Crystallization

Module 4
R Gopinadh
Biotech Dept (GIT)
GITAM Deemed University
Visakhapatnam.
 Crystallization
Crystallization is a separation and purification method

• widely used in purification of components.

• Crystallization consists of two stages:
a) formation of nuclei and
b) growth of crystals.

For crystallization to occur the solution should be first

supersaturated.
The first step of crystallization is formation of nucleation where
crystals are formed when particles gather into clusters.
Crystallization
Crystallization
 Crystallization
There are two different nucleation formations –
• primary and
• secondary.

The second step of crystallization is crystal growth where nucleus

size increases after the critical cluster size is achieved.

Crystallization is widely used in chemical industry.

crystallization processes are cooling and evaporative

crystallization.
 Crystallization
• Crystallization, one of the oldest of unit operations in the
portfolio of industrial separations.

• It is a separation and purification method widely used for final

purification of components.

• Crystallization is especially used for high quality products,

which have high purity grade.

• The oldest crystallization techniques are applied in salt and

sugar production (Myerson, 2001).
 Crystallization
• Many organic liquids are purified by crystallization rather than
by distillation,
• because enthalpies of crystallization are usually lower than
enthalpies of vaporization.
• Crystallization is also an important technique in the
desalination of seawater,
• the freeze-concentration of fruit juices,
• the recovery of valuable materials such as metal salts from
electroplating processes,
• the production of materials for the electronic industries and in
biotechnological operations such as the
• processing of proteins.
 Crystallization
• The industrial applications of crystallization are not necessarily
confined to the production of pure solids substances.
• Lately large-scale purification techniques have been developed for
substances that are normally liquid at room temperature.
E.g. low-temperature crystallisation can be used as purification
method for liquid hydrocarbon mixtures in petroleum industry.

Mechanism and processes

Several methods can be used to obtain supersaturation such as solvent
evaporation, cooling, chemical reaction and addition of a second
solvent to reduce the solubility of the solute, solvent layering and
sublimation along with other methods.
(Coulson & Richardson, 2002)
Crystallization
 Mechanism of Crystallization
• The first step of crystallization is formation of nucleation where crystals are formed
when particles gather into clusters.

• The clusters become stable nuclei after achieving the critical cluster size.
• There are two different nucleation formations – primary and secondary as seen
figure

• Primary nucleation is spontaneous and homogeneous in the absence of foreign

particles. Thus, in the presence of foreign particles nucleation formation is
heterogeneous and then the formation is induced by foreign particles and occurs
lower supersaturation concentration compared to homogeneous primary
nucleation as shown in figure

• Secondary nucleation appears when crystals already exist in the solution and it is
caused by collision of crystals. This type of nucleation formation is typical
mechanism in industrial crystallization because of low supersaturation
concentration as shown in figure
Mechanism of Crystallization
 Mechanism of Crystallization
The supersaturation must be above a certain value before nucleation will
begin.

In a part of the phase diagram called the metastable region,

In metastable region the supersaturation is so low that nucleation will not

start.

Once the supersaturation has been raised enough to be in the labile region
of the phase diagram, nucleation can begin.

At this point, crystals begin to grow, and the supersaturation decreases.

A possible way of carrying out a crystallization is indicated by the lines with

arrows in .
If the supersaturation becomes too high, the nucleation rate will be too great,
and an amorphous precipitate will result.
 Mechanism of Crystallization
crystal growth where nucleus size increases after the critical cluster
size is achieved.

• Crystal growth increases its own dimension in thin layers.

• Crystal growth rate is affected by various physical factors, such as

a. Surface tension of solution

b. Pressure,
c. Temperature,
d. Relative crystal velocity in the solution,
e. Reynolds number
 Mechanism of Crystallization
Chemical industry produces 70% of all solid materials by :
crystallization and precipitation.

• low temperatures and low energy consumptions in operations.

• High purity level can be achieved with single step operation.

• Main crystallization processes are cooling and evaporative crystallization.

• In cooling crystallization, crystals are formed by cooling the solution.

• In evaporative crystallization the solvent is removed by evaporation to

form crystals and thus requires a lot more energy than cooling
crystallization.

• In industrial scale the crystallization reactors may be either batch or

continuous reactors e.g. crystallizers.
 Mechanism of Crystallization
Crystallization is typical downstream processing method for high quality
products with high purity requirements.

The method is widely used for example in organic acid production.

One of the most common organic acids is citric acid which is used in several
industries such as pharmaceutical, food and beverage industries.

After fermentation the broth is filtered and precipitated with Ca(OH)2 at pH of

7.2 and temperature of 70-90 °C. Calcium citrate crystals are formed in the
reaction. After filtration the calcium citrate is reacted with sulfuric acid to
precipitate the calcium in the form of calcium sulfate. Anhydrous citric
acid is released (when reaction occurs above 40 °C) and then clarified with
active carbon and crystallized with evaporation. The resulted product has
very high purity level due to crystallization and therefore is suitable for
foodstuffs or pharmaceuticals.
 Mechanism of Crystallization
The schematic block diagram of the production process is presented in figure
Mechanism of Crystallization
Crystal Structure
 Mechanism of Crystallization

• Primary Nucleation

Power Law :
where B is the number of nuclei formed per unit volume per unit time,
N is the number of nuclei per unit volume,
kn is a rate constant,
c is the instantaneous solute concentration, and
c∗ is the solute concentration at saturation.
(c − c∗) term is called the supersaturation.
 Mechanism of Crystallization

Experimental data from industrial crystallizers have indicated that secondary

nucleation usually predominates.
Two types of secondary nucleation are shear nucleation and contact
nucleation
Shear nucleation occurs as a result of fluid shear on growing crystal faces,
and contact nucleation happens because of crystals colliding with each
other and with the impeller and other vessel internal surfaces. The most
widely used relation for the rate of secondary nucleation in crystallization
is the following
 Mechanism of Crystallization
Secondary Nucleation

Power Law :
where B is the number of nuclei formed per unit volume per unit time,
N is the number of nuclei per unit volume,
kn is a rate constant,
c is the instantaneous solute concentration, and
c∗ is the solute concentration at saturation.
(c − c∗) term is called the supersaturation.

where k1 is a rate constant, and MT is the suspension density.

The exponent b can range up to 5 but has a most probable value of 2.
The exponent j ranges up to 1.5, with 1 being the most probable value.
• Mixed-suspension, mixed-product-removal (MSMPR)
model
• Mixed-suspension, mixed-product-removal (MSMPR) model is useful for the
design and analysis of draft-tube, baffled crystallizer

(1) Continuous, steay-flow, steay-state operation

(2) Perfect mixing of the magma
(3) No classification of crystals
(4) Uniform degree of supersaturation for the magma
(5) Crystal growth rate independent of crystal size
(6) No crystals in the feed, but seeds are added initially
(7) No crystal breakage
(8) Uniform temperature
(9) Mother liquor in product magma in equilibrium with the crystals
(10) Nucleation rate is constant, uniform, and due to secondary nucleation
by crystal contact
(11) Crystal-size distribution is uniform in the crystallizer and equal to that in
the magma
(12) All crystals have the same shape
• Mixed-suspension, mixed-product-removal (MSMPR)
Crystallizer
The crystal-size distribution can be estimated as a function of the rpm of the
draft-tube propeller and external circulation rate by a crystal-population balance
in the MSMPR model.

The MSMPR model was

used to estimate the
nucleation and crystal
growth rate kinetic
parameters for cyclosporine
crystallization and to
evaluate the effect of
process conditions on the
purity of the crystals and the
process yield
 SCALEUP AND DESIGN

SCALEUP AND DESIGN

The challenge in scaleup is to generate conditions at the large scale that are similar to
those at the small scale.

The key problem is in the scaleup of mixing is to control the supersaturation level
throughout the crystallizer

To ensure that the crystals are carried throughout the volume of the crystallizer under
controlled conditions of frequency and intensity of crystal–crystal interactions.

Crystallizer scaleup ratios of 50 to 500 from pilot plant to commercial scale are
reasonable

As with precipitation, it is often recommended that geometric similarity and constant

power per volume be used in scaleup of crystallizers.

For turbulent flow, constant power per volume means that

 SCALEUP AND DESIGN
For turbulent flow, constant power per volume

where Ni is the impeller rotation rate and di is the impeller diameter

For an agitated tank, the Reynolds number is given by

where Ni is in revolutions per unit time,

ρ is the fluid density, and
μ is the fluid viscosity
 SCALEUP AND DESIGN

Two additional strategies are also sometimes used in scaleup of crystallizers :

1. Maintaining constant impeller tip speed, which implies that

2. Scale up at the minimum speed required for particle suspension, which has
been shown to require
 Summary of Crystallization
The process of producing crystals from a homogeneous phase is called
crystallization.

Bioproductscan be obtained at very high purity (say, 99.9%) by crystallization.

This process is considered to be both a polishing step and a purification step.

Purification that is achieved by crystallization is so significant that

chromatography can be avoided.

• Crystallization differs primarily from precipitation in that when a substance

comes out of solution as a solid it also forms a regular lattice of molecules, or
crystal.
 Summary of Crystallization
• Crystals nucleate either by primary or secondary nucleation.

Primary nucleation occurs in the absence of crystals, while

secondary nucleation is attributed to the influence of existing crystals.

Secondary nucleation dominates in industrial crystallizers.

Two types of primary nucleation are possible:

homogeneous and heterogeneous,

where heterogeneous nucleation requires the presence of foreign particles

for nucleation to occur and
homogeneous nucleation does not.
 Summary of Crystallization
• The rate of increase in the concentration of nuclei is proportional to a power
of the supersaturation, c − c∗, where c∗ is the concentration at equilibrium
(“saturation”).

The power has a most probable value of 3 to 4 for primary nucleation and
2 for secondary nucleation.

• The crystal growth rate is also proportional to a power of the

supersaturation, with a power of 1 being the most common.

The differential equation for a material balance on a crystal size interval can be
subjected to a moment transformation.

The zeroth moment is the number of nuclei (crystals), the first moment is the
linear size, the second moment is proportional to the area, and the third
moment is proportional to the mass (or volume).
 Summary of Crystallization
The crystal nucleation and growth rates can be determined from the moments
of the experimental population density function.

• Batch crystallizers can be analyzed by the population balance equation.

• Scaleup of crystallizers, like scaleup of precipitation units, emphasizes
mixing.

The mixing parameters that can be held constant are

power input per volume,
impeller tip speed,
and agitation sufficient to keep crystals in suspension.

All three of these variables cannot be held absolutely constant upon scaleup at
the same time, because each depends differently on the impeller diameter.

Therefore, scaling priorities are also based on experimental measurements

and plant-scale design for flexibility.
Quiz time