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Purpose of |rystallizer
Methods of |rystallization
Design Specifications
Engineering Drawing
Alternative |ost and Suppliers
Alternative Processes
Questions
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Used to recover pure solids from solution
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Benefits of |ontinuous
± |an maintain solution in supersaturated state
± Large fluidized bed for crystallization
± Minimizes operation costs
± Minimize down time (startup and shutdown)
Benefits of Batch
± Good when have low concentration of product, high
viscosity or many impurities
± |an produce high quality crystal
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h%( !|" #$#
#
#: liquid (solvent) contains more
dissolved solids (solute) than can ordinarily be
accommodated at that temperature
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|oncentrated solution
gradually cooled below
saturation temperature
(50-60°|) to generate a
supersaturated state
Yields well defined
micron-sized crystals
Shell and tube heat
exchanger is used to
cool solution
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Advantages:
± High purity downstream
Disadvantages:
± Temperature change does not always have a positive
effect on supersaturation in proteins
± Protein stability may be at risk
± Solubility can be relatively insensitive to temperature
at high salt concentrations
± |ooling will only help reach supersaturation in
systems where solubility and temperature are directly
related
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Solute dissolves in solution when heated to a
certain temperature (75°|)
Slowly cooled until crystals precipitate
Shell and tube heat exchanger is used to heat
and cool solution
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)# #h%(
Advantages:
± high purity levels downstream
Disadvantages:
± Vaporization chamber requires high pressures
± Protein viability very sensitive to high
temperatures
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Solvents are generally good protein
precipitants
Their low dielectric constants lower the
solvating power of their aqueous solutions
Requires acidic solvent
± For crystallization, an insulin protein falls
out of solution at isoelectric point
pH 5.4-5.7
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Advantages:
± Proteins viability not at risk due to
temperature change
Disadvantages:
± Possible protein contamination due to
insufficient downstream solvent recovery
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((!
In the presence of zinc ions, insulin proteins
orient to form hexamer structures
Y Y
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(%*
Primary nucleation is the first step in
crystallization - growth of a new crystal
± |an bypass primary nucleation (creation of
new crystals) by "seeding" the solution
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http://www.cheresources.com/cryst.shtml
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|rystal size distribution is important for the production
process; affects:
± downstream processing
± solids transport
± caking and storage properties of the material
|orrect crystal size vital for economic production
|rystals produced in commercial crystallization
processes are usually small
± 30 to 100 um in diameter
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Assumptions:
± |ontinuous
± |onstant-volume
± Isothermal
± Well-mixed
Uß Ë Ò
Relates population density
and crystal size
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|" #$
Addition of acidic solvent to decrease pH to
achieve supersaturation
Addition of Zinc ions to initiate Insulin
precipitation
Implementing of ³seeding´ technique
Minimize heat variation to maintain protein
stability
Washing and extensive solvent recovery
downstream
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Temperature 25 °|
Pressure 1.013 bar
Flowrate 111.842 kg/batch
Volume 0.29 m3
Diameter 0.529 m
Height 1.325 m
Residence Time 23.98 h
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#,
http://sundoc.bibliothek.uni-halle.de/diss-online/04/04H181/prom.pdf
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% ))(
± |rystallizer unit
± Zinc |hloride Solution and Water
± Power Requirements
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|" #$www.matche.com
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|%(
± Many suppliers
± $15.00 - $27.00 for 500g
,*
&
± |anadian Hydro: 8.99 cents/kWh (April, 2006)
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|" #$
GEA Niro Inc.
± |ompanies in over 50 countries
± |openhagen, |olumbia, Germany, USA
Ò
HPD Inc.
± Illinois, USA
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#)
For special drug purposes and when a
zinc-free product is needed
Alternative processes that can be used
include:
± Isoelectric Precipitation
± Gel |hromatography
± Ultrafiltration
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#
Protein purification
procedure that can be
used with crystallization
or on its own
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+2#|%&## %"
Molecules are separated
according to their size and
shape
Filtration column is filled with
porous beads
Solution passes through
column
Elution through the gel occurs
in order of decreasing
molecular masses
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#!#
Ultrafiltration used to concentrate
macromolecular solutions
Forced under pressure or by centrifugation
through a semipermeable membranous disk
Solvent and small solutes pass
through the membrane, leaving
behind a more concentrated
macromolecular solution
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QUESTIONS?
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