CRYSTALLIZATION

• Crystallization;
• Crystallization from aqueous, non aqueous solutions;
• Factors affecting crystallization & nucleation;

PRESENTED BY
A B H I M A N Y U AWA S T H I
I M . P H A R M ( P H A R M A C E U T I C A L C H E M I S T RY )
D E P T. O F P H A R M A C E U T I C A L C H E M I S T RY
CONTENTS
..TOPICS
COVERED

CRYSTALLIZATION

CRYSTALLIZATION FROM AQUEOUS &

NON AQUEOUS SOLUTION

FACTORS AFFTECTING
CRYSTALLIZATION

FACTORS AFFTECTING NUCLEATION

 CRYSTALLIZATION
• Crystallization may be defined as a phase change in which a crystalline product is obtained
from a solution. A solution is a mixture of two or more species that form a homogeneous
single phase.

• Crystallization is a chemical solid–liquid separation technique, in which mass transfer of a

solute from the liquid solution to a pure solid. The process involves inducing the formation of
crystals through controlled cooling or evaporation of a solution or melt, with the resulting
solid crystals being pure than the starting material.

• Crystallization is a process in which a substance (solute) dissolved in a liquid (solvent) is

allowed to form crystals by cooling or evaporating the solution, resulting in the separation of
the solute from the solvent.

• The process is based on the principles of solubility and supersaturation and is widely used in
chemistry for the purification, isolation, and characterization of substances.

• Crystal is defined as a solid particle, which is formed by the solidification process in which
structural units are arranged by a fixed geometric pattern or lattice.
CRYSTALLIZATION PROCESS THERMODYNAMIC
STABLE
SUPERSATURATION
Supersaturation is a state in which a solution contains more solute
than it would normally dissolve at a given temperature and pressure.
In other words, the solution is metastable and has a higher
concentration of solute than its saturation point.

NUCLEATION
This is the initial step where a few molecules come together to form
a tiny solid cluster or nucleus. The formation of the nucleus is the
most critical step in crystallization because it determines the size
Fig. 1 - Crystal Lattice and shape of the final crystal.
Chlorine

CRYSTAL GROWTH
Once the nucleus is formed, more molecules attach to the surface
of the nucleus and build up the crystal. The growth rate of the
crystal depends on factors such as temperature, concentration, and
the rate of diffusion of the molecules.

Sodium AGGLOMERATION
THERMODYNAMIC
This step involves the aggregation of smaller crystals to form larger
UNSTABLE
crystals which are thermodynamic stabled.
 CRYSTALLIZATION FROM AQUEOUS
SOLUTIONS.
Aqueous solutions are commonly used to crystallize inorganic salts, organic acids, and some organic compounds. The
general steps for crystallization from an aqueous solution are as follows:

• Dissolve the compound in a minimum amount of hot solvent.

• Filter the hot solution to remove any insoluble impurities.
• Allow the solution to cool slowly to room temperature, which will cause the compound to crystallize out.
• Collect the crystals by filtration and wash them with a small amount of cold solvent.

The slow cooling process is essential because it allows for crucial large, well-defined crystals. Small, poorly-formed
crystals may result if the solution is cooled slowly.

aqueous solvents- water.

CRYSTALLIZATION FROM NON
AQUEOUS SOLUTIONS.
Non-aqueous solvents are commonly used for the crystallization of organic compounds that are insoluble or
poorly soluble in water. The general steps for crystallization from a non-aqueous solution are as follows:

• Dissolve the compound in a minimum amount of hot solvent.

• Add a small amount of a different solvent that will cause the compound to precipitate out of solution.
• Allow the solution to cool slowly to room temperature, which will cause the compound to crystallize out.
• Collect the crystals by filtration and wash them with a small amount of cold solvent.

The choice of solvent is important, as it can affect the properties of the resulting crystals. Common non-aqueous
solvents include ethanol, methanol, acetone, and diethyl ether.
FACTORS AFFECTING CRYSTALLIZATION
1. PRESENCE OF ANOTHER SUBSTANCE PRESENCE OF ANOTHER
2. SOLVENT SUBSTANCE
3. NUCLEATION
PRESENCE OF ANOTHER SUBSTANCE IN
4. CRYSTAL GROWTH
MOTHER LIQUOR:
5. TIME
• 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.

• Both types of crystals belong to the cubic

crystal form but differ in habit.
SOLVENT CONSIDERATIONS: NUCLEATIO
N
• Moderate solubility is best (avoid
• Crystals initially form via
supersaturation).
“nucleating events”.
• Like dissolves like.
• After a crystallite has nucleated it
must grow.
• Hydrogen bonding can help or hinder
crystallization.
• Nucleation sites are necessary.
• Presence of benzene can help crystal
• Excess nucleation sites cause
growth.
smaller average crystal size.
• Avoid highly volatile solvents.

• Avoid long chain alkyl solvents can be

significantly disordered in crystals.

• Choose solvents with “rigid geometries”.

 CRYSTAL GROWTH: TIME:
• Crystals grow by the ordered
deposition of the solute molecules
onto the surface of a pre-existing • Quality crystals grow best over time in
crystal. near equilibrium conditions.

• Crystal growth is facilitated by the • The longer the time, the better the crystals.
environment changing slowly over • Faster crystallization is not as good as
time. slow crystallization.

• Keep crystal growth vessel away from • Faster crystallization higher chance of
sources of mechanical agitation (e.g. lower quality crystals
vibrations).

• Set-up away from vacuum pumps,

rotovaps, hoods, doors, drawers, and
soon.

• Leave samples alone for 1 week, don't

“check in” with it. Your crystals are not
lonely.
NUCLEATION
Two common types of nucleation mechanisms

• Primary nucleation:

Homegeneous: occurs at the onset of crystallization,

when the concentration of the solvent exceeds the
metastable region.
Heterogeneous:occurs when solid particles of foreign
substances cause an increase in the
rate of nucleation.

• Secondary nucleation: is caused by contacts between a crystal

and another surface, and occurs within the metastable region
(difficult to scale up).

Two step nucleation theory

Classical nucleation theory

FACTORS AFFECTING NUCLEATION

Several factors influence these processes:

• The supersaturation

• The rate of cooling

• The degree of agitation

• The presence of impurities.

REFERENCES
• Black, S. (2019). Crystallization in the Pharmaceutical Industry. In A.
Myerson, D. Erdemir, & A. Lee (Eds.), Handbook of Industrial
Crystallization (pp. 380-413). Cambridge: Cambridge University Press.
doi:10.1017/9781139026949.013

• Melia, T., & Moffitt, W. (1964). Crystallization from aqueous solution.

Journal of Colloid Science, 19(5), 433-447. https://doi.org/10.1016/0095-
8522(64)90043-1

• Bentley Textbook of Pharmaceutics, Eighth edition, edited by E.A Rawlins,

chapter 25 and 26, page 347-350, 351.

• Pharmaceutical Practice, Fourth Edition, edited by Arthur J. Winfield, Judith

Rees and Smith, Chapter 25. •Handbook of Pharmacy, Embracing the theory
and the practice of pharmacy and Art of Dispensing (1894), page 352.
Thank you!
ANY QUESTIONS?