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

Raman Spectroscopy

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Stuart Farquharson, Chetan Shende, Frank Inscore, and Wayne Smith

www.rta.biz

Contracts: NSF: DMI-0215819, DMI-0349687, DMI-0512701,

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

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 PharmaceuticalChemical PolymerEnvironmental MedicalHomeland Security R&D

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

• 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:

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

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

Esterification Reaction (Demonstration)

OH

O

OCH3

O

+ +

Benzoic Acid + Methyl

Benzoate +

HOCH3H2O

Methanol Water

H+

acid

Protection of a carboxylic acid group by esterification, represents one of the most often used reaction steps during the synthesis of pharmaceuticals.

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

Small-Scale Reactor: (5 mL coil)

F ib e r O p tic C ap illa ry(O p tica l A cce s s)

B A /M eO H

S y rin g e P u m p

R a m a n A n a ly ze r O p t ic s P ro b e

P e r is ta lt ic P u m p

H 2 S O 4

L ase r

M ix in gC h a m b e r

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Small-Scale Reactor: Photograph

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Volume = 5 ml

Capillary

Dr. Brian Marquardt University of Washington

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

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

RTA Advantage: No Fluorescence

785 nmLaser

Excitation

1064 nm Laser

Excitation

Diesel Fuel

8P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

Virtually all natural materials fluoresce using 785 nm

RTA Advantage: No X-Axis Shift

Aspirin

Aspirin Shifted

Ibuprofen

9P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

X axis shifts limit: quantitation, multi-component analysis, and unknown identification

Sample Cell:

1 mm glass capillary

1-min, 375 mW of 785 nmGlass background = noise

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

Chemicals:

Benzoic AcidMethanolSulfuric Acid

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Chemicals: Reactant & Product

Benzoic Acid (BA)Methyl Benzoate (MBZ)

780 and 817 cm-1 => COO deformation mode

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

Benzoic Acid(0.5-4M)

Methyl Benzoate(0.5-4M)

Calibration:

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Peak Height Peak Area

Calibration:

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 1 2 3 4 5

Concentration (M)

Ra

man

Pe

ak

Inte

ns

ity

MBZ BA

0

2

4

6

8

10

12

14

0 1 2 3 4 5

Concentration (M)R

am

an

Pe

ak

Inte

ns

ity

MBZ (817)

BA (780)

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Real-Time Monitoring by Raman

Spectra generated using 375 mW of 785 nm and stored every 30 sec (every 3 min shown).

60 oC

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Small discrepancy between rate constants

Reaction Rates:

40 oC

50 oC

60 oC

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Activation Energy:

y = 6.1561x - 12.008

R2 = 0.9964

6.00

6.20

6.40

6.60

6.80

7.00

7.20

7.40

7.60

7.80

8.00

2.95 3 3.05 3.1 3.15 3.2 3.25

1000/T (K)

Ln

k

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SPIE, 6371 (2006)

NeSSI-Based Small-Scale Batch Reactor

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

Mike CostParker-Hannifin

Raman Probes:

5 ”

3 ”

1 .5 ”

1 .5 ”th re a d e d fo r

d e v ic e a tta c h m e n t

S E R S -C a p illa ryIn te rf a ce B lo c k

h o le to p a s sm o u n tin g

sc re w

1 /8 ” Ty g o ntu b in g

S E R S -a c tiv ec a p il la ry

o p e n in g to p a s s l ig h t

F ib e r O p tic c a b le

to in s tru m e n t

F O P ro b e& M o u n t

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

Swagelok

NeSSI-Based Small-Scale Batch Reactor

BA

Syringe Pumps

H2SO4

Methanol

LOAD

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

NeSSI-Based Small-Scale Batch Reactor

Monitor & ControlRamanProbe

REACT

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PeristalticPump

NeSSI-Based Small-Scale Batch Reactor

MBZ

RamanProbe

Syringe Pumps

EMPTY

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• 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:

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

Reg

ula

ted

W

ater

Sample Bottle

Waste Bottle

MeOH Pump

3-Way 3-Way Surface Ex- Surface 3-Way Surface SERS Surface Valve Valve Connection tractor Connection Valve Connection Sensor Connection

Loa

d S

ampl

e In

to E

xtra

ctor

(5

min

)

Future Work: NeSSI & SERS

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

Reg

ula

ted

W

ater

Sample Bottle

Waste Bottle

MeOH Pump

3-Way 3-Way Surface Ex- Surface 3-Way Surface SERS Surface Valve Valve Connection tractor Connection Valve Connection Sensor Connection

Loa

d S

ampl

e In

to S

ER

S C

apil

lary

(10

sec

)

Future Work: NeSSI & SERS

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

Reg

ula

ted

W

ater

Sample Bottle

Waste Bottle

MeOH Pump

3-Way 3-Way Surface Ex- Surface 3-Way Surface SERS Surface Valve Valve Connection tractor Connection Valve Connection Sensor Connection

Mea

sure

SE

RS

Loa

d N

ext

Sam

ple

Int

o E

xtra

ctor

(5

min

)

Future Work: NeSSI & SERS

R&D: SERS Lab-On-Chip

5FU & 5FUH2

5FdUrd

Leucovorin

A

B

C

600 800 1000 1200 1400 1600 Wavenumbers (cm-1)

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

ABC

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

R&D: SERS Lab-On-Chip

P rov id in g C h em ica l In fo rm a tion W h en & W h ere You N eed I t

R&D: SERS Lab-On-Chip

Multiplexed Sample Analysis

on CD Style LOC