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Rapid chiral separation of atenolol, metoprolol, propranolol and the zwitterionic metoprolol acid using supercritical fluid chromatography-tandem mass spectrometry - Application to wetland microcosms
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.
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2015 (English)In: Journal of Chromatography A, ISSN 0021-9673, E-ISSN 1873-3778, Vol. 1409, p. 251-258Article in journal (Refereed) Published
Abstract [en]

A method for enantiomeric separation of the three beta-blocking agents atenolol, metoprolol, propranolol and the zwitterionic metoprolol acid, a major metabolite of both metoprolol and in environmental matrices also atenolol, has been developed. By use of supercritical fluid chromatography and the polysaccharide-based Chiralpak (R) IB-3, all four compounds were simultaneously enantiomerically separated (R-s >1.5) within 8 min. Detection was performed using tandem mass spectrometry, and to avoid isobaric interference between the co-eluting metoprolol and metoprolol acid, the achiral column Acquity (R) UPC2 BEH 2-EP was attached ahead of to the chiral column. Carbon dioxide with 18% methanol containing 0.5% (v/v) of the additives trifluoroacetic acid and ammonia in a 2:1 molar ratio were used as mobile phase. A post column make-up flow (0.3 mL/min) of methanol containing 0.1% (v/v) formic acid was used to enhance the positive electrospray ionization. Detection was carried out using a triple quadrupole mass spectrometer operating in the selected reaction monitoring mode, using one transition per analyte and internal standard. The method was successfully applied for monitoring the enantiomeric fraction change over time in a laboratory scale wetland degradation study. It showed good precision, recovery, sensitivity and low effect of the sample matrix.

Place, publisher, year, edition, pages
2015. Vol. 1409, p. 251-258
Keyword [en]
Enantiomeric separation, SFC-MS, Metoprolol acid, Wetland microcosm, Chiralpak IB-3, UPC2
National Category
Chemical Sciences
Identifiers
URN: urn:nbn:se:uu:diva-262417DOI: 10.1016/j.chroma.2015.07.075ISI: 000359882600029PubMedID: 26228849OAI: oai:DiVA.org:uu-262417DiVA, id: diva2:854974
Available from: 2015-09-18 Created: 2015-09-15 Last updated: 2018-03-15Bibliographically approved
In thesis
1. Determination of the Environmental Fate of Drug Substances and the Matrix Effects of Complex Samples in SFC/ESI-MS
Open this publication in new window or tab >>Determination of the Environmental Fate of Drug Substances and the Matrix Effects of Complex Samples in SFC/ESI-MS
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Awareness of the potential problems caused by drug compounds in the environment has increased over the last decade, both among researchers and with the public. This thesis describes the development of analytical methods and their application to wetlands constructed for purification of wastewater from e.g. drug compounds. Different wetlands were investigated using microcosm-models, to determine their biodegradation. An enantioselective and sensitive SFC/ESI-QqQ method was developed and validated for the enantiomeric separation of atenolol, metoprolol, propranolol and metoprolol acid. It was applied measuring the enantiomeric fraction of the compounds in three different microcosm-models. The same microcosms were also used to investigate the transformation products formed in these wetlands. In this work, LC/ESI-QToF was used to identify the transformation products using standard references, the original compounds or analogs, comparing their accurate mass and product ions. One not previously observed major transformation product identified from propranolol were 1-naphthol. Several minor transformation products were also identified, showing how diverse the formation might be in wetlands.

A second part compares the matrix effect of ESI/MS using SFC and reversed phase LC, utilizing general screening methods for drug compounds in plasma, horse urine and influent/effluent wastewater. These matrices are known to suffer from matrix effects when using the ESI-source, and if SFC would suffer less than LC it could be a great benefit. The matrix profiles showed that this is likely not the case: although SFC was affected by different interferences then LC. One example is the formation of clusters causing major ion suppression. This unique SFC-phenomenon was investigated further, showing that metal ions were separated and eluted at different retention times, forming clusters in the ion source between metal ions and the organic modifier and/or make-up solvent.

In conclusion, the first part of this thesis describes analytical methods for determination of drug compounds in the environment, using LC and SFC, connected to both high and low resolving MS. The second part focuses on fundamental analytical chemistry, comparing the matrix effects of SFC/ESI-MS with LC/ESI-MS, and investigates the cluster phenomena observed for samples containing alkali ions and an organic modifier in the mobile phase in SFC/ESI-MS.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 44
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 1651-6192 ; 252
Keyword
SFC-MS, matrix effect, ion cluster, Supercritical fluid chromatography; ESI, chiral separation, transformation products, LC-QToF, wetland microcosms
National Category
Analytical Chemistry
Research subject
Analytical Pharmaceutical Chemistry
Identifiers
urn:nbn:se:uu:diva-346164 (URN)978-91-513-0281-2 (ISBN)
Public defence
2018-05-09, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2018-04-17 Created: 2018-03-15 Last updated: 2018-04-17

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Svan, AlfredHedeland, MikaelArvidsson, TorbjornPettersson, Curt E.

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