Interplay of Supersaturation and Solubilization: Lack of Correlation between Concentration-Based Supersaturation Measurements and Membrane Transport Rates in Simulated and Aspirated Human Fluids.

Abstract

Supersaturating formulations are increasingly being used to improve the absorption of orally administered poorly water-soluble drugs. To better predict outcomes in vivo, we must be able to accurately determine the degree of supersaturation in complex media designed to provide a surrogate for the gastrointestinal environment. Herein, we demonstrate that relying on measurements based on consideration of the total dissolved concentration leads to underestimation of supersaturation and consequently membrane transport rates. Crystalline and amorphous solubilities of two compounds, atazanavir and posaconazole, were evaluated in six different media. Concurrently, diffusive flux measurements were performed in a side-by-side diffusion cell to determine the activity-based supersaturation by evaluating membrane transport rates at the crystalline and amorphous solubilities. Solubility values were found to vary in each medium because of different solubilization capacities. Concentration-based supersaturation ratios were also found to vary for the different media. Activity-based measurements, however, were largely independent of the medium, leading to relatively constant values for the estimated supersaturation. These findings have important consequences for modeling and prediction of supersaturation impact on the absorption rate as well as for better defining the thermodynamic driving force for crystallization in complex media.