Mechanistic analysis of solute transport in an in vitro physiological two phase dissolution apparatus- October 2012

DM Mudie, Y Shi, H Ping, et al. – Biopharmaceutics & Drug Disposition Vol 33(I.7), pp 378-402, 2012.
In vitro dissolution methodologies that adequately capture oral bioperformance of solid dosage forms are critical tools needed to aid formulation development. Such methodologies must encompass important physiological parameters and be designed with drug properties in mind. Two-phase dissolution apparatuses, which contain an aqueous phase in which the drug dissolves (representing the dissolution/solubility component) and an organic phase into which the drug partitions (representing the absorption component), have the potential to provide meaningful predictions of in vivo oral bioperformance for some BCS II, and possibly some BCS IV drug products. Before such an apparatus can be properly evaluated, it is important to understand the kinetics of drug substance partitioning from the aqueous to the organic medium. We performed a mass transport analysis of the kinetics of partitioning of drug substance solutions from the aqueous to the organic phase of a two-phase dissolution apparatus. Major assumptions include pseudo-steady-state conditions, a dilute aqueous solution, and diffusion-controlled transport. Input parameters can be measured or estimated a priori. In this paper we present the theory and derivation of our analysis, compare it to a recent kinetic approach, and demonstrate its effectiveness in predicting in vitro partitioning profiles of three BCS II weak acids in four different in vitro two-phase dissolution apparatuses. Very importantly, we discuss how a two-phase apparatus can be scaled to reflect in vivo absorption kinetics and for which drug substances the two-phase dissolution systems may be appropriate tools for measuring oral bioperformance… buffer. The concentration in each phase was measured as a function of time until a plateau was reached in each phase (in most cases). In all cases, calibrated, UV Fiber Optic Probes (StellarNet Inc. Black Comet, Tampa, Florida.