Enhanced Aqueous Solubility of the Solid Forms of a BCS Class-II Anti-Tuberculosis Drug, Prothionamide

Abstract

The second-line anti-tuberculosis (TB) drug prothionamide (PRT) has poor aqueous solubility but high permeability; hence, it belongs to the Biopharmaceutical Classification System (BCS) Class II. We report new solid forms—a novel polymorph, 6 molecular complexes, and 11 eutectics—of PRT. The solid forms showed superior aqueous solubility compared to the pristine PRT. The single-crystal and powder X-ray diffraction, thermal, spectroscopic, and microscopic data provide in-depth structural, compositional, stability, and phase correlations in the solid forms. Fast evaporation using a rotary evaporator, a kinetically controlled crystallization method, offers an effective strategy to access the coordinates in the landscape that otherwise remain inaccessible. Identified sets of H-bond donor and acceptor sites on PRT, based on the calculated gas-phase molecular electrostatic potential surfaces, provide an empirical route to screen for coformers. The torsional flexibility enjoyed by the thioamide moiety and the propyl chain introduce diversity in the conformational possibilities for PRT.