Crystallization

(Dr.) Mirza Salman Baig

Assistant Professor (Pharmaceutics)
AIKTC, School of Pharmacy,New Panvel
Affiliated to University of Mumbai (INDIA)

Crystallization
It is the spontaneous arrangement of
particles into a repeatitave orderly
array.
In regular geometric patterns.

Applications
Purification
Change micromeritics
Better chemical stability (Amorphous
penicillin G is more stable than
crystalline)
Improved physical stability
Improved bioavailability

Crystal Lattice
Crystal can be defined as solid
particle which is formed by
solidification processes (under
suitable environment)
During this proceses structural units
are arranged by fixed geometric
pattern.
It is orderly internal arrangement of
particles in 3 Dimentional space.

contd...
Units are ions, atoms or molecules.
Units are bond by covalent bond
(dimond) or Van der Walls forces
(Naphthalene)
Smallest geometric portion which
repeat to built up whole structure is a
unit cell.
Crystal bonded by plane surfaces
calles faces.

Contd...
Angle between the perpendicular to
faces is called axial angle.
Distance between centers of two
atom axial length.
Structural units arrangement is
determined by X ray diffraction (XRD)

Crystal form
Cubic
Hexagonal
tetragonal
Orthorhombic
monoclinic

Crystal Habit
Crystal is a polyhedral solid with
number of planer surface.
Angle between given pair of face is
same in all specimens.
It is characterstics irrespective of size.
Size and shape depend on medium
using which crystallization is carried
out.
Ex. Plate, Tubular, Columnar,
Acicular...

Simple cubic (a)

Body-centered cubic (b)
Face centered cubic (c)

Crystal Habit
Columnar
Plate
Columnar
Acicular

Steps of Crystallization

Steps
1.Supersaturation
2.Nucleation
3.Crystal Growth

1.Super saturation
The termsuper saturationrefers to
asolutionthat contains more of the
dissolved material than could be dissolved
by thesolvent under normal
circumstances.
Super saturation can be achieved by
adding more of a substance (to a solution)
than can normally be dissolved. This is a
thermodynamically unstable state

2.Nucleation
Nucleationis the process of forming a

nucleus (small clusters of ion /atom). It is

the initial process in crystallization.

It is the process in which ions, atoms, or molecules

arrange themselves in a pattern characteristic of a
crystalline solid, forming asite in which additional
particles deposits as the crystal grows.
Examples: Dust andpollutents provide
nucleationsites forwater vaporin the atmosphere
to form clouds.

Types of Nucleation
Formation of stable nucleus depends
on number of units (cluster)
assemble together
Spurious nucleation (gives poor
qualitycrystals)
Primary nucleation
Secondary nucleation.

Growth of crystals is optimum at low

super saturation

Homogeneous and
hydrogenous nucleation
Nucleation normally occurs atnucleation
siteson surfaces contacting the liquid or vapor.
Suspended particles or minute bubbles also
provide nucleation sites.
This is calledheterogeneous nucleation.
Nucleation without preferential nucleation sites
ishomogeneous nucleation.
Homogeneous nucleation occurs spontaneously
and randomly, but it requiressuperheating or
supercooling of the medium

The rate of nucleation

The rate of nucleation is the number of new particles
formed per unit time per unit volume of magma or
solid free mother liquor.
Steps
Cluster--> embryo--> nucleus--> crystal

Nuclei are in a state of unstable equilibrium if

it looses units (atom or moleculles) it dissolves,
if it gains units, it grows and becomes a
crystals.
Cluster formation occer when several
molecules/atoms of solute come into contact
due to random collision

3.Crystal Growth
Growth & nucleation are competing
processes!
Crystal growth is a diffusion process;
solute molecules reach the growing
surface by diffusion through the liquid
phase and are organized into space
lattice.
Growth rate of most crystals is linear
with super saturation.

Crystal growth
The rate of deposition is proportional to
driving force between
the bulk of the liquor and
wetting the surface of the crystal that is approximately
saturated with respect to crystals of that size.

The driving force will vary because of the

increasing solubility for crystals with lower size
range.
Crystal growth takes place in metastable zone
that lies between saturation and nucleation
limits.
In this region the solution is supersaturated
and no nucleation occurs when crystals are
growing.

Oswald Ripening

Oswald Ripening
Solubility of large crystal is less than
that of smaller crystals
It is because of significant surface
energy per unit mass on smaller
crystals.
Smaller crystals are in a state of
unstable equilibrium in a
supersaturated solution.
As a result larger crystals grow until
the small crystals disappear.

Ostwald Ripening
Larger crystals are more stable than smaller
crystals the energy of a system will naturally
trend towards the formation of larger crystals
at the expense of smaller ones

In a sense, the smaller crystals are feeding

the larger ones through a series of
dissolution and precipitation reactions

What is Ostwald ripening?

This is a spontaneous process that occurs

because larger crystals are more energetically

favored than smaller crystals.
While the formation of many small crystals is
kinetically favored, (i.e. they nucleate more
easily) large crystals are thermodynamically
favored.
Small crystals have a larger surface area to
volume ratio than large crystals.
Molecules on the surface are energetically less
stable than the ones already well ordered and
packed in the interior.
Large crystals, with their greater volume to
surface area ratio, represent a lower energy
state.
Thus, many small crystals will attain a lower
energy state by getting transformed into large
crystals and this is Ostwald ripening.

Theory of Crystallization

Miers theory
It is related to Supersaturation.
It postulate definate relation between
concentration and temperature at
which crystal will spontaneously form
in an unseeded solution.
Supersolubility curve represent the
limit at which nucleus formation
begins spontaneously in absence of
any solid particle (seed)

Solubility curve
When equilibrium is attained at final
temperature,mother liquor becomes
saturated in crystallization process
Rate of formation of nucleus is balanced
by the rate of dissolution of nucleus
The equilibrium relationship is the
solubility curve.
It represent maximum conc. of solution
that can be obtained by bringing solute in
eqilibrium of solvent.
Supersaturation is achived by reducing
temp. or evaporation of solvent.

Supersolubility curve
AC normal solubility
curve (Maximum
solubility)
EF supersolubility
curve (nucleus
formation begin)
Region between two
curves is metastable
region.
Crystallization starts
at point E.

Conditions for obeying Mier's law

Solute and solvent must be pure.
Solution must be free from solid
particles.
Soft/ weak crystal must not form
during processes.
There should not be any fluctuation
in temperature.

Limitation of theory
Crystallization start in region rather
than a point
Crystallization occer below
supersolubility curve after long term
storage.
It is difficult to obtain pure solute
and solvent.

Solubility curves

Solubility curve
It is useful in prediction of
experimental condition for
crystallization.
KNO3 solubility increases with temp.
NaCl Solubility increases with temp.
but with marginal extent.
Na2SO4 solubility increases when it
is in hydrated form. Once compound
turns into unhydrate form its
solubility decreases.

Methods of acieving
Crystallization
Supersaturation can be achieved by
several methods:

Cooling
Evaporation
Solvent addition
Precipitant Addition

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Cooling Method
Concentrated
solution gradually
cooled below
saturation
temperature (5060C) to generate a
supersaturated state
Yields well defined
micron-sized crystals
Shell and tube heat
exchanger is used to
cool solution

Cooling Method
Advantages:
High purity downstream

Disadvantages:
Temperature change does not always have a
positive effect on supersaturation in proteins
Protein stability may be at risk
Solubility can be relatively insensitive to
temperature at high salt concentrations
Cooling will only help reach supersaturation in
systems where solubility and temperature are
directly related
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Evaporation Method
Solute dissolves in solution when heated
to a certain temperature (75C)
Slowly cooled until crystals precipitate
Shell and tube heat exchanger is used to
heat and cool solution

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Evaporation Method
Advantages:
high purity levels downstream

Disadvantages:
Vaporization chamber requires high
pressures
Protein viability very sensitive to high
temperatures
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Solvent Method
Solvents are generally good protein
precipitants
Their low dielectric constants lower the
solvating power of their aqueous
solutions
Requires acidic solvent
For crystallization, an insulin protein falls
out of solution at isoelectric point
pH 5.4-5.7
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Solvent Method
Advantages:
Proteins viability not at risk due to
temperature change

Disadvantages:
Possible protein contamination due to
insufficient downstream solvent
recovery

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Seeding Techniques
Primary nucleation is the first step in
crystallization Growth of a new crystal
Can bypass primary nucleation (creation of
new crystals) by "seeding" the solution

Secondary nucleation is crystal growth

initiated by contact
Accelerated by "seeding"

CRYSTALLIZER

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Swenson Walker crystallizer

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Krystal Crystallizer

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Vacuum Crystallizer

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