INTRODUCTION:

Granulation may be defined as a size enlargement process which converts fine or coarse particles into physically stronger and larger agglomerates having good flow property, better compression characteristics and uniformity. The art and science for process and production of granules is known as Granulation Technology.

Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical granules typically have a size range between 0.2 and 4.0 mm, depending on their subsequent use. In the majority of cases this will be in the production of tablets or capsules, when granules will be made as an intermediate product and have a typical size range between 0.2 and 0.5 mm, but larger granules are used as a dosage form in their own right. Granulation normally commences after initial dry mixing of the necessary powdered ingredients so that a uniform distribution of each ingredient through the mix is achieved. After granulation the granules will either be packed (when used as a dosage form), or they may be mixed with other excipients prior to tablet compaction or capsule filling.

Reasons for granulation ⁽³⁾

· To prevent segregation of the constituents of the powder mixture

· To improve the flow properties of the mixture

· To improve the compaction characteristics of the powder

· The granulation of toxic materials will reduce the hazard associated with the generation of toxic dust that may arise when handling powders. Suitable precautions must be taken to ensure that such dust is not a hazard during the granulation process. Thus, granules should be non-friable and have a suitable mechanical strength.

· Materials which are slightly hygroscopic may adhere and form a cake if stored as a powder. Granulation may reduce this hazard, as the granules will be able to absorb some moisture and yet retain their flowability because of their size.

· Granules, being denser than the parent powder mix, occupy less volume per unit weight. They are therefore more convenient for storage or shipment.

· Increase the uniformity of drug distribution in the product

· Improve appearance of the product

· Improve compression properties of the mixture

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)

· Wet massing time (less or more)

· Amount of shear applied

· Drying rate (Hydrate formation and polymorphism)

Methods of granulation:

Generally, there are three methods of granulation

· Dry granulation

· Direct compression

· Wet granulation

In a suitable formulation a number of different excipients are used. The common types used are diluents, to produce a unit dose weight of suitable size, and disintegrating agents, which are added to aid the break-up of the granule when it reaches a liquid medium, e.g. on ingestion by the patient. Adhesives in the form of a dry powder may also be added, particularly if dry granulation is employed. These ingredients will be mixed before granulation.

Dry granulation

In the dry methods of granulation the primary powder particles are aggregated under high pressure. There are two main processes. Either a large tablet (known as a ‘slug’) is produced in a heavy-duty tabletting press (a process known as ‘slugging’) or the powder is squeezed between two rollers to produce a sheet of material (‘roller compaction’). In both cases these intermediate products are broken using a suitable milling technique to produce granular material, which is usually sieved to separate the desired size fraction. The unused fine material may be reworked to avoid waste. This dry method may be used for drugs that do not compress well after wet granulation, or those which are sensitive to moisture. In dry granulation process the powder mixture is compressed without the use of heat and solvent. It is the least desirable of all methods of granulation. The two basic procedures are to form a compact of material by compression and then to mill the compact to obtain a granules. Two methods are used for dry granulation. The more widely used method is slugging, where the powder is precompressed and the resulting tablet or slug are milled to yield the granules. The other method is to precompress the powder with pressure rolls using a machine such as Chilosonator. Steps involved in dry granulation process are

1. Milling of drugs and excipients

2. Mixing of milled powders

3. Compression into large, hard tablets to make slug

4. Screening of slugs

5. Mixing with lubricant and disintegrating agent

6. Tablet compression

Advantages of dry Granulation:

The main advantages of dry granulation or slugging are that it uses less equipments and space. It eliminates the need for binder solution, heavy mixing equipment and the costly and time consuming drying step required for wet granulation. Slugging can be advantages for moisture and heat sensitive materials and improved disintegration since powder particles are not bonded together by a binder.

Disadvantages of dry granulation

It requires a specialized heavy-duty tablet press to form slug. It does not permit uniform color distribution as can be achieved with wet granulation where the dye can be incorporated into binder liquid. The process tends to create more dust than wet granulation, increasing the potential contamination.

Direct compression:

Direct compression involves comparatively few steps:

1. Milling of drug and excipients

2. Mixing of drug and excipients

3. Tablet compression

Disadvantages:

Capping, lamination, splitting, or layering of tablets is sometimes related to air entrapment during direct compression. When air is trapped, the resulting tablets expand when the pressure of tablet is released, resulting in splits or layers in the tablet. In some cases, require greater sophistication in blending and compression equipments. Direct compression equipments are expensive.

Wet Granulation:

Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid. The fluid contains a solvent which must be volatile so that it can be removed by drying, and be non-toxic. Typical liquids include water, ethanol and isopropanol, either alone or in combination. The granulation liquid may be used alone or, more usually, as a solvent containing a dissolved adhesive (also referred to as a binder or binding agent) which is used to ensure particle adhesion once the granule is dry. Water is commonly used for economical and ecological reasons. Its disadvantage is, solvents may adversely affect drug stability, causing hydrolysis of susceptible products, and it needs a longer drying time than do organic solvents. This increases the length of the process and again may affect stability because of the extended exposure to heat. The primary advantage of water is that it is non-flammable, which means that expensive safety precautions such as the use of flameproof equipment need not be taken. Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry granulation, or when a rapid drying time is required. In the traditional wet granulation method the wet mass is forced through a sieve to produce wet granules which are then dried. A subsequent screening stage breaks agglomerates of granules and removes the fine material, which can then be recycled. Variations of this traditional method depend on the equipment used, but the general principle of initial particle aggregation using a liquid remains in all of the processes. Important steps involved in the wet granulation are,

1. Mixing of the drug(s) and excipients

2. Preparation of binder solution

3. Mixing of binder solution with powder mixture to form wet mass

4. Coarse screening of wet mass using a suitable sieve (6-12 # screens)

5. Drying of moist granules

6. Screening of dry granules through a suitable sieve (14-20 # screen)

7. Mixing of screened granules with disintegrant, glidant, and lubricants.

Role of binder in wet granulation:

Binders are adhesives that are added to solid dosage formulations. The primary role of binders is to provide the cohesiveness essential for the bonding of the solid particles under compaction to form a tablet. In a wet-granulation process, binders promote size enlargement to produce granules and thus improve flowability of the blend during the manufacturing process. Binders may also improve the hardness of the tablets by enhancing intragranular as well as intergranular forces. In a direct compression process, binders often act as fillers and impart compressibility to the powder blend. The cohesive properties of binders may reduce friability of the tablets and thus aid in their durability and elegance.

Examples:

Natural Polymers: Starch, pregelatinized starch

Synthetic polymers: PVP, methylcellulose, HPMC

New Natural and Synthetic binders: Khaya gum, leucocephala seed gum, anacardium occidentale gum, gellan gum, combination of detarium gum and veegum.

New synthetic binders: Maltrodextrins, chitosan derivatives

Limitations of wet granulation:

· The greatest disadvantage of wet granulation is its cost. It is an expensive process because of labor, time, equipment, energy and space requirements.

· Loss of material during various stages of processing

· Stability may be major concern for moisture sensitive or thermo labile drugs

· Multiple processing steps add complexity and make validation and control difficult

· An inherent limitation of wet granulation is that any incompatibility between formulation components is aggravated.

Wet granulation techniques ⁽⁹⁾

Following are the four major techniques which are used for wet granulation process.

Single pot granulation

A mixer/granulator that dries granules in the same equipment without discharging is commonly called a Single Pot Processor (or One-Pot Processor). The granulation is done in a normal high shear processor; however, care must be taken to avoid the formation of lumps as they cannot be broken down before drying. There are various options for drying in Single Pots. The basic drying principle relies on the application of a vacuum in the bowl thus lowering the evaporation temperature of the used granulation liquid drastically. The traditional heat source comes from the heated dryer walls. The heat transfer is related to the surface area of the dryer walls and the volume of product treated. Therefore, this direct heating method is most effective for small scale, organic solvents or low quantities of binder fluids. Introducing stripping gas into the pot allows lower final moisture content to be achieved. This very low moisture content is only required in some particular applications. A small quantity of gas is introduced in the bottom of the equipment, which passes through the product bed, improving the efficiency of vapour removal. However, as the heated wall is the only source of drying energy, linear scale-up is not possible.

High shear mixture granulation:

High shear mixture has been widely used in pharmaceutical industries for blending and granulation. In this type of equipment, the particles are set into movement by an impeller rotating at a high speed (50- 100 rpm). Equipment also contains a chopper which rotates at around 1500-4000 rpm. The primary function of chopper is to cut large lumps into smaller fragments thus increases the binder distribution into the blend. The binder liquid is added by pouring, pumping or spraying from the top. Wet agglomeration in a high-shear mixer involves typically three phases,

1 Dry Powder mixing

2 Liquid binder addition

3 Wet massing

After the wet mass is produced, it is further processed to obtain dried grade particle size granules.

1 Wet sieving of granules

2 Drying

3 Dry sieving of granules

First the materials are dry, mixed, where after liquid is added during mixing. Then the moist mass is wet massed in order to achieve a narrow particle size distribution. Thereafter the granules are wet sieved, dried and sieved again. The liquid amount is critical, because the process is susceptible for over-wetting, which leads to uncontrollable agglomerate growth.

Advantages:

1. Short processing time

2. Lesser amount of liquid binders required compared with fluid bed granulation.

3. Highly cohesive material can be granulated.

Disadvantages:

1 Mechanical degradation could take place in case of fragile particles.

2 Due to increase in temperature chemical degradation of thermolabile material could be resulted.

3 Over wetting of granules may leads to large size lumps formation.

Fluid bed granulation ⁽⁹⁾

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 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. The system involves the heating of air and then directing it through the material to be processed. Later, the same air exit through the voids of the product. Fluid bed processing of pharmaceuticals was first reported by Wurster, by using air suspension technique to coat tablets later used this technique in granulating and drying of pharmaceuticals, for the preparation of compressed tablets. Fluidized bed system contains various components such as,

· Air Handling Unit (AHU)

· Product container and air distributor

· Spray nozzle

· Disengagement area and process filters

· Exhaust blower or fan

· Control system

· Solution delivery system

Advantages:

1 It reduces dust formation during processing, thus improves housekeeping

2 It reduces product loss

3 It improves worker safety

Disadvantages:

1 The Fluid Bed cleaning is labor-intensive and time consuming

2 Difficulty of assuring reproducibility

Application of Fluid bed granulator:

· In pharmaceutical industry: Tablet, capsule, low sugar or no sugar granule of chinese medicine.

· Foodstuff: Cocoa, coffee, milk powder, juices

· Other industries: Pesticide, feed chemical fertilizer, pigment, dyestuffs

· Drying: Powder or granule material

· Coating: Granule, protecting coat of pellet, spare color, slow release film, bowel dissolve coating,

Extrusion-Spheronization:

This process is primarily used as a method to produce multi-particulates for controlled release application. It is a multiple step process involving at least five steps capable of making uniform sized spherical particles.

1 Dry mixing of materials to achieve homogeneous dispersion

2 Wet granulation of the resulted mixture to form wet mass

3 Extrusion of wet mass to form rod shaped particles.

4 Rounding off (in spheronizer)

5 Drying

These dried rounded particles can be optionally screened to achieve a targeted mean size distribution. Following figure describes schematically the steps involved in the extrusion spheronization process.

Figure 1: Different steps involved in the Extrusion- Spheronization process

Figure 2: Extrusion Spheronizer

Advantages:

1 Ability to incorporate higher levels of active components without producing excessively larger particles.

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

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

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

Disadvantages:

This process is more labor and time intensive than other commonly used granulation techniques

Spray drying:

Spray Drying as a process has been used to produce microcapsules, food ingredients, flavors and various biotechnological preparations. This process differs from the methods discussed above in that it is a continuous process in which a dry granular product is made from a solution or a suspension rather than initially dried the primary powder particles. The solution or suspension may be of drug alone, a mixture of different excipients or a complete formulation. As long as the liquid solution or suspension feed to the drying system, dry powder product continues to be produced. 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 evaporate and leave dried solids.

3. Separation of the dried powder from the gas stream

Advantages:

1 Rapid and continuous process

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

3 Offers minimal product handling and operator exposure to dust.

4 OTC products are good candidates.

5 Suitable for heat sensitive product

Liquisolid technique⁽⁴⁾

The poor dissolution rate of water insoluble drugs is still a substantial problem confronting the pharmaceutical industry. A great number of new and possibly, beneficial chemical entities do not reach the public merely because of their poor oral bioavailability due to inadequate dissolution. Over the years, various solid dosage formulation techniques, to enhance the dissolution of poorly soluble substances, have been introduced with different degrees of success. The technique of ‘liquisolid compacts’ is a new and promising addition towards such a novel aim. The active ingredient in a solid dosage form must undergo dissolution before it is available for absorption from the gastrointestinal tract. The poor dissolution characteristics of water-insoluble drugs are a major challenge for pharmaceutical formulation scientists. The absorption rate of a poorly water-soluble drug, formulated as an orally administered solid dosage form, is controlled by its dissolution rate in the fluid present at the absorption site, i.e. the dissolution rate is often the rate-determining step in drug absorption. There are several methods for enhancing dissolution rate of poorly water-soluble drugs includes,

· Reducing particle size to increase surface area, thus increasing dissolution rate of drug

· Solubilization in surfactant systems

· Formation of water-soluble complexes

· Drug dramatization such as a strong electrolyte salt forms that usually have higher dissolution rate

· Manipulation of solid state of drug substance to improve drug dissolution, i.e. by decreasing crystallinity of drug substance through formation of solid solutions

The use of water soluble salts and polymorphic forms, the formation of water soluble molecular complexes, drug micronization, solid dispersion, co-precipitation, lyophilization, microencapsulation and the inclusion of drug solutions or liquid drugs into soft gelatin capsules are some of the major formulation tools which have been shown to enhance the dissolution characteristics of water-insoluble drugs. However, among them, the technique of ‘‘liquisolid compacts” is one of the most promising technique. The most common method is to increase surface area of the drug by micronization. But in practice, the effect of micronization is often disappointing, especially when the drugs are encapsulated or tableted. Micronized drugs also have the tendency to agglomerate as a result of their hydrophobicity, thus reducing their available surface area. Several researchers have shown that the liquisolid technique is the most promising method for promoting dissolution rate of poorly water-soluble drugs.

Advantages:

Simplicity, Low cost, Capability of industrial production.

Application of Liquisolid Techniques ⁽⁴⁾

Solubility and dissolution improvement:

In order to overcome the limited solubility of the pharmaceutical, pharmaceuticals were formulated as liquisolid tablets. In fact, when the therapeutic dose of drug is more than 50 mg, dissolution enhancement in the presence of low levels of hydrophilic carrier and coating material is not significant. However, by adding some materials such as poly Vinyl Pyrrolidone (PVP) to liquid medication (Microsystems), it would be possible to produce dry powder formulations containing liquid with high concentration of drug. By adding such materials to the liquid medication, low amount of carrier is required to obtain dry powder with free flowability and good compatibility.

Flowability and compressibility:

Liquisolid compacts possess acceptable flowability and compressibility properties. They are prepared by simple blending with selected powder excipients referred to as the carriers and the coating materials. Many grades of cellulose, starch, lactose, etc. can be used as carriers, whereas silicas of very fine particle size can be used as coating materials. In order to have acceptable flowability and compactability for liquisolid powder formulation, high levels of carrier and coating materials should be added and that in turn will increase the weight of each tablet above 1 gm which is very difficult to swallow. Therefore, in practice it is impossible with conventional method to convert high dose drugs to liquisolid tablet with the tablet weight of less than 1 gm.

For designing of sustain release tablet:

Development of sustained release oral dosage forms is beneficial for optimal therapy in terms of efficacy, safety and patient compliance. Liquisolid technique is a new and promising method that can change the dissolution rate of drugs. It is claimed that if hydrophobic carriers such as Eudragit RL and RS are used instead of hydrophilic carries in liquisolid systems, sustained release systems can be obtained. Therefore, it is suggested that the method have the potential to be optimized for the reduction of drug dissolution rate and thereby production of sustained release systems.

Bioavailability improvement:

In the liquisolid and powdered solution systems the drug might be in a solid dosage form, it is held within the powder substrate in solution, or in a solubilized, almost molecularly dispersed state. Therefore, due to their significantly increased wetting properties and surface of drug available for dissolution, liquisolid compacts of water insoluble substances may be expected to display enhanced drug release properties, and consequently, improved bioavailability.

Table 1. Various Drying Techniques for Granulation

Sr. No.	Granulation Techniques	Drying techniques
1	Wet granulation	Tray or fluid-bed dryer
		Tray or fluid-bed dryer
		Vacuum/gas stripping/microwave
		Spray dryer
		Extrusion/ Spheronization / Pelletization
2	Dry granulation Process	Direct compression
		Slugging Mill
		Roller compactor Compacts milled

Advanced granulation techniques:

Over a period of time, due to technological advancements and in an urgue to improve commercial output various, newer granulation technologies have been evolved such as,

· Steam Granulation

· Melt Granulation Technology

· Moisture Activated Dry Granulation (MADG)

· Moist Granulation Technique (MGT)

· Thermal Adhesion Granulation Process (TAGP)

· Foamed Binder Technologies (FBT)

· Pneumatic Dry Granulation (PDG)

· Freeze granulation Technology

Steam granulation⁽⁸⁾

Pure steam is a transparent gas. At standard temperature and pressure, pure steam (unmixed with air, but in equilibrium with liquid water) occupies about 1,600 times the volume of an equal mass of liquid water. This process is simply a modification of conventional wet granulation method. Here steam is used as a binder instead of water. Process offers several advantages and disadvantages over other conventional granulation methods such as,

Advantages:

1 Uniformly distributed in the powder particles

2 Higher diffusion rate

3 Results in more spherical granule formation

4 Thermally aids in drying process

5 Higher dissolution rate of granules because of larger surface area generated

6 Time efficient

7 Environment friendly

8 No health hazards to operator

9 Regulatory compliance

10 Maintain sterility

Disadvantages:

1 Requires special equipment for steam generation and transportation

2 Requires high energy inputs

3 Thermolabile materials are poor candidates

4 More safety measure required

5 Not suitable for all the binders

Melt granulation⁽¹⁾

Melt granulation process has been widely used in the pharmaceutical industry for the preparation of both immediate and controlled release formulations such as pellets, granules, and tablets. This process has also been widely accepted for the enhancement of dissolution profile and bioavailability of poorly water soluble drugs by forming solid dispersion. 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 in the temperature range of 50^oC-80^oC. No further addition of liquid binder or water is required in the process as the binder in the melted state itself act as granulating liquid and dried granules can be easily obtained by simple cooling at room temperature.

Advantages:

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

2 Water sensitive drugs are good candidates

3 Controlling and modifying the release of drugs

4 Regulatory compliance

Disadvantages:

1 Heat sensitive materials are poor candidates

2 Binders having melting point in the specific range can only be utilized in the process

Table 2. Hydrophilic meltable binders used in the melt granulation technique

Hydrophilic Meltable Binder

Typical Melting Range (°C)

Gelucire 50/13

Poloxamer 188

Polyethylene glycols :

PEG 2000

PEG 3000

PEG 6000

PEG 8000

44 – 50

50.9

42 – 53

48 – 63

49 – 63

54 – 63

Table 3. Hydrophobic meltable binders used in the melt granulation technique

Hydrophobic Meltable Binder

Typical Melting Range (°C)

Bees wax

Carnauba wax

Cetyl Palmitate

Glyceryl stearate

Hydrogenated castor oil

Microcrystalline wax

Paraffin wax

Stearic acid

Stearic alcohol

56 – 60

75 – 83

47 – 50

54 – 63

62 – 86

58 – 72

47 – 65

46 – 69

56 – 60

In pharmaceutical industry the melt extrusion has been used for various purposes, such as,

· Improving the dissolution rate and bioavailability of the drug by forming a solid dispersion or solid solution

· Controlling or modifying the release of the drug

· Masking the bitter taste of an active drug

Moisture Activated Dry Granulation (MADG)⁽¹⁾

MADG is a process in which moisture is used to activate granule formation, without the need to apply heat to dry the granules. There are two main stages in MADG are,

1. Agglomeration

2. Moisture distribution/ Absorption

During agglomeration, drug is blended with diluents and binder in the powder form, to obtain a uniform mixture. This blend constitutes approximately 50-80% of formula weight. While mixing, a small amount of water (1-4%) is sprayed as small droplets onto the powder blend, which moistens the binder and makes it tacky. The binder facilitates the binding of the drug and excipients as they move in a circular motion forced by the mixer blades. The process does not results in larger lumps formation as the amount of water used in this process is very small as compared to the other conventional wet granulation techniques. The particle size of the agglomerates generally falls in the range of 150-500 μm. In moisture distribution/absorption, moisture absorbents, such as microcrystalline cellulose or silicon dioxide, are added while mixing continues. When they come into contact, the moisture absorbents pick up moisture from the moist agglomerates, resulting in moisture redistribution within the mixture. When this happens, the entire mixture becomes relatively dry. While some of the moisture is removed from the wet agglomerates, some of these agglomerates remain almost intact and some usually the larger particles may break up. This process results in granulation with more uniform particle size distribution.

Advantages:

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

2. Time efficient

3. Very few variables involved in the process

4. Suitable for continuous processing

5. Less energy involved during processing

Disadvantages:

1 Moisture sensitive and high moisture absorbing APIs are poor candidates

2 Formulations with high drug loading are difficult to develop

Moist Granulation Technique (MGT):

MGT works on the same principle as Moisture Activated Dry Granulation (MADG) described earlier. It involves binder activation by adding a minimum amount of liquid. Then, excess of moisture present in the blend is removed by adding moisture absorbing material like Microcrystalline Cellulose (MCC) which eliminates the drying step. It is applicable for developing a controlled release formulation.

Thermal Adhesion Granulation Process (TAGP):

TGAP involves granulation by adding very less amount of water or solvent as compared to the traditional wet granulation methods. In this process drug and excipient mixture heated at a temperature range from 30^oC to about 130^oC in a closed system under mixing by tumble rotation until the formation of granules take place. Drying step is not required in most instances due to low amount of moisture added in the process. Granules of required particles size can be obtained after cooling and screening. 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.

Foam Granulation⁽¹⁾

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. The rate of addition of foam is greater than rate of addition of sprayed liquids, no detrimental effects on granulate, tablet, or in vitro drug dissolution properties, no plugging problems since use of spray nozzles is eliminated, no over wetting. It is 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. Foam granulation technique involves addition of liquid binders as aqueous foam. The advantages of foamed binder addition conventional binder addition method includes,

1 No spray nozzle is used

2 Improve process robustness

3 Less water required for granulation

4 Time efficient drying

5 Cost effective

6 Uniform distribution of binder

7 No over wetting

8 Applicable for water sensitive formulation

Pneumatic Dry Granulation Technology (PDGT)⁽¹⁾

Is based on a pneumatic dry granulation process, a novel dry method for automatic or semi-automatic production of granules. This enables flexible modification of drug loading, disintegration time and tablet hardness. It is compatible with other technologies, such as sustained release, fast release, coating etc. It is suitable for heat labile and moisture sensitive drugs. The PDG Technology produces porous granules with excellent compressibility and flowability characteristics. The pneumatic dry granulation process can granulate virtually any pharmaceutical solid dosage ingredient. The granulated material has exceptionally good flowability and compressibility properties. PDG Technology has been used with superior results in developing fast-release, controlled-release, fixed-dose, and orally disintegrating tablets. The technology is applicable to practically any solid dosage pharmaceutical product. PDG technology can achieve,

· High drug loading, even with difficult APIs and combinations

· Taste masking

· Excellent stability

Today, wet granulation is the most commonly used granulation method. Formulation teams will usually target a direct compression or dry granulation formulation where possible but in approximately 80 % of the cases they end up with a wet granulation formulation due to processing issues. Wet granulation is also unsuitable for moisture sensitive and heat sensitive drugs, it is more expensive than dry granulation, it is relatively labour intensive and can take a long time. There are a large number of process steps and each step requires qualification, cleaning, and cleaning validation, high material losses can be incurred because of the transfer between stages, there is the need for long drying times. Scale up is usually an issue, and there are considerable capital requirements. PDG Technology solves the above problems. PDG Technology granules have excellent properties compared to wet granulation, dry granulation and direct compression. At the same time, the granules show both high compressibility and flowability. The results can be archived without using exotic and expensive excipients.

PDG Technology is the key solution to challenges faced by pharmaceutical companies in development of solid oral dosage forms. The technology replaces existing solid dosage form development and manufacturing technologies, offering more rapid development and better quality.

Figure 3: PDG Technology and wet granulation Comparison

Advantages:

1. Good granulation results even at high drug loading have been achieved even with materials known to be historically difficult to handle,

2. Faster speed of manufacturing compared with wet granulation

3. Lower cost of manufacturing compared with wet granulation

4. The system is closed offering safety advantages due to low dust levels and potential for sterile production or handling of toxic materials

5. The end products are very stable - shelf life may be enhanced

6. Little or no waste of material

7. Scale-up is straightforward

8. The granules and tablets produced show fast disintegration properties, offering the potential for fast release dosage forms

9. Release time can be tailored to requirements

Freeze Granulation Technology:

Swedish Ceramic Institute (SCI) has adopted and developed an alternative technique that is freeze granulation, which enables preservation of the homogeneity from suspension to dry granules by spraying a powder suspension into liquid nitrogen, the drops (granules) are instantaneously frozen. In a subsequent freeze-drying the granules are dried by sublimation of the ice without any segregation effects as in the case of conventional drying in air. The result will be spherical, free flowing granules, with optimal homogeneity.

Figure 4: Freeze granulation

Melt Extrusion Technology:

Melt extrusion technology has proven to be a suitable method for the production of controlled release reservoir systems consisting of polyethylene vinyl acetate (EVA) co-polymers. Based on this technology, two controlled release systems Implanon® and Nuvaring® have been developed. A melt extrusion process for manufacturing matrix drug delivery system was reported by Sprockel and co-workers. In 1994, Follonier and co-workers investigated hot-melt extrusion technology to produce sustained-release pellets. Another application of hot-melt extrusion was described by Miyagawa, Sato, and coworkers in 1996 and 1977-8. They studied the controlled release and mechanism of release of diclofenac.

Melt Agglomeration⁽¹⁾

Melt agglomeration is a process by which the solid fine particles are bound together into agglomerates, by agitation, kneading, and layering, in the presence of a molten binding liquid. Dry agglomerates are obtained as the molten binding liquid solidifies by cooling. Typical examples of melt agglomeration processes are melt pelletization and melt granulation. During the agglomeration process, a gradual change in the size and shape of the agglomerates would take place. It is usually not possible to differentiate between granulation and pelletization. Thus granulation is considered a pelletization process when highly spherical agglomerates of narrow size distribution are produced.

TOPO Technology⁽⁶⁾

Hermes Pharma has developed unique technology for carrying out single pot granulation. Patented TOPO technology produces granules for tablets which contain at least one solid crystalline, organic acid and one alkaline or alkaline earth metal carbonate that reacts with the organic acid in aqueous solution to form carbon dioxide. TOPO granulation technology comprises a one-step vacuum system, under fully instrumented in-process control (IPC). The process modifies the surface of carrier materials with resultant alterations in their binding mechanisms. Tablets from these granules have excellent hardness and stability. TOPO granulation requires only a very small quantity of liquid to start the chain reaction. In contrast to other technologies that require e.g. acetone, TOPO uses only pure water or water-ethanol mixtures for granulation. As a result, there are no solvent residues in the finished products.

Continuous Flow Technology (CFT):

Continuous Flow (CF) technology is our second generation granulation technology and is designed especially for high throughput granulation. The technology does not need any liquid to start the chain reaction. Granulation is carried out in an inclined drum into which powder is fed at one end and granulate removed at the other. The drum is rotated in a way, which is designed to eliminate almost all shear forces. The process results in granules with a surface protected by inactive components that do not harm sensitive APIs. CF technology enables us to produce up to 12 tons of granules every day – ideal for products that require large volumes of granules per single dosage form. With no need to add any solvents like acetone, there are no solvent residues in the finished product.

Advantages:

1. Sensitive APIs are protected against acids or bases

2. Granules are less sensitive to humidity and high temperature

3. Granules form extremely stable products

4. No solvent residues in the final products

Granulation characterization:

Granulation is a process used to prevent segregation of formulation components in a powder blend, bulk volume of granulation, improve blend flow, content uniformity, compressibility, and other properties. Chemical properties are equally important due to their impact on specifications of a dosage form such as content uniformity, chemical purity, and in vitro performance. In vivo performance such as bioequivalence done because it determines whether a pivotal bioequivalency batch passes or fails. Granule Size affect the dissolution performance which ultimately affect bioequivalence study. Physical characterization can be performed at molecular, particulate, or bulk (macroscopic) levels.

Table No. 4. Different Parameters and Methods for Characterization of Granules

Sr. No.	Parameters	Method
1	Particle Morphology	Optical microscopy
2	Particle Size Distribution	Sieve analysis, laser light scattering
3	Nature	Powder X-Ray Diffraction
4	Thermal Analysis	DSC, TGA, DTA
5	Identification	Near-infrared (NIR) spectroscopy
6	Surface Area	Gas adsorption
7	Granule Porosity	Mercury intrusion methods
8	Granule Strength	Development of a Formulation
9	Granule Flowability and Density	Mechanical Method, Hopper Method, Density Apparatus

CONCLUSION:

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.

ACKNOWLEDGEMENTS:

The authors express their sense of gratitude towards management of Satara College of Pharmacy, Satara for providing all obligatory facilities necessary to carry out present work. Also Prof. (Dr.) S. P. Gawade, Dr. A. S. Kulkarni deserves a special mention for their timely suggestions.

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Received on 25.11.2013 Accepted on 15.01.2014

Asian J. Res. Pharm. Sci. 4(1): Jan.-Mar. 2014; Page 38-47