Granules

Presented By:
Anirudh Sharma
B.Pharm (ayurveda)
Granules are aggregations of fine particles
of powders in a mass of about spherical
.shape
Why we prepare granules when we have
powders?

1. To avoid powder segregation,

if the powder is composed of particles with
different dimensions & different densities, a
separation between these particles will
occur.

2.To enhance the flow of powder,

Higher flowability gives better filling of the dies
or containers, during a volumetric dosage.
3. Granules have higher porosity than
powders,

4. To improve the compressibility of powders.

5. The granulation of toxic materials will

reduce the hazard of generation of toxic
dust, which may arise during the handling of
the powders.

6. Materials, which are slightly hygroscope,

may adhere & form a cake if stored as a
powder.
 Technologically, granules are used
according to two visions:
1. As a true & proper pharmaceutical dosage
form form,

These granules are used to prepare an instant

solution or suspension.

Granules, can be packaged as:

 Bulk granules (Multi-dosage containers),

 Divided granules (Mono-dosage

containers ).
2. Semi-finished
products for the
preparation of tablets or other dosage
forms.

Usually, granules have an excellent

compressibility,
Methods of Granulation
 Some of the available methods in the
industrial field for the preparation of
granules:
1. Wet Granulation.

2. Dry granulation methods.

3. Granulation by Crystallization.

I. Granulation by Crystallization.

 This method exploits the presence of

crystallization water in the active
material; this method is rarely used.
II. Dry Granulation.

Pharmaceutical powders that were mixed

homogeneously together are compressed to
obtain large tablets.

The high compression forces are obtained by using

one of the following procedures:

1.Tabling machines (see industrial pharmacy).

These machines are provided with dies of 2-3 cm
diameters (the fine powders have low flowability)
So,
large dies are easily filled in this case, the dies
travel between two punches, which press the
powder forming large tablets, with 2-3 cm of
diameters.
2. Roller compaction (see industrial
pharmacy).

The powder mixture flow between two

rollers to form a compressed sheet.

These large tablets or sheets are milled.

The milled sheets are sieved.

The sieving process gives three fractions
of granules :
1. Very coarse granules, which return back
to the milling process.

2. Very fine fraction, which return back to

the compaction.

3. Fraction with optimal dimensions for

following manufacturing steps.
This system produces granules with:
 irregular shape,

 low rate of dissolution due to the high

compression force used to aggregate the
powders.

These granules are poorly water-permeable due to

the low porosity.
So, water can’t permeate them easily in order to
disintegrate & dissolve them.

This will extremely reduce the velocity of

dissolution & so the bioavailability of the active
material.
 Vice versa if the granules have high
porosity the molecules of water can
penetrate easily into the pores, &
disintegrate the granules.

 High Porosity means high specific

surface area, leading to an increasing in
the dissolution velocity of the granules, &
thus their bioavailability.

 Thus, we can say that the dry granulation

method is used only for those powders,
which cannot be granulated with the wet
granulation method.
Wet Granulation
 This is the most used method to
prepare granules.

 The main disadvantage of this

method is the higher number of
steps present in this process when
compared with the other two
methods.
Steps of Wet Granulation:
1. The 1st step is the wetting of the powder with
a liquid or solution to form a paste.
Characteristics of the granulating liquid:
 It should have all required characteristics of
pharmaceutical excipient, &
 It should dissolve the powder only within a
certain limit (mild solvent):

If the powder is soluble in the solvent, a solution

or suspension will be obtained instead of the
paste.
 From another side, if the solvent cannot
absolutely dissolve the powder, we
cannot obtain the liquid forces, which
stick together the powder particles.

 The fraction of powder, which dissolves

in the solvent, & then re-crystallizes,
after the drying, will form bridges
between the particles of the powder.
 When two particles become in contact
between each other by certain forces,
they institute:
 forces of electrostatic nature (week
forces) &

 forces of viscous or/and adhesive natures

(which are the most important) so the
particles remain attached to each others.

 Thus the used liquid in the wet

granulation must be mild solvent for the
powder.
 There is a few number of solvents
available for pharmaceutical
granulation.

 This is because we can’t totally

eliminate the solvent, so if traces of the
solvent remain in the formula at the end
of the manufacturing, these traces must
be non toxic for the patient.
 The most used solvents in wet granulation :
1. Water.
2. Ethanol.
3. Isopropanol.

 If we want to use water for granulation, the

powder must be:
 fairly or discreetly soluble in the water, &
 compatible with it.

 If the powder is very soluble in water, we can

use another liquid or the following
arrangements:

4. Water Solutions.
Simple Syrup
This syrup has less dissolving capacity than the
pure water, because the majority of water
molecules are involved in the hydration &
dissolving of the sugar molecules instead of
the powder molecules.

 But if the powder is water insoluble,

5. A co-solvent is recommended.
This is a mixture between water & another
water-soluble pharmaceutical solvent with
high dissolving capacity toward the powder.

6.We can also use a water solution of polymers,

The evaporation of water can determine the
adhesion between the particles of the powder.
 Polymers solutions that can be used in the wet
granulation:
1. Gelatin solution at 5-10%.

Such viscose solutions determine the adhesion of the

particles of the powders,
When water evaporates the gelatin solidifies between
the two particles of powder and maintain them stuck
together.

2.Starch past 5 -10%.

Pre-gelatinized starch, which has the characteristic to
swell in a cold water.

3. Semi-synthetic polymers like CMC, MC.

4. Synthetic polymers like P.V.P.

Some of these compounds can be used in
organic solvent like ethanol,
 This is useful in case of thermo-sensitive
compounds, &

 To reduce the cost of production.

The granules obtained in this way are

called agglutinated granules.
2. The 2nd step is the granulation or the
formation of granules starting from the
paste.

To achieve this, many granulators are

available (see industrial pharmacy):
1. Rotative granulator,

2. Oscillating granulator,

3. High speed mixer granulator,

4. Fluidized bed granulator,

5. Freund granulator,

6. Roller compaction granulator.

 The quality of the granules depends on the:
1. Granulation solvent,

2. Type of granulator,

3. Powder nature.

 The paste that we have to obtain mustn’t

drains between the fingers of the hand,
which means that must remain aggregated
& easily crumbled.

 This is a very coarse reference, but

nowadays there is the possibility to have a
qualitative evaluation.
 we can measure the energy that we must
provide to the system in which we carry out
the wetting process.

How?

1. Put the powder for granulation in the

granulator,

2. Add gradually the granulating liquid,

3. Then mix by the use of electrical motor

This motor measures the absorbed power in

function of the time & so in function of the
putted liquid.
How can we calculate the exact volume of
granulating liquid for powder kneading?
 We can evaluate the liquid quantity for the
kneading process by measuring continuously
the absorbed power during the addition of
the granulating liquid.

 The increase in the required power is

connected with the increase of the viscosity
of the dough mass, due to the formation of
the liquid bonds (adhesive & viscous types).

 Generally, all instruments are able to form a

curve, as in the following figure:
4. Perform the curve by putting the absorbed
power in Y- axis, & the volume of the
granulating liquid in X- axis.

5. Interpretation of the obtained curve:

 Initially, the addition of the granulating

liquid doesn’t produce a significant change
in the absorbed power,

 At point 2 we fined that any added quantity

of the granulating liquid, increases
proportionally the absorbed power.
 At this point we have initial formation of:

1. Electrostatic bonds (less important),

2. Liquid bonds (more important).

 These bonds start to bind together the

powder particles & to form the granules.

 Therefore the equipment meet higher

resistance to maintain constant the
number of rounds/minute.
 Then continuing in the liquid addition, we note
that the absorbed power will be stabilized on a
certain value (interval between 3-4), this
means that the system was reached an
equilibrium state.

 At points 3-4, we have an excellent adhesion

between the various particles of powder &

 The granule shape depends on the type of the

used granulator.
 The addition of further liquid, will give
phase 5 where we note a sharp drop in
the absorbed power, because the
granulate will be transformed in a
suspension.

In this manner we have an idea about the

percentage quantity of the granulating
liquid, which we have to add, by
evaluating the curve.
This curve can subdivide the granulators in:
1. Slow granulator (fluidized bed granulator and
dryer).

2. Speed granulators (e.g. plates and rotate

granulators…etc, see industrial pharmacy).

The 3rd step is the Drying Process.

III.
Water is more difficult to be eliminated than the
organic solvents, therefore the water gives some
problems:

1. When the powder is thermosensitive the heating

for long period of time can alter the stability of
the powder,

2. The consumption of energy is higher than the

organic solvents.
 We have three kinds of water in the granulate
mass:
1. Water of Crystallization,
It is very difficult to be eliminated without
causing the decomposition of the product or
variation of its crystalline form.

2.Adsorped water,
The amount of water, which was absorbed by a
drug present in a moist air, this amount
depends on the nature of the drug & the
relative humidity of the air.

3.Imbibition of water,
The amount of water, which impregnates the
granules, this water is easy to be eliminated
by simple evaporation.
According to the used dryer, we can
eliminate the total amount of imbibition’s
water & a portion of the adsorpted water .

 The elimination of the total amount of the

adsorbed water is not advisable.

 For example the elimination of the total

amount of the adsorbed water, may create
electrostatic charges,
 This lead to the attraction or repulsion of
the granules between themselves & the
walls of the equipment,

 This type of granules are very difficult to

be managed.
 If we use a hydrophilic polymer solution,
as a granulating liquid, & we proceed for
long time in the drying process, the
hydrophilic polymer will assume a glassy
consistency.

 These glassy characteristics cause the

fragmentation of the granules during the
following manufacturing processes.

 Thus, a certain quantity of moisture is

useful to improve the manipulation of the
granules.
 The dryers are (see industrial pharmacy):
1. Static Oven,

2. Rotary Drier,

3. Fluidized Bed Drier,

4. Vacuum Oven,

5. Microwave Drier,

6. Spray Drier,

7. Rotary Atomizer,

8. I.R Drier.
IV. The 4th step is the Classification of the
granules.

The last step is the classification according

to particles dimension:
1. Coarse granules, which must be milled,

2. Fine granules, which must be re-

granulated.

3. Optimum granules with optimum

dimensions, which are ready for use.
We have two problems correlated to the size of
granules:
1. Concerning the filling of big volume (i.e. sachets or
bottles).

If we have big granules we can use big measuring

tool, while if the granules have small size, we can
use small measuring tool.

The most critical problem is :

2. when we must to fill the die of the tableting machine
in order to prepare the tablet.

In this case:
it is not only important to have granules with equal
dimensions, but
it is also important that the size of these granules are
within a certain range, which is in function with the
diameter of the die.
 The essential concept when producing
tablets, is that the granules which we
want to fill the die with, must be more
fine as the die becomes smaller.

 In fact there are well-defined relations

between the size of the granules & the
diameters of the die, in order to have a
filling uniformity of the die, &
so to obtain tablets, which remain within
the limits of the weight uniformity.
For example:
 If we have a die with diameter of 3/16 of
inch, we should prepare granules, which
pass through a sieve with mesh 20 (20
mesh /1 linear inch).

 If we have a die with diameters of 7/16

inch, we have to have granules with
dimensions that pass through a sieve of
mesh 12.
Quality Controls
1. Weight uniformity test.

2. Dissolution profile.

3.Friability test.
The granules must be:
packaged in order to be used as final
pharmaceutical dosage form, or

added to other substances for example to

prepare the tablets,

So, we must avoid the transformation of the

granules into powder during the manipulation
processes.
Friability tester
Some Particular Granules:
1. Sustained release granules.

2. Enteric coated granules.

3. Effervescent granules.