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DRYING

Drying is an important operation in primary pharmaceutical manufacture as it is usually

the last stage of manufacturing before packaging, and it is very important that the residual

moisture is rendered low enough to prevent product deterioration or spoilage during

storage and ensure free-flowing properties during usage. It is very important (and probably

encountered more frequently) in secondary manufacture (dosage form) following the

commonly performed operation of wet granulation during the preparation of granules prior

to tablet compaction. Hence, stability, flow properties and compressibility are all

influenced by residual moisture. Drying can be defined as the removal of all or most of the

liquid by supplying latent heat to cause thermal vaporization, i.e. a liquid is converted into

a vapour. In majority of cases the 'liquid' will be water, but volatile solvents such as

isopropanol may also need to be removed in a drying process.

Equilibrium moisture content

Evaporative drying processes does not remove all the possible moisture present in a wet

product because the solid equilibrates with the moisture present in the air. The moisture

content present in a solid under steady-state ambient conditions is termed the equilibrium

moisture content. Its value changes with temperature, humidity, and the nature of the

solid.

Relative humidity (RH) of air

Air, at a given temperature, can take up water vapour until it is saturated (at 100% RH). It

is a simple solution of water in air, therefore can exhibit increased solubility with increasing

temperature, a maximum solubility at a particular temperature (saturation) and

precipitation of the solute on cooling (condensation, rain). If the temperature is raised,

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then the air will be able to take up more moisture and the relative humidity falls. This is

because the percentage RH may be defined as:

Vapour pressure of water vapour in the air x 100

Vapour pressure of water vapour in air
saturated at the same temperature

This is approximately equal to the percentage saturation, which is the ratio:

Mass of vapour present per kg of dry air x 100

Mass of vapour required to saturate 1 kg
of air at the same temperature

This relationship shows that the relative humidity of air is dependent not only on the

amount of moisture in the air, but also on its temperature, as the amount of water

required to saturate air is itself dependent on temperature.

TYPES OF DRYING METHOD

When considering how to dry a material, the following points should be considered:

• Heat sensitivity of the material being dried

• Physical characteristics of the material

• The need for asepsis

• Nature of the liquid to be removed

• The scale of the operation

• Available sources of heat (steam, electrical).

The general principles for efficient drying can be summarized as follows:

• Large surface area for heat transfer

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• Efficient heat transfer per unit area (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,

i.e. sufficient turbulence to minimize boundary layer thickness

• Efficient vapour removal, which requires low relative humidity air at adequate velocity.

It is convenient to categorize pharmaceutical driers according to the heat transfer method

they use, i.e. convective, conductive or radiant.

Fixed (or static) bed convective drying

Tray drier

An efficient type of tray drier is the directed circulation form. Air flows in the direction of

the arrows over each shelf in turn. The wet material is spread on shallow trays resting on

the shelves. Electrical elements or steam-heated pipes are positioned as shown, so that

the air is periodically reheated after it has cooled by passage over the wet material on one

shelf before it passes over the material on the next. The required latent heat of evaporation

is transferred convectively from the air and the rate of heat transfer may be written as:

Rate of heat transfer, (dH/dt) = hc A ΔT

where hc is a heat transfer coefficient for convective heat transfer. The value of hc is

commonly around only 10-20 W m-2 K-2. Heat transfer from air is therefore relatively

inefficient and so convective drying is slow and wet materials can take upto 24 hours to

dry. In drying, the water vapour must pass through the boundary layers present at the

surface into the turbulent airstream. For this to occur the relative humidity of the air must

be kept very much below the saturation level and the boundary layers small. These
 4

conditions are achieved by having a brisk turbulent air flow over the surface and by the

periodic reheating of the air as the temperature falls, so that it can

pick up further moisture.

Rate of drying in fixed beds

The rate at which drying occurs has been found to show certain phases (Fig) in which

the change in moisture content is plotted against time. From A to B the relationship is

linear, which is known as the constant-rate period, whereas from B to C the rate of loss

of moisture decreases and is known as the falling-rate period. The end of the constant

rate period, B, is referred to as the critical moisture content.

The first falling-rate period has a linear relationship, that is, the decrease in drying rate

is uniform, whereas in the second falling-rate period there is a continuous decrease in

the rate of drying until the equilibrium moisture content is reached. Each of these periods

will be considered in more detail.

Constant-rate period.

For given conditions of temperature and humidity, most substances dry at a similar rate

in the constant-rate period. It is found that the evaporation rate from the drying bed is

similar to that of the solvent alone from a free liquid surface under the same conditions,

indicating that the evaporation takes place from the wet surface of the solid, and that the

surface remains wet in this period because of the liquid being replaced from below as fast

as it is vaporized. Controlling factors in this period include the rate at which heat can be

transferred and the rate of removal of the vapour.

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First falling-rate period

As moisture is removed from the surface, a point will be reached when the rate of

vaporization is insufficient to saturate the air in contact with the surface. Under these

conditions, the rate of drying will be limited by the rate of capillary transfer of the liquid to

the surface of the wet bed, and as this becomes increasingly difficult as the bed dries, the

solvent level decreases and thus has further to travel to the point of evaporation.

Consequently, the rate of drying decreases continuously. Moisture movement may cause

the 'migration' of soluble drugs or excipients. Eventually, movement of solvent to the

surface can no longer occur, for example when the water is in the pendular state, at which

migration cannot continue as there is no longer a continuous layer of mobile liquid water

within the wet solid and drying at the surface will end. As the drying rate decreases, less

heat is used as latent heat of vaporization, so that the heat input should be reduced.

Second falling-rate period

Any moisture that remains within the drying bed at the end of the first falling-rate period is

unable to move, so that drying cannot take place on the surface. Hence, the plane of

vaporization retreats from the surface into the body of the solid, and the drying rate

depends on the movement of the vapour through the pores of the bed to the surface, in

general by molecular diffusion. Minimal atmospheric humidity above the solid will assist

in maintaining the maximum vapour pressure gradient. In addition, the thermal

conductivity of the solid decreases as it becomes dry. if the solid is thermostable, it is safe

to allow temperature gradients to increase to maintain the rate of heat transfer, but if the

material is thermolabile the heating must be decreased. In the operation of a tray drier, it

is usual to remove the dry material on the trays near the air inlet and replace them with

the trays with partially dry material from further away. Trays with fresh wet material are
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placed on the empty shelves. In this way the outgoing (more wet) air contacts the material

that is most wet.

Dynamic convective driers

Fluidized-bed drier

This is an excellent method of obtaining good contact between the warm drying air and

wet particles. Particulate matter is contained in a vessel, the base of which is perforated,

enabling a fluid to pass through the bed of solids from below. The fluid can be liquid or

gas, but for the purposes of this description, air will be assumed, as it is directly relevant

to the drying process. Increase in the air velocity causes the particles to separate and

move freely and the bed is fully fluidized. Hence if hot air is used the turbulent conditions

lead to high heat and mass transfer rates. The fluidized-bed technique therefore offers a

means of rapid drying.

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. A batch of tablet granules, for example,

can be dried in 20-30 minutes, whereas a tray drier would require many hours. Apart

from obvious economic advantages, 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 and not just from the surface of the bed. Therefore, most of the

drying will be at constant rate and the falling-rate period (when the danger of

overheating is greatest) is very short.

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3. The temperature of a fluidized bed is uniform throughout and can be controlled with

high degree of precision

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 eliminates the risk of soluble materials

migrating, as may occur in static beds

6. The containers can be mobile, making handling and movement around the production

area simple and so reducing labour costs.

7. Short drying times mean that the unit has a high 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,

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, 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 static

electricity charges, and suitable precautions must be taken. A mixture of air with a fine

dust of organic materials such as 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 such as isopropanol. Adequate electrical earthing is essential.

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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

This equipment is a good example of a conduction drier, though it is not used so

extensively as it was formerly. The vacuum oven consists of a jacketed vessel sufficiently

stout in construction to withstand vacuum within the oven and 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 can be closed by a door that can be locked 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. Vacuum ovens are rarely used nowadays for production, although

they are frequently found in development laboratories, where they are commonly used for

the drying of small development samples, particularly when the heat stability of the drug

or formulation is uncertain. The main advantage of a vacuum oven is that 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.

Vacuum tumbling drier

Vacuum tumbling drying has found application in the pharmaceutical industry. 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
 9

heated surface as the vessel slowly revolves. Heat transfer rates in this equipment are

much higher than can be attained in a conventional vacuum oven, where the material is

static.

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) need 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 may be reflected or transmitted.

Use of infrared radiation

Infrared heating has been used in the past to dry pharmaceutical products such as wet

granules, but it suffers from the disadvantage that it is absorbed very quickly and does 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. For this reason, infrared radiation is now seldom used as

a heat source in pharmaceutical manufacture.

The use of microwave radiation

Although energy in the infrared region is more easily generated there are other, longer,

wavelengths that can generate heat when the radiation is absorbed by a wet solid.

Microwave radiation in the wavelength range 10 mm to 1 m penetrates much better than

IR radiation. Microwave driers are finding some application in the pharmaceutical industry.

Generation and action of microwaves

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Microwaves are produced by an electronic device known as a magnetron. Microwave

energy can be reflected down a rectangular duct (termed a waveguide) or simply beamed

through a transparent polypropylene window into the drying chamber. To avoid

interference with radio and television it is permitted to operate only at certain frequencies,

which are normally 960 and 2450 MHz. The penetration of microwaves into the wet

product is so good that heat is generated uniformly within the solid. When microwaves fall

on substances of suitable electronic structure (small polar molecules, such as water), the

electrons in the molecule attempt to resonate in sympathy with the radiation and the

resulting molecular 'friction' results in the generation of heat. Dry solids do not resonate

as well as water, so further heating may be avoided once the water is removed. This is

indicated clearly by the loss factors (different substances have different loss factor values).

The loss factor is a measure of the ratio of the microwave energy absorbed by individual

molecules, the higher the number the greater the absorption of microwave energy. The

absorption of the microwave energy is far greater for small polar molecules than for larger

and less polar molecules.

A microwave drier for granulates

Microwave driers are designed to operate under a slight vacuum. This in itself is not

essential for the use of microwaves, but the air flow allows the continuous removal of

evaporated solvent. The radiation is generated by multiple magnetrons, each producing

0.75 kW at 2450 MHz. The radiation passes through the polypropylene window into the

drying chamber, where 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 air flow as it is formed. When drying is nearly complete the radiation
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field intensity will rise, as the dry solids do not absorb as readily as water. This rise is

detected, and the magnetrons are progressively turned off automatically, to give an

accurate control of the final moisture content and minimize the danger of overheating.

Advantages of microwave drying

The following advantages are claimed for 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 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. All the requirements of product and operator
safety have been incorporated into machines without detracting from GMP
considerations.

6. Granulation end-point is possible by measuring the residual microwave energy (as

this rises sharply when there is little solvent left to evaporate).

Disadvantages of microwave drying

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 the microwave radiation, which can

cause damage to organs such as the eyes and testes. This is ensured by 'failsafe'

devices preventing the generation of microwaves until the drying chamber is sealed.
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DRIERS FOR DILUTE SOLUTIONS AND SUSPENSIONS

The objective of these driers is to spread the liquid to a large surface area for heat and

mass transfer and to provide an effective means of collecting the dry solid. Two main

types are used, the first spreading the liquid to a thin film on to a drum and the second

dispersing the liquid to a spray of small droplets.

Drum drier

the drum drier consists of a drum 0.75-1.5 m 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 that shown in the diagram, 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 a doctor knife.

Advantages of the drum drier

1. The method 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, for

example.

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 solutions or as suspensions; substances that are dried by this method include

starch products, ferrous salts and suspensions of kaolin and zinc oxide.

Spray drier

The spray drier 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 an individual solid particle. There are many forms of spray drier and in some

typical designs, the drying chamber resembles a cyclone. This ensures good air

circulation, facilitates heat and mass transfer and encourages the separation of dried

particles from the moving air by the centrifugal action.

The character of the particles is controlled by the droplet size, and so the type of atomizer

is important. Jet atomizers are easily blocked by rapid evaporation and deposition of solid

on the nozzle, and the droplet size is likely to vary. This is not the case with rotary types

of atomizer. Liquid is fed on to the disc, which is rotated at high speed (up to 20 000 rpm).

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, uniform spray.

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. 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.
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Dust carried over in the air outlet stream may be recovered by a cyclone separator or filter

bag. Spray-dried products are easily recognizable, being uniform in appearance. The

particles have a characteristic shape, in the form of hollow spheres sometimes with a

small hole. This arises from the drying process, as 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.

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 drier 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 so the temperature of the particles

is kept low by evaporative cooling.

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

rapid dissolution (large surface area).

4. Provided that a suitable atomizer is used the resulting powder will have a uniform and

controllable particle size.

5. The product is free flowing, with almost spherical particles, and is especially

convenient for tablet manufacture as it has excellent flow and compaction properties.

6. Labour costs are low, the process yielding a dry, free-flowing powder from a dilute

solution in a single operation with no handling.

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Disadvantages of the spray drying process

1. 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 15 m in height and 6 m in

diameter.

2. 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. Also, large volumes of heated air

pass through the chamber without contacting a particle, thus not contributing directly to

the drying process.

Uses of the spray drying process

The spray drier can be used for drying almost any substance, in solution or in

suspension. It is most useful for thermolabile materials, particularly if handled

continuously and in large quantities; outputs of 2000 kg h-1 can be attained, although

pharmaceutical plants are usually somewhat smaller.

Examples of both soluble and insoluble substances that are spray dried include citric acid,

sodium phosphate gelatin, starch, barium sulphate, calcium phosphate, and some

powdered antibiotic formulations for reconstitution into syrup. Spray drying is also capable

of producing spherical particles in the respirable range of 1-7 mm that have been used

satisfactorily for the delivery of drugs from dry powder inhalers. It is possible to operate

spray driers aseptically using heated filtered air to dry products such as serum

hydrolysate. Also, 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.
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FREEZE DRYING

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. 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. Thus, a liquid-to-vapour transition takes place, as with all the

previous driers discussed, but here there are three states of matter involved: liquid to solid,

then solid to vapour. The theory and practice of freeze drying is based, therefore, on an

understanding and application of the phase diagram for the water system. Freeze driers

apply these principles

The phase diagram for water

The phase diagram for the water system is shown in the Figure. The diagram consists of

three separate areas, each representing a single phase of water, either solid, liquid or

vapour. Two phases can coexist 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

three phases can coexist and is known as the triple point. Its coordinates are a pressure

of 610 Pa and a temperature of 0.0075°C. The lines on the phase diagram represent the

interphase equilibrium lines, which show:

1. The boiling point of water as it is lowered by reduction of the external pressure above

the water (BO in Fig.);

2. The variation of the melting point of ice on reduction of the external pressure above it.

There is a very slight rise in the melting point (AO);

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3. The reduction of the vapour pressure exerted by ice as the temperature is reduced

(CO). On heating at constant atmospheric pressure ice will melt when the temperature

rises to 0°C. At this constant temperature and pressure, it will then change to water.

Continued heating will raise the temperature of the water to 100°C where if heat

addition is continued, the liquid water will be converted into water vapour at 100°C. 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 0°C. This will

only happen if the pressure is prevented from rising above the triple point pressure and,

to ensure that this is the case, the vapour evolved must be removed as fast as it is formed.

It may be thought that as the process takes place at a low temperature the heat required

to sublime the ice will be small. In fact, the latent heat of sublimation of ice at 2900 kJ kg-
1 is appreciably greater than the latent heat of evaporation of water at atmospheric

pressure, and this heat must be supplied for the

process to take place.

Application of the phase diagram of water to freeze drying

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 to well below the normal freezing temperature for

pure water, and it is usual to work in the range -10 to -30°C. In part this is because it is

obviously not pure water that is being dried, and thus the presence of dissolved solutes

will shift the pure-water phase diagram.

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2. Sublimation can only occur at the frozen surface and is a slow process (approximately

1 mm thickness of ice per hour). For all but very small volumes the surface area must

therefore be increased and the liquid thickness prior to freezing be reduced in order to

reduce the thickness of ice to be sublimated.

3. At low pressures large volumes of water vapour are produced which must be rapidly

removed to prevent the pressure rising above the triple point pressure.

Advantages

As a result of the character of the process, freeze drying has certain special advantages:

1. Drying takes place at very low temperatures, so that enzyme action is inhibited and

chemical decomposition, particularly hydrolysis, is minimized.

2. 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.

3. 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

There are two main disadvantages of freeze drying:

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, packaging requires

special conditions.
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2. The process is very slow and uses complicated plant, which is very expensive. It is

not a 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 of freeze drying

The method is used for products that cannot be dried by any other heat method. These

include biological products, for example some antibiotics, blood products, vaccines

(such as BCG, yellow fever, smallpox), enzyme preparations (such as hyaluronidase)

and microbiological cultures. The latter enables specific microbiological species and

strains to be stored for long periods with a viability of about 10% on reconstitution.

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 convective 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

(between granules) and intragranular (within individual granules).

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Intergranular migration

In intergranular migration, the solutes move from granule to granule and may result in

gross maldistribution of the active drug. It can occur during the drying of static beds of

granules (e.g., tray drying), as 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 or an excess of drug.

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.

Consequences of solute migration

Solute migration of either type can result in several problems and occasional benefits.

Loss of active drug

The periphery of each granule may become enriched, with the interior suffering a

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 can be eluted

in the air and carried to the filter bag or lost. The granules suffer a net loss of drug and,

as a result, will be below specification with respect to quantity of active ingredient.

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 (Fig.). During compaction granules are fractured and
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the colourless interior is exposed. The eye then sees the coloured fragments against a

colourless background and the tablets appear mottled. Migration may be reduced by using

the insoluble aluminium 'lake' of the colouring material (in which the soluble dye is

adsorbed strongly on to insoluble alumina particles) in preference to the soluble dye itself.

This is not the complete answer, as factors such as an unfavourable pH can allow dyes

to detach from lakes and then migrate. They suggest that small granules, which do not

fracture so readily, are preferable to larger ones if mottling is troublesome.

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 because

of binder-binder (rather than drug-drug or drug-excipient) contact and is therefore

sometimes beneficial. Many other factors, such as granulate formulation, drying method

and moisture content, have been shown to affect solute migration.

Some practical means of minimizing solute migration

It may be useful to list the measures that can be taken to minimize migration.

1. 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.

2. Prepare the smallest granules that will flow easily. These are generally satisfactory if

mottling is troublesome.

3. Avoid tray drying unless there is no alternative.