Temozolomide cocrystals with carboxamide coformers

Abstract

Temozolomide (TMZ) is an antitumor prodrug of broad spectrum antineoplastic activity. TMZ is stable in acidic medium (pH < 4) but starts to decompose at alkaline pH ( > 7). In continuation of our efforts to design stable cocrystals of TMZ with partners such as organic acids (pKa 2-5) and a salt dihydrate with hydrochloric acid, we report herein TMZ cocrystals with amide coformers, e.g., isonicotinamide, nicotinamide, pyrazinamide, p-hydroxybenzamide, saccharin, and caffeine. TMZ exhibits polymorphs in the p-hydroxybenzamide cocrystal (synthon polymorphism). The occurrence of the stable conformation A of temozolomide and metastable conformation B (energy difference 1.44 kcal mol-1) in amide cocrystals is compared with the overall statistics in temozolomide cocrystal structures and polymorphs. The novel cocrystals were characterized by spectroscopic, X-ray diffraction, and thermal methods. © 2013 American Chemical Society.