scix faccs minneapolis october 2016
TRANSCRIPT
In situ Analytics: A technological
Shift in Continuous Processing
Dom Hebrault, Ph.D.
Traditional Lab Techniques
Current limited availability of convenient, specific, online techniques.
Chemical and crystallization processes are often poorly understood , and can be
major development bottlenecks
3
Scientist must be present to sample
Reactors are
poorly controlled
Process Parameters
aren't recorded
Gaps or delays in
results
start isolate
Results: Offline Analysis
Info
rma
tio
n
Time
No data
collected Sample 2
Sample 1
Sample 3
Analytical Challenges of Continuous Chemistry
Current limited available of convenient, specific, online techniques
Chemical information
- Continuous reaction monitoring superior to traditional sampling for offline analysis for
steady state monitoring, in addition to:
→ Stability of reactive intermediates and catalysts
→ Rapid optimization procedures
Technical knowledge
- Dispersion and diffusion: Side effects of continuous flow – must be characterized
Evaluation of in-line techniques for the monitoring of flowing streams in real time
4
FTIR* Raman HPLC NMR UV MS
Destructive Lack of
specificity
Expensive Clogging Solid samples More universal
F.T. Mattrey , S. Dolman, J. Nyrop, P.J. Skrdla, Merck Research, American Pharmaceutical Review January 2012
(*) quantification can be achieved by calibration using standards
The Lab of Today
Make Informed Decisions, Faster
Reactors are
precisely controlled
and run overnight
Parameters are automatically
recorded with PAT
Unattended,
Representative Analytics
5
Results: Real-Time Data Capture
Info
rma
tio
n
Temperature
mL
Real time process knowledge reduces the cost and pain of chemical and
crystallization development
Sample
In Situ Analytics
start isolate Time
Data suited for chemometrics
modeling
Fully Controlled Continuous Stirred Tank Reactors
Example of application to MSMPR crystallization
8
Brian Glennon et al.; Solid State Pharmaceutical Cluster, The School of Chemical and Bioprocess Engineering, University College Dublin,
Dublin, Ireland, Chemical Engineering Science, 2013, 104, 44–54
ReactIR Mid-IR in-situ Analytics in Flow 9
Low-maintenance and robust
- No need for liquid nitrogen cooling
- No N2 purge, no alignment
- Small footprint
- Full spectral range 600-4000 cm-1
- Wetted parts: HC276, Diamond, (Silicon) & Gold
Small sample size
- 20 or 50 µL flow cell, up to 50b (725psi)
- Auxiliary flow cell heater and temp controlled (-40→120°C)
- Microscale reaction in flow cell (sealed reactor)
- stability studies
- rapid reaction screening, DOE
- reaction kinetics studies at variable temperature
Unpublished, presentation at the Mettler Toledo Autochem Conference, May 26th 2016, Eric Fang, Snapdragon, Cambridge, MA, USA
FlowIR with internal flow cell
ReactIR 15 with external flow cell
From MIT to Flow Chemistry Services
Development of Continuous Flow Chemistry Using Online
PAT Analyses
Most Recent Collaborations,
Research Articles
Development of Continuous Flow Chemistry Using Online
PAT Analyses
17 Research Article 1
Lorenzo Di Marco, Morgan Hans, Lionel Delaude, Jean-Christophe M. Monbaliu*, Department of Chemistry, University of Liège,
Liège (Belgium); A European Journal, 22(13), 4508–4514, 2016
Continuous-Flow N-Heterocyclic Carbene Generation and Organocatalysis
Outlet of the reactor connected to a FlowIR for in-line reaction
monitoring
Disappearance of 4 (3438cm-1), 5 (1764 cm-1, 1648cm-1)
Appearance of 6 (1743cm-1), 7 (1730cm-1)
Real-time IR monitoring with FlowIR, DTGS detector using
SiComp probe
Wavelenght range 4000-650cm-1/8cm-1 resolution, 208 scans.
+ +
18 Research Article 2
Klavs F. Jensen et al., Department of Chemical Engineering, MIT, Cambridge, MA, USA; Science, 1 APRIL 2016 • VOL 352
ISSUE 6281 PP 61-66
On-demand continuous-flow production of pharmaceuticals in a compact,
reconfigurable system
Small FlowIR size allowed integration into the
refrigerator-sized end-to-end system.
Produces sufficient quantities to supply hundreds to
thousands of oral or topical liquid doses of
diphenhydramine hydrochloride, lidocaine hydrochloride,
diazepam, and fluoxetine hydrochloride
Inline monitoring of APIs concentration
FlowIR
19
Jason S. Moore, Christopher D. Smithac, Klavs F. Jensen*, Department of Chemical Engineering, MIT, Cambridge, MA, USA;
React. Chem. Eng. 2016, 1, 272-279
Research Article 3
Kinetics analysis and automated online screening of aminocarbonylation
of aryl halides in flow
ReactIR time dependent concentration
profile with increase in temperature
T° Mono
Di
Silicon microreactor
Automation of reaction system and analysis enabled
facile and repeatable analytical results with no or
minimal operator supervision
Temperature ramp with online mid-IR offered a "one-
experiment" determination of activation energy
20
Richard J. Ingham, Claudio Battilocchio, Joel M. Hawkins, Steven V. Ley, Innovative Technology Centre,
Department of Chemistry, University of Cambridge, Pfizer,, Groton, Beilstein J. Org. Chem. 2014, 10, 641–652.
Research Article 4
Integration of enabling methods for the automated flow preparation of
piperazine-2-carboxamide
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Catherine F. Carter, Ian R. Baxendale, Matthew O’Brien,, John B. J. Pavey, Steven V. Ley, Innovative Technology Centre,
Department of Chemistry, University of Cambridge, Org. Biomol. Chem., 2009, 7, 4594–4597
Research Article 5
Synthesis of acetal protected building blocks using flow chemistry with
flow I.R. analysis: preparation of butane-2,3-diacetal tartrates
22 Research Article 6
Joel M. Hawkins, Steven V. Ley et al., Innovative Technology Centre, Department of Chemistry, University
of Cambridge, Pfizer, Groton, Org., Chem. Sci., 2014, 00, 1-3
Flow Chemistry as a Discovery Tool to Access sp2-sp3 Cross-Coupling
Reactions via Diazo Compounds
A Wealth of Web and Literature Resources
Building and supporting a worldwide
community of chemical development
experts
Acknowledgements 24
Shane Krska et al.
Jerry Salan et al.
Matt Bio, Eric Fang et al.
Joel Hawkins et al.
Steve Ley et al.
Klavs Jensen et al.
JC Monbaliu et al.
Thank you!
Questions