Polymorphism of Mechanochemically Synthesized Cocrystals: A Case Study

The liquid-assisted grinding cocrystallization of theophylline with benzamide leading to polymorphic compounds was investigated. A solvent screening with 17 different solvents was performed. The dipole moment of the solvent used in the synthesis determines the structure of the polymorphic product. A detailed investigation leads to the determination of the kinetically and thermodynamically favored product. In situ observations of the formation pathway during the grinding process of both polymorphs show that the thermodynamically favored cocrystal is formed in a two-step mechanism with the kinetic cocrystal as an intermediate.