Friday, January 14, 2011

Tablet:Manufacturing methods/Granulation


Granulation may be defined as a size enlargement process which converts small particles into physically stronger & larger agglomerates.
Granulation method can be broadly classified into two types: Wet granulation and Dry granulation
Ideal characteristics of granules
The ideal characteristics of granules include 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
i) Particle size of the drug and excipients
ii) Type of binder (strong or weak)
iii) Volume of binder (less or more)
iv) Wet massing time ( less or more)
v) Amount of shear applied
vi) Drying rate ( Hydrate formation and polymorphism)

Wet granulation


The most widely used process of agglomeration in pharmaceutical industry is wet granulation. 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

i) Mixing of the drug(s) and excipients
ii) Preparation of binder solution
iii) Mixing of binder solution with powder mixture to form wet mass.
iv) Coarse screening of wet mass using a suitable sieve (6-12  screens).
v) Drying of moist granules.
vi) Screening of dry granules through a suitable sieve (14-20  screen).
vii) Mixing of screened granules with disintegrant, glidant, and lubricant.

Limitation of wet granulation

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

Special wet granulation techniques

i) High shear mixture granulation
ii) Fluid bed granulation
iii) Extrusion-spheronization
iv) Spray drying

High shear mixture granulation

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 shear and compaction force exerted by the impeller.
i) Short processing time
ii) Less amount of liquid binders required compared with fluid bed.
iii) Highly cohesive material can be granulated.

Fluid bed granulation

Fluidization is the operation by which fine solids are transformed into a fluid like state through contact with a gas. At 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 equipment by spraying a binder solution onto a fluidized powder bed. The material processed by fluid bed granulation are finer, free flowing and homogeneous.

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 application.
i) Ability to incorporate higher levels of active components without producing excessively larger particles.
ii) Applicable to both immediate and controlled release dosage form.

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 a dry powder.
i) Rapid process
ii) Ability to be operated continuously
iii) Suitable for heat sensitive product

Lists of equipments for wet granulation

High Shear granulation:
i)Little ford Lodgie granulator
ii)Little ford MGT granulator
iii)Diosna granulator
iv)Gral mixer

Granulator with drying facility:
i) Fluidized bed granulator
ii) Day nauta mixer processor
iii) Double cone or twin shell processor
iv) Topo granulator
Special granulator:
i) Roto granulator
ii) Marumerizer

Current topics related to wet granulation

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

Dry granulation


In 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 granules. 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 are 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 equipments 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:
i) For moisture sensitive material
ii) For heat sensitive material
iii) For improved disintegration since powder particles are not bonded together by a binder


i) It requires a specialized heavy duty tablet press to form slug
ii) It does not permit uniform colour distribution as can be
iii) Achieved with wet granulation where the dye can be incorporated into binder liquid.
iv) The process tends to create more dust than wet granulation, increasing the potential contamination.

Steps in dry granulation

i) Milling of drugs and excipients
ii) Mixing of milled powders
iii) Compression into large, hard tablets to make slug
iv) Screening of slugs
v) Mixing with lubricant and disintegrating agent
vi) Tablet compression

Two main dry granulation processes

Slugging process

Granulation by slugging is the process of compressing dry powder of tablet formulation with tablet press having die cavity large enough in diameter to fill quickly. The accuracy or condition of 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 appropriate granule size for final compression by screening and milling.

Factors which determine how well a material may slug
i) Compressibility or cohesiveness of the mater
ii) Compression ratio of powder
iii) Density of the powder
iv) Machine type
v) Punch and die size
vi) Slug thickness
vii) Speed of compression
viii) Pressure used to produce slug

Roller compaction

The compaction of powder by means of pressure roll can also be accomplished by a machine called chilsonator. Unlike tablet machine, 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.

Formulation for dry granulation

The excipients used for dry granulation are basically same as that of wet granulation or that 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 sulphate, Sta-Rx® etc.
Examples of some tablet formulation prepared by dry granulation

Advancement in Granulations

Steam Granulation

It is modification of wet granulation. Here steam is used as a binder instead of water. Its several benefits includes higher distribution uniformity, higher diffusion rate into powders, more favourable thermal balance during drying step, steam granules are more spherical, have large surface area hence increased dissolution rate of the drug from granules, processing time is shorter therefore more number of tablets are produced per batch, compared to the use of organic solvent water vapour 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 preparation of taste masked granules without modifying availability of the drug. But the limitation is that it is unsuitable for thermolabile drugs. Moreover special equipments are required and are unsuitable for binders that cannot be later activated by contact with water vapour.

Melt Granulation / Thermoplastic Granulation

Here granulation is achieved by the addition of meltable binder. That is binder is in 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 of drying phase since dried granules are obtained by cooling it to room temperature. Moreover, 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 has 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 granulating fluid is added to activate 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 traditional wet granulation method. It provides granules with good flow properties and binding capacity to form tablets of low friability, adequate hardness and have 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, 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


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  4. This is a great article. I love finding out about new stuff, and this sort of thing is important to everyday life, even though we may not know it. I wonder which way is best, wet or dry overall for pharmaceutical granulation?

  5. It's really very much helpful for my preparations...

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  9. Thanks so much for a really concise and wide coverage of granulation. The importance of granulation has been well understood for years and generally the amount of liquid binder added is considered to be one of the most important parameters. There is a iso a lot of discussion about the effect of the mixing regime to influence the final granulation properties but in reality it seems that for many practical applications the difficulties of reaching the right end point is both difficult to study and sometimes does not receive the attention that is deserves in practise. A couple of examples where this has caused problems and where these problems can be resolved can be see here and here

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