Pharmaceutical salts/cocrystals of enoxacin with dicarboxylic acids: Enhancing in vitro antibacterial activity of enoxacin by improving the solubility and permeability

Abstract

Base on improving the solubility and permeability of enoxacin (EX) to enhance the antibacterial activity in vitro, three new pharmaceutical salts/cocrystals of EX with oxalic acid (EX·0.5(C2H2O4)·2(H2O)), malonic acid ((HEX)·C3H3O4) and fumaric acid ((HEX)·C4H3O4) have been designed, synthesized and characterized. Comprehensive analysis structure and Hirshfeld surface reveal that the hydrogen bonds/CAHBs formed by the N atom in the piperazine ring from EX molecule with the carboxylic acid group in the coformer could form a stable crystal structure. It is universally acknowledged that improving the solubility of the EX (BCS class II) to make it a BCS class I drug would obtain a Bioequivalence of immunity to the drug trial. The solubilities of three pharmaceutical salts/cocrystals of EX with dicarboxylic acids are consistent with expectation that they are dramatically improved in pure water than pure enoxacin, and the solubility order of three pharmaceutical salts/cocrystals of EX is consistent with coformers solubility. The permeabilities of three pharmaceutical salts/cocrystals of EX are improved compared with the pure enoxacin, and the variation tendency is consistent with the solubilities of three pharmaceutical salts/cocrystals of EX. In addition, the antibacterial activities in vitro of three pharmaceutical salts/cocrystals of EX are improved compared with the corresponding parent compound (EX), which change the order is consistent with the solubility and permeability. Simultaneously, the hygroscopic stabilities of three pharmaceutical salts/cocrystals are surpassing pure EX, and the hygroscopic stability of molecular cocrystal EX-OXA is better than ionic cocrystal EX-MLO and EX-FUM. This implies that preparation of the pharmaceutical salts/cocrystals of EX with oxalic acid, malonic acid and fumaric acid could not only enhance the antibacterial activity of EX, which base on improving the solubility and permeability of EX, but also improve the hygroscopic stability of EX.