1 bms confidential pubd 13745 green process analysis for solvent reduction in pharmaceutical...

1BMS Confidential PUBD 13745

Green Process Analysis for Solvent Reduction in Pharmaceutical Synthesis

C. Stewart Slater and Mariano J. Savelski, Rowan University, Department of Chemical Engineering,

Glassboro, NJ

The 11th Annual Green Chemistry & Engineering Conference

U. S. Environmental Protection Agency - Region 2

New York, NY March 17, 2010

Adapted from the following papers:

Slater and Savelski, Trends in Solvent Management in the Pharmaceutical Industry”, Paper 656a, 2009 Meeting of the American Institute of Chemical Engineers, Nashville, TN, November, 2009.

Savelski and Slater, Hounsell, Pilipauskas, Urbanski,“Analysis of Separation Methods for Isopropanol Recovery in the Celecoxib Process,” Paper 290b, 2008 Meeting of the American Institute of Chemical Engineers, Philadelphia, PA, November 2008.


Academic-Industrial Interaction

• Process case studies with a green chemistry and engineering component

• Three pharmaceutical company partners– Bristol-Myers Squibb*– Novartis– Pfizer

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

• “Paper-projects” / design-based, experimentally-based or combination thereof

B

R

P

N

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


Pharmaceutical Industry

• Highly regulated

• Long R&D timeline

• Batch processes

• High valued final product – API (Active Pharmaceutical

Ingredient)

• High E-factor– High solvent use and waste

generated per final product


Typical Drug Synthesis – “Campaigns”

• Multi-step transformations – Intermediate compounds

• Isolations (purification)

ReactionCrystallization/

Recrystallization

Filtration or Wash Step

DIstillation

R-1API

WasteWaste

I-1 I-1

Crystallization/Recrystallization

I-5I-5

S-16R-5 S-15S-2S-1

Filtration

Waste

S-17

I-5

Reaction

I-1I-5

S = Solvent – vary in number and complexity for each stepR = Reactant – vary in number and complexity for each stepI = IntermediateAPI = Active Pharmaceutical Ingredient


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

• E-Factor 25->100 kg/kg of API

• Not optimal by any standard

• Practice green chemistry & engineering

Sheldon, Chem Ind, 1 (1997) 12Slater and Savelski, J. Environ. Sci. Health, A42, 1595-1605, 2007


Methanol

Dichloromethane

Toluene

Acetonitrile

Chlorobenzene

N-Butyl Alcohol

N-Methyl-2-Pyrrolidone

N,N-Dimethylformamide

Ammonia

Formic Acid

Various Other Solvents

Pharma Industry Profile

• US EPA Toxic Release Inventory (TRI) 2008

• 88 MMkg waste

• Top ten solvents account for 72% of waste

TRI.NET. Washington (DC): Environmental Protection Agency (US), Office of Environmental Information. 2009 - [modified 12/5/2009, cited 2/23/2009].


LCA System Boundaries

Raw Materials

Solvent Manufacturing

Utilities

APIManufacture

Waste Incineration

Emissions

Emissions

Emissions

Emissions

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


Life Cycle Assessment Tools

• SimaPro 7.1 (Pré Consultants, Amersfoort, Netherlands)

– Features a large database of chemicals, materials, and processes (utilities)

– Generate modular LCAs for processes

– LCIs of raw material and energy use; emissions to the air, water, and ground

– Analysis of green house gas (GHG) emissions

• Ecosolvent (Safety and Environment Group, Zurich, Switz.)

– Moderate size database of chemicals

– Used to generate LCAs for waste solvent treatment and compare options


Solvent Manufacture

45%Incineration

55%

– Basic Life Cycle Analysis

– Shown for typical solvent manufacture

– Waste Incineration w/ energy recovery – still method commonly used

– Neglecting in-process use

Major Waste Contributions


Water6%

Air94%

Solvent Life Cycle Inventory

Total Raw Materials Used* kg 1.74

Total Water Used kg 1506

Total Cumulative Energy Demand MJ-Eq 65.1

Total Air Emissions kg 1.78

CO2 Emissions kg 1.75

CO Emissions kg 2.61E-03

Methane Emissions kg 1.28E-02

NOX Emissions kg 4.42E-03

NMVOC Emissions kg 1.97E-03

Particulate Emissions kg 1.40E-03

SO2 Emissions kg 5.89E-03

Total Water Emissions kg 1.22E-01

VOC Emissions kg 5.01E-07

Total Soil Emissions kg 1.66E-04

Total Emissions kg 1.91

*Excluding water

Based on manufacture of 1 kg of Generic Solvent

Soil <0.01%

CO2 is 92% of life cycle emissions


Green Chemistry and Engineering

• 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

Slater and Savelski, Trends in Solvent Management in the Pharmaceutical Industry”, Paper 656a, 2009 Meeting of the American Institute of Chemical Engineers, Nashville, TN, November, 2009.


Rowan University Clinics

• Modeled after medical schools

• Student-faculty problem solving teams

• Applied research, development, design

• Partnership: Industry, Federal/State Agency, Foundation

• Multidisciplinary

• Two 3 hour labs/wk, 1 hr/wk meeting with professor/industry

• Both semesters of Junior & Senior year and Masters students


Rowan’s Project Based Curriculum

Industry

Courses

Clinics


• Development of greener adsorption process for pharmaceutical synthesis at East Hanover, NJ R&D facility

• Heck coupling reaction used to produce pharmaceutical intermediate, A3, for multiple drug syntheses

• Batch adsorption technique is currently used to remove palladium (Pd) catalyst from a reactor producing drug intermediate; A3

– Requires solvent and detergent rinses

Novartis Project


• Proposed greener fixed bed adsorption design is more efficient in Pd removal, reduces solvent and waste

• Evaluate potential impact; lab scale process run at R&D facility was scaled-up in a simulation and analyzed for economic impact and environmental footprint

Green Approach


Batch Adsorption – Base Case

• Scaling-up current process to 100 kg of A3 manufacturing scale

Reaction

150 kg A1

1 kg B1

5 kg B2

383 kg B3

155 kg Ay

72 kg A2

P-5

Adsorption

Activated carbon120 kg

P-7

Cleaning

650 kg MeOH4,093 kg water

Micro-90

120 kg Activated carbon Crude Rxn. Mix

Cleaning Waste650 kg MeOH4,093 kg water

Micro-90Filtration

4-8 hr & 70 °C

Crude Rxn. Mix

w/ 100 kg A3

B1

B2

Palladium CatalystA1 + A2 + AX A3 + AY


Greener Fixed Bed Adsorber (FBA) Design

• Scaling-up proposed process to 100 kg of A3 manufacturing scale

Reaction

144 kg A1

1 kg B1

5 kg B2

365 kg B3

148 kg Ay

69 kg A2

PumpIn-linefilter

FBA

In-linefilter

Crude Rxn. Mix

w/100 kg of A3

Qua

drap

ure

TU

B1

B2

Palladium CatalystA1 + A2 + AX A3 + AY


Comparison of Two Processes

Significant methanol solvent reduction: 31,850 kg/yrSignificant water savings: 160,433 kg/yrValues shown are kg/yr for annual production of 4,900 kg A3


Economic Comparison

$1,558,000

$597,000

80 %

32 %

4 %

64 %

18 %2 %

*Values shown are kg/yr for annual production of 4,900 kg A3


Life Cycle Inventory

Component Base Case(kg/yr)

FBA(kg/yr)

Reduction(kg/yr)

%

Raw Materials

406,000 22,400 383,600 94

Process Utilities

665 146 519 78

Disposal 81,600 4,700 76,800 94

TOTAL 488,300 27,200 460,900 94

CO2 315,700 18,600 297,100 94

• Emissions generated by the various components of the solvent life cycle; from cradle to grave

• Scaled up to annual production of 4,900 kg A3


Project Summary

• Fixed Bed Adsorber design greener when examined through LCA

• Total life cycle emissions reduced by 383,600 kg/yr, 94% reduction

– CO2 reduced by 297,100 kg/y

• Water utilization reduced 9.16 MM kg/yr, 95% reduction

• Operating cost savings of $0.96 MM/yr, 62% reduction


Pfizer Project

• Investigate solvent recovery alternatives to minimize waste from the Celecoxib manufacturing process

• Compare current process route with green engineering options– Waste stream reduction and solvent

recovery– Define operational sequences– Equipment and process steps required– Estimate costs and environmental

impacts– Make proposal / recommendations


• Student team interacts with– Manufacturing group in New York, NY

– Engineering group in Peapack, NJ

– Plant operations in Barceloneta, PR

Project Approach

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

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

Mas

s F

ract

ion

IP

A in

Vap

or

760 torr

150 torr

3 bar

10 bar

25 bar

45 deg

• Analysis of large-scale API production at PR plant– Recovery of isopropanol from

water, other alcohols and dissolved solids

– Multiple waste streams with varying compositions

– Azeotropic mixtures add complexity


Process Flow Diagram

• IPA solvent recovery from final purification steps

• Segregate waste streams for best process design – Dryer Distillates and

(Centrifuge) Wash– Mother Liquor

• Pre-concentration for Incineration or Sale

• Integration of existing separation equipment inventory at plant


Centrifuge

IPA / Water Washes50% IPA

50% WaterIPA / Water Washes 49.2% IPA 49.6% H2O 0.71% MeOH & 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 & EtOH 0% TDS

Celecoxib

Conc. & Sell ML

Recovery

SolventsWaterAPI

Other


Green Design Analysis

• 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)

SoldSavelski and Slater, Hounsell, Pilipauskas, Urbanski,“Analysis of Separation Methods for Isopropanol Recovery in the Celecoxib Process,” Paper 290b, 2008 Meeting of the American Institute of Chemical Engineers, Philadelphia, PA, November 2008.


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

Design basis of 1000 kg waste/hr is used for illustrative purposes



Life Cycle Inventory Comparison

Total Base Case Emissions: 13.7 MM kg/yr

Total Dist-PV-Dist Emissions: 1.12 MM kg/yr


~92% decrease in total emissions


Environmental Summary

• Operation of Distill-PV-Distill system adds small environmental burden from utilities consumed when compared to overall LCA

• Pre-concentration of ML and sale off-sets environmental impact of producing virgin “generic” solvent when examining LCA

• Major LCI reductions from IPA manufacture and incineration avoidance

• LCA summary: Distill-PV-Distill/sell ML– Yearly reduction of 12.63 MM kg emissions/yr

(92% reduction from base case)– Yearly reduction of 11.55 MM kg CO2/yr (95%

reduction from base case)Savelski and Slater, Hounsell, Pilipauskas, Urbanski,“Analysis of Separation Methods for Isopropanol Recovery in the Celecoxib Process,” Paper 290b, 2008 Meeting of the American Institute of Chemical Engineers, Philadelphia, PA, November 2008.


Economic Analysis

-1,000,000

0

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

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


$3.82 MM/yr operating cost saving


Benefits of Partnership

• Exchange of new technical ideas

• Publicity/community relations

• Presentations/papers – dissemination to wider audience

• Industry gains knowledge, new approaches to R&D → manufacturing

• University develops expertise to advance the state-of-the-art

• New engineers graduate with knowledge in green processes


Looking into the future: FY 2010 P2 Grant Initiative

• Top Most Used Solvents: typical mixtures– Creation of a ready-to-use design tool to test candidate

streams for source reduction

• Examine separation feasibility

• Modular recovery system design

• Calculate the environmental footprint reduction (LCA)

• Calculate profitability (less raw materials, less energy, and less waste disposal)

• Advancing the knowledge base and transferability across region 2– Workshops on current practices in pharmaceutical solvent

reduction/reuse

– Workshops on Design Strategies for Solvent Recovery


Acknowledgements

PfizerJorge Belgodere, Peter Dunn, Greg

Hounsell, Daniel Pilipauskas, Frank Urbanski

NovartisThomas Blacklock, Michael Girgis

U.S. EPA Region 2 Grant NP97257006-0

Rowan University StudentsAnthony Furiato, Kyle Lynch, Timothy Moroz, Michael Raymond, Nydia Ruiz


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