GRANULATION

Granulation
- Granulation is the process in which primary powder particles are made to

adhere to form larger, multiparticle entities called granules.

- Pharmaceutical granules typically have a size range between 0.2 and 4.0 mm,

depending on their subsequent use.

- In the majority of cases this will be in the production of tablets or capsules,

when granules will be made as an intermediate product and have a typical size

range between 0.2 and 0.5 mm,

 Reasons for granulation
To produce uniform mix. not separating i.e.
prevent segregation of constituents of the powder mix
Render material free flowing
Improve compression
 Reduce hazard of toxic dust
 Reduce the hazard of hygroscopic powder adhesion
 Densify materials- convenient storage
 Facilitate metering or volume dispensing
 Control rate of release
 Reduce dust improve appearance

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 Powder Granules

Granulation

sieving

Segregated Powder Monosized Granules

 Granulation advantages:
Increase cohesiveness & compressibility
Lower pressure, increase life time of compression tools
Uniform content distribution
Good handling for bulky & dusty powder
Improve dissolution rate of insoluble Ds
Controlled release preparations

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 Granulation limitations:
Large no. of unit operations
Expensive pieces
Time consuming
Material loss during processing
Cross contamination
Problems in processing sticky materials

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Granulation Techniques
1- dry Granulation
Procedure:
 Powder compressed into slugs screened into granules
 For moist & heat sensitive active ingredients
 Drugs that don’t compress well after wet granulation
Advantages:
 Less space & equipments
 Eliminate need for binder sol’n & drying
Machines used:
 Chilsonator roller compactor
 Hutt compactor
 Dry granulation
In the dry methods 2 steps:
 Granulation: (aggregation) under high pressure without the use of a liquid
using one of the following processes.
 Using Sluggers: large tablet compacts (known as a slug) is
produced in a heavy-duty tabletting press (a process
known as sluggin’)
 or using Roller compactors the powder is squeezed
between two rollers to produce a sheet of material (roller
compaction).
 Milling: the intermediate products 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 reworked to avoid waste.
Roller compactors

Alexanderwerk
Roller compactor
Hutt Roller compactor
Advantages of dry granulation:

 Avoids heat–temperature combinations that might cause

degradation of the product.

 This dry method may be used for drugs which are

sensitive to moisture.
 Wet granulation
 Wet granulation involves the massing of a mix of dry primary powder particles
using a granulating fluid.
 The fluid contains a solvent which must be volatile so that it can be removed by
drying, and be non-toxic.
 The granulating liquid may be used alone or, more usually, as a solvent containing
a dissolved adhesive (binding agent) which is used to ensure particle adhesion once
the granule is dry.
 In the traditional wet granulation method the wet mass is forced through a sieve to
produce wet granules which are then dried.
 A subsequent screening stage breaks agglomerates of granules and removes the
fine material, which can than be recycled.
 Typical liquids include water, ethanol and isopropanol, either alone or in
combination.
The primary advantages of water are that:
it is non-flammable, which means that expensive safety precautions not be taken.
Water is commonly used for economical reasons.
disadvantages of water as a solvent are that:
It may adversely affect drug stability, causing drug hydrolysis.
It needs a longer drying time than do organic solvents, that increases the length of
the process and again 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.
 Effect of granulation method on granule structure
The properties of the granules are influenced by the manufacturing process.
The method and conditions of granulation affect intergranular and intragranular pore
structure by changing the degree of packing within the granules.
Precompressed granules (dry granulation), consisting of compressed drug and binder
particles, are held together by simple bonding during compaction.
Granules prepared by wet massing (wet granulation), consist of intact drug particles
held together in a sponge-like matrix of binder.
Fluidized-bed granules are similar to those prepared by the wet granulation, but
possess greater porosity and the granule surface is covered by a film of binding agent.
With spray-dried systems the granules consist of spherical particles composed of an
outer shell and an inner core of particles.
 Granulation mechanisms:
 Adh & coh Forces form immobile liquid film
-immobile liq film increase bond strength between
particles-vander Waal forces increased
- viscous adhesives soln
 Interfacial forces mobile liquid film
-pendular state: prticle held by lens-shaped rings of liq->
surface tension forces
-Capillary state: particle held by capillary suction due to
air displacement
-Funicular state: intermed state,
-moist granule tensile strength increased 3 times from
pendular to capillary state
-droplet “susp state”
-continued kneeding/mixing in pendular state densify wet
mass lead to funicular or capillary state without liquid
addition

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 Mechanisms of granule formation:

 Nucleation
- No. of particles join to form pendular state or
capillary state
 Transition: particles add to nuclii or 2 nuclii unite
- Suitable end point for tablet and caps filling
 Ball Growth:
- Coalescence
- Breakage
- Abrasion transfer
- layering

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 Wet Granulation procedure:

1. Preparation of A.I. & excipients

2. Preparation of binding liquid

3. Moistening the A.I. & excipients with binder

4. Sieving into coarse granules

5. Drying

6. Sieving
7. Mix with lubricant and compress

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 Pharmaceutical granulation equipments:
Wet Granulators
1. Shear granulators

2. High speed mixer

3. Fluidized – bed granulators

4. Spray dryers

5. Spheronizers/pelletizers

6. Rotor granulators
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 Shear granulator (Planetary mixer)
 Formulation ingredients may be mixed in it.
 Mixed powders are fed, granulating liquid is
added, moist mass to oscillating granulator; rotor
bars force moist mass through sieve.
 Mass sufficiently moist.
 Granules collected and dried.
 Disadvantages of shear granulator: Long duration, several
pieces of equipment, matrial loss.
 Advantages of shear granulator: Process is not sensitive
to changings ingredients characteristics, end point
determined by inspection.

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 High speed granulator (Diosna, Fielder)

 Stainless steel mixing bowel, contains three-bladed impeller (horizontally), three bladed auxiliary chopper.

 Mix dry powders, add binder, granular product discharged through wire mish to fluidized bed dryer.

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 Advantages: mixing, massing, & granulation all in same equip.
 Use suitable monitoring system to indicate end of granulation.
 Process is sensitive to variations in raw materials.

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 High speed granulator (Collette-Garl)

 Bowl with an overhead drive of planetary mixer, two mixing shafts, one three bladed & horizontal, second
smaller blades & horizontally.

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 Fluidized bed granulators

 Powder particles are fluidized in a stream of heated filtered air.

 Binder pumped from reservoir &sprayed from a nozzle on powder
bed.
 Exhaust filters prevent material escape.
 Advantages: all process in one unit, saving labor, time & transfer
loss. Automated process.
 Disadvantages:equip. initially expensive, optimization of process
parameters needs extensive development work; (bed load, fluidized
air flow rate, air temp, air humidity, nozzel type, & droplet size).

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Material container

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Spherorizers/pelletizers

 Producing dense, spherical pellets used for

CDR, following coating with suitable polymer,

filling in hard gelatin capsule.

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 Spheronizers /Pelletizers

For some applications it may be desirable to have a

dense, spherical pellet of the type difficult to produce with
the previous equipments. Such pellets are used for controlled
drug release.
A commonly used process involves:
 Separation of wet massing.
 Extrusion of this wet mass into
rod-shaped granules and
subsequent spheronization of
these granules.
 The main steps of the process are:

1. Dry mixing of ingredients to achieve a homogenous powder dispersion

2. Wet massing to produce a sufficiently plastic wet mass
3. Extrusion to form rod-shaped particles of uniform diameter
4. Spheronization to round off these rods into spherical particles
5. Drying to achieve the desired final moisture content
6. Screening to achieve the desired narrow size distribution.
Extrusion

Schematic representation of production extruder

Spheronization
• The function of spheronization is to round off the rods produced
by extrusion into spherical particles.
• This is carried out in Spheronizer which consists of a bowl with
fixed side walls and a rapidly rotating bottom plate or disc.
• The rounding of the extrudate into spheres is dependent on
frictional forces generated by particle–particle
and particle
equipment collisions.
 Advantages of granulation using Extrusion/spheronization

Extrusion/spheronization process is used to make uniformly sized spherical particles.

It is used primarily to produce multiparticulates for controlled drug release
applications.
The major advantage over other methods of producing drug loaded spheres or
pellets is the ability to incorporat high levels of active ingredients without producing
excessively large particles (minimal excipients).
Ideal flow behaviour and dosability
Compact structure
Low hygroscopicity
High bulk density