Achieving Polymorphic and Stoichiometric Diversity in Cocrystal Formation:  Importance of Solid-State Grinding, Powder X-ray Structure Determination, and Seeding

Solid-state grinding is explored as a means of selectively preparing specific stoichiometric or polymorphic modifications of crystalline supramolecular complexes, or cocrystals. In research involving cocrystals of the model pharmaceutical compound caffeine prepared via solid-state grinding and solution crystallization, it has been demonstrated that these two methods of preparation are not always coterminous with respect to the cocrystal product obtained. Examined herein are the structures of five previously unreported caffeine cocrystals with monocarboxylic acids, including formic acid, acetic acid, and trifluoroacetic acid. This system illustrates three different possibilities in performing cocrystal preparation via the dual methods of solid-state grinding and solution crystallization: (1) the same cocrystal can result from both methods; (2) different cocrystal stoichiometries can result from each method; (3) different cocrystal polymorphs can result from each method. Materials that at first could be prepared only by solid-state grinding were later induced to crystallize from solution by seeding with the grinding material. Because some cocrystals from grinding contained minor residual unreacted starting components, a phase-subtraction method was used to enable subsequent crystal structure determination from powder X-ray diffraction data. The findings herein assign a significance to solid-state grinding as a technique of choice in widespread screening efforts for novel supramolecular materials.