Highlights overview Analytical measurements - CPACT and Industry

1. Highlights overviewAnalytical measurements - CPACT and Industry David Rudd GlaxoSmithKline

2. CPACT measurement projects • Use of model process systems to devise and evaluate improvements in process control • Robust calibration of spectral data using small data sets • Process (low-field) NMR • On-line liquid chromatography

3. Project 1 - Model process systems Objectives • To provide a reactor facility with associated analytical instrumentation • To compare existing and new approaches to on-line chemical analysis • To evaluate improved calibration methods • To test novel control procedures

4. Project 1 achievements • Two triple-jacketed 5 litre reactors available, each capable of operating in batch mode • Temperatures, stirring rate, pressure, reaction level, and mass of reactants may be monitored continuously • LabVIEW control programme

5. Project 1 achievements • In-line analytical methods using Raman, NIR and UV-vis have been developed for a crotonic acid/2-butanol esterification • At-line NMR from Project 3 • Sampling loop designed for on-line NMR • Programmes have been written to take spectroscopic data into LabVIEW • Novel iridium oxide pH probes

6. Project 1 achievements • Kinetic studies carried out on the crotonic acid esterification allowing the reaction to be modelled • Some work on the use of Raman for monitoring the esterification of ethanoic acid and the use of microwave spectroscopy for moisture and fat determinations in tobacco and foodstuffs

7. Project 1 deliverables • Five IMB reports (with another six in preparation) • Four oral presentations • Four posters • Three publications (with more in preparation)

8. Success of Project 1? • Reactor facility is available with associated analytical instrumentation • Comparison of analytical monitoring technologies is possible • Calibration methods - see Project 2 • More work needed in the area of process control

9. Project 1 in CPACT Phase 2 • Facility could be used to provide information on the influence of scale-up • Interfacing of novel analytical technologies • Allows investigation of analytical sampling strategies

10. Project 2 - Robust calibration Objectives • To investigate the signal processing and experimental design requirements to select the optimum combination of samples and variables that facilitate the development of robust calibration when only small data sets are available, and to identify the mathematical tools that enable the user to utilise only a minimum number of samples

11. Project 2 achievements • Established a basis for method comparisons • standard set of result reporting methodologies • Novel method of Variable Selection for NIR data • Identified optimal methods for sample selection allowing calibration models to be updated

12. Project 2 deliverables • Software for use by industrial members • Workshops and tutorials • Several IMB reports • Series of posters and presentations • Publications (including the application of microwave spectroscopy for the determination of moisture in tobacco)

13. Success of Project 2? • Applicability to real industrial problems needs to be established • Emphasis on working without calibration? • Maintenance and update of calibration model established • Alignment of spectral data with process data, allowing trending (eg control charts)

14. Project 2 in CPACT Phase 2 • Process characterisation and description (process tomography) • Transferability of calibration models (eg due to changes resulting from scale-up or to types of processing equipment) • Novel types of analytical data (eg acoustics)

15. Project 3 - Process NMR Objectives • To investigate the potential (at-line and on-line) and to develop a low-field instrument for process analysis • To develop signal and data processing methods for overlapping signals • To compare with other analytical techniques • To conduct plant-based evaluations

16. Project 3 achievements • Low-field instrument developed (29MHz) by Resonance Instruments (Witney, UK) • Magnet homogeneity improved • 1H, 19F and 31P spectra obtained with sufficient resolution to enable chemical shift information to be obtained • At-line and on-line measurements possible

17. At-line applications (1H) • Strong acid concentrations • Alkyl chain length • Methacrylamide process monitoring • Benzene production • Polyether polyols • Crotonic and itaconic acid esterifications

18. At-line applications (19F) • Dehydroxylation of tetrafluorohydroquinone • Aminolysis of 4-fluorobenzoyl chloride • Quantitative analysis of an Avecia process -------------------------------------------------------- • On-line analysis of crotonic acid esterification

19. Project 3 achievements • PLS analysis of spectral data • Continuous wavelet transform in the time domain • Modified generalised rank annihilation method (FID-GRAM) • Direct exponential curve resolution algorithm (FID- DECRA)

20. Project 3 deliverables • Six IMB reports (with another six in preparation) • Oral presentations (IFPAC, FACSS, CAC, Pittcon etc) • Three publications (with another six in preparation)

21. Success of Project 3? • Low-field, high resolution NMR spectrometer developed • At-line and on-line NMR evaluated using a range of samples from member companies • Time domain signal analysis methods developed (in conjunction with Project 2) • Project 1 facilities used to allow comparison of analytical monitoring techniques

22. Project 3 in CPACT Phase 2 • Plant-based trials within member companies’ facilities? • Part of the range of measurement techniques required for process characterisation and description (process tomography) • On-line impurity analysis

23. Project 7 - On-line liquid chromatography Objectives • To understand the reasons for the current low level of usage of on-line LC • To identify industrial applications with good ‘payback’ • To identify areas of weakness and to establish ways of overcoming such aspects

24. Project 7 achievements • Failure of on-line applications of LC identified • Emphasis placed on improving methods of sampling with new sampling probes designed and fabricated • Control system re-programmed to provide additional flexibility with revised probe

25. Project 7 deliverables • Sampling probes designed and fabricated • Report describing probe design • IMB report on on-line LC • Report on fast LC analysis strategies (less than 2 minutes) with application to batch reactions

26. Success of Project 7? • Reasons established for low use of on-line LC • Potential applications identified, although with no practical follow-up with industry to date • Project direction altered to concentrate on sampling probes for LC and other on-line techniques

27. Project 7 in CPACT Phase 2 • Impurity monitoring technique? • Sampling/interfacing issues • Process tomography applications

28. Summary • Phase 1 has formed a useful basis on which the Phase 2 programme can build • Considerable commonality of ‘themes’ • interfacing of analytical instrumentation • sampling strategies • impurity determinations • influence of scale-up • process tomography