Improving the Hygroscopic Stability and Permeability of Berberine While Maintaining its Solubility by Forming a Berberine‐Benzenesulfonic Acid Pharmaceutical Salt via Charge‐Assisted Hydrogen Bonding with Water Bridging

In order to improve the hygroscopic stability of berberine(BER) and maintain its solubility, an unreported berberine‐benzenesulfonic acid (BER‐H 2 O‐BSA) pharmaceutical salt is designed and synthesized through incorporating benzenesulfonic acid (BSA) to form charge‐assisted hydrogen (CAHBs) via water bridging. To the best knowledge, the building unit of BER‐H 2 O‐BSA is the first asymmetric unit that connects BER and BSA through hydrogen bonds and CAHBs formed with water bridging. These adjacent asymmetric units are further linked by hydrogen bonds C10‐H10···O10, leading to the generation of the cyclic synthetic unit R 6 6 (22). As expected, the hygroscopic stability and permeability of BER‐H 2 O‐BSA have been significantly improved compared to BERCl. This study underscores the potential of BERCl to form a pharmaceutical salt by introducing benzenesulfonate, thereby optimizing its physicochemical properties and providing a theoretical basis for future advancements in the physicochemical properties of parent berberine‐like compounds.