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

2. 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 We Do Raman – All analyses performed by Raman & SER Spectroscopy

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 Project Goal:Project Drivers: 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

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

7. RTA’s Raman Analyzer 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 It’s an Interferometer…no x-axis drift! $75,000

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

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

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

11. Chemicals: Benzoic Acid Methanol Sulfuric Acid

12. Chemicals: Reactant & Product Benzoic Acid (BA) Methyl Benzoate (MBZ) 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. Real-Time Monitoring by Raman Spectra generated using 375 mW of 785 nm and stored every 30 sec (every 3 min shown). 60 oC

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

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 BA Syringe Pumps H 2 SO 4 Methanol LOAD

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

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

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 o C Activation Energy determined at 50.1 kJ/mole Best yield, 91% obtained at 60 o C Continuous Reactor requires 72 m tube Summary:

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

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

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

27. R&D: SERS Lab-On-Chip 5FU & 5FUH 2 5FdUrd Leucovorin ABCABC 600 800 1000 1200 1400 1600 Wavenumbers (cm-1) ABCABC

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

29. Multiplexed Sample Analysis on CD Style LOC