This document discusses the process of crystallization. It begins with an introduction that defines crystallization as the spontaneous arrangement of particles into repetitive, orderly arrays. It then describes three key characteristics of crystals: crystal lattice, crystal systems, and crystal habit. The bulk of the document discusses various aspects of crystallization theory and mechanisms. It explains super saturation, nucleation, and crystal growth. It also covers Miers' super saturation theory, solubility curves, types of crystallizers like batch and continuous crystallizers, and factors that influence caking of crystals. Numerical examples are provided to demonstrate calculating crystallization yield. The document concludes by listing references used.

1. Presented by
DR.K.KAVITHA
Asst. Professor,
University College of Engineering,
BIT campus, Anna University,
Tiruchirappalli.

2. INTRODUCTION
 Crystallization is the spontaneous arrangement of the
particles into a repetitive orderly array that is regular
geometric patterns.
 A crystal is defined as a solid particle, which is formed by
the solidification process in which structural units are
arranged by a fixed geometric pattern or lattice.
 Crystals are commonly obtained from liquid state. Example
salt from brine solution.
 Crystallization differ from precipitation in that product is
deposited from a supersaturated solution.
 Precipitation occurs when solutions of materials react
chemically to form a product which is sparingly soluble in
the liquid and therefore deposits outs.

3. CHARACTERISTICS OF CRYSTALS
 Crystal lattice
 Crystal systems
 Crystal habit

4. 1. Crystal lattice
 it is defined as an orderly internal arrangement of particles
in the three dimensional space.
 The geometric form of the arrangement in a crystal is
determined by means of x-ray diffraction method.
 The units that constitute the crystal structure are the ions,
atoms, or molecules.
 Ions with opposite charges bonded by the electrostatic
attraction. (e.g.) NaCl
 Atoms are bonded by covalent bonds. (e.g.) diamond and
graphite
 Organic molecules held together by vanderwaals forces and
hydrogen bonding.

5. 2. Crystal systems or forms
 A finite number of symmetrical arrangement are possible
for a crystal lattice and these are termed as crystal forms
or systems.
 In the crystal, the angle between two perpendiculars to
the intersecting faces is termed as the axial angle.
 Axial length can be defined as the distance between the
centers of the two atoms.
 Depending upon the axial length and the axial angle,
crystals are cubic, hexagonal, tetragonal, orthorhombic,
monoclinic, triclinic.

7. 3. Crystal habit
 a substance crystallizes in such a way that the angle
between a given pair of faces irrespective of the relative
sizes of the faces.
 The shape and sizes of the crystals formed are markedly
dependent on the condition under which crystallization
is carried out.
 For example, griseofulvin crystallized from acetone has
a different forms from the same drug crystallized from
benzene or chloroform.

9. Theory of crystallization
Mechanism of crystallization:
The formation of the crystals from solution
involves three steps,
Super saturation
Nucleus formation
Crystal growth

11. A. Super saturation
when the solubility of a compound in a solvent
exceeds the saturation solubility, the solution becomes super
saturated and the compound may precipitate or crystallize.
super saturation can be achieved thorough the
following ways:
Evaporation of solvent from the solution.
Formation of new solute due to chemical reaction.
Addition of a substance which is more soluble in solvent than
the solid to be crystallized.

12. B. Nucleation
Nucleation refers to the birth of very small bodies of a new
phase within a homogenous supersaturated liquid phase
Initially several molecules or ions or atoms associate to form
a clusters. These are loose aggregates which usually disappear
quickly.
When enough particles associate to form an embryo, there is a
beginning of the lattice arrangement and the formation of a
new solid phase.
The initially formed crystals are of molecular size which are
termed as the nuclei.

13. Method of nucleation
There are several ways available for nucleation. They are
Soft or weak crystals on impact with moving parts can break
into fragments which act as nuclei.
Small crystals which are formed in the previous process are
added to act as nuclei.
C. Crystal growth
It is the diffusion process and surface phenomenon.
From solution the solute molecules or ions reach the faces of a
crystal by diffusion. On reaching the surface the molecules or ions
must be accepted by the crystals and organized into the space
lattice. Neither the diffusion nor the interfacial step will proceed
unless the solution is super saturated.

14. Mier’s super saturation theory
Mier’s super saturation theory
postulates a definite relationship between concentration
and temperature at which crystals will spontaneously
form in an initially unseeded solution.
according to it the super solubility
curve represent the limit at which nucleus formation
begins spontaneously and consequently the point at
which crystallization can start in the absence of any
solid particles.

15.  AB represent normal
solubility
 FG represent super
solubility
 Region enclosed between
AB and FG refers to the
meta stable state
 Consider a point C with a
definite composition and
temperature
 On cooling this solution,
crystallization is expected
to start from point P,
however it does not
happen

16.  According to this theory
crystallization does not
start at point P but it
takes place somewhere
near the point D
 Mier states that under
ideal condition of
crystallization nucleus
formation starts at FG
and crystal growth begins
 The concentration roughly
follows the curve DE

17. Condition for obeying Mier’s theory:
 The solute and the solvent must be pure
 The solution must be free from solid solute particles
 The solution must be free from foreign solid particles
 Soft and weak crystals must not form during the process
 No temperature fluctuation should be there
Limitation:
 According to the theory crystallization starts at super
solubility curve but general tendency is that crystallization
take place in an area rather than in a line

18.  If the solution is kept for a longer time nucleation starts
well before the super solubility curve
 If the solution is available in large volume, nucleation
starts well below the super solubility curve
 It is only applicable when pure solvents and pure solute are
used
 For crystallization it should be stored or a longer duration,
during which dust may enter which may also initiate the
nucleation

19. Solubility curve
 Solubility curves are useful in predicting the
experimental condition desired for crystallizing a
substance
 Since super saturation is achieved by reducing the
temperature the influence of temperature on the
solubility is important
 A substance dissolves and goes into solution, if the
solution is not saturated. If the solution is super
saturated crystallization takes place
 The graph drawn by taking temperature in the x-
axis and solubility on y- axis gives solubility curve

20. Solubility curves

21. Classification of crystallizers
crystallizers
Method1
(Super
saturation by
cooling)
Method2 (super
saturation by
evaporation)
(i)Krystal
crystallizer
Method3 (super
saturation by
adiabatic
evaporation)
(I) Vacuum
crystallizer
Method4 (super
saturation by
salting out)
Batch
crystallizer
(i)Tank
crystallizer
(ii)Agitated
batch
crystallizer
Continuous
crystallizer
(i)swenson
walker
(ii)others

22. Agitated batch crystallizer
Principle:
In this, saturated solution is made super saturated by
reducing the temperature. The crystals formed from super
saturated solution. Agitation of the solution facilitates the
production of uniform crystals

23. Agitated batch crystallizer

24. Advantages:
Crystals formed are more uniform and also fine
compared to other crystallizers
Disadvantages:
It is a batch process
Solubility is least at the surface of the cooling coils and
hence crystal growth is more at this point. The coil rapidly
builds up a mass of crystals that decreases the rate of heat
transfer

25. Tank crystallizers:
Hot , nearly saturated solution is run into an open
rectangular tank in which the solution is allowed to cool
and deposit crystals.
No attempt is made to seed the tanks, to provide for
agitation or to accelerate or control the rate of
crystallization.
When the solution has sufficiently cooled which normally
takes a number of days, the remaining mother liquor is
drained off and the crystals removed manually.

26. Disadvantage:
 Needs more labor
 Crystals are contaminated with impurities that settle at
the bottom of the tank
 Needs more floor space
Advantage:
 Produces large crystals
 Simpler
 Cheaper process

27. Swenson walker crystallizer
Principle:
crystallization is induced by passing the cold
water in a direction opposite to the flow of hot
concentrated solution. This results in the super
saturation and subsequently crystals are deposited.
Agitation prevents the accumulation of crystals on
the cooling surface. The crystals are simultaneously
separated from the mother liquor.

28. Swenson walker crystallizer

29. Advantages:
 large saving in the floor space, material and labor cost
It is a continuous process
Crystals of uniform size and free from inclusions and
aggregates can be obtained
Disadvantage:
 the scrapper may break the crystals to a little extent while
agitating the suspension

30. Krystal crystallizer :
Principle:
In this type the concentration of the liquid and
crystallization are obtained in different chambers. The super
saturation is induced by evaporation of hot solvent with
the help of a vacuum pump. In the crystallization chamber
the super saturated solution and crystals are maintained in
a fluidized state for uniform crystal growth. As the crystals
of desired size settle down by gravity the fine crystals and
the super saturated solution is recirculated for further
crystallization.

31. Krystal crystallizer

32. Use:
 for the crystallization of sodium chloride and magnesium
sulphate
Advantage:
 large quantities of crystals of required size
 available in large size with a body up to 4.5m diameter
and 6.0m height

33. Vacuum crystallizer :
Principle:
super saturation is obtained by adiabatic
evaporation cooling. When warm saturated solution is
introduced into the crystallizer, due to high vacuum the
solution undergoes flashing. A part of the solvent gets
evaporated there by causing cooling of solution resulting in
crystal formation.

34. Vacuum crystallizer

35. Use:
vacuum crystallizer suitable for thermo labile
substances.
Advantages:
 simple without any moving parts
 corrosive material can be used, as the inner surface can be
made acid resistant
 it can be constructed as large size as desired
 operated as either batch process or continuous

36. Caking of crystals
Definition:
caking is defined as the process of formation of clumps or
cakes when crystals are improperly stored.
After crystallization, the crystals are required to
be stored in bulk either for use or for transportation or for
formulation of dosage form. The crystals must retain good flow
properties during storage.
During storage crystals tend to form cakes. This
is a serious problem in case of small packages than in bulk
packages.

37. Factors affecting caking:
 Size of the crystals:
Larger crystals have less point of contact and
smaller particle have more point of contact. The more the point
of contact the higher will be rate of caking. Hence, smaller
particle tend to cake more than larger particle.
 Shape of crystals:
Spherical particle possess the least point of
contact. Hence, distorted crystals tend to cake more than
spherical particle.
 Humidity:
The higher the humidity of the atmosphere to
which the crystals are exposed , more will be the rate of caking.

38.  Time of exposure:
The higher the time of exposure the more will be
the caking, provided the exposed atmosphere has humidity more
than critical humidity.
 Impurities in crystals:
The crystals can be coated with the impurities
derived from mother liquor. This may increase or decrease
critical humidity. Once the critical humidity changes, the
property of caking also changes.
 Melting point of crystals:
Melting point of crystals is near room
temperature, crystals may melt. Then solidification by fusion of
the melt leads to caking.

39. Prevention of caking:
 crystals must be more spherical in shape with least point of
contact.
 crystals must be larger in size with more voids.
 crystals should have highest possible critical humidity.
 crystals must be coated with powdery inert substances to
prevent absorption of moisture. For example, table salt coated
with magnesium or tricalcium phosphate.

40. calculation
 The yield of crystallization process can be calculated from
solubility data if the initial concentration and final
temperature of the solution are known.
 The case of anhydrous form, it is only necessary to take the
difference between the initial composition of the solution
and the solubility corresponding to the final temperature to
get the yield.
 Both the concentration must be expressed in terms of water
content of the solution and not in % solids, because it is the
water content of the solution that is inert and goes through
the process unchanged.
 This calculation is not possible if the material precipitates
as hydrated salts since the solid salt contains a definite
amount of water & the total water does not pass through
the process unchanged.

41. Numerical calculation
 what will be the yield of the sodium
sulphate (hydrated with 10 water
molecules), if a pure 32% sample is cooled
to 20 degree with out any loss due to
evaporation ? The solubility of the salt in
water at 20 degree is 19.4 gram per 100
gram of water.
Given:
32% solution
solubility 19.4g/100g water

42. Solution:
Initial solution contains – 32% salt
Which means it contains 32 kg of salt and
68 kg of water
Ratio of water of crystallization of
anhydrous salt
COMPOUND MOL . WT
Sodium sulphate 142
water 18
sodium sulphate has 10 mol of water of
crystallization
ratio is 142:180
i.e. 142kg anhydrous salt contains
180kg water

43. Now for 32 kg anhydrous salt carry ?
32*180/142=40.66 kg
Water associated with sodium sulphate=40.66
kg
Free water=(total water-water associated with
the salt)
=(68-40.66)
=27034 Kg
Now we find for 100 Kg of free water.
27.34 water (32+40.66) salt
100 water ?
=100*(32+40.66)/27.34
=265.8 Kg salt with water of
crystallization

44. Now find out salt remaining in mother liquor.
Given that solubility of the salt is 19.4 Kg per
100 Kg
Water.
Now we find the water associated with the salt
present in
the mother liquor.
142 salt (anhydrous) 180 water
19.4 ?
=1904*180/142
=24.6 Kg water of crystallization
Now free water in mother liquor = total water –
water of
crystallization

45. Now for 100 Kg free water
75.4 Kg free water contain (19.4+24.6)
hydrated
salt
For 100 Kg free water contains=
(19.4+24.6)*100/75.4
=58.33 Kg hydrated
salt in mother
liquor
Yield per 100 Kg free water = initial hydrated
salt – hydrated
salt in mother
liquor
=265.8 - 58.33
=207.47 Kg

46. 100 Kg ?
= 100*207.47/265.8
=75.05% yield

47. References
 Pharmaceutical Technology by C.V.S.Subrahmanyam
 Pharmaceutical Engineering by K.Sambamurthy
Pharmaceutical Engineering – 2 by Dr. Girish k. Jani