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Aspects of Optimisation of Separation of Drugs by Chemometrics
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
2003 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Statistical experimental designs have been used for method development and optimisation of separation. Two reversed phase HPLC methods were optimised. Parameters such as the pH, the amount of tetrabutylammonium (TBA; co-ion) and the gradient slope (acetonitrile) were investigated and optimised for separation of erythromycin A and eight related compounds. In the second method, a statistical experimental design was used, where the amounts of acetonitrile and octane sulphonate (OSA; counter ion) and the buffer concentration were studied, and generation of an α-plot with chromatogram simulations optimised the separation of six analytes.

The partial filling technique was used in capillary electrophoresis to introduce the chiral selector Cel7A. The effect of the pH, the ionic strength and the amount of acetonitrile on the separation and the peak shape of R- and S-propranolol were investigated.

Microemulsion electrokinetic chromatography (MEEKC) is a technique similar to micellar electrokinetic chromatography (MEKC), except that the microemulsion has a core of tiny droplets of oil inside the micelles. A large number of factors can be varied when using this technique. A screening design using the amounts of sodium dodecyl sulphate (SDS), Brij 35, 1-butanol and 2-propanol, the buffer concentration and the temperature as factors revealed that the amounts of SDS and 2-propanol were the most important factors for migration time and selectivity manipulation of eight different compounds varying in charge and hydrophobicity. SDS and 2-propanol in the MEEKC method were further investigated in a three-level full factorial design analysing 29 different compounds sorted into five different groups. Different optimisation strategies were evaluated such as generating response surface plots of the selectivity/resolution of the most critical pair of peaks, employing chromatographic functions, simplex optimisation in MODDE and 3D resolution maps in DryLab™.

Molecular descriptors were fitted in a PLS model to retention data from the three-level full factorial design of the MEEKC system. Two different test sets were used to study the predictive ability of the training set. It was concluded that 86 – 89% of the retention data could be predicted correctly for new molecules (80 – 120% of the experimental values) with different settings of SDS and 2-propanol.

Statistical experimental designs and chemometrics are valuable tools for the development and optimisation of analytical methods. The same chemometric strategies can be employed for all types of separation techniques.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2003. , p. 75
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 300
Keywords [en]
Pharmaceutical chemistry, optimisation, separation, chemometrics, high performance liquid chromatography, electrodriven techniques, microemulsion electrokinetic chromatography, statistical experimental design, molecular modelling, chiral separation, cellobiohydrolase
Keywords [sv]
Farmaceutisk kemi
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-3738ISBN: 91-554-5778-9 (print)OAI: oai:DiVA.org:uu-3738DiVA, id: diva2:163562
Public defence
2003-11-28, B41, Uppsala Biomedical Centre, Uppsala, 13:15
Opponent
Supervisors
Available from: 2003-11-06 Created: 2003-11-06 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Optimization of an HPLC Method for the Separation of Erythromycin and Related Compounds using Factorial Design
Open this publication in new window or tab >>Optimization of an HPLC Method for the Separation of Erythromycin and Related Compounds using Factorial Design
1999 In: Chromatographia, ISSN 0009-5893-99-11-525-07, Vol. 50, no 9/10, p. 525-531Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90998 (URN)
Available from: 2003-11-06 Created: 2003-11-06Bibliographically approved
2. Liquid Chromatography Method Development and Optimization by Statistical Experimental Design and Chromatogram Simulations
Open this publication in new window or tab >>Liquid Chromatography Method Development and Optimization by Statistical Experimental Design and Chromatogram Simulations
2001 In: Chromatographia, ISSN 0009-5893-00-02-703-07, Vol. 54, no 11/12, p. 703-709Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-90999 (URN)
Available from: 2003-11-06 Created: 2003-11-06Bibliographically approved
3. A statistical experimental design to study factors affecting enantioseparation of propranolol by capillary electrophoresis with cellobiohydrolase (Cel7A) as chiral selector.
Open this publication in new window or tab >>A statistical experimental design to study factors affecting enantioseparation of propranolol by capillary electrophoresis with cellobiohydrolase (Cel7A) as chiral selector.
Show others...
2002 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 23, no 14, p. 2306-2319Article in journal (Refereed) Published
Abstract [en]

The capillary electrophoretic enantioseparation of rac-propranolol using cellobiohydrolase Tr Cel7A as selector was optimized by an unbiased statistical experimental design. A set of pre-experiments was performed in order to identify critical experimental factors. In the definitive chemometric design pH, ranging from 5 to 7, ionic strength ranging between 0.01 and 0.02 and organic solvent additive in concentration from 1 to 19% v/v were studied. The response surface plot revealed a separation optimum in the pH interval studied. When all parameters were taken into account, a background electrolyte consisting of 0.016 M bistris-acetate buffer with pH 6.5 and 17% v/v acetonitrile gave the optimum separation. The significance of the statistical design was confirmed by the generally good agreement obtained between predicted response and actual experimental data.

Keywords
Capillary electrophoresis, chiral separation, CBHI, propranolol, statistical experimental design
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91000 (URN)000177337000021 ()12210237 (PubMedID)
Available from: 2003-11-06 Created: 2003-11-06 Last updated: 2017-12-14Bibliographically approved
4. Microemulsion electrokinetic chromatography of drugs varying in charge and hydrophobicity: I. Impact of parameters on separation performance evaluated by multiple linear regression models
Open this publication in new window or tab >>Microemulsion electrokinetic chromatography of drugs varying in charge and hydrophobicity: I. Impact of parameters on separation performance evaluated by multiple linear regression models
Show others...
2004 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 25, no 1, p. 80-93Article in journal (Refereed) Published
Abstract [en]

The separation of anionic, cationic and neutral drugs in microemulsion electrokinetic chromatography (MEEKC) was studied with a statistical experimental design. The concentration of sodium dodecyl sulfate (SDS, surfactant), 1-butanol (co-surfactant) and borate buffer and the factors Brij 35 (surfactant), 2-propanol (organic solvent) and cassette temperature were varied simultaneously, while the parameters pH (9.2), the concentration of octane (oil, 0.8% w/w), the voltage (10 kV) and the dimension of the fused-silica capillary, were kept constant. Eight different model substances were chosen with different hydrophobicities. Two of the analytes were positively charged, two were negatively charged, and the remaining four were neutral or close to neutral at the pH explored. The importance of each parameter on the separation window, the plate height and the retention factor for each of the analytes was studied by means of multiple linear regression (MLR) models. A new response was evaluated for anions, the quotient between the effective mobility in the microemulsion and the effective mobility in the corresponding buffer. Factors affecting selectivity changes were also explored, and it was found that SDS and 2-propanol had the largest effect on selectivity.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91001 (URN)10.1002/elps.200305671 (DOI)14730572 (PubMedID)
Available from: 2003-11-06 Created: 2003-11-06 Last updated: 2017-12-14Bibliographically approved
5. Microemulsion electrokinetic chromatography of drugs varying in charge and hydrophobicity: II. Strategies for optimisation of separation
Open this publication in new window or tab >>Microemulsion electrokinetic chromatography of drugs varying in charge and hydrophobicity: II. Strategies for optimisation of separation
2004 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 25, no 12, p. 1792-1809Article in journal (Refereed) Published
Abstract [en]

The separation of anionic, cationic, and neutral drugs in microemulsion electrokinetic chromatography (MEEKC) was studied. The concentration of sodium dodecyl sulfate (SDS; surfactant) and 2-propanol (organic solvent) was varied in a three-level full factorial design. 29 different model substances were chosen with different hydrophobicities and charges (neutral, positive, and negative). The models were calculated by means of multiple linear regression (MLR). The compounds were divided into five different subgroups, and different strategies for optimization of the separation within each group were investigated. The optimization was done by maximizing the selectivity using response surface plots in MODDE, by calculation of different chromatographic functions, and by using the software DryLab. For all the different groups, MODDE, almost all chromatographic functions and DryLab gave approximately the same settings of the factors for optimum separation. Attempts were made to fit descriptors of the compounds to the retention data from the three-level full factorial design by means of partial least squares projection to latent structures (PLS). Between 86 and 89% of all predictions of migration times were acceptable (80-120% of the observed value).

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-91002 (URN)10.1002/elps.200305812 (DOI)15213977 (PubMedID)
Available from: 2003-11-06 Created: 2003-11-06 Last updated: 2017-12-14Bibliographically approved

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