Multicomponent Crystals of Clozapine with Improved Solubility: A Combined Theoretical and Experimental Strategy on Coformer Screening and Structure–Property

It is extremely challenging but greatly significant to predict the appropriate cocrystal/salt coformers for the design and preparation of functional multicomponent crystals without an inefficient "trial-error method". The crystal engineering approach was employed to evaluate 46 coformers and obtain eight new clozapine (CLZ) multicomponent crystals so as to improve CLZ solubility. Potential coformers were initially screened by the conductor-like screening model for real solvents (COSMO-RS) approach, Cambridge Structural Database molecular complementarity analysis, and Hansen solubility parameters (HSPs) method with success hit rates of 82.4, 55.6, and 52.2%, respectively. Furthermore, eight multicomponent crystals of CLZ with maleic acid, oxalic acid, fumaric acid, succinic acid, and citric acid were investigated to reveal the detailed crystal structures and the properties, via single-crystal X-ray diffraction (SCXRD), powder X-ray diffraction, Fourier-transformed infrared spectroscopy, differential scanning calorimetry, solubility, RH (relative humidity) stability, and dynamic water vapor adsorption tests. Their relationship between crystal structures and intermolecular interactions were also discussed. The structures of eight multicomponent crystals were first resolved by SCXRD, proving the transfer of protons from the carboxyl radical of the acid to the CLZ piperazine. Four of eight the multicomponent crystals not only achieved higher water solubility than CLZ but also showed excellent humidity stability. Additionally, Hirshfeld surface analysis and molecular electrostatic potential surface analysis were carried out to investigate interactions in multicomponent crystals and the provenance of salt crystals. Finally, the atoms-in-molecules analysis was performed to compare the interaction energy and assess the strength of intermolecular hydrogen bonds within the multicomponent crystals. This study not only diversified the solid form of CLZ and demonstrated the practicability of the COSMO-RS screening method but also served as a role model for the selection of coformers for the preparation of multicomponent crystals.