Prediction of in vitro drug dissolution into fasted-state biorelevant media: Contributions of solubility enhancement and relatively low colloid diffusivity

Abstract

A previously developed model showed good predictability for in vitro drug dissolution into FeSSGF and FeSSIF-V2, where biorelevant media-mediated enhanced drug dissolution by only about one-tenth as much as it enhanced solubility, due to drug-loaded fat globules and mixed micelles exhibiting far slower diffusivity than free drug. The present objective was to quantitatively assess the contributions of fasted biorelevant media-mediated solubility and diffusivity on enhanced drug dissolution in FaSSGF and FaSSIF-V2. Griseofulvin, ketoconazole, and ibuprofen were subjected to dissolution into FaSSGF and FaSSIF-V2, as well as their corresponding “surfactant-free” media. Solubility and dynamic light-scattering studies (DLS) of drug in FaSSGF and FaSSIF-V2 were conducted. Results showed that FaSSGF and FaSSIF-V2 mixed micelles were large and slowly diffusing (diffusivities about 2 × 10−8 cm2/s and 12×10−8 cm2/s, respectively), compared to free drug (about 7 × 10−6 cm2/s), although were smaller and more rapidly diffusing compared to drug-bound fat globules and mixed micelles from FeSSGF and FeSSIF-V2 (about 1 × 10−9 cm2/s and 7 × 10−8 cm2/s, respectively). Dissolution enhancement in FaSSGF and FaSSIF-V2 was the same as solubility enhancement, which was minimal. FaSSGF and FaSSIF-V2 practically did not enhance drug dissolution, since solubility was at best minimally increased, but also since micelles were relatively slowly diffusing relative to free drug diffusivity.