Salts of Mefenamic Acid With Amines: Structure, Thermal Stability, Desolvation, and Solubility

Salt formation has been known to improve some physicochemical properties of active pharmaceutical ingredients particularly solubility. In this study, mefenamic acid (MA) formed salts with ethylenediamine (EDM), triethylamine (TA), 1-methylpiperazine (MP), and morpholine (MOP). In the salt structures studied, the proton of the carboxylic acid group of the MA molecule was transferred to a nitrogen atom of the amine. Both crystal structures of the ethylenediammonium and morpholinium salts were solved successfully by single-crystal X-ray diffraction in the space group PĪ. The triethylammonium and the 1-methylpiperazinium salts solved in Pbca and P2₁/c, respectively. The thermal behavior of the salts was investigated, and the desolvated powders were analyzed using powder X-ray diffraction. Grinding and slurry experiments were also investigated as alternate methods for preparation of the salts. The desolvation experiments yielded interesting results with the desolvation of (MA^-)(MP⁺) resulting in MA form I, desolvation of (MA^-)(TA⁺) gave mixtures of MA form I and MA form II, whereas desolvation of (MA^-)(MOP⁺) gave MA form II. The solubility trend in water was determined as (MA^-)(MP⁺) > (MA^-)(TA⁺) > (MA^-)(MOP⁺) > (MA^-)(EDM⁺), with (MA^-)(MP⁺) the most-soluble and (MA^-)(EDM⁺) the least-soluble salt.