1. 1 BMS Confidential PUBD 13745 Green Process Analysis for Solvent Reduction in Pharmaceutical Synthesis C. Stewart Slater and Mariano J. Savelski, Rowan University, Department of Chemical Engineering, Glassboro, NJ The 11th Annual Green Chemistry & Engineering Conference U. S. Environmental Protection Agency - Region 2 New York, NY March 17, 2010 Adapted from the following papers: Slater and Savelski, Trends in Solvent Management in the Pharmaceutical Industry”, Paper 656a, 2009 Meeting of the American Institute of Chemical Engineers, Nashville, TN, November, 2009. Savelski and Slater, Hounsell, Pilipauskas, Urbanski,“Analysis of Separation Methods for Isopropanol Recovery in the Celecoxib Process,” Paper 290b, 2008 Meeting of the American Institute of Chemical Engineers, Philadelphia, PA, November 2008.

2. 2 BMS Confidential PUBD 13745 Academic-Industrial Interaction Process case studies with a green chemistry and engineering component Three pharmaceutical company partners –Bristol-Myers Squibb* –Novartis –Pfizer Project outcomes show P2 impact –Waste reduced –Energy saved –Carbon footprint reduced –Cost saved “Paper-projects” / design-based, experimentally-based or combination thereof B R P N Slater and Savelski, “Partnerships between Academia and the Pharmaceutical Industry to Advance Green Engineering,” EPA Conference on Creating Business Value: Green Quality through Green Chemistry and Green Engineering in the Pharmaceutical Industry, New York, NY, January 2008

3. 3 BMS Confidential PUBD 13745 Pharmaceutical Industry Highly regulated Long R&D timeline Batch processes High valued final product –API (Active Pharmaceutical Ingredient) High E-factor –High solvent use and waste generated per final product

4. 4 BMS Confidential PUBD 13745 Typical Drug Synthesis – “Campaigns” Multi-step transformations – Intermediate compounds Isolations (purification) R-1 API I-1 I-5 S-16 R-5 S-15 S-2 S-1 S-17 I-5 I-1 I-5 S = Solvent – vary in number and complexity for each step R = Reactant – vary in number and complexity for each step I = Intermediate API = Active Pharmaceutical Ingredient

5. 5 BMS Confidential PUBD 13745 Solvent Issues Solvent use can account for up to 80-90% of total mass of an API synthesis –Majority are organic solvents Solvent costs over life cycle –Pay to purchase –Pay to use (energy and associated costs) –Pay to dispose E-Factor 25->100 kg/kg of API Not optimal by any standard Practice green chemistry & engineering Sheldon, Chem Ind, 1 (1997) 12 Slater and Savelski, J. Environ. Sci. Health, A42, 1595-1605, 2007

6. 6 BMS Confidential PUBD 13745 Pharma Industry Profile US EPA Toxic Release Inventory (TRI) 2008 88 MMkg waste Top ten solvents account for 72% of waste TRI.NET. Washington (DC): Environmental Protection Agency (US), Office of Environmental Information. 2009 - [modified 12/5/2009, cited 2/23/2009].

7. 7 BMS Confidential PUBD 13745 LCA System Boundaries Slater and Savelski, Innov. Pharma. Tech., 29, 78-83, 2009

8. 8 BMS Confidential PUBD 13745 Life Cycle Assessment Tools SimaPro 7.1 (Pré Consultants, Amersfoort, Netherlands) –Features a large database of chemicals, materials, and processes (utilities) –Generate modular LCAs for processes –LCIs of raw material and energy use; emissions to the air, water, and ground –Analysis of green house gas (GHG) emissions Ecosolvent (Safety and Environment Group, Zurich, Switz.) –Moderate size database of chemicals –Used to generate LCAs for waste solvent treatment and compare options

9. 9 BMS Confidential PUBD 13745 –Basic Life Cycle Analysis –Shown for typical solvent manufacture –Waste Incineration w/ energy recovery – still method commonly used –Neglecting in-process use Major Waste Contributions

10. 10 BMS Confidential PUBD 13745 Solvent Life Cycle Inventory Total Raw Materials Used* kg1.74 Total Water Used kg1506 Total Cumulative Energy Demand MJ-Eq65.1 Total Air Emissions kg1.78 CO 2 Emissions kg1.75 CO Emissions kg2.61E-03 Methane Emissions kg1.28E-02 NO X Emissions kg4.42E-03 NMVOC Emissions kg1.97E-03 Particulate Emissions kg1.40E-03 SO 2 Emissions kg5.89E-03 Total Water Emissions kg1.22E-01 VOC Emissions kg5.01E-07 Total Soil Emissions kg1.66E-04 Total Emissions kg1.91 *Excluding water Based on manufacture of 1 kg of Generic Solvent Soil <0.01% CO 2 is 92% of life cycle emissions

11. 11 BMS Confidential PUBD 13745 Green Chemistry and Engineering Greener solvent selection / solvent substitution –Elimination of highly hazardous solvents Solvent reduction –Recovery techniques –Novel approaches to separations –Telescoping –Novel reaction media (ionic liquids) –Biocatalytic routes –Solid-state chemistry Slater and Savelski, Trends in Solvent Management in the Pharmaceutical Industry”, Paper 656a, 2009 Meeting of the American Institute of Chemical Engineers, Nashville, TN, November, 2009.

12. 12 BMS Confidential PUBD 13745 Rowan University Clinics Modeled after medical schools Student-faculty problem solving teams Applied research, development, design Partnership: Industry, Federal/State Agency, Foundation Multidisciplinary Two 3 hour labs/wk, 1 hr/wk meeting with professor/industry Both semesters of Junior & Senior year and Masters students

13. 13 BMS Confidential PUBD 13745 Rowan’s Project Based Curriculum

14. 14 BMS Confidential PUBD 13745 Development of greener adsorption process for pharmaceutical synthesis at East Hanover, NJ R&D facility Heck coupling reaction used to produce pharmaceutical intermediate, A 3, for multiple drug syntheses Batch adsorption technique is currently used to remove palladium (Pd) catalyst from a reactor producing drug intermediate; A 3 – Requires solvent and detergent rinses Novartis Project

15. 15 BMS Confidential PUBD 13745 Proposed greener fixed bed adsorption design is more efficient in Pd removal, reduces solvent and waste Evaluate potential impact; lab scale process run at R&D facility was scaled- up in a simulation and analyzed for economic impact and environmental footprint Green Approach

16. 16 BMS Confidential PUBD 13745 Batch Adsorption – Base Case Scaling-up current process to 100 kg of A 3 manufacturing scale

17. 17 BMS Confidential PUBD 13745 Greener Fixed Bed Adsorber (FBA) Design Scaling-up proposed process to 100 kg of A 3 manufacturing scale

18. 18 BMS Confidential PUBD 13745 Comparison of Two Processes Significant methanol solvent reduction: 31,850 kg/yr Significant water savings: 160,433 kg/yr Values shown are kg/yr for annual production of 4,900 kg A 3

19. 19 BMS Confidential PUBD 13745 Economic Comparison $1,558,000 $597,000 80 % 32 % 4 % 64 % 18 % 2 % *Values shown are kg/yr for annual production of 4,900 kg A 3

20. 20 BMS Confidential PUBD 13745 Life Cycle Inventory ComponentBase Case (kg/yr) FBA (kg/yr) Reduction (kg/yr) % Raw Materials 406,00022,400383,60094 Process Utilities 66514651978 Disposal81,6004,70076,80094 TOTAL488,30027,200460,90094 CO 2 315,70018,600297,10094 Emissions generated by the various components of the solvent life cycle; from cradle to grave Scaled up to annual production of 4,900 kg A 3

21. 21 BMS Confidential PUBD 13745 Project Summary Fixed Bed Adsorber design greener when examined through LCA Total life cycle emissions reduced by 383,600 kg/yr, 94% reduction –CO 2 reduced by 297,100 kg/y Water utilization reduced 9.16 MM kg/yr, 95% reduction Operating cost savings of $0.96 MM/yr, 62% reduction

22. 22 BMS Confidential PUBD 13745 Pfizer Project Investigate solvent recovery alternatives to minimize waste from the Celecoxib manufacturing process Compare current process route with green engineering options –Waste stream reduction and solvent recovery –Define operational sequences –Equipment and process steps required –Estimate costs and environmental impacts –Make proposal / recommendations

23. 23 BMS Confidential PUBD 13745 Student team interacts with –Manufacturing group in New York, NY –Engineering group in Peapack, NJ –Plant operations in Barceloneta, PR Project Approach Analysis of large-scale API production at PR plant –Recovery of isopropanol from water, other alcohols and dissolved solids –Multiple waste streams with varying compositions –Azeotropic mixtures add complexity

24. 24 BMS Confidential PUBD 13745 Process Flow Diagram IPA solvent recovery from final purification steps Segregate waste streams for best process design –Dryer Distillates and (Centrifuge) Wash –Mother Liquor Pre-concentration for Incineration or Sale Integration of existing separation equipment inventory at plant Savelski and Slater, Hounsell, Pilipauskas, Urbanski,“Analysis of Separation Methods for Isopropanol Recovery in the Celecoxib Process,” Paper 290b, 2008 Meeting of the American Institute of Chemical Engineers, Philadelphia, PA, November 2008. Centrifuge IPA / Water Washes 50% IPA 50% Water IPA / Water Washes 49.2% IPA 49.6% H 2 O 0.71% MeOH & EtOH 0.5% TDS Mother Liquor 34.5% IPA 45.2% H 2 O 8.45% MeOH 2.71% EtOH 9.10% TDS Dryer Wet Product Solids Dryer Distillates 50.7% IPA 48.8% H 2 O 0.47% MeOH & EtOH 0% TDS Celecoxib Conc. & Sell ML Recovery Solvents Water API Other

25. 25 BMS Confidential PUBD 13745 Green Design Analysis Base case Various design alternatives simulated with ASPEN –Distillation (Distill)-Pervaporation (PV) and Distill-PV-Distill –Distill-Molecular Sieve Adsorption Sale of Mother Liquor or incineration options Detailed analysis shown for –Distill–PV–Distill with Mother Liquor (ML) Sold Savelski and Slater, Hounsell, Pilipauskas, Urbanski,“Analysis of Separation Methods for Isopropanol Recovery in the Celecoxib Process,” Paper 290b, 2008 Meeting of the American Institute of Chemical Engineers, Philadelphia, PA, November 2008.

26. 26 BMS Confidential PUBD 13745 Proposed Distillation-PV-Distillation Process Purification for only part of waste stream – Centrifuge wash and Dyer distillates for recovery – Mother liquor for (sale) use as generic solvent Overall 57% IPA recovered @ 99.1 wt% for reuse in process Other options of Distill-PV or PV only, yield different recoveries and purities Design basis of 1000 kg waste/hr is used for illustrative purposes Savelski and Slater, Hounsell, Pilipauskas, Urbanski,“Analysis of Separation Methods for Isopropanol Recovery in the Celecoxib Process,” Paper 290b, 2008 Meeting of the American Institute of Chemical Engineers, Philadelphia, PA, November 2008.

27. 27 BMS Confidential PUBD 13745 Life Cycle Inventory Comparison Total Base Case Emissions: 13.7 MM kg/yr Total Dist-PV-Dist Emissions: 1.12 MM kg/yr Savelski and Slater, Hounsell, Pilipauskas, Urbanski,“Analysis of Separation Methods for Isopropanol Recovery in the Celecoxib Process,” Paper 290b, 2008 Meeting of the American Institute of Chemical Engineers, Philadelphia, PA, November 2008. ~92% decrease in total emissions

28. 28 BMS Confidential PUBD 13745 Environmental Summary Operation of Distill-PV-Distill system adds small environmental burden from utilities consumed when compared to overall LCA Pre-concentration of ML and sale off-sets environmental impact of producing virgin “generic” solvent when examining LCA Major LCI reductions from IPA manufacture and incineration avoidance LCA summary: 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) Savelski and Slater, Hounsell, Pilipauskas, Urbanski,“Analysis of Separation Methods for Isopropanol Recovery in the Celecoxib Process,” Paper 290b, 2008 Meeting of the American Institute of Chemical Engineers, Philadelphia, PA, November 2008.

29. 29 BMS Confidential PUBD 13745 Economic Analysis 72% Annual Cost Savings Savelski and Slater, Hounsell, Pilipauskas, Urbanski,“Analysis of Separation Methods for Isopropanol Recovery in the Celecoxib Process,” Paper 290b, 2008 Meeting of the American Institute of Chemical Engineers, Philadelphia, PA, November 2008. $3.82 MM/yr operating cost saving

30. 30 BMS Confidential PUBD 13745 Benefits of Partnership Exchange of new technical ideas Publicity/community relations Presentations/papers – dissemination to wider audience Industry gains knowledge, new approaches to R&D → manufacturing University develops expertise to advance the state-of-the-art New engineers graduate with knowledge in green processes

31. 31 BMS Confidential PUBD 13745 Looking into the future: FY 2010 P2 Grant Initiative Top Most Used Solvents: typical mixtures – Creation of a ready-to-use design tool to test candidate streams for source reduction Examine separation feasibility Modular recovery system design Calculate the environmental footprint reduction (LCA) Calculate profitability (less raw materials, less energy, and less waste disposal) Advancing the knowledge base and transferability across region 2 – Workshops on current practices in pharmaceutical solvent reduction/reuse – Workshops on Design Strategies for Solvent Recovery

32. 32 BMS Confidential PUBD 13745 Acknowledgements Pfizer Jorge Belgodere, Peter Dunn, Greg Hounsell, Daniel Pilipauskas, Frank Urbanski Novartis Thomas Blacklock, Michael Girgis U.S. EPA Region 2 Grant NP97257006-0 Rowan University Students Anthony Furiato, Kyle Lynch, Timothy Moroz, Michael Raymond, Nydia Ruiz

33. 33 BMS Confidential PUBD 13745 Already on Amazon.com