PHYSICOCHEMICAL PROCESSES

a. Precipitation: Process of precipitation and its applications in Pharmacy.

b. Crystallization: Types of crystals, Mechanism and methods of crystallization
and its applications in Pharmacy.
c. Distillation: Simple, fractional, steam distillation, vacuum distillation,
destructive distillation and their applications in Pharmacy.
d. Miscellaneous Processes: Efflorescence, deliquescence, lyophilization,
elutriation, exsiccation, ignition, sublimation, fusion, calcination, adsorption,
decantation, evaporation, vaporization, centrifugation, desiccation, levigation
and trituration
MISCELLANEOUS
PROCESSES
1. Levigation 9. Sublimation
2. Trituration 10. Fusion
3. Elutriation 11. Desiccation
4. Efflorescence 12. Adsorption
5. Exsiccation 13. Ignition
6. Deliquescence 14. Calcination
7. Decantation 15. Centrifugation
8. Evaporation 16. Lyophillization
 1. LEVIGATION
• The process of levigation is also known as wet grinding.
•It is a method of particle size reduction.
• In this method the particle size of a substance is reduced to fine state by
triturating the substance with a few drops of liquids to which it is insoluble, in a
mortar with the pestle or on a slab with spatula.
• Commonly used levigating agents includes mineral oils and glycerin.
 Most commonly used in incorporation of solid into semisolids e.g. ointments,
creams.

Incorporation of drug by levigation:

 Small Scale: tile & spatula and pestle & mortar are used where the drug material
is first levigated with small amount of vehicle to form concentrate, which is then
diluted geometrically with the remaining base.
 Large Scale: mechanical mixers are used where the drug in finely divided form is
added to vehicle contained in a rotating mixer, the mixture is ultimately passed
through a roller mill to get uniform product
 LEVIGATION
Uses
Can be use to incorporate solid substances into:

1. dermatological preparations
2. ophthalmic ointments
3. suspensions
 2. TRITURATION
“The pharmaceutical process of reducing the particle size of powders with a
mortar and pestle to produce fine powders”
OR
“Process for reducing particle size of a substance by grinding”
 Trituration is achieved by firmly holding the pestle and exerting a downward
pressure with it while moving it in successively larger concentric circles.
 2. TRITURATION
The term trituration is also applied to dilution of a potent substance with inert
substance like lactose.
Geometrical dilutions or geometric mixing technique is used to mix potent drug
powder with bulk substance (substance in larger quantity).
Small amount of substance in greater amount is mixed with whole of potent
substance. The substance in large amount is then gradually added and then
subsequently increased till whole of the inert substance is used.
 LEVIGATION TRITURATION

1. Levigation is wet grinding 1. Trituration is dry grinding.

2. Levigation is the process of reducing 2. Triturate is the continual rubbing of
the particle size of a solid by a solid in a mortar with a pestle to
triturating in a mortar with a small reduce particle size to a degree of
amount of liquid or melted base fineness
 3. ELUTRIATION
Elutriation is a process for separating particles based on their size, shape and density,
using a stream of gas or liquid flowing in a direction usually opposite to the direction of
sedimentation.
Elutriation is the process of separating substances in powders of different degree of fineness by
stirring the substance with large volume of liquids in which it is insoluble and withdrawing the
liquid at different heights.
Elutriation is the process in which the particles of the fluid move in a direction opposite to that
of the sedimentation i.e. the particles move vertically downwards while the fluid moves
vertically upwards”
•Explanation:
•If the velocity of the fluid is less then the setting velocity of the particles, then the
particles will move downward against the stream of fluid.
•If the setting velocity of particles is less then the velocity fluid, the particles will
move upward.

•“In other words small size particles will move upward while the large
size particles will move downward. “

•By varying fluid velocities, the sample may be separated in various fractions.
Hence, the particles size can also be measured by this process.
• So Elutriation is the process of separation of fine particles from course particles.
 ELUTRIATION
• Elutriating tanks can be used (taps placed at intervals for desired
collection)
Uses of Elutriation
Chalk and calamine are produced by this method.
Heavy and light Kaolin can be separated by this process, because the
particles of heavy Kaolin move downward and those of the light Kaolin
move upward.
Kaolin (hydrated aluminum silicate) is a type of naturally occurring clay, acts as
drying agent in topical skincare products and used in pharmaceutical preparations
as a filtering agent to clarify liquids.
 4. EFFLORESCENCE
“Efflorescence is the loss of water of crystallization from the hydrated substances
into the atmosphere so that an equilibrium is formed between the hydrated
substance and the surrounding atmosphere” 

• The large no of chemical compound exist in hydrated form. In hydrated form the
water molecule attached to the compound are called the water of crystallization.
(e.g. CuSO4.5H2O) The surrounding atmosphere also has vapours and definite
vapour pressure, due to water in atmosphere.
•If the vapour pressure of the hydrated substance is greater than the surrounding
atmosphere, than the hydrated substance loses water molecule to become less
hydrous and to make an equilibrium between the hydrated substance and the
atmosphere. This phenomenon is known as efflorescence.
 EFFLORESCENCE
Example: Sodium carbonate (Na2CO3.10H2O)
The process can lead to product instability or deterioration.
Prevention
Efflorescence or loss of water of crystallization can be prevented by the following ways:
1. Use of containers that prevent loss of water
2. By closing the container immediately after use.
3. By filling the container completely so that no space for air storage is available above the liquid
in the container. 
4. Storing in a cool place
 5. EXSICCATION
• Rate of efflorescence increases with rise in temperature
“The process of accelerating the rate of efflorescence by increasing
the temperature in order to remove water of crystallization from a
hydrated salt”
Exsiccation = controlled and accelerated efflorescence
Example: In case of Copper sulfate (CuSO4. 5H2 0)
 EXSICCATION
Applications
1. Exsiccation is done to get an anhydrous product required in the formulation
of certain medicaments.
2. It is also carried out to reduce the bulk and weight of certain drugs so that
they can be easily administered.
Generally on exsiccation a fine powder of the substance is obtained. 
 6. DELIQUESCENCE
• Deliquescence is a reverse of efflorescence.
• If a hydrated substance has a lower vapour pressure, than the surrounding
atmosphere than the water molecule transfer from the atmosphere to the less
hydrated substance to make them more hydrated and to produce a equilibrium.
This phenomenon is called deliquescence.
Example: Sodium hydroxide (NaOH)
 DELIQUESCENCE
“A material takes up water vapors from the atmosphere and converted to more
hydrated form (eventual formation of a liquid phase i.e. a solution)”
Hygroscopic substance: these substances remain in solid form even after taking up of water vapors

Prevention of Deliquescence:
1. By closing the container immediately after using it
2. keeping the product in “well-closed containers”
3. By filling the container completely so that no space for air storage is available above the liquid in the container.
4. By placing the dehydrating agent in containers of susceptible products e.g: Silica gel packets to absorb water. 
Anhydrous cobalt chloride (indicator with silica gel) changes its color from blue to pink when silica gel has
adsorbed maximum amount of water vapors.
 7. DECANTATION
“Decantation is a process for the separation of mixtures by removing a top layer of
liquid from which a precipitate has settled”
 Method
• Method consists of allowing the slurry to stand in a suitable vessel until the solids settle
down at the bottom.
• Now carefully pouring a solution from a container in order to leave the precipitate
(sediment) in the bottom of the original container.
• Usually a small amount of solution must be left in the container, and care must be
taken to prevent a small amount of precipitate from flowing with the solution out of the
container.
• It is generally used to separate a liquid from an insoluble solid (e.g. in red wine, where
the wine is decanted from the potassium bi tartrate crystals).
 DECANTATION
•Removing of clear liquid from top is decantation and settling of solids at bottom is called
sedimentation
•Separation of liquid from any other immiscible liquid can also be done by decantation.
• Example:
1. The oil and water extracted from olives may be decanted to obtain the olive oil.
2. A mixture of kerosene and water can also be separated through decantation
 VAPORIZATION
“Vaporization of an element or compound is a phase transition from the liquid
phase to gaseous phase”

Liquid Gaseous phase

In this process, the molecules of liquid in a closed container continually leave
the surface and go into the free space above it.
 8. EVAPORATION
“Evaporation is a phase transition from the liquid phase to gas phase that
occurs at temperatures below the boiling temperature at a given pressure”
 Note: evaporation usually occurs on the surface.
Evaporation is a slow process and can take place even at room temperature.
Evaporation takes place at all temperatures and is maximum at boiling point of
a substance.
Boiling is a phase transition from the liquid phase to gas phase that occurs at
or above the boiling temperature
Note: boiling occurs below the surface (from whole of liquid).
 8. EVAPORATION
Factors effecting Evaporation:
1. Temperature (direct)
2. Surface area (direct)
3. Agitation (direct; to remove scum layer)
4. Atmospheric aqueous vapor pressure (indirect)
5. Atmospheric pressure on the liquid under evaporation (indirect)
6. Selection of apparatus and method for evaporation depends upon the type of product required
(for liquids or dry products, use evaporating pans)
7. Economic factors should be taken under consideration when selecting a method and apparatus
for evaporation
9. SUBLIMATION
 9. SUBLIMATION
“A process in which, on heating, the solid gets converted directly to vapors without
intermediate formation of a liquid state and on condensation, the vapours get
converted back to the solid state.”
• The product obtained is called sublimate.
• No specific apparatus required, can be done by using simple lab apparatus like china
dish, a perforated filter paper, funnel and a plug of cotton.
Applications:
1. To purify many pharmaceuticals e.g. iodine, sublimed Sulphur etc.
2. Used in manufacturing of iodine, ammonium chloride, naphthalene
3. Also used to purify volatile solids with non-volatile impurities
 10. FUSION
“The process in which solid gets converted into liquid without adding any
solvent”
OR
“Process of heating the solids until they melt”
Applications:
1. To purify certain solids and semi solids e.g. hard paraffin, wool fat, bees wax
2. For the Preparation of ointment (substances with high melting point should
be melted first to prevent overheating of the remaining substances)
 11. DESICCATION
“Process of removing of adhere moisture from liquid or solid substance”
The term “desiccated” is applied for substances from which water has been completely
removed.
Commonly used Desiccating agents: silica gel, concentrated sulphuric acid, anhydrous
calcium chloride, phosphorous pentoxide
On lab scale, desiccation is carried out is Desiccator which are tightly closed glass vessels
containing a drying agent at its bottom which absorbs moisture from the substance being
desiccated.
The substance to be dried is placed in a china dish (petri dish) in a desiccator, above the
surface of drying agent.
A vacuum pump may also be connected to desiccator
Silica gel packs are placed in the bottles of moisture sensitive tablets and
capsules where silica gel acts as desiccant.

Applications:
1. Helps in preservation of animal and vegetable drugs which get destroyed in
the presence of moisture
2. Facilitates in grinding of drugs (as grinding of wet drugs is difficult)
3. Stability of drugs can be enhanced
4. Reduction in the bulk and weight of substances
 13. IGNITION
“The process in which an organic substance is strongly heated until
whole of the carbonaceous matter burns and an inorganic residue
known as ash is left behind”
The process is also called ashing or incineration
Ash limit test
There is a specific limit of compounds from which it should not exceed, the limit
is known as overall ash limit
 14. CALCINATION
“Process in which the inorganic substances are strongly heated so
as to remove their volatile contents and get a fixed residue”

Lab scale: calcination is done in silica or platinum Crucibles

Industrial scale: Metallic vessels
Calcination is used in preparation of certain inorganic substances like calcium oxide,
zinc oxide, red mercuric oxide, heavy magnesium oxide
 15. CENTRIFUGATION
The separation of the different substances from the solution on the basis of their
density gradient in a centrifuge is called centrifugation.
Centrifugation is a process that involves the use of the centrifugal force for the
separation of mixtures, used in industry and in laboratory settings.
Apparatus for centrifugation (Centrifuges):
Container is the most important part of centrifugation apparatus i.e. Centrifuges.
This container is used for the placement of a mixture or solution of solid and liquid or
of a solution of two liquids.
This container is then rotated at greater speed resulting in the separation of the
ingredients of the mixture takes place by the use of centrifugal force.
 15. CENTRIFUGATION
Principle: 
When a mixture of two components is rotated in a centrifuge the component of
mixture separates out as a result of centrifugation or rotation under the action of
centrifugal force. The component of lower density will float at the surface while
the components of higher density will precipitate at the base.
•More-dense components of the mixture migrate away from the axis of the
centrifuge, while less-dense components of the mixture migrate towards the
axis.
 15. CENTRIFUGATION
•The precipitate ("pellet") gather on the bottom of the tube. The remaining solution is
called the "supernate" or "supernatant liquid".
• The supernatant liquid is then either quickly decanted from the tube without
disturbing the precipitate, or withdrawn with a Pasteur pipette.
•The rate of centrifugation is specified by the acceleration applied to the sample,
typically measured in revolutions per minute (RPM).
Factors affecting centrifugation:
Centrifugation is basically affected by centrifugal effect.
The nature of the liquid medium in which the particles are placed also affects the
centrifugation.
 15. CENTRIFUGATION
Types:
There are two types of centrifugation
 Sedimentation:
The basic principle, in the sedimentation type of centrifuges, is difference in the densities
of the ingredients of the mixture. In these types of centrifuges, the particles are settled to
the wall by the action of the centrifugal force.
These types of centrifuges are used for the separation of ingredients of the mixture of solid
in liquid as well as liquid in liquid.
Two types of centrifuges are based on the principle of sedimentation:
1. Bottle centrifuge
2. Disc type centrifuge
 15. CENTRIFUGATION
 Filtration:
These types of centrifuges are used for the separation of the mixture of solid
in liquid only performing the operation similar to the filtration process. These
are also sometimes referred to as clarifiers.
Centrifuge based on the principle of filtration is “Basket centrifuge”.
 15. CENTRIFUGATION
Applications:
used for the separation of two miscible substances
usually used for separation of mixture where filtration is difficult i.e. separation
of liquids
Separation is more rapid using centrifuge
Stability check of emulsions
SUBLIMATION
 SUBLIMATION
“A process in which, on heating, the solid gets converted directly to vapors without
intermediate formation of a liquid state and on condensation, the vapours get
converted back to the solid state.”
• The product obtained is called sublimate.
• No specific apparatus required, can be done by using simple lab apparatus like china
dish, a perforated filter paper, funnel and a plug of cotton.
Applications:
1. To purify many pharmaceuticals e.g. iodine, sublimed Sulphur etc.
2. Used in manufacturing of iodine, ammonium chloride, naphthalene
3. Also used to purify volatile solids with non-volatile impurities
Triple point:
The triple point is the point possessing a fixed pressure and temperature at
which the solid, liquid and gaseous phases of a material are able to co-exist
independently. 

If the vapor pressure over the solid substance is more than that of the triple
point, the solid will convert to vapor after passage through the liquid phase.
The following phase diagram will help to understand the triple point.
Line OA: 
In this diagram, line OA shows the melting points of the solid substance at different pressures. In
this line, left side shows the existence of solid form while the right side shows the existence of
liquid form. This line shows the points of co-existence of the solid and the liquid.
Line OB:
The line OB shows the vapor-pressure curve of the liquid at different temperatures. Above this
line liquid phase exists and below this line vapor phase of the substance exists. This line shows
the points of co-existence of the liquid and the vapors.
Line OC:
The line OC shows the sublimation curve of the solid. This line shows the points of co-existence
of the solid and the vapors at different states of temperatures and pressure.
Point O:
In this diagram, the point O represents the triple point.
Enthalpy:
Enthalpy of sublimation is equal to the sum of enthalpy of fusion and enthalpy of vaporization.
some of the chemical substances such as compounds and elements at certain
pressures go directly from solid state to the gaseous state.
 This occurs when the atmospheric pressure applied on the material is very less
to inhibit the molecules from going out of the solid state i.e. a substance go
through the process of sublimation only if the vapor pressure is less than that of
the triple point for that substance. This is called true sublimation.
Sublimation is used to create freeze-dried substances, for example tea, soup
or drugs in a process called lyophilization, which consists of freezing a solution
or suspension and heating it very slowly under medium to high vacuum.
 16. LYOPHILIZATION
Lyophilization or Freeze-drying is a process of drying in which water is
sublimed from the product after it is frozen. This is also known as sublimation
drying.
As the dried product has great affinity for water (lyophilic – liquid loving)
therefore this process is also known as lyophilization.
In this process the liquid is first frozen to ice before application of vaccum,
then sublimation of frozen ice is carried out under reduced pressure.

 Removal of water from frozen solution is called freeze-drying

 16. LYOPHILIZATION
PRINCIPLE:
The main principle involved in freeze drying is a phenomenon called
sublimation, where water passes directly from solid state (ice) to the vapor state
without passing through the liquid state.
Sublimation of water can take place at pressures and temperature below triple
point i.e. 4.579 mm of Hg and 0.0099 degree Celsius.
The material to be dried is first frozen and then subjected under vacuum to
heat so that frozen liquid sublimes leaving only solid, dried components of the
original liquid.
 16. LYOPHILIZATION
The fundamental processes involved are:
1. Freezing: The product is frozen. This provides a necessary condition for low
temperature drying.
2. Vacuum: After freezing, the product is placed under vacuum. This enables the
frozen solvent in the product to vaporize without passing through liquid phase, a
process known as sublimation.
3. Heat: Heat is applied to the frozen product to accelerate sublimation.
4. Condensation: Low-temperature condenser plates remove the vaporized
solvent from the vacuum chamber by converting it back to a solid. This
completes the separation process.
 16. LYOPHILIZATION
The drugs which:
lose their viability in the liquid state
readily deteriorate if dried in air at normal atmospheric pressures,
these may be heat sensitive or
they may react readily with oxygen,
so in order to be stabilized, they must be dehydrated to a solid state and this is
carried out by Lyophilization.
The dried product can be readily redissolved or resuspended by the addition of
water prior to use, a procedure known as reconstitution.
THE FREEZE DRYING PROCESS:
There are 4 stages in complete drying process:
1. Pretreatment
2. Freezing
3. Primary drying
4. Secondary drying.
 Under appropriate lyophilization conditions, the ice is removed by
sublimation during primary drying.

 Residual water in the freeze concentrate is removed in the

secondary drying step.

The process involves the following steps:

1. Pretreatment:
It includes any method of treating prior to freezing like formulation revision
where different components are added to increase product’s stability, improve
processing or preserve appearance etc
2. Freezing:
Freezing is usually done using a Freeze drying machine. In this step it is
important to cool the materials below its triple point, the lowest temperature at
which solids and liquids phases of the material coexist. This ensures sublimation
rather than melting
3. Primary drying:
During the primary drying the pressure is lowered, and enough heat is supplied to
the material for the water to sublimate.
In this phase about 95% of water in the material gets sublimated. This phase may be
slow (can be several days in the industry) because, if too much heat is added, the
material’s structure could be altered. Pressure is controlled through the application
of partial vacuum.
4. Secondary drying:
The secondary drying phase aims to remove unfrozen water molecules, since the ice
was removed in primary drying phase. In this phase the temperature is raised than
primary drying phase and can be above 0 °C. Usually the pressure is lowered in this
phase.
At the end of the operation, the final residual water content in the product is
extremely low, around 1% to 4%.
 16. LYOPHILIZATION
ADVANTAGES:
1. Product is stored in dry state (few stability problems).
2. Product is dried without elevated temperatures (good for thermolabiles)
3. Good for oxygen and/or air-sensitive drugs.
4. Rapid reconstitution/ rehydration.
5. Constituents of the dried material remain homogenously dispersed.
6. Sterility of product can be achieved and maintained.
 16. LYOPHILIZATION
DISADVANTAGES:
1. Volatile compounds may be removed by high vacuum.
2. Single most expensive unit operation.
3. High energy costs (2-3times more than other methods).
4. Long process time.
 16. LYOPHILIZATION
APPLICATIONS:
Lyophilization (freeze-drying) is often used to prepare dry pharmaceutical
formulations to achieve commercially viable shelf lives.
Freeze drying is used for the manufacture of certain pharmaceutical and
biological products which are thermolabile. It is also used for drying blood
plasma, vitamins, enzymes, hormones and antibiotics.
Freeze dried product has definite physical properties as compared to products
dried by other methods. Freeze dried products are more stable than vacuum
dried products and often more readily soluble. (hence, increases the shelf life
of some pharmaceuticals for many years.)
By removing the water from the material and sealing the material in a vial, the
material can be easily stored, shipped, and later reconstituted to its original
form for injection.
Since freeze drying is very slow and expensive process it is preferably used for
those products which cannot be dried by any other method.
Furthermore, it is capable of concentrating substances with low molecular
weights that are too small to be removed by a filtration membrane.