trends in solvent management in the pharmaceutical industry c. stewart slater and mariano j....
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Trends in Solvent Management in the Pharmaceutical Industry
C. Stewart Slater and Mariano J. SavelskiDepartment 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
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
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
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
– CO2 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
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Mass Fraction IPA in Liquid
Mas
s Fr
actio
n IP
A in
Vap
or
760 torr
150 torr
3 bar
10 bar
25 bar
45 deg
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 = blueSolvent = green
www.sulzerchemtech.com
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)
THFWater
THFTrace water
1,2-Propanediol
WASTE
Extractive Distillation
Pervaporation
THFWater
THFTrace Water
WaterTHF
No Recovery
THFWater
THFWater
WASTE RECOVERY
RECOVERY
RECOVERY
Green Integration Illustrative ExampleProcess optimizationEmissions reduction
Cost savingsEnergy savings
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 Washes50% IPA
50% Water IPA / Water Washes 49.2% IPA 49.6% H2O 0.71% MeOH and EtOH 0.5% TDS
Mother Liquor 34.5% IPA 45.2% H2O 8.45% MeOH 2.71% EtOH 9.10% TDS
Dryer
Wet Product Solids
Dryer Distillates
50.7% IPA 48.8% H2O 0.47% MeOH and EtOH 0% TDS
Celecoxib
Conc. & Sell ML
Recovery
SolventsWater
APIOther
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
Water WasteWith TDS
CelecoxibWaste
IPA Product
Initial Distillation
Alcohol Waste
Second Distillation
Vacuum Pump Vacuum Pump
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,
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, 8th Inter. Conf. EcoBalance, Tokyo, Japan, December 2008.
Economic Analysis
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2,000,000
3,000,000
4,000,000
5,000,000
6,000,000
Base Case Distil-PV-Distil-Sell ML
Design Case
An
nu
al C
ost
ML Concentrate sale
Membrane Modules
Operating Labor
Maintenance
Cooling Water
Electricity
Steam
Waste Disposal
Fresh IPA
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 practicesGreen advantage• Waste minimization• Cost effective
Acknowledgements
• Pfizer
• U.S. Environmental Protection
Agency P2 grant #NP97257006-0