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The Crystallizer

The Crystallizer. Simone Houng April 2 nd , 2004. Where We Are. 191 kg insulin input from ultrafilter Recovery from acetonitrile using zinc chloride 188 kg insulin crystal out of crystallizer to basket centrifuge 98% recovery of insulin crystals. Crystallization.

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The Crystallizer

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  1. The Crystallizer Simone Houng April 2nd, 2004.

  2. Where We Are • 191 kg insulin input from ultrafilter • Recovery from acetonitrile using zinc chloride • 188 kg insulin crystal out of crystallizer to basket centrifuge • 98% recovery of insulin crystals

  3. Crystallization • Formation of solid crystals from a solution • Important S-L separation technique Goals: • Isolate insulin from the product streams • Remove impurities • Acetonitrile (RP-HPLC) • Host cell proteins, trypsin enzyme, by-products of the transpeptidation reaction, insulin ester

  4. Nucleation 1o nucleation – 1st crystals in unseeded matrix • Can be modeled = rate of nucleation 2o nucleation- growth, dominant in bulk crystallization • Much more complicated process

  5. Crystal Growth Rate Affect: • Morphology (physical characteristics) • May determine future product handling Is affected by: • Solvent and impurities - large effect • Supersaturation • Imperfections in crystal lattice

  6. CSD (Crystal Size Distribution) Determines processing and product procedures • Size distribution • Morphology • Polymorphism • Impurities in crystal lattice

  7. What we Need • Define supersaturation- size and properties of product • Vessel with sufficient residence time for crystal growth • Mixing to ensure uniform crystal growth

  8. Difficulties in Scaling Up • Need to assume well-mixed and well-suspended crystals • Quality is sensitive to size of reactor • Difficult to model because fluid dynamics at different areas affect kinetics  crystal quality • For batch processes, modeling is often too complex and experimental data is used instead

  9. Most Common Methods 1. Cooling- heat sink 2. Solvent evaporation – [solute] 3. Drowning- add non-solvent to  solute solubility 4. Chemical reaction- may  solubility of solid

  10. Alternative Crystallizers Dominant types: • Tank Crystallizers • Forced Circulation (FC) • Fluidized Bed • Draft Tube Baffles(DTB)

  11. Tank Crystallization • Simple stirred batch reactor Advantages: • For pharmaceuticals, where uniform, well-defined crystals are important • High value, low volume products Disadvantage: • Labor is costly • Longer time

  12. Forced Circulation (FC) • For evaporation & cooling Advantage: • Can easily control circulation rates and velocities Disadvantages: • High heat • No stirrer  large range of concentrations and temperatures • Full cross-section of vessel is not used for crystallization http://www.setprocess.com/technology/fcc.html

  13. Fluidized Bed Advantages: • Large, uniform size Disadvantages: • Low production rate compared to FC • velocity restricted by fluidized requirements • Supersaturation of liquid must be low • Low birth rate of new crystals http://scholarsportal.info/pdflinks/04030101195012367.pdf

  14. Draft Tube Baffles (DTB) • Propeller inside fixed tube • Preferential fines removal and classified product • Little crushing of crystals • Uniform concentration with little dead space • Large crystals http://www.tsk-g.co.jp/en/tech/uni/uni1.

  15. Choosing a Crystallizer Based on: • Properties of compound (solubility, temperature dependence) • Crystallization process • Required product specifications May also use: • Fines removal • Clear liquor • Product removal • Recycle loops

  16. Design of the Crystallizer From another process: • Batch process at 5oC for 12 hours • Zinc chloride added to initiate crystallization • insulin6- Zn2 stoichiometry • 0.5m3 reactor: 12 kg insulin to 11.31 kg of crystal (~95%)

  17. Proposed Design • Seeded batch reactor with mixer • Use 1 reactor OR multiple batches to create more continuous process • 17 mini-batches of 316 L per day from ultrafilter(Andrea)  = residence time of crystals V = volume Qo = flow rate out

  18. Calculating V’s and Batch Times Their Process: 11.31kg/12 hr batch 0.5 m3 reactor volume Residence time gives 95% recovery Our Process: 188kg/batch with 98% recovery 1 batch for 6 h V = 17.04m3, C = US$239 500 1 b for 12 h V = 8.52 m3,C = US$156 200 2 b for 12 h  V = 4.26 m3 each, C = US$105 300 3 b for 12 h V = 2.84 m3 each, C = US$85 200

  19. Alaqua, Inc. Ellett Industries, Ltd. GEA Evaporation Technologies Hosokawa Bepex Corp. Ionics Novatec, Inc. Walton/Stout, Inc. Resources Conservation Co., Div. Of Ionics Inc. Sulzer Chemtech USA, Inc. Swenson Technology, Inc. USFilter USFilter / HPD Products LIST, Inc. Suppliers

  20. Questions?

  21. References • Bioprocess Design: • http://cheserver.ent.ohiou.edu/ChE482/MoreBiosepExamples.pdf • http://cheserver.ent.ohiou.edu/ChE482/biosep-examples.pdf • http://www.cheresources.com/cryst.shtml • http://www.tsk-g.co.jp/en/tech/uni/unil

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