Mechanochemical Synthesis of Praziquantel Hemihydrate in the Presence of Five Solvents with Different Water Miscibility

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.