Crystallization: Aissms College of Pharmacy, Pune 01

Crystallization
By,
PADVI KALUSING SEGA
(Pharmaceutical chemistry)
Subject: Pharmaceutical Process Chemistry
AISSMS COLLEGE OF PHARMACY, PUNE 01
1
Contents:
Principle
general methods of Preparation of
1)polymorphs,
2)hydrates,
3)solvates and
4)amorphous APIs.
2
Principle:
 Pharmaceutical solids are classified as
thermodynamically stable crystalline and unstable
amorphous forms.
 A crystalline solid can be characterized by the presence
of three-dimensional long-range order.
 However, amorphous solids are characterized by the
presence of random atomic structure and a short range
order of molecules.
 These molecules are randomly oriented in different
directions and show different conformational states.
3
 The fundamental characteristics and trends observed for
pharmaceutical hydrates, solvates and amorphous forms are
presented, with special emphasis, due to their relative
abundance, on pharmaceutical hydrates with single and two-
component (i.e. cocrystal) host molecules. 4
CLASSIFICATION OF SOLIDS
5
6
Polymorphism
Definition:
 A solid crystalline phase of a given compound resulting from
the possibility of at least two different arrangements of the
molecules of that compound in the solid state (W.C.
McCrone, 1965)
or
 When a substance can exist in more than one crystalline state
it is said to exhibit polymorphism (Rosenstein and Lamy,
1969)
7
POLYMORPHS
 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.
8
Occurence of polymorphs
 The existence of more than one crystal form

(polymorphs and/or solvates) is not predictable.
 However, it is not surprising when new crystal forms

are discovered, either by systematic searching, or by
serendipity.
9
 Complex molecules may crystallize in many different
forms.
 At a certain temperature only one crystalline form can

be stable.
 In some cases the metastable forms can be stored for a

long period.
 The crystalline forms can be thermodinamically or

kinetaically favoured.
10
Properties of polymorphs
 Polymorphs show the same properties in the liquid or
gaseous state but theybehave differently in solid state.
1) Melting and sublimation temperature.

2) Vapour pressure
3) Solubility and dissolution rate
4) Stability
5) Optical and electrical property
6) Crystal habit
7) Hygroscopicity
8) Heat capacity
9) Solid-state reaction
10) Conductivity
11) Compression characteristics 11
CLASSIFICATION OF POLYMORPHS
BASED ON THEIR STABILITY
12
TYPES OF POLYMORPHS
13
PREPARATION OF POLYMORPHS
A) Solvent evaporation method
 Saturated solution of drug is prepared.
 If single solvent solution do not yield the desired phase,
mixtures of solvents can be tried.
 Multicomponent solvent evaporation methods depend on
the difference in the solubility of the solute in different
solvents.
 Solvent is removed by evaporation.
 Air drying is done.
14
B) Sublimation:
 On heating approximately two thirds of all organic

compounds are converted partially from the solid to
gaseous state and back to solid i.e. they sublime.
 The sublimation temperature and the distance of the
collecting surface from the material undergoing
sublimation have a great influence on the form and size
of crystal produced
15
C) Crystallization from a single solvent:
 Slow solvent evaporation is a valuable method for

producing crystals.
 solutions of the material being crystallized, preferably
saturated or nearly so are filtered to remove most
nuclei and then left undisturbed for a reasonable
period of time.
16
D) Vapour diffusion:
 In this a solution of the solute in a good solvent is

placed in a small, open container that is then stored in
a larger vessel containing a small amount of a
miscible, volatile nonsolvent.
 The larger vessel is then tightly closed. As solvent
equilibrium is approached the nonsolvent diffuses
through the vapour phase into the solution and
saturation or super saturation is achieved.
17
E) Thermal Treatment:
 Sometimes there is an exothermic peak between
the two endotherms, representing a crystallization
step. In these cases it is possible to prepare higher
melting polymorph by thermal treatment.
F) Crystallization from the melt:

 The cooling of melts of polymorphic substances
often yields the least stable modification which
rearrange to the stable modification in stages.
18
G) Rapidly changing solution pH to precipitate
acidic or basic substances
 Many drug substances fall in the category of slightly
soluble weak acids or bases, whose salt forms are
much more soluble in water.
 Upon addition of acid to an aqueous solution of a
soluble salt of weak acidor alkali crystals often
results.
19
H) Thermal desolvation of crystalline solvates:
 Desolvated solvates has been applied to compounds

that were originally crystallized as solvents but from
which the solvent has been removed by heat and
vacuum.
 There is only small change in the crystal lattice
parameters hence it is called as pseudopolymorphic
solvates.
20
I) Growth in the presence of additives :
 The presence of impurities can have profound effect
on the growth of crystals.
 Some impurities can inhibit growth completelyand
some may enhance the growth.
 J) Grinding:
 Polymorphic transformation have been observed to
occur on grinding of certain materials.
 This transformation require the three steps a)
molecular loosening (nucleation by separation of the
lattice b) solid solution formation c) separation of the
product (crystallization of the new phase).
21
CRYSTAL SOLVATE
 These substances have greater tendency to associate

with solvents.
 Synthetic estrogen ‘ethynylestradiol ’ is crystallized

from the solvent acetonitrile , methanol , chloroform.
22
TYPES OF SOLVATES
23
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
24
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 hydrate or clathrate
25
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)
 Sodium tetraborate decahydrate (borax)

26
 Cobalt (ll) chloride is sky blue in its anhydrous form
and purple in its hydrated form (cobalt (ll) chloride
hexahydrate).
27
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.
28
GAS HYDRATE
 It is made at low temperature and high pressure when

water molecules surround a gas molecule, forming a
frozen mesh or cage.
29
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.
30
AMORPHOUS
 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.
31
METHOD OF PREPARATION OF
AMORPHOUS
A)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.
32
B) Solidification of the melt
 Amorphous solids are often created by rapidly cooling a
liquid so that crystallization nuclei can neither be created
nor grow sufficiently, whereas the liquid then remains in
the fluid state well below the normal freezing point.
C) Reduction of particle size

 Reduction of the particle size of crystalline materials to
the microcrystalline level can yield a material incapable
of exhibiting on x-ray powder diffraction pattern.
33
D) Lyophilisation
 This technique is useful for compounds susceptible

to decomposition in the presence of moisture but
that are more stable as dry solids.
34
E) Removal of solvent from solvate or hydrate:
 Solids can sometimes be converted to amorphous

forms by simply allowing solvent molecules of
crystallization to evaporate at modest temperature.
35
F)Precipitation of acids or bases by change in pH
 If the level of supersaturation is carefully controlled, it

is often possible to avoid crystallization when a water
soluble salt of weak acid is precipitated with a base or
water soluble salt of weak base is precipitated with a
acid.
G) Miscellaneous methods
 In this doping of crystals is done.

36
REFERENCES:
1) Biopharmaceutics and pharmacokinetics by- DM Bhramankar,
Sunil Jaiswal.
2) Pharmaceutical Engineering Unit Operation I; II edition; by
CVS Subrahmanyam.
3) https://owlcation.com/stem/What-is-a-Hydrate-Chemistry
4) https://link.springer.com/article/10.1007/s13203-017-0191-4
5) http://shodhganga.inflibnet.ac.in/bitstream/10603/25204/10/10
chapter%203.pdf
6) Pharmaceutical solvates, hydrates and amorphous forms: A
special emphasis on cocrystals☆ Anne Marie Healy a, Zelalem
Ayenew Worku.
37
Thank you !
38

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Crystallization

Subject: Pharmaceutical Process Chemistry

AISSMS COLLEGE OF PHARMACY, PUNE 01

 When a substance exists in more than one crystalline

 Diamond in a cubic ( tetrahedral lattice arrangement )

 Graphite in sheet of a hexagonal lattice.

 The existence of more than one crystal form

 However, it is not surprising when new crystal forms

 At a certain temperature only one crystalline form can

 In some cases the metastable forms can be stored for a

 The crystalline forms can be thermodinamically or

1) Melting and sublimation temperature.

 On heating approximately two thirds of all organic

 Slow solvent evaporation is a valuable method for

 In this a solution of the solute in a good solvent is

F) Crystallization from the melt:

 Desolvated solvates has been applied to compounds

 These substances have greater tendency to associate

 Synthetic estrogen ‘ethynylestradiol ’ is crystallized

The reaction solution was left at room temperature for 3 days

The needle-shaped crystals were obtained

 The anhydrous form of the substance can absorb water,

 The water is known as the water of hydration or the

 Eg: Magnesium sulphate heptahydrate (Epsom salts)

 Sodium tetraborate decahydrate (borax)

 Hydrate is formed from formaldehyde by the reaction of

 The water molecule splits into H and OH and the the

 It is made at low temperature and high pressure when

Slurry then filtered through a glass filter funnel

Which is then cooled in ice bath, chlorine hydrates are

 No regular arrangement of constituent particles in

 Eg: glass, rubber, plastics, etc.

 Higher thermodynamic energy

 Greater solubility and dissolution rate.

The liquid feed stream first atomized

The particles are dried in air in air stream

Spherical particles of amorphous substances are formed.

C) Reduction of particle size

 This technique is useful for compounds susceptible

 Solids can sometimes be converted to amorphous

 If the level of supersaturation is carefully controlled, it

 In this doping of crystals is done.

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