Supramolecular Self‐Assembly with <i>p</i> ‐Coumaric Acid Provides New Pharmaceutical Salt Cocrystal for Palmatine Hydrochloride to Improve Drug Properties and Synergies: Theoretical and Experimental Integration Study

ABSTRACT To enhance the hygroscopic properties of palmatine chloride (PCl), a novel salt cocrystal is synthesized through the combination of water‐assisted grinding and solvent evaporation methods applying p ‐coumaric acid (CA) as the cocrystal co‐formers. Single crystal X‐ray analysis revealed that four chloride ions, two water molecules, and two coumaric acid molecules interacted via hydrogen bonding to form the typically basic structural units, which connected through weak interactions to form 2D planar structures in the boc plane. The palmatine molecules are arranged vertically between the planes and continuously stacked to form a 3D crystal structure. In comparison to PCl, the hygroscopic stability of the PCl‐CA salt cocrystal is notably improved, indicating that CA molecules occupied the binding site between chloride ions with strong hydration ability and external water molecules in the self‐assembly of the salt cocrystal, thus reducing the binding affinity of PCl‐CA to water. Although the hygroscopic stability of PCl‐CA is considerably enhanced compared to PCl itself, its solubility is regrettably lower, warranting further investigation. Notably, the introduction of CA molecules significantly boosted the antibacterial potency of the PCl‐CA salt cocrystal in vitro. The aforementioned experimental outcomes are corroborated by theoretical calculations, encompassing frontier molecular orbitals analysis and Hirshfeld surface analysis.