Cocrystals, Salts, and Supramolecular Gels of Nonsteroidal Anti-Inflammatory Drug Niflumic Acid

Niflumic acid (NFA) is a nonsteroidal anti-inflammatory drug (NSAID) classified under the BCS (Biopharmaceutical Classification System) Class II category of poor aqueous solubility and high permeability. In an attempt to improve the physicochemical properties of NFA, particularly solubility and dissolution rate by cocrystallization and salt formation, cocrystals of NFA were prepared with caprolactam (CPR, 1:1) and 2-hydroxy pyridine (2HP, 1:1) as well as salts with piperazine (PIP, 1:0.5), benzenesulfonic acid (BSA, 1:1), benzyl amine (BZA, 1:1 and 2:2), and tyramine (TYA, 1:1). The new solid forms were characterized by powder X-ray diffraction, infrared spectroscopy, and differential scanning calorimetry and confirmed by single crystal X-ray diffraction. In the cocrystals NFA–CPR and NFA–2HP, the cyclic amide of the coformer forms a dimer synthon through N–H···O hydrogen bonds and such dimers extend through O–H···O hydrogen bonds. In piperazine, benzyl amine, and tyramine salts, proton transfer occurs fr...