Purpose: Plasticizers are commonly used in the preparation of amorphous solid dispersions (ASDs) with the main goal of aiding processability; however, to the best of our knowledge, the impact of plasticizers on drug release has not been explored. The goal of this study was to evaluate diverse plasticizers, including glycerol and citrate derivatives, as additives to increase the drug loading where good drug release could be achieved from copovidone (PVPVA)-based dispersions, focusing on high glass transition (Tg) drugs, atazanavir (ATZ) and ledipasvir (LED). Methods: ASDs were prepared using the high Tg compounds, atazanavir (ATZ) and ledipasvir (LED), as model drugs. Release was evaluated using surface normalized dissolution testing. Differential scanning calorimetry was used to measure glass transition temperature and water vapor sorption was performed on select samples. Results: The presence of a plasticizer at 5% w/w for ATZ and 10% w/w for LED ASDs, led to improved drug release. For ATZ ASDs, in the absence of plasticizer, release was very poor at drug loadings of 10% w/w and above. Good release was obtained for plasticized ASDs up to a drug loading of 25%. The corresponding improvement for LED was from 5 to 20% DL. Interestingly, for a low Tg compound, ritonavir, relatively smaller improvements in release as a function of drug loading were achieved through plasticizer incorporation. Conclusions: The use of plasticizers represents a potential new strategy to increase drug loading in ASDs for high Tg compounds with a low tendency to crystallize and may help improve a major limitation of ASD formulations, namely the high excipient burden. [ABSTRACT FROM AUTHOR]