Improving hygroscopic stability of palmatine chloride by forming a pharmaceutical salt cocrystal of palmatine chloride-gallic acid with neutral molecule

Abstract

In order to ameliorate the hygroscopicity of palmatine chloride (PMTCl), an unreported salt cocrystal (2(C21H22O4NCl)·C7H6O5·2CH3OH, PMTCl-GA) of palmatine chloride with gallic acid (GA) has been designed and synthesized by a solvent evaporation method. Structure analysis shows that the asymmetric unit of PMTCl-GA includes two PMT cations, two chloride anions, a GA neutral molecule and two methanol molecules. Simultaneously, two PMT cations, two chloride anions, two GA neutral molecule are alternately linked by O–H⋯Cl, C–H⋯Cl and C–H⋯O hydrogen bonds to form synthon R46 (30). On this basis, the 2D layered structure is formed by C–H⋯O hydrogen bond connection, and then adjacent 2D layered structures are connected by C–H⋯O hydrogen bond to form a 3D supramolecular structure. The hygroscopic stability of PMTCl-GA is significantly higher than that of PMTCl, thus it is conjectured that in PMTCl-GA, GA neutral molecule and methanol participate in the self-assembly process of a salt cocrystal, occupying the binding sites between chloride anions with strong hydration ability and external water molecules, which reduces the binding ability of PMTCl-GA with external water molecules. This work has suggested that the physicochemical properties of ionic active pharmaceutical ingredients can be improved by introducing neutral components to form a salt cocrystal. Although the hygroscopic stability of PMTCl-GA was markedly improved compared to that of PMTCl, unfortunately, the solubility of PMTCl-GA was reduced compared to PMTCl, which still needs to be discussed in the subsequent research. In addition, the antibacterial activity of PMTCl-GA against S. aureus, S. albus and E. coli compared with the PMTCl was improved in vitro at different concentrations.