Trends in Solvent Management in the Pharmaceutical Industry

transcript

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

0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1

Mass Fraction IPA in Liquid

760 torr

150 torr

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

Extractive Distillation

Pervaporation

THFWater

THFTrace Water

WaterTHF

No Recovery

THFWater

WASTE 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

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

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

-1,000,000

1,000,000

2,000,000

3,000,000

4,000,000

5,000,000

6,000,000

Base Case Distil-PV-Distil-Sell ML

Design Case

ML Concentrate sale

Membrane Modules

Operating Labor

Maintenance

Cooling Water

Electricity

Waste Disposal

Fresh IPA

72% Annual Cost Savings

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

Trends in Solvent Management in the Pharmaceutical Industry

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