CRYSTALLIZATION

Crystallization

Spontaneous arrangement of particles into a repetitive

orderly array, i.e regular geometric patterns.

Crystallization differs from precipitation process

• Precipitation – chemical reaction to form product which

is sparingly soluble in liquid and therefore deposits out.
• Crystallization – here product is deposited from a
supersaturated solution.
 Applications

• Removing impurities from pharmaceutical

Purification of products.
drug • Recrystallization technique.

Better Processing • Change the micromeritics of the drugs such

characteristics as compressibility and wettability.

Ease of handling • During transportation and storage.

• Increases stability of the drug.

Better chemical • Eg: Amorphous Penicillin G less stable than
stability crystalline salts.
 Applications

Improved
• Suspension stability and tablet
physical hardness.
stability

• Some drugs more effective in

Improved crystalline form.
Bioavailability. • Eg: Penicillin G crystalline salts.

• Different size of crystals used in sustained

Sustained release dosage form.
• Eg: Protamine zinc insulin crystalline form
Release release insulin from site of injection for
prolonged period.
 Crystal Forms
A finite number of symmetrical arrangements are possible for
a crystal lattice termed as crystal forms or crystal systems.

Crystals Forms
(Axial Length &
Axial Angle)

Cubic Hexagonal Tetragonal Orthorhombic Monoclinic Triclinic

 Crystal Habit

Crystal is a polyhedral solid with number of planar

surfaces.

A substance crystallizes in such way that the angle

between given pair of faces is same.

It is the characteristics of a particular substance

irrespective of the size of the faces.

Crystal Habits are described depending on the

arrangement of the faces.
• Acicular - Needle like prisms.

• Blade - Long, thin and flat

particles, which can also be
referred to as being lath
shaped.

• Columnar - Rod like particles

having a width and thickness
exceeding that of needle type
particles.
• Equant – particles of similar
length, width and thickness.

• Tabular – Flat particles of

similar length and width, but
possessing greater thickness
and flakes.

• Plate - Flat particles of similar

length and width
 Mechanism of crystallization

Nucleus
Supersaturation. Crystal Growth
Formation
 Particles (ions,
atoms or molecules)
Loose aggregates

Addition
of crystal/ ………………
Solution Cooling of Clusters
(saturated or solution
unsaturated) breaking
of crystal
Super-saturated * * * **
solution Embryo
(Lattice
arrangement)

Nuclei
Crystal growth
 Supersaturation.
Solubility of compound exceeds saturated solubility, compound
precipitate or crystallize.
Supersaturation can be achieved through -

Evaporation of solvent
from solution.

Addition of
substance Cooling of the
which is more solution, if the
soluble in solute has a
solvent than positive heat of
the solid to be solution.
crystallized.

Formation of a new solute

as a result of chemical
reaction.
Absence of seed crystals needs significant
supersaturation to initiate crystallization
through formation of nuclei.

Rate of separation, particle size uniformity

and distribution depends on Nucleation and
growth of nuclei.
 Nucleation

Refers to birth of very small bodies of a new phase within a

homogenous supersaturated liquid phase.

Consequence of rapid local fluctuations at the molecular level -

molecules or ions or atoms are in random motion in any small
volume.

Initially several molecules or ions or atoms associate to form

clusters. These are loose aggregates which usually disappear
quickly.

Enough particles associate to form embryo - beginning of lattice

arrangement – formation of new solid phase.
 Nucleation

Embryos have short lives and dissolve as soon as they

form.

An embryo may grow to such a size that it is in

thermodynamic equilibrium with the solution.

The initially formed crystals of molecular size are termed

as nuclei.

Sometimes nuclei grow in dimensions that are limited by

amount of material available and thus forms crystals.
 Methods for nucleation
1. Soft or weak crystals on impact with moving parts
in a crystallizer can break into fragments which acts as
nuclei.

2. Small crystals which are formed in the previous

process are added to act as nuclei.

3. In a supersaturated solution or under poor mixing,

needle like structures are observed on the ends of the
crystals.

These structures grow faster than the sides of the

crystals and come out to give crystals of poor quality.
 Crystal Growth

Diffusion Process and

surface phenomenon.

Neither diffusion nor the

Solute molecules or ions
interfacial step will
reach the surfaces of
proceed unless the
crystal by diffusion.
solution is supersaturated.

Molecules or ions must be

accepted by the crystal and This phenomenon
organized into the space continues at a finite rate.
lattice.
 Mier’s Super saturation Theory
Postulates a definite relationship between concentration and
temperature at which crystals will spontaneously form in an
initially unseeded solution.

Acc. to it the super solubility curve represents the limit at which

nucleus formation begins spontaneously.

Consequently the point where the crystallization can start in

absence of any solid particle.
 Meir’s Supersaturation Theory
• Curve AB – Normal
solubility curve.
– Any point on the curve
represents the solute in
equilibrium with the solvent.
– This is maximum limit for the
solubility of the substance.
• Curve FG – Super solubility.
– Roughly parallel to normal
solubility curve.
– Represents the limit at which
nucleus formation begins
spontaneously.
• The region enclosed between
these two curves AB and FG –
metastable state i.e. system is
unstable undergoing changes.
 Meir’s Super saturation Theory
Liquid may be cooled a few degrees below its freezing
point without crystallization taking place.

Crystallization starts if the limit is exceeded.

Consider a point ‘C’ with definite composition and

temperature.

On cooling this solution, crystallization is expected to

start from point ‘P’ but it does not happen.

Acc. To Miers theory, crystallization do not start at point

‘P’ but near to point ‘D’ when certain conditions are
specified.

Under ideal conditions of crystallization nucleus

formations starts at FG and crystal growth begins.
Conditions for obeying Mier’s Theory:
1. Solute and solvent must be pure.
2. Solution must be free from foreign solid
matter.
3. Solution must be protected from entry of any
particle.
4. Soft or weak crystals must not form during
the process.
5. No fluctuations in temperature
Limitations:
1. Acc. To Mier’s theory crystallization starts at supersolubility curve.
But generally it takes in an area rather on a line.
2. If solution is kept for longer periods, nucleation starts well below the
supersolubility curve.
3. If solution is available in large volumes, nucleation starts well below
the supersolubility curve. This is because, formation of nuclei depends
on accidental collisions of molecules of solute. These collisions are
more in large volumes than in small volumes.
4. Applicable to pure solute and solvent which is impossible to get them
in pure state.
5. For crystallization solution must be stored for longer periods. During
storage, millions of dust particles can enter. Nucleation can be
initiated by these particles.
Classification of crystallizers
Crystallization equipment are classified by the methods by which
supersaturation is bought about.

(i) Tank crystallizers

A. Batch processes
(ii) Agitated batch
Supersaturation by crystallizers
cooling alone
B. Continuous
(i) Swenson-Walker
processes

Supersaturation by
A. Vacuum crystallizers
adiabatic cooling

A. Salting evaporators
Supersaturation by
evaporation
B. Krystal evaporators
 Tank
Crystallizer
 Tank Crystallizer
A hot nearly saturated solution is run into an open
rectangular tank – the solution is allowed to cool
and deposit crystals.

No attempt is made to seed these tanks – agitation

or accelerate or control the rate of crystallization.

Sometimes rod or strings are hung in the tank to

give the crystals additional surface on which to
grow.

Under these conditions crystal growth is slow, and

the crystals formed tend to be large and
considerably interlocked.
 Tank Crystallizer

This interlocking results in the occlusion of

mother liquor, thus introducing impurities.

When the solution is sufficiently cooled after

few days the remaining mother liquor is
drained off and the crystals are removed
manually.
 Much
labour
cost.
Crystals are
Method contaminated
now with impurities
almost that settle to
obsolute. bottom of the
tank.

Disadvantages

Produces It needs
large more floor
crystals. space.
Material is
tied up in
the process
for a long
time.
Agitated Batch
Crystallizer
 Agitated Batch Crystallizer

PRINCIPLE PRINCIPLE PRINCIPLE

Saturated The crystals Agitation of
solution is are formed solution
made super from the facilitates
saturated by super the
reducing the saturated production
temperature. solution of crystals.
Construction:
• It consists of
cylindrical container
with a conical bottom.
• A propeller is fixed
centrally, which
rotates on its own axis
with the help of motor.
• Pipes made up of good
material for
conducting heat are
run from right bottom
to left top of the
crystallizer.
 Working

Solution for crystallization is placed in the

crystallizer.

Cold water is passed through the pipes continuously.

Due to cooling the solution becomes supersaturated and

crystals are formed.

The crystals are collected from the bottom by a suitable

mechanism for the separation of mother liquor.
 Working

Propeller
serves 2
purposes.

It keeps the fine crystals in

Maintaining the
temperature of solution
uniform - Increases the
rate of heat transfer.
suspension, which
facilitates them to grow
uniformly. Otherwise large
crystals or aggregates may
form.
Advantages: Formation of uniform and fine
crystals - Compared to tank crystallizers.

Disadvantages:

Solubility is least
Coils rapidly build
at the surface of
Batch or up with a mass of
the cooling coils.
discontinuous crystals that
Hence crystal
equipment. decrease the rate
growth is most
of heat transfer.
rapid at this point
SWENSON WALKER CRYSTALLIZER
 SWENSON WALKER CRYSTALLIZER

PRINCIPLE

The crystals
Crystallization are
is induced by Agitation simultaneously
This results in
passing cold prevents the separated from
super
water in accumulation the mother
saturation and
direction of crystals on liquor and
subsequently
opposite to the the cooling therefore it can
crystallization.
flow of hot surface. be used as a
conc. Solution. continuous
process.
Construction

Long open trough

Long pitched spiral
about 0.6 meters wide Trough is welded
scrapper is fixed as
and 3 meters long with a water jacket
close to the bottom as
with semi-cylindrical externally.
possible.
bottom.

Further higher
Spiral scarper rotates For higher capacities capacities – several
on its own axis with fours such units are such sets are placed
the help of a motor. joined together. for one above the
other.
 Working
Cooling – super
Hot conc. Solution is Cooling water enters
saturation is achieved
fed at left side of the through right side in
and crystals begin to
trough. the jacket.
form.

Spiral scrapper Size of the crystals –

Helps in rotating a controlled by injecting
rotates at a speed of
mixture & conveying an extra amount of
7 revolutions per cooling water into
of the crystals.
minute. selected sections.

Prevents the
This results in a
accumulation of
suspension, which Thus aggregation is
crystals on cooling
allows crystals to prevented.
surfaces by lifting
grow individually.
them.
 Working
Mother liquor and While crystals are
Draining table is
crystals together over retained, the mother
attached to one end of
flows into the liquor is sent back to
the crystallizer.
draining table. the crystallizer.

Screw conveyor with

a slight inclination A screw conveyor can The wet crystals are
lifts the crystals from also be used in place conveyed to a
solution and delivers of the draining table. centrifuge.
to a centrifuge.

Mother liquor
overflows at a
convenient point.
 Advantages:

Crystals of uniform
Large saving in
size and free from
floor space, It is a continuous
inclusions or
material and labour process.
aggregations can be
costs.
obtained.

Disadvantage: The scrapper may break the

crystals to a little extent, while agitating the
suspension.
Vaccum Crystallizer
 Vaccum Crystallizer

Warm saturated
Super saturation
solution – due
is obtained by
to high vaccum
adiabatic
the solution
evaporative
undergoes
cooling.
flashing.
PRINCIPLE
PRINCIPLE
A part of the
From resulting
solvent gets
super saturation
evaporated –
crystals are
cooling of the
produced.
solution.
 Construction

2. Condensor attached
1. Cylindrical body
to crystallizer with a
with a conical bottom.
vaccum pump.

4. Internally, body can

3. Bottom of the
be lined with acid
crystallizer is attached
resistant material such
to discharge pipe.
as lead or rubber.

5. Two propellers are

placed above discharge
pipe to prevent short
circuit of the feed(to
the discharge pipe)
 Working
Vaccum must
High vaccum
correspond to the But lower than the
created using a
boiling point of the feed temperature.
vaccum pump.
solution.

This is allowed Solution undergoes Hot saturated

adiabatically so flashing – results in solution is fed in
that the crystallizer evaporation of crystallizer at
body is cooled. solvent. convenient point.

Resultant cooling
Evaporation of
causes super Flashing of solution
solvent enhances
saturation & leads to ebullition.
yield.
crystallization.
 Working
Until they become
Ebullition keeps
large enough to fall Propellers - mix the
crystals in
into the discharge contents thoroughly.
suspension.
pipe.

Further subjected to Propellers – prevent

With the help of
filtration or the contents reaching
pump product is
centrifugation to the discharge pipe
collected.
obtain crystals. without flashing.

The filtrate returns to

the feed.
 Very
simple
without
any
moving
parts.

Suitable for Corrosive

thermolabile materials
substances
due to low can be
temp. used.
Advantages

Operated as Can be
batch wise constructed
or as large as
continuously desired.
 Circulating
Magma Vacuum
Crystallizer
Circulating Magma
Vacuum Crystallizer

1. In this type of crystallizer,

the crystal/solution mixture
(magma) is circulated out of
the vessel body.
2. The magma is heated
gently and mixed back into
the vessel.
3. A vacuum in the vapor
space causes boiling at the
surface of the liquid.
4. The evaporation causes
crystallization and the
crystals are drawn off near
the bottom of the vessel
body.
Vaccum Draft Tube Baffle
crystallizer
 Vaccum Draft Tube Baffle crystallizer
1. In the DTB crystallizer the
crystal slurry is circulated
through a Draft Tube by means
of an agitator.
2. This crystallizer has a fines
removal / destruction facility by
removing mother liquor with
small crystals (fines) from the
baffle zone.
3. Energy needed for evaporation is
brought into system by heating
this mother liquor circulation.
4. Heating also dissolves back fines
and thus product crystal size and
size distribution can be affected
 Low
operating
costs

Superior Long
filtration and operating
centrifugation cycles
Advantages

Crystal size Crystal size

range can be can be
selected controlled
 Used to produce very high slurry
density in the active volume of the
crystallizer.

A selective range of small crystals

can be removed and dissolved.

Continuous operation.

Typical liquids suitable for DTB

Crystallizers - Sodium chlorate,
Ammonium sulphates, Copper
sulphates
 Krystal
Crystallizer
 Krystal Crystallizer
Concentration of liquid and crystallization are obtained in different
chambers - Vapour head and crystallizing chamber.

Super saturation is induced by evaporation of hot solvent with the

help of vaccum pump.

Super saturated solution and crystals are maintained in fluidized

state for uniform crystal growth.

Crystals settle down by gravity – fine crystals and super saturated

solution is recirculated for further crystallization.

Crystals are collected from crystal growth chamber.

Construction:
• Consists of vapour head
and crystallizing chamber.
• Vapour head consists of a
long tube, which extends
almost to the bottom of
crystallizing chamber.
• Other end of vapour head is
connected to condensor and
vaccum pump.
• A pump is provided which
allows the feed to enter the
vapour head.
• On its way to vapour head
heater is provided.
 Solution is pumped Because of reduced
Hot solution enters
which passes through pressure hot solution
the vapour head.
heater. undergoes flashing.

Super saturated Results in formation

solution passes Vapour is removed by of solvent vapour and
through long tube suction pump. super saturated
below. solution.

Controlled operation Crystallizing chamber Super saturated liquid

– crystals do not form consists of bed of flows through the bed
in the vapor head but crystals suspended in of the crystals –
form in the an upward flowing of maintained in
crystallizing chamber. stream of liquid. fluidized state.
Uniform temperature is Continuous gradation
thereby attained. of crystals in chamber.

Very fine crystals

overflow through
Coarse crystals-
liquid and enter into
bottom; fine crystals –
recirculating system &
above coarser one.
then combine with
fresh feed.

From time to time

coarse crystals are
taken out through the
opening at the bottom
of the chamber.
 Factors affecting crystallization

Moderate solubility is best

Like dissolves like

Solvent

Hydrogen bonding can help or hinder crystallization.

Avoid highly volatile solvents

Avoid long chain alkyl solvents. They can significantly disorder the
crystals. Choose solvents with “rigid geometries”
 Factors affecting crystallization

Crystals initially form via “nucleating events”

Nucleation

After a crystallite has nucleated it must grow

Nucleation sites are necessary, but ...excess nucleation sites

cause smaller average crystal size

Ambient dust, filter paper fibers, hair, broken off pipette tips all
provide opportunities for nucleation – take steps to remove
them.
 Factors affecting crystallization
Crystals grow by the ordered deposition of the solute molecules onto
Mechanics (Crystal Growth)

the surface of a pre-existing crystal

Crystal growth is facilitated by the environment changing slowly over

time.

Keep crystal growth vessel away from sources of mechanical agitation

(e.g.vibrations)

Set-up away from vacuum pumps, rotovaps, hoods, doors, drawers,

and so on

Leave samples alone for 1 week, don't “check in” with it. Your crystals are
not lonely.
 Factors affecting crystallization

faster crystallization is not as good as slow crystallization.

Faster crystallization higher chance of lower quality crystals

Time

Quality crystals grow best over time in near equilibrium

conditions

The longer the time, the better the crystals

Patience, patience & patience

 Factors affecting crystallization - Crystal Growing Techniques

Slow Evaporation Slow Cooling Variations

• simplest to set up. • Soluble when hot, • use binary or

Has drawbacks: insoluble when tertiary solvent
solute can “oil out”, cool. mixtures.
crystals • Use Dewar(vaccum • Use solvent with
• stick to sides of flask) to slow the similar b.p's and
vessel making cooling process. other properties.
them difficult to • Use a Oil Bath, and
extract from vessel cut the heat to the
without breaking bath for slow
them.. cooling.
• Use a thermally
insulated
environment (bed
of vermiculite).
 CAKING OF CRYSTALS

• What is caking?
Caking can be defined as the process of
formation of clumps when crystals are
improperly stored.
Critical Humidity

Above CH – absorbs
moisture – forms saturated
solution

Below CH – does not

absorbs moisture -
powder remains dry
Above critical humidity moisture is absorbed - forms
saturated solution – now due to cooling or evaporation of
solvent solid particles crystallize out.

It may form solid bridges in between two adjacent crystals,

called crystal bridges.

Thus the crystal particles will join together to form hard

aggregate. This aggregates or lumps are called caking.
 Problems of caking
No uniform Powder
flow from the hopper
into the die-cavity of
tablet punch machine.

Capsule filling will not be

uniform.

Filling of pouches will not be

uniform.

FLOW PROPERTIES OF THE

POWDER DECREASES.
FACTORS AFFECTING CAKING
 Size of the crystals

large crystal –
less caking – less
contact points –
less solid
bridges

Small crystal –
more caking –
more contact
points – more
solid bridges
 Shape of the crystals

Spherical shape -
least possible point
of contacts than
any other form

Distorted
form tends –
more caking
 Humidity

Higher humidity –
higher rate of caking

Lower humidity –
lower rate of caking
Time of exposure to moisture – if atmosphere has humidity more
than critical humidity

Higher the time of exposure -

more will be the caking

Lesser the time of exposure -

less will be the caking
 Impurities in the crystals

The crystals may be coated with impurities

from the mother liquor.
This may increase the value of critical
humidity.
For example MgCl2 and CaCl2 alters the critical
humidity of NaCl crystals.
Melting points of crystals

M.P higher than

room temp –
crystal will fuse –
forms cake

M.P lower than

room temp.-
crystals will melt
 Temperature fluctuations

When temperature is increased solubility of

crystals increases.
Subsequent decrease of temperature will
produce a supersaturated solution from which
crystals will be precipitated.
So fluctuations of temperature produce
crystals rapidly.
 Prevention of caking
1. Crystals must be more spherical in shape, with least
points of contact.
2. Crystals must be larger in size with more voids and
must be of a narrow size distribution (i.e. must be more
uniform in size).
3. Crystals are packed and stored in atmosphere where
the humidity is less than critical humidity.
4. Crystals may be coated with powdery inert material
to prevent absorption of moisture like NaCl is coated
with magnesia (MgO) or tricalcium phosphate