Multimodal characterization and density functional theory insights into the molecular structure and intermolecular...

Aspirin and ligustrazine both possess high pharmacological activity, and their cocrystal form excels at increasing dissolution rate, bioavailability, and physical stability. However, the molecular vibrational characteristics and intermolecular interactions of the cocrystal have been largely neglected. This limitation impedes the advancement of structure-based design and mechanistic understanding. To bridge the knowledge gap regarding the assembly of aspirin and ligustrazine, our study employed a crystallization strategy and conducted a comprehensive investigation of the aspirin-ligustrazine cocrystal using a multimodal characterization approach, including differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) for assessing its thermal behavior and stability, followed by powder X-ray diffraction (PXRD), terahertz time-domain spectroscopy (THz-TDS), and Raman spectroscopy for probing its crystal structure and vibrational properties. In parallel, three plausible cocrystal structures were modeled and optimized via density functional theory (DFT) calculations to evaluate their relative stabilities and interaction patterns. Among the proposed models, the cocrystal form III structure exhibited the strongest correlation with experimental data. The combined experimental results revealed distinct endothermic transitions, spectral changes, and characteristic vibrational signals, confirming the formation of the cocrystal and structural reorganization driven by intermolecular interactions, particularly hydrogen bonding. Intermolecular hydrogen bonds and weak interactions play a key role in stabilizing the cocrystal, which is corroborated by subsequent vibrational mode assignments. The new results of this study represent the first comprehensive vibrational-level analysis of the aspirin-ligustrazine cocrystal structure, providing novel theoretical insights and technical guidance for pharmaceutical cocrystal design and optimization.