Emodepside

Drug release from four different formulations of the poorly soluble drug emodepside was determined in absence and presence of an absorptive sink (absorptive compartment separated by a barrier) by analyzing both molecularly dissolved and apparently dissolved drug concentrations in parallel. To this end, microdialysis and in situ 2nd derivative UV spectroscopy were employed. Two dose strengths each were investigated of crystalline conventional release tablets, pH-dependent hydroxypropyl methylcellulose acetate succinate-based amorphous solid dispersion (ASD) tablets, pH-independent polyvinylpyrrolidone vinyl acetate ASD tablets, and a polyethylene glycol 400 (PEG₄₀₀)-based oral solution. The presence of the absorptive sink did significantly increase the (molecularly dissolved) supersaturation in the case of the PEG₄₀₀-based oral solution as compared to previously published dissolution data while the supersaturation enhancement caused by the absorptive sink for the other formulations was moderate to marginal. This indicates that, for different formulation types, the dynamic interplay between dissolution, supersaturation, colloid-association, and precipitation is captured better by combined dissolution-permeation. Furthermore, the predictive potential of combined dissolution-permeation testing compared to mere dissolution testing was evaluated. The extent and duration of both molecular and apparent dissolution were compared to human plasma concentration time curves to establish in vitro in vivo correlation (IVIVC). Likewise, the initial flux as well as cumulative amount permeated across the PAMPA barrier of the dissolution-permeation assays were compared to human plasma concentration time curves to establish IVIVCs. While apparent dissolution yielded poor IVIVC, both molecular dissolution and dissolution-permeation yielded good and comparable IVIVCs. Finally, a refined mechanistic understanding is derived from the aforementioned dissolution and dissolution-permeation data to explain the observed differences.