The history of aspirin and the medical use of it and related substances stretches back to antiquity, though pure ASA has only been manufactured and marketed since 1899. Medicines made from willow and other salicylate-rich plants appear in Egyptian pharonic pharmacology papyri from the second millennium BCE. Hippocrates referred to their use of salicylic tea to reduce fevers around 400 BCE, and were part of the pharmacopoeia of Western medicine in Classical antiquity and the Middle Ages. Willow bark extract became recognized for its specific effects on fever, pain and inflammation in the mid-eighteenth century. Lewis and Clark allegedly used willow bark tea in 1803-1806 as a remedy for fever for members of the famous expedition. By the nineteenth century pharmacists were experimenting with and prescribing a variety of chemicals related to salicylic acid, the active component of willow extract.
In 1853, chemist Charles Frédéric Gerhardt treated acetyl chloride with sodium salicylate to produce acetylsalicylic acid for the first time; in the second half of the nineteenth century, other academic chemists established the compound's chemical structure and devised more efficient methods of synthesis. In 1897, scientists at the drug and dye firm Bayer began investigating acetylsalicylic acid as a less-irritating replacement for standard common salicylate medicines. By 1899, Bayer had dubbed this drug Aspirin and was selling it around the world. The word Aspirin was Bayer's brand name, rather than the generic name of the drug; however, Bayer's rights to the trademark were lost or sold in many countries.Aspirin's popularity grew over the first half of the twentieth century, spurred by its effectiveness in the wake of Spanish flu pandemic of 1918, and aspirin's profitability led to fierce competition and the proliferation of aspirin brands and products. Some of the 1918 flu deaths were probably due to Aspirin poisoning.
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.
Synthesis of ASA
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 Hoffman joined the pharmaceutical group. Dreser, Eichengrün and Hoffman 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, Hoffman started working to find a less irritating substitute for salicylic acid. It is generally accepted that he turned to this idea because his father was suffering the side effects of taking sodium salicylate for rheumatism. Other chemists had attempted this before as well, by acetylating salicylic acid to make acetylsalicylic acid (ASA). Charles Frederic Gerhardt was the first to prepare acetylsalicylic acid in 1853. In the course of his work on the synthesis and properties of various acid anhydrides, he mixed acetyl chloride with a sodium salt of salicylic acid (sodium salicylate). A vigorous reaction ensued, and the resulting melt soon solidified.Since no structural theory existed at that time Gerhardt called the compound he obtained "salicylic-acetic anhydride" (wasserfreie Salicylsäure-Essigsäure). When Gerhardt tried to dissolve the solid in a diluted solution of sodium carbonate it immediately decomposed to sodium salts of salicylic and acetic acids.In 1859, von Gilm produced ASA (which he called "acetylirte Salicylsäure", acetylated salicylic acid) by a different method, the reaction of salicylic acid and acetyl chloride.In 1869 Schröder, Prinzhorn and Kraut repeated both Gerhardt's (from sodium salicylate) and von Gilm's (from salicylic acid) syntheses and concluded that both reactions gave the same compound—acetylsalicylic acid. (Prinzhorn is credited in the paper with conducting the experiments.) They were first to assign to it the correct structure with the acetyl group connected to the phenolic oxygen. Kraut's procedure was even being used by the drug company Heyden to make unbranded ASA. However, the published methods did not produce pure ASA—although Kraut's method was efficient enough to be useful. It is likely that Hoffman started by recreating the published methods. On October 10, 1897 (according to his laboratory notebooks), Hoffman found a better method for making ASA, from salicylic acid refluxed with acetic anhydride.
Eichengrün sent 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 Hoffman'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 Hoffman 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 Hoffman.
The controversy over who was primarily responsible for aspirin's development spread through much of the twentieth century and into the twenty-first. Although aspirin's origin was in academic research and Bayer was not the first to produce it commercially, Bayer insists that "The active ingredient in Aspirin, acetylsalicylic acid, was synthesized for the first time in a chemically pure and thus stable form in 1897 by a young chemist working for Bayer, Dr. Felix Hoffmann."Historians and others have also challenged Bayer's early accounts of Bayer's synthesis, in which Hoffman was primarily responsible for the Bayer breakthrough. In 1949, shortly before his death, Eichengrün wrote an article, "Fifty Years of Asprin", claiming that he had not told Hoffman the purpose of his research, meaning that Hoffman 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.
