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CRYSTALLIZATION UNIT

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

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  1. CRYSTALLIZATIONUNIT Rachel Adams Jana Dengler Megan MacLeod Kyla Sask CHEE 450: Insulin Design Project

  2. Outline • Purpose of Crystallizer • Methods of Crystallization • Design Specifications • Engineering Drawing • Alternative Cost and Suppliers • Alternative Processes • Questions CRYSTALLIZATION UNIT

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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

  9. 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

  10. Evaporation Method • Advantages: • high purity levels downstream • Disadvantages: • Vaporization chamber requires high pressures • Protein viability very sensitive to high temperatures CRYSTALLIZATION UNIT

  11. 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

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

  13. 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

  14. 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

  15. Progression of Crystallization http://www.cheresources.com/cryst.shtml CRYSTALLIZATION UNIT

  16. 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

  17. 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

  18. 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

  19. Design Equations CRYSTALLIZATION UNIT

  20. Proposed Design CRYSTALLIZATION UNIT

  21. Engineering Drawing http://sundoc.bibliothek.uni-halle.de/diss-online/04/04H181/prom.pdf CRYSTALLIZATION UNIT

  22. Costing Estimates • Three costs involved: • Crystallizer unit • Zinc Chloride Solution and Water • Power Requirements CRYSTALLIZATION UNIT

  23. Costing Estimates • Crystallizer Unit www.matche.com CRYSTALLIZATION UNIT

  24. Costing Estimates • Crystallizer Unit CRYSTALLIZATION UNIT

  25. 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

  26. 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

  27. 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

  28. 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

  29. 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

  30. 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

  31. QUESTIONS? CRYSTALLIZATION UNIT

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