Theoretical Calculation and Structural Analysis of the Cocrystals of Three Flavonols with Praziquantel

The formation of cocrystals is closely related to the weak interaction between the participant molecules. Among the factors that influence the interaction between molecules in a cocrystal, the molecular conformation is crucially important. The analysis of molecular electrostatic potential surfaces (MEPS) using density functional theory (DFT) can accurately reflect changes in the intermolecular interaction sites caused by the conformational changes, providing a useful method for predicting the interactions of the participant molecules in a cocrystal. In this study, the conformations of three flavonols, namely, kaempferol (KAE), quercetin (QUE), and myricetin (MYR), with the cocrystal conformer praziquantel (PRA) were carefully analyzed by theoretical calculations. Boltzmann distributions of different conformations at 300 K were obtained, and the formation of the cocrystal was predicted by the analysis of possible interactions of the different conformations. Various analytical techniques were used in combination with experiments to verify the predicted cocrystal formation. All predicted cocrystals, named KAE-PRA, QUE-PRA 1, QUE-PRA 2, and MYR-PRA, were formed, and three single crystals of these cocrystals were successfully obtained. These crystals are reported for the first time. This study provides a way to improve the success rate of cocrystal prediction by MEPS.