Drug-drug Salts of Mefenamic Acid\Tolfenamic Acid and Piperazine to Improve Physicochemical Properties for Potential Veterinary Use

Drug-drug salt has been known as an attractive strategy to not only improve physicochemical properties but also extend the field of combination drugs delivery. Mefenamic acid (MFA) and tolfenamic acid (TFA) belong to effective but poorly soluble anti-inflammatory drugs treating both human and animals. Piperazine (PPZ) has anthelmintic activities with serious hygroscopic problem. To improve the physicochemical properties of such drugs and seek possible drug combinations, herein, four novel MFA\TFA-piperazine (PPZ) drug-drug salts with different stoichiometry (2:1 and 1:1) were designed and synthesized. As we expect, the experiments prove that their solubilities and dissolution properties are much better than that of MFA and TFA. Among them, the apparent solubility of MFA-PPZ salt (1:1) improved about 130 times higher than that of MFA in the mixture of water and ethanol. Meanwhile, these salts are non-hygroscopic through dynamic vapor sorption analysis. Moreover, the obtained crystals were fully analyzed by single-crystal X-ray diffraction (SXRD), Hirshfeld surface analysis and solvent mediated phase transformation study which make a better understand on the crystal structure. Thereinto, MFA-PPZ salt (2:1) and TFA-PPZ salt (2:1) possess a similar crystal structure and their solubilities are also similar. What’s more, incorporation of PPZ in the crystal lattice destroys the dimer form in the original MFA\TFA crystal, and form salts through new ionic hydrogen bond. When it contacts with the solvents, the PPZ is more likely to interact with solvents moleculars which may lead to the acceleration of dissolution.