Release Mechanisms of Amorphous Solid Dispersions: Role of Drug-Polymer Phase Separation and Morphology

Formulating poorly soluble molecules as amorphous solid dispersions (ASDs) is an effective strategy to improve drug release. However, drug release rate and extent tend to rapidly diminish with increasing drug loading (DL). The poor release at high DLs has been postulated to be linked to the process of amorphous-amorphous phase separation (AAPS), although the exact connection between phase separation and release properties remains somewhat unclear. Herein, release profiles of ASDs formulated with ritonavir (RTV) and polyvinylpyrrolidone/vinyl acetate (PVPVA) at different DLs were determined using surface normalized dis-solution. Surface morphologies of partially dissolved ASD compacts were evaluated with confocal fluores-cence microscopy, using Nile red and Alexa Fluor 488 as fluorescence markers to track the hydrophobic and hydrophilic phases respectively. ASD phase behavior during hydration and release of components were also visualized in real time using a newly developed in situ confocal fluorescence microscopy method. RTV-PVPVA ASDs showed complete and rapid drug release below 30% DL, partial drug release at 30% DL and no drug release above 30% DL. It was observed that formation of discrete drug-rich droplets at lower DLs led to rapid and congruent release of both drug and polymer, whereas formation of continuous drug-rich phase at the ASD matrix-solution interface was the cause of poor release above certain DLs. Thus, the domain size and interconnectivity of phase separated drug-rich domains appear to be critical factors impacting drug release from RTV-PVPVPA ASDs.(c) 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.

Automated summary

Formulating poorly soluble molecules as amorphous solid dispersions (ASDs) is an effective strategy to improve drug release, but the release rate diminishes with increasing drug loading. The study investigated the connection between phase separation and release properties in ritonavir (RTV)-polyvinylpyrrolidone/vinyl acetate (PVPVA) ASDs. It was found that discrete drug-rich droplets at lower drug loadings led to rapid release, while a continuous drug-rich phase at higher drug loadings caused poor release.