Zhou Deliang, Grant David J W, Zhang Geoff G Z, Law Devalina, Schmitt Eric A
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Weaver-Densford Hall, 308 Harvard Street SE, Minneapolis, MN 55455-0343, USA.
J Pharm Sci. 2007 Jan;96(1):71-83. doi: 10.1002/jps.20633.
The purpose of this work was to investigate the contribution of thermodynamics and mobility to the physical stability of two pharmaceutical glasses with similar glass transition temperatures (Tg), by comparing configurational thermodynamic quantities and molecular relaxation time constants (tau) at temperatures below Tg. Ritonavir and nifedipine were chosen as model glasses because they show excellent and poor physical stability, respectively. Although ritonavir and nifedipine have similar Tg values (50 and 46 degrees C, respectively), amorphous ritonavir is quite stable while nifedipine has been reported to crystallize at temperatures as low as 40 degrees C below Tg. Modulated temperature differential scanning calorimetry (MTDSC) was used to characterize both crystalline phases and freshly prepared glasses. The glasses were then annealed at Tg-Ta = 25 degrees C while monitoring the extent of relaxation and heat capacity change as a function of time via MTDSC. Configurational thermodynamic quantities (Gc, Hc, and Sc) and molecular relaxation time constants, tau, were calculated from the calorimetric data. Interestingly, the Gibbs free energy driving force for crystallization was nearly identical for the two compounds. The largest differences were found in the configurational entropy (Sc) values for the fresh glasses and in the Sc values over time. Configurational entropy values were approximately 50% higher for ritonavir. The tau values of freshly prepared glasses indicated that both materials had similar initial mobility at the annealing temperatures and the temperature dependence of tau was approximately Arrhenius, regardless of age. Although initial tau values were similar, the tau values after 3 days annealing were approximately sixfold greater for ritonavir. The relatively poor physical stability of nifedipine compared to ritonavir is attributed to both the lower entropic barrier to crystallization for fresh and annealed glass, and higher molecular mobility in aged glasses of nifedipine. These observations below Tg are consistent with the previous work on physical stability of amorphous pharmaceuticals performed above Tg.
本研究旨在通过比较低于玻璃化转变温度（Tg）时的构型热力学量和分子弛豫时间常数（tau），研究热力学和迁移率对两种具有相似玻璃化转变温度（Tg）的药用玻璃物理稳定性的贡献。选择利托那韦和硝苯地平作为模型玻璃，因为它们分别表现出优异和较差的物理稳定性。尽管利托那韦和硝苯地平具有相似的Tg值（分别为50和46摄氏度），但无定形利托那韦相当稳定，而据报道硝苯地平在低至比Tg低40摄氏度的温度下就会结晶。采用调制温度差示扫描量热法（MTDSC）对晶相和新制备的玻璃进行表征。然后将玻璃在Tg - Ta = 25摄氏度下退火，同时通过MTDSC监测弛豫程度和热容随时间的变化。根据量热数据计算构型热力学量（Gc、Hc和Sc）和分子弛豫时间常数tau。有趣的是，两种化合物结晶的吉布斯自由能驱动力几乎相同。新鲜玻璃的构型熵（Sc）值以及随时间变化的Sc值差异最大。利托那韦的构型熵值大约高50%。新制备玻璃的tau值表明，两种材料在退火温度下具有相似的初始迁移率，并且tau的温度依赖性近似为阿累尼乌斯型，与老化程度无关。尽管初始tau值相似，但退火3天后利托那韦的tau值大约大六倍。硝苯地平相对于利托那韦较差的物理稳定性归因于新鲜和退火玻璃结晶的熵垒较低，以及硝苯地平老化玻璃中较高的分子迁移率。低于Tg的这些观察结果与之前在高于Tg时对无定形药物物理稳定性的研究一致。
