Enhanced Development and Control of
Continuous Processes Using Real Time in
Situ FTIR Analytics
Dom Hebrault, Ph.D.
2012 AIChE Annual Meeting
October 31st 2012
Continuous Flow Chemistry - Analysis Challenges
ATR-FTIR In Situ Spectroscopy with ReactIR™
Case studies:
- Safer Use and Monitoring of Hazardous Substances: Development of Continuous
Process for Alkene Ozonolysis
- A Visual, Efficient, Method to Optimize Reaction Conditions, and Enhance Process
and Product Quality: Case study on a Doebner Modification
Today’s Agenda
Continuous Chemistry - Analysis Challenges
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
Today: Limited availability of convenient,
specific, in-line monitoring techniques
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
- No interference from bubbles, solid, color,…
Attenuated Total Reflectance (ATR)
Spectroscopy
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
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
ReactIRTM Flow Cell: An Analytical Accessory
for Continuous Flow Chemical Processing
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
In-Line FTIR Micro Flow Cell in the Laboratory
Internal volume: 10 & 50 ml
Up to 50 bar (725 psi)
-40 → 120 ºC
Wetted parts: HC276, Diamond/Silicon & Gold
Multiplexing
Spectral range 600-4000 cm-1
FlowIR: Flow chemistry and beyond…
Internal volume: 10 & 50 ml
Up to 50 bar (725 psi)
-40 → 120 ºC
Spectral range 600-4000 cm-1
FlowIRTM: A New Plug-and-Play
Instrument for Flow Chemistry and
Beyond
9-bounce ATR sensor
(SiComp, DiComp) and head
Small size, no purge, no
alignment, no liquid N2
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
In Situ Monitoring for Continuous Manufacturing of APIs
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
Understand: Steady state, rate,
intermediates, O3 efficiency, mass
transfer
Optimize: Residence time (flow rate,
reactor size)
Styrene
-50°C
In Situ Monitoring for Continuous Manufacturing of API
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
xxx
(37 mmol/ sec, 2L/min)
Feed rate limited
FTIR 780 cm-1
Results
Initial lab scale kinetic study in 100ml batch
Challenges
Ozonolysis highly efficient and selective
oxidation method
Hazardous and unreliable in batch
manufacturing: Exotherm, stability of
intermediates, ozone toxicity
Styrene / MeOH / DCM
-50°C
In Situ Monitoring for Continuous Manufacturing of API
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
Results
100mL batch vessel retrofitted with
overflow valve → CSTR
Residence time distribution experiment
FTIR data confirmed by off-line HPLC
Results
Oxidation of an isobutylene-type API
intermediate
300g prod., 4d, 12h/d, 81% isol. yield
One week lead time
(Residence time distribution experiment)
Acetone (/heptane)
Rate is O3 feed-controlled
2L/min
In Situ Monitoring for Continuous Manufacturing of API
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
Results
Jacketed bubble reactor setup
32g/h – O3 generation
Applied to styrene, isobutylene-type API
intermediate
Made 2.7kg ketone, 4d, 9h/d, rate: 80g/h
2-week lead time
Conversion 99%, O3 efficiency ≈ 85%
ReactIRTM probe
Coarse frit
17L/min
-33°C
In Situ Monitoring for Continuous Manufacturing of API
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
Styrene / O3 equimolar:
Steady state 15-20% styrene
In Situ Monitoring for Continuous Manufacturing of API
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
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
Outcome
Preliminary kinetic investigation in batch
Small scale CSTR for 300g production
Larger scale continuous bubble reactor
setup for 2.7kg
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
collection?
Rapid Analysis of Continuous Reaction Optimization
Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
On-the-fly reaction optimization with
inline FTIR analytics
Vapourtec R2+/R4
FlowIRTM
+ CO2
Results
Reference spectra of 4 main components
3 main/unique bands
7 reaction “plugs”, on-the-fly variation of
residence time and temperature (1:1.1
benzaldehyde/malonic acid ratio)
Few hours experiment only
Rapid Analysis of Continuous Reaction Optimization
Malonic
Acid
(1729cm-1)
Benzaldehyde
(828cm-1)
Cinnamic acid
(772cm-1)
Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
80°C, 10’
100°C, 10’
120°C, 20’
120°C, 10’ 100°C, 20’ 100°C, 30’
150°C, 10’
4.5 h
Results
Development of an in-situ real time assay
method
- ReactIR algorithm: iC Quant and iC IR
- Simple univariate model (trans-
cinnamic acid 772 cm-1 with 2 baseline
points)
“Proof of concept” univariate model
Limited number of datapoints
Model used to predict concentration
Rapid Analysis of Continuous Reaction Optimization
Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
Trans-cinnamic acid
(772 cm-1)
(0.1-0.5M)
Results
Development of an in-situ real time assay
method:
- Application to the previous screening
- 100°C, 20’ to 30’ represent an optimum
at (1:1.1 benzaldehyde / malonic acid
ratio)
Rapid Analysis of Continuous Reaction Optimization
Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
[M]
0.35
0.30
0.25
0.20
0.15
0.10
80°C, 10’
100°C, 10’
120°C, 20’
120°C, 10’ 100°C, 20’ 100°C, 30’
150°C, 10’
Variation of benzaldehyde / malonic acid:
- From 1:1.1 to 1:2 (100°C, 20’)
- No significant improvement
- Real time FTIR provides confirmation of
steady state and concentrations in the
plug
1:2
1: 1.1 1:1.5
1:1.2
1:2
Steady state
3.5 h
Conclusions
No issue with CO2 bubble
Faster, more efficient, optimization
Provides a picture of flow dispersion,
helps enhanced separation and off-line
analysis
Rapid Analysis of Continuous Reaction Optimization
Vapourtec – Flow Chemistry Solutions – Mettler Toledo collaboration project, U.K. 2011, White Paper
Compared to former in-house solutions
Can be heated, cooled, pressurized
Wide spectral range and high sensitivity
Turn-key, affordable, space efficient
Acknowledgements
Abbott, Process Research and Development, USA
- Ayman D. Allian et al
Vapourtec Ltd. (U.K.)
- Chris Butters, Duncan Guthrie
Flow Chemistry Solutions (U.K.)
- Andrew Mansfield
Mettler Toledo Autochem
- Will Kowalchyk (USA), Jon Goode (U.K.)