When this test was applied to the three specimens under examination,

the Merck and Heyden specimens complied, while the Research Council

specimen did not comply, with this requirement.

_Method 1._--About 1 gm. of bismuth tribromphenate was placed in a

flask, 20 c.c. of 95 per cent. alcohol added and shaken for fifteen

minutes, after which it was filtered by suction through a Gooch filter

into an Erlenmeyer flask. The flask was rinsed with 10 c.c. of alcohol

and finally the filter was washed with 10 c.c. of alcohol, 25 c.c.

of tenth-normal sodium hydroxid solution were added to the alcoholic

filtrate (which was nearly but not perfectly clear) containing the

tribromphenol, and the residual alkali titrated with tenth-normal

hydrochloric acid.

The number of cubic centimeters of tenth-normal alkali consumed

multiplied by 0.331 gave the weight of tribromphenol (Table 3).

TABLE 3.--DETERMINATION OF FREE TRIBROMPHENOL

Gm. Tribromphenol

Calculated from Per Cent.

Gm. of Theoretical Free

Salt Taken Factor Tribromphenol

Research Council Spec. 2.3351 0.3806 16.31

Merck & Co. 0.7980 0.0364 4.56

Heyden Chemical Works 1.9460 0.0132 0.68

_Method 2._--About 2 gm. of bismuth tribromphenate were placed in a

glass stoppered Erlenmeyer flask, 100 c.c. of alcohol were measured in

and shaken during one-half hour and allowed to stand over night. Fifty

c.c. of the supernatant liquid were then removed by means of a pipet,

a slight excess of tenth-normal sodium hydroxid added and the residual

alkali titrated with tenth-normal HCl.

Table 4 gives results obtained.

TABLE 4.--PER CENT. OF TRIBROMPHENOL BY METHOD 2

Gm. Tribromphenol

Calculated from Per Cent.

Gm. of Theoretical Free

Salt Taken Factor Tribromphenol

Research Council Spec. 2.0712 0.3905 18.85

Merck & Co. 1.9417 0.0760 3.92

Heyden Chemical Works 2.0440 0.0198 0.97

Table 5 gives a comparison of the results obtained by the two methods.

TABLE 5.--COMPARISON OF RESULTS BY METHODS 1 AND 2

Method 1 Method 2

Research Council Spec. 16.31 18.85

Merck & Co. 4.56 3.92

Heyden Chemical Works 0.68 0.97

The results obtained in Method 1 (the percolation method) apparently

are reliable and, as the method is the more simple, may be given

preference.

COMBINED TRIBROMPHENOL (TRIBROMPHENATE)

The amount of tribromphenol existing in the specimen in combination was

calculated by subtracting from the per cent. of total tribromphenol

determined, the per cent. of free tribromphenol found by Method 1.

The figures obtained are given in Table 6.

TABLE 6.--THE TRIBROMPHENATE CONTENT OF BISMUTH TRIBROMPHENATE

Per Cent. of

Combined

Tribromphenol

Research Council Specimen 43.13

Merck & Co. 53.19

Heyden Chemical Works 20.36

SUMMARY

From the foregoing the specimens examined contain the percentages

shown in Table 7 of bismuth (Bi), combined tribromphenate and free

tribromphenol.

TABLE 7.--PERCENTAGES OF BISMUTH AND OF COMBINED TRIBROMPHENATE AND

FREE TRIBROMPHENOL

Per Cent. Per Cent.

Per Cent. Combined Free

Bismuth Tribromphenate Tribromphenol

Research Council Specimen 44.8 43.13 16.31

Merck & Co. 46.6 53.19 4.56

Heyden Chemical Works 60.7 20.36 0.68

This examination shows:

1. The Bismuth Tribromphenolate submitted to the Council of

National Defense, does not correspond to the description of bismuth

tribromphenate in New and Nonofficial Remedies.

2. As now supplied, Xeroform-Heyden does not meet the requirements for

bismuth tribromphenate, nor does its composition correspond to that of

the product formerly supplied.

3. The description in New and Nonofficial Remedies of bismuth

tribromphenate should provide an upper, as well as a lower, limit

for the bismuth content; it should provide tests for the absence

of adulterants, and also set a limit of permissible uncombined

tribromphenol.

Report to Council of National Defense

The results of this examination with reference to the Research

Council specimen having been submitted to the Council on Pharmacy and

Chemistry, this body advised the Medical Section of the Council of

National Defense as follows:

1. The specimen of “Bismuth Tribromphenolate” sent to the Council

of National Defense complies with the New and Nonofficial Remedies

description for bismuth tribromphenate, except that it contains

considerable amounts (approximately 16 per cent.) of alcohol-soluble,

uncombined tribromphenol.

Revision of N. N. R. Standards

The results of the examination of the three specimens were sent

to the Heyden Chemical Works and to Merck and Co. (in each case

disclosing the identity of the particular firm’s product), asking

aid in the standardization of the product. After Merck and Co. had

submitted valuable advice for a revision of the somewhat loosely drawn

standards for bismuth tribromphenate in N. N. R., 1918, the inquiry

whether the following proposed revision of the description of bismuth

tribromphenate in New and Nonofficial Remedies was acceptable, was

submitted to both firms:

=BISMUTH TRIBROMPHENATE.--Bismuthi Tribromphenas.--Bismuth

Tribromphenol.--Xeroform.=--A basic bismuth tribromphenate of variable

composition.

An amorphous, yellow, nearly odorless and tasteless powder, neutral

to moistened litmus paper.

It is only slightly soluble in water, alcohol, chloroform, liquid

petrolatum and vegetable oils. Alkalies and strong acids decompose

it. It is stable at temperatures below 120 C.

When about 1 gm. of the salt is boiled with 10 c.c. of sodium

hydroxide test solution, the liquid filtered, and the filtrate

acidulated with sulphuric acid, the white curdy precipitate produced,

when washed and dried, melts at 90 to 95 C. (_tribromphenol_). The

contents of the filter dissolve completely in dilute hydrochloric

acid (insoluble _inert material_).

Boil 1 gm. of bismuth tribromphenate with 20 c.c. of a mixture of

equal parts of acetic acid and distilled water, cool the solution and

filter. Free the filtrate from bismuth by the addition of hydrogen

sulphide, boil the mixture and again filter. The latter filtrate

leaves not more than 0.005 gm. of residue on evaporation and gentle

ignition (_alkalies and alkali earths_).

Shake for one minute in a separatory funnel, 2 gm. of bismuth

tribromphenate, 20 c.c. of ether, and 20 c.c. of a mixture of

equal volumes of hydrochloric acid and distilled water. Draw off

the aqueous portion and concentrate to about 4 c.c.; pour it into

100 c.c. distilled water, filter, evaporate the filtrate on the water

bath to 30 c.c., again filter and divide this filtrate into portions

of 5 c.c. each. Mix one portion with an equal volume of dilute

sulphuric acid; it does not become cloudy (_lead_). Treat another

portion with a slight excess of ammonia water; the supernatant liquid

does not exhibit a bluish tint (_copper_). Another portion is not

immediately affected by barium nitrate test solution (_sulphate_).

Heat gently a mixture of about 0.2 gm. of bismuth tribromphenate

with 5 c.c. of potassium hydroxide test solution and about 0.2 gm.

of aluminum wire; the vapors evolved do not turn red litmus blue

(_nitrates_).

Shake 1 gm. of bismuth tribromphenate frequently during fifteen

minutes with 30 c.c. of alcohol (95 per cent.), filter and rinse

flask with two separate 10 c.c. portions of alcohol, allowing the

washings to run through filter. To the combined filtrate and washings

add 20 c.c. of tenth-normal sodium hydroxide and a few drops of

phenolphthalein solution and determine the excess of alkali with

tenth-normal hydrochloric acid. Not more than 1 c.c. of tenth-normal

sodium hydroxide should have been consumed by the alcoholic liquid

(_free tribromphenol_).

Add 2 c.c. of nitric acid to 2 gm. of bismuth tribromphenate in a

porcelain crucible, carefully evaporate to dryness on a sand bath

and incinerate. Dissolve the residue in 5 c.c. of concentrated

hydrochloric acid and add to the solution 10 c.c. of a saturated

solution of stannous chloride in concentrated hydrochloric acid. The

mixture should not darken on standing thirty minutes (_arsenic_).

Mix 0.5 gm. of the salt with 10 c.c. of a mixture of equal parts of

hydrochloric acid, U. S. P., and distilled water. No effervescence

should occur (_carbonate_).

To about 0.5 gm. of bismuth tribromphenate, accurately weighed, add

20 c.c. of hydrochloric acid and digest on water bath. Add 150 c.c.

of distilled water and filter. Rinse the beaker with 30 c.c. of

distilled water and allow the washings to run through the filter.

Saturate the combined filtrate and washings with hydrogen sulphide,

filter off the bismuth sulphide, wash and dissolve in hot dilute

nitric acid. Add a slight excess of ammonia water followed by 2 c.c.

of ammonium carbonate test solution. Allow to stand thirty minutes,

filter off the precipitated bismuth hydroxide and heat to constant

weight at dull red heat. The residue of bismuth oxide (Bi₂O₃) should

not be less than 45 per cent. nor more than 55 per cent. of the

original weight of bismuth tribromphenate taken, corresponding to not

less than 40 per cent. nor more than 49 per cent. of bismuth.

The Heyden Chemical Works accepted the proposed monograph. Regarding

the Laboratory’s findings, the firm stated that “the product had to be

made in this country after importations from Europe became impossible

and the first lots were not fully up to the standard.” Later the firm

stated that it could furnish a product which it considered equal to

that which was previously imported and offered to submit “samples of

the new material.”

Merck and Co. acknowledged the receipt of the monograph but made no

statement as to its acceptance or suggestions for its revision. As the

new monograph was accepted by the Heyden Chemical Works and as Merck

and Co. offered no objections, it was adopted for N. N. R., 1919, by

the Council on Pharmacy and Chemistry.

In November, 1918, Merck and Co. sent a specimen labeled “Bismuth

Tribromphenate-Merck,” “Merck and Co., New York, Distributors and

Guarantors” and wrote: “You will notice this sample conforms in nearly

all details to the tests submitted with our letter of June 4. We have

been able to produce better goods, but just at present unsatisfactory

starting material confronts us.”

Examination of the specimen demonstrated that it was soluble to a

considerable extent in alcohol (the N. N. R., 1918, description

provides that it should be only slightly soluble in alcohol) and,

according to the standards adopted for New and Nonofficial Remedies,

1919, contained 18 per cent. of uncombined tribromphenol (more than

five times the permitted amount).

In December, 1918, Merck and Co. submitted another specimen and said:

“We believe this is a better grade than we have been able to make in

the recent past. It seems to meet all the tests for N. N. R., 1919,

with two exceptions: these are (a) solubility in alcohol, and (b) the

test for uncombined tribromphenol.{”}

When the two recent samples of bismuth tribromphenate-Merck and two

samples of Xeroform-Heyden were examined according to the new monograph

the results given in Table 8 were obtained.

TABLE 8.--EXAMINATION OF TRIBROMPHENATE AND XEROFORM

1. BISMUTH.

Weight of Per Cent.

Weight Bi₂O₃ of

Brand and Date Received Taken, Obtained, Bismuth,

Gm. Gm. Gm.

Xeroform-Heyden (from mfr.) July, 1918 0.6754 0.3565 47.2

Xeroform-Heyden (open market) July, 1918 0.8259 0.6156 66.7

Bismuth tribromphenate-Merck Nov., 1918 0.4882 0.2512 46.1

Bismuth tribromphenate-Merck Dec., 1918 0.8869 0.4495 45.5

2. UNCOMBINED TRIBROMPHENOL.

No. C.c. Per Cent.

Weight of Tenth- of Free

Brand and Date Received Taken, Normal NaOH Tribrom-

Gm. Consumed, phenol

C.c.

Xeroform-Heyden (from mfr.) July, 1918 1 7.4 24.5

Xeroform-Heyden (open market) July, 1918 1 0.7 2.3

Bismuth Tribromphenate-Merck Nov., 1918 1 5.7 18.8

Bismuth Tribromphenate-Merck Dec., 1918 1 5 16.5

In view of the laboratory’s report the referee of the Council on

Pharmacy and Chemistry in charge of bismuth tribromphenate recommended

that the acceptance of Xeroform-Heyden and bismuth tribromphenate-Merck

be withdrawn, but that this should be without prejudice to their

reinstatement when satisfactory products are again offered for sale.

The Council adopted the recommendation of the referee and accordingly

Xeroform-Heyden and bismuth tribromphenate-Merck are omitted from New

and Nonofficial Remedies, 1919.

When the laboratory’s findings with regard to Xeroform-Heyden and the

action of the Council deleting the article from New and Nonofficial

Remedies was reported to the Heyden Chemical Works, the firm expressed

regret that efforts to produce a product equal to that formerly

obtained from Germany had so far not been successful and announced

that it had decided to withdraw Xeroform-Heyden from the market for

the present. When Merck and Co. was advised in regard to the report

of the laboratory and Council’s action, this firm questioned the

feasibility of producing a product meeting the Council’s standards and

suggested that the test for free tribromphenol be revised to permit

as much as 15 per cent. of this constituent. When Merck and Co. was

reminded that its product submitted in 1915 essentially complied with

the adopted standards (an old sample of Xeroform-Heyden was also found

to comply) and that the estimate of the therapeutic value of bismuth

tribromphenate is based on a product essentially devoid of free

tribromphenol, the firm replied:

“As stated in our letter of the 12th inst., we do not wish to market

the chemical unless it meets all legitimate requirements of the

physicians that use it. If, therefore, your standard proves to be good

and it is commercially possible to make supplies conforming to it, we

shall do so. We shall discontinue the article unless it is of suitable

quality.”--(_From Reports A. M. A. Chemical Laboratory, 1918, p. 93._)

THE STANDARDIZATION OF PROCAIN AND EXAMINATION OF THE MARKET SUPPLY

Procain, which chemically is the mono-hydrochlorid of

para-amino-benzoyldiethyl-amino-ethanol, is the nonproprietary name

selected by the Federal Trade Commission as the official designation

for the drug previously known under the proprietary name “novocaine.”

Before the war procain was obtainable in this country only through

the Farbwerke Hoechst Co., the American representative of the German

establishment, Farbwerke, vorm, Meister, Lucius and Bruening, under

the name “novocaine.” This monopoly on “novocaine” was exercised by

virtue of United States patent No. 812554, which was issued to Alfred

Einhorn, Munich, Germany, assignor to Farbwerke, vorm, Meister, Lucius

and Bruening, Hoechst a. M., in 1906. With the outbreak of hostilities,

Congress passed the Trading with the Enemy Act, and under this, the

Federal Trade Commission took charge of the novocain patent with a

view of securing the production of this product in the United States.

To ensure an adequate supply of the drug, the Federal Trade Commission

on recommendation of the Committee on Synthetic Drugs of the National

Research Council, in addition to issuing a license to the Farbwerke

Hoechst Company (which license was later transferred to the H. A. Metz

Laboratories) granted authority to the Abbott Laboratories and the

Rector Chemical Company to manufacture it under the U. S. patent after

specimens submitted by these firms had been found satisfactory in the

Association’s laboratory and at the Cornell Pharmacologic Laboratory.

When the first specimen of American made procain was sent to the

American Medical Association Chemical Laboratory it was necessary to

work out adequate standards. The standards were formulated on the basis

of the novocain monograph in the German Pharmacopeia, 1910, Ed. 5,

p. 363, Remedia “Hoechst,” p. 242, and New and Nonofficial Remedies,

1918, p. 32, and the work carried out in this laboratory.

The following description has been adopted for New and Nonofficial

Remedies, 1919, and all specimens of procain were subjected to these

tests:

Procain occurs in small colorless and odorless crystals, or a

crystalline powder which if placed on the tongue produces a transient

sense of numbness.

It melts at 153-155 C.[212]

[212] U. S. patent number 812,554--the novocain patent--declares

that the salt melts at 156 C. Evidently based on this, the German

Pharmacopoeia Remedia “Hoechst” and past editions of New and

Nonofficial Remedies give this melting point. Two specimens of German

made novocain obtained from our files, stated to be manufactured by

Farbwerke-Hoechst vorm. Meister, Lucius and Bruening, Hoechst a.M.

were found to melt, respectively, between 154 and 155 C. and between

153.5 and 154.5 C. when the melting point was determined according to

the directions of the U. S. Pharmacopoeia, 9th revision. The various

specimens examined at that time melted between 153 and 155 C. and it

was decided to permit this range.

One gm. of procain is soluble in 0.7 c.c. of water and in 20 c.c. of

alcohol U. S. P. (95 per cent.) at 20 C. From the aqueous solution,

which is neutral, alkali hydroxids and carbonates precipitate the

free base in the form of a colorless oil, which soon congeals to a

crystalline mass, but solutions of sodium bicarbonate are miscible with

solutions of procain without producing precipitations or turbidity.

Dissolve 1 gm. of procain in water. Separate portions of the solution

yield a white precipitate with potassium mercuric iodid solution,

a white precipitate with mercuric chlorid test solution, a brown

precipitate with iodin test solution and a yellow precipitate with

picric acid test solution. Acidify a portion with dilute nitric acid.

A white curdy precipitate is thrown down on the addition of silver

nitrate test solution.

Dissolve about 0.1 gm. of procain in 5 c.c. of water, add 2 drops of

dilute hydrochloric acid and 2 drops of sodium nitrite solution (10 per

cent.) and mix with a solution of 0.2 gm. of betanaphthol in 10 c.c. of

sodium hydroxid solution (10 per cent.). A scarlet red precipitate is

thrown down.

To a solution of about 0.1 gm. of procain in 5 c.c. of water add 3

drops of dilute sulphuric acid and mix with 5 drops of potassium

permanganate test solution. The violet color of the latter disappears

immediately (distinction from cocain).

Dissolve about 0.1 gm. procain in 1 c.c. sulphuric acid U. S. P. The

solution is colorless (organic impurities).

Dissolve 0.1 gm. of the salt in 10 c.c. of water and saturate with

hydrogen sulphid. No coloration or precipitation occurs (salts of the

heavy metals).

Incinerate about 0.5 gm. of procain accurately weighed. Not more than

0.1 per cent. of residue remains.

To obtain specimens representing the market supply, orders for the

three brands of procain were placed with pharmaceutical firms in New

York, Baltimore and San Francisco. The Baltimore and San Francisco

firms supplied specimens of procain-novocain brand and procain-Rector

brand but reported that the Abbott brand was not procurable. The

New York correspondent was able to supply procain-Rector only. As

the entire output of the Abbott Laboratories was stated to go to

the government, specimens of this product were obtained through the

surgeon-general of the army from the general purchasing office, Medical

Dept., U. S. Army. The following specimens were obtained and examined:

_1. Procain-Abbott, 6 specimens:_ The first specimen bore no serial

number but the five later specimens were designated respectively, No.

89999, No. 89998, No. 89997, No. 89996, and No. 810995, representing

batches from which shipments are to be made on contracts placed by the

general purchasing office, Medical Department, U. S. Army, with the

Abbott Laboratories of Chicago.

_2. Procain-novocain brand, 4 specimens:_ These were designated

respectively, A56, A57, A63, and A67. The first two specimens were

labeled “Manufactured by the Farbwerke-Hoechst Co. at the H. A.

Metz Laboratories.” The third specimen (not in original container)

was labeled “H. A. Metz Laboratories” and the fourth was marked

“Manufactured by the H. A. Metz Laboratories.”

_3. Procain-Rector, 3 specimens:_ Each bore the statement “Manufactured

by the Rector Chemical Company” but had no “lot number.”

From this examination it appears that all the specimens of procain

received complied satisfactorily with all tests of identity and purity

with the following exceptions: (1) One specimen of procain-Abbott had

a melting point slightly below the permitted range; however, the last

five specimens had the required melting point. (2) Five specimens of

procain-Abbott and the last three specimens of procain-Rector were not

entirely colorless, but had a yellow or light brown tinge.

The toxicity experiments, which were carried out by Dr. R. A. Hatcher

of the Cornell Pharmacologic Laboratory, were reported as being

satisfactory.

When the Council on Pharmacy and Chemistry referred the matter of

the discolored specimens of procain to the Rector Chemical Company

for explanation, the firm wrote that for a short time for some

unexplainable reason its procain had been slightly yellowish in color,

but that every batch had been carefully tested and found to answer all

chemical requirements. The firm stated that the product which it had

sent out for some time past had been white and yielded a colorless

solution.

To a like inquiry from the Council the Abbott Laboratories replied that

the five samples which were found discolored were products manufactured

by the Rector Chemical Company and represented goods which it had

purchased to assist in filling delayed orders, because the firm had

found itself unable to keep pace with the demand on account of delay in

securing needed apparatus. The firm submitted protocols to show that

the procain made by it, by Rector and by Metz were of equal toxicity.

In the accompanying table the results of the examination are given.

For comparison the findings for the specimens examined previously are

included.

====================================================================

Date Melting Ash

Brand Received Color Point, C. %

Procain (Abbott), from

Committee on Synthetic

Drugs 12/21/17 White 154-155 None

Procain (Abbott),

submitted to Council P.

and C 1/29/18 White 153.5-154.5 None

Procain (Abbott), Gen. Pur.

Off. U. S. Army 8/31/18 White 152.5-153.5 None

Procain (Abbott), Gen. Pur. Slight

Off. U. S. Army, No. 89999 9/30/18 brownish 153.5-154.5 None

tint

Procain (Abbott), Gen. Pur. Slight

Off. U. S. Army, No. 89998 9/30/18 brownish 153-154.5 0.005

tint

Procain (Abbott), Gen. Pur. Slight

Off. U. S. Army, No. 89997 10/ 8/18 brownish 153-154 None

tint

Procain (Abbott), Gen. Pur. Slight

Off. U. S. Army, No. 89996 11/ 4/18 brownish 153.5-154.5 None

tint

Procain (Abbott), Gen. Pur. Slight

Off. U. S. Army, No. 810995 11/ 4/18 brownish 153.5-154.5 None

tint

Procain (Farbwerke Hoechst

Co.), submitted to Council 10/24/17 White 153-154 None

Procain (Farbwerke Hoechst

Co.), submitted to Council 12/10/17 White 153-154.5 None

Procain (Farbwerke Hoechst

Co.), submitted to Council,

market spec. “A56” 8/ 9/18 White 153.5-154.5 None

Procain (Farbwerke Hoechst

Co.), submitted to Council,

market spec. “A57” 9/ 9/18 White 153.5-154.5 None

Procain (H. A. Metz Lab.),

market spec. “A63” 8/23/18 White 153-154 None

Procain (H. A. Metz Lab.),

market spec. “A67” 9/23/18 White 153-154 0.018

Procain (Rector), from Com.

on Synthetic Drugs 12/18/17 White 153-154.5 None

Procain (Rector), market Slight

spec. 8/20/18 brownish 153-155 None

tint

Procain (Rector), market Slight

spec. 8/23/18 brownish 153-155 None

tint

Procain (Rector), market Slight

spec. 8/23/18 brownish 153-154.5 None

tint

--------------------------------------------------------------------

So far as the evidence goes, there was nothing to indicate that the

yellowish or brownish colored specimens of procain were seriously

impure. On the contrary, the compliance with the chemical and

toxicologic tests indicated that the color was due to an insignificant

trace of some colored substance produced in the manufacturing process.

In view of this, the Council considered the use of the discolored

product to be justified in the present emergency, although it urged

that the future supply of procain should be free from color and also

comply to the tests of purity. It made this request in the interest of

the medical and dental professions, which use the drug, and also in a

desire that in the manufacture of synthetic drugs, the United States

should occupy a high place.--(_From The Journal A. M. A., Jan. 11,

1919, with additions._)

DETERIORATION OF SODIUM HYPOCHLORITE SOLUTIONS

(“Chlorinated Soda” Solutions)

The following note on two hypochlorite solutions is published as a

slight addition to the inconclusive available information concerning

the rate of deterioration of solutions containing sodium hypochlorite:

=Hyclorite.=--This is a solution of chlorinated soda, 100 gm. of

which is said to contain sodium hypochlorite 4.05 gm., sodium chlorid

3.20 gm., calcium hydroxid 0.25 gm., inert ingredients 0.92 gm. It is

declared to contain, when placed on the market, not less than 3.85 per

cent. of available chlorin, and to deteriorate at the rate of about

12 per cent. per year. In order that the available chlorin content

at the time of use may be judged, the date of bottling is stamped on

each package. The solution is prepared by decomposing chlorinated lime

suspended in water with sodium carbonate and adding to the solution

obtained a freshly prepared solution of electrolyzed sodium chlorid.

The composition and keeping qualities of hyclorite were reported on

by this laboratory (Ann. Rep. Chem. Lab., A. M. A. =9=:123, 1916).

Hyclorite is fully described in New and Nonofficial Remedies, 1918,

p. 153.

To further check the keeping qualities of hyclorite, a specimen

received from the manufacturer in June, 1918, and said to have been

bottled in April, 1918, was examined in September, 1918. It was found

to contain 3.6 per cent, “available chlorin” (equivalent to 3.79 gm.

sodium hypochlorite in 100 gm.). This indicated a loss of 6.2 per cent.

during five months (equivalent to 14.9 per cent. per year) on the

assumption that it contained the amount of “available chlorin” declared

on the label.

=Concentrated Solution Sodium Hypochlorite-Mulford.=--This is described

as a 5 per cent, aqueous solution of sodium hypochlorite containing

free chlorin equivalent to from 0.2 to 1 per cent. sodium hypochlorite.

It is prepared by treating a solution of sodium carbonate and sodium

bicarbonate with chlorinated lime. The solution is filtered and

standardized by determining the “available chlorin” and adjusting it to

contain the equivalent of 5 per cent. of sodium hypochlorite.

It is proposed for use in the irrigation treatment of infected wounds

after dilution with nine times its volume of water and the addition

of a determined amount (stated on the label of each bottle) of boric

acid to render it neutral to phenolphthalein. The manufacturer has

found that development of a red color (due to formation of permanganate

from the manganese contained in the chlorinated lime) is indicative

of deterioration, and therefore warns against any solution which has

become pink.

A specimen of concentrated solution of sodium hypochlorite-Mulford was

sent the Council on Pharmacy and Chemistry in June, 1917, with a view

of having the product admitted to New and Nonofficial Remedies. At

that time it was found to contain 4.18 per cent. “available chlorin”

(equivalent to 4.4 gm. sodium hypochlorite in 100 gm.). Another

specimen received at the same time and kept unopened in a dark place,

was examined in September, 1918, and was found to contain 2.88 per

cent. available chlorin (equivalent to 3 gm. sodium hypochlorite per

100 gm.). On the assumption that the second specimen contained, at

the time of its receipt, the amount of “available chlorin” found in

the first, this second specimen lost 31 per cent. of its “available

chlorin” during fifteen months.

At the time the specimens were received from the Mulford Company,

the firm reported experiments which were under way to determine the

keeping qualities of the solution. These experiments indicated marked

deterioration of the specimens, which had become red from permanganate

formation, and also that one specimen, which had not become red, had

lost 5 per cent. of its available chlorin in one month. The Mulford

Company explained that when sufficient data had been accumulated,

a decision would be made either as to placing a time limit on the

solution or making a claim as to the rate of deterioration. When the

extreme deterioration found by this laboratory was reported to the

Mulford Company, the firm replied that this was a much greater loss

than the average deterioration found in its chemical laboratory,

namely, an average of 10 or 12 per cent. per year. It advised that

because of the instability of concentrated solution of sodium

hypochlorite, its manufacture had been discontinued.--(_From Reports

A. M. A. Chemical Laboratory, 1918, p. 81._)

SYPHILODOL

The shortage of arsphenamin (salvarsan) has made the sale of

substitutes a profitable business. In many of these substitutes the

earmarks of dishonesty have been obvious, so that detection of their

falsity was relatively simple. In the case of “Syphilodol” marketed

by the French Medicinal Company, Inc., New York, the deception has

been practiced more skilfully. In the circular announcing their

preparations, we read:

“It seems fitting at this time, when the American physicians are

doing so much for France, that there should be a reciprocation in

some way.

“Attempting to enhance somewhat this mutual interchange, we are

presenting some of those scientific products, which have been so

successfully used in France, ----”

“The effect of SYPHILODOL is very similar to salvarsan and

neosalvarsan, but it has the advantage of being more lasting in

its results and more pleasing in the manner of its preparations,

in that it is put up in the form of tablets, and, also, in

hermetically closed glass syringes or ampules, so that it may be

administered either by the mouth, intravenously or intramuscularly,

at the discretion of the physician. Patients averse to the use of

the hypodermic needle may be treated expeditiously by the use of

the tablet form of the medicine.”

In addition to Syphilodol, the French Medicinal Co. also sells “Vichi

Fruti,” a combination of salts, “Urodol,” an “alkaline salt of the

famous European Springs which is noted for breaking up and dissolving

uric acid rapidly” and “Syloiodol,” “French Preventive,” which is

described as “a solution of iodol incorporated into bougie.”

“Syphilodol,” we are told, is “a synthetic chemical product of

_silver_, _arsenic_ and _antimony_, scientifically prepared after

the formula of the _late_ Dr. Alfred Fournier of Paris.” (Italics

ours--Ed.). It is also claimed that “Prof. Metchnikoff and other noted

French scientists have made exhaustive tests of syphilodol and found it

superior to the other products, in the treatment of syphilis.” In the

advertisements, Fournier and Metchnikoff are the only names given of

alleged endorsers; both of these men are dead and cannot protest. True,

Fournier did considerable work on a legitimate synthetic of antimony,

silver and arsenic having a general chemical constitution similar to

arsphenamin, but so far as we are aware, there has been no publication

by these men on “Syphilodol.” It would seem that the valuable work and

high reputation of Fournier and Metchnikoff are being capitalized by

the French Medicinal Company in their endeavor to foist a nostrum on

the medical profession of this country.

“Syphilodol” comes in two forms--ampules and tablets. An order for

two 0.4 ampules brought an elaborate case, much like those used to

hold the popular style safety razors. The ampule itself was a “classy”

affair evidently made by a glass expert; the hypodermic needle was

enclosed in a novel sealed glass device. The price of each ampule is

$3. No such fancy garnishments came with the tablets, although they are

listed at $4.50 for twenty-five--18 cents a tablet! In the “Syphilodol”

advertising it is emphasized that both the tablets and ampules are to

be administered. For example:

“Syphilodol is dispensed in the form of tablets and also

hermetically closed glass syringes or ampules so that it may be

used either by the mouth, intravenously or intramuscularly at

the discretion of the physician. An advantage of the tablets is

that they can and should be given during the interim between the

injections.”

LABORATORY REPORT ON SYPHILODOL

Several samples of “Syphilodol” were sent to the American Medical

Association Chemical Laboratory by readers of The Journal. An original

bottle of tablets was ordered direct from the French Medicinal Company.

The bottle contained 25 yellow tablets, having an average weight of

0.276 gm. (4-1/4 grains). After being powdered, “Syphilodol” was found

to be only partially soluble in water (the excipient is soluble) and

to be neutral in reaction. These findings contradict the claims on

the circular accompanying the bottle to the effect that “Syphilodol

is a yellow powder, soluble in water, and has an acid reaction.”

Qualitative tests indicated the presence of mercury, sucrose (cane

sugar), iodid, calcium, sulphate, fatty material, a trace of silver,

a trace of arsenic and a very minute trace of antimony; a red dye was

also present. Both qualitative and quantitative data showed that the

mercury was present in the form of mercurous iodid (yellow iodid of

mercury--hydrargyri iodidum flavum). Quantitative estimations yielded

the following:

Silver (Ag+) 0.001 per cent.

Mercury (Hg+) 11.1 per cent.

Iodid (I-) 7.8 per cent.

Sucrose (cane sugar) 72.0 per cent.

Ash (calcium sulphate) 2.5 per cent.

Ether-soluble material (fatty material--petrolatum) 3.5 per cent.

Thus each tablet of “Syphilodol” contains approximately, 3/4 grain

of mercurous iodid. An ampule of “Syphilodol,” labeled 0.4 gram,

contained approximately 1.5 c.c. of a liquid which after evaporation

on a water-bath left a residue weighing 0.8 mg., or 1/80 grain. A

second ampule held about 2 c.c. of liquid, which contained a trace of

arsenic (less than 0.00001 gm., or 1/6000 grain); a very small amount

of mercury was indicated but not definitely established. The liquid had

the physical characteristics of water.

Accompanying “Syphilodol” advertising sent to physicians is a circular

letter inviting the doctor to become a member in the “United States

Bacteriological and Research Institute.” The “institute” seems to be a

means of suggesting that the physician have bacteriologic, pathologic

and serologic examinations made on behalf of his patients. In view of

the fact that it is to the commercial interest of the French Medicinal

Company to have as many users of “Syphilodol” as possible, it would

be interesting to know what proportion of the Wassermann tests are

reported negative.

Shorn of its mystery, Syphilodol the “synthetic chemical product of

silver, arsenic and antimony” is essentially mercurous iodid--yellow

iodid of mercury.

Details of Analysis

SYPHILODOL TABLETS

In France there has been on the market for some time a synthetic

compound of silver, arsenic and antimony having the general structure

of arsphenamin. Structurally, the formula as given by Bonard, Danyss

and Tournier is (C₁₂H₁₂N₂As₂) 2AgBrSbO (H₂SO₄)₂--dioxy = diamino

arsenobensolstibicosilver sulphate. As the advertising matter for

“Syphilodol” referred to the synthetic compound of silver, antimony

and arsenic, and also to its use in syphilis by Fournier, the above

compound was first suspected. However, the general characteristics

of syphilodol tablets, such as partial solubility in water, but not

soluble in sodium hydroxid, sodium bicarbonate or acids, threw doubt on

the hypothesis. When a small amount of the powdered tablets was treated

with water, a yellow residue could be filtered off; the filtrate was

pink, opalescent, which on standing gave a clear pink solution, and

a small yellow precipitate. The residue, when allowed to remain in

sulphuric acid solution (20 per cent.) over night became red; on

boiling, the red precipitate with sulphuric acid, the precipitate

volatilized and could be condensed in a watch glass. Adding a pinch of

manganese dioxid to the hot sulphuric acid mixture caused an evolution

of iodin fumes. A small amount of powdered syphilodol tablets was

placed in the sunlight; they turned from yellow to black. All these

reactions are typical of mercurous iodid--yellow iodid of mercury.

MERCURY, SILVER, ARSENIC, ANTIMONY

I. _Mercury._--Two methods were used to determine the mercury: (_a_)

1.4535 gm. of powdered syphilodol was treated with 10 c.c. of a 50 per

cent. sodium sulphid solution. The solution was then transferred with

washings (about 20 c.c.) to a cathode cup, previously weighed with its

contained mercury. The mercury compound was electrolyzed by a current

of about 8 volts and 3 amperes, using a rotating anode. The solution

(and some sulphur suspension) was removed by siphon, pouring in water

until the amperage of the current was close to zero (U. S. P., IX,

p. 587). The increased weight in mercury was 0.1612 gm.

II. To serve as a check on the foregoing method, mercury was also

determined in the following method, which also allowed systematic tests

for silver, antimony and arsenic. (_b_) 1.1023 gm. of the sample was

placed in an Erlenmeyer flask, 50 c.c. of water, 50 c.c. of sodium

hydroxid solution (10 per cent.) and 20 c.c. of formaldehyd solution,

U. S. P., added. The solution was boiled for ten minutes and maintained

at temperature of steam bath for two hours. (This reduces the mercury

salt to mercury and any silver salt to silver; antimony would probably

be likewise reduced.) The precipitated mercury was transferred by

water, and concentrated nitric acid added. (The nitric acid solution

is boiled to oxidize all mercurous nitrate to mercuric nitrate.) A

small white precipitate was obtained at this point which seemed to be

insoluble in aqua regia (calcium sulphate). The filtrate from this

precipitate, which was washed well, was tested with one or two drops

of dilute hydrochloric acid and a faint precipitate formed; this was

filtered off through extra fine filter paper and washed repeatedly. The

paper and precipitate was heated with potassium cyanid solution over

night, filtered and the filtrate electrolyzed in a platinum dish. The

increase in weight of the dish was 0.00018 gm., or 0.001 per cent. Into

the platinum dish some nitric acid was poured, then diluted, and a drop

of hydrochloric acid added. A turbidity was produced which cleared on

the addition of excess of ammonium hydroxid solution (_silver_). The

filtrate from the nitric acid treatment was electrolyzed, this time in

a platinum dish, and the liquid carefully removed, washed carefully

with redistilled alcohol and ether. The mercury, which could be seen

easily by the naked eye, weighed 0.1200 gm., equivalent to 10.89 per

cent. of mercury.

III. _Arsenic and Antimony._--About 3 gm. of the powdered specimen was

digested with sulphuric acid in a Kjeldahl flask. One-half portion

(which was evaporated almost to dryness and treated with 5 c.c. of

concentrated hydrochloric acid) was submitted to treatment with

hydrogen sulphid, diluted, and saturated with hydrogen sulphid. The

precipitate was treated in the usual manner of the group separation

with warm ammonium sulphid solution. The filtrate from this treatment

was acidulated with hydrochloric acid, the precipitate removed, and

treated with concentrated hydrochloric acid. The substance insoluble

in hydrochloric acid was treated with more concentrated hydrochloric

acid and a crystal of potassium chlorate. The solution was tested after

the Gutzeit method of the Pharmacopeia IX, for _arsenic_. A very small

amount was indicated. The hydrogen sulphid test was not indicative. The

solution which might contain the _antimony_ was tested with hydrogen

sulphid. In one case only was a slight orange coloration produced. No

antimony was deposited on platinum foil in the presence of granulated

zinc. These tests were run in triplicate.

_Iodid._--Iodid was determined by the Carius method (_a_) 0.7412 gm.

yielded 0.1112 gm. silver iodid, equivalent to 8.09 per cent.; (_b_)

0.5319 gm. yielded 0.0751 gm., equivalent to 7.80 per cent. The iodid

and mercury were in proportions comparable to mercurous iodid.

_Ash._--(_a_) 0.9159 gm. when ignited to constant weight yielded

0.0232 gm., equivalent to 2.52 per cent. ash; (_b_) 1.3008 gm. treated

with water and the residue filtered on a Gooch filter and ignited.

The ash of the residue was 2.51 per cent. (the mercurous iodid

volatilized). The ash was calcium sulphate.

_Sucrose._--1.3008 gm. of the sample was treated with water and

filtered by suction through a Gooch crucible. The filtrate and washing

were carefully transferred to 500 c.c. volumetric flask, and allowed to

stand one week; 50 c.c. portions were used to determine sugar according

to the Daufresne-O’Sullivan method. The weights of cupric oxid averaged

210 mg., or 72 per cent.

_Ether Soluble Material._--1.6998 gm. of the powdered specimen was

extracted with ether and the ether extract evaporated to dryness. The

residue weighed 0.0600 gm., equivalent to 3.53 per cent.

SYPHILODOL AMPULES

_Water._--The liquid from one ampule was distilled over very carefully.

The freezing point of the liquid was +0.1 C., and it was neutral to

methyl orange and phenolphthalein.

_Arsenic._--The contents of one ampule was placed in a small florence

flask, 20 c.c. of concentrated sulphuric acid added and heated to

70 C.; 0.5 gm. of potassium permanganate was added in small amounts.

The procedure was then carried on as described by Engelhardt and

Winters in _J. Am. Pharm. Assn._, 1915, p. 1469. To the mixture

from 5 to 10 c.c. of hydrogen peroxid solution were added drop by

drop until the color had disappeared. The liquid was diluted with

20 c.c. of water, boiled fifteen minutes, diluted again and boiled

fifteen minutes, then cooled and made up to exactly 100 c.c. A blank

was also run alongside. Five c.c. of this solution was then tested

quantitatively for arsenic according to the U. S. P. IX method, using

all precautions. Comparisons of stains showed less than 0.00001 gm. of

arsenic (As).--(_From The Journal A. M. A., May 18, 1918._)

CERELENE

Cerelene, a paraffin preparation for the treatment of burns, was

submitted to the Council by the Holliday Laboratories, with the

statement that it was composed of 84 per cent. paraffin, 15 per cent.

myricyl palmitate, and 1 per cent. purified elemi gum to which is added

oil of eucalyptus 2 per cent. and betanaphthol 0.25 per cent. It was

explained:

“Myricyl Palmitate is a purified form of Beeswax, free from all

impurities, acids, etc., which is solely manufactured by this

Company....”

It was also stated that on “special order” Cerelene has been made

containing oil of eucalyptus and resorcin, oil of eucalyptus and picric

acid, and picric acid alone. The following report on the preparation

was presented to the Council by the referee to whom Cerelene had been

assigned:

Cerelene is another compound wax for the treatment of burns. According

to the work of Sollmann (J. A. M. A. =68=:1799, 1917) it is highly

improbable that compound mixtures have any advantage over simple

paraffin of low melting point. Cerelene must therefore be considered as

an unessential modification of paraffin, and as in conflict with Rule

10, unless definite evidence of superiority be submitted. Cerelene

mixtures containing medicinal ingredients also appear unscientific

since the evidence that the ingredients do not leave the wax has not

been successfully contradicted. Finally, the claims made for Cerelene

are rather extreme, and would need some revision before they could be

accepted.

The A. M. A. Chemical Laboratory reports:

The physical properties of Cerelene are as follows:

Melting point by U. S. P. method 50.0 C.

Ductility limit 30.5 C.

Plasticity limit 26.4 C.

Not strong at 38.0 C.

Adheres moderately well; detaches with “pulling.” On heating,

readily loses eucalyptol, and a small amount of resinous substance

forms in the bottom of the beaker. If Cerelene be heated to 145 C.

and cooled, the resulting product no longer has the properties of

the original Cerelene.

After two years’ delay on the part of the manufacturer, the Council

authorized publication declaring Cerelene inadmissible for New and

Nonofficial Remedies because its superiority over single paraffins

had not been demonstrated and the unwarranted claims had not been

abandoned.--(_Abstracted from The Journal A. M. A., Feb. 15, 1919._)

DR. DE SANCTIS’ RHEUMATIC AND GOUT PILLS

Dr. DeSanctis’ Rheumatic and Gout Pills are sold by Edward Cleaver, 13

Clerkenwell Road, London, England. The American agents are E. Fougera

and Co., Inc., New York. The package is a round pill box and contains

twelve pills and a circular, which directs that one pill be taken every

eight hours until relieved. In the package there is also a circular

advertising Dr. DeSanctis’ Gout and Rheumatic Paint, with directions

for its use. On the cover of a box, which contained six of the retail

packages, is the statement that these pills have been in general use

for nearly 100 years, and that their sale has been built up without

advertising.

DeSanctis’ pills are round, uncoated, and have a light brown color.

There was some variation in the color of different lots, one lot in

particular being gray rather than brown. A little arrowroot starch

was found in each box, this evidently having been used as a dusting

powder. The pills were very hard, rather brittle, but quite difficult

to powder. The pills were not readily disintegrated by water or diluted

acids, even when warmed, but when warmed with a dilute sodium hydroxid

solution they readily disintegrated.

Ten pills weighed 3.213 gm., an average of 0.3213 gm., or 5 grains. The

arrowroot starch used as a dusting powder was removed as completely as

possible by rolling the pills in a cloth. Several dozen pills were then

powdered and the powder thus obtained used for the analysis.

A microscopic examination of the powder showed powdered colchicum seed

in abundance and also traces of arrowroot starch, no doubt from that

used as the dusting powder.

Since colchicum seed was so abundant, the powder was assayed by the

U. S. Pharmacopeial method for colchicum seed (U. S. P. IX, p. 120),

slightly modified so that less of the powdered pills than directed

there could be used. In one assay 3.75 gm. gave 0.0204 gm. of colchicin

or 0.54 per cent. In a duplicate, 5 gm. gave 0.0234 gm. of colchicin or

0.47 per cent.; average 0.5 per cent.

The alkaloid obtained had the characteristic appearance and odor of

colchicin when separated from the seed under these conditions. The

solution in water and acid was yellow; the aqueous solution was

intensely bitter, and the yellow color intensified with acids. The dry

residue became intensely yellow with concentrated sulphuric acid; with

nitric acid it became violet turning to yellow, and with concentrated

sulphuric acid and potassium nitrate it gave a yellowish green color,

turning to violet and finally to a wine color. All these reactions are

typical of colchicin.

From 1 gm. of the powdered pills there was obtained 0.0425 gm. of ash,

or 4.25 per cent.

When the powdered pills were extracted with chloroform in a Soxhlet

apparatus, a very uniform quantity of extract was obtained. From 5 gm.

there was obtained, in one case, 0.581 gm.; in another, 0.5755 gm., and

in a third, 0.588 gm., the average being 0.5815 gm. or 11.63 per cent.

On still further extracting with alcohol, a small amount of extractive

was obtained, the amount depending on the length of time the extraction

was continued.

On extracting with hot water the residue left after exhaustion with

chloroform and with alcohol, a further extract was obtained. In one

case, it amounted to 0.4763 gm. or 9.53 per cent., and in another case

it amounted to 0.470 gm., or 9.40 per cent.; average 9.47 per cent.

In attempting to dry the pills or the above-mentioned chloroformic

extract at 100 C., a crystalline sublimate was obtained which had the

odor of benzoic acid. The crystals were acid, their neutral solution

gave a flesh-colored precipitate with ferric chlorid, and they melted

at 120-121 C. This crystalline substance appeared to be benzoic acid.

The quantity of benzoic acid in this extract was determined by heating

it to about 140 C. A current of air was drawn through the flask and

the sublimed benzoic acid collected in a cooled tube. The benzoic acid

was washed out of the tube with neutral alcohol, and the solution was

titrated with tenth normal potassium hydroxid. In one case, 11.25 c.c.

of tenth-normal alkali was used, indicating 0.1373 gm, of benzoic acid;

in another, 12.27 c.c., indicating 0.1498 gm. of benzoic acid; average

0.1436 gm., or 2.87 per cent. In a third case the temperature reached

250 C., and there was some decomposition of the fat in the flask and

some colored material distilled over. For this sublimate 15.54 c.c. of

tenth-normal alkali were required.

After evaporating the alcohol and acidulating the solutions obtained

in the previous experiments, the benzoic acid was extracted with

chloroform. In the first case, 0.1383 gm. was obtained; in the second,

0.1541 gm.; average 0.1462 gm., or 2.92 per cent. of benzoic acid.

When the original chloroformic extract was heated until all of the

benzoic acid had been driven off, the residue had the appearance of a

semisolid fat. It compared quite closely in color, odor, etc., with the

fatty material obtained by extracting colchicum seed with chloroform,

although the odor was more suggestive of oleic or stearic acid. It was

distinctly acid, which is also true of the fatty material obtained from

a sample of colchicum seed.

The extract obtained with hot water was light yellow; gummy, at first,

but dried to a glass-like brittle mass. It had a slight burned-sugar

odor and taste, and was neutral in reaction. It was strongly

dextrogyrate and at once reduced Fehling’s solution as well as alkaline

silver nitrate solution. On boiling with potassium hydroxid solution,

it turned deep red. It also gave the Molisch carbohydrate reaction,

and the ozazone test in seventeen minutes as described in Mulliken

(Identification of Pure Organic Compounds, Ed. 1, 1905, p. 26). These

are all characteristic reactions of lactose or milk sugar.

From this examination we conclude that DeSanctis’ pills contain

powdered colchicum seed, benzoic acid, and sugar of milk. There is also

present fatty material which resembles the fat of colchicum seed, but

may be, in part, added fatty acid. The percentage of colchicin found

(0.50) is about that of a good quality of colchicum seed, the U. S.

Pharmacopeial standard being not less than 0.45 per cent. Since the

pills contain material other than colchicum seed, this assay would

indicate a colchicum seed of high alkaloidal content, or the possible

reinforcement of the pills with colchicum extract or colchicin.

The amount of benzoic acid, 2.92 per cent., or about 1/7 grain per

pill, is insignificant from a therapeutic standpoint, since an average

dose is 0.5 gm., or 8 grains. Fatty acids, and the fatty matter from

colchicum seed are inert, at least in the quantities found here. The

only office which fatty acids might perform, would be to give the pills

an enteric quality, preventing their absorption until they reach the

intestine. The sugar of milk, about 10 per cent., or 1/2 grain per

pill, no doubt is simply an excipient.

DeSanctis’ pills are therefore essentially 5 grain doses of powdered

colchicum seed, of which the average dose is 0.2 gm., or 3 grains

(U. S. P. IX, p. 120).

The Journal in presenting the facts contained in the above report made

the following comments:

“Here then, we have sold for self-medication an extremely poisonous

drug, with no warning of the risk the public runs in using it. While

the directions call for “one pill every eight hours until relieved,”

it is notorious that the public takes the attitude toward “patent

medicines” that, if a little is good, more is better, and the average

user of remedies for self-treatment is likely, unless there is some

warning, to use his own discretion as to the amount taken.

“The individual dose is above that of the average recommended in the

United States Pharmacopeia. Colchicum or its alkaloids--or for that

matter, any drug as toxic as colchicum--have no place in preparations

of the home-remedy type. In the case of all “patent medicines,”

public interest demands that the full quantitative formula of the

therapeutically active ingredients should be given on the label, for

when the public prescribes for itself, it has a right to know what it

is taking. Unfortunately, public interest clashes with vested interests

and, as usual, vested interests get the better of it. In the case of

such dangerous preparations as DeSanctis’ pills, if their sale is to

be permitted at all, not only should the names and quantities of all

therapeutically active ingredients in the mixture be given, but the

law should require that the word Poison be plainly printed on the

label.”--(_Abstracted from The Journal A. M. A., July 19, 1919._)

IODEX AND LIQUID IODEX

The A. M. A. Chemical Laboratory examined Iodex in 1915.[213] The

claims made, at that time, by the exploiters, Menley & James, were

shown to be contrary to facts in that Iodex contained only traces of

free iodin while they claimed “5 per cent. Therapeutically Free Iodin.”

Even the _total_ quantity of iodin was shown to be only about one half

of the 5 per cent. claimed to be present as free iodin.

[213] Annual Reports of the Chem. Lab. of the A. M. A., 1915, p. 89.

An examination of the advertising matter sent out by Menley & James

in 1919 showed that substantially the same claims were being made as

in 1915. This at once suggested the inquiry: Since the claims are the

same as previously made, have the manufacturers altered the composition

to conform to the claims? The answer is found in the results of the

analysis of two samples purchased in the open market early in 1919.

This analysis shows conclusively that Iodex is essentially the same as

in 1915, that is, that it contains no free iodin and only about three

fifths of the total amount of iodin claimed.

It would seem that Iodex (Ung. Iodi., M. & J.) is in obvious conflict

with Section 7 of the Food and Drugs Act. While it is sold under a name

recognized by the U. S. Pharmacopeia, namely, Ung. Iodi., it does not

conform to the standards of the U. S. Pharmacopeia for that product.

Iodin ointment U. S. P. is made with 4 per cent. of free iodin, 4 per

cent. of potassium iodid, 12 per cent. of glycerin, and a benzoinated

lard base. It should then contain approximately 7 per cent. of total

iodin. It has been shown by Warren[214] that about 75 per cent. of the

iodin in the U. S. P. ointment remains in the free state even after

months of standing. Ung. Iodi., U. S. P., then, should contain about 3

per cent. of free iodin. Iodex contains no free iodin, or but traces,

and no potassium iodid. Furthermore, the Iodex label declares the

presence of 5 per cent. of “therapeutically free” iodin. As a matter of

fact, the amount of iodin is variable, the highest amount found being

3.5 per cent. and samples containing as low as 2.63 per cent. have been

examined.

[214] Warren, L. E.: Iodin Ointment, Am. J. Pharm., August, 1917,

p. 339.

It would seem further that Iodex is misbranded under the Sherley

amendment in that it is said that it “may be used externally with

advantage in all cases where the action of iodin is desired.” Since

it contains no iodin as such this cannot possibly be true. It is also

stated in a circular accompanying the trade package that “Thirty

minutes after inunction iodin can be found in the urine.” This

statement has also been shown to be untrue.--(_Annual Reports A. M. A.

Chem. Lab., 1915, p. 89._)

Details of Analysis

=Iodex.=--This is a rather soft ointment, almost black but with a

decided greenish cast in thin layers. It is soluble in chloroform

but is only partly saponified and dissolved by alcoholic potassium

hydroxid. Iodex has a distinct odor like oleic acid.

_Free Iodin._--When examined by the method previously used[215] only

minute traces of free iodin were found.

[215] Ibid., p. 90.

_Total Iodin._--The methods employed were as follows: 1. Iodex was

saponified by boiling for from two to three hours with alcoholic

potassium hydroxid. The alcohol was then evaporated and the iodin

determined by the method described in the U. S. Pharmacopeia for thymol

iodid.

2. The same as Method 1, except that after ignition of the saponified

mixture the halogen was determined by weighing as silver iodid.

3. The Carius method.

It should be noted that Methods 2 and 3 determine chlorin and bromin

should any be present with the iodin.

When 5 gm. of Sample 1 was assayed by Method 1, it required 73.56 c.c.

of tenth-normal sodium thiosulphate, equivalent to 3.11 per cent.

of iodin. In a duplicate, 2.7565 gm. of Iodex required 38 c.c. of

tenth-normal sodium thiosulphate, equivalent to 2.92 per cent. of

iodin; average of the two, 3.02 per cent. of iodin.

A weight of 2.5800 gm. of Sample 1, assayed by Method 2, gave

0.1582 gm. of silver halid, equivalent to 0.0855 gm. of iodin, or 3.31

per cent.

A weight of 0.588 gm. of Sample 2, assayed by the Carius method, gave

0.0388 gm. of silver halid, indicating 0.02096 gm. of iodin, or 3.52

per cent. In a duplicate, 0.5342 gm. gave 0.0338 gm. of silver halid,

indicating 0.01826 gm. of iodin, or 3.42 per cent.; average, 3.49 per

cent. of iodin.

=Liquid Iodex.=--This is sold by Menley & James, Ltd., the firm selling

Iodex Ointment. According to a circular in a trade package “the

valuable properties of Free Iodine are available in Liquid ‘Iodex’ in a

state of greatly enhanced activity; but the irritating, corrosive and

hardening drawbacks of ordinary solutions of the drug are absent.” The

label on a bottle reads as follows: “Liquid ‘Iodex’ (Liq. Iodi. M.

& J.). A nonirritant preparation of iodine (2-1/2%) ... This product

contains Free Iodine....”

The sample of Liquid Iodex purchased on the open market was found to be

a reddish liquid with an odor like oleic acid. It dissolved completely

in chloroform.

_Free Iodin._--A weight of 6.2936 gm. was dissolved in chloroform and

the solution shaken with 25 c.c. of a solution of potassium iodid.

The iodin which passed into the potassium iodid solution was titrated

with tenth-normal sodium thiosulphate, 0.81 c.c. being required. This

indicates 0.01022 gm. of iodin, or 0.16 per cent.

_Total Iodin._--Total iodin was determined by Method 1 as given above

under Iodex. A weight of 4.466 gm. required 32.93 c.c. of tenth-normal

sodium thiosulphate, equivalent to 0.06964 gm. of iodin, or 1.55

per cent. In a duplicate, 5 gm. of material required 33.3 c.c. of

tenth-normal sodium thiosulphate, equivalent to 0.7043 gm. of iodin, or

1.41 per cent.; average, 1.48 per cent. of iodin.

Liquid Iodex, then, contains but little (0.16 per cent.) free iodin and

only about three fifths of the total iodin claimed.

I. G. O.

I. G. O. is an iodin ointment. It is said to be made by Dr. H. S.

Lambdin, Peru, Kansas. In a circular distributed by the manufacturer,

it is stated that “I. G. O. is a saturated solution of Iodine Gas in

petrolatum at 130 degrees with oil of eucalyptus. The heat of the body

liberates the iodine and it is absorbed as free iodine.”

A sample of I. G. O., received from a physician, was examined. It was

found to be a black ointment, green in thin layers, with a slight odor

like crude petroleum. By the methods used for the examination of Iodex,

I. G. O. was found to contain 0.59 per cent. of free iodin.--(_From

Reports A. M. A. Chemical Laboratory, 1919, p. 104._)

IODIN IN LIQUID PETROLATUM

A. H. Clark, Ph.G., Sc.B.

Of all the things used in medicine nothing seems to have attracted

the attention of all classes of users as has iodin. Perhaps more

romantic schemes for the cure of all the ills which afflict mankind

have centered in iodin therapy than in any other one drug. Iodin is

being used in every conceivable way from crystals to colloid; in vapor;

combined as iodid, iodate and the like; organic, inorganic, simple and

complex; internal, external and by injection, and yet there seems to be

no end to the ingenious schemes for its exploitation.

One of these schemes, and one so simple that it seems at first sight

to be hardly worth serious consideration, is that of a solution of

iodin in liquid petrolatum. Solutions of this kind have frequently been

offered to physicians and the laity. The thing of particular interest

is the claim made as to the percentage of free iodin. Five per cent.

is frequently claimed. Examination of some of these products in the

chemical laboratory of the A. M. A.[216] revealed the fact that they

did not contain the claimed amount of free iodin. These questions at

once arose: Was the low free iodin content due to intentional fraud,

the result of carelessness, or of ignorance? Was it impossible to

prepare a solution containing 5 per cent., or did the iodin slowly

combine with the oil and disappear?

[216] Reports A. M. A. Chemical Laboratory, 1915, p. 106; Ibid., 1917,

p. 87.

Several years ago the A. M. A. Chemical Laboratory[217] conducted some

experiments on the solubility of iodin in liquid petrolatum, which

indicated that a saturated solution would contain about 1.4 per cent.

These experiments did not show conclusively that no iodin was absorbed

by the petrolatum during the process of solution. For this reason,

further experiments were conducted with the view of determining both

the solubility in and the extent to which iodin is absorbed (disappears

as free iodin), if at all, by liquid petrolatums of various kinds.

Theoretically such hydrocarbons should not absorb iodin. The results of

these experiments are here given.

[217] Ibid., 1917, p. 87.

A sample of iodin was prepared by sublimation from a mixture with

potassium iodid. This sample when dried over sulphuric acid assayed

99.98 per cent. of iodin. Portions of this sample were used in all

of the subsequent experiments. To prepare solutions of definite

concentrations, in all cases expressed as percentage by weight, an

accurately weighed quantity of iodin was placed in a glass-stoppered

bottle and an accurately weighed quantity of liquid petrolatum added.

The mixture was subjected to treatment as indicated in the various

experiments and from the weights of iodin and petrolatum used the

percentage of iodin was calculated.

The method of assay employed was as follows: A weighed quantity of

the iodin solution was transferred to a bottle or flask by means of

several small amounts of chloroform, about 50 c.c. in all. To this

was added about 25 c.c. of potassium iodid solution. The mixture was

then titrated with tenth-normal sodium thiosulphate until on thorough

shaking no iodin passed into the aqueous layer.

To 2.1248 gm. of iodin was added 199.3 gm. of liquid petrolatum.

The mixture was shaken frequently each day and after forty days

there seemed to be still a few particles of iodin undissolved. The

supernatant solution was assayed, however, and found to contain 1.038

per cent. of iodin. The iodin added was 1.055 per cent. Six months

later 1.025 per cent. of iodin was found.

To 5.1832 gm. of iodin was added 199.5 gm. of liquid petrolatum. The

mixture was heated to 100 C. for four hours with frequent shaking.

The iodin was in perfect solution. The per cent. of iodin would then

be 4.95. Upon cooling, iodin in abundance crystallized out. After

standing a few hours, with frequent shaking, the iodin in solution was

determined. This was found to be 1.425 per cent.

These two experiments indicate: First, that the previous findings of

the A. M. A. Chemical Laboratory are correct in that only about 1.4

per cent. of free iodin is retained in solution in liquid petrolatum

at room temperature. Second, that the quantity of iodin absorbed by

liquid petrolatum at room temperature, in seven months at least, is

practically none. Third, that iodin dissolves rather slowly in liquid

petrolatum at room temperature.

In the experiments, the results of which are tabulated below, the iodin

and liquid petrolatum were heated at 100 C. for about four hours,

shaking frequently to hasten solution. After cooling, the specimens

were assayed and were again assayed at intervals as indicated in the

table.

Date of Per Per

Kind of Manufac- Weight Per Per Cent. Cent.

Liquid ture and ┌─────┴─────┐ Cent. Cent. Iodin Iodin†

Petrolatum First Iodin Petrolatum Iodin Iodin Nov. 17, Nov. 19,

Used Assay Used Found 1918 1919

Stanolind 10/17/18 2.089 188.4 1.096 1.085 1.068 1.067

Squibb 10/14/18 1.9569 186.78 1.0306 1.0232 1.013 1.009

Unknown, bulk* 10/28/18 1.9497 158.2 1.225 1.133 1.075 1.095

Parke, Davis 10/24/18 2.0869 167.43 1.241 1.2488 1.191 1.180

& Co

* Considerable dark sediment formed in this sample during the heating

process.

† It should be pointed out here that while every sample showed some

absorption, the amount, with the exception of the unknown bulk,

is so small that it might even be accounted for on the basis of

“experimental error.” Every ordinary precaution was taken to insure

accuracy, but since about 15 gm. of the solution was used for each

determination, it is seen that an error of 0.3 c.c. in the titration

would indicate a greater absorption of iodin than that noted.

Conclusions: These experiments show: A solution of iodin in liquid

petrolatum is saturated when it contains about 1.4 per cent. of iodin.

The amount of iodin absorbed (disappearing as free iodin) by liquid

petrolatum, when in contact at room temperature for as long as seven

months, or in contact at 100 C. for four hours, or both, is relatively

insignificant. Also all the absorption seems to take place during the

heating and in the first month of contact.--(_From Reports A. M. A.

Chemical Laboratory, 1919, p. 21._)

AMERICAN-MADE SYNTHETIC DRUGS--II

Examination of Procain (Novocain), Barbital (Veronal), Phenetidyl-

Acetphenetidin (Holocain), Cinchophen or Phenylcinchoninic

Acid (Atophan), Manufactured Under Federal

Trade Commission Licenses[G]

Paul Nicholas Leech, Ph.D.; William Rabak, Ph.G., Sc.B.,

and A. H. Clark, Ph.G., Sc.B.

[G] From the Chemical Laboratory of the American Medical Association.

[G] The first article of this series dealt with the purity of

acetylsalicylic acid. Leech, P. N.: Examination of American-Made

Acetylsalicylic Acid, J. Indust. & Engin. Chem., April, 1918, p. 288.

“What’s in a Name?” ibid., p. 255. Acetylsalicylic Acid, or “What’s in

a Name?” Editorial, J. A. M. A. 70: 1097 (April 13) 1918.

Before European hostilities, the United States was so dependent on

Germany for synthetic drugs that the dependence was considered a

necessity; this was strikingly manifested by the precipitous rise in

prices immediately after the embargo was declared against Germany.

Since then the shortage of German-made synthetics has caused two

important results: 1. The physician can do without most of the German

drugs, because the prewar demand had been stimulated artificially.

2. Those few synthetics, which were in great need, are being rapidly

replaced by the American-made drugs.[218] In connection with the second

result, the Chemical Laboratory of the American Medical Association has

endeavored to contribute its services.

[218] Stieglitz, Julius: Synthetic Drugs II, J. A. M. A. 70: 688

(March 9) 1918. Leech, P. N.: The Vindication of the American Chemist;

Synthetic Drugs, Chicago Chem. Bull. January, 1918, p. 230.

In September, 1917, it was announced[219] that the A. M. A. Chemical

Laboratory would make studies of American-made synthetics. Just prior

to this announcement, the National Research Council established a

committee on synthetic drugs[220] “to facilitate the manufacture of

synthetic drugs in this country and thus to relieve shortage and reduce

the exorbitant prices which have resulted from the war.”[221] Also

during this time Congress was considering the “trading with enemy” act,

first known as the Adamson bill--the purpose of which was to confer

authority on the President to license American firms to use U. S.

patents owned by German subjects. The act became law, September 28; the

Federal Trade Commission was designated by the President to carry out

the provisions of the law as it referred to enemy-owned patents. As a

result of a conference, Oct. 30, 1917,[222] with various agencies, the

Federal Trade Commission decided to consider licenses for manufacturers

of synthetic drugs, _after_ recommendations had been made by the

Committee on Synthetic Drugs of the National Research Council; this

committee in turn invoked the aid of the A. M. A. Chemical Laboratory

in testing the manufacturer’s products. The essence of the laboratory’s

work up to July 1, 1919, is reported in this paper.

[219] The Quality of American-Made Synthetics, J. A. M. A. 69: 1018

(Sept. 22) 1917.

[220] This committee is composed of Julius Stieglitz, chairman,

professor of chemistry, University of Chicago; W. A. Puckner, secretary

of the Council on Pharmacy and Chemistry, American Medical Association,

and Moses Gomberg, professor of chemistry, University of Michigan.

[221] Stieglitz, Julius: Shortage of Synthetic Remedies, J. A. M. A.

69: 400 (Aug. 4) 1917.

[222] Foreign Patents to Be Open to American Manufacturers, J. A. M. A.

69: 1550 (Nov. 3) 1917.

THE NAMING OF LICENSED DRUGS

“Partly in order to help insure to licensees a market for their

products after the war, in larger part inspired by the idea of

encouraging the establishment of a permanent American industry in these

important articles, the [Federal Trade] Commission wisely decided that

American houses should be put on the same footing as competing foreign

houses for after-the-war competition, by imposing on all licensees

the obligation to use _new official names_ for the articles, names

which after the war will be open to all competitors, domestic and

foreign.”[223]

[223] For an interesting discussion, see Stieglitz, Julius: Synthetic

Drugs, J. A. M. A. 70: 536 (Feb. 23); 688 (March 9); 923 (March 30)

1918. Bracken, L. L.: Federal Trade Commission Requests Use of Official

Names, ibid. 70: 558 (Feb. 23) 1918.

The new American names are:

Arsphenamin[224] (contracted from the scientific name arsenphenolamin)

for salvarsan, arsenobenzol, diarsanol, arsaminol.

[224] The testing and standardizing of arsphenamin is being done by the

Hygienic Laboratory, U. S. Public Health Service. For chemical tests

see reprint 472, Public Health Reports. For a review of the patent

literature see article by H. F. Lewis, J. Indust. Engin. Chem., Feb. 1,

1919, p. 141.

Barbital (contracted from the scientific name diethyl-barbituric acid)

for veronal.

Barbital-sodium (the sodium salt of barbital) for “veronal-sodium” and

“medinal.”

Cinchophen for atophan or phenylcinchoninic acid (the U. S. P. IX name).

Procain for novocain hydrochlorid (from “pro” and “(co)caine”).

Procain nitrate for novocain nitrate.

EXAMINATION OF SYNTHETIC DRUGS

In testing chemically the products which had been submitted to the

Federal Trade Commission, the aims were that the product should conform

to a high degree of purity; at the same time the candidate for license

should not be inflicted with undue hardships in making the product,

such as an unnecessarily high degree of purity. It was insisted that

the purity of the drugs should be equal to, if not greater than, that

of the respective former German-made products, in order to uphold the

name and reputation of the American manufacturers in the after-the-war

competition. Consequently, in the chemical work the American product

was always examined parallel with the German-made product, authentic

samples of the latter of which the laboratory had in its possession.

Whenever possible, the tests described in books of standards were

carried out.

BARBITAL (VERONAL)

Barbital was introduced into medicine under the proprietary name

“veronal,” and was manufactured in Germany by Friedr. Bayer &

Co., Leverkusen, and E. Merck & Co., Darmstadt, Germany. Barbital

is described in New and Nonofficial Remedies, 1919,[225] as

diethylbarbituric acid (diethylmalonyl urea) having the formula:

NH—CO C₂H₅

/ \ /

OC C

\ / \

NH—CO C₂H₅

[225] New and Nonofficial Remedies, 1919, published by The Council on

Pharmacy and Chemistry of the American Medical Association, p. 82.

It is official in the British Pharmacopeia under the name

“barbitone,” and in the German Pharmacopeia as “acidum

diethylbarbituricum.” Barbital “may be prepared by the interaction

of esters of diethylmalonic acid with urea in the presence of

metallic alcoholates.... It is also obtained by condensation of

diethylcyanacetic ester with urea by means of sodium alcoholate.”

Barbital is used in medicine chiefly as a hypnotic.

The different brands of barbital which were submitted to the laboratory

were subjected to the tests given in the books referred to above.[226]

The products were:

[226] The pharmaceutic monograph on barbital has been omitted. It was

published in the 1918 edition of the Annual Reports of the Chemical

Laboratory of the American Medical Association.

1. Barbital (Abbott) Sample A, to Federal Trade Commission.

2. Barbital (Abbott) Sample B, to Federal Trade Commission.

3. Barbital (Abbott) Sample C, to Red Cross.

4. Barbital (Antoine Chiris), to Federal Trade Commission.

5. Barbital (V. Halter), to Federal Trade Commission.

6. Barbital (Rector Chemical Company) to Federal Trade Commission.

7. Diethylbarbituric acid (Merck), to Council.

8. “Veronal,” manufactured by Farb. vorm Fried. Bayer & Co., Germany.

All responded satisfactorily to the tests. In Table 1 are given the

respective melting points and percentages of ash found. (The melting

point of a mixture of the sample with the original “veronal” was always

taken.)

TABLE 1.--MELTING POINT

Ash Ash

1 188.5-189.0 0.01 5 188.0-188.5 0.01

2 188.5-189.0 0.01 6 188.0-188.5 0.01

3 188.0-188.5 0.01 7 188.0-188.5 0.01

4 188.0-188.5 0.04 8 188.0-188.5 0.02

Barbital does not seem to form an insoluble salt with chlorplatinic

acid; nor an ether-insoluble hydrochlorid or oxalate; nor an insoluble

barium salt. It does not respond to many urea tests, and is not

affected by urease as would be expected in light of the extensive

investigations made on this enzyme by Van Slyke and Cullen.

As barbital is also sold in the form of tablets or mixtures, a reliable

method for its quantitative determination in the presence of other

substances is needed. Some experiments in this direction were made, but

the press of other work did not permit their continuation. When time

permits, this work will be resumed.

At the time of writing this article, licenses for manufacture had been

granted by the Federal Trade Commission to the Abbott Laboratories, to

Antoine Chiris Company, and to the Rector Chemical Company.

BARBITAL SODIUM (MEDINAL OR VERONAL-SODIUM)

Barbital sodium, formerly sold under the proprietary names

“veronal-sodium” and “medinal,” is, as the former name suggests, the

sodium salt of diethylbarbituric acid. Its therapeutic advantages

are stated to be that more rapid results are obtained because of

its increased solubility over barbital alone.[227] Barbital sodium

should yield, according to theory, 11.19 per cent. of sodium and 89.31

per cent. of diethylbarbituric acid. A number of years ago, when

“veronal-sodium” and “medinal” were being introduced, Puckner and

Hilpert[228] found that these products yielded results corresponding

closely to the theoretical amounts of sodium and diethylbarbituric

acid. A recent examination of veronal-sodium, Merck, made for the

Council on Pharmacy and Chemistry, showed it to be of the same

composition as that previously reported.

[227] New and Nonofficial Remedies, 1918, p. 96.

[228] Puckner, W. A., and Hilpert, W. S.: Veronal-Sodium and Medinal,

J. A. M. A. =52=:311 (Jan. 23) 1909; Rep. A. M. A. Chemical Lab.,

=2=:13.

Only one firm’s product has been submitted to the laboratory through

the Committee on Synthetic Drugs, but because of the unsatisfactory

results, it was not recommended for license, nor, as far as we are

aware, has the firm investigated its anomalies.[229] The amount of

moisture in this specimen was 0.04 per cent. It yielded 10.94 and 10.97

per cent, of sodium. Puckner and Hilpert found 11.02 per cent. of

sodium in “medinal,” and 11.01 per cent. of sodium in “veronal-sodium.”

The theoretical amount, according to the formula given for medinal by

the proprietors (C₂H₅)₂ CCONNaCONHCO is 11.19 per cent. When an aqueous

└───────┘

solution of barbital sodium was acidified, and the diethylbarbituric

acid extracted with ether, it was found that theamount of freed acid

extracted varied directly with the length of time after acidification.

[229] Since this was written, the Council on Pharmacy and Chemistry has

also accepted “Barbital-Sodium Abbott.”

It is possible that in preparing the sodium salt of diethylbarbituric

acid, the ring opens up, forming a compound not so easily affected by

dilute mineral acids.

TABLE 2.--EXTRACTION OF A SAMPLE OF BARBITAL-SODIUM

Diethylbarbituric Acid

Length of Time per Cent.

a. Immediately 75.5

a^1. 3/4 hour 82.0

b. Immediately 82.0

c. 1-1/2 hours 80.5

d. 4 hours 82.82

e. 4 hours 83.56

f. 4 hours 83.41

g. 45-1/2 hours 84.89

h. 45-1/2 hours 84.73

Theory ........ 89.31

Veronal-Sodium (Puckner and Hilpert) 89.01 (average)

Medinal (Puckner and Hilpert) 88.95 (average)

PHENETIDYL-ACETPHENETIDIN HYDROCHLORID[230] (HOLOCAIN HYDROCHLORID)

Phenetidyl-acetphenetidin hydrochlorid was introduced in the

United States under the name of “holocain hydrochloride” by

Farbwerke, vorm Meister Lucius and Bruening, Hoechst a. M. Germany;

the product apparently had not been patented in this country,

although it was protected in Germany under patents No. 78868 and

80568. New and Nonofficial Remedies, 1918, describes “holocain

hydrochlorid” as ethenyl-paradiethoxy-diphenyl-amidin hydrochlorid

CH₃:(NC₆H₄OC₂H₅)(NHC₆H₄OC₂H₅)HCl. It is used as a local anesthetic for

the eye.

[230] No short, scientific name has been given for this substance

although several are under consideration.

The standards, such as had been described, were meager and

unsatisfactory. Hence when the first specimen of American-made

phenetidyl-acetphenetidin was sent to the A. M. A. Chemical Laboratory

through the agency of the Federal Trade Commission and the Committee

on Synthetic Drugs, it was necessary for the laboratory to work out

adequate standards.[231] As a result of the chemical work, a rather

comprehensive monograph was drawn up, which was published in the 1918

Laboratory Reports. A summary of the products examined, with some

of the chemical data, is given in Table 3. It will be seen that one

specimen had a deficiency of about 2 per cent. of free base.

[231] Certain chemical tests are described by E. H. Rankin, Indian

J. M. Res. =4=:237, 1916; also Chem. Abst. =10=:524. Other references

are Schmidt: Pharmazeutische Chemie =2=:990, Beilstein II, (403).

Arends, G.: Neue Arzneimittel und pharmazeutische Spezialitäten, Ed. 4,

1913, p. 271.

TABLE 3.--DATA ON PHENETIDYL-ACETPHENETIDIN HYDROCHLORID [table split

by transcriber to fit small screen]

======================================================================

Melting Phosphorus

Manufacturer Appearance Moisture Point Compounds Phenetidin*

John T. White 5.13 191.5 to 192 Absent Negative

Milliken Co. crystalline

powder

Synthetic White 2.90 192 to 192.5 Absent Negative

Products Co. crystalline

powder

H. A. Metz White 4.99 192 to 192.5 Absent Negative

Laboratories, crystalline

Inc. powder

Farbwerke- Slightly 5.09 190 to 191 Absent Negative

Hoechst Co. pink

(German crystal

specimen)

----------------------------------------------------------------------

======================================================================

Per Per Per Cent.

Cent. Cent. Melting Platinum in

Indol Base by Base by Point Platinum

Manufacturer Reaction Ash Weight Titration of Base Salt +

John T.

Milliken Co. Positive 0.00 89.16 89.16 116 to 117 19.02

Synthetic

Products Co. Positive 0.13 87.49 87.26 116 to 117 19.3

H. A. Metz

Laboratories, Positive 0.00 89.14 88.55 117 19.34

Inc.

Farbwerke-

Hoechst Co. Positive 0.16 89.65 89.64 116 to 117 19.00

(German

specimen)

----------------------------------------------------------------------

* The phenetidin test is not very sensitive.

The melting point of the free base is given by a number of writers at

121 C. Although Kennert[232] stated it to be 117 C. and not 121 C., his

findings seemingly went unheeded. It will be noted that our work shows

the melting point to be in accord with that announced by Kennert.

[232] Kennert: Chem. Zentralbl. =2=:556, 1897.

The Federal Trade Commission has not issued any licenses for the

manufacture of “holocain hydrochlorid.” The John T. Milliken Company

has withdrawn its application. The H. A. Metz Laboratories (Successor

to Farbwerke Hoechst Company, New York) are making the product in this

country.

CINCHOPHEN (PHENYLCINCHONINIC ACID, U. S. P.; ATOPHAN)

Cinchophen (phenylcinchoninic acid) was introduced in the United States

as a medicine under the proprietary name “atophan,” by Schering and

Glatz, New York City, who before the war were the American agents for

the German manufacturers “Chemische Fabric auf Actien von E. Schering,

Berlin.” Phenylcinchoninic acid (2 phenyl-quinolin-4 carboxylic acid)

was first described by Doebner and Gieseke[233] in 1887, who prepared

it by warming together pyro-racemic acid, benzaldehyd and anilin in

alcoholic solution; it has the structural formula:

COOH

╽

╱╲ ╱╲   __

╽ ╽ ╽__╱   ╲

╲╱ ╲╱ ╲ __╱

N

[233] Doebner and Gieseke: Ann. d. Chem. (Liebigs) =240=:291, 1887.

The chief use of phenylcinchoninic acid is as an antiuric acid agent,

especially indicated in gout.

In 1913, the German house of Schering was made the assignee of

patent 1045759 granted by the United States government[234] for the

manufacture of phenylcinchoninic acid: at about the same time the

product was admitted to the U. S. Pharmacopeia IX, under very loosely

constructed standards.

[234] The validity of this patent is to be doubted.

Some time after the beginning of the European war the proprietary

“atophan” became scarce in America. In 1917, however, Schering and

Glatz, New York, placed American-made atophan on the market and

submitted it to the Council on Pharmacy and Chemistry. Later, other

firms began to manufacture the product and also submitted specimens.

During the time it was investigating these products, the Federal

Trade Commission decided that a license was needed to manufacture

phenylcinchoninic acid under the patent just referred to, so that

altogether the laboratory had a number of specimens to examine.

In making the examinations for the Council, the laboratory was

practically confined, by virtue of the Food and Drugs Law, to limit

its requirements of purity to those of the Pharmacopeia. Practically,

the only tests were melting point, ash and solubility. According

to the U. S. Pharmacopeia the melting point is “about 210.” In New

and Nonofficial Remedies, 1918, it was explained that atophan

“complies with the standards for phenylcinchoninic acid, U. S. P.,

but melts between 208 and 212 C.” The U. S. Pharmacopeia requires

that no weighable ash remains on incinerating about 0.5 gm. of

phenylcinchoninic acid. Considerable variations, especially in melting

points, were found, as can be seen from Table 4.

TABLE 4.--MELTING POINTS AND ASH

Product Manufacturer Melting Ash,

No. Point, C. %

1 Abbott Laboratories, Chicago 208.5-210.5 0.05

2 Abbott Laboratories, Chicago 212-213 0.05

1 Calco Chem. Co., Bound Brook 209-210.5 0.07

1 Morgenstern, New York 204.5-207.5 2.8

2 Morgenstern, New York 208.5-211.5 None

1 Schering and Glatz, New York 206-208 None

2 Schering and Glatz, New York 209-211 None

3 Schering and Glatz, New York 208.5-210 0.17

4a Schering and Glatz, New York (1) 208.5-210 0.2

4b Schering and Glatz, New York (2) 208.5-209.5 0.3

4c Schering and Glatz, New York (3) 208.5-210 0.025

1 Wm. H. Sweet and Co., Columbus 204-208 None

2 Wm. H. Sweet and Co., Columbus 209.5-211.5 0.04

1 German specimen from Schering and Glatz 210-212 None

By referring to this table on melting points and ash content it will be

noted that the production of a better grade of products resulted after

the respective firms had submitted samples to the A. M. A. Chemical

Laboratory for criticism, and from a chemical standpoint, the last

products examined were found to be as satisfactory as the German-made

“atophan.”

_Solubility of Cinchophen (Phenylcinchoninic Acid)._--As methods

of determining impurities, or estimating the degree of purity of

phenylcinchoninic acid were not described in the U. S. Pharmacopeia,

it was decided to try extraction methods.[235] This in turn led to the

question of solubilities. The U. S. Pharmacopeia gives the solubility

of phenylcinchoninic acid only in general terms; hence it was deemed

advisable to determine its solubilities and describe them in more

definite terms. The sample of phenylcinchoninic acid employed to

determine the solubility was obtained by repeated recrystallization

from alcohol of a commercial specimen. Solubilities were determined in

water; 95.0 per cent. alcohol; 48.5 per cent. alcohol;[236] chloroform

and ethyl acetate.[237] Complete saturation of the solvent was attained

according to the U. S. P. IX method (p. 599). The bath was maintained

at a temperature of 25 C., with a range of ± 0.2 degrees. The solution

was analyzed by the method of Seidell.[238] The data obtained for the

solubility of phenylcinchoninic acid are given in Table 5.

TABLE 5.--SOLUBILITY OF CINCOPHEN

Gm. per Hundred Solubility,

Gm. of Parts by

Solvent Sat. Solution Weight

Distilled water 0.0160 1 in 6,216.0

95 per cent. ethyl alcohol 0.8343 1 in 119.0

Dilute ethyl alcohol 0.0875 1 in 1,142.6

Chloroform, 0.1075 1 in 929.7

Ethyl acetate 1.4151 1 in 70.6

[235] Attempts were made to make salts of phenylcinchoninic acid

with metals such as copper, mercury, barium and calcium, and also

the chloroplatinic acid or periodid addition products. Reliable

quantitative results could not be obtained.

[236] This corresponds to “diluted alcohol, U. S. P.”

[237] The ethyl acetate was Merck’s product (redistilled), stated to

contain 81.6 per cent. of ethyl acetate, 10 per cent. alcohol and

alcohol derivatives.

[238] Seidell, A.: Bull. 67, Hyg. Lab., U. S. P. H. S., p. 11.

The Abbott Laboratories, Chicago, have been licensed by the Federal

Trade Commission to manufacture cinchophen. Other firms, however, have

decided to manufacture it without the formality of obtaining a license,

evidently considering the German-obtained patent not to be valid.[239]

[239] Very recently the Chemical Foundation, Inc., has undertaken to

grant licenses for cinchophen. The Calco Chemical Company has obtained

one.

PROCAIN (NOVOCAIN)

Procain was introduced in medicine under the proprietary name

“novocain,” and before the war was obtainable in this country only

through the Farbwerke Hoechst Company, the American representative

of the German establishment, Farbwerke vorm Meister Lucius

Bruening, Hoechst a. M. Chemically it is the mono-hydrochlorid of

para-amino-benzoyl-diethyl-amino-ethanol, having the structural formula:

[Illustration: NH₂--(benzene ring)COO-CH₂-CH₂--N(C₂H₅)₂.HCl]

It is prepared according to U. S. patent No. 812554 (issued to Alfred

Einhorn, Munich, Germany) by treating para-nitro-benzoylchlorid with

ethylene chlorhydrin and diethylamin with subsequent reduction of the

nitro groups, the resulting product being purified by recrystallization.

Procain is employed largely in infiltration anesthesia. It is less

toxic than cocain, but its anesthetic action is not sustained. This

drawback is overcome by the simultaneous injection of epinephrin, and

for this reason procain is often compounded with epinephrin in tablets,

thus obviating the necessity of separate solutions.

When the first specimens of the American-made product were submitted

through the channels of the Federal Trade Commission, it was necessary

to compile a monograph.[240] This was prepared from descriptions in

the available literature, mostly from tests described in New and

Nonofficial Remedies, 1918, and the German Pharmacopeia V.

[240] The monograph appears in New and Nonofficial Remedies, 1919.

The submitted products were found satisfactory chemically. The toxicity

determinations made by Dr. R. A. Hatcher, with the assistance of

Dr. Carey Eggleston[241] indicated that none of the specimens are

to be considered dangerous when used in ordinary dosage for normal

individuals. Therefore the Federal Trade Commission, on recommendation

of the Committee on Synthetic Drugs of the National Research Council

(aided by the A. M. A. Chemical Laboratory), issued licenses for the

manufacture of procain to the Farbwerke-Hoechst Company (which license

was later transferred to the H. A. Metz Laboratories), to the Abbott

Laboratories, to the Calco Chemical Company and to the Rector Chemical

Company.

[241] The report of these and subsequent toxicity experiments on

procain appeared in the report of the Council on Pharmacy and

Chemistry, J. A. M. A. 72: 136 (Jan. 11) 1919.

Subsequently the products of the licensed firms were submitted to the

Council on Pharmacy and Chemistry, which in turn invoked the aid of the

A. M. A. Chemical Laboratory and the Cornell University Pharmacologic

Laboratory. Later the Council asked the laboratory to examine the

_market_ supply. Altogether, therefore, a number of products were

examined which were found to respond satisfactorily to the tests

outlined (Table 6).

TABLE 6

=============================================================

Date Melting Ash,

Brand Received Color Point, C.* %

Procain (Abbott), 12/21/17 White 154-155 None

from Committee

on Synthetic Drugs

Procain (Abbott), 1/29/18 White 153.5-154.5 None

submitted to Coun-

cil P. and C.

Procain (Abbott), 8/31/18 White 152.5-153.5 None

Gen. Pur. Off.

U. S. Army

Procain (Abbott), 9/30/18 Slight 153-154.5 None

Gen. Pur. Off. brownish

U. S. Army, tint

No. 89999

Procain (Abbott), 9/30/18 Slight 153-154. 0.005

Gen. Pur. Off. brownish

U. S. Army, tint

No. 89998

Procain (Abbott), 10/8/18 Slight 153-154 None

Gen. Pur. Off. brownish

U. S. Army, tint

No. 89997

Procain (Abbott), 11/4/18 Slight 153.5-154.5 None

Gen. Pur. Off. brownish

U. S. Army, tint

No. 89996

Procain (Abbott), 11/4/18 Slight 153.5-154.5 None

Gen. Pur. Off. brownish

U. S. Army, tint

No. 810995

Procain (Calco), 2/7/18 White 153.5-154.5 None

from Committee

on Synthetic Drugs

Procain (Farbwerke- 10/24/18 White 153-154 None

Hoechst Co.), sub-

mitted to Council

Procain (Farbwerke- 12/10/17 White 153-154.5 None

Hoechst Co.),sub-

mitted to Council

Procain (Farbwerke- 8/9/18 White 153.5-154.5 None

Hoechst Co.), sub-

mitted to Council,

market spec. “A 56”

Procain (Farbwerke- 9/9/18 White 153.5-154.5 None

Hoechst Co.), sub-

mitted to Council,

market spec. “A 57”

Procain (H. A. Metz 8/23/18 White 153-154 None

Lab.), market spec.

“A 63”

Procain (H. A. Metz 9/23/18 White 153-154 None

Lab.), market spec.

“A 57”

Procain (Rector), 12/18/17 White 153-154.5 None

from Committee on

Synthetic Drugs

Procain (Rector), 5/2/18 White 152.5-153 None

from Committee on

Synthetic Drugs

Procain (Rector), 8/20/18 Slight 153-155 None

market spec brownish

tint

Procain (Rector), 8/23/18 Slight 153-155 None

market spec brownish

tint

Procain (Rector), 8/23/18 Slight 153-154.5 None

market spec brownish

tint

-------------------------------------------------------------

* U. S. Patent 812,554--the novocain patent--declares that the salt

melts at 156 C. Evidently based on this, both the German Pharmacopeia

and past editions of New and Nonofficial Remedies give this melting

point. Two specimens of German-made novocain obtained from our files,

stated to be manufactured by Farbwerke-Hoechst vorm. Meister, Lucius

and Bruening, Hoechst a. M., were found to melt, respectively,

between 154 and 155 C. and between 153.5 and 154.5 C. when the

melting point was determined according to the direction of the U. S.

Pharmacopeia, ninth revision. The various specimens examined at that

time melted between 153 and 155 C., and it was decided to permit this

range.

An examination of some American-made procain-suprarenin tablets was

also made. The procain was determined by liberation of the alkaloid

with ammonia water, extraction with chloroform, evaporation of the

chloroform, dissolving the alkaloid in one hundredth normal sulphuric

acid solution and titrating excess acid with one hundredth normal

sodium hydroxid solution. The epinephrin was determined according to

the method employed by Seidell,[242] with slight modifications. The

tablets contained the claimed amounts of ingredients.

[242] Seidell: J. Biol. Chem. 14: 19, 1913.

THE SYNTHETIC DRUG SITUATION

Before the war, the American physician was literally bombarded with new

and wonderful (?) coal-tar synthetics, most of which were originated

in Germany. In fact, it seemed that if a by-product in the manufacture

of dyes could not be used for a dye per se, then a place might be

found for it in the ever increasing lists of medicaments. By clever

advertising and propaganda among physicians, an artificial stimulation

for coal-tar drugs was created which evidently yielded lucrative

financial returns. As a result of the war, it is interesting to observe

that of all the synthetic drugs imported into this country from Germany

and on which the American patents were controlled by the Germans (up

to the time of our entrance into the war), the demand was really

sufficient enough to warrant the commercial manufacture of only four

of them by American firms. Of course, a larger number of _nonpatented

drugs_, also imported from Germany, are now being made in sufficient

quantities in this country; many of the drugs in this class were never

patented or are the ones which have survived after the patent had

expired, such as acetanilid, acetphenetidin, and acetylsalicylic acid.

In view of the agitation to found an institute for cooperative research

as an aid to the American drug industry under the auspices of the

American Chemical Society, it will be well for the medical profession

to be on its guard against too enthusiastic propaganda on the part of

those engaged in the laudable enterprise of promoting American chemical

industry. Unless it is, it may be inflicted in the future, as in the

past, with a large number of drugs that are either useless, harmful or

unessential modifications of well-known pharmaceuticals. It will be

well also for the chemists--those engaged in this enterprise--to be

sure that the product is of therapeutic value before asking its use as

a medicine. The American medical profession has learned that relatively

few of the many German synthetics were really valuable or decided

improvements over established drugs. If American chemists desire

to retain their prestige with the medical profession, they should

earnestly endeavor to see that the advantages derived from the war and

from such an institute as proposed are not abused in the worthy desire

to popularize chemistry both educationally and commercially. They

should realize that physicians are in no receptive mood for a flood of

synthetics, even though “American-made.”

On the other hand, the constructive possibilities of chemistry in the

service of medicine should serve as a stimulus for American research.

Notwithstanding all the pharmaceutical shrubbery which Germany sent

to us, still it did contain some synthetics that were worth while.

As therapeutics has been benefited by these organic chemicals, it is

logical to reason by analogy that there remain other synthetics to be

discovered which will occupy places of equal distinction in the modern

materia medica. For example, vaccines are of undoubted merit in the

field of immunology, but their action is, in the end, chemical; as soon

as chemical technic is refined by medicochemical research, it is quite

possible that a definite chemical agent (synthetic) will supersede

the indefinite bacterial vaccine. Obviously the American chemist has

the opportunity of showing his resourcefulness in aiding the public

health of America and the world. In this connection, a cooperative

institute devoted to purely scientific drug research, and governed

in such a manner as to inspire confidence in its humanitarianism

and unbiased judgment, should serve a most commendable purpose.

The hopes of American men of science are for a monumental research

institution--cooperative with all the allied professions--and, as the

_Chicago Chemical Bulletin stated_, “Stripped of all professional

or commercial pettishness and not dominated by any one group of

scientists.”[243]

[243] Proposed Institute for Drug Research, editorial Chicago Chem.

Bull., April, 1919, p. 67.

CONCLUSIONS

As for the results of the work so far, they can be summed up in two

sentences.

1. American chemists are producing synthetic drugs formerly controlled

by Germany, and thus have declared their independence of German

chemicals.

2. Judging from the evidence at hand, we can feel assured that the

quality of American synthetics will be second to none.--(_From The

Journal A. M. A., Sept. 6, 1919._)