Modulating the Solubility and Dissolution of Berberine Hydrochloride Cocrystals Through Structural Design of Cocrystal Formers

ABSTRACT In this study, a 1:1 cocrystal composed of berberine hydrochloride (BCl) and 2‐hydroxyphenylacetic acid (2HPAA), denoted as BCl‐2HPAA, was successfully prepared. Its crystal structure, physicochemical properties, equilibrium solubility, and dissolution behavior were systematically investigated. At the same time, previously reported BCl‐3HBA and BCl‐4HBA cocrystals were included for comparison to evaluate the influence of the molecular structures of different cocrystal formers (CCFs) on the performance of BCl cocrystals. The results showed that significant differences existed in the solubility and dissolution behaviors among different cocrystal systems, and these differences were closely related to the molecular structural features of the CCFs. Although the solubility of some cocrystals in water was improved, their dissolution rates did not show a corresponding enhancement. This phenomenon confirms that solubility is not the only key factor determining the dissolution behavior of cocrystals. Further analysis revealed that cocrystal dissolution performance is more strongly regulated by overall crystal structural features, such as molecular packing modes and hydrogen‐bonding network configurations. These experimental results demonstrate that effective modulation of cocrystal solubility and dissolution properties can be achieved through the precise regulation of the molecular structures of CCFs, providing experimental evidence and data support for the performance optimization of pharmaceutical cocrystal systems.