Temozolomide–Hesperetin Drug–Drug Cocrystal with Optimized Performance in Stability, Dissolution, and Tabletability

Abstract

A new 1:1 drug–drug cocrystal of temozolomide and hesperetin was successfully prepared by liquid-assisted grinding, slurry conversion crystallization, and evaporation crystallization. The obtained cocrystal was comprehensively characterized by single-crystal and powder X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis, as well as by Fourier transform infrared and nuclear magnetic resonance spectroscopy. The two drug molecules in the cocrystal are connected via O–H···O hydrogen bonds between the carbonyl oxygen of temozolomide and the phenolic hydroxyl group of hesperetin. The drug–drug cocrystal enhances the hydroscopic stability of hesperetin and the physicochemical stability of temozolomide. In addition, the cocrystal optimizes the dissolution behavior of temozolomide and hesperetin at pH 1.2 and pH 6.8 in comparison to the pristine drugs. Further, a compressibility assessment was also conducted, and the cocrystal exhibits a superior tabletability in comparison with temozolomide. Therefore, the drug–drug cocrystal has the potential to be developed as an efficient oral formulation of a drug combination which will overcome the weaknesses of each parent drug.