1 The world leader in serving science Dr. J. Mark Dixon NMR Product Marketing Manager Thermo Fisher Scientific Advantages of the picoSpin 80 NMR Spectrometer in Pharmaceutical Research & Development
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The world leader in serving science
Dr. J. Mark Dixon
NMR Product Marketing Manager
Thermo Fisher Scientific
Advantages of the picoSpin 80 NMR Spectrometer in Pharmaceutical Research & Development
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Agenda
• Introducing the Thermo Scientific™ picoSpin™
80 NMR Spectrometer
• NMR analysis in a research laboratory
• Practical challenges facing the chemist in order to obtain
chemical information using NMR
• Solutions to those challenges using the picoSpin 80 NMR
Spectrometer
• Structure Verification/Confirmation
• Quantification/Mixture Analysis
• Reaction Monitoring
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Our Family Has Grown
• picoSpin 80 NMR • 82 MHz Larmor Frequency
• Replaceable Capillary Cartridge
• Small Sample Volume
• Compact & Portable
• Remote Operation
• Web Browser Interface
• picoSpin 45 NMR • 45 MHz Larmor Frequency
• Replaceable Capillary Cartridge
• Small Sample Volume
• Compact & Portable
• Remote Operation
• Web Browser Interface
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Minimal Maintenance
Ease of Use
Larger Field Strength
Greater Shift Dispersion
Higher Sensitivity
Easier Access to
Richer Information
The picoSpin 80 Value Proposition
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Larmor Frequency: 82 MHz
1H or 19F NMR of Liquids
Compact & Portable: 19 kg (43 lbs)
Total Weight
Chemical Shift Resolution: 18 ppb
Replaceable Capillary Cartridge
40 µL Sample Volume
Controlled by web browser
No Cryogens, Compressed Gas, etc.
Standard Lab Environment
All Solid-State Technology, No Moving Parts
picoSpin 80 Spectrometer Features
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Why Now?
• Nd2Fe14B magnets
• Microcoil NMR experiments by A.G. Webb et al., U. of Ill.
• Advances in Rf (Tx and Rx) Electronics… (Mobile Phones)
Magnetic Materials Micro Coil Technology Radiofrequency Electronics
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1H NMR Analysis In A Research Lab
• Go-to technique for structure confirmation • Often used daily for rapid decision making
• Used extensively for structure elucidation • Powerful tool when used in tandem with other techniques, e.g. LC/MS
• Ideal method to study mixtures & kinetics of reactions • Reaction monitoring in real time can unveil mechanistic behavior
• Excels in determination of stereo- & regio-chemistry • Look “inside” the molecule at topological information
• Good predictive tools available • Educationally useful, or as a helping hand
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Typical 1H Spectrum @ 82MHz
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Practical Challenges Using High-Field NMR
• High-field instrument - good ; Remote location - bad • Could be in another building, or even on another site
• Central facilities are expensive, and popular • That combination usually leads to an over-subscribed service
• Calendar-based operation is inefficient when busy
• Long wait times impact productivity • Robotic systems help but queues grow quickly at peak times
• Even one hour can mean a half-day lost due to lab safety restrictions
• Real-time experiments need exclusive access • Magnet time is precious, yet shared instrument sits idle waiting for the
next sample
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Solutions Using The picoSpin 80
• 82 MHz offers rich chemical information content • Disproportionately so compared to drop in field strength from 300+MHz
• And also when compared to lower magnetic field strengths
• Proximity of instrument = precious time re-gained • No trekking between buildings in the rain, use time productively
• One instrument per 10 chemists is better than one per 100+ • Shorter wait times, even when longer acquisition time taken into account
• Lightweight : can be hand-carried around the lab or between labs
• Reaction monitoring made simple • Syringe aliquot from reactor, inject into pS80, press ‘Run’ – No delay
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Ibuprofen 1H Spectrum @ 82MHz and @ 42MHz
82MHz
42MHz
Note the
complete
resolution of
H-14
1,2,3,5 7
14
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13,15
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TMS
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Structure Verification/Confirmation
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Did I Make What I Think I Made?
• Most chemical reactions affect few functional groups • Can manifest as obvious changes to 1H spectrum
• Looking for identifying marker(s) as proof of synthesis
• Simple example : hydrolysis of isobutene • Markovnikov’s Rule applies
OR H2O
[H2SO4]
0ºC
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1H Spectrum of Starting Material : Isobutene
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1H Spectrum of Favored Product : t-Butanol
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1H Spectrum of Disfavored Product : 2-Methylpropanol
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Easily Distinguish Products From Starting Material
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Quantification/Mixture Analysis
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• NMR signal area is proportional to concentration
• Relative Quantification • Relative proportion of compounds in mixture
• Normalize signal areas – determine mass ratios (%w/w)
• Easy and free with NMR
• Absolute Quantification • Accurate determination of the purity levels of active pharmaceutical
ingredients (APIs), and drug analysis
• Pharmaceutical compound libraries
• Forensic analysis
• Food sciences
Quantitative NMR (aka qNMR)
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Quantification: Simple Example
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Quantification: Simple Example
3 H’s
1 area “unit”
2 H’s
3 area “units”
200mM
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Quantification: Easily Calculate Relative & Absolute
Lidocaine :
0.33 units per ‘H’
CH2Cl2 :
1.53 units per ‘H’
Relatively :
4.6 to 1 mixture
or
82.2% CH2Cl2
17.8% Lidocaine
Lidocaine : 200mM
Absolutely :
4.6 to 1 mixture
920mM CH2Cl2
200mM
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Reaction Monitoring
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Example Experimental Procedure
Acetic acid 3-Methylbutanol HCl
250 µL 200 µL 1 drop
5.3 mmol 2.3 mmol Conc.
• Weigh and mix starting materials
• Add acid, start timer
• Inject 40 µL aliquot into picoSpin 80 capillary cartridge
• Start NMR data acquisition
• Set delay and scans for multi-hour acquisition
• Save individual spectra
• Process data off-line
-H2O
H+
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Predicted Spectrum Of All Components Combined
Starting Materials Product
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Track Highlighted Signals To Monitor The Chemistry
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Stacked Spectral Display Of All Data
time axis
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Stacked Spectral Display Of All Data
time axis
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A Snapshot Every So Often Tells The Story
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In Summary
Today, we have
• Explored the advantages of the picoSpin 80
NMR spectrometer in a Research Laboratory
• Explored the richness of 80 MHz NMR using
• Structure Verification
• Quantitative NMR
• Reaction Monitoring