High Solubility Piperazine Salts of the Nonsteroidal Anti-Inflammatory Drug (NSAID) Meclofenamic Acid

Meclofenamic acid (MFA) is the most potent anti-inflammatory drug among the fenamic acids. We report (1) two cocrystals of MFA with isonicotinamide (INA) and 4,4′-bipyridine (BPY); (2) polymorphs of MFA and piperazine (PPZ) 1:1 salt (orthorhombic <i>P</i>2<sub>1</sub>2<sub>1</sub>2<sub>1</sub> O and monoclinic <i>P</i>2<sub>1</sub>/<i>c</i> M), MFA–PPZ–H<sub>2</sub>O 1:1:1 salt hydrate, MFA–PPZ 2:1 salt; and (3) MFA and 2-aminopyridine (2-APY) 1:1 salt, MFA and 4-aminopyridine (4-APY) 1:1:1 salt hydrate. Sublimation of MFA gave single crystals for X-ray diffraction which provided good quality data for refinement and all atomic coordinates. The cocrystal and salt structures are assembled via neutral O–H···O, O–H···N, N–H···O, N–H···N, and ionic O–H···O<sup>–</sup>, N<sup>+</sup>–H···O<sup>–</sup> hydrogen bonds. The disorder of the methyl group in the MFA crystal structure is absent in the cocrystal and salt structures, which contain different conformers (A or B) of methyl group orientation. The solubility of MFA–INA (1:1) and MFA–BPY (1:0.5) cocrystals is 2.9 and 7.6 times higher than that of MFA at 37 °C in 50% EtOH–water. Interestingly, MFA–PPZ-M 1:1 salt and its 1:1:1 hydrate are 2724- and 1334-fold more soluble than MFA. Both of these salts transformed in 50% EtOH–water slurry at 37 °C to MFA–PPZ 2:1 salt after 24 h, which in turn transformed to MFA after another 24 h of slurry stirring. Remarkably, the dissolution rate of MFA–PPZ-M (1:1) salt in water is just slightly lower than that of the marketed sodium meclofenamate.