Department of Pharmacy, Uppsala University, Husargatan 3, 75 123 Uppsala, Sweden.
Cockrell School of Engineering, The University of Texas at Austin, Austin, TX 78712, USA.
Int J Pharm. 2022 Feb 5;613:121360. doi: 10.1016/j.ijpharm.2021.121360. Epub 2021 Dec 9.
Robust and reliable in vivo performance of medicines based on amorphous solid dispersions (ASDs) depend on maintenance of physical stability and efficient supersaturation. However, molecular drivers of these two kinetic processes are poorly understood. Here we used molecular dynamics (MD) simulations coupled with experimental assessments to explore supersaturation, nucleation, and crystal growth. The effect of drug loading on physical stability and supersaturation potential was highly drug specific. Storage under humid conditions influenced crystallization, but also resulted in morphological changes and particle fusion. This led to increased particle size, which significantly reduced dissolution rate. MD simulations identified the importance of nano-compartmentalization in the crystallization rate of the ASDs. Nucleation during storage did not inherently compromise the ASD. Rather, the poorer performance resulted from a combination of properties of the compound, nanostructures formed in the formulation, and crystallization.
基于无定形固体分散体（ASD）的药物具有稳健可靠的体内性能，这取决于其物理稳定性和高效过饱和度的维持。然而，这两个动力学过程的分子驱动因素还了解甚少。在这里，我们使用分子动力学（MD）模拟结合实验评估来探索过饱和度、成核和晶体生长。药物载药量对物理稳定性和过饱和度潜力的影响具有很强的药物特异性。在潮湿条件下储存会影响结晶，但也会导致形态变化和颗粒融合。这导致粒径增大，从而显著降低了溶解速率。MD 模拟确定了纳米分隔在 ASD 结晶速率中的重要性。储存过程中的成核本身并不影响 ASD。相反，较差的性能是由于化合物的性质、配方中形成的纳米结构以及结晶的共同作用。
