e-content of Evaporation, Distillation and Crystallization for M.pharm students.

1. EVAPORATION
DISTILLATION &
CRYSTALLIZATION
PRESENTING BY,
Mr. PURUSHOTHAM K.N
ASSI.PROFESSOR
DEPT.OF.PH.CHEMISTRY
SACCP, B.G.NAGARA.
2022-2023
1

2. Contents
1. Evaporation
• Factors affecting evaporation
• Types of evaporator
2. Distillation
• Steam distillation
• Azeotropic distillation
3. Crystallization
• Aqueous and non aqueous solution from crystallization
• Factors affecting crystallization
• Nucleation
2

3. EVAPORATION
Evaporation is a process of vaporising large quantities of volatile
liquid to get a concentrated product.
OR
Evaporation is the removal of solvent from the solution by boiling the
liquor in a suitable vessel and withdrawing the vapour, leaving a
concentrated liquid residue in the vessel.
Equipment used for evaporation is Evaporator.
3

4. Factors affecting evaporation
1. Temperature
2. Surface area
3. Moisture content of the feed
4. Type of product required
5. Vapour pressure
6. Time of evaporation
7. Film and deposits
8. Economic factors
4

5. Temperature
• Higher the temperature greater will be the evaporation
• When temp of liquid raises molecules aquire sufficient kinetic energy &escape
from the surface to vapour state
• The vapour pressure of a liquid is lowered when a substance is dissolved in it &
consequently the boiling point of the liquid increases.
• Ex:
i. Glycosides &alkaloids decompose at high temp
ii. Hormones, enzymes & antibiotics are even more heat sensitive
iii. Antibiotics are concentrated by freeze drying.
5

6. Vapour pressure
• Rate of evaporation is directly proportional to the vapour pressure of
the liquid.
• Lower the atmospheric pressure, greater the evaporation
• Liquid with low boiling point evaporate quickly because of high
vapour pressure at low temp
• Lower the external pressure, lower the BP of liquid &hence, greater
the rate of evaporation
6

7. Surface area
• The greater the surface area of the liquid the greater will be the
evaporation
• Because of this, evaporation is conducted in evaporators with larger
heating surface area.
Moisture content the feed
• Some drug constituents undergo hydrolysis readily in presence of
moisture at high temp.
• To prevent decomposition, the material is exposed to lower temp and
then exposed to higher temp for final concentration.
• Eg: The drug extract of Belladonna is prepared in this manner.
7

8. Type of product required
• It decides the apparatus for evaporation
• Open pan produces liquid concentrate
• Film evaporation yields liquid concentrate
• Spray dryer produces drug products with good solubility vaccum
evaporator gives porous product suitable for conversion to granules
• Eg: Preparation of granular extract of Cascara for tablet making
Economic factors
• Economics of labour, fuel, floor space and materials are of primary
considerations.
8

9. Time of evaporation
• If the time of exposure is longer, greater will be the evaporation , provided
the constituents are thermostable.
• Exposure of a drug to a relatively high temp for a short time may be less
destructive of active principle then a lower temp with long exposure period.
• For this reason film evaporators are used.
Film and deposits
• When vegetable extracts are concentrated in steam pan, a film may be
formed on the surface and/or precipitated matter may deposit on the heating
surface.
• The film reduces the evaporating surface & precipitated matter hinders the
transfer of heat.
• To avoid these problems efficient stirring is necessary.
9

10. Types of evaporators
1. Steam jacketed kettle or evaporating pan
2. Horizontal tube evaporator
3. Vertical tube evaporator
4. Climbing film evaporator
5. Falling film evaporator
6. Forced circulation evaporator
7. Multiple effect evaporator
10

11. Steam jacketed kettle or Evaporating pan
Principle:The mechanisms involved in this evaporation process is conduction
and convection so that the heat is transferred by this mechanism to the
extract. Evaporating pan containing aqueous extract is provided with steam,
which gives out heat to a jacketed kettle. The temperature raises and the
escaping tendency of the solvent molecules in to the vapour increases and
enhances the vaporization of the solvent molecules.
Working: Steam evaporating pan consists of
a hemispherical structure with an inner pan
called a kettle which is enveloped with an
outer pan called a jacket. These two pans are
joined to enclose a space through which steam
is passed.
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12. Several metals have been used for the construction of the kettle. Copper
is an excellent material for the kettle due to its superior conductivity. If
acidic preparation evaporated in the copper kettle, some of the copper
gets dissolved in preparation. In order to avoid this, for acidic
preparation is tinned copper kettle is used. Iron is also used for the
construction of the jacket because it has low conductivity. Rusting of
iron with use is a major problem and to prevent this iron jacket is tinned
or enameled on the inner surface. An inlet for the steam and non-
condensed gases is provided near the top of the jacket. Condensate
leaves the jacket through the outlet provided at the bottom. The kettle is
provided with the outlet for the product discharge at its bottom.
12

13. Working: The solution to be evaporated is placed in the kettle, and steam is
fed through the inlet and condensate exits through the outlet, providing heat
to the content. Manual stirring is required for lesser volumes, and mechanical
stirring is required for greater volumes. In the beginning, the rate of
evaporation is rapid. To avoid the production of fog from condensed vapour,
the chamber where evaporation takes place must have adequate ventilation to
evacuate the vapour. Fans are installed to prevent condensation in the room
and to speed up the rate of evaporation. The kettle can either be fixed or
tilted. A kettle with a capacity of up to 90 litres can be tilted. The
concentrated goods are collected at the bottom outlet.
Applications:
• Evaporating pan is suitable for concentrating aqueous liquids.
• It is suitable for concentrating thermostable liquors, for example, liquorices
extracts.
13

14. Horizontal tube evaporator
Principle: In a Horizontal tube evaporator, the steam is passed through
tubes placed horizontally. As a result solvent outside tubes gets
evaporated and passed from the top and concentrated liquid is
discharged from the bottom.
construction: It consists of a vertical cylindrical
body with a dome-shaped top and bottom part
made of cast iron. The lower part of the cylindrical
body is fitted to a steam inlet and outlet for
condensate. Inside the cylinder horizontal tubes
are placed. Horizontal tubes are 6 to 8 in
number and made of stainless steel.
14

15. The lower portion also consists of a vent for noncondensed gases. Feed
inlet is also provided. There is one outlet for vapour at the top of the
vessel, and the concentrated product is discharged from the bottom of
the body.
Working: Feed is introduced through the inlet. Steam is also introduced
into the body. Therefore tubes get heated. The condensate pass-through
outlet. The heat is absorbed by the feed and the solvent gets evaporated.
The vapour formed a pass-through outlet at the top of the body. The
process repeats to get a concentrated product which is collected from the
bottom.
Applications:
• A horizontal tube evaporator is used in the pharmaceutical, pulp, and
paper industries.
• Also used for making distilled water for boiler feed.
15

16. Verticle tube evaporator /short tubr evaporator:
Principle: In a standard vertical tube evaporator, the 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 tubes gets heated. The solvent evaporates and the vapour escapes
from the top. The concentrated liquid is collected from the bottom.
Construction: The construction of a standard vertical
tube evaporator is shown. It consists of a large
cylindrical body made up of cast iron with a
dome-shaped top and bottom. Inside the body
calandria is fitted at the bottom.
16

17. Calandria consists of a number of vertical tubes, whose diameter ranges
from 0.05 to 0.075 metres and lengths of 1-2 metres. About 100 such
tubes are fitted in a body measuring 2.5 metres or more in diameter.
Inlets are provided for steam and feed. Outlets are provided for vapour,
concentrated product, non-condensed gases and condensate.
Working: Steam is introduced outside the tubes. The condensate is
passed through the corresponding outlet and non-condensed gases
escape through the vent. 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. As the liquid
boils, it spouts up through the tubes and returns through the central
down-take. It sets up a circulation of hot liquid, which enhances the rate
of heat transfer. The vapour escapes through the top outlet. Steam is
supplied until the required concentration of the product is obtained.
Finally, the product can be withdrawn from the bottom outlet.
Uses: Vertical tube evaporator is used in the manufacture of Cascara
extract, sugar, salt, and caustic soda.
17

18. Climbing film evaporator:
Principle: In a climbing film evaporator, 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 the enhanced
overall coefficient of the preheated feed.) The liquid near the wall
becomes vapor 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 a strikes
entrainment separator (deflector) kept above. This throws the liquid
concentrate down into the lower part from where it is withdrawn.
Construction: In this evaporator, the heating unit consists of steam
jacketed tubes. Here, the tubes (long and narrow) are held between two
plates. An entrainment separator is placed at the top of the vapour head.
The evaporator carries a steam inlet, vent outlet, and condensate outlet.
The feed inlet is from the bottom of the steam compartment.
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19. Working: The preheated liquid feed (to be evaporated) is introduced
from the bottom of the unit. The height of the liquid column is
maintained low, i.e., 0.6 or 1.2 metres above the bottom tube sheet.
Steam enters into the spaces outside the tubes through the inlet. Heat is
transferred to the liquor through the walls of the tubes. The liquid
becomes vapour and forms smaller bubbles, which tend to fuse to larger
bubbles. These are of the width of the tubes, thereby the bubbles trap a
part of the liquid (slug) on its way up in the tubes. As more vapour is
formed, the slug of liquid is blown up in the tubes facilitating the liquid
to spread like a film over the walls. This film of liquid continues to
vaporise rapidly. Finally, the mixture of liquid concentrate and vapour
eject at a high velocity from the top of the tubes.
The entrainment separator not only prevents entrainment but also acts as
a foam breaker. The vapour leaves from the top, while the concentrate is
collected from the bottom.
19

20. Uses: Using a climbing film evaporator, thermolabile substances such as
insulin, liver extracts, and vitamins can be concentrated.
• Clear liquids. foaming liquids and corrosive solutions in large
quantities can be operated.
• Deposit of scales can be removed quickly by increasing the feed rate
or reducing the steam rate so that the product is unsaturated for a short
time.
20

21. Falling film evaporator:
Principle: In a falling film evaporator feed enters from the top and
flows down the walls of the tubes. The liquid gets heated rapidly due to
heat transfer from stream. The liquid boils &becomes vapour, which
forms small bubbles. They tend to fuse to form layers of bubbles, which
travel down the tubes. Concentration takes place during this downward
journey. Vapour &liquid are separated at the bottom.
Construction: It resembles climbing film evaporator, but is inverted. In
this evaporator, the heating unit consists of steam jacketed tubes. The
feed inlet is from the top of the steam compartment. The other
provisions are steam inlet, vent & condensate outlet remains same. The
outlet for the product is provided at the bottom & is connected to a
cyclone separator.
21

22. Working: steam is supplied into the steam compartment. Feed enters
from the top of the tubes. The temp of boiling liquid is same as that of
vapour head. The feed flows down the walls &becomes vapour, which
forms smaller bubbles. These tend to fuse to form layers of bubbles,
which travel down the tubes. Concentration takes place during this
downward journey. Vapour & liuid are separated in the cyclone
separator.
22

23. Uses:
• Used to separate volatile &non volatile materials, when the feed is of
low viscosity.
• Used for concentration of yeast extract, manufacture of gelatin,
extracts of tea &coffee.
• Useful for concentrating the heat sensitive materials like fruit juices.
23

24. Forced film evaporators
Principle: Liquid is circulated through the tubes at high pressures by
means of pump. Hence boiling does not take places because the boiling
point is elevated. Forced circulation of the liquids also creates some
form of agitation. When the liquid leaves the tubes and enters the vapor
head, the pressure falls suddenly. This leads to the flashing of super
heated liquor leading to evaporation of feed.
Construction: Pumps are fitted to circulate the
heating of the contents in it. The forced
circulation evaporator consists of steam
jacketed tubes held between two tube
sheets. The tube measures 0.1 m inside
diameter and 2.5 m long.
24

25. The parts of the tubes project into the vapour head which consists of a
deflector. The vapour head is connected to a return pipe which runs
downwards and enters in to the inlet of a pump. The liquid is circulated by
means of a pump. As it is under pressure in the tubes the boiling point is
raised (but no boiling take places) and it enters into the body of the
evaporator.
Working: Steam is introduced in to the calendria. The pump sends the liquid
to the tube with a positive velocity. As the liquid move up through the tube it
gets heated and begins to boil. As result, the vapour and liquid mixture rushes
out of the tubes at a high velocity. This mixture strikes the deflector in a
manner that effective separation of liquid and vapour takes place. The vapour
enters the cyclone separator and leaves the equipment. The concentrated
liquid is circulated through the pump for further evaporation. Finally, the
concentrated product is collected at the bottom from the discharge outlet.
25

26. Uses:
• Forced circulation evaporator is used to concentrate thermolabile
substance solutions.
• It is used for the concentration of insulin and liver extracts.
• It is well suited for crystallizing operations where crystals are to be
suspended at all times.
• These evaporators are used in the production of salt, corn steep water,
and calcium carbonate.
• It is used for effluent treatment in pharmaceutical industries.
• Forced circulation chambers can be superimposed on each other to
form a multi-effect tower which can be utilized for the increasing
concentration of refined sugar and syrups.
26

27. Multiple effect evaporator
The vertical tube evaporator discussed earlier is a single effect evaporator.
Such evaporators are connected in several ways to achieve large-scale
evaporation as well as a greater economy. Although multiple effect
evaporators are not used in the pharmaceutical industry, the principles are of
interest and should be understood. This is illustrated using an example of a
triple effect evaporator with a parallel feed mechanism.
27

28. Construction: The construction of a multiple-effect evaporator is shown
using 3 evaporators, i.e. triple effect evaporator. The other aspects of the
construction of the vertical tube evaporator remain the same as
mentioned earlier. It indicates that the vapour from the first evaporator
serves as a heating medium for the 2nd evaporator. Similarly, vapour
from the 2nd evaporator serves as a heating medium for the 3rd
evaporator. The last evaporator is connected to a vacuum pump.
Working:
Parallel feed: In this method, a hot saturated solution of the feed is
directly fed to each of the three effects (evaporation) in parallel without
transferring the material from one effect to the other. The parallel feed
arrangement is commonly used in the concentration of salt solution s.
where the solute crystallizes on concentration without increasing the
viscosity.
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29. Operations: In the beginning, the equipment is at room temperature and
atmospheric pressure. The liquid feed is introduced to all three evaporators up
to the level of the upper tube sheets. The following operations are attempted
to achieve the effects as specified below.
• The vent valves V1 V2 and V3 are kept open and all other valves are closed
(not shown in Figure).
• Now a high vacuum is created in the liquid chambers of evaporators.
• The steam valve S₁ and condensate valve C₁ are opened. Steam is supplied.
Steam first replaces cold air in the steam space of 1st evaporator. When all
the cold air is removed, the valve, Vi is closed.
• The supply of steam is continued until the desired pressure p0 is created in
the steam space of 1st evaporator. At this pressure. the temperature of the
steam is t0
• Steam gives its temperature to the liquid feed in the 1st evaporator and gets
condensed. Condensate is removed through the valve C₁.
• Due to heat transfer, the liquid temperature increases and reaches the boiling
point. During this process, vapor will be generated from the liquid feed.
29

30. • So formed vapour displaces air in the upper part of the 1st evaporator.
Moreover, the vapour also displaces the air in the steam space of the
2nd evaporator.
• After the complete displacement of air by a vapour in the steam
compartment of the 2nd evaporator, valve V2 is closed.
• The vapour of 1st evaporator transmits its heat to the liquid of 2nd
evaporator and gets condensed. Condensate is removed through valve
C2. These steps continue in the 3rd evaporator also.
• As the liquid in the 1st evaporator gains temperature, the difference in
temperatures between the liquid and steam decreases, hence, the rate
of condensation decreases. As a result, the pressure in the vapour
space of the 1st evaporator gradually increases to P₁ by increasing the
temperature to which is the boiling point of the liquid in the 1st
evaporator and decreasing the temperature difference (t0-t1).
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31. • A similar change takes place in the 2nd evaporator and the liquid
reaches the boiling point. Similarly, the process will be repeated in 3rd
evaporator. Finally, three evaporators (or effects as they are called)
come to a steady-state with the liquid boiling in all three bodies.
Advantages:
• It is suitable for large-scale and continuous operations.
• It is highly economical when compared with a single effect.
• About 5 evaporators can be attached.
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32. Distillation
Distillation is the process of separating the components of a liquid
mixture through selective evaporation and condensation. The basis of
separation is the difference in the vapour pressures (volatilities) of the
respective components.
The distillation performed on a laboratory scale often uses batches of
the liquid mixture whereas industrial distillation processes are generally
continuous, requiring a constant composition of the mixture to be
maintained.
For a mixture of liquids, the distillation process is dependent
on Dalton’s law and Raoult’s law.
32

33. Steam distillation
• Steam distillation is often used to separate heat-sensitive components
in a mixture.
• This is done by passing steam through the mixture (which is slightly
heated) to vaporize some of it. The process establishes a high heat-
transfer rate without the need for high temperatures.
• The resulting vapour is condensed to afford the required distillate.
• The process of steam distillation is used to obtain essential oils and
herbal distillates from several aromatic flowers/herbs.
33

34. Principle
When a mixture of two liquids that are immiscible (e.g., water and
organics) is heated and disturbed, each liquid's surface exerts its own
vapour pressure as though another component of the mixture was
absent.
Here, the specific constituent independently extracts the vapour
pressure on its own, and the vapour pressure of the system consequently
increases.
The two immiscible liquids tend to boil when the vapour pressure of
these liquids exceeds the atmospheric pressure.
Most of the organic compounds are insoluble in water.
At an absolute temperature, we can purify it because that is below the
point at which such compounds decompose
34

35. Applications
1. It is used for the separation of immiscible liquids. Eg: Toluene &
Water
2. This method is used for extracting most volatile oils such as clove,
anise and eucalyptus
3. It is useful in purification of liquid with high boiling point.
Eg: Essential oil of almond
4. Aromatic waters are prepared by this method
35

36. 36

37. Construction:
It consists of steam can with two holes. Through one hole safety tube
passes to relieve pressure if high pressure generated. Through other
holes, a bent tube is passed whose other end is attached to the flask
having non-aqueous liquid. There is also a provision to heat steam can
and flask. A delivery tube is also attached to the flask and condenser.
The condenser is attached to the receiver.
Working:
The steam can is filled with water. The non-aqueous liquid is placed into
a flask and a small quantity of water is added. The flask is then heated
gently. Now steam is bubbled through the contents in the flask. The
vapours of the compound mix up with steam and escape into the
condenser. The condensate thus obtained is a mixture of water and non-
aqueous liquid which can be separated.
37

38. 38

39. • It consists of a still having a mesh or perforation near the bottom.
Steam is produced by boiling water below the mesh. The steam passes
through the materials (to be extracted) packed over the mesh. The
vapor containing the volatile oil is then passed to the condenser. The
distillate is collected in Florentine receivers. Florentine receiver
separates the oil and water according to their densities. The aqueous
phase can be recycled again to avoid the loss of volatile oil in the
water.
• Florentine Receiver is of two types: Type-I is used for the separation
of oil heavier than water. While Type-II is used for the separation of
oil lighter than water. In Type-I receiver, the tap fitted near the bottom
of the vessel is used for collecting oil, whereas the tap fitted near the
top of the vessel is used for water to overflow. In Type-II receiver is
fitted with a siphon at the bottom that works when it gets filled with
water whereas the tap fitted near the top is an outlet for the flow of oil.
39

40. Advantages:
• Steam distillation is useful for extracting most fats, oils, and waxes.
This process works well for types of substances that do not mix with
water.
• Steam distillation is used for oil extraction and also used in the
fragrance and essential oil industry.
Disadvantages:
Steam distillation has the disadvantage of having a higher initial cost for
investment in the equipment.
40

41. Azeotropic distillation:
• In chemistry, azeotropic distillation is a technique which is used to
break an azeotrope in distillation. Azeotropic distillation is the specific
technique of adding another component to generate new, lower-boiling
azeotrope that is heterogenous. This practice of adding an entrainer
which forms a separate phase is a specific sub-set of (industrial)
azeotropic distillation methods, or combination thereof. In some
senses, adding an entrainer is similar to extractive distillation.
• An azeotrope can be either homogeneous or heterogeneous.
• Homogeneous azeotrope contains one liquid phase, while
heterogeneous azeotrope contains two liquid phase. Heterogeneous
azeotrope easily separated by distillation while homogenous azeotrope
are pressure sensitive and it can be separated by pressure swing
distillation.
41

42. 42

43. • Solvent selection for azeotropic distillation is more difficult than for
extractive distillation. There are fewer solvents that will form
azeotropes that boil at a low temperature to be easy to remove in the
distillate or boil at high temperature to be easy to remove in the
bottoms.
• The binary or ternary azeotrope formed must be separated. In practice
this requirement is met by heterogeneous azeotrope and by azeotrope
that are easy to separate with water wash.
43

44. Importance and industrial relevance of azeotropic distillation
• Need for efficient recovery and recycle of organic solvents in chemical
industry
• Distillation is the most common unit operation in recovery processes
because of its ability to produce high purity products
• Most liquid mixtures of organic solvents form azeotropes that complicate
the design of recovery processes
• Azeotropes make separation impossible by normal distillation but can be
also utilised to separate mixtures not ordinarily separable by normal
distillation
• Azeotropic mixtures may often be effectively separated by distillation by
adding a third component, called entrainer.
44

45. Definitions:
• The methods and tools presented in this lecture also apply for:
• − Azeotropic mixtures, close boiling systems, low relative volatility systems
• Original components A and B: The components that form the azeotrope and need
• to be separated
• Entrainer: A third component (E or C) added to enhance separation
• Binary azeotrope: Azeotrope formed by two components
• Ternary azeotrope: Azeotrope formed by three components
• Homogeneous azeotrope: Azeotrope where the forming components are miscible
• Heterogeneous azeotrope: Azeotrope where the forming components are immiscible
• Minimum boiling azeotrope: Azeotrope with lower boiling point than its constituent components
(most common)
• Maximum boiling azeotrope: Azeotrope with higher boiling point than its constituent
components (less common)
45

46. Azeotropic distillation methods
1) Pressure swing distillation
2)Homogeneous azeotropic (homoazeotropic) distillation
3)Heterogeneous azeotropic (heteroazeotropic) distillation
4)Extractive distillation
• Where as in case of Hybrid methods, the membrane is used as the
mass separating agent by absorbing and diffusing one of the azeotrope
forming component.
46

47. ENTRAINER
• An entrainer was added to separate homogeneous azeotropic mixture
by distillation. Entrainer are also used to enable the separation of non-
azeotropic mixtures were the direct separation is either not feasible
due to process constraints or highly uneconomical. An entrainer
facilitates the separation by selectively altering the relative volatilities
of the component in azeotropic mixture.
• The choice of an entrainer determines the separation sequence and
hence the overall economics of the process, entrainer selection is a
critical step in the synthesis and conceptual design of azeotrope
distillation process. Entrainers are commonly selected based in on
prior experience with the same or a similar process.
47

48. Selection of entrainer :
For selection of entrainer following properties are desirable.
It should boil within limited range of the hydrocarbon to be separated
Should form azeotrope, on mixing with the hydrocarbon, a large
deviation from Raoult’s law to give a minimum azeotrope with one or
more of the hydrocarbons types in the mixture
It should be soluble in hydrocarbons
It should be easily separable from the azeotrope
It should be inexpensive and easily available
It should be stable at distillation temperature
It should be nonreactive with the hydrocarbon being separated and
with the material of construction of the equipment
48

49. 1) Pressure swing distillation
• Principle: Overcome the azeotropic composition by changing the
system pressure
• Azeotrope sensitive to pressure changes, recycle ratio which increases
costs
• Application: Tetrahydrofuran/water
49

50. 2) Homogeneous azeotropic distillation
oEntrainer completely miscible with the original components
oEntrainer may (or not) form additional azeotropes with the original
components
oThe distillation is carried out in a sequence of columns
• Principle:
oThe addition of the entrainer results in a residue curve map
promising for separation
oBoth original components must belong to the
same distillation region
50

51. 3) Heterogeneous azeotropic distillation
o Entrainer is immiscible and forms azeotrope with at least one of the original azeotropic
components
o The distillation is carried out in a combined column-
decanter column
o Entrainer is recovered and recycled to the first column
• Principle:
o Liquid-liquid immiscibility's are used to overcome
azeotropic compositions
o Distillation boundaries can be crossed by immiscibility
• Applicability:
o Widely used in the industry
o One of the oldest methods of azeotropic distillation
51

52. 4) Extractive distillation
o Heavy entrainer is used with high boiling point
o Distillation is carried out in a two-feed column with a heavy entrainer added continuously at
the top
o Entrainer is recovered in a second column
Principle:
o The entrainer alters the relative volatility of the original components
o The entrainer has a substantial higher affinity to one of the
original components and ‘‘extracts’’it downwards the azeotropic column
Applicability:
o Most widely used method in the industry
52

53. Common equipment used in azeotropic distillation
53

54. A common historical example of azeotropic distillation is its use in
dehydrating ethanol and water mixtures.
For this, a near azeotropic mixture is sent to the final column where
azeotropic distillation takes place.
Several entrainers can be used for this specific
process: benzene, pentane, cyclohexane, hexane, heptane, isooctane, ac
etone, and diethyl ether are all options as the mixture. Of these benzene
and cyclohexane have been used the most extensively.
However, because benzene has been discovered to be a carcinogenic
compound, its use has declined. While this method was the standard for
dehydrating ethanol in the past, it has lost favour due to the high capital
and energy costs associated with it.
Another favourable method and less toxic than using benzene to break
the azeotrope of the ethanol-water system is to use toluene instead.
54

55. A Dean-Stark apparatus is used
in azeotropic drying or
dehydration processes: 1 stirrer
bar/anti-bumping granules, 2
still pot, 3 fractionating
column, 4 thermometer/boiling
point temperature, 5 condenser,
6 cooling water in, 7 cooling
water out, 8 burette, 9 tap, 10
collection vessel
55

56. Application of Azeotropic distillation
• The purification of products, such as acetic acid, pyridine, and other
common compounds, also uses azeotropic distillation, which has clear
advantages. Additionally, it is employed in the allyl alcohol, butenal,
and tetrahydrofuran solvent purification processes.
• It is also used by many people to break an azeotrope in the distillation
process.
• It is also used to separate benzene from the mixture of benzene
cyclohexane during the production of cyclohexane from benzene
through hydrogenation
56

57. Crystallization
Crystallization is the spontaneous arrangement of the particles into a
respective orderly array i.e., regular geometric patterns.
Particles are present randomly due to thermal agitation.
Crystallization takes place directly from vapour of substance.
Eg: Solid camphor from camphor vapour &iodine from iodine vapour.
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58. Crystallization From Aqueous Solution
 Water of Crystallization are water molecules that are present inside the
crystal.
 Water is often incorporated in the formation of crystals from aqueous
solution.
 Water of crystallization is the total mass of water in substances at a given
temperature and is mostly present in a definite ration.
 Water of crystallization refers to water that is found in the crystallization
frame work 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 frame work.
 Water of crystallization can generally be removed by heating a sample but
the crystalline properties are often lost.
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59. Aqueous solution from crystllization
Method of crystallizing from aqueous solution an inorganic solute,
whose solubility in water varies relatively little with temperature such
that crystallizing by adjustment of temperature results in low yield, such
method comprising contacting a concentrated aqueous solution of the
solute with a hydrophilic organic solvent at a temperature T1, T1 and the
organic solvent being selected such that at T1 a water-rich phase is
formed in which the ratio of solute to water is less than the ratio found
in the incoming aqueous solution, resulting in formation of crystals of
solute.
Advantageous method of operating this process that is applicable for
many salts less hydrophilic than sodium hydroxide and that uses organic
liquids that are more hydrophilic than those suitable for extracting water
from sodium hydroxide solutions.
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60. Crystallization of CaCO3 in Aqueous Solutions with Extremely
High Concentrations of NaCl
• First, 25 mL of 0.04 mol/L CaCl2 solution and 200 mL of NaCl (3.5
wt.%–14 wt.%) were prepared in advance. Then, the mixture was
introduced into a three–necked glass reactor which was equipped with
a calcium ion selective electrode and pH electrode. The reactor was
placed in a constant temperature thermostatic water bath at 25 °C with
continuous stirring. Before the addition of carbonate, the initial pH
value of each solution was adjusted to 6.4 using 0.01 mol/L HCl. In
the following stage, 25 mL of 0.04 mol/L Na2CO3 was added rapidly
into the vessel. The pH values and the calcium ion concentrations were
measured continuously.
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61. The crystallization process of CaCO3 included nucleation, crystal
growth, agglomeration and recrystallization. The crucial driving force
for both nucleation and growth was the supersaturation level. The
degree of mineral supersaturation could be quantified by the
supersaturation ratio (SR), which was the ratio of dissolved CaCO3 ionic
activity product (IAP) to the solubility product (Ksp).
the effect of concentration of NaCl on CaCO3 crystallization was
studied by a static test. The results of η increased with the promotion of
the NaCl concentration, which demonstrated that an extremely high
concentration of NaCl could hinder the crystallization of CaCO3.
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62. 62

63. Example of this method of solvent-induced crystallization,
1. consider the recovery of sodium carbonate from water. At
temperatures above 40° C. the solubility of sodium carbonate in pure
water decreases slightly with increasing temperature
2. Normal-propyl alcohol (1-propanol) is completely miscible with
water at ambient temperatures and pressures.
Procedure
A method of crystallizing an inorganic solute from an aqueous solution,
said solute having a solubility (in water) that changes relatively little
with temperature such that the crystallization of solute from aqueous
solution by adjustment of temperature results in a low yield, said
method comprising:
(a) providing an aqueous solution of such solute which is saturated or
substantially saturated at T1
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64. (b) providing a hydrophilic organic solvent
(c) contacting solution (a) with solvent (b) at T1 in a crystallizing zone, thereby producing (1) a
solvent-rich phase and a water-rich phase or (2) a single solvent-rich liquid phase, T1 being selected
so that the ratio of the solute to water in the solvent-rich phase is substantially less than in solution
(a), thereby causing crystallization of a portion of the solute,
(d) separating crystals of solute,
(e) separating all or a major portion of the solvent rich phase,
(f) adjusting the temperature of the separated solvent-rich stream by heating or cooling it from T1 to
T2,
(g) contacting the solvent-rich stream from step (f) in an extraction zone with a concentrated aqueous
solution of said solute at T2, the temperature T2 (differing from T1) and the concentration of solute in
the aqueous solution being such that the resulting dried solvent phase is suitable for recycling to the
crystallizing zone,
(h) separating from the extraction zone the dried solvent phase and recycling it to the crystallizing
zone
(i) separating from the extraction zone the diluted aqueous solution of solute
(j) employing all or a portion of the diluted solution separated i step (i) to dissolve solute from a solid
source, resulting in solution (a) and
(k) employing the resulting solution (a) from step (j) in the crystallizing zone
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65. Crystallization from Non Aqueous Solution
 Growth of Non aqueous solution often allows realization of special
crystallization, aims by control of the solution properties.
 Solvents are further classified according to their solubility of
electrolytes and Non electrolytes.
 Several solvents and solubility effects are then pointed out such as the
effect on the nucleation, which is easier when solubility is higher than
Ion of the crystallization of polymers and on the surface morphology
of the crystals.
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66. Examples :
liquid ammonia, liquid sulfur dioxide, sulfuryl chloride and sulfuryl
chloride fluoride, phosphoryl chloride, dinitrogen tetroxide, antimony
trichloride, bromine pentafluoride, hydrogen fluoride, pure sulfuric acid
and other inorganic acids.
Barium sulfate crystallization in non-aqueous solvent
Crystallisation is performed in a non-aqueous solvent,
dimethylsulfoxide (DMSO), in order to determine what the role of water
is on the crystallisation pathway.
In both water and DMSO environments the particles do not appear to
grow by ion addition but rather appear to grow through aggregation.
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67. • In DMSO, the aggregation processes appear less oriented and while
there is some lattice registry, lattice mismatch is also observed and the
aggregate shape is spherical overall a strained solid is formed.
• It is observed that the solubility of Barium sulfate in DMSO is higher
than in water, which explains the lower nucleation rates in DMSO
compared to water at same concentration.
• Lower nucleation rate observed when Ba+2 is solvated with DMSO .
• Higher activation energy in DMSO than in water.
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68. 68

69. Factors Affecting Crystallization
• Solvent – moderate solubility is best. Super saturation leads to sudden
precipitation and smaller crystal size.
Solvent Considerations
o Moderate solubility is best (avoid super saturation)
o Like dissolves like
o Hydrogen bonding can help or hinder crystallization.
o Presence of benzene can help crystal growth
o Avoid highly volatile solvents
o Avoid long chain alkyl solvents can be significantly disordered in
crystals. Choose solvents with “rigid geometries”
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70. Nucleation – fewer nucleation sites are better. Too many nucleation
sites (i.e. dust, hairs, etc.) lower the average crystal size.
Nucleation & Growth
o Crystals initially form via “nucleating events”
o After a crystallite has nucleated it must grow
o Nucleation sites are necessary, but ...
o Excess nucleation sites cause smaller average crystal size
o Ambient dust, filter paper fibers, hair, broken off pipette tips all provide
opportunities for nucleation – take steps to remove them
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71. Mechanics (Crystal Growth)
o Crystals grow by the ordered deposition of the solute molecules onto
the surface of
a pre-existing crystal
o Crystal growth is facilitated by the environment changing slowly over
time.
o Keep crystal growth vessel away from sources of mechanical
agitation (e.g.
vibrations)
o Set-up away from vacuum pumps, rotovaps, hoods, doors, drawers,
and so on
o Leave samples alone for 1 week, don't “check in” with it. Your
crystals are not lonely.
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72. Time – faster crystallization is not as good as slow crystallization.
Faster crystallization higher chance of lower quality crystals.
o Quality crystals grow best over time in near equilibrium conditions.
o The longer the time, the better the crystals.
Presence of another Substance
o Sodium Cloride crystalized from aqueous solution produces cubic
crystals.
oIf Sodium chloride is crystalized from a solution containing a small
amount urea, the crystals obtained will have octahedral faces.
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73. Crystal Growing Techniques
Slow Evaporation: simplest to set up. Has drawbacks: solute can “oil
out”, crystals
stick to sides of vessel making them difficult to extract from vessel
without breaking
them..
o Slow Cooling: Soluble when hot, insoluble when cool.
Use Dewar to slow the cooling process.
Use a Oil Bath, and cut the heat to the bath for slow cooling.
Use a thermally insulated environment (bed of vermiculite).
o Variations: use binary or tertiary solvent mixtures. Use solvent with
similar boiling point and other properties.
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74. Nucleation
 Nucleation refers to the birth of very small crystal in bodies of new
phase within a homogeneous super saturated liquid phase.
 Nucleation is a consequence ofrapidlocal fluctuations at the molecular
level when molecules or ions or atoms are in random motion in any
small volume.
 Initially several molecules or ions or atoms associate to form clusters.
These are loose aggregates, which usually disappear quickly.
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75. 1. Primary Nucleation(Homegeneous): In the absence of crystals
The phenomenon is based on sequences of bimolecular collisions and
interactions in a super saturated fluid, which results in the buildup of
lattice: Structured bodies that may or may not achieve thermodynamic
stability.
2. Secondary Nucleation(Heterogenous): In the presence of crystals
Can take place only if crystals of the species under consideration are
already present.
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76. Polymorphs
• Certain drugs can exist in more than one crystalline form. Such a
phetnomenon is known as polymorphism.
• About 63% of barbiturates, 67% of steroids and 40% of sulphonamides
exhibit polymorphism.
• Polymorphs differ significantly with respect to a number of properties such
as density, melting point, solubility and dissolution rate.
Metastable polymorphs :
Metastable polymorphs have lower melting point, higher solubility and higher
dissolution than their stable polymorphs.
If the rate of conversion is slow as to be negligible during the expected life of
a drug product, metastable polymorphs are preferred because of their unique
physicochemical properties.
These polymorphs slowly convert stable polymorphs.
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77. REFERENCE
• Pharmaceutical Engineering- C.V.S. Subrahmanyam. 293-381.
• https://www.slideshare.net/JoonJyotiSahariah/crystalli-zation-ppt
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78. thank you
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