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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