cryst dev case study dec 2011
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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
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