Aspirin (acetylsalicylic acid), an organic compound that does not occur in nature, was first synthesised in 1899.
In 1897, scientists at the drug and dye firm Bayer began investigating acetylated organic compounds as possible new medicines, following the success of acetanilide ten years earlier. Two years later, Bayer created acetylsalicylic acid, which they marketed around the world under the brand name "Aspirin". The drug was sold widely in the first half of the twentieth century, both by Bayer and by competing drug manufacturers. The name "aspirin" was so widely used that Bayer lost (or sold) the rights to the trademark in many countries.
Aspirin's popularity declined after the development of acetaminophen/paracetamol in 1956 and ibuprofen in 1962. In the 1960s and 1970s, John Vane and others discovered the basic mechanism of aspirin's effects, while clinical trials and other studies from the 1960s to the 1980s established aspirin's efficacy as an anti-clotting agent that reduces the risk of clotting diseases. Aspirin sales revived considerably in the last decades of the twentieth century, and remain strong in the twenty-first with widespread use as a preventive treatment for heart attacks and strokes.
History of willow in medicine Numerous authors have claimed that willow was used by the ancients as a painkiller, but there is no evidence that this is true. All such accounts date from after the discovery of aspirin, and are possibly based on a misunderstanding of the chemistry. Bartram's 1998 Encyclopedia of Herbal Medicine states, 'in 1838 chemists identified salicylic acid in the bark of White Willow. After many years, it was synthesised as acetylsalicylic acid, now known as aspirin.' It goes on to claim that willow extract has the same medical properties as aspirin, which is incorrect.
Ancient medical uses for willow were more varied. The Roman author Aulus Cornelius Celsus recommended using the leaves, pounded and boiled in vinegar, as treatment for uterine prolapse, but it is unclear what he considered the therapeutic action to be; it is unlikely to have been pain relief, as he recommended cauterization in the following paragraph (De Medicina, book VI, p. 287, chapter 18, section 10). Gerard quotes Dioscorides, 'that [the bark] being burnt to ashes, and steeped in vinegar, takes away corns and other like risings in the feet and toes,' which is similar to modern uses of salicylic acid. Translations of Hippocrates make no mention of willow at all.
Nicholas Culpeper, in The Complete Herbal, gave many uses for willow, including to staunch wounds, to 'stay the heat of lust' in man or woman, and to provoke urine ('if stopped') but, like Celsus, made no mention of any analgesic properties. He also used the burnt ashes of willow bark, mixed with vinegar, to 'take away warts, corns, and superfluous flesh.'
Although Turner (1551) thought that fevers could be cured by 'cooling the air' with boughs and leaves of willow, the earliest known mention of willow bark extract for treating fever came in 1763, when a letter from English chaplain Edward Stone to the Royal Society described the dramatic power of powdered white willow bark to cure intermittent fevers, or 'ague'. Stone had 'accidentally' tasted the bark of a willow tree in 1758 and noticed an astringency reminiscent of Peruvian bark, which he knew was used to treat malaria. Over the next five years he treated some 50 ague sufferers, with universal success, except in a few severe cases, where it merely reduced their symptoms. Stone's remedy was trialled by a few pharmacists, but was never widely adopted. During the American Civil War, Confederate forces experimented with willow as a cure for malaria, without success.
Synthesis of acetylsalicylic acid In the 19th century, as the young discipline of organic chemistry began to grow in Europe, scientists attempted to isolate and purify alkaloids and other novel organic chemicals. After unsuccessful attempts by Italian chemists Brugnatelli and Fontana in 1826, Johann Buchner obtained relatively pure salicin crystals from willow bark in 1828; the following year, Pierre-Joseph Leroux developed another procedure for extracting modest yields of salicin. In 1834, Swiss pharmacist Johann Pagenstecher extracted a substance from meadowsweet which, he suggested, might reveal an "excellent therapeutic aspect", although he was uninterested in increasing the number of chemicals available to pharmaceutical science. The author's full name is Johann Samuel Friedrich Pagenstecher (1783–1856). By 1838, Italian chemist Raffaele Piria found a method of obtaining a more potent acid form of willow extract, which he named salicylic acid. On page 622, Piria mentions "Hydrure de salicyle" (hydrogen salicylate, i.e., salicylic acid). The German chemist who had been working to identify the Spiraea extract, Karl Jacob Löwig, soon realized that it was in fact the same salicylic acid that Piria had found. From page 82: "Bis jetzt ist nur eine organische Verbindung bekannt, welche mit der Spiräasäure verglichen werden kann; diese ist der Salicylwasserstoff von Piria (Compt. rend. VI, p. 620)." (Until now only one organic compound is known, which can be compared with Spiraea acid [i.e., salicylic acid]; this is the hydrogen salicylate of Piria (Compt. rend. VI, p. 620).)
The first evidence that salicylates might have medical uses came in 1876, when the Scottish physician Thomas MacLagan experimented with salicin as a treatment for acute rheumatism, with considerable success, as he reported in The Lancet. Meanwhile, German scientists tried salicylic acid in the form of sodium salicylate with less success and more severe side effects. The treatment of rheumatic fever with salicin gradually gained some acceptance in medical circles.
By the 1880s, the German chemical industry, jump-started by the lucrative development of dyes from coal tar, was branching out to investigate the potential of new tar-derived medicines. The turning point was the advent of Kalle & Company's Antifebrine, the branded version of acetanilide —the fever-reducing properties of which were discovered by accident in 1886. Antifebrine's success inspired Carl Duisberg, the head of research at the small dye firm Friedrich Bayer & Company, to start a systematic search for other useful drugs by acetylation of various alkaloids and aromatic compounds. Bayer chemists soon developed Phenacetin, followed by the sedatives Sulfonal and Trional.
Upon taking control of Bayer's overall management in 1890, Duisberg began to expand the company's drug research program. He created a pharmaceutical group for creating new drugs, headed by former university chemist Arthur Eichengrün, and a pharmacology group for testing the drugs, headed by Heinrich Dreser (beginning in 1897, after periods under Wilhelm Siebel and Hermann Hildebrandt). In 1894, the young chemist Felix Hoffmann joined the pharmaceutical group. Dreser, Eichengrün and Hoffmann would be the key figures in the development of acetylsalicylic acid as the drug Aspirin (though their respective roles have been the subject of some contention).
In 1897, Hoffmann used salicylic acid refluxed with acetic anhydride to synthesise acetylsalicylic acid. Eichengrün sent the ASA to Dreser's pharmacology group for testing, and the initial results were very positive. The next step would normally have been clinical trials, but Dreser opposed further investigation of ASA because of salicylic acid's reputation for weakening the heart—possibly a side effect of the high doses often used to treat rheumatism. Dreser's group was soon busy testing Felix Hoffmann's next chemical success: diacetylmorphine (which the Bayer team soon branded as heroin because of the heroic feeling it gave them). Eichengrün, frustrated by Dreser's rejection of ASA, went directly to Bayer's Berlin representative Felix Goldmann to arrange low-profile trials with doctors. Though the results of those trials were also very positive, with no reports of the typical salicylic acid complications, Dreser still demurred. However, Carl Duisberg intervened and scheduled full testing. Soon, Dreser admitted ASA's potential and Bayer decided to proceed with production. Dreser wrote a report of the findings to publicize the new drug; in it, he omitted any mention of Hoffmann or Eichengrün. He would also be the only one of the three to receive royalties for the drug (for testing it), since it was ineligible for any patent the chemists might have taken out for creating it. For many years, however, he attributed Aspirin's discovery solely to Hoffmann.
The controversy over who was primarily responsible for aspirin's development spread through much of the twentieth century and into the twenty-first. As of 2016 Bayer still described Hoffmann as having "discovered a pain-relieving, fever-lowering and anti-inflammatory substance." Historians and others have also challenged Bayer's early accounts of Bayer's synthesis, in which Hoffmann was primarily responsible for the Bayer breakthrough. In 1949, shortly before his death, Eichengrün wrote an article, "Fifty Years of Aspirin", claiming that he had not told Hoffmann the purpose of his research, meaning that Hoffmann merely carried out Eichengrün's research plan, and that the drug would never have gone to the market without his direction. This claim was later supported by research conducted by historian Walter Sneader. Axel Helmstaedter, General Secretary of the International Society for the History of Pharmacy, subsequently questioned the novelty of Sneader's research, noting that several earlier articles discussed the Hoffmann–Eichengrün controversy in detail. Bayer countered Sneader in a press release stating that according to the records, Hoffmann and Eichengrün held equal positions, and Eichengrün was not Hoffmann's supervisor. Hoffmann was named on the US Patent as the inventor, which Sneader did not mention. Eichengrün, who left Bayer in 1908, had multiple opportunities to claim the priority and had never before 1949 done it; he neither claimed nor received any percentage of the profit from aspirin sales.
Naming the drug
The name Aspirin was derived from the name of the chemical ASA—Acetylspirsäure in German. Spirsäure (salicylic acid) was named for the meadowsweet plant, Spirea ulmaria, from which it could be derived. Aspirin took a- for the acetylation, -spir- from Spirsäure, and added -in as a typical drug name ending to make it easy to say. In the final round of naming proposals that circulated through Bayer, it came down to Aspirin and Euspirin; Aspirin, they feared, might remind customers of aspiration, but Arthur Eichengrün argued that Eu- (meaning "good") was inappropriate because it usually indicated an improvement over an earlier version of a similar drug. Since the substance itself was already known, Bayer intended to use the new name to establish their drug as something new; in January 1899 they settled on Aspirin.
Rights and sale
Under Carl Duisberg's leadership, Bayer was firmly committed to the standards of ethical drugs, as opposed to patent medicines. Ethical drugs were drugs that could be obtained only through a pharmacist, usually with a doctor's prescription. Advertising drugs directly to consumers was considered unethical and strongly opposed by many medical organizations; that was the domain of patent medicines. Therefore, Bayer was limited to marketing Aspirin directly to doctors.