title: Hydrodynamic Effects on Drug Dissolution and Deaggregation in the Small Intestine-A Study with Felodipine as a Model Drug.
abstract: The aim of this study was to understand and predict the influence of hydrodynamic effects in the small intestine on dissolution of primary and aggregated drug particles. Dissolution tests of suspensions with a low-solubility drug, felodipine, were performed in a Couette cell under hydrodynamic test conditions corresponding to the fed small intestine. Dissolution was also performed in the USP II apparatus at two paddle speeds of 25 and 200 rpm and at different surfactant concentrations below critical micelle concentration. The experimental dissolution rates were compared with theoretical calculations. The different levels of shear stress in the in vitro tests did not influence the dissolution of primary or aggregated particles and experimental dissolution rates corresponded very well to calculations. The dissolution rate for the aggregated drug particles increased after addition of surfactant because of deaggregation, but there were still no effect of hydrodynamics. In conclusion, hydrodynamics do not influence dissolution and deaggregation of micronized drug particles in the small intestine of this model drug. Surface tension has a strong effect on the deaggregation and subsequent dissolution. Addition of surfactants at in vivo relevant surface tension levels is thus critical for in vivo predictive in vitro dissolution testing.
authors.affiliation: AstraZeneca R&D, Pharmaceutical Development, Mölndal, Sweden.
authors.forename: Lennart
authors.initials: L
authors.lastname: Lindfors
authors.affiliation: AstraZeneca R&D, Pharmaceutical Development, Mölndal, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Jonsson
authors.affiliation: AstraZeneca R&D, Pharmaceutical Development, Mölndal, Sweden.
authors.forename: Emelie
authors.initials: E
authors.lastname: Weibull
authors.affiliation: Department of Mechanical Engineering, The Pennsylvania State University, University Park, Pennsylvania, 16802.
authors.forename: James G
authors.initials: JG
authors.lastname: Brasseur
authors.affiliation: AstraZeneca R&D, Pharmaceutical Development, Mölndal, Sweden.
authors.forename: Bertil
authors.initials: B
authors.lastname: Abrahamsson
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003198:Computer Simulation; D065546:Drug Liberation / Q000502:physiology; D015736:Felodipine / Q000737:chemistry* / Q000493:pharmacokinetics*; D057446:Hydrodynamics; D007408:Intestinal Absorption / Q000502:physiology; D007421:Intestine, Small / Q000378:metabolism*; D008962:Models, Theoretical; D051381:Rats; D012995:Solubility; D013501:Surface-Active Agents / Q000737:chemistry; D013535:Suspensions / Q000737:chemistry / Q000493:pharmacokinetics
chemical_list: D013501:Surface-Active Agents; D013535:Suspensions; D015736:Felodipine
keywords: Fick's first law; ab initio calculations; de-aggregation; dissolution; felodipine; gastrointestinal; in silico modeling; in vitro models; particle sizing