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