The discovery of aspirin: a reappraisal

Walter Sneader, deputy head. 

Department of Pharmaceutical Sciences, University of Strathclyde, Glasgow G4 0NR

w.e.sneader{at}strath.ac.uk

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 Farbenindustriethe organisation into which F Bayer & Co had been incorporated in 1925.¹

	Challenge to the accepted account

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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

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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 Ätzwirkung unterscheidet sich die Acetylsalicylsäure vorteilhaft von der Salicylsäure und wird dieselbe in diesem Sinne auf ihre Verwendbarkeit geprüft"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 Eichengrün, 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 Eichengrün.

	The claims of Arthur Eichengrün

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In a paper published in Pharmazie in 1949, Eichengrün 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 Eichengrün 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, Eichengrün 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.

Convinced of the potential of acetylsalicylic acid, Eichengrün tested it on himself, experiencing no ill effects. He stated that he then surreptitiously gave a supply of it to his colleague Dr Felix Goldmann, who then recruited physicians to evaluate the drug in strict secrecy. Their reports were most encouraging. Tinnitus was rare, while the antirheumatic effects were unmistakable. But there was morea dentist had given the drug to a patient with a raised temperature as well as toothache. Hardly was he out of the chair before he exclaimed, "My toothache's gone!" Such a rapid onset of analgesia was unique. After a similar response was confirmed in other patients, Goldmann sent a report to the Bayer management. According to Eichengrün, when Dreser was asked to comment, he scribbled on it, "This is the usual loud-mouthing of Berlinthe product has no value."

Eichengrün goes on to tell us that Carl Duisberg, the renowned head of research for Bayer, had ordered Dreser's results to be checked by an independent pharmacologist. This intervention might explain why Hoffmann synthesised stable, pure acetylsalicylic acid on 10 August 1897. If the meaning of the last sentence in Hoffmann's report is that acetylsalicylic acid was already under test at that time, it would be consistent with all that Eichengrün has written. Had acetylsalicylic acid been tested along with the other salicylic acid derivatives in April 1897, there would have been no written record of its original synthesis, since Hoffmann did not write any reports between 13 March 1896 and 5 May 1897. Significantly, in none of his laboratory reports did he mention the synthesis of any of the other salicylates known to have been tested by Dreser. Presumably they were prepared for evaluation in April 1897.

In his 1949 paper Eichengrün went on to claim that acetylsalicylic acid was sent to several leading clinics for expert assessment. Confirmation of this claim is found in the first published clinical report on aspirin by Kurt Witthauer of the Deaconess Hospital in Halle, which appeared in the April 1899 issue of Die Heilkunde.¹¹ Revealingly, Witthauer remarked, "After long hesitation, the factory was able to be convinced by my favourable experiences to bring aspirin on to the market." Further light is thrown on this statement by Friedrich Fischer, the head of the Elberfeld pharmaceutical laboratory in 1897, when he wrote that Witthauer had energetically pushed for the introduction of the drug owing to its excellent success in the clinic.¹² It should be noted that Witthauer stated that he had received the new salicylate compound nearly one year earlierthat is, around April 1898.

Eichengrün claimed that Dreser was then instructed to write a report that would give scientific credibility to the new drug. This explains why Dreser reinvestigated acetylsalicylic acid on its own in September 1898.

	The credibility of the claims by Eichengrün

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Why did Eichengrün wait 15 years before refuting what had been written in 1934 about the role of Hoffmann? The answer may be found by considering Eichengrün's situation at that time. After the introduction of aspirin, he had developed not only several more drugs but also cellulose acetate, acetate silk, and acetate safety film before leaving Bayer in 1908 to establish his own factory in Berlin. There, he produced flame resistant materials based on acetyl cellulose and also pioneered the process of injection moulding of plastics. Consequently, he enjoyed the affluent life style of a successful industrialist, yet because he was a Jew all this was put at risk after the Nazi party gained power.

By the time the claim that Hoffmann had initiated the development of aspirin was published, the Nazis had banned Jews from the civil service and from independent positions in the professions and in economic life. Even as a prominent industrialist, Eichengrün was not exempt from their attentions. He was forced to take an associate into his company to avoid loss of contracts from state enterprises. A low profile was the order of the day, but that was not enough to prevent his company being forcibly transferred to another owner in 1938. His marriage to an "Aryan" wife enabled him to retain his freedom until 1944, when at the age of 76 he was interned for 14 months in Theresienstadt, languishing there until its liberation by the Soviet Army.

During the Nazi era, Eichengrün was in no position to issue a public rebuttal of what had been published about Hoffmann. Some insight into his feelings at that time is given by a paragraph in his 1949 paper: "In 1941, there stood in the Hall of Honour of the chemical section of the German Museum in Munich a showcase filled with white crystals, with the inscription, `Aspirin: inventors Dreser and Hoffmann'. Dreser had nothing whatsoever to do with the discovery, and Hoffmann carried out my chemical instructions in the first place without knowing the aim of the work. Next to the showcase was a similar one filled with acetylcellulose, today also a product of worldwide importance, whose discovery by me it is impossible to doubt since it was established in a series of German patents from 1901 to 1920. It was simply described by the expression `AcetylcelluloseCellit'; they had refrained from naming the inventor. But, at the main entrance to the museum there hung a large sign which forbade non-Aryans from entering this institute! Those who understand will read between the lines."

In his letter from Theresienstadt, Eichengrün concluded a similar paragraph with a different sentence: "To what influences this omission is to be attributed, can be only assumed." There can be little doubt that he felt that he had been written out of history because he was a Jew. Such historical revisionism was not unknown in the Nazi era.

Two years after the war ended, Eichengrün celebrated his 80th birthday amid glowing tributes in German scientific journals.^13-15 He died in Berlin on 23 December 1949, in the same month that his account of the discovery of aspirin was published. He was spared from knowing that it would remain largely ignored for another half century.

	Conclusion

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Everything that Eichengrün claimed in 1949 about the discovery of aspirin is compatible with the chronology of events presented here, which in turn depends to a great extent upon the reliability of the statement by Eichengrün that Dreser set acetylsalicylic acid aside for 18 months. This statement, however, has never been challenged. As Eichengrün did not refer to his own role in the discovery of aspirin in the chapter in which the statement appeared in 1918, it would be unreasonable to argue that the source is tainted. Also, Hoffmannwho lived until 1946 without ever publishing his own account of the discovery of aspirinrepeatedly spoke of Dreser setting the drug aside, albeit without indicating for how long. But had it only been for a short period, he would not have mentioned it.

In deciding whether it is Hoffmann or Eichengrün who initiated the events leading to the introduction of aspirin, the unreliability of the 1934 footnote about Hoffmann must be balanced against the plausibility of the 1949 paper by Eichengrün. The most reasonable conclusion is that Arthur Eichengrün was telling the truth when he wrote that acetylsalicylic acid was synthesised under his direction and that the drug would not have been introduced in 1899 without his intervention.

F Bayer & Co was truly fortunate in having Eichengrün as an employee, yet it is unlikely that he would have discovered aspirin had he not been working for the company. Its successor, Bayer AG, had every reason last year to celebrate proudly the centenary of the most widely used drug in history.

	Acknowledgments

I thank M Frings and H-H Pogarell of Bayer-Archiv, Leverkusen, as well as their former colleague Dr M Busch, for valuable assistance throughout the course of my investigations and visits to the archive. I am also indebted to Joan Girling for the translation of the paper in Pharmazi.

	Footnotes

Funding: None.

Competing interests: None declared.

	References

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1.	Schmidt A. Die industrielle Chemie in ihrer Bedeutung im Wetbild und Errinnerungen an ihren Aufban. Berlin: De Greuter, 1934:775.
2.	Dreser H. Pharmakologisches über aspirin (Acetylsalicylsäure). Pflugers Arch 1899; 76: 306-318[CrossRef].
3.	Bayer-Archiv. Pharmakologisches Labor Elberfeld. 103/12.1. Prof Dreser, 27.07.1907. Die pharmakologische Laboratorium der Farbenfabriken, pp 6-7.
4.	Dreser H. Das pharmakologische Laboratorium der Farbenfabriken. In: Geschichte und Entwicklung der Farbenfabriken vorm Friedr Bayer & Co, Elberfield, in den ersten 50 Jahren. Munich: Meisenbach-Riffrath, 1918:419-424.
5.	Bonhoeffer O. The manufacture or production of acidyl salicylic acids. British Patent 9123, 3 March 1900.
6.	Bonhoeffer O. Propionyl-salicylic acid and process of making same. US Patent 656435, 21 August 1900.
7.	Eichengrün A. Pharmaceutisch-wissenschafliche Abteilung. In: Geschichte und Entwicklung der Farbenfabriken vorm Friedr Bayer & Co, Elberfield, in den ersten 50 Jahren. Munich: Meisenbach-Riffrath, 1918:409-416.
8.	Zündorf U. 100 Years of aspirin : the future has just begun. In: Leverkusen: Bayer, 1997:33.
9.	Eichengrün A. 50 Jahre Aspirin. Pharmazie 1949; 4: 582-584.
10.	Bayer-Archiv. 271/2.1 Personal data on Eichengrün. Dr A. Eichengrün, Aspirin, KZ Theresienstadt. 1944:2.
11.	Witthauer K. Aspirin, eine neues Salicylpräparat. Die Heilkunde 1899; 3: 396.
12.	Fischer F. Die Pharmazeutischen Betriebe. In: Geschichte und Entwicklung der Farbenfabriken vorm Friedr Bayer & Co, Elberfield, in den ersten 50 Jahren. Munich: Meisenbach-Riffrath, 1918:427-436.
13.	Stadlinger H. Gedenktage. Dr Ing eh, dr phil Arthur Eichengrün 80 Jahre. Pharmazie 1947; 2: 383-384.
14.	Escales E. A Eichengrün 80 Jahre. Kunstoffe 1947; 37: 180.
15.	Bodenbender HG. A Eichengrün zum 80 Geburtstag. Angewandte Chemie 1948; 60: 111-112.