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29th April 2003 Duncan Thompson, Chemical Development, GSK

29th April 2003 Duncan Thompson, Chemical Development, GSK. Comparison of different chemometric techniques for reaction monitoring using Raman and UV spectroscopy . Outline of the presentation . Setting the scene Techniques used Reaction monitoring results Kinetics Conclusions Questions .

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29th April 2003 Duncan Thompson, Chemical Development, GSK

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  1. 29th April 2003Duncan Thompson, Chemical Development, GSK Comparison of different chemometric techniques for reaction monitoring using Raman and UV spectroscopy

  2. Outline of the presentation • Setting the scene • Techniques used • Reaction monitoring results • Kinetics • Conclusions • Questions

  3. Chemometrics and Process Analytics team • Analytical project support • Chemometric techniques • MSPC • Reaction monitoring/Solubility determinations Areas of work

  4. Bromination Chemistry • Exothermic reaction • Variable initiation time - plant safety issues • Auto catalytic • Fast initiation • Hazardous product - severe lachrymator

  5. Kaiser Raman 1/4” hasteloy probe 785nm laser 20 secs acquisition Cycle time - 1 min Data collected using GRAMS Zeiss MCS spectrometer 1/2” equitech hasteloy probe 500ms integration time Wavelength range - 220 to 400nm Cycle time - 1 min Techniques used in parallel

  6. Product Starting material C-Br band Solvent Results - Raman spectra

  7. 4 3 2 1 Peak area using HOLOREACT software

  8. Time Results - UV spectra

  9. 1 4 3 2 3 components accounts for 99.9% of the data PCA analysis - data centred

  10. PCA analysis - scores against time

  11. X=C.S X.S’=C.(S.S’) (X.S’).(S.S’)-1=C.(S.S’).(S.S’)-1 Cest= (X.S’).(S.S’)-1 MLR - estimation of concentration using reference spectra

  12. MLR results

  13. Iterative Target Transform Factor Analysis • Estimate spectral and concentration profiles from reaction data set • Initial targets manually selected • Iterative process, refining concentration and target estimates according to certain restrictions • Minimise error • Non negativity • Unimodality

  14. Target/Spectral estimates Concentration profiles Iterative Target Transform Factor Analysis

  15. Comparison of product profile by technique

  16. 1 0.9 10 deg 0.8 20 deg 30 deg 0.7 0.6 0.5 Amount of starting material 0.4 0.3 0.2 0.1 0 0 100 200 300 400 500 600 700 800 Time / secs Kinetics of reaction • Reaction under various conditions • Monitored by UV, data collected every 10 secs

  17. Dynochem results Proposed mechanism

  18. Dynochem model prediction

  19. Choosing a monitoring technique • Both UV and Raman can be used to follow initiation and reaction progress • Factors to consider • Structure of molecules • Speed of data acquisition • Raman scattering • Complexity of problem • Software limitations • Cost

  20. Conclusions • Hazardous reaction successfully monitored with 2 spectroscopic techniques • Kinetics determined for a very fast reaction • Comparison of techniques and data processing methods has demonstrated confidence in chemometric data analysis techniques • Improved knowledge (kinetics, initiation point, safety)

  21. Acknowledgements • Team members • Richard Escott, Christian Airiau • Process chemists • Mark Hughes, Alan Negus, Richard Atkins

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