Biorelevant In Vitro Dissolution Models to Evaluate Poorly Soluble Drugs

Abstract

Biorelevant media have been devised to mimic the composition of fluids present in the stomach and intestine in fasted and fed states. They are increasingly being used in pharmaceutical product development and to predict in vivo drug dissolution. Since biorelevant media are more complex, their fabrication has been described as challenging and much remains to be understood about the mechanisms by which they are able to enhance dissolution of poorly soluble drugs. The first aim of this work was to assess the repeatability and reproducibility of current biorelevant media and determine the sources of variability when biorelevant media are used to perform dissolution across different study conditions for two model poorly soluble drugs (i.e., ibuprofen and ketoconazole). The effect of volume on small-volume dissolution using biorelevant media was also predicted. Results indicated favorable interday repeatability, favorable interanalyst repeatability, and favorable interlaboratory reproducibility. Commercial media showed greater interlaboratory reproducibility than “from scratch” media. From a nested and then crossed statistical analysis of variance (ANOVA), the rank-order importance of sources of variation overall were location > operator (nested in location) > day > fabrication method > residual. An algorithm to predict the effect of volume on biorelevant media dissolution in high, intermediate, and low solubility scenarios proved to be accurate in 13 of 16 cases. The second aim of this work was to predict dissolution into fasted and fed state biorelevant media and further devise a new model to predict the food effects on dissolution. Solubility studies, intrinsic dissolution studies, particle size analysis, and high-performance liquid chromatography (HPLC) were used to predict dissolution rate as well as dissolution and solubility enhancement of three model poorly soluble drugs (i.e., griseofulvin, ketoconazole, and ibuprofen) in fasted and fed state gastric and intestinal media over their surfactant-free counterparts. Drug dissolution rate into fed state biorelevant media was attenuated relative to drug solubility enhancement due to low colloid diffusivity. Dissolution enhancement in fasted state media was about as much as solubility enhancement due to minimal incorporation of drug into the mixed micelles. A model was also devised to predict the food effect on dissolution by considering the rate of dissolution in fed state biorelevant media over the rate of dissolution in fasted state biorelevant media and the diffusivity of colloids in each. The resulting model allowed for the prediction of a food effect on dissolution and agreed with food effects observed in vivo for the three model drugs