The American Journal of Pharmacy 1929-08: Vol 101 Iss 8

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THE AMERICAN

JOURNAL OF PHARMACY

VoL. 101 AUGUST, 1929 No. 8

EDITORIAL

PHARMACOPCEIAL POLICIES

LSEWHERE in this issue there is printed a timely article by

Professor E. Fullerton Cook, Chairman of the Committee of
Revision of the United States Pharmacopeeia. It enumerates and
explains the twelve cardinal points in pharmacopeeial policy. Chair-
man Cook is well qualified to pick these points of policy. His famil-
iarity with revision technic dates back to his association with Rem-
ington, the greater part of whose useful life was spent in
pharmacopceial service. Almost a decade has passed since the last
Pharmacopeeial Convention met in Washington (1920). The duties
entrusted by that convention to its Revision Committee have been
promptly and ably performed. The current Pharmacopceia, known
the world over as the outstanding book of medicinal standards is a
tribute to the intelligence and industry of that great group of work-
ers constituting the Revision Committee. Quoted from /nternational
Clinics the following paragraph affords a very fair estimate of the
work turned out by this committee, and the great credit which came
to pharmacy through its medium:

“T have before me as I write the last revisions of the United
States Pharmacopceia and of the National Formulary. Here are
master works of medicinal standards, works accepted the world
over as the finest of their kind. Here are the legal instruments
whereby the government of the greatest Republic in the world
regulates the standards of manufacture and dispensing of medic-
inals within its boundaries. Here are the mechanisms whereby
drug importations are controlled. Here are the authorities
whereby drugs are made safe for democracy, and here are stand-
ards that provide the means whereby a potent tincture in Kala-
mazoo is no less and no more potent than the same galenical
in Tompkins’ Corner.

(549)

550 Illicium Religiosum, Siebold a

“And organized American pharmacy is eighty per cent. re-
sponsible for the high character of these world known books of
standards. This performance alone, to our mind, entitles phar-
macy to recognition as a profession of high caliber.”

And so do we respectfully urge those who have an abiding inter-
est in the future welfare of Pharmacy to read carefully the afore-
mentioned article.

For only with a correct understanding of these points of policy
will it be possible for Pharmacy to be worthily represented in the
work of the Convention, which will shortly meet, and in the work,
too, of the Revision Committee which will be responsible for the
character and caliber of the Eleventh Decennial Revision of the
Pharmacopeeia of the United States.

Ivor GRIFFITH.

ORIGINAL ARTICLES

ILLICIUM RELIGIOSUM, SIEBOLD*
Mang Tsao
A PHYTOCHEMICAL STUDY
By Sze Yee Chen
(To be Continued in the September Issue)

Introduction

LLICIUM RELIGIOSUM, Siebold, Mang Tsao in Chinese, Shik-

tmi no ki in Japanese, or commonly known as Japanese star anise,
is a plant belonging to the family Magnoliaceae and is generally con-
sidered by the Chinese and the Japanese, and indeed from the earliest
times, to be a poisonous plant. It is directed not to be used intern-
ally nor to be applied to the eye.!' Since the fruit resembles that of
the true star anise, J/licium verum, Hooker, so closely that it is often
mistaken for the latter, or sold as adulterant, many cases of poison-
ing have been attributed to this plant, especially to its fruit. In

*Thesis submitted for the degree of Doctor of Philosophy, University
of Wisconsin, 1927.

* Li Shih-Cheng, Pentaso Kang Mu, 1506 A. D., chap. 17.

Jour. Illicium Religiosum, Siebold 551
1880, death due to intoxication occurred at Leeuwarden, in the Neth-
erlands, through the use of commercial star anise in the preparation
of anise milk which was usually made of oil of anise. According to
a report of the commission at Leeuwarden which was charged with
the investigation of the poisoning case and which was supplemented
by a committee of Amsterdam,’ Japanese star anise is said to have
been used in the preparation. Since that time many cases of poison-
ing have been recorded by Eykman,* by Langgaard,* in the Journal
de Pharmacie et Chimie,> by Inoko,® in the New York Med Jour.,’
by Mense,* by Guerrero, Paz and Guerrero,® by Read,*® and others.
The morphological description and the anatomical structure of
this drug have been worked out at length, yet the chemical investiga-
tion is still in a very imperfect stage. The present study deals with
the dry fruit and consists of a preliminary analysis, an investigation
of the fatty and volatile oils, a study of the shikimic acid which it
contains, and the attempted isolation of the toxic principle.
History of Name. Illicium religiosum, Sieb. is commonly known
in Chinese as mangtsao and as shikimi in Japan. During his travel
in Japan in 1690-1692, Kaempfer’ fully described this tree under
the names Somo, Shihim, Fanna shikimi, Fanna skiba, and Fanna.
Linné first designated the plant as Badianifera anisata later as Illicium
anisata* and finally as Jllicium anisatum,’ and thought the tree de-
scribed in Kaempfer’s amoenitates as the mother plant of the star
anise on the market. Loureiro * in 1790 first noticed the differences
between the Chinese and the Japanese star anise. Siebold* in 1827
differentiated the two fruits by the poisonous action of the shikimi

* Pharm. Weekbl. 17 (1880), No. 4; Pharm. Jour. 40, p. 1067.

* Pharm. Jour. 40 (1881), p. 1046.

*Virchow’s Archiv 86 (1881), p. 222.

5J. de Pharm. et de Chim. (Editorial) 118 (1884), p. 367.

* Chiugai Iji Shipo (Medical News of the World), Tokyo (1890), pp. 1245-
1248 and 1317-1320.

7 Editorial, vol. 23 (1901), p. 642.

® Handb. der Tropenkrankheiten, 2d ed. (1914), vol. 2, p. 549.

* Philippine Jour. Sc. 11-B (1916), p. 203.

* China Med. Jour. 36 (1922), p. 303.

* Amoenitates exoticarum, 1712, p. 880.

* Sp. pl., 1764, p. 664.

® Systema naturae, 1825, p. 643.

* Flora Cochinchinensis (1790), I, p. 353.

5 Synopsis plant. oeconom. regn. Japon.; Tschirch, Handb. d. Pharmakog. II,
2 (1915), p. 1215.

Jour. Pharm.
August, 1929

552 Illicium Religiosum, Siebold

fruit and renamed the tree as I/licium Japonicum which was accepted
in the Flora Japonica (1835) by Siebold and Zuccharini.* This name
was again changed into J/licium religiosum in 1837 by Vriese, since
it is planted on graves or near temples and used in religious cere-
mony.’

In order to avoid confusion in using the term J/licitum anisatum,
Hooker * designated the tree of the true star anise by J/licium verum

in 1888.

Synonyms. Besides Mang Tsao in Chinese and Shikimi in Jap-
anese, Illicium religiosum is also known by many other names. Since
very frequently the Chinese and Japanese names are written in the
same characters it is hard to tell their ultimate origin. The follow-
ing synonyms are, therefore, grouped according to the language in
which they appear.

Description of the plant. IIllicium religiosum has been fully de-
scribed by Li Shih-Cheng in Peng Tsao Kang Mu (1596) chapter 17
under the name Mangtsao; by Kaempfer in his Amoenitatum (1712)
p. 880, under the name Somo, Shikimi etc.; by Loureiro in the Flora
Cochinchinensis (1790), p. 353 under the name J/licium anisatum;
and by Siebold in the Flora Japonica (1871), p. 5, under the name
Illicitum Japonicum. Holmes Eykman ? Tambon [hoko * and others
have reported additional information.

The plant is about 6 to 20 feet high. The bark has an aromatic
odor and a gray color. The leaves resemble those of the laurus or
bay tree. They are shortly (about 1 cm.) petioled, coriaceous, thick,
feel waxy to the touch, are evergreen, oblong or oblong obovate,
acuminate, cuneate at the base, entire at the margins, free from hairs,
about 7 cm. long, 3-4 cm. broad and have an odor like that of the
essential oil present in them. They are smaller than those of the true
star anise. The plant flowers in April. At a distance the flower

® Flora Japonica, 1835, p. 5.

* Het Gezag van Kaempfer, Thunberg, Linnaaeus en anderen, Omtrent den
bot. oorsprong van der Ster-anijs des Handels; Tschirch, Handb. d. Pharmakog.
II, 2 (1913), p. 1215.

* Bot. Magazine, 1888; Tschirch, Handb. d. Pharmakog. II, 2, p. 1215.

* Pharm. Jour. 40 (1880-1881), pp. 489-91.

® Pharm. Jour. 40 (1880-1881), pp. 1066.

* Des Illicium en Genera, de la badiane et de son huile essentielle en particu-
lier, Montpellier. A thesis (1886).

* Chiugai iji shipo, Tokyo (Medical news of the world), (1890), pp. 1245-48:
also pp. 1317-20.

| Illicium Religiosum, Siebold 553

looks like that of the narcissus. It is about an inch and a half in
diameter. The petals are greenish, or very slightly yellowish-white
and have a wax-like appearance ; they are from 1-3 cm. long and 5 cm.
broad, 12 to 20 in number with 15 to 20 stamens.

Chinese

Synonyms: Mang Tsao oS + (mad herb)
Shu Mang (rat poison)
Ao Woo Soo

ing herb
Chun Psao y (Spr ng )
Synonyms; Shikimi & + Sikimi AZ
Ashikimi (evil fruit)
A
Seke At
Kake +
Yoka
bh

Tse Hip

Yin Ba 44

Hari ma

Tsi ku sen ne g

Yeun kian +

554 Illicium Religiosum, Siebold

The fruit is about one-third less in diameter than that of Illicium
verum °—the diameter is about 25 mm. while that of J/licium verum
is about 32 mm.® It consists of 8 carpels arranged side by side
in a close circle which has a depth of about 0.5 cm. Each carpel has
on the upper side the pistil. In the unripe condition the fruit is green,
juicy, and contains much essential oil. When it commences to ripen
in the autumn, the carpel rapidly dries up especially on the dorsal side,
shrivels, and becomes of a red-brown color, and opens so rapidly
along the upper side that the seeds are very often hurled out with
considerable force. Generally only a few of the carpels develop to
maturity and the fruit is, therefore, very irregular. However, accord-
ing to Menir’ and Oberdorffer * they are quite regularly developed
and rarely abortive. According to the writer’s experience the par-
tially developed carpels occur much more commonly among the
Japanese than the Chinese star anise, yet it was much easier to find
some completely developed fruits of the former than the latter. In
other words the fruits of /licium verum are more uniformly matured
than those of Jllicium religiosum. The fruit has a less agreeable odor
than the bark and a taste somewhat saline and decidedly bitter, faintly
resembling cardamom.

Habitat of the plant. Illicium religiosum is indigenous in Sze-
chaung, China and was introduced in ancient times into Japan by
Buddhist priests (Kaempfer). Now it grows wild in Japan on the
mountain sides near Nagasaki, Yokosuka, and Tokyo and in large
numbers upon the Island of Hackijo. In earlier times it was found
also in the provinces of Izu, Sayami, Enshu, Tamba, Mussashi, Hizen,
Chozhu, etc. The plant is frequently cultivated in the gardens of
eastern France.®

Uses. In China the poisonous star anise is used as local ap-
plication in the treatment of toothache; also in certain forms of der-
niatitis, parasitism, etc. As a fish poison the powder of the leaves
is thrown into the water and, when intoxicated, the fishes are easily
caught. When cooked these fishes are said not to be poisonous to the
people who eat them. It was also used to destroy rats. As already

5 Vogl, Mittheil. des Wien. Med. Dokt. Coll. 7 (1881), p. 167.

*Tschirch und O6esterle, Anatom. Atlas d. Pharmakog. u. Nahrungsm.
(1900), Pp. 241-44.

7 Jour. de Med. de ’ Ouest. Nantes. 8 (1884), 2 S., p. 113.

® Pharm. Centralb. 22 (1881), pp. 162, 177, 276 and 400.

® Murakoshi, Flora of Japan (1925), p. 592.

Am. Jour. Pharm.
1929

Illicium Religiosum, Siebold 555

stated the Japanese plant the tree around temples, the flowers being
used for the adornment of the altar. They are also displayed in con-
secrated vessels for the use in religious feasts. The tree is also
planted near graves, because of the general veneration for the tree,
perhaps also on the ground that as a poisonous plant it has the re-
puted power to keep away insects and wild animals. The aromatic
bark is used by the Buddhists as an ingredient in pastilles which
are so made as to burn a certain length of time and thus serve as a
sort of chronometer. The fruit is not used as a spice nor for any
other purposes, but the oil expressed from the seed is used as a cheap
lighting material and as a lubricating oil.’

Morphology

The fruit of Jilicium religiosum was only briefly described by
Kaempfer,’ Baillon,? Siebold,* Loureire,* and Berg.’ After the oc-
currence of the poisoning cases at Leeuwarden in the Netherlands
in 1880, the morphology of this fruit was fully investigated: by
Holmes,® Husemann,’ and Geerts,* in 1880; Vogl,®1°*
and Oberdoerffer,’* in 1881; Pabst,’* in 1883; Ménier,’® in 1884;
Tambon,’* in 1886; Fliickiger,’” in 1891; Waage, ** in 1893; Collin

* Husemann, Pharm. Jour. 40 (1880-81), pp. 453-54.
* Loc. cit.

*Le Regne végétale, (1864-1869), Flora médicale, vol. 5, p. 143; and
vol. 6, p. 20.

*Siebold, Flora Japonica (1871), p. 5.

* Flora Cochinchinensis 1, p. 353 (1790).

° Pharmakog. d. Pflan. u. Thiere, 5th ed. (1879), p. 361.

* Pharm. Jour. 40 (1880-1881), p. 480.

Tbid., p. 453.

®N. Tijdsch. v. Pharm. 1880, p. 2908; Pharm. Weekbl. 17 no. 15; Jahresb.
d. Pharmakogn., 1880, p. 50.

® Mitth. d. Wien. Med. Dokt. Coll. 7 (1881), p. 167-173.

* Commentar z. 7 Ausg. d. Oesterreich. Pharmacopoee II, (1892), p. 137.

4 Nahrungs- u. Genussm. mit besonderer Berueck. d. mikroscop. Unter-
suchung (1899), pp. 465-76.

% Pharm. Jour. 40 (1880-1881), p. 1066.

*% Pharm. Zeitschr. 22 (1881), pp. 162, 177, 276, and 400.

“ Koeler’s Medizinal Pflanzen, I (1883), p. 117.

% Jour. de Med. de Ouest. Nantes (1884), 2d s. 8, p. 113.

16 Des Illicium en général, de la badiane et de son huile essen. en particulier.
Thése, Montpellier (1886).

7 Pharmkogn. d. Pflanz. (1891), 3d ed. pp. 932-37.

% Ber. d. Pharm. Gesells. 3 (1893), p. 161.

556 Illicium Religiosum, Siebold

and Planchon *® and Lauren ?° in 1896; Lenz,”* in 1899; Tschirch
and Oesterle,?* and Villiers and Collin,?* in 1900; Beuttner ** and
Hartwich,” in 1907. Illustrations are found in the articles by Kaemp-
fer, Holmes, Vogl, Tambon, Collin and Planchon, and Villiers and
Collin. The most detailed illustrations by Vogl are reproduced in
Winton’s Microscopy of Foods and Drugs.”® In order to make
the description and comparison of the fruits more readily compre-
hensible samples of both J/licium religiosum and Illiciwm verum were
selected from sixty pound lots and photographed.

The whole fruit. On the average the fruit of the poisonous star
anise is smaller than that of the genuine, the diameter of the former
being from 16-33 mm., mostly about 25 mm., according to Vogl and
from I5 to 31 mm., mostly from 22 to 29 mm., according to Hart-

Tllicium Illicium
religiosum Verum

wich, the diameter of the latter being from 22 mm. to 42 mm., mostly
about 30 mm., according to Vogl and from 17 to 40 mm., mostly from
30 to 37 mm., according to Hartwich. Vogl’s values are quoted by
Tschirch and Oesterle. The color of the poisonous fruit is lighter
and the structure is less woody than that of the genuine. As a rule
only a few of the carpels are developed to maturity. Abortive car-

* Les Drogues simples d'origine végétale, (1806), 2, pp. 890-93.

® Scheiz. Wochenschr. f. Chem. u. Pharm. 34 (1806), pp. 278-81; 37
(1899), Pp. 45-50.

Tbid.

= Anatom. Atlas, (1900), pp. 241-44.

* Traité des alterations et falsif. des subs. aliment. 1900, pp. 205-303.

* Schweiz. Wochenschr. 45 (1907), pp. 277-82.

* Ibid., 45 (1907), pp. 798-809, 39 (1901), p. 104.

*° Microscopy of vegetable Foods, 2d ed. (1916), pp. 572-73.

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b
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Am, Jour, Illicium Religiosum, Stebold 557
pels are rare. The middle of the lower side, A, either projects or
is at the same level as the base of the carpel as shown in the figure
which was taken from Tschirch’s Handbuch der Pharmakognosie, II,
2, p. 1216. The fruit is about 0.5 cm. high.

The carpel. The carpel is from 10 to 13 mm. long and 5 to 8
mm. wide forming a sharp and thin point curved upward. It is more
woody and rougher on the surface, more wrinkled and shriveled,
lighter in color and more boat-like and compressed than the rosette-
formed star anise. When dried it opens at the dehiscent line more
than the true star anise so that the lighter-colored interior is more
exposed. The color of the carpel is a shining red-brown. ‘The car-
pels are usually shrunk upon one another. Its taste is bitter, some-
what saline, faintly resembling that of cardamom, but disagreeable.
The odor is spicy but not at all like anise.

The columella, The upper side of the columella, B, is a sharp
point and usually does not reach the same height as the carpels but
sinks to a depth as shown in the above illustration (Lenz).

The fruit stem. The stem is generally straight (Moeller)*
and lacking (Oberdoerffer). It is 10-13 mm. long, I mm. thick,
with a light, circular cork nobe at both ends while the middle part
is of uniform size. It is grayish-brown or reddish-brown deeply
striated with longitudinal furrows (Vogl).

The seed. The size and the shape of the seed varies with the
degree of ripeness. Usually it is about 0.7 cm. long and 0.5 cm.
broad. It is provided with a hard testa and occurs one in a carpel.
It is bulgy round, full, less compressed, with a brown color, but
lighter than that of a true star anise. The wart-like hilum is light
yellow nearly white (Vogl). The apex of the seed is not rounded, but
at the end of the keel terminates in a raised point, which is not the
case in true star anise. The exception to this becomes more frequent
in the larger well-developed seeds (Eykman). It tastes oily and has
no aromatic odor.

Histology*

Although in even a superficial comparison of a sample of shikimi
fruit with one of true star anise differences of form can not be de-

*™ Mikroskopie d. Nahrungs- u. Genussm. (1886), p. 276.

_ *® Acknowledgment is hereby made to Dr. R. H. Denniston under whose
directions this study was performed. He also made all the slides.

558 Illicium Religiosum, Siebold

nied, yet none of the morphological features, which are very probably
connected with the age, the manner and time of collection, the con-
veyance, the climate, etc. (Eykman), can be regarded as sufficiently
constant to tell apart with certainty the two drugs in a mixture. For
this reason many authors have thought a histological investigation de-
sirable. Such examinations have been made by Tambon,' in 1886;
Fitickiger,? in 1891; Pfister,* in 1892; Waage,* in 1893; Lauren,®
also Collin and Planchon,*® in 1896; Lenz’ also Vogl,* in 1899;

*

* Des Illicium en général, de la badiane et de son huile en particulier. Thése,
Montpellier, 1886.

* Pharmakognosie des Pflanzenr. 3d ed. (1891), pp. 932-37.

* Vierteljahreschr. Naturforsch. Gesell., Zirich, 37 (1802), pp. 313-322;
Schweiz. Wochenschr. 32 (1894), p. 233.

* Ber. d. Pharm. Gesell. 3 (1803), p. 161.

Les Drogues simples d’origine végétale, 1896, 2, p. 800.

®° Schweiz. Wochenschr. 34 (1806), p. 278.

"Ibid., 37 (1809), pp. 45-50; Pharm. Ztg. 44, pp. 44-46.

8 Mittheil. des Med. Coll. 7 (1881), pp. 167-73; Nahrungs- u. Genussm.
1899, pp. 465-76.

. Pharm,
SURGICAL |

dss, Jour, Illicium Religiosum, Siebold 559
Tschirch and Oesterle,® in 1900; Hartwich, *° in 1907 and Plahls,™
in IQII.

According to Tschirch and Oesterle there is no difference in the
anatomical structure of the fruit of Jllicium verum and that of Illicium
religiosum. For this reason the microscopic picture of the former
only is given in their Anatomical Atlas. Although others, like Tam-
bon, Collin and Planchon, and Vogl, have published drawings of the
structure of the latter, they are by no means complete. In order to
make comparison easier sections of the carpel, seed and stem of
Illicium religiosum were made and drawn.

Palisade cells of the endocarp are mostly from 348-360 yu
(Plahls), 325-400 uw. (Tschirch and Oesterle) and occasionsally 180-
260 w (Hartwich) long and are highest on the under side of the
fruit cavity (the side furthest from the dehiscent surface) passing
abruptly into the cells of the dehiscence surface. In the stem and
fruit column there are rounded stone cells (longest up to 300 u mostly
from 103 to 164 w Lenz) with uniformly thickened wall; while in
the star anise the palisade cells of the endocarp are longest (up to
600 “) near the dehiscence surface and gradually pass into the cells
of that surface.

Astrocleides are present only in the fruit column of the true but
not in that of the false star anise (Collin and Planchon). According
to Pfister the most striking anatomical difference between the seeds
of the two species is to be found in the aleurone grains. Those in
the Jilicium religiosum are smooth, lustrous and contain one to
three distinct big crystalloids (15-20 mw for the larger and 4-8 mu for
the smallest) and many globoids. While in J/licium verum they are
rougher on the surface and contain generally globoids rarely single
crystalloids. Tschirch and Oesterle make the same statement. But
these statements are not proved by Waage. The writer had the same
difficulty as Waage, that is, no distinct difference could be seen. The
reason is probably that the aleurone grains are so minute that even
under the best microscope available in the laboratory they are not
readily seen.

To the writer, the features which will render the differentiation
between the two fruits easily are the oil cells and the cross section
of the fruit stems. The former are present abundantly in the true

° Anatom. Atlas, 1900, pp. 241-44.
” Sweiz. Wochenschr. 45 (1907), pp. 798-812.

™ Arch. f. Chem u. Mikrosk. (1911), cited by Tschirch in his Handb. d.
Pharmakog. II, 2, p. 1217.

560 Illicium Religiosum, Siebold

star anise, but few in number in the other. The cross section of the
stem of shikimi fruit is very irregular while that of the true star
anise is of uniformly circular shape.

This study was discontinued before commencement 1927. In
the issue for September 13, 1928, the following article appeared in
the Pharmazeutische Zentrhalle: Zur Mikrochemie von Illicium verum
Hook, und Illicium religiosum Sieb. By Editha Siersch. The paper
is a contribution from the Institute for Plant Physiology of the Uni-
versity of Vienna.

Material. Several attempts to secure poisonous star anise from
China resulted in the delivery of the true star anise. The materials
thus obtained were used for a comparative study of the two drugs.
Finally, through the personal efforts of Mr. S. S. Chi, 14 ko. of the
desired material were obtained in Peking. It was identified as
Iilicium religiosum by Dr. B. E. Read, the well known investigator
of Chinese drugs in the Peking Union Medical College. The carpels
were irregular, the taste bitter and odor spicy, whereas true star
anise has more regular carpels, a pleasant odor and a sweet taste.
Certainty as to its poisonous character was obtained by a pharma-
cological test. 5 g. of powdered drug were macerated with 75 cc. of
alcohol for 24 hours. 25 cc. of the solution thus obtained were evap-
orated under greatly reduced pressure to about I cc. and the residue
diluted with water to about 3 cc. one-half of this solution, representing
0.83 g. of drug, was injected subcutaneously into a rat weighing about
200 grams. Five minutes after injection the animal showed symptoms
of distress. It died within two hours. Another rat which was given an
injection similarly prepared from 4 g. of true star anise was still
living after two weeks.

Proportion of seed to carpel. A. Fifty and one hundred gram
samples respectively were weighed off without selection and separated
into seed and carpel, each part weighed and the percentage as to the
whole computed.

Wt. of Wt.of Percentage Wt. of Percentage of
sample seed of seed car pel carpel

I. 50 g. 3.8 g. 7.0 p.c. 45.5 g. 92.4 p.c.

2. 100 “ 7.0 “ 7m 93.0 “

3 100 7.5 7.4 91.8 92.5 “ce

Average 7.4 92.6

[

Illicium Religiosum, Siebold 561

B. Twelve complete and well developed fruits were selected
and each weighed separately. Each fruit was then separated into
carpels and seeds and the carpels and seeds of each fruit weighed
separately.

Wt. of fruit Wt.of 8 Percentageof Av.wt.ofa

No. seeds seed single seed
I. 1.5468 g. 0.5689 g. 30.90 p.c. 0.0712 g.
2. 1.5329 “ 0.5216 “ 34.02 “ 0.0652 “
3. 1.5658 “ 0.5028 “ 3.17 .“ 0.0629 “
4. 1.8004 “ 0.5674 “ 31.52 “ 0.0709 “
5. 1.4584 0.4589 “ 31-43 “ 0.0574
6. 2.1199 “ 0.6544 “ 30.87 “ 0.0818 “
7. 2.2094 “ 0.6134 “ 27.77 0.0767
8. 2.1071 “ 0.5834 “ 0.0729 ‘
9. 2.1901 “ 0.6744 “ 30.79 “ 0.0843 “
10. 1.5200 “ 0.6026 “ 39.64 “ 0.0753 “
II. 1.6564 “ 0.5859 “ 35-38 “ 0.0782 “
12. 1.5959 “ 0.5684 “ 35.61 “ 0.0711 “

Average ‘1.7755 g. 0.5749 g. 32.82 p.c. 0.0719 g.

The heaviest fruit (No. 7) weighed 2.2094 g. or 0.4339 g. 4. @.
24.43 p.c. more than the average.

The lightest fruit (No. 5) weighed 1.4584 g. or 0.7510 g. 1. ¢.
42.29 p.c. less than the average.

It becomes apparent from the average weights of true and poison-
ous star anise fruits, viz. 1.5929 g. and 1.7755 g. respectively that the
average difference of 0.1826 g. is appreciably less than the fluctuations
between the weights of fruits of the same species.

Moisture determination. The water content of the air dried
drug was determined by means of the xylene method? using Io g.
of powdered material in each case.

Two determinations for the carpel yielded 3.5 p.c. and 4.0 p.c.
respectively.

Two determinations for the seed yielded 4.8 and 5.2 p.c. respec-
tively.

, *A. L. Dean, Forest Service Circular 134 (1908), U. S. Dept. of Agri-
culture.

562 Illicium Religiosum, Siebold (ee

K. K. Chen? found 3.44 p.c. for the seed and 3.46 p.c. for the
carpel.

Ash determination. The determinations were made separately
for carpel and seed.

3.5039 g. of carpel yielded 0.0027 g. (=0.077 p.c.) of ash insolu-
ble in acid and 0.1020 g. (3.367 p.c.) of total ash.

3.8742 g. of carpel yielded 0.0016 g. (=0.042 p.c.) of ash insolu-
ble in acid and 0.1290 g. (=3.356 p.c.) of total ash.

3.8378 g. of seed yielded 0.0026 g. (0.068 p.c.) of ash insolu-
ble in acid and 0.0554 g. (=1.445 p.c.) of total ash.

4.0875 g. of seed yielded 0.0040 g. (0.098 p.c.) of ash insolu-
ble in acid and 0.0600 g. (1.443 p.c.) of total ash.

The difference in total ash content of carpel and seed is very
marked, that of the acid insoluble ash is not so great.

K. K. Chen? found 0.1921 p.c. acid-insoluble ash and 1.472 p.c.
total ash in the seed; also 0.172 p.c. of acid-insoluble ash and 3.432
p.c. total ash in the carpel.

Extraction of seeds and carpels with selective solvents. Two
samples each of 15 grams of seed and 20 grams of carpel, both in
fine powder, were extracted successively with petroleum ether, ether,
alcohol, and water. With the exception of the aqueous extract, the
extracts were allowed to evaporate spontaneously and dried over
sulphuric acid. In the case of the aqueous extract, gentle heat was
used to evaporate the solvent. The results are herewith recorded:

A. Seed

Solvent Wt. of extract Percentage of | Average
extract percentage
I II I II
Petr. ether 3.1622 g. 2.9234 g. 21.12 19.49 20.31
Ether 0.2989 “ 0.2744 “ 11.99 1.83 1.QI
Alcohol 0.6185 “ 0.6295 “ 4.1 4.19 4.16
Water 0.2230 “ 0.2351 “ 1.49 1.56 1.52
Total extractives 27.90 pe.

* Jour. A. Ph. A. 15 (1926), p. 625.
1 Jour. A. Ph. A. 15 (1926), p. 625.

A

Illicium Religiosum, Siebold 563

B. Carpel
'
Solvent Wt. of extract Percentage of Average
extract percentage
I II I II
Petr. ether 0.2876 g. 0.2910 g. 1.44 1.46 1.45
Ether 2.8620 “ 3.2370 “ 14.31 16.18 15.25
Alcohol 4.5635 “ 4.2750 “ 22.82 21.38 22.10
Water 1.2280 “ 1.5135 “ 6.14 7.57 6.76
Total extractives 44.56 p.c

The petroleum ether extract of the seed consists of a yellow oil
without the characteristic odor of the fruit. It thickens on standing.
The ethereal extract is a yellowish-brown powder. The alcoholic ex-
tract is dark reddish-brown resembling a resin.

The petroleum ether extract of the carpel is a greenish-yellow
oil which on standing in a desiccator over sulphuric acid becomes
semi-solid. The ethereal extract consists of a white crystalline ma-
terial, probably shikimic acid, which is only sparingly soluble in
cold ether, but to a greater extent in the hot solvent. This may also
account for the fact that the ethereal extraction took more than 100
hours before exhaustion was reached. The alcoholic extract con-
sists of a resinous residue which is thick and sticky and of a reddish-
brown color.

The aqueous extracts of both seed and carpel are brownish-red,
solid, and very readily pulverized.

Extraction with alcohol. 14.5 ko. of finely powdered fruit were
exhausted with alcohol in a Lloyd extractor. After the removal of
the residual alcohol from the extract drawn from the apparatus, the
extract was shaken repeatedly with heptane and the liquid portion
separated by straining. The filtrate separated into two layers: a hy-
drocarbon layer and an aqueous layer.

From the former the hydrocarbon was recovered by distillation.
Steam was passed through the residue thus separating it into a vola-
tile oil (A) and a residual fatty oil (B). Of the former 37 g.
(=0.25 p.c. of the original drug) were obtained and of the latter
240 g. (=1.65 p.c.).

564 Illicium Religiosum, Siebold
The aqueous filtrate was shaken successively with ether and

chloroform. The solid material in the strainer was also washed
with ether and chloroform. The ether washings of both aqueous
filtrate and solid residue were mixed, the chloroform washings like-
wise. The solvents were recovered. Thus four different substances
were obtained.

C. Material soluble in ether

D. Material soluble in chloroform

E. Aqueous liquid shaken with both ether and chloroform
F. Solid material washed with both ether and chloroform.

A. Volatile oil. As previously stated, 37 g. of volatile oil were
obtained by steam distillation from the oily material separated from
the alcoholic extract by shaking and washing with heptane and re-
moval of the hydrocarbon. d21° =0.9834; np,25° 1.4874; ap
=5.2° at 21° in a 100 mm. tube; it did not congeal in a freezing
mixture at —10°, A. V. =0.42; S. V. =28.83.

The volatile oil was prepared by Eykman,’ in 1881, by Schim-
mel & Co.,? in 1893 and 1909, by Tardy,® in 1902 and K. K. Chen,*
in 1926. For better comparison the results are herewith tabulated
together with those of the investigators recorded:

Eykman S.& Co. Tardy K. K. Chen S. Y. Chen

Yield 1.00 p.c. 0.4 p.c. 0.6 p.c. 0.25 pc.
d 1.006 0.984- 0.9905* 0.9834
0.994 0.9790T
Np 1.5007* 11.4874
1.49607
ap -8.6° —9.50° —6.159°* —5.20°
-6.539°F
Cong. not at not at not at
pt. -20° —18° -6° —10°
A. V. 1.8 4.25* 0.42
4.287
S. V. 12.9 37-99* 28.83
24.69

1 Pharm. Jour. 41 (1881), p. 1048.

? Bericht S. & Co., Oct., 1893, p. 46; Apr., 1900, p. 51.

5 Etude analytique sur quelques essences des génere anisique. Thése, Paris,
1902.
“Jour. A. Ph. A. 15 (1926), p. 865.
* Original oil.

+ Cohobated oil.

Illicium Religiosum, Siebold 565
B. Fatty oil. The fatty oil remaining after the distillation of the
volatile from the heptane extract of the alcoholic extract of the entire
fruit was thick and green. Its density at 21° was ogeens A. A.V. =
17.25 and 17.79 respectively in two determinations; S. V. = 210.2
. and 210.9 respectively, hence E, V. = 210.6-17.54 or 193.1; I. V.
= 101.0 and 103.9 respectively.

The fatty oil has been prepared by Bulir* (1912) and Chen?
(1926).

Saponification of the fatty oil. 220 grams of the fatty oil were
heated with an excess of alcoholic potash on a water bath for one
hour. At the end of this period the alcohol was distilled off. The
residue which formed a semi-solid cake after cooling was dissolved
in water with the aid of heat. Having been allowed to resume room
temperature once more the aqueous solution was shaken several
times with ether. Upon spontaneous evaporation of the solvent,
a yellow semi-solid substance with an aromatic odor resembling that
of ginger, was obtained. (Unsaponifiable matter.)

After being washed with ether, the aqueous alkaline solution
containing the potassium soap was neutralized with 1:1 HCl and the
free organic acid thus liberated was separated from the aqueous solu-
tion mechanically.

Separation of solid and liquid fatty acids by means of lead-
salt-petroleum-ether method. (Gusserow *-Varrentrapp* method.)
The free acid was neutralized with aqueous potassa using phenolph-
thalein as indicator. 140 g. of lead acetate, dissolved in 700 cc. of
water at boiling temperature, were added gradually to the well-stirred
neutral salt of the fatty acids. The stirring was continued until the
solution was cold when a solid cake had formed. After having been
washed several times with warm water the lead soap or plaster was
separated from the water, first by draining and finally by heating on
a water bath under reduced pressure. To the lead soap petroleum
ether was added. This solvent was chosen instead of ether because
of its less solvent action than ether upon the lead salts of some of
the solid acids as suggested by Twitchell ° & Lane.* The extraction of

1 Zeitsch. f. Unters. d. Nahrungs- u. Genussm. 24, p. 309; through Analyst
37 (1912) p. 495.

* Loc. cit.

® Ann. 27 (1838), p. 153.

*Ibidem, 35 (1840), p. 197.

5 Jour. A. C. S. 17 (1895), p. 209; also Jour. S. C. I. 14 (1895), p. 515.
*J. S. C. I. 26 (1907), p. 597.

_

566 Illicium Religiosum, Siebold
the soluble lead soap of the unsaturated acids by the petroleum ether
was accomplished by heating the mixture to boiling under a reflux-
condenser for half an hour and placing the flask in an ice box over
night. The undissolved portion was separated by filtration.

Solid fatty acids. The lead soap which was insoluble in pe-
troleum ether was decomposed under ether with 1:1 HCl and the
ether solution containing the acids was washed with water until the
solution was neutral to litmus paper.

After the removal of the ether a solid green cake amounting to
40.0 g. was left. The acid value was determined. Due to the slight
solubility of this acid in cold alcohol a mixture of alcohol and ether
(1:1) was used as solvent in the acid value determination. The
results are herewith tabulated :

Sample (1) 0.3271 g. A. V. 184.9
(2) 01806 g. A. V. 184.1
Average 184.5

Calculated acid value for stearic acid = 196.1
for palmitic acid = 217.5

This low A. V. indicates the presence of some acid with higher
molecular weight than stearic acid.

Separation of solid fatty acids. The solid cake of acids was
crystallized from a 20 p.c. solution in absolute alcohol. The greenish
acid which thus separated amounted to 0.4 g. It had a m.p. of 73-76°.
After repeated recrystallization the m.p. rose to 82°; the following
acid values were found:

Sample (1) 0.0728 g. A. V. 117.2
(2) 01172 g. A. 117.9
Average 117.6

An attempt was made to remove completely the greenish color
of this acid by filtering through charcoal but was not very satisfac-
tory. The alcoholic filtrate was then evaporated and the residue was
recrystallized from ethyl acetate; this solvent being used by F. B.
Power in his isolation of behenic acid from Micromeria Chamissonis.
The acid thus recrystallized has a m.p. of 82.5° and an acid value
(Sample 0.4502 g.) of 118.4.

Although it is still colored green, the slight increase of m.p. and
in A. V. after filtration through charcoal and recrystallization from

Am, Jour, } Illicium Religiosum, Siebold 567
ethyl acetate indicate it to be purer than before. Its molecular weight
was computed at 473.7. The following data are taken from Lew-
kowitsch, Tech. & anal. of fats, oils and waxes."

M. W. for Cz2H¢g4Oe is 480.0
M. W. for melissic acid Cs9Hg0O2 is 452 m.p. g1-98°

M. W. for psyllostearylic acid C3i1H¢402 is m.p.
PSY is 494 P. 94°95
M. W. for geomyricin C34H¢ggQO2 is 508 m.p. 80-83°

Stearic and palmitic acids. The filtrate from the acid was evap-
orated to half its volume and placed in an ice box over night. A
crop of crystals was formed. On recrystallization from alcohol an
almost colorless acid was obtained. It melted at 56° and has the fol-
lowing acid value:

Sample (1) 0.0659 g. A. V. 201.6
(2) o0o615 g. A. V. 202.0
Average 201.8

The last filtrate was decolorized by means of charcoal and crys-
tallized by cooling. An acid melting at 56° was obtained. Its acid
value is 203.8. Since this acid has the same m.p. and approximately
an equal A. V. with the previous one they were mixed.

While trying to separate the constituents of this acid mixture,
namely the palmitic acid and stearic acids, a part of this mixture was
dissolved in 50 p.c. warm alcohol following the suggestion of Lew-
kowitsch. On cooling at room temperature most of the fatty acid was
separated and filtered. The filtrate gave another crop of crystals
(only 0.15 g. from 10 g. of mixture) on cooling in an ice mixture.
The following constants for both acids were determined :

Acid insol. in 50 p.c. alcohol m.p. 57° A. V. 202.3
Acid sol. in 50 p.c. alcohol m.p. 57° A. V. 208.5

These results show that neither of the two components is pure
palmitic or stearic acid.

Taking 201.8 as the A. V. the percentage of palmitic and stearic
acid in the total mixture of 40.0 grams can be calculated.

Total acid 40.0 g.

Purified acid OS g. = 12 pe.
Stearic acid 80.0 p.c.
Palmitic acid 19.8 p.c.

*Tech. & anal. of fats, oils and waxes, 6th ed. (1923), p. 118.

568 Illicium Religiosum, Siebold Jone.

According to Lewkowitsch the melting points of mixtures of
palmitic and stearic acids are as tabulated:

Stearic Palmitic m.p.
80 p.c. 20 p.c. 64.51°
55 p.c. 45 p.c. 57:0°

Separation of the liquid acids. The petroleum ether solution ob-
tained by filtering off the insoluble lead soap of the saturated acid
was treated with HCl (1:1) and the precipitate thrown down filtered
off. The acid solution was washed several times with water until
all the mineral acid had been removed. The solution was next dried
over anhydrous sodium sulphate, the solvent distilled off, and the
residue dissolved in ether. 50 cc. of 735 cc. of this ether solution, upon
evaporation to constant weight, left 5.4414 g. as oily residue. The
total liquid acid therefore, amounts to 76.2 grams. ‘The following
constants were determined :

Acid value 134.4
Iodine value ® 97.95
I. V. of oleic acid is 90.07

This iodine value shows the presence of some acid which is
less saturated than oleic.

Bromuination of the liquid acid. Farnsteiner’s method was used.®
To the ether solution of the acid 40 cc. of glacial acetic acid were
added and the mixture was cooled to -10°. Bromine was dropped in
with constant shaking. When the solution had acquired a permanent
color of bromine it was cooled in an ice box over night. 20 cc. of
bromine were used. A small amount of white precipitate had de-
posited and was identified as a lead compound.

Tetrabromide. After the removal of the precipitate the ether
solution was washed with saturated solution of NagSeOx until the
excess of free bromine was completely removed. The trace of
NagS2Oz was in turn removed by washing with pure water and finally
the moisture by means of anhydrous NagS Oy. The ether was dis-
tilled off and the residue treated with hot petroleum ether. After
standing for 3 hours 40 grams were obtained as a precipitate. This
precipitate was purified by dissolving in benzene, filtering through

®The U. S. P. method was used.
® Zeitsch. f. Unters. d. Nahrungsm. u. Genussm. 2 (1899), p. I.

Am. Jour. Pharm. Illicium Religiosum, Siebold 569

August, 1929

charcoal, and recrystallizing from the same solvent. A _ perfectly
white compound was thus obtained which had a m.p. of 113.5°. The
tetrabromide of linoleic acid melts at 114°.

The bromine content was determined according to Stepanow.’®

Sample (1) 0.2274 g._ Br. 53-09 p.c.
(2) 0.2302 g._ Br. 52.77 p.c.
Average 52.93 p.c.

Tetrabrom linoleic acid contains 53.33 p.c. Br.

Dibrom compound. The solution after the removal of the tetra-
bromide was placed in an ice box for two days but no more precipi-
tate was obtained. It was then evaporated spontaneously and finally
on a steam bath to remove the last traces of petroleum ether. In this
highly colored liquid the bromine content was determined.

Sample (1) 0.3321 g. Br. = 36.95 p.c.
(2) 0.3074 g. Br. = 38.38 p.c.

(3) 0.3044 g. Br. = 36.95 p.c.
Br. in dibrom oleic acid = 36.36 p.c.

Non-saponifiable matter. Upon evaporation of the ethereal solu-
tion 9 grams were obtained as a yellowish soft material with a ginger-
like odor. Charcoal did not remove any appreciable amount of color.
Hot alcohol yielded a small amount of soft crystals melting at 70-73°
and an oily residue (7 g.).

The crystals gave the Salkowski-Liebermann " reaction for phy-
tosterol. Attempts to recrystallize it from alcohol resulted, for the
most part, in jelly-like masses. Treatment with petroleum ether,
however, made possible a separation into a soluble portion (70 mg.)
that melted at 63-64°, and an insoluble portion (40 mg.) that
melted at 78-81°.

From the fat of rice bran, Nabenhauer and Anderson ** have
recently isolated myricyl alcohol which melted at 80° in the impure
condition and at 85° after several recrystallizations. Possibly the
portion insoluble in petroleum ether melting at 78-81° is identical with
this alcohol. The acetate prepared, if it was such, melted at 64°,
whereas myricyl acetate is said to melt at 73°. However, the amount
available was too small to admit of purification.

* Ber. 39 (1906), p. 4056.
™ Zeitsch. f. physiol. Chem. 57 (1908), p. 515.
® Jour. A. C. S. 48 (1926), p. 2972.

{ Am. Jour. Pharm,

570 Illicium Religiosum, Siebold ‘August, 1929

From the unsaponifiable matter of the fat of rice bran Wein-
hage ** isolated a hydrocarbon Cyg7H4g which melted at 79.5° to
80.5°.

The combined mother liquids from recrystallization were reduced
to an alcoholic strength of about 70 p.c. when practically all of the
material separated. It had a m.p. of 121-126°. After recrystalliza-
tion from alcohol the m.p. was raised to 134-135°. Sitosterol melts
at 135°.’* An acetate prepared from the laminar crystals which, un-
der the microscope appeared typically sitosterol-like, melted at 100°,
whereas sitosterol acetate melts at 125°. Again the amount was too
small to admit of purification.

Glycerin. After the organic acids had been removed from the
potassium soap, the aqueous portion was neutralized with sodium
hydroxide and evaporated on a water bath. When the solution was
fairly concentrated the salt which had separated out was filtered off,
the coloring matter taken up by means of charcoal and the clear
solution was distilled under a pressure of 60 mm. When the tempera-
ture reached 148° nothing more distilled over and the residue was
taken up with ether. On the removal of the solvent the ethereal solu-
tion yielded a thick liquid with a sweet taste. Upon this liquid the
following tests were made:

When about 1 g. of the liquid was heated in a test tube with
2 g. of KHSO, vapors having the odor of acrolein were evolved.
These vapors reduced ammoniacal silver solution very readily and
reddened Schiff’s reagent.

Following the method devised by Chapman for the identifica-
tion of glycerol in tobacco, about one-half gram of this liquid was
gently heated with a-napthol isocynate in a dry tube until a vigorous
reaction took place. This solid mass was treated with hot pyridine
and the insoluble material was filtered off. On cooling the pyridine
solution yielded a white crystalline powder melting at 260°.

A similar compound made from commercial glycerin melted at
268°. According to Chapman the glycerol urethane melts at 278-
280° although softening may commence at about 270° or even below.

Bickel and French made the same urethane from glycerol and
isocynate, but instead of pyridine they used ligroin boiling at 100-
120°. The melting point of the urethane was found at 19gI—192°.

% Zeitsch. f. physiol. Chem. 100 (1917), p. 159.
“Windaus and Hauth, Ber. 39 (1906), p. 4379.

i

i

Am, Jour. = Illicium Religiosum, Siedold 571

Since dinaphthyl urea is easily formed in the presence of moisture the
compound obtained by Chapman might be dinaphthyl urea which
melts at 268°.

To repeat Bickel and French’s experiment some urethane was
made from commercial glycerin and treated with boiling heptane
since no ligroin boiling at 100—-120° was readily available. Nothing
separated from the heptane solution on cooling, and the solvent was
removed by evaporation at 60°. The residue had no definite melting
point.

Tests for toxicity upon rats. In order to ascertain in which of
the different portions, into which the alcoholic extract of the drug
had been separated, the toxic principle is located pharmacological
tests were made upon white rats.

1. Heptane soluble portion. After the removal of the solvent
from the heptane soluble portion 0.225 gram of the residue which con-
stituted a green oil, were shaken vigorously with 4.5 cc. of water.
2 cc. representing 0.10 g. of the original extract were injected sub-
cutaneously into a white rat of 280 g. Twenty minutes after injec-
tion the animal showed distress: paralysis of the hind legs and violent
convulsions in the opisthotonus position. It died 15 minutes after
the appearance of the first symptom.

2. Ether soluble portion. 1.0 cc. of the aqueous solution pre-
pared from 0.1 gram of the dried ethereal extract was injected sub-
cutaneously into a white rat of 260 g. Twenty-four minutes after
injection the animal sat down showing weakness in the hind ex-
tremities. This symptom was followed by the retraction of the head
and paroxysm of violent convulsion; finally by death which resulted
40 minutes after injection.

3. Chloroform soluble portion. A portion of the chloroform ex-
tract was washed with ether and dried. 0.32 g. of the dried material
were treated with 32 cc. of water, the insoluble matter removed by
filtration and 2 cc. of the solution representing 0.02 g. of the extract
were injected subcutaneously into a rat weighing 270 g. One hour
after injection it showed weakness. After two hours diarrhea was
observed. After 10 hours the rat had recovered completely.

4. Volatile oil. 2.6 g. of the volatile oil were emulsified by shak-
ing vigorously with 2 cc. of water and half of the emulsion was in-
jected subcutaneously into a white rat weighing 260 g. before separa-
tion into oil and water had taken place. Muscular weakness, espe-

572 Illicium Religiosum, Siebold Tous.
cially in the legs was observed 2 hours after injection. The animal
had recovered completely after 4 hours.

5. Aqueous residue from steam distillation. 1 cc. of this liquid
injected hypodermically into a white rat of 280 grams caused weak-
ness and quietness in the animal which, however, recovered after
20 hours.

The effect of heat on the toxic principle. 1.00 gram of the
ethereal extract was triturated with hot water for three successive
times until the aqueous solution no longer became colored. The
aqueous solution was filtered to remove the insoluble matter and the
filtrate boiled gently for one hour. The final solution was made up
to 10 cc. and 1 cc. of this solution was injected hypodermically into
a rat weighing 250 g. Twenty minutes after the injection the animal
lay down showing weakness in the extremities and 28 minutes later
paroxysm of violent convulsion in the opisthotonus position started
and continued until death. The interval between the time of injec-
tion and death was 50 minutes.

The effect of acid upon the toxic principle. 1.00 g. of the
ethereal extract was treated thoroughly with water and the aqueous
solution of about 30 cc. was acidified with 3.0 cc. of N/6 H2SO,
and boiled for 40 minutes; the loss by volume by boiling being
made up by frequent additions of water. During the boiling an aro-
niatic odor was very noticeable. Some black resinous substance was
formed at the same time. After the mixture had boiled for 40 min-
utes it was allowed to cool and treated with BaCOsz until neutral to
litmus paper and the solution filtered. The aqueous filtrate thus ob-
tained was diluted to 10 cc. and one-tenth of this quantity was in-
jected hypodermically into a rat of 200 grams body weight. Thirty-
six minutes after injection the animal showed distress, weakness, and
slowing of respiration. Complete paralysis of the legs was shown by
its lying down upon its side and this was followed by death. No
convulsion whatever was observed. The interval between the time
of injection and death was 66 minutes.

Test for alkaloids. ‘The aqueous solution made from the ethereal
extract was used to test for alkaloid. It gave precipitates with solu-
tions of potassium mercuric iodide and of iodine in potassium iodide.
As tannins also form precipitates with these reagents these reactions
can not be considered as conclusive evidence of the presence of al-
kaloid. Certainty as to the presence of the latter was obtained by
applying these reagents to aqueous solutions detanninized by means

A
Ww
T
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Al
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a
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t
I
b
t

Illicium Religiosum, Siebold 573
of hide powder. While the aqueous infusion of pure hide powder
which served as blank yielded no reactions the unknown solution gave
distinct precipitates. The presence of alkaloid is, therefore, indicated.

Extraction of the ether-soluble portion with different solvents.
The ether extract of the alcoholic extract, after the removal of the
solvent, resembled an oleoresin. It was, therefore, first freed from
oils by washing repeatedly with heptane and then extracted, by re-
fluxing on a water bath, successively with chloroform and ethyl ace-
tate. After the removal of the solvents, the chloroform soluble por-
tion left a semi-solid residue with a greenish color, and the ethyl ace-
tate extract formed a solid cake with some crystalline substance, prob-
ably a glucoside. These portions are designated as following:

A. Chloroform-soluble portion.

B. Ethyl acetate-soluble portion.

C. Resin (insoluble in both solvents).

Resin. The resin consisted of a brown powder, was insoluble in
ether, water, ammonium bicarbonate, and sodium bicarbonate, par-
tially soluble in sodium carbonate and soluble in sodium hydroxide.
It was acid in character and dissolved freely in acetone and alcohol.
The resin was precipitated when its alkaline solution was acidified,
but the amount of the precipitate was only about 50 p.c. of the original
material.

Test for toxic albuminose.’ The solubility of the toxic principle
in water and the precipitates caused by alkaloidal reagents suggested
the possible presence of toxic albuminose. A portion of the ethereal
extract was triturated with distilled water and filtered, the filtrate
being detanninized and used for the following tests.

1. Boiling of the solution, which had been acidified with acetic
acid, did not coagulate the solution.

2. No coagulation was observed on boiling the solution which had
been acidified with nitric acid.

3. With concentrated HNO: toxic albuminose forms a white
ring, which on heating changes to yellow. In its place a brown color,
but no precipitate was observed.

4. A brown solution resulted on heating with concentrated sodium
hydroxide with the subsequent addition of a few drops of CuSO,
solution.

* Trier, Chem. d. Pflanzenstoffe, Berlin, 1924, p. 464; Rosenthaler, Grund-
suege d. chem. Pflanzenuntersuch., Berlin, 1923, p. 23; Mathews, Physiol. chem.,
3d. ed., 1921, p. 928.

U

574 Illicium Religiosum, Siebold (ho,

5. When boiled with concentrated KOH and lead acetate no
precipitate was formed.

6. With Millon’s reagent it produced a red coloration.

7. On the addition of two volumes of a saturated solution of
ammonium sulphate to one volume of the aqueous solution, turbidity
of the solution was observed.

Some of these reactions (Nos. 3, 6 and 7) show the possible
presence of some proteins but since the substance failed to give a test
for sulphur it may not be a toxic albuminoid since sulphur is sup-
posed to be a characteristic element.

Test for tannins.1. For this purpose the aqueous solution pre-
pared from the ethereal extract was used.

1. The aqueous solution was distinctly acid to litmus paper.

2. With ferric chloride solution it produced a blue coloration
which turned brown on the addition of sodium hydroxide.

3. It reduced Fehling’s solution rapidly.

4. With K»Cr2O7 solution a dark red color developed which
changed immediately to a brown crystalline precipitate.

5. It caused precipitation with an aqueous solution of lead ace-
tate.

6. With ammoniacal solution of K3Fe(CN)g¢ a red-brown color
appeared.

7. With lime water it produced a white precipitate which turned
rapidly to brown.

8. With gelatine solution a white curdy precipitate was formed.

g. As has already been stated this solution formed precipitates
with alkaloidal reagents.

* Haas and Hill, Introduction to Chem. of Plant Products (1922), p. 93.

(To be Continued)

if

Am, Jour. oot Twelve Points in U. S. P. Policy 575

August, 1929

TWELVE POINTS IN U.S. P. POLICY

By E. Fullerton Cook, Chairman of the Committee of
Revision of the United States Pharmacopeeia

NE HUNDRED and ten years of experience and earnest and

honest planning for the health and welfare of this nation provide
the background for the United States Pharmacopeeia.

Happily, however, its age is no handicap,
for the present Pharmacopoeia is an aggres-
sive, progressive and modern guide to med-
icine and pharmacy, fully in keeping with
the spirit of up-to-date scientific progress.

As another decennial convention ap-
proaches there is rightly an intensified inter-
est in every phase of the new revision and
especially in its basic policies. Fortunately
these policies are not fixed by immutable
laws. In fact, most of them were estab-
lished by no law but through the combined
judgment and mutual acceptance of the

E. Fullerton Cook, Ph. M. various committees and are not even in
print or writing.

For a more clear understanding of their character, a better oppor-
tunity to study them, and for their possible betterment, the chairman
of the present committee is endeavoring to correlate the more impor-
tant policies and explain their purpose and operation. While many
other points might be brought under discussion in each division of the
book, the following general considerations, basic in their applications,
have been selected for this study:

1, Each New Pharmacopeeia Should Represent the Best Medical
and Pharmaceutical Knowledge of Its Day

In studying the life and words of Dr. Lyman Spalding, to whom
almost alone we are indebted for the establishment of our National
Pharmacopeeia in 1820, the present chairman has been strongly im-
pressed by his unselfish spirit and purpose. Dr. Spalding embodied
this in the preface to the first U. S. P. when he wrote:

576 Twelve Points in U.S. P. Policy Jour. Pharm,

August, 1929

“It is the object of a Pharmacopceia to select from among
substances which possess medicinal power, those, the utility of
which is most fully established and best understood ; and to form
from them preparations and compositions, in which their powers
may be exerted to the greatest advantage.

“The value of a Pharmacopceia depends upon the fidelity
with which it conforms to the best state of medical knowledge of
the day. Its usefulness depends upon the sanction it receives
from the medical community and the public; and the extent to
which it governs the language and practice of those for whose use
it is intended.”

The chairman was recently asked whether he advocates a small
Pharmacopeeia, and his reply then and today is that he is not con-
cerned over the size of the Pharmacopceia, but only that it shall repre-
sent fully and completely and accurately the best medical and pharma-
ceutical knowledge of this our scientific and progressive age. Let it
be large if we have the knowledge to justify it.

2. The First Requisite as a Guide to U. S. P. Admission is “Thera-
peutic Usefulness” or “Pharmaceutical Necessity”

These were the words adopted by the 1920 convention in deter-
mining the scope pulicy for the Tenth Revision. The committees are
bound by this program in which therapeutic value and not use is clearly
set forth as the deciding factor for admission, but the valuable drug
must be sufficiently used to justify recognition.

In determining whether a therapeutic agent is useful we must
depend upon the experts best qualified to judge the known facts.

3. The Committee of Revision Directed That Physicians Shall
Decide Therapeutic Usefulness; Pharmacists Shall Decide
Pharmaceutical Necessity

A calm survey of the facts will help many to develop their own
judgment on this policy which was adopted by the Committee of Re-
vision by a vote of 33 to 16 (1 not voting) after a thorough discussion
in personal conference at Washington and later in the official circulars.

Let us follow the sequence of events:

The Pharmacopceia was founded by physicians and was under
their exclusive control up to 1850. In 1850 the physicians invited
pharmacists to co-operate because of splendid pharmaceutical help
given voluntarily by pharmacists during the 1840 revision.

Am, Jour. Fes } Twelve Points in U.S. P. Policy 577

In the Ninth Revision (1910-1920) the vote of the Scope Sub-
Committee was for the first time subjected to review by the larger
committee (the Executive Committee), upon which physicians were in
the minority, only five out of sixteen having an M. D. degree.

This action so incensed the physicians of the country that
the Ninth Revision of the Pharmacopeeia was largely discredited as
an authority by the medical colleges and journals, and in the 1920
convention the chairman of the Revision Committee, Charles H.
LaWall, who succeeded Chairman Remington when the latter died,
made the following specific recommendation when discussing the
weakness of a policy which required every member oi the committee
to vote on technical questions upon which they were not informed.

Chairman LaWall said :*

“T believe it would be weli for the convention at this time to
give some very careful thought to this subject and to issue binding
instructions to the incoming committee covering this very impor-
tant phase of the work. For example, it certainly is exclusively
the province of the medical members of the Revision Committee
to decide what substances should be officially included for reme-
dial purposes, and this list, after having been decided upon by the
physicians, should not be subject to review or alteration by phar-
macists and chemists. On the other hand, when the list of official
remedial agents has once been clearly outlined, it should be the
province and privilege of the pharmacists and chemists to decide
upon such additions and inclusions of materials used as ingre-
dients as will make it possible and practicable to prepare the
medicine of proper uniformity, quality, and potency. These are
the basic and fundamental prerogatives, and a workable plan
should be devised to maintain their integrity.”

This recommendation was referred by the convention to a com-
mittee consisting of Professors Wortley F. Rudd and J. A. Koch, who
reported back to the convention as follows :?

“The second matter has to do with the manner of arriving at
decisions in matters of detail by the Committee of Revision, the
chairman stating the belief that the convention should issue bind-
ing instructions to the incoming Committee of Revision covering
this very important phase of the work. It has been the consistent
policy heretofore not to hamper the Committee of Revision in its
work by binding instructions of any kind and your committee

1 Abstract of Proceedings, U. S. P. Convention, 1920, p. 60.
* Abstract of Proceedings, U. S. P. Convention, 1920, p. 87.

578 Twelve Points in U. S. P. Policy ~ je

believes that it would be unwise to change the policy. The Com-
mittee of Revision should be left free, and should have full au-
thority to deal with these questions to serve the end in view.”

This recommendation was adopted by the convention and became
‘ a mandate to the chairman of the Committee of Revision and to the
Committee of Revision. Note that there is no recorded opposition to
this policy expressed by any member of the convention.

The adoption of a policy on this point was now squarely up to the
Committee of Revision and was brought before the Committee for
discussion by Dr. H. C. Wood, who requested that the General Com-
mittee define the status and relation of the Sub-Committee on Scope.®
The first discussion was at Washington in the conference of the com-
mittee immediately following the convention. After “voluminous dis-
cussion,” the following motions offered by George M. Beringer, a
practicing pharmacist, were adopted, the first by a vote of 22 to 8, the
second unanimously.

Mr. Beringer’s motions were:

“Tn questions concerning the inclusion of substances of ther-
apeutic usefulness in the Pharmacopceia the entire body of physi-
cians on the Committee of Revision shail have the deciding vote.

“(n all questions regarding the inclusion of substances of
pharmaceutical necessity the entire body of pharmacists on the
Committee of Revision have the deciding vote.”

As all members had not been able to attend this meeting of the
committee, on request of the chairman immediately declared the entire
question open for reccnsideration and asked for discussion and a new
vote, all by mail.

The meeting at Washington was held on May 12, 1920, the min-
utes were mailed to all members on May 22d, the question opened for
rediscussion on July 2d, the discussion published and a new vote called
on July 17th, and the result of the final vote announced on July 31st,
when 32 members voted in favor of the Beringer motions, 16 were
opposed, and 1 did not vote.

Those who discussed this policy when it was before the committee
a second time were Messrs. Dohme, Dye, Eldred, Fantus, Francis,
Havenhill, Houghton, Jordan, Kelly, Kraemer, McCoy, Newcomb,
Nitardy, Sollmann, Stitt and Wood.*

*See U. S. P. X Official Circulars, p. 7.
“See the Official Circulars of the Committee of Revision, pp. 73 to 79, pp.
130 to 137.

ay Twelve Points in U. S. P. Policy 579

Those who voted in favor of this policy and gave the responsihil-
ity to the physicians alone to decide the admission of therapeutically
active substances were: Messrs. Alsberg, Anderson, Arny, Barbour,
Bastedo, Beringer, Bradley, Christian, Clark, Craig, DuMez, Ed-
munds, Fantus, Fussell, Gathercoal, Hamburger, Hatcher, Havenhill,
Hodge, Hunt, LaWall, Leonard, McCoy, Nitardy, Pittenger, Rosen-
garten, Rowntree, Schneider, Seltzer, Sollmann, Stitt, Wood and
Zeigler.

Those who opposed this policy were Messrs. Caspari, Cully,
Dohme, Dye, Eldred, Francis, Houghton, Johnson, Jordan, Kelly,
Kraemer, Murray, Newcomb, Richtmann, Ruddiman and Scoville.
Dr. Diner did not vote.

Here was again a clear mandate to the chairman which he was
called upon to administer. It is a remarkable fact that in a nation-
wide campaign the chairman is charged with the responsibility for this
policy with which he is in sympathy, but which he never proposed,
never even discussed before the committee and which was approved by
the General Committee by an overwhelming majority and placed in
his hands to administer.

Evidently a fact brought to the attention of the committee in the
original discussion by Dr. Sollmann is forgotten. He wrote:*

“The real question is then: Who shall decide whether the
therapeutic usefulness of a drug is such as to entitle it to admis-
sion to the Pharmacopoeia? Who are the logical judges of this
strictly therapeutic question, the physicians or the pharmacists ?

“The pharmacists doubtless have much information on this
subject ; there is every opportunity in the Beringer plan to make
that information effective, but should the pharmacists be the final
arbiters of a strictly medical question?

“This would be the effect of leaving the decision either to
the General Committee or to the Executive Committee ; for it was
planned by all parties that the pharmacists should predominate
greatly on both conimittees. This plan received the hearty sup-
port of the medical delegates because they felt assured that there
would be no serious question about leaving the therapeutic sub-
jects to the judgment of the medical members, and therefore felt
safe in furthering the election of a majority of pharmacists on
both committees.”

5 Official Circulars, U. S. P. X p. 134.

580 Twelve Pomts in U.S. P. Policy Jour,

As to the qualifications of the physicians of the committee to de-
cide the value of drugs, a qualification which is also being questioned,
Dr. Wood in the original discussion said :°

“The medical men on the Revision Committee were chosen
by the physicians of the convention in a widely announced caucus,
and it is fair to assume that they were regarded by the medical
delegates as those best qualified to represent medical science upon
the Revision Committee. Why should we assume that they are
less competent or less sincere than those selected by the pharma-
ceutical delegates to the convention? There seems to be a fear in
the minds of some that the medical men are not fit to be trusted to
make a decision in a matter which is peculiarly the province of
physicians.

“Dr. Dohme objects to leaving these decisions to Sub-
committee No. I on the ground that ‘pharmacologists are usually
men not in actual practice.’ Of the medical members of the
Sub-committee on Scope, ten are today engaged in the practice of
medicine, some of whom have never performed a pharmacological
experiment in their lives; four are laboratory pharmacologists,
that is men who are not practicing physicians at present. I do not
know what experience these latter gentlemen may have had in the
past in clinical medicine, but when the clinical physicians can out-
vote the purely laboratory men more than two to one, it seems to
me rather far-fetched to fear that the committee will be dominated
by the pharmacologists.”

4. U.S. P. Standards of Quality Insure Maximum of Efficiency
and Minimum Cost

When the U.S. P. became the official standard under the Food
and Drugs Act in 1906, it became necessary to fix exact degrees of
purity for its drugs, chemicals and preparations where these could be
provided.

Chairman Remington was greatly interested in this policy and
suggested the term “Purity Rubric” to apply to the clause which fixed
the minimum degree oi purity required. He often said that the
Pharmacopeeia prevented no manufacturer from exceeding the U. S.
P. purity requirement, and rather stimulated that effort, but at the
same time it conserved the interests of the sick by not demanding 100
per cent. purity and the corresponding cost when those impurities were
harmless. At the same time that the U.S. P. tests ignored harmless
foreign substances such as moisture, if the chemical was still sensibly
dry, a little soda in a potassium salt, a little cinchonine in a quinine

®See the Official Circulars, p. 136.

Am, Jour Font Twelve Points in U.S. P. Policy 581
salt, etc., yet it rigidly excluded or limited dangerous foreign sub-
stances such as arsenic and lead.

This policy keeps up the quality of the medicines of the Pharma-
copeeia without making their cost needlessly high.

5. The Revision Committee is made up of Experts in All
Related Fields
In the U.S. P., 1920 convention, when nominations were being
made for members of the Committee of Revision, the question, ““What
policy is to govern the convention in the selecting of such members ?”
was asked, and it was clearly understood that the individual’s personal
qualifications for work on the committee were to be the basis of selec-
tion and not geographic location or other such irrelevant reasons.
Such a policy will always insure a creditable and up-to-date Phar-
macopceia for the United States.

6. Chiefly Volunteer Work on the Committee of Revision

This policy has always prevailed, for there is no financial reward
for the members except a modest salary for the chairman, a small
honoraria for each member of committee at the close of the revision,
and necessary clerical expenses.

Small amounts have been allowed several of the sub-committee
chairmen for laboratory assistants on certain experiments, but the pol-
icv of volunteer work is well established.

In discussing this recently in relation to the revision of the British
Pharmacopoeia the chairman pointed out that over a period of many
years the Pharmacopeeia has been able to command the interest and
assistance of the most able men in medicine and pharmacy who were
glad to contribute their experience and time to this philanthropic serv-
ice. The help of such men could not have been secured by pay and
the amount available for a few salaries, if all work had been on that
basis, would have attracted other types of workers to the detriment of
the Pharmacopceia.

7. Opportunity is Always Given Every Member to Discuss
Every Question and See the Other Members’ Opinions Be-
fore a Vote is Called
This has been a fixed policy of revision and has proven very sat-

isfactory. When a question is placed before the committee, all mem-
hers are invited to discuss it. Ample time is given for a reply (never

582 Twelve Points in U.S. P. Policy Jour. Eharm.
less than two weeks and often four weeks) before the discussion is
copied in full in the official circulars, and a vote called.

Again two weeks is allowed for the return of the vote when the
names of each and how they vote is published to the entire committee.
The chairman has never heard a compliant from the working of this
policy.

8. Maximum of General Publicity Concerning All Decisions
Before Printing the U. S. P.

In the U.S. P. IX and again in the U.S. P.X the policy was
followed of publishing in the pharmaceutical press an announcement
of all important changes proposed for the new Pharmacopeeia by the
Committee of Revision and inviting comments or criticisms from any
one who was interested. This policy also applied to all proposed
deletions and new admissions.

All comments received by the chairman were published in full in
the official circulars and considered in the final make-up of manuscript.

In the U. S. P. X, when the book had reached page proof this was
sent for reading and criticism to about 200 selected experts in every
field of the revision.

This policy increased the general interest in the revision, assisted
the committee in correcting possible errors, and insured a much more
acceptable Pharmacopeceia.

9. Harmonious Cooperation Was a Notable Feature of the
U. S. P. X Revision

Each group of experts worked in their special field throughout
the revision and contributed their quota toward the finished revision.
All members discussed and gracefully accepted the majority decision
on all general questions. Over two hundred additional experts were
elected as auxiliary members of sub-committees, and received all sub-
committee bulletins and the privilege of discussion, but without vote.

In addition the Government organization, including the Hygienic
Laboratory, the laboratories of the Bureau of Chemistry, the Bureau
of Standards and the Prohibition Enforcement Division and also the
Army and Navy Laboratories associated with offices of the Surgeon-
General and many college, private, and manufacturers’ laboratories
combined in a remarkable illustration of harmonious co-operation to-
ward a common goal.

Am, Jour. Feo t = Twelve Points in U. S. P. Policy 583

August, 1929

10. A Convention and Committee of Technical Experts

Technical experts in therapeutics, pharmacy, chemistry, pharma-
cology, botany, pharmacognosy, serology, nomenclature and other
related sciences, here gather on a common plane for an unselfish under-
taking in the interest of public health. It is not duplicated by any
other country in the world.

11. A New Convention and a New Pharmacopceia Every
Ten Years

We owe this policy to the wisdom and foresight of Dr. Lyman
Spalding, who suggested and established it at the first convention
in 1820.

It has just been adopted as the policy for Great Britain, although
they propose to adopt the fifth year of each decade for the start of a
new revision. This period has proven satisfactory to most users of
the book, as it gives ample time for adjustment between revisions,
does not upset standards too frequently and provides ample time to
develop and try new remedies and new technical methods.

12. A Policy of Independent Research

The Pharmacopoeia Committee has, from time to time, under-
taken independent studies of some of its problems by financing re-
searches in private or other laboratories, but until recently this has
been intermittent and no fixed policy.

In the current revision the chairman and the Executive Com-
mittee, under the authority of the by-laws of the convention, have
adopted a definite policy for research and eight or ten such studies are
under way, through the modest grants established by the Board of
Trustees. As was recently announced, the Board of Trustees also
recommends to the next convention the setting aside, as a memorial
to Chairman Remington, of an initial amount of twenty thousand
dollars the income of which is to be available for research on Pharma-
copeeial problems.

=
=
=

Notes on Tests for Methanol (a

NOTES ON TESTS FOR METHANOL
By Henry Leffmann and Charles C. Pines

HE DETECTION of methanol has become of much importance

of recent years on account of its use in crude form as a de-
naturant and its commercial production in high purity at a moderate
price, the latter condition rendering it liable to be substituted for
ethyl alcohol, a very dangerous practice. Our attention has been
specially drawn to the question of the tests used for the detection of
methanol in the presence of ethanol, by noting the procedure pre-
scribed in the current (6th, 1926) edition of the Deutsches Arznei-
buch and comparing this with the procedure directed in U. S. P. X.
In the issue of this JouRNAL for April last, the German method was
unfavorably criticised, attention being particularly called to the tedious
routine for carrying out the oxidation by permanganate. Other
minor objections were noted.

The criticism attracted the attention of Dr. R. Brieger, of the
staff of the Pharmazeutische Zeitung, who kindly sent an explana-
tory letter and a clipping from that journal (1926, #96) being an
article by H. Matthes, in which one phase of the procedure is depre-
cated, namely the use of guaiacol dissolved in strong sulphuric acid.
Matthes substitutes potassium guaiacolsulphonate in equivalent
amount. Runge about the same date had expressed disapproval of
the reagent, suggesting guaiacolsulphonic acid, but it seems likely
that a solution of guaiacol in strong sulphuric acid would produce
some sulphonic acid promptly. It will be noted that both these criti-
cisms were published shortly after the appearance of the German
work. The reagent directed in the D. A. is 20 mg. of guaiacol dis-
solved in 10 cc. of strong sulphuric acid. Matthes recommends 40
mg. of the sulphonate on acount of the much higher molecular
weight, more than double that of guaiacol. It seems better to use
much more.

We have experimented with the process as suggested by Mat-
thes and find it delicate. With careful attention to details, formal-
dehyde may be detected in very small amount and acetaldehyde does
not simulate it. It is important that the sulphonate is in complete
solution and the substances at room temperature. The colorless solu-
tion obtained in the U. S. P. process after the addition of the dilute
sulphuric acid will give a satisfactory, though faint reaction with the

i

eo Notes on Tests for Methanol 585
sulphonate solution, if methanol was present in the sample. A few
drops of the colorless liquid should be placed on the reagent, and the
rest tested with the fuchsin-sulphurous acid.

Matthes states that the test as modified will detect 1 part of for-
maldehyde in 6000. This is about equivalent to 0.6 cc. to the U. S.
gallon. The German work directs that 10 cc. of the sample should
be distilled, collecting 2 cc. 1 cc. is reserved for detection of acetone,
and the other for methanol. This procedure will give a strong alco-
hol, and hence the German process prescribes I gram of perman-
ganate for oxidation. The U. S. P. process requires the sample to
be diluted so as to contain but about 5 per cent. of alcohol, and 5 cc.
of this to be used. A small amount of permanganate is sufficient for
oxidation. The use of the permanganate in dilute solution is much
more satisfactory than the D. A. method (adding very small portions
of powder at intervals). This is a serious objection to the German
method, and in view of the fact as we noted above that the oxida-
tion as obtained by U. S. P. method gives enough formaldehyde to
react distinctly with Matthes’ reagent, the use of dilute permanganate
solution in small amount seems to be entirely safe.

LaWall, to whose comprehensive examination of the literature
and extensive experimentation the present process is due, found that
in ordinary application the delicacy is about I in 500. This is suffi-
cient for the routine work in connection with control of lawful and
unlawful traffic in alcoholic liquors. By distilling 10 cc. of the sam-
ple, collecting 1 cc. a delicacy of I in 10,000 may be reached, beyond
which it is of course not necessary to go.

The U. S. P. X process has been extensively used and has proved
satisfactory, but LaWall found that glycerol which is a not infre-
quent ingredient of factitious liquors, will simulate exactly the meth-
anol reaction. Distillation of the sample would seem to be the method
to eliminate this error, but Dr. Hepburn informed us that Dr. T. M.
Price, of the Department of Agriculture, had found that enough of
the glycerol or some decomposition product thereof will pass over to
simulate methanol with the fuchsin-sulphurous test. Potassium
guaiacolsulphonate, however, gives no reaction with the glycerol prod-
uct. In these tests we have used a solution containing 100 mg. of the
sulphonate in 10 cc. of sulphuric acid, which is more than double the
amount recommended by Matthes.

The German work recommends that the color test should be
made on a watch glass resting on a white surface, but Matthes states

586 Solubility of Sodium Salicylate in Alcohol {Am Jour. Hoasm.
that procelain dishes are much more satisfactory. We have found
this to be the case, but have also found that small porcelain crucibles
ere still more suitable. We have used those holding about 10 cc.
designated by dealers as No. oo. If the colorless liquid obtained
after addition of sulphuric acid in the U. S. P. test is distilled, col-
lecting about half the original volume, a still more marked color can
be obtained with Matthes’ reagent.

Summary

The substitution of potassium guaiacolsulphonate for guaiacol
is a marked improvement in the test for formaldehyde.

The test is a useful check on the fuchsin-sulphurous acid test,
serving especially to distinguish the glycerol from the methanol reac-
tion, preliminary distillation seeming not to be entirely safe for such
purpose.

The U. S. P. process for oxidation is accurate, delicate and con-
venient. The tedious piecemeal addition of powdered permanganate
as directed by the Deutsches Arzneibuch is unnecessary.

Research Laboratory,
Philadelphia College of Pharmacy and Science.

SOLUBILITY OF SODIUM SALICYLATE IN
ALCOHOL?

By W. Schnellbach

HE SOLUBILITY of sodium salicylate in alcohol as stated in

the U. S. P. X was recently questioned. The U. S. P. gives
the solubility as “I gm. of sodium salicylate in 9.2 cc. of alcohol at
25 degrees C.” The following experiments were made to settle the
question.

A mixture of U. S. P. alcohol and an excess of U. S. P. pow-
dered sodium salicylate was placed in a Pyrex test tube, tightly stop-
pered and constantly shaken by a mechanical stirring apparatus in a
water bath at a temperature of 25 degrees + 0.05 degrees C. After

* This investigation was conducted under the direction of Dr. George D.
Rosengarten in the Laboratory of the Philadelphia College of Pharmacy and
Science under a grant provided by the Board of Trustees of the U. S. Pharmaco-
poeial Convention.

f
t
i
C
t

a | Water Content of Strychnine Sulphate 587

four days a portion of the solution was withdrawn and quickly fil-
tered under precautions which avoided the volatilisation of the
solvent. An adequate portion of the solution was accurately weighed
in a weighing bottle, the alcohol evaporated and the residue finally
dried at 100 degree C. to constant weight.? After eleven days of
continued agitation two additional samples of the solution were with-
drawn and dried in the same manner. All three analyses yielded
the same result as indicated in the table below.

Gm. of Sodium

Time of Shak- Gm. of Solution Gm. of Residue Salicylate Present in
ingin Days Taken for Analysis Obtained 100 Gm. of Solution
4 5.1580 0.5890 11.74
II 2.2708 0.2666 11.74
II 1.8938 0.2160 11.74

Conclusion: 11.74 gm. of sodium salicylate are present in 100
gm. of an alcohol solution saturated at 25 degrees C. Therefore:
I gm. of sodium salicylate is soluble in 9.33 cc. (= 7.52 gm.) of
U. S. P. alcohol* at 25 degrees C.

This result is very close to the U. S. P. X statement.

DETERMINATION OF THE WATER CONTENT OF
STRYCHNINE SULPHATE

By W. Schnellbach

HE STRYCHNINE sulphate of the U. S. P. contains five mole-

cules of water of crystallization and it is required that it should

not lose more than II per cent. of its weight on drying at 100 degrees

C. The theoretical percentage of water of crystallization in strych-

nine sulphate pentahydrate is 10.57. The U. S. P. therefore permits
a small amount of “moisture” water.

? The original sodium salicylate lost on drying at 100° C. less than 0.1%, an
amount which may be safely ignored.

* The specific gravity of the alcohol used in this determination was 0.8176
-.™ corresponding to a density of 0.8083 25
15.5

1This investigation was conducted under the direction of Dr. George D.
Rosengarten in the Laboratory of the Philadelphia College of Pharmacy and
Science under a grant provided by the Board of Trustees of the U. S. Pharmaco-
poeial Convention.

=

588 Water Content of Strychnine Sulphate {Am Jour, Pharm.

The claim was made by a strychnine manufacturer that their
product contains 11.5 per cent. of water corresponding to five and
one-half molecules of water of crystallization. A check of the water
content of the commercial strychnine sulphate was therefore desir-
able.

First the literature was consulted. Beilstein mentions two modi-
fications of crystallized strychnine sulphate: a pentahydrate crystal-
lizing in monoclinic prisms, and a hexahydrate crystallizing in tetrag-
onal form, mostly in square octahedrons. Beilstein refers to the in-
vestigation of Rammelsberg,” who obtained from a hot solution thin
prisms containing 10.82 per cent. of water. From a cold saturated
solution which was allowed to evaporate slowly at room temperature
he obtained octahedrons, containing 12.77 per cent. of water. Both
results are close to the theoretical values of the pentahydrate and the
hexahydrate respectively, as may be seen from the following table:

Theoretical % H2eO

Modification Percentage Found
Pentahydrate 10.51 10.82
Hexahydrate 12.36 12.77

Samples of strychnine sulphate U. S. P. were procured from two
sources. They were designated A and B. Sample A was from the
regular stock of a well known chemical manufacturer. Sample B
was furnished by the firm which claimed their product contains five
and one-half molecules of water of crystallization.

Sample A consisted of thin, perfectly colorless needles of about
5 mm. average length. Some of the crystals were slightly effloresced.
Sample B was presented by two specimens: crystals (designated B
I) and powder (designated B II). The crystals, B I, consisted of
long, thick needles. Crystals 10 mm. long and more were quite nu-
merous. They were slightly discolored as compared with sample A.
Small crystals of cubic shape and slightly yellow color were also
observed in this sample. They were either loose or clinging to the
large crystals. These (the small cubic shaped crystals) could easily
be selected and were separately analyzed. The powder, B II, was
perfectly white and no particular crystalline form could be recognized
under the microscope. Later another sample of strychnine sulphate

* Berichte der Deutschen Chemischen Gesellschaft 14, 1231 (1881).

aaa

|

et Water Content of Strychnine Sulphate 589
(B III) was procured from the same firm. The crystals were color-
less and slightly effloresced. Crystals of square shape could not be
observed.

Sample A, which was provided in a larger quantity, was used
for many crystallization experiments under varying conditions. The
original sample is designated A I. A II was prepared by recrystal-
lizing a portion of A I in the following manner. About 4 gm. of
the sample were heated with 60 cc. of water and some decolorizing
carbon and the solution hot-filtered into an Erlenmeyer flask, which
was rapidly cooled under the running tap water with constant agita-
tion. The first crystals appeared when the solution had reached a
temperature of 27 degrees C. When the temperature fell to 25 de-
grees C. it remained constant until the excess of dissolved strychnine
sulphate had separated. The crystalline powder so obtained was col-
lected on a disc of filter paper in a Gooch crucible and the adher-
ing solution removed by suction.* The product was dried over sul-
phuric acid for about two hours and finally kept in a desiccator, con-
taining anhydrous strychnine sulphate, until costant weight was
obtained. The crystalline powder, when observed under the micro-
scope, appeared as square plates indicating the crystals to be of
tetragonal form.

A III was obtained by allowing a cold saturated solution to
evaporate spontaneously at room temperature in a beaker covered
with filter paper. This solution as well as the following were treated
with decolorizing carbon. Plate like crystals appeared in a few days
and grew to almost cubic form.‘

A IV was crystallized at 56 degrees + 1 degree C. It yielded
granular crystalline masses of no particular form.

A V was crystallized at 44 degrees + 1 degree C. The final
product consisted of crystalline masses which included considerable
amounts of mother liquor which could be seen under the microscope.
The analysis also yielded a higher percentage of water than was
expected.

The series of A IV to A IX was made to determine the limit-
ing crystallization temperature of the two modifications. The crystal-

*In many cases a high speed centrifuge was employed for this purpose. The
filter, containing the damp crystals, was placed in a weighing bottle on top of a
pledget of cotton and centrifuged.

*The tetragonal crystals are mostly of tabular development, showing very
prominent basal pinacoid, in combination with prism, consequently the hexahy-
drate always appears in (fairly thick) square plates.

590 Water Content of Strychnine Sulphate Jour,

lizations were made in a suction flask under vacuum, the flask being
immersed in a water bath. The temperature in the flask as well as
that of the water bath were constantly observed during the crystal-
lization, and they could be kept constant with + 1 degree C. The
temperature of the water bath had to be from 10 degrees to 15 de-
grees C. higher than that desired for the crystallization. All these
crystallizations yielded small but loose crystals. They were collected
and dried in the manner already described. The temperature of the
crystallization and the appearance of the product under the micro-
scope are shown in table A.

Analytical

The original samples A and B and all products obtained by re-
crystallization were analyzed by determining the water and the sul-
phuric acid. For the estimation of water a special apparatus > was
used which allowed the determination not only of the loss of weight
hut also the actual amount of water expelled on drying. For the
sulphuric acid the method of Winkler and Schulek * was employed.

Theoretical percentage of HzO and H2SOy in strychnine sul-
phate pentahydrate and hexahydrate.

Modification % H20 % H2SO4
Pentahydrate 10.51 11.45
Hexahydrate 12.36 11.21

Described subsequently.

* Zeitschrift fiir angewandte Chemie 33, I, 59-60, 159-160, 161-163 (1917).
See for description in details the paper on solubilities in the August issue of the
Journal of the American Pharmaceutical Association, 1929.

591

Sulphate

} Water Content of Strychr

Pharm.
1929

Am. Jour.
August,

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Am. Jour. Pharm.
August, 1929

Water Content of Strychnine Sulphate ,

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An, Jour. ot Water Content of Strychnine Sulphate 593
The water content of the sample A was in accordance with the
U. S. P. requirement. In the three samples B it varied between 11 and
12 per cent., confirming the claim of the manufacturer. The analyses
of the sample B I is of particular interest. This sample consisted,
as already mentioned, of needles and small square shaped crystals.
The latter form, suspected as representing the hexahydrate, was sep-
arated and analyzed. About 0.15 gm. were obtained from about 7
gm. of the material. The sulphuric acid found corresponded to some-
what more than six molecules of water of crystallization. The devia-
tion from the theoretical value may be due to the small quantity of
crystals analyzed thus introducing the possibility of a larger analyt-
ical error. The analysis of some of the largest needles present in
the sample B I, yielded a result corresponding to somewhat more
than five molecules of water of crystallization. This was probably
due to the small tetragonal crystals (hexahydrate) which under the
miscroscope were observed to cling to the needles (pentahydrate).

Summary

The determination of the water content in commercial crystal-
lized strychnine indicated that it may vary and will sometimes ex-
ceed the 11 per cent. allowed by the U. S. P. X.

On consulting the literature it was found that two crystalline
modifications of strychnine sulpnate, a pentahydrate (monoclinic)
and a hexahydrate (tetragonal) have been definitely known since
1881.

One specimen of crystallized strychnine sulphate, claimed by the
manufacturer to contain 11% per cent. of water of crystallization
(5%4 molecules), was found to consist of a mixture of the two hy-
drates.

A series of crystallizations was made at different temperatures.
In accordance with the statement, found in the literature,?° they
vielded the pentahydrate at temperatures above 40 degrees C. and
the hexahydrate below this temperature.

In recrystallizing strychnine sulphate at various temperatures no
form containing exactly five and one-half molecules of water of crys-
tallization was found. Preparations with a water contents deviating
from the theoretical values of the pentahydrate or the hexahydrate,
are considered to be a mixture of the two hydrates.

* Groth, Chemische Kristallographie (W. Engelmann, Leipzig, 1919), Vol.
V, page 971.

594 Water Content of Strychnine Sulphate {Am, Jour,

The apparatus used for the determination of the water in strych-
nine sulphate is shown in the accompanying sketch. The tared boat,
A, weighed with the chemical to be examined, is placed in a glass
tube, B, which is surrounded by a larger metal tube and through
which steam, generated in the flask, J, is passed. A slow stream of
air is conducted through the inner tube, B. The water escaping from
the chemical in the boat is absorbed in the U-tubes, D and E.** These

Figure 1—This photograph shows Strychnine Sulphate, Pentahydrate and Hexahydrate
(square plates) on the bottom of a beaker, natural size.

tubes were weighed before and after the completion of the experi-
ment. The same absorbing agent was used in the entire absorbing

4 After the first few experiments with calcium chloride as absorbent it was
found much more convenient to use a potassium bulb containing sulphuric acid.
In this case also sulphuric acid was used to dry the air before passing through
the tube, B.

|
Pe
\

nie. } Water Content of Strychnine Sulphate 595
train and all the tubes were kept at the same temperature during the
run of the experiment.

K is a constant-level device. A relatively wide tube, a, connects
the boiler, 7, with the water reservoir, K, furnishing the boiler with
water as it boils off. The tube a, must be of fairly wide size so that
steam or air is able to escape into the reservoir. The tubes, b and c,
are provided to permit filling of the reservoir without disconnecting.
To refill the apparatus the tube, a, is closed by a pinch cock, tube, b,
is connected with the suction pump and tube, c, is lengthened and

Figure 2

passed into a bottle of distilled water (the steam was condensed in a
bottle after passing the heating tube, C, and used to refill the reser-
voir). The suction pump is then turned on and the water sucked
into the reservoir, K. Both tubes, b and c, are closed again and the
pinch cock opened. The refilling can easily be done during the run
of an experiment.

%
|
3 on. &

596 Mercuric Iodide by Iodate Reactions {an i.

In determining the absorbed water by this apparatus a more re-
liable result is obtained than by simply drying the chemical in a dry-
ing oven, especially in cases of chemicals which, if dehydrated, rap-
idly absorb moisture from the air and therefore do not permit an
accurate determination of the loss of weight.

SUCTION

DETERMINATION OF MERCURIC IODIDE BY IODATE
REACTIONS*

By Frank G. Brockman, Ph. C.
Introduction

F THE various strictly chemical methods for the determination
of the purity of mercuric iodide none is of sufficient reliability
and simplicity to warrant its acceptance by the United States Phar-
macopeeial Revision Committee, with the result that the present
method is an electrolytic one. With this in mind the following work

*An abstract of the thesis presented to the Faculty of the Philadelphia Col-
lege of Pharmacy and Science as a partial fulfilment of the requirements for the
degree of Bachelor of Science and representing an investigation conducted in the
Analytical Chemistry Laboratory of the College.

| , 1929
|
|

Am, Jour Mercuric Iodide by Iodate Reactions 597
was carried out in an attempt to develop a practical, routine method
for the analysis of mercuric iodide, which would necessitate nothing
other than ordinary apparatus.

1. Oxidation by Potassium Iodate

George S. Jamieson, in a compilation’ of practical volumetric
methods using potassium iodate as the volumetric reagent, gives a
method for soluble iodides which consists in titrating the iodide di-
rectly in the presence of hydrochloric acid. The iodate first decom-
poses the iodide by the reaction:

5KI + KIO; + 6HCl = 6KCl + +

the reaction, in the presence of 12 per cent. or more of HCl, then
proceeds as follows:

ale + KIO; + 6HC1=KCI+ sICl + 3H,0.

Completion of the reaction is indicated by the discharge of the
color of the liberated iodine imparted to chloroform added near the
end of the reaction.

This method was applied to the insoluble mercuric iodide in the
following manner :

Transfer a sample of about 0.5 gm., accurately weighed, of
mercuric iodide to a 125 cc. glass stoppered bottle, add 20 cc. of
hydrochloric acid (1.16) and about one-half the calculated volume
of approximately fifth normal potassium iodate (i. e. for a 0.5 gm.
sample add 13 cc.). Stopper the bottle and shake vigorously. Again
add the volumetric solution but now more slowly, stopper and shake
the bottle thoroughly after each addition, until the mercuric iodide
has completely entered into solution. Up to this time about three-
quarters of the necessary volume of the volumetric solution will have
been required. Introduce five cc. of chloroform and continue titrat-
ing until the color imparted to the chloroform by the liberated iodine
is just discharged.

The results of some determinations carried out by this method
are tabulated below:

I cc. KIOgz v. s. 0.009367 gm. KIO;

= 0.01989 “

: * Volumetric Iodate Methods, Geo. S. Jamieson, The Chemical Catalog Co.,
nec.

598 Mercuric Iodide by Iodate Reactions eee room.

Weight Purity
KIOsv.s.
0.5012 gm. 25.08 cc. 99.53%
0.4998 “ 25.04 “ 99.65 “
0.3005 “ 15.10 “ 99.95 “
0.4012 “ 20.10 “ 99.65 “
0.4038 “ 20.24 “ 99.69 “
0.4017 “ 20.00 “ 99.03 “
0.5001 “ 25.00 “ 99.43 “
0.5124 “ 25.66 “ 99.60 “
0.4390 “ 21.96 “ 99.50 “
0.4916 “ 93 “ 100.05 “
0.5353 “ 26.81 “ 99.62 “
0.3597 “ 18.24 “ 100.80 “
0.5726 “ 28.60 “ 99.35 “
0.4795 “ 24.04 “ 99.72 “
0.3446 “ 17.20 “ 99.28 “
0.3485 “ 17.51 “ 99.93 “
0.3681 “ 18.42 “ 99.53 “

Average purity 99.62 per cent.,

Greatest deviations from this average + 1.2, —o.6.

It is the author’s conviction that the error of weighing is one
of the primary causes of the variable results of this method. The
difficult solubility of the mercuric iodide also made the process tedious
but the ready solubility of mercuric iodide in potassium cyanide solu-
tion, which was called to the attention of the author by Prof. Frank
X. Moerk, was considered worthy of investigation.

The results follow of 18 titrations of 10 cc. portions of a solu-
tion containing 7.2500 gms. of mercuric iodide and 3.68 gms. of
potassium cyanide in 200 cc. The process was in accord with the
previous directions.

1 cc. KIOgv.s. 0.010607 gm. KIO;

= 0.022523 “ Helo.

|
|

Am, Jour Mercuric Iodide by Iodate Reactions 599

Weight Purity
Hgl. KIOsv.s.
0.3625 gm. 16.02 cc. 99.54%
16.00 “ 99.41 “
16.05 “ 99.72 “
se 16.00 “ 99.41 “
15.97 “ gg.22 “
a 16.01 “ 99.47 “
16.00 “ 99.41 “
15.98 “ 99.29 “
15.97 “ g9.22 “
16.00 “ 99.41 “
16.00 “ 99.41 “
16.02 “ 99.54
16.00 “ 99.41 “
90 - 16.00 “ 99.41 “
16.00 “ 99.41 “
16.05 “ 99.72 “
16.00 “ 99.41

Average purity 99.41 per cent.

Greatest deviation from this average -+-0.3 per cent., —0.2 per
cent.

In order to show that the potassium cyanide did not react with
any of the iodate, two solutions, one of 3.68 gms. of potassium cyan-
ide in 200 cc. and the other of 5.2000 gms. of potassium iodide in
200 cc. were prepared. Three ten cc. portions of the iodide solution
were titrated with potassium iodate, factor 0.01063 gm. KIOs, by
the same method used for the mercuric iodide; and then three more,
but with ten cc. of the potassium cyanide solution added to each ten
cc. of the potassium iodide solution, before titration. There was no
effect to be noted due to the presence of the potassium cyanide as is
to be seen from the results:

}

Mercuric Iodide by Iodate Reactions { Am, Jour. Eharm.

KI Without KCN.

August, 1929

Weight Purity
KI KIOsv.s. KI
0.2600 gm 15.73 cc. 99.75%
15.70 “ 99.57
15.70 “cc 99.57
KI with KCN.
Weight Purity
KI KIOgv.s. KI
0.2600 gm 15-71 cc. 99.63 %

The results of this method were much more concordant than
those of the first and formed the basis of the following procedure:

2. Modified KIO; Method

Dry about 5 gms. of mercuric iodide to constant weight over
sulphuric acid, weigh accurately, transfer to a 100 cc. volumetric
flask, add 50 cc. of a 5 per cent. solution of potassium cyanide and
40 cc. of distilled water, dissolve by gentle agitation, dilute to accu-
rately 100 cc. and mix. Titrate a 10 cc. aliquot portion of the solu-
tion contained in a 125 cc. glass stoppered bottle, with fifth normal
potassium iodate, adding about half the necessary volume at once
(about 13 cc.). Then add 20 cc. of hydrochloric acid and 5 cc. of
chloroform. Continue titrating, stoppering and shaking the bottle
thoroughly after each addition of volumetric solution, until the color
imparted to the chloroform by the liberated iodine is just discharged.
Each cc. of fifth normal potassium iodate contains 0.01070 gm. KIO3
and corresponds to 0.02272 gm. of Hglo.

The following tabulation contains the results of twelve titra-
tions of different complete operations carried out according to the
above method.

6o0

Am. Jour. Pharm.
ge 1929 i Cacao Butter 601

1 cc. KIOgv.s. = 0.010627 gm. KIO3g
= 0.02257 “ Hglo.

Weight Purity
KIOsv.s.
0.5000 gm. 22.00 cc. 99.31%
22.02 “ 99.40 “
22.05 “ 99.53 “
22.06 “ 99.58 “
22.05 “ 99.53
va 22.05 “ 99.53 “
22.10 “ 99.76 “
“ 99.80 “
we 23.12 “ 99.85 “
22.05 “ 99.53 “
22.00 “ 99.31 “

Average purity 99.55 per cent.
Greatest deviation from this average +0.3 per cent., —0.2 per
cent.

CACAO BUTTER
By David Wilbur Horn and Arthur Osol *

HOCOLATE COATINGS, for confectionery, cakes, etc., are

distributed in the trade with little respect to geographical fac-
tors, although climate and season affect coatings considerably. Gen-
uine chocolate coatings for low temperature products (such as ice
cream bricks) offer serious problems. Such considerations some years
ago led one of us to the preparation on a small scale of an oleine
and a stearine from cacao butter. It is obvious that in modifying
coatings an autogenous oleine or stearine would be preferable to a
similar extraneous product such as one from the coconut. The oleine

* Many of the results in this paper are from work submitted by Arthur Osol
to the Philadelphia College of Pharmacy and Science in partial fulfilment of the
requirements for the degree of M. S.

1

and stearine from cacao butter were later prepared on a manufactur-
ing scale.

The object of the present paper is primarily to present the experi-
mental results obtained in the laboratory in comparison of this com-
mercial-scale oleine and stearine with cacao butter. At the same time
a comparison was made with cacao butter from liquor “Dutched” in
the nib.

Refractive Index

Our measurements were made on the Abbe refractometer with
heated prisms. This instrument is stated by Zeiss to give readings
“with a degree of exactness approaching to within about two units
of the fourth decimal.”

In the literature of the trade the scale readings on the Zeiss
butyro-refractometer at 40 degrees C. are usually given. Some of
these statements along with the corresponding refractive indices are
given.

TABLE I.
Limiting Corresponding
Trade Authority * Scale Readings Refractive Indices

Zipperer 46.0 to 47.8 1.4565 to 1.4578
Whymper 46.0 to 47.0 1.4565 to 1.4573
Bolton & Revis 46.0 to 47.5 1.4565 to 1.4576
Bolton & Revis,
“Typical Specimen” 46.7 1.4571
Allen 4th Ed. p. 702 46.0 to 48.0 1.4565 to 1.4580

In order to be able to form an opinion as to the probable value of
the refractive index of run-of-mill cacao butter known not to be so-
phisticated, measurements were made of butters produced under
widely varying conditions. The results are given in Table 2. Sam-
ples were taken from different presses of different types operating
upon the same and different liquors at such times as to include first-

*Zipperer, Die Schokoladen-Fabrikation, 3d Ed., p. 60. Whymper, Cocoa
and Chocolate, Chemisiry and Manufacture, p. 256. Bolton & Revis, Fatty
Foods, Practical Examination, p. 165. Allen’s Commercial Organic Analysis,
4th Ed., VI, p. 702.

Cacao Butter 603
runnings, middle portions and tailings from the presses, from liquors
made from one kind of bean and from many kinds blended, in winter
and in summer, at brief intervals and after long intervals, and from
tanks containing large accumulations of butters collected from gen-
uine liquors of many kinds. Finally cacao butters from various fac-
tories after varying lengths of time were examined. These results
ali appear in Table 2.

TABLE 2.
on No. of Kinds
Time of Nibs in R. I.
Date inMin. Press Liquor Liquor at 40° C. Location
1/26 ) 6 I 4 1.4571
go 5 I + 1.4571
105 6 I 4 1.4572
112 3 2 3 1.4571 Start
120 3 2 3 1.4571 Intermediate
127 3 3 1.4571
140 4 3 2 1.4573 Middle
148 4 3 2 1.4570 Near end
155 4 3 2 1.4571 Tailings
163 6 2 3 1.4571
170 3 + I 1.4571
178 2 2 3 1.4570
187 7 4 I 1.4572
190 Tank C3 1.4571
197 I 3 < 1.4572
2/2 oO 6 5 6 1.4571
5 4+ 4 I 1.4571
2/9 oO 4 6 4 1.4570
7 5 6 4 1.4571
14 2 5 6 1.4570
2! 3 5 6 1.4571
28 6 5 6 1.4570
2/16 O I 7 4 1.4571
13 2 7 4 1.4571
18 5 6 4 1.4571

_ *“C” means Composite, 1. €., made up of a mixture of cacao butters from
s1X Or more presses working on liquors No. 1 to No. 4, inclusive.

604 Cacao Butter

No. of Kinds
Time of Nibs in R. I. ‘
Date in Min. Press Liquor Liquor at 40° C. Location 1
26 3 6 4 1.4572
37 3 6 4 1.4571
2/26 fe) 5 8 4 1.4571
7 I 8 4 1.4571
18 2 8 4 1.4571
24 3 8 4 1.4570 |
32 5 8 4 1.4571 :
39 6 8 4 1.4571
53 Tank 8&7 6 1.4571 |
63 Tank 7 4 1.4570 (
6/10 oO 3 6 4 1.4572
7 5 6 4 1.4572
15 2 8 4 1.4572
25 2 8 4 1.4573
Factory Age of Sample Refractive Index
No. 1 Domestic 4 years 1.4573
No. 2. Foreign 3 years 1.4573
No. 3. Domestic I year 1.4572
No. 4 Foreign I year 1.4570

We believe these measurements justify the conclusion that run-
of-mill cacao butter (if pure) may reasonably be expected to show
2 refractive index at 40 degreec C. of 1.4571 = .o002. This agrees
with Revis and Bolton’s figure for their “Typical Specimen,” cited
in Table 1.

The four products which are primarily the subject of this paper
showed refractive indices as follows:

TABLE 3.
Pure cacao butter 1.4572 at 40 degrees C.
Commercial oleine of cacao butter 1.4579 “ “ = =
Commercial stearine of cacao butter 1.4580 “ “

Dutched cacao butter 1.4578 “

iat Cacao Butter 605

It is evident that all four products fall within the trade limits
set forth in Table 1, but that the oleine, stearine and Dutched butter
run higher in refractive index than does “typical” cacao butter.

Surface Tension

The surface tension at the surface between the melted substance
and air was determined with a du Noiiy Tensiometer by the ring
method. The differences in scale reading upon the four different
products were so slight as to leave doubt as to whether or not they
were significant.

Table 4 sets forth the results. They were obtained at 40 degrees
C., maintained pretty constantly in the fat by placing the fat in a
quartz dish mounted upon an “Electric Incubator for the Microscopic
Stage”—a thermostated device that was placed upon the adjustable
“table” of the du Noity apparatus. Between experiments, the plati-
num ring was washed in petroleum ether and then heated red hot in
the Bunsen flame.

TABLE 4.
Surface Tension
in Dynes
Article Scale Reading per Centimeter
Cacao butter 49.6 35-5
Oleine 49.1 35.2
Stearine 48.8 34-9
Dutched cacao butter 49.7 35-7

The greatest difference in surface tension among these products
is only 0.9 dyne per centimeter. We are not aware that the surface
tension of cacao butter has been measured before.

Viscosity

When we attempted to determine the viscosities of these four
products at 80 degrees C. in the Sayboldt Universal viscosimeter,
there was always more or less clogging of the outlet and satisfactory
results were not possible. In a Stormer viscosimeter it was possible
to make a comparison of these four products. The results are given
in Table 5. In column 5 of this table we also give the cane sugar
solution that we found to give the same result at 25 degrees C., as

it
}
=

606 Cacao Butter { fam, 5 Pharm.

the cocoa butter at 80 degrees C., in the Stormer viscosimeter. The
exact values were gotten by interpolation along a short curve obtained
by plotting seconds required for 100 revolutions of the drum of the
viscosimeter in 38, 40 and 42 per cent. by weight cane sugar solutions,‘

TABLE 5.

Secs. Re- Sucrose
quired for 100 No. of De- Average Sol. with

Revolutions at terminations Deviation Same Running

Article 80° C. (Average) Averaged (Secs.) Time (at 25° C.)
Cacao butter 21.8 8 +0.2 39.50%
Oleine 22.7 II +0.2 40.18%
Stearine 22.0 II +0.2 39.65%

Dutch cacao

butter 21.1 II 0.3 38.97%

Melting Point

Only by the use of the Wiley method was it possible to get con-
cordant results upon the melting points of these products.° Table 6
sets forth the results of several examinations and the average melting
point found in the case of each product. The determinations were
all made on small discs that had previously been kept in a cool place
more than twenty-four hours.

TABLE 6.
Average

Melting Pt.

Product Det.No.t Det.No.2 Det.No.3 Degrees C.
Cacao butter 33.4 33.0 33.2 33.2
Oleine 31.5 31.7 ease 31.6
Stearine 34.7 34.7 34.5 34.6
Dutched cacao butter 33.2 33.5 33.2 33.3

*See “Standard Substances for the Calibration of Viscometers,” Bingham
& Jackson, U. S. Bureau of Standards Scientific Paper, No. 208.

° The capillary tube method given for cocoa butter in the Official Methods
of Analysis of the Association of Official Agricultural Chemists gave results that
were very difficult to use. There was as great a difference as 6° found by this
method between the temperatures of incipient fusion and of complete fusion.
See Methods of Analysis of A. O. A. C., 2d Ed., pages 347 and 284.

ae t Cacao Butter 607

These measurements of melting point bring out clearly the char-
acteristic differences usually noted between a fat and its oleine and
stearine.

Specific Gravity

The specific gravities of the melted products were determined
by filling the pycnometer at 99 degrees C. with the fat and at 15 de-
grees C. with distilled water. The capacity of the pycnometer was
approximately 10 cc. Table 7 sets forth the average results obtained.

TABLE 7.
Average Wt. of Specific.
Article Fat in Pycnometer Gravity a
Cacao butter 8.5830 0.8572
Oleine 8.5827 0.8572
Stearine 8.5845 0.8574
Dutched cacao butter 8.5868 0.8576

No characteristic differences appear in these specific gravities.

Transition Point

The four products were subjected to a study as follows: The
melted fat was placed in a Dewar test tube, which was held firmly
in the center of a bath of water and ice. The fat was stirred con-
stantly with a thermometer and when its temperature had fallen
to 33 degrees C. or thereabout, the readings of the thermometer every
minute were written down. The results were then plotted, the tem-
peratures vertically and the time horizontally. In general the form
of the resulting graph is that of the root-sign of algebra VY. The
liquids gradually cool until they are undercooled as much as 5 to 10
degrees ; finally crystallization sets in accompanied by a gradual rise
in temperature. This rise continues to a maximum, which maximum
is maintained quite exactly to within 0.1 degree for a period (in our
experiments) of from 8 to 20 minutes. This temperature we have
called the transition point of the product. Table 8 sets forth the
transition points thus obtained.

i

608 Cacao Butter { Am. Jour. Pharm.

August, 1929

TABLE 8.

Transition Point

Product Set No. 1 Set No. 2 Average
Cacao butter 29.4 29.3 29.3
Oleine 27.9 27.8 27.8
Stearine 28.8 28.9 28.9
Dutched cacao butter 30.0 30.0 30.0

In order to make clear the procedure, we give the results and the
graph in one such determination. Table 9 is an abbreviated table of
results, omissions having been made whenever such omissions did not
change the path of the graph.

TABLE

Time Temp. Time Temp. Time Temp.
oO 32.5 32 29.1 46 30.0
6 28.9 34 29.6 47 30.0

I2 26.0 35 29.7 48 30.0
18 23.8 36 29.8 49 30.0
19 23-5 37 29.9 50 30.0
20 24.0 51 30.0
21 24.7 38 30.0 52 30.0
22 26.3 39 30.0 53 30.0
23 27.0 40 30.0 54 29.9
24 27.3 41 30.0 58 29.7
26 27.9 42 30.0 63 29.3
43 30.0
28 28.3 44 30.0 70 28.8
30 28.8 45 30.0 75 28.4

The transition points seem about as satisfactory as the melting
points by the Wiley method for bringing out the difference among
these four products.

Acidity
The acidity stated as milligrams of KOH required to neutralize

the acid in 1 gram of fat was determined in duplicate on all four prod-
ucts. Table 10 sets forth the results.

Am. Jour. Pharm. > a

TABLE I0.
Cubic
Centimeters
NaOH Mean
Product Weight Taken Required Acidity Acidity

Cacao butter 3.4232 1.50 2.49
2.6081 1.10 2.40 2.44

Oleine 3.1660 1.80 3.24
“ 3-2694 1.95 3-39 3-31

Stearine 2.1973 1.00 2.59
i 2.6103 1.20 2.62 2.60

Dutched cacao butter 2.1511 1.05 2.78
3.1074 1.55 2.84 2.81

5 ao 28 so 35 40 45 SO sS 6 65 7

“DUTCHED" COCOA BUTTER

The acidity value brings out a distinct difference between the
oleine and stearine, but the stearine differs in acidity from cacao but-
ter less than the Dutched cacao butter differs from cacao butter. To
what extent these acidity values may involve “rancidity” we are how-
ever unable to say.

August, 1929 = 609
3
32
26

610 Cacao Butter

Liquid Fatty Acids

The “lead salt ether” method was used, applied however only to
the oleine and stearine. Table 11 gives the results.

TABLE II.
Weight Weight of
Product of Fat Taken Acids Found Per Cent. Acids
Oleine 5.1495 1.9020 36.9
Stearine 5.0741 1.9206 37.8

The results are of no assistance in distinguishing these products.

Saponification Number and Unsaponifiable Matter

These values were gotten by the usual procedure, giving results
which would scarcely enable one to differentiate the four products.

TABLE I2.

Per Cent. of
cc. Saponi- Unsaponi-
Weight for Excess fication Average Weightof fiable
Product Taken NaOH #£Number S.N. Residue Matter

Cacao Butter 1.8168 13.20 194.68

ia - 2,1818 15.85 194.64 194.66 0.0157 0.76
Oleine 2.2166 16.10 194.61
- 2.2366 16.25 194.66 194.63
: 3.3206 0.0299 0.90
Stearine 2.0725 15.00 193.92
i 2.5350 18.30 193.42 193.67
2.2504 0.0209 0.93
Dutched C.B. 2.9278 21.32 195.01 0.0143 0.90
1.5878 11.50 194.03 194.52 0.0264 0.90

Iodine Number

The results of these determinations (made with Hanus’ solu-
tion) enable one to distinguish the oleine and stearine analytically
from the cacao butters.

|

|

Cacao Butter 6x1

TABLE 13.
Iodine Number Average Iodine
Product Weight Taken Found Number
Cacao butter 1.2183 37-74
I.1919 37-72 37-73
Oleine 0.3507 40.87
0.7195 41.51
0.4220 41.27
0.5422 40.45 41.02
Stearine 0.6984 38.60
0.6000 38.66
7 0.3049 38.90
a 0.5519 38.62 38.69
Dutched cacao butter 0.9912 36.95
1.9116 37.09 37.02
Summary

We have conducted comparative tests upon commercial samples
of cacao butter, cacao butter oleine, cacao butter stearine, and cacao
butter from “Dutched” nibs.

Although these four products are different, the differences lie
within the range of experimental error in our determinations of spe-
cific gravity of saponification number, of unsaponifiable residue and
of liquid fatty acids by the lead salt ether method.

The differences lie not far outside the range of experimental
error in our determinations of refractive index at 40 degrees C., of
surface tension at 40 degrees C., of viscosity (Stormer) at 80 de-
grees C.

Distinct indications of differences are brought out in our deter-
minations of iodine number (Hanus), of melting point (Wiley)
and of “transition point” and possibly also, of acidity.

We are not aware that “transition point” of fats and oils have
heretofore been determined ; we find the procedure simple and regard
it as well worth trying in other similar cases.

Our experiments show some change in the cacao butter in the
process of “Dutching,” > i. e., heating > with mixtures of carbonates
or hydroxides of the alkalis and alkaline earths, so that this cacao
Lutter is not exactly the same as pure cacao butter.

612 Medical and Pharmaceutical Notes {Am Jour. Harm.

MEDICAL AND PHARMACEUTICAL
NOTES

New Foop DyE Approved BY DEPARTMENT OF AGRICUL-
TURE—An additional food dye has been approved for inclusion in the
list of colors that will be certified by the United States Department
of Agriculture, according to a recent announcement by the Food,
Drug and Insecticide Administration.

This color, which will be known as Brilliant Blue FCF and which
has been known chemically for many years, has been tested both
chemically and physiologically and found to be harmless to health
and otherwise suitable for food use, according to the Federal food
officials.

CueEmIcALs No HEtp 1n Keepinc Cut FLowers—Placing cut
flowers in a bath of aspirin or other chemicals in an effort to pro-
long their life is useless according to this authority. Experiments
conducted at the Boyce Thompson Institute for Plant Research here
showed that none of fifty different chemicals, used in the hope of
increasing the life of cut flowers, were noticeably effective. Potas-
sium permanganate did prevent decay of the stems of phlox and
asters but it did not make the floral parts last any longer. Other
chemicals in some cases actually caused injury to the flowers.

Low temperatures were a great help in keeping roses, carna-
tions, and coreopsis, but the cold did not greatly benefit either cosmos
or dahlias. Humidity is also an important factor in keeping cut flow-
ers. Carnations kept two to three times as long in an atmosphere
which was nearly saturated with moisture.

AVERAGE LENGTH OF Lire DEcLINING—In spite of the efforts of
physicians and public health workers, and notwithstanding the proud
boasts of some of them, we are not living as long as men of earlier
generations and the average length of life is declining, Prof. C. H.
Forsyth of Dartmouth College has found. For the American adult,
the odds are at present heavily against his living as long as his father
or grandfather, Prof. Forsyth declares in a report in the forthcoming
issue of Science. The average American adult is in the midst of a

An Journ Book Reviews 613
decidedly losing fight which he cannot win until he applies himself
energetically to being superior to his environment.

Prof. Forsyth takes issue “with those who are so elated with
results obtained in their own immediate fields leading to significant
reductions not only in certain death rates but also in the prevalence
of certain diseases that they feel justified in predicting marvelous
increases in the average length of the whole of life in the no great
future.”

“Most of these optimistic authorities have failed to appreciate
that practically all these results have been attained in children’s dis-
eases and that little or no attention has been given to the situation
at ages beyond the prime of life,” stated Prof. Forsyth.

The expectation of life at advanced ages, that is, the number
of years that a man of fifty, for example, may expect to live, is defi-
nitely declining, Prof. Forsyth found from his exhaustive study of
many mortality tables and population statistics.

“The expectation of life from age forty-five or fifty on is the
lowest of which we have any record-—far lower than it was even forty
years ago—and it is still going down, not up,” Prof. Forsyth de-
clared. “With all the improvement in the world at the early ages,
the present downward trend at the advanced ages, if unchecked, will
continue to dominate and produce a greater and greater net decline
in the average length of life-—Science Service.

BOOK REVIEWS

Botany, by William J. Robbins and Harold W. Rickett. Van Nos-
trand Co., New York, 1929. 535 pages-—382 illustrations, 101
book references. Net price $3.75.

In twenty-seven chapters we find an interesting discussion of
cells and tissues, their contents, growth and function, of origin and
meaning of life, relations, energy of representative groups of lower
and higher plant life, their vegetative and sexual life cycle inheritance,
evolution and distribution.

In spite of the “many excellent textbooks available on botany
allied subjects,’ as the authors admit, they have prepared the elab-
orated course of lectures, given at the University of Missouri, in an

> Am. Jour. Pharm.
614 Book Reviews ‘August, 1929

attempt “to present the fundamental biological principles rather than
to lay the foundation for professional botany, and to give “a correct
idea of the true nature of the aim of science its methods of work,
and the value and limitations of its results.”

To illustrate the author’s treatment we quote from the chapters
of reactions of plants. “Teleology is a very human point of view
and we do many things with purpose; and we assume that the things
which a plant or animal does are also caused by purposes . . . It
must be emphasized that science cannot deny the possibility that plants
have wills and purposes, and that they govern its life, or that there is
some all-knowing Power directing their activities. Teleology may
represent, for all we know, the truth; but it is unscientific nevertheless,
because it assumes things for which there is as yet no evidence in
the sense of observable or demonstratable facts. Therefore we must
avoid it in Biology—the scientific consideration of life. We must
give as reasons for structures and function only known causes; and
we must be prepared, when we cannot find the cause, frankly to admit
our ignorance—and to go on looking for one.”

Curiously we find no references to lignin, so characteristic of all
woody tissue, of hemicellulose, mucilage and the cellose of sieve tubes.
We also feel with regret, that bio-chemistry and bio-physics have not
been given more place as they form such an integral part of modern
biological science.

Appended is a questionnaire of over 500 questions for review
and discussion which will prove helpful to the student who all too
frequently is at a loss to formulate his own questions and to deter-
mine the extent of his understanding and knowledge.

The book will prove suggestive to the teacher of botany or biol-
ogy—and be welcomed by students of plant life.

ARNO VIEHOEVER.

THE PHARMACEUTICAL REcIPE Book.

Over eighteen years have elapsed since the Committee on the
Recipe Book of the American Pharmaceutical Association was ap-
pointed to consider the advisability of the Association publishing a
druggists’ recipe book. While the committee labored long to do the
work allotted to it, it also labored well and faithfully to bring into
being a book that reflects great credit to the Association as well as to
the committee itself.

Jour Book Reviews 615

The first edition of the Pharmaceutical Recipe Book embodies a
list of formulas of preparations not published in any other official
publication. That there was a keen need for such a book goes with-
out saying. Scattered throughout the literature of medicine and
pharmacy were many valuable remedial preparations, for which phar-
macists were constantly receiving demands, without having access to
any reliable source for supplying these demands. Now all this is
altered. As time goes on, this book will, we believe, become almost
as necessary to the practice of pharmacy as the National Formulary.

The comprehensiveness of the matter embodied in the book will
undoubtedly appeal to all types of pharmacists. Retail pharmacists,
hospital pharmacists, and laboratory workers will find much to aid and
stimulate them to endeavor in their particular branches of pharmacue-
tical work. We believe that, as time goes on, the value to pharmacy
in general, of having an authentic reference book, of matter of inter-
est to the different branches of pharmacy, will be more clearly per-
ceived and appreciated by the profession.

Pharmacy today is confronted with a spirit of competition which
is sharper than ever, arid made doubly so because it comes from many
directions. How to meet that competition and survive is the problem
of the average pharmacist. Of course, he is a professional man,
trained along scientific lines, but no matter how well trained, he is
bound to fail if he does not know how to capitalize his professional
training by sound business sense. Indeed, business itself is a science.
No professional man, no matter how great his ability, be he clergyman,
physician, lawyer, etc., can bring complete service to those he would
serve, if he neglects to study how best to direct notice to his wares
and to his ability.

In the Recipe Book there is material galore, with which the phar-
macist can direct the attention of the medical profession toward him-
self. The average physician is always on the lookout for prescrip-
tions and new ways of prescribing the well-known remedies. In that
part of the book, devoted to hospital formulas, the pharmacist will
find much that should interest the physicians whom he serves, pro-
vided he has learned how to give information without giving offense.

The physician takes kindly to any prescription or formula that
claims the distinction of having originated in some hospital of stand-
ing and reputation. He knows, and the writer would emphasize this
point, that such formulas are the result of long, practical experience.

616 Book Reviews

Twelve of the great hospitals of the country are aes in this
collection of hospital formulas.

Another department of the Recipe Book that should be of value
to the pharmacist, in his endeavor to serve the medical profession, is
that devoted to laboratory reagents. Many physicians do some lab-
oratory work, and who should be better qualified to sell them the
necessary reagents and stains to carry out clinical tests than the neigh-
boring pharmacist. The chapter on laboratory reagents contains
much that the pharmacist could profitably utilize.

Under the heading, “Pharmaceutical Formulas,” one hundred
and ninety pages embrace a variety of formulas that the pharmacist
could, with perfect propriety, bring to the attention of his medical
friends. Ten pages are devoted to ampuls, formulas for various
solutions of drugs that are best administered in this manner, and a
brief but clear description of the technic involved in the sterilization
of ampuls. If the retail pharmacist can convince his medical clientele
that he is equipped and able to prepare extemporaneous solutions in
ampul dosage form, he will, undoubtedly, find a ready response. Hypo-
dermic medication is becoming increasingly popular ; the Recipe Book
helps to meet this demand.

Under the heading, “Surgical Dressings,” information, pertain-
ing to the preparation of medicated cotton and medicated gauze, is
presented briefly but clearly. While it may be true that the average
retailer rarely has occasion to prepare these, such things being gen-
erally supplied by the large manufacturers of surgical supplies, he
should know how such surgical material is prepared and have ready
access to information on the subject.

To the retail pharmacist who wishes to cater to the “cosmetic
urge,” the chapter on cosmetics presents many inviting opportunities
for profit. Never before in the history of the world has the weaker
sex been so interested in the things that will enhance beauty.

In certain localities, veterinary remedies are needed and who,
other than the pharmacist, should or could be better equipped by
training and experience to take care of such needs? The same can
be said in reference to the needs of photography. The material in
the Recipe Book covering photographic work is most comprehensive.

It has always been a cause of wonder to the writer as to why the
pharmacist fails to go after the flavoring extract business. The
profit is more than good. And if the pharmacist would call to the

”

r. Pharm.
|
i

ie t Book Reviews 617
attention of his housewife customers the fact that he not only sup-
plies all kinds of flavoring extracts, but makes all that he supplies
as well, he surely would add to his prestige. It should not be hard
to convince such customers that flavoring extracts from the “drug
store” are far superior to those from the grocery store. The Recipe
Book, then, gives information on the subject of flavoring extracts
that certainly should enable the pharmacist to absorb a large share
of this business.

Part Nine of this really useful book contains, under the title,
“Technical and Miscellaneous Formulas,” a variety of recipes on such
subjects as Cements, Fumigators and Deodorants, Inks, Insecticides
(how best to exterminate the Japanese beetle), Fly Exterminators,
laundry Accessories, Moth Preparations, Paints and Lacquers, Fur-
niture Polishes, Ebony Stain for Wood, Fertilizers for Potted Plants,
Anti-Freeze Mixtures and so-forth.

In a number of states the law requires that factories and work-
shops be equipped with “First Aid” outfits. The Recipe Book de-
scribes in detail what such an outfit should contain. The kinds of in-
struments, the different drugs, and dressings are all mentioned.

A careful perusal of the Recipe Book will convince anyone that
the pharmacist who neglects to add this book to his reference library
is most certainly cheating himself.

Joun K. Tuum, Ph. M.
Lankenau Hospital, Philadelphia.

ENGLER-PRANTL. DrE NATUERLICHEN PFLANZENFAMILIEN (The
Natural Plant-Families)—2nd Edition, 1928, 447 illustrations.

In this new volume of the remarkable well-known series, Linde-
mann discusses the peridinez (dinoflagellates), Karsten the diatomes,
and, Jahn the slime molds (myxomycetes).

Lindemann first mentions an elaborate list of references, then
the characteristics, the vegetative organs, the biology, occurrence, gen-
eral position and relationship and concludes with the statements that
fossil (silicified) forms occur in certain firestones, that they and the
diatoms represent the main food of the sea and that certain forms
may grow so abundantly as to cause pollution and death of other
animals. Surprisingly, no statement is made of their occurrence and

Am. Jour. Pharm,
618 Book Reviews eae

usefulness and their clearing of polluted waters, such as originates
from sewage-disposal plants.

Karsten, before treating in detail the main‘ representatives, cites
the literature, general characteristics, occurrence, morphology, physiol-
ogy, their migration with sea currents, and the usefulness of the fos-
sil forms as diatomaceous earth, of the living forms as fish food.

Jahn, discussing the slime molds, enumerates literature, charac-
teristics, occurrence, morphology, physiology, distribution, history, and
the harm that may occur to germinating plants in seed beds, to wet
meadow grasses and moist hay, due to the development of common
slime molds.

The volume is another testimonial to the scientific workmanship
exhibited in this series.

ARNO VIEHOEVER.