Decoding intermolecular forces in drug Co-Crystallization: A Temozolomide-p-Coumaric acid system with enhanced stability and tunable dissolution profiles

Cocrystal engineering presents a promising strategy to optimize the physicochemical properties of active pharmaceutical ingredients (APIs). In this work, we successfully synthesized a TMZ-p-CA·H₂O cocrystal, whose formation and structural characteristics were confirmed through SCXRD, PXRD, TG-DSC, FT-IR, and NMR characterization. Computational investigations including DFT, FMO analysis, QTAIM analysis, IGMH analyses, Hirshfeld surface, and MEPS confirmed that O–H hydrogen bonds serve as the primary driving forces for cocrystal formation. Stability assessments under accelerated conditions and dynamic vapor sorption (DVS) revealed enhanced stability of the cocrystal relative to Temozolomide (TMZ). Despite exhibiting greater moisture affinity, the cocrystal maintained a total mass change below 2 % (indicating slight hygroscopicity) during DVS analysis. Notably, the cocrystal demonstrated significantly improved dissolution at pH 6.8, exhibiting 1.7-fold higher apparent solubility than TMZ alone. In summary, this work not only demonstrates a stable cocrystal overcoming TMZ's solubility and stability limitations, but also validates computational-guided rational design as a synergistic strategy for pharmaceutical crystal engineering.