Sustainable preparation of spherical particles of novel carbamazepine-hesperetin cocrystal via different crystallization strategies: From mechanism to application

Spherical crystallization is widely employed in pharmaceutical industry to produce spherical particles that exhibit improved micrometric performances of active pharmaceutical ingredients (APIs), including particle size, morphology, flowability, and compressibility. Especially for APIs with poor powder performance and low solubility, spherical co-crystallization offers the potential to enhance both dissolution properties and tablet manufacturability by combining the API and cocrystal coformer (CCF) into a spherical particle. In this study, we aimed to enhance the physicochemical properties of carbamazepine (CBZ) and hesperetin (HPE) by synthesizing a novel cocrystal with the stoichiometric ratio of 1:1. Crystal structure of the CBZ-HPE cocrystal was determined using single crystal X-ray diffraction (SCXRD). To further improve the poor powder performances such as low flowability and compressibility resulting from the needle morphology of the cocrystals, we designed three spherical crystallization strategies: common spherical agglomeration, oil-out-induced spherical agglomeration and spherulitic growth method. The spherical particles of CBZ-HPE cocrystals were characterized by powder X-ray diffraction (PXRD), polarized light microscopy (PLM), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), thermogravimetric analysis (TGA), particle size instrumentation, and Fourier transform infrared spectroscopy (FTIR) to provide information about crystal structure, particle morphology, particle size and circularity distribution. The results revealed significant differences in particle morphology, flowability, particle size and dissolution rate among the various spherical crystallization strategies. Theoretical calculations elucidated three spherical crystallization mechanisms: spherical agglomeration (SA), oil-out-induced spherical agglomeration (OOSA) and spherulite growth (SG). This study offers both experimental and theoretical foundations for the application of different spherical crystallization techniques in the pharmaceutical industry.