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.
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.
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.
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]
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]
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
| Brand | Melting Point Corrected | Free Salicylic Acid Colorimetrically |
| Acetylsalicylic acid, P. W. R.¹ | 130.0–131.0° | Colored, but showing less than 0.1 per cent. |
| Acetylsalicylic acid, Millikin² | 130.0–131.0° | No color |
| Acetylsalicylic acid, Millikin² | ||
| 5-grain capsules | 129.0–130.0° | No color |
| Acetylsalicylic acid, Millikin,¹ | ||
| 5-grain capsules³ | 128.0–129.0° (a) | Colored, but showing less than 0.1 per cent. (a) |
| 125.5–126.5° (b) | Considerably more than 0.1 per cent. (b) | |
| Acetylsalicylic acid, Squibb² | 131.0–132.0° | No color |
| Acetylsalicylic acid (Aspirin),¹ Monsanto | 131.0–132.0° | No color |
| Acetylsalicylic acid, M. C. W.¹ | 130.5–131.5° | Colored, but showing less than 0.1 per cent. |
| Acetylsalicylic acid, M. C. W.¹ | 131.5–132.5° | Colored, but showing less than 0.1 per cent. |
| Acetylsalicylic acid, M. C. W.¹ | 131.0–132.0° | Colored, but showing less than 0.1 per cent. |
| Aspirin, Bayer¹ (before patent expired) | 131.5–132.5° | No color |
| Aspirin, Bayer¹ ⁴ (after patent expired) | 128.5–129.5° | Colored, but showing less than 0.1 per cent. |
| Aspirin, Bayer¹ ⁴ (after patent expired) | 129.5–130.5° | Colored, but showing less than 0.1 per cent. |
| Aspirin, Lehn and Fink² | 130.5–131.5° | 0.1 per cent. |
| Aspirin, Lehn and Fink² | 130.5–131.5° | Colored, but showing less than 0.1 per cent. |
| Aspirin, Lehn and Fink¹ | 131.0–132.0° | Colored, but showing less 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]
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.
I express my appreciation to Dr. W. A. Puckner for his kind interest.—(From the Journal of Industrial and Engineering Chemistry, April, 1918.)