GranulesGranules

Granules are aggregations of fine particles Granules are aggregations of fine particles of powders in a mass of about spherical of powders in a mass of about spherical shapeshape..

Why we prepare granules when we have Why we prepare granules when we have powders?powders?

1.1. To avoid powder segregation, To avoid powder segregation, if the powder is composed of particles with if the powder is composed of particles with

different dimensions & different densities, different dimensions & different densities, a separation between these particles will a separation between these particles will occur. occur.

2.2. To enhance the flow of powder,To enhance the flow of powder,Higher flowability gives better filling of the Higher flowability gives better filling of the

dies or containers, during a volumetric dies or containers, during a volumetric dosage.dosage.

3.3. Granules have higher porosity than Granules have higher porosity than powders,powders,

4.4. To improve the compressibility of powders.To improve the compressibility of powders.

5.5. The granulation of toxic materials will The granulation of toxic materials will reduce the hazard of generation of toxic reduce the hazard of generation of toxic dust, which may arise during the handling dust, which may arise during the handling of the powders.of the powders.

6.6. Materials, which are slightly hygroscope, Materials, which are slightly hygroscope, may adhere & form a cake if stored as a may adhere & form a cake if stored as a powder.powder.

Technologically, granules are used Technologically, granules are used according to two visions:according to two visions:

1.1. As a true & proper pharmaceutical dosage As a true & proper pharmaceutical dosage form form,form form,

These granules are used to prepare an These granules are used to prepare an instant solution or suspension.instant solution or suspension.

Granules, can be packaged as:Granules, can be packaged as: Bulk granules (Multi-dosage containers),Bulk granules (Multi-dosage containers),

Divided granules (Mono-dosage Divided granules (Mono-dosage containers ).containers ).

2.2. Semi-finished products for the Semi-finished products for the preparation of tablets or other dosage preparation of tablets or other dosage forms.forms.

Usually, granules have an excellent Usually, granules have an excellent compressibility, compressibility,

Methods of GranulationMethods of Granulation Some of the available methods in the Some of the available methods in the

industrial field for the preparation of industrial field for the preparation of granules: granules:

1.1. Wet Granulation.Wet Granulation.

2.2. Dry granulation methods.Dry granulation methods.

3.3. Granulation by Crystallization.Granulation by Crystallization.

I.I. Granulation by Crystallization.Granulation by Crystallization.

This method exploits the This method exploits the presence of presence of crystallization water in the active crystallization water in the active materialmaterial; this method is rarely used.; this method is rarely used.

II.II. Dry Granulation.Dry Granulation.

Pharmaceutical powders that were mixed Pharmaceutical powders that were mixed homogeneously together are compressed to homogeneously together are compressed to obtain large tablets. obtain large tablets.

The high compression forces are obtained by using The high compression forces are obtained by using one of the following procedures:one of the following procedures:

1.1. Tabling machines (see industrial pharmacy).Tabling machines (see industrial pharmacy).These machines are provided with dies of 2-3 cm These machines are provided with dies of 2-3 cm

diameters (the fine powders have low diameters (the fine powders have low flowability) flowability)

So,So, large dies are easily filled in this case, the dies large dies are easily filled in this case, the dies

travel between two punches, which press the travel between two punches, which press the powder forming large tablets, with 2-3 cm of powder forming large tablets, with 2-3 cm of diameters.diameters.

2.2. Roller compaction (see industrial Roller compaction (see industrial pharmacy).pharmacy).

The powder mixture flow between two The powder mixture flow between two rollers to form a compressed sheet.rollers to form a compressed sheet.

These large tablets or sheets are milled.These large tablets or sheets are milled.

The milled sheets are sieved. The milled sheets are sieved.

The sieving process gives three fractions The sieving process gives three fractions of granules :of granules :

1.1. Very coarse granules, which return back Very coarse granules, which return back to the milling process.to the milling process.

2.2. Very fine fraction, which return back to Very fine fraction, which return back to the compaction.the compaction.

3.3. Fraction with optimal dimensions for Fraction with optimal dimensions for following manufacturing steps. following manufacturing steps.

This system produces granules with:This system produces granules with: irregular shape, irregular shape,

low rate of dissolution due to the low rate of dissolution due to the high high compression forcecompression force used to aggregate the used to aggregate the powders. powders.

These granules are poorly These granules are poorly water-permeablewater-permeable due due to the low porosity.to the low porosity.

So, water canSo, water can’’t permeate them easily in order to t permeate them easily in order to disintegrate & dissolve them. disintegrate & dissolve them.

This will extremely reduce the velocity of This will extremely reduce the velocity of dissolution & so the bioavailability of the active dissolution & so the bioavailability of the active material.material.

Vice versa if the granules have high Vice versa if the granules have high porosity the molecules of water can porosity the molecules of water can penetrate easily into the pores, & penetrate easily into the pores, & disintegrate the granules. disintegrate the granules.

High Porosity means high specific High Porosity means high specific surface area, leading to an increasing in surface area, leading to an increasing in the dissolution velocity of the granules, the dissolution velocity of the granules, & thus their bioavailability.& thus their bioavailability.

Thus, we can say that the dry Thus, we can say that the dry granulation method is used only for granulation method is used only for those powders, which cannot be those powders, which cannot be granulated with the wet granulation granulated with the wet granulation method.method.

Wet GranulationWet Granulation This is the most used method to This is the most used method to

prepare granules.prepare granules.

The main disadvantage of this The main disadvantage of this method is the higher number of method is the higher number of steps present in this process when steps present in this process when compared with the other two compared with the other two methods.methods.

Steps of Wet Granulation:Steps of Wet Granulation:1.1. The 1The 1stst step is the wetting of the powder with step is the wetting of the powder with

a liquid or solution to form a paste.a liquid or solution to form a paste.Characteristics of the granulating liquid:Characteristics of the granulating liquid: It should have all required characteristics of It should have all required characteristics of

pharmaceutical excipient, &pharmaceutical excipient, & It should dissolve the powder only within a It should dissolve the powder only within a

certain limit (mild solvent):certain limit (mild solvent):

If the powder is soluble in the solvent, a solution If the powder is soluble in the solvent, a solution or suspension will be obtained instead of the or suspension will be obtained instead of the paste.paste.

From another side, if the solvent cannot From another side, if the solvent cannot absolutely dissolve the powder, we absolutely dissolve the powder, we cannot obtain the liquid forces, which cannot obtain the liquid forces, which stick together the powder particles.stick together the powder particles.

The fraction of powder, which dissolves The fraction of powder, which dissolves in the solvent, & then re-crystallizes, in the solvent, & then re-crystallizes, after the drying, will form bridges after the drying, will form bridges between the particles of the powder.between the particles of the powder.

When two particles become in contact When two particles become in contact between each other by certain forces, between each other by certain forces, they institute:they institute:

forces of electrostatic nature (week forces of electrostatic nature (week forces) &forces) &

forces of viscous or/and adhesive natures forces of viscous or/and adhesive natures (which are the most important) so the (which are the most important) so the particles remain attached to each others.particles remain attached to each others.

Thus the used liquid in the wet Thus the used liquid in the wet granulation must be mild solvent for the granulation must be mild solvent for the powder.powder.

There is a few number of solvents There is a few number of solvents available for pharmaceutical available for pharmaceutical granulation.granulation.

This is because we canThis is because we can’’t totally t totally eliminate the solvent, so if traces of the eliminate the solvent, so if traces of the solvent remain in the formula at the end solvent remain in the formula at the end of the manufacturing, these traces must of the manufacturing, these traces must be non toxic for the patient.be non toxic for the patient.

The most used solvents in wet granulation :The most used solvents in wet granulation :1.1. Water.Water.2.2. Ethanol.Ethanol.3.3. Isopropanol.Isopropanol.

If we want to use water for granulation, the If we want to use water for granulation, the powder must be:powder must be:

fairly or discreetly soluble in the water, &fairly or discreetly soluble in the water, & compatible with it.compatible with it.

If the powder is very soluble in water, we can If the powder is very soluble in water, we can use another liquid or the following use another liquid or the following arrangements:arrangements:

4.4. Water Solutions.Water Solutions.

Simple SyrupSimple Syrup This syrup has less dissolving capacity than the This syrup has less dissolving capacity than the

pure water, because the majority of water pure water, because the majority of water molecules are involved in the hydration & molecules are involved in the hydration & dissolving of the sugar molecules instead of dissolving of the sugar molecules instead of the powder molecules.the powder molecules.

But if the powder is water insoluble, But if the powder is water insoluble, 5.5. A co-solvent is recommended.A co-solvent is recommended.This is a This is a mixturemixture between water & another between water & another

water-soluble pharmaceutical solvent with water-soluble pharmaceutical solvent with high dissolving capacity toward the powder.high dissolving capacity toward the powder.

6.6. We can also use a water solution of polymers,We can also use a water solution of polymers,The evaporation of water can determine the The evaporation of water can determine the

adhesion between the particles of the powder.adhesion between the particles of the powder.

Polymers solutions that can be used in the wet Polymers solutions that can be used in the wet granulation:granulation:

1.1. Gelatin solution at 5-10%.Gelatin solution at 5-10%.

Such viscose solutions determine the adhesion of the Such viscose solutions determine the adhesion of the particles of the powders, particles of the powders,

When water evaporates the gelatin solidifies When water evaporates the gelatin solidifies between the two particles of powder and maintain between the two particles of powder and maintain them stuck together.them stuck together.

2.2. Starch past 5 -10%.Starch past 5 -10%.Pre-gelatinized starch, which has the characteristic Pre-gelatinized starch, which has the characteristic

to swell in a cold water.to swell in a cold water.

3.3. Semi-synthetic polymers like CMC, MC.Semi-synthetic polymers like CMC, MC.

4.4. Synthetic polymers like P.V.P.Synthetic polymers like P.V.P.

Some of these compounds can be used in Some of these compounds can be used in organic solvent like ethanol, organic solvent like ethanol,

This is useful in case of thermo-sensitive This is useful in case of thermo-sensitive compounds, & compounds, &

To reduce the cost of production.To reduce the cost of production.

The granules obtained in this way are The granules obtained in this way are called agglutinated granules.called agglutinated granules.

2.2. The 2The 2ndnd step is the granulation or the step is the granulation or the formation of granules starting from the formation of granules starting from the paste.paste.

To achieve this, many granulators are To achieve this, many granulators are available (see industrial pharmacy):available (see industrial pharmacy):

1.1. Rotative granulator,Rotative granulator,

2.2. Oscillating granulator,Oscillating granulator,

3.3. High speed mixer granulator,High speed mixer granulator,

4.4. Fluidized bed granulator,Fluidized bed granulator,

5.5. Freund granulator,Freund granulator,

6.6. Roller compaction granulator.Roller compaction granulator.

The quality of the granules depends on the:The quality of the granules depends on the:1.1. Granulation solvent,Granulation solvent,

2.2. Type of granulator,Type of granulator,

3.3. Powder nature.Powder nature.

The paste that we have to obtain mustnThe paste that we have to obtain mustn’’t t drains between the fingers of the hand, drains between the fingers of the hand, which means that must remain aggregated which means that must remain aggregated & easily crumbled.& easily crumbled.

This is a very coarse reference, but This is a very coarse reference, but nowadays there is the possibility to have a nowadays there is the possibility to have a qualitative evaluation.qualitative evaluation.

we can measure the energy that we must we can measure the energy that we must provide to the system in which we carry provide to the system in which we carry out the wetting process.out the wetting process.

How?How?

1.1. Put the powder for granulation in the Put the powder for granulation in the granulator,granulator,

2.2. Add gradually the granulating liquid,Add gradually the granulating liquid,

3.3. Then mix by the use of electrical motorThen mix by the use of electrical motor

This motor measures the absorbed power in This motor measures the absorbed power in function of the time & so in function of function of the time & so in function of the putted liquid.the putted liquid.

How can we calculate the exact volume of How can we calculate the exact volume of granulating liquid for powder kneading?granulating liquid for powder kneading?

We can evaluate the liquid quantity for the We can evaluate the liquid quantity for the kneading process by measuring kneading process by measuring continuously the absorbed power during the continuously the absorbed power during the addition of the granulating liquid.addition of the granulating liquid.

The increase in the required power is The increase in the required power is connected with the increase of the viscosity connected with the increase of the viscosity of the dough mass, due to the formation of of the dough mass, due to the formation of the liquid bonds (adhesive & viscous types). the liquid bonds (adhesive & viscous types).

Generally, all instruments are able to form a Generally, all instruments are able to form a curve, as in the following figure: curve, as in the following figure:

4.4. Perform the curve by putting the absorbed Perform the curve by putting the absorbed power in Y- axis, & the volume of the power in Y- axis, & the volume of the granulating liquid in X- axis.granulating liquid in X- axis.

5.5. Interpretation of the obtained curve:Interpretation of the obtained curve:

Initially, the addition of the granulating Initially, the addition of the granulating liquid doesnliquid doesn’’t produce a significant change t produce a significant change in the absorbed power, in the absorbed power,

At point 2 we fined that any added quantity At point 2 we fined that any added quantity of the granulating liquid, increases of the granulating liquid, increases proportionally the absorbed power.proportionally the absorbed power.

At this point we have initial formation At this point we have initial formation of:of:

1.1. Electrostatic bonds (less important),Electrostatic bonds (less important),

2.2. Liquid bonds (more important).Liquid bonds (more important).

These bonds start to bind together the These bonds start to bind together the powder particles & to form the powder particles & to form the granules.granules.

Therefore the equipment meet higher Therefore the equipment meet higher resistance to maintain constant the resistance to maintain constant the number of rounds/minute.number of rounds/minute.

Then continuing in the liquid addition, we note Then continuing in the liquid addition, we note that the absorbed power will be stabilized on a that the absorbed power will be stabilized on a certain value (interval between 3-4), this certain value (interval between 3-4), this means that the system was reached an means that the system was reached an equilibrium state.equilibrium state.

At points 3-4, we have an excellent adhesion At points 3-4, we have an excellent adhesion between the various particles of powder &between the various particles of powder &

The granule shape depends on the type of the The granule shape depends on the type of the used granulator.used granulator.

The addition of further liquid, will give The addition of further liquid, will give phase 5 where we note a sharp drop in phase 5 where we note a sharp drop in the absorbed power, the absorbed power, because the because the granulate will be transformed in a granulate will be transformed in a suspensionsuspension..

In this manner we have an idea about the In this manner we have an idea about the percentage quantity of the granulating percentage quantity of the granulating liquid, which we have to add, by liquid, which we have to add, by evaluating the curve.evaluating the curve.

This curve can subdivide the granulators in:This curve can subdivide the granulators in:1.1. Slow granulator (fluidized bed granulator and Slow granulator (fluidized bed granulator and

dryer).dryer).

2.2. Speed granulators (e.g. plates and rotate Speed granulators (e.g. plates and rotate granulatorsgranulators……etc, see industrial pharmacy).etc, see industrial pharmacy).

III.III. The 3The 3rdrd step is the step is the Drying ProcessDrying Process. . Water is more difficult to be eliminated than the Water is more difficult to be eliminated than the

organic solvents, therefore the water gives organic solvents, therefore the water gives some problems:some problems:

1.1. When the powder is thermosensitive the When the powder is thermosensitive the heating for long period of time can alter the heating for long period of time can alter the stability of the powder,stability of the powder,

2.2. The consumption of energy is higher than the The consumption of energy is higher than the organic solvents. organic solvents.

We have three kinds of water in the granulate We have three kinds of water in the granulate mass:mass:

1.1. Water of Crystallization,Water of Crystallization, It is very difficult to be eliminated without It is very difficult to be eliminated without

causing the decomposition of the product or causing the decomposition of the product or variation of its crystalline form.variation of its crystalline form.

2.2. Adsorped water,Adsorped water, The amount of water, which was absorbed by a The amount of water, which was absorbed by a

drug present in a moist air, this amount drug present in a moist air, this amount depends on the nature of the drug & the depends on the nature of the drug & the relative humidity of the air.relative humidity of the air.

3.3. Imbibition of water,Imbibition of water, The amount of water, which impregnates the The amount of water, which impregnates the

granules, this water is easy to be eliminated granules, this water is easy to be eliminated by simple evaporation.by simple evaporation.

According to the used dryer, we can According to the used dryer, we can eliminate the total amount of eliminate the total amount of imbibition’s imbibition’s water & a portion of the adsorpted waterwater & a portion of the adsorpted water..

The elimination of the total amount of the The elimination of the total amount of the adsorbed water is not advisable.adsorbed water is not advisable.

For example the elimination of the total For example the elimination of the total amount of the adsorbed water, may create amount of the adsorbed water, may create electrostatic charges, electrostatic charges,

This lead to the attraction or repulsion of This lead to the attraction or repulsion of the granules between themselves & the the granules between themselves & the walls of the equipment, walls of the equipment,

This type of granules are very difficult to This type of granules are very difficult to be managed.be managed.

If we use a hydrophilic polymer solution, If we use a hydrophilic polymer solution, as a granulating liquid, & we proceed for as a granulating liquid, & we proceed for long time in the drying process, the long time in the drying process, the hydrophilic polymer will assume a glassy hydrophilic polymer will assume a glassy consistency. consistency.

These glassy characteristics cause the These glassy characteristics cause the fragmentation of the granules during the fragmentation of the granules during the following manufacturing processes.following manufacturing processes.

Thus, a certain quantity of moisture is Thus, a certain quantity of moisture is useful to improve the manipulation of the useful to improve the manipulation of the granules.granules.

The dryers are (see industrial pharmacy):The dryers are (see industrial pharmacy):1.1. Static Oven,Static Oven,

2.2. Rotary Drier,Rotary Drier,

3.3. Fluidized Bed Drier,Fluidized Bed Drier,

4.4. Vacuum Oven,Vacuum Oven,

5.5. Microwave Drier, Microwave Drier,

6.6. Spray Drier,Spray Drier,

7.7. Rotary Atomizer,Rotary Atomizer,

8.8. I.R Drier.I.R Drier.

IV.IV. The 4The 4thth step is the Classification of the step is the Classification of the granules.granules.

The last step is the classification according The last step is the classification according to particles dimension:to particles dimension:

1.1. Coarse granules, which must be milled,Coarse granules, which must be milled,

2.2. Fine granules, which must be re-Fine granules, which must be re-granulated.granulated.

3.3. Optimum granules with optimum Optimum granules with optimum dimensions, which are ready for use.dimensions, which are ready for use.

We have two problems correlated to the size of We have two problems correlated to the size of granules:granules:

1.1. Concerning the filling of big volume (i.e. sachets Concerning the filling of big volume (i.e. sachets or bottles).or bottles).

If we have big granules we can use big measuring If we have big granules we can use big measuring tool, while if the granules have small size, we can tool, while if the granules have small size, we can use small measuring tool.use small measuring tool.

The most critical problem is :The most critical problem is :2.2. when we must to fill the die of the tableting when we must to fill the die of the tableting

machine in order to prepare the tablet.machine in order to prepare the tablet.

In this case:In this case:it is not only important to have granules with equal it is not only important to have granules with equal

dimensionsdimensions, but, butit is also important that the size of these granules it is also important that the size of these granules

are within a certain range, which is in function are within a certain range, which is in function with the diameter of the die.with the diameter of the die.

The essential concept when producing The essential concept when producing tablets, is that the granules which we tablets, is that the granules which we want to fill the die with, must be want to fill the die with, must be more more fine as the diefine as the die becomes becomes smaller.smaller.

In fact there are well-defined relations In fact there are well-defined relations between the size of the granules & the between the size of the granules & the diameters of the die, in order to have a diameters of the die, in order to have a filling uniformity of the die, & filling uniformity of the die, &

so to obtain tablets, which remain within so to obtain tablets, which remain within the limits of the weight uniformity.the limits of the weight uniformity.

For example:For example: If we have a die with diameter of 3/16 of If we have a die with diameter of 3/16 of

inch, we should prepare granules, which inch, we should prepare granules, which pass through a sieve with mesh 20 (20 pass through a sieve with mesh 20 (20 mesh /1 linear inch).mesh /1 linear inch).

If we have a die with diameters of 7/16 If we have a die with diameters of 7/16 inch, we have to have granules with inch, we have to have granules with dimensions that pass through a sieve of dimensions that pass through a sieve of mesh 12.mesh 12.

Quality ControlsQuality Controls1.1. Weight uniformity test.Weight uniformity test.

2.2. Dissolution profile.Dissolution profile.

3.3. Friability test. Friability test. The granules must be:The granules must be:packaged in order to be used as final packaged in order to be used as final

pharmaceutical dosage form, orpharmaceutical dosage form, or

added to other substances for example to added to other substances for example to prepare the tablets,prepare the tablets,

So, we must avoid the transformation of the So, we must avoid the transformation of the granules into powder during the manipulation granules into powder during the manipulation processes. processes.

Friability testerFriability tester

Some Particular Granules:Some Particular Granules:

1.1. Sustained release granules.Sustained release granules.

2.2. Enteric coated granules.Enteric coated granules.

3.3. Effervescent granules.Effervescent granules.