Crystallization is a major process in pharmaceutical chemistry, involving the formation of solid particles from vapor or solution and estimated to produce over 70% of solid materials. The process includes nucleation, which can be primary or secondary, and is influenced by factors such as supersaturation, temperature, and the nature of the crystallizing substance. Various mechanisms for nucleation and crystal growth are discussed, including the effects of agitation, impurities, and the type of solvent used.

1. Crystallization
Name: shrddhaba j chudasama
Sub: pharmaceutical process chemistry
Enroll: 202280822007
Department: pharmaceutical chemistry
L.M College of pharmacy,Navrangpura
Ahmedabad.

2. Definition and understanding
 Crystallization refers to the formation of solid particles
from a vapour, the solidification from a liquid melt or
the formation of dispersed solids from a solution.
 Crystallization, incorporating wider definition to
include precipitation and solid-state transitions, is a
major technological process for particle formation in
pharmaceutical industry .
 It is estimated that over 70% of all solid materials are
produced by crystallization. ....

3. Mechanism of crystallization
The formation of crystals from solution involve three
step:
1. Super saturation
2. Nucleus formation
3. Crystal growth Mechanism of Crystallization.
In this in the second steps there was further types of
nucleation divided in to two primary and secondary
and primary further divided in to two
(a) heterogeneous nucleation
(b) homogenous nucleation

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.

5. Mechanism of crystallization
 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 divided in to two types
 (1) primary nucleation
 (2) secondary nucleation.

6. Nucleation
 (1) 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. Homogeneous nucleation is used to describe precipitates that form at
random in a perfect lattice. True homogeneous nucleation that is
independent of any lattice defect is very rare. Homogeneous nucleation
can only become viable if the strain energy and surface energy involved
in creating a nucleus are small.

8. Homogenous nucleation
 There are, however, many important age hardening phases
that do not develop at dislocations, grain boundaries, or
interfaces, and precipitate homogeneously throughout the
grain interiors.
 Typically, the phases involved are metastable and the
precipitation occurs at low temperatures and
large supersaturations. In aluminium alloys the majority of
these phases develop from solute clusters, or GP zones
(GPZs), by spinodal decomposition, and involve strong
interactions with vacancies .

9. Homogenous nucleation
 For example, recent atom probe investigations of
precipitation in Al–Cu–Mg and Al–Mg–Si alloys
have shown that initially separate elemental
clusters are formed and this is followed by co-
clustering of alloying elements from which GPZs
form and transition phases nucleate .

10. Homogenous nucleation
 Solute clustering and GPZ formation results in a
natural aging response. This is a technologically
important property of some aluminium alloys as it
allows them to be formable in the solution treated
condition and then strengthen with time at room
temperature after fabrication.

11. Homogenous nucleation
 In aluminium alloys, generally, “homogeneously
nucleated” phases evolve from solute clusters and
GPZs formed during the low-temperature
decomposition of the solid solution.
 The excess vacancies quenched by rapid cooling
following solution treatment play an important
role in solute clustering and GPZ formation. Excess
vacancies significantly increase the diffusion rate
and facilitate the formation of solute clusters by
relieving misfit strains.

12. Heterogeneous nucleation : If effect holds that if the nucleus wets the
surface of the catalyst ,then nucleation formation is reduced by a factor
that is a function of the angle of wetting between the nucleus and the
catalyst .

13. Heterogeneous nucleation
 Many phase transformations take place
heterogeneously in the solid state. Grain
boundaries are favoured sites for such reactions
because excess interfacial energy is available there
for nucleation of new phases.
 This is why proeutectoid phases like α-Fe and Fe3C,
as well as two-phase mixtures of pearlite, nucleate
at prior austenite grain boundaries. Precipitates and
inclusions in the matrix also serve as heterogeneous
nucleation sites.

14. Secondary nucleation
 Secondary nucleation is the formation of nuclei attributable to the
influence of the existing microscopic crystals in the
magma. Simply put, secondary nucleation is when crystal growth
is initiated with contact of other existing crystals or “seeds”.
 The first type of known secondary crystallization is attributable
to fluid shear, the other due to collisions between already existing
crystals with either a solid surface of the crystallizer or with other
crystals themselves.
 Fluid-shear nucleation occurs when liquid travels across a crystal
at a high speed, sweeping away nuclei that would otherwise be
incorporated in to a crystal, causing the swept-away nuclei to
become new crystals. Contact nucleation has been found to be the
most effective and common method for nucleation. The benefits
include the following.

15. Secondary nucleation
 Low kinetic order and rate-proportional to
supersaturation, allowing easy control without
unstable operation.
 Occurs at low supersaturation, where growth rate is
optimal for good quality.
 The quantitative fundamentals have already been
isolated and are being incorporated into practice.

16. Crystal growth
 Once the first small crystal, the nucleus, forms it
acts as a convergence point (if unstable due to
supersaturation) for molecules of solute touching
or adjacent to the crystal so that it increases its
own dimension in successive layers.
 The supersaturated solute mass the original
nucleus may capture in a time unit is called
the growth rate expressed in kg/(m2*h), and is a
constant specific to the process.

17. Factors affecting Crystal growth
 Growth rate is influenced by several
physical factors, such as surface tension of
solution, pressure, temperature, relative
crystal velocity in the solution, Reynolds
number, and so forth.

18. Factors affecting crystallization
 Both formation of nuclei and occurring of crystallization
affected by the nature of the substances factors like
temperature,concentration,agitation, and impurities
present in the solution etc.
 (1) Nature of crystallizing substance:Nature of the
crystallizing substance: Some substances like salt
crystallize readily from water solution.
 It requires only a very slight super-saturation to start
nuclear formation, and all excess salt in the solution
beyond the saturation point is precipitated as crystals.
Some substances do not form nuclei or crystallize so readily
as salt. With sucrose it is often necessary to have a
considerable degree of supersaturation before
crystallization commences. Sucrose crystallizes more
readily than levulose.

19. Factors
 (2)Formation of nuclei: Nuclei cannot form and
crystallization cannot occur except from a
supersaturated solution.
 The formation of nuclei, that is the uniting of
atoms to form nuclei, is influenced by several
factors. If a solution is left to stand, a few nuclei
may form spontaneously in various places, and
from these nuclei crystallization proceeds. When
only a few nuclei develop spontaneously in the
solution, the crystals grow to large size. Usually
nuclei formation and crystallization do not begin
immediately after supersaturation occurs.

20. Factors
 The rate of nuclear formation may be favoured by
specks of dust in the solution. Agitation or stirring of a
solution increases the rate of nuclear formation. A
drop in temperature at first favours, and then retards,
the formation of nuclei. Instead of spontaneous
formation of nuclei, seeding a solution may be used to
start crystallization.

21. Factors
 Seeding: When crystals of the same material are added to
start crystallization the process is called seeding. These
crystals serve as nuclei for crystal growth. If the quantity of
crystals added is large and the size of the crystals small, it
serves as many nuclei in the solution and the resulting
crystals are small.
 If the quantity of material added is very small, the nuclei
formed are few in number and the crystals formed are
large. One may think of all crystals as being large enough
to be visible, whereas many of them may be very small, so
small in fact that they may float in the air. If crystals are
floating in the air there is the possibility that they may
serve to seed solutions, and thus start crystallization.

22. Factors
 Rate of crystallization: To the nuclei formed in the
solution new molecules from the solution are
deposited, in a regular order or manner, so that each
crystal has a typical shape. One side or face of a crystal
may grow more rapidly than another. The rate at which
the nuclei grow to larger size is called the rate of
crystallization. This rate may be favoured by the
concentration of the solution and its temperature; it
may be hindered by foreign substances.

23. Factors
 Concentration of the solution: A more concentrated
solution favours the formation of nuclei. Fondant syrup
cooked to 114°C. Contains less water and is more
concentrated than one cooked to 111°C. Thus nuclei form
more readily in the one cooked to 114°C. Large, well-shaped
crystals form more readily if the degree of supersaturation
is not too great.
 The most favourable supersaturation for crystal growth, of
a sucrose solution boiled to 112°C, is that between 70° and
90°C. Although crystallization occurs in a very short time
when the syrup is stirred at these temperatures, the crystals
formed are larger than when the syrup is cooled to a lower
temperature. Supersaturation and a low temperature are
desirable for the development of small crystals.

24. Factors
 Temperature at which crystallization occurs: It is a
well-known fact that, in general, chemical precipitates
come down more coarsely crystalline if crystallized at
high temperatures.
 The sugars follow this general rule. Other things being
equal, concentration, etc., the higher the temperature
at which crystal formation occurs, the coarser the
crystals formed.

25. Factors
 A drop in temperature at first favours the formation of
nuclei, and then hinders it. Crystallization is favoured
in sugar syrups by cooling to a certain temperature,
but is hindered when cooled to a lower temperature.
Since the viscosity of a saturated sugar solution
becomes increasingly greater as the temperature falls
below 70°C, crystal formation is also slower as the
temperature falls.

26. Factors
 Agitation: Stirring a solution favours the formation of
nuclei and hinders the depositing of the material of
the solution on the nuclei already formed. Hence,
crystals in solutions that are stirred do not develop to
the size that they do in spontaneous crystallization.
 If small crystals are desired, then the conditions
should be such that many nuclei are formed. Small
crystals are obtained in syrups of definite
concentration and temperature, if the syrup is stirred
until the mass is kneadable.

27. Factors
 However, if the syrup is stirred for only a short
time, some nuclei are formed, but after agitation is
stopped, the formation of new nuclei is not favoured
and crystal growth is favoured. This emphasizes the
importance of stirring candy and icing syrups until
practically all the material is crystallized, if small
crystals are desired.
 Impurities in the sugar syrup may also result in the
formation large sugar crystals. Impurities promote
premature crystal formation, which will grow to big
unwanted crystals.

28. Crystallization form non aqueous
forms
 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 nucleation , which is
easier when solubility is higher ion the crystallization
of polymorph and on the surface morphology of the
crystals.

29. Form Non aqueous solvent
 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.

30. Form Non aqueous solvent
 There are three main classes of solvents:
 1. Hydrogen donors ( methanol, formamide)are protic
solvents.
 2. dipolar aprotic solvents (acetonitrile ,
nitrobenzene).
 3. If the dielectric constant is weak , the solvent is
non- polar aprotic (pentane, benzene)

31. Form Aqueous solvents
 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.

32. Form non aqueous solvent
 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.

33. Summery
• Crystallization, is the process of atoms
or molecules arranging into a well-
defined, rigid crystal lattice in order to
minimize their energetic state.
crystallization
• supersaturation
• nucleation
• crystal growth.
Mechanism
• concentration,temperature and
nature of subtances matters the
most
• It is done by non aqueous and
aqueous solution in which most
probably used aqueous solution.
Factors &

35. References
 technolwww.researchgate.net/publication/222800
531_Crystallization_Processes_in_Pharmaceutical
_Technologyogy/crystallizationhttps://
 Drug_Delivery_Designhttps://pubs.rsc.org/en/co
ntent/articlelanding/2018/CC/c8cc02381f#!divAbst
ract

36. Reference
 https://www.jbc.org/article/S0021-9258(20)72585-
8/fulltext
 https://www.sciencedirect.com/topics/engineerin
g/homogeneous-
nucleationhttps://www.allfordrugs.com/crystalliz
ation/
 https://www.slideshare.net/ShikhaPopali1/crystal
lization-easily-described

37. Thank you