Crystallization EASILY DESCRIBED

1. 1. CRYSTALLIZATION
2. 2. CRYSTALLIZATION Crystallization is the spontaneous Arrangement of the particles into a
repetative orderly array, i.e regular geometric patterns.
3. 3.  The formation of crystals from solution involve three step: 1. Super saturation 2. Nucleus
formation 3. Crystal growth Mechanism of Crystallization
4. 4. 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
5. 5.  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
6. 6. 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
7. 7. 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.
8. 8. Rate of nucleation: The rate of nucleation from the theory of chemical kinetics ,is given by the
equation
9. 9. 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.
10. 10.  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:
11. 11. 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 subs tantial 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.
12. 12.  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 supersaturatio n ad allowed to stand while
nuclei grow to macroscopic size.
13. 13. 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.
14. 14. 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.
15. 15.  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.
16. 16.  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)
17. 17. 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.
18. 18.  Upon crystallization from water or moist solvents, many compounds incorp orate 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.
19. 19. Factors Affecting Crystallization  1. Presence of another substance  2. Solvent  3. Nucleation
 4. Crystal growth  5. Rate of cooling/ Time
20. 20. 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.
21. 21. 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.
22. 22. 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.
23. 23.  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, h ydrate, solvates and amorphous API
24. 24. 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.
25. 25.  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) Solven t 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.
26. 26.  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 s lip. The cover
slip with the hanging drop is sitted on silicon oil over a solution, containing high concentration of
precipitate.
27. 27.  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.
28. 28.  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.
29. 29.  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 cr ystals
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.
30. 30.  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.
31. 31. 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.
32. 32. 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 t o evaporate at modest
temperature.