Advanced FlowTM Reactors

Céline GUERMEUR

Commercial Technology ManagerHead of application and reactor engineering

2Advanced FlowTM Glass Reactors

Advanced flow reactors: Continuous processes becomeeconomical where batch was the only option

3Advanced FlowTM Glass Reactors

Industrial production

This “bank”of 12 continuousflow reactors is processing3,000 tons/year

4Advanced FlowTM Glass Reactors

Glass fluidic modules

1 €

16 cm

13 cm

Gen I Gen II Gen III(Under development)

5Advanced FlowTM Glass Reactors

Design Dimensions: Optimized for performance andthroughput

Mixing300-1000 microns

Reactants

700 to 1500 microns

4 –50 mm

Heat transfer

Reactants

Heat exchange fluid

700 to 1500 microns

6Advanced FlowTM Glass Reactors

Customized reactors made from standardparts

Fluidic modules REACTORS

A few 10’s ofdesigns 1000’s Product Designs

7Advanced FlowTM Glass Reactors

Processed liquid flow rate for one reactor

800

560

100

1600

Tons / 8000h

Tons / 5600h

kg/h

g/min

1600320200807

1120220140565

2004025101

320066040016015

Gen I

Gen II

Gen III (Under development)

8Advanced FlowTM Glass Reactors

From one reactor to industrial productionStraightforward scale-up

• Increased production duration3 kg/h is 1.4 Tons/month (480h)

• Increased throughput per reactor with Gen I / II reactorskeeping performance and operating conditions the same

• A limited number of reactors in parallel with engineereddistribution

9Advanced FlowTM Glass Reactors

A limited number of reactors in parallel

3 5 20 50 100100 58 35 9 4 2400 234 140 35 14 7600 351 211 53 21 11

1000 585 351 88 35 185000 2924 1754 439 175 88

10000 5848 3509 877 351 175

% of product in the output stream

met

ric T

ons

per

5700

h

10 kg/h perreactor

3 5 20 50 100100 15 9 2 1 0400 58 35 9 4 2600 88 53 13 5 3

1000 146 88 22 9 45000 731 439 110 44 22

10000 1462 877 219 88 44met

ric T

ons

per

5700

h

% of product in the output stream40 kg/h perreactor

10Advanced FlowTM Glass Reactors

Industrial Production

Courtesy of DSM

• Conventional productionenvironment

• Plant utilities• Grounding. Explosion proof• Material certificates• Mechanical protections• Containment and fluid collecting

parts• Operated by shift workers

Taken into account by Corning engineering: ATEX,GMP related materials certificates, collecting plates,mechanical protection, lifting, fluid distribution

11Advanced FlowTM Glass Reactors

Industrial productionFluids are distributed within the reactors of the same bank

Example of Gen II bank3000 tons/year processed

12Advanced FlowTM Glass Reactors

cGMP in flow reactors• Ensuring full traceability of each part with corresponding certificate:

– Material certificates EN 10204-3.1 for all parts of process side in contact withthe product.

– Certificate of Compliance/Typical Material Certification EN 10204-2.2 for allmetallic parts which are not in contact with the product.

• Make lots for downstream and use standard procedures (LONZA, DSMcommunication)

• Adapt the cleaning procedure to advanced-flow reactors:– Internal volume of a production bank is about 1 liter: The amount of solvent

to clean is low.– High flow velocities, pressure, temperature are possible for cleaning.– Cleaning can be confirmed by analysis (Conventional analytical methods

such as HPLC, GC,… ) of the solvent at the exit of the reactor• FDA is promoting of the use of continuous processing, heading toward

robust Quality by Design manufacturing.

13Advanced FlowTM Glass Reactors

( ) ( )cp TTVSUHkA

ddTC −⋅⋅−∆−= )(

τρ

Fluidic modules integrate mass and heattransfer

Heat generation

Heat removal

Reactants Product

14Advanced FlowTM Glass Reactors

Corning Fluidic module heat exchange performance

Apparatus Specificarea, m2/m3

Volumetric heattransfer coefficient

(MW/m3K)Jacketed batch 2.5 10-3

Batch with external heatexchanger

10 10-2

Shell and tubes (metallic;water/water; 1 m/s)

400 0.2

Plate (metallic, 4 mm spaced;water/water, 1 m/s)

800 1.25

Corning glass fluidic modules

(water/water, ~ 0.7 m/s)

2500 1.7

D. Lavric, Thermal performance of Corning glass microstructures, Proceedings of the Heat Transfer and Fluid Flow in Microscale IIIConference, Hilton Whistler, BC, Canada, ECI international, 2008

15Advanced FlowTM Glass Reactors

Mixing of miscible liquids

30000-6500015804000Shear rate (s-1)

10 - 203000-10000400-150010 - 60Mixing time (ms)

4000-8000620.1Flow rates mL/h

700-4000100050050Critical size (µm)

Measurement at LGC(1)

(mixing time)Modelling (shear rates)

PhD from F. SarrazinMicroréacteurs diphasiques pour le

développement rapide des procédés, INPG(2), 2006

Source of the data

Corning micro-structure (NIM)One phase system

Biphasicbubble system

Biphasicbubble system

Biphasicbubblesystem

(1)Laboratoire de Génie Chimique –Toulouse –France(2)Institut National Polytechnique de Toulouse –France

16Advanced FlowTM Glass Reactors

Characterization of reactive emulsion performanceIodine in water / Heptane Extraction

§ Immiscible Liquid-Liquid system:- Organic phase: n-heptane- Water phase: iodine (I2) in water

(C0)

§ Measure residual iodineconcentration in water after Liquid-Liquid mixing (Cresidual)

§ Calculate how much iodineextracted by n-heptane from water(Extraction Efficiency, η)

o

residual

CCC −

= 0η

I2/H2ON-heptane droplet

I2/H2O

N-heptane dropletI2 (water à heptane)

I2/H2O

N-heptane dropletmore I2 (water à heptane)

I2 (residual)/H2O

I2/Heptane

C0Cresidual

Chemical Engineering Journal 135S (2008) S199-S202

n-heptane

I2/H2O

MF

MF

Experiment Setup

FluidicmoduleFluidicFluidicmodulemodule

Ratio = heptane / water

17Advanced FlowTM Glass Reactors

0,0

0,2

0,4

0,6

0,8

0 50 100 150 200

t (s)

Extr

actio

n ef

ficie

ncy

(%)

Extraction results in a 50 ml vessel

0.000.100.200.300.400.500.600.700.800.901.00

0 500 1000 1500 2000 2500

rpm

Extra

ctio

n Ef

ficie

ncy 0.25

0.50.75124

At 1020 rpm

At 30 seconds

Ratio = 0.1

50 ml vessel - 750 RPM0.25 ratio30 s residence timeExtraction efficiency = 42%

Extraction efficiency increases:- With time until a plateau isreached- With stirring speed- With heptane/water ratio

Max with 0.25 ratio = 0.72

18Advanced FlowTM Glass Reactors

Gen II fluidic modulesExtraction efficiency is at least 2 to 3 times the

one of the 50 ml vessel at 750 rpm

2X microstructures at Ratio 0.25(at small Y-axis scale)

0.75

0.77

0.79

0.81

0.83

0.85

0.87

0.89

0.91

0.93

0 50 100 150 200 250 300

Total Flow Rate

Extr

actio

n Ef

ficie

ncy

X2RTH 08-095-DX2SJHH -08-211-BX2SJHS-08-211-AX2RT-09-015-B1

Gen II fluidic moduleHeptane/water = 0.25

Residence times from 24 seconds down to 4 seconds(ml/min)

19Advanced FlowTM Glass Reactors

Multi-phase: Gas/Liquid

Gas / liquid

14000Corning FluidicModule DTH(air/water)

100-2000Mechanically stirredbubble column

10-100Spray columns50-100(11)Stirred vessel

50-600 (11)Bubble columns

10-35010-1700

Packed columnCounter current flowCo-current flow

Specificinterfacial area

[m²/m3]

Type of conventionalreactor (7)

20Advanced FlowTM Glass Reactors

Processing of high viscosity fluids

1

10

100

1000

0 50 100 150 200

TEMPERATURE (°C)

VISC

OSI

TY (c

P) Pressure drop <10 bars (6 kg/h)

0

50

100

150

200

Tem

pera

ture

(°C

)

Rules of thumb:•Fluid with viscosities up toapproximately 500 cP•Viscosities at operating temperatureup to approximately 100 cP•Non Newtonian behavior may help

21Advanced FlowTM Glass Reactors

Example of DSM

OHR

OHONO2

R

OHONO2R

O2NO+ HNO3

Extraction decomposition

X

X

Substrate

Solvent

HNO3

H2O NaOH NaOH NaOH

Product

FlushH2O

Feedpreparation

Nitration Quench and neutralization

•Strict control of reactionparameters is crucial forboth quality and safety

•Temperature

•Stoichiometry

•Residence time

Published with DSM: Chimica oggi, Chemistry Today, Vol 26 n°5, Sept-Oct 2008

22Advanced FlowTM Glass Reactors

From lab process development to Industrial Production

In 9 months demonstration of a commercially viable approach to a cGMP nitration

reaction – Starting with 1 kg lab sample

– Parallelization of 8 identical reactors,

integration into the production plant

– Execution of a campaign under cGMP

conditions

– More than 25 mT materials processed

– Less solvent, better yield

– More 500 kg of quality product

produced

– Safety performance and product quality

were perfectly maintained

23Advanced FlowTM Glass Reactors

Cost breakdown for 300 T/years

0

1 000

2 000

3 000

4 000

5 000

6 000

7 000

8 000

10 25

Vessel size (m3)

prod

uctio

n co

sts

(k€)

Labor costRaw material cost

348 batchesper year

(Need 2 equipment)

155 batchesper year

Data for 10 m3 vessel sizeRaw material per batchSubstrate: 1100 kgAcetonitrile: 1469 kgAcetic acid: 5797 kgSulphuric acid: 1820 kg

Labour cost per batchVessel charging: 4 hHeat-up time: 2 hAddition of Sulphuric acid: 8hAddition of water: 8 hNeutralisation: 12 hCooling time: 4 hFiltration time: 12 hReactor clean down/drying: 16 hTotal labor: 66 h at 200€/hour

Substrate cost are not included

24Advanced FlowTM Glass Reactors

Heat exchange impacts manufacturing cost through vesselsize and dilution

4 000

4 500

5 000

5 500

6 000

6 500

7 000

7 500

8 000

0 10 20 30

Vessel size (m3)

Prod

uctio

n co

st (k

€)

Dilution 5 VDilution 10 VDilution 1 V

Run-away during scale-upConcentration notcompatible with 10 m3vessel

Cost may bedecreased by

increased vesselsize

Except whenfurther dilution is

required

25Advanced FlowTM Glass Reactors

With AFR, the process is run at the lowest dilution

Assumption: AFR labor cost = labor cost for 25 m3 vessel at same dilution

0

1 000

2 000

3 000

4 000

5 000

6 000

7 000

8 000

AFR 10 m3 - 5V 25 m3 - 5V

prod

uctio

n co

sts

(k€)

Labor costRaw material cost

26Advanced FlowTM Glass Reactors

Broad range of applications and valueReactions which have already benefited from Corning reactor

technologies– Nitration– Ritter reaction– Metal Organic– Oxidation– Reduction– Coupling, substitution– Rearrangement– Amidation– Bromination– Alkylation

New chemical routes

Process Intensification

Safer and more Environment friendlyprocessing

Shorten development cycles

Decrease overall manufacturing costs

27Advanced FlowTM Glass Reactors

The operating conditions in flow reactors are significantlydifferent from those in batch

• Temperature– Commonly 50°C to 100°C higher

• Pressure– Commonly above 6 bars

• Enhanced mass transfer

• Narrow residence time distribution

The industry is developing its « cookbook »and expertise,… each company independently

28Advanced FlowTM Glass Reactors

On-line analysis for process development in flow reactors

Conversion

TimeT1

Conversion

ZZ1

29Advanced FlowTM Glass Reactors

OUTLINEAdvanced flow reactors:•Continuous processes become economical

where batch was the only option•Currently on the field for full scale production

up to several 1,000s tons/year

On-line analytics and sampling:•Facilitate reactor and process development•Manufacturing control (QbD)