1. Trends in Solvent Management in the Pharmaceutical Industry C. Stewart Slater and Mariano J. Savelski Department of Chemical Engineering Rowan University Glassboro, NJ Session 656: Green Engineering in the Fine Chemical and Pharmaceutical Industry AIChE Annual Meeting Nashville, TN November 8-13, 2009

2. 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 of E-Factor 25->100 kg/kg of API* Not optimal for a ChE!!! Practice green chemistry & engineering Sheldon, Chem Ind, 1 (1997) 12

3. Pharma Industry Profile US EPA Toxic Release Inventory (TRI) 2006 128 MM kg waste Top ten solvents account for 80% of waste Lopez, Toxic Release Inventory, US EPA, 2006

4. Solvent Waste Management Trends ~70% of waste is treated or recycled* ~30% of waste is used for energy recovery* Only a small percent is directly released into the environment Incineration remains the disposal method of choice –CO 2 emissions –Heat recovery Increasing trend towards solvent recovery Lopez, Toxic Release Inventory, US EPA, 2006

5. Optimization of Solvent Use and Waste Reduction 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

6. “Plant of the Future” The plant of the future will likely use a limited number of ‘universal’ green solvents –Properties allow for easy recovery –Used with other campaigns –Integrated solvent recovery systems Continuous processing simplifies recovery design strategies Energy exchange networks Slater and Savelski, Innov Pharma Tech, 29 (2009) 78

7. Solvent Recovery Solvent recovery has increased, On-site and Off-site recovery facilities Distillation still dominates - straightforward separation for ideal mixtures Pharmaceutical wastes typically contain –Multiple solvents –Azeotropic mixtures –Unconverted reactants, etc Complex separation trains to obtain high quality solvent for reuse Centralized solvent recovery facility > New approach - integrate separation processes at the point of use

8. Solvent Recovery Azeotropic separations pose the most challenge in processing Entrainer-based distillation –More energy intensive –Entrainers pose additional source of pollution Membrane pervaporation is a “greener” alternative for azeotropic separations

9. Pervaporation Membrane Processes Applications: - Selective solvent-water separations / Dehydration - Azeotrope separations Advantages: - Energy savings over distillation - No entrainer (e.g., benzene) needed for azeotropic separations - Solvent reuse; solvent savings - Avoid solvent disposal / solvent thermal oxidation Water = blue Solvent = green www.sulzerchemtech.com

10. PV Process Integration Solvent-water waste stream Pervaporation Dehydrated solvent for reuse Solvent-water azeotropic mixture Low flow rate stream: water with some solvent Typical Solvents Isopropanol (az) Ethanol (az) Methanol Ethyl acetate Butyl acetate Acetone Acetronitrile (az) Tetrahydrofuran (az) n-Butanol Methylethylketone (az)

11. THF Water THF Trace water 1,2- Propanediol WASTE Extractive Distillation Pervaporation THF Water THF Trace Water Water THF No Recovery THF Water THF Water WASTE RECOVERY Green Integration Illustrative Example Process optimization Emissions reduction Cost savings Energy savings

12. Process Case Study - Pfizer Investigation of solvent recovery alternatives to reduce solvent waste in celecoxib process IPA solvent recovery from final purification steps Integration of pervaporation with distillation using existing equipment inventory Slater, Savelski, Hounsell, Pilipauskas, Urbanski, ACS Green Chem & Eng Annual Conf, Washington DC, June 2008, Centrifuge IPA / Water Washes 50% IPA 50% Water IPA / Water Washes 49.2% IPA 49.6% H 2 O 0.71% MeOH and 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 and EtOH 0% TDS Celecoxib Conc. & Sell ML Recovery Solvents Water API Other

13. 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 A design basis of 1000 kg waste/hr is used for illustrative purposes Slater, Savelski, Hounsell, Pilipauskas, Urbanski, ACS Green Chem & Eng Annual Conf, Washington DC, June 2008,

14. Life Cycle Emissions Comparison Total Base Case Emissions: 29.5 kg waste/kg API Total Dist-PV-Dist Emissions: 2.4 kg waste/kg API ~92% decrease in total emissions Savelski, Slater, Carole, 8 th Inter. Conf. EcoBalance, Tokyo, Japan, December 2008.

15. Economic Analysis 72% Annual Cost Savings Slater, Savelski, Hounsell, Pilipauskas, Urbanski, ACS Green Chem & Eng Annual Conf, Washington DC, June 2008,

16. Summary Solvent use and waste practices should be constantly reviewed Development of sustainable practices Green advantage Waste minimization Cost effective

17. Acknowledgements Pfizer U.S. Environmental Protection Agency P2 grant #NP97257006-0