1. CPAC Webinar Feb. 2009 Process Spectroscopy and Optical Sensing
Brian Marquardt Ph.D.
Director – Applied Optical Sensing Lab
Applied Physics Lab
University of Washington
Seattle, Washington 98105

2. Process Raman Applications
Pharmaceuticals
Food quality and safety
Polymers/coatings
Fermentation/biotech
Cellular/tissue
Oil/fuels/petrochemicals
Oceanography/environment
Challenges
Reproducible sampling
Fluorescence

3. Quantitative Raman = Effective Sampling
no moving parts
sapphire spherical lens
constant focal length and sample volume
probe is ALWAYS aligned when in
contact with sample
effective sampling of liquids, slurries,
powders, pastes and solids
high sampling precision allows it to
be used effectively to monitor dynamic
mixing systems (powder/slurry/particle)
improved measurement precision leads to robust multivariate calibration of process Raman data
CPAC developed, patented and licensed Raman ballprobe

4. Analysis of a Batch Fermentation Process
Real-time Fermentation
Monitoring
Yeast Fermentation Process
Image from Purves et al., Life: The Science of Biology, 4th Edition

5. Raw Raman Data for Fermentation Batch Reaction (8 day run)
Fluorescence

6. Raman Data After Fluorescence Correction Algorithm Applied

7. 3D Plot of fluorescence corrected Raman fermentation data
Brian Marquardt - confidential

8. Raman Analysis and Optical Trapping of Single Cells
Raman Microscope and Instrument
Raman Microscope and Microchip

9. Micro-reactors and Raman lead to improved understanding and control
500
1000
1500
2000
2,4-dinitrotoluene
2,6-dinitrotoluene
2-nitrotoluene
3-nitrotoluene
4-nitrotoluene
nitric acid
sulfuric acid
toluene
Raman Shift (cm-1)

10. Real-time Understanding and Control
without residence time module
flow rate: 0.89 ml/min (residence time ~ 5 min)
PCA Analysis on data after mixing:
1st PCA scores  Increase in reaction yield after each temperature step

11. CPAC/FDA/Corning MicroReactor
Goal: to improve reaction development and optimization through the use of continuous glass microreactors, NeSSI and analytics
Funded by the FDA to demonstrate the benefits of improved reactor design, effective sampling and online analytics to increase process understanding (QbD)
QbD Project began November 2008

12. What is NeSSI?
Industry-driven effort to define and promote a new standardized alternative to sample conditioning systems for analyzers and sensors
Standard fluidic interface for modular surface- mount components
Standard wiring and communications interfaces
Standard platform for micro analytics

13. What does NeSSI Provide
Simple “Lego-like” assembly
Easy to re-configure
No special tools or skills required
Standardized flow components
“Mix-and-match” compatibility between vendors
Growing list of components
Standardized electrical and comm. (Gen II)
“Plug-and-play” integration of multiple devices
Simplified interface for programmatic I/O and control
Advanced analytics (Gen III)
Micro-analyzers
Integrated analysis or “smart” systems

14. NeSSI Gas Generation System
Automated Circor NeSSI Gas/Vapor System N2 O2
Mixed Gases
Mass Flow
Controllers
Fully automated gas generation system for sensor calibration:
4 Stage dilution, able to produce and maintain gas concentrations of 100% to 0.1%(1000 ppm) from standard bottle gas
Fully calibrated, automated system with set and forget capability

15. Small Optical Sensors vapochromic chemistry
Oxygen
Moisture
Ammonia
Hydrogen
Common Solvents
Alcohols
Esters
Amines
Chlorinated Organics
Organic Hydrocarbons (BTEX)
Carbon Dioxide
(in development)
Hydrogen Sulfide
vapochromic chemistry
optical response to analytes
simple design
reversible response
low power
inexpensive
fast response times
high quantum efficiency
long term sensor stability
sensitive to a variety of analytes
wireless communication
battery powered

16. Vapochromic Humidity Sensor
- Measurment time – 100 ms
- 3 reps per concentration

17. Sensor response to O2 Gas
120
20 replicates at each concentration
Concentration range: % Oxygen
100
R2 = 0.990, 3 PC
RMSEC = 80
Predicted O2 % 60
Intensity (counts)
Wavelength (nm)
100 % 0%
This oxygen concentrations were calculated from the mass flow controllers 40 20 10 20 30 40 50 60 70 80 90
100
Calculated O2 %

18. Low Concentration Dissolved O2 Calibration
5 replicates at each concentration
Concentration range: 1 μmol/L μmol/L 39 31
R2=0.997, 2 PCs,
RMSEC= 24
Predicted [O2] (μmol/L) 16
39 μmol/L
1 μmol /L
Intensity (counts)
Wavelength (nm) 9 5 2 1
1 μmol/L = 32.5 ppb
Measured [O2] (μmol/L)

19. LIBS: Remote Elemental Analysis
Remote elemental analysis with no sample preparation
Fiber-optic delivery or long range delivery of laser by telescope for remote analysis
Laser-induced plasma ablates and super heats samples to provide elemental spectral data

20. Potential Applications
Analysis of metal complexes in food, cellulosic biomass, pharmaceuticals and fermentation apps.
Determination of ionic and inorganic species in a variety of chemical/production processes
Glasses, ceramics, zeolites, alloys, corrosion analysis
Quantitative analysis of catalyst composition for screening and development
Couple with vibrational techniques to develop a hyphenated technique (Raman/LIBS) to define both organic and inorganic analytes in a process system

21. Acknowledgements CPAC Washington Tech. Center
National Science Foundation
National Institute of Health,
Charlie Branham and Wes Thompson
Many current and past CPAC sponsors