The Value and Practice of NMR in Process Development
Mike Bernstein, VP R&D, Mestrelab Research
32nd SCI Process Development Symposium - 25 - 27 March 2015
What is the case for using NMR?
Familiarity to synthetic organic chemists
Structural information is very high
Common, useful nuclei to observe: 1H, 19F, 31P, 13C
… useful in different ways
Quantitation
Impurity structure elucidation without the need for isolation
Kinetics profiles without manual sampling
Mechanistic elucidation & Reaction Modelling
(HPLC Relative Response Factor determinations)
(Very briefly) NMR has application in…
Liquid-state NMR (high resolution)
•
•
•
API characterisation
Salt ratios
Purity determination / qNMR / impurity quantitation, e.g., PGIs
Solid-state NMR
•
•
API physical form
Drug formulation
MRI
•
•
Flow, crystallisation, emulsions
Tablet dissolution
NMR as a quantitative tool for pure compounds and mixtures
𝐶𝑖 = 𝑓 × 𝐼𝑛𝑡𝑒𝑔𝑟𝑎𝑙𝑁𝑖
All species in the sample have the same response factor
Purity determination by NMR
Me2SO2
PAT & QbD
"A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance"
Design, analysis, and control in manufacturing
Tools: Spectroscopy & Chemometrics
•
•
•
•
•
Risk Analysis (FMEA – Failure Mode Effect Analysis)
Process Analysers (sensors, spectrometers)
Process Control Tools (SPC, MSPC)
Design of Experiments (DoE)
Multivariate Data Analysis (MLR, PCA, PLS)
Conventional Spectroscopic Tools
Optical Molecular Spectroscopy
• Fluorescence
• NIR/MIR
• Raman
• UV / Vis -sNIR
Kessler & Kessler, Reutlingen University
NMR in this context
CHARACTERISE
Starting materials – structure and purity
Reaction products (isolated / worked up)
Reaction intermediates (often isolated, if important)
Reaction impurities (isolated)
AND
Kinetics
Subtle mechanistic insights, such as proton speciation
Isomers, etc.
Chromatographic Response factors
Time-sliced NMR data acquisition
Product
146.0
145.0
144.0
143.0
142.0
time
146.0
ppm (f2)
145.0
144.0
143.0
145.0
144.0
143.0
142.0
SM
146.0
142.0
141.0
Rich in information
Time-sliced NMR data acquisition
Every proton of every species shows in the NMR spectrum – at every time point
In situ characterisation performed at points in the time course of reaction
Reaction kinetics: NMR hardware
Conventional spectrometers
•
•
•
•
Best resolution, signal-to-noise
Versatile
More difficult to site
£x00,000
Benchtop NMR Spectrometers
• Can be used anywhere
• In- and at-line implementation
• <£100,000
Tube NMR experiment




Quick and easy to perform
No special equipment needed beyond what you already have
Small material consumption
Deuterated solvent




Homogeneous solution
May not reflect real kinetics
Residual O2 and H2O are more difficult to control
Limitations in reaction conditions
Flow reactor built at AstraZeneca Charnwood
Flow NMR
Applicable to almost all reactions




Biphasic
Heterogeneous
High pressure (> 1000 psig)
Heated or cooled
 Accurate reflection of kinetics
 Couple with other analytical methods (vibrational spectroscopy, etc.)
Larger scale (20-250 mL, typically)
 Material consumption
 Non-deuterated solvent
Information extraction from time-sliced NMR data
Chemistry that lends itself well to NMR monitoring
Chlorination reactions
Grignard
Schiffs Base formation
Poor chromophore / poorly column retained
Conformer and tautomer important to the reaction
Very quick to design and set up a set of experiments
FED of a sulphamide formation reaction
Temperature
Concentrations
A solvent-dependent reductive amination yield explained
conc / mol/L
Aminal
Imine
0.09
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0
0
time
50
100
150
200
time / min.
0
Toluene ~ 353 K
ln((A-Aeq)/(A0-Aeq))
-0.5 0
25
50
75
Keq = 9.4
-1
-1.5
-2
-2.5
-3
-3.5
time / min.
When using MeTHF solvent the equilibrium favours the aminal form
Typical kinetic profiles
Good software facilitates this analysis!
J. Buser (Eli Lilly)
Catalytic hydrogenation
J. Buser (Eli Lilly)
Grignard reaction
J. Buser (Eli Lilly)
Benchtop NMR systems
High resolution
Imaging
TD-NMR
… and other vendors
Acetic acid + 3-Methylbutanol  3-Methylbutyl acetate
Flow experiments at 80 MHz
Thermo Fisher
Real-time Reaction Monitoring by NMR
NMR as part of the PAT Toolbox: A Translational Tool
Conclusions - kinetics
NMR can be a practical part of the PAT/QbD Toolbox
Unique in the detailed structural information, and easy quantitation
Amenable to complex studies, and simple ones
Versatile in terms of hardware
Data can be combined with Chemometric analysis
Complements other measurements
It may not be the first choice method, but not using NMR at all is disadvantageous!
Future expectations
Wider incorporation of NMR into Development Analytical functions
Better process understanding and control
Analytical instrumentation located where it's needed
Added value: understanding/control/optimisation/production
Acknowledgements
Jonas Buser (Lilly, IN)
David Foley (Pfizer, Groton)
Steve Coombes, Andy Phillips (AstraZeneca, Macclesfield)
Chris Sleigh (formerly AstraZeneca, Charnwood)
Colleagues at Mestrelab
… and thank you for your attention
[email protected]