Searching for Conglomerate Cocrystals of the Racemic Compound Praziquantel

Chiral compounds that crystallize as conglomerates from racemic mixtures are desirable from the perspective of chiral resolution since they are relatively easy to resolve using, for instance, preferential crystallization. Here, a screening methodology to find conglomerate cocrystals is demonstrated using racemic praziquantel (rac-PZQ). Cocrystallization of rac-PZQ was performed using liquid-assisted grinding (LAG) with 20 potential achiral coformers. LAG screening results show that N-phenyl urea (PU) and 1,3-dimethylthiourea (DMTU) are the only two achiral coformers that form new cocrystal compounds with rac-PZQ. Single-crystal structure determination of cocrystals grown from solution shows that the rac-PZQ:PU cocrystal is a racemic cocrystal with space group P21/c, while the rac-PZQ:DMTU cocrystal is a conglomerate cocrystal with space group P21. Under gentle conditions, rac-PZQ:DMTU forms a true conglomerate cocrystal from solution. However, when grown from solution under higher supersaturations, the obtained single crystals of rac-PZQ:DMTU appear to be disordered racemic twin cocrystals: these contain alternating domains of (almost) pure enantiomers of PZQ that are related by inversion symmetry. The disordered racemic twin cocrystals probably form due to refreshment of the enantiomer at the crystal surface being diffusion-limited from the bulk solution to the boundary layer. Discovery of a conglomerate cocrystal form of PZQ opens up exciting possibilities for the optical resolution of PZQ by preferential crystallization, allowing for easy preparation of pure enantiomer formulations of this important API.