Abstract：Polymorphs refer to substances with the same chemical composition but in more than one crystal form. These polymorphs exist widely in nature, especially in pharmaceuticals. These polymorphs have the same chemical molecular composition, but their physical and chemical properties are different, ultimately affecting the effect of pharmaceuticals. In recent years, with the generation of terahertz (THz) wave becoming a conventional technology, the application fields of terahertz time-domain spectroscopy (THz-TDS) has been gradually broadened. THz wave is related to intramolecular interaction mode and closely related to weak interaction modes such as hydrogen bond and van der Waals force. THz radiation can induce low-frequency bond vibration, crystal phonon vibration, hydrogen bond stretching and torsional vibration, and the collective vibration modes of many organic molecules are located in this region, especially pharmaceutical molecules. Thus in this paper, THz-TDS was used to study the THz absorption spectra of maleic hydrazide polymorphs (MH2 and MH3) in the range of 0.25~2.25 THz. The experimental results show that the THz absorption peaks of MH2 and MH3 are completely different. Specifically, MH2 has three characteristic absorption peaks, which are located at 0.34, 1.41 and 1.76 THz. MH3 has two characteristic absorption peaks at 0.75 and 1.86 THz. These results show that the polymorphs of maleic hydrazide can be distinguished and characterized by their THz absorption peaks. Then, to analyze the THz experimental peaks, solid-state density functional theory (DFT) is used to simulate. In matching experimental and theoretical spectral data, the origins of the THz absorption peaks are analyzed and discussed. The results suggest that the THz absorption peaks of MH2 and MH3 are very sensitive to their three-dimensional structures, and the absorption peaks all originate from intermolecular interactions Finally, the THz spectra of the commercial tablets of maleic hydrazide were tested. By comparing the THz absorption peaks between MH2(MH3) and Qingxiansu, it is found that the crystal form of Qingxiansu is MH3. This result shows that THz-TDS is a potential tool for detecting pharmaceutical polymorphism. Our research is expected to promote the detection of maleic hydrazide polymorphs in industrial production and clinical application.
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