Elusive Nonsolvated Cocrystals of Aspirin: Two Polymorphs with Bipyridine Discovered with the Assistance of Mechanochemistry

We report the discovery two nonsolvated polymorphic cocrystals of acetylsalicylic acid (ASA) and 4,4'-bipyridine (4,4'-bipy) in the form of 2(ASA)center dot(4,4'-bipy). Form I was discovered through mechanical dry grinding, and Form II was discovered through rapid cooling in ethanol. Both polymorphs consist of three-component hydrogen-bonded assemblies sustained by O-H center dot center dot center dot N hydrogen bonds. The components of the assemblies adopt an anti-conformation. The polymorphs differ in terms of relative twists of carboxylic acid groups and pyridyl rings. In Form I the ASA molecules are linked by discrete catemeric methyl C-H center dot center dot center dot O forces of the acetyl substituents, while in Form II the ASA molecules are linked by both infinite methyl C-H center dot center dot center dot O catemers and centrosymmetric dimers of the acetyl groups. Our results demonstrate the importance of neat mechanical grinding in the discovery and design of pharmaceutical cocrystals and polymorphs.