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.
