PART II

CONTRIBUTIONS FROM THE A. M. A. CHEMICAL LABORATORY

FOREWORD

THE CHEMICAL LABORATORY OF THE AMERICAN MEDICAL ASSOCIATION

The Chemical Laboratory of the American Medical Association was established in 1906 to assist the Council on Pharmacy and Chemistry in the investigation of proprietary remedies.

In accordance with the principle of its foundation, the Laboratory examines and checks the claims made for the composition and chemical properties of the products under examination by the Council, and when these are admitted to New and Nonofficial Remedies, it insures the establishment of tests and standards whereby the identity and purity of these products may be controlled. In addition, the Laboratory supplies information, secured by reference to chemical and pharmaceutical literature or by actual analytic work, in regard to proprietary and unofficial medicines, either for publication in _The Journal of the American Medical Association_ or through direct correspondence.

Those portions of the Laboratory’s activities which are of special interest to physicians and which were not included in the Reports of the Council on Pharmacy and Chemistry were included in the Propaganda for Reform in Proprietary Medicines, ninth edition (1916), so far as they had been published up to the time when the edition was issued; those made during the last five years are included in Part II of this volume.

For a detailed report of the Laboratory’s work, the reader is referred to the article that follows on “The Work of the American Medical Association Chemical Laboratory.” Those who are interested in the analysis of drugs are referred to the Reports of the Chemical Laboratory issued annually for the details of the analyses which have been made by the Laboratory.

THE WORK OF THE AMERICAN MEDICAL ASSOCIATION CHEMICAL LABORATORY[E]

W. A. Puckner, Phar.D.

[E] Read before the Section on Pharmacology and Therapeutics at the Sixty-Seventh Annual Session of the American Medical Association, Detroit, June, 1916.

The American Medical Association Chemical Laboratory was established nearly ten years ago--in fall of 1906. The reason for its existence was primarily the fact that the Council on Pharmacy and Chemistry found it difficult to secure from outside sources such help as it needed in checking up the composition and properties of proprietary medicines under investigation. Medical schools and similar institutions were found ready to lend their assistance in pharmacologic and medical investigations; but the chemical investigation required the establishment of a laboratory under the control of the American Medical Association.

As years have passed, the scope of the laboratory has been extended: Its services have been requisitioned by The Journal in various ways. Thus, when requested, the laboratory reviews and verifies the chemical data contained in editorials and original contributions. The laboratory is often called on for information as to the character and composition of quack treatments and so-called “patent medicines.” Through the columns of The Journal and through direct correspondence, the laboratory responds to requests of physicians with information regarding the composition of medicines which they prescribe or in which they are interested. The laboratory attempts to be to the members of the American Medical Association what the prescription pharmacist is, or should be, to the prescribing physician--a storehouse of chemical and pharmaceutical information. In the belief that an insufficient familiarity with the chemistry and pharmacy of drugs constitutes the chief reason for the extensive use of unscientific, worthless or fraudulent proprietary remedies, this service is rendered by the laboratory as a contribution to the cause of rational therapy.

Since the efficiency of the American Medical Association Chemical Laboratory will increase as its activities are better known, the following more detailed statement of its work is offered:

THE LABORATORY AND THE COUNCIL

As stated in the rules of the Council on Pharmacy and Chemistry, it is “manifestly impossible for the Council to investigate the composition of every complex pharmaceutical mixture ...”; “it can only give an unbiased judgment on the available evidence.” In line with this, the laboratory does not undertake to prove the composition of constitution of all new synthetics, nor does it attempt to determine the individual composition of proprietary mixtures. It checks all claims that seem doubtful, however, and uses its best endeavors to secure correction of misstatements with regard to proprietary remedies and improvement in the quality of these products. Further, it reexamines, when this seems desirable, the products which have been admitted by the Council to New and Nonofficial Remedies, and thus determines, from time to time, their dependability. The fact that no product admitted to New and Nonofficial Remedies has later been shown to be untrue to its claimed composition is, it is believed, an indication that in this respect the laboratory has succeeded in performing the work for which it was primarily created.

In this connection the question may be asked, Are many proprietary medicines exploited to the medical profession with false claims in regard to their composition? Also it may be asked, Has the number of proprietaries marketed with false statements of composition decreased since the Council and the laboratory began their work? Answering the latter question first: There is no doubt that today fewer proprietary medicines are being sold with false claims as to composition than there were ten years ago. When the Council began its work, medical journal advertising teemed with statements regarding the composition of medicines which any chemist familiar with medicine would not hesitate at sight to brand as untrue. Today such manifestly false claims are rare. Coming to the former question: Many false statements regarding the identity and composition of remedies have been made in ignorance. This is not surprising when it is remembered that the most ignorant may and do engage in the manufacture of medicine. Besides ignorance, however, an accommodating conscience on the part of the manufacturer and a failure on the part of the medical profession to appreciate the danger which lies in the use of medicines of unknown composition unquestionably have greatly encouraged the marketing of falsely declared medicines. A glaring illustration of the ignorance of manufacturers--for it is hard to believe that any business concern would deliberately court prosecution by the federal authorities through false statements on labels--is the fact that nearly thirty years ago A. B. Lyons published a report[147] pointing out that the proprietary Iodia was falsely declared as to composition and that in 1914 when the Council examined this preparation such incorrect declaration appeared on the label.[148] That many physicians do not recognize the danger to their patients and their reputation in the use of medicines, the composition of which they do not know, is illustrated by the fact, disclosed by inquiries sent to the laboratory, that physicians were found willing to employ an arsenical preparation (Venarsen), advertised for intravenous use, although its promoters vouchsafed no information in regard to the nature of the arsenic compound contained therein.

[147] Lyons, A. B.: Detroit Lancet, 1882, 6, 157.

[148] The Journal A. M. A., Nov. 21, 1914, p. 1871.

UNRELIABILITY OF LITTLE USED DRUGS

The purpose of the federal Food and Drugs Act is to secure the prosecution and punishment of all who sell medicines which are adulterated or misrepresented as to composition. As a matter of fact, the wording of the law relating to the adulteration and misbranding of drugs is such that the federal authorities have been able to do little more than to require that the drugs for which standards are provided in the Pharmacopeia shall when sold comply with those standards. Similarly, those states which attempt to improve the quality of drugs sold within their borders--few states do efficient work along these lines--limit their work to the enforcement of the Pharmacopeial standards. This leaves the vast number of unofficial drugs and medicaments beyond the control of federal or state authorities. While most of these drugs are relatively unimportant, and while the amounts of them which are used are not great individually, the total consumption of them is large. With a view of furnishing to physicians standards for drugs of this sort the Council has described in New and Nonofficial Remedies not only distinctly proprietary drugs, but also some of the unofficial drugs which are apparently of therapeutic value and used to a considerable extent. Aiding the Council in this line of endeavor, the laboratory has attempted to establish standards for these little used drugs, and New and Nonofficial Remedies, 1916, provides standards for such unofficial and non-proprietary drugs as quinin and urea hydrochlorid quinin, tannate, sodium acid phosphate, and sodium perborate. An example of work which furnished much needed standards for an unofficial article is the investigation of zinc permanganate by W. S. Hilpert.[149] Reference to the published reports of the laboratory will give an idea of the amount of work such standardization entails. A reference to the new U. S. Pharmacopeia, when this comes from the press, will show that a considerable number of unofficial articles described in New and Nonofficial Remedies have been admitted to the Pharmacopeia along with the standards worked out in this laboratory.

[149] Zinc permanganate, J. A. M. A., Feb. 6, 1909, p. 488; Reports Chem. Lab. =2=:15, 1909.

While in a way the work done in connection with these less important drugs has attracted little attention from the medical profession, it has had an effect on pharmaceutical manufacturers. In the past, pharmaceutical houses, ever anxious to market something new, on the slightest provocation have placed on the market, in the form of pills, powder, elixir, ampule, etc., every drug for which some sort of medical recommendation could be found. In marketing these dosage forms, the manufacturer has too often been little concerned about the quality of the drugs used.[150] Just at present, for instance, some interest is being shown in iron cacodylate; but while manufacturers appear to be most ready to take advantage of this interest by offering the drug in the form of ampules, etc., they have given little help toward the establishment of standards for this arsenic compound. Manufacturers are ever ready to sell drugs of all sorts, but in view of the small demand they cannot or will not safeguard the identity and purity of such drugs. A further illustration of the unreliability of unofficial drugs is the recent report by Levy and Rowntree[151] showing not only that the various dosage forms of emetin hydrochlorid obtained from different manufacturers varied from manufacturer to manufacturer, but also that the product of the same manufacturer was variable and that the supply furnished by one pharmaceutical firm was so toxic as to make its use dangerous.

[150] The Unreliability of Unimportant Medicaments, The Journal A. M. A., Sept. 28, 1912, p. 1156.

[151] Levy, R. L., and Rowntree, L. G.: On the Toxicity of Various Commercial Preparations of Emetin Hydrochlorid, Arch. Int. Med., March, 1916, p. 420.

THE ANALYSIS OF “PATENT MEDICINES”

In the preface to the first annual report of the chemical laboratory it was stated that the laboratory “occasionally takes up the examination of ‘patent medicines’ ...” At that time it was felt that the widespread use by the medical profession of irrational and even secret medicines made it necessary to devote the laboratory’s attention to the correction of this evil. As the years have passed on, these conditions have been remedied to some extent, at least so far as chemical analysis can correct them. On the other hand, public opinion has been aroused to the many evils connected with the exploitation of “patent medicines,” and has more and more insistently demanded that the medical profession aid in the correction of this evil. Accordingly, the laboratory has paid much attention to the analysis of “patent medicines” during the last few years. As the chief asset of “patent medicines” is the element of secrecy which surrounds their composition, it is hoped that the laboratory’s analysis of such widely used “patent medicines” as Nature’s Creation,[152] Mayr’s Wonderful Stomach Remedy,[153] Sanatogen,[154] Eckman’s Alterative,[155] Tonsiline,[156] and Bromo-Quinin[157] has been worth the labor. In addition, the work of this laboratory has been published, including not only the results of its analyses, but also the methods which are used. In view of the dearth of published reports regarding the methods used in the analysis of “patent medicines,” it is hoped that this feature of the laboratory’s work has been of aid to chemists engaged in similar work.

[152] The Journal A. M. A., March 5, 1910, p. 806.

[153] The Journal A. M. A., Aug. 19, 1911, p. 671.

[154] The Journal A. M. A., April 20, 1912, p. 1216.

[155] The Journal A. M. A., April 27, 1912, p. 1298.

[156] The Journal A. M. A., April 4, 1914, p. 1109.

[157] The Journal A. M. A., Nov. 27, 1915, p. 1932.

The laboratory’s activities along these lines have done much to discount the claim of proprietary manufacturers that chemical analysis is unable to determine the character of “patent medicines.” The recent Wine of Cardui trial has brought it out prominently that chemical analysis can determine the presence of potent constituents, and that “patent medicines” which fail to reveal such potent ingredients to the analyst may safely be put down as worthless. The demonstration that the essential composition of medicinal preparations may be determined by chemical analysis should also prove an effective answer to the manufacturers in their protest against the requirement, now being urged for enactment into law in various states, that the medicinal ingredients of their wares must be declared on the label. Manufacturers have held that this would lay them open to competition with imitations and substitutions. The possibility of chemical identification proves, however, that secrecy of composition, though it prevents consumers from knowing the character of a “patent medicine,” will not be a hindrance to the imitator and substitutor.

IDENTITY OF DRUGS USED IN INVESTIGATIONS

In the past, much of the experimental work in medicine has seriously suffered in that the identity of the material used in such investigations was not established. In view of this the laboratory has watched the contributions submitted to The Journal, and whenever necessary and feasible has urged the authors to identify their material before publication of the findings. For instance, a number of staining agents--so-called “anilin dyes”--have been found to possess therapeutic action. Since the identity of many of these staining agents is today essentially secret, the laboratory has urged through The Journal that those who experiment with these substances make an effort to determine their identity whenever possible and to give preference to those the chemical identity of which is known. The need for such identification has been discussed in the reports of the laboratory.[158] The amount of work involved in the chemical identification of drugs used for experimental work is illustrated in a contribution entitled “An Examination of Several Commercial Specimens of Opium Alkaloids or Their Salts.”[159] by L. E. Warren, in which was determined the identity of the various opium products used in an investigation by D. I. Macht, carried out under a grant of the Therapeutic Research Committee.

[158] Reports A. M. A. Chemical Laboratory, 1912, v, 102.

[159] Am. Jour. Pharm., 1915, 87, 439.

THE LABORATORY AND PHARMACEUTICAL LITERATURE

In the past much of the information in regard to the composition and properties of medicines which has appeared in pharmaceutical journals has not become available to medicine. In many cases medical journals could not afford to publish such data because this would have been contrary to the interest of their advertisers, and hence the publications regarding the irrational character of Lactopeptine, of Bromidia, etc., which appeared in the pharmaceutical journals did not become a matter of common medical knowledge. Through the laboratory an attempt has been made to keep the medical profession informed in regard to pharmaceutical literature. The laboratory has a good working pharmaceutical and chemical library, and subscribes to the important American and foreign pharmaceutical and chemical publications. The discussion of new remedies, such as medinal and sodium veronal,[160] salvarsan, atoxyl and arsacetin,[161] and neosalvarsan[162] soon after their introduction, illustrates the work of the laboratory along these lines.

[160] The Journal A. M. A., Jan. 23, 1909, p. 311.

[161] The Journal A. M. A., Dec. 31, 1910, pp. 2303 and 2314.

[162] The Journal A. M. A., Oct. 5, 1912, p. 1295.

THE LABORATORY’S EFFORTS TOWARD RATIONAL PRESCRIBING

The laboratory naturally is in thorough sympathy with the present day efforts toward a more rational use of drugs, as exemplified in the Council’s publication “Useful Drugs.” Two recent contributions of the laboratory may be cited as a further support of the movement for limiting prescribing to the more widely used drugs. In line with the general tendency of manufacturers to put out all sorts of modifications and asserted improvements over official substances, there have been placed on the market a number of preparations said to represent some improvement over the pharmacopeial Blaud pills. The report, “The Quality of Commercial Blaud’s Pills,”[163] by L. E. Warren, shows that the ordinary pharmacopeial Blaud pill is in every way the equal of the semiproprietary preparations claimed to be improvements. Further, the examination of the various brands of sodium and theobromin salicylate as compared with the preparation diuretin by P. N. Leech[164] shows that the former preparations, sold at 35 cents per ounce at the time the examination was made, are fully the equal of the proprietary Diuretin, which then cost the druggist $1.75 per ounce.

[163] The Journal A. M. A., April 17, 1915, p. 1344.

[164] The Journal A. M. A., April 4, 1914, p. 1108.

THE LABORATORY AS AN INFORMATION BUREAU

It is generally admitted that the proprietary medicine business, particularly the exploitation of complex mixtures, attained the extensive vogue which it has or had because instruction in medical schools was deficient in materia medica, pharmacy and chemistry. As a result of lack of knowledge along these lines, the young graduate after some trial became fearful of formulating his own prescriptions, and in time became dependent on pharmaceutical firms which provided him with medicines ready to dispense. That physicians have been insufficiently trained in regard to the pharmacy and chemistry of drugs has often been emphasized in pharmaceutical journals where prescriptions containing incompatible drugs are reported and where even plans are brought forward whereby the pharmaceutical profession may aid in remedying this difficulty.

During my pharmaceutical experience I was often sorely vexed as to what to do when prescriptions contained drugs which on mixing would undergo decomposition which the physician surely did not anticipate. I remember well a prescription directing that potassium permanganate be made into pills with extract of gentian and other things, and how, the physician having spurned the suggestion to modify the prescription so as to avoid decomposition of the permanganate, I was obliged to select a mortar, gently triturate the drugs until a conflagration was started, and to finish the prescription after the combustion had subsided. However, in my pharmaceutical experience I generally found the physician most ready to receive suggestions from the pharmacist which would prevent incompatibilities, improve the palatability and appearance of his prescriptions, and protect the patient from unnecessary expense.

Similarly it has been my experience since the establishment of the Association’s laboratory that physicians are anxious to receive information in regard to the materia medica, pharmacy and chemistry of drugs. As the druggist earns the respect and support of the physician when he makes available to him the pharmaceutical knowledge and experience which he has, so this laboratory has aimed to gain the endorsement of the American Medical Association membership by furnishing to physicians information in regard to the composition, chemistry and pharmacy of drugs through replies in the Query and Minor Notes Department of The Journal as well as through direct correspondence. It has been most gratifying to the laboratory that The Journal receives an increasing number of inquiries both as regards the chemical and pharmaceutical questions involved in the writing of prescriptions and as regards the composition of secret and semisecret proprietaries (often because they are prescribed by the inquirer’s colleague) and “patent medicines” (which are taken by his patient). The laboratory has tried its best to answer the many inquiries received. Many of the questions which come in can be answered by a pharmacist or chemist without hesitation. Others, particularly as to the composition of medicines, the laboratory has been able to answer by reference to its library and its extensive card index. Still others have required experimentation and chemical analysis.

While, as stated a moment ago, the laboratory has encouraged the sending of inquiries and has earnestly striven to furnish the information asked for, it is obvious that the amount of chemical work which can be done is limited. The small size of the laboratory force, consisting of three chemists engaged in actual analytical work, makes it necessary to select for investigation those problems which shall be of general interest to the medical profession. As the American Medical Association is national in its scope, the laboratory has held that it can do analytical work only when such work will be of general interest to physicians and of value both to the medical profession and the public. In view of this it has refrained from undertaking analyses which would benefit only the physician making the inquiry and possibly his patient. The laboratory further has not felt justified in undertaking work of merely local interest; instead it has used its endeavors to secure the investigation of such local problems by municipal or state authorities.--(_From The Journal A. M. A., Nov. 25, 1916._)

LEAD IN “AKOZ”

Akoz is a mineral product sold by the Natura Company of San Francisco, and said to possess most remarkable medicinal properties.

A circular issued by the Natura Company begins thus:

“While scientists have been striving through the centuries to compound remedies for man’s various ills, Nature, greatest chemist of them all, has been working wonders in her crucibles and has achieved results far beyond man’s greatest expectation.”

“Nature’s chief handicap has been the difficulty of placing her gifts in the hands of those whom she would benefit. By accident or fate, as you will, one of Nature’s greatest medicinal products has just been discovered. It is the mineral given the name of Akoz by John D. Mackenzie, president and manager of the Natura Company of San Francisco, which is now giving this rare remedy of Nature to the public.”

The circular then describes how the power of the “rare remedy” to cure rheumatism is claimed to have been discovered and asserts that:

“Akoz was subjected to every known scientific test before being presented to the public. It was practically determined that the ore contained a new element having radium-like qualities but containing nothing poisonous or harmful.”

“After the curative virtues of Akoz for rheumatism, stomach trouble, eczema, catarrh, piles, ulcers and numerous other ailments had been fully established in chemical laboratory, hospital clinic, and the private practice of physicians in various parts of the world, Mr. Mackenzie effected the organization of the Natura Company.”

This product, put up in the form of “Akoz Medicinal Mineral Water, Akoz Ointment, Akoz Powder and Akoz Suppositories,” was submitted to the Council on Pharmacy and Chemistry for consideration some years ago with the claims that “Akoz” itself consists essentially of zinc sulphid, barium sulphate and aluminum oxid. The submitted analysis did not declare the presence of lead or of uranium though “special tests” for the latter had been “run.” Without checking the claimed composition, the Council at that time refused recognition to Akoz because there was no evidence submitted for the very extravagant and altogether improbable therapeutic claims.

After the Council had concluded the consideration of Akoz a letter was received from a California physician stating that according to an analysis submitted to him Akoz contained 0.34 per cent. of lead in the form of lead sulphate. The correspondent held that, while the lead sulphate did not pass into solution, persons drinking the supernatant liquid from Akoz (the “medicinal mineral water” is made by adding Akoz to ordinary water) might inadvertently swallow some of the powder. He was inclined to believe that this might account for a case of lead poisoning which had been observed in a patient who had been taking Akoz.

Inasmuch as it has been demonstrated by Carlson and Woelfel (Carlson, A. J., and Woelfel, A.: Solubility of Lead Sulphate and Basic Lead Carbonate in Human Gastric Juice.... In Hygiene of the Painter’s Trade by Alice Hamilton, Bull. of U. S. Bureau of Labor Statistics No. 120, May 13, 1913, pp. 22-32) that even small quantities of lead sulphate when taken into the system for a long time, have produced lead poisoning, the laboratory deemed it important that the products be examined for lead.

A specimen of “Akoz Powder” submitted to the Council by the Natura Company and contained in a sifter-top can was taken for analysis. The contents of the can were thoroughly mixed. To determine the presence of lead some of the powder was extracted with ammonium acetate solution.

Details of Analysis

Qualitative tests showed the presence of lead and sulphate in the ammonium acetate solution.

The presence of lead was demonstrated by the black precipitate with hydrogen sulphid, the yellow precipitate with potassium chromate and the typical yellowish crystalline precipitate with potassium iodin.

The presence of sulphates in the ammonium acetate solution was shown by the formation of a precipitate with barium chlorid solution and acetic acid.

Two 2 gm. samples (A and B) were taken for the quantitative determination of lead. Each was treated repeatedly with a saturated solution of ammonium acetate until the filtered ammonium acetate solution gave no appreciable precipitate with potassium chromate solution. The ammonium acetate extractions from each specimen were combined and treated with hydrogen sulphid, the precipitated lead sulphid filtered off and washed, and ignited with sulphuric acid at a low heat. The crucible with the residue of lead sulphate was cooled and weighed.

A yielded 0.0469 gm., or 2.34 per cent., lead sulphate.

B yielded 0.0440 gm., or 2.20 per cent., lead sulphate.

While the laboratory has no evidence to show that the amount of lead-sulphate thus found to be present is likely to prove harmful, the following cautionary letter was sent to the Natura Company:

“According to information which you sent to the Council on Pharmacy and Chemistry your product “Akoz” does not contain lead. In view of reports received ascribing symptoms, resulting from the internal use of Akoz, to chronic lead poisoning, an examination of a specimen of Akoz Powder, which you sent to the Council, was made. This examination indicates the presence in Akoz Powder of about 2.2 per cent. lead sulphate. In view of the disastrous results likely to follow the internal use of products containing even small amounts of lead, the above is submitted to you for your consideration.”

No reply to the foregoing was received from the Natura Company.--(_From Reports A. M. A. Chemical Laboratory, 1916, p. 103._)

SODIUM ACETATE IN WARMING BOTTLES

Recently the laboratory’s attention was called to the “ThermoR Waterless Hot Bottle,” manufactured by the Royal Thermophor Sales Co., New York. The following claims appear in one of the advertising pamphlets:

“There is moist heat.” “Rubber hot-water (? ? ?) naturally give a _moist_ heat.” It (ThermoR) gives a _dry_ heat.

“The ‘THERMOR’ Bottle is _not_ a hot-water bottle--it acts on a principle that is entirely different and new.”

“... gives you _first, last and all the time_ a fixed degree of dry usable heat--a heat that holds steadily at 125 degrees for fully twelve hours--you will easily see why it is that ‘THERMOR’ relieves and cures where hot-water bottles fail.”

The bottle was nickel plated, 8-3/8 inches in diameter and 1-1/2 inches thick, and in appearance resembled an exaggerated closed Ingersoll watch.

The bottle is not flexible and weighs 3-1/2 pounds. The contents consisted essentially of sodium acetate. This salt melts when heated. When it cools the temperature inside the bottle is relatively constant, as it will remain at the “freezing point” until all of the sodium acetate has solidified. The duration of the time that it remains warm when well wrapped is simply in inverse proportion to the conductivity of the surrounding environment. When two ordinary towels were carefully arranged about it, the air between the bottle and the wrappings was maintained at a temperature of 40-50 C. (104-122 F.) for a period of eight hours.

The company’s implication that the heat given out by the Thermor bottle differs from that given out by an ordinary hot-water bottle is an absurdity. The use of sodium acetate in the preparation of warming bottles has been in practice many years, and is not “a principle that is entirely different and new.” Furthermore, the therapeutic claims are extravagant.--(_From Reports A. M. A. Chemical Laboratory, 1916, p. 105._)

ANTI-SYPHILITIC COMPOUND (SWEENY)

A specimen of Anti-Syphilitic Compound (Sweeny), sold by The National Laboratories of Pittsburgh, was received from a physician. The package (1 ounce size) has been opened by the sender and about three fourths of the contents removed.

From the rather indefinite statements in the literature of the manufacturer it is gathered that the preparation is claimed to be a “sterile, oily emulsion” which contains 1/20 grain of mercuric benzoate in each 5 minims, together with some sodium chlorid. According to information furnished by the Laboratory’s correspondent, the price asked for the preparation is $15 an ounce.

The quantity of the preparation received was too small to permit a complete examination, but, from the tests which it was possible to make, the preparation appears to be an aqueous solution containing some suspended matter and small quantities of mercuric benzoate and a chlorid, presumably sodium chlorid. There was no evidence of the presence of an “oily emulsion.” Quantitative tests indicated the presence of a mercuric salt, equivalent to about 0.2783 gm. of crystallized mercuric benzoate per 100 c.c. This corresponds to about 0.00086 gm. in each 5 minims, or about 26.5 per cent. of the amount claimed.--(_From Reports A. M. A. Chemical Laboratory, 1916, p. 106._)

“AMBRINE” AND PARAFFIN FILMS[F]

Paul Nicholas Leech, Ph.D.

[F] Contribution from the Chemical Laboratory of the American Medical Association.

In the last year or so, the hot-wax or paraffin treatment of burns has been widely discussed both in medical and lay periodicals. Although the treatment is simply a modification of the well-known use of oil and ointments, it has received unusual attention, owing to the widespread sensationalism following the exploitation in France of a secret and therefore mysterious mixture, “Ambrine,” the formula of Dr. Barthe de Sandfort. Owing to this publicity, it seemed desirable to investigate the chemical composition, and to compare its physical properties with other waxlike substances.

“Ambrine” is promoted as a dressing for burns, frostbites, neuritis, varicose ulcers, phlebitis, neuralgia, rheumatism, sciatica, gout, etc. It is a smoky-appearing substance, resembling paraffin in consistency and without odor. For application, “Ambrine” is melted and applied to the wound either with a brush or with a specially devised atomizer. It cools quickly, and leaves a solid, protecting film.

It is said that de Sandfort “stumbled on this treatment by accident.”[165] Being a sufferer from rheumatism, he had been benefited by hot mud baths; on returning home he sought a substitute, and finally made a mixture of paraffin, oil of amber and amber resin. This was applied hot, serving as a firm poultice. “Years later, he went on service to a railway in China and was in Yunnan at the time of the incendiary insurrection, and many badly burned Chinese were brought in for treatment. Remembering that Ambroise Paré treated such cases with hot oil, he tried the effect of covering the burn with his melted ambrine, which at once glazes over, forming a coat impervious to the air, and his patients ceased to suffer.”[166]

[165] The Outlook, Jan. 17, 1917, p. 100.

[166] Med. Rec., New York, Jan. 27, 1917, p. 160.

“Ambrine” has been sold in America under two names: “Hyperthermine,” as exploited to physicians, and “Thermozine,” as advertised to the public. Physical comparison alone shows that Ambrine as now sold differs from “Hyperthermine” of a few years ago; the probable reason is that “Ambrine” has changed its formula. This is borne out by Matas,[167] who states that de Sandfort “admitted that Ambrine was a compound of paraffin, oil of sesame and resins, but was not at liberty to divulge its exact composition, as the formula and manufacture of this substance was now the property of a private corporation, which was exploiting it as a proprietary and secret remedy.” The later formula differs from the original.

[167] Matas, Rudolph: Burns Treated with Paraffin Mixtures, New Orleans Med. and Surg. Jour., April, 1917, p. 681.

Besides the foregoing paraffin preparations, two others have recently been placed on the American market, “Parresine” (nonsecret) and “Mulene” (secret).

ANALYSIS OF AMBRINE

“Ambrine” comes in rectangular cakes, about 1-1/2 inches wide, 6 inches long and 1/2 inch thick. It is moderately soft, but somewhat brittle at ordinary room temperature. A black substance is present, which evidently settles out during the compounding, as in one side of the cake these particles can be clearly discerned by holding it up to the light; in the other side there are no suspended particles. When melted, the solution is not clear, and a sediment forms. The melting point (U. S. P. method; see later) is 48.4 C. The plasticity and ductility[168] are 27 and 30.5, respectively. It is pliable and strong at body temperature. The saponification number and acid number are both very low, but a fatty oil is present. Tests indicated oil of sesame. Ninety-eight per cent. of “Ambrine” is soluble in ether; this soluble portion may be treated with low-boiling ligroin (petroleum ether), out of which, on standing, a black asphalt-like substance separates. Of the ether-insoluble substance, 65 per cent. is soluble in chloroform. The remaining insoluble substance contains a small amount of silica and vegetable fiber. The paraffin obtained from “Ambrine” melted at 48.6 C. As a result of various experiments, it appears that the composition of “Ambrine” is essentially as follows:

Paraffin (M. P. 48.6 C.) 97.0 per cent. Fatty oil (sesame?) 1.5 per cent. Asphalt-like body 0.5 per cent. Coloring matter, and undetermined 1.0 per cent. ----- 100.0

[168] These determinations will be described later.

OTHER PROPRIETARY FILMS

A cursory examination of “Mulene,” manufactured by the Mulene Company, Pittsburgh, was also made. This appears to contain paraffin, beeswax, a fat-soluble red dye and considerable rosin. When heated carefully in a beaker, the rosin “sticks” to the bottom, and does not go into solution readily.[169]

[169] When the sample was first obtained, this feature was not observed.

“Paresine,”[170] according to the manufactures, is a mixture composed of paraffin, 94 to 96 per cent.; gum elemi, 0.20 to 0.25 per cent.; Japan wax, 0.40 to 0.50 per cent.; asphalt, 0.20 to 0.25 per cent., and eucalyptol, 2 per cent., the whole being colored with alkannin and gentian violet.[171]

[170] Made by the Abbott Laboratories, Chicago, and accepted by the Council on Pharmacy and Chemistry for New and Nonofficial Remedies, The Journal, May 12, 1917, p. 1406.

[171] No chemical examination was made.

FORMULA FOR PARAFFIN FILM

In a recent article, Sollmann[172] presented various suggestions for the compounding of paraffin films. Some of the formulas were promising and others were not, but all were simple. He did not try to imitate “Ambrine.” Lieut.-Col. A. J. Hull[173] of the Royal Army Medical Corps, after experimenting with different combinations, concluded that a mixture of “1 part resorcin, 2 parts eucalyptus oil, 5 parts olive oil, 25 parts soft paraffin [petrolatum][174] and 67 parts hard paraffin” served the purpose as well as “Ambrine.” The following formula, which might be called Asphalt-Paraffin No. 21, much more closely resembles “Ambrine,” and it seems to have certain advantages, due to the use of a more suitable grade of paraffin:

Paraffin[175] (M. P. by U. S. P. method 47.2 C.) 97.5 gm. Asphalt from 3 to 5 drops Olive oil 1.5 c.c.

[172] Sollmann, Torald: Suggested Formulas for Paraffin Films, The Journal A. M. A., April 7, 1917, p. 1037.

[173] Hull, A. J.: The Treatment of Burns by Paraffin, Brit Med. Jour., Jan. 13, 1917, p. 37; The Treatment of Burns by Paraffin, Therapeutics, The Journal A. M. A., Feb. 3, 1917, p. 373.

[174] The “soft paraffin” of the British Pharmacopeia resembles petrolatum, U. S. P., Queries and Minor Notes, The Journal A. M. A., April 28, 1917, p. 1281.

[175] The paraffin used in this formula was supplied by the Standard Oil Company of Indiana; the melting point given by the manufacturers is from 120 to 122 F., which, according to the American Standard of taking melting points, gives higher results than the method described in the pharmacopeia.

About 10 c.c. of “asphalt varnish” (B. Asphaltum)[176] is placed in a beaker and heated on the steam bath for one-half hour. From 3 to 5 drops, delivered from a 1 c.c. pipet, are then placed in a casserole, and 1.5 c.c. of olive oil added. The mixture is heated and stirred for a few minutes until perfect solution is effected. To this is then added, with stirring, the paraffin, which has been previously melted. When it is cooled, a brown solid is obtained.[177] The physical factors of this paraffin mixture are, melting point 45.4 C. (U. S. P. method); plasticity, 28.5; ductility, 29; it is very pliable and strong at 38 C., and adheres exceedingly well to the skin, although it detaches easily. This mixture, which is easy to prepare, is inexpensive, the cost of the materials being approximately 10 cents a pound.

[176] The “Asphalt Varnish” used was obtained from Remien & Kuhnert Company, Chicago.

[177] While needless, a color resembling “Ambrine” may be obtained by the addition of coloring agents.

Both Hull and Sollmann noticed that tarlike substances and melted paraffin do not mix well. This is noticeable in “Ambrine,” which cannot be called an “elegant” preparation. The difficulty may be overcome by first mixing hot olive oil and asphalt; the asphalt will then go into solution. It is interesting to note that the suggested formula (as well as others which were also prepared) is not as plastic as the paraffin itself.[178] This is also true of “Ambrine.” On the other hand, the melting point of the paraffin is higher. _The important point, however, in compounding all paraffin preparations, is to select a proper grade of paraffin as elaborated below._

[178] In a personal communication Dr. Sollmann expressed the opinion that the synthetic preparation is inferior to the paraffin used in the formula, basing the view on the greater plasticity of the paraffin. For practical purposes, the paraffin will most probably serve as well as the mixture, especially when it is held in place by bandages, but I believe that the mixture is more adhesive.

EXAMINATION OF PARAFFINS AND PARAFFIN PREPARATIONS

The name “paraffin” generally applies to a colorless and tasteless waxlike substance that is solid at ordinary temperature. It is composed of saturated hydrocarbons, that is, they are unable to take up any more hydrogen, and thereby are quite stable; the hydrocarbons in paraffin have the general formula of C↓{n}H↓{2n+2}, ranging as high as C₂₄H₅₀ to C₂₇H₅₆. Paraffin may be found in crude form in coal, from which source the first paraffin candles were made. It may be produced from the distillation of brown coal, as in Germany, or from bituminous shale. In America, it is obtained chiefly from the distillation of crude petroleum, being in the residue after the distillation of such products as naphtha (gasoline), kerosene and the lubricating oils. The residue is treated by one of a number of processes causing the unpurified solid paraffin to be made available. The crude paraffin is either sold as such, or is refined. Paraffin or “paraffin waxes”[179] are designated in the trade by their melting points (which in the “American standard” is expressed in Fahrenheit degrees), and as to their state of refinement as “crude,” “semirefined” and “fully refined” paraffin. There are certain chemical and physical differences so that two refined waxes having the same melting point would not have the same plasticity. The higher melting point varieties of paraffin are hard and tough at room temperature: when melted, paraffin expands and forms a thin mobile liquid.

[179] Paraffin is sometimes spoken of as “white wax.” This is unfortunate, as “white wax” is an official name for “White Beeswax, U. S. P.” The term “white wax” is also often applied to “Chinese wax,” which is formed from an insect living on the tree Ligustrum lucidum.

The significant requirements of paraffin for surgical dressings are that it should be solid at body temperature, at the same time having flexibility and adhesiveness, together with a certain amount of strength. A number of brands of paraffin are sold in the United States, so that it seemed advisable to examine some of them and compare them with certain paraffin-film preparations. They were tested as to their melting points, plasticity, ductility, strength of film, etc.

_Melting Point Determination._--The melting point was determined by the method of the U. S. Pharmacopeia IX, p. 596. The melting point as obtained by this method is lower than the melting point used by manufacturers of paraffin (after conversion to Fahrenheit).

_Pliability and Ductility, Limit Temperature._[180]--A little of the melted wax was poured from a teaspoon on the surface of the water at about 40 C., in a tin pan (bread mold). This formed a fairly thin film. The temperature of the water was then lowered by the addition of cold water. At each temperature the pliability and ductility were tested thus:

[180] I am indebted to Dr. Torald Sollmann for these methods.

_Pliability Test._--The film, immersed in water, was doubled on itself, note being taken whether or not it broke.

_Ductility Test._--The film was pulled under water, note being taken whether it stretched on being pulled and broke with a ragged fracture; or whether it broke sharp without stretching. It is desirable that the pliability and ductility be preserved at as low a temperature as possible.

_Cotton Films, Adhesives and Detachability._[180]--The melted wax was applied as it would be for burns; namely, a thin layer was painted on the inner surface of the forearm with a camel’s hair brush,[181] a transverse strip about an inch wide being made. This was covered with a very thin layer of absorbent cotton, and over this another layer of melted wax was painted. As soon as this had cooled a little, it was covered by a few layers of bandage and left on for at least an hour. At the end of that time, the bandage was removed. The cotton film should be found at the place at which it was applied, showing that it is sufficiently adherent. It should detach without “pulling” the skin.

[181] When painting a surface with a paraffin film, I found that the temperature of the paraffin should not be too close to the melting point, but several degrees above; otherwise it does not “set” well.

The results of these tests are given in the accompanying table. It can be seen that nearly all the paraffins examined have properties which would make them useful, the notable exceptions being Nos. 8, 15 and 16. The more satisfactory products would be those having a melting point about 47 C., ductility of 30 or below, and plasticity of 28 or below. The paraffin described in the U. S. Pharmacopeia is not so satisfactory, the required melting point being between 50 and 57 C.

The use of paraffin bandages has been suggested by Fisher[182] and Sollmann.[183] In such cases, it may very likely be that a paraffin of higher melting point would be more satisfactory, owing to its greater resistance and tougher fiber.

[182] Fisher, H. E.: Nonadhering Surgical Gauze, The Journal A. M. A., March 25, 1916, p. 939.

[183] Sollmann, Torald: Paraffin-Covered Bandages, The Journal A. M. A., April 21, 1917, p. 1178.

SUMMARY

1. “Ambrine” is essentially paraffin in which a small amount of fatty and asphalt-like body is incorporated; like most secret mixtures, its composition varies.

2. A simple formula for a paraffin film, similar in chemical composition but superior in physical properties to “Ambrine,” is that described as Formula 21. The superiority is due to using a grade of paraffin that is better adapted to the purpose. The cost of materials is about 10 cents a pound.

3. The properties of the paraffin used for a surgical dressing are important. A number of different grades have been examined, in order to determine the ones that appear most promising. Paraffins Nos. 3, 4, 10, 11 and 25 are the best in the table, and surpass “Ambrine” itself.

4. It is exceedingly probable that further experience will show that for most purposes simple paraffin will serve just as well as the mixtures--if, indeed, not better.

Addenda

(_Reprinted from the Annual Report of the Chemical Laboratory of The American Medical Association, Vol. 10 (1917), p. 32_)

Since the foregoing was published, two other products--“Cerelene” and “Stanolind Surgical Wax”--were submitted to the Council on Pharmacy and Chemistry for investigation as to their acceptability for inclusion in New and Nonofficial Remedies. In this connection the Laboratory was requested to examine them.

“Cerelene” is manufactured by the Holliday Laboratories, Pittsburgh. According to the manufacturers, “Cerelene” is a compound composed of 84 per cent. paraffin, 15 per cent. myricyl palmitate and 1 per cent. elemi gum. As ordinarily marketed, “Cerelene” contains the following materials: To the beeswax is added Oil of Eucalyptus, U. S. P., 2 per cent., and Betanaphthol, U. S. P., 0.25 per cent. The manufacturer further states that the myricyl palmitate is a purified form of beeswax, free from all impurities, acids, etc., which is solely manufactured by this company and for which patents are pending. The properties described for “Cerelene” were as follows:

When cold, Cerelene is a solid wax-like cake of a fine yellow brown color. On exposure to air for long periods, the amber color darkens to some extent. It is entirely free from solids, odorless and tasteless; does not separate or change when melted repeatedly, and cannot in the melted state be separated by fractional crystallization. It is entirely neutral to indicators being perfectly free from both acids and bases.

Tests: Melting Point, U. S. P. method, 126 F. Density, U. S. P. method, 0.907. Iodin value, 0.5. Saponification number, 0.9.

“Stanolind Surgical Wax” is manufactured by the Standard Oil Company of Indiana. In the submission of the product to the Council on Pharmacy and Chemistry, it was stated that the product was a specially prepared paraffin “free from dirt or other deleterious matter.... It has been steamed and resteamed to drive out any free oil and repeatedly filtered.”

The examination of the foregoing products yielded the figures described in Table “B.”--(_From The Journal A. M. A., May 19, 1917._)

THE STABILITY OF IODINE OINTMENTS

L. E. Warren, Ph.C., B.S.

In general, the literature on the keeping qualities of iodine ointment, and on the stability of iodine if mixed with ointment bases, is confusing. The recorded evidence is often contradictory. The attention of the writer was brought to this condition by studies of several proprietary preparations, Iodex,[184] Iod-Izd-Oil,[185] Iocamfen, and Iocamfen Ointment.[186]

[184] Rep. Chem. Lab., A. M. A., 1915, 8, 89.

[185] Rep. Chem. Lab., A. M. A., 1915, 8, 106.

[186] Rep. Chem. Lab., A. M. A., 1916, 9, 118.

Iodex was sold under the claim that it is

“... an embodiment of vaporized iodine, in an organic base, reduced and standardized at 5 per cent. by incorporation with a refined petroleum product.”

The exact composition of Iodex is a trade secret. Analysis showed that it contains petrolatum-like substances and combined iodine, the latter probably in combination with oleic acid. Tests for free iodine were made in five specimens of Iodex. In one of these no free iodine was present; in the others the merest traces were found.

Two years ago a preparation called “Iod-Izd-Oil” was examined. This was claimed to contain 2 per cent. of free iodine in liquid petrolatum. At the time of the examination the age of the preparation was not known, but it had been obtained just prior to the analysis, and was thought not to be very old. The analysis showed that it contained but about 0.43 per cent. of iodine, all of which was in a free state. The fact that all of the iodine present was in the free state appeared to indicate that iodine is relatively stable in liquid petrolatum solutions.

Iocamfen is a liquid composed of iodine, camphor and phenol. It was claimed to contain 10 per cent. of free iodine. Analysis showed that it contained 9.3 per cent. of total iodine (of which 7.5 per cent. was present in an uncombined state), 66.1 per cent. of camphor and 19.7 per cent. of phenol. After storing for several months a second assay of Iocamfen showed no appreciable loss in iodine content. This would indicate that iodine is relatively stable in presence of phenol and camphor, although immediately after mixing there is some loss of free iodine. The Iocamfen Ointment was supposed to contain 50 per cent. of Iocamfen (equivalent to 5 per cent. of free iodine) in a lard-wax-cacaobutter base. The analysis showed that the ointment contained but 0.4 per cent. of free iodine, the balance being in combination. From the results of the examination, and from correspondence with the manufacturers (Schering and Glatz), it became evident that the only plausible explanation for the loss of free iodine in the preparation of Iocamfen Ointment from Iocamfen lay in the combination of the free iodine with the ingredients of the ointment base. It seems likely that the free iodine originally present in Iocamfen for the most part had gradually gone into combination with the fatty substances after the ointment had been prepared.

The literature was then examined to determine the consensus of opinion concerning the stability of iodine in iodine ointment. In the older literature the belief that iodine ointment is unstable appears to be quite general. Such statements as the following are typical:

The ointment should be prepared only when wanted for use, for it undergoes change if kept, losing its deep, orange-brown color, and becoming pale upon its surface.[187]

[187] U. S. Disp., ed. 19, p. 1315.

It is better to prepare it only as it is required for use.[188]

[188] Am. Disp., ed. 2, p. 2022.

This ointment must not be dispensed unless it has recently been prepared.[189]

[189] U. S. Pharmacopeia, IX, p. 481.

In 1909 Lythgoe,[190] of the Massachusetts Board of Health laboratory, reported an examination of four samples of iodine ointment. Three were found to be pure, the fourth was low in iodine. Experiments showed that iodine ointment deteriorates rapidly; consequently, no further collections of samples were made.

[190] Rep. Mass. Bd. Health, 1909, 41, 477.

In 1912 Pullen[191] reported that he had prepared two specimens of iodine ointment according to the British Pharmacopeia, one being from new lard and the other from a specimen of lard at least 2 years old. Assays for free iodine were carried out immediately after the preparations were made, and at intervals afterward up to four months. The following values were found:

[191] Pharm. Jour., 1912, 89, 610.

Sample I Sample II

Ointment from Ointment from new lard, old lard, per cent. per cent. Iodine introduced 4.0 4.0 Iodine found immediately after making 3.95 3.38 Iodine found after twenty-four hours 3.30 3.15 Iodine found on the third day 3.18 2.62 Iodine found on the seventh day 3.15 2.46 Iodine found on the fourteenth day 3.00 2.45 Iodine found after one month 3.00 2.39 Iodine found after two months 2.90 2.31 Iodine found after four months 2.92 2.26

Pullen found that the loss in free iodine could be accounted for by the iodine which had gone into combination with the fats of the ointment base.

Pullen also found that if the potassium iodide and glycerin were omitted in the preparation of the ointment, the loss in free iodine was very rapid, the preparation containing practically no free iodine (only 1/20) after a few hours. He concludes that the use of potassium iodide and glycerin is necessary for the preservation of the ointment. He obtained specimens of iodine ointment in drug stores, and assayed them for free iodine. It is to be presumed that the ages of the several specimens were not known. The results are found in the following table:

Specimen No. 1 2.74 per cent. Specimen No. 2 2.85 per cent. Specimen No. 3 2.62 per cent. Specimen No. 4 2.48 per cent. Specimen No. 5 2.53 per cent. Specimen No. 6 2.79 per cent.

Fried[192] prepared iodine ointment according to the U. S. P. VIII formula, and assayed it at intervals. His results are tabulated herewith:

[192] Pharm. Jour., 1912, 89, 610.

Per cent. Iodine introduced 4.00 Iodine found immediately after making 3.89 Iodine found one hour after making 3.51 Iodine found one day after making 3.48 Iodine found five days after making 3.06 Iodine found ten days after making 2.84 Iodine found thirty days after making 2.81 Iodine found ninety days after making 2.81 Iodine found eight months after making 2.81

Iodine ointment has been official in the U. S. Pharmacopeia since 1870. Briefly, the method now used for making the preparation is as follows:

Four gm. of iodine, 4 gm. of potassium iodide and 12 gm. of glycerin are weighed into a tared mortar and the mixture triturated until the iodine and potassium iodide are dissolved and a dark, reddish-brown, syrupy liquid is produced. Eighty gm. of benzoinated lard are then added in small portions and with trituration after each addition. The mass is then triturated until of uniform consistence.[193]

[193] The time required to complete the process after the initial portion of lard has been added should be about twenty minutes.

PARAFFINS AND PARAFFIN PREPARATIONS--TABLE A

KEY: A: Formula B: Substance C: Melting Point, U. S. P. D: Ductility Limit E: Plasticity Limit F: (a) Adhesiveness and Detachability (b) Strength of Film at 38 C.

======================================================================= A B C D E F 1 “Parowax,” 50.8 32.5 29.0 (a) Adheres and Stand. Oil Co. of Ind. detaches well; rather hard (b) Pliable and strong 3 “Paraffin 118-120 F.,” 46.8 28.5 24.5 (a) Does not adhere Stand. Oil Co. of Ind. well; detaches easily (b) Pliable but not strong 4 “Paraffin 120-122 F.,” 47.2 29.0 24.5 (a) Adheres well; Stand. Oil Co. of Ind. detaches well (b) Pliable and fairly strong 5 “Paraffin 123-125 F.,” 48.8 31.5 28.5 Same as 4 Stand. Oil Co. of Ind. 6 “Paraffin 128-130 F.,” 52.0 33.0 30.0 (a) Adheres well; Stand. Oil Co. of Ind. detaches not so easily (b) Pliable and strong 7 “Texwax,” Texas Co., 51.2 32.5 29.8 Same as 6 Port Arthur, Texas 8 “Paraffin Wax 122-124 F.,” 50.6 36.0 34-35 (a) Unsatisfactory; Warren Refining Co., does not adhere Warren, Pa. (b) Only slightly pliable; too tough 9 “Paraffin No. 910,” 47.0 30.5 26-27 (a) Adheres well; Waverly Oil Works, detaches well Pittsburgh (b) Pliable and strong 10 “Paraffin No. 920,” 44.4 27.5 25.0 (a) Adheres well; Waverly Oil Works, detaches well Pittsburgh (b) Pliable and fairly strong 11 “Hard Paraffin,” 48.0 28.5 24.5-25.5 (a) Adheres well; Rob’t Stevenson & Co., detaches well Chicago (b) Pliable and strong 12 “Paraffin,” 47.2 33.0 32.5 Not quite as good Island Petroleum Co., as 11 Chicago 13 “Paraffin 122 F.,” 46.8 30.5 27.5-28 (a) Does not adhere Gulf Refining Co., so well; Pittsburgh detaches well (b) Very pliable 14 “Paraffin 125 F.,” 50.0 32.0 31.0 About as 13 Gulf Refining Co., Pittsburgh 15 “Paraffin 132 F.,” 54.8 35.5 34.0 (a) Does not adhere Gulf Refining Co., well Pittsburgh (b) Not very pliable, but strong 16 “Paraffin No. 301,” 50.2 33.0 32-32.5 (a) Does not adhere National Refining Co., well Cleveland (b) Not very pliable 18 Paraffin recovered 48.6 30.5 28-28.5 (a) Adheres well; from “Ambrine” detaches well (b) Pliable but not strong 19 “Hyperthermine” 49.4 33.5 30.5-31 (a) Does not adhere well; detaches well (b) Very pliable and strong 20 “Ambrine” 48.4 30.5 27.0 (a) Adheres well; detaches well (b) Very pliable and strong 21 Paraffin 120-122 F. 45.4 29.0 28.5 (a) Adheres (see 3), 97.5; excellently; olive oil, 1.5; detaches well asphalt, 4 drops (b) Very pliable and strong 22 “Parowax” (see 1), 97.5; 49.2 32.0 30.5 (a) Adheres well; olive oil, 1.5; detaches well asphalt, 4 drops (b) Pliable and strong 23 “Mulene” 51.0 36.0 28.0 (a) Adheres but detaches with difficulty (b) Pliable but not strong 24 “Parresine,” 46.0 29.5 26.0 (a) Adheres well; Abbott Laboratories, detaches easily (b) Pliable and fairly strong 25 “Paraffin 118-121 F.,” 45.8 26.4 23.2 (a) Adheres well; The Atlantic Refining detaches easily Co., Philadelphia (b) Pliable and Chicago fairly strong

TABLE B

26 “Cerelene,” 50.0 30.5 26.5 (a) Adheres well; Holliday Lab.,* detaches with Pittsburgh pulling (b) Not strong at 38 C. 27 “Stanolind” Surgical 47.0 28.8 25.0 (a) Adheres well; Wax,† Standard detaches easily Oil Co. of Ind. (b) Fairly strong at 38 C.

* On being heated, it readily loses eucalyptol, and a small amount of resinous substance forms in the bottom of the beaker. If “Cerelene” is heated to 145 C. and cooled, the resulting product no longer has the properties of the original “Cerelene.”

† Accepted by the Council on Pharmacy and Chemistry for inclusion in New and Nonofficial Remedies.

Iodine ointment is officialized also in several foreign pharmacopeias, although the iodine strength of the several preparations is not uniform. The formula in the British Pharmacopeia is exactly like that in the U. S. Pharmacopeia except that pure lard is directed to be used instead of benzoinated lard. Some of the foreign pharmacopeias also specify that the preparation must be freshly prepared when wanted. In the earlier editions the U. S. Pharmacopeia directed the ointment to be prepared by using water as the solvent for the potassium iodide. In the U. S. Pharmacopeia VIII the formula was changed so as to employ glycerin, and that solvent is now official. Water is still prescribed as the potassium iodide solvent by the Pharmacopeias of the Netherlands and of France.

From the examination of the literature it seems probable that iodine ointments which contain petrolatum products only as the ointment bases are apt to be relatively stable, so far as the content of free iodine is concerned. On the other hand, ointments the bases of which contain fats of the unsaturated fatty acid series, such as oleic acid, do not satisfactorily preserve the iodine in the free state. In the latter class it seems likely that the iodine enters into combination with the unsaturated fatty acids. Accordingly, on theoretical grounds, an ointment base composed of pure stearin (if such substance were available) but softened by an admixture of liquid petrolatum would preserve the iodine satisfactorily. Cocoanut oil (iodine No. 8) ought to be suitable also if mixed with hard paraffin.

Since the literature was not sufficiently concordant to warrant positive conclusions concerning the stability of ointments containing free iodine, it seemed worth while to conduct experiments with preparations of known origin. Accordingly, a number of preparations containing free iodine were made under varying conditions and each was assayed for its free iodine content immediately after its manufacture and from time to time later.

Leaf lard of the best quality obtainable was purchased from a butcher. This was rendered in an open dish on the steam bath. The preparation was of a fine color, and uniform consistence and had a faint but not unpleasant odor. Two specimens of lard were furnished by the research department of Armour and Company. An effort was made to procure specimens of lard having iodine absorption numbers as far apart as possible, _i. e._, one with a low and the other with a high iodine value. This was done in order to determine whether the keeping qualities of the ointments prepared from the two would be alike.

One of the specimens (_a_) was described as

“Natural lard; iodine value, 57.1. Leaf lard used exclusively for butterine and benzoinated lard.”

The other specimen was described as

“Prime steam lard. Good, commercial grade of lard for general use; iodine value, 69.0.”

The iodine absorption numbers of the three specimens were determined by the U. S. P. process to be as follows:

Laboratory rendered specimen 57.1 Armour specimen (_a_) 57.65 Armour specimen (_b_) 67.55

Each specimen was benzoinated according to the process described in the U. S. P. IX and 100 gm. of iodine ointment were prepared from each according to the U. S. P. process. Another specimen was made from benzoinated lard and iodine only[194] without the addition of either glycerin or potassium iodide. This was made to contain 4 per cent. of iodine.

[194] In order to facilitate the incorporation of the iodine with the fatty base the iodine was first powdered by trituration with alcohol and drying the powder in the air.

Immediately after preparation each of these iodine ointments was assayed for free iodine, and each was reassayed at intervals later. The method for the determination of iodine in the ointment was that employed in this laboratory for the determination of iodine in Iocamfen Ointment.[195] It is essentially the same as was employed by Pullen for the determination of uncombined iodine in iodine ointment.[196] As carried out in this laboratory for iodine ointment it is as follows:

[195] Rep. Chem. Lab., A. M. A., 1916, 9, 118.

[196] Pharm. Jour., 1912, 89, 610.

From 5 to 8 gm. of the ointment were weighed in a small porcelain capsule, the capsule and contents placed in a 16 oz. salt mouth bottle together with 20 c.c. of chloroform, 10 c.c. of potassium iodide solution and 40 c.c. of water. Tenth-normal sodium thiosulphate was slowly added with agitation until the pink color of the chloroform layer had nearly disappeared. A little soluble starch was then added and the titration continued until a blue color in the aqueous layer could no longer be obtained by repeated shaking.

The findings for the several assays are tabulated herewith:

U. S. P. U. S. P. U. S. P. Ointment Ointment Ointment Ointment from Age at from from from lard and time laboratory commercial commercial iodine only of rendered lard lard (laboratory assay lard Grade I Grade II rendered lard)

(% I) (% I) (% I) (% I) Freshly made 3.32 3.26 3.30 0.32 After 3 days 3.25 .... .... 0.23 After 7 days 2.99 3.17 3.15 .... After 3 weeks 3.01 3.19 3.07 .... After 7 weeks 3.12* 3.10 3.02 .... After 3 months 2.98 2.88 2.88 ....

* This slight rise in iodine content followed by a fall could not be accounted for. The specimen was believed to have been very thoroughly mixed at the time of manufacture.

That the fatty constituents of the ointment contained iodine after the preparation had been made for some time was demonstrated. Some of the material was examined as follows:

A portion of the ointment which had been made for nearly three months was shaken in a separator with chloroform and a dilute mixture of potassium iodide and sodium thiosulphate solutions. After all of the free iodine had been removed the chloroformic solution of the fats was washed several times with a very dilute solution of sodium thiosulphate. The chloroformic solution was filtered, evaporated and the residue dried over sulphuric acid.[197]

[197] The resultant fatty residue was of a brownish-green color. It no longer had either the taste, color or odor of lard. It was noted that the fats, after removal by this method from the freshly prepared ointment, were nearly white. As the ointment aged the fat became successively darker in color.

The separated fat was then tested for iodine by Kendall’s method.[198] It was found to contain iodine in considerable amounts, but quantitative determinations were not made.

[198] The method depends upon the conversion of all of the iodine compounds into iodate by fusion with sodium hydroxide and oxidation with potassium nitrate. The melt is dissolved in water, a little sodium bisulphite added, the solution cooled and neutralized with phosphoric acid, using methyl orange as indicator. An excess of bromine water is added, and the mixture boiled to expel carbon dioxid and bromine. A little sodium salicylate is added, the solution cooled, an excess of potassium iodid added, and the liberated iodine titrated with tenth-normal sodium thiosulphate in the usual way. One sixth of the iodine found is obtained from the material assayed, the balance being furnished by the potassium iodide added.--_Jour. Biochem._, 1914, 19, 251.

The Pharmacopeia of the Netherlands directs that iodine ointment shall contain 3 per cent. of potassium iodide and 2 per cent. of iodine instead of equal proportions (4 per cent. of each) as prescribed by the U. S. Pharmacopeia. Likewise the French Pharmacopeia directs that 10 per cent. of potassium iodide and only 2 per cent. of iodine shall be used. Both of these pharmacopeias use water instead of glycerin as the solvent. Loose combinations of iodine and potassium iodide, such as are represented by the compound having the formula KI₃, have been described. The quantity of potassium iodide prescribed by the U. S. Pharmacopeia for the preparation of iodine ointment is not sufficient to form such a compound as KI₃ with all of the iodine directed to be used. Since some of the pharmacopeias use larger proportions of potassium iodide (more than sufficient to form the compound, KI₃), it seemed worth while to determine whether an ointment containing a greater proportion of potassium iodide than that required by the U. S. Pharmacopeia would be more stable than the official article. Accordingly a specimen was prepared to contain 4 per cent. of iodine, 8 per cent. of potassium iodide (twice the U. S. P. requirement), 12 per cent. of glycerin and 76 per cent. of lard. This was assayed for its free iodine content immediately after preparation, and found to contain 3.68 per cent. Nine days later it contained 3.70 per cent. Another specimen of the same iodine strength prepared from grade No. 2 of commercial lard assayed 3.69 per cent. at the initial assay, and seven days later 3.40 per cent. From these experiments it seems likely that the free iodine content of the U. S. Pharmacopeia iodine ointment could be raised somewhat by increasing the proportion of potassium iodide.

The results of these studies confirm the findings of Pullen and of Fried in all essential particulars. It appears that during the process of manufacture of iodine ointment about 20 per cent. of the free iodine goes into combination with the fatty constituents of the ointment. On standing for a month approximately an additional 5 per cent. goes into combination, after which there is practically no loss in free iodine content. In other words iodine ointment which is a month old is a relatively stable preparation. It appears to make no noticeable difference upon the rate and amount of iodine absorption whether the lard from which the ointment is made has a high or a low iodine absorption value. The composition of iodine ointment, which has been made sufficiently long to have reached equilibrium, is approximately as follows:

Free iodine 3 per cent. Iodine combined with fat 1 per cent. Potassium iodide 4 per cent. Benzoinated lard (containing iodine) 80 per cent.

The U. S. Pharmacopeia requirement that iodine ointment shall be freshly prepared when wanted appears to be unnecessary. Probably most pharmaceutical manufacturers are aware of this, for many of them include the preparation in their trade lists. The presence of an iodide appears to be necessary, to prevent practically all of the iodine from entering into combination with the fat.[199]--(_From the American Journal of Pharmacy, August, 1917._)

[199] In order to determine whether the iodine which is in combination with fat is absorbed through the skin, a few experiments were carried out. The dark-colored iodine-containing fat (obtained from the ointment and washed free from potassium iodide by the method described above) was rubbed thoroughly into the skin of the forearm. It was allowed to remain for four hours, after which the limb was scoured with soap suds. Beginning at the time of the application the urine was collected for forty-eight hours. This was evaporated to small bulk and the residue tested for iodine by Kendall’s method. Small amounts of iodine were found. These findings were taken to indicate that the iodine-containing fat is absorbed to some extent by the skin. It is generally believed that potassium iodide is not absorbed by the unbroken skin. Therefore it seems reasonable to suppose that the principal iodine effects obtainable from iodine ointment are those due to the free iodine contained in the preparation, supplemented to a slight extent by the iodine which is contained in the fatty ointment base.--_Jour. Biochem._, 1914, 19, 251.

IODOLENE AND THE SOLUBILITY OF IODIN IN LIQUID PETROLATUM

The Council on Pharmacy and Chemistry was asked to examine a preparation submitted with the statement that it was “iodin crystals incorporated in a petroleum product.” The name “Iodolene” was proposed by the promoters, providing the product was found eligible for New and Nonofficial Remedies.

Iodolene was stated to have been prepared by treating a liquid petrolatum, obtained from Gulf Coast petroleum, with an excess of iodin; the mixture was subsequently “placed in an oven for three hours.” The claim was made that this method of procedure produced a preparation containing more iodin than market specimens which had been examined, namely: “over 1.50 per cent. free iodine.”

Two specimens of the product were submitted, one stated to have been unfiltered, and the other filtered. Both of the specimens emitted a strong odor of hydrogen sulphide upon removing the stopper from the respective containers.

_Iodin Content of Iodolene._--The iodin content of the filtered specimen was determined thus: A weighed amount--3 to 5 gm.--was transferred to a separator by means of 20 c.c. of ligroin, used in portions. Twenty c.c. of 10 per cent. potassium iodid solution was added and the free iodin titrated with tenth-normal sodium thiosulphate solution (with agitation), the end point being the absence of a yellow color in the _aqueous_ layer. The amount of free iodin was found to be 1.32 per cent.

_The Solubility of Iodin in Liquid Petrolatum._--To determine the solubility of iodin in Liquid Petrolatum, 200 c.c. of Liquid Petrolatum-Squibb (said to be composed of hydrocarbons of the naphthene series) and 200 c.c. of Stanolind Liquid Paraffin (said to be composed chiefly of marsh gas hydrocarbons) were each treated with 5 gm. of iodin crystals. The two mixtures were maintained for a week at a temperature somewhat above that of the room and agitated occasionally. Each was then cooled to room temperature (about 22 C.), agitated for a day and then filtered. The amount of iodin in the preparation made with Liquid Petrolatum-Squibb was found to be 1.42 per cent. The iodin content of the preparation made with Stanolind Liquid Paraffin was 1.30 per cent.

In view of these findings the prospective manufacturer was advised that the Council cannot countenance a proprietary name for an unofficial, simple solution of iodin in liquid petrolatum.--(_From Reports A. M. A. Chemical Laboratory, 1917, p. 87._)

AMERICAN-MADE SYNTHETIC DRUGS--I

Examination of American-Made Acetylsalicylic Acid

Paul Nicholas Leech, Ph.D.

At the request of the Council on Pharmacy and Chemistry, the A. M. A. Chemical Laboratory has undertaken examinations of American-made synthetic drugs. The most extensively used synthetic is acetylsalicylic acid and hence an investigation of this product was deemed expedient.

For seventeen years acetylsalicylic acid was protected by a United States Patent (the proprietors were not given a patent in other countries) and sold under the name “Aspirin.” In February, 1917, the patent expired, and since then a number of firms have engaged in the manufacture of acetylsalicylic acid, selling it either as such or as aspirin, modified, of course, by a distinctive firm designation. During this period the former manufacturers (The Bayer Co., New York, in past years called Farbenfabriken of Elberfeld Co., New York) have been extensively advertising, both to physicians and the public, the alleged superior qualities of their product. The chemical examination, therefore, was concerned chiefly with tests of purity, and the comparison of the American brands with the formerly patented product.

In European countries, acetylsalicylic acid[200] is described in the various pharmacopeias as a condensation product of acetic anhydride or acetyl chloride with salicylic acid (_o_-hydroxybenzoic acid). Generally the test of identification is hydrolysis of acetylsalicylic acid and qualitative tests for acetic acid and salicylic acid. For purposes of purity the requirements are essentially that the specimen should have a certain melting point, should show absence of salicylic acid by means of ferric chloride (the manipulations for the tests are variously described) and leave no appreciable ash. The two tests of purity most generally employed, however, are the melting point and the reaction with ferric chloride.

[200] Unfortunately, the nondescriptive name “aspirin” has been used extensively in European literature and has even got into European pharmacopeias, instead of the scientific name “acetylsalicylic acid.”

MELTING POINT

The melting point of acetylsalicylic acid has been given at various temperatures from 118 to 137 C.[201]; the British Pharmacopeia describes the melting point at 133 to 135 C.; the German Pharmacopeia “about 135 C.;” the French Pharmacopeia at 135 C.; New and Nonofficial Remedies, 1917, 134 to 136 C. The Bayer Company, in the patent trial at Chicago a number of years ago, gave among the “four infallible tests” a melting point of “about 135 C.” Several men have carefully determined the melting point in recent years. Emery and Wright[202] in 1912 found that “Aspirin, Bayer” melted at 130.5 to 131 C. In France, François[203] has determined the melting point of pure acetylsalicylic acid, which, according to his method, is 132 C. When various samples of acetylsalicylic acid were examined in this laboratory, it was found that the melting point of none was as high as that described in New and Nonofficial Remedies or the British, French, or German pharmacopeias when taken according to the general method of the U. S. Pharmacopeia, Vol. 9, p. 596. On critical observation, it may be seen that the melting point of acetylsalicylic acid is preceded and accompanied by decomposition. If the sample in the melting tube is heated from the original room temperature of the bath to 120 C., the temperature of melting will be lower than if the bath is first heated to 120 C. and the melting-point tube then placed in the bath.[204] Thus the melting point of acetylsalicylic acid, like so many organic compounds which decompose and do not melt sharply, is unsatisfactory and cannot be taken as an “infallible test” of purity, especially when determined by different operators who do not give their method in detail. After making a large number of melting-point determinations of acetylsalicylic acid, alone and in parallel with other operators, it was decided to use the method described in the U. S. Pharmacopeia modified by first heating the bath to 120 C. before attaching the melting-point tube to the thermometer.

[201] For reference to older literature see Beilstein, II, 1496 (889).

[202] “The Melting Temperature of Aspirin and Salicylic Acid Mixtures,” _Proc. Assoc. Off. Agr. Chem._, 1912; Bureau of Chemistry, Department of Agriculture, _Bull._ 162.

[203] “Assay of Aspirin,” _J. Pharm. Chem._, 15 (117), No. 7, 213.

[204] Similar observations were made by Emery and Wright, who state: “An accurate determination of the melting temperature in this way (the rate of heating was such as to give a rise in temperature of about 1° per minute) is rendered difficult by the fact that ‘aspirin’ decomposes on heating, as evidenced in the depression of the melting temperature of the pure substance of about 1° for every five minutes’ heating just below its melting temperature.”

The melting point of purified acetylsalicylic acid was found to be 131.5 to 132.5 C. (corr.).[205] With the exception of one specimen, which was obviously impure, the various specimens examined melted between 128 and 133 C. as may be seen in the accompanying table. It would appear that this range of melting points would be more acceptable and reliable than the melting points described in various standards.

[205] Isolated crystals attached to the walls of the melting-point tube, apart from the bulk acetylsalicylic acid, melted at a lower temperature.

PRESENCE OR ABSENCE OF FREE SALICYLIC ACID

It is generally conceded that the presence of salicylic acid in amounts more than traces is deleterious. Furthermore, the amount of salicylic acid is a good index of the purity of the acetylsalicylic acid, because the test is so delicate that, under favorable conditions, mere traces may be determined and, as a rule, the better the product, the less the amount of free salicylic acid.

The tests appearing in various pharmacopeias for salicylic acid as an impurity in acetylsalicylic acid do not give concordant results, different workers interpreting the results differently, nor are they detailed in such a manner as to yield maximum delicacy.

After experimentation, it was decided to establish a “limit” test of approximately 0.1 per cent. free salicylic acid, when carried out according to the following method:

0.1 gm. of the substance was placed in a dry colorimeter tube and 1 c.c. of alcohol,[206] previously distilled over NaOH, was added. After the acetylsalicylic acid had dissolved, 48 c.c. of water and 1 c.c. of fresh 0.1 per cent. ferric chloride (FeCl₃.6H₂O) solution were added. At the same time a control was run by treating 1 c.c. of a “standard” salicylate solution the same as above.[207] If within two minutes the color given by acetylsalicylic acid is not more intense than the color given by the “standard,” the presence of not more than 0.1 per cent. free salicylic acid is proved.[208]

[206] An excess of alcohol destroys or lessens the color when only a very minute amount of salicylic acid is present.

[207] The control should be made each time as standing in the air changes its tinctorial power.

[208] The presence of pure acetylsalicylic acid does not seem to affect the iron (Fe+++) salicylic acid coloration. The small amount of acetic acid was added to the sodium salicylate control solution (1) to stimulate an acidity approximating the acidity of the acetylsalicylic acid, and (2) since acetylsalicylic acid gives by hydrolysis both acetic acid and salicylic acid, it was thought advisable to add acetic acid to the standard. If there is any free acetic acid in a sample of acetylsalicylic acid containing salicylic acid (which I believe is generally the case when salicylic acid is present) then it would modify the color given by the same amount of salicylic acid alone. For this reason it was thought to be more comparable to have the standard contain a slight amount of acetic acid.

The solutions used were prepared as follows:

Redistilled alcohol was treated with a small amount of sodium hydroxide for twenty-four hours, then again distilled.

The color standard was made by dissolving 0.116 gm. of dried sodium salicylate in water, adding 1 minim of glacial acetic acid, and making up to 1,000 c.c. Each c.c. represents 0.1 mg. of salicylic acid.[209]

[209] This standard is somewhat similar to the one proposed by T. W. Thoburn and Paul J. Hanzlik, _J. Biol. Chem._, 23, 175.

The ferric chloride solution was made by diluting 1 c.c. ferric chloride (FeCl₃.6H₂O) test solution U. S. P. with 99 c.c. of water. The diluted solution must be freshly prepared each day.

With one exception, all of the commercial specimens examined responded satisfactorily to the above test showing less than 1 part salicylic acid in 1,000 parts acetylsalicylic acid. The individual results are given in the accompanying table.

MELTING POINT AND SALICYLIC ACID DETERMINATIONS

Melting Point Free Salicylic Acid BRAND Corrected Colorimetrically

Acetylsalicylic acid, 130.0-131.0° Colored, but showing P. W. R.[1] less than 0.1 per cent.

Acetylsalicylic acid, 130.0-131.0° No color Millikin[2]

Acetylsalicylic acid, 129.0-130.0° No color Millikin[2] 5-grain capsules

Acetylsalicylic acid, 128.0-129.0° (_a_) Colored, but showing less Millikin,[1] than 0.1 per cent. (_a_) 5-grain capsules[3] 125.5-126.5° (_b_) Considerably more than 0.1 per cent. (_b_)

Acetylsalicylic acid, 131.0-132.0° No color Squibb[2]

Acetylsalicylic acid 131.0-132.0° No color (Aspirin),[1] Monsanto

Acetylsalicylic acid, 130.5-131.5° Colored, but showing less M. C. W.[1] than 0.1 per cent.

Acetylsalicylic acid, 131.5-132.5° Colored, but showing less M. C. W.[1] than 0.1 per cent.

Acetylsalicylic acid, 131.0-132.0° Colored, but showing less M. C. W.[1] than 0.1 per cent.

Aspirin, Bayer[1] (before patent 131.5-132.5° No color expired) Aspirin, Bayer[1] [4] (after patent 128.5-129.5° Colored, but showing less expired) than 0.1 per cent.

Aspirin, Bayer[1] [4] (after patent 129.5-130.5° Colored, but showing less expired) than 0.1 per cent.

Aspirin, Lehn 130.5-131.5° 0.1 per cent. and Fink[2]

Aspirin, Lehn 130.5-131.5° Colored, but showing less and Fink[2] than 0.1 per cent.

Aspirin, Lehn 131.0-132.0° Colored, but showing less and Fink[1] than 0.1 per cent.

[1] Obtained on the open market.

[2] Obtained from manufacturer.

[3] One-third of the capsules (_a_) contained a white powder; two-thirds of the capsules (_b_) contained a pink powder having strong odor of acetic acid and not complying with the tests.

[4] Not described in “New and Nonofficial Remedies, 1917”; the other products are.

OTHER TESTS

New and Nonofficial Remedies, 1917, requires that acetylsalicylic acid shall form a clear solution with warm sodium carbonate solution; that sulfates, chlorides and heavy metals shall be absent; that 0.5 gm. shall leave no weighable ash. All the brands reported in this paper complied with these requirements.

So far there has been no satisfactory quantitative estimation of acetylsalicylic acid. True, various methods have been proposed, but they are objectionable. It was thought that hydrolysis of acetylsalicylic acid and then titrating the solution by comparing the color formed by ferric chloride with that of a standard control might yield interesting results, providing that the conditions were alike. For this purpose 1 gm. of acetylsalicylic acid was dissolved in 10 c.c. of alcohol and diluted to 1,000 c.c. The solution was then heated at 98 to 100 C. for two hours, allowing the alcohol to evaporate, then allowed to stand at room temperature (22 C.) for twenty-two hours. After adding water sufficient to make 1,000 c.c., it was compared colorimetrically for salicylic acid strength. The amount of hydrolysis varied so with different samples under the same conditions, that it was realized that an approximate assay by this method was unreliable. If the assay were made under more exact conditions, quantitative comparisons might be possible. In one experiment, after sixty days the hydrolysis of the acetylsalicylic acid was 61 per cent., which is in rough agreement with the work of Tsaklatos and Horsh.[210]

[210] _Apoth. Ztg._, 1915, p. 247; _Bull. soc. chem._, 17 (1915), 401. “Studies of the decomposition of aspirin determined by titrametric methods and by conductivity measurements indicate that the reaction is exceedingly complex,” T. and H. _Chem. Abs._, 10, 591.

DISCUSSION

Apart from the proposed revision of the standards for the melting point and limit of salicylic acid in acetylsalicylic acid, the examination shows that there is no appreciable difference between the various brands of acetylsalicylic acid examined, all of them with one exception (acetylsalicylic acid, Millikin, 5-grain capsules, purchased on the open market) complying with the tests described in this paper. The Journal of the American Medical Association, in past years, has protested repeatedly against the monopoly given to the Bayer Company for their “Aspirin,” contending that acetylsalicylic acid (aspirin) was not new, and that “Aspirin, Bayer” was simply a good brand of acetylsalicylic acid which could be bought in foreign countries at much lower prices than here. Although the patent in the United States has expired, “Aspirin, Bayer” is still being retailed at higher prices than other products which are now enjoying the privilege of American manufacture.

Mr. Paul Bakewell,[211] in an opinion answering the warning circular of the Bayer Co. in reference to the use of the word “aspirin” by firms other than Bayer, argues very ably that acetylsalicylic acid, before the patent was granted, meant the impure substance which was not used therapeutically, while “aspirin” was designated as the improved product (a new article of manufacture, the particular acetylsalicylic acid made under the Hoffman patent) and “is the substance now known in pharmacy as aspirin” (statement made by an officer of the Farbenfabriken of Elberfeld Co. in U. S. Circuit Court, 1909). The products reported in this paper are (with the one exception) the same as described in the Hoffman patent, and, in the sense of Mr. Bakewell’s argument, are “aspirin.” However, it would seem better if the name acetylsalicylic acid, instead of aspirin, were used, especially by physicians in their prescriptions because (1) it is a generic, scientific name; (2) “Aspirin, Bayer” is sold at higher prices than other products, whereas chemically equivalent products sold under the descriptive name may be purchased at a lower price. Finally, the manufacture of acetylsalicylic acid in this country is another example of the fact that American chemists can produce the drug synthetics, and at the same time make products as good as, if not better than, those of German origin.

[211] “In the Matter of Aspirin. Answer to the warning circular of the Bayer Co. of June 1, 1917,” by Mr. Paul Bakewell, Monsanto Chemical Works.

I express my appreciation to Dr. W. A. Puckner for his kind interest.--(_From the Journal of Industrial and Engineering Chemistry, April, 1918._)

THE STANDARDIZATION OF COMMERCIAL BISMUTH TRIBROMPHENATE

William Rabak, Ph.G., Sc.B.

This work was begun in view of a request received by the Council on Pharmacy and Chemistry from the Medical Section of the Council of National Defense for a report on the quality of bismuth tribromphenate, offered to the government by a certain firm.

In submitting a specimen of its product, “Bismuth Tribromphenolate,” the firm claimed that “it is of high character, matching exactly the German product formerly imported into this country,” and expressed the belief that it would be found to conform to the standards for this preparation in New and Nonofficial Remedies. Later a second specimen was received from the same company, with the request that this be substituted for that first received. It was explained that the first had been taken from an experimental lot, and that the second, taken from the regular factory output, was identical with the first except that it was free from odor because of the more thorough washing to which it had been subjected. Accordingly, the examination which is reported below refers to the second specimen only.

New and Nonofficial Remedies, 1918, defines bismuth tribromphenate as basis bismuth tribromphenate having the formula Bi(C₆H₂Br₃O)₂OH.Bi₂O₃, and it is required to yield not less than 49.5 per cent. of bismuth oxid (the chemical formula requires 46.2 per cent. bismuth, or 51.6 per cent. bismuth oxid, Bi₂O₃, and 49.2 per cent. tribromphenate, C₆H₂Br₃.OH). It describes it as a “fine, yellow, nearly odorless and tasteless powder, neutral in reaction,” and “only slightly soluble in water, alcohol, chloroform, liquid petrolatum and vegetable oils.” It is required to yield tribromphenol (to which a melting point of 95 C. is assigned) when decomposed by alkali and the alkali tribromphenate decomposed by acid, the separated tribromphenol purified and dried.

As the New and Nonofficial Remedies description appeared loosely drawn--it had been based on information furnished for the product Xeroform when this, because of patent protection, was the only bismuth tribromphenate on the market--it was decided to include in the examination also specimens of the two brands of Bismuth Tribromphenate included in New and Nonofficial Remedies, namely, Bismuth Tribromphenate-Merck (Merck and Company) and Xeroform-Heyden (The Heyden Chemical Works). The Merck specimen had been received by the Council from Merck and Company in 1915, while the Heyden preparation was obtained direct from the firm’s Chicago branch in April, 1918. At this time Bismuth Tribromphenate-Merck could not be obtained from the Chicago wholesale houses.

All three specimens were nearly odorless. Two of the specimens (the Research Council Specimen and Merck products) were of a lemon-yellow color, while the Heyden preparation was of a grayish color.

BISMUTH DETERMINATION

Four methods for the determination of the bismuth content of the specimens were tried:

(_A_). _Direct Ignition to Bismuth Oxid._--This method was abandoned because of the tendency to ignite suddenly during the incineration and the consequent loss of material.

(_B_). _The Method of the Japanese Pharmacopeia, Third Revised Edition, Translated by the Pharmaceutical Society of Japan._--The method consists in treatment of the product with nitric acid, evaporation and subsequent heating to bismuth oxid. This method also was abandoned because of tendency toward sudden ignition with loss of material.

(_C_). _The Method of Kollo (Apotheker Zeitung, 1910, p. 99)._--The method consists in decomposition of the product by heating on water bath with normal sodium hydroxid solution, with formation of soluble sodium tribromphenate and insoluble bismuth hydroxid. The bismuth hydroxid is collected on a filter, washed with hot water until a few drops of the filtrate no longer turn litmus paper blue, dried and heated to constant weight and weighed as bismuth oxid.

(_D_). _A. M. A. Method (Reports A. M. A. Chem. Lab., 1911, p. 18)._--This method consists in dissolving the product in hot, strong hydrochloric acid, diluting, filtering and precipitating by saturation with hydrogen sulphid. The bismuth sulphid obtained is dissolved in nitric acid and from the solution obtained the bismuth is precipitated by addition of an excess of ammonium hydroxid and ammonium carbonate. The precipitate is collected and converted to bismuth oxid by heat.

The following tabulation shows the results obtained by Methods “C” and “D”:

TABLE 1.--BISMUTH CONTENT OF BISMUTH TRIBROMPHENATE

Gm. of Gm. of Per Cent. Method Salt Bi₂O₃ of Bi₂O₃ No. 1 Research Council Spec C 2.1312 1.1754 55.1 No. 1 Research Council Spec D 0.5151 0.2772 50.03 No. 2 (Merck & Company) C 2.0287 1.2543 61.8 No. 2 (Merck & Company) D 0.5064 0.2634 52.01 No. 3 (Heyden Chem. Works) C 2.0472 1.6020 78.2 No. 3 (Heyden Chem. Works) D 0.5227 0.3546 67.8

It is seen from the tabulation that the results obtained by the Kollo method (Method C) are higher than those by the sulphid method (Method D) and that duplicate determinations show a rather wide variation. The results by the sulphid method are somewhat lower than those by the Kollo method, but duplicates agree fairly well. In view of the fact that the Kollo method will give excessive results if impurities such as talcum, etc., are present and in consideration of the satisfactory results obtained in previous work with the sulphid method, the figures obtained by this method are taken as indicative of the bismuth content of the specimens examined. Calculating the per cent. of bismuth oxid obtained to bismuth (Bi), the following values are obtained:

Bismuth Tribromphenolate, Research Council Specimen: Bismuth, 44.8 per cent.

Bismuth Tribromphenate-Merck, Merck & Co.: Bismuth, 46.6 per cent.

Xeroform, Heyden Chemical Works: Bismuth, 60.7 per cent.

TOTAL TRIBROMPHENOL

The content of tribromphenate radical, C₆H₂Br₃O-, was determined by the method of Kollo (Apotheker Zeitung, 1910, p. 99). It consists in titrating the filtrate of the bismuth oxid determination of Kollo, described under “C” (bismuth determinations), with normal hydrochloric acid, using phenolphthalein as an indicator. The cubic centimeters of normal alkali consumed multiplied by the theoretical factor 0.331 gives the weight of tribromphenol (combined and free) contained in the specimen.

The following results were obtained:

TABLE 2.--DETERMINATION OF TOTAL TRIBROMPHENOL IN BISMUTH TRIBROMPHENATE

Gm. Tribromphenol Gm. of Calculated from Per Cent. Salt Theoretical of Total Taken Factor Tribromphenol No. 1 (Research Council Spec.) 1.7817 1.0592 59.44 No. 2 (Merck & Co.) 0.9743 0.5627 57.75 No. 3 (Heyden Chem. Works) 2.0440 0.4303 21.04

UNCOMBINED TRIBROMPHENOL

The definite chemical formula given in New and Nonofficial Remedies for bismuth tribromphenate and the statement that it is “only slightly soluble in ... alcohol ...” requires the absence of uncombined tribromphenol, but no method for its detection or determination is provided.

In the U. S. Patent 516,358 (expired March 13, 1911), issued to Bruno Richard Seifert, assignor to Dr. F. Von Heyden, for “Phenol Bismuth Compound” the freedom from uncombined tribromphenol was provided for by the direction to wash with alcohol the product obtained.

In the Swiss Pharmacopeia the permissible content of uncombined tribromphenol is limited thus:

“If 0.5 gm. be shaken with 5 c.c. of alcohol and 1 c.c. of the filtrate be diluted with 15 c.c. of water, neither a turbidity nor a flocculent precipitate should appear....”

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:

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._)