Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, United States.
Mol Pharm. 2022 Feb 7;19(2):472-483. doi: 10.1021/acs.molpharmaceut.1c00839. Epub 2022 Jan 3.
Four model compounds, nifedipine, indomethacin, felodipine, and ketoconazole, all with nearly identical glass transition temperatures, were chosen to study the effects of thermodynamics and molecular mobility on their crystallization propensities. The time and temperature dependence of the crystallization induction time of each compound was determined by differential scanning calorimetry (DSC) and enabled the generation of their time-temperature-transformation (TTT) diagrams. The relaxation times (τ) were measured by dielectric spectroscopy, and the Gibbs free energy (Δ) and entropy (Δ) difference between the crystalline and amorphous states were obtained by DSC. The temperature dependence of the crystallization induction time (τ()) is a function of the thermodynamic activation barrier and the frequency of "attempted jumps" (1/τ()) to overcome the barrier. Even though the four model compounds exhibited very similar molecular mobility (relaxation time) over a wide range of temperatures, their crystallization propensities were very different. The observed difference in crystallization propensity was explained in terms of the difference in the thermodynamic barrier, and it is correlated to the empirical relation (Δ)/Δ.
选择了四种模型化合物，硝苯地平、吲哚美辛、非洛地平、酮康唑，它们的玻璃化转变温度几乎相同，以研究热力学和分子迁移率对它们结晶倾向的影响。通过差示扫描量热法（DSC）确定了每种化合物结晶诱导时间的时间和温度依赖性，从而生成了它们的时-温转变（TTT）图。通过介电谱测量了弛豫时间（τ），并通过 DSC 获得了晶态和非晶态之间的吉布斯自由能（Δ）和熵（Δ）差。结晶诱导时间（τ（）的温度依赖性是热力学激活势垒和克服势垒的“尝试跳跃”（1/τ（））频率的函数。尽管这四种模型化合物在很宽的温度范围内表现出非常相似的分子迁移率（弛豫时间），但它们的结晶倾向却非常不同。用热力学势垒的差异来解释观察到的结晶倾向差异，并将其与经验关系（Δ）/Δ相关联。
