GRANULATION Presented By:

Mr. Santosh A. Payghan (Asst. Professor)

Tatyasaheb Kore college of Pharmacy,

Warananagar.

GRANULATION
Definition: Process in which powder particles are made to adhere to form larger particles called granules. Potential Benefits of Granulation The Effectiveness of Granulation Depends On:
An improvement in and excipients Particle size of the drugpowder flow An increase in bulk density Type of binder (strong or weak) A more uniform particle size Volume of binder (less or more)

A reduction in ( less face adherence Wet massing time punchor more)

A reduction in capping tendencies Amount of shear applied to distribute drug, binder and moisture. An rate (Hydrate in operator safety Drying improvement formation and polymorphism)

REASONS FOR GRANULATION:

1. To prevent segregation of constituents in powder mix.
1. Smaller particles concentrate at the base with larger particles above. 2. Segregation may result in weight variation.

Segregation

2.To improve flow properties of mixture. 3.To improve compression characteristics of the mixture. Some powders are difficult to compress but their granules are easily compressed. 4.Other reasons
1. Granulation of toxic materials to reduce toxic dust. 2. Hygroscopic powders form cake. 3. Granules are denser than parent powder hence occupy less volume per unit area.

METHODS OF GRANULATION
1. Dry granulation
Dry granulation Direct compression Milling and mixing of drugs and excipients Compression of tablet Compression granulation Milling and mixing of drugs and excipients Compression into slugs or roll compaction Milling and screening of slugs and compacted powder Mixing with lubricant and disintegrant Compression of tablet Milling and mixing of drugs and excipients Preparation of binder solution Wet massing by addition of binder solution or granulating solvent Screening and drying of wet mass Screening of dry granules Blending with lubricant and disintegrant Compression of Tablet

2. Wet granulation
Wet granulation

1. Dry granulation
Advantages of dry granulation: well a material may slug Factors which determine how 1. Requires less equipments and space. mater 1. dry granulation process the powder mixture is compressed without the In Compressibility or cohesiveness of the 2. It eliminates the need for binder solution, heavy mixing equipment and use of heat 2. the costlyand ratio of powder dryingprocedures are towet granulation. Compression solvent. The two basic step required for form a compact and time consuming of Density ofby compression and then to mill the compact to obtain a material the powder 3. For moisture sensitive material 3. granules. 4. For heat sensitive material Machine type 5. For improved disintegration since powder particles are not bonded Slugging: 5. Punch and die size together powder is Where the by a binderprecompressed and the resulting tablet or slug are 6. Slug thickness milled to yield the granules. Disadvantages of dry granulation: 7. Speed of compression 1. It requires a specialized heavy duty tablet press to form slug Roller compaction: 8. Pressure used to produce slug 2. It does not permit uniform colour distribution as can be The other method is granulation where powder with incorporated into 3. Achieved with wetto precompress thethe dye can bepressure rolls using a machineliquid.as Chilosonator. binder such 4. The process tends to create more dust than wet granulation, increasing the potential contamination.

2. Wet granulation
The process simply involves wet massing of the powder blend with a granulating liquid, wet sizing and drying.
Important of wet granulation wet granulation Limitation steps involved in the Mixing of the drug(s) and excipientsof labor, time, equipment, energy It is an expensive process because Preparation of binder solution and space requirements. Mixing of binder solution with powder mixture to form wet mass. Loss of material during various stages of processing Coarse screening of wet mass using a suitable sievelabile drugs stability concern for moisture sensitive or thermo (6-12 screens) Drying of moist granules. add complexity and make validation and Multiple processing steps Screening of dry granules through a suitable sieve (14-20 screen) control difficult Mixing of screened granules with disintegrant, glidant, and lubricant. Any incompatibility between formulation components is aggravated.

GRANULATION MECHANISMS
Particle Bonding Mechanisms: Five primary bonding mechanisms 1. Adhesion and cohesion forces in the immobile liquid films 2. Interfacial forces in mobile liquid films within the granules 3. The formation of solid bridges after solvent evaporation 4. Attractive forces between solid particles 5. Mechanical interlocking

1. Adhesion and cohesion forces in immobile liquid films:

In case of wet granulation sufficient liquid is present in a powder to form a very thin, immobile layer, there will be an effective decrease in interparticulate distance and an increase in contact area between the particles But immobile film forms residual liquid after drying and bond strength decreases. In dry granulation pressures used will increase the contact area between the adsorption layers and decrease the interparticulate distance, and this will contribute to the final granule strength.

2. Interfacial forces in mobile liquid films

Liquid added to powder mix will be distributed as films around and between the particles Three states of water distribution 1. Pendular 2. Funicular 3. Capillary 4. Additional droplet state

Droplet Capillary Funicular Pendular

3. Solid bridges:
It can be Formed by: 1. Partial melting 2. Hardening binders 3. Crystallization of dissolved substances

2. Hardening binders: 1. Partial melting:

Pressures used in dry granulation methods may cause 3. Crystallization of dissolved substances melting of low melting-point materials. Solvent used to mass the powder during wet granulation may
partially dissolve one of the powdered ingredients.

When the pressure is relieved, crystallization will take When the granules the dried, crystallization of this material will place and bind are particles together.
take place and the dissolved substance then acts as a hardening binder e.g: Lactose incorporated in dry powder.

ATTRACTIVE FORCES BETWEEN SOLID PARTICLES:

1. Electrostatic forces Important in causing initial formation of agglomerates during mixing Do not contribute significantly to the final strength of the granule 2. Van der Waals forces Four times greater than electrostatic forces Contribute significantly to the strength of granules produced by dry granulation

MECHANISMS OF GRANULE FORMATION:

Generalized process for granule formation: 1.Nucleation 2.Transition 3.Ball growth Ball growth: Nucleation: Transition: Characterized 1. Coalescence the presence of a large number of Liquid bridges by small granules 2. Breakage with a fairly wide size distribution. 3. number of particles will join to form the pendular A Abrasion transfer state further agitation densifies the pendular bodies 4. form the capillary state, and these bodies act as to Layering nuclei for further granule growth.

GRANULATION EQUIPMENTS:

1.

Wet granulators: Shear granulators High speed mixers/granulators Fluidized bed granulators Spray driers Spheronizers Dry granulators Sluggers Roller compactors

2.

SPECIAL WET GRANULATION TECHNIQUES

High Shear Mixture Granulation
It has been widely used for blending and granulation, which can be accompanied by high mechanical agitation by an impeller and a chopper. Mixing, densification & agglomeration are achieved through shear and compaction force exerted by the impeller. Advantages: 1. Short processing time 2. Less amount of liquid binders required compared with fluid bed. 3. Highly cohesive material can be granulated.

Powder SS mixing bowl

+
granulatin g fluid

Granulating liquid & Powder

Planetary Mixer

SPECIAL WET GRANULATION TECHNIQUES

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.
Air

Pow der Bed

SPECIAL WET GRANULATION TECHNIQUES

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. Advantages: 1. Ability to incorporate higher levels of active components without producing excessively larger particles. 2. Applicable to both immediate and controlled release dosage form.

SPECIAL WET GRANULATION TECHNIQUES

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. Advantages: 1. Rapid process. 2. Ability to be operated continuously. 3. Suitable for heat sensitive product.

ADVANCEMENT IN WET GRANULATION

Equipments for wet granulation 1. High Shear granulation 2. Little ford Lodgie granulator 3. Little ford MGT granulator 4. Diosna granulator 5. Gral mixeri Special granulator: 1. Roto granulator 2. Marumerizer Granulator with drying facility: 1. Fluidized bed granulator 2. Day nauta mixer processor 3. Double cone or twin shell processor 4. Topo granulator

CURRENT TOPICS RELATED TO WET GRANULATION

I. Hydrate formation The midpoint conversion occurs in three minutes after the binder solution is added. For example, theophylline anhydrous during high shear wet granulation transfers to theophylline monohydrate. 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 , , . is the

most stable form and is the metastable form. The stable Glycine polymorph
() converts to metastable form () when wet granulated with microcrystalline cellulose.

DRY GRANULATORS
Two piece of equipment are necessary First, a machine for compressing the dry powders into compacts or flakes, and

Secondly a mill for breaking up these intermediate products into granules. Sluggers: Tablet machine Heavy duty rotary Roller compactors

ADVANCEMENT IN GRANULATIONS
1. 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.

2. 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 80C. 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.

3. Moisture Activated Dry Granulation (MADG) It involves minimal moisture addition, distribution and agglomeration. No drying step is required. Water distribution is via high shear mixer, or low-shear mixer with highly atomized water

spray. Tablets prepared using MADG method have better content

uniformity than direct compression. This method utilizes very little granulating fluid and requires no drying, since any excess moisture is absorbed by hydrophilic polymers such as cellulose or silica added

to the moist pre-blend. It produces granules with excellent

flowability and uniformity, and is applicable to controlled release.

4. Moist Granulation Technique (MGT)

Same principle as Moisture Activated Dry Granulation (MADG) developed earlier. 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.

5. 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 30C to about 130C 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.

6. 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.

Collette Gralbed granulator Fluidized granulator

Freund granulator

Planatory mixer

Indian Manufactured Instruments

Rapid mixer granulator (CHITRA)

Rapid mixer granulator (SAMS)

Innovations

Ultima

Vertical gral