Abstract：
Pyrazinamide (PZA) is a widely-used anti-tuberculosis pharmaceutical, but its poor solubility prompts us to optimize pharmaceutical performance. Cocrystallization is a promising technique to improve physiochemical properties of active pharmaceutical ingredient (API) by connecting it with cocrystal former (CCF) via intermolecular interactions. Even though a series of alkyl dicarboxylic acids are employed to form cocrystal structures, systematic understanding on the role of intermolecular interactions is still missing. Therefore, terahertz (THz) spectroscopy and quantum chemical calculation are combined to elucidate the behavior of ubiquitous supramolecular synthons, such as hetero-synthons of acid-pyrazine, acid-amide and homo-synthon of amide-amide, from energy\'s view. Potential energy is calculated to differentiate the stability within polymorphs of PZA-MA cocrystal and free energy is evaluated to compare the solubility of PZA-CCF cocrystals respectively. With regard to vibrational energy, THz spectral fingerprints are theoretically assigned to specific vibrations and attributed to the flexibility deformation of supramolecular synthons based on oscillation theory, where stretching and twisting modes dominate the collective vibrational behavior. It provides a promising tool to evaluate cocrystal performance from its driving force and insightful guidance to discover new pharmaceutical cocrystals.
摘要：
吡嗪酰胺（PZA）是一种广泛使用的抗结核药物，但其溶解性差促使我们优化药物性能。共晶是一种通过分子间相互作用将活性药物成分（API）与共晶体形成剂（CCF）连接来改善其理化性质的有前途的技术。即使使用一系列烷基二羧酸来形成共晶结构，对分子间相互作用的作用的系统理解仍然缺失。因此,太赫兹（THz）光谱和量子化学计算相结合，以阐明普遍存在的超分子合成子的行为，如酸吡嗪的杂合成子，酸-酰胺和酰胺-酰胺的同型合成子，从能源的角度来看。计算势能以区分PZA-MA共晶多晶型物内的稳定性，并评估自由能以分别比较PZA-CCF共晶的溶解度。关于振动能量，THz光谱指纹在理论上被分配给特定的振动，并归因于基于振荡理论的超分子合成子的柔性变形。拉伸和扭曲模式主导着集体振动行为。它提供了一个有前途的工具，从其驱动力和有见地的指导来评估共晶性能，以发现新的药物共晶。
