The discovery of aspirin: a reappraisal

British Medical Journal, Dec 23, 2000 by Walter Sneader

The discovery of aspirin is customarily said to have resulted from Felix Hoffmann's rheumatic father encouraging his son to produce a medicine devoid of the unpleasant effects of sodium salicylate. Hoffmann, a chemist in the pharmaceutical laboratory of the German dye manufacturer Friedrich Bayer & Co in Elberfeld, consulted the chemical literature and came across the synthesis of acetylsalicylic acid and then prepared the first sample of pure acetylsalicylic acid on 10 August 1897. This was marketed in 1899 under the registered trademark of Aspirin. This account of the discovery first appeared in 1934 as a footnote in a history of chemical engineering written by Albrecht Schmidt' a chemist who had recently retired from IG Farbenindustrie--the organisation into which F Bayer & Co had been incorporated in 1925.[1]

Challenge to the accepted account

The footnote also stated that Hoffmann had arranged for several chemical derivatives of salicylic acid to be examined, not just its acetyl ester. No indication was given of what the others were, but in 1899 Heinrich Dreser, head of the experimental pharmacology laboratory at Elberfeld, named them in a paper as propionyl, butyryl, valeryl, and benzoyl salicylic acids.[2] He further alluded to them in 1907,[3] and again in 1918.[4] No earlier reports of the preparation of any of these are to be found, but three of them appear in a British patent awarded on 3 March 1900 to Hoffmann's colleague Otto Bonhoeffer,[5] and there is also a United States patent for propionylsalicylic acid, again in the name of Bonhoeffer.[6] The award of these patents is indicative of the absence of any prior mention of these compounds in the literature. It must therefore be concluded that the 1934 footnote is unreliable since it clearly stated that Hoffmann had examined "preparations of salicylic acid derivatives which remained unnoticed amongst several prepared a long time before for other purposes." The patents show that the derivatives were newly prepared for the specific purpose of finding a salicylic acid derivative that would be of therapeutic value. Is then the remainder of the footnote to be believed?

Laboratory reports of Hoffmann and Dreser

The page on which Hoffmann reported his synthesis of pure acetylsalicylic acid in 1897 is retained in the archives of Bayer AG in Leverkusen. The significance of the final sentence on it--"Durch ihre physikalischen Eigenschaften wie eine sauren Geschmack ohne jede Atzwirkung unterscheidet sich die Acetylsalicylsaure vorteilhaft von der Salicylsaure und wird dieselbe in diesem Sinne auf ihre Verwendbarkeit gepruft"--has been overlooked.

The correct translation is: "Due to its physical properties, such as an acid taste without any corrosive action, acetylsalicylic acid differs advantageously from salicylic acid and is being examined for its usefulness with just this in mind." The German is, however, grammatically awkward and the sentence is capable of being misread to mean that the compound was about to be tested rather than that it was being tested. The most likely interpretation, however, is that testing of acetylsalicylic acid was already taking place at the time Hoffmann wrote.

In a commemorative volume marking Bayer's 50th anniversary Arthur Eichengrun, a colleague of Hoffmann, pointed out that after examining acetylsalicylic acid Dreser had set it aside for nearly 18 months until he once again became involved with it in 1898.[7] This statement was never disputed by Dreser, who contributed the next article in the same publication.[4] A recent Bayer publication notes, too, that Hoffmann had repeatedly told his colleagues that Dreser had set acetylsalicylic acid aside.[8] Because Dreser did not begin to write laboratory reports until 16 May 1898 there is no record of his testing salicylic acid derivatives in 1897. However, his laboratory notebook shows that on 27 September 1898, and three more times that year, he investigated acetylsalicylic acid on its own. If there was an interval of nearly 18 months between Dreser's first and later experimenting with acetylsalicylic acid, this interval obviously could not have ended much before 27 September 1898, since he took up his appointment at Elberfield on 1 April 1897. His initial work testing salicylic acid derivatives must have been soon after his arrival there.

His laboratory reports from 27 September 1898 onward do not reveal why Dreser was then testing acetylsalicylic acid on its own rather than with the other four derivatives named in his 1899 paper. Something must have induced him to single out acetylsalicylic acid, and the explanation can be found in a paper written by Eichengrun.

The claims of Arthur Eichengrun

In a paper published in Pharmazie in 1949, Eichengrun claimed that he had instructed Hoffmann to synthesise acetylsalicylic acid and that the latter had done so without knowing the purpose of the work.[9] Five years earlier, while in Theresienstadt concentration camp, he had typed a letter (now in the Bayer archives) with wording similar to his 1949 paper.[10] Eichengrun wrote that his objective had been to obtain a salicylate that would not give rise to the adverse effects (gastric irritation, nausea, or tinnitus) frequently associated with sodium salicylate. He was present when the derivatives of salicylic acid were tested by Dreser and came to the conclusion that acetylsalicylic acid was superior to all the other compounds. At a management meeting, Eichengrun called for clinical studies to be initiated, but Dreser used his right of veto as head of the pharmacology division. He believed, mistakenly, that the drug was harmful to the heart.