Dissolution of amorphous solid dispersions (ASD) can lead to the formation of amorphous drug-rich nano species (nanodroplets) via liquid-liquid phase separation or glass-liquid phase separation when the drug concentration exceeds the amorphous solubility. These nanodroplets have been shown to be beneficial for ASD performance both in vitro and in vivo. Thus, understanding the generation and stability of nanodroplets from ASD formulations is important. In this study, the impacts of polymer selection and active pharmaceutical ingredient (API) physicochemical properties (wet glass transition temperature (T_g) and log P) on nanodroplet release were studied. Six APIs with different physicochemical properties were formulated as ASDs with two polymers, polyvinylpyrrolidone/vinyl acetate (PVPVA) and hydroxypropyl methylcellulose acetate succinate (HPMCAS). Their release performance was evaluated using both powder and surface normalized dissolution of compacts. In general, HPMCAS-based dispersions resulted in higher drug release compared to PVPVA-based dispersions. The two polymers also exhibited different trends in nanodroplet formation as a function of drug loading (DL). PVPVA ASDs exhibited a "falling-off-the-cliff" effect, with a dramatic decline in release performance with a small increase in drug loading, while HPMCAS ASDs exhibited a negative "slope" in the release rate as a function of drug loading. For both polymers, low T_g compounds achieved higher levels of nanodroplet formation compared to high T_g compounds. The nanodroplets generated from ASD dissolution were also monitored with dynamic light scattering, and HPMCAS was found to be more effective at stabilizing nanodroplets against size increase. Insights from this study may be used to guide formulation design and selection of excipients based on API physicochemical properties.

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