High Resolution FT-MRR Spectroscopy: Trace Residual Impurities Analysis Without Chromatography

Transcription

1 Rotational Resonance troscopy Molecular Rotational Resonance troscopy High Resolution FT-MRR troscopy: Trace Residual Impurities Analysis Without Chromatography Brent Harris, PhD. Director of Applications Development Linda Kidder, PhD. Director of Marketing Bright, Inc. 770 Harris St. #104B Charlottesville, VA (434) /10/ Bright, Inc. 1 of 18 slides

2 Analytical Chemistry Tools Pervasive challenge - dealing with gaps between instrumentation capabilities troscopy + 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 We want the best of both 5/10/ Bright, Inc. 1

3 Chirped Pulse Innovation Reinvention of Rotational troscopy* FT-MRR A Technique that Bridges the Gap? * A Broadband Fourier Transform Microwave trometer Based on Chirped Pulse Excitation, G.G.Brown et al., Rev. Sci. Instrum. 79, (2008). * Segmented chirped-pulse Fourier transform submillimeter spectroscopy for broadband gas analysis, J.L. Neill, B.J. Harris et al., Opt. Express, 21(3), (2013). 5/10/ Bright, Inc. 2

4 Molecular Rotational Resonance (MRR) Molecular Rotation Nuclear Magnetic Resonance Electron Spin Resonance Vibration Electronic Dissociation Nuclear Chemistry Radio Microwave Millimeter-wave/THz Infrared Vis UV X-ray, Gamma Bright FT-MRR ENERGY I=MR 2 Quantized angular momentum states related to rotational inertia (specific to mass distribution, fits a Hamiltonian to 0.1ppm freq. accuracy) Absolute specificity: direct structure calculation vs. structure elucidation Excellent selectivity: baseline resolved, highly specific spectral fingerprint... So, where has this been all of our lives? 5/10/ Bright, Inc. 3

5 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 troscopy, 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!!! 5/10/ Bright, Inc. 4

6 Re-invention of FT-MRR 100X sensitivity improvement Essential advances: 1 Chirped-pulse innovation (physical chemistry) 2 High power, solid state, light sources (telecommunication industry) 3 High speed digital electronics (digital warfare) FT P ~ (Nm) 2 5 Now, FT-MRR is ready for analytical chemistry 5/10/ Bright, Inc.

7 Enhanced Capabilities with FT-MRR 5/10/ Bright, Inc. 6

8 FT-MRR Applications CPAC 2015 Chiral Analysis CPAC 2016 Trace Residual Impurities 5/10/ Bright, Inc. 7

9 Intensity (mv) FT-MRR Broadband Survey Mode 10 minute, static headspace FT-MRR spectrum Chemically specific spectral fingerprint High dynamic range Frequency (MHZ) Solvents dissolved in N,N Dimethylacetamide at ~0.1 mg/ml. Chemical ID by spectral reference library match Baseline resolved, no chemometrics /10/ Bright, Inc. 8

10 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) tral 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 5/10/ Bright, Inc. 9

11 FT-MRR trometers 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 5/10/ Bright, Inc. 10

12 Headspace Analysis at-line? Solutions Static Headspace Solids Thermal Evolution Heater (50 C) Dissolved API (50 mg/ml, 1 ml) Heater (50 C) API/Tablet solid (10 50 mg) Heater ( C) Residual solvent 5 minute cycle time ppm detection limit Genotoxic impurity 10 minute cycle time ppb detection limit 5/10/ Bright, Inc. 11

13 Solution Headspace FT-MRR Volatile, strong FT-MRR emitter: Detection limit 8 ppm Linearity R 2 = RSD avg < 10 % Volatile, weaker FT-MRR emitter: Detection limit 200 ppm Linearity R 2 = RSD avg 6.3% (2 % real sample) 5/10/ Bright, Inc. 12

14 Evolved gas analysis by FT- MRR Thermal evolution from dry powders development goals: < 1 ppm detection limits Oxygen starved heating Truly direct, investigative analysis 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 (< ppm) Formaldehyde (< ppm) Sulfur Dioxide (< 10 ppm) Hydrogen cyanide (< ppm) 5/10/ Bright, Inc. 13

15 Advanced analysis modes with FT-MRR 5/10/ Bright, Inc. 14

16 Selective excitation mode Zero false-positives Absolute specificity of broadband FT-MRR without broadband data Presented Spring (2015) 5/10/ Bright, Inc. 15

17 Chiral Analysis First instrument installation to an academic group (Valladolid, Spain) November 2015 Bright Chiral FT-MRR Analyzer 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 S. Lobsinger, C. Perez, L. Evangelisti, K.K. Lehmann, and B.H. Pate, J. Phys. Chem. Lett. 6, (105) D. Patterson, M. Schnell, and J.M Doyle, Nature 497, (2013) 5/10/ Bright, Inc. 16

18 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 Bright 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): Dihydroartemisinic Acid (precursor to artemisinin) 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-tonoise ratio (99.9% purity) expected within a minute 5/10/ Bright, Inc. 17

19 Thank You FT-MRR for Analytical Chemistry and Scientific Discovery Chemists, solving chemistry problems Bright Inc. Charlottesville, VA Instrument Sales, Trials, Demos Method Development Analytical Services 770 Harris St. #104b Charlottesville, VA /10/ Bright, Inc. 18