GRANULATION TECHNIQUES: AN OVERVIEW

www.wjpps.com Vol 8, Issue 5, 2019.

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Shahidulla et al. World Journal of Pharmacy and Pharmaceutical Sciences

GRANULATION TECHNIQUES: AN OVERVIEW

Shahidulla S. M.*1, Amtul Hafsa

2 and S. A. Azeez

Department of Pharmaceutics, Deccan School of Pharmacy, Hyderabad-01.

ABSTRACT

Granulation, the process of particle enlargement by agglomeration

technique, is one of the most significant unit operations in the

production of pharmaceutical dosage form, mostly tablets and

capsules. Granulation process transforms fine powders into free

flowing, dust free granules that are easy to compress. Granulation

process can be divided into two types: wet granulation that utilize a

liquid in the process and dry granulation that requires no liquid. The

type of process selection requires thorough knowledge of

physiochemical properties of a drug, excipients, required flow and

release properties. Among currently available technologies, spray

drying, roller compaction, high shear mixing, and fluid bed granulation are worth of note.

This study focus on the recent progress in the granulation techniques and technologies such

as pneumatic dry granulation, reverse wet granulation, steam granulation, moisture-activated

dry granulation, thermal adhesion granulation, freeze granulation, and foamed binder or foam

granulation.

KEYWORDS: Pneumatic dry granulation; reverse wet granulation; steam granulation;

moisture-activated dry granulation.

INTRODUCTION

Granulation, a technique of particle enlargement by agglomeration, is one of the most

significant unit operations in the production of pharmaceutical dosage forms, mostly tablets

and capsules. During the granulation process, small fine or coarse particles are converted into

large agglomerates called granules. Generally, granulation commences after initial dry

mixing of the necessary powder ingredients along with the active pharmaceutical ingredient

(API), so that a uniform distribution of each ingredient throughout the powder mixture is

achieved. Although granules used in the pharmaceutical industry have particle size in the

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.421

Volume 8, Issue 5, 525-546 Review Article ISSN 2278 – 4357

Article Received on

11 March 2019,

Revised on 01 April 2019,

Accepted on 22 April 2019,

DOI: 10.20959/wjpps20195-13774

*Corresponding Author

Shahidulla S. M.

Department of

Pharmaceutics, Deccan

School of Pharmacy,

Hyderabad-01.


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range of 0.2-4.0 mm, they are primarily produced as an intermediary with a size range of 0.2-

0.5 mm to be either packed as a dosage form or be mixed with other excipients before tablet

compaction or capsule filling.[1,2]

Granules are produced to enhance the uniformity of the API in the final product, to increase

the density of the blend so that it occupies less volume per unit weight for better storage and

shipment, to facilitate metering or volumetric dispensing, to reduce dust during granulation

process to reduce toxic exposure and process-related hazards, and to improve the appearance

of the product.[2]

Consequently, the ideal characteristics of granules include spherical shape

for improved flow, narrow particle size distribution for content uniformity and volumetric

dispensing, sufficient fines to fill void spaces between granules for better compaction and

compression characteristics, and adequate moisture and hardness to prevent breaking and dust

formation during process.

Granulation process has been widely used in the pharmaceutical industry for the preparation

of material for tabletting. Other process which involves the granule formation includes

microencapsulation,multi-particulate system for modified release mechanism and to

preparegranules to be used by patient directly.

Primarily granules are prepared to improve flow and compression characteristics of the blend

but there are many other reasons and sometimes multiple reasons for granulation such as-

Improving flow properties of the mix and hence the uniformity of the dose;

Increasing the bulk density of a product;

Facilitating metering or volumetric dispensing.

1.1 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.[3]

Particle size of the drug and excipients

Type of binder (strong or weak)

Volume of binder (less or more)

Wet massing time (less or more)


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Drying rate (Hydrate formation and polymorphism)

1.2 Granulation

Granulation was a particle design process that involves gathering of small particles into large

masses in which the original particles can still be identified. Granulation was done for

improving flow and compression characteristics, improving content uniformity, reducing

segregation, facilitating metering or volumetric dispensing, controlling/manipulating release

rate, eliminating generation of excessive amounts of fine particles thereby increasing bulk

density of the product, decreasing dust generation thereby reducing employee exposure to the

product, and resulting in improvement of yield and productivity, reduced down time, and so

on.[4,5]

1.3 Granulation Technology

GT comprises the art and science for process and production of granules. All over the world

granulation was done either by wet- granulation or by dry-granulation process. Technological

breakthrough in the area of GT, over a period of time, as an urge to improve commercial

output, had leaded to evolution of diverse newer and novel GT like moisture activated dry

granulation (MADG), thermal adhesion granulation (TAG), pneumatic dry granulation

(PDG), melt/thermoplastic granulation (MTG), fluidized bed granulation, freeze granulation

(FG), foam binder granulation (FBG), steam granulation (SG), and so on.[4,5,6,7]

1.4 Stages of Granulations[8,9,10]

a) Pendular stage (Powder + binding agent): This is initial stage just after addition of

binding agent.

b) Funicular stage (Powder+ more binding agent): This is second stage were adequate

binding solution incorporated between the particles.

c) Capillary stage (Powder + even more binding agent): In this stage binding solution is

entrapped by capillary action. This is a perfect stage were good granules can be obtained.

d) Droplet stage (Powder +even more and more binding agent): here over wetting,

particles may from. This stage is not desirable stage.


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Figure 1: Stages In Granulation.

1.5 Reasons For Granulations

There are two types of reasons for granulation.

1.5.1 Primary reasons for granulation:

To prevent segregation.

To improve flow properties of the mix.

To improve compaction characteristics of the mix.

1.5.1 Secondary reasons for granulation

Reduce the hazard associated with the generation of toxic dust which may arise when

handling powder.

Reduce hazards associated with the storage of powder that is slightly hygroscopic and

may adhere to form cake.

More convenient for storage and shipment as it is denser than powder and occupies less

volume per unit weight.

2) Classification of Granulation Technologies[11]

Based upon the type of processing, that have been involved, in the granulation technologies

can be classified as follows.

Conventional Methods

Dry granulation

Wet granulation

a) High-shearing wet granulation


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b) Low-shearing wet granulation

Advanced Methods

Moisture activated dry granulation

Thermal adhesion granulation

Pneumatic dry granulation

Melt/thermoplastic granulation

Fluidized bed granulation

Spray drying granulation

Freeze granulation

Foam binder granulation

Steam granulation

CONVENTIONAL METHODS

Dry Granulation

This method is cheapest method of granulation and suitable for hydro-sensitive products. In

this method granules are prepared without binding solution and heat. This method involves

two steps.one is preparing large particles called slugging. Second one is milling and

screening of slugs into small granules.[12]

Figure 1 : Schematic Diagram of Dry Granulation.


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Steps involve in Dry Granulation

1. Milling of drug and excipients

2. Mixing of milled granules

3. Compression into large, hard tablets to make slug

4. Mixing with lubricant and disintegrating agent.

Advantages

Less equipments are needed.

Eliminate binding solution process.

Useful for heat moisture, sensitive materials.

Improve tablets disintegration.

Disadvantages

Requires specialized heavy duty tablet press.

Does not permit uniform color distribution.

Tends to create more dust with respect to wet granulation.

Applications

Suitable for hydrophobic and oily substances.

This method is used when direct compression is not applicable.

Vitamins and effervescent tablets are examples of product prepared by dry granulation

Wet Granulation

This method involves several steps. Initially by addition of binding agent (hydrophilic or

hydrophobic) to get wet mass. This wet mass is passed through the sieves followed by

drying.Wet granulation is the most widely used process of granulation in the pharmaceutical

industry.[13]


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Figure 2: Schematic Diagram Of Wet Granulation

Merits

The cohesiveness and compressibility of the powders are improved.

Good distribution and uniform content

Demerits

Because of large number of processing steps, it requires a large area with temperature and

humidity.

It requires a number of pieces of expensive equipments also time consuming.

Conventional wet granulation involved low shear granulation, high shear granulation and

fluid bed granulation.

Steps involved in wet granulation:

1. Weighing and BlendingPreparing the Damp Mass

2. Screening the Damp Mass into Pellets or Granules

3. Drying the Granulation

4. Sizing the Granulation by Dry Screening

5. Adding Lubrication and Blending.


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NOVEL OR ADVANCED METHOD

Moisture activated dry granulation (madg)

MADG is also known as single port granulation or moist granulation. Here drying step is

eliminated because very less amount of binding agent is used to activate binding process and

moreover moisture absorbing agents like microcrystalline cellulose, potato starch, a mixture

of MCC and potato starch (50% w/w), silicone dioxide etc. used to remove moisture present

in granules.[14,15]

FIGURE 3: schematic diagram of moisture activated granulation.

Advantages

A simple clean, lean process that utilizes very little granulating fluid

Economical and time efficient

Produced granules with more uniform particle size range of 150-500 micrometer and

excellent flow property

Disadvantages

Unsuitable for thermo-labile, moisture sensitive, high moisture absorbing substances

Difficult to develop formulation with high drug loading.

Moisture sensitive and high moisture absorbing api are poor candidates.


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Applications

Suitable for eutectic and hydrophobic substances.

The application of madg to an immediate-release and controlled-release dosage forms.

Thermal Adhesion Granulation (Tag)

In this process the binder and diluent mixture is first wetted by pouring water or ethanol.

Then this blend is placed in the pre warmed glass bottle, sealed and then heated by an IR

lamp to rise surface temperature of the equipment to 90C– 105C for water as solvent,

70C– 90C for ethanol as a binding agent and mixed under tumble rotation for 3 – 20

minutes until granules are formed. Resultant granules were immediately shifted with proper

sieve 22.[16,17]

FIGURE 4: schematic diagram of thermal adhesion granulation.

Advantages

Reduces the dust generation during powder processing.

Requires less amount of granulation fluid.

Disadvantages

Not suitable for substances with more than 130 degrees melting point and for material

with binding solvents other than water and ethanol.

Application

Applicable in research and development system.


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Pneumatic dry granulation (pdg)

It involves production of compact mass by using roller compaction method with a little

compression force. This material is introduced into a newly innovative fractionating device

that separates the granules and recycles rejected fraction.[18,19]

Figure 5: Schematic Diagram of Pneumatic Dry Granulation.

Advantages

Faster development even with historically proven difficult materials.

Lower scale up cost and problems

Compatible with other technologies like coating, sustain release, fast release.

Excellent stability with enhanced shelf life

Suitable for thermolabile and moisture sensitive drugs

Taste masking and tailoring of release rate and time can be achieved.

Disadvantages

High cost due to novelty in process.

Due to usage of double compression force material used may undergo degradation.

Applications

Suitable for drug with high melting point.

Applied widely because of compliment with regulatory bodies.


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Melt Or Thermoplast Granulation

Melt Granulation is also known as “Thermoplastic Granulation” as the granulation is

achieved by adding a meltable binder which is in solid state at room temperature but

preferably melts inthe temperature range of 50 C – 80 C. No further addition of liquid

binder or water is required in the process.[20,21,22]

Figure 6: Schematic Diagram of Melt Granulation.

Advantages

Time and cost effective, as it eliminates the liquid addition and drying steps.

Water sensitive drugs are good candidates.

Disadvantages

Heat sensitive materials are poor candidates.

Requires special equipment for steam generation and transportation.

Requires high energy inputs.

Applications

Controlling or modifying the release of the drug.

Masking the bitter taste of an active drug.

FLUIDISED BED GRANULATION

It is an air suspension technique. Fluidized bed granulation process involves spraying of

binder solution onto the fluidized powder bed to get finer, free flowing and homogenous

granules employing single equipment known as fluidized powder bed (FPB).[20,21,22,23,24,25]


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Figure 7: Schematic Representation of Fluidized Bed Granulation.

Advantages

Reduces dust formation during processing.

Suitable for subsequent coating and control release products and reduces product loss.

Disadvantages

Cleaning was labor intensive, time consuming.

Requires high energy input.

Limited number of available polymer.

Applications

Applicable for granulation, Drying, coating, mixing etc.

Masking the bitter taste of an active drug.

Preparation of sustained release floating tablets.

Enhancing the tabletting compactability of poorly compactible high dose drugs.

Extrusion-Spheroinization Granulation

A multiple step process involving at least five-steps capable of making uniform sized

spherical particles with narrow size distribution that were suitable for controlled release

formulations by extruding the tacky mass through extruder and subsequent pellatization or

spheronization using pelletizer or spheronizer.[26]

This process is primarily used as a method

to produce multi-particulates for controlled release application. It is a multiple step process


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involving at least five steps.

Dry mixing of materials to achieve homogeneous dispersion.

Wet granulation of the resulted mixture to form wet mass.

Extrusion of wet mass to form rod shaped particles.

Rounding off (in spheronizer).

Drying.

FIGURE 8: Extrusion-Spheroinization Granulation process.

Advantages

Two or more active agents can be easily combined in any ratio in the same unit.

Physical characteristics of the active ingredients and excipients can be modified.

Particles having high bulk density, low hygroscopicity, high spherocity, dust free, narrow

particle size distribution and smoother surface can be produced.

Disadvantages

This process needs more labor and time for granulation.

Cannot be used for moisture sensitive and thermo-labile materials.

Applications

Used in preparation of granules for tablets, capsules, suspensions and for dry powders.

Spray dry granulation

It is a continuous process where a dry granular product is obtained by feeding a binding


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solution or suspension of active agent with or without excipients to the drying system where

the feed is atomized and dried with a heated with a gas stream followed by subsequent

separation of granular product from the gas stream. Alternately particles agglomeration was

brought about by spraying the binder solution onto the bed of powder particles in fluidized

state achieved with the passage of air followed by drying using hot air.[27,28]

The spray drying process involves three fundamental steps,

1. Atomization of a liquid feed into fine droplets.

2. Mixing of these sprays droplets with a heated gas stream, allowing the liquid to

evaporated and leave dried solids.

3. Separation of the dried powder from the gas stream.

FIGURE 9: schematic diagram of spray drying.

Advantages

Rapid and continuous process.

Reduces overall cost by avoiding labor intensive drying and granulation steps.

Suitable for heat sensitive product.

Disadvantages

Substances which are sensitive to heat are poor candidates.

Improper spray leads to inadequate sized particles.

Applications

Applicable in the preparation of dry syrups and dusting powders.


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Used for forming materials in industries like chemicals, food products and

pharmaceuticals.

Its main purpose is to convert light, small powders into high-density free-flowing

granulates.

Freeze Granulation

Freeze granulation involves spraying of suspension containing powder into liquid nitrogen

where the drops were instantaneously frozen to form granules which upon subsequent freeze-

drying yields dry granules.[29]

Figure 10: Schematic Diagram of freeze dry granulation.

Advantages

Granule density can be controlled by the solid contents of the suspension

Non-oxides and metals can be handled as mild drying prevents their serious oxidation

Equipments can be easily cleaned up

Organic solvents can be recycled.

Disadvantages

There may be a chance of degradation of drug due to use of temperature which is less

than 0C.

Applications

In the formation of injectable granules.

Used for drying of pharmaceuticals and drugs and for drying of biomaterials like


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proteins,enzymes and fine chemicals.

Foam binder granulation

This technology involves continuous addition of liquid binders in the form of aqueous foam

(having consistency of shaving cream generated with foam generator) either onto the

previously blended powder bed contained in RMG with variable speeds of impeller or

chopper, or in FPB contained in FBP. After attaining granulation end point the wet granules

were dried in FBP till desired moisture content was achieved.[30,31]

Figure 15: Schematic diagram of foam binder granulation.

Advantges

Eliminates use of spray nozzle thereby eliminates plugging effects

Binder distribution was uniform

No over wetting

Cost effective as reduces drying, manufacturing, and equipment clean-up time.

Disadvantages

The process is success full in scale-up but it is difficult for production scale.

High sensitive materials are poor candidates

Lower-melting point binder may melt/soften during handling and storage.

Applications

Suitable for products with very low concentration or drug level (in mg or μg per tablet) as

generated foam can carry active ingredients at a very low concentration


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Can handle historically proven difficult materials including natural ingredients used in

nutritional supplements.

Steam Granulation

This technology was a simple modification of conventional wet granulation method in which

steam was used as binder instead of water and involves injection of a jet of steam into the bed

of fluidized particles to be granulated.[32]

FIGURE 16: Schematic diagram of Steam granulation.

Advantages

Uniformly distributed in the powder particles.

Higher diffusion rate.

Time efficient

environment friendly

Maintain sterility

Disadvantages

Requires special equipment for steam generation and transportation.

Requires high energy inputs.

Thermolabile materials are poor candidates.

Applications

Applied in the formulation of sterile products.


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Applications/Benefits of Granulation Technologies

1. Granulation is often required to improve the flow of powder and mechanical properties of

tablets

2. Granules are usually obtained by adding liquids binder or solvent solutions

3. Larger quantities of granulating liquid produce a narrower particle size range and coarser

and harder granules; that is, the proportion of fine granulate particles decreases

4. The optimal quantity of liquid needed to get a given particle size should be known to keep

batch-to-batch variations to a minimum.

5. Wet granulation is used to improve flow, compressibility, bioavailability, homogeneity,

electrostatic properties and the stability of solid dosage forms

6. The particle size of a granulate is determined by the quantity and feeding rate of the

granulating liquid

7. Granulation involves smaller particles adhering to each other to produce larger particles

or agglomerates

8. Particle size is critical: too large or too small, the particles will not produce high density,

free-flowing granulates

9. There are many variables in controlling a granulator process, ranging from feed rate of

the granulator liquid to the resonance time of the granulator chamber, all of which affect

the particle size in different ways

10. With an online sensor, the particle size is measured instantaneously and continuously in

real-time helping to monitor and control the granulation process.

Application of Granulation Technologies in Various Industries

11. Granulation technology in the feed industry is 48 %

12. Granulation technology in the pharmaceutical industry is 32 %

13. Technology of granulation in the production of polymer and polypropylene is 7,2 %

14. Technology of granulation in the production of biofuel is 5,5 %

15. Granulation technology in the production of fertilizers is 2,2 %

16. Granulation technology in the food industry is 2,0 %

17. Technology of granulation in the chemical industry is 1,4 %

18. Granulation technology in the manufacture of metal wares is 1,2 %


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SUMMARY OF GRANULATIONS

Granulation is the process to form multi-particle agglomerates/granules consisting of

primary particles

Liquid bridges are the strongest adhesion forces (disregarding solid bonds)

Granulation prevents segregation, improves flow properties and compaction to produce

uniform mixtures and dust free formulations

Two main types: dry and wet granulation

Granulation is a technique of particle enlargement by agglomeration in the production of

tablets and capsules.

During the granulation process, small fine or coarse particles are converted into larger

agglomerates called granules.

Granules enhance the uniformity of the API, increase the density of the blend, facilitate

metering or volumetric dispensing, reduce dust, and improve the appearance of product.

The granules are formed by the following methods: solid bridges, sintering, chemical

reaction, crystallization, and deposition of colloidal particles.

Granules are formed from the powder particles by wetting and nucleation, coalescence or

growth, consolidation, and attrition or breakage.

Granulation technique is broadly classified into two types, dry granulation and wet

granulation, with wet granulation being the most widely used granulation technique.

Currently available granulation technologies include roller compaction for dry

granulation, and spray drying, supercritical fluid, low/high shear mixing, fluid bed

granulation, and extrusion/spheronization for wet granulation.

Recent progress includes pneumatic dry granulation technology for dry granulation, and

reverse wet granulation, steam granulation, moisture-activated dry granulation or moist

granulation, thermal adhesion granulation, melt granulation, freeze granulation, foamed

binder or foam granulation for wet granulation.

CONCLUSION AND FUTURE SCOPE

The advances in granulation technology lead to the formulation of better dosage forms in

terms of content uniformity and stability aspects. Still lot of research works and study has to

be done for the promotion of content uniformity, stability not only in tablets and capsules but

also in dry syrups and various other formulations in pharmaceutical industries.

Technical breakthrough in the granulation field will came with latest technology. Depth


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knowledge was essential to adopt proper granulation process to get targeted granulation and

final product parameters. While application of newer technique by the pharmaceutical and

other industries will be a function of their inherent conservatism and regulatory controls.

Pharmaceutical products are processed all over the world using the direct compressing, wet-

granulation, or dry granulation methods. Which method is chosen depends on the ingredients

individual characteristics and ability to properly flow, compresses, eject, and disintegrate.

Choosing a method requires thorough investigation of each ingredient in the formula, the

combination of ingredients, and how they work with each other. Then the proper granulation

process can be applied. A judicial selection of appropriate technology for carrying out the

granulation process is the key to achieve a targeted granulation and final product parameters.

In depth knowledge of the processing techniques and their merits and demerits is required to

adopt during development stage of product. A systematic approach should be followed for

selecting the suitable granulation process.

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Documents

GRANULATION TECHNIQUES: AN OVERVIEW