Evolution of a mini-scale biphasic dissolution model: Impact of model parameters on partitioning of dissolved API and modelling of in vivo-relevant kinetics.
Biphasic dissolution models are proposed to have good predictive power for the in vivo absorption. The aim of this study was to improve our previously introduced mini-scale dissolution model to mimic in vivo situations more realistically and to increase the robustness of the experimental model. Six dissolved APIs (BCS II) were tested applying the improved mini-scale biphasic dissolution model (miBIdi-pH-II). The influence of experimental model parameters including various excipients, API concentrations, dual paddle and its rotation speed was investigated. The kinetics in the biphasic model was described applying a one- and four-compartment pharmacokinetic (PK) model. The improved biphasic dissolution model was robust related to differing APIs and excipient concentrations. The dual paddle guaranteed homogenous mixing in both phases; the optimal rotation speed was 25 and 75rpm for the aqueous and the octanol phase, respectively. A one-compartment PK model adequately characterised the data of fully dissolved APIs. A four-compartment PK model best quantified dissolution, precipitation, and partitioning also of undissolved amounts due to realistic pH profiles. The improved dissolution model is a powerful tool for investigating the interplay between dissolution, precipitation and partitioning of various poorly soluble APIs (BCS II). In vivo-relevant PK parameters could be estimated applying respective PK models.
Pharmaceutical Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach, Germany; Department of Pharmaceutical Technology, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, Germany.
Kathrin
K
Locher
Department of Clinical Pharmacy & Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Kelchstraße 31, 12169 Berlin, Germany.
Jens M
JM
Borghardt
Pharmaceutical Development, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397 Biberach, Germany.
Kerstin J
KJ
Frank
Department of Clinical Pharmacy & Biochemistry, Institute of Pharmacy, Freie Universität Berlin, Kelchstraße 31, 12169 Berlin, Germany.
Charlotte
C
Kloft
Department of Pharmaceutical Technology, University of Bonn, Gerhard-Domagk-Straße 3, 53121 Bonn, Germany. Electronic address: kgwagner@uni-bonn.de.
Karl G
KG
Wagner
D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008956:Models, Chemical; D010599:Pharmacokinetics; D012995:Solubility
Biphasic dissolution; Octanol model; Poorly soluble APIs