Volume to dissolve applied dose (VDAD) and apparent dissolution rate (ADR): Tools to predict in vivo bioavailability from orally applied drug suspensions

Low solubility of drug candidates generated in research contributes to their elimination during subsequent development due to insufficient oral bioavailability (BA) of crystalline compound. Therefore, the purpose of the study was to identify critical in vitro solubility and dissolution parameter that would predict critical in vivo dissolution by means of in vitro–in vivo correlation. Thermodynamic solubility and apparent dissolution rate (ADR) were determined using the shake-flask method and mini-flow-through-cell, respectively. Oral BA studies in rats and humans were conducted from drug solution and suspension/tablets. Relative BA was calculated using Frel [%] = AUCsuspension/AUCsolution * 100, representing a measure of in vivo dissolution. Roughly, Frel rat >50% translates into Frel human of >90%. Both, ADR and log volume to dissolve applied dose (VDAD), when plotted against Frel rat, revealed certain threshold levels, (ADR, ∼150–200 μg of compound dissolved under respective assay conditions; VDAD, ∼100–500 ml/kg) which translate into Frel in rats of >50%.Thus, assuming that Frel > 50% in rats is indicative of sufficient in vivo dissolution in humans after oral application, drugs should exhibit a VDAD of ∼100–500 ml/kg or less in aqueous media to avoid insufficient or varying drug absorption.

Graphical abstractIn vitro–in vivo correlation of dissolution and solubility data allows the deduction of critical dose/solubility ratios, which are predictive of whether or not a dissolution-related impairment of bioavailability can be expected after application of oral dosage forms containing crystalline API.Figure optionsDownload full-size imageDownload as PowerPoint slide