Itwashypothesizedandthendemonstrated1thatsmallintestinalmucuslayercouldstabilizesupersaturatedstateofotherwiseprecipitatinglowsolubilitydrugs.Itwasalsoconcluded2thatfluxmeasurementsprovidemorein-depthunderstandingofsupersaturatedsystemsthansoluteconcentrationmeasurementsalone.Thisstudyusedminiaturizeddissolution–permeationapparatus(μFLUX)tocomparefluxofcarvedilolthroughartificialmembranesfromasimplebuffersystemaswellasfrommediasimulatingthemucuslayerand/orcontainingsolubilizingexcipientslikehydroxypropyl-ß-cyclodextrin.

It was demonstrated recently that cocrystals of ketoconazole could lead to enhanced aqueous solubility1. However, the absorption of the drug from gastro-intestinal tract (GIT) depends also on dissolution rate and permeability that could be altered by cocrystal constituents. This study was aimed at investigating how cocrystal coformers affect the trans-membrane flux in the in vivo relevant dissolution – permeability setup

It was demonstrated [1] that flux measurements provide more in-depth understanding of supersaturated systems than solute concentration measurements alone. Such measurements were further employed to characterize and explain the differences between brand name and generic drug products that were reported from the bioequivalence studies [2]. The benefits of flux measurements are based on the fact that they capture the complex interplay between effects of formulation ingredients on solubility, dissolution rate and permeability of an active pharmaceutical ingredient (API). From the other hand, there has not been a predictive model that would use flux measurements as an input parameter for calculation of maximum absorbable dose (MAD) or fraction of the API absorbed (Fa) from an oral dosage form. This study demonstrated a feasibility of using flux measurements through gastro-intestinal tract (GIT) mimicking artificial membrane to predict MAD and Fa values in biopharmaceutics modelling for BCS Class 2 drugs.

In this work, two different approaches have been developed to predict the food effect and the bioequivalence of marketed itraconazole (ITRA) formulations. Kinetic solubility and simultaneous dissolution−permeation tests of three (ITRA) formulations (Sporanox capsules and solution and SUBA-ITRA capsules) were carried out in simulated fasted and fed states. Fraction of dose absorbed ratios estimating food effect and bioequivalence were calculated based on these results and were compared to the in vivo study results published by Medicines Agencies. The comparison demonstrated that kinetic solubility and flux values could be used as input parameters for biopharmaceutics modeling and simulations to estimate food effect and bioequivalence. Both prediction methods were able to determine a slightly negative food effect in the case of the Sporanox solution and also a pronounced positive food effect for the Sporanox capsule. Superior bioavailability was predicted when the Sporanox solution was compared to the Sporanox capsule (in agreement with in vivo data).

The challenge of developing poorly soluble drugs continues to grow as more and more new chemical entities (NCEs) are poorly soluble. Formulation strategies often rely on maintaining a supersaturated state for poorly soluble drugs. A large portion of modern patients are medicated to reduce stomach acidity, and Drug–Drug Interactions (DDI) with Acid Reducing Agents (ARAs) can dramatically increase pharmacokinetic variability and decrease bioavailability—especially for weak bases. This study evaluated pH-shift flux measurements as in vivo predictive tool for DDI assessment.

For generic formulation development, traditional (USP) dissolution tests provide primary input parameters for predicting in vivo performance of different drug formulations before conducting bioequivalence studies. Although USP dissolution tests are relatively simple to conduct for testing formulations, the in vivo predictive power of these tests is questionable1. Namely, when a poorly water-soluble API is formulated to enhance its dissolution, additives, such as surfactants, polymers and cyclodextrins have an effect not only on dissolution profile, but also on flux through the membrane.