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Title: Transfer of small molecules across membrane-mimetic interfaces
Author: Velicky, Matej
ISNI:       0000 0004 2718 812X
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2011
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The presented thesis investigates the transfer of drug molecules across interfaces that mimic biological membrane barriers. The permeability of drug molecules across biological membrane mimics has been investigated in a novel artificial membrane permeation assay configuration using an in situ time-dependent approach and reproducible rotation of the membrane. A method to determine the membrane permeability from the knowledge of measured permeability and the applied stirring rate is presented. The initial transient of the permeation response, previously not observed in situ, is investigated and its importance in data evaluation is discussed. The permeability coefficients of 31 drugs are optimised for the conditions found in vivo and a correlation with the fraction absorbed in humans is presented. The evidence for ionic and/or ion-pair flux across the artificial membrane obtained from measurement of permeability at different pH is supported by the investigation of the permeation assay with external membrane polarisation. The permeability coefficient of the solute's anionic form is determined. Liquid/liquid electrochemistry has been used to study the transfer of ionized species across the interface between water and 1,2-dichloroethane. An alternative method to study the transfer of partially ionised drug molecules employing a rotating liquid/liquid interface is presented. In addition, a bipolar electrochemical cell with a rotating-disc electrode is developed and its properties investigated in order to verify the hydrodynamics of the rotating artificial membrane configuration. Finally, in support of the electrochemical techniques used is this thesis, a detailed preparation and evaluation of the silver/silver sulphate reference electrode is presented.
Supervisor: Dryfe, Robert Sponsor: AstraZeneca ; EPSRC
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: membrane permeation ; membrane polarisation ; PAMPA ; drug absorption ; bioavailability ; in situ permeation ; controlled hydrodynamics ; Levich equation ; lag time ; supported liquid membrane ; PVDF membrane ; UV-Vis ; liquid/liquid electrochemistry ; ion transfer ; bipolar cell ; pH-partition hypothesis ; ion-pairing ; drug discovery ; reference electrode