The Value and Practice of NMR in Process Development
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]
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