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.)