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CRYSTALLIZATIO
N
Nitin Pandey
M-Pharm [Pharmaceutical
chemistry]

CONTENTS.
• Introduction
• Principle
• General method of Preparation of polymorphs
• Hydrates
• Solvates
• Amorphous APIs.

INTRODUCTION
• Crystallization is a process of cooling
,concentrated solution of a substance to obtain
crystals is called crystallization .
• It is the most commonly used technique for the
purification of a solid organic compound .
Principle of crystallization –
1.It is based on difference in solubility of the
compounds and the impurities in a suitable solvents.
2.The impure solid compound is dissolved in a solvent
in which it is sparingly soluble at room temperature
but appreciably soluble at room temperature.
3. The solution is then concentrated by heating gently
on a water bath to get a nearly saturated solution

4. Crystals of the pure compound is obtained by using
filtration method .
5. The filtrate [mother liquor ] contain dissolved
impurities and a small quantity of the compound .
6. Repeated crystallization becomes necessary for the
purification of compound containing impurities of
comparable solubility.
Example –
Crystal of pure Copper Sulphate can be obtained from
of copper sulphate .

General method of preparation
polymorphs
• When the substance exist in more than one crystalline
form ,the different form are designated as polymorph
and the phenomenon as polymorphism.
Method of preparation :
1. Solvent evaporation [Rota evaporation ]
In this approach ,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.
2.Slow cooling approach
This technique is frequently employed for the
polymorphic forms of less soluble drug in the solvent

• In brief the solute is heated in 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 solvents
.
• The Dewar flask is left in this condition for several
days .
• This technique may further be improved to obtained
better crystal forms using different solvent mixture
of different polarity .
• Various on the solvent composition may inhibit or
promote growth of particular crystal faces and hence
, can yield crystal of the desired morphology.

• A solution is placed in a sample tube then a second
less dense solvent is carefully dripped down the side
of the tube using either a pipette or a syringe to
form a discrete layer .
• The slow diffusion of the solvent results in the
crystallization of APIs at the interface .
• Most employed solvent combination is ethanol and is
prefer one ,and provide the sample in insoluble ether
.
4. Vapor diffusion method
• In vapor diffusion ,a drop containing mixture of
precipitants and protein solution is sealed in a
chamber with pure precipitants ,Water vapor then
diffuse out of drop and precipitants are equal .

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 .
• A small amount of sample is sealed under Vacuum in a
reactor in generally subject to a temperature
gradient in numerous manners .

Crystal solvates /hydrates
• Crystal solvates tends to form during the process of
crystallization with the help of solvents .
• The crystalline solid that contain the molecule of
solvents inside their crystal assembly which are known
as solvates.
Method of preparation
oHydrates and solvates can be prepared by
crystallization in water or an organic solvents or by
conversion of Anhydrous material through moisture or
solvent adsorption .
oIn quality control testing hydrates or solvates are
identified by the assay of water of crystallization or
solvent found in crystal.

HYDRATES
• The crystalline chemical compound or the substance
that contain a water molecule as a constituent of the
compound is called hydrate.
• The water in these molecules combined chemically in a
definite proportion .
• In hydrates compound the water molecule surround and
interact with solute ions or molecule .The water
molecule present in the compound are called water of
hydration .
EXAMPLES – Sodium hydrates
Copper hydrates
Calcium hydrates
Hydrates of carbon

• Types of Hydrates
1.Inorganic Hydrates
2. Organic Hydrates
3. Gas Hydrates
Inorganic Hydrates
• The water molecule in Inorganic hydrates are only
loosely bonded to the compound ,and there is no
chemical involved.
• The water molecules can be removed from the compound fairly easily,
such as through heating.
• An inorganic hydrate that has lost its water molecules is known as
anhydrous." Inorganic hydrates are the most common type of hydrate.
Organic Hydrates
• An organic hydrate is created when a water molecule is added to a
a carbonyl group of an aldehyde or ketone.

• In organic hydrates, the water molecules have chemically
reacted with the compound and bonded to it.
• Gas Hydrates
• In gas hydrates, water molecules form a loose framework
molecule, which is usually methane.
• Method of preparation
The basic method for preparing hydrates is by
dissolving a drug compound in an aqueous solvent .
This aqueous must be cooled tov established the
opportunity for the evaporation of process which
result in different crystal hydrates .

• AMORPHUS API:
• Its not have specific shape and their structural unit
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 remain in the
fluid state will below the normal freezing point.
2.Spray drying- In the spray drawing process a liquid
feed stream is first atomized for maximum air spray
contacts the particles then dried in air stream it can
be produced spherical particles that have good flow
properties.
3.Removal of solvent from solvates- Solid sometime be
amorphous form simply by allowing solvent molecules
of crystallization to evaporate at modest temperature.

REFERENCE
• https://blog.prepscholar.com/what-are-hydrates-
definition-naming-and-
examples#:~:text=A%20hydrate%20is%20any%20compound
,gas%20(or%20clathrate)%20hydrates
• https://www.sciencedirect.com/topics/biochemistry-
genetics-and-molecular-biology/solvate
• https://blog.prepscholar.com/what-are-hydrates-
definition-naming-and-
examples#:~:text=A%20hydrate%20is%20any%20compound
,gas%20(or%20clathrate)%20hydrates

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