Crystallization: A.Rajesh Pawan Asst .Prof Department of Pharmaceutics Otpri Anantapuramu
Crystallization: A.Rajesh Pawan Asst .Prof Department of Pharmaceutics Otpri Anantapuramu
Crystallization: A.Rajesh Pawan Asst .Prof Department of Pharmaceutics Otpri Anantapuramu
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
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:
as crystallography.
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
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
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
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: