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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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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


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


  • 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:


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.



Dr. Brian Marquardt

University of Washington

Small-Scale Reactor: Photograph

Capillary

Volume = 5 ml


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


RTA Advantage: No Fluorescence

Diesel Fuel

785 nm

Laser Excitation

1064 nm

Laser

Excitation

Virtually all natural materials fluoresce

using 785 nm

8


RTA Advantage: No X-Axis Shift

Aspirin

Aspirin Shifted

Ibuprofen

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

9


1 mm glass

capillary

Sample Cell:

1-min, 375 mW of 785 nm

Glass background = noise


Benzoic Acid

Methanol

Sulfuric Acid

Chemicals:


Benzoic Acid (BA)

Methyl Benzoate (MBZ)

Chemicals: Reactant & Product

780 and 817 cm-1 =>

COO deformation mode


Benzoic Acid

(0.5-4M)

Methyl Benzoate

(0.5-4M)

Calibration:


Peak Height Peak Area

Calibration:


60 oC

Real-Time Monitoring by Raman

Spectra generated using 375 mW of 785 nm

and stored every 30 sec (every 3 min shown).


40 oC

50 oC

60 oC

Small discrepancy between rate constants

Reaction Rates:


Activation Energy:

SPIE, 6371 (2006)


NeSSI-Based Small-Scale Batch Reactor

Mike Cost

Parker-Hannifin


Raman Probes:

Swagelok


NeSSI-Based Small-Scale Batch Reactor

Methanol

BA

LOAD

H2SO4

Syringe

Pumps


NeSSI-Based Small-Scale Batch Reactor

Raman

Probe

Monitor & Control

REACT

Peristaltic

Pump


NeSSI-Based Small-Scale Batch Reactor

Syringe Pumps

Raman

Probe

EMPTY

MBZ


  • 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:


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



Simple SERS Sample Vials

2001 U.S. Patent Number 6,623,977


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


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


Performance: reversibility

30 second “plug”

of benzoic acid

8 second spectra, 100 mW 785 nm


Analysis: SERS of Pesticide Mixture

Carbaryl

on gold

Chlorpyrifos

on silver


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


Approach: measure anthrax signature - CaDPA

CaDPA


B. cereus

Raman Spectroscopy

Pure samples

500 mW of 1064 nm

5-min acquisition time

CaDPA

J Raman Spec, 35, 82-86 (2004)


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)


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)


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


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)


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


Sensitivity:

10 ppb

75 mW of 785 nm

1 min


Pesticide: chlorpyrifos (methyl)

SERS: 10 & 5 ppm (mg/L)

RS: 50,000 ppm (50g/L), 350 mW-25 min


Standard Method vs SERS Method

10 min

1 hour


Gas Chromatography

After step 5a After step 7b

Professor James Stewart, U. Connecticut


Chlorpyrifos: 50 ppb

1) In dichloromethane

2) In OJ after evaporation & SPE

3) In OJ after SPE


Method: 10-minute analysis

sma


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)


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


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


Analysis: 5-Fluorouracil

Normal Raman

Surface-Enhanced Raman

J Raman Spec, 36, 208-212 (2005)

Vibrational Spec, 38, 79-84 (2005)


Simple Separation Devices

5FU

&

5FUH2

5FdUrd

Leucovorin

A

B

C

A

B

C

600 800 1000 1200 1400 1600

Wavenumbers (cm-1)



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