Improved solubility and hygroscopicity of enoxacin by pharmaceutical salts formation with hydroxybenzonic acids via charge assisted hydrogen bond

Abstract

With our ongoing purpose to improve the solubility of enoxacin (EX) and avoid its hygroscopicity by forming pharmaceutical salts, three unreported pharmaceutical salts of EX with m-hydroxybenzoic acid ((HEX)·C7H5O3·H2O, EX-MHBA) (1), protocatechuic acid ((HEX)·C7H5O4·2H2O, EX-PCA) (2) and gallic acid ((HEX)·C7H5O5, EX-GLA) (3) have been designed and synthesized by using solution evaporation approach and the description of their structures has been provided. Crystal structure and theoretical calculation analysis show that all three pharmaceutical salts undergo proton transfer and held stable crystal structure via charge assisted hydrogen bond. The solubility analysis of EX-MHBA, EX-PCA and EX-GLA showed that their solubilities were significantly higher than those of pure EX. The reason may be that both EX and the three hydroxybenzoic acids depend on charge assisted hydrogen bond to form EX-MHBA, EX-PCA and EX-GLA pharmaceutical salts, which increase the solubility of EX by ionizing it from the neutral molecule to the ionic state. Meanwhile, the hygroscopicity of EX-MHBA, EX-PCA and EX-GLA pharmaceutical salts was markedly improved compared to pure EX. This may be due to the near saturation of hydrogen bonds between the carboxylic acid group of hydroxybenzoic acid and its neighboring groups, resulting in the carboxylic acid group of hydroxybenzoic acid may have difficulty binding to external water molecules. The success of this work suggests that it may provide an encouraging approach to improve the solubility of insoluble active pharmaceutical ingredients while avoiding their hygroscopicity. Further to this, it is surprising that the antibacterial activities in vitro of three pharmaceutical salts of EX are better than that of the EX.