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

Abstract

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·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.

Metformin-Mediated Improvement in Solubility, Stability, and Permeability of Nonsteroidal Anti-Inflammatory Drugs

“…It is known from the literature that MET is highly hygroscopic. It absorbs a large amount of water after 60% RH, and the weight change is approximately 80%, leading to the deliquescence of the drug in a short period due to water adsorption [ 51 , 52 , 53 ]. Given the extremely strong hygroscopicity of MET, the investigation and validation of the hygroscopicity of NSAIDs-MET after salt formation was an important part of our study.…”

Improvement of the Thermal Stability and Aqueous Solubility of Three Matrine Salts Assembled by the Similar Structure Salt Formers

“…In addition, the solubility of the three salts Previously reported methods for improving the bioavailability of MAT include the modification of drug structures and the preparation of compounds, such as MAT derivatives and injectable S. flavescens compounds [15][16][17]. Cocrystal or salt formation is an effective method for improving the physicochemical properties and pharmacokinetic properties of drugs without changing their chemical structures [18][19][20][21][22]. The formation of salt is similar to the formation of cocrystals, which are complexes formed by the transfer of protons from acidic components to alkaline components and the combination of the active pharmaceutical ingredient (API) and cocrystal formers (CCFs) or salt formers (SFs) through hydrogen bonding [23][24][25].…”