School of Pharmacy, Henan University, Kaifeng, China; Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark; State Key Laboratory of Chemical Engineering, School of Chemical Engineering and Technology, Tianjin University, China.
Department of Chemistry and Nano-Science Center, University of Copenhagen, Copenhagen, Denmark.
Int J Pharm. 2024 Aug 15;661:124470. doi: 10.1016/j.ijpharm.2024.124470. Epub 2024 Jul 14.
The influence of different preparation methods on the physicochemical properties of amorphous solid forms have gained considerable attention, especially with recent publications on pharmaceutical polyamorphism. In the present study, we have investigated the possible occurrence of polyamorphism in the drug celecoxib (CEL) by investigating the thermal behavior, morphology, structure, molecular mobility and physical stability of amorphous CEL obtained by quench-cooling (QC), ball milling (BM) and spray drying (SD). Similar glass transition temperatures but different recrystallization behaviors were observed for CEL-QC, CEL-BM and CEL-SD using modulated differential scanning calorimetry analysis. A correlation between the different recrystallization behaviors of the three CEL amorphous forms and the respective distinct powder morphologies, was also found. Molecular dynamics simulations however, reveal that CEL presents similar molecular conformational distributions when subjected to QC and SD. Moreover, the obtained molecular conformational distributions of CEL are different from the ones found in its crystal structure and also from the ones found in the lowest-energy structure obtained by quantum mechanical calculations. The type and strength of CEL hydrogen bond interactions found in CEL-QC and CEL-SD systems are almost identical, though different from the ones presented in the crystal structure. Pair distribution function analyses and isothermal microcalorimetry show similar local structures and structural relaxation times, respectively, for CEL-QC, CEL-BM and CEL-SD. The present work shows that not only similar physicochemical properties (glass transition temperature, and structural relaxation time), but also similar molecular conformational distributions were observed for all prepared CEL amorphous systems. Hence, despite their different recrystallization behaviors, the three amorphous forms of CEL did not show any signs of polyamorphism.
不同制备方法对无定形固体形式的物理化学性质的影响引起了相当大的关注，特别是最近关于药物多晶型的出版物。在本研究中，我们通过研究淬火冷却（QC）、球磨（BM）和喷雾干燥（SD）获得的无定形塞来昔布（CEL）的热行为、形态、结构、分子迁移率和物理稳定性，研究了 CEL 可能发生的多晶型现象。使用调制差示扫描量热法分析，观察到 CEL-QC、CEL-BM 和 CEL-SD 的玻璃化转变温度相似，但重结晶行为不同。还发现三种 CEL 无定形形式的不同重结晶行为与各自独特的粉末形态之间存在相关性。然而，分子动力学模拟表明，CEL 受到 QC 和 SD 时呈现相似的分子构象分布。此外，CEL 获得的分子构象分布与其晶体结构中的构象分布以及量子力学计算得到的最低能量结构中的构象分布不同。CEL-QC 和 CEL-SD 系统中发现的 CEL 氢键相互作用的类型和强度几乎相同，尽管与晶体结构中呈现的氢键相互作用不同。配分函数分析和等温微量热法分别显示 CEL-QC、CEL-BM 和 CEL-SD 具有相似的局部结构和结构弛豫时间。本工作表明，不仅所有制备的 CEL 无定形系统具有相似的物理化学性质（玻璃化转变温度和结构弛豫时间），而且还具有相似的分子构象分布。因此，尽管三种 CEL 无定形形式的重结晶行为不同，但它们没有表现出任何多晶型的迹象。
