The More the Better?─Vitamin E TPGS as a Release Enhancer for Ritonavir/PVPVA Amorphous Solid Dispersions

Amorphous solid dispersions (ASDs) are state-of-the-art formulation strategies for improving the solubility and release of poorly water-soluble, small-molecule active pharmaceutical ingredients (APIs). However, high drug loads (DLs) in ASDs can lead to phase-separation phenomena, resulting in eventually incomplete/collapsed API release, classically referred to as loss of release. This study investigates the role of the surfactant d-α-tocopheryl polyethylene glycol succinate (Vitamin E TPGS) in mitigating this phenomenon in ASDs composed of ritonavir and poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA). As part of the investigations, we developed an improved sampling protocol to differentiate between ASD components molecularly dissolved and those released as nano droplets into the aqueous medium. The results showed that the addition of 3 wt % Vitamin E TPGS enhances release ability up to 30 wt % DL, compared to 25 wt % for the surfactant-free ASD. This enhancement is attributed to Vitamin E TPGS's ability to stabilize discrete RIT-rich domains in the ASD during phase separation. However, at 40 wt % DL, even high Vitamin E TPGS concentrations (up to 10 wt %) did not lead to full release of the API. This indicates that the aforementioned stabilization mechanism failed and could be traced back to a change in the phase separation behavior above an upper limit of Vitamin E TPGS concentrations. This study thus provides insights into the complex release mechanisms of high-DL ritonavir ASDs and the critical role of surfactants such as Vitamin E TPGS.