Process Control of Esterification in a
NeSSI-Based Micro-Reactor by
Raman Spectroscopy
Stuart Farquharson,
Chetan Shende, Frank Inscore, and Wayne Smith
Contracts:
NSF: DMI-0215819, DMI-0349687, DMI-0512701,
www.rta.biz
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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
Biopharmaceutical
Chemical
Environmental
Homeland Security
Petrochemical
Pharmaceutical
Polymer
Medical
R&D
We Do Raman – All analyses performed by Raman & SER Spectroscopy
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
Project Goal:
• 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
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Esterification Reaction (Demonstration)
O
O
OH
Benzoic
Acid
H+
+
HOCH3
+
Methanol
acid
OCH3
Methyl
Benzoate
+
H2O
+
Water
Protection of a carboxylic acid group by esterification,
represents one of the most often used reaction steps during the
synthesis of pharmaceuticals.
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Small-Scale Reactor: (5 mL coil)
Peristaltic
Pump
Raman Analyzer
Optics Probe
Laser
Capillary
(Optical
Access)
Fiber Optic
H2SO4
BA/MeOH
Mixing
Chamber
Syringe Pump
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Small-Scale Reactor: Photograph
Capillary
Volume = 5 ml
Dr. Brian Marquardt
University of Washington
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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
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RTA Advantage: No Fluorescence
Diesel Fuel
785 nm
Laser
Excitation
1064 nm
Laser
Excitation
8
Virtually all natural materials fluoresce
using 785 nm
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RTA Advantage: No X-Axis Shift
Aspirin
Aspirin Shifted
Ibuprofen
X axis shifts limit: quantitation, multi-component
analysis, and unknown identification
9
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Sample Cell:
1 mm glass
capillary
1-min, 375 mW of 785 nm
Glass background = noise
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Chemicals:
Benzoic Acid
Methanol
Sulfuric Acid
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Chemicals: Reactant & Product
Benzoic Acid (BA)
Methyl Benzoate (MBZ)
780 and 817 cm-1 =>
COO deformation mode
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Calibration:
Benzoic Acid
(0.5-4M)
Methyl Benzoate
(0.5-4M)
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Calibration:
14
1.4
MBZ (817)
1.2
MBZ
12
BA
Raman Peak Intensity
Raman Peak Intensity
BA (780)
1
0.8
0.6
0.4
10
8
6
4
0.2
2
0
0
0
1
2
3
Concentration (M)
Peak Height
4
5
0
1
2
3
4
5
Concentration (M)
Peak Area
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Real-Time Monitoring by Raman
60 oC
Spectra generated using 375 mW of 785 nm
and stored every 30 sec (every 3 min shown).
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Reaction Rates:
40 oC
50 oC
60 oC
Small discrepancy between rate constants
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Activation Energy:
8.00
7.80
7.60
Ln k
7.40
7.20
7.00
y = 6.1561x - 12.008
2
R = 0.9964
6.80
6.60
6.40
6.20
6.00
2.95
3
3.05
3.1
3.15
3.2
3.25
1000/T (K)
SPIE, 6371 (2006)
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NeSSI-Based Small-Scale Batch Reactor
Mike Cost
Parker-Hannifin
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Raman Probes:
Fiber Optic
cable
to instrument
1/8” Tygon
tubing
SERS-active
capillary
opening to
pass light
5”
FO Probe
& Mount
Swagelok
hole to pass
mounting
screw
1.5”
threaded for
device
attachment
1.5”
SERS-Capillary
Interface Block
3”
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NeSSI-Based Small-Scale Batch Reactor
Methanol
BA
LOAD
H2SO4
Syringe
Pumps
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NeSSI-Based Small-Scale Batch Reactor
Raman
Probe
Monitor & Control
REACT
Peristaltic
Pump
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NeSSI-Based Small-Scale Batch Reactor
Syringe Pumps
Raman
Probe
EMPTY
MBZ
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Summary:
• 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
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Future Work: NeSSI & SERS
3-Way
Valve
3-Way Surface
ExSurface 3-Way Surface
SERS
Surface
Valve Connection tractor Connection Valve Connection Sensor Connection
Regulated
Water
Sample
Bottle
MeOH
Pump
Waste
Bottle
Load Sample Into Extractor (5 min)
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Future Work: NeSSI & SERS
3-Way
Valve
3-Way Surface
ExSurface 3-Way Surface
SERS
Surface
Valve Connection tractor Connection Valve Connection Sensor Connection
Regulated
Water
Sample
Bottle
MeOH
Pump
Waste
Bottle
Load Sample Into SERS Capillary (10 sec)
Providing Chemical Information When & Where You Need It
Future Work: NeSSI & SERS
3-Way
Valve
3-Way Surface
ExSurface 3-Way Surface
SERS
Surface
Valve Connection tractor Connection Valve Connection Sensor Connection
Regulated
Water
Sample
Bottle
MeOH
Pump
Waste
Bottle
Measure SERS
Load Next Sample Into Extractor (5 min)
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R&D: SERS Lab-On-Chip
5FU
&
5FUH2
A
A
B
C
5FdUrd
B
C
600
Leucovorin
800
1000 1200
1400
Wavenumbers (cm-1)
1600
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R&D: SERS Lab-On-Chip
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R&D: SERS Lab-On-Chip
Multiplexed Sample
Analysis
on CD Style LOC
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