Institute of Chemistry, Faculty of Science and Technology, University of Silesia in Katowice, Szkolna 9, 40-007, Katowice, Poland.
Department of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia in Katowice, Jagiellonska 4, 41-200, Sosnowiec, Poland.
Sci Rep. 2023 Jun 1;13(1):8890. doi: 10.1038/s41598-023-35772-7.
In this paper, the molecular dynamics at different thermodynamic conditions of hydrogen-bonded (H-bonded) active pharmaceutical ingredient-ticagrelor (TICA) have been investigated. Extensive high-pressure (HP) dielectric studies revealed surprising high sensitivity of the structural (α)-relaxation to compression. They also showed that unexpectedly the shape of the α-peak remains invariable at various temperature (T) and pressure (p) conditions at constant α-relaxation time. Further infrared measurements on the ordinary and pressure densified glasses of the examined compound indicated that the hydrogen-bonding pattern in TICA is unchanged by the applied experimental conditions. Such behavior was in contrast to that observed recently for ritonavir (where the organization of hydrogen bonds varied at high p) and explained the lack of changes in the width of α-dispersion with compression. Moreover, HP dielectric measurements performed in the glassy state of TICA revealed the high sensitivity of the slow secondary (β)-relaxation (Johari-Goldstein type) to pressure and fulfillment of the isochronal superpositioning of α- and JG-β-relaxation times. Additionally, it was found that the activation entropy for the β-process, estimated from the Eyring equation (a high positive value at 0.1 MPa) slightly increases with compression. We suggested that the reason for that are probably small conformational variations of TICA molecules at elevated p.
本文研究了氢键（H-bonded）活性药物成分替卡格雷（TICA）在不同热力学条件下的分子动力学。广泛的高压（HP）介电研究表明，结构（α）松弛对压缩具有惊人的高敏感性。它们还表明，出乎意料的是，在恒定的α松弛时间下，α-峰的形状在各种温度（T）和压力（p）条件下保持不变。对所研究化合物的普通和加压致密玻璃的进一步红外测量表明，氢键模式在 TICA 中不受所施加的实验条件的影响。这种行为与最近在利托那韦（ritonavir）中观察到的行为形成对比（其中氢键的组织在高压下发生变化），并解释了在压缩过程中α-弥散宽度没有变化的原因。此外，在 TICA 的玻璃态下进行的高压介电测量显示，缓慢的次级（β）松弛（Johari-Goldstein 型）对压力高度敏感，并满足α-和 JG-β-松弛时间的等时叠加。此外，还发现β过程的活化熵（在 0.1 MPa 时为正值），可以根据 Eyring 方程（在 0.1 MPa 时为正值）进行估算，随着压缩略有增加。我们认为，原因可能是 TICA 分子在高压下的构象变化很小。
