The Crystallizer
Simone Houng
April 2nd, 2004.
Where We Are
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191 kg insulin input from ultrafilter
Recovery from acetonitrile using zinc
chloride
188 kg insulin crystal out of
crystallizer to basket centrifuge
98% recovery of insulin crystals
Crystallization
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
Formation of solid crystals from a solution
Important S-L separation technique
Goals:


Isolate insulin from the product streams
Remove impurities
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–
Acetonitrile (RP-HPLC)
Host cell proteins, trypsin enzyme, byproducts of the transpeptidation reaction,
insulin ester
Nucleation
1o nucleation – 1st crystals in unseeded
matrix
•
Can be modeled = rate of nucleation
2o nucleation- growth, dominant in
bulk crystallization
•
Much more complicated process
Crystal Growth Rate
Affect:
 Morphology (physical characteristics)
 May determine future product handling
Is affected by:
 Solvent and impurities - large effect
 Supersaturation
 Imperfections in crystal lattice
CSD (Crystal Size Distribution)
Determines processing and product
procedures
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Size distribution
Morphology
Polymorphism
Impurities in crystal lattice
What we Need
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Define supersaturation- size and
properties of product
Vessel with sufficient residence time
for crystal growth
Mixing to ensure uniform crystal
growth
Difficulties in Scaling Up
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Need to assume well-mixed and wellsuspended crystals
Quality is sensitive to size of reactor
Difficult to model because fluid dynamics
at different areas affect kinetics  crystal
quality
For batch processes, modeling is often
too complex and experimental data is
used instead
Most Common Methods
1. Cooling- heat sink
2. Solvent evaporation – [solute]
3. Drowning- add non-solvent to 
solute solubility
4. Chemical reaction- may  solubility
of solid
Alternative Crystallizers
Dominant types:
 Tank Crystallizers
 Forced Circulation (FC)
 Fluidized Bed
 Draft Tube Baffles(DTB)
Tank Crystallization
Simple stirred batch reactor
Advantages:

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For pharmaceuticals, where uniform,
well-defined crystals are important
High value, low volume products
Disadvantage:
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Labor is costly
Longer time
Forced Circulation (FC)
For evaporation & cooling
Advantage:

Can easily control circulation
rates and velocities
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Disadvantages:
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–
–
http://www.setprocess.com/technology/fcc.html
High heat
No stirrer  large range of concentrations and
temperatures
Full cross-section of vessel is not used for
crystallization
Fluidized Bed
Advantages:
–
Large, uniform size
http://scholarsportal.info/pdflinks/04030101195012367.pdf
Disadvantages:
–
Low production rate compared to FC
•
•
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velocity restricted by fluidized requirements
Supersaturation of liquid must be low
Low birth rate of new crystals
Draft Tube Baffles (DTB)
Propeller inside fixed tube
 Preferential fines removal
and classified product
 Little crushing of crystals
 Uniform concentration with little
dead space
 Large crystals

http://www.tsk-g.co.jp/en/tech/uni/uni1.
Choosing a Crystallizer
Based on:
 Properties of compound (solubility,
temperature dependence)
 Crystallization process
 Required product specifications
May also use:
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Fines removal
Clear liquor
Product removal
Recycle loops
Design of the Crystallizer
From another process:
o
 Batch process at 5 C for 12 hours
 Zinc chloride added to initiate
crystallization
–

insulin6- Zn2 stoichiometry
0.5m3 reactor: 12 kg insulin to 11.31
kg of crystal (~95%)
Proposed Design
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Seeded batch reactor with mixer
 Use 1 reactor OR multiple batches to
create more continuous process
– 17 mini-batches of 316 L per day from
ultrafilter(Andrea)
V
V


Q0 massrateinsulinout  densityinsulin
 = residence time of crystals
V = volume
Qo = flow rate out
Calculating V’s and Batch Times
Their Process:
11.31kg/12 hr batch
0.5 m3 reactor volume
Residence time gives 95% recovery
Our Process:
188kg/batch with 98% recovery
1 batch for 6 h V = 17.04m3, C = US$239 500
1 b for 12 h V = 8.52 m3, C = US$156 200
2 b for 12 h  V = 4.26 m3 each, C = US$105 300
3 b for 12 h V = 2.84 m3 each, C = US$85 200
Suppliers
Alaqua, Inc.
Ellett Industries, Ltd.
GEA Evaporation
Technologies
Hosokawa Bepex Corp.
Ionics
Novatec, Inc.
Walton/Stout, Inc.
Resources Conservation
Co., Div. Of Ionics Inc.
Sulzer Chemtech USA,
Inc.
Swenson Technology,
Inc.
USFilter
USFilter / HPD Products
LIST, Inc.
Questions?
References
•Bioprocess Design:
http://cheserver.ent.ohiou.edu/ChE482/MoreBiosepExamples.pdf
http://cheserver.ent.ohiou.edu/ChE482/biosep-examples.pdf
•http://www.cheresources.com/cryst.shtml
•http://www.tsk-g.co.jp/en/tech/uni/unil