Granulation Process in Pharmaceutical

What is Granulation?

Granulation, the process of particle enlargement by agglomeration technique, is one of the most significant unit operations in the production of pharmaceutical dosage forms, mostly tablets and capsules. The granulation process transforms fine powders into free-flowing, dust-free granules that are easy to compress.

What is the purpose of granulation?

Granulation aims to provide a more homogenous mixture by formulation of granules that contain both the drug substance and the excipient particles. Hence, granulation can be thought of as a process that aims to operate the desired attributes of a particle and powder system.

Why granulation is important in tablet preparation?

The granulation process is an inevitable step in tablet manufacturing as it improves flow properties and compressibility of powder mass intended for compression. Granulation prevents the segregation of the constituents of the powder mix.

What is granulation and how is it used?

Granulation is the process that converts fine materials like spray-dried powders or dust to larger particles called granules. This can be accomplished by various means. For example, compaction may be used to form tablets or pellets from solid materials.

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What are the types of granulation?

Granules are formed from the powder particles by wetting and nucleation, coalescence or growth, consolidation, and attrition or breakage. The granulation technique is broadly classified into two types, dry granulation, and wet granulation, with wet granulation being the most widely used granulation technique.

What is the difference between dry granulation and wet granulation?

Dry granulation uses mechanical compression (slugs) or compaction (roller compaction) to facilitate the agglomeration of dry powder particles, while wet granulation uses granulation liquid (binder/solvent) to facilitate the agglomeration by the formation of wet mass by adhesion.

What is the end point of granulation?

Fluctuation of torque/power consumption and intensity of spectrum obtained by FFT analysis can be used for end-point determination. It was observed that when the end-point region of granulation is reached, the frequency distribution of a power consumption signal reaches a steady state.

Granulation

Granulation is the most widely used technique to prepare powders for compaction. The term granulation is a generic description for a process of particle enlargement in which particles are agglomerated while retaining the integrity of the original particles.

A number of methods can be used to achieve agglomeration; these are normally classified as either wet granulation, where a liquid is used to aid the agglomeration process, or dry granulation, where no liquid is used.

The purpose of granulating is to transform the powdered starting materials, which would otherwise be unsuitable for tableting, into a form that will run smoothly on a tablet machine. This is achieved in a number of ways. The most obvious benefit of granulation is the improved flow properties resulting from the increase in particle size.

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In forming granules, individual particles of the starting ingredients are agglomerated together. If a homogeneous powder mix is achieved before commencing agglomeration, the granules will consist of a homogeneous mix of those ingredients. More importantly, the particles of drug substance will be bound to the particles of the excipients, thus reducing the potential for segregation, and improving the chances of content uniformity.

The granulation process usually involves the addition of a polymeric binder that sticks the individual particles together, this process can reduce the elasticity of starting materials, thus improving the compatibility.

The polymers used as binders are usually hydrophilic in nature. This can have a beneficial effect on the dissolution of hydrophobic drugs. During the granulation process, a film of hydrophilic polymer will form over the surface of hydrophobic drug particles, which will aid wetting.

One of the advantages of granulation is that it results in the densification and subsequent volume reduction of the starting material. This is particularly useful in the case of voluminous starting materials. A further benefit is that the densified, coarse material will reduce the amount of air entrapment.

A number of methods are routinely used within the pharmaceutical industry to produce granulations. These are traditionally classified as dry granulation and wet granulation, depending on whether a liquid is used to aid the agglomeration.

1.  Wet granulation

• Wet granulation methods are the most commonly used in tablet manufacture.
• These methods involve the addition of a liquid and, usually, a polymeric binder to the powdered starting materials, and a form of agitation to promote agglomeration followed by a drying process. In most cases, the liquid used is water, although in certain circumstances organic solvents such as ethanol or ethanol/water mixes are used. 
• Nonaqueous granulation will be considered when the active substance is particularly unstable in the presence of water, when water will not wet the powder or, possibly, if the drug substance forms a significant portion of the granulate, and demonstrates extreme solubility in aqueous media, and control of the granulation process becomes difficult due to the occurrence of significant dissolution.
• While there are a number of approaches to wet granulation used in the pharmaceutical industry, they all share the following basic principles:

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Dry mixing: 

The starting materials are mixed together. Prior to mixing, the ingredients may be deagglomerated by a milling or sieving process. If the granulate has a low drug content, the active substance may be premixed with one of the ingredients prior to being added to the granulation vessel to ensure good content uniformity.

Addition of granulating liquid: 

The granulating fluid is added to the dry ingredients and mixed to form a wet mass. The mixing of the fluid with the dry ingredients leads to the agglomeration of the powder. This agglomeration can be controlled by altering the amount of fluid added, the intensity of the mixing, and the duration of the mixing. Depending on the state of agglomeration achieved, this stage may be followed by a wet sieving process to break up the larger agglomerates.

Drying: 

The fluid is removed by a drying process.

Milling: 

The dried granulate undergoes a sieving or milling operation to obtain the

desired particle size distribution.

Lubrication: 

The final step is lubrication in order to make the particles adhere firmly together. This is done with the addition of a lubricating agent. The use of lubricating agents is particular to the types of API and excipients used. The most commonly used lubricating agent is magnesium stearate. The material formed is thus ready for further compression and manufacturing.

2.  Dry Granulation

• It is possible to form granulates without the addition of a granulating fluid, by techniques generically referred to as dry granulation. These methods are useful for materials that are sensitive to heat and moisture, but which may not be suitable for direct compression.
• Dry granulation involves the aggregation of particles by high pressure to form bonds between particles by virtue of their close proximity. Two approaches to dry granulation are used in the pharmaceutical industry: slugging and roller compaction. In either method, the material can be compacted with a binder to improve the bonding strength.

Slugging: 

Granulation by slugging is, in effect, the manufacture of large compacts by direct compression. The slugs produced are larger than tablets and are often poorly formed tablets exhibiting cracking and lamination. As with tablets, it may be necessary to add a lubricant to prevent the compacts from sticking to the punches and dies. The compressed material is broken up and sieved to form granules of the appropriate size. The granules are then blended with disintegrant and lubricant, and compressed on a normal tablet machine.

Roller compaction: 

In roller compaction, the powder is compacted by means of pressure rollers. It is fed between two cylindrical rollers, rotating in opposite directions. The rollers may be flat, which will produce sheets of compacted material, or they may be dimpled, in which case, briquettes in the shape of the dimples will be formed. If sheets are produced, they are milled and screened to the required size. Roller compaction requires less lubricant to be added than slugging.

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