Complexation with aromatic carboxylic acids expands the solid-state landscape of berberine

Two novel salt cocrystals of berberine chloride (BCl) with 4-aminobenzoic acid (BCl-4ABA) and 4-hydroxybenzoic acid (BCl-4HBA) and one new berberine salt with 2,6-dihydroxybenzoic acid (B)⁺(26DHBA)^- were prepared and characterized. The chloride anions form NH···Cl^- hydrogen bonds in BCl-4ABA and OH···Cl^- hydrogen bonds in BCl-4HBA. In (B)⁺(26DHBA)^-, the ionic interactions between 26DHBA^- and quaternary ammonium cation of berberine contribute to a stronger crystal lattice and a higher melting point. All three new crystal forms exhibit a lower hygroscopicity at 25 °C than BCl, which is the crystal form used in the commercial tablets. Compared to BCl, the dissolution rates of BCl-4ABA and BCl-4HBA in water are higher but that of (B)⁺(26DHBA)^- is lower. Among the three crystal forms, the form with a higher melting point also exhibits a lower dissolution rate, which is explained by the stronger intermolecular interactions in these crystals.