59

Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Embed Size (px)

Citation preview

Page 1: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical
Page 2: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Granulation is the process in which primary powder Granulation is the process in which primary powder

particles are made to adhere to form larger, particles are made to adhere to form larger,

multiparticle entities called granules.multiparticle entities called granules.

Pharmaceutical granules typically have a size range Pharmaceutical granules typically have a size range

between 0.2 and 4.0 mm, depending on their between 0.2 and 4.0 mm, depending on their

subsequent use.subsequent use.

In the majority of cases this will be in the production of In the majority of cases this will be in the production of

tablets or capsules, when granules will be made as an tablets or capsules, when granules will be made as an

intermediate product and have a typical size range intermediate product and have a typical size range

between 0.2 and 0.5 mm,between 0.2 and 0.5 mm,

GranulationGranulation

Page 3: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Reasons for granulationReasons for granulationTo prevent segregation of the constituents of the To prevent segregation of the constituents of the powder mixpowder mix

Segregation is due to differences in the size or density Segregation is due to differences in the size or density

of theof the

components of the mix, the smaller and/or denser components of the mix, the smaller and/or denser

particles concentrating at the base of a container with particles concentrating at the base of a container with

the larger and/or less dense ones above them.the larger and/or less dense ones above them.

An ideal granulation will contain all the constituents of An ideal granulation will contain all the constituents of

the mix in the correct proportion in each granule, and the mix in the correct proportion in each granule, and

segregation of the ingredients will not occursegregation of the ingredients will not occur

Page 4: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

PowderPowder GranulesGranules

GranulationGranulation

sievinsievingg

Segregated Segregated PowderPowder

Monosized Monosized GranulesGranules

Page 5: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

It is also important to control the particle size It is also important to control the particle size

distribution of the granules because, although the distribution of the granules because, although the

individual components may not segregate, if there is individual components may not segregate, if there is

a wide size distribution the granules themselves may a wide size distribution the granules themselves may

segregate.segregate.

If this occurs in the hoppers of capsule-filling If this occurs in the hoppers of capsule-filling

machines or tablet machines, products with large machines or tablet machines, products with large

weight variations will result. This is because these weight variations will result. This is because these

machines fill by volume rather than weight, and if machines fill by volume rather than weight, and if

different regions in the hopper contain granules of different regions in the hopper contain granules of

different sizes (and hence bulk density), a given different sizes (and hence bulk density), a given

volume in each region will contain a different weight volume in each region will contain a different weight

of granules. This will lead to an unacceptable of granules. This will lead to an unacceptable

distribution of the drug content within the batch of distribution of the drug content within the batch of

finished product.finished product.

Page 6: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Many powders, because of their small size, irregular Many powders, because of their small size, irregular

shape or surface characteristics, are cohesive and do shape or surface characteristics, are cohesive and do

not flow well. not flow well.

Poor flow will often result in a wide weight variation Poor flow will often result in a wide weight variation

within the final product owing to variable fill of tablet within the final product owing to variable fill of tablet

dies etc. dies etc.

Granules produced from such a cohesive system will Granules produced from such a cohesive system will

be larger and more isodiametric, both factors be larger and more isodiametric, both factors

contributing to improved flow properties.contributing to improved flow properties.

To improve the flow properties of the mixTo improve the flow properties of the mix

Page 7: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Some powders are difficult to compact even if a Some powders are difficult to compact even if a

readily compactable adhesive is included in the mix, readily compactable adhesive is included in the mix,

but granules of the same formulation are often more but granules of the same formulation are often more

easily compacted and produce stronger tablets. This easily compacted and produce stronger tablets. This

is associated with the distribution of the adhesive is associated with the distribution of the adhesive

within the granule. Often solutewithin the granule. Often solute

migration occurring during the postgranulation drying migration occurring during the postgranulation drying

stage results in a binder-rich outer layer to the stage results in a binder-rich outer layer to the

granules. This in turn leads to direct binder–binder granules. This in turn leads to direct binder–binder

bonding, which assists the consolidation of weakly bonding, which assists the consolidation of weakly

bonding materials.bonding materials.

To improve the compaction characteristics of the To improve the compaction characteristics of the mixturemixture

Page 8: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

The granulation of toxic materials will reduce the The granulation of toxic materials will reduce the

hazard associated with the generation of toxic dust hazard associated with the generation of toxic dust

that may arise when handling powders. that may arise when handling powders.

Suitable precautions must be taken to ensure that Suitable precautions must be taken to ensure that

such dust is not a hazard during the granulation such dust is not a hazard during the granulation

process. Thus granules should be non-friable and process. Thus granules should be non-friable and

have a suitable mechanical strength.have a suitable mechanical strength.

Reduce the hazard of toxic dust powdersReduce the hazard of toxic dust powders

Page 9: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Materials which are slightly hygroscopic may adhere Materials which are slightly hygroscopic may adhere

and form a cake if stored as a powder. and form a cake if stored as a powder.

Granulation may reduce this hazard, as the granules Granulation may reduce this hazard, as the granules

will be able to absorb some moisture and yet retain will be able to absorb some moisture and yet retain

their flowability because of their size.their flowability because of their size.

More convenient for storageMore convenient for storage

Because granules are denser than the powder mix, Because granules are denser than the powder mix,

they occupy less volume per unit weight. They are they occupy less volume per unit weight. They are

therefore more convenient for storage or shipment.therefore more convenient for storage or shipment.

Reduce the hazard of hygroscopic powder adhesionReduce the hazard of hygroscopic powder adhesion

Page 10: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Methods of granulation

Granulation methods can be divided into two types: Granulation methods can be divided into two types:

wet methodswet methods, which use a liquid in the process, , which use a liquid in the process,

dry methodsdry methods in which no liquid is used. in which no liquid is used.

In a suitable formulation a number of different In a suitable formulation a number of different

excipients will be needed in excipients will be needed in addition to the drug.addition to the drug.

DiluentsDiluents, to produce a unit dose weight of suitable , to produce a unit dose weight of suitable

size, size,

Disintegrating agentsDisintegrating agents, which are added to aid the , which are added to aid the

break-up of the granule when it reaches a liquid break-up of the granule when it reaches a liquid

medium, e.g. onmedium, e.g. on

ingestion by the patient.ingestion by the patient.

AdhesivesAdhesives in the form of a dry powder may also be in the form of a dry powder may also be

added, particularly if dry granulation is employed. added, particularly if dry granulation is employed.

These ingredients will be mixed before granulation.These ingredients will be mixed before granulation.

Page 11: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

In the dry methods of granulation the primary powder In the dry methods of granulation the primary powder

particles areparticles are

Granulation: (aggregation) under high pressure Granulation: (aggregation) under high pressure

without the use ofwithout the use of a liquida liquid using one of the following using one of the following

processes. processes.

Using Using SluggersSluggers: large tablet compacts (known as a : large tablet compacts (known as a

slugslug) is ) is

produced in a heavy-duty tabletting press (a produced in a heavy-duty tabletting press (a

process process

known as known as slugginsluggin’) ’)

or using or using Roller compactorsRoller compactors the powder is squeezed the powder is squeezed

between two rollers to produce a sheet of material between two rollers to produce a sheet of material

((roller roller

compactioncompaction).).

Milling: the intermediate products are broken using Milling: the intermediate products are broken using

a suitable milling technique to produce granular a suitable milling technique to produce granular

material, which is usually sieved to separate the material, which is usually sieved to separate the

desired size fraction. The unused fine material may be desired size fraction. The unused fine material may be

reworked to avoid waste. reworked to avoid waste.

Dry granulationDry granulation

Page 12: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Roller compactorsRoller compactors

AlexanderwerkAlexanderwerkRoller compactorRoller compactor

Page 13: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Hutt Roller Hutt Roller compactorcompactor

Page 14: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Advantages of dry granulation:Advantages of dry granulation:

Avoids heat–temperature combinations that might Avoids heat–temperature combinations that might

cause cause

degradation of the product.degradation of the product.

This dry method may be used for drugs which are This dry method may be used for drugs which are

sensitive to moisture.sensitive to moisture.

Page 15: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Wet granulationWet granulation Wet granulation involves the massing of a mix of dry Wet granulation involves the massing of a mix of dry

primary primary

powder particles using a granulating fluid. powder particles using a granulating fluid.

The fluid contains a solvent which must be volatile so The fluid contains a solvent which must be volatile so

that it that it

can be removed by drying, and be non-toxic.can be removed by drying, and be non-toxic.

The granulation liquid may be used alone or, more The granulation liquid may be used alone or, more

usually, as a usually, as a

solvent containing a dissolved adhesive (binding solvent containing a dissolved adhesive (binding

agent) which agent) which

is used to ensure particle adhesion once the granule is is used to ensure particle adhesion once the granule is

dry.dry.

In the traditional wet granulation method the wet mass In the traditional wet granulation method the wet mass

is is

forced through a sieve to produce wet granules which forced through a sieve to produce wet granules which

are then are then

dried. dried.

A subsequent screening stage breaks agglomerates of A subsequent screening stage breaks agglomerates of

granules granules

and removes the fine material, which can than be and removes the fine material, which can than be

recycled.recycled.

Page 16: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

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.

Page 17: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Effect of granulation method on granule structureEffect of granulation method on granule structure

The properties of the granules are influenced by the The properties of the granules are influenced by the

manufacturing process.manufacturing process.

The method and conditions of granulation affect The method and conditions of granulation affect

intergranular and intragranular pore structure by changing intergranular and intragranular pore structure by changing

the degree of packing within the granules. the degree of packing within the granules. Precompressed granules (dry granulation),Precompressed granules (dry granulation), consisting of consisting of

compressed drug and binder particles, are held together compressed drug and binder particles, are held together

by by

simple bonding during compaction. simple bonding during compaction. Granules prepared by wet massing (wet granulation),Granules prepared by wet massing (wet granulation),

consist of consist of

intact drug particles held together in a sponge-like matrix intact drug particles held together in a sponge-like matrix

of of

binder.binder.Fluidized-bed granulesFluidized-bed granules are similar to those prepared by are similar to those prepared by

the wet the wet

granulation, but possess greater porosity and the granule granulation, but possess greater porosity and the granule

surface is covered by a film of binding agent. surface is covered by a film of binding agent. With With spray-dried systemsspray-dried systems the granules consist of spherical the granules consist of spherical

particles composed of an outer shell and an inner core of particles composed of an outer shell and an inner core of

particles.particles.

Page 18: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

There are many types of granulator used in the There are many types of granulator used in the

pharmaceutical industry for wet granulation.pharmaceutical industry for wet granulation.

Wet granulatorsWet granulators

Shear granulatorsShear granulators

High-speed mixer/granulatorsHigh-speed mixer/granulators

Fluidized-bed granulatorsFluidized-bed granulators

Rotor granulatorsRotor granulators

Spray-driersSpray-driers

Spheronizers /PelletizersSpheronizers /Pelletizers

Page 19: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Powder mixing in a separate Powder mixing in a separate

operation operation

using suitable mixing equipment. using suitable mixing equipment.

A planetary mixer is used for wet A planetary mixer is used for wet

massing of the powdersmassing of the powders

With some formulations, such With some formulations, such

as as

those containing two or three those containing two or three

ingredients in equal quantities, ingredients in equal quantities,

it is it is

suitable to mix powder in the suitable to mix powder in the

planetary mixer. planetary mixer.

The mixed powders are fed into the The mixed powders are fed into the

bowl of the planetary mixer and bowl of the planetary mixer and

granulating liquid is added as the granulating liquid is added as the

paddle of the mixer agitates the paddle of the mixer agitates the

powders. powders.

Shear granulatorsShear granulators

Planetary MixerPlanetary Mixer

MixinMixing g bowlbowl

MixinMixing armg arm

Page 20: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

The moist mass has been The moist mass has been

transferred transferred

to a granulator, as oscillating to a granulator, as oscillating

granulator.granulator.

The rotor bars of the granulator The rotor bars of the granulator

oscillate and force the moist oscillate and force the moist

mass mass

through the sieve screen, the through the sieve screen, the

size of size of

which determines the granule which determines the granule

size. size.

The mass should be sufficiently moist to form discrete The mass should be sufficiently moist to form discrete

granules granules

when sieved. If excess liquid is added, string (filament) when sieved. If excess liquid is added, string (filament)

of of

material will be formed and if the mix is too dry the material will be formed and if the mix is too dry the

mass will be mass will be

sieved as powder and granules will not be formed.sieved as powder and granules will not be formed.

Oscillating Oscillating GranulatorGranulator

RotoRotorr

SievSievee

Page 21: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

The granules can be collected on trays and transferred to The granules can be collected on trays and transferred to

a drying a drying

oven. oven.

Tray drying has three major disadvantages:Tray drying has three major disadvantages:1. The drying time is long.1. The drying time is long.

2. Dissolved material can migrate 2. Dissolved material can migrate

to the to the

upper surface of granules’ bed, upper surface of granules’ bed,

as the as the

solvent is only removed from the solvent is only removed from the

upper surface of the bed on the upper surface of the bed on the

tray.tray.

3. Granules may aggregate owing 3. Granules may aggregate owing

to to

bridge formation at the points of bridge formation at the points of

contact of the granules.contact of the granules.

To deaggregate the granules and remix them, a sieving To deaggregate the granules and remix them, a sieving

stage is necessary after drying.stage is necessary after drying.

Page 22: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

An alternative method is to dry the granules using a An alternative method is to dry the granules using a

fluidized-bed drier. fluidized-bed drier.

This is quicker and, as it keeps the individual granules This is quicker and, as it keeps the individual granules

separated during drying, it reduces the problems of separated during drying, it reduces the problems of

aggregation and intergranular solute migration, thereby aggregation and intergranular solute migration, thereby

reducing the need for a sieving stage after drying.reducing the need for a sieving stage after drying.

Page 23: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Advantages of Shear granulation process:Advantages of Shear granulation process:

The process is not very sensitive to changes in the The process is not very sensitive to changes in the

characteristics of the granule ingredients (e.g. characteristics of the granule ingredients (e.g.

surface surface

area variations in different batches of an area variations in different batches of an

excipient)excipient)

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

determined by examination.determined by examination.

The disadvantages of Shear granulation process:The disadvantages of Shear granulation process:

Long durationLong duration

the need for several pieces of equipment the need for several pieces of equipment

The high material losses because of the transfer The high material losses because of the transfer

stages.stages.

Page 24: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

High-speed mixer/granulatorsHigh-speed mixer/granulators

The granulator has a stainless The granulator has a stainless

steel mixing bowl containing steel mixing bowl containing

a a three-bladed main impellerthree-bladed main impeller, ,

which revolves in the which revolves in the

horizontalhorizontal

plane, plane,

and a and a three-bladed auxiliary three-bladed auxiliary

chopperchopper (breaker blade) (breaker blade)

which revolves either in the which revolves either in the

vertical or the horizontal vertical or the horizontal

plane.plane.

chop

per

chop

per

Page 25: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

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

mixed mixed

by the rotating impeller for a few minutes.by the rotating impeller for a few minutes.

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

of the of the

granulator while the impeller is turning. granulator while the impeller is turning.

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

thethe

impeller. impeller.

The chopper is usually switched on when the moist The chopper is usually switched on when the moist

mass is mass is

formed, as its function is to break up the wet mass formed, as its function is to break up the wet mass

to to

produce a bed of granular material.produce a bed of granular material.

Once a granule has been Once a granule has been

produced, the granular product produced, the granular product

is discharged, passing through a is discharged, passing through a

wire mesh which breaks up any wire mesh which breaks up any

large aggregates, into the bowl large aggregates, into the bowl

of a fluidized-bed drier.of a fluidized-bed drier.

Page 26: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Advantages of High-speed mixer/granulation:Advantages of High-speed mixer/granulation:

Mixing and granulation are all performed within a Mixing and granulation are all performed within a

few minutes in the same piece of equipment. few minutes in the same piece of equipment.

Disadvantages of High-speed mixer/granulation:Disadvantages of High-speed mixer/granulation:

The process needs to be controlled with care as The process needs to be controlled with care as

the the

granulation progresses so rapidly that a usable granulation progresses so rapidly that a usable

granule granule

can be transformed very quickly into an unusable, can be transformed very quickly into an unusable,

overmassed system. Thus it is often necessary to overmassed system. Thus it is often necessary to

use a use a

suitable monitoring system to indicate the end of suitable monitoring system to indicate the end of

the the

granulation process, i.e. when a granule of the granulation process, i.e. when a granule of the

desired desired

properties has been attained. properties has been attained.

The process is also sensitive to variations in raw The process is also sensitive to variations in raw

materials, but this may be minimized by using a materials, but this may be minimized by using a

suitable suitable

end-point monitor.end-point monitor.

Page 27: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

GlattGlatt

Air inletAir inletAir Air filterfilter

Air outletAir outlet

Spray Spray nozzlenozzleProduct Product containecontainerr

GranulatinGranulating liquidg liquid

Exhaust Exhaust filterfilter

Fluidized-bed granulatorFluidized-bed granulator

Page 28: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

The powder particles are The powder particles are

fluidized in a stream of fluidized in a stream of

air.air.

Granulation fluid is Granulation fluid is

pumped pumped

from a reservoir and from a reservoir and

sprayed sprayed

from a nozzle on to the from a nozzle on to the

bed bed

of powders.of powders.

Heated and filtered air is Heated and filtered air is

blown through the bed of blown through the bed of

unmixed powders to unmixed powders to

fluidize fluidize

the particles and mix the the particles and mix the

powders.powders.

Fluidized-bed granulator (Glatt)Fluidized-bed granulator (Glatt)

Air Air inletinletAir Air filterfilter

Air outletAir outlet

Spray Spray nozzlenozzleProduct Product containercontainer

GranulatinGranulating liquidg liquid

Exhaust Exhaust filterfilter

Page 29: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

The fluid causes the primary The fluid causes the primary

powder particles to adhere powder particles to adhere

when the droplets and when the droplets and

powders collide. powders collide.

Escape of material from the Escape of material from the

granulation chamber is granulation chamber is

prevented by exhaust filters, prevented by exhaust filters,

which are periodically agitated which are periodically agitated

to reintroduce the collected to reintroduce the collected

material into the fluidized bed. material into the fluidized bed.

Sufficient liquid is sprayed to Sufficient liquid is sprayed to

produce granules of the produce granules of the

required size, at which point required size, at which point

the spray is turned off but the the spray is turned off but the

fluidizing air continued. fluidizing air continued.

The wet granules are then The wet granules are then

dried in the heated fluidizing dried in the heated fluidizing

air stream.air stream.

Air Air inletinletAir Air filterfilter

Air outletAir outlet

Spray Spray nozzlenozzleProduct Product containercontainer

GranulatinGranulating liquidg liquid

Exhaust Exhaust filterfilter

Page 30: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

All the granulation processes, which require All the granulation processes, which require

separate separate

equipment in the conventional method, are equipment in the conventional method, are

performed in performed in

one unit, saving labour costs, transfer losses and one unit, saving labour costs, transfer losses and

time.time.

The process can be automated once the conditions The process can be automated once the conditions

affecting the granulation have been optimized.affecting the granulation have been optimized.

The equipment is expensive.The equipment is expensive.

Optimization of process parameters affecting Optimization of process parameters affecting

granulation granulation

needs extensive development work.needs extensive development work.

Advantages of fluidized-bed granulationAdvantages of fluidized-bed granulation

Disadvantages of fluidized-bed granulationDisadvantages of fluidized-bed granulation

Page 31: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Spray-driersSpray-driers

Granular product is made Granular product is made

from a solution or a from a solution or a

suspension rather than suspension rather than

initially dry primary powder initially dry primary powder

particles.particles.

The resultant granules The resultant granules

are free-flowing hollow are free-flowing hollow

spheres and the spheres and the

distribution of the binder in distribution of the binder in

such granules results in such granules results in

good compaction good compaction

properties.properties.

suspensionsuspension

Fluidization Fluidization airair

screescreenn

Page 32: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Spray-drying can convert Spray-drying can convert

hard elastic materials into hard elastic materials into

more ductile ones.more ductile ones.

The primary advantages of The primary advantages of

the process are the short the process are the short

drying time and the minimal drying time and the minimal

exposure of theexposure of the

product to heat owing to the product to heat owing to the

short residence time in the short residence time in the

drying chamber. drying chamber.

This means that little This means that little

deteriorationdeterioration

of heat-sensitive materials of heat-sensitive materials

takes place.takes place.

suspensionsuspension

Fluidization Fluidization airair

screescreenn

Page 33: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Spheronizers /PelletizersSpheronizers /Pelletizers

For some applications it may be desirable to For some applications it may be desirable to

have ahave a

dense, spherical pellet of the type difficult to dense, spherical pellet of the type difficult to

produce with the previous equipments. Such produce with the previous equipments. Such

pellets are used for controlled drug release.pellets are used for controlled drug release.A commonly used process A commonly used process

involves:involves:

Separation of wet massing.Separation of wet massing.

Extrusion of this wet mass Extrusion of this wet mass

intointo

rod-shaped granules and rod-shaped granules and

subsequent spheronization subsequent spheronization

of of

these granules. these granules.

Page 34: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Extrusion/spheronization process is used to make Extrusion/spheronization process is used to make

uniformly uniformly

sized spherical particles. sized spherical particles.

It is used primarily to produce multiparticulates for It is used primarily to produce multiparticulates for

controlled controlled

drug release applications. drug release applications.

The major advantage over other methods of producing The major advantage over other methods of producing

drug drug

loaded spheres or pellets is the ability to incorporat loaded spheres or pellets is the ability to incorporat

high levels high levels

of active ingredients without producing excessively of active ingredients without producing excessively

large large

particles (minimal excipients).particles (minimal excipients).

Ideal flow behaviour and dosabilityIdeal flow behaviour and dosability

Compact structureCompact structure

Low hygroscopicityLow hygroscopicity

High bulk densityHigh bulk density

Advantages of granulation using Advantages of granulation using Extrusion/spheronization Extrusion/spheronization

Page 35: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

The main steps of the process are:The main steps of the process are:

1.1. Dry mixing of ingredients to achieve a homogenous Dry mixing of ingredients to achieve a homogenous

powder dispersionpowder dispersion

2. Wet massing to produce a sufficiently plastic wet mass2. Wet massing to produce a sufficiently plastic wet mass

3. Extrusion to form rod-shaped particles of uniform 3. Extrusion to form rod-shaped particles of uniform

diameterdiameter

4. Spheronization to round off these rods into spherical 4. Spheronization to round off these rods into spherical

particlesparticles

5. Drying to achieve the desired final moisture content5. Drying to achieve the desired final moisture content

6. Screening to achieve the desired narrow size 6. Screening to achieve the desired narrow size

distribution.distribution.

Page 36: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Schematic representation of production extruderSchematic representation of production extruder

ExtrusionExtrusion

Page 37: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Spheronization Spheronization • The function of spheronization is to round off the rods The function of spheronization is to round off the rods

produced produced

by extrusion into spherical particles.by extrusion into spherical particles.

• This is carried out in This is carried out in SpheronizerSpheronizer which consists of a bowl which consists of a bowl

with with

fixed side walls and a rapidly rotating bottom plate or fixed side walls and a rapidly rotating bottom plate or

disc. disc.

• The rounding of the extrudate into spheres is dependent The rounding of the extrudate into spheres is dependent

on on

frictional forces generated by particle–particle and frictional forces generated by particle–particle and

particle particle

equipment collisions.equipment collisions.

Page 38: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Rotor granulationRotor granulation

In the In the Freund granulatorFreund granulator,,

the powder mixture is the powder mixture is

added added

to the bowl and wetted to the bowl and wetted

with with

granulating liquid from a granulating liquid from a

spray. spray.

The base plate rotates at The base plate rotates at

high speed and high speed and

centrifugal centrifugal

force keeps the moist force keeps the moist

mass mass

at the edges of the rotor. at the edges of the rotor.

Page 39: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

The velocity difference The velocity difference

between between

the rotor and the static the rotor and the static

walls, walls,

combined with the upward combined with the upward

flow flow

of air around the rotor plate, of air around the rotor plate,

causes the mass to move in a causes the mass to move in a

toroidal motion, resulting in toroidal motion, resulting in

the the

formation of isolated formation of isolated

spherical spherical

pellets. pellets.

The spheres are dried by the The spheres are dried by the

heated inlet air from the air heated inlet air from the air

chamber, which acts as a chamber, which acts as a

positive positive

pressure seal during pressure seal during

granulation.granulation.

Page 40: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Process principleProcess principle

Powder is mixed and moistened and the powder bed set Powder is mixed and moistened and the powder bed set

into centrifugal motion (fluid bed pelletizing in the rotor).into centrifugal motion (fluid bed pelletizing in the rotor).

The impact and acceleration forces that occur in this The impact and acceleration forces that occur in this

process result in the formation of agglomerates, which process result in the formation of agglomerates, which

become rounded out into uniform and dense pellets and become rounded out into uniform and dense pellets and

are then dried. are then dried.

Page 41: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Principle of the powder layering processPrinciple of the powder layering process

Using this technique it is possible to continue the Using this technique it is possible to continue the process and coat the pellets by spraying coating solution process and coat the pellets by spraying coating solution on to the rotating dried pellets. on to the rotating dried pellets. In layered pellets can be produced by using uncoated In layered pellets can be produced by using uncoated pellets as nuclei in a second granulation with a powder pellets as nuclei in a second granulation with a powder mix of a second ingredient or ingredients.mix of a second ingredient or ingredients.

Page 42: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

GRANULATION MECHANISMS

To form granules, sufficiently strong bonds must be To form granules, sufficiently strong bonds must be

formed between powder particles so that they adhere formed between powder particles so that they adhere

and prevent breakdown of the granule to powder during and prevent breakdown of the granule to powder during

handling.handling.

There are four primary bonding mechanisms between There are four primary bonding mechanisms between

particles:particles:

1.1. Adhesion and cohesion forces in the immobile liquid Adhesion and cohesion forces in the immobile liquid

films films

between individual primary powder particles.between individual primary powder particles.

2. Interfacial forces in mobile liquid films within the 2. Interfacial forces in mobile liquid films within the

granules.granules.

3. The formation of solid bridges after solvent 3. The formation of solid bridges after solvent

evaporation.evaporation.

4. Attractive forces between solid particles.4. Attractive forces between solid particles.

Page 43: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

The process variables involved in the granulation The process variables involved in the granulation

steps (formulation ingredients and their steps (formulation ingredients and their

concentrations, the type of granulating equipment concentrations, the type of granulating equipment

and processing conditions employed) can affect the and processing conditions employed) can affect the

characteristics of the granulations produced. characteristics of the granulations produced. Particle Size and Shape.Particle Size and Shape.

Surface Area.Surface Area.

DensityDensity. .

Strength and Friability.Strength and Friability.

Flow PropertiesFlow Properties. .

Compaction. Compaction.

Page 44: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Particle Size and ShapeParticle Size and Shape..

The particle size of a granulation is known to The particle size of a granulation is known to

affect the average tablet weight, disintegration affect the average tablet weight, disintegration

time, granule friability, granulation flowability time, granule friability, granulation flowability

and the ding rate kinetics of wet granulations.and the ding rate kinetics of wet granulations.

Page 45: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Surface Area.Surface Area.The surface area of the drug has a significant effect The surface area of the drug has a significant effect

upon dissolution rate. An inverse relationship upon dissolution rate. An inverse relationship

normally exists between particle size and surface normally exists between particle size and surface

area; area;

Methods for determining surface area of solid Methods for determining surface area of solid

particles are gas adsorption and air permeability. particles are gas adsorption and air permeability.

In gas adsorption methodIn gas adsorption method, the amount of gas that is , the amount of gas that is

adsorbed onto the powder to form a monolayer is adsorbed onto the powder to form a monolayer is

measured and then used to calculate the surface area measured and then used to calculate the surface area

of the powder sample. of the powder sample.

Air permeabilityAir permeability, the rate at which air permeates a , the rate at which air permeates a

bed of powder, is used to calculate the surface area bed of powder, is used to calculate the surface area

of the powder sample. of the powder sample.

Page 46: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

DensityDensity.. Granule density may influence compressibility, Granule density may influence compressibility,

tablet tablet

porosity and dissolution. porosity and dissolution.

Dense, hard granules may require higher Dense, hard granules may require higher

compressible compressible

loads to produce a cohesive compact.loads to produce a cohesive compact.

The higher compression load, increase the tablet The higher compression load, increase the tablet

disintegration and drug dissolution times. Even if disintegration and drug dissolution times. Even if

the the

tablets disintegrate readily, the harder, denser tablets disintegrate readily, the harder, denser

granules granules

may dissolve less readily. may dissolve less readily.

Page 47: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Methods used to determine granule density Methods used to determine granule density

involve the involve the

use of a pycnometer. use of a pycnometer.

Where, the intrusion fluid is mercury, and in the Where, the intrusion fluid is mercury, and in the

other, it other, it

is a solvent of low surface tension (e.g., benzene) is a solvent of low surface tension (e.g., benzene)

in in

which the granules are not soluble. which the granules are not soluble.

These pycnometer methods depends on the ability These pycnometer methods depends on the ability

of the of the

intrusion fluids to penetrate the pores of the intrusion fluids to penetrate the pores of the

granules. granules.

Density is calculated from the volume of intrusion Density is calculated from the volume of intrusion

fluid fluid

displaced in the pycnometer by a given mass of displaced in the pycnometer by a given mass of

granulation granulation

Page 48: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Strength and Friability.Strength and Friability.

A granule is an aggregation of component particles A granule is an aggregation of component particles

that is held together by bonds of finite strength. that is held together by bonds of finite strength.

The strength of a wet granule is due to the surface The strength of a wet granule is due to the surface

tension of liquid and capillary forces. tension of liquid and capillary forces.

These forces are responsible for initial These forces are responsible for initial

agglomeration of the wet powder. agglomeration of the wet powder.

Upon drying, the granule has strong bonds Upon drying, the granule has strong bonds

resulting from fusion or recrystallization of resulting from fusion or recrystallization of

particles and curing of the adhesive or binder. particles and curing of the adhesive or binder.

Page 49: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Measurements of granule strength estimate the Measurements of granule strength estimate the

magnitude of attractive forces that hold the magnitude of attractive forces that hold the

granule together.granule together.

The resultant strength of a granule depends on The resultant strength of a granule depends on

base material, the kind and amount of granulating base material, the kind and amount of granulating

agent used and the granulating equipment used. agent used and the granulating equipment used.

Granule strength and friability are important, as Granule strength and friability are important, as

they affect changes in particle size distribution of they affect changes in particle size distribution of

granulations, and compressibility into cohesive granulations, and compressibility into cohesive

tablets. tablets.

Page 50: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Methods used for measuring granule strength are: Methods used for measuring granule strength are:

Compression strengthCompression strength. Where a granule is placed . Where a granule is placed

between anvils, and the force required to break the between anvils, and the force required to break the

granule is measured.granule is measured.

Friability measurementsFriability measurements. measuring the tendency . measuring the tendency

of granules to break into smaller pieces when of granules to break into smaller pieces when

subjected to disturbing forces.subjected to disturbing forces.

Page 51: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Flow PropertiesFlow Properties..Flow properties of a material result from many Flow properties of a material result from many

surface forces:surface forces:

(1)(1)frictional forces, (2) surface tension forces, frictional forces, (2) surface tension forces,

(3) mechanical forces caused by interlocking of (3) mechanical forces caused by interlocking of

particles of irregular shape, (4) electrostatic particles of irregular shape, (4) electrostatic

forces, (5) cohesive or van der Waals forces. forces, (5) cohesive or van der Waals forces.

They can affect granule properties such as: They can affect granule properties such as:

particle size,particle size,

particle size distribution, particle shape, surface particle size distribution, particle shape, surface

texture or roughness, surface energy, and surface texture or roughness, surface energy, and surface

area. area.

Page 52: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

With fine powders (<150µm), the magnitude of With fine powders (<150µm), the magnitude of

the the

frictional and van der Waals forces are frictional and van der Waals forces are

predominate. predominate.

For larger particles (>150µm) such as granules For larger particles (>150µm) such as granules

produced by a wet granulation, frictional forces produced by a wet granulation, frictional forces

are are

predominate over van der Waals forces. predominate over van der Waals forces.

Flow measur the effect of all the interparticulate Flow measur the effect of all the interparticulate

forces forces

acting at once. acting at once.

Two methods are used: Two methods are used:

(1) angle of repose, (1) angle of repose,

(2) hopper flow rate measurements.(2) hopper flow rate measurements.

Page 53: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

CompactionCompaction

The process of compacting powder or granule The process of compacting powder or granule

materials to materials to

form a tablet is complex, owing to the numerous form a tablet is complex, owing to the numerous

internal internal

events that act simultaneously.events that act simultaneously.

The basic tool that has been developed for studying The basic tool that has been developed for studying

the the

compression process is the tablet press. compression process is the tablet press.

Tablet presses are instrumented by affixing Tablet presses are instrumented by affixing

transducers transducers

to measure the forces applied during the to measure the forces applied during the

compression compression

process. The signals produced by the transducer process. The signals produced by the transducer

system system

are monitored by computer. are monitored by computer.

Page 54: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Effervescent salts are granules or coarse Effervescent salts are granules or coarse

to very coarse powders containing a medicinal agent to very coarse powders containing a medicinal agent

in a dry mixture usually composed of sodium in a dry mixture usually composed of sodium

bicarbonate, citric acid, and tartaric acid. bicarbonate, citric acid, and tartaric acid.

When added to water, the acids and base react to When added to water, the acids and base react to

liberate carbon dioxide, resulting in effervescence. liberate carbon dioxide, resulting in effervescence.

The resulting carbonated solution masks the usually The resulting carbonated solution masks the usually

saline or undesirable taste of the medicinal agent saline or undesirable taste of the medicinal agent

present.present.

Page 55: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

A good effervescent blend consists of both citric acid A good effervescent blend consists of both citric acid

and tartaric acid (1 :2 ratio), since the former is and tartaric acid (1 :2 ratio), since the former is

rather sticky to manipulate and the latter produces a rather sticky to manipulate and the latter produces a

chalky, friable granule. chalky, friable granule. Citric AcidCitric Acid

3 NaHC03 NaHC033 + C + C66HH88OO77.H.H22O 4 HO 4 H220 + 3C00 + 3C022 + +

NaNa33CC66HH55OO77

3 x 843 x 84 210 210

One gram of citric acid (MW = 210) reacts with 1.2 g One gram of citric acid (MW = 210) reacts with 1.2 g

of sodium bicarbonate (MW = 84) of sodium bicarbonate (MW = 84)

210

1==

843X

XX = 1.2 gX = 1.2 g

Page 56: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

Tartaric AcidTartaric Acid

2 NaHC02 NaHC033 + C + C44HH660066 2 H 2 H220 + 2C00 + 2C022 -+ Na -+ Na22CC44HH44OO66

2 x 84 1502 x 84 150

Since it is desired to use a 1:2 ratio of critic acid to Since it is desired to use a 1:2 ratio of critic acid to

tartaric acid, two grams of tartaric acid (MW = 150) tartaric acid, two grams of tartaric acid (MW = 150)

reacts with 2.24 g of sodium bicarbonate. reacts with 2.24 g of sodium bicarbonate.

150

2==

842X

XX = 2.24 gX = 2.24 g

Page 57: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

From the above, it has been calculated that 1.2 g and From the above, it has been calculated that 1.2 g and

2.24 g of sodium bicarbonate is required to react 2.24 g of sodium bicarbonate is required to react

with 1 + 2 g of the citric : tartaric acid combination.with 1 + 2 g of the citric : tartaric acid combination.

Since it is desired to leave a small amount of the Since it is desired to leave a small amount of the

acids unreacted to enhance palatability and taste, acids unreacted to enhance palatability and taste,

2.24 g + 1.2 g= 3.44 g, only 3.4 g of sodium 2.24 g + 1.2 g= 3.44 g, only 3.4 g of sodium

bicarbonate will be utilized. Therefore, the ratio of bicarbonate will be utilized. Therefore, the ratio of

the effervescent ingredients is the effervescent ingredients is

1 : 2 : 3.4 for the citric acid : tartaric acid : sodium 1 : 2 : 3.4 for the citric acid : tartaric acid : sodium

bicarbonate. bicarbonate.

Page 59: Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical

The Supercell™ Tablet Coater feature continuous small-batch capabilities and the coating process are predictable and efficient