The 11th Annual Green Chemistry & Engineering Conference

Solvent Recovery Strategies for the

Sustainable Design of APIs
Mariano J. Savelski and C. Stewart Slater
Rowan University, Department of Chemical Engineering
USA

Chemspec Europe
Green Chemistry & Engineering Workshop
Munich, Germany
June 5, 2013

BMS Confidential PUBD 13745

1
 Rowan University
• Located in New Jersey
• Formerly Glassboro State
College
(September 4, 1923)
• Summit between
President Lyndon Johnson
& Soviet Premier
Aleksei Kosygin in 1967

BMS Confidential PUBD 13745

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 Rowan
Engineering
• Henry Rowan Gift in 1992
of $100 Million
• First Graduating Class in 2000
• Primary focus on undergraduate
education
– Small class sizes
– Student-faculty interaction
– Educational innovation
and novel pedagogy
BMS Confidential PUBD 13745
3
 Overview
• Introduction to Solvent Use
• Life Cycle Analysis
• Solvent Reduction / Recovery
• Rowan Green Engineering Case Studies
– Bristol-Myers Squibb
– Pfizer
• Selamectin
• Hydrocortisone
• Nelfinavir
– PennAkem
• Software Tool

BMS Confidential PUBD 13745

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 Academic-Industrial Interaction
• Process case studies with a green chemistry
and engineering component
• Three pharmaceutical company partners
P

– Bristol-Myers Squibb*
– Pfizer R

– PennAKem (Memphis, TN)

• Project outcomes show P2 impact
– Waste reduced
– Energy saved
– Carbon footprint reduced
– Cost saved

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

R-1 I-1 I-1 I-5 I-5 I-5

I-1 I-5 API
Filtration or Filtration
Reaction Wash Step
Reaction
Crystallization/ DIstillation Crystallization/
Recrystallization Recrystallization

Waste Waste Waste

S = Solvent – vary in number and complexity for each step

R = Reactant – vary in number and complexity for each step
I = Intermediate
API = Active Pharmaceutical Ingredient

BMS Confidential PUBD 13745

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 Solvent Issues
• Solvent use can account for up to 80-90% of total
mass of an API synthesis
– Majority are organic solvents
• Solvent implications over life cycle
– Purchase cost, energy, waste generated
– Cost to use (energy and associated costs)
– Disposal cost and emissions
• E-Factor 25->100 kg/kg of API
• Not optimal by any standard

Sheldon, Chem . Indus., 1 (1997) 12

Slater and Savelski, J. Environ. Sci. Health, PUBD
BMS Confidential A42 (2007) 1595-1605
13745
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 Pharma Industry Profile
Ammonia Other Solvents
N-methyl-2- MTBE
pyrrolidone Cyclohexane
N,N-
Dimethylformiamide
Formic Acid • US EPA Toxic
Chloroform
Release Inventory
Methanol (TRI) 2010
Acetonitrile • 71 MM kg waste
• Top ten solvents
Toluene account for 94% of
waste
Dichloromethane

TRI.NET. Washington (DC): Environmental Protection Agency (US), Office of

Environmental Information. 2010

BMS Confidential PUBD 13745

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 Pharma Industry Profile
250
Mass of Solvent Waste (MMkg)

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

80.0 From 2001 to 2010, the

60.0 top 4 TRI chemicals were
40.0
the same
20.0

0.0
2001 2002 2003 2004 2005 2006 2007 2008 2010

Methanol Toluene Dichloromethane Acetonitrile

BMS Confidential PUBD 13745
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Life Cycle System Boundaries

Emissions

Emissions Solvent Emissions

Manufacturing

API Waste
Raw Materials
Manufacture Incineration

Utilities

CRADLE Emissions GRAVE

Slater and Savelski, Innov. Pharma. Tech., 29 (2009) 78-83.

BMS Confidential PUBD 13745

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 Life Cycle Emissions
1.6

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

0.4 • Life cycle emissions equal

0.2
3.4 MM kg/year
0
Manufacture Incineration In Process Use
– 75% of emissions result from
Manufacture manufacture and incineration
Emissions = 3.4 MM kg
Incineration
of solvents
25% In Process Use – Solvent use may account for
36%
80-90% of the total mass in an
API synthesis
39%

• High potential for “green”

process improvements
Jimenez-Gonzalez, Curzons,BMS
Constable, and Cunningham,
Confidential PUBD 13745 Int J LCA, 9 (2) (2004) 114-121
12
Solvent Life Cycle Inventory - Cradle
Based on Total Air Emissions kg 1.78
manufacture of 1 kg CO2 Emissions kg 1.75

of “Generic” CO Emissions kg 2.61E-03

Methane Emissions kg 1.28E-02
Solvent
NOX Emissions kg 4.42E-03
Soil
<0.01% NMVOC Emissions kg 1.97E-03
Water
6% Particulate Emissions kg 1.40E-03
SO2 Emissions kg 5.89E-03
Total Water Emissions kg 1.22E-01
Air
94% VOC Emissions kg 5.01E-07
Total Soil Emissions kg 1.66E-04
Total Emissions kg 1.91

CO2 is 92% of life

cycle emissions
SimaPro 7.1 (Pré Consultants, Amersfoort,
BMS Confidential Netherlands)
PUBD 13745
13
 In-Process Use – Energy Profile

• 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

BMS Confidential PUBD 13745

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 Optimization of Solvent Use
• Greener solvent selection / solvent
substitution
– Reduce solvent’s carbon footprint
– Elimination of highly hazardous solvents
• Solvent reduction
– Recovery techniques
– Novel approaches to separations
– Telescoping
– Novel reaction media (ionic liquids)
– Biocatalytic routes
– Solid-state chemistry
Slater, Savelski, Carole, Constable, Chapter 3, in Green Chemistry in the Pharmaceutical
Industry, Dunn, Wells, Williams, Eds., Wiley-VCH Verlag Publishers, (2010) 49-82.

BMS Confidential PUBD 13745

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Green Eng the “Avg” Pharma Facility
1.6
Solvent Recovery Scenario 1.6
“Greener” Solvent Scenario
1.4 1.4
1.2 1.2 BASE
MMkg of Emissions

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

BMS Confidential PUBD 13745

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Green Eng the “Avg” Pharma Facility

Best case: Implementation of all three green scenarios

Best Scenario
1.6
• Total Life Cycle
1.4
Emissions: 78%
1.2 reduction
MMkg of Emissions

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

• Manufacture Emissions: 96% reduction

• Incineration Emissions: 90% reduction
• In Process Use Emissions: 34% reduction

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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,

BMS Confidential PUBD 13745US EPA, 2006
19
 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
Slater, Savelski, Carole, Constable, Chapter 3, in Green Chemistry in the Pharmaceutical Industry,
Dunn, Wells, Williams, Eds., Wiley-VCH Verlag Publishers, (2010) 49-82.
BMS Confidential PUBD 13745
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 Solvent Recovery

• Azeotropic separations pose the most Wilson Pressure Analysis

challenge in processing 0.9

0.8

0.7

• Entrainer-based distillation

Mass Fraction IPA in Vapor

0.6 760 torr
150 torr
3 bar
0.5
10 bar
25 bar
0.4 45 deg

– More energy intensive

0.3

0.2

0.1

– Entrainers pose additional source of

0
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

pollution
• Membrane pervaporation is a “greener”
alternative for azeotropic separations

BMS Confidential PUBD 13745

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Pervaporation Membrane Processes

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

BMS Confidential PUBD www.sulzerchemtech.com

13745
22
 PV Process Integration

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.
BMS Confidential PUBD 13745
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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

6.1 kg THF/kg API; 56% reduction

0.65 kg Waste/kg API; 93% reduction
0 kg THF Entrainer/kg API; 100% reduction

CVD Basis: 68 kg API / batch PV

Slater, Savelski, Moroz, Raymond, Green Chem.

BMS Confidential PUBD Lett.
13745Reviews 5 (2012), 55-64
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 Bristol-Myers Squibb cont.

Slater, Savelski, Moroz, Raymond, Green Chem.

BMS Confidential PUBD Lett.
13745Reviews 5 (2012), 55-64
27
 Bristol-Myers Squibb cont.
• Reductions in THF 1000
948

900
used and waste 800
4000
3697

produced 700 3500

626
600

• Environmental

kilograms
3000
500
414
savings 400
2500

Cost ($)
300 2000

• Cost savings 200

1500
1615

100

• But this is only one

44

0 1000
THF Purchased Waste
part of story 500 With Pervaporation Current
267
19
0
THF Waste Disposal

With Pervaporation Current

Slater, Savelski, Moroz, Raymond, Green Chem. Lett. Reviews 5 (2012), 55-64
.
BMS Confidential PUBD 13745
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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%

Total Emissions Due to

Waste Treatment
Total Emissions Due to
THF
Total Emissions Due to
Steam
THF = 68.5%

Total CVD-PV Life Cycle Emissions:

272 kg, 4.0 kg waste/kg API
Total Emissions Due to Waste
Treatment
THF = 8.3%
Waste < 1% Total Emissions Due to THF

Total Emissions Due to

Electricity = 9.2% Electricity
Total Emissions Due to Steam

Steam = 82%

Slater, Savelski, Moroz, Raymond, Green Chem.

BMS Confidential PUBDLett.
13745Reviews 5 (2012), 55-64
29
 Pfizer – Celecoxib
• Investigate solvent recovery
alternatives to minimize waste from
the Celecoxib manufacturing
process
• Compare current process route
with green engineering options 1
Wilson Pressure Analysis

– Recovery of isopropanol 0.9

0.8

from water, other alcohols 0.7

Mass Fraction IPA in Vapor

and dissolved solids
0.6

0.5

– Multiple waste streams with 0.4

0.3

varying compositions 0.2

– Azeotropic mixtures add

0.1

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

BMS Confidential PUBD 13745

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 Pfizer – Celecoxib cont.

• IPA solvent recovery from

final purification steps Recovery
• Segregate waste streams IPA / Water
Washes
for best process design 50% IPA
50% Water IPA / Water Washes
– Dryer Distillates and 49.2% IPA
(Centrifuge) Wash Solvents
Water
49.6% H2O
0.71% MeOH & EtOH
– Mother Liquor API
Other
0.5% TDS
Centrifuge Mother Liquor Conc.
• Pre-concentration for & Sell ML
Incineration or Sale 34.5% IPA
45.2% H2O
Wet Product 8.45% MeOH

• Integration of existing Solids 2.71% EtOH

9.10% TDS

separation equipment
Celecoxib Dryer Distillates
inventory at plant Dryer 50.7% IPA
48.8% H2O
0.47% MeOH & EtOH
0% TDS

Slater, Savelski, Hounsell, Pilipauskas, Urbanski, Clean

BMS Confidential PUBD Technol.
13745Environ. Policy, 14 (2012) 687-698
31
 Pfizer – Celecoxib cont.
• Base case
• Various design alternatives simulated
with ASPEN
– Distillation (Distill)-Pervaporation (PV) and
Distill-PV-Distill
– Distill-Molecular Sieve Adsorption
• Sale of Mother Liquor or incineration
options
• Detailed analysis shown for
– Distill–PV–Distill with Mother Liquor (ML)
Sold
Slater, Savelski, Hounsell, Pilipauskas, Urbanski, Clean Technol. Environ. Policy, 14 (2012) 687-698

BMS Confidential PUBD 13745

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 Pfizer – Celecoxib cont.

Proposed Distillation-PV-Distillation Process

Design basis of 1000 kg waste/hr Alcohol Waste

Second Distillation

Celecoxib
Waste

IPA
Vacuum Pump Vacuum Pump Product

Initial Distillation
Water Waste
With TDS

• 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
BMSPilipauskas,
Slater, Savelski, Hounsell, ConfidentialUrbanski,
PUBD 13745Clean Technol. Environ. Policy, 14 (2012) 687-698
33
 Life Cycle Inventory Comparison

Total Base Case Emissions: 13.7 MM kg/yr

IPA Manufacture
40%

Incineration
60%

Total Dist-PV-Dist Emissions:

1.12 MM kg/yr
ML
Dist-PV-Dist
Distillation
12.63 MM kg/y emissions reduced 22%
19%
(92% decrease)
IPA
11.55 MM kg/y CO2 reduced Manufacture
59%
(95% decrease)

Slater, Savelski, Hounsell,BMS Confidential

Pilipauskas, PUBDClean
Urbanski, 13745Technol. Environ. Policy, 14 (2012) 687-698
34
 Economic Analysis

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

$3.82 MM/yr operating cost saving

Slater, Savelski, Hounsell, Pilipauskas, Urbanski, Clean Technol. Environ. Policy, 14 (2012) 687-698
BMS Confidential PUBD 13745
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 Case Study - Pfizer’s LVWS
Case Selamectin Nelfinavir Hydrocortisone
Acetone-
THF-IPA Acetone-Toluene
Waste Composition Acetonitrile
(14-86 wt.%) (9-91 wt.%)
(28-72 wt.%)
Waste Mass (kg/yr) 84,500 78,700 257,600
Acetonitrile at Toluene at
Desired Recovery IPA at 98 wt.%
99 wt.% 99 wt.%
Life Cycle Carbon
Footprint Savings 235.8 220.2 1,161
(MMkg CO2eq./yr)
Cumulative Energy
3.9 3.5 16.3
Savings (TJ/yr)
Cost Savings (k$/yr) 215.5 98.7 271.1

Recovery Method: Simple Distillation

BMS Confidential PUBD 13745
36
 Pfizer’s LVWS
14,00,000

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

BMS Confidential PUBD 13745

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PennAKem Case – Green Solvent
ecoMeTHFTM as a green solvent – Manufacture LCA
Chemical
Solvent ecoTHFTM ecoMeTHFTM
THF
Total Raw Materials Used, kg 4.01E+00 5.33E+02 1.21E+02
Total CED, MJ-Eq 1.32E+02 6.15E+00 -2.00E+01
Total Air Emissions, kg 5.52E+00 1.45E+00 1.62E-01
CO2, kg 5.46E+00 1.39E+00 1.50E-01
Total Water Emissions, kg 1.26E-01 3.41E-02 2.73E-02
Total Soil Emissions, kg 2.31E-03 2.08E-03 1.94E-03
Total Emissions, kg 5.65E+00 1.49E+00 1.91E-01
Production Routes
• Chemical THF: 1,4 butanediol => THF
• ecoTHFTM : Corn Cobs Waste => Furfural => Furan => THF
• ecoMeTHFTM : Corn Cobs Waste => Furfural => Methyl Furan => 2-MeTHF

ecoMeTHFTM is 30 times more environmentally friendly than chemical THF

BMS Confidential PUBD 13745
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 Pennakem Case – Green Solvent
ecoMeTHFTM as a green solvent – Recovery from water
1.40E+00
Recovery
kg total life cycle emissions / kg

1.20E+00

1.00E+00 Raw Materials and

Incineration
solvent

8.00E-01

6.00E-01

4.00E-01

2.00E-01

0.00E+00
ecoTHF (Extractive Distillation) ecoTHF (Dist+PV) ecoMeTHF

• 2-MeTHF is more easily recovered than THF due to

heterogeneous system
• Pervaporation shows an environmental advantage over
extractive distillation (in THF recovery)
BMS Confidential PUBD 13745
39
 Case Studies Conclusions
• Solvent recovery / reduction systems can be designed to
target the most common and/or environmentally unfriendly
solvents
• Solvent manufacture and incineration play a significant
role in the life cycle emissions of an API
• These emissions can be reduced by implementing a
solvent recovery / reduction system
• The environmental potential of implementing the solvent
recovery system is significantly increased by examining all
possible applications
• By looking at the entire life cycle these emission
reductions become apparent
BMS Confidential PUBD 13745
40
 R.SWEED Software tool
• Modular software to be implemented in industry
– Combine design software (ASPEN®) and LCA software
(SimaPro®)
– User friendly interface (Excel®)
• Aid design of solvent recovery systems
– Determines recovery process based on thermodynamics
• Predict resulting emissions reductions
• Predict economic benefits
• Environmental and economic optimization

BMS Confidential PUBD 13745

41
 R.SWEED Software tool
Simple Distillation
ASPEN Plus®

ASW/Excel

BMS Confidential PUBD 13745

42
 R.SWEED Software tool
Pervaporation Modeling – Transport through membrane

Data Fitting – Pervaporation membrane Sulzer’s PERVAP 2201

1.8
y = 2,13,154x5 - 9,70,290x4 + 17,64,345x3 - 16,01,961x2 + 7,26,280x - 1,31,529
1.6 R² = 1
1.4
T = 90 °C
Water Flux (kg/m2h)

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

BMS Confidential PUBD 13745

44
 R.SWEED Software tool
Pervaporation Modeling – Tool Screenshot

BMS Confidential PUBD 13745

45
 R.SWEED Software tool
Process Optimization – Optimum Reflux Ratio
LC Emissions Avoided (kg/hr) & Operating Cost Savings ($/hr)

Maximum Life
Cycle
Emissions
Avoided
RR = 9

BMS Confidential PUBD 13745

46
 R.SWEED Software tool
Process Optimization – Optimum Feed Stage
120 1.0
Operating
Cost
LC Emissions Avoided (kg/hr) & Operating Cost

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

20 Feed Stage = 4 0.2

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
48
 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

U.S. EPA Region 2

Grants NP97257006-0 and NP97212311-0
Rowan University
Students
UPDATE
Scott Barnes, William Carole,
Anthony Furiato, Kyle Lynch,
Colleen McGinness, Timothy
Moroz, Michael Raymond,
David Walsh
BMS Confidential PUBD 13745
49
Further Reading

BMS Confidential PUBD 13745

50
 How the Tool Works
Solvent Recovery Processes

Solvents in
Waste
Mixture
Classifier
Solvent Recovery
Process Selection

BMS Confidential PUBD 13745

51
 Economic Analysis
• Not economical
$2,000,000.00
at pilot scale
$1,500,000.00

• 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

– 12,000 kg API/yr -$500,000.00

– 72,000 kg/yr THF -$1,000,000.00

or other solvent -$1,500,000.00
processed
-$2,000,000.00
kg Solvent

Slater, Savelski, Moroz, Raymond, Green Chem. Lett. Reviews 5 (2012), 55-64

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

WASTE THF
Water

RECOVER
Y
Water
THF