不同制备方法对无定形固体物化性质的影响已获得相当多的关注,特别是最近关于药物多变质的出版物。在本研究中,我们通过研究热行为来研究药物塞来昔布(CEL)中可能发生的多变质作用,形态学,结构,通过淬火冷却(QC)获得的无定形CEL的分子迁移率和物理稳定性,球磨(BM)和喷雾干燥(SD)。对于CEL-QC,观察到相似的玻璃化转变温度,但不同的再结晶行为,CEL-BM和CEL-SD使用调制差示扫描量热分析。三种CEL无定形形式的不同再结晶行为与各自不同的粉末形态之间的相关性,也被发现了。然而,分子动力学模拟,表明CEL在进行QC和SD时呈现相似的分子构象分布。此外,获得的CEL的分子构象分布不同于其晶体结构中发现的分布,也不同于通过量子力学计算获得的最低能结构中发现的分布。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,虽然与晶体结构中呈现的不同。对分布函数分析和等温微量热法显示出相似的局部结构和结构弛豫时间,分别,对于CEL-QC,CEL-BM和CEL-SD。目前的工作表明,不仅相似的物理化学性质(玻璃化转变温度,和结构弛豫时间),但对于所有制备的CEL无定形体系也观察到相似的分子构象分布。因此,尽管它们的再结晶行为不同,CEL的三种无定形形式没有任何多变质迹象。
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.