Improving hygroscopic stability of palmatine by replacing Clˉ and preparing single crystal of palmatine-salicylic acid

Abstract

In order to improve the hygroscopic stability of palmatine (PMT), an unreported single crystal of palmatine-salicylic acid (PMT-SA, [C21H22NO4]C7H5O3) was designed and synthesized by replacing Clˉ of PMTCl, and the hygroscopic stability of PMT was remarkably improved. The crystal structures and intermolecular interactions were characterized by single crystal X-ray diffraction, elemental analysis, NMR (1H and 13C), FT-IR, PXRD, TGA-DSC and Hirshfeld surface analysis, and its properties were studied. Single crystal X-ray diffraction analysis revealed that asymmetric unit of PMT-SA contains one PMT and one SA, and adjacent asymmetric unit are connected via hydrogen bond C6-H6A…O6 to form an annular synthon R44(22). Adjacent synthons form 1D chain by intermolecular hydrogen bond C25-H25…O5 and π…π packing, as if PMT+ are sandwiched between SAˉ chains. Furthermore, 1D chains are interwoven through C27-H27…O5 of SAˉ chains on the both sides to fabricate 2D layers, then 2D layers overlaps into a fascinating 3D framework. Comprehensive structural analysis and Hirshfeld surface analysis reveal that the weak interaction force of hydrogen bonds formed between H atom of aromatic ring in PMT and carboxylic acid group of SA can promote stable crystal structure. Hygroscopic stability and DVS experiments show that hygroscopic stability of PMT-SA is tremendously enhanced, which might attribute to the replacement of Clˉ by SAˉ and the preparation of PMT-SA with a stable crystal structure. This successful work implies that a new approach to design protoberberines pharmaceutical salt with good hygroscopic stability by replacing anions, and provides inspiration for improving physicochemical properties of active pharmaceutical ingredients. Further to this, antibacterial activities of PMT-SA resist Staphylococcus aureus, Staphylococcus albus, and Escherichia coli are higher than PMTCl in vitro at gradient concentrations.