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 three types: Wet granulation, Dry granulation, and Dry Granulation incorporating bound moisture (see MADG and MGT below). Ideal characteristics of granules The ideal characteristics of granules include uniformity, good flow, and compactibility. These are usually accomplished through creation of increased density, spherical shape, narrow particle size distribution with sufficient fines to fill void spaces between granules, adequate moisture (between 1-2%), and incorporation of binder, if necessary. 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 to distribute drug, binder and moisture. 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. screens).iv) Coarse screening of wet mass using a suitable sieve (6-12 v) Drying of moist granules. screen).vi) Screening of dry granules through a suitable sieve (14-20 vii) Mixing of screened granules with disintegrant, glidant, and lubricant.

Extrusion and Spheronization It is a multiple step process capable of making uniform sized spherical particles. free flowing and homogeneous. It is an expensive process because of labor. The material processed by fluid bed granulation are finer. Advantages: i) Short processing time ii) Less amount of liquid binders required compared with fluid bed. 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. equipment. 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. time. densification and agglomeration are achieved through shear and compaction force exerted by the impeller. Mixing. . 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. Blending and wet massing is accompanied by high mechanical agitation by an impeller and a chopper. 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. iii) Highly cohesive material can be granulated.Limitation of wet granulation i)The greatest disadvantage of wet granulation is its cost. It is primarily used as a method to produce multi-particulates for controlled release application. energy and space requirements.

Hydrate formation For example. The midpoint conversion occurs in three minutes after the binder solution is added. This method removes moisture instantly and converts pumpable liquids into a dry powder. . Advantages: 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. 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. theophylline anhydrous during high shear wet granulation transfers to theophylline monohydrate.Advantages: i) Ability to incorporate higher levels of active components without producing excessively larger particles.

is the most stable form and is the metastable form. It eliminates the need for binder solution. For example. The stable Glycine polymorph ( ) converts to metastable form ( ) when wet granulated with microcrystalline cellulose. . where the powder is precompressed and the resulting tablet or slug are milled to yield the granules. It is the least desirable of all methods of granulation.For online monitoring of the transformation from one form to another. The other method is to precompress the powder with pressure rolls using a machine such as Chilosonator. Advantages The main advantages of dry granulation or slugging are that it uses less equipments and space. Raman spectroscopy is most widely used. glycine which exist in three polymorphs that is . 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 Disadvantages 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. increasing the potential contamination. The two basic procedures are to form a compact of material by compression and then to mill the compact to obtain a granules. The more widely used method is slugging.Polymorphic transformation The drying phase of wet granulation plays a vital role for conversion of one form to another. Two methods are used for dry granulation. Dry granulation Introduction In dry granulation process the powder mixture is compressed without the use of heat and solvent. heavy mixing equipment and the costly and time consuming drying step required for wet granulation. II. iv) The process tends to create more dust than wet granulation.

Formulation for dry granulation The excipients used for dry granulation are basically same as that of wet granulation or that of direct compression. 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. With dry granulation it is often possible to compact the active ingredient with a minor addition of lubricant and disintegrating agent. Like slugs. Unlike tablet machine. 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. Only sufficient pressure to compact the powder into uniform slugs should be used. The powder is fed down between the rollers from the hopper which contains a spiral auger to feed the powder into the compaction zone. The accuracy or condition of slug is not too important. Once slugs are produced they are reduced to appropriate granule size for final compression by screening and milling. Fillers . the aggregates are screened or milled for production into granules.Steps in dry granulation i) Milling of drugs and excipients ii) Mixing of milled powders iii) Compression into large. the chilsonator turns out a compacted mass in a steady continuous flow.

. no restriction by ICH on traces left in the granules. MCC. Its several benefits includes higher distribution uniformity. Melt Granulation / Thermoplastic Granulation Here granulation is achieved by the addition of meltable binder. no health hazards to operators. Moreover special equipments are required and are unsuitable for binders that cannot be later activated by contact with water vapour. Sta-Rx® etc. higher diffusion rate into powders. processing time is shorter therefore more number of tablets are produced per batch. dextrose. Examples of some tablet formulation prepared by dry granulation Advancement in Granulations Steam Granulation It is modification of wet granulation. But the limitation is that it is unsuitable for thermolabile drugs. compared to the use of organic solvent water vapour is environmentally friendly. lowers dissolution rate so can be used for preparation of taste masked granules without modifying availability of the drug. steam granules are more spherical. That is binder is in solid state at room temperature but melts in the temperature range of 50 ± 80ÛC.that are used in dry granulation include the following examples: Lactose. calcium sulphate. freshly distilled steam is sterile and therefore the total count can be kept under control. more favourable thermal balance during drying step. Here steam is used as a binder instead of water. have large surface area hence increased dissolution rate of the drug from granules. sucrose.

This method utilizes very little granulating fluid and requires no drying. and is applicable to controlled release. Moist Granulation Technique (MGT) Same principle as Moisture Activated Dry Granulation (MADG) devleoped earlier. Stearic acid. no overwetting. less binder required for Immediate Release (IR) and Controlled Release (CR) formulations. When water soluble binders are needed. useful for granulating water sensitive formulations. It produces granules with excellent flowability and uniformity. Tablets prepared using MADG method have better content uniformity than direct compression. reduce manufacturing time. Foam Granulation Here liquid binders are added as aqueous foam. Polyethylene Glycol (PEG) is used as melting binders. Water distribution is via high shear mixer. There is no need of drying phase since dried granules are obtained by cooling it to room temperature. It is applicable for developing a controlled release formulation. reduces drying time. rate of addition of foam is greater than rate of addition of sprayed liquids. When water insoluble binders are needed. di-. cetyl or stearyl alcohol. or invitro drug dissolution properties. It is useful for granulating water sensitive material and producing SR granulation or solid dispersion. No drying step is required. no plugging problems since use of spray nozzles is eliminated.Melted binder then acts like a binding liquid. no detrimental effects on granulate. Moisture Activated Dry Granulation (MADG) It involves minimal moisture addition. . 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. distribution and agglomeration. Moreover. This method utilizes less water or solvent than traditional wet granulation method. amount of liquid binder can be controlled precisely and the production and equipment costs are reduced. requires less water to wet granulate. since any excess moisture is absorbed by hydrophilic polymers such as cellulose or silica added to the moist pre-blend. But this method is not suitable for thermolabile substances. or low-shear mixer with highly atomized water spray. uniform distribution of binder throughout the powder bed. tablet. It provides granules with good flow properties and binding capacity to form tablets of low friability. various waxes and mono-. 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. & triglycerides are used as melting binders. It has several benefits over spray(wet) granulation such as it requires less binder than Spray Granulation. adequate hardness and have a high uptake capacity for active substances whose tableting is poor. Thermal Adhesion Granulation Process (TAGP) It is applicable for preparing direct tableting formulations. By adding MCC in this way drying step is not necessary.

y y . Foam Granulation are some of the new advancements in granulation and show better quality granule formation as compared to conventional granulation methods. 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 slug or by rolled compaction.Key Phrases y In wet granulation process a granulating liquid is used to facilitate the 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. MADG. TAGP. Steam Granulation. Melt Granulation. MGT. Wet granulation has been and continues to be the most widely used agglomeration process.

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