Temozolomide Cocrystals with Carboxamide Coformers
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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><sub>a</sub> 2β5) 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<sup>β1</sup>) 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