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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 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis , 2004. , s. 56
Serie
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1104-232X ; 947
Nyckelord [en]
Analytical chemistry, capillary electrophoresis (CE), micellar electrokinetic chromatography (MEKC), drug, liposome, microemulsion, coating, pKa, lipophilicity, multivariate analysis, molecular descriptor, hierarchical analysis, passiv absorption
Nyckelord [sv]
Analytisk kemi
Nationell ämneskategori
Analytisk kemi
Identifikatorer
URN: urn:nbn:se:uu:diva-4008ISBN: 91-554-5881-5 (tryckt)OAI: oai:DiVA.org:uu-4008DiVA, id: diva2:164113
Disputation
2004-03-05, B:22, BMC, Husargatan 3, Uppsala, 10:15
Opponent
Handledare
Tillgänglig från: 2004-02-13 Skapad: 2004-02-13Bibliografiskt granskad
Delarbeten
1. Determination of Dissociation Constants of Labile Drug Compounds by Capillary Electrophoresis
Öppna denna publikation i ny flik eller fönster >>Determination of Dissociation Constants of Labile Drug Compounds by Capillary Electrophoresis
2003 Ingår i: Journal of Pharmaceutical and Biomedical Analysis, Vol. 33, s. 379-391Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:uu:diva-91392 (URN)
Tillgänglig från: 2004-02-13 Skapad: 2004-02-13Bibliografiskt granskad
2. Statistical Molecular Design, Parallel Synthesis and Biological Evaluation of a Library of Thrombin Inhibitors
Öppna denna publikation i ny flik eller fönster >>Statistical Molecular Design, Parallel Synthesis and Biological Evaluation of a Library of Thrombin Inhibitors
Visa övriga...
2001 Ingår i: Journal of Medicinal Chemistry, Vol. 44, s. 3424-3439Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:uu:diva-91393 (URN)
Tillgänglig från: 2004-02-13 Skapad: 2004-02-13Bibliografiskt granskad
3. Experimental Modeling of Passive Drug Absorption by Capillary Electrophoresis using Liposomal, Micellar and Microemulsion Electrolytes
Öppna denna publikation i ny flik eller fönster >>Experimental Modeling of Passive Drug Absorption by Capillary Electrophoresis using Liposomal, Micellar and Microemulsion Electrolytes
Ingår i: Journal of Pharmacy & PharmacologyArtikel i tidskrift (Refereegranskat) Submitted
Identifikatorer
urn:nbn:se:uu:diva-91394 (URN)
Tillgänglig från: 2004-02-13 Skapad: 2004-02-13Bibliografiskt granskad
4. Method for Immobilization of Liposomes in Capillary Electrophoresis by Electrostatic Interaction with Derivatized Agarose
Öppna denna publikation i ny flik eller fönster >>Method for Immobilization of Liposomes in Capillary Electrophoresis by Electrostatic Interaction with Derivatized Agarose
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2002 Ingår i: Electrophoresis, Vol. 23, nr 19, s. 3381-3384Artikel i tidskrift (Refereegranskat) Published
Identifikatorer
urn:nbn:se:uu:diva-91395 (URN)
Tillgänglig från: 2004-02-13 Skapad: 2004-02-13Bibliografiskt granskad
5. Immobilised-Liposome Capillary Electrophoresis - On-line Mass Spectrometry for Biopharmaceutical Drug Profiling
Öppna denna publikation i ny flik eller fönster >>Immobilised-Liposome Capillary Electrophoresis - On-line Mass Spectrometry for Biopharmaceutical Drug Profiling
Visa övriga...
Manuskript (Övrigt vetenskapligt)
Identifikatorer
urn:nbn:se:uu:diva-91396 (URN)
Tillgänglig från: 2004-02-13 Skapad: 2004-02-13 Senast uppdaterad: 2011-03-21
6. Hierarchical Multivariate Modelling and Prediction of MEKC Migration using Analyte and Micellar Media Molecular Descriptors
Öppna denna publikation i ny flik eller fönster >>Hierarchical Multivariate Modelling and Prediction of MEKC Migration using Analyte and Micellar Media Molecular Descriptors
Ingår i: ElectrophoresisArtikel i tidskrift (Refereegranskat) Submitted
Identifikatorer
urn:nbn:se:uu:diva-91397 (URN)
Tillgänglig från: 2004-02-13 Skapad: 2004-02-13Bibliografiskt granskad

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