In Vitro Assessment of Supersaturation/Precipitation and Biological Membrane Permeation of Poorly Water-Soluble Drugs: A Case Study With Albendazole and Ketoconazole.

This study aimed to elucidate the relationship between supersaturation and precipitation and the effect of a supersaturated state on drug membrane permeation. Stock solutions of albendazole (ALB) and ketoconazole (KTZ) dissolved in dimethyl sulfoxide (0.1-50 mg/mL) were diluted 100-fold with buffer solution (pH 6.8, 37°C). In the case of ALB, a supersaturated state and immediate precipitation were observed at 10 μg/mL or less and 20 μg/mL or higher, respectively. When KTZ was used, at an initial concentration of 200 μg/mL or higher, precipitation was observed, although the dissolved concentration remained at approximately 120 μg/mL for at least 30 min. These dissolved concentrations of ALB and KTZ related to approximately 10-fold and 14-fold over the saturated solubility from respective bulk powder. An in vitro permeation study implied that the rate of drug permeation across a biological membrane increased with increasing supersaturation. These results suggested favorable strategies for development of a supersaturable formulation could depend on the precipitation properties of the drug. Immediate- and controlled-release forms might be suitable for supersaturable formulations for KTZ and ALB, respectively.
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