DRYING
hot surface and the bulk of heat transfer occurs
- Last stage of manufacturing before packaging
- Important that the residual moisture is rendered
low
o Prevents deterioration during storage
o Ensures free flowing properties during use
TYPES OF DRYING METHODS
I. Drying of wet solids
A. Convective drying
1. Fixed/ static bed convective drying
2. Dynamic convective driers
- Fluidized bed drier
- Where an excellent method of obtaining good
contact between the warm drying air and wet
particles is found
- General principle: Fluidization
- ADVANTAGES:
 Efficient heat and mass transfer give high
drying rates so that drying times are shorter
than with static bed convection drying
 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
 The temperature of a fluidized bed is uniform
throughout and can be controlled precisely
 The turbulence in a fluidized bed causes some
attrition to the surface of the granule
 Free movement of individual particles
eliminates the risk of soluble materials
migrating, as may occur in static beds
 The containers can be mobile, making handling
and movement around the production area
simple and so reducing labor costs
 Short drying times mean that the unit has a high
product output from a small floor space
- DISADVANTAGES:
 The turbulence of the fluidized bed state may
cause excessive attrition of some materials with
damage to some granules and the production of
too much dust
 Fine particles may become entrained in the
fluidizing air and must be collected by bag
filters, with care to avoid segregation and loss
of lines
 The vigorous movement of particles in hot dry
air can lead to the generation of static electricity
charges, and suitable precautions must be
taken
B. Conductive drying
- The wet solid is in the thermal contact with a
by conduction
1. Vacuum oven
- Consists of a jacketed vessel sufficiently stout
in construction to withstand vacuum within the
oven and steam pressure in the jacket
- MAIN ADVANTAGE: drying takes place at a low
temperature and as there is little air present
there is minimum risk of oxidation
 The temperature of the drying solid will rise to
the steam or water temperature at the end of
the drying but this is not usually harmful.
2. Vacuum tumbling drier
- One design of tumbler drier resembles a large Y
cone mixer
- The vessel is steam jacketed and is connected
to a vacuum
- It can be used for drying tablet granules which
tumble over the heated surface as the vessel
slowly revolves
- Heat transfer rates in this equipment are much
higher than those attained in a convectional
vacuum oven where the material is static
C. Radiation drying
1. Radiant heat transmission
- Differs from heat transfer by conduction or
convection in that no transfer medium (solid,
liquid, or gaseous) needs to 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 proportion maybe reflected or transmitted
- Infrared radiation is seldom used as heat
source because it is absorbed very quickly and
dose not penetrate far into the wet mass. The
surface layers dry quickly and the absorption of
further energy then raises the temperature of
the dry material to a high value, which is often
detrimental to the product
2. The use of microwave radiation
- Microwave radiation in the wavelength range
10mm to 1m penetrates much better than IR
radiation
- Microwaves are produced by an electronic
device known as magnetron. To avoid
interference with radio and television, it is
permitted to operate only at certain frequencies
which are normally 960 and 2450MHz
3I-PHARMACY // DATU
- The penetration of microwaves into the wet
product is so good that heat is generated
uniformly within the solid
- ADVANTAGES:
 Provides rapid drying at fairly low temperature
 Thermal efficiency is high, as the drier casing
and the air remain cool
 The bed is stationary, avoiding the problems of
dust and attrition
 Solute migration is reduced as there is uniform
heating of the wet mass
 Equipment is highly efficient and refined
 Granulation end point is possible by measuring
the residual microwave energy (as this rises
sharply when there is little solvent left to
evaporate
- DISADVANTAGES:
 Batch size of commercial production microwave
driers is smaller than those available for
fluidized bed driers
 Care must be taken to shield operators from the
microwave radiation, which can cause damage
to organs such as the eyes and tastes, This is
ensured by failsafe devices preventing the
generation of microwaves until the drying
chamber is sealed
II. Drying of dilute solutions and suspensions
- OBJECTIVE:
 to spread the liquid to a large surface area for
heat and mass transfer
 To provide and effective means of collecting the
dry solids
a. Drum driers
- Spreading the liquid to a thin film on to a drum
- The liquid is applied to the surface of the drum
and spread to a film
- Can handle a variety of materials either as
solutions or as suspensions
- i.e., starch products, ferrous salts, and
suspensions of kaolin and zinc oxide.
- ADVANTAGES:
Gives rapid drying, the thin film spread over a
large area resulting in rapid heat and mass
transfer
The equipment is compact, occupying much less
space than the spray drier
Heating time is short (few seconds)
The drum can be enclosed in vacuum jacket,
enabling the temperature of drying to be reduced
The product is obtained in flake form, which is
convenient for many purposes
- DISADVANTAGES:
 Operating conditions are critical
 It is necessary to impose careful control on feed
rate, film thickness, speed of drum rotation and
drum temperature
b. Spray driers
- Dispersing the liquid to a spray of small droplets
- Provides a large surface area for heat and
mass transfer by atomizing the liquid to small
droplets
- Sprayed into a stream of hot air so that each
droplet dries to an individual solid particle
- ADVANTAGES:
 There are millions of small droplets which give a
large surface area for heat and mass transfer so
that evaporation is very rapid
 Because evaporation is very rapid, the droplets
do not attain a high temperature
 The characteristic particle form allows efficient
particle packing and thus gives the product high
bulk density. (Large surface area = rapid
dissolution)
 Provided that a suitable atomizer is used, the
resulting powder will have a uniform and
controllable particle size
 The product is free-flowing, with almost spherical
particles, and is especially convenient for tablet
manufacture as it has excellent flow and
compaction properties
 In many cases, spray drying will increase the
dissolution rate and bioavailability of poorly water-
soluble drugs (APIs)
 Labor costs are low, the process yielding a dry,
free-flowing powder from a dilute solution, in a
single operation with no handling
- DISADVANTAGES:
 The equipment is very bulky, and with the
ancillary equipment is expensive. In a large
installation the drying chamber alone may be as
much as 15m in height and 6m in diameter
 The overall thermal efficiency is rather low, as the
air must still be hot enough when it leaves the
drier to avoid condensation of moisture
- USES:
 For drying almost any substance in solution or
suspension
 Most useful for thermolabile materials particularly
if handled continuously and in large quantities;
outputs of 2000 kg/h can be attained although
pharmaceutical plants are usually somewhat
smaller
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Soluble and insoluble substances that are spray
dried include citric acid, sodium phosphate
gelatin, starch, barium sulfate, calcium phosphate
and some powdered antibiotic formulations for
reconstitution into syrup
Capable of producing spherical particles in the
respirable range of 1-7mm that have been used
satisfactory for the delivery of drugs from dry
powder inhalers
To operate spray driers aseptically using heated
filtered air to dry
III. Freeze drying
- Process used to dry extremely heat sensitive
materials
- Allows the drying, without excessive damage, of
proteins, blood products, and even
microorganisms
- The initial liquid solution or suspension is
forced, the pressure above the frozen state is
reduce and the water removed by sublimation.
Thus, a liquid to vapor transition takes place.
There are 3 states of matter involved: liquid to
solid then solid to vapor
- STAGES:
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
- Shell freezing is employed for fairly large
volumes such as blood products
- Centrifugal evaporative freezing, where the
solution is spun in small containers within the
centrifuge. This prevents foaming when vacuum
is applied.
2. Vacuum application stage
- 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 vapor formed
during drying
- Again an excess vacuum is normal in practice
to ensure that the product in question is below
in triple point
- Commonly a number of bottles or vials are
attached to individual outlets of a manifold
which is connected to a vacuum
3. Sublimation stage
- The ice slowly sublimes leaving a porous solid
which still contains about 0.5% of moisture after
primary drying
- Involves the following steps:
 Primary drying
 Heat transfer
 Vapor removal
 Rate of drying
4. Secondary drying
- 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
- A high temperature is permissible for many
materials because the small amount of moisture
remaining is not sufficient to cause spoilage
5. Packaging
- Containers should be closed without contacting
the atmosphere
- If possible, and ampoules, for example, are
sealed on the manifold while still under vacuum.
Otherwise, the closing must be carried out
under controlled atmosphere conditions
- ADVANTAGES:
 Drying takes place at very low temperatures so
that enzyme action is inhibited and chemical
decomposition, particularly hydrolysis, is
minimized
 The solution is frozen such that the final dry
product is a network of solid occupying the same
volume as the original solution. Thus, the product
is light and porous
 The porous form of the product gives ready
solubility
 There is no concentration of the solution prior to
drying. Hence, salts do not concentrate and
denature proteins, as occurs with other drying
methods
 As the process takes place under high vacuum,
there is little contact with air and oxidation is
minimized
- DISADVANTAGES:
 The porosity, ready solubility and complete
dryness yield a very hygroscopic product
 The process is very slow and uses complicated
plant, which is very expensive,
 It is not general method of drying therefore but is
limited to certain types of valuable products
which, because of their heat sensitivity, cannot be
dried by any other means
- USES:
 For products that cannot be dried by any other
heat method
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Biological products (blood products, vaccines),
enzyme preparations (e.g., hyaluronidase),
microbiological cultures. The latter enables
specific microbiological species and strains to be
stored for long periods with a viability of about
10% on reconstitution
POINTS CONSIDERED ON HOW TO DRY A
MATERIAL
- Heat sensitivity of the material being dried
- Physical characteristics of the material
- Necessity for asepsis
- Nature of the liquid to be removed
- Scale of the operation
- Available sources of heat (steam, electrical)
GENERAL PRINCIPLES FOR EFFICIENT
DRYING:
- Large surface area for heat transfer
- Efficient heat transfer per unit area
o To supply 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
o i.e., sufficient turbulence to minimize boundary
layer thickness
- Efficient vapor removal
o Low relative humidity air at adequate velocity
SOLUTE MIGRATION DURING DRYING
- Solute migration Is the phenomenon that can
occur during drying which can result from the
movement of 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 convective
drying of granules these solutes can move
towards the surface of the drying bed or granule
and be deposited there when the solvent
evaporated
- Can lead to localized variability in the
concentration of soluble drugs and excipients
within the dried products
- TWO TYPES:
o Intergranular: between granules
 Where the solutes move from granule to
granule, may result in gross maldistribution of
the active drug
 Can occur during the drying of static beds of
granules (e.g., tray drying), as the solvent and
accompanying solute 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 or an excess of drug
o Intragranular (within)
 Drying methods based on fluidization and
vacuum tumbling keep the granules separate
during and so prevent the intergranular
migration that may occur in fixed beds
 Intragranular migration, where the solutes move
towards the periphery of each granule, may
take place
- CONSEQUENCES:
o Loss of active drug
o Mottling of colored tablets
o Migration of soluble binders
- INFLUENCE OF FORMULATION FACTORS
ON SOLUTE MIGRATION
o Nature of substrate
o Viscosity of granulating fluid
- INFLUENCE OF PROCESS FACTORS ON
SOLUTE MIGRATION
o Drying method
o Initial moisture content
- SOME PRACTICAL MEANS OF MINIMIZING
SOLUTE MIGRATION
o Use the minimum quantity of granulating fluid
and ensure that it is well distributed
o Prepare the smallest granules that will flow
easily
o Avoid tray drying unless there is no alternative
o If tray drying is unavoidable, the granules
should be remixed before compression. If
intragranular migration is likely to be
troublesome, consider vacuum or microwave
drying as an alternative to fluidized bed drying
3I-PHARMACY // DATU