1. 1 BMS Confidential PUBD 13745 A Collaborative Partnership to Develop Strategies for Waste Minimization and Solvent Recovery for the Celecoxib Process Mariano J. Savelski 1, C. Stewart Slater 1, Gregory Hounsell 2, Daniel Pilipauskas 2, Frank Urbanski 2 1 Rowan University, Glassboro, NJ 2 Pfizer, Inc., New York, NY The 11th Annual Green Chemistry & Engineering Conference Session: Fine Chemical Process Design 12 th Green Chemistry & Engineering Conference Washington, DC June 24-27, 2008

2. 2 BMS Confidential PUBD 13745 Pfizer has long considered maintaining safe workplaces and environmentally-sound operations one of our highest priorities. We were a Green Chemistry “Early Adopter” in the USA, starting a Green Chemistry Program in 2001 at Groton, CT Senior Leadership is committed to program success –Appoint full time Green Chemistry Leader, Dr. Peter Dunn, in 2006 –Cross-divisional steering committee (R&D and Mfg sites globally) –Fully aligned efforts –Leverage each other’s expertise and experience Pfizer Green Chemistry History

3. 3 BMS Confidential PUBD 13745 Pfizer Green Chemistry Objectives Foster openness and dialogue with colleagues, the pharmaceutical industry, regulatory authorities, academia and the public Educate current and future generations of scientists and engineers about Green Chemistry so it becomes intrinsic to the way they work Proactively integrate Green Chemistry into research and product development, and retroactively into current Pfizer products where feasible Use metrics to track and improve our environmental performance

4. 4 BMS Confidential PUBD 13745 Solvent Recovery has long been a common practice at most API manufacturing sites, when –technically feasible, –economically justified, –acceptable to product quality Composition and volume of process waste streams, and the costs for waste disposal, fresh solvent purchase, and energy all must be considered Solvent Recovery processes therefore lag Process Chemistry developments Solvent Recovery at Pfizer

5. 5 BMS Confidential PUBD 13745 Celecoxib Solvent Recovery 1 st Generation Chemistry at Augusta site –Solvent recovery practiced on one stream 2 nd Generation Chemistry at Cruce Davilla site –New waste streams needed new recovery process –Limited recovery scheme proposed in 2005 –Required multi-million dollar equipment investment –Mfg site consolidation pre-empted an investment 2 nd Generation Chemistry, at Barceloneta site –Substantial solvent recovery equipment base exists –Rowan collaboration provided opportunity to consider new technological approaches to maximize cost and environmental benefits –Provided student team with a real-world challenge

6. 6 BMS Confidential PUBD 13745 Project Objectives Investigate solvent recovery alternatives to minimize waste from the Celecoxib manufacturing process Compare current process route with green engineering options –Waste stream reduction and isopropanol (IPA) recovery –Define operational sequences –Equipment and process steps required –Estimate costs and environmental impacts –Make proposal / recommendations

7. 7 BMS Confidential PUBD 13745 General Celecoxib Process BFD E-Factor = 9.0

8. 8 BMS Confidential PUBD 13745 Project Approach Analyze waste flows per batch of Celecoxib Examine capabilities of existing equipment at Barceloneta for IPA recovery Segregate waste streams for best process design –Dryer Distillates and (Centrifuge) Wash –Mother Liquor Pre-concentration for Incineration or Sale Utilize/schedule separation process units based upon Barceloneta’s batch production

9. 9 BMS Confidential PUBD 13745 Process Review Traditional and non-traditional –Distillation –Liquid-Liquid Extraction –Extractive Distillation –Reactive Distillation –Molecular Sieves –Pervaporation Water forms an azeotrope with IPA at 87.4 wt% IPA and not pressure sensitive Need a sequential separation approach – Distill to azeotrope first

10. 10 BMS Confidential PUBD 13745 Extractive Distillation Diisopropyl Ether –Produces 99% purity IPA product in a binary (IPA/water) system –High operating pressure required for distillation column (30 atm) Ethylene Glycol –Produces 94% purity IPA product –High column utilization (4 columns) Dimethyl sulfoxide –Produces 99% purity IPA product –High column utilization (4 columns) Summary: all methods exceed equipment capabilities at Barceloneta

11. 11 BMS Confidential PUBD 13745 Molecular Sieve (MS) Distill - MS High purity IPA product achievable –99.5% IPA * Based on Installation Factor estimate Capital cost of system required –Base module cost: $500,000 –Total cost estimate to get system to operation: $1.5 MM*

12. 12 BMS Confidential PUBD 13745 Pervaporation (PV) Various Distill – PV design configurations using existing Barceloneta units –Pervaporation units run in series or parallel –Distillation followed by pervaporation –Distillation followed by pervaporation followed by another distillation column Modeled using –Combined waste streams –Dryer distillates and centrifuge wash Model limitations – cannot predict relative transport of MeOH and EtOH

13. 13 BMS Confidential PUBD 13745 Pervaporation Most promising results are seen at treating a moderate throughput of dryer distillates and wash –The total amount of steam required for the system is 1,100 kg/hr –12 kW of work is needed for pervaporation –Increasing the flowrate significantly decreases the IPA product purity A design basis of 1000 kg waste/hr is used for illustrative purposes

14. 14 BMS Confidential PUBD 13745 Pervaporation The use of a polishing distillation column will increase IPA purity to 99.1 wt% –Additional 65 kg/hr of steam is required Using the total waste stream feed composition: –Distill-PV produces an IPA product of 93.3 wt% IPA –Distill-PV-Distill produces an IPA product of 96.2 wt% IPA Based on scheduling of the pervaporation system, only dryer –distillates and wash are treated

15. 15 BMS Confidential PUBD 13745 Distillation-Pervaporation-Distillation IPA Recovered2325 kg/batch IPA Purity99.1% Waste Water Treated5,020 kg/batch Solvent Waste Treated 2,740 kg/batch Steam Used10,700 kg/batch Electricity Used59 kWh/batch Cooling Water Used 91,200 gal/batch

16. 16 BMS Confidential PUBD 13745 Annual Operating Costs Base Case: $5.28 MM Distill-PV-Distill/Sell ML $1.46 MM

17. 17 BMS Confidential PUBD 13745

18. 18 BMS Confidential PUBD 13745 Economic Conclusions PV and MS options provide comparable operating savings (64-73%) to base case MS requires $1.5 MM capital investment PV provides non-capital alternative to MS –Adding “touch-up” column to get 99.1% IPA: +0.51% increase to operating costs (72% savings) Selling the concentrated mother liquor will decrease operating costs by 24% Best case: Distill-PV-Distill & sell mother liquor, $3.82 MM/yr savings

19. 19 BMS Confidential PUBD 13745 Life Cycle Emissions

20. 20 BMS Confidential PUBD 13745 Environmental Conclusions All PV and MS options provide substantial life cycle emissions savings from base case –64 - 93% savings in total emissions –65 - 96% savings in CO 2 emissions Selling of the mother liquor significantly reduces life cycle emissions –Improves alternatives by 75% Summary of Distill-PV-Distill/sell ML –Yearly reduction of 12.63 MM kg emissions/yr (92% reduction from base case) –Yearly reduction of 11.55 MM kg CO 2 /yr (95% reduction from base case)

21. 21 BMS Confidential PUBD 13745 Conclusions Distillation-Pervaporation-Distillation is recommended –Pervaporation system currently at Barceloneta with no capital investment required, only new membranes Higher purity than distillation-pervaporation with small increase of costs and environmental emissions Pilot testing recommended due to model limitations

22. 22 BMS Confidential PUBD 13745 Acknowledgements Rowan Clinic students –Anthony Furiato –Kyle Lynch –Timothy Moroz Support of Pfizer Green Chemistry Program –Jorge Belgodere –Peter Dunn –Greg Hounsell –Daniel Pilipauskas –Frank Urbanski Support of U.S. Environmental Protection Agency – P2 Program ( NP97257006-0)