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Enantioseparation of drugs and related compounds using chiral mobile phase additives
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
1998 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neutral and anionic chiral mobile phase additives have been employed to separate enantiomers of drugs and related compounds using aqueous buffer solution and hydro-organic solvent mixtures as mobile phases.

Ester derivatives of tartaric acid, e. g. (2R,3R)-dicyclohexyl tartrate, was adsorbed on an achiral solid phase of porous graphitic carbon (PGC) and acted as a chiral stationary phase for the enantiomer separation of neutral, acidic and basic compounds (e.g. atropine, mandelic acid, ephedrine) The antipode, (2S,3S)-dicyclohexyl tartrate was applied for the determination of the enantiomeric impurity of a pharmaceutical preparation of (S)-atropine.

(2R,3R)-(-)-Dibenzoyl-tartaric acid mono (dimethylamide), a tartaric acid amide derivative having a free carboxylic group was also adsorbed on PGC and simultaneously acted as a chiral counter ion to several racemic drugs. Complete chiral resolution was obtained for several β-blocking agents (e.g. alprenolol, metoprolol and propranolol) and antiulcer agents (e.g. omeprazole and lansoprazole)

In contrast to the tartaric acid derivatives, N-protected di-and tripeptides, e.g. N-benzyloxycarbonyl-glycyl-L-proline (L-ZGP), had low affinity to PGC when dissolved in mobile phase of methanol. Nevertheless they gave high enantiomeric resolution for several racemic drugs of pharmacological interest (e.g. terbutalin, alprenolol, trimipramine and promethazine) by acting as a counter ion to the solute enantiomers. This chiral counter ion enabled the determination of the enantiomeric composition of mefloquine at micro-molar levels in biological fluids.

When charged selectors were used, solute retention conformed with ion-pair retention mechanism. Counter ion concentration and pH were the main parameters utilized to control both retention and enantioselectivity. Other achiral additives e.g. organic modifiers, co-ions etc might also influence the enantioselective retetion. Thus many factors could be used to regulate the chiral separation by ion-pair chromatography. The chemometric approach, using experimental design and multivariate data analysis, was shown to be an effective tool for optimization of the separation of mefloquine. (1S,3S,4S)-(+)-3-bromocamphor-10-sulfonic acid was used as a counter ion.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1998. , 38 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 193
Keyword [en]
Pharmaceutical chemistry
Keyword [sv]
Farmaceutisk kemi
National Category
Medicinal Chemistry
Research subject
Analytical Pharmaceutical Chemistry
URN: urn:nbn:se:uu:diva-926ISBN: 91-554-4327-3OAI: oai:DiVA.org:uu-926DiVA: diva2:172459
Public defence
1998-12-07, sal B42, Uppsala Biomedicinska Centrum, Uppsala, 10:15
Available from: 1998-11-16 Created: 1998-11-16Bibliographically approved

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