1. Enhanced Development and Control of
Continuous Processes using
Real Time In Situ FTIR Analytics
Dominique Hebrault, Ph.D.
Gainesville, March 5th 2012

2. For further conversation…

3. Many Development & Collaboration Projects

4. Continuous Chemistry - Analysis Challenges
Today: Limited availability of convenient,
specific, in-line monitoring techniques
 Chemical information
- Continuous reaction monitoring superior to traditional sampling for offline
analysis (TLC, LCMS, UV, etc.)
→ Stability of reactive intermediates
→ Rapid optimization procedures
 Technical knowledge
- Dispersion and diffusion: Side effects of continuous flow – must be
characterized

5. In-Line IR Monitoring
 Monitor Chemistry In Situ, Under Reaction Conditions
- Non-destructive
- Hazardous, air sensitive or unstable reaction species (ozonolysis, azides etc)
- Extremes in temperature or pressure

6. In-Line IR Monitoring
 Real-Time Analysis, “Movie” of the reaction
- Track instantaneous concentration changes (trends, endpoint, conversion)
- Minimize time delay in receiving analytical results

7. In-Line IR Monitoring
 Determine Reaction Kinetics, Mechanism and Pathway
- Monitor key species as a function of reaction parameters
- Track changes in structure and functional groups

8. In-Line FTIR Micro Flow Cell in the Laboratory
ReactIRTM Flow Cell: An Analytical Accessory
for Continuous Flow Chemical Processing
Internal volume: 10 & 50 ml
Up to 50 bar (725 psi)
-40 → 120ºC
Wetted parts: HC276, Diamond, (Silicon) & Gold
Multiplexing
Spectral range 600-4000 cm-1
Carter, C. F.; Lange, H.; Ley, S. V.; Baxendale, I. R.; Goode, J. G.; Gaunt, N. L.; Wittkamp, B. Org. Res. Proc. Dev. 2010, 14, 393-404

9. FlowIR: Flow chemistry and beyond…
FlowIRTM: A New Plug-and-Play
Instrument for Flow Chemistry and
Beyond
9-bounce ATR sensor
(SiComp, DiComp) and head
Internal volume: 10 & 50 ml
Up to 50 bar (725 psi)
-40 → 120ºC
Small size, no purge, no
Spectral range 600-4000 cm-1 alignment, no liquid N2

10. Agenda
 The Development of Continuous Process for Alkene Ozonolysis Based
on Combined in Situ FTIR, Calorimetry, and Computational Chemistry
 A Visual Method to Optimize Reaction Conditions: Case study on a
Doebner Modification of Knoevenagel Reaction

11. In Situ Monitoring for Continuous Manufacturing of APIs
The Development of Continuous Process
for Alkene Ozonolysis Based on
Combined in Situ FTIR, Calorimetry, and
Computational Chemistry
 Introduction
Continuous reaction setup for ozonolysis
reactions
Instantaneous “view” of the chemistry
using in situ FTIR
Investigation resulted in 2.7kg production
of API intermediate in 2 weeks
Steady state, rate, intermediates
-50°C
Residence time (flow rate, reactor size)
Styrene
O3 efficiency, mass transfer
Ayman D. Allian, Steve M. Richter, Jeffrey M. Kallemeyn, Timothy A. Robbins, and Vimal Kishore, Abbott, Process Research and Development, 1401
Sheridan Road, North Chicago, Illinois 60064, USA, Organic Process Research and Development, 2011, 15, 91-97

12. In Situ Monitoring for Continuous Manufacturing of API
 Challenges
-50°C
Ozonolysis highly efficient and selective
oxidation method
Hazardous and unreliable in batch
manufacturing: Exotherm, stability of
intermediates, ozone toxicity  Results
Initial lab scale kinetic study in 100ml batch
(37 mmol/ sec, 2L/min)
FTIR 780 cm-1
xxx
Feed rate limited
Styrene / MeOH / DCM
Ayman D. Allian, Steve M. Richter, Jeffrey M. Kallemeyn, Timothy A. Robbins, and Vimal Kishore, Abbott, Process Research and Development, 1401
Sheridan Road, North Chicago, Illinois 60064, USA, Organic Process Research and Development, 2011, 15, 91-97

13. In Situ Monitoring for Continuous Manufacturing of API
Acetone (/heptane)
 Results
100mL batch vessel retrofitted with
overflow valve → CSTR
Residence time distribution experiment
(Residence time distribution experiment)
FTIR data confirmed by off-line HPLC
 Results
2L/min
Oxidation of an isobutylene-type API
intermediate
300g prod., 4d, 12h/d, 81% isol. yield
One week lead time
Rate is O3 feed-controlled
Ayman D. Allian, Steve M. Richter, Jeffrey M. Kallemeyn, Timothy A. Robbins, and Vimal Kishore, Abbott, Process Research and Development, 1401
Sheridan Road, North Chicago, Illinois 60064, USA, Organic Process Research and Development, 2011, 15, 91-97

14. In Situ Monitoring for Continuous Manufacturing of API
 Results
ReactIRTM probe
Jacketed bubble reactor setup
32g/h – O3 generation
Applied to styrene, isobutylene-type API
intermediate
Coarse frit
-33°C Made 2.7kg ketone, 4d, 9h/d, rate: 80g/h
2-week lead time
17L/min Conversion 99%, O3 efficiency ≈ 85%
Ayman D. Allian, Steve M. Richter, Jeffrey M. Kallemeyn, Timothy A. Robbins, and Vimal Kishore, Abbott, Process Research and Development, 1401
Sheridan Road, North Chicago, Illinois 60064, USA, Organic Process Research and Development, 2011, 15, 91-97

15. In Situ Monitoring for Continuous Manufacturing of API
Styrene / O3 equimolar:
Steady state 15-20% styrene
Ayman D. Allian, Steve M. Richter, Jeffrey M. Kallemeyn, Timothy A. Robbins, and Vimal Kishore, Abbott, Process Research and Development, 1401
Sheridan Road, North Chicago, Illinois 60064, USA, Organic Process Research and Development, 2011, 15, 91-97

16. In Situ Monitoring for Continuous Manufacturing of API
 Outcome
Preliminary kinetic investigation in batch
Small scale CSTR for 300g production
Larger scale continuous bubble reactor
setup for 2.7kg
 in situ FTIR allowed to
Monitor reaction progress, detect
process upsets in real time
Ensure highest degree of product quality
and yield
Eliminate need for sampling and offline
analyses → improved productivity and
safety
Ayman D. Allian, Steve M. Richter, Jeffrey M. Kallemeyn, Timothy A. Robbins, and Vimal Kishore, Abbott, Process Research and Development, 1401
Sheridan Road, North Chicago, Illinois 60064, USA, Organic Process Research and Development, 2011, 15, 91-97

17. Agenda
 The Development of Continuous Process for Alkene Ozonolysis Based
on Combined in Situ FTIR, Calorimetry, and Computational Chemistry
 A Visual Method to Optimize Reaction Conditions: Case study on a
Doebner Modification of Knoevenagel Reaction

18. A visual method to optimize reaction conditions
Optimization of a Doebner Modification of
Knoevenagel Reaction in a Continuous
Mode
 Introduction
Can reaction optimization and conditions
screening be conducted inline?
How does dispersion affect fraction Vapourtec R2+/R4
collection?
FlowIRTM
On-the-fly reaction optimization with
inline FTIR analytics
Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper under review

19. A visual method to optimize reaction conditions
 Results
100°C, 10’
Reference spectra of 4 main components
150°C, 10’ 120°C, 20’
3 main/unique bands
Cinnamic acid
(772cm-1)
Malonic
Acid
80°C, 10’ 120°C, 10’ 100°C, 20’ 100°C, 30’
(1729cm-1)
Benzaldehyde
7 reaction “plugs”, on-the-fly variation of
(828cm-1)
residence time and temperature (1:1.1)
Few hours experiment only
Ongoing further investigation
Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper under review

20. Acknowledgements
 Abbott, Process Research and Development (USA)
- Ayman D. Allian*, Steve M. Richter, Jeffrey M. Kallemeyn, Timothy A.
Robbins, and Vimal Kishore
 Vapourtec Ltd. (U.K.)
- Chris Butters and Duncan Guthrie
 Flow Chemistry Solutions (U.K.)
- Andrew Mansfield
 Mettler Toledo Autochem
- Will Kowalchyk (USA)
- Jon Goode (U.K.)
Email us at dominique.hebrault@mt.com
OR
autochem@mt.com
OR
Call us + 1.410.910.8500