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

• Five new cocrystals of TMZ with aromatic acids, aromatic amide, and TMZ monohydrate were synthesized. • The cocrystal formations are stabilized by N–H···O, O–H···O, O–H···N hydrogen bonds and π⋅⋅⋅π interactions. • The cocrystals demonstrated better stability and dissolution properties compared to pure TMZ. • TMZ-4NO 2 BA⋅H 2 O cocrystal hydrate showed improved cytotoxicity than the pure drug on LN229 Glioblastoma cells. 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 (4NO 2 BA), 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–4NO 2 BA⋅H 2 O 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–4NO 2 BA⋅H 2 O 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–4NO 2 BA⋅H 2 O cocrystal hydrate. [Display omitted] [ABSTRACT FROM AUTHOR]