Abstract：Ternary cocrystal is a new cocrystal design strategy developed based on binary cocrystal, which can improve the physicochemical properties of drugs without affecting their biological and pharmacological activities. Therefore, ternary cocrystal shows much potential in the development and research of drugs. Since ternary cocrystal involves the complex assembly of three different molecules, the complexity of which increases with the type and number of molecules involved in pharmaceutical cocrystal, and the number of potential cocrystal hydrogen-bonding sites also increases, it is difficult to obtain a specific ternary cocrystal. There are few reports on the microscopic molecular structure of a specific ternary cocrystal system. In order to understand the hydrogen-bonding form of the ternary cocrystal structure, it is crucial to obtain the molecular structure information of the related binary and ternary cocrystals in the ternary cocrystal system by detecting means to understand the complex formation process of the ternary pharmaceutical cocrystal. In this paper, the isonicotinamide-glutaric acid, pyrazinamide-glutaric acid binary cocrystals and isonicotinamide-glutaric acid-pyrazinamide ternary cocrystal were successfully synthesized by mechanical grinding. The binary and ternary cocrystal structures were studied by terahertz time domain spectroscopy (THz-TDS) and density functional theory (DFT). The experimental results of THz spectroscopy showed that both binary and ternary cocrystals showed their unique spectral characteristics. The crystal structure analysis showed that in the isonicotinamide-glutaric acid-pyrazinamide ternary cocrystal structure, the hydroxyl group in the carboxyl group on the glutaric acid side and the pyridine N in isonicotinamide formed a carboxyl-pyridine N hydrogen bond heterosynthon, while the amide in isonicotinamide forms an amide-amide hydrogen bond homosynthon with the amide in pyrazinamide. Finally, the theoretical THz spectra calculated by DFT were compared with the experiment, and it was found that the superposition of hydrogen bond forms of isonicotinamide-glutaric acid and pyrazinamide-glutaric acid binary cocrystals is not completely consistent with the hydrogen bond form of isonicotinamide-glutaric acid-pyrazinamide ternary cocrystal. However, the hydrogen bond forms of the two binary cocrystals are of great reference value for predicting the hydrogen bond forms of the ternary cocrystal. These results provide a wealth of information and unique methods for the emerging field of pharmaceutical cocrystals to study the molecular assembly and intermolecular interactions of specific ternary cocrystals at the molecular level.
Key words：Ternary cocrystal; Terahertz time-domain spectroscopy; Density functional theory; Hydrogen bond
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