CRYSTALLIZATIO

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 CONTENTS
 THEORY OF CRYSTALLIZATION
 MECHANISM
 FACTORS AFFECTING CRYSTALLIZATION
 PRINCIPLE AND METHOD OF PREPARATION
OF
 POLYMORPHS
 HYDRATES
 SOVATES
 AMORPHOUS

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 INTRODUCTION
Definition of crystallization
Spontaneous arrangement of the particle into a repetitive order
(regular geometric patterns).

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 IMPORTANT TERMS IN
CRYSTALLIZATION
Crystal
It is 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.

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 UNIT CELL.
It is the smallest geometric portion, which repeats to build
up the whole crystal.

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Space lattice
The 3 D arrangement of a particle in a crystal is called space
lattice.
Face
A crystal is bounded by plane surface called face.
Axial angle
The angle between the two perpendiculars to the intersecting
faces is termed as axial angle.
Axial length
Distance between the centre of two atoms.
Crystal form
A finite number of symmetrical arrangements are possible for
a crystal lattice.
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TYPES OF CRYSTAL
FORMS

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 MECHANISM OF
CRYSTALLIZATION
The formation of crystal from solution involves three
steps.

1.Supersaturation
2.Nucleation
3.Crystal growth

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 SUPERSATURATIO
N
Supersaturation can be achieved by the following methods

1.Evaporation of solvent from the solution. 2.Cooling of the

saturated solution.
3.Addition of a substance, which is more soluble in solvent than
the solid to be crystallized.

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 NUCLEATIO
N
 Birth of very small bodies of molecules are called nucleation.

 Some clusters may become so big they may arrange

themselves in lattice arrangement. These bodies of aggregates
are called embryo.

 Embryos are unstable and they may break into clusters again.
These stable structures together form a nuclei.

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 NUCLEATIO
N
• It is the birth of very small bodies of molecules from which
the crystal forms.
Nucleation

Primary nucleation Secondary nucleation

(induced by crystals)

Homogenous Heterogenous
(Spontaneous) ( Induced by foreign
particles)

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 STAGES OF
NUCLEATION

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 CRYSTAL GROWTH
• 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 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.

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

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 FACTORS AFFECTING
CRYSTALLIZATION
1. Presence of another substance
2. Solvent
3. Nucleation
4. Crystal growth
5. Rate of cooling/ Time

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 1) PRESENCE OF ANOTHER
SUBSTANCE
• 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.

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 2) SOLVENT
CONSIDERATIONS
•The solvent with moderate solubility is prefer crystallization.
for
•Presence of benzene can help crystal growth.
•Avoid highly volatile solvents.

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 3)
NUCLEATION

• Crystals initially form via “nucleating events”.

• After a crystallite has nucleated it must grow.

• Nucleation sites are necessary for formation of crystal.

• Excess nucleation sites cause smaller average crystal

size.

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 4) CRYSTAL
GROWTH
•Keep crystal growth vessel away from sources of mechanical
agitation (e.g. vibrations).

•Set-up away from vacuum pumps, hoods, doors, drawers,

and so on.

•Leave samples alone for 1 week, don't “check in” with it.

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 5) TIME

• Qualitycrystals 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.

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CLASSIFICATION OF
SOLIDS

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 POLYMORPH
S
• When a substance exists in more than one crystalline form,
the different form are designated as polymorphs and the
phenomenon as polymorphism.
• Eg: carbon
• Diamond in a cubic ( tetrahedral lattice arrangement )
• Graphite in sheet of a hexagonal lattice.

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 CLASSIFICATION OF POLYMORPHS BASED
ON
THEIR STABILITY

POLYMORPHS

STABLE
POLYMORPH META
S STABLE
POLYMORPH
S

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 TYPES OF
POLYMORPHS

POLYMORPH
S

ENANTIOTROPIC
MONOTROPIC
POLYMORPHS
POLYMORPHS

Eg: Chloramphenicol
Eg: Sulphur palmitate 26
 PREPARATION OF
POLYMORPHS
1) Solvent evaporation method
•Saturated solution of drug is prepared.
•Solvent is removed by evaporation.
•Air drying is done.

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2) Solvent diffusion method

•Solution is placed in a sample tube.

•Solvent is dripped down the side of tube to form a discrete layer.
•Slow diffusion of solvent results in the crystallization of drug at the
interface.

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 CRYSTAL
•
SOLVATE
These substances have greater tendency to associate with
solvents.
• Synthetic estrogen ‘ethynylestradiol ’ is crystallized from
the solvent acetonitrile , methanol , chloroform.

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 TYPES OF
SOLVATES
CRYSTAL SOLVATES

POLYMORPHIC PSEUDOPOLYMORP
SOLVATES HIC SOLVATE

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 PREPATION OF
SOLVATE
Eg: Synthesis of dimethyl formamide solvate of Thiocyanuric acid
(TCUA)
Combining a solution of TCUA (21.27 mg) in DMF (2.0 mL)
with an aqueous solution of NaNO3 (2.0 mL, 1.0 M).

The reaction solution was left at room temperature for 3 days yellow
crystals of Thiocyanuric acid were obtained.

The resulting crystals were filtered off and were washed three times
with DMF/water (1:1 v/v).

The needle-shaped crystals were obtained.

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 CRYSTAL
HYDRATE
• Some drugs have greater tendency to associate with water, this
substance is called hydrates.
Types of hydrates
1) Inorganic hydrate
2) Organic hydrate
3) Gas hydrateor clathrate

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 INORGANIC
HYDRATE
• It release its water molecules when it heated and
becoming anhydrous.
• The
anhydrous form
of the
substance
can
absorb water,
becoming hydrated.
• The water is known as the water of hydration or the water of
crystallization.
• Eg:
• Magnesium sulphate heptahydrate (Epsom salts) 32
• Cobalt (ll) chloride is sky blue in its anhydrous form and
purple in its hydrated form (cobalt (ll) chloride
hexahydrate).

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Hydrated form Anhydrous form
 ORGANIC
HYDRATE
• In organic hydrate the water molecules chemically react with
other compounds.
• Eg: Formaldehyde
• Hydrate is formed from formaldehyde by the
reaction of its carbonyl group with water.
• The water molecule splits into H and OH and the the
hydrate is formed.

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 GAS
HYDRATE
• It is made at low temperature and high pressure when water
molecules surround a gas molecule, forming a frozen mesh or
cage.

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 PREPARATION OF
HYDRATE
• Eg: Preparation of chloral hydrate
• Chlorine is dissolved in water, forming a thin slurry.

• Slurry then filtered through a glass filter funnel surrounded by

jacket.

• Which is then cooled in ice bath, chlorine hydrates are

formed.

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 AMORPHOUS
SUBSTANCE
• In which particles are arranged in a random manner.
• No regular arrangement of constituent particles in structure is
called amorphous solid.
• Eg: glass, rubber, plastics, etc.
• Higher thermodynamic energy
• Greater solubility and dissolution rate.

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 METHOD OF PREPARATION
OF AMORPHOUS
1) Spray drying method

The liquid feed stream first atomized The particles are dried in

air in air stream

Spherical particles of amorphous substances are formed

2) Removal of solvent from sovate

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 REFERENCE
• Biopharmaceutics and pharmacokinetics by- DM Bhramankar,
Sunil Jaiswal.
• Pharmaceutical Engineering Unit Operation I;
II edition; by CVS Subrahmanyam.
• https://owlcation.com/stem/What-is-a-Hydrate-Chemistry
• https://link.springer.com/article/10.1007/s13203-017-0191-4
• http://shodhganga.inflibnet.ac.in/bitstream/10603/25204/10/10

chapter%203.pdf

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