UNIT OPERATIONS

Krishna Patel
M.Pharm (Pharm. Chemistry)
Sem - 2
1
 ● Topics covered in the presentation :

• Evaporation : Types of evaporators, factors affecting

evaporation.
• Crystallization : Crystallization from aqueous, non-
aqueous solutions, factors affecting crystallization,
nucleation, Principle and general methods of
Preparation of polymorphs, hydrates, solvates and
amorphous APIs.

2
● UNIT OPERATIONS :

• A unit operation is a basic step in a process.

• Each chemical process frequently consists of a fewer
number of distinct individual steps. Each step is called
unit operation.
• Unit operation involves a physical change or chemical
transformation such as separation, crystallization,
evaporation, filtration, polymerization, isomerization,
filtration, distillation, extraction etc.

3
 ● EVAPORATION :

• Theoretically,
• “Evaporation means simply vaporization from the surface of
a liquid. Vaporization of a liquid below its boiling point is
called evaporation.”

• Practically,
• “The removal of liquid from a solution by boiling the solution
in a suitable vesel and withdrawing the vapour, leaving a
concentrated residue”

4
● Mechanism of Evaporation :

• When the heat is applied to the solution, the motion of

molecules increase and molecules present on the
surface overcome the surface tension of the liquid and it
evaporated because the molecules on surface have less
cohesive force than the other molecules in the solution.

5
 ● Types of Evaporators :
1. Evaporators with heating medium in jacket
2. e.g. Steam jacketed kettle (evaporating pan).
3. 2. Vapour heated evaporators with tubular heating surfaces
A. Evaporators with tubes placed horizontally
e.g. Horizontal tube evaporator
B. Evaporators with tubes places vertically
i. Single evaporators with short tubes
a. Single effect evaporators
e.g. Short tube vertical evaporator
Short tube vertical evaporator with propellor
Basket type evaporator
b. Multiple effect evaporator
e.g. Triple effect evaporator
6
● Types of Evaporators :

i. Evaporators with long tubes

a. Evaporators with natural circulation
e.g. Climbing film evaporator (Rising film evaporator)
Falling film evaporator
b. Evaporation with forced circulation
e.g. Forced circulation evaporator

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• Steam jacketed kettle (evaporating pan) :

• Principle : Steam is applied to a jacketed kettle (evaporating pan) in

which aqueous extract is placed.
• Steam gives out heat to the kettle.
• The heat is transferred to the aqueous extract by conduction and
convection.
• The temperature raises and the escaping tendency of the solvent into
vapour inreases.

• Construction : It is a hemispherical structure consisting of an inner pan

called kettle.
• It is enveloped with an outer pan called jacket.
• For kettle Copper is generally used due to good conductivity.
• For jacket Iron is used due to minimum conductivity.
• An inlet for the steam and outlet (vent) for non-condensed gases are
provided near the top of jacket.
• Condensate leaves the jacket through outlet at bottom.
• The kettle has one outlet for product discharge at bottom.

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• Working :

• Aqueous extract to be
evaporated is placed in kettle
• Steam is supplied through inlet.
• Steam gives out its heat to the
contents and the condensate
leaves through the outlet.
• The rate is fast initially and
decreases gradually as the liquid
gets concentrated.
• There should be proper
ventillation in the room.
• The kettle may be fixed or made
to tilt.

Evaporating Pan

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• Uses :
• Suitable for concentrating aqueous and thermostable liquids e.g.
liquorice extract.

• Advantages :
• Both small and large scale operations.
• Easy to operate, clean and maintain.
• Wide variety of material can be use for construction e.g. SS, Al etc.
• Removal of products is easy.
• Low cost.

• Disadvantages :
• Heat economy is less.
• Not suitable of heat sensitive materials.
• Heating area decreases as the products gets concentrated.
• As it is open type, vapour passes in atmosphere and causes saturation
which slows evaporation and may cause discomfort.
• Boiling of water cannot be accelerated by imparting pressure since it an
open type evaporator.
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• Horizontal Tube Evaporator :

• Principle : Steam is passed through the horizontal tubes, which are

immersed in a pool of liquid to be evaporated.
• Heat transfer takes places through the tubes and the liquid outside the
tube gets heated.
• The solvent evaporates and escapes from the top.
• The concentrated liquid is collected from bottom.

• Construction : It consists of a large cylindrical body with conical or

dome-shaped top and bottom.
• It is made up of cast iron or steel.
• The lower part of the body has a steam compartment with an inlet for
steam at one end and vent for non-condensed gases on other end.
• Condensate outlet is provided at bottom.
• In steam compartment, 6-8 SS horizontal tubes are placed.
• The width of steam compartment is half the diameter of the body.
• Feed inlet is provided.
• One outlet for vapour is at top of dome and another outlet for thick liquid
is at centre of the conical bottom of the body.
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• Working :

• The feed is introduced into the

evaporator until the steam
compartment is immersed.
• Steam is introduced in the steam
compartment.
• The horizontal tubes receive
heat from the steam and conduct
it to the liquid.
• Steam condensate passes
through the corresponding outlet.
• The feed absorbs heats and
solvent gets evaporated.
• The vapour than escapes
through outlet at top.

Horizontal Tube Evaporator

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• Uses :
• Best suited for non-viscous solutions that don not deposit scales or
crystals on evaporation e.g. Cascara Extract.

• Advantages :
• The cost per square meter of heating surface is usually less in horizontal
tube evaporator.

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• Vertical Tube Evaporator (Short tube evaporator) :

• Principle : Liquid is passed through the vertical tubes and the steam is
supplied from outside the tubes.
• Heat transfer takes place through the tubes and the liquid inside the tube
gets heated.
• The solvent evaporates and the vapour escapes.

• Construction : It consists of a large cylindrical body made of cast iron

with dome shaped top and bottom.
• In the body, calandria is fitted at the bottom.
• Calandria consists of a number of vertical tubes.
• About 100 such tubes are fitted in a body measuring 2.5 meter or more
diameter.
• Inlets for steam and feed are provided.
• Outlets for vapour, concentrated product, non-condensed gases and
condensate are provided.
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• Working :

• Steam is introduced outside the

tubes.
• The feed is introduced in such a
way as to maintain the liquid
level slightly above the top of the
tubes.
• The liquid inside the tubes is
heated by the steam and begins
to boil.
• The vapour escaped through top
outlet.
• Steam is supplied until required
concentration of product is
obtained.
• The product is withdrawn from
the bottom.
• The non-condensed gases
escapes through the vent.
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Vertical Tube Evaporator
• Uses :
• In manufacturing of cascara extract, sugar, salt, caustic soda.

• Advantages :
• The vertical tubes increase the heating surface nearly 10-15 times.
• Vigorous circulation enhances the rate of heat transfer.

• Disadvantages :
• The liquid is maintained above the level of the calandria. Hence the
upper layers of the liquid need a long time for getting heated.
• It is complicated hence installation is costly.
• Cleaning and maintenance is difficult.
• During operation, pressure is created which causes elevation in
temperature which alters the temperature gradient and may affect heat
sensitive materials.

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• Variants of Vertical tube evaporator :

• Short tube vertical evaporator with propellor :

• In such equipment, circulation depends completely on boiling. Steam is
supplied into the calandria to induce boiling. When steam supply stops,
boiling stops. As a result the particles settle, act as nuclei and grow as
crystals. Therefore this evaporator is sometimes used as crystallizing
evaporator.

• Basket type evaporator :

• It has a conical bottom and a flat bottom. The complete unit can be
removed for cleaning and repairs.

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• Multiple Effect Evaporator (Triple Effect
Evaporator) :

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• Climbing Film Evaporator (Rising Film Evaporator) :

• Principle : Tubes are heated externally by steam.

• The preheated feed enters from the bottom and flows up through the
heated tubes.
• The liquid gets heated rapidly due to preheated heat.
• The liquid near the walls becomes vapour and forms small bubbles.
• These tend to fuse to larger bubbles which travel up in the tubes along
with entrapped slug.
• The liquid films are blown up from the top of the tubes and strikes
entrainment separator (deflector).
• This throws the liquid concentrate down into the lower part from where it
is withdrawn.

• Construction : The heating unit consists of steam jacketed tubes (long

and narrow) which are held between two plates.
• Deflector is placed at top of vapour head.
• The evaporator carries steam inlet, vent outlet and condensate outlet.
• The feed inlet is from the bottom of the steam compartment.

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• Working :

• The preheated feed is introduced

from bottom.
• Steam enters into the spaces
outside the tubes through inlet.
• Heat is transferred to liquid
through walls of the tube.
• The liquid becomes vapour and
forms bubbles, which fuse.
• These are of width of tubes,
thereby the bubbles trap part of
liquid(slug) on their way up.
• As more vapour is formed, slug
is blown up facilitating the liquid
to spread as a film over the
walls.
• This film continue to vaporize
rapidly.
• The deflector acts as foam
breaker.
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Climbing Film Evaporator
• Uses :
• Thermolabile substances such as insulin, liver extracts and vitamins
can be concentrated.
• Clear liquids, foaming liquids and corrosive solutions can be operated.

• Advantages :
• Large area for heat transfer is provided employing long and narrow
tubes.
• Since liquid flows at high velocity, the resistance for heat transfer at the
boundary layers is reduced.
• Tubes are not submerged hence there is no elevation in boiling point.

• Disadvantages :
• Expensive, construction is complicated.
• Difficult to clean and maintain.
• Not used for viscous liquids, salting liquids and scaling liquids.

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• Falling Film Evaporator :

• Principle : Feed enters from the top and flows down the walls of the
tubes.
• The liquid gets heated rapidly due to heat transfer from steam.
• The liquid boils and becomes vapour, which forms bubbles.
• The bubbles fuse and travel down the tubes. Concentration takes place
during downward journey.

• Construction : It resembles climbing film evaporator, but it is inverted.

• The heating unit consists of steam jacketed tubes.
• The feed inlet is from top.
• For easy distribution of feed perforated plates or spray nozzles can be
used.
• The outlet for the product is at bottom and is connected to a cyclone
separator.
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• Working :

• Steam is supplied in steam

compartment.
• Feed enters from the top of the
tubes.
• The temperature of boiling liquid
is same as that of vapour.
• The liquid gets heated, starts
boiling, becomes vapour, forms
bubbles, these bubbles fuses
and travel down the tubes.
• Concentration takes place.
• Vapour and liquid are separated
in the cyclone separator at the
bottom.

Falling Film Evaporator 23

• Uses :
• Used to separate volatile and non-volatile materials.
• Used for concentration of yeast extracts, manufacturing of gelatin,
extracts of tea and coffee.
• Useful in concentrating the heat sensitive materials such as fruit juices.

• Advantages :
• Suitable for highly viscous liquids.
• Liquid is not overheated.
• Highly acidic and corrosive feeds can be concentrated.

• Disadvantages :
• Not suitable for suspensions, as solids clog the perforated plates.
• Not suitable for salting and scaling liquids.

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• Forced Circulation Evaporator :

• Principle : Liquid is circulated through the tubes at high pressure by

means of a pump.
• Hence boiling does not take place as boiling point is elevated.
• Forced circulation of liquid also causes some form of agitation.
• When the liquid leaves the tubes and enters the vapour head, pressure
falls suddenly.

• Construction : The steam jacketed tubes are held between two tube
sheets.
• The tube measures 0.1 m inside diameter and 2.5 m long.
• The part of the tube projects into the vapour head (flash chamber), which
consists of a deflector.
• The vapour head is connected to a return pipe, which runs downwards
and enters into the inlet of the pump.

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• Working :

• Steam is introduced into

calandria.
• Pump sends the liquid to the
tubes with positive velocity.
• As the liquid moves up, it gets
heated and begins to boil.
• So, the vapour and liquid mixture
rushes out of the tube at a high
velocity.
• This mixture strikes the deflector,
which thows the liquid
downward.
• The vapor enters the cyclone
separator.
• The concentrated liquid returns
to the pump for further
evaporation.
• Finally the concentrated product
is collected.
Forced Circulation Evaporator
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• Uses :
• For concentration of insulin and liver extracts.

• Advantages :
• The heat transfer is high due to rapid liquid movement.
• Due to forced circulation scaling does not occur.
• Suitable for thermolabile substances.
• Suitable for high viscous solutions because pump is used.

• Disadvantages :
• Expensive, because power is required to operate the pump required for
circulation of fluid.

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 ● Factors Affecting Evaporation :
• The rate of evaporation depends on several factors.
• The relation may be expressed mathematically as :

• M = KS (b-b’) / p

• Where,
• M= mass of vapour formed per unit time (Rate), m3/s.
• S= surface area of the liquid exposed, m2.
• p= atmospheric pressure, kPa.
• b= maximum vapour pressure at the air temperature, kPa.
• b’= pressure due to the vapour of the liquid, actually present in the air,
kPa.
• K= constant, m/s.

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• Factors affecting evaporation :

• 1. Temperature : The higher the temperature, the greater the value of b

and hence greater the evaporation.
• At a given temperature, some molecules have higher kinetic energy than
average, while others have lower kinetic energy than average.

• 2. Vapour Pressure : Rate of evaporation is directly proportional to

vapour pressure.
• The lower the p value, greater the evaporation.
• If the outer atmosphere is dry, b’ will be low hence greater the
evaporation.

• 3. Surface Area : Greater the surface area, greater the evaporation.

• 4. Moisture Content of the Feed : Some drug constituents undergo

hydrolysis readily in presence of moisture at high temperatures.
• To prevent decomposition, the material is exposed to lower temperature
initially.
• E.g. Dry extract of Belladona is prepared in this manner.
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• 5. Type of Product required : Open pan produce liquid or dry
concentrate.
• Film evaporators yields liquid concentrate.
• Vacuum evaporator gives porous product suitable for conversion to
granules.
• E.g. Preparation of granular extract of Cascara for tablet making.

• 6. Time of Evaporation : If time exposure is longer, greater will be

evaporation, provided the content are thermostable.

• 7. Films and Deposits : When vegetable extracts are concentrated in a

steam pan, a film may be formed on surface and/or precipitated matter
may deposit on heating surface.
• Films reduce evaporating surface and precipitated matter hinders
transfer of heat.

• 8. Economic Factors : Labour, fuel, floor space and materials are of

primary considerations.
• The recovery of solvents and utilization of waste heat are also important
as they involve considerable reduction of costs. 30
 ● CRYSTALLIZATION :

• Crystallization is the spontaneous arrangement of particles

into a repetitive orderly array i.e. regular geometric patterns.

• Crystallization is the separation technique that is used to

separate solid that has dissolved in a liquid forming solution.

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 ● Crystallization from Aqueous Solutions :

• Water of crystallization are water molecules that are present inside the
crystals.
• Water is often incorporated in the formation of crystals from aqueous
solution.
• Water of crystallization is the total mass of water in a substance at a
given temperature.
• Water of crystallization refers to water that is found in the crystalline
framework of metal complex or a salt, which is not directly bonded to the
metal cation.
• Upon crystallization from water or moist solvents, many compounds
incorporate water molecules in their crystalline frameworks.
• Water of crystallization can be removed by heating a sample but the
crystalline properties are often lost.
• E.g. In case of sodium chloride, the dehydrate is unstable at room
temperature compared to organic salts.
• Proteins crystallize with large amount of water in the crystal lattice.
• E.g. Crystallization of Amylopectin,Magnesite etc. from aqueous
solutions. 32
 ●Crystallization from Non- Aqueous Solutions :

• Crystal growth from non aqueous solutions often allows realization of

special crystallization aims by control of solution properties.

• Solvent and solubility effects on crystallization:

• Several solvents and solubility effects are then pointed out such as the
effect on the nucleation on the crystallization of polymorph and on the
surface morphology of the crystals which is easier when solubility is
higher.
• Solvent also change growth rate and alters properties of adsorption
layer.
• In non-electrolyte solution, the molecules of the solute are not
dissociated during the dissolution process.
• With the use of non-aqueous solvent it is sometimes possible to modify
morphology of crystals using high/low solute concentration.
• All the phenomenon results from solvent-solute or crystal-solvent
interaction.
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• There are three main classes of solvents :

• 1. Protic solvents → Hydrogen donors

• E.g. Methanol

• 2. Dipolar Aprotic solvents → Solvents with dielectric constant > 15 but w

hich cannot donate hydrogen atom to form hydrogen bonds with solute.
• E.g. Acetonitrile

• 3. Aprotic solvents → Solvents with weak dielectric constant and are no

n-polar.
• E.g. Benzene, Pentane.

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● Factors Affecting Crystallization :

1. Presence of another substance.

2. Solvent.
3. Nucleation.
4. Crystal growth.
5. Rate of cooling/Time.

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• 1. Presence of another substance :
• 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.

• 2. Solvent :
• The solvent with moderate solubility is preferred for crystallization → To
avoid supersaturation.
• Presence of benzene can help crystal growth.
• Highly volatile solvents are not preferred.

• 3. Nucleation :
• Crystals initially forms via “nucleating events”.
• After a crystal is nucleated it must grow.
• Nucleation sites are necessary for formation of crystals.
• Excess nucleation sites cause smaller average crystal size.
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• 4. Crystal Growth :
• Crystals grow by the ordered deposition of the solute molecules onto the
surface of a pre-existing crystal.
• Crystal growth is facilitated by the environment changing slowly over
time.
• Crystal growth vessels are kept away from sources of mechanical
agitation (e.g. vibrations).

• 5. Rate of Cooling/Time :
• Quality crystals grow best over time in near equilibrium conditions.
• The longer the time, better the crystals.
• Slow crystallization is preferred over fast crystallization.

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● Mechanism of Crystallization :

• The formation of crystals from solution involves three

steps :

1. Supersaturation.
2. Nucleation / Nucleus Formation.
3. Crystal Growth.

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• ● Mechanism of Crystallization :

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• 1. Supersaturation :

• When the solubility of a compound in a solvent exceeds the saturation

solubility, the solution becomes supersaturated and the compound may
precipitate or crystallize.

• Supersaturation can be achieved through :

• A. Evaporation of solvent from the solution.
• B. Cooling of the solution.
• C. Formation of new solute due to chemical reaction.
• D. Addition of a substance, which is more soluble in solvent than the solid
to be crystallized.

• In the absence of seed crystals, significant supersaturation is necessary to

initiate the crystallization through formation of nuclei.
• The rate of separation, particle size, uniformity and distribution depend on
two successive largely independent processes :
• i. Nuclei formation or nucleation.
• Ii. Growth of Nuclei. 40
• 2. Nucleation / Nucleus Formation :

• Nucleation refers to the birth of very small bodies of a new phase within
a homogeneous supersaturated liquid phase.
• Nucleation is a consequence of rapid local fluctuations at the molecular
level when molecules or ions are in random motion in any small volume.
• Sometimes the nuclei grow in dimensions that are limited by the amount
of material available and thus form crystals.

• Several methods for nucleation are :

• A. Soft or Weak crystals on impact with moving parts in a crystallizer can
break into fragments which acts as a nuclei.
• B. Small crystals which are formed in previous process are added to act
as nuclei.

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• If all the sources of particles are subsumed under the term nucleation, a
number of types of nucleation may occur :

• A. Primary Nucleation.
• B. Secondary Nucleation.

• A. Primary Nucleation :

• The phenomenon of nucleation is the same for crystallization from

solution, crystallization from melt, condensation of fog drops in a
supercooled vapour and generation of bubbles in a superheated liquids.

• There are two types :

• 1. Homogeneous Nucleation.
• 2. Heterogeneous Nucleation. 42
• 1. Homogeneous Nucleation :

• In crystallization from solution, homogeneous nucleation almost never

happens except in some precipitation reactions.
• Because of random motion, in any small volume several particles
associate to form cluster- a loose aggregation that disappears quickly.

• Occasionally enough particles associate to form embryo- beginning of a

lattice arrangement and formation of a new and separate phase- short
lived.

• If the supersaturation is large enough, an embryo may grow to a size

which is in thermodynamic equilibrium with the solution, it is than called
nucleus- smallest assemblage that will not re dissolve and can therefore
grow to form a crystal.
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• Rate of Nucleation :
• The rate of the nucleation, from the theory of chemical
kinetics, is given by the following equation :

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• 2. Heterogeneous Nucleation :

• Solid particles of foreign substances do influence the nucleation process

by catalyzing an increase of nucleation rate.

• The catalytic effect of the solid particles on the rate of nucleation is the
reduction in energy required for nucleation.

• One theory of this effects holds that if the nucleus “wets” the surface of
the catalyst, the work of nucleus formation is reduced.

• Experimental data on the heterogeneous nucleation of potassium

chloride solutions show that the nucleation of this substance is consistent
with an apparent value of the interfacial tension in the range of 2 to 3
ergs/cm2 for both catalyzed and non-catalyzed nucleation.

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• B. Secondary Nucleation:

• The formation of nuclei due to the influence of the

macroscopic crystals in the magma is called as Secondary
Nucleation.

• The two types are :

• 1. Fluid-Shear Nucleation.
• 2. Contact Nucleation.

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• 1. Fluid-Shear Nucleation :

• When supersaturated solution moves past the surface of a growing

crystal at a substantial velocity, the shear stresses in the boundary layer
may sweep away embryos or nuclei that would otherwise incorporated
into growing crystals.
• This has been reported in the work on sucrose crystallization.
• It is demonstrated in the nucleation of MgSO4 • 7H2O, if the solution is s
ubjected to shear at the crystal face at one supersaturation and then qui
ckly cooled at a higher supersaturation and allowed to stand while nuclei
grow to macroscopic size.

• 2. Contact Nucleation :

• The influence on secondary nucleation by the intensity of agitation or con

tact is a phenomenon of contact nucleation.
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• 3. Crystal Growth :

• It is a diffusion process and surface phenomenon.

• From solution, solute molecules or ions reach the faces of the crystals by
diffusion.

• On reaching the surface, the molecules or ions must be accepted by the

crystal and organized into the space lattice.

• This phenomenon continues at a finite rate.

• The diffusion will not proceed until the solution is supersaturated.

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• Polymorphs :

• When the substance exist in more than one crystalline form are
designated as polymorphs and the phenomenon as polymorphism.
• E.g. Steroids, Sulphonamides, Barbiturates.

• Method of Preparation :

• 1. Solvent Evaporation (Rota Evaporation) :

• The saturated solution of the drug is prepared in an appropriate solvent

and the solvent is removed by rotary evaporation.
• Air drying at various temperatures can also be employed to obtain
different potential polymer.

49
• 2. Slow Cooling Approach :

• This technique is frequently employed for the polymorphic forms of less

soluble drugs in the solvent system having boiling point range of 30-90 º
C.
• The solute is heated in the solvent just above the boiling point of solvent
to produce a saturated solution.
• The solution is then transferred to stopper tube and is connected to dewa
r flask containing water at a temperature just below the boiling point of so
lvent.
• The dewar flask is left in this condition for several days.

50
• 3. Solvent diffusion technique :

• This method is employed when the amount of drug available is less and
the drug is sensitive to air and/or solvent.
• In this, the solution is placed in a sample tube, subsequently a less
dense solvent is carefully dripped down the sides of the tube using either
a pipette or a syringe to form a layer.
• The slow diffusion of the solvent results in the crystallization of drug at
interface.
• Most employed solvent combination is dichloromethane/methanol.

51
• 4. Vapour diffusion method :

• In this method, the concentrated drug solution (0.5μl – 2 μl) is placed in a

drop hanging on the underside of a microscope cover slip.
• The cover slip with the hanging drop is kept on silicon oil over a solution,
containing high concentration of precipitate.
• Due to higher precipitate concentration, the solution has lower vapour pr
essure than the drug solution.
• This results in diffusion of the solvent from the drop towards the reservoir
and subsequent crystallization of drug occurs within hours to weeks.

52
• 5. Vacuum Sublimation :

• Sublimation is known to offer excellent crystals of variety of compounds,

especially the air sensitive ones.
• This method is frequently employed to induce crystallization with
numerous variation of static and dynamic vacuum.
• A small amount of sample sealed under vacuum in a reactor is subjected
to temperature gradient.
• Temperature of about 250 ºC can be easily employed at a pressure of ab
out 2-10 mm of Hg.
• The crystals grow from the wall to the centre of the reactor.

53
Sr. Method Characteristics Advantages Disadvantages Examples
No.
1 Rota Evaporation Applicable for High purity and Expensive, Famotidine
high melting yield small
substances production
volume

2 Slow cooling approach Easy and simple Large scale Low yield, high Sodium
production input, Chloride,
disordered Copper
crystals Sulphate

3 Solvent diffusion Best for less Large surface Low yield, Tolbutamide
technique quantity area, higher tedioud
substances and solubility, high
material sensitive mechanical
to air and strength of
moisture crystals

4 Vapour diffusion Requires less Less quantity of Time Proteins

technique sample sample consuming,
difficult,
expensive, low
yield

5 Vacuum Sublimation Thermolabile Excellent Disordered Haloprogin

sample crystal variety crystals
54
• Solvates :

• A crystal solvate forms during the process when a compound is

crystallized with the inclusion of solvent.

• Method of Preparation :
• Solvates are generally obtained through crystallization from either a single
solvent or mixture of solvents.
• E.g. Synthesis of dimethyl formamide solvate of thiocyanuric acid (TCUA)
• Combining a solution of TCUA in DMF with an aqueous solution of
NaNO3

• The reaction solution was left at room temperature for 3 days

• Yellow crystals of thiocyanuric acid are obtained

• Crystals were filtered off and washed three times with DMF : water (1:1)

• The needle shaped crystals were obtained. 55

• Hydrates :

• Some drugs have tendency to associate with water, this substance is

called hydrate.

• Types :
• 1. Inorganic Hydrate : When drug is heated water molecules is
removed and it becomes anhydrous. The anhydrous form can absorb
water becoming hydrated.
• The water is known as water of hydration.
• E.g. Cobalt Chloride is sky blue in anhydrous form and purple in
hydrated form.
• 2. Organic Hydrate : The water molecule chemically react with other
compounds.
• E.g. Formaldehyde hydrate is formed from formaldehyde by the
reaction of its carbonyl group with water.
• 3. Gas hydrate : It is made at low temperatures and high pressure.
When water molecule surrounds a gas molecule, a frozen mesh or
cage is formed. 56
• Method of Preparation :

• The basic method for preparing hydrate is by dissolving a drug

compound in an aqueous solvent.
• This aqueous solvent must be then cooled or evaporated to form crystal
hydrate.
• Variable temperatures are used for evaporation that yield variable types
of crystals.

• E.g. Chlorine is dissolved in water, forming a thin slurry

• Slurry then is filtered through a glass filter funnel surrounded by jacket

• Which is than cooled on ice bath

• Chloride hydrate is formed.

57
• Amorphous API :

• Amorphous solids do not have a specific shape. The structural units are
arranged randomly.

• Method of Preparation :

• 1. Solidification of the Melt : Amorphous solids are 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 below
the normal freezing point.

• 2. Spray Drying : In this process, a liquid feed stream is first atomized

for maximal air spray contact. The particles are than dried in air stream.
It can produce spherical particles that have a good flow properties.

• 3. Removal of solvent from solvate : Solid sometimes can be

converted to amorphous form simply by allowing solvent molecules of
crystallization to evaporate at moderate temperature.
58
 ● Key References :
• J.W. Cooper; S.J. Carter; “Copper and gunn’s tutorial pharmacy”; 6th
edition; CBS Publication; New Delhi; Pharma Technology; unit 14;
Page No: 164-172.
• W.L. McCabe, J.C Smith, Peter Harriott. “Unit operations of chemical
engineering”; 7th edition; McGraw Hill Publications; Chennai; 2014;
Page No: 486-515,929-959.
• W.L Badger; W.L McCabe; “Elements of Chemical Engineering”; 2nd
edition; McGraw Hill Publications; New York and London; 1936;
Page No: 172-235,438-465.
• C.V.S Subhramanyam; J. Thimma Shetty; S. Suresh; V. Kusum
Devi; “Pharmaceutical Engineering-Principles and Practices”; 1st
edition; Vallabh Prakashan; Delhi; 2002; Page No: 337-360,361-381.
• Research gate (www.symbiosisonline.org).
• R. Hilfiker; M.V. Raumer; "Polymorphism in the Pharmaceutical
Industry-Solid form and drug development "; Wiley Publication; 2018.
• Research Paper (Crystal growth from non-aqueous solution -
Springer Publications).
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