A drug–drug cocrystal strategy to regulate stability and solubility: A case study of temozolomide/caffeic acid

Abstract

Temozolomide (TMZ) is a common clinical drug widely used to treat glioblastoma multiforme and gradual astrocytoma. Despite its widespread use in cancer treatment, issues remain with the solubility and stability of TMZ, which can be addressed by synthesizing novel pharmaceutical cocrystals. This study sought to enhance the physiochemical properties of TMZ. To this end, a pioneering pharmaceutical cocrystal of TMZ and caffeic acid (CAF), 2TMZ–CAF·0·5H2O (2:1:0.5) was synthesized and characterized using a solution method. The cocrystal structure was analyzed by molecular surface electrostatic potential (MESP), Hirshfeld surface analysis, and 2D fingerprinting. They were further characterized by single crystal X-ray diffraction, power X-ray diffraction, proton nuclear magnetic resonance, thermogravimetry-differential scanning calorimetry, dynamic vapor sorption, and Fourier transform infrared spectroscopy. Furthermore, the hygroscopicity, stability, and solubility of the TMZ–CAF cocrystal were investigated to evaluate their pharmaceutical applicability. In the asymmetric unit of the novel synthesized cocrystal, two complementary molecules of TMZ and CAF were found, forming planar hydrogen bonding pairs such as O–H···O, N–H···O, and O–H···N. Moreover, the cocrystals exhibited excellent stability compared to TMZ alone and regulated solubility during accelerated stabilization and dissolution processes. Hence, the cocrystals boast characteristics that can circumvent the rapid release of TMZ. In conclusion, the newly synthesized 2TMZ–CAF·0·5H2O cocrystals demonstrate enhanced physiochemical properties, including improved stability and solubility, compared to pure TMZ. This suggests potential utility in drug delivery systems. Additionally, the findings underscore the growing importance of pharmaceutical cocrystals in drug development, with implications for advancing cancer treatment and drug formulation strategies.