content of 0.87 per cent, 
(p. 160.) 

A sample of extract of maje fern D. A. IV, gave a *' moisture" content 
of 5.06 per cent., an ash content of 0.46 per cent, and yielded 23.22 per 
cent, of crude filicin (p. 161.) 

Dieterich 1905 

Khizoma Zingiberis. 
Helfenberger Ann., 1905, p. 131. 

The following percentages of extract were obtained by exhausting ginger 
with different solvents, evaporating the latter and dryiag the residue at 
lOO'C: 

1) One part alcohol, 8 parts water — 7.86 per cent. 

2) Sixty-eight per cent, alcohol — 4.88 per cent. 

3) Ninety per cent, alcohol — 2.79 per cent. 

Dieterich , * 1905 

Rhizoma Filicis. 
Helfenberger Ann., 1905, p. 130. 

During the year, a number of lots of male fern rhizomes were examined. 
The air-dried rhizomes yielded 9.94 to 10.60 per cent, of ethereal extract. 
The rhizomes when dried at lOO^C yilded as high as 11.20 per cent, to 
the same solvent. 

Francis, J. M. 1905 

The New Pharmacopoeia: A Detailed Commentary on the 

Eighth Revision of the U. S. P. 

Bull, of Pharm., 19, p. 317. [Am. Joum. Pharm., 78, p. 412.] 

Under acetone, it is stated that oleoresins prepared with this solvent will 
separate in two layers on standing owing to the fact that this ketone pos- 
sesses in a measure the combined solvent properties of both alcohol and 
ether. 



264 ^^ MEZ— THE GALENICAL. OLEORESINS 

Vanderkleed, C. E. 1905 

Report of the Committee on Adulterations. 
Proe. Peixna. Pharm. Assoc., 28, p. 47. 

Eight assays of capsicum gave 9.4 to 23.9 per cent, of oleoresin, the 
average being 18.13 per cent. The standard for a good drug is stated 
to be 15 per cent. 

Vieth, H. 1905 

Ueber die Beziehung zwischen chemischer Zusammenset- 

zung und medizinisclier Wirkung einiger Balsamika. 

Verh. d. Ges. deutsch. Naturf. u. Aerzte, 2, p. 364. [Jah- 

resber. d. Pharm., 66, p. 13.] 

Kubetenextrakt is reported to consist of terpenes (65 per cent.), resin 
acids (10 per cent.), and resins (25 per cent.) 



1906 



Apiolin 

Merck's Ann. Eep., 20, p. 34. 

Apiolin is the raw ethereal oil obtained from the seed of Petroselinum 
sativum or from Apiol viride by extraction with a suitable solvent. It is a 
yellow fluid, sp. gr. 1.25 to 1.135, boiling at 280 to 300*C. 



1906 



Extractum Filieis. 

Caesar and Loretz, Geschaefts-Ber., Sept. 1906, pp. 82 and 
99. 

The firm reports that the crude filicin content of the extract obtained 
from the current year's crop of male fern averages 27 per cent. (p. 82). 
Fromme's method for estimating the crude filicin is given (p. 99). 

Naylor, A. H. 1906 

Progress in pharmacapoeias : drugs and their constituents* 
Year-Book of Pharm., 43, p. 204. 

It is stated that in the present state of our knowledge, neither Daccpmo 
and Scoccianti 's, Kraft's nor Stoeder's process for the quantitative esti- 
mation of filicic acid is a measure of the anthelmintic value of the ex- 
tract of male fern. 



BIBLIOGRAPHY 265 

Roeder, Ph. 1906 

Ehizoma Filicis. 
Jahresb. d. Pharm., 41, p. 46. 

The author states that the rhizomes of Aspidium filix mas should give at 
most 3 per cent, of ash and should yield at least 8 per cent, of extractive 
matter to ether, allowing the latter to evaporate spontaneously and then 
heating for 2 hours at 95 "C, cooling in a desiccator and weighing. Three 
samples of rhizomes gave 2.52 to 2.92 per cent, of ash, respectively, and 
9.22 to 10.1 per cent, of ether-soluble extract. 

WoUenweber, W. 1906 

Ueber Filixgerbsaeure. 
Arch. d. Pharm., 244, p. 466. 

In connection with his work on the tannic acid in the male fern rhizomes, 
"the author presents the results obtained in extracting the drug in a Soxh- 
let's apparatus with various solvents, ether, benzol, and petroleum ether. 
At the end of six hours, extraction was found to be practically complete in 
all cases. The yield obtained in each case is given as follows; ether, 10.0 
per cent., benzol, 9.06 per cent., petroleum ether, 9.08 per cent. 

Extraction with alcohol of varying strength yielded extractive matter 
in the following quantities: alcohol (90 per cent.), 20.0 per cent., alcohol 
(96 per cent.), 16.6 per cent. 

The fixed oil content of the ethereal extract is stated to be 70 to 75 
per cent. 



1907 



Cubebs. 

Evans Sons Lescher & Webb, Analyt. Notes, 1, p. 21. 

The oleoresin extracted by ether from four samples of cubebs amounted 
to (1) 22.08, (2) 22.6, (3) 21.13 and (4) 22.8 per cent., respectively. 



Blome, W. H. 1907 

Cubeba. 

Proc. Mich. Pharm. Assoc, 1907, p. 68. [Bull. Hygienic 
Lab., No. 63, p. 225.] 

Five samples of cubeb are reported which assayed from 18.85 to 26.88 
per cent, of oleoresin. 



266 



DU MBZ— THE GALENICAL OLEORESINS 



Van der Harst, J. C. 1907 

Lupulin. 
Pharm. AVeekbl., 44, p. 1506. [Bull. Hygienic Lab., No. 63, 

p. 301.] 

Two samples of lupulin were found to contain 52 and 65 per cent, of 
ether-soluble matter, respectively. 

Patch, E. L. 1907 

Report of Committee on Drug Market. 
Proc. Am. Pharm. Assoc, 55, p. 314. 

The samples of capsicum examined yielded from 16.2 to 26.5 per cent, 
of alcoholic extract (p. 324.) 

Smith, 0. W. 1907 

Galenicals of the U. S. P. VIII. 
Proc. Mo. Pharm. Assoc, 29, p. 132. 

The author is of the opinion that the oleoresin of eubeb might well have 
been included in the class made with acetone, as the drug yields but little 
on subsequent extraction with alcohol. Alcohol on the other hand is 
/Open to the objection that its boiling point is so high that a considerable 
loss of volatile substances from the cubeb occurs when the solvent ia 
evaporated (p. 134.) 



1908 



Extractum Filicis. 

Caesar and Loretz, Geschaefts-Ber., Sept. 1908, pp. 76 

and 99. 

It is stated that for years the firm has estimated the crude filicin con- 
tent of the extract of male fern and marketed a standard product contain- 
ing 28 per cent, of this constituent as required by the Swiss PharmacopcEia, 
VI, (p. 76.) 

Fromme's method for estimating the crude filicin is given (p. 99.) 



Dohme and Engelhardt 1908 

Purity of some official and non-official drugs and chemicals. 
Proc Am. Pharm., Assoc, 56, p. 814. 

A sample of lupulin yielding only 56 per cent, of ether-soluble matter is 
reported (p. 817.) 



BIBLIOGRAPHY 267 

Patch, E. L. 1908 

Report of Committee on Drug Market. 

Proc. Am. Pharm. Assoc., 56, p. 765. 
The different samples of capsicum examined yielded from 15 to 25.2 per 
cent, of alcoholic extract (p. 768.) 

Spaeth, Eduard 1908 

Die chemische und mikroskopische Untersuchung der 

Gewiirze und deren Berurteilung. 
Pharm. Centralh., 49, p. 581. 

The paper discusses the characteristics of several commercial varieties 
of ginger and the composition of the drug. The quantity of material 
extracted by ether, alcohol, petroleum ether and methyl alcohol is given. 

Vanderkleed, C. E. 1908 

Report of Committee on Adulteration. 
Proc. Penna. Pharm. Assoc, 31, p. 65. 

Three samples of capsicum yielded from 11.59 to 18.35 per cent, of oleo- 
resin; four samples of cubebs, 16.39 to 23.6 per cent; two samples of 
ginger, 5.58 to 9.55 per cent; three samples of male fern, 6.68 to 17.9 per 
cent., average 10.002 per cent. (p. 88.) 

1909 



Pharmacy Committee's Report. 
Chem. & Drugg., 74, p. 288. 

The Committee of Reference in Pharmacy asserts that cubebs should 
yield not less than 20 per cent, of oleoresin to ether, sp. gr. not over 
0.720. (p. 292.) 

1909 



Extractum Filicis. 

Caesar and Loretz, Geschaefts-Ber. Sept. 1909, pp. 67 and 84. 

A crude filicin content of 28 per cent, is guaranteed by the firm for the 
new lot of extract of male fern (p. 67.) 

Fromme's method for the estimation of the crude filicin is given (p. 84.) 

1909 



Apiol. 

Evans Sons Lescher & Webb, Analyt. Notes, 4, p. 11. 

A sample of apiol of French manufacture examined by the firm is re- 
ported as having been liquid and green in color. It yielded 40 per cent, of 



268 



DU MEZ— THE GALENICAL OLEORESINS 



Its bulk to steam distillation. It is^ therefore, thought that the sample 
was prepared by the extraction of parsley fruits with a suitable light 
solvent. ' 



Bernegau, L. H. 1909 

Report of the Committee on Adulteration. 
Proe. Penna. Pharm. Assoc, 32, p. 119. 

Ten samples of lupulin examined yielded from 34 to 65.8 per cent, of 
ether-soluble matter (p. 125.) 



Dohme and Engelhardt 1909 

Purity of some official and non-official drugs and chemicals. 
Proc. A. Ph. A., Assoc, 57, p. 713. 

* Three samples of lupulin examined were low in ether-soluble matter 
yielding but 47.50, and 43 per cent., respectively (p. 716.) 

Dunn, J. A. 1909 

Suggested Modifications of U. S. P. and N. F. Formulas. 
Proc A. Ph. A., 57, p. 942. 

It is stated that the oleoresin of male fern prepared by the TJ. S. P. 
method, using acetone, contains so much undesirable extractive matter that 
it is necessary to purify it by dissolving in ether. It is suggested that it 
might be worth while to consider whether the U. S. P. should not go 
back to the use of ether (p. 949.) 

Parson, W. A. 1909 

Report of the Committee on Adulteration. 
Proc Penna. Pharm. Assoc, 32, p. 119. 

Three samples of lupulin yielded 66.1 and 54 per cent, of ether-soluble 
matter, respectively (p. 125.) 



Patch, E. L. 1909 

Report of Committee on Drug Market. 
Proc A. Ph. A., 57, p. 721. 

The alcoholic extract from specimens of ginger examined varied from 
3.7 to 6.2 per cent. (p. 739.) 



BIBLIOGRAPHY 269 

Vanderkeed, C. A. 1909 

Report of the Committee on Adulteration. 
Proc. Penna. Pharm., Assoc., 32, p. 119. 

Samples of capsicum, cubebs, ginger, and male fern examined are re- 
ported to have yielded oleoresin as follows: five samples of capsicum, 14.34 
to 17.95 per cent; four samples of cubebs, 16.49 to 24.34 per cent; sixteen 
samples of Jamaica ginger, 3.142 to 6.91 per cent; two samples of African 
ginger, 8.2 and 9.036 per cent; one sample of male fern, 10.33 per cent, 
(p. 129.) 



i9ia 



Extr actum Filicis. 

Caesar and Loretz, Jahres-Ber., Sept. 1910, p. 90. 

Fromme's method for the estimation of crude filicin is given. 



1910 



Cubebs. 

Southall Bros. & Barclay, Lab. Rep., 17, p. 11. 



Eight samples of cubebs, when extracted with petroleum spirits, yielded 
from 3.88 to 18.08 per cent, of extractive matter. The same samples on- 
subsequent extraction with alcohol (90 per cent.) yielded from 3.4 to 5.6(ii 
per cent, of extractive matter. 



1910 



Capsicum. 

Southall Bros. & Barclay, Lab. Rep., 17, p. 8. 

Two samples of capsicum (B. P. C.) yielded 15.4 and 14.0 per cent., 
respectively, of extract to benzol. 



Dohme and Engelhardt 1910 

The new Hungarian Pharmacopoeia. 
Proc. Am. Pharm. Assoc, 58, p. 1168. 

The extraction of male fern with ether, as directed in the Ph. Hung. Ill, 
instead of acetone as in the U. S. P., VIII, is thought to be desirable since 
the latter is liable to extract substances which might produce injurioni 
after effects (p. 1179.) 

It is further stated that the yield of ether extract as given in the Hun- 
garian Pharmacopoeia is 8 per cent. (p. 1184.) 



nfQ DU MEZ— THE GALENICAL OLEORESINS 

Eldred, F. R. 1910 

Some data obtained in the examination of official substances. 
Proc. A. Ph. A., 58, p. 889. 

Forty-eight lots of capsicum were examined. The yield of ether-soluble 
oleoresin, when the latter was dried for one hour on a water bath, was 
found to vary from 11 to 26 per cent., the average 18 per cent. (p.891.) 

Gane, E. H. 1910 

Pharmacopoeial notes and comments. 
Drug Topics, 25, p. 212. 
It is stated that a good sample of cubebs should yield 20 per cent, of 
ether-soluble extract. 

Gane and Webster 1910 

Pharmacopoeial notes and comments. 

Drug Topics, 25, p. 
Aspidium is stated to be one of the most useful of drugs when carefully 
collected and preserved, but that much of the rhizome is inert and is ob- 
tained from any old species of fern. It is said to be falling into disuse 
on this account. It is thought that the observance of more care in the 
collection of the drug and the preparation of the oleoresin would restore 
•its popularity as an anthelmintic. 

La Wall, C. H. 1910 

Some suggested standards and changes, for the U. S. P. 
Am. Joum. Pharm., 82, p. 21. 

The author asserts that a test for capsicum should be included in the 
U. S. P. requirements for the oleoresin of ginger as many commercial 
samples used in making ginger ale extracts contain oleoresin of capsicum 
and these occasionally find their way into the pharmaceutical trade. 

A method for the detection of capsicum in the oleoresin of ginger based 
on the neutralization of the pungent principle of the ginger with potassium 
hydroxide is described (p. 25.) 

Vanderkleed, C. E. 1910 

Report of the Committee on Adulterations. 
Proc. Penna. Pharm. Assoc, 33, p. 131. 
Seven samples of capsicum yielded from 15.10 to 22.27 per cent, of 
oleoresin; one sample of African ginger 10.12 per cent; two samples of 
Jamaica ginger 5.636 and 6.316 per cent., respectively (p. 147.) 



BIBLIOGRAPHY 271 

1911 

Extractum Filicis. 

Caesar and Loretz Jahres.-Ber., Aug. 1911, pp. 76 and 105. 

Eegret is expressed in that the Ph. Germ. V. has not included an assay 
for oleoresin of aspidium. The crude filicin content is thought to be a 
satisfactory indication of the value of this preparation. A filicin con- 
tent of 27 per cent, is guaranteed by the firm for the new lot of the ex- 
tract prepared by them (p. 76.) 

Fromme's method of estimating the crude filicin is given (p. 105.) 

1911 



Male fern extract. 

Evans Sons Lescher & Webb, Analyt. Notes, 6, p. 48. 

Five samples of male fern extract were tested. Two were found to 
be adulterated with castor oil (55 to 70 per cent.) 

The Kraft and the Swiss pharmacopoeial methods for evaluating the 
extracts are discussed and the results obtained in each case, along with other 
physical and chemical constants, are tabulated. 

1911 



Cubebs. 

Southall Bros. & Barclay Lab. Rep., 19, p. 9. 

Five samples of cubebs yielded from 4.66 to 8.78 per cent, of extract 
to petroleum spirit, the average being 6.95 per cent. 

: 1911 



Insect Powder. 

Southall Bros. & Barclay, Lab. Rep., 19, p. 10. 

Two samples of insect powder yielded 8.28 and 7.57 per cent, of oleo 
resin when tested by Durant's method. 

One sample of Japanese insect flowers yielded 13.98 per cent, of oleo- 
resin of an orange brown color. 



1911 



Oil of male fern. 

Brit. & Col. Drugg., 60, p. 388. 



In this article, it is stated that parcels of the extract of male fern are 
being condemned in London as they have been found to contain large 
quantities of castor oil. 

Suspicion was first aroused through the low selling price of some 



272 DU MEZ — THE GALENICAL. OLEORESINS 

of the extracts.- The adulterated extract was being sold for 4s per 
pound while reliable manufacturers would not quote prices below 5 s 6 d 
per pound. 

1911 



Ext. Filicis maris. 

Chem. & Drugg., 79, p. 749 and 798. 

This editorial commenting on Parry's observation, that extract of male 
fern is commonly adulterated with castor oil, calls attention to the testj* 
given in the Netherlands and Swiss pharmacopoeias. 

Bernegau, L. H. 1911 

Keport of the Committee on Adulterations. 
Proc. Penna. Pharm. Assoc. 34, p. 117. 

Three lots of lupulin tested 58.9, 57.7 and 62.1 per cent, soluble in 
ether (p. 125.) 

Beythien, Hemple & Others 1911 

Kurze Mitteilungen aus der Praxis des Chemischen Unter- 

siichungsamtes der Stadt Dresden. 

Zeitschr. Unters. Nahr. u. Genussm., 21, p. 666. 

A table is presented showing the ash content and extract content of a 
number of samples of ginger (p. 668.) 

According to Eeich the volatile ether extract content varied from 0.80 
to 4.02 per cent., the non volatile from 1.66 to 6.93 per cent; the alcoholic 
extract from 1.33 to 4.08 per cent; the petroleum ether extract from 1.14 
to 4.49 per cent; and the methyl alcohol extract from 4.40 to 12.53 per 
cent. 

Deane, Harold 1911 

Oleoresina Capsici, B. P. C. 
Pharm. Journ., 87, p. 804. 

The author criticises the British Pharmaceutical Codex with respect to 
the title Oleoresina Capsioi. He is of the opinion that the preparation 
has no right to the name oleoresin, as it corresponds more closely to the 
product sold as capsicin or soluble capsicin for the use of pill makers 
and mineral water manufacturers. 

Francis, J. M. 1911 

Report of the Committee on Adulterations. 
Proc. Penna. Pharm. Assoc, 34, p. 117. 

Only one of eight lots of lupulin examined failed to exceed the required 
60 per cent, of ether-soluble matter (p. 125.) 



, BIBLIOGRAPHY 273 

Glueeksmann, G. 1911 

Ueber eine neue Identitaetsreaktion des Extractum Cube- 

barum. 

Pharm. Praxis, 1911, p. 98. [Apoth.-Ztg., 27, p. 334.] 

A test in which hydrochloric acid is used fo^ producing a color reaction 
is described in detail. 

Parry, E. J. 1911 

Extract of male fern. 

Pharm. Journ. 87, p. 778. [Chem. & Drugg., 79, p. 860; 
Am. Journ. Pharm., 84, p. 136; Apoth-Ztg., 26, p. 1046.] 

The author reports on the examination of commercial extracts of male 
fern and finds that the greater part are undoubtedly adulterated with from 
30 to 60 per cent, of castor oil. The physical and chemical constants 
of the commercial samples and of genuine extracts are tabulated for com- 
parison. 

Pearson, W. A. 1911 

Report of the Committee on Adulterations. 
Proc. Penna. Pharm. Assoc, 34, p. 126. [Bull. A. Ph. A., 

6, p. 346.] 

The author reports that two lots of oleoresin of aspidium were rejected 
because they were not green in color. 

Rosendahl, H. V. 1911 

Fern rhizomes, yield of extract and relative activity of. 
Year-Book of Pharm., 48, p. 286. [Apoth.-Ztg., 26, p. 588 ; 

Svensk. farmac. Tidsk., 1911, p. 85.] 

The yield of ethereal extract obtained from various species of ferm 
harvested during different months of the year was found to be as follows: 



Aspidium filix mas 

Dryopteris spinulosa 

Dryopteris dliatata 

Fteris aquUina 

Athyrium filix femina 

Aspidium alpestris 
Two grams of the extract of Dryopteris dilataia are stated to be thera- 
peutically equivalent to 8 to 10 grams of the extract of Aspidium filix maa 
or four grams of the extract of Dryopteris spinulosa. 



May 


August 


October 


Per cent. 


Per cent. 


Per cent. 


— 


12.5 


11.0 


— 


17.0 


— 


10.0 


— 


— 


2.0 


— 


— 


0.9 








0.7 


__ 


«_ 



>274 I5U MEZ— THE GALENICAL OLEORESINS 

Vanderkleed, C. E. 1911 

Eeport of the Committee on Adulterations. 
Proc. Penna. Pharm. Assoc., 34, p. 117. 

Two samples of capsicum are reported to have yielded 14.7 to 17.93 per 
^ent., respectively, of oleoresin; one sample of subebs, 22.14 per cent; 
eleven samples of African ginger, 7.128 to 9.484 per cent; and eight 
samples of Jamaica ginger, 3.4 to 6.6 per cent. (p. 132.) 

1912 



Extractum Filicis. 

Caesar and Loretz, Jahres-Ber., Sept. 1912, p. 128. 

The firm's method for estimating the crude filicin is given. 



1912 



Capsicine. 

Evans Sons Lescher & Webb, Anaylt. Notes, 7, p. 18. 

Five samples of capsicvne examined were all entirely soluble in 10 vol- 
lunes of 90 per cent, alcohol. 



1912 



Male fern extract. 

Evans Sons Lescher & Webb, Analyt. Notes, 7, p. 51. 

Sixteen samples of male fern extract examined in 1912 were free from 
castor oil and of satisfactory purity. They showed a refractive index of 
1.507 to 1.509 at 15''C, and gave a filicin content of 22.9 to 26.3 per cent., 
when assayed according to the method given in the Swiss Pharmacopoeia. 



1912 



Capsicum. 

Johnson & Johnson, Lab. Notes, 1912, p. 14. 



The yield of ether extract obtained from capsicum is reported to have 
varied from 16 to 19 per cent. 



1912 



Cheap extract of male fern found badly adulterated. 
Merck's Eeport, 21, p. 29 [Apothecary, 24, p. 14.] 

A sample of cheap extract of male fern examined by Merck was found 
to be adulterated with 25 per cent, of castor oil, and to contain only 8 per 
cent, of crude filicin. 



BIBLIOGRAPHY 275 

1912 

Male fern extract. 

Southall Bros., & Barclay, Lab. Kep., 20, p. 15. 

The statement of Parry that much of the male fern extract is adulterated 
is confirmed. The physical and chemical constants obtained in the ex- 
amination of six commercial extracts are tabulated. 

Dohme and Engelhardt 1912 

Drug quality during the period 1906-1911. 
Journ. A. Ph. A., 1, p. 99. 

It is stated that there was hardly any variation in the percentage of 
oleoresin in the samples of cubebs examined during the last six years, 
(p. 101.) 

Goris and Voisin 1912 

The determination of the ether extract of male fern, and the 
unification of the methods of analysis. 

Bull. Sci. Pharmacolog., 19, p. 705, [Pharm. Ztg., 58, p. 
129; Journ. 90, p. 81; Year-Book of Pharm., 50, p. 337.] 

It is stated that the method of the Swiss Codex gives values for crude 
filicin which are about 30 per cent, too high owing to the solubility of 
the ether solution in ' the solution of barium hydroxide. If the ether be 
driven off by heating to 50 °C before filtering, the results will be com- 
parable with those obtained by the magnesia methods. 

Hooper, D. 1912 

Notes on Indian drugs. 
Pharm. Journ. 89, p. 391. 

The examination of the rhizomes of Indian ginger, with reference to de- 
termining the relationship between maturity and oleoresin content, showed 
that young rhizomes develop oleoresin as they are allowed to grow. Those 
gathered in December yielded 6.4 per cent, of extract to alcohol (90 per 
cent.), while those gathered in February gave 8.3 per cent. Upon washing 
the extracts with water, the remaining insoluble residue amounted to 3.0 
per cent, and 3.5 per cent., respectively. Some of the more mature rhizomes 
gave as high as 11.8 per cent, of alcoholic extract or 8.1 per cent, of 
washed resin. 

Patch, E. L. 1912 

Report of the Committee on Drug Market. 
Journ. A. Ph. A., 1, p. 499. 

Eight samples of Jamaica ginger gave from 3.3 to 6.0 per cent, of alco- 
holic extract (p. 500.) 



276 DU MEZ— THE GALENICAL OLEORESINS 

V'anderkleed, C. E. 1912 

Report of Committee on Drug Market. 
Proe. Penna. Pharm. Assoc., 35, p. 165. 
The assay of 4 samples of capsicum showed the oleoresin content to ba 
from 14.41 to 16.7 per cent; five samples of cubebs yielded 1.735 to 24.49 
per cent, of oleoresin; seventeen samples of Jamaica ginger, 3.444 to 6.b'4<> 
per cent; ten samples of African ginger, 6.85 to 11.10 per cent (p. 179.) 



1913 



Miscellaneous Inquiries. • 
Chem. & Drugg., 82, p. 470. 
Gingerin is stated to be the extract obtained upon evaporating the tinc- 
ture of ginger. It is said to vary with the variety of ginger used in the 
preparation of the tincture. 

Capsicin is stated to be commercially indefinite. It may be a strong alco- 
holic extract, an ethereal, a chloroformic or an acetone preparation. The 
accepted capsicin of commerce, however, is the oleoresin prepared with 
ether. 



1913 



Die Methoden zur Wertbestimmung des Filixextrakts. 
Pharm. Ztg., 58, p. 129. 
The methods of Goris and Voisin, and E. Schmidt for the evaluation of 
the extract of male fern are discussed. 



1913 



Extractum Filicis. 

Caesar and Loretz, Jahres.-Ber., Sept. 1913, pp. 98 and 106. 
Four samples of extract of male fern prepared by the firm showed a 
crude filicin content of 32.64, 23.7, 28.15 and 30.4 per cent., respectively, 
(p. 98.) 

The firm guarantees the filicin content of their extract to be 27 per 
cent. 



1913 



Male fern extract. 

Evans Sons Lescher & Webb, Analyt. Notes, 8, p. 44. [Year- 
Book of Pharm., 51, p. 244.] 

Seven samples of extract of male fern examined during the year showed 

a filicin content of 21.3 to 25.3 per cent, and a refractive index of 1.5 to 1.51. 

Three eamples were impure or suspicious. They showed a refractive 

index of 1.495, 1,497 and 1.499, and a filicin content of 15.6, 19.6 and 

19.7 per cent., respectively. 



BIBLIOGRAPHY 277 
1913 

Male fern extract. 

Southall Bros., & Barclay, Lab. Rep., 21, p. 14. 

The analytical data obtained in the examination of two commercial 
samples of the extract of male fern are given. 

Bohrisch, P. 1913 

Ueber Extractum Filicis. 
Pharm. Ztg., 58, p. 601. [Chem. Abs. 8, p. 206.] 

A comprehensive review of the constituents and the methods of evaluat- 
ing the extract of male fern is given. 

Four samples of commercial extracts in bulk were examined for density 
and crude filicin content. The findings for density were 0.9888, 0.9842, 
0.9836 and 1.0109; for crude filicin 14.85; 15.42, 16.00 and 24.00 per cent. 
The same tests for five samples of the extract in capsules showed: density, 
0.9824, not determined, 1.0135, 1.0255 and 0.9910; crude filicin, 15.02, 
23.42, 26.77, 27.72 and 14.45 per cent. 

Dobme and Engelhardt ' 1913 

Cubebs. 

Oil, Paint and Drug Rep., 83, p. 55. 
The quantities of oleoresin obtained from cubebs ranged between 16 
and 22 per cent. 

DuMez, A. G. 1913 

The physical and chemical properties of the oleoresin of As- 

pidium with respect to the detection of adulterations. 
Philippine Journ. of Sc, 8, Sec. B., p. 523. 

The methods of adulterating the oleoresin are discussed in detail The 
physical and chemical constants of samples prepared in the laboratory and 
those obtained from various commercial sourcee are presented with the 
idea of indicating to what extent they may be relied upon in detecting 
a deteriorated or adulterated product. 

Engelhardt, H. 1913 

Purity of chemicals and drugs. 

Journ. A. Ph. A., 2, p. 163. 
Four samples of black pepper are reported to have yielded 10.6, If^.S, 
9.2 and 11 per cent., respectively, of oleoresin; six samples of capsicum, 
13.1, 41.8, 15.26, 15,8, 11.3 and 11 per cent; cubebs from 18 to 25 per 
cent; Jamaica ginger from 2.81 to 5.24 per cent; lupulin, eight samples 
out of twelve, less than 60 per cent; three samples of parsley seed. 14.7, 
11.4 and 13.04 per cent. (pp. 164 and 165.) 



278 I^U MEZ — THE GALENICAL OLEORESINS 

Gane, E. H. 1913 

Report of Committee on Drug Market, August, 1912. 
Journ. A. Ph. A., 2, p. 677. 

Four lots of lupulin gave 44.94 to 65.5 per cent, of ether-soluble material,. 

(p. 681.) 



Harrison and Self. 1913 

Analytical constants of extract of male fern. 
Chem. & Drugg. 83, p. 182. [ Year-Book of Pharm., 50, p. 

494 ; Pharm. Journ. 91, p. 128 ; Pharm. Ztg., 58, p. 643.] 

The analytical constants of genuine and commercial extracts of mala 
fern are tabulated. The authors do not approve of the standards sug- 
gested by Parry. 

Hm, C. A. 1913 

Analytical notes on extract of male fern. 

Chem. & Drugg., 83, p. 181. [Pharm. Ztg., 58, p. 643.] 

The analytical constants of 23 samples of extract of male fern are 
discussed and tabulated. The chemical and physical constants of the oily 
portion are also given for comparison with those of castor oil. One com- 
mercial sample is reported to have contained 59 per cent, of the latter. 

Osborne, Oliver F. 1913 

A last plea for a useful Pharmacopoeia. 
Journ. Am. Med. Assoc, 60, p. 1427. 

Among the ''useless" preparations adopted by the Committee of Re- 
vision, the author includes the oleoresins of lupulin and parsley seed^ 
(p. 1429.) 

Parry, E. J. 1913 

Extract of male fern. 
Chem. & Drugg., 83, p. 231. 
The author confirms the results which he published in an earlier paper. 

Patch, E. L. 1913 

Report of the Committee on Drug Market. 
Journ. A. Ph. A., 2, p. 1081. 

The percentage of alcoholic extract obtained from the drugs tested is 
reported as follows: 



BIBLIOGRAPHY 279^ 

Capsicum, four samples, 19 to 24 per cent; ginger, nine samples, 5.2, 
5.7, 4.2, 4.0, 4.5, 4.9, 3.5, 4.8 and 4.3 per cent. pp. 1088 and 1094. 
The yield of ether extract reported by Kebler is as follows: 
Fifty-three samples, lupulin, 63.96 to 77..82 per cent; black pepper 
three lots, 10.04, 10.87 and 12.88 per cent; red pepper, eight samples, 
13.0, 10.6, 14.7, 18.91, 13.12, 10.4, 13.25 and 14.7 per cent. The iodine^ 
values for the same were 132, 138, 123.4, 107, 127.3, 25.2 and 137.3. 
Seventeen other samples yielded from 11.22 to 20.77 per cent. The iodine 
value of these varied from 110 to 145.7 (pp. 1098 and 1101.) 

Umney, J. C. 1913 

What is capsicin? 

Pharm. Journ., 91, p. 594. 
Capsicin is stated to be a synonym for Oleo-Besin of Capsicum of the 
B. P. Codex, and, is made by extracting capsicum with 60 per cent. alcohoL 
and subsequently evaporating off the solvent. It should not be con- 
fused with the preparations made with strong alcohol (90 per cent.)^ 
ether or acetone. 

Vanderkleed, C. E. 1913 

Report of the Committee on Drug Market. 
Proc. Penna. Pharm. Assoc, 36, p. 77. 
Thirty-seven samples of Jamaica ginger are reported to have yielded 
3.10 to 5.75 per cent, of oleoresin; seventeen samples of African ginger,, 
6.85 to 9.92 per cent; seven samples of capsicum, 13.1 to 18.1 per cent;, 
one sample of cubebs, 21.8 per cent. 

Yagi, S. 1913 

Physiologische Wertbestimmung von Filixsubstanzen nnd' 

Filixextrakten. 

Zeitschr, f. d. ges. exp. Med., 3, p. 64. [Therap. Monatsch.,. 

1914, p. 443; Apoth-Ztg., 29, p. 544.] 
A method in which earth worms are used for the purpose of testing the- 

relative activity of extract of male fern and its constituents is described. 

1914 



Untersuchung der offizinellen vegetablischen Drogen. 
Riedel's Ber. 58, p. 29. 

The samples of cubebs examined are reported as having yielded 11.1 to- 
14.7 per cent, of extract soluble in ether 1 part and alcohol 1 part (p. 31.) 

The alcohol extract obtained from capsicum varied from 31.9 to 35.3- 
per cent. (p. 32.) 

The samples of aspidium examined gave 9.4 to 9.7 per cent, of ether- 
soluble extract. 



DU MEZ— THE GALENICAL. OLEORESINS 

1914' 



Ueber Gelatinkapsel-Fabrikate. 

RiedePs Ber. 58, p. 45. [Apoth.-Ztg., 29, p. 310.] 

Capsules from only two manufacturers contained extract of male fern 
of which the crude filicin content was higher than 20 per cent. The ex- 
tract of male fern in capsules from four other sources showed a filicin 
content of from 8.57" to 16.02 per cent. (p. 48.) 



1914 



Extractum Filicis. 

Caesar and Loretz, Jahres-Ber., Oct., pp. 23, 37, and 96. 

The method of S. Yagi for the physiological standardization of the extract 
of male fern is stated to be too cumbersome for practical use. (p. 23.) 

Extracts prepared in the laboratory showed the following crude filicin 
content, 25.48, 24.85, 29.7, 26.04, 26.0, 35.58, 27.35 and 33.79 per cent, 
(p. 37.) 

It is further stated that the yield of ether extract, after evaporating on 
& water bath at 60 °C to constant weight and drying in a desiccator for 
half an hour, should be about 15 to 18 per cent. (p. 96.) 



1914 



United States Pharmacopoeia Ninth Kevision. Abstracts of 
proposed changes with new standards and descriptions. 

Journ. A. Ph. A., 3, pp. 524 and 1573. [Year-Book of 
Pharm., 52, p. 324.] 

It is stated that the former solvent, acetone, is to be changed to ether 
in the following: Oleoresina Aspidii, Oleoresina Capsici, Oleoresina 
Zingiheris and Oleoresina Piperis. (p. 551.) 

Directions are also given for the preparation of Oleoresina Petroselini 
(p. 573.) 

Bohrisch, P. 1914 

Ueber verschiedene verbessemngbeduerftige Artikel des 

Deutschen Arzneibuches V. 
Apoth.-Ztg., 29, p. 901. 

It ih stated that a large portion of the extract of male fern made in Ger- 
many shows a crude filicin content of less than 15 per cent., while the Swls^ 
Pharmacopoeia requires a content of 26 to 28 per cent. The author, 
therefore, thinks it desirable that a method for the estimation of the crude 
filicin in this preparation be given in the German PharmacopcBia. 



6IBLJOGRAPSY 281 

E'we, G. E. 1^14 

Report of Committee on Drug Market. 
Proc. Penna. Pharm. Assoc, 37, p. 125. 

The author reports as follows on the oleoresins examined: 

Four samples of oleoresin of capsicum were found to be pungent m 
dilutions of 1 to 150,000, the arbitrary standard of H. K. MulforcT 
Company. 

Seven samples of oleoresin of ginger were pungent to the taste in 
dilutions of 1 to 20,000, the arbitrary standard of H. K. Mulford Company. 

Oiie lot of oleoresin of cubeb contained the waxy deposit which the U. 
S. P. directs should be rejected. 

One lot of oleoresin of say palmetto, ''U. S. P." contained 15 per cent, 
of water which separated on standing. It also contained a large amount 
of insoluble matter (p. 152.) 

Linke, H. 1914 

Ergebnisse, Beobachtungen und Betrachtungen bei der 

Untersuchung unserer Arzneimittel. 
Apoth.-Ztg., 30, pp. 606 and 628. 
The results obtained in the examination of extract of male fern, in bulk 

and in capsules, obtained from various sources are tabulated. Especially 

the extract marketed in capsules was found to be low in filicin content. 

Patch, E. L. 1914 

Report of Committee on Quality of Medicinal Products. 
Journ. A. Ph. A., 3, p. 1283. 
A sample of oleoresin of capsicum examined is reported as having been? 
found to be insoluble in ether, only slightly soluble in alcohol and almost 
completely soluble in water (p. 1298.) 

Rippetoe, J. R. 1914 

The examination of some drugs with special reference to* 

the anhydrous alcohol and ether extracts, and ash. 
Am. Journ. Pharm., 86, p. 435. 

Four samples of capsicum are reported as having yielded 17.02 to 24.46" 
per cent, of extract to alcohol, and 16.49 to 17.88 per cent to ether, (p. 437.) 

Six samples of cubebs gave 8.87 to 11.04 per cent, of alcoholic extract^ 
and 7.68 to 9.80 per cent, of ethereal extract, (p. 438.) 

Two samples of Jamaica ginger yielded 4.98 to 5.5 per cent, of extractive 
matter to alcohol, and 2.79 to 4.97 per cent, to ether. Two samples of 
African ginger yielded 6.20 to 6.23 per cent, to alcohol, and 5.3 to 5.45- 
per cent, to ether, (p. 439.) 

Three samples of lupulin yielded 32.49, 55.18 and 57.06 per cent.,, 
respectively, of ethereal extract, (p. 440.) 



282 ^U MEZ— THE GALENICAL. OL.EORESINS 

Scoville, W. L. 1914 

Report of Committee on Quality of Medicinal Products. 
Joura. A. Ph. A., 3, p. 1283. 

It is stated that the samples of cubebs examined during the year gave 
from 18.1 to 22 per cent, of oleoresin, (p. 1287.) 

Vanderkleed, C. E. 1914 

Report of Committees on Drug Market. 

Proc. Penna. Pharm. Assoc, 37, p. 125. 
On page 160, analytical data obtained from the laboratory of H. K. 
Mulford Company are reported showing the following yield of oleoresin 
for capsicum, cubebs and ginger: 



Capsicum (15 samples) 
Cubebs (6 samples) 
African ginger (3 samples) 
Jamaica ginger (3 samples) 
Male fern (4 samples) 



Lowest 


Highest 




Yield, 


Yield 


Average. 


Per cent. 


Per cent. 


Per cent 


13.0 


18.0 


16.0 


13.9 


19.8 


16.9 


8.50 


9.61 


9.0 


4.33 


5.75 


5.06 


6.85 


10.12 


8.23 



1915 



Male fern extract. 

Southall Bros. & Barclay, Ann. Rep., 22 and 23, p. 17. 

The filicin content of five samples of extract of male fern examined is 
reported as having varied from, 20.4 to 27.7 per cent., the specific gravity 
from 0.9885 to 1.030. 

Olickman, L. H. 1915 

Report of Committee on Drug Market. 
Proc. Penna. Pharm. Assoc, 38, p. 138. 

Ten lots of lupulin examined are reported to have yielded the following 
percentages of ether-soluble matter: 55.5, 55.0, 57.1, 58.6, 54.7, 55.3, 44.2, 
€9.2, and 68.2, (p. 149.) 

Yanderkleed, C. E. 1915 

Report of Committee on Drug Market. 
Proc. Penna. Pharm. Assoc, 38, p. 138. 
On page 155, the following data concerning the yield of oleoresin are 



BIBLIOGRAPHY 283 

reported as having been obtained from the analytical laboratory of H. K. 
Mulford Company. 

Lowest Highest 

Yield. Yield. Average. 

Per cent. Per cent. Per cent. 

Capsicum (6 samples) 13.85 20.84 16.65 

African ginger (2 samples) 7.99 8.90 8.44 

Jamaica ginger (1 sample) 3.93 3.93 3.93 

Beringer, G. M. 1916 

The reasons for some of the changes in the formulas of galeni- 
cals made in the ninth revision of the United States Pharma- 
copoeia. 

Journ. A. Ph. A., vol. 5, No. 12, p. 1390. 

It is stated that acetone was the menstruum directed to be used in the 
preparation of the oleoresins by U. S. P., eighth revision, on account of 
cheapness. It is further stated that, since permission has been obtained 
to use denatured alcohol in the manufacture of ether, the cost of the latter 
has been reduced to such an extent that it has again become advantageous 
to use it in place of acetone. Hence, its use in the new Pharmacopoeia. 



284 



DU MEZ— THE GALENICAL OLEORESINS 



INDEX TO BIBLIOGEAPHY 



Oleoresin of Aspidium 


1891. 


Kuersten, R. 


1824. 


Geiger, Ph. L. 


1891. 


Poulsson, E. 


1824. 


Morin 


1891. 


Raymon 


1826. 


Buchner, A. 


1891. 


Eeuter, Ludwig 


1826. 


Von Esenbeck, Nees 


1892. 


Beringer, G. M. 


1826. 


Peschier, Ch. 


1892. 


Duhourcau 


1827. 


Batso, V. 


1892. 


Kobert 


1827. 


Brandes, E. 


1892. 


Sherrard, C. 0. 


1827. 


Buchner, A. 


1892. 


Weppen & Lueders 


1827. 


Van Dyk 


1892. 


Dieterich 


1827. 


Geiger, Ph. L. 


1893. 


Bechurts & Peters 


1827. 


Tilloy 


1893. 


Dieterich 


1827. 


Zeller 


1893. 


Gehe & Co. 


1828. 


Meylink 


1894. 


Poulsson, E. 


1828. 


Peschier, Ch. 


1894. 


Dieterich 


1828. 


Winkler, F. L. 


1894. 


Hell & Co. 


1829. 


Allard 


1895. 


Van Aubel 


1829. 


Haendess 


1895. 


Boehm, R. 


1829. 


Voget 


1895. 


Dieterich 


1844. 


Hornung ' 


1896. 


Bocchi, I. 


1845. 


Luck 


1896. 


Daccomo and Scoccianti 


1851. 


Bock 


1896. 


Dieterich 


1851. 


Luck, E. 


1896. 


Kraft, F. 


1852. 


von der Marck 


1896. 


Caesar and Loretz 


1859. 


Procter, Wm., Jr. 


1897. 


Boehm, R. 


1861. 


Pavesi 


1897. 


Candussio 


1871. 


Hager 


1897. 


Lauren, W. 


1875. 


Patterson, J. 


1897. 


Madsen, H. P. 


1876. 


Kruse 


1897. 


Caesar and Loretz 


1878. 


Cressler, C. H. 


1897. 


Dieterich 


1878. 


Rohn, E. 


1897. 


Gehe & Co. 


1879. 


Kennedy 


1897. 


Chem. C^tralb. 


1881. 


Bowman, J. 


1898. 


Bellingrodt, Fr. 


1881. 


Seifert, 0. 


1898. 


Dieterich, Karl 


1883. 


Maish, J. M. 


1898. 


Duesterbehn, F. 


1884. 


Kramer 


1898. 


Katz, Julius 


1886. 


Berenger-Feraud 


1898. 


Lefils 


1887. 


Kremel, A. 


1898. 


Miehle, Feodor 


1888. 


Keefer, C. D. 


1898. 


Plzak, F. 


1888. 


Trimble, H. 


1898. 


Caesar & Loretz 


1889. 


Greenwalt, W. G. 


1898. 


Gehe & Co. 


1891. 


Dieterich 


1898. 


Pharm. Centralh. 



BIBLIOQRAPHY 



285 



Oleoresin of Aspidium. — Con. 



Oleoresin of Aspidium. — Con. 



1899. 


Hausmann, A. 


1912. 


Caesar & Loretz 


1899. 


Am. Drugg. & Pharm. Eec. 


1912. 


Evans Sons Lescher & Webb 


1899. 


Caesar & Loretz 


1912. 


Merck's Eep. 


1900. 


Caesar and Loretz 


1912. 


Southall Bros. & Barclay 


1900. 


Geh€ & Co. 


1913. 


Bohrisch, P. 


1901. 


Linda, O. 


1913. 


Du Mez, A. G. 


1901. 


Matzdorff, M. 


1913. 


Goris & Voisin 


1901. 


Schmidt, M. E. 


1913. 


Harrison and Self 


1901. 


Stoeder 


1913. 


Hill, C. A. 


1901. 


Caesar and Loretz 


1913. 


Parry, E. J. 


1901. 


Dieterich 


1913. 


Yagi, E. 


1902. 


Buttin, L. 


1913. 


Caesar and Loretz 


1902. 


Kraft, F. 


1913. 


Evans Sons Lescher & Webb 


1902. 


Caesar and Loretz 


1913. 


Southall Bros. & Barclay 


1903. 


Pendorff, 0. 


1914. 


Bohrisch, P. 


1903. 


Schmidt, E. 


1914. 


Linke, H. 


1903. 


Caesar and Loretz 


1914. 


Vanderkleed, C. E. 


1903. 


Dieterich 


1914. 


Caesar & Loretz 


1903. 


Southall Bros. & Barclay 


1914. 


Journ. A. Ph. A. 


1904. 


Caesar and Loretz 


1914. 


Riedel's Ber. 


1904. 


Dieterich 


1915. 


Sherman, H. B. 


1905. 


Kiezka, M. 


1915. 


Southall Bros. & Barclay. 


1905. 


Pharm. Ztg. 






1905. 


Caesar and Loretz 


Oleoresin of Capsicum 


1905. 


Dieterich 


1849. 


Procter, Wm. Jr. 


1906. 


Naylor, A. H 


1853. 


Bakes, W. C. 


1906. 


Eoeder, Ph. 


1864. 


Parrish, E. 


1906. 


Wollenweber, W. 


1872. 


Maish, J. M. 


1906. 


Apoth.-Ztg. 


1873. 


Bucheim 


1906. 


Caesar & Loretz 


1888. 


Trimble, H. 


1908. 


Caesar and Loretz 


1892. 


Sherrad, C. C. 


1908. 


Vanderkleed, C. E. 


1898. 


Winton, Ogden and MitchelL 


1909. 


Dunn, J. A. 


1903. 


Beythien 


1909. 


Vanderkleed, C. E. 


1903. 


Southall Bros. & Barclay 


1909. 


Caesar & Loretz 


1905. 


Vanderkleed, C. E. 


1910. 


Dohme & Engelhardt 


1905. 


Am. Drugg. & Pharm. Rec. 


1910. 


Gandini, V. 


1907. 


Patch, E. L. 


1910. 


Gane & Webster 


1908. 


Patch, E. L. 


1910. 


Caesar & Loretz 


1908. 


Vanderkleed, C. E. 


1911. 


Parry, E. J. 


1909. 


Vanderkleed, C. E. 


1911. 


Pearson, W. A. 


1910. 


Brown, L. A. 


1911. 


Rosendahl, H. V. 


1910. 


Eldred, F. R. 


1911. 


Chem, & Drng. 


1910. 


Southall Bros. & Barclay 


1911. 


Brit. & Col. Drugg. 


1910. 


Vanderkleed, C. E. 


1911. 


Caesar & Loretz 


1911. 


Deane, Harold 


1911. 


Evans Sons Lescher & Webb 


1911. 


Vanderkleed, C. E. 


1912. 


Roberts, H. G. 


1912. 


Vanderkleed, C. E. 



286 



DU MEZ— THE GALENICAL OLEORESINS 



Oleoresin of Capsicum. — Con. 

1913. Chem. & Drugg. 

1913. Engelhardt, H. 

1913. Patch, E. L. 

1912. Evans Sons Lescher & Webb 

1912. Johnson & Johnson 

1913. Unmey, J. C. 

1913. Vanderkleed, C. E. 

1914. Patch, E. L. 
1914. Rippetoe, J. R. 
1914. Vanderkleed, C. E. 
1914. Journ. A. Ph. A. 

1914. Riedel's Ber. 

1915. Vanderkleed, C. E. 

Oleoresin of Cube!) 

1828. Dublane, H. 

1828. Oberdoerffer 

1838. Hausmann 

1846. Bell 

1846. Procter, Wm., Jr. 

1857. Garot and Schaeuffele 

1857. Landerer, X. 

1859. Procter, Wm., Jr. 

1863. Girtle 

1865. Bernatzik, W. 

1866. Procter, Wm., Jr. 

1866. Rittenhouse, H. N. 

1867. Paul, C. 

1867. Pile 

1868. Heydenreich, F. V. 
1872. Maish, J. M. 
1877. Griffin, L. P. 
1877. WolflF, L. 

1883. Maish, J. M. 

1887. Kremel, A. ' 

1887. Gehe & Co. 

1888. Trimble, H. 

1892. Sherrard, C. C. 

1893. Dieterich 

1894. Bedall 

1894. Hell & Co. 

1895. Hyers, P. 

1895. Dieterich ^ 

1895. Gehe & Co. 

1905. Vieth, R. 

1905. Dieterich -?? t • - 



Oleoresin of Cubeb. — Con. 

1907. Blome, W. H. 

1907. Smith, A. W. 

1907. Evans Sons Lescher & Webb 

1908. Vanderkleed, C. E. 

1909. Vanderkleed, C. E. 

1909. Chem. & Drugg. 

1910. Gane, E. H. 
1910. Vanderkleed, C. E. 

1910. Southall Bros. & Barclay 

1911. Southall Bros. & Barclay 

1911. Vanderkleed, C. E. 

1912. Dohme & Engelhardt ' 
1912. Gluecksmann, G. 

1912. Vanderkleed, C. B. 

1913. Dohme & Engelhardt 

1913. Vanderkleed, C. E. 

1914. Maines and Gardner 
1914. Rippetoe, J. R. 
1914. Scoville, W. L. 
1914. Vanderkleed, C. E. 
1914. Journ. A. Ph. A. 
1914. Riedel'B Ber. 

Oleoresin of Ginger 

1834. Beral 

1849. Procter, Wm., Jr. 

1859. Procter, Wm., Jr. 

1866. Rittenhouse, H. N. 

1867. Pile 

1872. Maish, J. M. 

1877. Wolflf, L. 

1879. Thresh 

1886. Jones, E. W. : 

1888. Trimble, H. 

1891. Riegel, S. J. 

1892. Sherrard, C. C. 

1893. Dyer and Gilbard 

1895. Davis, R. G. 

1896. Liverseege 

1897. Glass and Thresh 
1901. Bennet 

1903. Ballard 

1903. Southall Bros. & Barclay 

1905. Helfenberger Ann. 

1908. Spaeth, Eduard 

1908. Vanderkleed, C. E. 

1909. Patch, E. L. 



BIBLJOGRAPHT 



287 



Oleoresin of Ginger. — Con. 

1909. Vanderkleed, C. E. 

1910. La Wall, C. H. 

1910. Vanderkleed, C. E. 

1911. Beythien, Hemple & Others 

1911. Vanderkleed, C. E. 

1912. Hooper, D. 
1912. Patch, E. L. 

1912. Vanderkleed, C. E. 

1913. Engelhardt, H. • 
1913. Patch. E. L. 
1913. Vanderkleed, C. E. 

1913. Chem. & Drugg. 

1914. Eippetoe, J. K. 
1914. Vanderkleed, C. E. 

1914. Journ. A. Ph. A. 

1915. Vanderkleed, C. E. 



Oleoresin 
1825. 
1829. 
1859. 
1877. 
1888. 
1892. 
1903. 
1913. 
1913. 
1913. 
1914. 



of Pepper 
Meli 

Carpenter, G. W. 
Procter, Wm. Jr. 
Wolff, L. 
Trimble, H. 
Sherrard, C. C. 
Ballard 

La Wall, C. H. 
Engelhardt, H. 
Patch, E. L. 
Journ. A. Ph. A. 



Oleoresin of Lupulin 


1823. 


Planche 


1853. 


Livermore 


1859. 


Procter, Wm. Jr. 


1869. 


Kump, C. 


1888. 


Trimble, H. 


1892. 


Sherrard, C. C. 


1907. 


Van der Harst, J. C. 


1908. 


Dohme & Engelhardt 


1909. 


Bernegau, L. H. 


1909. 


Dohme & Engelhardt 


1909. 


Parson, W. A. 


1911. 


Bernegau, L. H. 


1911. 


Francis, J. H. 


1913. 


Gane, E. H. 


1913. 


Engelhardt, H. 


1913. 


Osborne, 0. T, 


1913. 


Patch, E. L. 


1914. 


Eippetoe, J. E. 


1915. 


Glickman, L. H. 


Oleoresin of Parsley Fruit 


1877. 


Wolff, L. 


1892. 


Beringer, G. M. 


1906. 


Merck's Ann. Eep. 


1909. 


Evans Sons, Lescher & Webb 


1913. 


Engelhardt, H. 



1913. Osborne, O. P. 

1914. Jonm. A. Ph. A. 



Oleoresin of AlTcanet Boot 
1892. Gehe & Co. 

Oleoresin of Annatto ! 

1895. Gehe & Co. 

Oleoresin of Cardamom Seed 
1849. Procter, Wm., Jr. 
1859. " '« <' 

Oleoresin of Chenopodvum 
1849. Procter, Wm., Jr. 
1877. Wolff, L. 

Oleoresin of Clove 

1849. Procter, Wm., Jr. 

Oleoresin of Coni/um Leaves 
1870. Lefort, M. J. 

Oleoresin of Pepo 
1890. Minner, L. A. 

Oleoresin of Pyrethrum 
1849. Procter, Wm., Jr. 
1859. ** *' " 

1902. Southall Bros, and Bardaj 
1911. ** *' " ** 



Oleoresin of Santonica 
1830. Schuppmann 
1849. Procter, Wm., Jr. 
1877. Wolff, L. 



•288 



DU MEZ— THE GALENICAL. OLEORESINS 



Oleoresin of Savine 

' 1849. Procter, Wm., Jr. 

Oleoresin of Saw Palmetto 
1914. E'we, G. E. 

Oleoresin of Xanthoxylum 
1849. Procter, Wm., Jr. 



Oleoresins (General) 

1869. Squibb, E. 

1873. Remington, J. P. 

1887. Lippincott, C. P. 

1900. Maish, H. C. 

1905. Francis, J. M. 

1905. Drug Topics 

1916. Beringer, G. M. 



C-UIDS 

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Anaesthesin 

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vT. O. Schlotterbeck (Biography) 

J. O. Schlotterbeck (Original Publications) 

J. O. Schlotterbeck (Miscellaneous Writings, 

views) 
Liquor* Potassii Arsenitis, U. S. P. 1890 
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Linoliment 
Linoval 
Parogen (um) 
Penetrole 
Petrogen 

Petrolatum Saponatum 
Petroliment 
Petroxolin (um) 
Valselol 
Valsol 
Vasapon 
Vascosan 
Vaselon 
Vaseloxyne 
Vasenol 
Vasogen(um) 
Vasol 

Vasoliment (um) 
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Vasoval 



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