Improvement of the water solubility of tolfenamic acid by new multiple-component crystals produced by mechanochemical methodsElectronic supplementary information (ESI) available. See DOI: 10.1039/c4ce00549j

• Main Authors: Gaglioti, K, Chierotti, M. R, Grifasi, F, Gobetto, R, Griesser, U. J, Hasa, D, Voinovich, D
• Format: Journal Article
• Language: English
• Published: 12.08.2014
• ISSN: 1466-8033
• DOI: 10.1039/c4ce00549j

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·0.5H 2 O and NaTA HT Form ), a co-crystal of salts ( NaTA·HTA·0.5NaAc·2H 2 O ) and two salt co-crystals ( NaTA·HTA·H 2 O/NaHCO 3 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 ( 1 H MAS, 13 C CPMAS, 1 H- 13 C FSLG LG-CP HETCOR and 15 N 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·H 2 O/NaHCO 3 , NaTA HT Form and NaTA·0.5H 2 O . Tolfenamic acid (HTA) is a drug characterized by very poor solubility in water. By mechanochemical methods, new solid-state forms of HTA were obtained, showing better thermal stability than pure HTA and an improved dissolution rate.