continuous crystallisation using oscillatory baffled … crystallisation using oscillatory baffled...

Continuous crystallisation using oscillatory baffled plug flow

crystalliser

Professor Xiong-Wei Ni, BSc, PhD, CEng, CSci, FIChemENiTech Solutions Ltd

Scottish Enterprise Technology ParkEast Kilbride, Glasgow G75 0QF, UK

www.nitechsolutions.co.uk

1818thth June 2008June 2008

© NiTech Solutions, 2008 Confidential

Structure

1. Crystallisation science

2. Challenges in industrial crystallisation

3. Continuous oscillatory baffled crystalliser

4. Case studies

5. Forward remarks


• Crystallisation is a relatively simple process

• But the underlying science and its control are very complex!

• In industrial scales, operators’experience still plays a major part

1. Crystallisation Science

Supersolubility or metastable limit is thermodynamically not found and kinetically not well defined, depending on temperature, rate of generating supersaturation, solution history, impurities, fluid dynamics, scale and etc.

Under-saturated

Solubility

Metastablezone

Temperature

Concentration

Supersolubility

Labile

Crystallisation “pathway”


Science

Nucleation mechanism

Nucleation rate

Growth mechanism

Growth rate

Supersaturation

Concentration

Temperature

Cooling profile

Mixing

Solvent/additives

Seeding

Crystal size and shape

Morphology

PurityProcess

Science

ProductProduct

Functionality (materials)

Bio-availability (drugs)

Surface activity (catalysts)

Texture (foods)


• How does it happen?• Primary nucleation – without the presence of any crystalline

matter

• Secondary nucleation – collision breeding, seeding

Nucleation• What initiates?

• not well understood

• 3-D assembly of molecular clusters on nm scale

• very fast kinetics

• not easy to detect (soft X-ray absorption spectroscopy)

• modelling available, lack of validation


Determination of metastable zone width (MSZW) using a turbidity probe

Tsat

On-set dissolution

On-set nucleation

Tcry

crysat TTMSZW −=

Detection of post-nucleation


MetastableMetastable zone width (MSZW) zone width (MSZW)

concentration = 45 g/L, f = 2 Hz, xo = 10 mm

MSZW depends on reactor, scale and operating conditions

• Dissolution – a thermodynamic process

• Crystallisation –a kinetic process


• Mass transfer phenomenon

• Crystal growth phase must take place within the MSZW

Crystal growth

• Nucleation dominates small crystals

• Growth dominates large crystals

the degree of supersaturation is changed by crystal growth, simultaneously MSZW is altered due to different temperature levels and changes in impurity concentration

Under-saturated

Solubility

Metastablezone

Temperature

Concentration

Supersolubility

Labile

Crystallisation “pathway”


Crystal Size

PolymorphicForm

Supersaturation

ProcessConditions

Shape

MSZW


Crystal Size

PolymorphicForm

Supersaturation

ProcessConditions

Shape

MSZW

Growth Kinetics Nucleation Kinetics

Hydrodynamics Heat Transfer


Chemicals Behaving Badly (CBB)Chemicals Behaving Badly (CBB)

Crystal Size

PolymorphicForm

Supersaturation

ProcessConditions

Shape

MSZW

Growth Kinetics Nucleation Kinetics

Hydrodynamics Heat Transfer

FTIR

USS

VideoMicroscopy

PIV/LDA ReactionCalorimetry

Flow thruXRD

UV Vis

CFD

Courtesy of Dr White, Heriot-Watt University


• Simultaneous multi-technique measurements during a crystallisation process

• Have promoted better understanding of crystallisation in lab scale

• Promoted better operation of crystallisation in small scale

• Linear cooling identified as one of the key operational parameters

Lab scale batch crystallisation

• Data rich

• Lack of correlations between data

• Disturbing flow conditions


• Nucleation via collision breeding:

• Walls of vessel

• free surface of liquid

• internals, e.g. stirrer, baffle

• impurities, e.g. particulates, seeds

• crystal/crystal & crystal/vessel collision

• inhomogeneities due to mixing

Mixing affects

0

5

10

15

20

25

30

35

0 5000 10000 15000

Reynolds Number, Re o [-]

MSZ

W [

o C]

30g/L 0.5°C/min

35g/L 0.5°C/min

30g/L 2.0°C/min

35g/L 2.0°C/min

0

20

40

60

80

100

120

140

160

180

200

0 5000 10000 15000 20000 25000 30000

Reynolds Number, Re o [-]

Cry

stal

Siz

e [ µ

m]

30g/L 2.0°C/min

35g/L 2.0°C/min• MSZW

• Crystal size distribution


• Our understanding in scaling up STR is limited

• There is no agreed rule or parameter on scaling

• Velocity gradient or non-homogeneity increases with scale

• Mixing gradient leads to temperature and mass gradient

2. Challenges in industrial crystallisation


ScaleScale--up of stirred tanksup of stirred tanks

Mixing cannot linearly be scaled in STR

Laboratory

Industrial scale

Kinetic control

Mass/heat transfer control


Heat Transfer on ScaleHeat Transfer on Scale--UpUp

Specific heat transfer area decreases with scale

2.315.86.82Typical 6500 litre STR

100.90.09Typical 90 litre STR

Area / unit Volume (m2/m3)

Area (m2)Volume (m3)


Industrial batch crystallisation

Temperature

gradient

MSZW and

Crystallisation path

nucleation

& growth

Polymorph

& size

Inconsistent morphology

Wide size distribution

Difficult to filter

Mixing

gradient

Concentration

gradient

supersaturtion

gradientpolymorph

MSZW

Temperature

Concentration

∆C

∆T


Practical issues

• Linear cooling is difficult to achieve in large STR

• Implementation of lab multi-measurement techniques is practically impossible in industrial scale


i) consistent product quality can only be achieved in plug flows;

ii) it is very rare to obtain plug flow conditions in batch STR!

iii) Plug flow conditions can only be attained in continuous operation.

From the viewpoint of fluid mechanics

3. Continuous crystallisation


The conventional ways to achieve plug flow include

a) Using a series of CSTRs

b) Employing a tubular reactor


a) Using a series of a) Using a series of CSTRsCSTRs

Conclusions: a) significant increase in inventory, running and capital costs

b) far from plug flow

…..

Plug flow is achieved when the number of CSTRsgoes to infinite


b) Employ a tubular reactor

Conclusion: a) significant high flow rates, leading to very long reactor and large capital costs

b) very short residence time

Operating a tubular reactor at turbulent flow regime in order to obtain near to plug flow


NiTech’s oscillatory baffled reactor (OBR)


Reo = 1250 (xo = 4 mm, f = 1 Hz)

Real system

Demonstration of radial mixingDemonstration of radial mixingwith good dispersionwith good dispersion

3-D CFD simulation


NiTechNiTech’’ss Continuous OBR Continuous OBR (COBR(COBRTMTM))

Oscillation

Out

Tracer

liquid

Conductivity probes


Residence time distribution (RTD) in a COBR

Probe 13.7 meters away from injectionProbe 27.9 meters away from injectionProbe 310.1 meters away from injection

Mixing controlled by the combination of oscillation and bafflesEach baffled cell is a CTSR Plug flow at laminar flowsHandles particulatesLong residence times

D = 0.00007~0.0003 m2/s


20

0

0.1

0.2

0.3

0.4

0.5

0 500 1000 1500 2000Drop diameter (µm)

Dro

p N

umbe

r Fr

actio

n

15mm, 1Hz,Ren = 50015mm, 2Hz,Ren = 50015mm, 3Hz,Ren = 500

Drop/Particle/crystal size distribution obtained in a COBR


• Mixing is not controlled by net flow

• Plug flow achieved at laminar flows

• Excellent heat & mass transfers

• No concentration gradients

• Good with solids

Key differences from other tubular devices on the market


Continuous oscillatory baffled crystalliser

(COBCTM)


Heat Transfer on Scale-Up

COBC™ has larger specific surface area for HT

4022.60.56Typical 72m long 100mm

diameter COBCTM

2.315.86.82Typical 6500 litre STR

100.90.09Typical 90 litre STR

Area / unit Volume (m2/m3)

Area (m2)Volume (m3)


Tube side heat transfer coefficient (w/m2K)

Plug flow delivers excellent heat transfer

47 - 1965,209 - 23,730232,744 - 1,067,5341500 kg/m3

21 - 822,327 - 10,575133,315 - 611,4471000 kg/m3

7 - 28817 - 3,69461,654 - 282,717600 kg/m3

100cp10cp1cp


Control over cooling profile

90-10 oC Flow Rate 0.3 L/min Cooling Rate 2.0 oC/min

y = -1.7118x + 81.031R2 = 0.9934

y = -1.7103x + 80.986R2 = 0.9935

y = -1.7106x + 80.97R2 = 0.9933

y = -1.7112x + 80.972R2 = 0.9933

y = -1.7121x + 81.032R2 = 0.9936

0

10

20

30

40

50

60

70

80

90

0 10 20 30 40 50

Time (min)

Tem

p (o

C)

80-10oC Flow Rate 0.945 L/min Cooling Rate 6.5oC/min

y = -6.5517x + 83.727R2 = 0.9918

y = -6.5524x + 83.696R2 = 0.9916

y = -6.5657x + 83.8R2 = 0.9919

y = -6.5541x + 83.668R2 = 0.9917

y = -6.5629x + 83.699R2 = 0.9919

0

10

20

30

40

50

60

70

80

90

0 2 4 6 8 10 12

Time (min)

Tem

p (o

C)

Any cooling profile, e.g. linear, parabolic, non-continuous, step-wise and etc, can be obtained along COBCTM

Multi-monitoring techniques in lab scale can be implemented along COBCTM


4. Case studies

COBCTM enables greater control over crystallisation path

Able to be more selective on crystal morphology β crystals

α crystals

α + β crystals

a) Morphology of a pharma crystal

Seed α crystals

Seed β crystals


Change on crystal sizeImpact on filtration

The residence time in the COBCtranslates to 12 minutes, compared to a batch cycle time of 8 hours, demonstrating a significant potential improvement in throughput relative to a batch manufacturing facility.

b) Pharma API - size on filtration


c) Filtration index for a pharma product

COBCTM affects outcomes achievedProduct characteristics/performanceConsistent filtration index of 25

STR COBCTM


d) Crystal size distribution of a fine chemical product

More uniform size can be achieved

Greater control on outcome

µ

0

5

10

15

20

25

0 250 500

Particle Diameter (um)

Vol

umn

(%)

STR

OBCEXP 1OBCEXP 2

0

5

10

15

20

25

0 250 500

Particle Diameter (um)

Vol

umn

(%)

STR

OBCEXP 1OBCEXP 2

0

5

10

15

20

25

0 250 500

Particle Diameter (µm)

Vol

umn

(%)

STR

OBCEXP 1OBCEXP 2


e) Fractionation of edible oils

Two stage cooling (17 and 0.3 oC/min)

Consistent IV achieved0

5

10

15

20

25

0 50 100 150 200

Process Time (min)Fi

ltrat

ion

time

(min

)

Benchmark

T05C

T08C

T10C

T11C

T12C

T13C

T14C

T16C

• Significant reduction of crystallisation time

• Improved filtration time


f) Combined reaction & crystallisationCrash cooling Variable mean sizes from crystallisation after a reaction Crystals stuck to the walls of the vessel and surfaces of the impeller

Consistent mean crystal sizeLinear cooling profiles in COBCTM eliminated the events of crystal-stickingMinimise the down-time of washing/cleaning

0

10

20

30

40

50

60

70

80

90

0 50 100 150

Oscillation velocity (mm/s)

d 90 (

µm

)

2 oC/minUncontrolled cooling

0

20

40

60

80

100

120

140

0 1 2 3 4 5 6

Cooling rate (oC/min)

d 90 (

µm

)


• Plug flow tubular crystallisation technology, such as COBCTM, can be used to bridge the gap between lab and industrial scale crystallisation operations

• Multi-monitoring techniques from lab scale crystallisation can directly be fitted along the COBCTM

• COBCTM can be incorporated into existing plants

• Continuous filtration could also be implemented in COBCTM

4. Forward remarks


Colleagues from NiTech

Gareth Jenkins, Excelsyn

Ruth Lane

Acknowledgement

continuous crystallisation using oscillatory baffled … crystallisation using oscillatory baffled...

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