Crystallization
Make Solvent Bad
• Lower T
• Evaporate solvent
• Change PH or salt concentra-
tion
What does the solute do?
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Crystallization
Where do insoluble solutes go?
To a condensed phase with lower free energy
Crystal Glass
Solid Phases are in equilibrium with solution
2
Crystallization Advantages
• High Purity
• High Selectivity
• Separate enantiomers/stereoisomers (new FDA requirement)
• Crystal is desired product form
3
Separation Principle
• Equilibrium
Insolubility/ Free energy minimization
• Rate/Diffusional
Formation (Nucleation) of new crystals
Rate of Addition to the growing surface
Transport of Material to the growing surface
4
Process
• Dissolve Solute
• Lower T until solubility is ex-
Mixture at Tcrys(L)
ceeded
• Evaporate solvent until solubil-
Mixture at Tsol(F)
ity is exceeded
• New solid phase forms
Crystal Solid (S)
All phase are in equilibrium
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Process
Mixture at Tcrys(L)
• Dissolve Solute
Mixture at Tsol(F)
• Lower T until solubility is ex-
Crystal Solid (S) ceeded
• Evaporate solvent until solubil-
Concentration
Tsol ity is exceeded
Tcrys
• New solid phase forms
Temperature
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Thermodynamics of Solubility
Need Solubility as a function of T
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Material Balance
Given:
• Feed Composition and flow
Mixture at Tcrys(L)
• Output streams are at equilib-
rium
Mixture at Tsol(F)
• crystal composition
Crystal Solid (S)
• solvent composition
Solve for mass in each output stream
Yield = mass fraction recovered in crystal
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Example Material Balance
Tsol = 90 Cf eed = 100mg/g F = 100g
Tcrys = 0 Cliq = 60mg/g Csolid = 1000mg/g pure
Mass Balances
F =L+S Cf eed F = Cliq L + Csolid S
Solve for L and S
S = 4.25g there were 10g of solid in the feed so 42 % yield
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Improve the Yield
How to improve the yield: Reduce Concentration in solvent
Tnew Tcrys
Concentration
Mixture at Tcrys(L) Tsol
Mixture at Tsol(F)
Crystal Solid (S) Temperature
• Other Components Precipitate
• Crystal Grows Faster (Impurities, Glass)
• Crystal size, shape, size distribution
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Solid Processing
Mixture at Tcrys(L)
Assumes solid phase totally re-
Mixture at Tsol(F) moved from solvent
Should include a process to do this
Crystal Solid (S)
Solvent and
Mixture at Tsol Crystals at Tcrys Mixture at Tcrys
Crystal Solid
Crystallization Filtration
Sedimentation
Centrifugation
Solid-Liquid Separation depends on size, shape, and density of the
dispersed crystals
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Salts and Ions and Hydration
Solvent or Ions can be incorporated into the crystal
Crystal form can change as a function of T
Need to include in material balance
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Rate Processes in Crystallization
• Formation (Nucleation) of new crystals
• Rate of Addition to the growing surface (Like Chemical
Reaction)
• Transport of Material to the growing surface
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Supersaturation
Concentration
Tcrys Tsol
Temperature
• Concentration above the equilibrium solubility but no new phase
• Cool water below freezing point but no ice
How is this possible? Not thermodynamics.
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Formation of New Phases
How do new phases form?
A little at a time. First a small region must nucleate.
But small bits of new phase are different
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Surface Free Energy
2σ
Pin − Pout = Effect of Surface Tension
r
• Higher pressure in the
drop
• Changes fugacity
• Changes equilibrium
• Only particles bigger
than rc will be insoluble
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Effect of Nucleation on Design
Low Supersaturations
• Slow Nucleation
• Slow growth, fewer larger crystals
• Closer to equilibrium control
• Low Yield
High Supersaturations
• Fast Nucleation
• Faster growth, more smaller crystals
• Rate controlled, Nonequilibrium crystal structures
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Why is Crystallization a Billion Dollar
Problem
What if one crystal structure has a lower free energy but the other
grows faster?
Which one your process generates will depend on process
conditions and scale up.
Having a reproducible crystal structure is critical to the
pharmaceutical industry.
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