Tablet Manufacturing Method - Granulation

Granulation may be defined as a size enlargement process that converts small particles into physically stronger & larger agglomerates.
The granulation method can be broadly classified into two types: 
  1. Wet granulation
  2. Dry granulation

Ideal characteristics of granules
  • The ideal characteristics of granules include a spherical shape, smaller particle size distribution with sufficient fines to fill void spaces between granules, adequate moisture (between 1-2%), good flow, good compressibility, and sufficient hardness.
  • The effectiveness of granulation depends on the following properties
  1. The particle size of the drug and excipients
  2. Type of binder (strong or weak)
  3. The volume of binder (less or more)
  4. Wet massing time ( less or more)
  5. Amount of shear applied
  6. Drying rate ( Hydrate formation and polymorphism).

1. Wet granulation
  • The most widely used process of agglomeration in the pharmaceutical industry is wet granulation.
  • The wet granulation process simply involves wet massing of the powder blend with a granulating liquid, wet sizing, and drying.
  • Important steps involved in the wet granulation
  1. Mixing of the drug(s) and excipients
  2. Preparation of binder solution
  3. Mixing of binder solution with powder mixture to form a wet mass. Coarse screening of wet mass using a suitable sieve (6-12)
  4. Drying of moist granules. Screening of dry granules through a suitable sieve (14-20)
  5. Mixing of screened granules with disintegrant, glidant, and lubricant.

Limitation of wet granulation
  • The greatest disadvantage of wet granulation is its cost. It is an expensive process because of labor, time, equipment, energy, and space requirements.
  • Loss of material during various stages of processing
  • Stability may be a major concern for moisture-sensitive or thermo-labile drugs
  • Multiple processing steps add complexity and make the validation and control difficult
  • An inherent limitation of wet granulation is that any incompatibility between formulation components is aggravated.

Special wet granulation techniques
  1. High-shear mixture granulation
  2. Fluid bed granulation
  3. Extrusion-spheronization
  4. Spray drying

1. High-shear mixture granulation
  • The high-shear mixture has been widely used in Pharmaceutical industries for blending and granulation. Blending and wet massing is accompanied by high mechanical agitation by an impeller and a chopper. Mixing, densification, and agglomeration are achieved through the shear and compaction force exerted by the impeller.
  • Short processing time
  • Less amount of liquid binders are required compared with a fluid bed.
  • Highly cohesive material can be granulated.

2. Fluid bed granulation
  • Fluidization is the operation by which fine solids are transformed into a fluid-like state through contact with a gas. At a certain gas velocity, the fluid will support the particles giving them free mobility without entrapment.
  • Fluid bed granulation is a process by which granules are produced in a single piece of equipment by spraying a binder solution onto a fluidized powder bed. The material processed by the fluid bed granulation is finer, free-flowing, and homogeneous.

3. Extrusion and Spheronization
  • It is a multiple-step process capable of making uniform-sized spherical particles. It is primarily used as a method to produce multi-particulates for controlled-release applications.
  • Ability to incorporate higher levels of active components without producing excessively larger particles.
  • Applicable to both immediate and controlled-release dosage forms.

4. Spray drying granulation
  • It is a unique granulation technique that directly converts liquids into dry powder in a single step.
  • This method removes moisture instantly and converts pumpable liquids into dry powder.
  • Rapid process
  • Ability to be operated continuously
  • Suitable for heat sensitive product

Lists of equipment for wet granulation

High Shear granulation:
  1. Little ford Lodgie granulator
  2. Little ford MGT granulator
  3. Diosna granulator
  4. Gral mixer

Granulator with drying facility:
  1. Fluidized bed granulator
  2. Day Nauta mixer processor
  3. Double cone or twin shell processor
  4. Topo granulator

Special granulator:
  1. Roto granulator
  2. Marumerizer

Current topics related to wet granulation

Hydrate Formation
  • For example, theophylline anhydrous during high shear wet granulation transfers to theophylline monohydrate. The midpoint conversion occurs in three minutes after the binder solution is added.
  • For online monitoring of the transformation from one form to another, Raman spectroscopy is most widely used.

Polymorphic Transformation
  • The drying phase of wet granulation plays a vital role in the conversion of one form to another.
  • For example, glycine exists in three polymorphs that are α β γ. 
  • γ is the most stable form and α is the metastable form. The stable Glycine polymorph (γ) converts to metastable form (α) when wet granulated with microcrystalline cellulose.

2. Dry Granulation
  • In the dry granulation process, the powder mixture is compressed without the use of heat and solvent.
  • It is the least desirable of all methods of granulation. The two basic procedures are to form a compact of material by compression and then to mill the compact to obtain a granule. 
  • Two methods are used for dry granulation. The more widely used method is slugging, where the powder is precompressed and the resulting tablet or slug is milled to yield the granules. The other method is to precompress the powder with pressure rolls using a machine such as Chilosonator.

The main advantages of dry granulation or slugging are that it uses less equipment and space. It eliminates the need for binder solution, heavy mixing equipment, and the costly and time-consuming drying step required for wet granulation. Slugging can be used for advantages in the
following situations:
  1. For moisture-sensitive material
  2. For heat-sensitive material
  3. For improved disintegration since powder particles are not bonded together by a binder.

  1. It requires a specialized heavy-duty tablet press to form a slug
  2. It does not permit uniform color distribution as can be
  3. Achieved with wet granulation where the dye can be incorporated into binder liquid.
  4. The process tends to create more dust than wet granulation, increasing the potential contamination.

Steps in dry granulation
  1. Milling of drugs and excipients
  2. Mixing of milled powders
  3. Compression into large, hard tablets to make slug
  4. Screening of slugs
  5. Mixing with lubricant and disintegrating agent
  6. Tablet compression

Two main dry granulation processes

Slugging Process
Granulation by slugging is the process of compressing dry powder of tablet formulation with a tablet press having a die cavity large enough in diameter to fill quickly. The accuracy or condition of a slug is not too important. Only sufficient pressure to compact the powder into uniform slugs should be used. Once slugs are produced they are reduced to the appropriate granule size for final compression by screening and milling.

  1. Factors that determine how well a material may slug
  2. Compressibility or cohesiveness of the mater
  3. A compression ratio of powder
  4. The density of the powder
  5. Machine type
  6. Punch and die size
  7. Slug thickness
  8. Speed of compression
  9. The pressure used to produce slug

Roller Compaction
The compaction of powder by means of pressure roll can also be accomplished by a machine called a chilsonator. Unlike tablet machines, the chilsonator turns out a compacted mass in a steady continuous flow. The powder is fed down between the rollers from the hopper which contains a spiral auger to feed the powder into the compaction zone. Like slugs, the aggregates are screened or milled for production into granules.

The formulation for dry granulation
The excipients used for dry granulation are basically the same as that of wet granulation or of direct compression. With dry granulation, it is often possible to compact the active ingredient with a minor addition of lubricant and disintegrating agent. Fillers that are used in dry granulation include the following examples: Lactose, dextrose, sucrose, MCC, calcium sulfate, Sta-Rx®, etc.

Advancement in Granulations
Steam Granulation
It is the modification of wet granulation. Here steam is used as a binder instead of water. It is several benefits include higher distribution uniformity, higher diffusion rate into powders, more favorable thermal balance during the drying step, steam granules are more spherical, have a large surface area hence increasing the dissolution rate of the drug from granules, the processing time is shorter, therefore, more number of tablets are produced per batch, compared to the use of organic solvent water vapor is environmentally friendly, no health hazards to operators, no restriction by ICH on traces left in the granules, freshly distilled steam is sterile and therefore the total count can be kept under control, lowers dissolution rate so can be used for the preparation of taste masked granules without modifying the availability of the drug. But the limitation is that it is unsuitable for thermolabile drugs. Moreover, special equipment is required and is unsuitable for binders that cannot be later activated by contact with water vapor.

Melt Granulation / Thermoplastic Granulation
Here granulation is achieved by the addition of a meltable binder. That is binder is in a solid state at room temperature but melts in the temperature range of 50 – 80˚C. Melted binder then acts like a binding liquid. There is no need for a drying phase since dried granules are obtained by cooling them to room temperature. 

Moreover, the amount of liquid binder can be controlled precisely and the production and equipment costs are reduced. It is useful for granulating water-sensitive material and producing SR granulation or solid dispersion. But this method is not suitable for thermolabile substances. When water-soluble binders are needed, Polyethylene Glycol (PEG) is used as melting binders. When water-insoluble binders are needed, Stearic acid, cetyl or stearyl alcohol, various waxes, and mono-, di-, & triglycerides are used as melting binders.

Moisture Activated Dry Granulation (MADG)
It involves moisture distribution and agglomeration. Tablets prepared using MADG method have better content uniformity. This method utilizes very little granulating fluid. It decreases drying time and produces granules with excellent flowability.

Moist Granulation Technique (MGT)
A small amount of granulating fluid is added to activate the dry binder and to facilitate agglomeration. Then a moisture-absorbing material like Microcrystalline Cellulose (MCC) is added to absorb any excess moisture. By adding MCC in this way drying step is not necessary. It is applicable for developing a controlled-release formulation.

Thermal Adhesion Granulation Process (TAGP)
It is applicable for preparing direct tableting formulations. TAGP is performed under low moisture content or low content of pharmaceutically acceptable solvent by subjecting a mixture containing excipients to heating at a temperature in the range from about 30ºC to about 130ºC in a closed system under mixing by tumble rotation until the formation of granules. 

This method utilizes less water or solvent than the traditional wet granulation method. It provides granules with good flow properties and binding capacity to form tablets of low friability, and adequate hardness and has a high uptake capacity for active substances whose tableting is poor.

Foam Granulation
Here liquid binders are added as aqueous foam. It has several benefits over spray(wet) granulation such as it requires less binder than Spray Granulation, requires less water to wet granulate, the rate of addition of foam is greater than rate of addition of sprayed liquids, no detrimental effects on granulate, tablet, or invitro drug dissolution properties, no plugging problems since use of spray nozzles is eliminated, no overwetting, useful for granulating water sensitive formulations, reduces drying time, uniform distribution of binder throughout the powder bed, reduce manufacturing time, less binder required for Immediate Release (IR) and Controlled Release (CR) formulations.

Key Phrases
  • In the wet granulation process, a granulating liquid is used to facilitate the agglomeration process. Wet granulation has been and continues to be the most widely used agglomeration process. Typically wet massing of pharmaceutical powder is carried out in the high shear mixture before wet screening and dried in fluidized bed equipment.
  • In the dry granulation process, granulation takes place without utilizing liquid. In this process, dry powder particles may be brought together mechanically by compression into a slug or by rolled compaction.
  • Steam Granulation, Melt Granulation, MADG, MGT, TAGP, and Foam Granulation are some of the new advancements in granulation and show better quality granule formation as compared to conventional granulation methods.

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