三元共晶是在二元共晶的基础上发展的一种新型共晶设计策略, 可以在不影响药物固有生物活性和相应药理活性的情况下改善药物的理化性质, 因此三元共晶在药物研究和开发方面具有巨大的潜力。 由于三元共晶会涉及三种不同分子的复杂组装, 其复杂程度随着参与药物共晶的分子种类和数量的增加而增加, 潜在的共晶氢键结合位点数量也随之增加, 所以很难获得特定的三元共晶, 关于特定三元共晶系统的微观分子结构方面的报道也很少。 为了理解三元共晶结构的氢键形式, 通过检测手段获取三元共晶体系中相关二元及三元共晶的分子结构信息对了解三元药物共晶的复杂形成过程尤为重要。 采用机械研磨方法成功地合成了异烟酰胺-戊二酸、 吡嗪酰胺-戊二酸二元共晶和异烟酰胺-戊二酸-吡嗪酰胺三元共晶, 通过太赫兹时域光谱（THz-TDS）和密度泛函理论（DFT）计算对二元共晶和三元共晶结构进行研究。 太赫兹光谱实验结果表明, 二元和三元共晶都显示出各自独特的光谱特征。 晶体结构分析表明异烟酰胺-戊二酸-吡嗪酰胺三元共晶结构中戊二酸一侧羧基中的羟基与异烟酰胺中的吡啶N形成羧基-吡啶N氢键异合成元, 而异烟酰胺中的酰胺与吡嗪酰胺中的酰胺形成酰胺-酰胺氢键同合成元。 最后, 将DFT计算得到的理论太赫兹光谱与实验进行对比, 发现异烟酰胺-戊二酸、 吡嗪酰胺-戊二酸二元共晶氢键形式的叠加与异烟酰胺-戊二酸-吡嗪酰胺三元共晶的氢键形式并不是完全一致的, 但是这两种二元共晶的氢键形式对预测三元共晶的氢键形式具有极为重要的参考价值。 这些结果为新兴的药物共晶领域在分子水平上研究特定三元共晶的分子组装和分子间相互作用提供了丰富的信息和独特的方法。

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.