The Crystallizer

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/04030101195012
367.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 Vs 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 US239 500
• 1 b for 12 h? V 8.52 m3, C US156 200
• 2 b for 12 h ? V 4.26 m3 each, C US105 300
• 3 b for 12 h? V 2.84 m3 each, C US85 200

19
Suppliers

• 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.

20
Questions?
21
References

• Bioprocess Design
• http//cheserver.ent.ohiou.edu/ChE482/MoreBiosepEx
  amples.pdf
• http//cheserver.ent.ohiou.edu/ChE482/biosep-examp
  les.pdf
• http//www.cheresources.com/cryst.shtml
• http//www.tsk-g.co.jp/en/tech/uni/unil