Structural landscape on a series of rhein: Berberine cocrystal salt solvates: The formation, dissolution elucidation from experimental and theoretical investigations

The specific crystalline form of a compound remarkably affects its physicochemical properties. Therefore, a detailed analysis of the structural features and intermolecular interactions of a multi-component crystal is feasible to understand the relationships among the structure, physicochemical properties and the formation mechanism. In the present study, three novel cocrystal salt solvates of rhein and berberine were reported for the first time. Various solid characterizations and theoretical computations based on density functional theory (DFT) were carried out to demonstrate the intermolecular interactions. The theoretical computation shows that the strongest interaction existed between berberine cation and rhein anion, and the electrostatic interaction play a dominant role. However, no salt bond was observed between them. Further intrinsic dissolution rate analysis in water shows that the monohydrate exhibits 17 times enhancement in comparison with rhein. The rhein and berberine combined in ionic state in cocrystal salt is the main reason for the solubility improvement. This paper suggests that the interactions between the different components can be visualized and qualitatively and quantitatively analyzed by theoretical computation, which is helpful to understand the relationship between stereochemical structure and physicochemical properties of multi-component complex. (C) 2022 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.