The Propaganda for Reform in Proprietary Medicines, Vol. 2 of 2

Chapter XXIX: Foreword: The Chemical Laboratory of the American Medical Association (1)

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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.

“Ambrine” has been exploited in the United States for some time. To physicians it was sold under the name “Hyperthermine.” Above is a photographic reproduction (reduced) of a portion of a booklet describing “Hyperthermine,” which has been in The Journal office for some years.]

+ - - - - - - - - - - - - - - - - - +
| _HYPERTHERMINE’S FIELD._ |
| |
| Hyperthermine can be used in practically all in- |
| flammatory conditions. During the past ten years, |
| under the name of L’Ambrine, our product has been |
| widely used in the hospitals in France, as well as |
| in private practice, and we have very many clinical |
| reports on a variety of subjects. Its greatest use |
| has been in such conditions as sciatica, lumbago, |
| articular and muscular rheumatism, gout, arthritis, |
| burns of all degrees, pneumonia, bronchitis, orchit-|
| is, buboes, soft chancres, peritonitis, dysmenor- |
| rhea, adenitis, mastitis, periostitis, synovitis, |
| conjunctivitis, iritis, irido-choroiditis, abscess- |
| es, bruises, furuncles, whitlow, paronychia, car- |
| buncles, moist eczema and similar dermatological |
| affections, and varicose and tubercular ulcers. |
+ - - - - - - - - - - - - - - - - - +

Photographic reproduction (reduced) from the “Hyperthermine” (“Ambrine”) booklet recommending it for use in rheumatism, gout, pneumonia, buboes, dysmenorrhea, eczema, tuberculous ulcers, etc.]

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.

Photographic reproduction from a booklet on “Thermozine” showing that it is identical with “Ambrine.”]

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.

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The Propaganda for Reform in Proprietary Medicines, Vol. 2 of 2Chapter XXIX: Foreword: The Chemical Laboratory of the American Medical Association (1)

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