Monitoring by NMR in the Pharmaceutical Industry. Michael Bernstein

Transcription

1 The Role of Reaction Monitoring by NMR in the Pharmaceutical Industry Michael Bernstein At AstraZeneca R&DCharnwood

2 Talk outline The need The utility of NMR Performing NMR experiments options and examples Cheminformatics and statistical approaches

3 Chemical process understanding PAT: a process centric focus on quality QbD: designing a process centric approach having quality built in Quality

4 Fundamental to success Greater understanding di of reactions Kinetics & mechanism Etblih Establish reaction end points it Facilitate telescoped reactions Guide the design of synthetic route development Improved yields Improved yields Cost savings Reduce by-product formation or reaction quenching Reduce by product formation or reaction quenching Environmental impact

5 Why NMR? All species will be seen Easier quantification NMR is a molar detector Powerful tools available to determine structure Subtle effects are reported Conventional methods Sampling for HPLC Vibrational spectroscopy (IR, NIR)

6 Time sliced NMR measurements Finish time ppm (f2) Start

7 Simple data extraction ppm ppm Product Buildup Curve from NMR Data Concn MestReNova software Time

8 More complex data extraction

9 Optimising a telescoped reaction A quick look-see : Identification of intermediates O N H S N N - Imid O N S +NH 3 O N H S NH 2 relative in ntegrals Conditions 1 Conditions time / min

10 Speciation in condensation reaction R O + fast H 2N OH R N OH See by NMR Marked solvent dependence H N R O time Imine conc / m ol/l time / min.

11 Hit Lead Lead Pre-CD Pre-Clinical Principle Testing Concept Identification Identification Optimisation Development Testing MS1 MS2 MS3 MS4 TG2.5 TG3 FGLPD FTIM FDIP C1 / C2 C3 / C4 C5 * high information content HPLC and LC-MS NMR* vibrational spectroscopy Understand chemistry at early developmental stage Correlate e.g. NMR data to techniques that can be used easily at scale

12 Bromination (over)reaction O O O O NH O OH OH HBr / AcOH NH O O Br Over-Reaction NH O OH Br OH OH OH AZD4818 diol AZD4818 bromide AZD4818 bromohydrin + Impurities Route design for 40g 40Kg scale Can we prove the over-reaction was occurring? HPLC area perc cent Formation of AZD4818 bromide (03-kvbm921-50) time (hours) bromohydrin bromide Impurities Need for real time reaction monitoring in pilot plant

13 Bromination: overlapping technology HPLC % are eahplc BromideNear InfraRed Bromohydrin Hours Scores on PC 2 (0.09% %) NMR Sample NMR provided initial in-depth structural work to complement HPLC In ntegral (raw) time (min) Profiles matched to NIR profiles for monitoring at scale.

14 Bromination : NIR monitoring at scale 12 x Proposed time-elapsed sampling point based upon laboratory experience 5 Samples taken in PP3 at Laboratory reaction 30 to 40 minutes passed Batch 1 (MPP012005) IPC criteria. Batch 2 (MPP012006) Time (mins)

15 NMR Analysers in Production

16 Kinetics in an NMR tube Pros quick and easy to set up can use any available probe / observation nucleus temperature control and good range small amounts of material required (ca. 0.5 ml) Cons no inerting evaporation no stirring inhomogeneous reactions not tolerated

17 NMR on-flow: Sample limited A flexible NMR flow cell leak detector pump reactor tube flow cell M Khajeh, MA Bernstein, and GA Morris, Magn Reson Chem, 48 (2010) 516.

18 Disassembled leak detector Teflon pieces 5mm NMR tube In situ

19 Reaction followed using flow tube Data collected on-flow

20 NMR on-flow using new flow cell Sample limited Pros controlled reaction conditions agitation, temperature control, inerting relatively easy to set up inhomogeneous reactions carry out chemical reaction whilst monitoring by NMR can use any NMR probe/nucleus eus availablea ab Cons reaction done at laboratory scale reaction done at laboratory scale blockages are not tolerated temperature control is imperfect

21 NMR monitoring with experiment control overhead stirrer NIR probe to and from heater / chiller pump NMR flow probe tap Maiwald et al., J Magn Reson 2004, 166, 135 MA Bernstein, M Štefinović, C Sleigh, Magn Reson Chem 2007, 45, 564

22 Implementation at AZ Charnwood pump sampling port reactor

23 N-alkylation over K 2 CO 3 (s) CH 3 Br CH 3 K 2 CO 3 (s) NH O CH NH O CH3 3 O O + HBr

24 NMR on-flow Not sample limited Pros closely-controlled reaction conditions agitation, temp. control, inerting inhomogeneous reactions simultaneous monitoring carry out chemical reaction Cons relatively difficult to set up reaction done at relatively large scale reaction done at relatively large scale blockages are not tolerated restricted to one probe ( 1 H, 13 C observe)

25 Using chemometrics A solution to the problem of signal overlap General applicability Better data integration across methods

26 Measuring diffusion using NMR (DOSY) Spectroscopic separation of a mixture based on diffusion rates D G

27 PARAFAC analysis compound spectrum diffusion & concentration time evolution PARAFAC G Tomasi & R Bro, Comput. Stat. Data Anal. 2006, 50,

28 Practically... Perform a quick DOSY experiment at regular time points through the course of a chemical reaction M Nilsson, M Khajeh, A Botana, MA Bernstein, & GA Morris, Chem. Commun., 2009,

29 Maltotriose hydrolysis maltotriose glucose + maltose 2 glucose maltotriose maltose glucose PARAFAC Reference glucose maltotriose maltose

30 Species at low concentration sucrose glucose + fructose 1.1 mm glucose and fructose sucrose glucose and fructose sucrose M Khajeh, A Botana, MA Bernstein, M Nilsson,* & GA Morris Anal. Chem. 2010, 82, 2102

31 Future prospects Wider use Complete kinetic studies Quick, chemistry assistance Impact on PAT and QbD Chemometrics Integration with other measurements

32 Acknowledgements and thanks Chris Sleigh (Chemistry) Marijan Štefinović Steve Eyley Dave Ennis Dave Lathbury Gareth Morris Mathias Nilsson Maryam Khajeh Adolfo Botana