INCLUDES THE INTRODUCTION TO CRYSTALLIZATION, FOLLOWED BY MECHANISM LIKE SUPER SATURATION, NUCLEUS FORMATION, CRYSTAL GROWTH, IN DETAIL ACCOUNT HOMOGENOUS AND HETEROGENOUS NUCLEATION AS PRIMARY AND SECONDARY NUCLEATION.

1. CRYSTALLIZATION

2. CRYSTALLIZATION
Crystallization is the spontaneous Arrangement of the
particles into a repetative orderly array, i.e regular
geometric patterns.

3.  The formation of crystals from solution involve three
step:
1. Super saturation
2. Nucleus formation
3. Crystal growth
Mechanism of Crystallization

5. 1) Supersaturation
 The solubility of a compound In a solvent exceeds the
saturation solubility , the solution becomes
supersaturated and the compound may precipitate or
crystallize.
 Supersaturation can be achieved through:
1. Evaporation of solvent from the solution
2. Cooling of the solution, if the solute has a positive
heat solution
3. Formation of a new solute as a result of chemical
reaction
4. Addition of a substance, which is more soluble In
solvent than the solid to be crystallised

6.  In the absence of seed crystals, significants
supersaturation is necessary to initiate the
crystallization through formation of nuclei.
 The rate of separation, particle size, uniformity and
distribution depend on two successive largely
independent processes, namely, nucleation and growth
of nuclei.
2. Nucleation
Nucleation refers to the birth of very small bodies of new
phase with In a homogenous supersaturated liquid phase.
If all sources of partition are subsumed under the term
nucleation, a number of kinds of nucleation may occur.
They may be classified into two groups
1. Primary nucleation
2. Secondary nucleation

7. A. Primary nucleation
 The phenomenon of the nucleation is the same for
crystallization from the solution , crystallization from a
melt , condensation of fog drops in a super cooled
vapour and generation of bubble In a supersaturated
liquid
 There are two types
a) Homogeneous nucleation
b) Heterogeneous nucleation

8. a) Homogeneous nucleation
 In crystallization from solution , homogenous nucleation
almost never happens, except perhaps in some
precipitation reaction.
 Initially several molecule or ions or atoms associated to
from clusters.
 These are loose aggregates, which usually disappear
quickly.
 When enough particles associate to form a embryo , then
is beginning of the lattice arrangement and the formation
of new solid phase .
 The initially formed crystals are of molecuar size, which are
termed as nuclei.

9. Rate of nucleation:
The rate of nucleation from the theory of chemical kinetics ,is given by
the equation

10. b) Heterogeneous nucleation
 If effect holds that if the nucleus wets the surface of
the catalyst , then ucleation formation is reduced by a
factor that is a function of the angle of wetting
between the nucleus and the catalyst .
 Experiment data on the heterogeneous nucleation of
potassium chloride solution shows that the nucleation
of the substance is consists with an apparent value of
the interfacial tension in the range 2 to 3 ergs/Cm2 for
both catalyzed nucleation and nucleation without an
added catalyst.

11.  If the latter the situation was actually a secondary
nucleation self catalyzed by microscopic seeds, the
value of ϭ for seeded solution of kcl would be 2.8
erg/cm2 of temperature of 300k.
 If the 6a is used to denote the apparent interfacial
tension, if C is taken as 1025,and if the mathematical
approximation ,can may e written as:

12. B. Secondary nucleation
 The formation of nuclei attributable to the influence
of the existing macroscopic crystal I the magma is
called secondary nucleation.
 Fluid share nucleation:
when supersaturated solution moves past the
surface of a growing crystals at substantial velocity,
the shear stresses in the boundary layer may sweep
away embryos or nuclei that would otherwise be
incorporated into the growing crystals and so appear
as new crystals.

13.  This has been reported in work on sucrose
crystallization.
 It also has been demonstreted in the nucliatin of
MgSO4 7H2O, if the solution is subjected to share
at the crystals face at one supersaturation and
then quickly cooled to a higher supersaturation ad
allowed to stand while nuclei grow to macroscopic
size.

14. 3) Crystal growth
 Crystal growth is the diffusion process and surface
phenomenon.
 From solution, solute molecules or ions reach the fous
of crystals by diffusion.
 On reaching the surface , the molecule or ions must
be accepted by the crystal and organized into the
space lattice.
 This phenomenon continues at the surface at a finite
rate.
 Neither the diffusion nor the interfacial step will
proceed unless the solution is supersaturated.

15. Crystallization from non- aqueous
solution
 Growth of non aqueous solutions often allows
realization of special crystallization aims by control of
the solution properties.
 Solvents are classified to further understand solubility
of electrolytes and non electrolytes.
 Several solvents and solubility effects are then pointed
out such as the effect on the nuleation , which is
easier when solubility is higher ion the crystallization
of polymorph and on the surface morphology of the
crystals.

16.  Solvent also change growth rate altering properties of
the adsorption layer.
 In non electrolyte solution , the molecules of the
solute are not dissociate during that dissolution
process.
 SOLVENT AND SOLUILITY:
With the use of non aqueous solvent it is sometime
possible to fit the solvent-solute system to some aims
such as modification of habit and morphology or even
simple use of high low solute concentration.

17.  All there phenomenon result from solentn-solute or
crystal-solvent interaction.
 There are three main classes of solents:
1. Hydrogen donors ( methanol, foramide)are protic
solvents.
2. Solvents dielectric constant greater than 15 but which
cannot donate suitably labile hydrogen atom to from
hydrogen bonds with the solute, are dipolar aprotic
solvents (acetonitrile , nitrobenzene).
3. If the dielectric constant is weak , the solvent is non-
polar and therefore also aprotic (pentane, benzenne)

18. Crystallization of aqueous solvent
 Water of crystallization are water molecules that are
present inside the crystals.
 Water is often incorporated in the formation of
crystals from aqueous solution.
 Water of crystallization is the total mass of water in a
substance at a given temperature and is mostly
present define ration.
 Water of crystallization refers to water that is found in
the crystalline framework of metal complex or a salt,
which is not directly bonded to the metal cation.

19.  Upon crystallization from water or moist solvents,
many compounds incorporate water molecule in their
crystalline frameworks.
 Water of crystallization can generally be removed by
heating a sample but the crystalline properties are
often lost.
 Ex. In case of sodium chloride, the dehydrate unstable
at room temperature compared to inorganic salts ,
proteins crystallize with large amount of water in the
crystal lattice.

20. Factors Affecting Crystallization
 1. Presence of another substance
 2. Solvent
 3. Nucleation
 4. Crystal growth
 5. Rate of cooling/ Time

21. 1) PRESENCE OF ANOTHER SUBSTANCE
 Sodium chloride crystallized from aqueous solutions
produces cubic crystals.
 If sodium chloride is crystallized from a solution
containing a small amount of urea, the crystals
obtained will have octahedral faces .
2) SOLVENT CONSIDERATIONS
 The solvent with moderate solubility is prefer for
crystallization.
 Presence of benzene can help crystal growth.
 Avoid highly volatile solvents.

22. 3. NUCLEATION
 Crystals initially form via “nucleating events”.
 After a crystallite has nucleated it must grow.
 Nucleation sites are necessary for formation of crystal.
 Excess nucleation sites cause smaller average crystal
size.
4. TIME
 Quality crystals grow best over time in near equilibrium
conditions.
 The longer the time, the better the crystals.
 Faster crystallization is not as good as slow crystallization.
 Faster crystallization higher chance of lower quality
Crystals.

23. 5) CRYSTAL GROWTH
 Crystals grow by the ordered deposition of the solute
molecules onto 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, hoods, doors,
drawers, and so on.

24.  Polymorph
 When the substance exist in more than one crystalline form,the
different form are designated as polymorph and the
phenomenon as polymorphism.
 Eg.
METHOD OF PREPARATION :
1) Solvent evaporation(Rota evaporation)
In this aproach,the saturated solution of the drug is prepared in an
appropriate solvent and the solvent is removed by rotatory
evaporation.
Air drying at various temperature,can also be employed to
obtained different potential polymer.
 Principle and general method of preparation of
polymorph, hydrate, solvates and amorphous API

25. 2)Slow cooling aproach
This technique is frequently employed for the
polymorpic forms of less soluble drugs in the solvent
system having boiling point range of 30-90 C.
In brief the solute is heated in the solvent just above the
boiling point of the later to produce the saturated
solution.
This solution is then transferred to stopper tube and is
connected to dewar flask containing water at a
temperature just below the boiling point of solvent.

26.  The dewar flask is left in this condition for several
days.
 This technique may further be improved to obtain
better crystal forms using different solvent mixture of
different polarity.
 Various in the solvent composition may inhibit or
promote growth of particular crystal faces and
hence,can yeild crystals of the desired morphology.
3) Solvent diffusion technique:
This method is employed when the amount of drug available is
loss and the dry is sensitive to air and/or solvent.
In this,the solution is placed in a sample tube, subsequently a less
dense solvent is carefully dripped down the sides of the tube
using either a pipette or a syringe to form a descreate layer.

27.  The slow diffusion of the solvent results in the
crystallization of API at the interface.
 Most employed solvent combination is CH2Cl2
/ethanol and is preffered one,provide the sample in
insoluble in ether.
4) Vapour diffusion method :
This method is analogous to the previous one and is also
applicable for us quantitative of the sample.
In this case,the concentrated drug solution (0.5цl – 0.20цl)
is placed in a drop hanging on the underside of microscope
cover slip.
The cover slip with the hanging drop is sitted on silicon oil
over a solution, containing high concentration of
precipitate.

28.  Due to higher precipitant concentration,the later has
lower vapour pressure than the drug solution.
 This result is in diffusion of the solvent from the drop
towards the reservoir and subsequent crystallisation
of API within hours to weeks.
5) Vacuum sublimation :
Sublimation is known to offer excellent crystals of variety of
compounds, especially the air sensitive once.
This approach is frequently employed to induced crystallization
with numerous variation of static and dynamic vacuum.
Asmall amount of sample sealed under vacuum in a reactor in
generally subject to a temperature gradient in numerous
manners.

29.  Temperature of the order of 250 C can be easily
employed at a pressure of around 10-2 mm of Hg.
 The crystals grow from the wall to the centre of the
reactor.

30.  Solvates : A crystal solvate forms during the process of when a
compound is crystallized with the inclusion of solvent.
Method of preparation : Solvates are generally attained through
crystallization from either a single solvent or a mixture of solvent.
e.g : Synthesis of dimethyl foramide solvate of thiocyanuric acid (TCUA)
Combining a solution of TCUA in DMF with an aqueous solution of NaNO3
The reaction solution was left at room temp. For 3 days yellow crystals of
thiocyanuric acid were obtained
The resulting crystal were filtered off and were washed three times with
DMF: water (1:1)
The needle shaped crystal were obtained.

31.  Hydrates :
Some drugs have tendency to associate with water, this substance is called
hydrate.
 Types :
1) Inorganic Hydrate : Water molecule when it heated becoming
the anhydrous. The anhydrous form of the substance can
absorbs water becoming hydrated.
The water is known as the water of hydration.
e.g : Cobalt chloride is sky blue in its amorphous form and
purple in its hydrated form.
2) Organic hydrate :In organic hydrate , the water molecule ,
chemically react with other compounds.
e.g : formaldehyde
hydrate is formed from formaldehyde by the reaction of
its carbonyl group with water.
The water molecules splits into H and OH and the hydrate is
formed.

32. 3) Gas hydrate :
It is made at low temperature and high pressure,
when water molecules surrounds a gas molecule , forming a
frozen mesh or cage.
Method of preparation :
The basic method for preparing hydrate is by dissolving a drug
compound in an aqueous solvent . This aqueous solution must
be then cooled or evaporated to establish the opportunity for
crystal hydrate formation. Variable temperature used for the
evaporation of process will ultimately result in different crystal
hydrate.
e.g : chlorine is dissolved in water , forming a thin slurry,
Slurry then filtered through a glass filter funnel surrounded by jacket
which is then cooled in ice bath , chlorine hydrate formed.

33. Amorphous API :
Amorphous solid do not have specific shape.
The structural units are arranged randomly in the solid.
Method of preparation :
1) Solidification of the melt : Amorphous solid are created by rapidly
cooling a liquid so that crystallization nuclei can neither be created
nor grow sufficiently where as the liquid then remains in the fluid
state well below the normal freezing point.
2) Spray drying : In the spray drying process, a liquid feed stream is first
atomized for maximal air spray contact. The particles then dried in
airstream . It can be produce spherical particles that have good flow
properties.
3) Removal of solvent from solvate : Solid sometimes be converted to
amorphous form simply by allowing solvent molecule of
crystallization to evaporate at modest temperature.