Transforming aspirin into novel molecular salts of salicylic acid

Abstract

Aspirin is one of the most widely used analgesic, antipyretic, and anti-inflammatory drugs. Herein we disclose a way to transform aspirin into novel multicomponent crystal forms of salicylic acid, also a long-known analgesic with anti-inflammatory properties, among others, covering a broad spectrum of applications, including skin care products. A salicylic acid:salicylate ammonium salt and a salicylate:2-methyl-4-oxopentan-2-aminium molecular salt are concomitantly formed in acetone/ammonia solutions, resulting from aspirin decomposition. Furthermore the 2-methyl-4-oxopentan-2-aminium cation results from a sequence of in situ reactions: (i) imine formation, in which acetone is known to undergo under basic pH conditions; (ii) nucleophilic attack of α-carbon of the deprotonated acetone to the imine yielding 4-amino-4-methylpentan-2-one; and (iii) protonation of 4-amino-4-methylpentan-2-one. In the structures obtained for the novel multicomponent crystal forms, the strong charge-assisted N+–H···O/O− hydrogen bonds between the drug molecule and the co-former play a key function in the supramolecular arrangement. The typical $${\mathbf{R}}_{{\mathbf{2}}}^{{\mathbf{2}}} ({\mathbf{8}})$$ carboxylic···carboxylic homosynthon observed in salicylic acid was inhibited by the salt formation. These results are in agreement with the results of a careful survey on the Cambridge Structural Database.