Mechanistic analysis of solute transport in an in vitro physiological two‐phase dissolution apparatus

Abstract

In vitro dissolution methodologies that adequately capture the 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 evaluated properly, it is important to understand the kinetics of drug substance partitioning from the aqueous to the organic medium. A mass transport analysis was performed 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. This paper presents the theory and derivation of our analysis, compares it with a recent kinetic approach, and demonstrates 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, the paper discusses 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.

In vitro dissolution methodology, mini-Gastrointestinal Simulator (mGIS), predicts better in vivo dissolution of a weak base drug, dasatinib

“…The implementation of biorelevant media into mGIS could improve the prediction of in vivo dissolution. Also, the implementation of the absorptive phase into in vitro dissolution methodologies, which have been developed as biphase/two-phase dissolution methodology, would contribute the better prediction of in vivo dissolution for poorly water-soluble drugs (Frank et al, 2014;Grundy et al, 1997;Heigoldt et al, 2010;Mudie et al, 2012). The incorporated absorptive phase will apparently remove dissolved drug from aqueous phase, which represents drug absorption from the GI tract and, thus, the biphase/two-phase dissolution methodologies have the potential applicability for improved prediction of in vivo performance for poorly water-soluble drugs.…”

“…Incorporating those in vivo environmental factors into an in vitro dissolution apparatus would be necessary to predict more reasonable in vivo dissolution. Newer dissolution methodologies, that consider the in vivo physiological conditions, have been investigated (Barker et al, 2014;Bevernage et al, 2013;Brouwers et al, 2011;Carino et al, 2010;Carlert et al, 2010;Dickinson et al, 2012;Dressman et al, 1998;Koziolek et al, 2013aKoziolek et al, , 2013dKrieg et al, 2014;Mudie et al, 2012;Perez de la Cruz Moreno et al, 2006;Psachoulias et al, 2012Psachoulias et al, , 2011Takeuchi et al, 2014;Vertzoni et al, 2010). TNO intestinal model (TIM-1), especially, is an advanced dissolution model to capture most of the physiological conditions in the GI tract (Barker et al, 2014;Brouwers et al, 2011;Dickinson et al, 2012;Koziolek et al, 2013aKoziolek et al, , 2013d.…”

Evolution of a mini-scale biphasic dissolution model: Impact of model parameters on partitioning of dissolved API and modelling of in vivo-relevant kinetics

“…The applied paddle speed in these experiments varied from 50 to 100 rpm [2,15,23,24]. Mudie et al [11] illustrated that rotation speeds higher than 75 rpm should be avoided causing a vortex in the dissolution vessel. Paddle speeds less than 60 rpm, however, generated insufficient hydrodynamics [13].…”

“…Their experiments with AMG 517 formulations showed the necessity of a dual paddle because of negligible partitioning of the dissolved API with the single paddle. Shi et al [24] and Mudie et al [11] used a dual paddle as well to guarantee sufficient mixing in both phases. As mentioned above, the miBIdipH-II did not show significant differences using the dual paddle with regard to k a of the dissolved API.…”

“…Various biphasic dissolution models are described in the literature [10][11][12] which are regarded as advantageous as they implement sink conditions by introducing a partitioning process of the non-protonated base into a second lipophilic phase [13]. The implementation of a lipophilic phase mimics the absorption step, which is an alternative process to precipitation of a weak base at elevated pH in the GIT, showing superior predictive power for APIs with dissolution-limited absorption [14].…”