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1 Use of Life Cycle Assessment to Evaluate the Sustainable Manufacture of the Active Pharmaceutical Ingredient Pregabalin Mariano Savelski, C. Stewart.

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Presentation on theme: "1 Use of Life Cycle Assessment to Evaluate the Sustainable Manufacture of the Active Pharmaceutical Ingredient Pregabalin Mariano Savelski, C. Stewart."— Presentation transcript:

1 1 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

2  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 2

3  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) Process 1 – Launch Process 3

4 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) H2OH2O H2OH2O H2OH2O Incinerated 4

5 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. 5

6 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 H2OH2O H2OH2O H2OH2O Recycled 6

7 Comparison of Pregabalin Processes Energy (in house) MJ/Kg 85.6 MJ/Kg MJ/Kg

8 Comparison of Pregabalin Processes Energy (in house) MJ/Kg 85.6 MJ/Kg MJ/Kg Energy (total) MJ/Kg MJ/Kg MJ/Kg

9 Summary of Three Processes WasteEnergy Process 1High Process 2Low/MediumLow Process 3LowLow/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 9

10 LCA Evaluation  Emissions generated  Raw materials production  API manufacture energy  Waste disposal  Based on API synthesis  SimaPro ® 7.2, EcoSolvent ® and ASPEN ®   R i = Raw Materials, E i = API Manufacture Energy, W i = Wastes 10

11  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 11

12 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 12

13 547 kg Total Raw Material Manufacturing Emissions/kg API On a per kg of API produced basis for API synthesis Other Acetic Acid1.29% Nickel Catalyst0.81% Ethanol0.80% Methanol0.23% Hydrogen0.02% DIW<0.01% Process 1 Life Cycle Emissions from Raw Materials 13

14 954 kg Total Life Cycle Emissions/kg API On a per kg of API produced basis for API synthesis Process 1 LCA 14

15 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 3 Raw Material Life Cycle Inventories 15

16 148 kg Total Raw Material Manufacturing Emissions/kg API On a per kg of API produced basis for API synthesis 16 Process 2 Life Cycle Emissions from Raw Materials

17 242 kg Total Life Cycle Emissions/kg API On a per kg of API produced basis for API synthesis Process 2 LCA 17

18 87.4 kg Total Raw Material Manufacturing Life Cycle Emissions/kg API On a per kg of API produced basis for API synthesis 18 Process 3 Life Cycle Emissions from Raw Materials

19 183 kg Total Life Cycle Emissions/kg API On a per kg of API produced basis for API synthesis 19 Process 3 LCA

20 Comparison of Selected Raw Material Life Cycle Emissions 20

21 21 LCA of Process 1, 2 and 3

22 Lyrica Drug Product Manufacturing Site Geothermal Heating & Cooling Photovoltaic Wood Pellets Steam 5,410 kW (91 % of total site energy) are generated from renewable energies, reducing 6,760 tons CO 2 emission per year. The vision: A CO 2 neutral facility by

23 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% CO 2 )  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 CO 2 emissions 23

24 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 artwork 24


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