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Effect of alkali metal hydroxides on the enantioseparation of amines using di-O-isopropylidene-keto-L-gulonic acid as the selector in NACE
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.ORCID iD: 0000-0002-0156-8242
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
2006 (English)In: Electrophoresis, ISSN 0173-0835, E-ISSN 1522-2683, Vol. 27, no 22, 4469-4479 p.Article in journal (Refereed) Published
Abstract [en]

The present work demonstrates the importance of the ionic composition in the BGE for enantioseparation. (-)-2,3:4,6-di-O-Isopropylidene-2-keto-L-gulonic acid ((-)-DIKGA) has been used as the chiral selector in methanolic and ethanolic BGEs. The influence of added alkali metal hydroxides on the EOF and the chiral separation of amines; (atenolol, isoprenaline, pindolol and propranolol) have been studied. The ion-pair formation constants in ethanol were determined by precision conductometry for the enantiomers of pindolol with (-)-DIKGA, for Li+, Na+ and Cs+ with (-)-DIKGA, and also for the corresponding alkali metal hydroxides. The effective mobilities and the enantiomeric mobility differences were affected by the type of alkali metal hydroxide (LiOH, NaOH, KOH, RbOH or CsOH) added to the BGE. The effective mobility and mobility difference were increased with decrease in solvated radius of the alkali metal cation. These differences could partly be correlated to the ion-pair formation constants of the alkali metal cations with the chiral selector, affecting the equilibrium concentration of the free selector. The electroosmosis was also affected by the alkali metal hydroxide added to the BGE. The cathodic electroosmosis decreased with decreasing solvated radius of the alkali metal cation added to the BGE. Interestingly, the cathodic EOF was even reversed, i.e. became anodic in the ethanolic BGEs containing KOH, RbOH or CsOH and the methanolic ones with RbOH and CsOH.

Place, publisher, year, edition, pages
2006. Vol. 27, no 22, 4469-4479 p.
Keyword [en]
Alkali metal cation, Chiral separation, Electroosmosis, NACE, Precision conductometry
National Category
Pharmaceutical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-94280DOI: 10.1002/elps.200600297ISI: 000242695900010PubMedID: 17066385OAI: oai:DiVA.org:uu-94280DiVA: diva2:168076
Available from: 2006-04-12 Created: 2006-04-12 Last updated: 2016-04-08
In thesis
1. Chiral Separation of Amines by Non-Aqueous Capillary Electrophoresis using Low Molecular Weight Selectors
Open this publication in new window or tab >>Chiral Separation of Amines by Non-Aqueous Capillary Electrophoresis using Low Molecular Weight Selectors
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Three chiral selectors (diketogulonic acid, benzoxycarbonylglycylproline and ketopinic acid) have been introduced for enantioseparation of pharmacologically active amines in non-aqueous capillary electrophoresis. The use of organic solvents, instead of aqueous buffers in the background electrolyte facilitated ion-pair formation between the analytes and the chiral selectors. The enantioresolution was strongly affected by the choice of selector and organic solvent but also depended on the other electrolytes. The most important parameter for the enantioresolution, apart from the choice of chiral selector, was the direction and magnitude of the electro-osmosis. Thus, covalently coated capillaries were used to suppress and to reverse this flow. Furthermore, the alkali metal hydroxide added to the background electrolyte had a great influence on the electro-osmosis. Exchanging LiOH for NaOH, was found to decrease the electro-osmotic flow. Interestingly, the flow was altered from cathodic to anodic, with KOH, RbOH or CsOH added to the ethanolic BGE. The occurrence of a reversed electro-osmosis had a great positive effect on the enantioresolution. An appropriate choice of solvent and electrolytes promoted also fast chiral separations, e.g., the enantiomers of isoprenaline were resolved within one minute.

The capillary electrophoresis systems developed within this work were applied for enantiomeric purity determinations of different pharmaceutical forms of drug products. A detection limit of 0.033 % was achieved for 1S,2R-ephedrine, the enantiomeric impurity in Efedrin®, when diketogulonic acid was used as the selector.

By using the pre-concentration technique, transient isotachophoresis, the peak efficiency was enhanced for the enantiomers of timolol. This facilitated the introduction of a higher concentration of the sample into the capillary electrophoretic system containing ketopinic acid as the selector, and lowered the detection limit from 2.5 % to 0.2 % for the enantiomeric impurity R-timolol compared with injection without transient isotachophoresis.

The volatility of the non-aqueous media in capillary electrophoresis facilitated the hyphenation to mass spectrometry. The partial filling technique ensured that the selector did not contaminate the mass spectrometer, and the separated enantiomers of e.g., pronethalol were detected in the selector-free zone.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 46 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 31
Keyword
Pharmaceutical chemistry, Chiral Separation, Non-Aqueous Capillary Electrophoresis, Enantioresolution, Electro-osmotic Flow, Pharmaceuticals, Enantiomeric Amines, Low Molecular Weight Selector, Farmaceutisk kemi
National Category
Analytical Chemistry
Research subject
Chemistry with specialization in Analytical Chemistry; Analytical Pharmaceutical Chemistry
Identifiers
urn:nbn:se:uu:diva-6759 (URN)91-554-6524-2 (ISBN)
Public defence
2006-05-05, B22, Biomedicinska centrum (BMC), Husargatan, Uppsala, 09:15
Opponent
Supervisors
Available from: 2006-04-12 Created: 2006-04-12 Last updated: 2012-05-25Bibliographically approved

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Hedeland, YlvaHaglöf, JakobBeronius, PerPettersson, Curt

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