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  • 1. The Role of Process AnalyticalTechnology (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 2
  • 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 OutlineIntroduction 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 OutlineIntroduction 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
  • 6. About Chemical Process Safety…
  • 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 IntroductionEn route toward API CP-865,569 8, a CCR1 antagonist Selection of a greener oxidation pathway (no salt) Performic acidDavid 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 ChallengesKey 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% ( / ) RC1eDavid 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 ConclusionsHighly exothermic oxidationFast reaction, no delayed onsetFed-controlled process will be safeDosing time adjusted to cooling capacityin 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 assayDavid 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 OutlineIntroduction 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
  • 13. On Adopting Continuous Processing… Source: Chemistry Today, 2009, Copyright Teknoscienze Publications
  • 14. ATR-FTIR as a PAT for Continuous ChemistryFlowIR™: 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 mmContinuous Flow Production of ThermallyUnstable Intermediates in a Microreactorwith Inline IR-Analysis: ControlledVilsmeier−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 FutureChemistryA. 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/hA. 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 ReagentsThe Development of Continuous Processfor Alkene Ozonolysis Based on ReactIRTM probeCombined in Situ FTIR, Calorimetry, andComputational 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 transferAyman D. Allian, Steve M. Richter, Jeffrey M. Kallemeyn, Timothy A. Robbins, and Vimal Kishore, Abbott, Process Research and Development, 1401Sheridan 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, 1401Sheridan 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 safetyAyman D. Allian, Steve M. Richter, Jeffrey M. Kallemeyn, Timothy A. Robbins, and Vimal Kishore, Abbott, Process Research and Development, 1401Sheridan Road, North Chicago, Illinois 60064, USA, Organic Process Research and Development, 2011, 15, 91-97
  • 21. Presentation OutlineIntroduction 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
  • 22. About Bioprocessing…
  • 23. Enzymatic Catalysis/ATR-FTIR: Enhanced selectivityMonitoring of Baeyer-Villiger bio-transformation kinetics and finger-printing using ReactIR™ spectroscopy IntroductionCyclopentadecanone mono-oxygenase(CPDMO) for highly selective enzymecatalyzed 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 recombinantCPDMO 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 mMbatch 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.)