Molecular Crystal Forms of Antitubercular Ethionamide with Dicarboxylic Acids: Solid-State Properties and a Combined Structural and Spectroscopic Study

We report on the preparation, characterization, and bioavailability properties of three new crystal forms of ethionamide, an antitubercular agent used in the treatment of drug-resistant tuberculosis. The new adducts were obtained by combining the active pharmaceutical ingredient with three dicarboxylic acids, namely glutaric, malonic and tartaric acid, in equimolar ratios. Crystal structures were obtained for all three adducts and were compared with two previously reported multicomponent systems of ethionamide with maleic and fumaric acid. The ethionamide-glutaric acid and the ethionamide-malonic acid adducts were thoroughly characterized by means of solid-state NMR ((13)C and (15)N Cross-Polarization Magic Angle Spinning or CPMAS) to confirm the position of the carboxylic proton, and they were found to be a cocrystal and a salt, respectively; they were compared with two previously reported multicomponent systems of ethionamide with maleic and fumaric acid. Ethionamide-tartaric acid was found to be a rare example of kryptoracemic cocrystal. In vitro bioavailability enhancements up to a factor 3 compared to pure ethionamide were assessed for all obtained adducts.