Passkey Providers and Enabling Portability: FIDO Paris Seminar.pptx
Role of PAT in Green Chemistry and Engineering
1. The Role of Process Analytical
Technology (PAT) in Green Chemistry
and Green Engineering
Dom Hebrault, Ph.D.
Principal Technology and
Application Consultant
May 16th 2012
3. My Past and Current Involvement in Green Chemistry
Conference presentation “Going Green Using Real-Time Analytics and Controlled Reactor
Systems” presented at the 5th eChemExpo, May (2008), Kingsport, TN
Webinar “Going Green: The Role of Process Analytical Technology (PAT) in Green
Chemistry” Dom Hebrault (2008)
Webinar “Going Green: The Role of Process Analytical Technology (PAT) in Green Chemistry
and Green Engineering” Dom Hebrault (2009)
Conference presentation “PAT and Green Chemistry” presented at the 23rd International
Forum on Process Analytical Technology (IFPAC®), January (2009), Baltimore, MD
Webinar “Building Green Pharmaceutical Manufacturing on a Foundation of PAT and QbD”
Paul Thomas, Dom Hebrault and Kurt Hiltbrunner (2010)
Publication “Going Green Using Real-Time Analytics” Dom Hebrault, Jon Goode,
CHEManager Europe, (2011), 1-2, 15
Book Chapter “Scalable Green Chemistry” Dom Hebrault, Terry Redman, (2012)
4. Presentation Outline
Introduction
Case Studies
- Make Processes Safer with Calorimetry
- Minimize Chemical Hazard with Continuous Processing and ATR-FTIR
- More Nature-like Bio-processes with ATR-FTIR and Calorimetry
5. Presentation Outline
Introduction
Case Studies
- Make Processes Safer with Calorimetry
- Minimize Chemical Hazard with Continuous Processing and ATR-FTIR
- More Nature-like Bio-processes with ATR-FTIR and Calorimetry
7. Enzymatic Catalysis/ATR-FTIR: Enhanced selectivity
Outcome
- Rapid monitoring and quantification of
enzyme catalyzed BV bio-
transformations of CDD to LL, in situ
- Better understanding of reaction kinetics
- Simple calibration mode applied without
interference from the complex cell
culture medium
- Further development: Expansion to a
wider range of cycloketones (Lineweaver-Burk plot for reaction kinetics; V=reaction rate,
Cr=initial concentration)
Source: Peter C.K. Lau et al, Biotechnology Research Institute, National Research Council, Canada; Industrial Biotechnology 2006, 138–142;
Applied and Environmental Microbiology, 2006, 2707–2720
8. Synthesis Workstations/Reaction Calorimeters - Lab to Pilot Plant
Small scale Medium scale Large scale
(15 -150ml) (40 -1000ml) ( 8 ml - 22L)
EasyMax® OptiMax™ RC1e™
no cryostat no cryostat Process scale-up/down
Ease of use Process information Process safety
Productivity Quick synthesis work Pilot batches (6 - 12 - 22L)
Process information
9. Reaction Calorimetry as a PAT for Process Safety
Execution of a Performic Acid Oxidation on Multikilogram Scale
Introduction
En route toward API CP-865,569 8, a CCR1 antagonist
Selection of a greener oxidation pathway (no salt)
Performic acid
David H. Brown Ripin, Gerald A. Weisenburger, David J. am Ende, David R. Bill, Pamela J. Clifford, Clifford N. Meltz, and James E. Phillips;
Pfizer Global Research; Organic Process Research & Development 2007, 11, 762-765
10. Reaction Calorimetry as a PAT for Process Safety
Challenges
Key process safety questions
Reaction enthalpy?
Instantaneous heat output?
Thermal accumulation?
Reaction heat: - 975 kJ/mol ( )
ARC
DSC DTadbatch 172 ºC
Maximum heat output 44 W/Kg
Thermal accumulation: 9% ( / )
RC1e
David H. Brown Ripin, Gerald A. Weisenburger, David J. am Ende, David R. Bill, Pamela J. Clifford, Clifford N. Meltz, and James E. Phillips;
Pfizer Global Research; Organic Process Research & Development 2007, 11, 762-765
11. Reaction Calorimetry as a PAT for Process Safety
Conclusions
Highly exothermic oxidation
Fast reaction, no delayed onset
Fed-controlled process will be safe
Dosing time adjusted to cooling capacity
in plant
Five 30-35 kg batches CP-865,569
prepared in 300-gal pilot plant vessel
Real time monitoring using MonARC and
sampling for offline HPLC assay
David H. Brown Ripin, Gerald A. Weisenburger, David J. am Ende, David R. Bill, Pamela J. Clifford, Clifford N. Meltz, and James E. Phillips;
Pfizer Global Research; Organic Process Research & Development 2007, 11, 762-765
12. Presentation Outline
Introduction
Case Studies
- Make Processes Safer with Calorimetry
- Minimize Chemical Hazard with Continuous Processing and ATR-FTIR
- More Nature-like Bio-processes with ATR-FTIR and Calorimetry
14. ATR-FTIR as a PAT for Continuous Chemistry
FlowIR™: A New Plug-and-Play Instrument
for Flow Chemistry
9-bounce ATR sensor
(SiComp, DiComp) and
head
Internal volume: 10ml and
50ml
Up to 50bar (725psi)
Small size, no purge, no
-40ºC → 120ºC
alignment, no liquid N2
Spectral range 600-4000cm-1
15. ATR-FTIR as a PAT for Continuous Chemistry
3-D Spectra
Absorbance
Flow cells ATR-FTIR
Time
In-line, real time, faster turnover rate
Structural specificity
Software designed for reaction monitoring
Intermediates, component spectra Steady state, component profiles
Relative concentration
Absorbance
or
Time
16. Combined ATR-FTIR - Flow for Unstable Intermediates
Vol. 92 μL, channel W 600 μm, D 500 μm, L 360 mm
Continuous Flow Production of Thermally
Unstable Intermediates in a Microreactor
with Inline IR-Analysis: Controlled
Vilsmeier−Haack
Introduction
Vilsmeier−Haack formylation hazardous
to scale-up: Unstable chloroiminium
intermediate 1- Formation of the VH-reagent
Enhanced safety in microreactors thanks 2- Arene oxidation – Iminium formation
to better heat dissipation and smaller
volume 3- Quench of iminium salt
FlowStart Evo
FutureChemistry
A. M. W. van den Broek, J. R. Leliveld, R. Becker, M. M. E. Delville, P. J. Nieuwland, Kaspar Koch, F. P. J. T. Rutjes; FutureChemistry Holding BV,
Institute for Molecules and Materials, Radboud University Nijmegen; The Netherlands; Organic Process Research and Development, 2012, 16, 5,
934-938
17. Combined ATR-FTIR - Flow for Unstable Intermediates
At-line ATR-FTIR measurements
required to prevent partial conversion of FlowIRTM`
POCl3: Pyrrole → polymers → clogging
At-line UV unpractical because DMF
shows absorbance around 300 nm
P-O-C
Residence time Conclusions
10 s
C-Cl VH formylation easily conducted in flow
microreactor
180 s FlowIR key to solve at-line UV limitations
Optimization of reaction time (180 s),
temperature (60 °C, molar ratio 1.5 eq.)
→ 5.98 g/h
A. M. W. van den Broek, J. R. Leliveld, R. Becker, M. M. E. Delville, P. J. Nieuwland, Kaspar Koch, F. P. J. T. Rutjes; FutureChemistry Holding BV,
Institute for Molecules and Materials, Radboud University Nijmegen; The Netherlands; Organic Process Research and Development, 2012, 16, 5,
934-938
18. Combined ATR-FTIR - Flow for Hazardous Reagents
The Development of Continuous Process
for Alkene Ozonolysis Based on ReactIRTM probe
Combined in Situ FTIR, Calorimetry, and
Computational Chemistry
Introduction
Ozonolysis highly efficient and selective Coarse frit
oxidation method
Hazardous and unreliable in batch:
Exotherm, stability of intermediates,
ozone toxicity Instantaneous “view” of the chemistry
with in situ FTIR:
- Steady state, rate, intermediates
-50°C
Styrene
- Residence time
- 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
19. Combined ATR-FTIR - Flow for Hazardous Reagents
FTIR 780 cm-1
Results
xxx
Jacketed bubble reactor setup Feed rate limited
32g/h – O3 generation
Applied to styrene, isobutylene-type API
intermediate
(Initial lab scale kinetic study)
Acetone (/heptane)
-33°C
17L/min
(Residence time distribution experiment)
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
20. Combined ATR-FTIR - Flow for Hazardous Reagents
Outcome
Preliminary kinetic investigation in batch
Small scale CSTR for 300g production
Styrene / O3 equimolar:
Larger scale continuous bubble reactor Steady state 15-20% styrene
setup for 2.7kg
Real time in situ FTIR allowed to
Monitor reaction progress, detect
process upsets
Ensure high product quality and yield
No need for sampling/ 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
21. Presentation Outline
Introduction
Case Studies
- Make Processes Safer with Calorimetry
- Minimize Chemical Hazard with Continuous Processing and ATR-FTIR
- More Nature-like Bio-processes with ATR-FTIR and Calorimetry
23. Enzymatic Catalysis/ATR-FTIR: Enhanced selectivity
Monitoring of Baeyer-Villiger bio-
transformation kinetics and finger-
printing using ReactIR™ spectroscopy
Introduction
Cyclopentadecanone mono-oxygenase
(CPDMO) for highly selective enzyme
catalyzed Baeyer-Villiger reaction
(ketones → lactones)
Real time in situ ReactIR™ for kinetics,
conversion, of isolated enzyme and
whole cell processes (modified E. Coli)
Source: Peter C.K. Lau et al, Biotechnology Research Institute, National Research Council, Canada; Industrial Biotechnology 2006, 138–142;
Applied and Environmental Microbiology, 2006, 2707–2720
24. Enzymatic Catalysis/ATR-FTIR: Enhanced selectivity
Results from in situ monitoring:
Whole cell BV catalyzed by recombinant
CPDMO expressed by E. coli BL21.
Qualitative:
- CDD absorbance at 1713 cm-1
- LL absorbance at 1741 cm-1
(Overlaid ReactIR™ infrared spectra: monitoring of
cyclododecanone conversion to lauryl lactone)
Quantitative: Peak profiling, calibration
9h (steady state) model using iC Quant for monitoring
- Use of authentic standards of CDD, LL
(CDD concentration profile as a function of cell growth in a fed- - Detection sensitivity for LL: 0.2 mM
batch culture: E. coli BL21)
Source: Peter C.K. Lau et al, Biotechnology Research Institute, National Research Council, Canada; Industrial Biotechnology 2006, 138–142;
Applied and Environmental Microbiology, 2006, 2707–2720
25. Enzymatic Catalysis/ATR-FTIR: Enhanced selectivity
Outcome
- Rapid monitoring and quantification of
enzyme catalyzed BV bio-
transformations of CDD to LL, in situ
- Better understanding of reaction kinetics
- Simple calibration mode applied without
interference from the complex cell
culture medium
- Further development: Expansion to a
wider range of cycloketones (Lineweaver-Burk plot for reaction kinetics; V=reaction rate,
Cr=initial concentration)
Source: Peter C.K. Lau et al, Biotechnology Research Institute, National Research Council, Canada; Industrial Biotechnology 2006, 138–142;
Applied and Environmental Microbiology, 2006, 2707–2720
26. In-Situ FTIR Helps Green (Batch) Processing
Real time monitoring of toxic compounds to reduce personnel’s exposure
Lynette M. Oh, Huan Wang, Susan C. Shilcrat, Robert E. Herrmann, Daniel B. Patience, P. Grant Spoors, and Joseph
Sisko GlaxoSmithKline, Organic Process Research & Development 2007, 11, 1032–1042
Jacques Wiss, Arne Zilian, Novartis, Organic Process Research & Development 2003, 7, 1059-1066
Real time process control for improved safety and efficiency
Terrence J. Connolly, John L. Considine, Zhixian Ding, Brian Forsatz, Mellard N. Jennings, Michael F. MacEwan, Kevin M.
McCoy, David W. Place, Archana Sharma, and Karen Sutherland; Wyeth Research; Organic Process Research &
Development 2010, 14, 459–465
Holger Kryk, Günther Hessel, and Wilfried Schmitt, Institute of Safety Research Germany, Organic Process Research &
Development 2007, 11, 1135–1140
Atsushi Akao, Nobuaki Nonoyama, Toshiaki Mase, Nobuyoshi Yasuda, Merck, Organic Process Research & Development
2006, 10, 1178-1183
Large scale use of in-situ real time FTIR
Lynette M. Oh et al, GlaxoSmithKline, Organic Process Research & Development, 2009, 13, 729-738
Jaan Pesti, Chien-Kuang Chen et al, Organic Process Research & Development, 2009, 13, 716-728
David H. Brown Ripin, Gerald A. Weisenburger, David J. am Ende, David R. Bill, Pamela J. Clifford, Clifford N. Meltz, and
James E. Phillips; Pfizer Global Research; Organic Process Research & Development 2007, 11, 762-765
27. Acknowledgements
Pfizer Global Research Division, Groton, CT
- David H. Brown Ripin, and Gerald A. Weisenburger et al.
Institute for Molecules and Materials, Radboud University (The
Netherlands)
- Pr. Floris P. J. T. Rutjes et al.
Abbott, Process Research and Development, USA
- Ayman D. Allian et al.
Biotechnology Research Institute, National Research Council, Canada
- Peter C.K. Lau et al.
METTLER TOLEDO
- Will Kowalchyk, Wes Walker, Paul Scholl (USA), Jon Goode (U.K.)