Pharmaceutical Cocrystals and Salt of Ethionamide with Fluorobenzoic Acids for Improved Drug Delivery

Ethionamide (ETH) is a second-line antituberculosis drug, but its aqueous solubility is poor. A cocrystal/salt screen of ETH with fluorobenzoic acid (FBA) coformers afforded four cocrystals and one salt of ETH, namely, ETH-4-fluorobenzoic acid (4FBA, cocrystal), ETH-3,4-difluorobenzoic acid (34DFBA, cocrystal), ETH-2,4,5-trifluorobenzoic acid (245TFBA, cocrystal), ETH-2,3,4,5-tetrafluorobenzoic acid (2345TFBA, cocrystal), and ethionamidium-2-fluoro-6-hydroxybenzoate (2F6HBA, salt). The new crystalline multicomponent cocrystal-salt (MCCS) forms were characterized by powder X-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, single crystal X-ray diffraction, and FT-IR analysis. Structural analysis showed that the acid-pyridine, hydroxyl-pyridine, and thioamide dimer synthons stabilize ETH cocrystals/salt structures. The cocrystals/salt exhibit remarkable improvement in solubility, dissolution, and diffusion at pH 7 in phosphate buffer solution. The ability of fluoro compounds to increase membrane diffusion and bioavailability of drugs as MCCS complexes may be of general applicability for poor solubility and permeability drugs.