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

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

PowderPowder GranulesGranules

GranulationGranulation

sievinsievingg

Segregated Segregated PowderPowder

Monosized Monosized GranulesGranules

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.

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

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

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

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

Methods of granulationGranulation 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. oningestion 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.

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

Roller compactorsRoller compactors

AlexanderwerkAlexanderwerkRoller compactorRoller compactor

Hutt Roller Hutt Roller compactorcompactor

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.

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.

Typical liquids include water, ethanol and isopropanol, either alone or in combination.

The primary advantages of water are that: it is non-flammable, which means that expensive safety precautions not be taken. Water is commonly used for economical reasons.

disadvantages of water as a solvent are that: It may adversely affect drug stability, causing drug hydrolysis. It needs a longer drying time than do organic solvents, that increases the length of the process and again may affect stability because of the extended exposure to heat. Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry granulation, or when a rapid drying time is required.

Effect of granulation method on granule structureEffect of granulation method on granule structureThe 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.

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-driersSpheronizers /PelletizersSpheronizers /Pelletizers

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

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

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.

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.

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.

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 horizontalhorizontalplane, 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

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.

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.

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

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

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

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

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

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

Spheronizers /PelletizersSpheronizers /Pelletizers

For some applications it may be desirable to For some applications it may be desirable to have ahave adense, 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.

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

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 mass3. Extrusion to form rod-shaped particles of uniform 3. Extrusion to form rod-shaped particles of uniform

diameterdiameter4. Spheronization to round off these rods into spherical 4. Spheronization to round off these rods into spherical

particlesparticles5. Drying to achieve the desired final moisture content5. Drying to achieve the desired final moisture content6. Screening to achieve the desired narrow size 6. Screening to achieve the desired narrow size

distribution.distribution.

Schematic representation of production extruderSchematic representation of production extruder

ExtrusionExtrusion

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.

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.

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.

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.

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.

GRANULATION MECHANISMSTo 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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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)

2101

==843XX

X = 1.2 gX = 1.2 g

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.

1502

==842XX

X = 2.24 gX = 2.24 g

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.

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