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Use of Life Cycle Assessment to Evaluate the Sustainable Manufacture of the Active

Pharmaceutical Ingredient Pregabalin

Mariano Savelski, C. Stewart Slater Rowan University

Peter Dunn, Donald Knoechel, Christine Visnic Pfizer, Inc.

Paper 124c

2011 AIChE Annual Meeting

Minneapolis, MN October 2011

Pregabalin is a Drug for the treatment of Neuropathic Pain Launched in the US in September 2005 Sales $1.16 billion (2006), $3.06 billion (2010)

Pregabalin the active ingredient in Lyrica

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Reasonable synthesis of racemic Pregabalin

Final Step Classical Resolution

Wrong enantiomer difficult to recycle

E factor 86 (ie 86 kilos waste per kilo of product)

Two reactions performed at reflux (High energy use)

CN

CO2EtEtO2C

NH2

CO2H

NH2

CO2H

CN

CO2HCO2EtEtO2C

(S)-Mandelicacid

25-29 % overall

> 99.5 % ee

High EnergyProcess performed at reflux

Chemistry in RacemicForm, half materials andEnergy Wasted

Process 1 – Launch Process

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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)

Biocatalysis reaction is very concentrated

Significant waste reduction (see later)

CO2EtEtO2C

CN

CO2Et

CN

O2C

CO2EtEtO2C

CN

CO2Et

CNNH2

CO2H

Lipase

(S)-enantiomer

> 98 % ee

_Racemic CNDE

H2 5 % Ni

Pregabalin

(R)-CNDE

H2OH2O

H2O

Incinerated

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Enzymatic Resolution of CNDE

Enzymatic hydrolysis of Cyano diester enabled early resolution of chiral center

Enzyme screen revealed 2 (S)-selective hits with E>200:

Both Lipases

Selected the Lipase with the highest specific activity for commercialization less waste.

(CH3)2CHCH2 CN

CO2EtEtO2C

(CH3)2CHCH2

CO2EtO2C

CN(CH3)2CHCH2

CO2EtEtO2C

CNEnzyme

Water

R-Diester

_

S-MonoesterOrganic Soluble

+

Water Soluble

RacemicDiester

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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 11

CO2EtEtO2C

CN

CO2Et

CN

O2C

CO2EtEtO2C

CN

CO2Et

CNNH2

CO2H

Lipase

(S)-enantiomer

> 98 % ee

_Racemic CNDE

H2 5 % Ni

Pregabalin

(R)-CNDE

H2OH2O

H2O

Recycled

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Comparison of Pregabalin 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) 475.2 MJ/Kg 85.6 MJ/Kg 169.6 MJ/Kg

Comparison of Pregabalin 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) 475.2 MJ/Kg 85.6 MJ/Kg 169.6 MJ/Kg

Energy (total) 511.4 MJ/Kg 113.5 MJ/Kg 185.9 MJ/Kg

Summary of Three Processes

Waste Energy

Process 1 High High

Process 2 Low/Medium Low

Process 3 Low Low/Medium

Easy to see that Process 1 is the worst To determine whether process 2 or process 3 is the best from an environmental standpoint requires a more detailed Life Cycle Assessment

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LCA Evaluation

Emissions generated Raw materials production API manufacture energy Waste disposal

Based on API synthesis SimaPro® 7.2,

EcoSolvent® and ASPEN ®

Ri = Raw Materials, Ei = API Manufacture Energy, Wi = Wastes

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e

i

w

iiii

r

iii LCAWELCIRLCI )()(

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

Utilities based on fuel mix at plant site Waste disposal determined by EcoSolvent based

on disposal method Incineration WWTP Recovery process, e.g., distillation

Life Cycle Inventory Generation

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

24.8 kg

Process 1 Raw Material Life Cycle Inventories

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547 kg Total Raw Material Manufacturing Emissions/kg API

On a per kg of API produced basis for API synthesis

Other Acetic Acid 1.29% Nickel Catalyst 0.81% Ethanol 0.80% Methanol 0.23% Hydrogen 0.02% DIW <0.01%

racemic-CNDE28.2%

KOH3.08%IPA

28.3%Mandelic Acid

13.94%

THF23.4%

Other3.16%

Process 1Life Cycle Emissions from Raw Materials

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954 kg Total Life Cycle Emissions/kg API

On a per kg of API produced basis for API synthesis

Process 1 LCA

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Raw Material Manufacturing

55.5%

In-process Energy10.32%

Waste Disposal & Recovery

34.2%

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

Process 2 and 3Raw Material Life Cycle Inventories

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148 kg Total Raw Material Manufacturing Emissions/kg API

On a per kg of API produced basis for API synthesis16

Process 2Life Cycle Emissions from Raw Materials

242 kg Total Life Cycle Emissions/kg API

On a per kg of API produced basis for API synthesis

Process 2 LCA

Raw Material Manufacturing

61.2%

In-process Energy7.58%

Waste Disposal & Recovery

31.2%

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87.4 kg Total Raw Material Manufacturing Life Cycle Emissions/kg API

On a per kg of API produced basis for API synthesis

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Process 3Life Cycle Emissions from Raw Materials

183 kg Total Life Cycle Emissions/kg API

On a per kg of API produced basis for API synthesis

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Process 3 LCA

Comparison of Selected Raw Material Life Cycle Emissions

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0

100

200

300

400

500

600

700

800

900

1000

Life

Cyc

le E

mis

sion

s (k

g/kg

API

)

Total Carbon Dioxide Emissions

Waste Disposal & Recovery

In-process Energy

Raw Material Manufacturing

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LCA of Process 1, 2 and 3

Lyrica Drug Product Manufacturing Site

Geothermal Heating& Cooling

Photovoltaic

Wood PelletsSteam

5,410 kW (91 % of total site energy) are generated from renewable energies, reducing 6,760 tons CO2 emission per year.

The vision: A CO2 neutral facility by 2012 22

Summary

Biocatalytic route significantly reduces emissions and energy use

Cradle to gate life cycle analysis shows 81.2% 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 increases Recycle operations integrated Waste disposal reduced

Between 2007 and 2020 we estimate that the enzymatic processes will save 3 MM tons of CO2 emissions

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Thanks and Acknowledgments

LCA - Rowan Univ Engineering Clinic Team David Hitchcock, Christopher Mazurek, James Peterson, Michael Raymond

Energy Calculations Kevin Hettenbach, David Place, Michael St Pierre, Jay McCauley

Waste data Chong-Seng Teng, Ramalingam Anbuchelian, RK Ramachandran

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

To YOU – today’s audience

Thanks also to ICIS Business Magazine for artwork24