Untangling "dissolved" drug species from various formulations of a poorly soluble drug: Sampling methods, mechanistic...

Our study aimed to both provide comprehensive mechanistic enlightenment of the dissolution, supersaturation, and precipitation behavior of different formulations using various sampling approaches, as well as evaluate the predictive capabilities by in vitro in vivo correlation (IVIVC). In vitro two-stage dissolution tests, that simulate the transfer from gastric to intestinal phases, using four different formulations at two dose strengths of the poorly water-soluble and weakly basic drug emodepside were performed. During the two-stage dissolution tests, five different sampling approaches were employed simultaneously (in situ 2^nd derivative UV spectroscopy, benchtop centrifugation, filtration, nanofiltration, and microdialysis). Comparison of the different fractions captured by alternative sampling approaches allowed for mechanistic understandings of the interrelated processes occurring during non-sink biomimetic dissolution of the various formulations (drug-rich submicron particles, bile salt micelle-association, supersaturation/precipitation). The selective insights into the various "dissolved" fractions are discussed in the light of analogous literature findings. Furthermore, the bio-predictive capabilities of the sampling approaches were evaluated by IVIVC. Microdialysis and nanofiltration reflected human oral bioavailability best, followed by conventional filtration and benchtop centrifugation, while in situ UV spectroscopy showed the poorest correlation. Analysis of molecularly dissolved drug thus appears to better predict formulation behavior in vivo.