INTRODUCTION:

Granulation is a process of forming grains or granules from a powdery or solid substance producing a granular material. It is applied in several technological processes in the chemical and pharmaceutical industries. Granulation involves agglomeration of fine particles into large granules, typically of size range between 0.2 and 0.4mm depending upon their requirement.

The conversion of powder into granules avoids powder segregation, enhances the flow properties of powders, produces uniform mixtures, produces dust free formulations and improves compaction characteristics of mix.[1]

Ideal characteristics of granulation:

The effectiveness of granulation depends on the following properties:

· Particle size of the drug and excipients

· Type of Binder (strong or weak)

· Volume of Binder (less or more)

· Time for wet mass preparation (Hydrate and polymorphism)

· Amount of shear applied

Granulation Techniques:

Conventional Methods:

1. Dry granulation

2. Wet granulation

· High- shearing wet granulation

· Low – shearing wet granulation

Novel or Advanced Methods:

· Moisture activated dry granulation

· Thermal adhesion granulation

· Pneumatic dry granulation

· Melt or Thermoplastic granulation

· Fluidized bed granulation

· Extrusion-Spheroinization

· Spray dry granulation

· Freeze granulation

· Foam-binder granulation

· Steam granulation

DRY GRANULATION:

Dry granulation is a process whereby granules are formed without the aid of any liquid solution. The process is used if the ingredients to be granulated are sensitive to moisture or heat. Compaction is used to densify the powder and form granules. The process is carried out using a slugging tool, roller compactor or a tablet press machine. [2]

Advantages:

· Requires less equipments and space.

· Eliminates need of binder solution.

Disadvantages:

· No uniform color distribution.

· Process creates more dust.

WET GRANULATION:

Wet granulation method is a process in which fine powder particles are agglomerated or brought together into larger, strong and relatively permanent structure called granules using a suitable non-toxic granulating fluid such as water, isopropanol or ethanol. The granulating fluid can be used alone or as a solvent containing binder or granulating agent. [3]

High-shearing wet granulation:

High shear wet granulation (HSWG) can be broadly considered to be interplay of three rate limiting processes:

1. Wetting of particles to create nuclei

2. Consolidation and coalescence of these nuclei to give growth and agglomeration, and

3. Breakage of these nuclei under high shear because of attrition.

Low-shearing wet granulation:

Low shear wet granulation, is an important unit operation in the pharmaceutical, detergent and food industries. This granulation mechanism of wet granulation includes wetting, nucleation, consolidation, growth, attrition and breakage.

Advantages of wet granulation:

High-speed mixer-granulators, fluidized bed granulators and an ever increasing use of automation have served to make wet granulation a much more efficient and economic process than it was.

Disadvantages of wet granulation:

Problems include choice and method of addition of the binder and the effect of drying time and temperature on drug stability and its distribution within the solid mass. [4]

NOVEL OR ADVANCED METHODS:

MOISTURE ACTIVATED DRY GRANULATION:

Moisture Activated Dry Granulation (MADG) was developed in response to the difficulties experienced with wet granulation, in terms of endpoint, drying and milling. Wet granulation process endpoint is very sensitive to granulation time and shear. The wet granules need to be dried to a narrow range of moisture contens, which is difficult [5]. The dried granules need to be milled, but the milled granules often have either too many fines or too many coarse particles — an undesirable bimodal distribution. Here drying step is eliminated because very less amount of binding agent is used to activate binding process and remove moisture present in granules. Moisture activated dry granulation have two steps:

· Agglomeration

· Moisture distribution

During agglomeration, a major portion of the formulation containing the drug is agglomerated. The drug is blended with filler and binder in the powder form, and this blend constitutes approximately 50–80% of the formula weight. In the second stage, a small amount (1–4%) of water is sprayed as small droplets onto the blend (while blending). Water moistens the blend and causes the binder to become tacky, which causes particles, particularly fines, to form moist agglomerates. The remaining formula ingredients are then added (while blending), which results in dry and free flowing granulation. Most tablet granulations contain dry binders, such as microcrystalline cellulose, a disintegrant, a lubricant and, quite often, some colloidal silica. These common ingredients are also used in this process, but are added in a specific order. [6]

Advantages:

· Applicable to more than 90% of the granulation needs for pharmaceutical, food and nutritional industry.

· Short processing time

· Very few variables, resulting in less need for expensive PAT technology

· Applicable to a number of formulations, including high and low drug loaded formulations, polymer matrix typecontrolled release formulations, and soluble and insoluble drug formulations

· Suitable for continuous processing

· It uses very little energy, so it is a green process.

· Utilizes very little amount of granulating fluid.

· Excellent flow property.

· Produces granules of particle size range 150-500μm.

Disadvantages:

· Not suitable for thermolabile, and moisture sensitive drugs.

· Difficult to develop formulation with high drug loading.

Fig. 1. Schematic diagram of Moisture-Activated Dry Granulation.

THERMAL ADHESION GRANULATION:

Wei-Ming Pharmaceutical Company (Taipei, Taiwan) has developed this technique, and the thermal adhesion granulation, analogous to moist granulation, utilizes addition of a small amount of granulation liquid and heat for agglomeration. Unlike moisture activated dry granulation which uses water alone as granulation liquid, this process uses both water and solvent as granulation liquid. In addition to this, heat is used to facilitate the granulation process. In this process, the drug and excipient mixture is heated to a temperature range of 30–130 °C in a closed system under tumble rotation to facilitate the agglomeration of the powder particles. This technique eliminates the drying process due to the addition of low amount of granulation liquid, which is mostly consumed by the powder particles during agglomeration [7]. Granules of the required particle size can be obtained after cooling and sieving. In this technique, it utilizes a small amount of granulation liquid and heat for agglomeration. The drug and excipients mixture is heated to a temperature range of 30-130℃ in a closed system under tumble rotation for 3-20 minutes until granules are formed. This technique is quite simple and convenient with low moisture and binder contents in a closed system for preparing highly compressible materials or for modifying the poor characteristics of excipients. Besides, this technique provides granules with better particle size, good flow properties and high tensile strength that could be directly compressed into tablets with adequate hardness and low friability. The limitations of this technique are requirement of considerably high energy inputs and special equipment for heat generation and regulation. This technique is not suitable for all binders and is sensitive to thermolabile drugs. [8]

Advantages:

· Requires less amount of granulation fluid.

· Reduces the dust generation during powder processing.

Disadvantages:

· Unsuitable of substances with melting point more than 130⁰C and for material with binding solvents other than water and ethanol.

Fig 2: Schematic diagram of Thermal Adhesion Granulation

PNEUMATIC DRY GRANULATION:

Pneumatic dry granulation (PDG), an innovative dry granulation technology, utilizes roller compaction together with a proprietary air classification method to produce granules with extraordinary combination of flowability and compressibility. In this method, granules are produced from powder particles by initially applying mild compaction force by roller compactor to produce a compacted mass comprising a mixture of fine particles and granules. The fine particles and/or smaller granules are separated from the intended size granules in a fractioning chamber by entraining in a gas stream (pneumatic system), whereas the intended size granules pass through the fractioning chamber to be compressed into tablets. The entrained fine particles and/or small granules are then transferred to a device such as a cyclone separator and are either returned to the roller compactor for immediate re-processing or placed in a container for reprocessing later to achieve the granules of desired size. [9] PDG technology could successfully be used to produce good flowing granules for any formulations that produce compacts with a tensile strength of ~ 0.5 MPa. Also, this technology enables the use of high drug loads of up to 70-100%, because sufficient flowability could be achieved even at lower roll compaction forces compared to usual roller compaction. In addition to these, this technology avails various other benefits such as faster processing speed, low cost, little or no material wastage, low dust exposure due to the closed nature of this unit, etc. However, the influence of recycling on the granule quality, suitability with low dose formulations, friability, etc. remains as a major issue regarding this technology. [10]

Advantages:

· Excellent stability.

· Suitable for thermolabile and moisture sensitive drugs.

Disadvantages:

· High cost.

· Degradation of the material due to usage of double compression force.

Fig.3. Schematic diagram of Pneumatic Dry Granulation

MELT OR THERMOPLASTIC GRANULATION:

Melt granulation or thermoplastic granulation is a technique that facilitates the agglomeration of powder particles using meltable binders, which melts or softens at relatively low temperature (50–90 °C). Cooling of the agglomerated powder and the consequent solidification of the molten or soften binder complete the granulation process. Low melting binders can be added to the granulation process either in the form of solid particles that melt during the process (melt-in procedure or in situ melt granulation) or in the form of molten liquid, optionally containing the dispersed drug (spray-on or pump-on procedure), which displays a variety of options to design final granular properties. [11] More specifically, the melt-in procedure of melt granulation process includes heating a mixture of drug, binder and other excipients to a temperature within or above the melting range of the binder. On the contrary, the spray-on procedure encompasses spraying of a molten binder, optionally containing the drug, onto the heated powders. Melt granulation is an appropriate alternative to other wet granulation techniques used for water sensitive materials.

The binders used for this process could be either hydrophilic or hydrophobic. The selection of a meltable binder with a hydrophilic/hydrophobic feature is critical factor for the dissolution behavior of the drugs. The equipments that could be used for melt granulation are high-shear mixer and fluidized bed granulator. Interest in melt granulation has increased in recent years, owing to the numerous advantages of th-is technique over conventional wet granulation process. [12]

Advantages:

· Water sensitive drugs are good candidates.

· It eliminates the liquid addition and drying steps.

Disadvantages:

· Requires high energy inputs.

· Heat sensitive materials are poor candidates.

Fig. 5. Schematic diagram of melt granulation

FLUIDIZED BED GRANULATION:

Fluid-bed granulation offers a number of advantages such as better containment, being a one-pot process (combining mixing, granulation, and drying in the same unit operation), and generating agglomerated products of superior compressibility. Top, bottom, and tangential spray machines have been used by the pharmaceutical industry for decades. Recent advances in semicontinuous and continuous models have made this granulation methodology even more cost effective at commercial scale. Formulation variables such as percentage of water-soluble excipients and process variables such as air conditions and droplet size all affect the critical quality attributes of the end product. Maintaining drying efficiency and correlating droplet size between laboratory and commercial scales constitute key scale-up considerations. It involves the spraying of binder solution onto the fluidized powder bed to get fine, free flowing, homogenous granules employing single equipment known as fluidized powder bed. [13]

Advantages:

· Reduces the dust formation during processing.

· It reduces product loss.

Disadvantages:

· Requires high energy input.

· Limited number of polymers available.

EXTRUSION-SPHEROINIZATION: GRANULATION:

The main objective of the extrusion spheronization is to produce pellets/spheroids of uniform size with high drug loading capacity. Extrusion spheronization is a multiple process of wet mass extrusion followed by spheronization to produce uniform size spherical particles, called as spheroids, pellets, beads or matrix pellets depending upon the material as well as process used for extrusion Extrusion spheronization is primarily used for the production of multi particulates for oral controlled drug delivery system. [14] It is more labour intensive than other granulation method, but it is useful when uniform spherical shape, uniform size, good flow properties, reproducibility in packing, high strength, low friability and smooth surface of granules is desired. Extrusionspheronization process has gained worldwide attention because it is a simple and fast processing technology. Any pharmaceutical products utilizes pellets or beads as a drug delivery system can be effectively produced by the extrusion spheronization process. Wet mass extrusion and spheronization is established method for the production of spherical pellets, and are coated effectively to achieve controlled release product. [15]

It is a multiple step process which involves:

· 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.

Advantages:

· Particles having high bulk density, low hygroscopicity, high spherocity, dust free, narrow particle size distribution and smoother surface can be produced.

Disadvantages:

· Unsuitable for moisture sensitive and thermolabile materials.

Fig.4. Schematic diagram Extrusion-Spheroinization Granulation

SPRAY DRY GRANULATION:

In the spray dry granulation process a granulation seed is enveloped in several layers. The layers come about through the drying of fine particles dissolved in a liquid sprayed into the fluidized bed. The result is a granulate with very little dust and the further benefits of a compact and firm structure.

The spray drying involves three steps:

· Atomization of a liquid feed into fine droplets.

· Mixing of these sprays droplets with a heated gas stream, allowing the liquid to evaporate and leave dried solids.

· Separation of the dried powder from the gas stream.[16]

Advantages:

· Suitable for heat sensitive products.

· Rapid and continuous process

Disadvantages:

· Improper spray leads to inadequate sized particles.

FREEZE GRANULATION:

Freeze granulation technology, spray freezing and subsequent freeze drying, involves spraying droplets of a liquid slurry or suspension into liquid nitrogen followed by freeze-drying of the frozen droplets. By spraying a powder suspension into liquid nitrogen, the drops are instantly frozen into granules, and in the subsequent freeze drying process, the granules are dried by sublimation of ice without any segregation effects. This process yields spherical free-flowing granules that could be formed by using both water based and solvent based slurries. The significance of this technology is that the structure and homogeneity of the particles in the slurry or suspension are retained in the granules. Although various kinds of material in dispersed form can be granulated using this technology, it is suitable for the preparation of fine powder mixes with proper additives for subsequent processing. [17]

Advantages:

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

Disadvantages:

· Chance of degradation of drug is high due to use of low temperature i.e. less than 0℃.

Fig. 5. Schematic diagram of freeze granulation

FOAM BINDER GRANULATION:

Foam granulation or foamed binder granulation technology, analogous to spray agglomeration, involves the addition of liquid/aqueous binder as foam instead of spraying or pouring liquid onto the powder particles. This foam binder technology was first introduced by Dow Chemical Company (Midland, MI) in 2003 for delivering aqueous binder systems in high shear and fluid bed wet granulation applications. A foam generator can be installed in the binder solution tank with high-shear granulator or fluid bed granulator to introduce the binder as foam rather than spraying or pouring in binder onto the moving powder particles. Adding the binder solution as foam rather than a spray eliminates the problems of inconsistent and unpredictable binder distribution that can affect tablet hardness and drug release. It involves continuous addition of liquid binders in the form of aqueous foam instead of spraying or pouring liquid onto the powder particles. [18]

Advantages:

· Eliminates use of spray nozzle thereby eliminates plugging effects.

· Binder distribution was uniform.

Disadvantages:

· Heat sensitive materials are poor candidates.

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

Fig. 6. Schematic diagram of foam binder granulation

STEAM GRANULATION:

Steam granulation is a new wet granulation technique; water steam is used as binder instead of traditional liquid water as granulation liquid. It involves injection of a jet of steam into the bed of fluidized particles to be granulated. Steam, at its pure form is transparent gas, and provides a higher diffusion rate into the powder and a more favorable thermal balance during the drying step. After condensation of the steam, water forms a hot thin film on the powder particles, requiring only a small amount of extra energy for its elimination, and evaporates more easily. [19]

Advantages:

· Higher diffusion rate.

· Uniformly distributed in the powder particles.

Disadvantages:

· Thermolabile materials are poor candidates.

· Requires high energy inputs.

Fig. 7. Schematic diagram of steam granulation

APPLICATIONS/BENEFITS OF ADVANCED GRANULATION TECHNIQUES: [20]

· Granulation is required to improve the flow of powder and mechanical properties of tablets.

· The particle size of the granule is determined by the quantity and feeding rate of the granulating fluid.

· Wet granulation is used to improve flow, compressibility, bioavailability, homogeneity, electrostatic properties and the stability of solid dosage forms.

· Granulation involves smaller particles adhering to each other to produce larger particles or agglomerates.

· It enhances the uniformity of the API in the final product and increases the density of the blend.

CONCLUSION:

· The novel pharmaceutical granulation techniques contribute to improved processabilty and quality of product formulations.

· They also have impact on product development, time and economy.

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Received on 01.04.2020 Modified on 18.04.2020

Res. J. Pharma. Dosage Forms and Tech.2020; 12(2): 98-104.

DOI: 10.5958/0975-4377.2020.00018.X