Crystallization is a chemical process where a solute forms solid crystalline structures when its concentration in a solution exceeds its maximum solubility point. There are three main steps: 1) supersaturation of the solution, 2) nucleation where solute molecules start to cluster and form crystal nuclei, and 3) crystal growth as more solute molecules deposit onto the crystal surfaces in an ordered lattice structure. The rate and yield of crystallization depends on factors like temperature, solvent, impurities, agitation and time. Crystallization is used industrially to purify compounds and produce stable crystalline drug forms with improved properties for pharmaceutical applications.

1. CRYSTALLIZATION

2. DEFINITION:
“Crystallization is a chemical solid–liquid
separation technique, in which mass
transfer of a solute from the liquid solution
to a pure solid.”

3. •Spontaneous arrangement of the particle into a
repetitive order.
•i.e regular geometric patterns.

4. CRYSTALS:
• Crystal can be defined
as a solid particle,
which is formed by
the solidification
process under
suitable environment
in which structural
units are arranged by
a fixed geometric
pattern or lattice.
CRYSTAL STRUCTURE OF NACL

5. • The smallest Geometric portion, Which repeats to build up the whole
crystal is called a UNIT CELL.

6. In the Crystal, the angle
between the two
perpendiculars to the
intersecting faces is
termed as the axial angle.
Axial length can be
defined as distance
between the centre of
two atoms.

7. • A finite number of symmetrical arrangement are
possible for a crystal lattice and these may termed as
crystal forms or crystal system.
• A chemical substance may exists more than one
crystalline form is called polymorphs and these
phenomenon is called polymorphism.

8. • Crystalline solid have definite shapes and orderly arrangement of
the unit.
• They have low solubility and dissolution.
• Amorphous Solid: They do not have specific shape Amorphe means
without form Randomly arrangement of solid particles in the
structure.

9. • CRYSTAL HYDRATES:
Some drugs have greater tendency to associate with water.
• The resulting product or substance is called Drug hydrates e.g.
Na2CO3. 10H2O

10. • CRYSTAL SOLVATES:
Some drugs have greater tendency to associate with Solvents to
produce crystalline forms of solvates
• The solvates are also called pseudomorphs.
• ISOMORPHS :
When two or more substances posses the same crystalline form they
are called as isomorphs.

11. CHARACTERISTICS OF CRYSTAL:
1. Crystal lattice
2. Crystal system or forms
3. Crystal habit

12. CRYSTALLIZATION PROCESSES:
A) Cooling Crystallization
B) Evaporative Crystallization

13. COOLING
CRYSTALLIZATION:
• The cooling crystallization can be applied when the solubility gradient
of the solution increases steeply with falling temperature or when a
vaporisation of the solvent has to be avoided.
EVAPORATIVE
CRYSTALLIZATION:
• Generating crystals by evaporating a solution at const. temperature
• Most of the industrial crystallizers are evaporative

14. CRYSTALLIZERS:
Crystallizer can be of 3 types:
• Batch type crystallizer
• Continuous type crystallizer
• Forced circulation type crystallizer

16. A typical laboratory
technique for crystal
formation is to
dissolve the solid in a
solution in which it is
partially soluble,
usually at high
temperatures to
obtain
supersaturation. The
hot mixture is then
filtered to remove
any insoluble
impurities. The
filtrate is allowed to
slowly cool which
results in crystals
formation.

17. MECHANISM OF CRYSTALLIZATION:
Three major steps are involved in crystallization:
1. Super Saturation.
2. Nucleation.
3. Crystal Growth.

18. 1.Super Saturation of the solution :
Supersaturation can be achieved by the following
methods:
1. Evaporation of solvent from the solution.
2. Cooling of the solution.
3. Formation of new solute molecule as a result of
chemical reaction
4. Addition of a substance, which is more soluble in
solvent than the solid to be crystallized.

19.  When the concentration of a compound in its solution
is greater than the saturation solubility of that
compound in that solvent the condition is known as
supersaturation.
 This is an unstable state.
 From this supersaturates solution the excess
compound may be precipitated out or crystallize.

20. Supersaturation
Phase diagrams
Precipitatant concentration (salt, PEG etc.)
Proteinconcentration
Under-saturation
(protein remains soluble; crystals dissolve)
Nucleation zone
Precipitation zone
Solubility
curve
Metastable zone
Crystals grow, but
Nuclei form only infinitely
slowly

21. 2.Nucleation:
 These stable structures together form a nuclei.
 It is at the stage of nucleation that atoms arrange in periodic
manner to form crystal structure.
 Step where solute molecules dispersed in the solvent start to
gather into clusters on the nanometer scale.
 Some clusters may become so big that they may arrange
themselves in lattice arrangement. These bodies of
aggregates are called embryo.
 However, embryos are unstable and they may break into
clusters again.

22. 3.Crystal Growth:
“Crystal growth is a diffusion process and a surface
phenomenon. Every crystal is surrounded by a layer of liquid
known as stagnant layer.”
• Once the crystals are formed, nuclei formation stops and crystal
growth begins.
• From the bulk solution a solute particle (molecule, atom or ion)
diffuse through this stagnant layer and then reaches the surface of
the crystal.
• These particles then organize themselves in the crystal lattice. This
phenomenon continues at the surface at a slow rate. This process
will happen if the bulk solution is supersaturated.

23. Crystallization Principles
Figure 1: Typical phase diagram. The components in
solution consist of the product (ordinate) and the
precipitating reagent (abscissa). The lines with arrows
out line one possible way of performing the
crystallization.
- The supersaturation must be above the a
certain value before nucleation will begin
- Metastable region : the supersaturation is low
that nucleation will not start
- Once the supersaturation has been raised
enough to be in the labile region, nucleation
can begin.
- At this point, crystals begin to grow, and the
supersaturation decreases
- If the supersaturation becomes too high, the
nucleation rate will be too great, and
amorphous precipitate will result.

24. 24
 Batch Crystallization Process
 Formation of solid particles within a homogeneous phase by
modifying the solubility of the component of interest
 The change in solubility is accomplished by:
 decreasing the temperature of the solution
 Changing composition of solvent by adding a solvent in
which the compound is insoluble
 In some cases crystallization is not achieved by a change in
solubility →reactive crystallization
MkS
NjC
T
V
k
i
j
i
i
i
..1
..1


MkS
NjC
T
V
k
f
j
f
f
f
..1
..1


Solutes and
Solvents
Solutes

25. Yields and Heat and Material Balances in
Crystallization
• Yields and material balance in crystallization
• The solution (mother liquor) and the solid crystals are in contact for
enough time to reach equilibrium. Hence, the mother liquor is saturated at
the final temperature at the final temperature of the process, and the final
process, and the final concentration of the solute in the solution can be
obtained from the solubility curve.
• The yield can be calculated knowing the initial concentration of solute,
the final temperature, and the solubility at this temperature.
• In making the material balances, the calculations are straightforward when
the solute crystals are anhydrous. Simple water and solute material
balances are made. When the crystallizations are hydrated, some of the
water in solution is removed with the crystals as a hydrate.

26. MIER’S SUPERSATURATION THEORY:
Mier and Issac proposed a theory explaining a relationship between
supersaturation and spontaneous crystallization.
Mier’s theory points out that :
(i) The greater the degree of supersaturation, the more chance is of
nuclei formation
(ii) if the super-saturation passes a certain range of values, nuclei
formation is extremely rapid.

27. • Assumption:
1. The solute and the solvent must be pure.
2. The solution must be free from solid solute particles.
3. The solution must be free from foreign solid particles.

28. Limitations of the Mier’s theory
1.According to Mier’s theory, crystallization starts at supersolubility curve
(FG). But the general tendency is that crystallization takes place in an area
rather than a line.
2. If the solution is kept for long periods, nucleation starts well below the
super-solubility curve.
3. If the solution is available in large volume, nucleation starts well below the
super-solubility curve.
4. Mier’s theory is applicable only when pure solute and pure solvent is
taken. In practice, it is impossible to get them in pure state.
5. During crystallization the solution may become contaminated with dust,
particles from container etc. Nucleation may be initiated from these foreign
particles also.

29. FACTORS AFFECTING CRYSTALLIZATION:
1. PRESENCE OF ANOTHER SUBSTANCE
2. SOLVENT
3. NUCLEATION
4. CRYSTAL GROWTH
5. RATE OF COOLING
6. TIME

30. PRESENCE OF ANOTHER SUBSTANCE IN
MOTHER LIQUOR:
• 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. Both
types of crystals belong to the cubic crystal form but differ in habit.

31.  SOLVENT CONSIDERATIONS:
• Moderate solubility is best (avoid supersaturation).
• Like dissolves like.
• Hydrogen bonding can help or hinder crystallization.
• Presence of benzene can help crystal growth.
• Avoid highly volatile solvents.
• Avoid long chain alkyl solvents can be significantly
disordered in crystals.
• Choose solvents with “rigid geometries”.

32. NUCLEATION:
• Crystals initially form via “nucleating events”.
• After a crystallite has nucleated it must grow.
• Nucleation sites are necessary.
• Excess nucleation sites cause smaller average crystal size.

33. 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, rotovaps, hoods, doors, drawers,
and so on
• Leave samples alone for 1 week, don't “check in” with it. Your crystals
are not lonely.

34.  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

35. 1. Purification of Drugs.
2. Better processing characteristics.
3. Ease of handling.
4. Better chemical stability.
5. Improved physical stability.
6. Improved bioavailability.
7. Sustained release formulation.
8. Miscellaneous.
OBJECTIVES AND APPLICATIONS :

36. IMPORTANCE OF CRYSTALLIZATION
1- purification of drugs .
2- improve bioavailability of the drug and choose the most stable form.
3- a crystalline powder is easily handled ,stable , possesses good flow
properties and an attractive appearance .
4- Crystallization from solution is important industrially because of the
variety of materials that are marketed in the crystalline form.
5-Crystallization affords a practical method of obtaining pure chemical
substances in a satisfactory condition for packaging and storing. A
crystal formed from an impure solution is itself pure (unless mixed
crystals occur).

37. 6- A drug may remain in different crystalline forms, some are stable, and
rests are metastable.
7- The metastable forms have greater solubility in water, thus have better
bioavailability. By controlling the conditions during crystallization, the
quantity of metastable to stable forms may be controlled.
8- After crystallization water or solvent molecules may be entrapped within
the crystal structure and thus form hydrates or solvates which have different
physical properties that may be utilized in various pharmaceutical purpose.
9- Particles with various micromeritic properties, compressibility and
wettability can be prepared by controlling the crystallization process.