Assessing the impact on aqueous solubility of berberine chloride via co-crystallization with different stoichiometric ratios of pyromellitic dianhydride

Abstract The impact of pharmaceutical co-crystallization with pyromellitic dianhydride (PMDA) on the aqueous solubility of the poorly water-soluble drug Berberine (Bb+), an isoquinoline alkaloid has been investigated. The design of multicomponent solids (especially different stoichiomorphs with same coformer) using principles of crystal engineering was undertaken to achieve salt/ionic cocrystal hydrate of Bb+ with PMDA [which converts into pyromellitic acid (PMA)/pyromellitic dicarboxylate (PMA2−) during liquid-assisted grinding]. Four multicomponent stoichiomorphs, namely, two salts (1Bb+:0.5PMA2−, 1Bb+:0.5PMA2−:0.5PMA), one salt polymorph (1Bb+:0.5PMA2−:0.5PMA), and one ionic cocrystal hydrate (2Bb+:1PMA:2Cl-:2H2O), were successfully obtained from liquid-assisted grinding followed by crystallization in different solvents. The aqueous solubility of the drug, its corresponding salts and hydrate were determined in phosphate buffer (pH = 7) at 25 °C using UV–vis absorption spectroscopy experiments, and it was found that the co-crystals exhibit much reduced water solubility in comparison to its parent drug.