Versatile Solid Modifications of Multicomponent Pharmaceutical Salts: Novel Metformin-Rhein Salts Based on Advantage Complementary Strategy Design

This study aimed to develop an effective treatment for diabetes and diabetic complications, based on the advantage complementary strategy of drug-drug salt, by designing and synthesizing the multicomponent molecular salts containing metformin (MET) and rhein (RHE). Finally, the salts of MET-RHE (1:1), MET-RHE-H2O (1:1:1), MET-RHE-ethanol-H2O (1:1:1:1), and MET-RHE-acetonitrile (2:2:1) were obtained, indicating the polymorphism of salts formed by MET and RHE. The structures were analyzed by the combination of characterization experiments and theoretical calculation, and the formation mechanism of polymorphism was discussed. The obtained results of in vitro evaluation showed that MET-RHE had a similar hygroscopicity with metformin hydrochloride (MET center dot HCl), and the solubility of the component of RHE increased by approximately 93 times, which laid a foundation for improving the bioavailability of MET and RHE in vivo. The evaluation of hypoglycemic activity in mice (C57BL/6N) indicated that MET-RHE exhibited better hypoglycemic activity than the parent drugs and the physical mixtures of MET and RHE. The above findings demonstrate that this study achieved the complementary advantages of MET and RHE through the multicomponent pharmaceutical salification technique, and provides new possibilities for the treatment of diabetic complications.

Automated summary

This study aimed to develop an effective treatment for diabetes and diabetic complications by using the complementary strategy of drug-drug salt. Multicomponent molecular salts containing metformin (MET) and rhein (RHE) were synthesized, and their structures were analyzed. The evaluation results showed that the salts had similar hygroscopicity with metformin hydrochloride (MET center dot HCl) and the solubility of RHE component increased significantly. The MET-RHE salt exhibited better hypoglycemic activity compared to the individual drugs and physical mixtures. This study provides new possibilities for the treatment of diabetic complications.