太赫兹光谱可以反映与固体中晶格振动有关的信息, 特别适合于检测相同分子形成的不同晶体, 因此利用太赫兹光谱对检测并控制药物的不同晶型具有重要的意义。 而药物分子的晶型会影响药物在存储中的稳定性等性质。 选取最早使用的喹诺酮类抗生素萘啶酸作为研究对象, 首先合成了萘啶酸的两种晶型NA-Ⅰ和NA-Ⅱ。 通过X射线粉末衍射确认了两种晶型。 使用太赫兹时域光谱技术在室温下对合成的两种萘啶酸不同晶型NA-Ⅰ和NA-Ⅱ在0.2～2.4 THz范围内进行检测, NA-Ⅰ和NA-Ⅱ在太赫兹光谱中表现出明显的差异。 NA-Ⅰ在0.94, 1.41, 1.88, 2.05和2.17THz处有五处特征峰, 而NA-Ⅱ在0.72, 0.96, 1.38, 1.80, 2.04和2.16 THz处有六处特征峰。 二者最明显的差异是NA-Ⅱ在2.04 THz处的峰为肩峰, 而NA-Ⅰ在2.05 THz处的吸收强度要大得多。 不同于其他光谱, 如红外光谱, 太赫兹光谱中的特征峰不对应特定的官能团, 因此对光谱峰的指认尤为重要。 利用密度泛函理论对两种晶型进行理论计算, 理论峰与实验特征峰基本对应, 得出萘啶酸两种晶型在此低频范围的振动模式主要是分子的骨架运动, 并从两种晶体堆积方式的不同阐述了光谱显著差异的原因。 该研究为利用太赫兹光谱检测药物的同质多晶提供了依据。

Terahertz spectroscopy can provide the lattice vibration information of solid materials, which is different from previous measuring methods. And particularly, it is suitable to test polymorphs. Thus it has an important meaning for controlling and detecting the polymorphs of drugs. The polymorphs should affect the properties, such as stability,of the drugs in storage. Nalidixic acid, the earliest quinolone antibacterials used, was investigated in this work. Two polymorphs NA-Ⅰ and NA-Ⅱ were synthesized and were confirmed by X-ray powder diffraction experiments. Different absorption spectra in the range of 0.2~2.4 THz of two synthesized polymorphs of nalidixic acid were obtained with terahertz time-domain spectroscopy at room temperature. Significant differences existed in the terahertz spectra of NA-Ⅰ and NA-Ⅱ. Five characteristic absorption peaks observed in the terahertz spectrum of NA-Ⅰ were at 0.94, 1.41, 1.88, 2.05, and 2.16 THz, while six peaks of NA-Ⅱ were at 0.72, 0.96, 1.38, 1.80, 2.04 and 2.16 THz. The most obvious difference was that there was a shoulder peak at 2.04 THz for NA-Ⅱ, while the intensity of the peak at 2.05 THz for NA-Ⅱ was much larger. Unlike other spectroscopies, such as infrared spectroscopy, the characteristic peaks in terahertz spectra were not related to specific functional groups. Thus the assignment of the characteristic peaks in terahertz spectra was essential. Theoretical calculations for the two polymorphs were performed based on density functional theory. The calculated characteristic peaks were in accord with those in the experiments. The vibrational modes in this low frequency region were mainly skeletal vibrations. Also the difference of the two spectra was explained by the different packing modes of the two crystals. This work provides evidence for identification of drug polymorphs using terahertz spectroscopy.