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CRYSTALLIZATION UNIT. Rachel Adams Jana Dengler Megan MacLeod Kyla Sask. Outline. Purpose of Crystallizer Methods of Crystallization Design Specifications Engineering Drawing Alternative Cost and Suppliers Alternative Processes Questions. Purpose of Crystallizer.

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crystallization unit

CRYSTALLIZATIONUNIT

Rachel Adams

Jana Dengler

Megan MacLeod

Kyla Sask

CHEE 450: Insulin Design Project

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

CRYSTALLIZATION UNIT

purpose of crystallizer
Purpose 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

CRYSTALLIZATION UNIT

mechanism of crystallization
Mechanism 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

CRYSTALLIZATION UNIT

continuous or batch design
Continuous 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

CRYSTALLIZATION UNIT

methods of crystallization
Methods 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

CRYSTALLIZATION UNIT

cooling method
Cooling 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

CRYSTALLIZATION UNIT

cooling method1
Cooling 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

CRYSTALLIZATION UNIT

evaporation method
Evaporation 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

CRYSTALLIZATION UNIT

evaporation method1
Evaporation Method
  • Advantages:
    • high purity levels downstream
  • Disadvantages:
    • Vaporization chamber requires high pressures
    • Protein viability very sensitive to high temperatures

CRYSTALLIZATION UNIT

solvent method
Solvent 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

CRYSTALLIZATION UNIT

solvent method1
Solvent Method
  • Advantages:
    • Proteins viability not at risk due to temperature change
  • Disadvantages:
    • Possible protein contamination due to insufficient downstream solvent recovery

CRYSTALLIZATION UNIT

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

CRYSTALLIZATION UNIT

seeding techniques
Seeding 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

CRYSTALLIZATION UNIT

progression of crystallization
Progression of Crystallization

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

CRYSTALLIZATION UNIT

crystal size and growth rate
Crystal 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

CRYSTALLIZATION UNIT

crystal size and growth rate1
Crystal Size and Growth Rate
  • Assumptions:
    • Continuous
    • Constant-volume
    • Isothermal
    • Well-mixed
  • Relates population density and crystal size
  • Mechanism of crystal growth to determine crystal growth

CRYSTALLIZATION UNIT

crystallizer design
Crystallizer 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

CRYSTALLIZATION UNIT

design equations
Design Equations

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proposed design
Proposed Design

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engineering drawing
Engineering Drawing

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

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costing estimates
Costing Estimates
  • Three costs involved:
    • Crystallizer unit
    • Zinc Chloride Solution and Water
    • Power Requirements

CRYSTALLIZATION UNIT

costing estimates1
Costing Estimates
  • Crystallizer Unit www.matche.com

CRYSTALLIZATION UNIT

costing estimates2
Costing Estimates
  • Crystallizer Unit

CRYSTALLIZATION UNIT

costing estimates3
Costing Estimates
  • Zinc Chloride Solution
    • Many suppliers
    • $15.00 - $27.00 for 500g
  • Power Requirements
    • Canadian Hydro: 8.99 cents/kWh (April, 2006)

CRYSTALLIZATION UNIT

crystallizer suppliers
Crystallizer 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

CRYSTALLIZATION UNIT

alternative processes
Alternative 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

CRYSTALLIZATION UNIT

isoelectric precipitation
Isoelectric 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

CRYSTALLIZATION UNIT

gel filtration chromatography
Gel 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

CRYSTALLIZATION UNIT

ultrafiltration
Ultrafiltration
  • 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

CRYSTALLIZATION UNIT

slide31
QUESTIONS?

CRYSTALLIZATION UNIT

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