Granulation Hha

A
seminar
on
GRANULATION
Presented by, Under the guidance of,

Mr. NAMDEO SHINDE Dr. N. H. ALOORKAR
M. PHARM. (sem. I) M.PHARM., Ph. D.
SATARA COLLEGE OF PHARMACY,

SATARA.
3/11/2018 1
CONTENTS
INTRODUCTION
METHODS OF GRANULATION
ADVANCED GRANULATION TECHNIQUES
CONCLUSION
REFERENCES
3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 2
Introduction
Granules
Granulation
Granulation Technology

Why we prepare granules when
we have powders….?

To avoid powder segregation.
To enhance the flow of powder.
To produce uniform mixtures.
To produce dust free formulations.
To eliminate poor content uniformity.
To improve compaction characteristics of mix.

To avoid powder segregation. Contd...
-Segregation may result in weight variation.

Contd...
To enhance the flow of powders.
(Higher flowability gives better filling of the dies or containers)
To produce uniform mixtures.

(Mixtures of various particles tend to segregate in
transport or handling because of differences in particle
size, shape and density)

SATARA. 3/11/2018 7
Dust free formulations.
(Decrease dust generation and reduce
employee exposure to drug product)
To eliminate poor content uniformity.

SATARA. 3/11/2018 8
Methods of granulation
DIRECT COMPRESSION
COMPRESSION GRANULATION
WET GRANULATION

SATARA. 3/11/2018 9
When To Choose DRY method?
Drug dose is too high.
Do not compress well after wet granulation.
Heat sensitive drugs.
Moisture sensitive drugs.

e.g. Aspirin , Vitamins

SATARA. 3/11/2018 10
Steps in Dry Granulation
Compaction of powder
Milling
Screening

Contd…
How can
we do it………?

Contd…
By two ways
ROLLER
SLUGGING COMPACTION
Large tablet produced Powder is squeezed

in heavy duty tablet between two rollers to
press. produce sheet of material
e.g. Chilsonator
Contd…
Equipments
Has two parts,

Machine for compressing dry powder to
form compacts.
Mill for breaking these intermediates to

granule.
e.g. CHILSONATER
HAMMER MILL
Advantages Disadvantages
Less No uniform
equipments & color
space distribution
Eliminate
Process create
need of binder
more dust
solution
COMPRESSION granulation
It mainly involves three steps -
 Milling of drug and excipients
Mixing of drug and

excipients
Tablet compression

Contd…
CAPPING
LAMINATION
EQUIPMENTS
ARE
EXPENSIVE
wet granulation
In this, powdered medicament and

other excipients are moistened with
granulating agent.

Contd…
Steps in wet granulation
• Mixing of the drug(s) and excipients
1
• Mixing of binder solution with powder mix. to form
2 wet mass
• Coarse screening of wet mass using a suitable sieve .

3 (6-12 # screens)
4 • Drying of moist granules.
• Screening of dry granules through a suitable sieve

5 (14-20 # screen).

Contd…
Granulating Binding
liquid agent-
Natural Polymers:
-Volatile
Starch,
-Non-toxic Pregelatinized
Starch
e.g. synthetic binders:

PVP, MC, HPMC,
Water, Ethanol ,
Isopropanol Maltrodextrins
Contd…
TIME
LABOR EQUIPMENTS
Limitation
of wet
granulation
LOSS OF
ENERGY MATERIAL
SPACE

Methods
Contd…
Single pot granulation
High shear mixture granulation
Fluid bed granulation
Extrusion- Spheronization

Single pot granulation
The granulation is done in a normal
high shear processor and dried in same
equipment.
e.g. Single Pot Processor /

One-Pot Processor

Single pot granulator

 High shear mixture granulation
Dry Powder mixing (Approx 2-5 mins)
Liquid binder addition (Approx 1-2 mins)
Wet massing
Wet sieving of granules
Drying
Dry sieving of granules

Rapid mixer granulator

Contd..
ADVANTAGES DISADVANTAGES
Increase in
Short processing time. temperature may cause
chemical degradation of
Lesser amount of liquid thermolabile material.
binders required compared
with FBG. Over wetting of
granules can lead to large
Highly cohesive material size lumps formation.
can be granulated.

Fluid bed granulation
Fluidization is the operation by which fine

solids are transformed into a fluid like state
through contact with a gas.
Granulating and drying can be completed in one step

inside the machine.

Contd…
-Homogeneous granules.
---Gentle product handling.
--Uniform spraying of all

particles in the fluid bed.

Contd…
1.It reduces dust 1. The Fluid Bed cleaning is

formation during labor-intensive and time
processing consuming.
2. It reduces product loss

2. Difficulty of assuring
3. It improves worker reproducibility.
safety.

 Extrusion-Spheronization
1.Dry mixing of materials to achieve homogeneous
dispersion.
2. Wet granulation of the resulted mixture to form wet
mass.
3. Extrusion of wet mass to form rod shaped particles.
4. Rounding off (in spheronizer)
5. Drying

Extrusion-Spheronization
Different steps involved in the Extrusion- Spheronization process

Advanced Granulation Techniques
Steam Granulation
Melt Granulation
Moisture Activated Dry Granulation (MADG)
Moist Granulation Technique (MGT)

Thermal Adhesion Granulation Process (TAGP)
Foam Granulation
Pneumatic Dry Granulation (PDG)

Contd…
Freeze granulation Technology
Steam Granulation
Melt Extrusion Technology
Liquisolid Technique
TOPO Technology
Continuous Flow Technology

Steam Granulation
This process is a modification of conventional

wet granulation.
Here steam is used as a binder instead of water.

Contd…
Advantages
1.Uniformly distribution the powder particles.
2. Higher dissolution rate of granules because of larger

surface area generated.
3. Time efficient.
4. Maintain sterility.

Contd…
Disadvantages
1. Requires special equipment for steam generation and
transportation.
2. Requires high energy inputs.
3. Thermolabile materials are poor candidates.
4. More safety measure required.

Melt Granulation
Here granulation is achieved by the addition of meltable

binder.
Binder is in solid state at room temperature but melts in

the temperature range of 50 – 80˚C.
 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.

Contd…
water soluble binders-
e.g. Polyethylene Glycol (PEG)

2000, 4000, 6000, 8000
(40-60 0C)
water insoluble binders-
e.g.. Stearic acid (46-59 0C),

Cetyl or stearyl alcohol(56-60 0C)

Contd…
-Heat sensitive materials are

-Time and cost effective
poor candidates
- Lower-melting-point binder
-Controlling and may melt/ soften during
modifying the release of handling and storage
drugs
-Higher-melting-point binders
require high melting temp.
-Water sensitive drugs are and can contribute instability
good candidates problems for heat-labile
materials.

MOISTURE ACTIVATED DRY GRANULATION
In MADG, moisture is used to activate granule formation, without the

need to apply heat to dry the granules.
STAGES
MOISTURE DISTRIBUTION/
AGGLOMERATION
ABSORPTION
-Moisture absorbents like

-Drug is blended with diluents microcrystalline cellulose or
and powder silicon dioxide, are added while
mixing.
-A small amount of water (1-4%)
Is sprayed -Moisture redistribution within
the mixture.
-Agglomerate formation
(size 150–500μm) Entire mixture becomes
relatively dry.
Contd…
Advantages:
1.Applicable to more than 90% of the granulation need for

pharmaceutical, food and nutritional industry.
2. Time efficient.
3. Suitable for continuous processing
4. Less energy involved during processing.
Disadvantages:
1. Moisture sensitive and high moisture absorbing API are
poor candidates.

Moist Granulation Technique (MGT)
A small amount granulating fluid is added to activate dry

binder and to facilitate agglomeration.
Moisture absorbing material like Microcrystalline

Cellulose (MCC) is added to absorb any excess moisture.
Drying step is not necessary.
Applicable for developing a controlled release

formulation.

Thermal Adhesion Granulation Process (TAGP)
-It is applicable for preparing direct tableting formulations.

-Mixture of API and excipients are heated to a temp. 30-130ºC .
in closed system until granulation.
It provides granules with-
- Good flow properties.

- Binding capacity to form tablets of low friability.
- Adequate hardness.
3/11/2018 SATARA COLLEGE OF 45

PHARMACY, SATARA.
TIME
EFFICIENT
COST
NO EFFECTIVE
OVERWETTING
FOAM
GRANULATION
IR, CR
UNIFORM
FORMULATION
BINDER
DISTRIBUTION
WATER SENSITIVE
DRUGS
3/11/2018 SATARA COLLEGE OF 46

PHARMACY, SATARA.
Freeze granulation Technology
Developed and adopted by ,

Swedish Ceramic Institute (SCI).
-By spraying a powder suspension into liquid nitrogen, the drops
(granules) are instantaneously frozen. In a subsequent freeze-
drying the granules are dried by sublimation of the ice without
any segregation effects.
-Finally it produces spherical, free flowing granules.

Contd…

TOPO Technology
HERMES PHARMA has developed unique technology for

carrying out single pot granulation.
Requires very small quantity of liquid to start the chain

reaction
Pure water or water-ethanol mixtures are used.
Technology produces granules for tablets which contain at

least one solid crystalline, organic acid and one alkaline or
alkaline earth metal carbonate that reacts with the organic
acid in aqueous solution to form carbon dioxide.
As a result, there are no solvent residues in the finished

products, granules have excellent hardness and stability.
Continuous Flow Technology
The technology does not need any liquid to start the chain
reaction.
Granulation is carried out in an inclined drum into which

powder is fed at one end and granulate is removed at the
other.
The process produces granule with surface protected by

inactive component that do not harm to sensitive API.
CF technology can produce up to 12 tons of granules every

day.
Contd…
Key Benefits-
Sensitive APIs are protected .
Granules and effervescents become less sensitive to

humidity and high temperature.
Granules form extremely stable products.
No solvent residues in the final products.

GRANULATION CHARACTERIZATION:
Sr. No. Parameters Method

1 Particle Morphology Optical microscopy
2 Particle Size Distribution Sieve analysis, laser light scattering
3 Nature Powder X-Ray Diffraction
4 Surface Area Gas adsorption
5 Granule Porosity Mercury intrusion methods
6 Granule Strength Development of a Formulation
7 Granule Flowability and Density Hopper Method, Density Apparatus

CONCLUSION

6th INTERNATIONAL
GRANULATION CONFERENCE
At
Sheffield, UK.
Dates of Event-
26th June 2013 - 28th June 2013.

REFERENCES
1) Stahl H, A review article on latest process advancements and
innovations in Granulation technology.
2) Yadav V. B., Yadav A. V., Liquisolid granulation technique for tablet
manufacturing: an overview in Journal of Pharmacy Research.
3)Malcolm Summers, Michael Aulton, a review on Granulation.
4) Niro pharma system on current issues and troubleshooting fluid bed
granulation,may1998.
5)Harald Stahl,Senior pharmaceutical technologist, GEA Pharma
Systems, Germany
7)Detlev Haack . Hermes Arzneimittel GmbH – Division Hermes
Pharma, Grosshesselohe (Germany).

THANK
YOU….

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A

Presented by, Under the guidance of,

SATARA COLLEGE OF PHARMACY,

ADVANCED GRANULATION TECHNIQUES

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 3

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 4

To enhance the flow of powder.

To produce uniform mixtures.

To produce dust free formulations.

To eliminate poor content uniformity.

To improve compaction characteristics of mix.

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 5

-Segregation may result in weight variation.

To enhance the flow of powders.

(Higher flowability gives better filling of the dies or containers)

To produce uniform mixtures.

SATARA COLLEGE OF PHARMACY,

To eliminate poor content uniformity.

SATARA COLLEGE OF PHARMACY,

SATARA COLLEGE OF PHARMACY,

Drug dose is too high.

Do not compress well after wet granulation.

Heat sensitive drugs.

Moisture sensitive drugs.

SATARA COLLEGE OF PHARMACY,

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 11

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 12

Large tablet produced Powder is squeezed

Has two parts,

Mill for breaking these intermediates to

It mainly involves three steps -

 Milling of drug and excipients

Mixing of drug and

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 16

In this, powdered medicament and

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 18

• Coarse screening of wet mass using a suitable sieve .

4 • Drying of moist granules.

• Screening of dry granules through a suitable sieve

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 19

e.g. synthetic binders:

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 22

High shear mixture granulation

Fluid bed granulation

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 23

e.g. Single Pot Processor /

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 24

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 25

Liquid binder addition (Approx 1-2 mins)

Wet sieving of granules

Dry sieving of granules

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 27

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 28

Fluidization is the operation by which fine

Granulating and drying can be completed in one step

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 29

---Gentle product handling.

--Uniform spraying of all

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 30

1.It reduces dust 1. The Fluid Bed cleaning is

2. It reduces product loss

3/11/2018 SATARA COLLEGE OF PHARMACY, SATARA. 31

3. Extrusion of wet mass to form rod shaped particles.