NTA Level 6 • Semester 1 • PST06103

Granulation

Pharmaceutical Production • Source Session/Topic 17

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Session 17: Granulation

Total Session Time: 120 minutes

Pre-requisites

• None

Learning Tasks

By the end of this session students are expected to be able to:

• Define granulation

• List the reasons for granulation

• Explain the types of granulation

• Explain the process of granulation

Resources Needed:

• Flip charts, marker pens, and masking tape

• Black/white board and chalk/whiteboard markers

SESSION OVERVIEW

SESSION CONTENTS

STEP 1: Presentation of Session Title and Learning Tasks (5 minutes)

READ or ASK students to read the learning tasks and clarify

ASK students if they have any questions before continuing

STEP 2: Introduction to Granulation (15 minutes)

Granulation has been defined as “any process whereby small particles are

gathered into larger, permanent masses in which the original particles can

still be identified

• Granulation is a process whereby small (powder) particles are gathered

into large permanent masses (granules) in which the original particles

can still be identified

• It is a process whereby primary powder particles are made to adhere to

form larger, multiparticle entities called granules

• In granulation process, powder particles are collected together by

creating bonds between them through compression or by using a binding

agent

• Pharmaceutical granules for tablets or capsule production typically have

a size range between 0.2 and 0.5 mm depending on their use

• Ability to produce reproducible tablets, batch to batch, lot to lot, is

directly related to the ability to produce reproducible granulation

• Uses of granules;

o As dosage form

▪ Where they are packed as bulk granules or divided granules

o As intermediate product in preparation tablets

▪ Granules have excellent compressability

STEP 3: Importance of Granulation (25 minutes)

• Granulation is important for various reasons including;

o To prevent segregation of the constituents of powder mix

▪ Segregation is caused by difference is particle size or density

of components of the powder mix

▪ The small and/or denser particles concentrate at the base of a

container with the larger and/or less denser particles above them

▪ An ideal granulation process will contain all the particles in

the mix (smaller or larger and denser or less denser) in the

correct proportion in each granule, and thus segregation of

ingredients will not occur

o To improve flow properties of the mix

▪ Because of small size, irregular shape or surface

characteristics, many powders are cohesive and do not flow well

▪ Poor flow will result in weight variation in the final product

due variable fill of tablet dies or capsule shells, etc

▪ Granules are larger and flow is improved

o To improve compaction characteristics of powder mix

▪ Granules are easier to compress than powders. Some powers are

difficult to compact even after inclusion of compactable adhesives

o To reduce hazards of toxic dust powders

▪ Powders produce dust during handling, and when toxic powders are

being handled it is hazardous to the personnel

▪ Production of non friable granules with suitable strength

eliminate the problem of dust production

o To reduce the hazard of hygroscopic powders adhesion

▪ Materials that are slightly hygroscopic may adhere to form cake

if stored as powder

▪ Granulation reduces this problem because granules can absorb

moisture while retaining their flowability due to their larger size

o To improve storage

▪ Granules are more convenient to store or ship as they occupy

less volume per unit weight (granules are denser than powders)

STEP 4: Granulation Methods (50 minutes)

• There are two main methods for granulation

o Wet granulation, which uses liquid in the process

o Dry granulation, which does not use any liquid

o Granulation by crystallization is a rarely used method in granulation

which exploits the presence of crystallization water in the active

materials

• During granulation process, a number of different excipients are added in

addition to the drug (Diluents, disintegrants, adhesives/binders)

• Equipment for granulation process are known as granulators

o Different types of granulators are employed depending on the process

• Wet granulation

o It is the most commonly used method

o Wet granulation involves wet massing of a mix of dry primary powder

particles using a granulating ﬂuid

o It involves the formation of granules by aggregating primary powder

particle by using a solution (liquid) containing binding agents

dissolved in a solvent. The liquid may also be used without adding

binding agent

▪ This liquid or the solution of binding agent is known as

granulation fluid

▪ Granulating fluid contains a solvent which must be volatile so

that it can be removed by drying, and be non-toxic

▪ Solvents commonly used in wet granulation are water, ethanol and

isopropanol either alone or in combination

• Organic solvents are used when water-sensitive drugs are

processed

• Water is used when water-stable drugs are processed.

▪ Advantages of water include non flammability and economical

▪ Disadvantages of using water include

▪ Water may affect stability of the drug e.g. causing

hydrolysis

▪ Needs longer drying time than volatile solvents

o Granulation fluid ensures particles adhere together once the granule

is formed and dried

o Steps in wet granulation

➢ Dry mixing (of powder particles)

➢ Wet mixing (addition of granulating fluid) to form a wet mass

➢ Squeezing the wet mass through a sieve to produce wet ribbons

➢ Drying the ribbons

➢ Milling to produce granules of suitable size

o Wet granulation uses a variety of granulators

▪ Shear granulators

• Powders are mixed in a separate operation using suitable mixers

▪ Planetary mixer is used for a wet massing of the powders i.e.

to form the wet mass

▪ Powders are fed into the mixer followed by granulating fluid

▪ Then the wet mass is transferred to the share granulator such

as oscillating granulator where the rotor bars of the granulator

oscillate and force the moist mass through a sieve screen to

form granules which are collected on trays and transferred to

drying oven or fluidized bed drier

▪ Advantage of shear granulation process

o Not very sensitive to change in characteristics of granule

ingredients e.g. surface area variations

o The end point of massing process can be determined by

examination

▪ Disadvantages of shear granulation

o Long duration

o Need several pieces of equipment e.g. mixers, granulator,

drier

o High material loss due to transfers stages

• High speed mixer/Rapid Mix Granulator (RMG)

o Have stainless steel mixing bowl containing a three-bladed

main impeller which revolves in horizontal plane and a three-

bladed auxiliary chopper (breaker blade) which revolve either

in the vertical or horizontal plane

o Unmixed powders are placed in the bowl and mixed by the

rotating impeller for a few minutes

o Granulating fluid is then added through a pot 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 switched on once the granules have been formed

o The granular product is discharged through a wire mesh which

break up any large aggregates into the bowl of a fluidized

bed drier

o Advantages of high speed mixer/granulators

▪ Mixing and granulation are performed in one piece of

equipment with a few minutes

▪ No transfers of materials required

o Disadvantages of high speed mixer/granulators

▪ Process needs to be controlled with care as granulation

process is so fast

▪ Usable granules can be quickly transformed into an

unusable, over massed system hence a suitable monitoring

system is required to monitor when granules of desired

properties are attained

▪ The process is sensitive to variation in raw materials

• Fluidized bed granulators

o Powder particles are fluidized in a stream of air

o Granulation fluid is pumped from a reservoir and sprayed from a nozzle

onto the bed of powders

o Heated and filtered air is blown through the bed of unmixed powders to

fluidize the particles and mix them

o The fluid causes the primary particles to adhere when droplets and

powders collide

o Exhaust filters prevent escape of materials from the granulation

chamber

o The filters are periodically agitated to reintroduce the collected

materials into the fluidized bed

o Sufficient fluid is sprayed to produce granules of required size

o The wet granules are then dried in the heated fluidizing air stream

▪ Advantages of fluidized bed granulation

• All processes are carried out in one equipment

• Saves labour costs, transfer losses and time

• The process can be automated

▪ Disadvantages of fluidized bed granulation

• The equipment is expensive

• Optimization of parameters affecting granulation needs extensive

development work

• Spray drier granulators

o Granular product is made from a solution or a suspension rather than

initially dry powder particles

o Resulting granules are free-flowing hollow spheres and the

distribution of the binder in such granules results in good compaction

properties

o Spray drying can covert hard elastic materials into more ductile ones

o Primary advantage of this process is short drying time and minimal

exposure to heat due to short residence time in the drying chamber

▪ Spheronizers/pelletizers

o Employed when dense, spherical pellets are needed. These are difficult

to produce by other (previous described) equipments

o The process involves;

▪ Separation of wet massing

▪ Extrusion of this mass into rod-shaped granules

▪ Spheronization to round off these rods into spherical particles

(pellets)

• This is done by using a spheronizer Consists of a bowl with

fixed side walls and rapidly rotating bottom plate or disc

▪ Drying to achieve desired final moisture content

▪ Screening to achieve desired narrow size distribution of pellets

• Advantages of this process

o Uniform sized spherical particles are made

o Used primary to make multiparticulates for controlled release

products

o Achieves ideal flow behaviour and disability

o Produce compact structures

o Products produced are of low hygroscopicity

▪ Rotor granulators

o Powders are added and wetted with granulating fluid e.g. from a spray

followed by mixing with the rapid rotating base of the granulator

o The rotating base and stationary wall of the granulator cause the mass

to break into isolated spherical pellets

▪ The process involves

• Addition of powder into the granulator

• Spraying the granulating fluid

• Rolling of the wet mix

• Drying of the formed spheres (pellets)

• Dry Granulation

o Primary powder particles are aggregated under high pressure without

use of liquid

▪ Large aggregates are then comminuted and screened to granules of

suitable size

Methods used in dry granulation;

• Slugging (double compression)

o Involves the use of heavy duty presses called Sluggers to form large,

flat tablets (large compacts) known as slugs

o Slugging involves the following steps;

➢ Preparing the formula

➢ Milling

➢ Mixing of the ingredients (all ingredients and half of the

lubricant)

➢ Slugging (compressing the mix in slugger, which consists of large

die large punches)

➢ Grinding the slugs by dry granulator or homogenizer to convert

slug into granules

• Roller compaction

o Whereby powder particles are squeezed between rollers to produce a

sheet of material (large tablet mass) by using Roller compactors

o Roller compaction involves

▪ Two rolls rotate against each other, to increase the density of

powder by pressing it between the rollers and get a thin wide sheet

or ribbon equivalent to the slug produced by slugging

▪ The ribbons or aggregates are then screened to produce uniform

granules

o Generally, dry granulation produces an intermediate product (slugs or

ribbon/sheet)

o This intermediate product is then milled (and screened) into granular

materials using suitable milling equipment/technique

o Advantages of dry granulation

▪ It is more economical than wet granulation

▪ Less space and less equipment are employed

▪ It is less time consuming e.g. no drying process as no liquid is

used

▪ Used for moisture sensitive materials

▪ No migration of colours (mottling) that may occur as in wet

granulation because of presence of moisture

▪ Avoids head-temperature combinations that might cause degradation

of the product

Disadvantages of dry granulation

▪ Slugging required specialized heavy duty machine

▪ Produces more dust which may cause contamination of the product.

▪ Generation of charges of static electricity and lead to reduce

flowability

▪ Decreases the dissolution of insoluble drugs (lipophilic drug)

• Granulation mechanisms

o To form granules, strong bonds must be formed between powder particles

so that they adhere to prevent break down of granules to powder during

handling

o There four primary mechanisms

▪ Adhesion and cohesion forces in the immobile liquid films between

individual primary powder particles

▪ Interfacial forces in mobile liquid films within the granules

▪ Formation of solid bridges after solvent evaporation

▪ Attractive forces between solid particles

STEP 5: Characteristics of granules (15 minutes)

• Process variables, granulating equipment and processing conditions affect

characteristics of granules produced; these characters include;

➢ Particle size and shape

➢ Surface area

➢ Density

➢ Strength and friability (which measure the strength of the

granules)

➢ Flow properties

➢ Compaction

STEP 6: Key Points (5 minutes)

• Granulation is a process whereby primary powder particles are made to

adhere to form larger, multiparticle entities called granules

• In granulation process, powder particles are collected together by

creating bonds between them through compression or by using a binding

agent

• Pharmaceutical granules for tablets or capsule production typically have

a size range between 0.2 and 0.5 mm depending on their use

• Two methods are employed when forming granules; dry granulation and wet

granulation

• Granules are used as dosage form or as intermediate product for tablet

production

STEP 7: Evaluation (5 minutes)

• What is a granule?

• What is granulation?

• What is the difference between dry granulation and wet granulation?

• Why is wet granulation more common than dry granulation?

References

Aulton M.E. & Kevin M.G, Eds: (2013) Pharmaceutics: The design and

manufacture of medicines, (4th ed.) Churchill Livingstone

Hugo and Russell (2011), Pharmaceutical Microbiology (8th ed.), Willey-

Blackwel publications

Gennaro, R. A., et al. (Eds) (1995) Remington: The Science and Practice of

Pharmacy, Volume I & II, (19th ed.): Mack Publishing Company, Easton,

Pennsylvania 18042

Liebsch, B et al (1988): Tanzania Pharmaceutical Handbook, Dar es Salaam

University Press.

Lund, W., Editor (1994). The Pharmaceutical Codex, Principles and Practice

of Pharmaceutics (12th ed.): The Pharmaceutical Press, London

Polderman, J. (1990) Introduction to Pharmaceutical Production: Novib, The

Hague

Rawlins E.A., Editor: (1977) Bentley’s Textbook of Pharmaceutics, (8th

ed.) Baillie're Tindall.

London Kamm, G. and Kohler, B. Editors: (1995) Manual for Decentralized

Infusion Production, Infusion Unit Project Tanzania

Schmidt, O., (ed) (2000) Pharmaceutical Quality systems, Interpharm Press,

Colorado.

Shayne C et al. (2008), Pharmaceutical Manufacturing Handbook: Production

and processes, John Wiley & Sons

Watson, D. G., (1999) Pharmaceutical Analysis: A Textbook for Pharmacy

Students and Pharmaceutical Chemists: Churchill Livingstone,

Edinburgh.

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