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 P212121 O and monoclinic P21/c M), MFA–PPZ–H2O 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–, N+–H···O– 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.