Chirality and cocrystal systems : from fundamental understanding to development of a novel industrial chiral resolution technique

Abstract

The study of cocrystals is a research topic that is recently on the rise, particularly in the pharmaceutical field. The incorporation of active pharmaceutical ingredients as cocrystal in the formulation of a drug, allows modifying the physicochemical properties without altering its biological activity. However, the identification of coformers able to cocrystallize with the target molecule remains a tedious work usually performed using a trial-and-error approach. In this work, we propose a more rational approach, based on the structural similarity of two molecules, under the assumption that two molecules with similar molecular structures are more likely to cocrystallize with the same coformers. As a large number of active pharmaceutical ingredients (API) are chiral, we have studied the specificities of chiral compounds in cocrystallization. We highlighted that an enantiopure API seems to prefer forming a cocrystal with only one out of the two enantiomers of a chiral cocrystal former (or coformer). This enantiospecific behavior suggests that a racemic mixture of a given API can be resolved through cocrystallization in solution. In a study system, we not only validated our innovative resolution technique but also showed high efficiency. We also showed that the construction of ternary and quaternary phase diagrams is an effective tool in the pursuit of optimal conditions for chiral resolution. Finally, we looked for cocrystals between a racemate and an enantiopure coformer, as well as cocrystals between two racemates. We noticed that the tendency towards cocrystal formation strongly decreases when racemic compounds are involved.(FSA - Sciences de l) -- UCL, 201