Structure Characterization and Property Evaluation of a Drug–Drug Cocrystal Involving Temozolomide and Luteolin

A novel drug–drug cocrystal made up of two agents with glioma-inhibiting activity, temozolomide (TMZ) and luteolin (LUT), was synthesized and characterized using infrared spectroscopy, thermal analysis, and X-ray diffraction. Single-crystal analysis reveals that one TMZ, one LUT, and two water molecules are incorporated into the cocrystal lattice, with all linked through hydrogen bonds to form a layered packing architecture. This structure exhibits distinct characteristics from the reticulated and interlaced framework of pure TMZ and the tile-like packing pattern of pristine LUT. Molecular electrostatic potential and Hirshfeld surface analyses were employed to evaluate hydrogen-bonded assembly motifs and intensity of intermolecular interactions in the cocrystal and its component crystals. Compared with pure TMZ, the cocrystal hydrate exhibited enhanced stability and superior tabletability. Dissolution studies indicated that LUT’s maximum solubility of the cocrystal (55.6 μg/mL) was nearly twice as high as that of LUT·0.5H2O (27.5 μg/mL). Meanwhile, the discrepancy in solubility between LUT and TMZ was reduced from approximately 273 to 12 times. Overall, the TMZ/LUT·2H2O cocrystal enhances TMZ’s stability and tabletability, as well as improves the dissolution behavior of both drugs. The property improvement of the cocrystal is attributable to its framework architecture, stabilized by hydrogen bonds. This work presents a promising method for developing synergistic glioma-inhibiting agents featuring substantial potential in clinical settings.