Improvement of the water solubility of tolfenamic acid by new multiple-component crystals produced by mechanochemical methods

Tolfenamic acid (HTA) is a drug characterized by very poor water solubility (13.6 nM under acidic conditions) and moderate solubility in ethanol (0.17 M). A series of new multicomponent crystals have been obtained by applying mechanochemical methods (i.e. kneading) to mixtures of HTA with sodium acetate, sodium carbonate, sodium hydroxide and imidazole. These reactions resulted in two salts (NaTA·0.5H2O and NaTA HT Form), a co-crystal of salts (NaTA·HTA·0.5NaAc·2H2O) and two salt co-crystals (NaTA·HTA·H2O/NaHCO3 and IMH-TA·HTA). Due to the lack of suitable crystals for single-crystal X-ray diffraction analysis, the structural features of the samples have been characterized by solid-state NMR (1H MAS, 13C CPMAS, 1H-13C FSLG LG-CP HETCOR and 15N CPMAS), IR(ATR) and Raman spectroscopy, VT-XRPD and elemental analysis. The evaluation of thermal stability and dissolution behavior was performed using thermogravimetry, differential scanning calorimetry and dissolution kinetic tests. The new solid-state forms show better thermal stability than pure HTA and an improved dissolution rate, which is most pronounced in NaTA·HTA·H2O/NaHCO3, NaTA HT Form and NaTA·0.5H2O.