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Chiral analysis of metoprolol and two of its metabolites, alpha‑hydroxymetoprolol and deaminated metoprolol, in wastewater using liquid chromatography-tandem mass spectrometry
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.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
2012 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1269, no SI, 208-217 p.Article in journal (Refereed) Published
Abstract [en]

A LC–MS/MS method for the chiral separation of metoprolol and two of its main metabolites, α-hydroxymetoprolol (α-OH-Met) and deaminated metoprolol (COOH-Met), in environmental water samples has been developed. The target bases, metoprolol and α-OH-Met, as well as the acidic metabolite (COOH-Met) were extracted from water samples by a solid phase extraction method employing Oasis HLB cartridges. The extraction recoveries were ≥73% for all compounds in surface water. Four different types of chiral stationary phases were investigated for the separation of the eight stereoisomers of metoprolol and its metabolites, Chiralcel OD-H, Chirobiotic V, Chiral AGP and Chiral CBH. In the final method, the enantiomers of metoprolol and four stereoisomers of α-OH-Met were separated using Chiral CBH, the enantiomers of COOH-Met were separated employing Chiral AGP. The analytes were detected in SRM mode by triple quadrupole mass spectrometry. The method was applied for the chiral analysis of the analytes in treated wastewater samples from Uppsala, Sweden. The enantiomers and diastereoisomers of α-OH-Met were detected and analyzed in the samples. The concentrations of the three first eluting stereoisomers of α-OH-Met were between 54 and 61 pM. Interestingly, the last eluting stereoisomer was found to be present at a concentration of 151 pM at the same sampling occasion. This is, to the best of the authors’ knowledge, the first time the stereoisomers of α-OH-Met have been detected in wastewater samples. The enantiomers of metoprolol were determined to be 1.77 and 1.86 nM in the same matrix. The enantiomers of COOH-Met were not detected above the method detection limit (42 pM) in treated wastewater samples. The developed LC–MS/MS methods were validated in wastewater samples.

Place, publisher, year, edition, pages
2012. Vol. 1269, no SI, 208-217 p.
National Category
Pharmaceutical Sciences Analytical Chemistry
Research subject
Analytical Pharmaceutical Chemistry
Identifiers
URN: urn:nbn:se:uu:diva-171547DOI: 10.1016/j.chroma.2012.09.090ISI: 000312475300016OAI: oai:DiVA.org:uu-171547DiVA: diva2:511362
Available from: 2012-03-21 Created: 2012-03-21 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Development of LC-MS/MS Methods for the Analysis of Chiral and Achiral Pharmaceuticals and Metabolites in Aqueous Environmental Matrices
Open this publication in new window or tab >>Development of LC-MS/MS Methods for the Analysis of Chiral and Achiral Pharmaceuticals and Metabolites in Aqueous Environmental Matrices
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the development of liquid chromatography tandem mass spectrometry (LC-MS/MS) methods for the trace analysis of active pharmaceutical ingredients (APIs) and their metabolites in aqueous environmental matrices. The research was focused on the development of chiral LC-MS/MS methods for the analysis of fluoxetine and metoprolol, as well as their chiral metabolites in environmental water samples. A method was also developed for the achiral compounds, diazepam and nordiazepam.

The LC-MS/MS methods were validated by the use of the isotope-labeled compounds. As these isotope-labeled compounds were not found in the wastewater samples, the validation could be assessed at trace level concentrations in the actual matrices in which the analytes were detected.

The analytes were extracted from the water samples using solid phase extraction methods. Different types of solid phase extraction sorbents were evaluated. Fluoxetine and norfluoxetine were extracted through the use of a mixed mode polymeric based extraction sorbent. A hydrophilic and lipophilic balanced sorbent was employed for the simultaneous extraction of metoprolol and its metabolites, the base α-hydroxymetoprolol and the acidic metabolite deaminated metoprolol. Moreover, silica based C18 extraction discs were applied for the sample preparation of diazepam and nordiazepam.

The chromatographic separations were conducted in reversed phase LC with MS compatible mobile phases. The enantiomers of fluoxetine and norfluoxetine were simultaneously separated using the chiral stationary phase (CSP), α1-acid glycoprotein (AGP). The Chiral AGP column was also applied for the separation of the enantiomers of deaminated metoprolol. For the simultaneous separation of the metoprolol enantiomers and the four stereoisomers of α-hydroxymetoprolol, the cellobiohydrolase (CBH) protein based CSP was used. An octadecyl silica based LC column was applied for the separation of diazepam and nordiazepam.

The analytes were detected by the use of tandem quadrupole mass spectrometry operating in selective reactive monitoring mode. High resolution MS, employing a quadrupole time-of-flight (QqTOF) mass analyzer, was utilized for the identification of an unknown compound in wastewater samples.

The APIs and their metabolites, as well as their respective enantiomers, were quantified in raw and treated wastewater from Uppsala, Sweden along with surface water from the River Fyris in Uppsala.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 158
Keyword
Environmental water matrices, chiral separation, LC-MS/MS, trace analysis, method development, active pharmaceutical ingredients, metabolites
National Category
Analytical Chemistry Pharmaceutical Sciences
Research subject
Analytical Pharmaceutical Chemistry
Identifiers
urn:nbn:se:uu:diva-171550 (URN)978-91-554-8313-5 (ISBN)
Public defence
2012-05-04, B22, BMC, Husargatan 3, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2012-04-13 Created: 2012-03-21 Last updated: 2012-04-19

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Barclay, Victoria K.H.Tyrefors, Niklas L.Johansson, I. MonikaPettersson, Curt

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