Assembly of two palmatine pharmaceutical salts: Changing the motifs and affecting the physicochemical properties by adjusting the position of –COOH on salt formers

Abstract

In purpose of studying the effects of different positions of salt/cocrystal formers acidic groups on the physicochemical properties of pharmaceutical salt/cocrystal, two novel pharmaceutical salts of palmatine (PLT), PLT-PA and PLT-IPA, were synthesized based on the summary of the structures and properties of the pharmaceutical salts/cocrystals of palmatine chloride, using phthalic acid (PA) and isophthalic acid (IPA) as model compounds. Single crystal X-ray diffraction analysis shows that PLT-PA and PLT-IPA have similar columnar supramolecular chain structure formation, which is assembled by supramolecular synthons R44 (18) and R66 (22), respectively. This may be due to the fact that the two carboxy groups from IPA are in allotropic position and allow water molecules to enter the lattice and provide hydrogen donors to form larger ring motif, and the lattice water and other molecules in PLT-IPA jointly support the three-dimensional crystal structure. The results of solubility measurements and hygroscopicity tests showed that the order of solubility of PLT and its salts was PLT-IPA > PLTCl > PLT-PA, and the order of hygroscopicity was PLT-IPA > PLTCl > PLT-PA. Compared to PLTCl, PLT-PA has better against hygroscopic, while PLT-IPA has increased moisture absorption, but correspondingly has higher water solubility. This may be related to the involvement of water molecules in the formation of the motif during cocrystallization of PLT and IPA. This conclusion is also supported by theoretical calculation. Furthermore, since PLT-PA and PLT-IPA were synthesized and cocrystallized in the same conditions, the role of positional isomerism of carboxy groups in the construction of crystals is of particular importance. This work shows that positional isomerism of –COOH on salt/cocrystal formers may lead to changes in crystal structure, which in turn affects changes in physicochemical properties of the pharmaceutical. This provides a theoretical basis for the design and prediction of drug salts/cocrystals with targeted physicochemical properties.