Crystallization

Make Solvent Bad

• Lower T
• Evaporate solvent
• Change PH or salt concentra-
tion

What does the solute do?

1
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

5
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

6
Thermodynamics of Solubility

Need Solubility as a function of T

7
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

9
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

10
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

11
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

12
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

13
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.

14
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

15
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

16
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
17
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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