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

 

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

Nucleation

1 o nucleation – 1 st matrix crystals in unseeded

•

Can be modeled = rate of nucleation 2 o nucleation- growth, dominant in bulk crystallization

•

Much more complicated process

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

CSD (Crystal Size Distribution)

Determines processing and product procedures

– – – –

Size distribution Morphology Polymorphism Impurities in crystal lattice

What we Need



Define supersaturation- size and properties of product



Vessel with sufficient residence time for crystal growth



Mixing to ensure uniform crystal growth

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

Most Common Methods

1. Cooling- heat sink 2. Solvent evaporation –



[solute] 3. Drowning- add non-solvent to



solute solubility 4. Chemical reaction- may



of solid solubility

Alternative Crystallizers

Dominant types:



Tank Crystallizers



Forced Circulation (FC)



Fluidized Bed



Draft Tube Baffles(DTB)

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

Forced Circulation (FC)



For evaporation & cooling Advantage:

–

Can easily control circulation rates and velocities Disadvantages:

– – – http://www.setprocess.com/technology/fcc.html

High heat No stirrer



large range of concentrations and temperatures Full cross-section of vessel is not used for crystallization

Fluidized Bed

Advantages:

–

Large, uniform size

http://scholarsportal.info/pdflinks/04030101195012367.pdf

Disadvantages:

–

Low production rate compared to FC

•

velocity restricted by fluidized requirements

•

Supersaturation of liquid must be low

–

Low birth rate of new crystals

Draft Tube Baffles (DTB)



Propeller inside fixed tube



Preferential fines removal

http://www.tsk-g.co.jp/en/tech/uni/uni1.

and classified product



Little crushing of crystals



Uniform concentration with little dead space



Large crystals

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

Design of the Crystallizer



From another process: Batch process at 5 o C for 12 hours



Zinc chloride added to initiate crystallization

 –

insulin 6 - Zn 2 stoichiometry 0.5m

3 reactor: 12 kg insulin to 11.31 kg of crystal (~95%)

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)

 

V Q

0 

V massrate insulinout



density insulin



= residence time of crystals V = volume Q o = flow rate out

Calculating V’s and Batch Times

Their Process: 11.31kg/12 hr batch 0.5 m 3 reactor volume Residence time gives 95% recovery Our Process: 188kg/batch with 98% recovery 1 batch for 6 h



1 b for 12 h



V = 17.04m

V = 8.52 m 3 3 , C = US$239 500 , C = US$156 200 2 b for 12 h



3 b for 12 h



V = 4.26 m V = 2.84 m 3 3 each, C = US$105 300 each, C = US$85 200

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.

Questions?

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