In this study, we report the mechanochemical synthesis of praziquantel hemihydrate in the presence of five solvents with different water miscibility. The commercially available praziquantel Form A (a racemic anhydrate structure) was ground in the presence of several water–solvent mixtures using two grinding procedures (i.e., direct liquid-assisted grinding and neat grinding plus liquidassisted grinding). Five organic solvents (i.e., acetic acid, 2-pyrrolidone, ethanol, ethyl acetate and hexane) were chosen considering their different miscibility with water and their capability to form solvates with praziquantel (documented for acetic acid and 2-pyrrolidone). The results suggested that the use of a second solvent has a detrimental effect on the formation of the hemihydrate. The inclusion of water in the solid is even worse in the case of water-miscible solvents, probably due to the favored interactions between the liquids. In fact, hexane is the only solvent permitting the mechanochemical crystallization of praziquantel hemihydrate to a limited extent. Importantly, interconversion studies between the hydrate/monosolvate/anhydrous forms revealed a preferential inclusion of solvents over water in the crystal lattice when using acetic acid or 2-pyrrolidone and complete dehydration of the hemihydrate and conversion in the most thermodynamically stable polymorph A of praziquantel with ethanol, ethyl acetate and hexane.
