Crystallization unit
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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

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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

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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

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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

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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

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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

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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

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Evaporation method1

Evaporation Method

  • Advantages:

    • high purity levels downstream

  • Disadvantages:

    • Vaporization chamber requires high pressures

    • Protein viability very sensitive to high temperatures

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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

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Solvent method1

Solvent Method

  • Advantages:

    • Proteins viability not at risk due to temperature change

  • Disadvantages:

    • Possible protein contamination due to insufficient downstream solvent recovery

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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

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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

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Progression of crystallization

Progression of Crystallization

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

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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

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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

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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

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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

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Costing estimates1

Costing Estimates

  • Crystallizer Unit www.matche.com

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Costing estimates2

Costing Estimates

  • Crystallizer Unit

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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)

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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

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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

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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

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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

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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

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Crystallization unit

QUESTIONS?

CRYSTALLIZATION UNIT


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