Pharmaceutical Granulation

Granules

Granules are prepared aggregates of powdered materials to form a larger particles (2-4 mm).

Advantages of Granules over powder:

⇨ More flow properties

⇨ Segregation avoided

⇨ more stable against humidity & atmosphere

⇨ Granules are more easily wetted by liquids

Granulation

Granulation is the process in which powder particles are made to adhere to form larger particles, called granules. Pharmaceutical granules typically have size range between 0.2 mm to 0.4 mm.

⇨ Granulation process transforms fine powder into free-flowing, dust-free granules that are easy to compression.

⇨ During granulation process small fine or coarse particles are converted into large agglomerates called granules.

⇨ Generally granulation commences after initial dry mixing of the necessary powders/ingredients along with  the active pharmaceutical ingredients so that a uniform distribution of each ingredient throughout the powder mixture is achieved.

Reason for granulation:

⇨ To prevent segregation

⇨ To improve flow properties

⇨ To acheive uniform size distribution of particles.

⇨ To improve compression characteristics

⇨ To increase the apparent density of the tablet

⇨ To reduce toxic dust

⇨ To reduce volume by reducing voids

⇨ Small amount of active ingredients can be dispersed

The most common reasons given to justifying granulating are:

1. To impart good flow properties to the material so that the tablet presses and encapsulators can be properly fed and a uniform tablet or capsule weight maintained.

2. To increase the apparent density of the powder

3. To change the particle size distribution so that the binding properties on compaction can be improved.

Particticle bonding mechanisms in Granulation (5 mechanisms):

1.) Adhesion and cohesion forces in the immobile liquid films between individual primary powder particles

2) Interfacial forces in mobile liquid films within the granules

3) The formation of solid bridge after solvent evaporation

4) Attraction forces between solid particles

5) Mechanical interlocking

Mechanism of Granule formation (Pan granulation stages):

1) Nucleation

2) Transition

3) Ball growth

Mechanisms of Ball growth production of granules:

1) Coalescence (The merging of two segments into one)

2) Breakage

3) Abrasion transfer

4) Layering (Ater mixing second batch of power)

Methods of Granules Preparation (Methods in Granulation techque)

1. Wet Granulation

2. Dry Granulation

3. Direct Compression

See Also: 4 Basic Granulation Properties

Wet granulation

Wet granulation is a process of dry mixing, wet mixing and particle size enlargement and is a process of particle attachment. In wet granulation the powder mixer is compressed with the use of heat and solvent.

Traditionally wet granulation has been carried out using sigma blade or heavy-duty planetary mixers. Wet granulations can also be prepared using tumble blenders equipped with high speed chopper blades.

High-shear mixers are often more effective in densifying powders, but require large amounts of energy and have limited load size.

Occasionally, nonaqueous solvents or solutions that are composed of water and water-miscible solvents are used to improve the granulating properties of a formulation or to disperse poorly soluble drugs.

⇨ Wet mix granulation is a process in which dry ingredients are mixed together with a liquid to form a slurry or a wet mixture.

⇨ In the wet mix granulation process, the ingredients are typically mixed in a blender or a mixer and then granulated using a machine such as a roll compactor or a wet granulator. The granulated material is then dried and may be coated or blended with other ingredients to produce the final product.

Reasons for wet granulation:

⇨ For reducimg or prevent segregation of powder

⇨ For improving free flowing properties of powder

⇨ For improving Compression characteristics of powder

⇨To increase the apparent density of the powder

Advantages of wet granulation:

⇨ Cost effectiveness

⇨ Stability improve

⇨ Faster dissolution

⇨ Less wear & tear of punches [Tear ⇨ বিচ্ছিন্ন করা/হওয়া]

⇨ Simplified validation (Validation & documentation requirements are reduced)

Limitations of Wet granulation:

⇨ Stability concern for moisture sensitive of thermo labile drugs.

⇨ It is time consuming process

⇨ It is expensive process

⇨ Materials become loss during various stages of processing

Steps of wet granulation of tablet

Requisition of raw material

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Weighing

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Dispensing

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Crushing of all ingredients

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Sieving of all ingredients

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Dry mixing in the Rapid mixer granulator

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Addition of binder solution (Spray onto fluidized powder bed)

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Wet mixing

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Co-milling

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Drying in Flyidized Bed Dryer (Granule creating)

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Dry milling/ Size reductiom

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Lubrication/Glidant added

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Compression of tablet

Reason for adding lubricants & glidants to the final blend not to blender:

⇨ To overcome agglomeration specially when magnesium stearate is added

Reason for granulatipn process done only in manufacturing steps not in development steps:

⇨ For Cost reduction

Reason for Blending:

⇨ to ensure good distribution

Problems of overloading of blender:

⇨ Retard the free flow of the granulation

⇨ Reduces the efficiencies of the blender

⇨ Overblending is associated with physical degradation of material properties.

Problems of too small loading of blender:

⇨ The powder slide rather than roll in the blender

⇨ Time increases for uniform mixing of powder

Equipments for wet granulation (Wet granulators):

⇨ Fluidized bed granulator

⇨ Heavy duty planetary mixer

⇨ High speed mixers/ High speed mixing granulator

⇨ Shear granulators

⇨ Spray drier

⇨ Spheronizer

⇨ Sigma blade

⇨ Tumble blender

Dry Granulation (Slugging)

In dry granulation process, the powder mixture is compressed without use of heat and solvent. This method is specially applicable to materials that cannot be prepared by wet granulation method due to their sensitivity to moisture or to the elevated temperature required for drying.

Examples:

⇨ Aspirin tablet

⇨ Montelucast tablet

Two Basic procedures of dry granulation process

1) Compaction of material by compression

2) Milling of the compact material to obtain a granules.

For which type of materials should be granules by using dry granulation process?

⇨ Moisture sensitive material

⇨ Heat sensitive material

What is the blending/Blend?

Advantages of dry granulation

⇨ For moisture sensitive material

⇨ For heat sensitive material

⇨ For improve disintegration properties

⇨ It eliminate the need for binder solution, heavy mixing equipment

⇨ Require less equpments and space

Steps of Dry granulation of tablet (6 steps)

Requisition of raw materials

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Weighing/ Dispensing

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Compression into slugs by slugging/ Roll compaction

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Milling & Screening of slugs

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Lubrication / Blending (Mixture of two or more things)

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Compression of tablet

Reason for Screening:

⇨ To ensure all ingredients are free of lumps and agglomeration. 

[Lumps⇨ Sticks together

Agglomeration = Act of collecting in a mass]

Types of Dry granulators:

1. Slugger

2. Roller compactor

Slugging (Dry granulation)

Slughing is the precompression process for the formation of extra large tablets (slugs).

A dry powder blend that cannot be directly compressed because of poor flow properties or poor compression properties may in some instances be processed using a slugging operation.

It is operates at pressures of about 15 tons, compared with a normal tablet press, which operates at pressures of 4 tons or less.

Usually extra-large tablet punches are used to form compressed slugs of the powdered material.

This procedure is slow because, the inherently poor compressibility of the powders requires slower press speeds to provide the extended compression dwell time under load needed to hold the compacted material together.

Granulation by dry compaction can also be achieved by passing powders between two rollers that compact the material at pressures of up to 10 tons per linear inch.

Dry granulation vs Wet Granulation

⇨ In dry granulation,  No solvent is used.

⇨ In wet granulation, Suitable solvent is used.

⇨ In dry granulation, No heat is used.

⇨ In wet granulation, heat is used.

⇨ For dry granulation, there is little chance of contamination.

⇨ For wet granulation, as water is used, contamination may be occured.

⇨ Production cost is less for dry granulation in compare with wet granulation.

⇨ Production cost is high for wet granulation in compare with dry granulation.

⇨ Dry granulation process is very simple.

⇨ Wet granulation is a complex process.

Direct compression

Direct compression process is done for those materials that possess free flowing as well as cohesive properties that enables them to be compressed directly in a tablet machine.

Direct compression process can avoid hydrolysis of water sensitive drugs.

Steps of direct compression:

Requisition of raw materials

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Weighing/dispensing

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Lubrication/ Blending (Dry blending)

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Compression of tablets

For Which types of materials should be compressed by direct compression process?

Processes that yield free-flowing granulatons without the aid of granulating solutions are desirable in that they do not require the time and energy necessary to volatilize the solvent used in conventional wet granulation procedures.

When exploring this option, a careful analysis  of particle characteristics that influence mixing and segregation, 

such as size, size distribution, shape and static charge should be evaluated.

Special attention during dry blending for direct compressible formulation:

⇨ Blender loading

⇨ Blending time

⇨ Optimum mixing speeds

⇨ Mixing time

⇨ Mixing action

Advantages of Direct Compression:

⇨ Low labour imparts (Impart = Deliver)

⇨ Few processing steps

⇨ Capping or splitting problem is reduced due to deacreation (Decreation⇨ Destruction)

Examples: NaCl, NaBr, KCl, NH4Cl etc.

Granulation techniques-Four types

1. High Shear mixer granulation

2. Fluid Bed Granulation

3. Extrusion and spheronization

4. Spray dryng granulation

Advantages of high shear mixture granulation

⇨ Highly cohesive material can be granulated.

⇨ Short processing time

⇨ Less amount of liquids are required

[Cohesive: Properties being stick together)

Fluidization

Fluidization is the operation by which fine solids are transfered into a fluid like state through contact with a gas.

Fluid bed granulation

Fluid bed granulation is a process by which granules are produced in single equipment by spraying a binder solution onto a fluidized powder bed.

Reason for Fluid bed granulation

⇨ For more fine granules

⇨ For geting free flowing granules

⇨ For homogenous granules

⇨ For high drying rate, so shorter drying time

⇨ For high output 

⇨ For more thermal efficiency

Critical Quality Attributes of Fluid Bed Granulation Process

⇨ Moisture Content

⇨ Particle size

Critical process parameters of Fluid Bed Granulation Process

⇨ Inlet air flow

⇨ Inlet air temperature

⇨ Spray rate

⇨ Atomising pressure

Extrusion & Spheronization

It is a multiple step process capable of making uniform sized spherical particles.

It is primarily used as a method to produce multi-particlulates for controlled release application.

Spray drying granulation (Transfer Liquid to dry powder)

It is a unique granulation technique that directly converts liquids into dry powder in a single step.

Dryer

Dryer is an equipment used for drying wet materials.

Types of dryers

1. Static bed dryer

2. Moving bed dryer

3. Fluidized bed dryer (System in which the solid particles are partially suspended in an upward moving gas stream)

4. Pneumatic dryer

5. Freeze dryer

6. Microwave drying

Types of Fluidized bed dryer

⇨ Vertical fluidized bed dryer

⇨ Horizontal fluidized bed dryer

Mechanism of Fluidized Bed Dryer

⇨ Hot air (hot gas) is passed at high pressure through a perforated bottom of the container containing granules to dried

⇨ The granules are lifted from the bottom of container. 

⇨ The granules are suspended in the stream of hot air. 

⇨ The hot air is surrounded every granules to completly dry them.

Advantage of Fluidized bed dryer

⇨ Reduction in drying time (usually less than 1 hour)

Drying

Drying is defined as the removal of liquid (moiature content) from  a material by the application of heat and accomplished by the transfer of a liquid from a surface into an unsaturated vapour phase.

Importance of drying/Reason of drying

⇨ For remove moisture content from material

⇨ For improve fluidity

⇨ For spherical shape, uniform size, free flowing and enhanced solubility

⇨ For avoid deterioration

⇨ For easily size reduction

⇨ For improve compression characteristics

⇨ For preparation of bulk drugs

⇨ For preservation drug products by avoiding deterioration.

Freeze drying

Freeze dryng is a conduction drying method that is operated under vacuum followed by heat transfer in the dryers

Mill

Mill is an equipment used to reduce the size of solids.

Solid particles present in semisolids and suspensions can be reduced by using mills.

Types of mills

⇨ Cutter mill

⇨ Hammer mill

⇨ Rolar mill

⇨ Revolving mill

⇨ Attrition mill

⇨ Fluid-energy mill

Reason for mill

⇨ For reduce particle size of solids

Problems of too large size particles

⇨ Unable to fill the die cavity uniformly during compression

⇨ Weight of tablet fluctuate considerably

⇨ Affect tablet content uniformity

Problems of too many fines:

⇨ Weight variation occurs because of flow problem

⇨ Tendency of capping increase

Problems of remaining porosity

⇨ Enhance the rate of liquid uptake by tablets.

⇨ Increase the rate of disintegration.