Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Chemspec Europe
Green Chemistry & Engineering Workshop
Munich, Germany
June 5, 2013
– Bristol-Myers Squibb*
– Pfizer R
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
BMS Confidential PUBD 13745
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Pharmaceutical Industry
• Highly regulated
• Long R&D timeline
• High valued final product (API)
• Batch processes
• Multi-step transformations and
isolations
• Solvents used vary in quantity
and complexity for each step
• High E-factor
– High solvent use and waste
generated per final product
BMS Confidential PUBD 13745
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Typical Drug Synthesis – “Campaigns”
• Multi-step transformations – Intermediate compounds
• Isolations (purification)
S-1 S-2 R-5 S-15 S-16 S-17
200
150
Between 2001 and 2010,
100 the mass of waste from
50 the top 20 TRI chemicals
0 from the pharmaceutical
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
Year sector has decreased
Top 4 TRI Organic Solvents from 227 MM kg to 71
120.0
MM kg
Mass of Solvent Waste (MMkg/yr)
100.0
0.0
2001 2002 2003 2004 2005 2006 2007 2008 2010
Emissions
API Waste
Raw Materials
Manufacture Incineration
Utilities
1.4
• Based on values for a single
1.2 pharmaceutical production
Emissions (MM kg)
1
facility (from average of reported
0.8
historic TRI data)
0.6
• Energy use
– Mixing
– Fluid transport
– Pumping, Conveying
– Temperature control
– Heating, Cooling
– Drying
– Filtration
– Other unit operations
– Mechanical Equipment Emissions depend on
source of energy
generation (fuel, etc)
Kim and Overcash, J Chem Technol Biotechnol, 78 (2003) 995-1005
BMS Confidential PUBD 13745
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Solvent Life Cycle Inventory - Grave
Based on Total Air Emissions kg 2.24
Incineration of 1 kg CO2 Emissions kg 1.49
of “Generic” CO Emissions kg 2.29E-05
Methane Emissions kg
Solvent 0.00
NOX Emissions kg 2.73E-03
NMVOC Emissions kg 3.13E-06
Water and Soil
<0.01%
Particulate Emissions kg 3.81E-05
SO2 Emissions kg 0.00
Total Water Emissions kg 3.44E-04
VOC Emissions kg 0.00
Total Soil Emissions kg 0.00
Total Emissions kg 2.24
MMkg of Emissions
1 1
UNCHANGED
0.8 UNCHANGED
0.8
0.6 BASE BA SE BASE
0.6
0.4
0.4
0.2
GREEN GREEN 0.2 GREEN
0 GREEN
Manufacture Incineration In Process Use 0
Manufacture Incineration In Process Use
Telescoping Scenario
1.6
• Solvent Recovery Scenario
1.4
– 80% of solvent waste is recovered and
1.2 recycled back into the process
MMkg of Emissions
1 BASE BASE
0.8
• “Greener” Solvent Scenario
0.6
BASE
– Solvents that release fewer emissions during
manufacture and incineration are employed
0.4
GREEN GREEN GREEN in the process, replacing the original solvents
0.2
0
• Telescoping Scenario
Manufacture Incineration In Process Use
– A process employing multiple steps is
reduced to a process employing 2/3 the
number of steps
1
– Base Case Scenario:
0.8
BASE
3.4 MM kg
BASE BASE
0.6
– Best Scenario: 0.76
0.4
MM kg
0.2
GREEN
0
GREEN GREEN
– Total Reduction:
Manufacture Incineration In Process Use
2.65 MM kg
0.8
0.7
• Entrainer-based distillation
0.2
0.1
pollution
• Membrane pervaporation is a “greener”
alternative for azeotropic separations
Water = blue
• Applications: Solvent = green
- 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
Dehydrated
solvent for reuse
Solvent-water
azeotropic mixture
Pervaporation
Typical Solvents
• Isopropanol (az)
• Ethanol (az)
• Methanol
Solvent-water • Ethyl acetate
waste stream
• Butyl acetate
• Acetone
Low flow rate
stream: water with • Acetronitrile (az)
some solvent • Tetrahydrofuran (az)
• n-Butanol
• Methylethylketone (az)
Slater and Savelski, Innov. Pharma. Tech., 29 (2009) 78-83.
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Case Studies
Solvent Recovery
• Bristol-Myers Squibb – THF/Water
• Pfizer – Celecoxib – IPA/Water
• Pfizer – Selamectin – Acetone/Acetonitrile
• Pfizer – Nelfinavir – THF/IPA
• Pfizer – Hydrocortisone – Acetone/Toluene
Green Solvent Assessment
• PennAkem – MeTHF vs THF
BMS Confidential PUBD 13745
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Bristol-Myers Squibb
• Integration of PV technology with a Constant
Volume Distillation (CVD) operation
• One step in synthesis of new oncology drug
• Current process: Decrease water content in
THF solvent phase to 0.5%
– Requires 13.9 kg THF/kg API
7.85 kg THF entrainer/kg API
– Generates 9.2 kg Waste/kg API
• LCI / LCA analysis indicates emissions are
significant based on solvent life cycle
Slater, Savelski, Moroz, Raymond, Green Chem. Lett. Reviews 5 (2012), 55-64
BMS Confidential PUBD 13745
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Bristol-Myers Squibb cont.
Proposed CVD-PV Hybrid Process
900
used and waste 800
4000
3697
• Environmental
kilograms
3000
500
414
savings 400
2500
Cost ($)
300 2000
100
0 1000
THF Purchased Waste
part of story 500 With Pervaporation Current
267
19
0
THF Waste Disposal
Slater, Savelski, Moroz, Raymond, Green Chem. Lett. Reviews 5 (2012), 55-64
.
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Life Cycle Inventory Comparison
Total CVD Life Cycle Emissions:
4,390 kg, 64.6 kg waste/kg API
Waste = 5.5%
Steam 26%
Steam = 82%
0.8
0.5
0.3
0
0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
complexity
Mass Fraction IPA in Liquid
separation equipment
Celecoxib Dryer Distillates
inventory at plant Dryer 50.7% IPA
48.8% H2O
0.47% MeOH & EtOH
0% TDS
Second Distillation
Celecoxib
Waste
IPA
Vacuum Pump Vacuum Pump Product
Initial Distillation
Water Waste
With TDS
IPA Manufacture
40%
Incineration
60%
6,000,000
5,000,000
72% Annual Cost ML Concentrate sale
4,000,000
Savings Membrane Modules
Operating Labor
Annual Cost
3,000,000 Maintenance
Cooling Water
2,000,000 Electricity
Steam
1,000,000 Waste Disposal
Fresh IPA
0
Base Case Distil-PV-Distil-Sell ML
-1,000,000
Design Case
Utilities
12,00,000
Incineration
Raw Materials
Total Life Cycle Emissions (kg/yr)
10,00,000
8,00,000
6,00,000
4,00,000
2,00,000
0
Base Case Recovery Case Base Case Recovery Case Base Case Recovery Case
Selamectin Nelfinavir Hydrocortisone
1.20E+00
8.00E-01
6.00E-01
4.00E-01
2.00E-01
0.00E+00
ecoTHF (Extractive Distillation) ecoTHF (Dist+PV) ecoMeTHF
ASW/Excel
1.2
0.8
0.6
0.4
0.2
0
0.8 0.825 0.85 0.875 0.9 0.925 0.95 0.975 1
XIPA
BMS Confidential PUBD 13745
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R.SWEED Software tool
Pervaporation Modeling – Unit Design
F,T1
R1,T2 R2,T3 R3,T4 R4,T5 R5,T6
A1 A2 A3 A4 A5
P1 P2 P3 P4 P5
Mass Balance
Energy Balance
Maximum Life
Cycle
Emissions
Avoided
RR = 9
0.9 Savings
100
0.8
LCA
Avoided
0.7 Emissions
80
Savings (USD/yr)
0.6 Recovery
Recovery
60 0.5
Maximum Life Cycle
0.4
40
Emissions Avoided and
Cost Savings 0.3
0.1
0 0.0
2 3 4 5 6 7 8
Feed Stage
BMS Confidential PUBD 13745
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“Plant of the Future”
• Green concepts integrated in drug
development → more sustainable
manufacturing platform
• Limited number of ‘universal’ green solvents
utilized
– 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
BMS Confidential PUBD 13745
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Acknowledgements
Bristol-Myers Squibb
San Kiang, Thomas LaPorte,
Lori Spangler, Stephan Taylor
Pfizer
Peter Dunn, Greg Hounsell, Daniel
Pilipauskas, Frank Urbanski
PennAKem
Steve Prescott, Dave Aycock, Bogdan
Comanita, Jeff Shifflette
Solvents in
Waste
Mixture
Classifier
Solvent Recovery
Process Selection
• Economic $1,000,000.00
feasibility $500,000.00
NPV=TAS TAS
$
$0.00
NPV
0 10000 20000 30000 40000 50000 60000 70000 80000 90000 100000
Slater, Savelski, Moroz, Raymond, Green Chem. Lett. Reviews 5 (2012), 55-64
WASTE THF
Water
RECOVER
Y
Water
THF