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. (41⁄4 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.)