Slow-Release Drug–Drug Cocrystals of Oxaliplatin with Flavonoids: Delaying Hydrolysis and Reducing Toxicity

Oxaliplatin (OXA) is a third-generation, platinum-based anticancer agent that is reported to induce cell toxicity in normal cells, which severely limits its applications. Its instability in aqua solution plays an important role in the cytotoxic effects. In this study, two novel drug–drug cocrystals of OXA were synthesized using baicalein (BAI) and naringenin (NAR) as cocrystal formers, as well as characterized by single crystal X-ray diffraction, powder X-ray diffraction, Fourier transform-infrared spectroscopy, and thermal analysis. Further evaluation of the dissolution profiles of the two cocrystals presented that they both have a reduced release rate and delayed hydrolysis compared to OXA. Theoretical analyses of the correlation between the structure and dissolution indicate that heterosynthons O–H···O and N–H···O hydrogen bonds are essential for reducing the dissolution rate of the two cocrystals. In addition, cell toxicity was studied using the CCK-8 assay, with the result that OXANAR may possess higher safety and OXABAI may have more significant effects on inhibiting cancer cells when compared to OXA.