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.