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 (p<i>K</i>_a 2–5) and a salt dihydrate with hydrochloric acid, we report herein TMZ cocrystals with amide coformers, e.g., isonicotinamide, nicotinamide, pyrazinamide, <i>p</i>-hydroxybenzamide, saccharin, and caffeine. TMZ exhibits polymorphs in the <i>p</i>-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