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.

甲氯芬那酸（Meclofenamic acid, MFA）是芬那酸类药物中抗炎活性最强的化合物。本研究报道了以下内容：(1) 甲氯芬那酸分别与异烟酰胺（isonicotinamide, INA）、4,4′-联吡啶（4,4′-bipyridine, BPY）形成的两种共晶；(2) 甲氯芬那酸与哌嗪（piperazine, PPZ）1:1盐的多晶型（正交晶系P212121型O与单斜晶系P21/c型M）、甲氯芬那酸-哌嗪-水1:1:1盐水合物、甲氯芬那酸-哌嗪2:1盐；(3) 甲氯芬那酸与2-氨基吡啶（2-aminopyridine, 2-APY）1:1盐，以及甲氯芬那酸与4-氨基吡啶（4-aminopyridine, 4-APY）1:1:1盐水合物。对甲氯芬那酸进行升华可获得适用于X射线衍射（X-ray diffraction）的单晶，其衍射数据质量优异，可用于结构精修与全部原子坐标的确定。上述共晶与盐类结构通过中性O–H···O、O–H···N、N–H···O、N–H···N以及离子型O–H···O–、N+–H···O–氢键组装得到。甲氯芬那酸晶体结构中存在的甲基无序现象在共晶与盐类结构中均未出现，此类结构中甲基取向存在A、B两种不同构象。在37 ℃的50%乙醇-水溶液中，甲氯芬那酸-INA（1:1）与甲氯芬那酸-BPY（1:0.5）共晶的溶解度分别为纯甲氯芬那酸的2.9倍与7.6倍。值得注意的是，甲氯芬那酸-PPZ-M型1:1盐及其1:1:1水合物的溶解度分别为纯甲氯芬那酸的2724倍与1334倍。这两种盐在37 ℃的50%乙醇-水溶液中经24 h浆化后，均会转化为甲氯芬那酸-PPZ 2:1盐；该2:1盐再经24 h浆化搅拌后，又会进一步转化为纯甲氯芬那酸。尤为值得关注的是，甲氯芬那酸-PPZ-M型（1:1）盐在水中的溶出速率仅略低于市售的甲氯芬那酸钠（sodium meclofenamate）。