3rd international symposium on green processing
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Going Green Using Combined Real-Time
Analytics and Process Automation
Dominique Hebrault
Sr. Technology & Application
Consultant
Boston, October 1, 2010
The Paradigm of Faster and Better…
Source: Chemistry Today, 2008, Copyright Teknoscienze Publications
How Can Process Analytical Technology Help?
“Greener Processes: PAT & QbD take root” Pharmaceutical Manufacturing at www.pharmamanufacturing.doc, May 2010, 9, (5), 18-24; “Building
Green Pharmaceutical Manufacturing on a Foundation of PAT and QbD” Paul Thomas, Sr Editor Pharmaceutical Manufacturing magazine, webinar
Nov. 3rd 2010
Introduction
Case Studies
- PAT for Continuous Processing and Micro-Reaction Technology
- PAT for the Greening of Batch Processing
- Applying the Principles of Green Chemistry to Crystallization and
Downstream Processing
Beyond Today’s PAT
Presentation Outline
On Adopting New Technologies…
Source: Chemistry Today, 2009, Copyright Teknoscienze Publications
Drug discovery
- Microflow and small scale flow reactors
- Safer and more space efficient than RBF
- Used to prepare g to kg material
- Used for highly energetic transformation: nitration,
diazotation, hydrogenation, high temperatures (> 200 ºC).
Where is Continuous Flow Chemistry Used?
Chemical development
- Avoid scale-up issues, improves safety profile and yield at
production scale
- Kinetics and thermodynamics properties studied in a
batch mode
Special Feature Section: Process Intensification/Continuous Processing, Org. Process Res. Dev., 2001, 5 (6), 612-664, Chemical & Engineering
News, 2006, 84, 10, p17; Katsunori Tanaka and Koichi Fukase, Org. Process Res. Dev., 2009, 13, 983-990
Intermediates, component spectra Steady state, component profiles
ATR-FTIR
In-line, real time, faster turnover rate
Structural specificity
Software designed for reaction monitoring
Mid-IR In-Line Reaction Analysis for Flow Chemistry
Time
Absorb
ance
or
Rela
tive c
oncentr
ation
Time
Ab
so
rba
nce
Flow cells
3-D Spectra
Development and Scale-up of Three
Consecutive Continuous Reactions for
Production of 6-Hydroxybuspirone
In-Line FTIR in Continuous Manufacturing of API
Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb Pharmaceutical
Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time Analytics Users’
Forum 2005 - New York
Introduction
Active metabolite of Buspirone,
manufactured and marketed as Buspar,
employed for the treatment of anxiety
disorders and depressionMulti Kg amount needed for clinical
development, initially made in batch
Process lack of ruggedness and
unreliable product quality
Challenge
Control base / buspirone stoichiometry is
critical to product quality
Undercharged of base → unreacted 1
Overcharge of base → dihydroxy 8
Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb Pharmaceutical
Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time Analytics Users’
Forum 2005 - New York
KHMDS
Base feed adjusted
in real time based on
inline FTIR data
1677cm-1
1627cm-1
In-Line FTIR in Continuous Manufacturing of API
Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb Pharmaceutical
Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time Analytics Users’
Forum 2005 - New York
3. Flow rate increased at 1%
increments until no decrease of
buspirone 1 signal is observed
4. Base feed rate was reduced 1-3%
5. The base is slightly undercharged,
diol 8 impurity minimized
1. Pump solvent and 1 through the
column
2. Solvent replace by KHMDS feed,
slight undercharge of base
Buspirone 1 signal
In-Line FTIR in Continuous Manufacturing of API
Outcome
-Ensure product quality via real-time
adjustment of base feed rate
-Prevent time and resource consuming
final purification stages
-Faster and more accurate reach of
steady state via real-time detection of
phase transitions
-Minimize waste of starting material
Scale-up
-Lab reactor: Over 40 hours at steady
state
-Pilot-plant reactor: Successful
implementation (3-batch, 47kg/batch)
Thomas L. LaPorte,* Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson, and Daniel Hsieh, Bristol-Myers Squibb Pharmaceutical
Research Institute, NJ, USA, Organic Process Research and Development, 2008, 12, 956-966; Mettler Toledo Real Time Analytics Users’
Forum 2005 - New York
In-Line FTIR in Continuous Manufacturing of API
ReactIRTM Micro Flow Cell
A New Analytical Tool 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
ATR-FTIR
Internal volume: 10 & 50 ml
Up to 30 bar (435 psi)
Up to 60ºC
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
Heterocycle saturation
In-Line FTIR Micro Flow Cell in the Laboratory
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
BDA protection of halopropane diols
IR flow cell used for screening
Screening results consistent with batch
screening (required five separate
experiments!)
Used to make a large sample over
almost 24 h
In-Line FTIR Micro Flow Cell in the Laboratory
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
Peptide coupling in batch mode
IR monitoring of batch processes:
Withdrawing/returning 200 µL from
reaction mixture (5 mL) through the cell
Flow cell more convenient than probe for
mL scale experiments
In-Line FTIR Micro Flow Cell in the Laboratory
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
Conclusions
Faster screening of process variables
PAT for continuous or batch processes
on a small volume (< 1ml) , less solvent
and reagent waste
Gain information about reactive
intermediates
Monitoring of hazardous substances
(azide derivatives)
In-Line FTIR Micro Flow Cell in the Laboratory
No More Batch Processing?
Use of existing equipment, no capital
investment
More concise measurements
Better suited, more flexible, for small
batches in the pharma and fine
chemicals industries
Heat transfer limitations, process safety
Mass transfer issues
Solvent extraction problems
Crystallization and polymorphism
Dr. Trevor Laird; Chemical Industry Digest July 2010, 51-56
Introduction
Case Studies
- PAT for Continuous Processing and Micro-Reaction Technology
- PAT for the Greening of Batch Processing
- Applying the Principles of Green Chemistry to Crystallization and
Downstream Processing
Beyond Today’s PAT
Presentation Outline
Execution of a Performic Acid Oxidation on Multikilogram Scale
Reaction Calorimetry: Process Safety and PAT
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 CP-865,569 8, a CCR1 antagonist
Selection of a greener oxidation pathway
Performic acid
Challenges
Key process safety questions
How much energy does the reaction
release?
What is the instantaneous heat
output?
How much 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: Process Safety and PAT
Conclusions
Highly exothermic performic acid
oxidation
Fast reaction, no delayed onset
Fed-controlled process will be safe
Dosing time will be adjusted based on
the cooling capacity of plant equipment
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: Process Safety and PAT
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
Introduction
Case Studies
- PAT for Continuous Processing and Micro-Reaction Technology
- PAT for the Greening of Batch Processing
- Applying the Principles of Green Chemistry to Crystallization and
Downstream Processing
Beyond Today’s PAT
Presentation Outline
Green Crystallization and Downstream Processing
How much product is wasted during your crystallization and downstream
processing steps?
• Dry milling can cause 10+% loss due to hold up in the milling equipment
• Also, generation of fine particles during milling results in potential exposure
and explosion hazard
• Crystals are easy to get but crystallization processes difficult to optimize
Holistic approach to achieving energy and material efficiency gain
Crystallization Improvements of a
Diastereomeric Kinetic Resolution
through Understanding of Secondary
Nucleation
PAT in Crystallization: Reduce Waste, Improve Throughput
Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Sepracor Inc.; Organic Process Research and Development, 2008, 12, 243-248
Introduction
Target product fails optical purity specs
at contract manufacturing site
Failed batches exhibit longer filtration
and drying times
Significance of secondary nucleation:
Induction temperature, stirring speed,
seed surface area
PAT in Crystallization: Reduce Waste, Improve Throughput
Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Organic Process Research and Development, 2008, 12, 243-248
Conditions
Lab scale-down (L) with real time FBRM
Seeded (46ºC) cooling crystallization
Seeding process not immediately
followed by significant growth
High TN: Low supersaturation, higher
purity, better separation
How can nucleation be forced earlier, at
higher temperature?
46ºC
Rate of particle formation versus time
TN: temperature of nucleation
PAT in Crystallization: Reduce Waste, Improve Throughput
Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Organic Process Research and Development, 2008, 12, 243-248
Results
Mixing: TN (higher purity, better
separation) correlated to shear rate
Seeding: Surface area, not amount,
increases TN
PAT in Crystallization: Reduce Waste, Improve Throughput
Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Organic Process Research and Development, 2008, 12, 243-248
Different seeding and agitation condition
Faster filtration rate
Shorter cycle time
Improved optical purity
PAT in Crystallization: Reduce Waste, Improve Throughput
Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Organic Process Research and Development, 2008, 12, 243-248
Scale-up at 50 and 400 L, and
implemented at contract manufacturing
site
Centrifugation time divided by 3
No need to scrape the product out
Higher optical purity, above specs
Results consistency Increased time and energy efficiency
Safer working conditions
Improved quality and process reliability
PAT to Enhance Crystallization Processes
Process analytics to ensure quality consistency and reliability at scale
M.D. Argentine, T.M. Braden, J. Czarnik, E.W. Conder, S.E. Dunlap, J.W. Fennell, M.A. LaPack, R.R. Rothhaar, R.B.
Scherer, C.R. Schmid, J.T. Vicenzi, J.G. Wei, J.A. Werner*, and R.T. Roginski, Org. Process Res. Dev., 2009, 13, 131–
143.
Vincenzo Liotta, Vijay Sabesan, Org. Process Res. Dev., 2004, 8, 488-494
Particle Engineering: Design the crystal product to avoid unnecessary
processing
S. Kim, B. Lotz, M. Lindrud, K. Girard, T. Moore, K. Nagarajan, M. Alvarez, T. Lee, F. Nikfar, M. Davidovich, S. Srivastava,
and S. Kiang, Org. Process Res. Dev., 2005, 9, 894-901
Sridhar Desikan, Rodney L. Parsons, Jr.,, Wayne P. Davis,, James E. Ward,, Will J. Marshall, and, Pascal H. Toma., Org.
Process Res. Dev., 2005, 9, 933-942
Automating Metastable Zone Width Determination and Supersaturation
Control
Barrett, P. and B. Glennon, Chem. Eng. Res. Des. 2002, 80, 799-805
Mark Barrett, Mairtin McNamara, HongXun Hao, Paul Barrett, Brian Glennon, Chem. Eng. Res. & Des., 2010, 88, 8, 1108-
1119
Cote, A., G. Zhou, M. Stanik, Org. Process Res. Dev., 2009,13, 1276-1283
Introduction
Case Studies
- PAT for Continuous Processing and Micro-Reaction Technology
- PAT for the Greening of Batch Processing
- Applying the Principles of Green Chemistry to Crystallization and
Downstream Processing
Beyond Today’s PAT
Presentation Outline
Beyond Today’s PAT
Reaction Progress Kinetic Analysis - RPKA
Blackmond, D. G. Angew. Chemie Int. Ed. 2005, 44, 4302; Blackmond, D. G. et al., J. Org. Chem. 2006, 71, 4711
Continuous real time reaction
monitoring (calorimetry, FTIR…)
Graphical, intuitive data
manipulation
RPKA provides a full kinetic
analysis from 3+ experiments
• Less experiments, more knowledge
• Catalyst performance
• Process robustness
• Driving force analysis
Early-on kinetic simulation
Acknowledgements
University of Cambridge, UK
- Catherine F. Carter, Heiko Lange, and Pr. Steven V. Ley*
Bristol-Myers Squibb Pharmaceutical Research, New Brunswick, NJ, USA
- Thomas L. LaPorte, Mourad Hamedi, Jeffrey S. DePue, Lifen Shen, Daniel Watson,
and Daniel Hsieh
Pfizer Global Research, Groton, CT, USA
- David H. Brown Ripin, Gerald A. Weisenburger, David J. am Ende, David R. Bill,
Pamela J. Clifford, Clifford N. Meltz, and James E. Phillips
Sepracor Inc., Marlborough, MA, USA
- Patrick Mousaw, Kostas Saranteas, Bob Prytko
Mettler Toledo Autochem
- Jon G. Goode, Nigel L. Gaunt, Brian Wittkamp, and Jian Wang
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