PRESENTAION ON

Drying
Group members
1. Md. Rasel mia
2. Mostafizur rahman rimon
3. Md. Abu Bakar Siddique
 INTRODUCTION

Drying is an important operation in primary

pharmaceutical manufacture (i.e. the synthesis of active
pharmaceutical ingredients or excipients) since it is
usually the last stage of manufacturing before packaging.
It is important that the residual moisture, say from the final
crystallization step, is rendered low enough to prevent
product deterioration during storage and ensure free-
owing properties during use.
DRYING OF WET SOLIDS
Fundamental properties and interrelationships:
An understanding of this operation requires some preliminary
explanation of the following important terms. To avoid
confusion and repetition, these terms will be defined and
explained in the context of water (the most commonly used
pharmaceutical solvent) but the explanations and concepts are
equally applicable to other relevant liquids (e.g. ethanol,
isopropanol, etc.).
MOISTURE CONTENT OF WET SOLIDS
The moisture content of a wet solid is expressed as kg of
moisture associated with 1 kg of the moisture free or
‘bone-dry’ solid. Thus, a moisture content of 0.4 means
that 0.4 kg of water is present per kg of the ‘bone-dry’
solid that will remain after complete drying. It is
sometimes calculated as percentage moisture content;
thus this example would be quoted as 40% moisture
content.
TOTAL MOISTURE CONTENT
This is the total amount of liquid associated with a wet solid. Some
of this water can be easily removed by the simple evaporative
processes employed by most pharmaceutical dryers and some
cannot. The amount of easily removable water (unbound water)
is known as the free moisture content and the moisture content of
the water that is more dif cult to remove in practice (bound
water) is the equilibrium moisture content. Thus, the total
moisture content of a solid is equal to its free moisture content
plus its equilibrium moisture content.Unbound water. The
unbound water associated with a wet solid exists as a liquid and it
exerts its full vapour pressure. During a drying process this
unbound water is readily lost but the resulting solid will not be
completely free from water molecules as it remains in contact
with atmospheric air that inevitably contains dissolved water.
EQUILIBRIUM MOISTURE CONTENT
Evaporative drying processes will not remove all the possible
moisture present in a wet product because the drying solid
equilibrates with the moisture that is naturally present in
air.The moisture content of a solid under steady-state ambient
conditions is termed the equilibrium moisture content. Its
value will change with the temperature and humidity of the
air, and with the nature of the solid (see later in this
chapter).Bound water. Part of the moisture present in a wet
solid may be adsorbed on surfaces of the solid or be absorbed
within its structure to such an extent that it is prevented from
developing its full vapour pressure and therefore from being
easily removed by evaporation. Such moisture is described as
bound water and is more difficult to remove than unbound
water.
MOISTURE CONTENT OF AIR
An added complication to the drying process is that the
drying air also contains moisture. Many pharmaceutical
plants have air-conditioning systems to reduce the
humidity of the incoming process air, but removing
water from air is a very expensive process and therefore
not all the water will be removed.
The moisture content of air is expressed as kg of water per
kg of ‘bone-dry’ (water-free) dry air.
The moisture content of air should be carefully
distinguished from the relative humidity.
RELATIVE HUMIDITY OF AIR
Ambient air is a simple solution of water in a mixture of gases and as
such follows the rules of most solutions– such as increased water
solubility with increasing temperature, a maximum solubility at a
particular temperature (saturation) and precipitation of thesolute on
cooling (condensation, rain!). The term relative humidity (RH) expresses
the relationship between the moisture content of air at a certain temperature
and the moisture content of moisture-saturated air at the same temperature.
It is given as a percentage from 0 to 100. 100% RH means that the saturation
with moisture, the dew point is reached. Lower relative humidities can be
quantified in terms of percentage relative humidity, which is given
by vapour pressure of water vapour in air vapour pressure of water
vapour in the air saturated at the same temperature
×100
This is approximately equal to the percentage saturation, which is mass
of water vapour present per kilogram of dry air mass of water
vapour required to saturate 1kg of dry air at the same temperature
×100 (29.2)
Percentage saturation is the more fundamental measure but the
expression ‘relative humidity’ is most commonly used. The two
differ only very slightly in practice and only because water vapour
does not behave exactly like an ideal gas.
These relationships show that the relative humidity of air is dependent
not only on the amount of moisture in the air but also on its
temperature. This is because the amount of water required to
saturate air is itself dependent on temperature. As mentioned before,
in ambient air, water is in solution in the air gases, and in this case
its solubility increases with increasing temperature. If the
temperature of the air is raised whilst its moisture content remains
constant, the air will theoretically be capable of taking up more
It is important to understand the difference between moisture content and
relative humidity of air. This is important in many contexts (powder
properties, granulation, drying, compaction, storage conditions) but
these terms are often confused.
An additional complication to be taken into account is that during a
drying process both the temperature and the moisture content of the
drying air (and therefore its relative humidity) could change
significantly. This arises from two separate factors:
• Uptake into the drying air of water vapour that has evaporated from the
drying solid. If evaporation is high and vapour removal inefficient, the
drying efficiency will rapidly fall.
• The cooling of the supply air (and consequently the product) as the air
transfers latent heat to the wet solid. This phenomenon is known as
evaporative cooling. If the cooling is excessive, the temperature of the
air may fall to a value known as the dew point. Here the solubility of
water in the cooler air is reduced to such a point that the saturated
solubility is exceeded and liquid water will condense and be deposited.
CHOICE OF DRYING METHOD
When considering how to dry a particular material, one should consider the
following points:
• the heat sensitivity of the material being dried;
• the physical characteristics of the material;
• the nature of the liquid to be removed;
• the scale of the operation;
• the necessity for asepsis; and
• the available sources of heat (steam, electrical).
The general principles for efficient drying can be summarized as:
• large surface area for heat transfer;
• efficient heat transfer per unit area (to provide sufficient latent heat of
vaporization or heat of sublimation in the case of freeze-drying);
• efficient mass transfer of evaporated water through any surrounding
boundary layers, i.e. sufficient turbulence to minimize boundary
layer thickness; and
• efficient vapour removal, i.e. low relativehumidity air moving at adequate
DRYERS IN THE PHARMACEUTICAL
INDUSTRY
A variety of pharmaceutical dryers are still used, and it is
convenient to categorize these according to the heat
transfer method that they use, i.e. convection, conduction
or radiation.
Convective drying of wet solids
Fluidized-bed dryer
FLUIDIZED-BED DRYER
An excellent method of obtaining good contact between the
warm drying air and wet particles is found in the fluidized-
bed dryer. Fluidized bed dryer is a equipment used to reduce
the moisture content of pharmaceutical powder and granules.

In fluidization process, hot air is introduced at high pressure

through a perforated bed of moist solid particulate. The wet
solids are lifted from the bottom and suspended in a stream
of air (fluidized state). Heat transfer is accomplished by
direct contact between the wet solid and hot gases. The
vaporized liquid is carried away by the drying gasses.
Advantages of fluidized-bed drying
1) Drying times are short.
2) The heat challenge to thermolabile materials is minimized.
3) Most of the drying will occur at a constant rate.
4) The temperature of a fluidized bed is uniform.
5) Produces a more spherical free-flowing product.
6) Reduces the risk of soluble materials migrating during drying.

Disadvantages of fluidized-bed drying

1. The turbulence of the fluidized state may result in excessive
attrition of some materials.
2. Fine particles may become entrained in the fluidizing air.
3. Can lead to the generation of charges of static electricity.
VACUUM OVEN:

This equipment is a good example of a conduction dryer, though it is

not used as extensively as it was formerly.

Figure: Vacuum Oven

The vacuum oven consists of a jacketed vessel suffciently strong in

construction to withstand a vacuum within the oven and possibly
steam pressure in the jacket. In addition, 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 25–35 °C. Some ovens may be large (for
The main advantage of a vacuum oven is that drying
takesplace at a low temperature, and since there is little
air present, there is minimal risk of oxidation.
RADIATION DRYING OF WET SOLIDS
Radiant heat transmission:
Heat transmission by radiation differs from heat transfer by
conduction or convection in that no transfer medium
(solid, liquid or gaseous) needs be present. Heat energy
in the form of radiation can cross empty space or travel
through the atmosphere virtually without loss. If it falls
on a body capable of absorbing it, then it appears as heat
although a proportionmay be reflected or transmitted.
Use of Microwave Radiation
Microwave radiation in the wavelength range 10mm to 1m
has been found to be an ef cient heating and drying
method. Microwave dryers are used in the
pharmaceutical industry.
MICROWAVE DRYERS FOR
GRANULATES
In microwave dryers radiation is generated by multiple
magnetrons each producing 0.75 kW at 2450 MHz. The
radiation passes through the poly-propylene window into
the drying chamber, where it is absorbed by the liquid.
The heat generated in the mass drives off the moisture.
The evolved vapour is drawn away in the air flow as it is
formed. When drying is nearly complete, the radiation
field intensity within the chamber will rise because the
dry solids do not absorb as readily as water. This rise is
detected, and the magnetrons are progressively turned
down 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 dryer casing and the air remain
cool. 3. The bed is stationary, avoiding problems 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. 6. Granulation end point detection
is possible by measurement of the residual microwave
energy. Disadvantages of microwave drying: 1. The
batch size of commercial production microwave dryers
is smaller than the batch sizes available for fluidized-bed
drying. 2. Care must be taken to shield operators from
the microwave radiation.
Drying of solutions and suspensions: The objective of the
dryers used for drying of solutions and suspensions is to
generate a large surface area in the liquid for heat and
mass transfer.
SPRAY DRYER
The spray dryer provides a large surface area for heat and
mass transfer by atomizing the liquid into small droplets.
These are sprayed into a stream of circulating 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 dryer. e.g. GEA Niro spray
dryer has a typical design in which the drying chamber
resembles a cyclone. This ensures good circulation of air,
facilitates heat and mass transfer and encourages the
separation of dried particles from the moving air by the
centrifugal action.
 ATOMIZER
The character of the particles is controlled by the droplet size, so the
type of atomizer is important. Early simple jet atomizers tended to
block easily as a result of rapid evaporation and deposition of solid
on the nozzle. This caused the flow rate to vary and this had a
detrimental effect on the uniformity and predictability of droplet
size. This was resolved by the use of rotary types of atomizer. Liquid
is fed on to the disc that is rotated at high speed (10000–30000
revolutions per minute). 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. In addition, 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.
Modern two-fluid nozzles have overcome the problems of
earlier jet atomizers and have proved successful. In this
context, the two fluids are the liquid product and the
atomizing air. Two-fluid nozzles can handle feed rates
between 30 and 80 litres per hour. 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 what is known as ‘fountain mode’. The
two-fluid nozzles produce a narrow droplet size range
with the mean size being affected by nozzle position. In
general, a nozzle used co-currently will produce smaller
droplets than one used in fountain mode. Rotary
atomizers produce droplets in the mid-range.
Product
Spray-dried products are easily recognizable, being uniform
in their 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. Intelligent computer control
is available to control process parameters as these, in
turn, can 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 such 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 is 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. Provided that a suitable atomizer is used and well controlled, the
resulting powder will have a uniform and controllable particle size.
4. Labour costs are low, and the process yields a dry, free-flowing
powder from a dilute solution, with no handling.
5. It can be used as a continuous process if required.
6. The resulting product has many beneficial properties for
pharmaceutical applications.
Disadvantages of the spray-drying process :
1. The equipment is very bulky and the ancillary equipment is
expensive.
2. The overall thermal efficiency is rather low as the air must
still be hot enough when it leaves the dryer to avoid
condensation of moisture.
In addition, large volumes of heated air pass through the chamber
without contacting a particle and thus not contributing
directly to the drying process.
FREEZE DRYING
Freeze-drying is the process of choice in the pharmaceutical industry to
stabilize and extend the shelf life of both small molecular therapeutics and
biopharmaceuticals. Freeze-drying is used to dry extremely heat-sensitive
materials, and can allow drying, without excessive damage of proteins,
blood products, hormones, vaccines and even microorganisms, which retain
a small but significant viability.
Freezing stage:
The freezing step is critical in the freeze-drying process. Freezing determines
the morphology of the frozen material, which has an influence on the final
freeze-dried product.
The freezing process involves:
>Nucleation
>Crystallization of freeze concentrate &
>Freeze separation in eutectic products or amorphous products.
FREEZING STAGE
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 from –10 °C to –30 °C.
Because the subsequent stage of sublimation is slow, several methods are used at
this stage to produce a larger frozen surface to speed up that later stage.

Shell freezing:
>used for fairly large volumes, such as blood products.
>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, a drawback of this method as they may
damage blood cells and reduce the viability of microbial cultures.
>In vertical spin freezing, the bottles are spun individually in a vertical position so
that centrifugal force produces a circumferential layer of solution, which is cooled
by a blast of cold air. The solution supercools and freezes rapidly, with the
formation of small ice crystals.
Centrifugal evaporative freezing:
>This is a similar method where the solution is spun in small
containers within a centrifuge.
>This prevents foaming when the vacuum is applied.
>The vacuum causes boiling at room temperature, and this
removes so much latent heat that the solution cools quickly
and ‘snap’ freezes.
>Approximately 20% of the water is removed before freeze-
drying, and there is no need for separate refrigeration.
>Ampoules are usually frozen in this way, a number being spun
in an angled position (approximately 30° to the horizontal) in
a special centrifuge head so that the liquid is thrown outwards
and freezes as a wedge with a larger surface area.
VACUUM APPLICATION STAGE

The containers and the frozen material must be connected to a source

of a vacuum which is

Sufficient to reduce the pressure below the triple point

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 the triple point of the formulation.

a number of bottles or vials are attached to individual outlets of a

manifold which is connected to a vacuum
Sublimation stage:
1) Sublimation can occur only at the frozen surface
2) It is a slow process (approximately 1 mm thickness of ice per hour)
3) Surface area dependent
4) Heat must be supplied for the process to occur.
PRIMARY DRYING
 Primary drying is the most time-consuming and energy-
intensive step in pharmaceutical freeze-drying.
 Minimizing the duration of this stage is of paramount
importance to speed up process development and product
manufacturing.
 Primary drying optimization consists of identifying the
optimal combination of the manipulated inputs, namely,
1. shelf temperature and
2. chamber pressure, that allows sublimation to be
completed in all of the vials of the batch in the shortest
possible time while fulfilling tight constraints on both
product temperature and sublimation rate
SECONDARY DRYING
(adsorption) removes the bound water molecules. The
temperature is slowly raised to higher than that in the
primary drying phase. Bonds are broken between the
material and the bound water molecules. The
temperature for this process is usually between 10°C and
50°C and usually requires a long duration.
VAPOUR REMOVAL
The vapour formed must be removed continually to
prevent the pressure within the container rising above the
triple point pressure and thus preventing sublimation. To
reduce the pressure suf ciently, it is necessary to use ef
cient vacuum pumps, usually two-stage rotary pumps on
the small scale and ejector pumps on the large scale. On
the small scale, vapour is absorbed by a desiccant such
as phosphorus pentoxide, or is cooled in a small
condenser with solid carbon dioxide. Mechanically
refrigerated condensers are used on the large scale
Advantages of freeze-drying :
1) Freeze-drying, as a result of the character of the process, has
certain special advantages:
2) Drying occurs at very low temperatures, so enzyme action is
inhibited and chemical decomposition, particularly hydrolysis, is
minimized.
3) As it is a frozen solution or suspension that sublimes, the final
dry product is a porous solid occupying the same volume as the
original solution. Thus the product is light and porous.
4) The porous form of the product gives rapid dissolution of the
freeze-dried product.
5) There is no concentration of the solution before drying. Hence
salts do not concentrate in the wet state and denature proteins, as
occurs with other drying methods.
6) As the process occurs under a high vacuum, there is little contact
with air, and oxidation is minimized.
Disadvantages of freeze-drying:
There are two main disadvantages of freeze-drying:
1. The porosity, easy dissolution and complete dryness of the
product results in it being very hygroscopic. Unless the product
is dried in the final container and the container is sealed in-situ,
packaging requires special consideration.
2. The process is very slow and uses complicated equipment
that is very expensive. It is not a general method of drying, but
should be limited to certain types of valuable products that,
because of their heat sensitivity, cannot be dried by any other
means.
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