The document discusses how real-time process analytical technology (PAT) tools like in-line FTIR and reaction calorimetry can help optimize continuous flow chemistry and batch processes to make them more efficient and environmentally friendly by allowing for real-time process monitoring and control. Case studies show how PAT has been used to improve crystallization processes, downstream processing, and assess process safety.

1. Going Green Using Combined Real-Time
Analytics and Process Automation
Dominique Hebrault
Sr. Technology & Application
Consultant
Boston, October 1, 2010

2. The Paradigm of Faster and Better…
Source: Chemistry Today, 2008, Copyright Teknoscienze Publications

3. 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

4. Presentation Outline
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

5. On Adopting New Technologies…
Source: Chemistry Today, 2009, Copyright Teknoscienze Publications

6. Where is Continuous Flow Chemistry Used?
 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).
 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

7. Mid-IR In-Line Reaction Analysis for Flow 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

8. In-Line FTIR in Continuous Manufacturing of API
Development and Scale-up of Three
Consecutive Continuous Reactions for
Production of 6-Hydroxybuspirone
 Introduction
Active metabolite of Buspirone,
manufactured and marketed as Buspar,
employed for the treatment of anxiety
disorders and depression
Multi Kg amount needed for clinical
development, initially made in batch
Process lack of ruggedness and
unreliable product quality
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

9. In-Line FTIR in Continuous Manufacturing of API
 Challenge KHMDS
Control base / buspirone stoichiometry is
critical to product quality
Undercharged of base → unreacted 1
Overcharge of base → dihydroxy 8
1627cm-1
1677cm-1
Base feed adjusted
in real time based on
inline FTIR data
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

10. In-Line FTIR in Continuous Manufacturing of API
Buspirone 1 signal
1. Pump solvent and 1 through the
column
2. Solvent replace by KHMDS feed,
slight undercharge of base
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
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

11. 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

12. In-Line FTIR Micro Flow Cell in the Laboratory
ReactIRTM Micro Flow Cell
A New Analytical Tool for Continuous Flow
Chemical Processing
Internal volume: 10 & 50 ml
ATR-FTIR 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

13. In-Line FTIR Micro Flow Cell in the Laboratory
 Heterocycle saturation
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

14. In-Line FTIR Micro Flow Cell in the Laboratory
 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
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

15. In-Line FTIR Micro Flow Cell in the Laboratory
 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
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

16. In-Line FTIR Micro Flow Cell in the Laboratory
 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)
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

17. 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

18. Presentation Outline
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

19. Reaction Calorimetry: Process Safety and PAT
Execution of a Performic Acid Oxidation on Multikilogram Scale
 Introduction
En route toward CP-865,569 8, a CCR1 antagonist
Selection of a greener oxidation pathway
Performic acid
David H. Brown Ripin, Gerald A. Weisenburger, David J. am Ende, David R. Bill, Pamela J. Clifford, Clifford N. Meltz, and Jam es E. Phillips;
Pfizer Global Research; Organic Process Research & Development 2007, 11, 762-765

20. Reaction Calorimetry: Process Safety and PAT
 Challenges
Key process safety questions
How much energy does the reaction
release?
What is the instantaneous heat
output?
How much thermal accumulation? Reaction heat: - 975 kJ/mol ( )
DTadbatch 172 ºC
DSC
ARC 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 Jam es E. Phillips;
Pfizer Global Research; Organic Process Research & Development 2007, 11, 762-765

21. 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
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 Jam es E. Phillips;
Pfizer Global Research; Organic Process Research & Development 2007, 11, 762-765

22. 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

23. Presentation Outline
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

24. 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

25. PAT in Crystallization: Reduce Waste, Improve Throughput
Crystallization Improvements of a
Diastereomeric Kinetic Resolution
through Understanding of Secondary
Nucleation
 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
Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Sepracor Inc.; Organic Process Research and Development, 2008, 12, 243-248

26. PAT in Crystallization: Reduce Waste, Improve Throughput
 Conditions
Lab scale-down (L) with real time FBRM 46ºC
Seeded (46ºC) cooling crystallization
Seeding process not immediately
followed by significant growth
Rate of particle formation versus time
TN: temperature of nucleation
High TN: Low supersaturation, higher
purity, better separation
How can nucleation be forced earlier, at
higher temperature?
Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Organic Process Research and Development, 2008, 12, 243-248

27. PAT in Crystallization: Reduce Waste, Improve Throughput
 Results
Mixing: TN (higher purity, better
separation) correlated to shear rate
Seeding: Surface area, not amount,
increases TN
Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Organic Process Research and Development, 2008, 12, 243-248

28. PAT in Crystallization: Reduce Waste, Improve Throughput
Different seeding and agitation condition
 Faster filtration rate
 Shorter cycle time
 Improved optical purity
Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Organic Process Research and Development, 2008, 12, 243-248

29. PAT in Crystallization: Reduce Waste, Improve Throughput
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
Patrick Mousaw, Kostas Saranteas, and Bob Prytko, Organic Process Research and Development, 2008, 12, 243-248

30. 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

31. Presentation Outline
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

32. Beyond Today’s PAT

33. Reaction Progress Kinetic Analysis - RPKA
Continuous real time reaction Graphical, intuitive data
monitoring (calorimetry, FTIR…) manipulation
• Less experiments, more knowledge
• Catalyst performance
• Process robustness
• Driving force analysis
Early-on kinetic simulation
RPKA provides a full kinetic
analysis from 3+ experiments
Blackmond, D. G. Angew. Chemie Int. Ed. 2005, 44, 4302; Blackmond, D. G. et al., J. Org. Chem. 2006, 71, 4711

34. 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