Definition
Aggregates of fine particles of powder in a mass approximately spherical
in shape
Reasons to prepare granules
To avoid powder segregation
If the powder is composed of particles with different dimensions and
densities, separation between these particles will occur
To improve powder flow
Higher flowability results in better filling of dies or containers during
volumetric dose filling
Improve the compressibility of powders
Granules have higher porosity than powders allowing for better compaction
Reasons to prepare granules
Reduction of toxic dusts:
Granulation of toxic powdered materials will reduce the hazard of generation
of toxic dust, which may arise during their handling
Prevention of agglomeration and adhesion problems
Materials that are slightly hygroscopic may adhere and form a cake if stored
as a powder
Modification of drug release
Uses of granules
Granules can be used pharmaceutically as:
Individual proper pharmaceutical dosage form
Semi-finished product for the preparation of tablets or other dosage forms
(granules have excellent compressibility)
Uses of granules
As a proper pharmaceutical dosage form
Example: granules used to prepare solutions or suspensions
This type can be packaged as: (examples)
Bulk granules (multi-dosage containers)
Divided granules (single-dosage containers)
Granulation methods
Small-scale:
In the lab example
Industrial preparation of granules:
Wet granulation
Dry granulation
Crystallization
Rarely used
Depends the presence of water of crystallization in the active material
Dry granulation
Powders that were mixed homogeneously are compacted into large tablets
or sheets then milled and sieved
High compression forces are obtained using:
Special tableting machines
Roller compaction
These methods will be discussed in details in your future industrial pharmacy
course
Dry granulation
Tableting machines (special)
In this method, powders that were mixed homogeneously are compressed to
obtain large tablets
These machines are provided with large dies of diameter 2-3 cm (this will
allow better filling as fine powders have low flowability)
The die content is compressed using 2 punches forming large tablets of 2-3
cm in length
The tablets are then milled and sieved
Dry granulation
Roller compaction:
The powder mixture flows between two rollers to form a compressed sheets
The sheets are then milled and sieved
Dry granulation
Sieving:
The sieving process gives three fractions of granules:
Very coarse: can be subjected to repeated milling
Very fine: can be granulated again
A fraction with optimal dimensions for subsequent manufacturing steps
Dry granulation
Dry granulation methods produce granules with:
Irregular shapes
Slow dissolution rates due to the high compression force used to compact the
powders
Poor dissolution:
The resulting granules are poorly permeable to water due to low porosity
(water cannot permeate them easily in order for disintegration and
dissolution to occur)
Can have substantial effect in the reduction of in vivo dissolution and
bioavailability
Dry granulation
Dry granulation issues (contd):
If the granules are highly porous, water can penetrate easily into the pores
and disintegrate the granules
Higher porosity and high specific surface area increase the dissolution rate
and higher bioavailability
Dry granulation is only used for powders which cannot be granulated with
wet granulation
Wet granulation
The most commonly used method to prepare granules
The main disadvantage of this method is the number of steps present in
this process compared with the other methods
Wet granulation
Steps:
Wetting of the powder with a liquid or solution to form a paste (wet massing)
Formation of granules starting from the paste
Drying
Sieving and separation
Wet granulation
Wetting of the powder with a liquid or solution to form a paste
Characteristics of the granulating liquid:
Should have all required characteristics of pharmaceutical excipient (purity,
safety, etc)
Should be a mild solvent for the powder in question (if the powder is soluble
in the solvent, a solution or suspension will be obtained instead of a wet
mass)
Wet granulation
Characteristics of the granulating liquid (contd):
If the solvent cannot dissolve the powder, sufficient cohesion between the
particles forming the granules will not be obtained
Dissolved particles can re-crystallize again forming solid bridges between the
undissolved particles after drying
Granule formation
When two particles become in contact with each other, they interact with
each others:
Forces of electrostatic nature (week in nature)
Forces of adhesive natures (most important)
If these forces are sufficiently strong, the particles remain attached to each
others forming granules
The liquid used in the wet granulation must be mild solvent for the
powder
Granule formation
Granule formation
Steps in granule formation:
At low moisture levels, the particles are held together by lens-shaped rings of
liquid (pendular state)
These cause adhesion because of the surface tension forces of the liquid/air
interface and the hydrostatic suction pressure in the liquid bridge
When all the air has been displaced from the space between the particles the
capillary state is reached, and the particles are held by capillary suction at the
liquid/air interface, which is now only at the granule surface
Granule formation
Steps in granule formation:
The funicular state represents an intermediate stage between the pendular
and capillary states
Moist granule tensile strength increases about three times between the
pendular and the capillary state
Granule formation
Steps in granule formation:
It may appear that the state of the powder bed is dependent upon the total
moisture content of the wetted powders, but the capillary state may also be
reached by decreasing the separation of the particles
In the massing process during wet granulation, continued kneading/mixing
of material originally in the pendular state will condense the wet mass,
decreasing the pore volume occupied by air and eventually producing the
funicular or capillary state without further liquid addition
Granule formation
Steps in granule formation:
The suspension state:
Important in the process of granulation by spray drying of a suspension
In this state, the strength of the droplet is dependent upon the surface tension of the
liquid used
Wet granulation: solvents
The most used solvents in wet granulation:
Water
Ethanol
Isopropanol
Others
Wet granulation: solvents
Considerations:
Few solvents are suitable for pharmaceutical granulation
We cannot totally eliminate the solvent
If traces of the solvent remain in the formula at the end of the
manufacturing, these traces must be nontoxic
Wet granulation: solvents
Water:
If we want to use water for granulation, the powder must be:
Partially soluble in the water
Compatible with water
Wet granulation: solvents
If water cannot be used for some reason, another liquid is used such as:
Aqueous solutions (e.g., syrup)
Co-solvents
Aqueous polymeric solutions
Wet granulation: solvents
Simple syrup
Syrup has lower dissolving capacity than the pure water
The majority of water molecules are involved in the hydrating and dissolving
sugar molecules instead of powder molecules
Wet granulation: solvents
Co-solvent system:
If the powder is water insoluble
A mixture between water and another water-soluble solvent with high
dissolving capacity toward the powder
Wet granulation: solvents
Aqueous solutions of polymers
Upon the evaporation of water, these polymers can increase the adhesion
between the particles of the powder
Wet granulation: solvents
Polymeric solutions that can be used in wet granulation include:
Gelatin solution, 5 -10%
Such viscous solutions increase the adhesion of the particles of the powders
When water evaporates, gelatin solidifies between the two particles of powder and
maintains them glued together
Starch paste, 5 -10%
Pre-gelatinized starch, which has the characteristic to swell in a cold water
Semi-synthetic polymers like MC and CMC
Synthetic polymers like PVP (polyvinly pyrrolidone)
Wet granulation: solvents
Some of these polymeric materials can be used in organic solvent (e.g.,
ethanol) as a granulation fluid
Useful in case of thermo-sensitive compounds
Reduce the cost of production
Granules obtained using this method (polymeric solutions) are called
agglutinated granules
Granulation
The second step is the granulation or the formation of granules
starting from the paste (wet mass)
To achieve this, several granulators are available (see industrial
pharmacy):
Rotatory granulator
Oscillating granulator
High speed mixer-granulator
Fluidized bed granulator
Freund granulator
Roller compaction granulator
Granulation
The quality of the granules depends on the:
Granulating solvent
Type of granulator
Nature of the powder
Granulation endpoint
On a lab scale, the granulation endpoint is identified when the resulting
wet mass does not slip between the fingers of the hand (i.e., it should
remain aggregated but easily crumbled)
Very broad reference point
Modern granulating equipment can provide qualitative and quantitative
evaluation of the process
Granulation endpoint
One way is to measure the energy consumption of the granulating
machine.
The powder is placed in the granulator
The granulating liquid is gradually added
The contents are mixed using electrical motor
This motor measures the absorbed power as a function of time and as a
function of the quantity of added liquid
A plot of the absorbed power vs. the percentage of the added liquid is
constructed
Granulation endpoint
Granulation endpoint
How is the appropriate volume of granulating liquid required for
granulation is estimated?
By measuring the absorbed power (in real time) during the addition of the
granulating liquid
The increase in the required power is related to the increase of the viscosity of
the wet mass, due to the formation of the liquid bridges (adhesive and viscous
types)
Generally, most modern granulation equipment are able to generate the
power consumption plot
Granulation endpoint
Interpretation of the plot:
Initially, the addition of the granulating liquid does not produce a significant
change in the absorbed power
At point II, increasing quantity of the granulating liquid increases the
absorbed power
Granulation endpoint
Interpretation of the plot:
At this point (II), the following type of interactions are formed:
Electrostatic interactions (less important)
Liquid bridging between particles (important)
These forces bind the powder particles together to form the granules
The granulating equipment requires higher power to maintain constant the
number of rounds/minute
Granulation endpoint
Interpretation of the plot:
With continued addition of the liquid, the absorbed power become constant
on a certain value (between points (III) and (IV) on the plot)
At this point, optimal adhesion between the particles is achieved
The shape of the resulting plot depends on the type of the granulating
equipment
Granulation endpoint
Interpretation of the plot:
After point (IV), a sharp drop in the absorbed power is observed
This occurs because the wet mass become a suspension with increasing
amount of liquid
The plot provides information on the appropriate quantity of the liquid
required for granulation
Granulation endpoint
The plot can also subdivide the granulators in:
Slow granulator (low-shear, e.g., fluidized-bed granulator and dryer)
Speed granulators (high-shear, e.g., plates and rotate granulators)
See industrial pharmacy
Drying of granules
The last step in granulation is the evaporation of the granulation liquid
Water is more difficult to dry compared to organic solvents:
If the powder is thermosensitive, heating for long period can affect the
stability of the drug
The energy consumption is higher than the organic solvents
Slower
Drying
Three forms of water in the granulated mass:
Water of crystallization: very difficult to remove without causing the
decomposition of the product or changing its crystalline form
Adsorbed water: water that is absorbed by the powder from moist air,
depends on the nature of the drug and the relative humidity of the air
Imbibed water: water which impregnates the granules, this water is easily
removed by simple evaporation
Drying
Depending on the dryer, imbibed water and a part of adsorbed water can
be removed
Total removal of adsorbed water is not recommended:
May create electrostatic charges leading to electrostatic interaction between
granules, and with the walls of the equipment, these charged granules are
difficult to handle
Drying
Total removal of adsorbed water (contd):
If a hydrophilic polymer solution is used n the granulation, the hydrophilic
polymer may assume a glassy consistency
These glassy characteristics cause the fragmentation of granules during
subsequent manufacturing steps
A defined quantity of moisture is useful to improve the manipulation of
the granules
Dryers
The dryers include (see industrial pharmacy):
Static oven
Rotary dryer
Fluidized-bed dryer
Vacuum oven
Microwave dryer
Spray dryer
Rotary atomizer
IR dryer
Sieving and classification
The last step in granulation:
Coarse granules
Fine granules
Granules with the optimal size
Sieving and classification
Granule size:
Large granules require large measuring tools, small granules can be measured
using small measuring tools
Granules should have uniform size, and a size range compatible with the
diameter of the die
Sieving and classification
Granule size
The granules should be finer as the die becomes smaller
There are well-defined correlations between the size of the granules and the
diameter of the die to obtain uniform filling of the die to produce tablets that
remain within the limits of the weight uniformity tests
Sieving and classification
Example:
A die with diameter of 3/16 of inch, requires granules which pass through a
sieve with mesh no. 20
A die with diameters of 7/16 inch, requires granules that pass through a sieve
of mesh no. 12
Quality control of granules
Weight uniformity test
Dissolution profile
Friability test
Granules should be:
Packaged in order to be used as final pharmaceutical dosage form
Added to other substances to prepare other dosage forms such as tablets
The transformation of the granules back into powder should be
avoided during granule manipulation processes
QC
Friability Tester
Miscellaneous
Some special function granules:
Sustained release granules
Enteric coated granules
Effervescent granules
