The Green Paradox (Novasep, rev2) - Pharma Manufacturing...Synthesis: 260 kg mat’l + 164 kg...
Transcript of The Green Paradox (Novasep, rev2) - Pharma Manufacturing...Synthesis: 260 kg mat’l + 164 kg...
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Large-Scale Chromatography:
The Green Paradox
Presented by Jeff Mitten Novasep, Inc.
Boothwyn, PA, USA
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Table of Contents
Chromatography – an Industrial
Process?
Choosing the Right Chromatography
Process
Impact of Efficient Solvent RecyclingIntegration in the Chromatography
ProcessOptimization of Energy
Requirements
Use of CO2 as a Green Solvent: SFCprincipleapplications
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Preparative Chromatography 1950’s Style… Not an Industrial Solution!
Time consumingExpensivePainfulLow yieldsSolvent consuming
Photo: courtesy FDA
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… But Chromatography has Evolved!
FastCost-EffectiveAutomatedEnvironmentallyFriendly
Today, preparative chromatography is:
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Largest chromatography units produce:
100’sPharmaceutical
chiral separations
10,000’sFood / Feed
glucose, betaine
100,000’sPetrochemical
p-xylene
Volume(Mtons / Year)
Industryapplication
Chromatography –an Industrial Process?
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Choosing the Right Chromatography Process
Highest productivity (+10 to 30% over SMB)Requires less CSP than SMB (fewer columns)Lowest Dilution (-5% to -20%)
Continuous: Varicol®
Higher productivity (2 to 10x over Batch)Fewer operators required Lower Dilution (5 to 20x over Batch)
Continuous: SMB
Ideal for complex mixtures and small scaleHigh DilutionHigh Operating costs (SP, manpower, energy)
Batch: HPLC
Main FeaturesProcess
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A Technology for Each Need
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Non-Chiral Separations at Industrial Scale
“Classical” Commercial-Scale Separations by HPLC technology:
InsulinSteroids (synthetic, semi-synthetic, natural)Cyclosporin (and derivatives)ProteinsPeptides (synthetic, semi-synthetic, natural)PaclitaxelDocitaxel
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0 1000 2000 3000 4000 5000 6000 7000 8000 9000ELUTION VOLUME (L)
SimulationExperimental
0 1000 2000 3000 4000 5000 6000 7000 8000 9000ELUTION VOLUME (L)
0 1000 2000 3000 4000 5000 6000 7000 8000 9000ELUTION VOLUME (L)
SimulationExperimental
The World’s Largest HPLC
DAC technologyD=1.6 m, L=4.0 mOperating Pressure : 35 bar3,500 kg of Stationary Phase
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Chiral Separations by Chromatography
SMB and VARICOL are now industrial production tools.
Chiral separation capacity exceeds 1,500 M tons in 2008:
Keppra®, Escitalopram®/Lexapro®, Xyzal®, Armodafinil/Nuvigil®, and Zoloft®…
are all produced using SMB/Varicol Technologies!
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Industrial-Scale Varicol® Systems
Column diameter = 1,000 mm – Bed length < 100 mm
Only 5 or 6 columns needed for a continuous process
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Detail of Piston (1m diameter)
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Solvent Recycling at Industrial-Scale
COMPOSITION ADJUSTMENT
Evaporator X
Evaporator R
EluentEtOH/Hept
Conc. RFeed
Feed
product
waste
VARICOL
Dry Feed
concentration
distillation
BufferA
Concproduct
wasteFeed
Buffer BBuffer A
HPLC
Vacuum pump
Dry Feed
BufferB
COMPOSITION ADJUSTMENT
Evaporator X
Evaporator R
EluentEtOH/Hept
Conc. RFeed
Feed
product
waste
VARICOL
Dry Feed
concentration
distillation
BufferA
Concproduct
wasteFeed
Buffer BBuffer A
HPLC
Vacuum pump
Dry Feed
BufferB
Eluent recycling integrated in gradient chromatography
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Fully Integrated Solvent Recycling
A single unit operation
Chromato +evaporation Evaporator X
Evaporator R
Dryer R
EluentConc. X
Conc. RFeed
Eluent
Feed
Recycled Solvent
Extract
Raffinate
VARICOL
Continuous ChromatographyComprehensive Process Scheme
DryExtract
DryRaffinate
Fresh Eluent
Vacuum pump / scrubber
Dryer X
Dry Feed
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Product Concentration and Solvent Recycling
Fully continuousNo storage of dilute products before evaporation
Reduction of investmentReduction of investmentReduction of solvent volume / risksReduction of solvent volume / risksReduction of operating (operators, analysis) costsReduction of operating (operators, analysis) costs
Proprietary process controls of complete unitControl of the product concentration
No “breathing” of the evaporator: no emitted VOC’s
“more losses from sampling than from the vacuum pump”
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Energy Recovery at Scale
Steam
Condensate
DilutedRaffinate
DilutedExtract
ConcentratedRaffinate
ConcentratedExtract
Vacuum
CoolingWater Supply
CoolingWater Return
Distillate
Raffinate: Non-Desired Enantiomer
Extract:Desired Enantiomer
s olv
ent v
apo r
s
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Solvent Recycling Pay-Back
An Example at Industrial Scale (UCB-Pharma):
Efficient solvent recycling: 99.97% on a Varicol® 5-1000 unit with integrated solvent recycling.35% of overall process costs recovered.Chromatography cost significantly lower compared to stereoselective chemical process.Only 180 mL solvent consumed per kg of pure enantiomer!
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GSK: production of radafaxine (GSK PCT/EP2005/012093)
Comparison of Synthetic vs. Chromatography route:Synthesis: 260 kg mat’l + 164 kg solvent / kg product Chromatography: 20 kg mat’l + 19kg solvent / kg product
⇒Reduction of overall waste by 5,000 Mtons/year
⇒ 2004 Astra Zeneca Award for Excellence in Green Chemistry, IChemEAward program
⇒ GSK CEO Award for Green Chemistry
Modern Industrial Chromatography is a Green Process!
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CO2: green or… greenhouse?
What is Supercritical Fluid Chromatography?
Application Examples
Using a True Green Solvent
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The Principle of SFC
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Preparative SFC System: SupersepTM 50
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Preparative SFC Principles: In Summary
Eluent for the chromatographic separation: CO2 + organic solvent (5-20%)
Operating pressure: 100 - 200 bar
5-10x improvement of productivity (vs. HPLC)
5-20x reduction of product dilution
CO2 recycling
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Applications
Pure CO2Natural productsFatty acid esters
Modified CO2Chiral solutesSmall molecules, small peptides
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YMC C18 120 A 10-20µmMeOH/H2O 7/3
Liquid Chromatography
Lichrosphere 12µmCO2/2-propanol 97/3 mass
150 bar 40°C
impurity
Supercritical Fluid Chromatography
An Example of Multi-Component Separation
selectivity
between the
two isomers:
1.13
selectivity
between the
two isomers:
1.30
impurity
selectivity
between the
impurity and
first isomer:
1.40
selectivity
between the
impurity and
first isomer:
1.18
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3.3 mg/g silica injected
YMC C18 120 A 10-20µmMeOH/H2O 7/3
8.3 mg feed/g silica injected
Lichrosphere 12µmCO2/2-propanol 97/3 mass
150 bar 40°C
Overloaded Chromatograms
Liquid Chromatography Supercritical Fluid Chromatography
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SFC HPLC
Stationary Phase Lichrosphere Si60 12µm YMC C18
Eluent CO2/2-propanol 97/3 MeOH/H2O 7/3 Conditions 150 bar, 40°C 25°C
mg feed /g silica 8.3 3.3 Cycle time 4 min 15 min Productivity
(kg feed/kg Silica/day) 3 0.32
Solvent Consumption (l / kg product) 35 1200
Comparison of SFC vs. HPLC
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14 minHPLC
SFC Accelerates Chromatography
Low viscosity
High diffusivity
2,5 minSFC
3 to 5 times faster
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SFC: Fast and Environmentally Friendly
System Type Preparative HPLC SupersepTM
Without CO2 recyclingSupersepTM
With CO2 recycling
Column Size (I.D.) 80 mm 50 mm 50 mm
Organic SolventConsumption (kg/kg of feed)
3100 (n-heptane/ IPA
98:2)
352 (IPA + DMEA)
352 (IPA + DMEA)
CO2 Consumption (kg/kg of feed)
NA 1700 170
Productivity (kg product/day/kg CSP)
0.24 2.2 2.2
Productivity (time to purify 1kg)
100h 36h 36h
Direct Cost (w/o CSP) (k€/kg feed)
17.1 8.4 1.5
Source: Separation of Indol derivatives (B.Bonnier - R&D Sr Scientist, Eli Lilly, Belgium)
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Example: Separation of TSO
Trans-stilbene oxide regioisomers
CSP: Chiralcel OD (Chiral Technologies, Illkirch, France)Eluent: CO2/2-propanol 90/10 w/w eluent
• DAC column :Dcol=50mm, Lcol=200mm
• Q = 700 g/min
• P = 100 bars
• Injected quantity: 1 g/injection
• Feed concentration: 16g/L in IPA
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Separation of TSO: Optimized SFC
0 10 20 30 40 50 60 70 80
TSO (2) TSO (1)
0 10 20 30 40 50 60 70 80
TSO (2) TSO (1)
Time (sec)
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Separation of TSO: Results
Cycle time = 80 seconds
Collected fraction :Purity > 99% for both regioisomersRecovery > 94%
Productivity = 4.6 kgrac/kg Si/day
Collected fractions: conc. ~ 12 g/L (80 L IPA/kg product)Dilution factor = 1.33
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SFC: an emerging, large scale purification technology
Currently used for low volume API’s
Semi-Industrial SFC: Supersep 150
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Conclusions
Large-Scale Multi-Column Continuous Chromatography produces tons to metric tons of API’s in the Pharmaceutical Industry.Solvent recycling can be efficiently integrated into all Chromatography processes.Solvent recycling rates greater than 99.9% have been achieved at commercial production scale.SFC is an ideal green purification technique for development and low volume production scale API’s.
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Acknowledgements
Dr. Wieslaw MajewskiDr. Olivier Ludemann-HombourgerMr. François RomelaerMr. Jean BlehautMr. Eric Lang