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.
[Illustration:
+ - - - - - - - - - - - - - - - - - +
| _HYPERTHERMALITY A REALITY._ |
| |
| Hyperthermality is a fact, however, through the |
| agency of a keri-resinous product which has been |
| used in France since 1900 under the name of |
| L’Ambrine. Hyperthermine, as the remedial agent |
| will be known in this country, is a combination |
| of several kinds of waxes and resins, scientific- |
| ally blended and containing no medicinal elements |
| whatever. It comes in the form of waxy flakes. It |
| melts at 124° and on cooling resembles a dark |
| colored wax. |
| |
| Hyperthermine is the discovery of Dr. Barthe de |
| Sandfort, an eminent retired French naval surgeon |
| and a member of numerous foreign medical societies. |
| He |
+ - - - - - - - - - - - - - - - - - +
“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.]
[Illustration:
+ - - - - - - - - - - - - - - - - - +
| _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.
[Illustration:
+ - - - - - - - - - - - - - - - - - +
| inception. |
| |
| Where the Dry Wax Poultice has been used |
| |
| Thermozine known in France as l’Ambrine, has been |
| used in the following Parisian hospitals, with |
| 92% of cures: |
| |
| Hospital de la Pitie, services of Drs. Lion, Darier |
+ - - - - - - - - - - - - - - - - - +
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
[Illustration: Photographic reproduction (greatly reduced) of a full
page magazine advertisement of “Thermozine,” the name under which
“Ambrine” was sold to the public.]
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.
[Illustration: Photographic reproduction from a booklet on “Thermozine”
giving the conditions in which the stuff was alleged to be “very
useful.”]
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.
[Illustration: Photographic reproduction (greatly reduced) of the
carton in which “Ambrine” is now sold.]
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....”