Green Chemistry, Biocatalysis and Environmental Assessment

1 Celebrating a decade of Green Chemistry Leadership 2002-2012

Peter Dunn, Pfizer Green Chemistry Lead

Presentation Outline

Brief Introduction to the Pfizer Green Chemistry Program

Green Chemistry Tools with a focus on the Pfizer Solvent Guides

Pregabalin case history focusing on some recent results from a detailed life cycle assessment

Celebrating a decade of Green Chemistry Leadership 2002-2012 2

Pfizer Green Chemistry Mission

Celebrating a decade of Green Chemistry Leadership 2002-2012

To introduce, educate and promote the application of Green Chemistry across Pfizer and in our key research partners.

Key Philosophy: Voluntary restraint is better than enforced constraint.

Green Chemistry includes protection of the environment and worker safety.

Informing and influencing the Green Chemistry research agenda.

3

• Success required attention to Green Chemistry across all our

locations: research, scale-up, and manufacturing facilities.

• We have:

A full-time GC leader with a company-wide responsibility.

A company GC Policy and Steering Committee (responsible for the

strategic plan, communications plans, key policy decisions, and

monitoring of performance).

Developed practical tools to help chemists go green.

GC teams at all chemistry research Sites– Set annual objectives,

manage site-based awards programs, hold annual green chemistry

seminars, raise awareness, and drive behavior change

Integrated GC into our co-development process with manufacturing

and initiated Manufacturing GC Awards

Engagement and Alignment

4

Pfizer Green Chemistry Tools

5

Solvent Guides – simple, more detailed

Biocatalysis Guide

Reagent Guide

Acid / Base Guide

Metrics Tool

Predictive Distillation Tool

Simple Carbon Footprint Tool

Developed 2 Solvent Selection Tools

• Developed two Solvent Tools, one detailed for our process chemists, the other more simple for our medicinal chemists but for both tools the evaluation approach is the same and includes: – Worker Safety- Includes carcinogenicity, mutagenicity,

reprotoxicity, skin absorption, skin sensitisation and toxicity

– Process Safety – Includes flammability, potential for high emissions, static charge, potential for peroxide formation, odour issues.

– Environmental and Regulatory Considerations – Includes ecotoxicity, ground water contamination potential, EHS regulatory restrictions, ozone depletion potential, photo reactive potential.

Simple Solvent Selection Guide

Preferred

Water

Acetone

Ethanol

2-Propanol

1-Propanol

Ethyl Acetate

Isopropyl acetate

Methanol

MEK

1-Butanol

t-Butanol

Usable

Cyclohexane

Heptane

Toluene

Methylcyclohexane

TBME

Isooctane

Acetonitrile

2-MeTHF

THF

Xylenes

DMSO

Acetic Acid

Ethylene Glycol

Undesirable

Pentane

Hexane(s)

Di-isopropyl ether

Diethyl ether

Dichloromethane

Dichloroethane

Chloroform

NMP

DMF

Pyridine

DMAc

Dioxane

Dimethoxyethane

Benzene

Carbon tetrachloride

Solvent Replacement Table

Red Solvents Alternative

Pentane Heptane

Hexane(s) Heptane

Di-isopropyl ether or ether 2-MeTHF or t-Butyl methyl ether

Dioxane or dimethoxyethane 2-MeTHF or t-Butyl methyl ether

Chloroform, dichloroethane or

carbon tetrachloride

DCM

DMF NMP or DMAc Acetonitrile

Pyridine Et3N (if pyridine used as base)

DCM (extractions) EtOAc, MTBE, toluene, 2-MeTHF

DCM (chromatography) EtOAc / Heptanes

Benzene Toluene

Solvent Replacement Table Solvent Replacement Table

Red Solvents Alternative

Pentane Heptane

Hexane(s) Heptane

Di-isopropyl ether or ether 2-MeTHF or t-Butyl methyl ether

Dioxane or dimethoxyethane 2-MeTHF or t-Butyl methyl ether

Chloroform, dichloroethane or

carbon tetrachloride

DCM

DMF NMP or DMAc Acetonitrile

Pyridine Et3N (if pyridine used as base)

DCM (extractions) EtOAc, MTBE, toluene, 2-MeTHF

DCM (chromatography) EtOAc / Heptanes

Benzene Toluene

Chloroform Reduction Program

0

200

400

600

800

1000

1200

3Q 07 4Q 07 1Q 08 2Q 08 3Q 08 4Q 08 1Q 09 2Q 09 3Q 09 4Q 09

Time

Ch

loro

form

us

e/K

g/q

ua

rte

r

1150 kg 1150 kg

811 kg

268 kg

63.5 kg

21 kg 13 kg 18 kg 15 kg 15 kg

Chloroform usage, Pfizer Research Division

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Solvent Program

0

5000

10000

15000

20000

25000

2004 2005 2006 2007 2008

Iso

pro

pyle

the

r (I

PE

) U

se

/lb

s/y

ea

r

Year

20771

6243

666 108

PGRD Global Diisopropylether Use

O O

O O

O

O

Shock Sensitive Explosive

2

Pregabalin Case History

Pregabalin is a Drug for the treatment of Neuropathic Pain

Launched in the US in September 2005

Sales $3.69 billion (2011) $ 4.16 billion (2012)

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Medicinal Chemical Synthesis

10 steps, 33% overall yield

Cost was 6x target

Early Syntheses

R. B. Silverman et al., Synthesis, 1989, 953. (racemic)

P-w. Yuen et al., Biorg. Med. Chem. Lett., 1994, 4, 823. (chiral) shown on slide

13

Process 1 – Launch Process

Reasonable synthesis of racemic Pregabalin

Final Step Classical Resolution

Wrong enantiomer difficult to recycle

E factor 86 (i.e., 86 kilos waste per kilo of product)

Two reactions performed at reflux (high energy use)

CN

CO2EtEtO

2C

NH2

CO2H

NH2

CO2H

CN

CO2H

CO2EtEtO

2C

(S)-Mandelic

acid

25-29 % overall

> 99.5 % ee

High EnergyProcess performed at reflux

Chemistry in RacemicForm, half materials andEnergy Wasted

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Process 2

Biocatalytic with low levels of protein loading

All 4 reactions are conducted in water

Resolution at first step

Wrong enantiomer is incinerated

Significant waste reduction (see later)

Biocatalysis reaction is very concentrated

CO2EtEtO

2C

CN

CO2Et

CN

O2C

CO2EtEtO

2C

CN

CO2Et

CNNH

2

CO2H

Lipase

(S)-enantiomer

> 98 % ee

_Racemic CNDE

H2 5 % Ni

Pregabalin

(R)-CNDE

H2O H2O

H2O

Incinerated

15

Process 3

Wrong enantiomer is no longer incinerated but is now recycled and

converted to high quality product

All 4 reactions are still performed in water

E-Factor improved from 86 to 10

CO2EtEtO

2C

CN

CO2Et

CN

O2C

CO2EtEtO

2C

CN

CO2Et

CNNH

2

CO2H

Lipase

(S)-enantiomer

> 98 % ee

_Racemic CNDE

H2 5 % Ni

Pregabalin

(R)-CNDE

H2O

H2O

H2O

Recycled

16

Comparison of Processes

Key Inputs for Pregabalin via 1st Generation and Routes (on a % basis)

Key Inputs Classical Route

Enzymatic

Enzymatic Route Route & Recycle

CNDE 100 % 81 % 46 %

Enzyme 0 100 % 57 %

(S)-Mandelic acid 100 % 0 0

Raney Nickel 100 % 7 % 7 %

Solvents 100 % 9 % 6 %

Total 100 % 13 % 10 %

Energy (in house) 118.8 MJ/Kg 21.4 MJ/Kg 42.4 MJ/Kg

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Comparison of Processes

Key Inputs for Pregabalin via 1st Generation and Routes (on a % basis)

Key Inputs Classical Route

Enzymatic

Enzymatic Route Route & Recycle

CNDE 100 % 81 % 46 %

Enzyme 0 100 % 57 %

(S)-Mandelic acid 100 % 0 0

Raney Nickel 100 % 7 % 7 %

Solvents 100 % 9 % 6 %

Total 100 % 13 % 10 %

Energy (in house) 118.8 MJ/Kg 21.4 MJ/Kg 42.4 MJ/Kg

Energy (total) 155.0 MJ/Kg 49.3 MJ/Kg 58.7 MJ/Kg

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Process Waste Energy

Process 1 High High

Process 2 Low / Medium Low

Process 3 Low Low / Medium

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Comparison of Processes

Easy to see Process 1 is the worst

To determine whether Process 2 or Process 3 is best from an environmental

standpoint required a more detailed Life Cycle Assessment

Life Cycle Assessment Concepts

SimaPro® - detailed environmental analysis tool

Used for a product or process

Quantification of the raw material, energy use, and emissions to

the air, water, and soil

Characterization of environmental impacts

Ecosolvent® - used to compare waste treatment

processes by determining the environmental impact

Used for solvents or other chemicals that are incinerated,

distilled, or sent to waste water treatment

Quantification of emissions due to disposal and recovery of

solvents

ASPEN Batch Process Developer

Used to model the energy for all three processes

Although Pfizer used SimaPro, Ecosolvent and Aspen software for this evaluation, this does not mean Pfizer endorses these products.

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LCA for Pregabalin Process

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Life Cycle Inventory Generation

LCIs for each of the compounds from the

racemic-CNDE process and the three process

routes for pregabalin production 20 different compounds total

12 compounds included in SimaPro® database

LCI for enzyme provided by manufacturer

Seven compounds not included in the data

base Can model as a compound that is included in the data

base e.g. Isovalderaldehyde 3-methyl-1-butanol

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Sample Life Cycle Inventory

This database entry

includes the process

for materials,

infrastructure of the

plant, all energy uses,

and all emissions

Emission Type Unit Total

Total CED MJ-Eq 1.32E+02

Total Air Emissions kg 5.52E+00

CO2 kg 5.46E+00

CO kg 4.82E-03

Methane kg 1.45E-02

NOX kg 8.67E-03

NMVOC kg 3.25E-03

Particulates kg 3.57E-03

SO2 kg 1.15E-02

Total Water Emissions kg 1.26E-01

VOCs kg 7.93E-06

Total Soil Emissions kg 2.31E-03

Total Emissions kg 5.65E+00

Life Cycle Inventory Summary for 1 kg THF

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Process 1

Raw Material Life Cycle Inventories

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Total emissions of raw materials from Process 1 on 1 kg basis of each chemical manufactured

24.8 kg

24

0

2

4

6

8

10

12

14

16

Tota

l Em

issi

on

s. k

g

Methanol

Potassium Hydroxide

Hydrogen

Sponge Nickel

IPA

THF

Mandelic Acid

Acetic Acid

Ethanol

Racemic CNDE

DIW

Process 2 and 3

Process 3 is the same as Process 2 with the exception of a recycle stream

Total emissions of compounds from Processes 2 and 3 on 1 kg basis of each compound

24.8 kg Raw Material Life Cycle Inventories

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LCA of Process 1, 2 and 3

0

100

200

300

400

500

600

700

800

900

1000

Life

Cyc

le E

mis

sio

ns

(kg

/kg

AP

I)

Total Carbon Dioxide Emissions

Waste Disposal & Recovery

In-process Energy

Raw Material Manufacturing

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Summary

Biocatalytic route significantly reduces emissions and energy use

Cradle to gate life cycle analysis shows 81.8% reduction in life cycle

emissions (80.8 % CO2)

Majority of life cycle emissions generated from raw materials

manufacture

Evolution of green process improvements

Raw material decreases

Organic solvent use decreases

Water use small increase

Recycle operations integrated

Waste disposal reduced

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Environmental Benefits

• Between 2007 and 2020 the new synthesis will eliminate:

• 185,000 tonnes of solvent, >90 % reduction

• 4800 tonnes of mandelic acid, a 100 % reduction

• 2000 tonnes of Raney nickel catalyst, a 90 % reduction

• More than 3.0 million tonnes of CO2 emissions

Equivalent to taking 1,000,000 European cars

off the road for a year!

Thanks and Acknowledgements

• LCA –Leadership: Professor Stewart Slater,

Professor Mariano Savelski (Rowan University)

•LCA - Rowan University Engineering Student Team:

David Hitchcock, Christopher Mazurek, James

Peterson, Michael Raymond

Energy Calculations: Kevin Hettenbach, David

Place, Michael St Pierre, Jay McCauley, Christine Visnic

• Waste Data: Chong-Seng Teng, Ramalingam

Anbuchelian, RK Ramachandran

Pregabalin: C. Martinez, S. Hu, J. Tao, P. Kelleher, D.

Knoechel

ICIS Business Magazine – for the artwork

To YOU – today’s audience

Celebrating a decade of Green Chemistry Leadership 2002-2012 29