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Physicochemical and Biopharmaceutical Characterisation of Small Drug Molecules by Capillary Electrophoresis
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för analytisk kemi.
2004 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Capillary Electrophoresis (CE) was explored as a means for physicochemical and biopharmaceutical characterisation of small drug molecules. Special attention was paid to the characterisation of acid-base and lipophilic properties of drug compounds by analysing their migration behaviour in different CE systems. The thesis comprises an overview of the field together with separate studies on the different topics.

The utility of CE for the determination of pKa of labile drug compounds was investigated. A general methodology was developed comprising key steps such as the use of a stabilising sample diluent, electromigration injection, and analyte characterisation by UV-Vis spectroscopy. The methodology was successfully applied for two sets of drug compounds, labile at low and high pH, respectively.

CE was also evaluated for experimental modelling of passive intestinal membrane permeability by studying analyte migration in liposomal, microemulsion and micellar electrolytes. Good correlation is reported between CE migration and Caco-2 cell absorption estimates and for in vitro inhibition of thrombin. Interestingly, a slightly better correlation was obtained for liposomal electrolytes.

The utility of liposomes in CE was further extended by developing a novel procedure for immobilising liposomes inside fused silica capillaries. This approach enabled direct on-line coupling of liposome CE to high sensitivity mass spectrometry. The utility of liposome-coated capillaries is demonstrated for estimating drug passive intestinal membrane permeability. Its use in biopharmaceutical drug profiling is discussed.

Utilising advanced molecular descriptors, commonly applied to in silico prediction of passive intestinal membrane permeability, migration of analytes in micellar CE systems could be well predicted. The novel approach was based on hierarchical multivariate analytics and use of molecular descriptors for both analytes and micellar media surfactants. Demonstrated results propose that the CE format could be useful to validate how representative molecular descriptors are for describing molecular behaviour in complex liquid media, e.g. physiological systems.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis , 2004. , s. 56
Serie
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 947
Emneord [en]
Analytical chemistry, capillary electrophoresis (CE), micellar electrokinetic chromatography (MEKC), drug, liposome, microemulsion, coating, pKa, lipophilicity, multivariate analysis, molecular descriptor, hierarchical analysis, passiv absorption
Emneord [sv]
Analytisk kemi
HSV kategori
Identifikatorer
URN: urn:nbn:se:uu:diva-4008ISBN: 91-554-5881-5 (tryckt)OAI: oai:DiVA.org:uu-4008DiVA, id: diva2:164113
Disputas
2004-03-05, B:22, BMC, Husargatan 3, Uppsala, 10:15
Opponent
Veileder
Tilgjengelig fra: 2004-02-13 Laget: 2004-02-13bibliografisk kontrollert
Delarbeid
1. Determination of Dissociation Constants of Labile Drug Compounds by Capillary Electrophoresis
Åpne denne publikasjonen i ny fane eller vindu >>Determination of Dissociation Constants of Labile Drug Compounds by Capillary Electrophoresis
2003 Inngår i: Journal of Pharmaceutical and Biomedical Analysis, Vol. 33, s. 379-391Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:uu:diva-91392 (URN)
Tilgjengelig fra: 2004-02-13 Laget: 2004-02-13bibliografisk kontrollert
2. Statistical Molecular Design, Parallel Synthesis and Biological Evaluation of a Library of Thrombin Inhibitors
Åpne denne publikasjonen i ny fane eller vindu >>Statistical Molecular Design, Parallel Synthesis and Biological Evaluation of a Library of Thrombin Inhibitors
Vise andre…
2001 Inngår i: Journal of Medicinal Chemistry, Vol. 44, s. 3424-3439Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:uu:diva-91393 (URN)
Tilgjengelig fra: 2004-02-13 Laget: 2004-02-13bibliografisk kontrollert
3. Experimental Modeling of Passive Drug Absorption by Capillary Electrophoresis using Liposomal, Micellar and Microemulsion Electrolytes
Åpne denne publikasjonen i ny fane eller vindu >>Experimental Modeling of Passive Drug Absorption by Capillary Electrophoresis using Liposomal, Micellar and Microemulsion Electrolytes
Inngår i: Journal of Pharmacy & PharmacologyArtikkel i tidsskrift (Fagfellevurdert) Submitted
Identifikatorer
urn:nbn:se:uu:diva-91394 (URN)
Tilgjengelig fra: 2004-02-13 Laget: 2004-02-13bibliografisk kontrollert
4. Method for Immobilization of Liposomes in Capillary Electrophoresis by Electrostatic Interaction with Derivatized Agarose
Åpne denne publikasjonen i ny fane eller vindu >>Method for Immobilization of Liposomes in Capillary Electrophoresis by Electrostatic Interaction with Derivatized Agarose
Vise andre…
2002 Inngår i: Electrophoresis, Vol. 23, nr 19, s. 3381-3384Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:uu:diva-91395 (URN)
Tilgjengelig fra: 2004-02-13 Laget: 2004-02-13bibliografisk kontrollert
5. Immobilised-Liposome Capillary Electrophoresis - On-line Mass Spectrometry for Biopharmaceutical Drug Profiling
Åpne denne publikasjonen i ny fane eller vindu >>Immobilised-Liposome Capillary Electrophoresis - On-line Mass Spectrometry for Biopharmaceutical Drug Profiling
Vise andre…
Manuskript (Annet vitenskapelig)
Identifikatorer
urn:nbn:se:uu:diva-91396 (URN)
Tilgjengelig fra: 2004-02-13 Laget: 2004-02-13 Sist oppdatert: 2011-03-21
6. Hierarchical Multivariate Modelling and Prediction of MEKC Migration using Analyte and Micellar Media Molecular Descriptors
Åpne denne publikasjonen i ny fane eller vindu >>Hierarchical Multivariate Modelling and Prediction of MEKC Migration using Analyte and Micellar Media Molecular Descriptors
Inngår i: ElectrophoresisArtikkel i tidsskrift (Fagfellevurdert) Submitted
Identifikatorer
urn:nbn:se:uu:diva-91397 (URN)
Tilgjengelig fra: 2004-02-13 Laget: 2004-02-13bibliografisk kontrollert

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