Crystallization Himel-46 batch

Crystallization

Crystal

A crystal is a solid in which the constituent atoms, molecules, or ions are packed in a regularly ordered
in different dimensions.

 The word crystal originates from the Greek word krystallos meaning clear ice, as it was thought to
be an especially solid form of water. The word once referred particularly to quartz, or "rock
crystal".
 Most metals encountered in everyday life are poly-crystals.

CRYSTALLIZATION

Crystallization is the (natural or artificial) process of formation of solid crystals from a uniform
solution.

 Crystallization is also a chemical solid-liquid separation technique, in which mass transfer of a

solute from the liquid solution to a pure solid crystalline phase occurs.

 Crystallization is a technique which chemists use to purify solid compounds.

History

 Crystallization is one of the primitive unit processes.

 It may be assumed that our ancestors used sodium chloride found in the surface rocks after drying
caused by solar radiation.
 This process is still in use in modern solar ponds.

Applications

 Conversion to the less soluble & most stable polymorph may contribute to the growth of crystals in
suspension formulations.

E.g. Steroids, Sulphonamides, Barbiturates etc.

 The polymorphic form with the lowest free energy will be the most stable & possess the highest
melting point.
 Metastable polymorph provides a means of increasing the solubility, rate of dissolution &
bioavailability of some drugs. E.g. Chloramphenicol palmitate.

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Crystallization Himel-46 batch

 Amorphous powder may also lead to an increase in the solubility of drug.

 The lattice structures of crystalline materials may be altered by the incorporation of liquor
molecule.

Pharmaceutical Importance

 Two polymorphs of spiperone, which is a antipsychotic agent used in the treatment of

schizophrenia.

 Crystalline form of tamoxifen citrate, which is an anti estrogenic & antineoplastic drug used in the
treatment of breast cancer & post menopausal symptom.

 Form-2 of sulfameter, which is an antibacterial agent, is more orally active than form-3.

 Theobroma oil & cacao butter oil, which is a polymorphous natural fat, used in the preparation of
suppositories.

 Carbamazepine, which is used in the treatment of epilepsy, is crystallized from solvents of aliphatic
alcoholes.

 Estrogen ethynylestradiol is crystallized from the solvents acetonitrile, methanol & chloroform
saturated with water, which is essential hormone for development of female characteristics

Principles

 Crystallization is based on the principles of solubility. Compounds (solutes) tend to be more soluble
in hot liquids (solvents) than they are in cold liquids.
 If a saturated hot solution is allowed to cool, the solute is no longer soluble in the solvent and
forms crystals of pure compound.
 Impurities are excluded from the growing crystals and the pure solid crystals can be separated
from the dissolved impurities by filtration.

Process of Crystallization

The crystallization process consists of following two major events:

1. Nucleation & 2. Crystal growth

For crystallization to occur the solution must be supersaturated i.e. the solution has to contain
more solute entities dissolved than it would contain under the equilibrium (saturated solution).

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Supersaturation is the driving force of the crystallization.

The rate of nucleation and crystal growth is driven by the existing supersaturation in the solution.

Supersaturated solutions are allowed to cooling for crystallization

Fig: If the solution is allowed to cool slowly, the

impurities may sit down briefly in the growing crystal
lattice, and eventually pure crystals of orange hexagons
are formed.

Fig: If you cool the solution too quickly, the yellow

triangle impurities are trapped inside the crystals being
formed by the orange hexagons, thus, the crystals
isolated are impure

1. Nucleation
 Nucleation is the step where the solute molecules dispersed in the solvent.
 Start to gather into clusters on the nanometer scale. These stable clusters constitute the nuclei.
 At the stage of nucleation, the atoms arrange in a defined and periodic manner that defines the
crystal structure.

 If the solution contains solid impurities such as dust particles in suspension, they may act as nuclei
centers of crystsllization.

 If the clusters are not stable, they redissolve. Therefore, the clusters need to reach a critical size in
order to become stable nuclei. Such critical size is dictated by the operating conditions
(temperature, supersaturating, etc.)

2. Crystal growth
 The crystal growth is the subsequent growth of the nuclei that succeed in achieving the critical
cluster size.
 Nucleation and growth continue to occur simultaneously while the supersaturation exists.

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Crystallization Himel-46 batch

 Once the supersaturation is exhausted, the solid-liquid system reaches equilibrium and the
crystallization is complete.

 Depending upon the conditions, either nucleation or growth may be predominant over the other,
and as a result, crystals with different sizes and shapes are obtained.

 Control of crystal size and shape constitutes one of the main challenges in industrial manufacturing,
such as for pharmaceuticals.

Defects in crystals

Real crystals feature defects or irregularities in the ideal arrangements critically determine many of the
electrical and mechanical properties of real materials.

Crystal defects

 Vacancy defect  Interstitial defect  Impurity defect

The main values to control the rate of crystal growth are:

 In a continuous crystallization process, a part of the partly grown crystal must always be kept in
suspension.
 In pharmaceutical crystallization process the rate of nuclei formation & the size of crystals must be
carefully controled.
 Supersaturation value, as an index of the quantity of solute available for the growth of the crystal.

 Total crystal surface, as an index of the capability of the solute to fix onto the crystal.

 Retention time, as an index of the probability of a molecule of solute to come into contact with an
existing crystal.

 Flow pattern, again as an index of the probability of a molecule of solute to come into contact with
an existing crystal (higher in laminar flow, lower in turbulent flow)

CRYSTALLIZERS
Tank Crystallizer Agitated Batch Crystallizer Vacuum Crystallizer

A hot, nearly saturated solution is In this Crystallizer water is It is very simple cone-bottomed
run into an open rectangular tank incirculated through the cooling coils vessel without any moving parts.
which the solution is allowed to and the solution is agitated by the
cool & deposit crystals. propellers on the central shift. It may be made of acid resistant
material or be given an acid
No need to seed the tanks, to Agitation increases the rate of resistant lining like rubber.
provide agitation, to accelerate or cooling and keeps the solution at a
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Crystallization Himel-46 batch

to control the rate of more uniform temperature. The feed which is a hot saturated
crystallization. solution enters at a convenient
point into the crystallizer.
Sometimes rods or strings are hung
in the tank to provide the crystal By using highly efficient steam jet
additional surface on which to ejector produce high vacuum. The
grow residue is discharged as a slurry by
the pump.
The crystals are considerably
interlocked, which results in the
occlusion of mother liquor

When the solution has sufficiently

cooled which normally take a
number of days, the remaining
mother liquor is drained off & the
crystals removed manually.
This method is now almost
obsolete
Advantages: Advantages: Advantages:
 Produces larger crystals.  It keeps the fine crystals in  It produce large yields of
suspension which can than crystal.
 Simpler & cheaper prosses grow uniformly without  Minimum amount of mother
forming too large crystals or liquor is left.
aggregates
 It keeps the crystals in
 The product is more uniform in suspension.
size and is finer than the tank
method.
Limitations: Limitations: Limitation:
 Rate of crystal growth is slow.  It is a batch process and the Probability of the solution from
 Needs much labour. capacity is low. reaching the discharge pipe
 The crystals are contaminated without flashing
with impurities.  Materials having less solubility
 It needs more floor space & build up rapid crystals.
 The material is tied up in the
processes for a long time.

Caking of crystal

Caking of Crystal

 Materials produced from heating, drying or crystallisation are caking during storage and
transport to such an extent that quality and handling properties are compromised.
 With this concern, If drugs, made up of crystal, are exposed to temperature & atmospheric
fluctuations may form caking. It's a serious problem that is often met with in handling crystalline
products is their tendency to cake or bind together.
 Susceptible materials: Sugars, salts, acids and other water-soluble materials containing drugs.

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Crystallization Himel-46 batch

Problem creat because of caking

 This is often troublesome in Storage & in large container but it is most serious in small packages.
 It hamper flow ability of product.
 The extent of caking may vary from formation of loose aggregates to solid lumps.

How to prevent caking problem

 Should maintain maximum critical humidity by removing impurities.

 Should maintain fewest possible points of contact in a product.
 Drug should contain uniform crystal with maximum percentage of voids.
 Coating of powdery inert material that can absorb moisture.
 Reducing moisture migration is the most effective way of controlling caking; this can be done in two
ways:
o educing the driving force which leads to moisture migration, i.e. temperature differences,
o reducing the quantity of moisture which is available to migrate

X-ray crystallography

X-ray crystallography is the science of determining the arrangement of atoms within a crystal from the
manner in which a beam of X-rays is scattered from the electrons within the crystal.

Importance of X-ray Crystallography

 X-ray Crystallography is used to determine the structures of molecules and extended solid state
lattices through the analysis of diffraction patterns.
 It gives elemental analysis, bond lengths, bond angles, stereochemistry, intermolecular
contacts, and even absolute configuration . . . in just a few hours!
 X-ray crystallography is useful in identifying known materials, characterizing new materials that
appear similar by other experiments.
 X-ray crystal structures can also account for unusual electronic or elastic properties of a material
or serve as the basis for understanding enzymatic mechanisms and designing pharmaceuticals
against diseases