3rd international symposium on green processing

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

http://www.pharmamanufacturing.doc/





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




KHMDS

Base feed adjusted

in real time based on

inline FTIR data

1677cm-1

1627cm-1





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


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)





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


Heterocycle saturation



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



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



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)


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







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



Reaction heat: - 975 kJ/mol ( )

DTadbatch 172 ºC

Maximum heat output 44 W/Kg

Thermal accumulation: 9% ( / )

DSC

RC1e


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


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







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


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



Results

Mixing: TN (higher purity, better

separation) correlated to shear rate

Seeding: Surface area, not amount,

increases TN



Different seeding and agitation condition

Faster filtration rate

Shorter cycle time

Improved optical purity



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







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

3rd international symposium on green processing

Documents

continuous flow chemistry

organic process research

flow rate

daniel hsieh

daniel watson

line ftir micro flow

new york

chemical development