Topic:-

Instruments for granules

manufacturing
Presented by group #04

GRANULATION:
Granulation is the process in which primary powder particles
are made to adhere to form larger multi particles entities
called granules.
Pharmaceutical granules typically have a size range between
0.2-4.0 mm.
Granulation generally commences after initial dry mixing of
the necessary powdered ingredients so that a uniform
distribution of each ingredient through the mix is achieved.

Reasons:
1)
2)
3)

4)
5)

6)

To prevent segregation of the constituents of the powder mix.

To improve the flow properties of the mix.
To improve the compaction characteristics of the mix.
To minimizing the hazards associated with toxic dust particles
during handling, transporting of powders.
Granules are generally occupy less volume per unit weight
and more denser than the powder mix, thus more convenient
for storage and shipment.
Granulation technique helps adhesion and cake formation of
hygroscopic materials. This occurs because the granules will
be able to absorb some moisture and still retain the flowability because of their size.

Advantages:
Granules have smaller surface area than a comparable
volume of powders. This makes granules more stable
physically and chemically than the corresponding powders.
Granules are less likely to cake or harden upon standing
than are powders.
Granules are more easily wetted by a solvent than are certain
powders, so that granules are also preferred in making
solutions.
Granules produce particle-size uniformity, thus content
uniformity.

Granules increase compressibility.

Methods of granulation:
Granulation methods can be divided into two types:

Wet
methods

Dry
methods

Dry granulation:

Dry granulation converts primary powder particles into granules

using the application of pressure without the intermediate use of a
liquid.

Compaction
of powder

Milling

Screening

Two pieces of equipments are necessary for dry granulation:

1.
Slugging
2. Roller compaction.

1. Slugging:

The dry powders can be compacted using a conventional

tablet machine or, more usually a large heavy duty rotary
press can be used. The process is known as slugging
The compacts made in the process having size range 25mm
diameter by about 10-15mm thick which is termed as slugs.

Initial granulation was forced down hoppers

of big tablet processes that were fitted with
large flat punches, about 1 inch in diameter.
These large slugs were subsequently broken
down using oscillators or mills to form
granules

Disadvantage:

The slugging method had several drawbacks,

such as damage to presses and tooling, frequent
cleaning and maintenance needed and oscillator
screens were damaged breaking down the hard
slugs.
Hence Fitz-Patrick came up with the roller
compaction machine which produced granules
75% faster than slugging

2.Roller compaction:
Roller compaction method is an alternative gentle method, the
powder mix being squeezed between two counter rotating rollers
to form a compressed sheet.
As the volume decreases through the region of maximum
pressure, the material is compressed into dense sticks or weak
sheets.
These sheets are then granulated through a milling system and
series of screens to achieve the precise, uniform granule size
specified.

Advantages:

The process is economical.

It can cope with wide range of materials, particle size, bulk density
and flow ability.
The process is easily scaled up.
The product has uniform properties with respect to its mechanical
strength.
No work hardening problem occurs. The resulting granules capable
of further compaction into tablets.

Instruments for Wet granulation

Shear granulators

In the traditional shear (or planetary)

granulation process, dry powder blending,
usually has to be performed as a separate
initial operation using different powdermixing equipment.

Process:

Mixing:

The mixed powders are fed into the bowl

of the planetary mixer and granulating liquid is
added as the paddle of the mixer agitates the
powders.
Mixing
arm
Mixing
bowl

Planetary Mixer

Granulation:

The moist mass has

been transferred to a granulator,
as oscillating granulator.
The rotor bars of the granulator
oscillate and force the moist
mass through the sieve screen,
the size of which determines the
granule size.

Drying:
The granules can be collected on trays and
transferred to a drying oven.

Sieving:

Granules may aggregate owing to bridge

formation at the points of contact of the
granules.
To disaggregate the granules and remix them, a
sieving stage is necessary after drying.

Advantages:
The process is not very sensitive to changes in the characteristics
of the granule ingredients (e.g. surface area variations in different

batches of an excipient)

The end-point of the massing process can often be determined by

examination.

Disadvantages:
Long duration

the need for several pieces of equipment

The high material losses because of the transfer stages.

High-shear mixer/granulators
The granulator has a stainless steel

mixing bowl containing a three-bladed

main impeller, which revolves in the
horizontal plane, and a three-bladed
auxiliary

chopper

(breaker

blade)

which revolves either in the vertical or

the horizontal plane.

Process:

The unmixed dry powders are placed in the bowl and mixed by the

rotating impeller for a few minutes.

Granulating liquid is then added via a port in the lid of the

granulator while the impeller is turning.

The granulating fluid is mixed into the powders by the impeller.

The chopper is usually switched on when the moist mass is

formed, as its function is to break up the wet mass to produce a bed
of granular material

Once a granule has been produced, the granular product is

discharged, passing through a wire mesh which breaks up any large
aggregates, into the bowl of a fluidized-bed drier.

Advantages:

Mixing and granulation are all performed

within a few minutes in the same piece of
equipment.

Disadvantages:
The process needs to be controlled with care.
The process is also sensitive to variations in
raw materials

Fluid bed granulation

Fluidization is the operation by which fine

solids are transformed into a fluid like state.

Granulating and drying can be completed in one

step inside the machine.

Process:

Powder
particles are
fluidized in a
stream of air

Heated and
filtered air is
blown

Granulating
fluid is
pumped
through spray
nozzles.

Granules
are
formed

Advantages.

Gentle product handling.

Uniform spraying of all particles in the fluid
bed.
It reduces dust formation during processing.
It reduces product loss.

Disadvantages

The Fluid Bed cleaning is labor-intensive and

time consuming.
Difficulty of assuring reproducibility

Spray drying
This process has been divided in three stages:
Atomization of
a liquid feed
into fine
droplets
The mixing of
spray droplets
with a heated
gas streams
The dried
powder is
separated from
the gas stream

Advantages:
It is a very rapid and continuous process.
Minimal exposure of product to heat due short
residence time.
It helps in the overall cost reduction by avoiding the
labour intensive drying and the granulation steps.
It is suitable for heat sensitive product

Disadvantages:

Equipment is very bulky and expensive

Thermal efficiency is rather low since the air must still
be hot enough when it leaves the dryer to avoid
moisture

Extrusion/spheronization
Extrusion/ spheronization is a multistep process
used to make uniformly sized spherical particles.
It is used primarily to produce multiparticulates for
controlled drug release applications.

The Process Of Spheronization

Dry mixing of
ingredients

Wet massing

Extrusion

Spheronization

Drying

Screening

Extrusion Spheronizer

Advantages:
1. Two or more active agents can be easily
combined in any ratio in the same unit.
2. Physical characteristics of the active
ingredients and excipients can be modified.
3. Particles having high bulk density, low
hygroscopicity, high spherocity, dust free, narrow
particle size distribution and smoother surface can
be produced.

Disadvantages & Limitation

It is more labour-intensive than more common
wet massing techniques.
Its use should be limited to those applications
where a sphere is required and other granulation
techniques are unsuitable.

Rotor granulator:

This process allows the direct manufacture of

spheres from dry powder.

In the Freund granulator, the powder mix is added to

the bowl and wetted with granulating liquid from a
spray .
The baseplate rotates at high speed and centrifugal
force keeps the moist mass at the edges of the rotor.

The velocity difference between the rotor and the

static walls, combined with the upward flow of air
around the rotor plate, causes the mass to move in a
toroidal motion, resulting in the formation of discrete
spherical pellets

Rotor Granulator

Continued.
These spheres are dried by the heated inlet air
from the air chamber, which also acts as a
positive- coating solution on to the rotating dried
pellets.
In pressure seal during granulation, layered
pellets can be produced.
By using this technique it is possible to continue
the uncoated pellets as nuclei in a second
granulation with process and coat the pellets by
subsequently spraying a powder mix of a second
ingredient
or
ingredients.

Advanced Formulation Techniques

Steam Granulation
Melt Granulation
Thermal Adhesion Granulation Process
(TAGP)
Freeze granulation Technology
Foam binder Technology
TOPO Technology

Steam Granulation Technique

Steam is used as a binder instead of water
Pure steam is a transparent gas with high diffusion rate into powder
particles
After condensation of steam, water forms a thin film on powder
particles. Only a small amount of extra energy required for its
elimination and evaporates easily

Instrument used will be high shear granulator with steam generator

Steam Granulation Process

Advantages

Uniform distribution into

Disadvantages

Requires special equipment

powder particles

for steam generation and

Higher dissolution rate of

transportation.

granules because of larger

Requires high energy inputs

surface area generated

Thermolabile materials are

poor candidates.

Time efficient

Maintain sterility

More safety measure required

Melt Granulation Technique

Granulation is achieved by the addition of melt able binder Binder is
in solid state at room temperature but melts in the temperature range
of 50 80c.
Melted binder then acts like a binding liquid.

There is no need of drying phase since dried granules are obtained by

cooling it to room temperature
Example: polyethylene glycol 4000 and lactose monohydrate used in
the formulation of rapid release carbamazepine tablets

Melt Granulation Process

water soluble binders Polyethylene Glycol

(PEG)
propylene glycol

water insoluble binders Stearic acid

Stearyl alcohol

Disadvantages

Advantages

Time and cost effective

Controlling and
modifying the release of
drugs

Water sensitive drugs

are good candidates

Heat sensitive materials are

poor candidates
Lower-melting-point binder
may melt/ soften during
handling and storage
Higher-melting-point
binders require high melting
temp. and can contribute
instability problems for
heat-labile materials

Thermal Adhesion Granulation Process (TAGP)

Wei-ming pharmaceutical company (taipei, taiwan) has

developed this technique.
Utilizes addition of a small amount of granulation liquid and
heat for agglomeration.
Drug and excipient mixture is heated to a temperature range
of 30130 C in a closed system under tumble rotation to
facilitate the agglomeration of the powder particles.
Eliminates the drying process due to the addition of low
amount of granulation liquid, which is mostly consumed by
the powder particles during agglomeration.
Granules of the required particle size can be obtained after
cooling and sieving.

Thermal Adhesion Granulation Process

Advantages

Disadvantages

Provides granules with better particle

size
Good flow properties and high
tensile strength that could be directly
compressed into tablets with
adequate hardness and low friability.

The limitations of this technique are:

Requirement of considerably high
energy inputs
Special
equipment
for
heat
generation and regulation. This
technique is not suitable for all
binders and is sensitive to
thermolabile drugs.

Freeze granulation technology

This technique has been adopted by Swedish Ceramic

Institute (SCI)
Working :

Preparation
of suspension

Spray the
suspension
into liquid
nitrogen

Homogenization

Freezing

Dried the
granules by
sublimation
of ice
Drying

Advantages:
Serious oxidation of non-oxides and metals is
prevented by mild drying.
There is low material waste (high yield)
Small (50-100 ml suspension) as well as large
granule quantities can be produced to equal
quality.

Foam Binder Technology(FBT)

FBT from the Dow chemical company helps in
achieving faster, simpler and safer wet
granulation.
Soluble polymeric excipients binders such as
METHOCEL hypromellose (hydroxyl propyl
methyl cellulose).

Processing:

Preparation
of binder
solution

Prepare the
powder bed

Binder
solution in
the form of
foam is
sprayed
throughout
the powder
bed

Granules are
formed

Advantages
Increase in the liquid surface area and volume
of polymeric binder foams
They spread very rapidly and evenly over
powder surface.

TOPO Technology
HERMES PHARMA has developed unique
technology for carrying out single pot
granulation
TOPO Granulator was employed for producing
effervescent granules or tablets
Ingredients:
API
Organic acid
Alkaline or alkaline earth metal carbonates

Processing:
Mixing of
ingredients

API, acid,
carbonates,
excipients

Addition of
small volume
of solvent

Water or
water/etanol

Formation of Hard and

stable
granules under
granules
vacuum

Characterization:
Parameters

Method

Granules Morphology

Microscopy

Particle Size Distribution

Sieve analysis, laser light scattering

Moisture content

IR balance, balance

Surface Area

Gas adsorption

Granules Porosity

Mercury intrusion methods

Density

Density apparatus

Granules Flow ability

Funnel and cone method