Trends in Solvent Management in the Pharmaceutical Industry

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 AICh. E Annual Meeting Nashville, TN November 8 -13, 2009

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 Ch. E!!! • Practice green chemistry & engineering Sheldon, Chem Ind, 1 (1997) 12

Pharma Industry Profile Various other solvents N, NDimethylformamide n-Butyl alcohol Methanol n-Hexane Chloroform Nitrate compounds Hydrochloric acid Acetonitrile Toluene • US EPA Toxic Release Inventory (TRI) 2006 • 128 MM kg waste • Top ten solvents account for 80% of waste Dichloromethan e Lopez, Toxic Release Inventory, US EPA, 2006

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

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

“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

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

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

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

PV Process Integration Dehydrated solvent for reuse Solvent-water azeotropic mixture Pervaporation Solvent-water waste stream 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 • Methylketone (az)

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

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 Recovery IPA / Water Washes 50% IPA 50% Water Solvents Water API Other Centrifuge Wet Product Solids Celecoxib Dryer IPA / Water Washes 49. 2% IPA 49. 6% H 2 O 0. 71% Me. OH and Et. OH 0. 5% TDS Mother Liquor 34. 5% IPA 45. 2% H 2 O 8. 45% Me. OH 2. 71% Et. OH 9. 10% TDS Conc. & Sell ML Dryer Distillates 50. 7% IPA 48. 8% H 2 O 0. 47% Me. OH and Et. OH 0% TDS Slater, Savelski, Hounsell, Pilipauskas, Urbanski, ACS Green Chem & Eng Annual Conf, Washington DC, June 2008,

Proposed Distillation-PV-Distillation Process A design basis of 1000 kg waste/hr is used for illustrative purposes • 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 Slater, Savelski, Hounsell, Pilipauskas, Urbanski, ACS Green Chem & Eng Annual Conf, Washington DC, June 2008,

Life Cycle Emissions Comparison Total Base Case Emissions: 29. 5 kg waste/kg API IPA Manufacture 40% Incineration 60% Total Dist-PV-Dist Emissions: 2. 4 kg waste/kg APIML Distillation 18% Dist-PV-Dist 22% ~92% decrease in total emissions Savelski, Slater, Carole, 8 th Inter. Conf. Eco. Balance, Tokyo, Japan, December 2008. IPA Manufacture 59%

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

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

Acknowledgements • Pfizer • U. S. Environmental Protection Agency P 2 grant #NP 97257006 -0