Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, TU Dortmund University, Emil-Figge-Str. 70, Dortmund D-44227, Germany.
Janssen Pharmaceutica R&D, Turnhoutseweg 30, Beerse B-2340, Belgium.
Mol Pharm. 2023 May 1;20(5):2568-2578. doi: 10.1021/acs.molpharmaceut.3c00008. Epub 2023 Apr 7.
Amorphous solid dispersions (ASDs) are commonly used to increase the dissolution rate of poorly soluble active pharmaceutical ingredients (APIs). Unfortunately, most ASDs are thermodynamically unstable and, even though kinetically stabilized, will thus eventually crystallize. The crystallization kinetics is determined by the thermodynamic driving force and by molecular mobility, which in turn depend on the drug load, temperature, and relative humidity (RH) at which the ASDs are stored. This work focuses on viscosity as an indicator for the molecular mobility in ASDs. The viscosity and shear moduli of ASDs consisting of the polymer poly(vinylpyrrolidone-co-vinyl acetate) or hydroxypropyl methylcellulose acetate succinate and the API nifedipine or celecoxib were studied using an oscillatory rheometer. The effects of temperature, drug load, and RH on the viscosity were investigated. With the knowledge of how much water is absorbed by the polymer or ASD and thereby also the knowledge of the glass-transition temperature of the wet polymer or ASD, the viscosity of dry and wet ASDs was predicted to be in very good agreement with experimental data just based on the viscosity of neat polymers and the glass-transition temperatures of wet ASDs.
无定形固体分散体（ASD）常用于提高难溶性活性药物成分（API）的溶解速率。不幸的是，大多数 ASD 热力学上不稳定，即使在动力学上稳定，最终也会结晶。结晶动力学取决于热力学驱动力和分子迁移率，而分子迁移率又取决于储存 ASD 的药物负载、温度和相对湿度（RH）。本工作重点研究粘度作为 ASD 中分子迁移率的指标。使用振荡流变仪研究了由聚合物聚乙烯吡咯烷酮-醋酸乙烯酯共聚物或羟丙基甲基纤维素醋酸琥珀酸酯和 API 硝苯地平或塞来昔布组成的 ASD 的粘度和剪切模量。研究了温度、药物负载和 RH 对粘度的影响。根据聚合物或 ASD 吸收了多少水以及湿聚合物或 ASD 的玻璃化转变温度的知识，仅基于纯聚合物的粘度和湿 ASD 的玻璃化转变温度，就可以很好地预测干 ASD 和湿 ASD 的粘度与实验数据吻合。
