Dissolution-microdialysis predicts oral bioavailability from phospholipid-based amorphous solid dispersions

We report dissolution of aprepitant from three phospholipid-based amorphous solid dispersions (ASDs), namely binary ASDs containing drug and either natural or hydrogenated phospholipid (HPL) and a ternary ASD containing HPL and hydroxypropyl methylcellulose acetate-succinate (HPMCAS) in fasted state simulated intestinal fluid (FaSSIF) under lipolytic and non-lipolytic conditions (with / without pancreatin). Dissolution samples were taken simultaneously by conventional sampling using centrifugation for separation and via microdialysis sampling. Solid-state analysis by XRPD indicated that the the binary and ternary natural phospholipid dispersions were amorphous, while the binary HPL dispersion showed small Bragg peaks indicating remaining crystallinity. Lipolysis did not influence aprepitant release from the natural phospholipid-based ASD. During dissolution centrifugation sampling indicated a huge burst and slow decline of apparent supersaturation. Microdialysis sampling revealed the "true" spring and parachute effect, meaning free drug concentrations initially above molecular solubility, which declined rapidly. Supersaturation was most pronounced for the ternary ASD. Comparing dissolution AUCs in terms of apparently dissolved drug with published rat plasma AUCs a decent IVIVC was seen (R² = 0.9198), but the IVIVC based on molecularly dissolved drug was superior (R² = 0.9677). This was on par with the published IVIVC based on in vitro dissolution/permeation data (R² = 0.9712) indicating that dissolution in conjunction with microdialysis sampling provided excellent oral bioavailability prediction. Furthermore, it allowed for unprecedented mechanistic insights.