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

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journal contribution
posted on 19.11.2018, 00:00 by Sudhir Mittapalli, M. K. Chaitanya Mannava, Rasmita Sahoo, Ashwini Nangia
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 from the NFA to the basic nitrogen of the coformer, and in NFA–BSA salt, the proton is transferred from benzenesulfonic acid to the pyridine nitrogen of NFA. In addition to the above salts and cocrystals, supramolecular gels of NFA–PIP and NFA–BZA salts are reported, which were obtained from nitrobenzene, methyl salicylate, menthol, and mesitylene solvents. These gels were studied by rheology. Solubility and dissolution rate of the novel solid forms (NFA–CPR, NFA–PIP, NFA–BSA, and NFA–TYA) in 20% EtOH–water showed the best behavior for NFA–TYA salt with improvement of 42- and 54-times in solubility and dissolution rate compared to the reference drug. The remaining solids such as NFA–PIP, NFA–BSA salts, and NFA–CPR cocrystal exhibited improvement of 39-, 18-, 1.4-times in solubility and 7.8-, 10-, 2-times for dissolution rate.