Granulation

Question 1

What is granulation

Answer 1

a size enlargement process by
which the fine powder particles are held together
to form large particles known as granules.

From 0.2-4 mm

Used in tablets and capsules or alone

Question 2

Why would we use granulation

Answer 2

1. Improve flow properties of the mix by size
   enlargement
2. Improve compression properties of the mix
3. Prevent segregation of components in the
   powder mix
4. Reduce the production of toxic dust during
   powder handling.

5 .Reduce the possibility of ‘cake’ formation

6. Increase convenience of transport and
   storage:

Question 3

How does granulation improve the flow properties

Answer 3

By making the surface area smaller

Before granulation, fine powder has high surface
area for contacts among the particles leading to
high cohesive forces. Thus, this powder does not flow
well.
Poor flow will often result in a wide weight variation
within the final product due to variable fill of tablet
dies, etc.
 In such cases granulation would provide larger
particles and narrower size distribution

Question 4

How would granulation improve the compression properties

Answer 4

By the better distribution of binders

Some powders are difficult to compress even if a
readily compressed adhesive binder is included
(as dry powder in the solid-solid mix) in the mix.
Conversely, granules of the same formulation
are often more easily compressed and produce
stronger tablets.
This is attributed to the more efficient distribution
of the adhesive binder (i.e. in solution) within the
granule.

Question 5

How can we decrease the segregation using granulation

Answer 5

Segregation is primarily due to differences in
size or density of the components, the small
particles concentrating at the base of a
container with the large particles above
them.
An ideal granulation will contain all the
constituents of the mixture in each granule
and separation of the ingredients will not
occur.
However, it is also important to control the
particle size distribution of the granules.
This is because, although the individual
components (i.e. drug and excipients) may not
segregate, if there is a wide size distribution,
granules themselves may segregate,
according to their sizes. → This might result in
large weight variation of final dosage forms.
In other words, granules of different sizes, occupying the
same volume (e.g. in tablet dies, or capsule shells),will
result in different weight of the dosage forms, owing to
their different bulk densities.

Question 6

How can we reduce caking with granulation

Answer 6

Materials which are slightly hygroscopic may
adhere and form cake if stored as a powder.
Granulation may reduce this hazard as the
granules will be able to absorb some moisture
and yet retain flowability because of their size.

Question 7

Why is it easier to transfer granules

Answer 7

Granules are denser than the parent powder
mix, (occupy less volume per weight), and thus
more convenient for storage or shipment.

Question 8

What are the granulation methods

Answer 8

 Wet granulation methods which utilize a
liquid in the process
 Dry granulation method in which no liquid
is used.

Question 9

What excipients do we use for granulation

Answer 9

– Diluents, to produce a unit dose weight of
suitable size
– Disintegrating agents which are added to
disintegrate the granule in a liquid medium, e.g.
on ingestion by the patient. – Adhesives (Binders) in the form of a dry powder
may also be added, particularly if dry
granulation is employed.
 These ingredients will be mixed before
granulation.

Question 10

What is wet granulation

Answer 10

Wet granulation involves the massing of the powder
mix using a solvent or a granulating liquid.
The solvents used must be volatile, so that they
can be removed by drying, and non-toxic.
Typical solvents include water, ethanol and
isopropanol either alone or in combination.
The solvent may be used alone or it may contain
a dissolved adhesive (also referred to as binder or
binding agent – e.g. hydroxypropyl
methylcellulose and polyvinylpyrrolidone) which is
used to cause particle adhesion.

Question 11

Why do we use water as the solvent choice for wet granulation

Answer 11

The primary advantage of water is that it is
nonflammable which means that expensive
safety precautions such as the use of
flame-proof equipment need not to be taken.

Question 12

What are the disadvantages for using water

Answer 12

The disadvantages of water as a solvent:
1. It may adversely affect drug stability, causing
hydrolysis of susceptible products
2. It needs a longer drying time than organic
solvents. This long drying time increases the
length of the process and may affect stability
because of the extended exposure to heat.
 Organic solvents are used when water-sensitive
drugs are processed (as an alternative to dry
granulation), or when a rapid drying time is required.

Question 13

How do powder particles adhere together

Answer 13

1. Adhesion and cohesion forces in immobile liquid films
2. Interfacial forces in mobile liquid films
3. Solid bridges
4. Attractive forces between solid particles

Question 14

Do the damp powders used on the adhesion and cohesion method help in forming strong bonds?

Answer 14

it is unlikely that
they contribute significantly to the final
granule strength.

Question 15

What are the interfacial forces stages in granulation process

Answer 15

Three states of water distribution between
particles are observed in granulation process:
a) Pendular
b) Funicular
c) Capillary

Question 16

a) At low moisture levels, the particles are held
together by lens shaped rings of liquid. These
cause adhesion.
This stage is termed the pendular stage.

b) The funicular state represents an
intermediate stage between the
pendular and capillary states.

c) When all the air has been
displaced from between the
particles the capillary stage is
reached

Question 17

Note

Answer 17

The state of the powder bed (pendular, funicular,
capillary state) is dependent upon the total
moisture content of the wetted powders.
However, the capillary state may also be reached
by decreasing the separation of the particles.

Question 18

What is the droplet state

Answer 18

In addition to these states, one more state can be
formed by further addition of liquid, which is the
droplet state to give a suspension. This last state is
not recommended.

Question 19

How can we form solid bridges

Answer 19

These can be formed by:
a) partial melting
b) hardening binders
c) crystallization of dissolved substances.

Question 20

How can we use partial melting in the formation in solid bridges

Answer 20

Not considered to be a predominant
mechanism in pharmaceutical materials and it
does not occur in wet granulation
The pressures used in dry granulation methods
may cause melting of low melting point
materials where the particles touch and high
pressures are developed.
When the pressure is relieved, crystallization will
take place and bind the particles together.

Question 21

How does the hardening binders help in solid bridges

Answer 21

The common mechanism in pharmaceutical wet
granulations.
An adhesive is included in the granulating
solvent. The liquid will form liquid bridges and the
adhesive will harden or crystallize on drying to
form solid bridges to bind the particles.
Adhesives such as polyvinylpyrrolidone, the
cellulose derivatives (such as carboxymethyl
cellulose) function in this way.

Question 22

How does crystallization help in making solid bridges

Answer 22

The liquid used to mass the powder during wet
granulation may dissolve one of the powdered
ingredients.
When the granules are dried, crystallization of
this material will take place and the dissolved
substance then acts as a hardening binder.
Any material soluble in the granulating liquid
will function in this manner.

Question 23

What attractive forces happened between solid particles

Answer 23

Electrostatic forces: of importance in causing
powder cohesion and the initial formation of
agglomerates, e.g. during mixing. In general
they do not contribute significantly to the final
strength of the granule.

Van der Waals forces: about four orders of
magnitude greater than electrostatic forces and
contribute significantly to the strength of
granules produced by dry granulation.

Question 24

Granule growth in the wet granulation procedures may
be described using three general granulation
mechanisms, name them.

Answer 24

Nucleation
Transition
Ball Growth

Question 25

What is nucleation

Answer 25

Granulation starts with particle-particle
contact and adhesion due to liquid bridges.
A number of particles will join to form the
pendular state and further agitation densifies
the pendular bodies to form the capillary
state.
These bodies act as nuclei for further granule
growth

Question 26

What is transition

Answer 26

Nuclei can grow in this stage by two possible
mechanism:
1. Single particles are added to the nuclei by
pendular bridges
2. Two or more nuclei may combine
This stage results in a large number of small granules
with a fairly wide size distribution.
if the size distribution is not excessively large, this point
represents a suitable end-point for granules used in
capsule and tablet manufacture: small granules will
produce a uniform tablet die or capsule fill.

Question 27

What is ball growth

Answer 27

Further granule growth produces large,
spherical granules and the mean particle size
of the granulating system will increase with
time. This phase is called ball growth.
If agitation is continued, granule
coalescence will continue and produce an
unusable overmassed system.

Question 28

Ball growth involves coalescence, breakage,
abrasion transfer or layering, what are these mechanisms

Answer 28

Coalescence: two or more granules join to form
a larger granule

Breakage: granules break into fragments which
adhere to other granules forming a layer of
material over the surviving granule

Abrasion Transfer: agitation of the granule bed
leads to attrition of material from granules. This
abraded material adheres to other granules
increasing their size.

Layering: when a second batch of powder mix is
added to a bed of granules, the powder will
adhere to the granules forming a layer over the
surface increasing the granule size.

Question 29

What are the main types of wet granulation equipments

Answer 29

Shear granulators
High speed mixer granulators
Fluidized bed granulators
Spheronizers/pellitizers

Question 30

What’s a shear granulator

Answer 30

Older granulators; mostly replaced by the much
more efficient high-speed mixer/granulators.
It is often used for wet massing of the powders.
The most common shear granulators is the
planetary mixer .
Generally, dry-powder blending has to be
performed as a separate initial operation using
different powder-mixer1
. The mixed powders are fed
into the bowl of the planetary mixer and
granulating liquid added as the paddle agitates
the powders2
. The moist mass is then transferred to
a granulator such as an oscillating granulator3

.The older process suffered from a number of
major disadvantages:
 its long duration,
 the need for several pieces of equipment
 high material losses which can be incurred
because of the transfer stages between the
different equipment

Advantages are:
The process is not very sensitive to changes in the
characteristics of the granule ingredients
The end-point of the massing process can often be
determined by inspection.

Question 31

What is a high-speed mixer granulator

Answer 31

This type of granulator (e.g. Diosna) was originally
designed solely for mixing purposes but is now
used extensively for granulation.
The machines have a stainless steel mixing bowl
containing a three-bladed impeller which
revolves in the horizontal plane and a
three-bladed auxiliary chopper which revolves in
the vertical plane.
A variation of the Diosna design is the
Collette-Gral mixer.
Based on the bowl and overhead drive of the
planetary mixer, the single paddle is replaced
with two mixing shafts.
One of these carries three blades which rotate
in the horizontal plane at the base of the bowl
and the second carries smaller blades which act
as the chopper in the upper regions of the
granulating mass.

Question 32

What are the mechanisms used in high-speed mixer granulator

Answer 32

1.The unmixed powders are placed in the bowl and
mixed by the rotating impeller.
2.Granulating liquid is then added via a port in the lid
and this is mixed into the powders by the impeller.
3.The chopper is usually switched on when the moist
mass is formed because its function is to break up
the mass to produce a granular material.
4.To remove large aggregates, this granular product
is usually sieved as it is being discharged into the
bowl of a fluid bed drier.

Question 33

What are the advantages of the high-speed mixer granulator

Answer 33

that mixing,
massing and granulation are all performed in a
short period in the same piece of equipment.
Granulation progresses so rapidly that a usable
granule can be transformed very quickly into an
unusable, overmassed system.
The process is also sensitive to variations in raw
materials but this may be minimized by using a
suitable end-point monitor

Question 34

What is the fluid bed granulator

Answer 34

1. Heated air is blown through a bed
   of unmixed powders to fluidize the
   particles and mix the powders.
2. Granulating liquid is pumped into
   the fluidized bed. Sufficient liquids
   added to produce granules of the
   required size.
3. Granules are then dried in the
   heated fluidizing air stream.

Advantages
All the processes which normally need separate
equipment in the traditional method are
performed in one unit:
Saving labor costs,
Minimizing transfer losses and
Saving processing time
Automation of the process can be achieved
once the conditions affecting the granulation
have been optimized.

Disadvantages
The equipment is initially expensive
The optimization of process and formula
parameters needs extensive development work
during the initial formulation development and
during scale up stages. Similar development
work for the traditional shear granulator and
using high-speed granulators is not as extensive

Question 35

What is the spheronizer / pelletizer

e.g. Caleva Spheroniser,
Freund CF Granulator.

Answer 35

For some applications it may be desirable to
have dense, spherical pellets that are difficult to
produce with the previous equipment types.
Such pellets could be used, for example, for
capsule filling when coated and non-coated
drug-containing pellets would give some
degree of programmed drug release after the
capsule disintegrates.

Question 36

How does the Freund granulator work

Answer 36

1. In the Freund granulator, the powder mix is added to the bowl and
   wetted with granulating liquid.
2. The base plate rotates at high speed and centrifugal force keeps the
   moist mass at the edges of the rotor where the velocity difference
   between the rotor and static walls causes the mass to roll and break
   up, forming spherical pellets.
3. Pellets are dried by the heated inlet air from the air chamber
   which also acts as a positive pressure seal during granulation.

By using this technique it is possible to coat the pellets by
spraying coating solution on to the rotating pellets.
In addition, layered pellets can be produced by using
the pellets as nuclei in a second granulation with a
powder mix of the coating ingredients.

Question 37

How does the extrusion spheronization work

Answer 37

Some spheronizers utilize a
feed of pregranulated
material which has been
massed and extruded into
short strings. A multi-step
process called “extrusion-
spheronization”.
For extrusion the wet mass can
be fed through a perforated
plate by an auger (screw)
feed, a principle similar to that
of the household mince

The strings are fed on to rotating base plate and
a velocity difference created by having static
walls at the edge of the rotating plate breaks
the material and rolls it into spheres. The spheres
have then to be transferred to a fluidized bed
drier for the drying process.

Question 38

What is dry granulation

Answer 38

May be used for drugs which are sensitive to
moisture or heat (necessary for drying wet
granules).
The necessary pieces of equipment for dry
granulation are:
A machine for processing the dry powders into
compacts
A mill for breaking the compacts so produced.

1. In the dry methods of granulation the powder particles
   are aggregated using high pressure by one of two
   methods:
   a) A large tablet (known as a slug) is produced in a
   heavy duty tableting press (a process known as
   slugging)
   b) Powders are squeezed between two rollers to
   produce a sheet of material (roller compaction).
2. The initial compacts are broken using a suitable milling
   technique to produce granular material which is usually
   sieved to separate the desired size fraction.
   The unused fine material may be recycled to avoid
   waste.