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Real-Time Raman-Based Analytics for Micro-Systems: Small-Scale Reactors Lab-on-a-chip Separations

Stuart Farquharson, Chetan Shende, Frank Inscore, and Wayne Smith. Real-Time Raman-Based Analytics for Micro-Systems: Small-Scale Reactors Lab-on-a-chip Separations. www.rta.biz. Contracts: NIH: 1R43CA94457-01 US Army: DAAD13-02-C-0015, NSF: DMI-0215819, DMI-0349687, DMI-0512701,

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Real-Time Raman-Based Analytics for Micro-Systems: Small-Scale Reactors Lab-on-a-chip Separations

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  1. Stuart Farquharson, Chetan Shende, Frank Inscore, and Wayne Smith • Real-Time Raman-Based Analytics • for Micro-Systems: • Small-Scale Reactors • Lab-on-a-chip Separations www.rta.biz Contracts: NIH: 1R43CA94457-01 US Army: DAAD13-02-C-0015, NSF: DMI-0215819, DMI-0349687, DMI-0512701, NASA: NNA05CP04C, NNC05CA09C USDA: 2006-33610-1683

  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. Lab-On-a-Chip Separations & Surface-Enhanced Raman Spectral Detection Basic SERS Concepts Anthrax Spores on Surfaces Pesticides in Fruits & Vegetables Chemotherapy Drugs in Saliva

  25. Surface-Enhanced Raman Spectroscopy

  26. Simple SERS Sample Vials 2001 U.S. Patent Number 6,623,977

  27. Which do you want: Sensitivity or Reproducibility? SERS: silver particles in sol-gel 1 square micron = 12.6 silver particles Laser spot (325 micron diameter) = 83,000 square microns i.e. contains 1.04 millionsilver particles Or the equivalent of 1 perfect hot spot generating 1012 enhancement 10 microns

  28. Separation and Analysis 1 2 3 4 5 6 1 2 3 4 5 6 PABA PA 800 1000 1200 1400 1600 1800 2000 Wavenumbers (cm-1) Farquharson & Maksymiuk Appl Spec, 57, 479 (2003), US Patents 6,943,031 & 2

  29. Performance: reversibility 30 second “plug” of benzoic acid 8 second spectra, 100 mW 785 nm

  30. Analysis: SERS of Pesticide Mixture Carbaryl on gold Chlorpyrifos on silver

  31. Professor Jay F. Sperry University of Rhode Island Trace Detection of Bacilli Spores on Surfaces using a Portable SERS-Based Analyzer • Anthrax LD50 ~10,000 spores • Goals: 100 spores/cm2 • 1-min • No False Positives

  32. Approach: measure anthrax signature - CaDPA CaDPA

  33. B. cereus Raman Spectroscopy Pure samples 500 mW of 1064 nm 5-min acquisition time CaDPA J Raman Spec, 35, 82-86 (2004)

  34. SERS and RS of dipicolinic acid (DPA) SERS 1 mg/L (1 ppm) 150 mW, 10 sec Raman 5.5 g/L (55,000 ppm) DPA in KOH 300 mW, 25 min Enhancement Factor = 105 Appl Spec, 58, 351 (2004)

  35. Extraction & Identification of DPA in 2-min! 0. Dried 2200 spores from 1 microliter (~0.2 cm2) 1. Added 10 micoliters of SporeDestroyer (1-min digestion) 2. Suck 1 microliter into SER-active capillary (10-sec) 3. Measure SERS of DPA (10% = 220 pg/microliter) (10-sec placement, 30-sec scan)

  36. 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 RTA’s Portable Raman Analyzer SERS-Active Capillary

  37. SERS: 220 Spores 1 spore = 10 pg, DPA =10% spore weight 220 pg/microL DPA 100 pg/microL (ppb) reference spectrum Internal Reference IJHSES, 20, 12-18 (2007)

  38. Rapid Analysis of pesticides on or in fruit & vegetables by SERS • Need pesticides to meet food demand • US imports 40-45% fruit & vegetables • 6.1% of imports exceed guidelines • Only 1% is tested • 3 Million tons of contaminated fruits & • vegetables reaches the market each year • Goals: • 10 ppb-1 ppm (0.01-1 mg/L) • 1-minute • No false positives • Minimum Reagents • Field-usable

  39. Sensitivity: 10 ppb 75 mW of 785 nm 1 min

  40. Pesticide: chlorpyrifos (methyl) SERS: 10 & 5 ppm (mg/L) RS: 50,000 ppm (50g/L), 350 mW-25 min

  41. Standard Method vs SERS Method 10 min 1 hour

  42. Gas Chromatography After step 5a After step 7b Professor James Stewart, U. Connecticut

  43. Chlorpyrifos: 50 ppb 1) In dichloromethane 2) In OJ after evaporation & SPE 3) In OJ after SPE

  44. Method: 10-minute analysis sma

  45. Prototyping SERS-chip A B C A) Endosulfan SERS-Active Lab-on-a-Chip Sample Injection Syringe B) Thiabendazole A B C C) Phosmet 500 750 1000 1250 1500 1750 Wavenumbers (cm-1)

  46. Controlling Chemotherapy Drug Dosage • 1,334,100 new cancer cases each year • >0.5 million Americans died of cancer in 2003 • Lung and bronchus – 28% Colon and rectum – 10% • Breast – 7% Prostate – 6% • Treatment involves Surgery, Radiation and Chemotherapy • Chemotherapy drugs also kill non-cancer cells • Dosage is critical • No clinical trials to establish statistical based dosage • Current analysis of drugs and metabolites use 10-20 ml blood • Consequently, measurements made on an “as needed” basis

  47. Detection of 5-fluorouracil in saliva using SERS • 5-FU, one of most widely used chemotherapy drugs • Wide genetic-based variation in metabolism,15-80% inactive • 10% of patients die the first time administered • Need: Monitor metabolism on individual basis • Solution: SERS of saliva • Concentrations in saliva 10-50% of blood plasma (1-10 microg/mL) • Saliva is 99.5% water, few interfering physiological chemicals • But Currently analyses require 10-20 cc - unsafe • Raman – chemical specificity • SERS – increased sensitivity • Simple SERS Syringe - 100 microL, 5-min total analysis time

  48. Analysis: 5-Fluorouracil Normal Raman Surface-Enhanced Raman J Raman Spec, 36, 208-212 (2005) Vibrational Spec, 38, 79-84 (2005)

  49. Simple Separation Devices 5FU & 5FUH2 5FdUrd Leucovorin A B C A B C 600 800 1000 1200 1400 1600 Wavenumbers (cm-1)

  50. Simple Separation Devices 100 micron

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