Medical College, Qinghai University, Xining, 810001, Qinghai, People's Republic of China.
State Key Laboratory of Plateau Ecology and Agriculture, Qinghai University, Xining, 810001, Qinghai, People's Republic of China.
Drug Deliv Transl Res. 2023 Oct;13(10):2677-2689. doi: 10.1007/s13346-023-01348-1. Epub 2023 Apr 25.
The focus of this investigation was to determine the mechanism of effective glass transition temperature (T) on the crystallization behavior and microstructure of drugs in crystalline solid dispersion (CSD). CSDs were prepared by rotary evaporation using ketoconazole (KET) as a model drug and the triblock copolymer poloxamer 188 as a carrier. The pharmaceutical properties of CSDs, such as crystallite size, crystallization kinetics, and dissolution behavior, were investigated to provide a foundation for studying the crystallization behavior and the microstructure of drugs in CSDs. According to classical nucleation theory, the relationship of treatment temperature-drug crystallite size-T of CSD was investigated. Voriconazole, a compound that is structurally similar to KET but with different physicochemical properties, was used to verify the conclusions. The dissolution behavior of KET was significantly enhanced compared to the raw drug due to smaller crystallite size. Crystallization kinetic studies revealed a two-step crystallization mechanism for KET-P188-CSD, in which P188 crystallized first and KET crystallized later. When the treatment temperature was near T, the drug crystallite size was smaller and more numerous, which suggests nucleation and slow growth. With the increase of temperature, the drug changed from nucleation to growth, and the number of crystallites decreased and the size of the drug increased. This result suggests it is possible to prepare CSDs with higher drug loading and smaller crystallite size by adjusting the treatment temperature and T, so as to maximize the drug dissolution rate. The VOR-P188-CSD maintained a relationship between treatment temperature, drug crystallite size, and T. The findings of our study demonstrate that T and the treatment temperature can be used to regulate the drug crystallite size and improve the drug solubility and dissolution rate.
本研究的重点是确定有效玻璃化转变温度（T）对药物在晶态固体分散体（CSD）中结晶行为和微观结构的影响机制。CSD 通过旋转蒸发法制备，使用酮康唑（KET）作为模型药物和三嵌段共聚物泊洛沙姆 188 作为载体。研究了 CSD 的药物性质，如结晶度、结晶动力学和溶解行为，为研究 CSD 中药物的结晶行为和微观结构提供了基础。根据经典成核理论，研究了处理温度-药物结晶度-T 的关系。使用结构上类似于 KET 但具有不同物理化学性质的伏立康唑来验证结论。由于结晶度较小，KET 的溶解行为明显优于原料药。结晶动力学研究表明，KET-P188-CSD 存在两步结晶机制，首先是 P188 结晶，然后是 KET 结晶。当处理温度接近 T 时，药物结晶度更小且更多，表明成核和生长缓慢。随着温度的升高，药物从成核转变为生长，结晶数减少，药物粒径增大。这一结果表明，通过调节处理温度和 T，可以制备出载药量更高、结晶度更小的 CSD，从而最大限度地提高药物的溶解速率。VOR-P188-CSD 保持了处理温度、药物结晶度和 T 之间的关系。我们的研究结果表明，T 和处理温度可以用来调节药物结晶度，提高药物的溶解度和溶解速率。
