Crystallization DevelopmentPhysical Sciences

December 2011

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Crystallization - one of the oldest unit ops….

Crystallization of sugar - Duhamel du Monceau's "Art de rafiner le sucre" 1764

….and still one of the most challenging

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Crystallization challenges

Purity

Yield

CSDSolids

handling

SLS

Polymorphism

Crystalshape

Scale-up

Solvation

Encrustation

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Consider the Whole Process

Solid liquid separation

Issues:

PurityYield

Particle sizePolymorph

Drying

Issues:

Solvent removalPolymorph

Particle sizeAgglomeration

LumpingBreakage

Micronise

Issues:

Form changeDe-lumping

Particle size reductionProvides consistency

Preferred FormDesired properties

Crystallization

Issues:

SupersaturationNucleationPolymorph

PurityYield

Particle sizeHabit

Final ProductPreferred Form

Desired properties

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Case studies: manufacturing

• API

• Issues with process and PSD at multi-ton scale

• Project milestones:– Review batch data– Simplify seeding– Control PSD– Tech transfer to new CMO

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• Exists as three forms• Require anhydrous form• Tight particle size distribution

Monohydrate Trihydrate Anhydrate

Background

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Temperature cycling experiments indicate wide MSZW (~30°C)

This provides larger space for experimental design

Experimental - measure solubility and metastable zone width

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MSZW

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Solubility & MSZW - issues

Temperature C

Co

nce

ntr

atio

n

Wide metastable zone,growth requires highsupersaturation

Slow growth and desupersaturation

Highend pointsolubility

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Lasentec Focussed Beam Reflectance Measurement (FBRM) and Particle Video Microscope (PVM) used for initial reactor-scale Screening Experiments

Parameters Varied:• Seed addition temperature• Seed size• Sonication of seed slurry• Ethanol content

Instrumentation

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• As a plot of one or more FBRM chord length distributions;

• As a comparative table of FBRM statistical values;

• As a Trend Graph plot of FBRM statistics as a function of time

• As representative PVM images

0

1

2

3

4

5

#/s

ec (

Sq

ua

re W

eig

ht)

1 10 100 1000

Chord Length (microns)

METTLER TOLEDO

0

500

1000

1500

2000

2500

counts

/sec (

fines)

02:00:00 04:00:00 06:00:00 08:00:00 10:00:00 12:00:00 14:00:00

Relative Time

METTLER TOLEDO

Results are presented in four forms:

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0

50

100

150

200

250

#/s

ec

1 10 100 1000

Chord Length (microns)

METTLER TOLEDO

Quantifying the Effect of Seeding Temperature Unweighted Data

0

1

2

3

4

5

#/s

ec (

Squ

are

Weig

ht)

1 10 100 1000

Chord Length (microns)

METTLER TOLEDO

Weighted Data

Seeding at 20°C yields an average size ~30% smaller than seeding at 30°C.

At 20°C more smaller crystals than at 30°C.

Unweighted data emphasizes the behaviour of the smaller particles.

Weighted data emphasized the behaviour of larger particles.

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Weighted vs. Unweighted Distributions

Example: A population of cubes

Mean = 7.1 µm Mean = 9.2 µm

Mean = 12.2 µm Mean = 15.2 µm

FBRM®

No Weight

FBRM®

Square Weight

Emphasizes changes to the fine (small) end of the distribution

Emphasizes changes to the coarse (large)

end of the distribution

This simple example of a population of cubes helps highlight what the number and volume distribution of the particle system looks like.

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Visualising the Effect of Seeding Temperature

PVM images.

The product consists of agglomerated crystals.

Seeding at 30°C crystals & agglomerates are larger than seeding at 20°C.

0

1

2

3

4

5

#/s

ec (

Sq

ua

re W

eigh

t)

1 10 100 1000

Chord Length (microns)

METTLER TOLEDO

15

0

1000

2000

3000

4000

5000

cou

nts

/se

c (fi

ne

s)

02:00:00 04:00:00 06:00:00 08:00:00 10:00:00 12:00:00 14:00:00 16:00:00

Relative Time

METTLER TOLEDO

Quantifying Rate and Degree of Change

Track the rate & degree of change to particles as they occur in the process. Can be used to directly compare crystal behaviour.

0

500

1000

1500

2000

2500

cou

nts

/se

c (fi

ne

s)

02:00:00 04:00:00 06:00:00 08:00:00 10:00:00 12:00:00 14:00:00

Relative Time

METTLER TOLEDO

#/sec <10μm#/sec 10-50μm

Seeding at 20°C rapid increase in small crystals over 1 one hour followed by gradual increase thereafter.Seeding at 30°C an initial modest increase in small crystals, and then a gradual increase over a seven hour period.

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0.0

1.0

2.0

3.0

4.0

#/s

ec

(Sq

uar

e W

eig

ht)

1 10 100 1000

Chord Length (microns)

METTLER TOLEDO

Comparing Seeding Events

Weighted Data

Seeding at 30°C, much greater degree of growth & agglomeration.

0.0

0.5

1.0

1.5

2.0

2.5 #/s

ec (

Sq

ua

re W

eig

ht)

1 10 100 1000

Chord Length (microns)

METTLER TOLEDO

Weighted Data

Weighted distributions show changes to crystal size and number for the period after seeding and cooling to 2°C.

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0.0

1.0

2.0

3.0

4.0

#/s

ec

(Sq

ua

re W

eig

ht)

1 10 100 1000

Chord Length (microns)

METTLER TOLEDO

Visualising Seeding Events at 20°C

Weighted Data

Seeding at 20°C the particles are small agglomerates.

During the cool to 2°C visible increase in the number & size of the agglomerates.

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0.0

0.5

1.0

1.5

2.0

2.5 #/s

ec

(Sq

ua

re W

eig

ht)

1 10 100 1000

Chord Length (microns)

METTLER TOLEDO

Visualising Seeding Events at 30°C

Weighted Data

Compared to seeding at 20°C, the initial hold after seeding at 30°C results in modest nucleation and growth.

However, at the end of the cooling to 2°C, the agglomerated crystals are already very large.

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0

25

50

75

100

125

150

#/s

ec

1 10 100 1000

Chord Length (microns)

METTLER TOLEDO

Quantifying the Effect of Attrition

Unweighted Data

The population of crystals smaller than 50μm has increased by about 35%.

However, there is very little effect on the large crystal population – suggesting that the fine particles are small crystals that were attached to the surfaces of the agglomerates, but have now become detached due to the higher agitation.

The effect of increased agitation is very much less than the effect of changing the seeding temperature.

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0

25

50

75

100

125

150

#/s

ec

1 10 100 1000

Chord Length (microns)

METTLER TOLEDO

Visualising The Effect of Attrition

Unweighted Data

These PVM images show the crystal system before and after the increase in agitator speed.

After 120 minutes of higher speed agitation a greater number of very small particles, very little change to the large crystals and agglomerates.

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• Control over difficult Crystallization

• Anhydrous form successfully isolated

• Challenging PSD specification achieved

Conclusion