Centre for THz Research, China Jiliang University, Hangzhou 310018, China.
Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, China.
Int J Mol Sci. 2022 Aug 1;23(15):8550. doi: 10.3390/ijms23158550.
Pharmaceutical cocrystals can offer another advanced strategy for drug preparation and development and can facilitate improvements to the physicochemical properties of active pharmaceutical ingredients (APIs) without altering their chemical structures and corresponding pharmacological activities. Therefore, cocrystals show a great deal of potential in the development and research of drugs. In this work, pharmaceutical cocrystals of ethenzamide (ETZ) with 2,6-dihydroxybenzoic acid (26DHBA), 2,4-dihydroxybenzoic acid (24DHBA) and gallic acid (GA) were synthesized by the solvent evaporation method. In order to gain a deeper understanding of the structural changes after ETZ cocrystallization, terahertz time domain spectroscopy (THz-TDS) and Raman spectroscopy were used to characterize the single starting samples, corresponding physical mixtures and the cocrystals. In addition, the possible molecular structures of ETZ-GA, ETZ-26DHBA and ETZ-24DHBA cocrystals were optimized by density functional theory (DFT). The results of THz and Raman spectra with the DFT simulations for the three cocrystals revealed that the ETZ-GA cocrystal formed an O-H∙∙∙O hydrogen bond between the -OH of GA and oxygen of the amide group of the ETZ molecule, and it was also found that ETZ formed a dimer through a supramolecular amide-amide homosynthon; meanwhile, the ETZ-26DHBA cocrystal was formed by a powerful supramolecular acid-amide heterosynthon, and the ETZ-24DHBA cocrystal formed the O-H∙∙∙O hydrogen bond between the 4-hydroxy group of 24DHBA and oxygen of the amide group of the ETZ molecule. It could be seen that in the molecular structure analysis of the three cocrystals, the position and number of hydroxyl groups in the coformers play an essential role in guiding the formation of specific supramolecular synthons.
药物共晶可以为药物制备和开发提供另一种先进策略，并可以改善活性药物成分（API）的物理化学性质，而不改变其化学结构和相应的药理活性。因此，共晶在药物的开发和研究中具有很大的潜力。在这项工作中，通过溶剂蒸发法合成了乙酰胺（ETZ）与 2,6-二羟基苯甲酸（26DHBA）、2,4-二羟基苯甲酸（24DHBA）和没食子酸（GA）的药物共晶。为了更深入地了解 ETZ 共晶化后结构的变化，使用太赫兹时域光谱（THz-TDS）和拉曼光谱对单起始样品、相应的物理混合物和共晶进行了表征。此外，通过密度泛函理论（DFT）对 ETZ-GA、ETZ-26DHBA 和 ETZ-24DHBA 共晶的可能分子结构进行了优化。三种共晶的 THz 和拉曼光谱结果与 DFT 模拟表明，ETZ-GA 共晶在 GA 的-OH 与 ETZ 分子酰胺基团的氧之间形成了 O-H∙∙∙O 氢键，并且还发现 ETZ 通过超分子酰胺-酰胺同二聚体形成二聚体；同时，ETZ-26DHBA 共晶是由强大的超分子酸-酰胺杂二聚体形成的，ETZ-24DHBA 共晶在 24DHBA 的 4-羟基与 ETZ 分子酰胺基团的氧之间形成了 O-H∙∙∙O 氢键。可以看出，在三种共晶的分子结构分析中，共晶体中羟基的位置和数量在引导特定超分子键合的形成方面起着至关重要的作用。
