DRYING

DR. Wahome
DRYING

Definition of Drying
Drying is defined as the removal of a liquid from a material by the application of heat
and is accomplished by the transfer of a liquid from a surface into an unsaturated
vapour phase.
It can also be defined as the removal of all or most of the liquid by supplying latent
heat to cause thermal evaporation i.e. a liquid is converted into vapour.
Drying and evaporation are distinguishable by the relative quantity of liquid
removed from the solid.
There are non-thermal methods of drying e.g.
i. Expression of a solid to remove liquid (squeezing)
ii. Extraction of liquid from a solid by use of a solvent ( solvent
extraction)
iii. Adsorption of water from a solvent by use of desiccants
iv. Absorption of moisture from gases
v. Desiccation of moisture from a solid by putting it in a moisture free
container with moisture removing material.

Purpose of Drying
1. It is used in pharmaceutical manufacturing as a unit process in the
preparation of granules which can be dispensed in bulk or converted
into tablets or capsules.
2. It is applied in processing of materials e.g. preparation of dried
aluminum hydroxide, spray drying of lactose and preparation
powdered extracts
3. It is used to reduce the bulk and weight and hence lowering the cost of
transportation and storage
4. It aids in the preservation of animal and vegetable drugs by
minimizing growth of moulds and bacteria in moisture laden material

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 5. Drying enhances stability in products e.g. in aspirin it reduces the
chemical activity of the remaining water which is expressed as a
reduction in water activity of the product

Drying of Wet Solids

The following terms are important in explaining operations of drying.
Moisture content – it is used in measuring the amount of moisture in wet solids
It is calculated in dry weight basis.
Percentage moisture content = Weight of water in sample x 100
Weight of dried sample
It may be expressed as kg of moisture associated with 1 kg of ‘bone dry’ solid
that will remain after complete drying.

Total moisture content – It is the total amount of liquid associated with wet
solid. Not all moisture can be removed by drying method.
Free moisture content
It is the moisture which is more difficult to remove. This water which is easily
removable by evaporation is referred to as unbound water.
It exists as a liquid and exerts its full vapour pressure.
The equilibrium moisture content is the moisture content present in a solid
under a steady state of ambient conditions.
Its values change with temperature, humidity and nature of the solid.
Bound water – it is the moisture part that is adsorbed on the surface of the solid
or adsorbed within its structures, to such an extent to prevent it from developing
its own vapour pressure.
It is adsorbed on solid surface as individual water molecules which may form
mono or bi-layer on the solid surface.
It presents as a liquid trapped within capillaries in the solid by surface tension.
It is not easily lost by evaporation

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Relative Humidity (R.H.)
The percentage Relative Humidity can be defined as:
Vapour pressure of water vapour in air over vapour pressure of water vapour in
air saturated at the same temperatures x 100
VP of water in air x 100
VP of water in air saturated at same temp

Relative humidity depends on:

-Temperature
-Amount of water present in the air
It may increase during drying process as a result of two factors.
i) Uptake of evaporated water vapour from the wet solid
ii) Cooling of the supply air as it transfers heat to the wet solid
If cooling is excessive, the temperature of air may fall to the ‘dew point’ values
when the liquid water condenses and is deposited.

Relationship between the moisture content MC the relative humidity R.H.

The equilibrium moisture content (EMC) of a solid exposed to moist air varies
with R.H.
The ordinary atmospheric conditions are of the order 200C and 70 – 75% RH.
Materials exposed to humid conditions will regain moisture and hence there is no
advantage of drying to moisture content lower than that which the material will have
under the conditions of use.

Loss of Water from Wet Solids

Unbound water is lost by evaporation until equilibrium moisture content of the
solid is reached. Further drying does not change the moisture content.

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The only way to reduce the moisture content of the material is to reduce the
relative humidity of the ambient air.
This can be done in large scale by air conditioning systems.
In small scale, a desiccant is used e.g. phosphorus pentoxide or silica gel.
The desiccant uses the water content of the surrounding air rather than from the
solid. This in turn uses the moisture content of the solid in the desiccation.
Moisture may be regained if a dry solid is exposed to ambient air. Hence it is
unnecessary to over-dry a product.
If low residual moisture content is necessary because of the hydrolytic instability
of the material, the dried material must be efficiently sealed from ingress of
moisture.
Types of Drying Method
The following factors should be considered while drying:
i) Heat sensitivity of the material being dried
ii) Physical characteristics of the material
iii) Necessity for sepsis (condition of absence of micro-organisms)
iv) The nature of liquid to be removed
v) Scale of operation- quantity of product to be dried
vi) Availability of sources of heat
vii) Cost involved

The general principles for efficient drying can be summarized as follows

i. Large surface area for heat transfer
ii. Efficient heat transfer per unit area (to supply sufficient latent heat of
vaporization or heat of sublimation in case of freeze drying).
iii. Efficient vapour removal i.e. relative humidity of air should be
adequate to provide vapor gradient
iv. Efficient mass transfer of evaporated water –turbulence to minimize
boundary layer thickness.

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 TYPES OF DRYERS
i) Dryers for damp solid material
a) Tray or shelf dryers
b) Tunnel dryers
c) Rotary dryers
d) Fluidized bed dryers
e) Vacuum dryers
f) Freeze drying
ii) Dryers for dilute solutions, suspensions and slurries
a) Drum dyers
b) Spray dryers

CONVECTION DRYING OF WET SOLIDS

Dynamic Convective dryers
Fluidized-bed dryer
Fluidization produces conditions of great turbulence where particles mix with
good contact between air and the particles. If hot air is used, the turbulent

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conditions lead to high heat and mass transfer rates, the fluidized-bed technique
therefore offering a means of rapid drying.
The fluidized-bed dryer was developed to improve the efficiency of heat transfer
and vapour removal compared with the older static tray dryers. A reason for this
is the more efficient transfer of the required latent heat of evaporation from the
air to the drying solid.
The rate of heat transfer in convective drying may be written as:

Where:
-hc is a heat transfer coefficient for convective heat transfer,
-A is the surface area available for heat transfer,
- ∆T is the difference in temperature between the drying air and the solid to be
dried.
The heat transfer coefficient is high in a fluidized bed as the vigorous motion of
the particles reduces the thickness of the boundary layer.
The process fluidizes individual powder particles or granules and thus the
surface area available for drying is maximized to the total surface area of the
powder bed.
Heat and mass transfer are therefore relatively efficient and the process takes
between about 20 and 40 minutes.

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 Fluidized bed dyer

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Advantages of fluidized-bed drying
1. Efficient heat and mass transfer give high drying rates, so that drying
times are short. The heat challenge to thermolabile materials is minimized.
2. The fluidized state of the bed ensures that drying occurs from the surface
of all the individual particles. Hence, most of the drying will occur at a
constant rate.
3. The temperature of a fluidized bed is uniform throughout (as a result of
the turbulence) and can be controlled precisely.
4. The turbulence in a fluidized bed causes some attrition to the surface of
the granule. This produces a more spherical free-flowing product.
5. The free movement of individual particles reduces the risk of soluble
materials migrating during drying.
6. Keeping the granules separate during drying also reduces the problems of
aggregation and reduces the need for a sieving stage after drying.
7. The fluidization containers can be mobile, making handling and
movement around the production area simple, thus reducing labour costs.
8. Short drying times mean that the unit has a high product output from a
small floor space.

Disadvantages of fluidized-bed drying

1. The turbulence of the fluidized state may cause excessive attrition of
some materials and the production of too much dust.

2. Fine particles may become entrained in the fluidizing air and must be
collected by bag filters with care to avoid segregation and loss of fines.

3. The vigorous movement of particles in hot dry air can lead to the
generation of charges of static electricity. A mixture of air with fine

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 dust of organic materials like starch and lactose can explode violently
if ignited by sparking caused by static charges.
The danger is increased if the fluidized material contains a volatile
solvent. Adequate electrical earthing is essential and is fitted on all
modern dryers.

CONDUCTIVE DRYING OF WET SOLIDS

In this process the wet solid is in thermal contact with a hot surface and the bulk
of heat transfer occurs by conduction.
Vacuum oven
The vacuum oven consists of a jacketed vessel sufficiently strong to withstand a
vacuum within the oven and possibly steam pressure in the jacket. The supports
for the shelves form part of the jacket, giving a larger area for conduction heat
transfer. The oven should be closed by a door that can be locked tightly to give
an airtight seal. The oven is connected through a condenser and liquid receiver to
a vacuum pump, although if the liquid to be removed is water and the pump is
of the ejector type that can handle water vapour, the pump can be connected
directly to the oven.
Operating pressure can be as low as 0.03—0.06 bar, at which water boils at 25—
350C. Some ovens may be large - about 1.5 m cube and with 20 shelves.
The main advantage of a vacuum oven is that drying takes place at a low
temperature and since there is little air present, there is minimum risk of
oxidation.
The temperature of the drying solid can rise to the steam or heating water
temperature at the end of the drying but this is not usually harmful.
Vacuum ovens are rarely used except to dry particularly thermolabile or oxygen-
sensitive materials. Small-scale ones are found in labs for the drying of small
samples when the heat stability of the drug or formulation is uncertain.

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 Schematic diagram of a Vacuum oven

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DRYERS FOR SOLUTIONS AND SUSPENSIONS
The objective of these dryers is to generate a large surface area in the liquid for
heat and mass transfer and to provide an effective means of collecting the dry
solid. The most useful type disperses the liquid to a spray of small droplets —
the spray dryer.

Spray dryer
The spray dryer provides a large surface area for the mass transfer by atomizing
the liquid to small droplets.
These are sprayed into a stream of hot air, so that each droplet dries to an
individual solid particle. Thus particle formation and drying occur in the one
process.
There are many forms of spray dryers. The typical design is one in which the
drying chamber resembles a cyclone. This ensures good circulation of air,

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facilitates heat and mass transfer and encourages the separation of dried particles
from the moving air by the centrifugal action.

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Atomizer
In a rotary type of atomizer liquid is fed on to the disc that is rotated at high
speed (10 000—30 000 revolution/min). A film is formed and spreads from the
small disc to a larger, inverted hemispherical bowl, becoming thinner, and
eventually being dispersed from the edge in a fine spray of uniform droplet size.

Rotary Atomizer

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Rotary atomizer
The rotary atomizer has the advantage of being equally effective with either
solutions or suspensions of solids and it can operate efficiently at various feed
rates.

Spray dryer

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Modern two-fluid nozzles have overcome the problems of earlier jet atomizers.
The two fluids are the liquid product and the atomizing air. Two-fluid nozzles
can handle feed rates between 30 and 80 L/h. They can be positioned either to
spray their droplets co-currently into the air stream from the top of the dryer, or
to spray from the base of the dryer in a ‘fountain mode’.
The two-fluid nozzles produce a narrow droplet size range with the mean size
being affected by nozzle position. Rotary atomizers produce droplets in the mid-
range.

Chamber
The air enters the chamber tangentially and rotates the drying droplets around
the chamber to increase their residence time and therefore time for drying. For
pharmaceutical purposes, it is usual to filter the air and to heat it indirectly by
means of a heat exchanger. Dust carried over in the air outlet stream may be
recovered by a cyclone separator or filter bag. It is also possible to recycle up to
60% of the exhaust air to the air inlet of the dryer. This greatly improves the
efficiency of the process.

Product
Spray-dried products are easily recognizable by their uniform appearance. The
particles have a characteristic shape, in the form of hollow spheres sometimes
with a small hole.
This arises from the drying process, since the droplet enters the hot air stream
and dries on the outside to form an outer crust with liquid still in the centre. This
liquid then vaporizes and the internal vapour escapes by blowing a hole in the
sphere.

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Formation of product in spray drying

Intelligent computer control is available to control process hence affect particle

size, bulk density, moisture content, dissolution rate and dispersibility of the
resulting product.

Advantages of the spray-drying process

1. There are millions of small droplets which give a large surface area for
heat and mass transfer, so that evaporation is very rapid. The actual
drying time of a droplet is only a fraction of a second, and the overall time
in the dryer only a few seconds.
2. Because evaporation is very rapid, the droplets do not attain a high
temperature. Most of the heat is used as latent heat of vaporization and
the temperature of the particles is kept low by evaporative cooling.
3. The characteristic particle form allows efficient particle packing and thus
gives the product a bulk density. It also leads to rapid dissolution because
of the large surface area.
4. Provided that a suitable atomizer is used, the resulting powder will have a
uniform and controllable particle size.

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 5. The product is free-flowing, with almost spherical particles, and is
especially convenient for manufacture as it has excellent flow and
compaction properties.
6. In many cases spray drying will increase the dissolution rate and
bioavailability of poorly water-soluble drugs (APIs).
7. Labour costs are low, the process yielding a free-flowing powder from a
dilute solution, in a single operation with no handling.
8. It can be used as a continuous process if required.

Disadvantages of the spray-drying process

1. The equipment is very bulky and, with the ancillary equipment, is
expensive.
2. The overall thermal efficiency is rather low as the air must still be hot
enough when it leaves dryer to avoid condensation of moisture.
Also large volumes of heated air pass through the chamber without
contacting a particle and contributing directly to the drying process.

Uses of the spray-drying process

The spray dryer can be used for drying almost any substance, in solution or in
suspension. It is mostly used for thermolabile materials, and particularly if
handled continuously and in reasonably large quantities.
Soluble and insoluble substances that are spray dried include citric acid, sodium
phosphate, gelatin, starch, barium sulfate and calcium phosphate. The process is
also used for some powdered antibiotic formulations where the spray-dried
powder is packaged and distributed. This is then reconstituted as syrup at the
time of dispensing. The spray dried formulation contains all the necessary
ingredients, including colours and flavours. Since only water is removed in the
spray-drying process, these products must be reconstituted with water only.

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Spray drying is also capable of producing spherical particles in the respirable
range of 1—7 um that is necessary for the delivery of drugs from dry powder.
It is possible to operate spray dryers aseptically using heated filtered air to dry
products such as serum hydrolysate. Some spray dryers operate in a closed
circuit mode with an inert gas to minimize oxidation of the product. Volatile
solvents can be recovered from such systems.

Fluidizing spray dryer

A development of the spray dryer is the fluidized spray dryer. This has a small
fluidized bed mounted in the base of the cone at the point where the product is
collected. The moving air created in the fluidized bed overcomes any cohesion of
spray-dried particles after they fall into the collection chamber. This allows
spheres with a higher moisture content to be handled and also ones made from
stickier and more cohesive substances than were previously possible to process.

DRUM DRYER:
The drum drier consists of a drum 0.45 – 1.5m in diameter and 2.4 m in length
heated internally, usually by steam and rotated on its longitudinal axis.
The liquid is applied to the surface of the drum and spread to a film. This may be
done in various ways but the simplest method is where the drum dips into a feed
pan.
Drying rate is controlled by manipulating the speed of rotation of the drum and
its temperature. The drum can be heated by either steam or warm water.
The product is scraped from the surface of the drum by means of doctor’s knife.

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Advantages
1. The process gives rapid drying, the thin film spread over a large area
resulting in rapid heat and mass transfer.
2. The equipment is compact, occupying much less space than the spray-
drier
3. Heating time is short, being only a few seconds.
4. The drum can be enclosed in a vacuum jacket, enabling the temperature of
drying to be reduced.
5. The product is obtained in flake form which is convenient for many
purposes.

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The only disadvantage is that operating conditions are critical and it is necessary
to impose careful control on feed rate, film thickness, speed of drum rotation and
drum temperature.

The drum drier can handle a variety of materials, either as solution or as

suspensions.
Substances that are dried by this method include starch products, ferrous salts
and suspensions of kaolin and zinc oxide.

SOLUTE MIGRATION DURING DRYING

Solute migration is the phenomenon that can occur during drying which results
from the movement of a solution within a wet system. The solvent moves
towards the surface of a solid (from where it evaporates), taking any dissolved
solute with it.
Many drugs and binding agents are soluble in granulating fluid and during the
drying of granulates these solutes can move towards the surface of the drying
bed or granule and be deposited there when the solvent evaporates.
Solute migration during drying can lead to localized variability in the
concentration of soluble drugs and excipients within the dried product.

Migration associated with drying granules can be of two types: intergranular

migration (between granules) and intragranular migration (within individual
granules).
Intergranular migration
The solutes move from granule to granule and this may result in gross
maldistribution of active drug. It can occur during the drying of static beds of
granules (e.g. tray drying) since the solvent and accompanying solute(s) move
from granule to granule towards the top surface of the bed where evaporation
takes place. When the granules are compressed, the tablets may have a deficiency

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or an excess of drug. An experiment found that only 12% of tablets made from a
tray-dried warfarin granulate were within the USP limits for drug content.

Intragranular migration
Drying methods based on fluidization and vacuum tumbling keep the granules
separate during drying and so prevent the intergranular migration that may
occur in fixed beds. However, intragranular migration, where the solutes move
towards the periphery of each granule, may take place.

Diagram of mottling caused by intragranular migration

Consequences of solute migration

Solute migration of either type can result in problems and occasional benefits.
Loss of active drug
The periphery of each granule may become enriched, with the interior suffering
depletion. This will be of no consequence unless the enriched outer layer is
abraded and lost, as may happen during fluidized-bed drying when the fine
drug-rich dust will be eluted in the air and carried to the filter bag or lost. The
granules suffer loss of drug and as a result will be below specification with
respect to quantity of active ingredient.

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Mottling of coloured tablets
Coloured tablets can be made by adding soluble colour during wet granulation.
Intragranular migration of the colour may give rise to dry granules with a highly
coloured outer zone and a colourless interior.
During compaction, granule fracture takes place and the colourless interior is
exposed. The eye then sees the coloured fragments against a colourless
background and the tablets appear mottled.

Migration of soluble binders

Intragranular migration may deposit a soluble binder at the periphery of the
granules and so confer a ‘hoop stress’ resistance, making the granules harder and
more resistant to abrasion. This migration can aid the bonding process during
tablet compaction as a result of binder—binder (rather than drug—drug or drug
—excipient) contact and is therefore sometimes beneficial.

Some practical means of minimizing solute migration

 Use the minimum quantity of granulating fluid and ensure that it is well
distributed. High-speed mixer/granulators give better moisture
distribution than earlier equipment and granulates prepared in this way
show less migration.
 Prepare the smallest granules that will flow easily and are generally
satisfactory if mottling is troublesome.
 Avoid tray drying unless there is no alternative.
 If tray drying is unavoidable, then the dry granules should be remixed
before compression. This will ensure that a random mix of enriched and
depleted granules will be fed on the tablet machines. This remixing will be
more effective if the granule size is small since there will be a greater
number of granules per die fill.

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  If intragranular migration is likely to be troublesome, consider vacuum or
microwave drying as an alternative to fluidized-bed drying.

RADIATION DRYING OF WET SOLIDS

Radiant Heat Transmission
In this method of heat transfer, a medium is not needed and this differentiates it
from conduction and convection. This form of energy /radiation can cross
through empty spaces or travel through the atmosphere without getting lost. If it
falls on a body capable of absorbing it, then it appears as heat, though a portion
of it may be reflected or transmitted.

Use of Infra red radiation

It has been used in the past to dry pharmaceutical products e.g. wet granules
though it penetrates quickly and does not penetrate far into the wet mass.
It is now seldom used as a heat source in pharmaceutical manufacture. The
surface layer dries quickly and absorption of further energy then raises the
temperature of the dry matter to an increased value which is detrimental to
product. It is time consuming and not efficient.

Use of Microwave Radiation

Microwave wavelength can generate energy when absorbed by a wet solid.
Its wavelength ranges from 10mm to 1m and penetrates much better than IR
radiation.

Generation and Action of Microwaves

They are produced by an electrical device called magnetron

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Its energy can be reflected down on a triangular duct (waveguide) or simply
beamed through a transparent polypropylene window into the drying chamber.
It operates at frequencies of 960 and 2450 MHz to avoid interference with radio
and TV waves. Its penetration into solids is so good that heat is generated
uniformly within the solid. There is no wastage of material in form of dust.
However it cannot be adapted for large scale manufacture.
Microwaves fall on substances of suitable electronic structure (small polar
molecules like water) causing the electrons to resonate in sympathy with
radiation resulting into “molecular friction” thus heat generation.
Dry solids don’t resonate well as the water is removed as indicated in the table
below by loss factor.
Microwave energy loss for some pharmaceutical solvents and excipients
Material Loss factor
Methanol 13.6
Ethanol 8.6
Water 6.1
Isopropanol 2.9
Acetone 1.25
Maize starch 0.41
Magnesium carbonate 0.08
Lactose 0.02

Loss factor: is the measure of the ratio of microwave energy absorbed by

individual molecules, the higher the number the greater the absorption of
microwave energy.
N.B. Microwave absorption is far greater for small polar molecules than for
larger and less polar material
Microwave dryers for granules

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It is designed to operate under a slight vacuum. This in itself is not essential for
the use of microwave but the air flow allows the continuous removal of
evaporated solvent.
The radiation is generated by the multiple magnetions, each producing 0.75 Kw
at 2450 MHz.
The radiation passes through the polypropylene window drying chamber.
It is absorbed by the liquid in the wet granules contained on a tray.
The heat generated in the mass drives off the moisture and the evolved vapour is
drawn away in the airflow.
When drying is nearly complete, the radiation field intensity will rise and is
detected. The magnetron is progressively turned off automatically to give an
accurate control of the final moisture content and minimize the danger of
overheating.

Advantages of Microwave Drying

1. It provides rapid drying at fairly low temperatures.
2. The thermal efficiency is high, as the drier casing and the air remain cool.
Most of the microwave energy is absorbed by the liquid in the wet
material.
3. The bed is stationary, avoiding the problem of dust and attrition.
4. Solute migration is reduced as there is uniform heating of the wet mass
5. Equipment is highly efficient and refined. All the requirements of product
and operator safety have been incorporated into machines and comply
with GMP specifications.
6. Granulation end point is possible by measuring the residual microwave
energy (as this rises sharply when there is little solvent left to operate).

Disadvantages

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 1. The batch size of commercial production microwave driers is smaller
than those available for fluidized bed driers.
2. Care must be taken to shield operators from microwave radiation
which can cause damage to organs e.g. eyes and testes. This is ensured
by ‘fail-safe’ devices preventing the generation of microwaves until the
drying chamber is sealed.

FREEZE DRYING
It is a process used to dry extremely heat-sensitive materials. It allows the drying
without excessive damage of proteins, blood products and micro-organisms
which retain a small but significant viability.
The initial liquid solution or suspension is frozen, the pressure above the frozen
state is reduced and the water removed by sublimation thus a solid to vapour
transition takes place.

Freeze drying equipment

The Triple Phase Diagram for Water

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It consists of 3 separate areas, each representing a single phase of water i.e solid,
liquid or vapor.
Two phases can co-exist along a line under the conditions of temperature and
pressure defined by any point on the line.
The point O is the one unique point where all the three phases can co-exist and is
known as the triple point. Its co-rodinates are pressure of 610 pa and a
temperature of 0.0075oC.
The lines on the phase diagram represents the interphase which shows:
i) The boiling point of water as it is lowered by reduction of the
external pressure above the water .
ii) The variation of the melting point of ice on reduction of the
external pressure above it.
iii) The reduction of the vapour pressure exerted by the ice as the
temperature is reduced.
On heating at constant atmospheric pressure, ice will melt when the temperature
rises to O0C. At this constant temperature and pressure it will then change to
liquid water. Continued heating will raise the temperature of water to 100 0C
where if heat addition is continued the liquid water will be converted into water
vapour at 1000C.
If however solid ice is maintained at a pressure below the triple point then on
heating, the ice will sublime and pass directly to water vapour without passing
through the liquid phase. This sublimation and therefore drying can occur at a
temperature below O0C.
This will only happen if the pressure is prevented from rising above the triple
point pressure and to ensure this, the vapour involved must be removed as fast
as it is formed.

Application of the phase diagram of water to freeze drying

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The freeze drying of thermolabile products like blood plasma, although simple in
theory presents a number of practical problems.
1. The depression of the freezing point caused by the presence of dissolved
solutes means that the solution must be cooled to well below the normal
freezing temperature for pure water. It is usual to work in the range – 10
to -30OC. In part, this is because it is not pure water that is being dried and
thus the presence of dissolved solutes will shift the pure water phase
diagram.
2. Sublimation can only occur at the frozen surface and is a slow process
being 1mm thickness of ice per hour. For all but very small volumes the
surface area must be increased and the liquid thickness prior to freezing
reduced in order to reduce the thickness of ice to be sublimated.
3. At low pressures, large volumes of water vapour is produced which must
be rapidly removed to prevent the pressure rising above the triple point
pressure.
4. The dry material often needs to be sterile and it must also be prevented
from regaining moisture prior to final packing.

STAGES OF THE FREEZE DRYING PROCESS

1. Freezing Stage
The liquid material is frozen before the application of vacuum to avoid
frothing. Several methods are used to produce a large frozen surface.
a) Shell freezing: Employed for fairly large volumes such as blood products.
The bottles are rotated slowly and almost horizontally in a refrigerated
bath. The liquid freezes in a thin shell around the inner circumference of
the bottle. Freezing is slow and large ice crystals form. This is a drawback
of this method as it damages blood cells and reduces the viability of
microbial cultures.
b) In vertical spin freezing the bottles are spun individually in a vertical
position so that centrifugal force forms a circumferential layer of solution,

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 which is cooled by a blast of cold air. The solution super cools and freezes
rapidly with the formation of small crystals.

2. Vacuum application stage

The containers and the frozen material must be connected to a vacuum source
sufficient to drop the pressure below the triple point and remove the large
volumes of low pressure vapour formed during drying. An excess vacuum is
normal in practice to ensure that the product in question is below its triple point.
Commonly a number of bottles or vials are attached to individual outlets which
is connected to a vacuum.

3. Sublimation stage
Heat of sublimation must be supplied under conditions where the ice slowly
sublimes, leaving a porous solid which still contains about 5% moisture after
drying.
Primary drying can reduce the moisture content of a freeze dried solid to around
0.5%. Further reduction can be effected by secondary drying in which, the latent
heat of sublimation must be provided and the vapour removed.
Heat transfer is critical as insufficient heat input prolongs the process which is
already slow, and excess heat will cause melting.

4. Vapour removal -vapour formed must be continuously removed to avoid a

pressure rise that would stop sublimation. To reduce pressure sufficiently, it is
necessary to use efficient vacuum pumps.
On a small scale, vapour is absorbed by a dessicant such as phosphorous
pentoxide, or is cooled in a small condenser with solid CO2.
Mechanically refrigerated condensers are used on large scale.

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For vapour flow to occur, the vapour pressure at the condenser must be less than
the frozen surface. Vapour is often removed by pumping but pumps must be of
large capacity and not affected by moisture.

Rate of Drying
The rate of freeze drying is very slow and the drying rate curve shows a similar
shape to a normal drying curve.
Computer control enables the drying cycle to be monitored. There is an optimum
vapour pressure for a maximum sublimation rate and the heat input and other
variables are adjusted to maintain this value.
Continuous freeze drying is possible in modern equipment, where the vacuum
chamber is fitted with a belt conveyor and vacuum locks but despite these
advances the overall drying rate is still low.
Secondary Drying
The removal of residual moisture at the end of primary drying is performed by
raising the temperature of the solid to as high as 50 or 60 0C. A high temperature
is permissible for many materials because the small amount of moisture
remaining is not sufficient to cause spoilage.
5. Packaging
Attention must be paid to packaging freeze-dried products to ensure protection
from moisture. Containers should be closed without contacting the atmosphere
if possible. Ampoules are sealed while still under vacuum. Otherwise, the
closing must be carried out under controlled atmospheric conditions.

Advantages of freeze drying

1. Drying takes place at very low temperatures so that enzymes action is
inhibited and chemical decomposition, particularly hydrolysis is
minimized.

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2. The solution is frozen such that the final dry product is a network of solid
occupying volumes of the original solution. Thus the product is light and
porous. The porous form of the product gives ready solubility.
4. There is no concentration of the solution prior to drying. Hence, salts do
not concentrate and denature proteins as occurs with other drying
methods.
5. As the process takes place under high vacuum, there is little contact with
air and oxidation is minimized.

Disadvantages
1. The porosity, ready solubility and complete dryness yield a very
hygroscopic product.
2. The process is very slow and uses complicated plant which is very
expensive.
3. It is not a generalized method of drying, but is limited to certain types of
valuable products which, because of their heat sensitivity, cannot be dried
by any other means.

Uses of Freeze Drying

The method is used for products that cannot be dried by any other heat method.
These include biological products like some antibiotics, blood products and
vaccines such as BCG, yellow fever, small pox and microbiological cultures. It
enables specific microbiological species and strains to be stored for long periods
with viability of about 10% on reconstitution.

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