productivity tools for nmr - bruker · productivity tools for nmr innovation with integrity . a...

Till Kühn

VP Applications Development

User’s meeting Brussels – November 2016

Productivity Tools for NMR

Innovation with Integrity

A week in the life of Brian

Brian

• … Works in a hypothetical pharma company / university

• … Runs the NMR service lab

• … Is the “resident NMR expert” in the organization

• … Has a solid NMR background from university

• … Used to work on polymers

At university …

… Academia benefits from

• Free TopSpin 3.5 processing SW!

• Download from website

At university …

… Brian worked on polymer NMR

The NEW SampleCase heated

• 24 samples

• up to 125°C

• Individually temperature controlled and adjustable

Today: The resident NMR expert…

… needs to handle a multitude of tasks and questions

• Small molecule structure elucidation

• NMR with labeled proteins

• Solid state NMR

• Fragment based drug discovery

• …

⇒ Brian can’t be the expert on everything!

⇒ He needs help to make the right choices for problem-taylored experiments

New: Experiment Selector

In TopSpin 3.5

Easy access to experiment libraries for all aspects of NMR research

• Grouping by application area

• Expandable and easy to personalize

• Scripted parameter optimization

• Single click experiment setup - also for multi-receive experiments

New in TopSpin: Experiment Selector

Easy access to experiment libraries for all aspects of NMR research

• Grouping by application area

• Expandable and easy to personalize

• Scripted parameter optimization

• Single click experiment setup - also for multi-receive experiments

• Automatic processing etc. possible

New in TopSpin: Experiment Selector

Parallel HC HMBC and FC HMBC

Work does not stop on weekends…

… automation is key for productivity and load factor on the instrument

• Nicole needs a fragment based bio-affinity screening project done: 2 x 96 protein samples in buffer

• Chu wants a quality check for integrity and concentration on a newly synthesized library: 96 samples in DMSO

• Aisha from development has 5 single samples, she needs the potency/purity

• Kim has one precious sample where she needs a full structure verification on. She already has the HRAM-MS data

New temperature control for SampleJet

• Individually temperature controlled

• 5 x 96 rack positions

• Temperature equilibration station

• 96 spinner-less open access positions

⇒ Storage of cold and warm samples at the same time

⇒ No more need for individual spinners

Nicole’s Fragment Based Screening Project






December 5, 2016 11

New: FBS data acquisition and analysis see separate talk

Brian’s rest of the weekend…






Michael’s multi sample quality control …

Brian needs to select the optimal experiments for QC of diverse samples

• Different concentrations

• Different structural complexity

• Different spectra complexity

• Some DMSO samples will need water suppression

⇒ Run all samples with a complete set of experiments to ensure optimal data (enough scans, HSQC on everything, maybe even auto water suppression…) not enough time for the other tasks

⇒ To heck with this, just run the 1D’s and let Chu figure it out on Monday (knowing that several spectra will need to be re-run )

⇒ Check back on the progress every few hours, look at the results and setup follow-up experiments where needed. IT’S THE WEEKEND!

Brian SmartDriveNMR

requests further experiment

The intelligent instrument SmartDriveNMR

• Additional data when useful

• Good quality spectra

• Higher confidence for auto generated results

OK OK

SmartDriveNMR: spectrum and structure

Expert:

Large molecule, complex structure and high overlap in 1H spectrum ⇒ not easy to assign

HSQC

SmartDriveNMR:

HSQC

Expert:

Larger Molecule, similarly complex structure

HSQC

M = 520 g mol-1

M = 422 g mol-1

SmartDriveNMR:

No HSQC

Expert:

Larger Molecule, similarly complex structure

but spectrum is quite simple ⇒ easy to assign

No HSQC

Chu’s multi sample quality control …

• Samples are acquired with optimal and optimized experiments

• Data is pre-interpreted, for Chu to review in CMC-assist

New: potency determination by CMC-assist

Aisha needs to know the absolute purity (potency) of some API’s

⇒ Setup in IconNMR

• Analyte: known compound

• Standard: certified refernce material

• Input: weight of standard & analyte

⇒ Automatic interpretation with detailed analysis result, for Aisha to review

Potency: 98%

Status: Consistent, potency = 98%

qNMR Potency = 98 %

Analyte: 23.70 mg, Reference: 21.30 mg

Analyte Integral Regions:

14_s_Q1 [2.21 ppm to 2.32 ppm]

13_m_Q2 [2.92 ppm to 3.21 ppm]

7,9,10_m_Q3 [7.22 ppm to 7.42 ppm]

Reference Integral Region:

CH [6.14 ppm to 6.41 ppm

Spectrum and structure are consistent. All signals could be assigned to features in the structure, to the

internal reference or to given impurities.

Area** IS Area** analyte

Prep. Wt a. [mg] Wt IS [mg] CH Region 1 Region 2 Region 3 Averaged Area a. SD Area a. Potency [%] RSD Potency [%]

1 10.30 5.10 1.03 1.00 0.99 0.98 0.99 0.01 99.11

2 13.10 5.60 0.88 1.00 0.98 0.97 0.98 0.01 99.19

3 12.40 17.80 2.93 1.00 0.98 0.82 0.94 0.08 95.42

Average 97.91 1.80

Kim’s full verification…

• She wants to be sure, not to file the wrong structure as a drug candidate

• Orthogonal data is needed to minimize the chance for false positives

• MS can do things NMR can not (Cl/Br, S/O …)

• Nominal mass leaves 1’000s of potential false positives

• HRAM-MS verifies the molecular formula

• NMR can do things MS can not

100’s of possible structures per molecular formula

• 1D1H

• HSQC

• HMBC

• 13C

Further reduction of potential wrong passes

shared projects

HRAM-MS and NMR data

info in a nutshell

one unified result

Details

New: Bruker Fusion-SV 1.1

accurate mass and isotopic pattern information

automated analysis and assignment of NMR data

Bruker Fusion-SV 1.1: Workbench

Automatic analysis of combined 1D1H, HSQC, HMBC and 1D13C data for

Automatic processing of NUS data (HSQC, HMBC)

Spectra interpretation easily understandable

13C assignment HMBC correlations



Brian – the “resident NMR expert”…

• … with academic background: free TopSpin processing SW

• … benefitted from SampleCase heated for polymer studies

• … can not be the expert on everything but TopSpin’s new Experiment Selector helps to make choices

• … uses the next generation SampleJet temperature control, for combined automation of bio- and chemistry samples

• … applies SmartDriveNMR which automatically provides his customers with the optimal set of optimized experiments

• … delivers pre-interpreted spectra by CMC-assist, which now also provides potency information against an internal standard

• … acquires NMR data for chemists which they can easily get auto-analyzed along with HRAM-MS by Fusion-SV 1.1.


Brian – the “resident NMR expert”…

… But, what about all the open access NMR users?

… Where are they?

… Doesn’t he have to run off to all the open access labs on the entire site?

Nope!

• … new,

• … all purpose routine,

• … cryogen free,

• … bench-top,

• … 400MHz high resolution NMR system

• that could also deliver 600 MHz CryoProbe performance

• and even delivers HPLC-MS results

And it is actually installed at Novartis, Basel!

And that is because of the …

• There must be strings attached!

• …and, that’s actually the case

• …not really a string, but rather a tube…

Lab2Lab sender

Sample router Sample buffer

HPLC MS systems NMR systems

Lab2Lab a sample tube-mail system

Too good to be true!

• Researcher submits analysis sample at the lab-bench

• Sample submitted in standard lab ware (no NMR tube handling etc.)

• Same interface for NMR or LC-MS

• Just asks the system the question, like:

“verify this structure within 15 minutes”

• After 10 – 15 minutes, the researcher gets a mail with the results

• lab2lab scheduling system will select the next available instrument

• SmartDriveNMR will select and run the optimal experiments for the given time and problem

December 5, 2016 29

Alavar Gossert, Wolfgang Jahnke, Marcel Blommers, Cesar Fernandez, Paul Erbel

Daniel Wyss and Hugh Eaton

Stefan Jehle, Pavel Kessler, Fabrice Moriaud, Anna Codina, Björn Heitmann, Jochen Klages, Christine Bolliger, Martin Wyser, Markus Lang, Oliver Horlacher, …

And many, many of you who take the time to discuss with us!

© Copyright Bruker Corporation. All rights reserved.

Innovation with Integrity

Copyright © 2011 Bruker Corporation. All rights reserved. www.bruker.com

Thank you for your attention

… and come see us for demos and discusions

Fully automatic analysis solution

for HRAM-MS and NMR structure

verification (SV)

• structure centered

• workflow oriented

• network embedded

⇨ made for chemists

NMR HRAM-MS


productivity tools for nmr - bruker · productivity tools for nmr innovation with integrity . a...

Documents