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Pharmaceutical Unit Operations (DRYING)

Introductory Principles of Drying
Drying is a very essential pharmaceutical unit operation which deals with removal of small
amount of moisture (water) or any other solvents from a material under the agency of heat. In
drying of pharmaceuticals, mass transfer is actually the results. In manufacturing of most of the
pharmaceutical dosage forms, drying is the vulnerable unit operation that is done by heat transfer
to the materials resulting the loss of material weight. This process is usually applied in the last
stage of the process. Drying process not only helps to remove water, but also in removing other
solvents like organic or inorganic solvents.

A source of heat and an agent to remove the vapor produced by the process are often involved. In
bio-products like food, grains, and pharmaceuticals like vaccines, the solvent to be removed is
almost invariably water. In the most common case, a gas stream, e.g., air, applies the heat by
convection and carries away the vapor as humidity. Other possibilities are vacuum drying, where
heat is supplied by conduction or radiation (or microwaves), while the vapor thus produced is
removed by the vacuum system. Another indirect technique is drum drying (used, for instance,
for manufacturing potato flakes), where a heated surface is used to provide the energy, and
aspirators draw the vapor outside the room. In contrast, the mechanical extraction of the solvent,
e.g., water, by centrifugation, is not considered "drying" but rather "draining".

Thermal drying of solids involves removing moisture from the material by vaporisation or
evaporation. The drying characteristics depend on how the moisture is retained within the
material. In the first instance, the liquid adhering to the surface of the material to be dried can be
removed by vaporisation or evaporation. Once this liquid has been removed, drying of the
moisture contained within the capillaries and pores of the material begins. The drying speed
reduces due to the need to overcome capillary forces and diffusion resistance. Crystal water
which is bonded into the crystal structure of the material, can only be removed by intense heating
in addition to low drying speed

Purposes of drying

In pharmaceutical technology, drying is carried out for one or more of the following reasons:

1. To avoid or eliminate moisture which may lead to corrosion and decrease the product or
drug stability.
2. To improve or keep the good properties of a material, e.g. flowability, compressibility.
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3. To reduce the cost of transportation of large volume materials ( liquids)

4. To make the material easy or more suitable for handling.
5. Preservation of pharmaceuticals.
6. The final step in: Evaporation- Filtration- Crystallization.

Drying Vs. Evaporation

In certain aspects, drying is look like evaporation process where evaporation is a complete
different unit operations for pharmaceuticals. Term Drying is different from Evaporation in
terms followings:

1. In evaporation water boils until it reaches it boiling point while drying just passage of
heat until the substance get dried.
2. In general, drying refers to the removal of moisture from solids, gases or liquids. For
drying gases and liquids, adsorption is normally used. In the context of thermal process
engineering, evaporation is understood to be the separation of a solvent from a solution.
3. In drying, dry solid is the product. In evaporation, product is either concentrated solutions
or suspensions or slurry.
4. Drying in most of the cases means the removal of relatively small amounts of water from
solids .Evaporation include the removal of large amounts of water from solutions.
5. In drying, water is usually removed by circulating air over the material in order to carry
away the water vapour , while in evaporation , water is removed from the material as pure
water vapour mixed with other gases.

Diversity in Drying
A wide range of process engineering principles are used in drying, due to the variety of
industrially moisture containing materials. These materials can have extremely different
behaviours.

The following unit operations can be distinguished:-

Convection drying
A flowing gas transfers the heat necessary for drying to the material by convection. As well as
delivering heat, the gas is also used to remove the moisture given off by the material.
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Contact drying
The material is placed on or is passed over heated surfaces. Heat is predominantly transferred to
the material by conduction.

Radiation drying
The material absorbs emitted electromagnetic radiation from sources of radiation (e.g. infrared
radiators). Heating and evaporation occur not only at the surface of the material but also within
it.

Freeze drying
The frozen material is placed in a vacuum below its triple point. Moisture is removed from the
material, by changing it directly from a solid to a gaseous state.

High frequency drying

The material is exposed to high frequency electrical fields between the electrodes of a plate
capacitor. A part of field energy is absorbed by the material resulting in internal heating and
removal of moisture.

Heat Source
Direct Heat
 Advantages
Energy exchange, high temperature, efficiency, economics

 Disadvantages
Combustion by-products, limited to clean burning fuels required
Indirect Heat

 Advantages
No combustion by-products, non-clean burning fuels
 Disadvantages
Temperature, energy exchange, efficiency, heat exchanger
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Theory of Drying Process

As we know that drying process need to apply onto a wet materials as for removal of moisture,
so it is important that in what conditions are the moisture presents there. In materials water
(moisture) can be present as bound or unbound form.
Bound water (Moisture): Bound moisture in a solid material is liquid that exerts an equilibrium
vapor pressure less than that of the pure water at the same temperature. This reduction of vapor
pressure may be because the liquid is in small capillaries, in solutions, in cell or is combined.
Example: adsorption to a surface.
Unbound water (Moisture): Bound moisture in a solid material is liquid that exerts an
equilibrium vapor pressure equal to that of the pure water at the same temperature. Thus, in a
non-hygroscopic materials all the liquid is unbound, and in a hygroscopic material the unbound
moisture is the liquid in excess of the EMC (Equilibrium Moisture Content), corresponding to
saturation humidity.

At the mean time of drying, water usually lost, but the resulting solid is not fully free from the
moisture. This is known as “air-dry”.
For better drying, the heat which applied on the materials need must to penetrate within the
materials so that the mass transfer (transfer of moisture) result smoothly via vaporization.
Water diffuses through the material to the surface and finally evaporates into the atmosphere.
Drying is the combination of heat transfer and mass transfer.

Drying Mechanisms

In the process of drying heat is necessary to evaporate moisture from the grain and a flow of air
is needed to carry away the evaporated moisture. There are two basic mechanisms involved in
the drying process; the migration of moisture from the interior of an individual grain to the
surface, and the evaporation of moisture from the surface to the surrounding air. The rate of
drying is determined by the moisture content and the temperature of the grain and the
temperature, the (relative) humidity and the velocity of the air in contact with the grain.
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The above diagram demonstrates the drying of a single layer of grain exposed to a constant flow
of air. The moisture content falls rapidly at first but as the grain loses moisture the rate of drying
slows. In general the drying rate decreases with moisture content, increases with increase in air
temperature or decreases with increase in air humidity. At very low air flows increasing the
velocity causes faster drying but at greater velocities the effect is minimal indicating that
moisture diffusion within the grain is the controlling mechanism.

Drying Equipments
1. Drum Dryer or Roller Dryer (Film Drum Dryer)

In drum dryers, slurries or pasty feedstocks are dried on the surface of a slowly rotating steam-
heated drum. A thin film of the paste is applied on the surface in various ways. The dried film is
doctored off once it is dry and collected as flakes (rather than powder).The design of applicator
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rolls is important since the drying performance depends on the thickness and evenness of the
film applied. The paste must stick to the surface of the drum for such a drop to be applicable.

Four key variables influence the drum dryer performance. They are:

 Steam pressure or heating medium temperature.

 Speed of rotation
 Thickness of film
 Feed properties, e.g., solids concentration, rheology and temperature.

Because it allows good control of the drying temperature, drum dryers may be used to produce a
precise hydrate of a chemical compound rather than a mixture of hydrates.

Figure 1: Drum dryer

Uses of Drum dryer: Drum dryer is used for drying of solutions, slurries, suspensions.
Advantages of drum dryer

1. In drum dryer, drying time is very short, being only a few seconds.
2. Drum dryer is very suitable one for thermo-labile materials.
3. This dryer occupies less space that the spray dryer.
4. Due to film spread over the large area, rapid heating as well as drying possible.
5. The product obtained is completely dried, which is convenient for many purposes.

Disadvantages of drum dryer

1. Operating conditions is very critical and necessary control required in control on feed
rate, film thickness, speed of rotation and temperature difference.
2. Maintenance cost is higher than spray dryer.
3. Drum dryer is not suitable for solution of salts with less solubility.
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2. Spray Dryer
Principles
In spray dryer, the fluid to be dried is atomized into fine droplets, which are thrown radially
into a moving stream of hot gas. The temperature of the droplets is immediately increased and
fine droplets get dried instantaneously in the form of spherical particles.
The spray dryer provides a large surface area for heat and mass transfer by atomizing the liquid
to small droplets. These are sprayed into a stream of hot air, so that each droplet dries to a solid
particle.

Characters of Spray Dryer

 The drying chamber resembles the cyclone ensuring good circulation of air, to facilitate
heat and mass transfer, and that dried particles are separated by the centrifugal action.....
 The character of the particles is controlled by the droplet form; hence the type of
atomizer is important.
 Rotary atomizer is preferable than jet which is easily blocked. Liquid is fed to the disc of
the atomizer which is rotated at high speed (up to 20,000 rpm), a film is formed and
spread as uniform spray. In addition, the rotary atomizer is effective with suspensions. It
can be operated efficiently at various feed rates.

Figure 2: Spray Dryer

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Characterization of spray dried products

 The products are uniform in appearance and have characteristic shape, in the form of
hollow spheres 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 center. This liquid then vaporizes, the vapor escaping by blowing a hole in the sphere.

 This method of drying allows a dry product to retain some properties of feed , e.g., a drop
from an emulsion dries with continuous phase on the outside.When reconstituted, the
emulsion is easily re- formed.

Advantages of the spray drying process

1. The droplets are small, giving a large surface area for heat 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 is only a few seconds.
2. Because evaporation is very rapid, the droplets do not attain a high temperature, most of
the heat being used as latent heat of vaporization.

3. The characteristic particle form gives the product a high bulk density and, in turn, ready
solubility.

4. The 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 tablet manufacture.
6. Labour costs are low, the process yielding a dry, free-flowing powder from a dilute
solution, in a single operation with no handling.
7. It is possible to operate spray driers aseptically using heated filtered air to dry products
such as serum hydrolysate.
8. Some spray driers operate in a closed-circuit mode with an inert gas to minimize
oxidation of the product. Volatile solvents can be recovered from such systems.

Disadvantages & Uses

1. The equipment is very bulky, connected to accessories, fans, heaters, that is make
it expensive.
2. Thermal efficiency is very low, much more heat lost in the discharged gases.

Uses:
1. Drying of any substance in solution or in suspension form.
2. It is most useful for drying of thermolabile materials e.g. antibiotics.
3. Suitable for large quantities solution.
4. Suitable for both soluble and insoluble substances e.g. citric acid, gelatin, starch.
5. It can produce spherical particles in the respiratory range e.g. dry powder inhalers.
6. Drying of milk, soap and detergents which is pharmaceutically related compounds.

3. Fluidised Bed Dryer/ Fluid Bed Dryer (FBD)

Principles
In fluidized bed dryer, hot air (Gas) is passed at high pressure through a perforated bottom of the
container containing granules to be dried. The granules are lifted from the bottom and suspended
in the stream of air. The condition is called fluidized state. The hot gas is surrounding every
granule to completely dry them. Thus, materials or granules are uniformly dried.
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Figure 3: Diagram of Fluid bed dryer

Figure 4: Original Fluid bed dryer

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Advantages of fluidized-bed drying

1. Efficient heat and mass transfer give high drying rates, so that drying times are shorter
than with static-bed convection driers. Economic, 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 and not just from the surface of the bed. Hence, most of the drying
will be at constant rate and the falling –rate period is very short.
3. The temperature of a fluidized bed is uniform and can be controlled precisely.
4. The turbulence in a fluidized bed causes some attrition to the surface of the granule.
5. This produces a more spherical free-flowing product.
6. The free movement of individual particles eliminates the risk of soluble materials
migrating, as may occur in static beds.

Disadvantages of fluidized-bed drying

1. The turbulence of the fluidized state may cause excessive attrition of some materials,
with damage to some granules and the production of too much dust.
2. Fine particles may become entrained in the fluidizing air and must be collected by bag
filters, leading to segregation and loss of fines.
3. The vigorous movement of particles in hot dry air can lead to the generation of static
electricity charges. The danger is increased if the fluidized material contains a volatile
solvent such as isopropanol. Adequate electrical earthing is essential.

4. Tray Dryer
By far the most common dryer for small tonnage products, a batch tray dryer consists of a stack
of trays or several stacks of trays placed in a large insulated chamber in which hot air is
circulated with appropriately designed fans and guide vanes. Often, a part of the exhausted air is
recirculated with a fan located within or outside the drying chamber. These dryers require large
amount of labor to load and unload the product. Typically, the drying times are long (10-60
hours). The key to successful operation is the uniform air flow distribution over the trays as the
slowest drying tray decides the residence time required and hence dryer capacity. Warpage of
trays can also cause poor distribution of drying air and hence poor dryer performance. Its useful
in dring of crude drugs, powders, tablet granules, or items of equipment.
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Figure 5: A batch tray dryer

Working Features
1. It is possible to convert the batch tray dryer into a continuous unit (Turbo dryer), which
consists of a stack of coaxial circular trays mounted on asingle vertical shaft.
2. The product layer fed onto the first shelf is leveled by a set of stationary blades, which
scratch a series of grooves into the layer surface.
3. The blades are staggered to ensure mixing of the material. After one rotation, the material
is wiped offthe shelf by the last blade and falls onto the next lower shelf. Up to 30 trays
or more canbe accommodated.
4. Hot air is supplied to the drying chamber by turbine fans. In the design shown, the air is
heated indirectly by passage over internal heaters.
5. The wet granular material is fed at the top and it falls under gravity to the next tray
through radial slots in each circular shelf.
6. A rotating rake mixes the solids and thus improves the drying performance. Such dryers
can be operated under vacuum for heat-sensitive materials or when solvents must be
recovered from the vapor.

Figure 6: A turbo dryer

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5. Freeze Drying & Dryer

Freeze drying is a process used to dry extremely heat – sensitive materials. It allows the drying,
without excessive damage, of proteins, blood products and even microorganisms, which retain a
small but significant viability.

Working Principles

1. In this process the initial liquid solution or suspension is frozen, the pressure above the
frozen state is reduced and the water removed by sublimation.
2. A liquid to vapour transition takes place, but here three states of matter involved: liquid
to solid, then solid to vapour.

Figure 7: Freeze Dryer

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Limitations of the freeze drying process

The freeze drying of products such as 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 below the normal freezing temperature for pure water (-
10-30).
2. Sublimation can only occur at the frozen surface and is slow process (1mm thickness of
ice per hour). So, the surface area must therefore be increased.
3. The liquid thickness prior to freezing be reduced in order to reduce the thickness of ice to
be sublimated.
4. At low pressure large volumes of water vapour are produced which must be removed to
prevent the pressure rising above the triple point pressure.
5. The dry material often needs to be sterile, and it must also be prevented from regaining
moisture prior to the final packaging.

Stages of the freeze drying process

1- Freezing stage:

The liquid material is frozen before the application of vacuum to avoid frothing, and several
methods are used to produce a large frozen surface.

Shell freezing : This is employed for 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 surface of the bottle.

 Freezing is slow and large ice crystals form, which is a drawback of this method.

 In vertical spin freezing the bottles are spun individually in a vertical position ,
centrifuged and cooled by a blast of cold air. The solution super cools and freezes
rapidly, with the formation of small ice crystals.

Centrifugal evaporative freezing: The solution is spun in small containers within a centrifuge.
This prevents the foaming when a vacuum is applied. The vacuum causes boiling at room
temperature. About 20% of the water is removed prior to freeze drying and there is no need for
refrigeration. Ampoules are usually frozen in this way.
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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 larger volumes of low – pressure vapour
formed during drying.

3 - Sublimation stage:

Heat of sublimation must be supplied. Under these conditions the ice slowly sublimes, leaving a
porous solid which still contains about 0.5% moisture after primary drying .

Primary drying: It can reduce the moisture content of a freeze-dried solid to around 0.5%.
Further reduction can be affected by secondary drying .

Heat transfer: Insufficient heat input prolongs the process, which is already slow, and excess
heat will cause melting.

Vapour removal: The vapour formed must be continually removed to avoid a pressure rise that
would stop sublimation.

Rate of drying: The rate of drying in freeze drying is very slow, the ice being removed at a rate
of about only 1mm depth per hour.

4- 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 C .

5- Packaging:

Attention must be paid to packaging freeze-dried products to ensure protection from moisture.
Containers should be closed without contacting the atmosphere.

Advantages of Freeze Drying

1. Drying takes place at very low temperatures, so the chemical decomposition, particularly
hydrolysis is minimized.
2. The solution is frozen occupying the same volume as the original solution, thus , the
product is light and porous.
3. The porous form of the product gives ready solubility.
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4. There is no concentration of 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 of Freeze Drying

There are two main disadvantages:

1. The porosity, ready solubility and complete dryness yield a very hygroscopic product.
Unless products are dried in their final container and sealed in situ, packing require
special conditions.
2. The process is very slow and uses complicated plant, which is very expensive .It is not a
general method of drying but limited to certain types of valuable products.

Uses of freeze drying

The method is used for products that can not be dried by any other heat method. These include
biological products, e.g. antibiotics, blood products, vaccines, enzyme preparations and
microbiological cultures.

SELECTION OF A DRYER

The different drying equipments are available, but the suitable dryer is selected based on the
Nature of material, cost, time and nature of the product required. As a minimum, the following
quantitative information is necessary to arrive at a suitable dryer:

a) Dryer throughput; mode of feedstock production (batch/continuous)

b) Physical, chemical and biochemical properties of the wet feed as well as
c) Desired product specifications; expected variability in feed characteristics
d) Upstream and downstream processing operations
e) Moisture content of the feed and product
f) Drying kinetics; moist solid sorption isotherms
g) Quality parameters (physical, chemical, biochemical)
h) Safety aspects, e.g., fire hazard and explosion hazards, toxicity
i) Value of the product
j) Need for automatic control
k) Toxicological properties of the product
l) Turndown ratio, flexibility in capacity requirements
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m) Type and cost of fuel, cost of electricity

n) Environmental regulations
o) Space in plant

For high value products like pharmaceuticals, certain foods and advanced materials, quality
considerations override other considerations since the cost of drying is unimportant. Throughputs
of such products are also relatively low, in general. In some cases, the feed may be conditioned
(e.g., size reduction, flaking, pelletizing, extrusion, back-mixing with dry product) prior to
drying which affects the choice of dryers.

Drying of food and biotechnological products require adherence to GMP (Good Manufacturing
Practice) and hygienic equipment design and operation. Such materials are subject to thermal as
well as microbiological degradation during drying as well as in storage. If the feed rate is low (<
100 kg/h), a batch-type dryer may be suited. Note that there is a limited choice of dryers that can
operate in the batch mode. In less than one percent of cases the liquid to be removed is a non-
aqueous (organic) solvent or a mixture of water with a solvent. This is not uncommon in drying
of pharmaceutical products, however. Special care is needed to recover the solvent and to avoid
potential danger of fire and explosion.

IMPORTANT DEFINITIONS & CALCULATIONS

Equilibrium moisture content (EMC): It is the amount of water present in the solid which exerts
a vapour pressure equal to the vapour pressure of the atmosphere surrounding it.

Free moisture content (FMC): Free moisture content (FMC) is the amount of water that is free
(easy) to evaporate from the solid surface.

Law for calculations

% Loss on drying (LOD) = mass of water in sample (kg)/ total mass of wet sample (kg) x 100

% Moisture content (MC) = mass of water in sample (kg) / mass of the dry sample (kg) x 100

Drying rate = weight of water lost from sample(kg) / Time(h) x weight of the dry solid(kg) X
Unit area
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References:

1. Kudra, T., Mujumdar, A.S., 2000, Advanced Drying Technologies, Marcel Dekker, New
York.
2. Mujumdar, A.S. (Ed.), 1995, Handbook of Industrial Drying, 2nd Edition, Marcel
Dekker,New York.
3. Subrahmanyam C.V.S (2013)., Pharmaceutical Enigineering- Unit Operations-2 (2013).
4. Carter S. J., (2007)., Copper and Gunn's Tutorial Pharmacy.
5. Bunker G.S.., (2002)., Modern Pharmaceutics-4th edition
6. www.answer.com & www.google.com (Wikipedia)