Terahertz Spectroscopic Characterization of a Daidzein-Piperazine Crystalline Solid Form Prepared by Liquid-Assisted Grinding

Abstract

Daidzein is a natural flavonoid with low aqueous solubility and bioavailability. The low-frequency terahertz spectroscopic characteristics and corresponding vibrational origins of the 1:1 daidzein–piperazine (DAI–PIP) crystalline system remain insufficiently explored. In this study, a DAI–PIP crystalline solid form was prepared by liquid-assisted grinding at a 1:1 starting-material molar ratio and characterized using powder X-ray diffraction (PXRD), differential scanning calorimetry–thermogravimetric analysis (DSC–TGA), terahertz time-domain spectroscopy (THz-TDS), and scanning electron microscopy (SEM). The experimental PXRD pattern exhibited characteristic reflections at 18.62° and 23.19°, while several reflections of the starting materials were absent. The good overall agreement between the experimental and simulated PXRD patterns supported the reasonableness of the periodic crystal-structure models used for the subsequent THz calculations. DSC–TGA revealed distinct endothermic events and multistage mass-loss behavior, while SEM showed finer and relatively uniform particle aggregates after grinding. The DAI–PIP product exhibited experimental THz absorption features at approximately 1.46, 1.84, and 2.28 THz. Periodic DFT calculations reasonably reproduced the principal experimental features. The calculated mode at 1.89 THz was mainly localized on the hydroxyl-substituted aromatic ring of DAI, whereas the modes at 1.35 and 2.20 THz involved coupled motions of DAI and PIP accompanied by intermolecular N–H···O hydrogen-bond deformation. These results provide a structurally supported interpretation of the characteristic low-frequency vibrations of the DAI–PIP crystalline system and demonstrate the value of combining THz-TDS with periodic DFT calculations for investigating its solid-state vibrational behavior.