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Granules

Granules - Pharmaceutics

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Granules

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

Definition !?

1. Avoid powder segregationif the powder is composed of particles with different dimensions &

different densities, a separation between these particles will occur.

2. To enhance the flow of powderHigher flowability gives better filling of the dies or containers, during a

volumetric dosage.

Why we prepare granules when we have powders?

3. Granules have higher porosity than powders

4. To improve the compressibility of powders

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

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

1. As a true & proper pharmaceutical dosage formThese granules are used to prepare an instant solution or suspension.

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

Divided granules (Mono-dosage containers )

Technologically, granules are used according to two visions

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

Usually, granules have an excellent compressibility

Some of the available methods in the industrial field for the preparation of granules:

1. Wet Granulation

2. Dry granulation methods

3. Granulation by Crystallization

Methods of Granulation

Dry Granulation

I. Granulation by Crystallization.

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

II. Dry Granulation.

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

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

1. Tabling machines (see industrial pharmacy).These machines are provided with dies of 2-3 cm diameters (the fine

powders have low flowability)

2. Roller compaction (see industrial pharmacy).

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

These large tablets or sheets are milled.

The milled sheets are sieved.

The sieving process gives three fractions of granules:1. Very coarse granules, which return back to the milling process.

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

3. Fraction with optimal dimensions for following manufacturing steps.

This system produces granules with: Irregular shape Low rate of dissolution due to the high compression force used to

aggregate the powders.

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

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

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

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

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

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

Wet Granulation

This is the most used method to prepare granules.

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

1. The 1st step is the wetting of the powder with a liquid or solution to form a paste.

Characteristics of the granulating liquid: It should have all required characteristics of pharmaceutical excipient It should dissolve the powder only within a certain limit (mild

solvent)

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

Steps of Wet Granulation

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

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

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

forces of electrostatic nature (week forces)

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

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

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

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

The most used solvents in wet granulation :1. Water.2. Ethanol.3. Isopropanol.

If we want to use water for granulation, the powder must be: fairly or discreetly soluble in the water compatible with it.

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

1. Water Solutions.

2. Simple Syrup This syrup has less dissolving capacity than the pure water, because the majority

of water molecules are involved in the hydration & dissolving of the sugar molecules instead of the powder molecules.

But if the powder is water insoluble,

1. A co-solvent is recommended.This is a mixture between water & another water-soluble pharmaceutical solvent

with high dissolving capacity toward the powder.

2. We can also use a water solution of polymers,The evaporation of water can determine the adhesion between the particles of

the powder.

Polymers solutions that can be used in the wet granulation:1. Gelatin solution at 5-10%.

2. Starch paste 5 -10%.

3. Semi-synthetic polymers like CMC, MC.

4. Synthetic polymers like P.V.P.

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

To achieve this, many granulators are available (see industrial pharmacy):3. Rotative granulator4. Oscillating granulator5. High speed mixer granulator6. Fluidized bed granulator7. Freund granulator8. Roller compaction granulator

The quality of the granules depends on the:1. Granulation solvent

2. Type of granulator

3. Powder nature

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

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

The 3rd step is the Drying Process. Water is more difficult to be eliminated than the organic solvents,

therefore the water gives some problems:

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

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

1.Static Oven

2.Rotary Drier

3.Fluidized Bed Drier

4.Vacuum Oven

5.Microwave Drier

6.Spray Drier

7.Rotary Atomizer

8.I.R Drier

The dryers are (see industrial pharmacy):

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

The last step is the classification according to particles dimension:1. Coarse granules, which must be milled

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

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

We have two problems correlated to the size of granules:1. Concerning the filling of big volume (i.e. sachets or bottles).

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

The most critical problem is :2. when we must to fill the die of the tableting machine in order to prepare the tablet.

In this case:it is not only important to have granules with equal dimensions, butit is also important that the size of these granules are within a certain range, which is in

function with the diameter of the die.

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

For example: If we have a die with diameter of 3/6 of inch, we should prepare

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

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

1. Weight uniformity test.

2. Dissolution profile.

3. Friability test.

The granules must be:packaged in order to be used as final pharmaceutical dosage form, or

added to other substances for example to prepare the tablets,

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

Quality Controls

Friability tester

Some Particular Granules

1. Sustained release granules.

2. Enteric coated granules.

3. Effervescent granules.

Effervescent salts are granules or coarse to very coarse powders containing a soluble medicinal agent in a dry mixture

Composition: Sodium bicarbonate, citric acid, and tartaric acid

Note: When added to water, the acids and base react to liberate CO2 resulting in effervescence

Effervescent granules

The resulting carbonated solution masks undesirable taste of any medicinal agent.

Using granules or coarse particles of the mixed powders rather than small powder particles decreases the rate of solution and prevents violent and uncontrollable effervescence.

Sudden and rapid effervescence could overflow the glass and leave little residual carbonation in the solution.

Using a combination of citric and tartaric acids rather than either acid alone avoids certain difficulties.

When tartaric acid is used as the sole acid, the resulting granules readily lose their firmness and crumble.

Citric acid alone results in a sticky mixture difficult to granulate.

Rx: Active drug 500 mg/5 g tsp in effervescent granule qs 120 g

Sig: Dissolve 1 teaspoonful in one-half glass of cool water and drink. Repeat this every 8 h.

It is desired to dispense this as a granule, so that the patient will measure out a teaspoon- ful (5g) dose, mix, and administer.

Since each dose weighs 5g and the prescription consists of 120g, there are 24 doses.

Each dose contains 0.5g of the active drug, which comes to 12g of the active drug for the entire prescription.

This requires 120g − 12g = 108g of effervescent vehicle. A good effervescent blend consists of both citric acid and tartaric acid (1:2 ratio), since the former is rather sticky and the latter produces a chalky, friable granule.

It is necessary to calculate the amount of each ingredient required to prepare 108 g of the granulation.

EXAMPLE

3NaHCO3 + C6H8O7.H2O → 4 H2O + 3 CO2 + Na3C6H5O7 3 × 84 150 Citric acid 1 g (MW = 210) of citric acid reacts with 1.2 g (MW = 84) of

sodium bicarbonate as obtained from the following:

1/120=x / 3×84 x = 1.2g

CITRIC ACID

2 NaHCO3 + C4H6O6 → 2 H2O + 2CO2 + Na2C4H4O6

2 × 84 150 Since it is desired to use a 1:2 ratio of citric acid to tartaric acid, 2 g

(MW = 150) of tartaric acid reacts with sodium 2.24 g of bicarbonate according to the following calculation:

2/150 =(x/2)×84 x = 2.24 g

TARTARIC ACID

Therefore, 1.2g and 2.24g of sodium bicarbonate is required to react with 1 + 2g of the combination of citric acid and tartaric acid. Since it is desired to leave a small amount of the acids unreacted to enhance palatability and taste, of the required 3.44 g (2.24 g + 1.2 g), only 3.4 g of sodium bicarbonate will be used.

Therefore, the ratio of the effervescent ingredients is 1:2:3.4 for the citric acid:tartaric acid:sodium bicar- bonate. Since the prescription requires 108g of the effervescent mix, the quantity of each ingredient can be calculated as follows:

1 + 2 + 3.4 = 6.41/6.4 × 108 g = 16.875 g of citric acid2/6.4 × 108 g = 33.750 g of tartaric acid3.4/6.4 × 108 g = 57.375 g of sodium bicarbonate Total = 108 g

The prescription will require 12 g of the active drug and 108 g of this effervescent vehicle.