Granules are aggregations of fine powder particles that are roughly spherical in shape. They are produced to improve powder flowability, enhance compressibility, reduce toxicity, and prevent caking. There are three main granulation methods: wet granulation, dry granulation, and granulation by crystallization. Wet granulation is most common and involves mixing powder with a liquid to form a paste, then granulating and drying the paste. Granules are sieved after drying to achieve a uniform size distribution suitable for their intended use as a final or intermediate pharmaceutical product. Quality tests such as dissolution and friability are performed to ensure granule properties are suitable.

1. Granules

2.  Granules are aggregations of fine particles of powders in a mass of
about spherical shape.
Definition !?

3. 1. 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.
Why we prepare granules when we have
powders?

4. 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

5. 1. As a true & proper pharmaceutical dosage 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 )
Technologically, granules are used according to two
visions

6. 2. Semi-finished products for the preparation of tablets or other dosage
forms.
Usually, granules have an excellent compressibility

7. 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
Methods of Granulation

9. Dry Granulation

10. I. Granulation by Crystallization.
 This method exploits the presence of crystallization water in the
active material; this method is rarely used.

11. 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)

13. 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.

14. 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.

15. 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.

16.  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.

17. 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.

18. 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.
Steps of Wet Granulation

19.  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.

20.  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.

22.  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.

23. 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:
1. Water Solutions.

24. 2. 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,
1. A co-solvent is recommended.
This is a mixture between water & another water-soluble pharmaceutical
solvent with high dissolving capacity toward the powder.
2. We can also use a water solution of polymers,
The evaporation of water can determine the adhesion between the particles
of the powder.

25. Polymers solutions that can be used in the wet granulation:
1. Gelatin solution at 5-10%.
2. Starch paste 5 -10%.
3. Semi-synthetic polymers like CMC, MC.
4. Synthetic polymers like P.V.P.

26. 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

27.  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.

29. The 3rd step is the Drying Process.
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.

30. 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
The dryers are (see industrial pharmacy):

31. 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.

32. 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.

33.  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.

34. For example:
 If we have a die with diameter of 3/6 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.

35. 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.
Quality Controls

36. Friability tester

37. Some Particular Granules
1. Sustained release granules.
2. Enteric coated granules.
3. Effervescent granules.

38.  Effervescent salts are granules or coarse to very coarse powders
containing a soluble medicinal agent in a dry mixture
 Composition: Sodium bicarbonate, citric acid, and tartaric acid
 Note: When added to water, the acids and base react to liberate CO2
resulting in effervescence
Effervescent granules

39.  The resulting carbonated solution masks undesirable taste of any medicinal
agent.
 Using granules or coarse particles of the mixed powders rather than small
powder particles decreases the rate of solution and prevents violent and
uncontrollable effervescence.
 Sudden and rapid effervescence could overflow the glass and leave little residual
carbonation in the solution.
 Using a combination of citric and tartaric acids rather than either acid alone
avoids certain difficulties.
 When tartaric acid is used as the sole acid, the resulting granules readily lose
their firmness and crumble.
 Citric acid alone results in a sticky mixture difficult to granulate.

40.  Rx:
 Active drug 500 mg/5 g tsp in effervescent granule qs 120 g
Sig: Dissolve 1 teaspoonful in one-half glass of cool water and drink. Repeat this every 8 h.
 It is desired to dispense this as a granule, so that the patient will measure out a teaspoon- ful (5g)
dose, mix, and administer.
 Since each dose weighs 5g and the prescription consists of 120g, there are 24 doses.
 Each dose contains 0.5g of the active drug, which comes to 12g of the active drug for the entire
prescription.
 This requires 120g − 12g = 108g of effervescent vehicle. A good effervescent blend consists of both
citric acid and tartaric acid (1:2 ratio), since the former is rather sticky and the latter produces a
chalky, friable granule.
 It is necessary to calculate the amount of each ingredient required to prepare 108 g of the
granulation.
EXAMPLE

41.  3NaHCO3 + C6H8O7.H2O → 4 H2O + 3 CO2 + Na3C6H5O7
3 × 84 150
 Citric acid 1 g (MW = 210) of citric acid reacts with 1.2 g (MW = 84) of
sodium bicarbonate as obtained from the following:
 1/120=x / 3×84  x = 1.2g
CITRIC ACID

42.  2 NaHCO3 + C4H6O6 → 2 H2O + 2CO2 + Na2C4H4O6
 2 × 84 150
 Since it is desired to use a 1:2 ratio of citric acid to tartaric acid, 2 g
(MW = 150) of tartaric acid reacts with sodium 2.24 g of bicarbonate
according to the following calculation:
 2/150 =(x/2)×84
 x = 2.24 g
TARTARIC ACID

43.  Therefore, 1.2g and 2.24g of sodium bicarbonate is required to react
with 1 + 2g of the combination of citric acid and tartaric acid. Since it
is desired to leave a small amount of the acids unreacted to enhance
palatability and taste, of the required 3.44 g (2.24 g + 1.2 g), only 3.4
g of sodium bicarbonate will be used.

44.  Therefore, the ratio of the effervescent ingredients is 1:2:3.4 for the
citric acid:tartaric acid:sodium bicar- bonate. Since the prescription
requires 108g of the effervescent mix, the quantity of each ingredient
can be calculated as follows:
 1 + 2 + 3.4 = 6.4
1/6.4 × 108 g = 16.875 g of citric acid
2/6.4 × 108 g = 33.750 g of tartaric acid
3.4/6.4 × 108 g = 57.375 g of sodium bicarbonate Total = 108 g
 The prescription will require 12 g of the active drug and 108 g of this
effervescent vehicle.