Temozolomide cocrystal forms with enhanced dissolution, stability and biological activity towards Glioblastoma

Abstract

Temozolomide (TMZ), the first-line anti-glioblastoma prodrug, hydrolyses at physiological pH (pH>7) in the aqueous medium. With a short elimination half-life (T1/2) of ∼1.8 h, TMZ hydrolytically metabolizes to its metabolites 5-(3-monomethyl-1-triazeno)imidazole-4-carboxamide (MTIC) and then further into 5-aminoimidazole-4-carboxamide (AIC). The objective of current work is to develop novel stable cocrystals of TMZ with safe coformers such as isonicotinic acid (INA), 4-nitrobenzoic acid (4NO2BA), 3-aminobenzoic acid (3ABA), salicylic acid (2-hydroxybenzoic acid, 2HBA) and aromatic amide 4-hydroxybenzamide (4HBz) to stabilize the drug in a cocrystal form. All the cocrystals were characterized by single crystal X-ray diffraction (SCXRD), powder XRD (PXRD), and thermogravimetry-differential scanning calorimetry (TG-DSC) analyses. Dissolution profiling in phosphate buffer saline pH 6.8 revealed that the drug release rate from TMZ–2HBA Form II cocrystals and TMZ–4NO2BA⋅H2O cocrystal hydrate were significantly higher than pure TMZ. The hydrolytic stability of all the cocrystals and hydrates in pH 6.8 buffer was longer than that of TMZ while showing three-fold hydrolytic stability in case of TMZ–4NO2BA⋅H2O and TMZ-2HBA cocrystals. Their lattice arrangements in SCXRD explain the improved hydrolytic stability in these two cases. In vitro studies on human glioblastoma cell lines showed a significant improvement in the cytotoxicity and possibly improved bioavailability of TMZ–4NO2BA⋅H2O cocrystal hydrate.