molecular rotational resonance spectroscopymolecular...

SpecMolecular Rotational Resonance SpectroscopyMolecular Rotational Resonance Spectroscopy

BrightSpec, Inc. | 770 Harris St. #104B | Charlottesville, VA 22903 | (434) 202-2391

Brent Harris, PhD.Director of Applications

Development

[email protected]

5/10/2016 © 2016 BrightSpec, Inc.

High Resolution FT-MRR Spectroscopy:

Trace Residual Impurities Analysis

Without Chromatography

1 of 18 slides

Linda Kidder, PhD.Director of Marketing

[email protected]

SpecMolecular Rotational Resonance Spectroscopy

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Analytical Chemistry Tools

We want the best of both

Spectroscopy

+ Simple, non-destructive

+ High degree of automation

+ Molecular specificity

- Poor selectivity in complex

mixtures

- High detection limits

Chromatography

+ High selectivity and

applicability

+ Low detection limits

- High degree of customization

- Complex methods

- Identification ambiguity

Pervasive challenge - dealing with gaps between instrumentation capabilities


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Reinvention of Rotational Spectroscopy*

FT-MRR

A Technique that Bridges the Gap?

*“A Broadband Fourier Transform Microwave Spectrometer Based on Chirped Pulse Excitation”, G.G.Brown et al., Rev. Sci. Instrum. 79, 053103 (2008).*”Segmented chirped-pulse Fourier transform submillimeter spectroscopy for broadband gas analysis,” J.L. Neill, B.J. Harris et al., Opt. Express, 21(3), 19743-19749 (2013).

Chirped Pulse Innovation


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Molecular Rotational Resonance (MRR)

BrightSpec FT-MRR

Radio

Nuclear Magnetic Resonance

Microwave Millimeter-wave/THz Infrared Vis UV X-ray, Gamma

Electron Spin Resonance

-------Molecular Rotation------- Vibration

Electronic Dissociation

Nuclear Chemistry

ENERGY

Absolute specificity: direct structure “calculation” vs. structure “elucidation”

Excellent selectivity: baseline resolved, highly specific spectral fingerprint

I=MR2 Quantized angular momentum states related to rotational inertia (specific to

mass distribution, fits a Hamiltonian to 0.1ppm freq. accuracy)

... So, where has this been all of our lives?


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MRR – microwave to millimeter wave

Direct absorption of transient, gas-phase molecules

(Klystrons, BWOs, Gunn oscillators, Schottky multipliers)

• Glow discharge, astrochemical studies

• Hewlett-Packard MW spectrometer (1960s)

• Millimeter, submillimeter spectrometers (1960s, 70s)

[gas mixtures ≥ 300 K - high temp complicates spectral profile]

© 1955 C.H. Townes, A.L.

Schawlow, Microwave

Spectroscopy, Dover (2012),

Mineola, NY

Pulsed jet, FT-spectroscopy for weakly bound complexes

(digital electronics – synthesizers and AWGs)• Fourier Transform cavity enhanced spectrometers (1970s)

• Chirped-pulse broadband spectrometers (2004)

[gas mixtures < 10 K – low temp simplifies spectral profile]

The Fourier transform evolution event !!!


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Re-invention of FT-MRR

Essential advances:

① Chirped-pulse innovation (physical

chemistry)

② High power, solid state, light sources

(telecommunication industry)

③ High speed digital electronics (digital

warfare)

100X sensitivity improvement

P ~ (Nm)2

FT

Now, FT-MRR is ready for analytical chemistry

© 2016 BrightSpec, Inc.


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Enhanced Capabilities with FT-MRR


FT-MRR Applications

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CPAC

2015

Trace Residual ImpuritiesCPAC

2016

Chiral Analysis


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FT-MRR Broadband Survey

Mode

271500 271550 271600

0

0.02

0.04

0.06

0.08

289850 289900 289950 290000 290050

0

0.02

0.04

0.06

0.08

0.1

Frequency (MHZ)

Inte

nsity (

mV

)

Solvents dissolved in N,N Dimethylacetamide at ~0.1 mg/mL.

Chemical ID by spectral reference library match

Chemically specific spectral fingerprint

High dynamic range Baseline resolved,

no chemometrics

10 minute, static headspace FT-MRR spectrum


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Target Analytes for FT-MRR

Millimeter-wave FT-MRR:

small (< 100 amu), conformationally rigid, branched molecules

polar (> 0.1 D), non-zero dipole moment

volatile (Pvap > 500 mTorr 25 C)

Spectral Library currently contains 150 molecules(and growing… )

Residual Solvents

Methanol, Acetone, Methylene Chloride, Toluene, THF, Pyridine, Acetonitrile….

Toxic Industrial Chemicals (TICs)

Formaldehyde, Ethylene Oxide/Propylene Oxide, Cyanides…

Other:

Haloalkanes, Haloalcohols, Mercaptans, Amines …


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FT-MRR Spectrometers – Method Transfer

For discovery, when you don’t know what’s there

Broadband FT-MRR

central process R&D – survey mode

For control, when you know what to look for

Targeted FT-MRR

process analysis and quality control – selective excitation mode


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Headspace Analysis – at-line?

Static Headspace

Solutions

Heater (50 C)

Dissolved API

(50 mg/mL, 1 mL)

Solids

Heater (30 – 200 C)

API/Tablet solid

(10 – 50 mg)

Thermal Evolution

Heater (50 C)

Residual solvent

• 5 minute cycle time

• 10 – 100 ppm detection limit

Genotoxic impurity

• 10 minute cycle time

• 10 – 100 ppb detection limit


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Solution Headspace FT-MRR

Volatile, strong FT-MRR emitter:

Detection limit – 8 ppm

Linearity – R2 = 0.9997

RSD avg – < 10 %

Volatile, weaker FT-MRR emitter:

Detection limit – 200 ppm

Linearity – R2 = 0.996

RSD avg – 6.3% (2 % real sample)


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Evolved gas analysis by FT-

MRR

Residual solvent - measured detection limits:• Isopropanol (< 10 ppm)

• Dichloromethane (< 10 ppm)

• Diethyl Ether (< 10 ppm) library match by simulation

• Isobutylene (< 10 ppm) ID initially by structure intuition, the add to library

• Acetaldehyde (< 0.100 ppm)

• Formaldehyde (< 0.100 ppm)

• Sulfur Dioxide (< 10 ppm)

• Hydrogen cyanide (< 0.010 ppm)

Thermal evolution from dry powders – development goals:• < 1 ppm detection limits

• Oxygen starved heating

• Truly direct, investigative analysis


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Chiral AnalysisFirst instrument installation to an academic group (Valladolid, Spain) – November 2015

D. Patterson, M. Schnell, and J.M Doyle, Nature 497, 475- 478 (2013)

Capabilities:• Absolute structure determination (diastereomer

resolution) for molecules with multiple chiral centers, as well as molecular complexes

• Direct enantiomeric excess measurement with no chromatography using a patented three-wave mixing technique

BrightSpec Chiral FT-MRR Analyzer

S. Lobsinger, C. Perez, L. Evangelisti, K.K. Lehmann, and B.H. Pate, J. Phys. Chem. Lett. 6, 196-200 (105)


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Chiral Analysis

Upcoming work: Collaboration with University of Virginia (Brooks Pate) and Virginia Commonwealth University (Frank Gupton) – Sponsored by Virginia Biosciences Health Research Corporation

The goal for BrightSpec is direct, rapid (<1 minute) diastereomer and enantiomer ratio analyses coupled to a continuous flow reactor

Initial results presented at the International Symposium on Chiral Discrimination (July 2015):

• Validation of the application of rotational spectroscopy to dihydroartemisinic acid (5 chiral centers)

• Structural confirmation against ab initio theory (~1% error on rotational constants)

• For single-frequency analyses, 1000:1 signal-to-noise ratio (99.9% purity) expectedwithin a minuteDihydroartemisinic Acid

(precursor to artemisinin)


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Thank You

BrightSpec Inc. Charlottesville, VA• Instrument Sales, Trials, Demos

• Method Development

• Analytical Services

Chemists, solving chemistry problems

FT-MRR for Analytical Chemistry …

… and Scientific Discovery

770 Harris St. #104b | Charlottesville, VA 22963

molecular rotational resonance spectroscopymolecular...

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