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Physicochemical and Biopharmaceutical Characterisation of Small Drug Molecules by Capillary Electrophoresis
Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Chemistry, Analytical Chemistry.
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2004. , p. 56
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 947
Keywords [en]
Analytical chemistry, capillary electrophoresis (CE), micellar electrokinetic chromatography (MEKC), drug, liposome, microemulsion, coating, pKa, lipophilicity, multivariate analysis, molecular descriptor, hierarchical analysis, passiv absorption
Keywords [sv]
Analytisk kemi
National Category
Analytical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-4008ISBN: 91-554-5881-5 (print)OAI: oai:DiVA.org:uu-4008DiVA, id: diva2:164113
Public defence
2004-03-05, B:22, BMC, Husargatan 3, Uppsala, 10:15
Opponent
Supervisors
Available from: 2004-02-13 Created: 2004-02-13Bibliographically approved
List of papers
1. Determination of Dissociation Constants of Labile Drug Compounds by Capillary Electrophoresis
Open this publication in new window or tab >>Determination of Dissociation Constants of Labile Drug Compounds by Capillary Electrophoresis
2003 In: Journal of Pharmaceutical and Biomedical Analysis, Vol. 33, p. 379-391Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91392 (URN)
Available from: 2004-02-13 Created: 2004-02-13Bibliographically approved
2. Statistical Molecular Design, Parallel Synthesis and Biological Evaluation of a Library of Thrombin Inhibitors
Open this publication in new window or tab >>Statistical Molecular Design, Parallel Synthesis and Biological Evaluation of a Library of Thrombin Inhibitors
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2001 In: Journal of Medicinal Chemistry, Vol. 44, p. 3424-3439Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91393 (URN)
Available from: 2004-02-13 Created: 2004-02-13Bibliographically approved
3. Experimental Modeling of Passive Drug Absorption by Capillary Electrophoresis using Liposomal, Micellar and Microemulsion Electrolytes
Open this publication in new window or tab >>Experimental Modeling of Passive Drug Absorption by Capillary Electrophoresis using Liposomal, Micellar and Microemulsion Electrolytes
In: Journal of Pharmacy & PharmacologyArticle in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-91394 (URN)
Available from: 2004-02-13 Created: 2004-02-13Bibliographically approved
4. Method for Immobilization of Liposomes in Capillary Electrophoresis by Electrostatic Interaction with Derivatized Agarose
Open this publication in new window or tab >>Method for Immobilization of Liposomes in Capillary Electrophoresis by Electrostatic Interaction with Derivatized Agarose
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2002 In: Electrophoresis, Vol. 23, no 19, p. 3381-3384Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-91395 (URN)
Available from: 2004-02-13 Created: 2004-02-13Bibliographically approved
5. Immobilised-Liposome Capillary Electrophoresis - On-line Mass Spectrometry for Biopharmaceutical Drug Profiling
Open this publication in new window or tab >>Immobilised-Liposome Capillary Electrophoresis - On-line Mass Spectrometry for Biopharmaceutical Drug Profiling
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-91396 (URN)
Available from: 2004-02-13 Created: 2004-02-13 Last updated: 2011-03-21
6. Hierarchical Multivariate Modelling and Prediction of MEKC Migration using Analyte and Micellar Media Molecular Descriptors
Open this publication in new window or tab >>Hierarchical Multivariate Modelling and Prediction of MEKC Migration using Analyte and Micellar Media Molecular Descriptors
In: ElectrophoresisArticle in journal (Refereed) Submitted
Identifiers
urn:nbn:se:uu:diva-91397 (URN)
Available from: 2004-02-13 Created: 2004-02-13Bibliographically approved

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