Cocrystals of the Tuberculosis Drug Isoniazid: Polymorphism, Isostructurality, and Stability

Isoniazid (INH) is a key drug ingredient in the fixed dose combination for the treatment of tuberculosis (TB). INH is highly soluble in aqueous medium and also stable in pure form, but it undergoes degradation when it is part of the FDC due to cross reactions. In continuation of our studies to improve the physiochemical properties of INH, we performed a cocrystal screen with pharmaceutically acceptable molecules selected from the generally regarded as safe (GRAS). Cocrystals with acidic conformers, such as vanillic acid (VLA), ferulic acid (FRA), caffeic acid (CFA), as well as with hydroxyl coformer resorcinol (RES), are reported. INH–VLA and INH–FRA are dimorphic, and INH–CFA is trimorphic. Form-1 of INH–FRA and INH–VLA are two-dimensional isostructural. All cocrystal structures are sustained by the expected acid–pyridine synthon, except the isostructural cocrystals which have the hydroxyl–pyridine synthon. The cocrystal forms were tested in accelerated ICH conditions of 40 °C and 75% RH for stability, and it was found that all the solid forms are stable for a test period of six months, except the INH–RES cocrystal. Slurry conditions and grinding experiments suggest that Form-2 of INH–FRA and INH–VLA have good stability, and Form-1 of INH–CFA is the most stable crystalline form of INH.