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Recent Advances in Understanding the Micro- and Nanoscale Phenomena of Amorphous Solid Dispersions

Cite this: Mol. Pharmaceutics 2019, 16, 10, 4089–4103
Publication Date (Web):September 5, 2019
Copyright © 2019 American Chemical Society

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    Many pharmaceutical drugs in the marketplace and discovery pipeline suffer from poor aqueous solubility, thereby limiting their effectiveness for oral delivery. The use of an amorphous solid dispersion (ASD), a mixture of an active pharmaceutical ingredient and a polymer excipient, greatly enhances the aqueous dissolution performance of a drug without the need for chemical modification. Although this method is versatile and scalable, deficient understanding of the interactions between drugs and polymers inhibits ASD rational design. This current Review details recent progress in understanding the mechanisms that control ASD performance. In the solid-state, the use of high-resolution theoretical, computational, and experimental tools resolved the influence of drug/polymer phase behavior and dynamics on stability during storage. During dissolution in aqueous media, novel characterization methods revealed that ASDs can form complex nanostructures, which maintain and improve supersaturation of the drug. The studies discussed here illustrate that nanoscale phenomena, which have been directly observed and quantified, strongly affect the stability and bioavailability of ASD systems, and provide a promising direction for optimizing drug/polymer formulations.

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    • Comparison of amorphous solid dispersion characterization techniques (PDF)

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    18. Preethi Mandati, Dinesh Nyavanandi, Sagar Narala, Abdullah Alzahrani, Sateesh Kumar Vemula, Michael A. Repka. A Comparative Assessment of Cocrystal and Amorphous Solid Dispersion Printlets Developed by Hot Melt Extrusion Paired Fused Deposition Modeling for Dissolution Enhancement and Stability of Ibuprofen. AAPS PharmSciTech 2023, 24 (7)
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