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© Pfizer Limited 2008 1 Cap and CASE: a step forward towards automatic structure elucidation Anna Codina, Ruth Boetzel, Ingrid Hamernig and Don Richards.

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Presentation on theme: "© Pfizer Limited 2008 1 Cap and CASE: a step forward towards automatic structure elucidation Anna Codina, Ruth Boetzel, Ingrid Hamernig and Don Richards."— Presentation transcript:

1 © Pfizer Limited Cap and CASE: a step forward towards automatic structure elucidation Anna Codina, Ruth Boetzel, Ingrid Hamernig and Don Richards Structure Elucidation, ARD, PGRD

2 © Pfizer Limited

3 3  Good ResultsMicro + Training

4 © Pfizer Limited Introduction 2.Applications/Examples: Identification of Impurities Challenging molecules: Arylpyrazoles Regulatory documents generation/checking 3.Conclusions

5 © Pfizer Limited Structure Elucidation LC - NMR ( 1 H) Structure ~> 0.5% Isolation 2D NMR + MS Report / Database LC-MS Low level impurities identification Proof of Structure / Structure confirmation for regulatory documentation

6 © Pfizer Limited NMR: How can we work faster? acquisition processing analysis results/report/LNB database

7 © Pfizer Limited Acquisition - Sensitivity of NMR spectroscopy MSlow nanogram UVlow nanogram NMR microgram

8 © Pfizer Limited NMR signal to noise

9 © Pfizer Limited Improving sensitivity High magnetic fields Performance enhancement of RF probe and electronics < V detection coil (microcoils) Cold probes and preamplifiers Coil built from low- loss materials (superconductors) Energy levels & population distribution Hyperpolarisation (DNP)

10 © Pfizer Limited Microcoils 5 mm Probe CapNMR TM Microcoil

11 © Pfizer Limited Microcoils and microflow NMR Flow cell

12 © Pfizer Limited Automation - OMNMR

13 © Pfizer Limited Analysis: Computer Assisted Structure Elucidator NMR: pp 2D MS: MF Generate MCD Generate Structures From MCD/s Check MCD Find the Best Structure ! Check data/ add information

14 © Pfizer Limited Introduction 2.Applications/Examples: Identification of Impurities Challenging molecules: Arylpyrazoles Regulatory documents generation/checking 3.Conclusions

15 © Pfizer Limited Structure elucidation of low level impurities ? LC - NMR ( 1 H) Structure ~> 0.5% Isolation 2D NMR + MS Report / Data base LC-MS

16 © Pfizer Limited CapNMR data for 1 of the impurities 9 mg/60ul injection ug in the active volume 13 C 27 h HMBC 4 h

17 © Pfizer Limited full data sets to analyse!

18 © Pfizer Limited Computer Assisted Structure Elucidation (CASE) Molecular Connectivities Diagram (MCD) GENERATION of STRUCTURES from MCD

19 © Pfizer Limited /97953 – 6h 52 m THE BEST STRUCTURE d_{N}(^{13}C) d_{N}(^{1}H) d_{A}(^{13}C+^{1}H) 1.570

20 © Pfizer Limited R R R

21 © Pfizer Limited

22 © Pfizer Limited Introduction 2.Applications/Examples: Identification of Impurities Challenging molecules: Arylpyrazoles Regulatory documents generation/checking 3.Conclusions

23 © Pfizer Limited Arylpyrazoles

24 © Pfizer Limited CASE of Example mg C 15 H 8 O 1 N 4 F 8 Cl 2 1 H, 13 C, 1 H- 13 C HSQC, 1 H- 13 C/N- HMBC

25 © Pfizer Limited

26 © Pfizer Limited No Filter: 3325/3409 – 2 minFilter: C CS and internal bad list 3/3409 – 2 min

27 © Pfizer Limited CASE of Example 2 – 0.5 mg C 15 H 7 O 2 N 3 F 8 Cl 2 1 H, 13 C, 1 H- 13 C HSQC, 1 H- 13 C/ 15 N- HMBC, 1 H 19 F-HSQC

28 © Pfizer Limited From MCD 26: 1476 – 11 s ACD + Arylpyrazole fragments

29 © Pfizer Limited CASE of Arylpyrazoles – challenging molecules Less information More Human intervention

30 © Pfizer Limited Introduction 2.Applications/Examples: Identification of Impurities Challenging molecules: Arylpyrazoles Regulatory documents generation/checking 3.Conclusions

31 © Pfizer Limited Cap and CASE in regulatory Regulatory documentation is required for drugs to go through clinical trials Structure confirmation or full prove of structure Not sample limited Cap is ideal: ‘all in one’ ( 13 C) and automation CASE: –Used as a checking tool for H and C assignments: data are peak picked and contain 13 C direct –Can be used as a automatic structure verification and assignment tool and maybe for proof of structure documents

32 © Pfizer Limited CASE and regulatory data

33 © Pfizer Limited Conclusions CASE can be used to elucidate the structure of unknowns, such as impurities. Training systems are a powerful tool, especially for molecules with low number of connectivities. Good data required and limited overlapping. Not a easy tool to use. Generation of structures from an unbiased position, avoiding wrong assumptions. The combination of capillary microcoil NMR and CASE significantly decreases the level of human intervention in SE.

34 © Pfizer Limited THE FUTURE?

35 © Pfizer Limited

36 © Pfizer Limited Acknowledgements SE team: Ingrid Hamernig Protasis: Dean Olson, Bob Albrecht, Tim Peck and David Strand ACD labs: Ryan Sasaki

37 © Pfizer Limited


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