Temozolomide Cocrystals with Carboxamide Coformers

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.