Chapter XXXI: Foreword: The Chemical Laboratory of the American Medical Association (3)

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.