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Process Control of Esterification in a NeSSI-Based Micro-Reactor by Raman Spectroscopy

Stuart Farquharson, Chetan Shende, Frank Inscore, and Wayne Smith. Process Control of Esterification in a NeSSI-Based Micro-Reactor by Raman Spectroscopy. www.rta.biz. Contracts: NSF: DMI-0215819, DMI-0349687, DMI-0512701,. We Do Raman – All analyses performed by Raman & SER Spectroscopy.

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Process Control of Esterification in a NeSSI-Based Micro-Reactor by Raman Spectroscopy

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  1. Stuart Farquharson, Chetan Shende, Frank Inscore, and Wayne Smith Process Control of Esterification in a NeSSI-Based Micro-Reactor by Raman Spectroscopy www.rta.biz Contracts: NSF: DMI-0215819, DMI-0349687, DMI-0512701,

  2. We Do Raman – All analyses performed by Raman & SER Spectroscopy Mission: Provide analyzers that perform continuous, real-time, trace chemical detection with the ability to operate in harsh environments. Our fiber optic probes allow easy installation and use in all industries employing chemicals. Such as: Agriculture Petrochemical Biopharmaceutical Pharmaceutical Chemical Polymer Environmental Medical Homeland Security R&D

  3. Rapid Optimization of New Reactions/Processes • Micro-Reactors => thermal & mass transport reduced • Numbering-Up => 2 years earlier to market, Improve yield • Process Analytical Technology => In spec, safety • New drugs improve health… • A blockbuster drug makes >$1 million/day! • Profits limited by patent expiration • Eliminate delays to market (5-7 years lab-to-pharmacy) • 16% of drugs out-of-specification (= $1.1 million/year loss) • 50% of production time = analyzing intermediates/product Project Goal: Project Drivers:

  4. Esterification Reaction (Demonstration) Protection of a carboxylic acid group by esterification, represents one of the most often used reaction steps during the synthesis of pharmaceuticals.

  5. Small-Scale Reactor: (5 mL coil)

  6. Dr. Brian Marquardt University of Washington Small-Scale Reactor: Photograph Capillary Volume = 5 ml

  7. RTA’s Raman Analyzer It’s an Interferometer…no x-axis drift! $75,000 • Advantages: • No sample preparation • Simple integration via fiber optics • Remote analysis, multi-component • No fluorescence interference • Complete spectral coverage • Wavelength stability • Confident spectral subtraction • and library search/match • Real-time, On-demand analysis • Long term stability • Temperature and vibration immune • Shock resistant

  8. RTA Advantage: No Fluorescence Diesel Fuel 785 nm Laser Excitation 1064 nm Laser Excitation Virtually all natural materials fluoresce using 785 nm 8

  9. RTA Advantage: No X-Axis Shift Aspirin Aspirin Shifted Ibuprofen X axis shifts limit: quantitation, multi-component analysis, and unknown identification 9

  10. 1 mm glass capillary Sample Cell: 1-min, 375 mW of 785 nm Glass background = noise

  11. Benzoic Acid Methanol Sulfuric Acid Chemicals:

  12. Benzoic Acid (BA) Methyl Benzoate (MBZ) Chemicals: Reactant & Product 780 and 817 cm-1 => COO deformation mode

  13. Benzoic Acid (0.5-4M) Methyl Benzoate (0.5-4M) Calibration:

  14. Peak Height Peak Area Calibration:

  15. 60 oC Real-Time Monitoring by Raman Spectra generated using 375 mW of 785 nm and stored every 30 sec (every 3 min shown).

  16. 40 oC 50 oC 60 oC Small discrepancy between rate constants Reaction Rates:

  17. Activation Energy: SPIE, 6371 (2006)

  18. NeSSI-Based Small-Scale Batch Reactor Mike Cost Parker-Hannifin

  19. Raman Probes: Swagelok

  20. NeSSI-Based Small-Scale Batch Reactor Methanol BA LOAD H2SO4 Syringe Pumps

  21. NeSSI-Based Small-Scale Batch Reactor Raman Probe Monitor & Control REACT Peristaltic Pump

  22. NeSSI-Based Small-Scale Batch Reactor Syringe Pumps Raman Probe EMPTY MBZ

  23. Batch mode small-scale reactor built & used • Esterification reaction successfully monitored • Limits of detection: BA = 0.9%, MBZ = 0.75% • Various acid catalysts used, sulfuric acid best • Rate constants easily determined from 25-65 oC • Activation Energy determined at 50.1 kJ/mole • Best yield, 91% obtained at 60 oC • Continuous Reactor requires 72 m tube Summary:

  24. Future Work: NeSSI & SERS 3-Way 3-Way Surface Ex- Surface 3-Way Surface SERS Surface Valve Valve Connection tractor Connection Valve Connection Sensor Connection Regulated Water Load Sample Into Extractor (5 min)

  25. Future Work: NeSSI & SERS 3-Way 3-Way Surface Ex- Surface 3-Way Surface SERS Surface Valve Valve Connection tractor Connection Valve Connection Sensor Connection Regulated Water Load Sample Into SERS Capillary (10 sec)

  26. Future Work: NeSSI & SERS 3-Way 3-Way Surface Ex- Surface 3-Way Surface SERS Surface Valve Valve Connection tractor Connection Valve Connection Sensor Connection Regulated Water Measure SERS Load Next Sample Into Extractor (5 min)

  27. R&D: SERS Lab-On-Chip 5FU & 5FUH2 5FdUrd Leucovorin A B C A B C 600 800 1000 1200 1400 1600 Wavenumbers (cm-1)

  28. R&D: SERS Lab-On-Chip

  29. R&D: SERS Lab-On-Chip Multiplexed Sample Analysis on CD Style LOC

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