15 crystallization

Crystallization
 Crystallization is a separation and purification technique
employed to produce a wide variety of materials.
 Crystallization is the process by which molecules or atoms
arrange themselves into definite geometrical patterns called
crystals.
 During crystallization, phase change takes place in which a
crystalline product is obtained from a solution.
 Importance of crystallization
1. Purification.
2. Improvement of flowability.
3. Improvement of stability.
4. Enhancement of filtration and washing.
5. Decrease of caking.
6. Improvement of appearance.

Crystallization from solution
Consists of 3 steps:
a. Induction of super saturation.
b. Nucleation.
c. Crystal growth.
A] Methods of induction of super saturation:
1. Cooling:
 Suitable for substances whose solubility increases with
temperature.
 It is common with inorganic salts such as KNO3 and NaNO3.
2. Solvent evaporation:
 Suitable for substances whose solubility is independent of
temperature.
 It is common with salts such as NaCl and calcium acetate.

3. Adiabatic evaporation:
 Suitable for thermolabile substances.
 It involves maintaining low pressure in a chamber
containing solution which will begin to evaporate to
balance lost pressure.
4. Addition of a third substance:
a. It has a higher affinity to the solvent, which will
result in ↓ solubility of solute in solvent  salting out.
b. It forms a precipitate by reacting with the solute
c. It changes the pH of the solution, resulting in the
precipitation of the solute.

B] Nucleation
Mier's Theory:
1. A solution with temperature and concentration A is
saturated by: a. cooling to temperature B
b. increasing its concentration to C by evaporation.
Upon further cooling or evaporation, super-saturation occurs.
2. In the metastable region (BB' or CC), there is no
spontaneous nucleation.
Crystallization requires the addition of external nuclei.
3. Upon further cooling or evaporation, the metastable
region is exceeded and spontaneous nucleation occurs.

C] Crystal Growth
The rate of crystal growth in a solution depends on:
1. Concentration gradient for transfer of solute from bulk of
liquid towards the crystal face.
2. Temperature gradient for deposition of heat of
crystallization at crystal face.
* Heat of crystallization:
Is the heat evolved or absorbed when 1 mole of a substance crystallizes.
3. Relative velocity (rotation speed) between solid and liquid.

Crystal Size
1. Fine Crystals are produced by:
 Rapid cooling and frequent agitation  a high
nucleation rate and slow rate of crystal growth.
 The obtained crystals are cohesive, form a cake and
are difficult to wash.
 The purity is generally less than medium or large size
crystals
2. Medium Crystals are produced by:
 Slow cooling without mechanical agitation.

3. Very Large Crystals are produced by:
(i) allowing large volume of solution to evaporate
spontaneously or
(ii) slow controlled cooling of the solution in the
reaction vessel.
 Crystal growth occurs more slowly and
subsequent filtration and washing results in the
formation of perfectly pure crystals.
 For large crystals to grow, the solution should
be perfectly clear by filtration and kept in a dust-
free environment.
The formation of large crystals may be
facilitated by seeding.

Factors affecting crystallization
process
1. Temperature
↑ temperature  ↑ or ↓ solubility of the solute.
KCl04 (potassium chlorate) possesses a large positive temperature
coefficient of solubility (↑ temperature  ↑ solubility).
It crystallizes by cooling of a saturated solution.
NaCl possesses a very small temperature coefficient of solubility.
Crystallization by cooling is not effective. Crystallization by solvent evaporation.
Sodium hydrogen phosphate and ferrous sulphate show changes in the
stable form of the material with temperature.
Crystallization of FeSO4< 50°C results in the formation of (FeSO4.7H2O)
At higher temperature yield FeSO4.4H2O or anhydrous FeSO4.

2. Presence of Impurities:
Adsorption of impurities on the surface of the nucleolus or
crystals may:
a. retard rate of nucleation and crystal growth
(0.1% HCl prevents the crystal growth of NaCl crystals).
b. result in crystal shape modification
(e.g. crystallization of NaCl in presence of urea form octahedral
instead of cubic crystals)
3. Nuclei Formation Versus Crystal Growth:
Growth rate is the increase in size per unit time.
Nucleation rate is the number of new crystals produced per
unit time.
At low super-saturation, growth predominates.
At higher super-saturation, nucleation predominates.

4. Effect of Agitation:
 Initially, it increases crystal growth rate by:
1. ↑ heat transfer rate by ↓ thermal resistance of the boundary
layer.
2. ↓ thickness and diffusional resistance of the boundary
layer.
 At certain point, no more increase in crystal growth rate
occurs.
Mother liquor
 The liquid remaining after a crop of crystals is obtained,
(generally subjected to further concentration to form crystals).
* The process is repeated until recovery of all of the dissolved
substances.
* Crops of crystals obtained by concentration of the mother
liquor are less pure than the 1st crop and require re-
crystallization.

A] Cooling Crystallizers
1. Oslo cooler crystallizer
 Supersaturation is produced in
one part of the crystallizer and is
released in another.
 The hot concentrated solution is
fed into the cooler, where super
saturation to the metastable
region occurs but without
crystallization.
 A pump circulates the solution
from the cooler to the tank.
 The supersaturated solution
passes through the control pipe to
the bottom of the crystallizer
containing a bed of seeds (act as
nuclei) where crystallization and
crystal growth occurs.

 Large crystals are collected from the bottom of the crystallizer
by Hydraulic classification.
 Small crystals are formed at a higher level of solution and are
removed by the cyclone separator.
 The mother liquor re-enters the crystallizer with the hot
incoming feed and the operation is repeated.
Advantages of Oslo cooler crystallizer
1. Smaller crystals can be separated from large ones.
2. No precipitation takes place in the cooler
3. Can be operated in batch & continuous modes.
4. High capacity.
5. Used to crystallize salts with a +ve temperature coefficient,
e. g. NaNO3, NaClO3, KCl03 and NH4Cl
Process Control Parameters:
1. Feed rate.
2. Feed temperature.
3. Heat removal in the cooler.

2. Howard Crystallizer It is a vertical conical device
through which the solution
flows in an upward direction.
 Cooling is used to achieve
super-saturation at which
stage nucleation occurs.
 Nuclei grow as they move
upward until their size is just
enough to overcome gravity.
 At this point, the crystals
settle with a uniform size.
 The crystal size is controlled
by feed velocity.

Oslo Evaporative Crystallizer
 The solution is fed and
heated by the heater, followed
by flashing the solution in the
flashing head to lose part of its
solvent as vapor and become
supersaturated.
 The supersaturated solution
falls down a central pipe and
up through a screen to the bed
of crystals that is suspended in
the crystallization chamber.
B] Evaporative Crystallizers

 The solution gets in contact with the
suspended crystals for crystallization and
crystal growth to occur.
 Large crystals are discharged from the bottom
 Fine crystals recirculate with the feed solution.
 This method is rapid and produces small uniform
crystals.
 It can be used for materials with zero or negative
temperature coefficient.

C] Vacuum Crystallizers
 They achieve super saturation by adiabatic
evaporation and cooling.
 A hot concentrated solution enters a chamber
(kept at a low pressure), the solution begins to
evaporate to balance lost pressure.
 The latent heat of evaporation will be taken
from the solution itself, which in turn becomes
cold and supersaturated without external heat
transfer.

Oslo vacuum crystallizer
Used for thermolabile
materials.
 Has similar design to oslo
evaporative crystallizer,
but without a heater.
Advantages:
a. Absence of heated head
make it of low cost.
b. Absence of cooling
medium prevents the
surface corrosion.

Separation of a Mixture by
Extraction: Crystallization

Objectives
 Separation of a mixture containing an
acidic and a neutral compounds by
extraction.
 Purification of the solid component by
crystallization.
 Identify those components from its IR
spectrum and its melting point.

Terms
 Separation
 Extraction
 Crystallization

Separation
Why we need to separate mixture??
 To isolate or concentrate components
from a mixture.
 To separate a components from other
species that would interfere in the
analysis

Methods of Separation
 Extraction
 Crystallization
 Distillation
 Chromatography

Extraction
 Extraction: Transfer of a solute from one
phase to another.

Types of Extraction
 Can use most any combination of
phases (solid, liquid, gas, supercritical
fluid).
 Solid – Liquid
- Useful for the isolation and
purification of naturally occurring
sources.

Extraction
 Making coffee is an example for extraction.

Extraction
 Liquid – Liquid
- More common method
- Depend on solubility properties of
components.
Like dissolves like
- So ideally, the extracting solvent
should be similar to the solute.

Extraction
 We will use two
immiscible liquids.
- Typically aqueous /
organic solvent combos

Extraction
 Organic solvents less dense than water.
- Diethyl ether, Toluene, Hexane
 Organic solvents more dense than
water.
- Dichloromethane, Chloroform and
Carbon tetrachloride.

Qualities of the Solvent
 Immiscible with other solvent.
 It should readily dissolve the compound
to be extracted.
 It should dissolve little or none of the
unwanted compounds / impurities.
 Easily separated from the compound.
 Should not undergo any reaction with the
compounds.

Extraction
 Equilibrium constant for this partitioning
is K (partition coefficient or distribution
coefficient)
K=
[S]2
[S]1

Extraction
 Chemically Inert Extraction.
 Chemically Active Extraction.

Chemically Active Extraction
 A reagent that reacts chemically with the
substance to be extracted.
 Solubility property changes after the
reaction.

COOH
COONa
Soluble in Diethyl ether
& Insoluble in Water
10 % NaOH
Soluble in Water & Stay in aqueous layer
10 % NaOH
No Reaction
& Stay in ether
layer

NO2
CH2NH2
CH2NH3+
Soluble in Diethyl ether
& Insoluble in Water
10 % HCl
Soluble in Water & Stay in aqueous layer
10 % HCl
No Reaction
& Stay in ether
layer

Procedure for Today’s Lab
 Get your unknown mixture.
 Transfer all your unknown into a 100 mL
beaker and find the mass of your
unknown.
 Add 30 mL of diethyl ether, stir slowly to
dissolve the mixture.
 Add 15 mL more of diethyl ether and
rinse the beaker.

Procedure for Today’s Lab
 Add 15 mL of 5 % sodium bicarbonate to
the ether solution.
 Swirl the separatory funnel first and
shake gently.
 Separate the two layers.
 Repeat these steps two times using
fresh 5 % sodium bicarbonate solution.
 Pool all the aqueous layers i.e. sodium
bicarbonate solution

Recovery of Acidic Compound
 Cool all the aqueous extracts for about 5
minutes in an ice – water bath.
 Add 3 mL of concentrated hydrochloric
acid.
 Test the acidity of this solution with blue
litmus paper (TURN RED).
 If it is not acidic enough; add 1 mL of
acid more.

Recovery of Neutral Compound
 Place a small piece of cotton in a dry
glass funnel.
 Keep a fresh and dry Erlenmeyer Flask
under the funnel.
 Add 5g. of anhydrous sodium sulfate
over the cotton plug and transfer all the
ether layer carefully through the neck.

Recovery of Neutral Compound
 Rinse the separatory funnel with 5 mL of
ether pour into drying agent.
 Add few boiling chips and keep on a
steam bath.
 Cork the flask tightly once all the ether
has gone.

Recrystallization
 It’s a technique to purify the solid organic
compounds.
1. Slow evaporation
2. Slow cooling
3. Liquid diffusion
4. Use of seed crystal

Recrystallization
 Compound to be purified:
1. Moderate or high solubility in hot solvent
2. Low in cold solvent
 Impurities:
1. Insoluble in hot solvent or high soluble in
cold solvent.
 Easily removed after crystallization.
 Should not react with substance being
purified.

Procedure for Recrystallization
 Dissolve all the acidic compound in
minimum amount of hot solvent.
 Filter the solution when it is hot.
 Slowly cool the solution to room
temperature; then keep on ice bath.
 Filter the crystals, wash it with minimum
amount of cold solvent.
 Allow to dry on its own.

Characterization
 Neutral Compound
1. Find the amount of neutral
compound you recovered from
the mixture.
2. Obtain its IR spectrum.
 Acidic Compound
1. Calculate the % of recovery.
2. Find its melting point.

Changes
 Use Blue Litmus instead of Congo
Red.

Notes
 Do not forget to add the boiling chips
when you evaporate diethyl ether.
 Vent the separatory funnel very often to
relieve the developed pressure.

Caution
NO FLAMES IN LAB TODAY

 Define the following terms:
[Crystallization, Nucleation, etc]
Respond to the following questions:
Give a detailed account of ………………
Explain in details the process of …………..
Describe in details with examples the…………
With examples, illustrate the pharmaceutical applications of ……………

Group work discussional questions:
Explain in details the process of………
Describe with examples in details the…………..
With examples, illustrate the pharmaceutical applications of…….

15 crystallization

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15 crystallization