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TRANSCRIPT
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
2
The Twelve Principles of Green Chemistry
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)
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
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
Presentation Outline
About Chemical Process Safety…
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
Enzymatic Catalysis/ATR-FTIR: Enhanced selectivity
(Lineweaver-Burk plot for reaction kinetics; V=reaction rate,
Cr=initial concentration)
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
Large scale
( 8 ml - 22L)
EasyMax®
no cryostat
Ease of use
Productivity
Process information
Medium scale
(40 -1000ml)
Synthesis Workstations/Reaction Calorimeters - Lab to Pilot Plant
Small scale
(15 -150ml)
OptiMax™
no cryostat
Process information
Quick synthesis work
RC1e™
Process scale-up/down
Process safety
Pilot batches (6 - 12 - 22L)
Execution of a Performic Acid Oxidation on Multikilogram Scale
Reaction Calorimetry as a PAT for Process Safety
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
Introduction
En route toward API CP-865,569 8, a CCR1 antagonist
Selection of a greener oxidation pathway (no salt)
Performic acid
Challenges
Key process safety questions
Reaction enthalpy?
Instantaneous heat output?
Thermal accumulation?
ARC
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
Reaction heat: - 975 kJ/mol ( )
DTadbatch 172 ºC
Maximum heat output 44 W/Kg
Thermal accumulation: 9% ( / )
DSC
RC1e
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
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
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
Reaction Calorimetry as a PAT for Process Safety
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
Presentation Outline
On Adopting Continuous Processing…
Source: Chemistry Today, 2009, Copyright Teknoscienze Publications
ATR-FTIR as a PAT for Continuous Chemistry
Internal volume: 10ml and
50ml
Up to 50bar (725psi)
-40ºC → 120ºC
Spectral range 600-4000cm-1
FlowIR™: A New Plug-and-Play Instrument
for Flow Chemistry
9-bounce ATR sensor
(SiComp, DiComp) and
head
Small size, no purge, no
alignment, no liquid N2
Intermediates, component spectra Steady state, component profiles
ATR-FTIR
In-line, real time, faster turnover rate
Structural specificity
Software designed for reaction monitoring
Time
Ab
so
rba
nce
or
Re
lative
co
nce
ntr
ation
Time
Absorb
ance
Flow cells
3-D Spectra
ATR-FTIR as a PAT for Continuous Chemistry
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
Enhanced safety in microreactors thanks
to better heat dissipation and smaller
volume
Combined ATR-FTIR - Flow for Unstable Intermediates
1- Formation of the VH-reagent
2- Arene oxidation – Iminium formation
3- Quench of iminium salt
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
FlowStart Evo
FutureChemistry
Vol. 92 μL, channel W 600 μm, D 500 μm, L 360 mm
Conclusions
VH formylation easily conducted in flow
microreactor
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
At-line ATR-FTIR measurements
required to prevent partial conversion of
POCl3: Pyrrole → polymers → clogging
At-line UV unpractical because DMF
shows absorbance around 300 nm
C-Cl
P-O-C
Residence time
10 s
180 s
FlowIRTM`
Combined ATR-FTIR - Flow for Unstable Intermediates
The Development of Continuous Process
for Alkene Ozonolysis Based on
Combined in Situ FTIR, Calorimetry, and
Computational Chemistry
Introduction
Ozonolysis highly efficient and selective
oxidation method
Hazardous and unreliable in batch:
Exotherm, stability of intermediates,
ozone toxicity
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
Instantaneous “view” of the chemistry
with in situ FTIR:
- Steady state, rate, intermediates
- Residence time
- O3 efficiency, mass transfer
Styrene
-50°C
Combined ATR-FTIR - Flow for Hazardous Reagents
ReactIRTM probe
Coarse frit
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
Feed rate limited
FTIR 780 cm-1
Results
Jacketed bubble reactor setup
32g/h – O3 generation
Applied to styrene, isobutylene-type API
intermediate
Combined ATR-FTIR - Flow for Hazardous Reagents
17L/min
-33°C
(Initial lab scale kinetic study)
(Residence time distribution experiment)
Acetone (/heptane)
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
Combined ATR-FTIR - Flow for Hazardous Reagents
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
Outcome
Preliminary kinetic investigation in batch
Small scale CSTR for 300g production
Larger scale continuous bubble reactor
setup for 2.7kg
Styrene / O3 equimolar:
Steady state 15-20% styrene
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
Presentation Outline
About Bioprocessing…
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)
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
Enzymatic Catalysis/ATR-FTIR: Enhanced selectivity
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
Quantitative: Peak profiling, calibration
model using iC Quant for monitoring
-Use of authentic standards of CDD, LL
-Detection sensitivity for LL: 0.2 mM
Enzymatic Catalysis/ATR-FTIR: Enhanced selectivity
(Overlaid ReactIR™ infrared spectra: monitoring of
cyclododecanone conversion to lauryl lactone)
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
(CDD concentration profile as a function of cell growth in a fed-
batch culture: E. coli BL21)
9h (steady state)
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
Enzymatic Catalysis/ATR-FTIR: Enhanced selectivity
(Lineweaver-Burk plot for reaction kinetics; V=reaction rate,
Cr=initial concentration)
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
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
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.)