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A Membrane Based Approach t o On-line Reaction Monitoring b y Mass Spectrometry. Rebecca Clinton The Nottingham Tren

A Membrane Based Approach t o On-line Reaction Monitoring b y Mass Spectrometry. Rebecca Clinton The Nottingham Trent University. Techniques Spectroscopy non-destructive low selectivity limited dynamic range. Chromatography higher selectivity

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A Membrane Based Approach t o On-line Reaction Monitoring b y Mass Spectrometry. Rebecca Clinton The Nottingham Tren

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  1. A Membrane Based Approach to On-line Reaction Monitoring by Mass Spectrometry. Rebecca Clinton The Nottingham Trent University

  2. Techniques Spectroscopy non-destructive low selectivity limited dynamic range Chromatography higher selectivity relatively slow separation and detection wider dynamic range Mass Spectrometry high selectivity potentially rapid technique wide dynamic range

  3. Mass Spectrometer Overview

  4. Process Monitoring by Mass Spectrometry Gaseous components simplest to monitor: • pre-concentration steps • MIMS • purge and trap • headspace analysis Liquid phases more of a challenge: • concentrated reaction mixtures • multiple analyte levels exceed the working limits of the instrument • complex samplepreparation systems required (without compromising mass spectrometer operation)

  5. Monitoring Organic Reactions With On-Line API MS: The Hydrolysis Of Isatin Dell’Orco P. Brum J. Matsuoka R. Badlani M. Muske K. Analytical Chemistry, 1999, 71, 5165 Brum J. Dell’Orco P. Lapka S. Muske K. Sisko J. Rapid Commun. Mass Spectrom, 2001, 15, 1548-1553

  6. Membrane Interfaces Volatile and semi-volatile compounds: membrane inlet mass spectrometry (MIMS) non-porous membrane for extracts sample from process stream Creaser C.S. et al, Anal. Chim. Acta., 2002, 454, 137 Dilute non-volatile compounds microporous membrane as enrichment devices coupled to HPLC Jönsson and Mathiasson, J. Chromatogr. A, 2000, 893, 123 Concentrated non-volatile compounds microporous membranes as dilution devices online mass spectrometry

  7. Membrane Dynamics

  8. The Michael Addition reaction of phenylethylamine with acrylonitrile in ethanol. Reactants: Products: HN N N H 2 N Main product: Mw 174 3-Phenylethylamino-propionitrile (PEAP) Phenylethylamine (PEA) Mw 121 N N CH2=CHCN Acrylonitrile Mw 53 Side reaction: Mw 227 3-[(2-Cyano-ethyl)-phenylethyl-amino] propionitrile (CPEAP)

  9. Membrane Selection

  10. Membrane Selection

  11. Membrane Selection

  12. Typical set-up of membrane holder and pumps

  13. Typical set-up of membrane holder and pumps

  14. Membrane Selected Polyvinylidene fluoride microporous membrane Pore size 0.1μm Hydrophobic Durapore®, Millipore

  15. Unidirectional Flow Extraction

  16. Unidirectional Flow Extraction

  17. Unidirectional Flow Extraction

  18. Unidirectional Flow Extraction

  19. Counter-Flow Extraction

  20. Instrument Conditions: Mass Spectrometer: Micromass Platform LC (Single Quadrupole MS) Ionisation Mode: APCI+ Mass range: 80-300 amu Loop Size: 20 μl Solvent composition Donor side: Absolute ethanol (Hayman) at 0.5 ml/min (HPLC pump) Acceptor side: Purified water/acetonitrile (Fisher Chemicals) 90/10 at 0.5 ml/min (HPLC pump) Restrictor Fused silica tubing and needle valve

  21. Presentation of data Single ion response for the main product, PEAP (m/z = 175)

  22. Direct 20 μl loop injection of reaction mixture diluted 270,000 fold 20 μl aliquot of undiluted reaction mixture using membrane system Time (minutes)  Dilution Effect Single ion response for the main product, PEAP (m/z = 175)

  23. Reproducibility of the membrane system Peak area ratios for PEAP (m/z = 175) to CPEAP (m/z = 228) RSD = 2.5% (n = 9) PEAP m/z=175 CPEAP m/z=228 Time (minutes) 

  24. Time zero PEA Time 60 minutes PEAP PEA Time 350 minutes PEAP CPEAP PEA Monitoring the course of the reaction

  25. Reaction monitoring

  26. PEAP Reaction components composition changes Peak Area Ratios of PEAP to PEA

  27. PEAP PEAP to PEA CPEAP to PEA CPEAP Reaction components composition changes Peak Area Ratios of PEAP to PEA

  28. Conclusions Reaction of phenylethylamine with acrylonitrile monitored using a novel membrane device with online APCI-MS Achieved a 270,000 fold dilution in a single step. minimal analyst intervention minimal sample preparation and handling This simple interface allowed the simultaneous determination of multiple components on a real time basis

  29. Potential Developments Different reaction systems non aqueous system (immiscible solvents) different membrane materials more complex systems Automate the process …

  30. Typical set-up of membrane holder and pumps

  31. Potential Developments Continuous monitoring real time minimal time lag Heterogeneous systems filtration and dilution in a single step

  32. Acknowledgements Prof. Colin Creaser - The Nottingham Trent University Dr Duncan Bryant - GlaxoSmithKline Claire Bramwell, Joanne Clayton, David Gómez Lamarca, Lucy Ratcliffe and James Reynolds Technical Staff at NTU GlaxoSmithKline for financial support of this work

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