| Popis: |
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. |
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