Innovative pharmaceutical amine salt strategy for enhancing the water solubility of mefenamic acid

This study focuses on significantly enhancing the water solubility of mefenamic acid (MFA) through an innovative pharmaceutical amine salt strategy. By analyzing the crystal structure of MFA single crystals, we found that the dimer structure formed through carboxylic acid O H⋯O hydrogen bonding between MFA molecules limits the exposure of its hydrophilic groups, which is a crucial factor contributing to its poor water solubility. To overcome this limitation, we meticulously synthesized three forms of MFA amine salts: MFA-DIP salt, MFA-DIPA salt, and MFA-HDA salt. Utilizing various technical approaches, including crystal structure analysis, Hirshfeld surface analysis, powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), infrared spectroscopy (IR), and fluorescence spectroscopy, we systematically investigated the structural characteristics and physicochemical properties of these amine salts. The results demonstrate that the hydrogen bonding interactions between MFA molecules are significantly enhanced upon salt formation, leading to favorable changes in the crystal structure and effective release of the previously restricted hydrophilic carboxylic acid groups, thereby significantly improving the water solubility of MFA. Notably, the solubility and dissolution rates of MFA-DIPA salt and MFA-HDA salt in water and pH 6.86 phosphate buffer solution were substantially increased. However, MFA-DIP salt exhibited salt decomposition during solubility testing, identified as a metastable crystalline form. This study not only provides practical strategies for improving the water solubility of MFA but also opens new perspectives for in-depth research on drug polymorphism stability and solubility optimization, offering potentially significant guidance for the field of pharmaceutical research and development.