crystallizer.ppt

CHEE 450: Insulin Design Project

CRYSTALLIZATIONCRYSTALLIZATIONUNITUNIT

CRYSTALLIZATIONCRYSTALLIZATIONUNITUNIT

Rachel Adams

Jana Dengler

Megan MacLeod

Kyla Sask

Rachel Adams

Jana Dengler

Megan MacLeod

Kyla Sask

CRYSTALLIZATION UNIT

OutlineOutline

• Purpose of Crystallizer• Methods of Crystallization• Design Specifications• Engineering Drawing• Alternative Cost and Suppliers• Alternative Processes• Questions


Purpose of CrystallizerPurpose of Crystallizer

• Used to recover pure solids from solution

• Highly desirable end product because of:– Exceptional purity– Ease of handling– Long shelf life

• One of the final treatment steps in the purification and concentration of insulin

• 98% of the insulin must be crystallized


Mechanism of CrystallizationMechanism of Crystallization

• Crystal nucleation and amorphous precipitates are in competition during supersaturation conditions

• Nucleation favored by slowly exceeding the equilibrium point of saturation – permits time for the protein structure

to orient in a crystalline lattice


Continuous or Batch DesignContinuous or Batch Design

• Benefits of Continuous– Can 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– Can produce high quality crystal


Methods of CrystallizationMethods of Crystallization

• Supersaturation: liquid (solvent) contains more dissolved solids (solute) than can ordinarily be accommodated at that temperature

• Can be achieved by several methods:– Cooling– Evaporation– Solvent addition– Precipitant Addition


Cooling MethodCooling Method

• Concentrated solution gradually cooled below saturation temperature (50-60°C) to generate a supersaturated state

• Yields well defined micron-sized crystals

• Shell and tube heat exchanger is used to cool solution


Cooling MethodCooling Method

• 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– Cooling will only help reach supersaturation in

systems where solubility and temperature are directly related


Evaporation MethodEvaporation Method

• Solute dissolves in solution when heated to a certain temperature (75°C)

• Slowly cooled until crystals precipitate• Shell and tube heat exchanger is used to heat

and cool solution


Evaporation MethodEvaporation Method

• Advantages: – high purity levels downstream

• Disadvantages:– Vaporization chamber requires high pressures– Protein viability very sensitive to high

temperatures


Solvent MethodSolvent Method

• 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


Solvent MethodSolvent Method

• Advantages:– Proteins viability not at risk due to

temperature change

• Disadvantages:– Possible protein contamination due to

insufficient downstream solvent recovery


Addition of Zinc Ions Addition of Zinc Ions

• In the presence of zinc ions, insulin proteins orient to form hexamer structures

• Zinc ions render insulin insoluble which results in micro-crystallization and precipitation

Human Insulin Hexamer with Zinc ion


Seeding TechniquesSeeding Techniques

• Primary nucleation is the first step in crystallization - growth of a new crystal – Can bypass primary nucleation (creation of

new crystals) by "seeding" the solution

• Secondary nucleation is crystal growth initiated by contact– Accelerated by "seeding" adding existing

insulin crystals to perpetuate crystal growth


Progression of CrystallizationProgression of Crystallization

http://www.cheresources.com/cryst.shtml


Crystal Size and Growth RateCrystal Size and Growth Rate

• Crystal size distribution is important for the production process; affects:– downstream processing– solids transport– caking and storage properties of the material

• Correct crystal size vital for economic production• Crystals produced in commercial crystallization

processes are usually small– 30 to 100 um in diameter


Crystal Size and Growth RateCrystal Size and Growth Rate

• Assumptions:– Continuous– Constant-volume– Isothermal– Well-mixed

• Relates population density and crystal size

GL

Lk

Lk

v

a

/expnn

M :Mass Crystal

A: AreaCrystal

o

3c

2c

• Mechanism of crystal growth to determine crystal growth

sv

as cc3dt

dL

kkk


Crystallizer DesignCrystallizer Design

• Addition of acidic solvent to decrease pH to achieve supersaturation

• Addition of Zinc ions to initiate Insulin precipitation

• Implementing of “seeding” technique • Minimize heat variation to maintain protein

stability• Washing and extensive solvent recovery

downstream


Design EquationsDesign Equations

2.5DH

H4

DV

slurry of gravity specific24.6

slurry of qualityVolume

crystals of sg75.0solutio of sg25.0

crystals of sgsolution of sgslurry of gravity Specific

.25quantity/0 crystalquality Slurry

flowratetime retentionquantity Crystal

2


Proposed DesignProposed Design

Temperature 25 °C

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


Engineering DrawingEngineering Drawing

http://sundoc.bibliothek.uni-halle.de/diss-online/04/04H181/prom.pdf


Costing EstimatesCosting Estimates

• Three costs involved:– Crystallizer unit– Zinc Chloride Solution and Water– Power Requirements



• Crystallizer Unit www.matche.com

http://www.matche.com/



• Crystallizer UnitBatch, Atmospheric Crystallizer

0

10000

20000

30000

40000

50000

60000

70000

80000

0.00

0.15

0.30

0.45

0.61

0.76

0.91

1.06

1.21

1.36

1.52

1.67

1.82

1.97

Size (m3)

Co

st (

US

$)

Carbon Steel Stainless Steel



• Zinc Chloride Solution– Many suppliers– $15.00 - $27.00 for 500g

• Power Requirements– Canadian Hydro: 8.99 cents/kWh (April, 2006)


Crystallizer SuppliersCrystallizer Suppliers

• GEA Niro Inc.– Companies in over 50 countries– Copenhagen, Columbia, Germany, USA

GEA Kestner Evaporator/Crystallizer

• Swenson Technology Inc. – Illinois, USA

• HPD Inc.– Illinois, USA


Alternative ProcessesAlternative Processes

• For special drug purposes and when a zinc-free product is needed

• Alternative processes that can be used include:– Isoelectric Precipitation– Gel Chromatography– Ultrafiltration


Isoelectric PrecipitationIsoelectric Precipitation

• Protein purification procedure that can be used with crystallization or on its own

• The pH of a mixture is adjusted to the pI of the protein to be isolated to selectively minimize its solubility


Gel Filtration ChromatographyGel Filtration Chromatography

• 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


UltrafiltrationUltrafiltration

• 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


QUESTIONS?

crystallizer.ppt

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