Structural and physicochemical evaluation of three amine salts of diclofenac with improved aqueous solubility

This study aimed to overcome the poor aqueous solubility of diclofenac (DIC), a BCS Class II drug, through the strategic formation of amine salts. Three novel salts with diisopropylamine (DIP), butanolamine (BUTA), and tromethamine (TRIS) were successfully synthesized and comprehensively characterized. Single-crystal X-ray diffraction revealed distinct hydrogen-bonded networks for each salt, ranging from cyclic tetramers (DIC-DIP) to extended three-dimensional frameworks (DIC-BUTA, DIC-TRIS). Solid-state characterization by PXRD, DSC and FTIR spectroscopy confirmed the formation of new, phase-pure crystalline materials, with FTIR clearly showing the disappearance of the carboxylic C=O band and the appearance of carboxylate bands, confirming proton transfer. The salts demonstrated dramatically enhanced equilibrium solubility and intrinsic dissolution rates (IDR) compared to the parent DIC, particularly in water. The most significant improvements were observed for DIC-BUTA and DIC-DIP, achieving solubility increases of 213.0-fold and 146.4-fold, and IDR increases of 276.0-fold and 222.7-fold, respectively. The superior dissolution performance of DIC-BUTA and DIC-DIP is correlated with their moderate hydrogen-bond networks (5 and 3 donor bonds, respectively) and lower crystal densities (1.326 and 1.262 g/cm³), which facilitate easier lattice disruption and solvation. Conversely, the densely packed, highly hydrogen-bonded structure of DIC-TRIS resulted in the highest lattice stability but the most modest solubility enhancement. All salts exhibited congruent dissolution without phase transformation. This work establishes DIC-BUTA and DIC-DIP as the most promising candidates for developing rapid-release oral formulations of diclofenac and provides fundamental insights into the structure-property relationships governing salt solubility.