CRYSTALLIZATION

A.RAJESH PAWAN
ASST .PROF
DEPARTMENT OF PHARMACEUTICS
OTPRI
ANANTAPURAMU
CONTENTS:

• TERMINOLOGIES
• DEF OF CRYSTALLIZATION
• CHARACTERISTICS OF CRYSTAL
• SIGNIFICANCE OF CRYSTALLIZATION
• FACTORS INFLUENCING CRYSTALLIZATION
• THEORY OF CRYSTALLIZATION
• TECHNIQUES
• CLASSIFICATION OF EQUIPMENT
• CAKING OF CRYSTALS
TERMINOLOGIES

CRYSTAL SYSTEM OR CRYSTAL FORM

A crystal is a three-dimensional ,periodic assembly of individual
molecules that align themselves in a repeating series of "unit
cells". This is true for small molecule (e.g. salt) crystals and large
molecule (protein) crystals.
or
A crystal is a regular polyhedral form, bounded by smooth faces,
which is assumed by a chemical compound, due to the action of
its interatomic forces, when passing, under suitable conditions,
from the state of a liquid or gas to that of a solid.
UNIT CELL: Smallest geometric portion which repeats to build up whole crystal. z

CRYSTAL LATTICE /SPACE LATTICE:  

 x
Orderly internal arrangement of particles in 3D
y
space. a three dimensional network of imaginary (b) Unit cell

lines connecting the atoms or molecules. (a) Lattice structure in crystal

FACES: A CRYTSAL is bounded by plane surfaces.

AXIAL ANGLE:
In the crystal angle two perpendiculars to intersecting faces.
the angle between the edges of a unit cell is called as lattice angle.

AXIAL LENGTH:
Distance between centers of 2 atoms. The distance between the center of two atoms (or
molecules) is called length of unit cell.
CRYSTAL SYSTEM:
A finite number of symmetrical arrangements are possible for a crystal lattice and these
may be termed as crystal forms/system.
Depending upon axial length and angle crystal forms are designated as
a) cubic (ex Nacl & Kcl )
b) Hexagonal(ice& thymol)
c) Tetragonal(urea & K.dihydrogen phosphate)
d) Orthorhombic(Ba. Sulphate & sulpha acetamide)
e) Monoclinic (Sucrose & EphedrineHcl)
f) Triclinic(Phenolpthalein)
POLYMORPHISM
c
A chemical substance may exist in more than +one
C
-A
form. c
b
c

b a b
-B +B a a
+A
-C
Crystallographic Cubic Tetragonal Orthorhombic
axes a = b =c a = b =c a = b =c
= 90 0 = 90 0 = 90 0
c
c
b
b a
a

Triclinic
Monoclinic a = b =c
a = b =c 0
bc = 90 0 0 bc = ac = ab = 90
ac = ab = 90
DEFINITION:

The word 'crystal' is derived from the Greek word

'krustallos' (clear ice). Like ice.

The scientific study of crystals & crystal formation is known

as crystallography.

crystal consists of matter that is formed from an ordered

arrangement of atoms, molecules, or ions. Because there

are repeated units, crystals have recognizable structures.

 DEFINATION

 Crystallization is the formation of solids

particles within a homogeneous phase
or
 Crystallization is a separation technique that
is used to separate a solid that has
dissolved in a liquid
CHARACTERISTICS OF CRYSTAL:
1) Purity
2) Size
3) Shape
4) Geometry
5) Habit
6) Form
1)PURITY
 Usually formed in pure state.
 They become impure when they absorb mother liquor during their removal.
2)SIZE
 Crystals should be uniform size ,possesing desired strength, Non-Aggregation
and Non caking properties.
 It helps to determine its purity
 Desired sizes of crystal is required when it is to be subjected to various processes of
filtration, Washing ,Transportation, Storage &Treatment with other solvents.
 Size can be influenced by
Internal symmetry
Growth rate along diff direction
3)SHAPE
 Shape of a crystal depends on internal symmetry & on its
direction of growth.
 Regular geometrical patters of crystal can be attained if it
is not influenced by neighboring grains of particles.
CRYSTAL TYPE SHAPE
Halite , Galena Cubes
Quartz Prisms

4)GEOMETRY
 It describes pattern /arrangement of components of
crystalline solids.
 Geometry of a crystal is determined by X-Ray
diffraction studies.
5.CRYSTAL HABIT:
• Crystal is a polyhedral solid with number of planar faces. The arrangement
of these faces is termed as habit. The crystal habit may change due to
changes in rate of deposition, shielding of certain faces, presence of
impurities in mother liquor.
• e.g. NaCl crystallizes out from aqueous solution with cubic faces only. On
the other hand, if NaCl is crystallized from aqueous solution containing a
small amount of urea, the crystals are found to have octahedral faces.
• Different crystal habits are acicular, columnar, blade, plate, tabular, equant
etc.
 It represents development of various kinds of faces but not shape of
resulting crystals.
 It depends on
Presence of impurities Needle or Acicular
Rate of deposition
Platy
Shielding of certain faces. Tabular

Bladed
Equant or Massive
Fig. 1
APPLICATIONS
Purification of drugs
Used for removing impurities frm P’Ceutical
prdts(recrystallization tech)
Better processing
Ease of handling
Chemical stability is enhanced for ex: crystalline pcn G is more
stable than amorphous salt.
It ensures physical stability of most of the formulations like
suspensions , tablets ,dry powders etc.
Improved bioavailability Certain drug (pcn G) shows enhanced in
their crystalline form.
Sustained release: forms basis for their use as SR like protamine-
Zn- insulin suspension for injection.
Purification and separation process for the isolation and synthesis
of pure (API)
FACTORS INFLUENCING CRYSTALLIZATION

Many factors affecting crystallization but the basic

factors are

1. The concentration of the solution

2. The temperature to which the solution is
heated or cooled
3. The nature of the solute like solubility
etc.
4. Pressure around
5. Time
6. The pureness of crystals
 Theory of crystallization(mechanism of crystallization )

1.evaporation of
Solution solvent Particle(Ions, atoms
2.cooling
(Saturated/ /molecules) Addition of
un saturated) 3.heating crystal/
of solution 1) SUPER SATURATED breakage of
SOLUTION weak crystal
4.additives
2)LOOSE
AGGREGATES
(NUCLEUS
FORMATION)
Clusters Diffusion &
deposition of 3.CRYSTAL
particles GROWTH

Embryo(lattice
arrangement)

Nuclei
Formation of crystals from solution involves 3 steps
1. SUPER SATURATION
2. NUCLEUS FORMATION
3. CRYSTAL GROWTH
1)Super saturation
 When solubility of a compound in a solvent exceeds saturated solubility, solution
becomes supersaturated and compound may precipitate/crystallize.
SUPER SATURATION CAN BE ACHIEVED BY
1. Evaporation of solvent from solution.
2. Cooling/heating of solution
3. By addition of third component
a) Salting out:
 Applicable when solubility is very high so super sat is difficult by methods 1& 2.
 Super sat is generated by addition of third component.
 Third component may act physically by forming with original solvent a mixed sol. In

which solubility of solute is sharply reduced.

b)Precipitation
 New solute may be created chemically by adding third component .
2)Nucleus formation
 It refers to birth of very small bodies of a new phase with in a
homogeneous supersaturated liquid phase.
 Nucleation is a consequence of rapid local fluctuation at
molecular level when molecules /Ions/atoms are in random
motion in any small volume.
 Initially several molecules /Ions/atoms associate to form
clusters and these are loose aggregates which usually
disappear quickly.
 When enough particles associate to form embryo there is
beginning of lattice arrangement and formation of a new solid
phase.
 In most of the cases embryos have short lives and dissolve as
soon as they form .
 Initially formed crystals are of molecular size which are termed
as nuclei.
 METHODS OF NUCLEATION
1) Soft or weak crystals on impact with moving parts in crystallizer
can break into fragments which act as nuclei.
2) Small crystals which are formed in previous process are added as
nuclei.
3) In a super saturation solution / under poor mixing, needle like
structures are observed on ends of crystals and these structures
grow faster than sides of crystals and come out to give crystals of
poor quality
3)Crystal growth
 It is a diffusion process and surface phenomenon
 From solution solute molecules /Ions must be accepted by crystal
and organized into space lattice.
 This continues at surface at a finite rate.(neither diffusion nor
interfacial step will proceed unless the solution is supersaturated.
Techniques
Commonly used techniques include
• solvent evaporation
• slow cooling of the solution
• solvent/ non-solvent diffusion
• vapour diffusion
• sublimation
 MIERS SUPERSATURATION THEORY
 It gives information on relationship between conc & temp at
which crystal will form spontaneously in unseeded solution.
A/c to this theory super saturation curve represents limit
at which nucleus formation begins spontaneously &
consequently the point where crystallization can start in
absence of any solid particle.

CONDITIONS :
 The solute & solvent must be pure.
 Solution must be free from solid & foreign solute particles.
 solution must be protected from entry of any particle.
 Soft/weak crystals must not form during the process.
 No fluctuations in temp.
 The curve AB represents normal solubility curve & any
Point on the curve represents solute in equilibrium with
Solvent, this is the maximum limit for the solubility of
a substance.
 The curve FG represents super solubility which is roughly
Parallel to normal solubility curve & it represents limit at
Which nucleus formation begins.
 The region enclosed between these two curves AB & FG
is metastable state indicating that the system is unstable & undergo changes.
 The liquid may be cooled a few degrees below its freezing point without
crystallization taking place & crystallization starts if this limit is exceeded.
 Consider a point C with a definite conc & temp. on cooling this solution
crystallization is expected to start from point P but it does not happen.
 A/C to Mier’s theory , crystallization don't start at P but it takes place some
where near point D when certain conditions are specified.
 Maier's states that under ideal conditions of crystallization nucleus formation
starts at FG & crystal growth begins. Then concentration of substance roughly
follows the curve DE.
LIMITATIONS

1)It is applicable to only when pure solute & solvents are used.

2)A/c to this theory crystallization starts @ supersolubilty curve. But it takes place in an
area than a line

3)If the solution is available in Lrg vol. nucleation starts well below the super solubility.
( more collisions in Lrg vol than small vol)

4)If the solution is kept for longer periods nucleation starts well below the super solubility
curve.

5)For crystallization the solution must be stored for longer periods. During storage
millions of dust particles can enter. Nucleation can be initiated not only by solute
molecules but also by dust particles.
 Classification of equipment
1)Super saturation by cooling alone
a)Batch type
Tank crystallizer
Agitated batch crystallizer
b)Continuous type
EX: Swenson walker crystallizer
Krystal cooling crystallizer

2)Super saturation by evaporation of solvent (without cooling)

a)Batch type
EX: Crystallizing evaporators
b)Continuous type
EX: Krystal evaporators
Circulating magma crystallizer

3)Super saturation by combination of cooling and evaporation (ADIABATIC) or Vacuum Crystallizer

A)continuous type
EX :Krystal vacuum crystallizer
Swenson vacuum crystallizer

4)Super saturation by salting out(addition of substances that reduce solublity of crystallizing

substance)
 TANK CRYSTALLIZER
Principle:
Simple cooling
Construction
Working:
 Hot sat sol is poured Into tank & allowed to cool by natural
convection. Cooling rate depends on humidity & air velocity.
 Some times rods or strings are hung in the tank to give crystals additional surface
on which crystal grow & prevent sediment of crystal.
 When tank have cooled sufficiently remaining mother liquor drained & crystals
removed by hand.
USES:
For synthetic sponge, glaubers salt(crystalline hydrated form of sodium sulphate, used
chiefly as a laxative), for Lrg crystals.
ADVANTAGES:
Simple operation & cheap.
LIMITATIONS:
Nucleation is not control, time consuming, Lrg floor space, low capacity, more labour.
 AGITATED BATCH CRYSTALLIZER
PRINCIPLE : sat sol is made supersaturated by decreasing temp &
agitation of the solution leads to production of uniform size crystal.

CONSTRUCTION:
 It consists of a cylindrical container with a conical bottom.
 A propeller is fixed centrally which rotates on its own axis with the help
of a rotor.

WORKING:
 Sol placed in equip & cold water is passed via pipes continuously. Due to cooling sol becomes
supersatd & crystals are formed.
 Propeller is allowed to rotate which carries 2 functions
 Firstly it ↑rate of heat transfer there by helps in maintaining temp of sol uniform.
 Secondly it keeps fine crystals in suspensions which facilitates them to grow uniformly other wise
Lrg Crystals or aggregates may form.
 Crystals are collected from bottom by a suitable mechanism for the separation of mother liquor.
ADVANTAGES:
Crystals formed are more uniform & fine compared to other crystallizers.

LIMITATIONS:
Batch process
SWENSON WALKER CRYSTALLIZER
(scraped surface crystallizer)
PRINCIPLE: Super sat by cooling
CONSTRUCTION:
 It consists of a U- Shaped open trough with
semi cylindrical bottom, water inlet and outlet ,
a slow speed spiral agitator running at about
7RPM and set as close to bottom of the trough
as possible.
 Water jacket welded to out side of trough & it divided into sections so that differential cooling
may be used in the various zones.
 It is built in 10 feet long and a number of units may be joined together to increase the capacity.
OPERATION/WORKING:
 The hot concentrate solution to be crystallized is fed at one of the trough & cooling water
usually flows through the jacket in counter current to the solution.
 Nucleation may be started by a short cold zone , followed by gradual cooling.
 At the end of crystallizer there is over flow gate where crystals & mother liquor overflow to
drain box
 From the mixture mother liquor is returned to the process & wet crystals are fed into centrifuge.
ADVANTAGES: less floor space required & less labour
KRYSTAL COOLING CRYSTALLIZER
PRINCIPLE:
Super sat is achieved by cooling to below
atmospheric pressure.
CONSTRUCTION:

WORKING:
 The feed sol is feed to cooler & cooled below atmospheric temperature by refrigerated
brine. Here no agitator is required as rapid circulation of pump create some agitation.
 The liquid being pumped so fast that growth does not occur until the super cooled liquid
has reached the static crystal bed in the body of crystallizer.
 The over flow of fine crystal & mother liquor combined with feed & recirculated via
cooler.
 The product is discharged from bottom by discharge tube.
ADVANTAGES:
No labour required
Process is controlled by: speed of rotor, rate of cooling, feed & removal of product.
KRYSTAL EVAPORATION
PRINCIPLE:
Super sat is achieved by evaporation of solvent.
CONSTRCTION/OPERATION:
 A is vapour head , E is crystallization chamber. Solution
is pumped frm chamber(E) by pump (F) to heater (H) &
discharged in to the vapour head .(Flash evaporation
occurs).
 Vapors from (A) discharges into a condenser & vacuum
pump.
 The operation is controlled so that crystals do not form
in the vessel (A, but the vessel is prolonged into tube (B)
extended almost to the bottom of vessel.
 The lower part of vessel contains a bed of crystals
suspended in an upward stream of liquid & super
saturation is produced in vessel is discharged as super
saturated liquid flows over the surface of the crystals in
vessel.
 After liquid has come to equilibrium with solids.(no
more deposition from liquid solution to solid)
 It escapes at C to be recirculated. From time to time
crystals are drawn out from bottom of the vessel via M.
 The coarse crystals settle down while very finest
overflow via external circulation system.
 Feed is introduced into suction of pump.
ADVANTAGES:
Evaporation & cooling takes place at same time
CIRCULATING MAGMA CRYSTALLIZER
PRINCIPLE:
Supersaturation is achieved by evaporation.
CONSTRUCTION:
 It consists of cone bottom vessel fitted with the Vapour
Draw off & vacuum equipment & a low head & speed,
Lrg vol, propeller agitator positioned in a Draft tube.
 The propeller lifts magma via draft tube & create
Circulation down via annular space between draft Tube
& wall of crystallizer & back to suction of propeller.
 Hot feed admitted @ suction of propeller where
static head is sufficient to prevent flash & unwanted
nucleation.
 The product classification is done in elutriation leg.
 The sat liquor is pumped to the bottom of elutriation leg
& used as a hydraulic sorting fluid to carry small
crytsals back into crystallizing zone for further growth.
 The discharge slurry is withdrawn from lower part
Elutriation leg & sent to a rotary filter & mother
liquor is returned to process.
WORKING
 Sat sol is introduced into closed
vessel in which vacuum is maintained
by condenser & booster.
 A magma volume is maintained by
controlling level Of liquid &
crystallizing solid in the vessel &
space Above magma for release of
vapour.
 The feed solution cools spontaneously
to the equilibrium temp.
 The product is drawn from the bottom
of the crystallizer.
USES :
Simple, less moving parts, capacity large
LIMITATIONS:
No control over nucleation, classification
or removal of excess nuclei.
 VACUUM CRYSTALLIZER
PRINCIPLE:
Supersat is obtained by adiabatic evaporation cooling. When warm sat sol is introduced
into crystallizer due high pressure vacuum sol undergoes flashing. A part of the solvent
gets evaporated there by causing cooling of the sol. Frm the resulting super sat crystals
are produced.

CONSTRUCTION:

 It is cylindrical body with a conical bottom. A condenser to the crystallizer with a

vacuum pump in between.
 The bottom of the crystallizer is attached to a discharge pipe.
 Internally body can be lined with acid resistant material such as lead/ rubber.
 Two propellers are placed above discharge pipe to prevent short circuit of the
feed(to the discharge pipe)
WORKING
 High vacuum is created using a vacuum pump & vacuum
created must correspond to a B.P of the solution but lower
than the feed temp.
 Hot sat sol is fed into the crystallizer @ a convenient
point. This process is allowed Adiabatically so that
crystallizer body is cooled & resultant cooling causes
supersat & crystallization.
 The evaporation of the solvent enhances the yield.
Flashing of the sol in the crystallizer leads to ebullition(boiling) which keeps the
crystals in suspension until they become Lrg enough to fall into the discharge pipe.
 The propellers mix the contents thoroughly & prevent them reaching discharge pipe
without flashing.
 With the help of pump the prdt is collected & subjected to filtration/Centrifugation to
obtain crystals. The filtrate returns to the feed.
USES:
Suitable for thermolabile substances due to low temp conditions.
ADVANTAGES:
Simple becoz no moving parts
Corrosive materials can be uses inner surface in acid resistant.
Can be operated either batch/ Continously
 CAKING OF CRYSTALS
Crystalline material have tendency to cake or bind together
upon storage & it is problem in small package.
Reasons:
 It is due to small amount dissolution taking place at the
surface of the crystals(at higher humidity) & consequent
re-evaporation (at lower humidity) of the solvent.
 Each salt have critical humidity.(humidity above which it
will always become damp & below which it will always stay
dry.)
 If crystals coated with impurities derived from mother liquor,
its critical humidity is changed ,it may be higher or lower
than pure crystals.
 A crystalline material will cake more readily if particles size
are small & non uniform than larger crystals.
PREVENTION
 Use larger and uniform crystal .
 Store below critical humidity.
 Coat the powder (crystal) with inert material which
absorb moisture for ex (Na.Ferrocyanide)
 Add small amount of insoluble material ex: Ca.phosphate
OR talc OR use water repellent agent ex: Stearic acid.
 Get crystal with highest critical humidity , it is obtained by
removing impurities.

Caking of Nacl is due to traces of Mgcl2 Impurities