Crystallization is a separation process very commonly used in the industry of many different materials, from commercially very common chemicals to very specific ones. It also plays an important role in the pharmaceutical industry, as more than 90% of active pharmaceutical ingredients (API) are synthesized as a crystalline product. Crystallization may have a significant direct and indirect influence on the quality of a product; therefore, it is one of the most important purification and separation methods in the production of APIs.

1. CRYSTALLIZATION
Sanjaykumar S. Patel
Professor – Pharmaceutics Department
Shri B. M. Shah College of Pharm. Edu. & Research, Modasa

2. Crystals
A crystal can be 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.

3. AgNO3 + 2HCl = AgCl2 + NO2 + H2O
Crystallization differs from precipitation in
that the product is deposited from
supersaturation solution.
Precipitation occurs when solution of material
reacts chemically to form a product, which is
sparingly soluble in liquid and therefore
deposits out.

4. Unit cell
• Smallest arrangement of atoms & molecules-
repeats regularly-true representation of
crystal structure
Drugs – used in solid state
• Bulk powders – internal use – fine
powder/Granules
• Bulk powder – external use- tooth powder,
dusting powder
• In form of compressed tablets & tablet
triturates.
• Powder enclosed in cachets and capsules.

5. The use of drugs in the solid state has many advantages
• Purification of drugs- Removing impurities from
pharmaceutical products i.e. recrystallization
• Better processing c’teristics – To change
micromeritics of drugs/excipients like compressibility
and wettability eg. Cellulose and MCC
• Ease of handling – Facilitates transportation & storage
• Better chemical stability – Amorphous Peicillin G
is less stable than crystalline salt. Amitryptyline is
more stable in crystalline form than amorphous.
• Improved physical stability- Hardness of tablets,
the stability of hygroscopic substance can be enhanced.
• Sustained release- Protamine zinc insulin in
crytalline form slowly and continuously releases insulin
form site of injection.

6. • Crystal lattice
• An orderly internal arrangement of particles in
three-dimensional space.
• Length of unit cell
• Distance between centre of two atoms
• Lattice angle
• Angle between edges of a unit cell

7. Space lattice
Three dimensional arrangement of
particles in a crystal.
The units are ions, atoms & molecules
• Ions with opposite charges – electrostatic
attractions eg. NaCl.
• Atoms – Covalent bond, eg Diamond,
graphite.
• Molecules – Vander Waals & hydrogen
bond eg. Napthalene
Crystal forms
A finite number of symmetrical arrangements
are possible for a crystal lattice and these
may be termed as crystal forms or systems.

8. Magma
Solution containing crystals
Mother liquor
The saturated solution left behind process of
crystallization
Co-Crystal
A crystal, often a large-molecule crystal,
having two or more distinct molecular
components within the crystal lattice.
e.g. Indomethacin & saccharin, Ibuprofen &
starch, Neproxen & sodium starch glycolate

11. Crystal habit
Crystal is a polyhedral solid with number of
planar surfaces. A substance crystallizes
such a way that the angle between a
given pair of faces is same in all
specimens.
The size and shape – dependent on the
conditions under which crystallization
carried out.
Eg. Griseofulvin crystallized from acetone
has different form from the same drug
crystallized from benzene or chloroform.

13. Amorphous
• Don’t have specific
shapes, melting points.
Eg. Glass, plastics
• More soluble than
corresponding
crystalline form.
Eg. Novobiocin
• Less attractive
• Compact cake
• Storage
• Impurities
Crystalline
• Definite shapes & melting
points. Eg. NaCl, Aspirin
• Incompressible
• Low solubility and
dissolution
• Always pure-attractive
• Easy-store & pack
• One step process
• Less energy then
distillation
• Small & large scale possible

14. What is polymorphism?
Certain drugs can exist in more than one
crystalline form. Such a phenomenon is
known as polymorphism.
Eg. 63 % barbiturates, 67% steroids and 40
% sulphonamides
Polymorph
Metastable polymorphs
These polymorphs slowly convert into stable
polymorphs.
Lower MP, higher solubility and dissolution
rate than their stable polymorphs.
Eg. Riboflavin - solubility – 60 mg–1.2 gm/litre
Physical properties
Density, MP, solubility

15. Crystal hydrates
Certain drugs have greater tendency to
associate with water. Eg. Caffine hydrate,
Ampicillin monohydrate.
• Anhydrous form gives Better
bioavailability than hydrous form.
Crystal solvates
Certain drugs have greater tendency to
associate with solvents to produce
crystalline form of solvates also called
pseudomorphs.
Eg. Fluorocortisone with n-pentanol or
ethyl acetate.

16. What is Crystallization
It is the spontaneous arrangement of the
particles into a repetitive orderly array. i.e.
regular geometric patterns.
Recrystallization
To take a crystallized impure solid and purify
it by dissolving it in a hot solvent and then
allowing it crystallize followed by vacuum
filtration and drying. Eg. MCC from Cellulose

17. Advantages
• Better appearance
• Ease of filtering & washing
• No batch to batch variation
• Minimize caking

18. Mechanism of Crystallization (Theory)
Supersaturation
Can be achieved
1. Evaporation of solvent
2. Cooling of the solution
3. Formation of new solute-Chemically
4. Addition of a substance (seeding)
Solution
Solubility
Saturation-equilibrium

19. • What is supersaturation?
Solution in which concentration of
solute greater than the saturation
concentration.
Supersaturation (S)
• S = C/C*
• C = concentration of solution
• C* = equilibrium saturation concentration at
given temperature

20. Nucleation
• Birth of very small bodies of a new phase
within a homogenous supersaturated phase.
• Consequence of rapid fluctuations at the
molecular level, in random motion in any small
volume.
• Initially molecules associate to form clusters
(loose aggregates), which usally disappear
quickly.
• When enough particles associate to form an
embryo, beginning of the lattice arrangement
& formation of new phase.
• Embryo may grow – thermodynamically
equilibrium with the solution.

21. The initially formed crystals are molecular
size, which are termed as nuclei.
Methods for nucleation
1. Soft and weak crystals on impact with
moving parts in crystallizer – fragments.
2. Small crystals are added to act as
nuclei.
3. Under poor mixing, needle like structures
are observed at the ends of crystals.
These structures grow faster and come
out to give crystals of poor quality.

22. Crystal growth
Is a diffusion process & surface phenomenon.
Solute molecules breaks bonds, Migration of solute
molecules at (crystal) solid-liquid interface
Adsorption & orientation in crystal lattice
This phenomenon continues at a finite rate.

24. Figure :- Mechanism of Crystallization

25. • Mier’s theory of supersaturation
• In a solution completely free from any
foreign particles spontaneous nucleation
occurs at supersaturation & not near the
saturation concentration.
Statement

26. • Curve AB
• Saturation or solubility curve
• Curve CD
• Supersolubility curve

27. • Stable zone
 Below the solubility curve
 unsaturation prevails-no crystallization
• Metastable zone
 Between solubility & supersolubility curve
 Spontaneous nucleation occurs-crystal
growth favored
• Labile or unstable zone
 High relative supersaturation
 Only nucleation is favored

30. Maximum supercooling
or
Supersaturation concentration
• Induction period
 Degree of supersaturation
 State of agitation
 Presence of impurities

31. • Molecular collisions
• Short lived cluster
• Formation of embryo or sub-nuclei
Failed to maturity
redissolve due to unstability Stable or critical nucleus
Statistical probability
Low significant
Vicinity of solubility curve supersolubility curve

32. • Crystallization –metastable zone

33. Limitation of Mier’s theory
 Crystallization’s starts at supersolubility curve.
But generally crystallization takes place in an
area rather than a line.
 Solution must completely free from foreign
particles - In practice, it is impossible.
 Large volume nucleates spontaneously at lower
degree of supersaturation then small volumes-
not considered.
 Spontaneous nucleation-solution kept at lower
degree of supersaturation for longer time-
contamination.
 Supersaturation occurs at particular
concentration but formation of nucleus-
chances of collision & can’t be specified by
particular concentration - should be in range of
conc. In which chances will be maximum.

34. Theory is no significant use in practice

35. • Nucleation
• Primary Secondary
• Do not contain nuclei generation in
crystalline matter vicinity of crystal

36. Curve 1 Potassium nitrate.
Curve 2 sodium chloride
Curve 3 sodium
thiosulphate
Curve 4 sodium carbonate

37. Crystallization
Nucleation
Primary Secondary
Homogeneous Heterogeneous
Initial breeding Collision breeding Needle
breeding

38. • Primary nucleation
• Occurs at high levels of supersaturation
• Unseeded crystallization or precipitation
• Two classes
• Homogeneous & Heterogeneous

39. • Primary nucleation
• Homogeneous nucleation
• Definition
• Molecules/ions –come together-not
redissolve
10-100 molecules
• Oriented in fixed lattice structure
• Can not happen by simultaneous collision
• How?

40. • Primary nucleation
• Homogeneous nucleation
• Bimolecular addition
• A + A A2
• A2 + A A3
• An-1 + A An (Critical cluster)
• Result in nucleus

41. • Secondary nucleation
• Presence of existing crystals
• Rate of nucleation-growth rate of parent crystal
1. Initial breeding
• Occurs-seeding
2. Needle breeding
• Growth of imperfect crystals-not expected in
regular crystal growth
3. Collision breeding
• Collision of crystals with stirrer, pump, impeller
or crystal wall contact under centrifugal force

42. • Dislocation theory- Kossel
• New molecules are added only at kink or
repeatable step.
• Many location - building unit can incorporate
• The position which involve maximum work of
separation & is most stable – Kossel site.

43. • Frank-Surface do not grow perfectly & takes
helical path – screw dislocation- low
supersaturation.
• Steady state growth α square of concentration

44. • Supersaturation by cooling
• Solubility is strongly temperature dependent
• Cooling – heat exchange- air ammonia or water
• Water- 50 in winter 20 0 in summer
• Crystallizer temperature is 20 higher-
considerable amount remain in solution - low
yields - cooling should be carried at 100 or
below
Factors to be considered
• Viscosity - mass transfer, heat transfer, mother
liquor remain adhered to crystal surface
• Maximum supersaturation near cooling surface
– crystal deposition – lower heat transfer

45. EQUIPMENTS - CRYSTALLIZERS
Method of
supersaturation
Batch process Continuous
process
By cooling alone 1. Tank crystallizer
2. Agitated batch
crystallizer
1. Swenson walker
2. Krystal cooling
crystallizer
By evaporation of
solvent
1. Crystallizing
evaporators
1. Krystal evaporator
2. Circulating magma
crystallizer
By adiabatic cooling
(evaporation &
cooling)
Or
Vacuum crystallizer
---------------
1. Krystal vacuum
crystallizer
2. Swenson vacuum
crystallizer

46. • Batch Operation
• Advantages
• Simple equipment, low mechanical trouble
• Low maintenance cost, production of
large crystals
• Limitation
• Variation from batch to batch
• Large head room
• Long operation time & more manual work

47. • Supersaturation by cooling
Tank crystallizer
• Simple rectangular tank
• Glass enameled or stainless steel vessel of
0.5 m diameter
• Saturated solution – cooling by natural
cooling or in contact with cooling medium
• No control of nucleation or crystal growth
• Product obtained in mass of interlocked
crystals by draining mother liquor

48. • Tank crystallizer
• Rate of cooling slow - several days
• Mother liquor act as impurities

49. • Tank crystallizer
Advantages
• Simple, cheap
• No special or complicated equipments are
required
Disadvantages
• No control on nucleation
• More labor, time consuming
• Low capacity, batch operation
Application
• Glaubers salts, synthetic sponge

50. • Agitated tank crystallizer
Principle
• Artificial cooling with agitation
Construction
• Modified tank crystallizer
• Cooling coils or cooling jackets- around wall
• Slow speed propellers on central shaft
Function
• Increase rate of heat transfer
• Keep crystals in solution give opportunity to grow
uniformly & no aggregates or large crystals form.

52. Advantages
• More efficient than tank crystallizer
• Uniform & more fine products
Disadvantages
• Low capacity, large floor space
• Salting on cooling surface
• Batch operation
Application
• For temperature dependent solubility
substances
• For small scale production

53. Swenson-Walker crystallizer
Principles
• Supersaturation by cooling
• Continuous crystallizer
• Semicylindrical open trough-60 cm wide, 5 m long
& 67.5 cm depth
• Jacket from outside trough – water circulation
• Low speed, long pitch spiral agitator placed as
close as possible to semicylindrical bottom.
• Angular velocity of agitator is 5-10 rpm.
• Cooling water flows in direction of crystallizing
solution parallel flow crystallizer. Counter current
contact is also possible.
• Jacket divided in different section-different
cooling rate.

55. Spiral agitator functions
 To prevent accumulation of crystals on the cooling
surface.
 To lift the crystals & shower down through the solution to
grow in free suspension.
 To move crystals mechanically towards the discharge.
• Gap between crystallizer wall & agitator should be
optimum.
• If large - tendency of crystals deposition on cooling
surface
• If close to trough-act as scraper & fines will be produced
• As solution enters the crystallizer slurry is agitated gently-
provide excellent condition for crystal growth & crystals
overflows with mother liquor-discharge.

56. • Wide crystal size distribution-why?
• Heat transfer is limited
• Advantages
• Less floor space,small volume in process
• Low labour cost & cheap cooling medium
• Application
• Trisodium phosphate, Oxalic acid, milk sugar &
Naphthaline

57. Krystal cooling crystallizer
Principle
• Supersaturation by cooling
Construction
• Tank (A)
• Cooler (H)
• Pump (C)
• Discharge tube (M)

58. • Solution feed in cooler
• Cooled below atmospheric
temperature by refrigerated
brine
• Rapid circulation of pump
create agitation.
• Growth doesn’t occur until
the supercooled liquid has
reached the static crystal
bed in the body of crystallizer
• Overflow of crystals & mother
liquor recirculated through
cooler.
• Discharge product from bottom

59. Advantages
• No labor for handling of crystals
• Operated at atmospheric pressure
• Process is controlled by
 Speed of rotor
 Rate of cooling
 Rate of feed
 Rate of removal of product

60. • Krystal evaporator crystallizer
Principle
• Supersaturation by
evaporation of solvent
Construction
• Vapor head (A)
• Crystallizing chamber (E)
• Pump (F)
• Heater (H)

61. • Solution is pumped from
chamber to heater &
discharged in vapor head for
flash evaporation
• Vapor discharge in
condenser & vacuum pump
• Operation is controlled –
crystals do not form in vessel
(A) but vessel (A) is
prolonged into tube (B)
extended to bottom of vessel
(E) containing bed of crystals
suspended in upward flowing
stream & supersaturation
produced in vessel (A) is
discharged as supersaturated
liquid flows over surface of
crystals in vessel (E).

62. • After equilibrium it escape at connection (C) for
recirculation
• Crystals are drown from bottom of vessel (E)
through connection (M).
• Coarse crystals settle down while finest
overflows for recirculation
Advantages
• Evaporation & cooling takes place in one vessel
– saving floor space
• Heat of crystallization is positive – used as part
of heat required for evaporation

63. Circulating magma crystallizer
Or
(Draft tube Circulating - magma crystallizer)
Principle
• Supersaturation by evaporation
Construction
• Cone-bottom vessel fitted with vapor draw off &
vacuum equipment
• Low speed, large volume, low head propeller
agitator in draft tube

65. • Propeller- lifts magma through draft tube &
create circulation down through annular space
between draft tube & wall of crystallizer & back
to suction of propeller
• Product classification is done in elutriation lag
bellow the cone-bottom of unit
• Saturated liquor act as hydraulic sorting fluid
carrying small crystals in crystallizing zone
• Discharge slurry is withdrawn from lower part of
elutriation lag & filtered mother liquor is
returned to process

66. • Saturated water solution is
introduced in closed vessel
(A) – vacuum is maintained
by condenser & booster
• Magma volume is
Maintained by controlling
level of liquid & crystallizing
solid & space above
magma for release of
vapor.
• Supersaturation generated
by both cooling &
evaporation - nucleation &
growth
• Product drawn from bottom

67. Advantages
• Simple, Few moving parts, Large capacity
• Not require heating or cooling surface
Disadvantages
• Not used-refrigeration or large boiling point
• Not used-salt having flat solubility curve
Limitation
• There is no control over – nucleation,
classification and removal of excess nuclei.
• Due to the effect of static head, evaporation
and cooling occur only in the liquid layer near
the magma surface.

68. Caking of Crystal
Reason :- Due to small amount of dissolution
taking place at the surface of the crystals (at high
humidity) and subsequent re-evaporation (at low
humidity) of the solvent.
• Each salt have critical humidity. (Humidity above
which it will become damp, below it stay dry).
• Impurities coated with crystals, can change
critical humidity. It may be higher or lower.
• A crystallize material will cake more readily if the
particles are non uniform and small.

69. Factor affecting caking
Crystals size- Smaller crystals contain less void space &
possess more contact points. Smaller sized particles
tend to cake more than larger particles.
Crystals Shape – Spherical crystals possess the less
possible contact points than irregular shape.
Humidity – Higher humidity –caking rate will be more.
Impurities in crystals – Fluctuation in critical humidity
Melting point of crystals – MP of certain crystals is
near room temperature, crystal may melt. Then
solidification by fusion of melt leads to caking.

70. Prevention of caking
• Use larger and uniform crystals.
• Store below critical humidity.
• Coat the crystals with inert material which
absorb moisture (e.g. Na. ferrocyanide).
• Add small amount of insoluble material
e.g. Cal. Phosphate, talc.
• Get crystal with highest critical humidity,
obtained by removing impurities.
• The caking of Nacl is attributable to traces of
Mgcl2 impurities (hygroscopic).

71. Key Questions
1. Explain co-crystals with example.
2. Explain nucleation. Describe factors affecting crystal
growth.
3. Describe Mier’s theory for supersaturation with
limitations.
4. Describe Swenson-Walker crystallizer with diagram.
5. How can we control crystal size? Explain the
construction and working of Swenson Walker
crystallizer.
6. Discuss caking in crystals and its remedy.
7. What is the importance of crystallization in
pharmaceutical industry?

72. Thank you