INTRODUCTION:

Active pharmaceutical compounds (drugs) are use for the treatment of a disease or for prophylactic purpose. An Active Pharmaceutical ingredient may exist in solid, liquid or semisolid form. They are rarely prescribed to the patients as such i.e. without adding excipients, since the desired effect may not be obtained. Earlier, it was thought that excipients are inert in nature but, in recent time it is well known that excipients can greatly modify the intended effect of a drug. The API and excipients are suitably processed in pharmaceutical industry to convert them into dosage forms such as tablet, capsule, suspension, solution, etc. The selection of excipients and processing of drug excipients mixture is as important as API itself ^1.

Granules:

Granules is defined as primary powder particles get adhere and form larger multi-particles entities having size range from 0.2 and 4.0 nm and mainly depend upon the use of granules.

Mostly during the production of tablets and capsules, when the granules will be made as an intermediate product and have a typical size range between 0.2 to 0.5 mm, whereas larger granules are used as a dosage form in their own right. Granulation generally commences after initial dry mixing of the necessary powdered ingredients so that a uniform distribution of each ingredient through the mix is achieved ².

Reasons for granulation:

1. To prevent segregation of the constituents of the powder mix:

Segregation or de-mixing is due to the differences in the size or density of the components of the mix, the smaller particles or denser particles concentrating at the base of a container with the large particle or more dense particles above them. In order to have an ideal granulation all the constituents of the mix are in correct proportion in each granule and segregation of the ingredients will not occur. It is necessary to control the particle size distribution of the granules because although the individual components might not segregate themselves, if there is a wide size distribution, the granules will get segregated by themselves. If this occurs in the hoppers of machines like sachet-filling, capsule- filling or tablet machines, products obtained will have large weight variations. The reason behind this is that these machines fill by volume rather than weight and if different regions in the hopper contain granules of different sizes (thereby bulk density), a given volume in each region will have variation in weight of granules. This leads to an unacceptable distribution of the drug content within the batch of finished product even if the drug has been evenly distributed, weight by weight, through the granules ³.

2. To improve the flow properties of the mix:

Large number of powders, because of their small size and irregular shape or surface characters, are cohesive and do not flow well. Poor flow often results in a wide weight variation within the final product due to variable fill of tablet dies, etc. The granules will be larger and more diametric when produced from such a cohesive system³.

3. Improvisation of the compaction characters of the mixture:

The primary powder particles are difficult to compress even though a readily compactable adhesive has been included in the mix but granules of the same formulation are often more easily compacted and produce stronger tablets. Mostly the solute migration which occurs during the post granulation drying stage results in a binder rich outer layer to the granules. This leads to the direct binder-binder bonding that helps in the consolidation of the weak bonding materials ³.

4. Other reasons:

· Granulation process is helpful to minimizing the hazards associated with toxic dust particles during handling, transporting of powders, thus precaution should be taken.

· Granules are generally occupy less volume per unit weight and more denser than the powder mix, thus more convenient for storage and shipment.

· Granulation technique helps adhesion and cake formation of hygroscopic materials. This occurs because the granules will be able to absorb some moisture and still retain the flow-ability because of their size ³.

Granulation method:

Granulation may be defined as a size enlargement process which converts small particles into physically stronger and larger agglomerates. Granulation method can be broadly classified into

three types¹:

· Wet granulation

· Dry granulation

^·Granulation incorporating bound moisture 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 properties⁴.

· 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

[A] Wet granulation:

It is the most widely used agglomeration process in the pharmaceutical industry. This process involves the mixing of the powder with the granulating liquid, wet sizing and drying ^{5-7 .}

a Important steps involved in the wet granulation

b Mixing of the drug(s) and excipients

c Preparation of binder solution

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

e Drying of moist granules

f Mixing of screened granules with disintegrant, glidant, and lubricant.

Advantages:

a. Permits mechanical handling of powders without loss of quality of blend.

b. The flow properties of powder are improved by increasing particle size and sphericity.

c. Increases and improves the uniformity of powder density.

d. Improves cohesion during and after compaction.

e. Air entrapment is reduced.

f. Reduces the level of dust and cross contamination.

g. Allows for the addition of a liquid phase to powders.

h. The hydrophobic surfaces are made hydrophilic.

The granulation effectiveness depends on the following properties⁸:

· Particle size of the drug as well as excipients

· Type of the 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)

Types of Wet Granulation:

i. High shear mixture granulation

ii. Fluid bed granulation

iii. Extrusion- Spheronization

iv. Spray drying

i. High Shear Mixture Granulation:

It has been widely used in various pharmaceutical industries for blending and granulation (Figure 2) ^9-12.

Wet aggregation in a high shear mixer involves 3 stages:

· Dry powder mixing (for 2-5 minutes)

· Liquid binder addition(1-2 minutes)

· Wet massing

Advantage of this technique is that even very highly cohesive material can also

granulated.

Figure no.2: High Shear Granulator

ii. Fluidized bed granulation:

Fluidized bed processing is a air suspension technique in which binder solution is sprayed on to the fluidized powder bed to get finer, free flowing and homogenous granules. This fluidized bed processor contains air handling unit, product container, air distributor, spay nozzle, disengagement area, process filters, exhaust blower/fan, control system, and solution delivery systems ^{13-18 .}

There are two different modes of fluid bed granulating

a) Wet stage: In wet stage granulation, the particles require a significant amount of moisture or granulating solution before they become tacky enough to stick to each other. The granulating solution is applied t a rate higher than the evaporating rate until the particles build up enough moisture to granulate.

b) Dry stage granulation: In dry stage granulation, the particles require only a slight wetting to become tacky and stick to each other. The granulating solution is applied at a rate less than or equal to its evaporation rate. Thus, the particles remain “dry” through the entire process. The particle formation in fluidized bed granulation is influenced by numerous parameters like

1 Moisture content in solids

2 Liquid spray flow rate

3 Airflow rates

4 Atomization pressure

Granulation in fluidized state can be achieved either by batch process or continuous process. For granulation in batch process, the dry starting product is placed in the product container, where it is mixed vigorously in the heated gas stream, held in the suspension and granulated by spraying with a suitable bonding material. The product is finally dried to the required end moisture content. Continuous granulators are sub-divide into several granulation zones, which are operated at different speeds and temperatures. E.g., Granulation in first and second sections, drying in the third section and cooling at the end of the process chamber.

Batch process:

Bottom Spray Top spray

Continuous process:

Bottom Spr Top spray

Figure No. 3: Fluidized bed granulation-continuous process

Advantages:

1. Reduces dust formation during processing.

2. Improves housekeeping and worker safety.

3. Suitable for subsequent coating and controlled release products.

4. Reduces product loss.

Disadvantages:

1. Cleaning isolabour-intensive and time consuming.

2. Assuring reproducibility is troublesome.

iii. Extrusion- Spheronization:

This is used as a method to produce multi-particulates for controlled release application. A multiple step process which involves 5 steps those are capable of making uniform sized spherical particles. The equipment used for spheronization is given in the figure 3. Steps

· Dry mixing of materials of achieves homogeneous dispersion.

· Wet granulation of the resulting mixture to form wet mass.

· The extrusion of wet mass to form rod shaped particles.

· The rounding of the particles in spheronizer.

· Drying of the round particles.

These dried particles are then screened I order to achieve a targeted mean size distribution ¹⁹.

Advantages:

· More than two active agents can be easily combined in any ratio in the same unit.

· Various physical characteristics of the ingredients and excipients can also be modified but using this technique.

· It helps in producing the particles with high bulk density, low hygroscopicity, high spherocity, dust free, narrow particle size distribution and smoother surface.

Disadvantages:

· This process is more laborious and time consuming as compared to other granulation techniques ^20.

iv. Spray Drying:

This process has been divided in three stages:

· Atomization of a liquid feed into fine droplets.

· The mixing of spray droplets with a heated gas streams allows the liquid to evaporate and leave behind the dried solids.

· The dried powder is separated from the gas stream ⁹.

Advantages:

It is a very rapid and continuous process.

· It helps in the overall cost reduction by avoiding the labour intensive drying and the granulation steps.

· It helps in minimal product handling and operator exposure to dust.

· It is suitable for heat sensitive product.

Limitation of wet granulation:

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

b. Loss of material during various stages of processing.

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

d. Multiple processing steps add complexity and make validation and control difficult.

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

2. Dry Granulation or Compression Granulation:

This technique involves the compaction of the components of a tablet formulation by means of a tablet press or with the help of specially designed machinery which is followed by milling and screening before the final compression into a tablet. This process is used for drugs which are sensitive to heat, moisture or both of which precludes wet granulation. In this dry method, the primary particles are aggregated at high pressure as is shown in the figure given below.

It is done by two processes; either a heavy duty tabletting press produces a large tablet or the powder is squeezed between the two rollers and a sheet of material is produced. In both the cases these intermediate products are broken using a suitable milling technique to produce a granular material which is usually sieved in order to separate the desired size fraction^21-23.

3.Novel granulation techniques:

1. Pneumatic Dry Granulation (PDG):

The PDG Technology:²⁴

· Is based on a pneumatic dry granulation process, a novel dry method for automatic or semi-automatic production of granules,

· Enables flexible modification of drug load, disintegration time and tablet hardness

· Can achieve:

i. High drug loading, even with ‘difficult’ APIs and combinations

ii. Taste masking

iii. Excellent stability,

· Is compatible with other technologies, such as sustained release, fast release, coating,

· Is suitable for heat labile and moisture sensitive drugs, and

· Is the subject of a number of patent applications.

The PDG Technology™ produces porous granules with excellent compressibility and flowability characteristics

Granulate Any API:

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.

Pneumatic Dry Granulation Replaces Wet Granulation:

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 excipients⁷.

Advantages of PDG Technology:

The PDG Technology has a number of advantages to support the above claims including the following:

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

· Faster speed of manufacturing compared with wet granulation,

· Lower cost of manufacturing compared with wet granulation,

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

· The end products are very stable - shelf life may be enhanced,

· Little or no waste of material,

· Scale-up is straightforward,

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

· Release time can be tailored to requirements.

Benefits to Pharmaceutical Companies:

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. The unique capabilities of the technology have been demonstrated in number of evaluation studies with top-tier pharmaceutical companies.

2. Freeze Granulation Technology:

This technique has been adopted by Swedish Ceramic Institute (SCI) which enables preservation of the homogeneity from suspension to dry granules. A powder suspension is sprayed into liquid nitrogen, the granules are frozen instantaneously. In a subsequent freeze-drying the granules are dried by using sublimation of the ice without any segregation effects as in case of conventional drying in air. The resulting granules will be spherical and free flowing with optimal homogeneity (Figure.9). This technique helps in easy crushing to homogeneous and dense powder compacts in processing operation ⁹.

Advantages:

· Control of granule density by the solid content of the suspension.

· Serious oxidation of non-oxides and metals is prevented by mild drying.

· Granules have no cavities.

· There is low material waste (high yield)

· Small (50-100 ml suspension) as well as large granule quantities can be produced to equal quality.

· The equipment is easily cleaned and latex binder can be used for cleaning.

· Recycling of the organic solvents is possible.

Typical ceramic powders: Oxides (aluminium oxides, silicon oxide), nitrides (Si3N4) and carbides (SiC), but also nano powders, diamonds and pharmaceuticals like proteins and enzymes.

3. Foamed Binder Technologies (FBT):

Foamed binder technology from The Dow Chemical Company can help you achieve faster, simpler, and safer wet granulation processing²⁵.Using familiar, proven METHOCEL polymers, this technology greatly improves binder distribution in the formulation mix and yields a remarkable array of processing advantages^26.

Compared to conventional spray processing, foamed binder technology can shorten processing times by reducing water requirements. It can improve reproducibility through more uniform binder distribution. Moreover, it eliminates spray nozzles and their many variables in granulation processing equipment. Foam processing also offers better end point determinations and reduced equipment clean-up time.

While foamed binder processing offers many advantages, this technology doesn’t demand new equipment or radical changes in processing techniques. You can very easily use it with familiar high shear, low shear, or fluid bed granulation equipment, in both laboratory- and production-scale settings.²⁷ Our evaluations also show it yields familiar metrics for particle size distributions, solid dose physical properties, and dissolution profiles.

How foam binder granulation works:

Foam granulation takes advantage of the tremendous increase in the liquid surface area and volume of polymeric binder foams to improve the distribution of the water/binder system throughout the powder bed of a solid dose pharmaceutical formulation.

A simple foam generation apparatus is used to incorporate air into a conventional water-soluble polymeric excipients binder such as METHOCEL hypromellose (hydroxypropyl methylcellulose). The resulting foam has a consistency like shaving cream. Hypromellose polymers are ideal candidates for this technology because they are excellent film formers and create exceptionally stable foams.

4. Melt Granulation Technology:

This is technique with the help of which granules are obtained through the addition of either a molten binder or a solid binder which melts during the process. This method is also called melt agglomeration and thermoplastic granulation ^9,30,31.

Principles of melt granulation:

This granulation process consists of three different phases:

· Wetting and nucleation

· Coalescence step

· Attrition and breakage

Wetting and nucleation stage:

In this stage, the binder comes in contact with the powder bed and liquid bridges are formed which leads to the formation of small agglomerates.

Two nucleation mechanisms used are:

· Immersion

· Distribution

Immersion:

· When the size of molten binder droplets is greater than that of fine solid particles, it leads to nucleation.

· This process proceeds by depositing fine solid particles onto the surfaces of molten binder droplets.

Distribution:

· The molten binding liquid is distributed onto the surfaces of fine solid particles.

· The collision of the wetted particles leads to nuclei formation.

· Smaller the binder droplet size, low binder viscosity and high shearing forces are favorable conditions for nucleation by distribution method.

Coalescence steps:

· It involves the nuclei that have residual surface liquid to promote successful fusion of nuclei.

· Plasticity to the nuclei is imparted to the surface liquid which is necessary for the deformation of nuclei surface for coalescence as well as promoting the rounding of granulation.

Attrition- breakage step:

· This is the phenomenon of granulation fragmentation in that are solidified by tray cooling to ambient temperature without the need for drying by a tumbling process.

· Breakage plays an essential role by affecting the properties of melt granulation during the granulation phase.

Requirements of melt granulation:

· 10-30% w/w of meltable binder with respect to that of fine particles is generally used.

· Meltable binder used in this has a melting point within a range of 50-100^°C.

· For immediate release dosage forms, hydrophilic molecules are used while for prolonged release dosage forms, hydrophobic molecules are used.

· Melting point of fine particles used should be at least 20^°C higher than that of the maximum processing temperature.

Requirements for meltable binders:

· It should be solid at room temperature and has melting point ranging from 10 and 80°C.

· These binders should be physically and chemically stable.

· HLB should ensure the correct release of active substance.

There are two types of meltable binders:-

· Hydrophilic meltable binders

· Hydrophobic meltable binders

Meltable binders:

1. Meltable binders should be solid at room temperature and the melting point should lie between 40 to 60° C.

2. The HLB value of the binder should ensure correct release of the active ingredient.

Advantages:

· No solvent is used and the processing steps needed are fewer thereby eliminating the time consuming drying steps.

· There is uniform dispersion of fine particles and it offers good stability at varying pH and moisture.

· They can be applied safely in humans due to their non swellable and water insoluble nature ⁹.

Table 1: List of Binders.

Hydrophilic meltable binders generally used in the melt granulation technique	Hydrophilic Meltable Binder Typical Melting Range (°C)
Gelucire50/13	44-50
Poloxamer 188	50.9
Polyethylene glycols :
PEG 2000	42-53
PEG 3000	48-63
PEG 6000	49-63
PEG 8000	54-63

5. Steam Granulation:

• It is modification of wet granulation. Here steam is used as a binder instead of water.

• In this method of granulating particles involves the injection of the required amount of liquid in the form of steam.

• This steam injection method, which employs steam at a temperature of about 150° C., tends to produce local overheating and excessive wetting of the particles in the vicinity of the steam nozzles, thereby causing the formation of lumps in the granulated product. ³²

Advantage:

· Higher distribution uniformity,

· Higher diffusion rate into powders,

· Steam granules are more spherical,

· Have large surface area hence increased dissolution rate of the drug from granules,

· Processing time is shorter therefore more number of tablets are produced per batch,

· Compared to the use of organic solvent water vapor is environmentally friendly,

· Lowers dissolution rate so can be used for preparation of taste masked granules without modifying availability of the drug.

· Compared to the use of organic solvent water vapor is environmentally friendly,

· Lowers dissolution rate so can be used for preparation of taste masked granules without modifying availability of the drug

· .Figure 12: Steam Granulation Technology

6. Moisture Activated Dry Granulation (MADG)

• In this method moisture is used to activate the granules formation but the granules drying step is not necessary due to moisture absorbing material such as MCC³³.

• The moisture-activated dry granulation process consists of two steps, wet agglomeration of the powder mixture followed by moisture absorption stages.

• A small amount of water (1–4%) is added first to agglomerate the mixture of the API, a binder, and excipients. Moisture absorbing material such as MCC and potato starch is then added to absorb any excessive moisture³⁴.

• After mixing with a lubricant, the resulting mixture can then be compressed directly into tablets. Hence, this process offers the advantage of wet granulation is that eliminates the need for a drying step.

• MCC, potato starch, or a mixture of 50% of each was used as moisture absorbing material. FMC Biopolymer has introduced two new excipient products to the Pharma market: Avicel HFE-102 and Avicel PH-200 LM, which are based on already existing excipients but have been generated to produce a different entity with improved benefits³⁵.

Avicel PH-200 LM, based on microcrystalline cellulose (MCC), has been formulated to reduce the amount of water added to the granulation process Avicel PH-200 LM is a step up from FMC Biopolymer’s Avicel PH-200 which had a moisture level of five per cent. The new product has a moisture level of no more than 1.5 per cent and can absorb approximately three to four times as much water from the granule. This advantage, along with enabling the use of MADG, meant the use of Avicel PH-200 LM could eliminate the extra steps of milling, drying and screening, thereby reducing manufacturing costs and energy used. The process also produced a larger particle size for optimal flow. This increases efficiencies to the manufacturing process. It takes aspects of wet granulation but eliminates the drawbacks of it. Also be useful for the use of active pharmaceutical ingredients (APIs) which were sensitive to moisture.

Avicel HFE-102 is a new, proprietary co-spray dried MCC/mannitol high functionality binding excipient for direct compression. The co-spray drying added extra benefits to the excipient as it changed its properties combining the high compressibility of MCC and the low lubricant sensitivity of Mannitol.

The outcome was a harder, less friable and faster disintegrating tablet³⁶.

Advantage:

· It utilizes very little granulating fluid.

· It decreases drying time and produces granules with excellent flow ability.

· Single production equipment (high shear granulator)

· No equipment change

· Lower tablet capping

No over and under granulation

7. Granulex® Technology:

The Granurex® precisely and consistently performs both coating and powder layering processes. In the pictures to the right, multiple coating and powder (ingredient) layers demonstrate the accuracy and control of a Granurex® rotor processor, including the creation of the nonpareil.

Key feature:

Unique, Efficient Granulation Processes: Granules produced by the Granurex® are dense and spherical in shape. The pictures and graphs shown below demonstrate how the Granurex® processes Ciprofloxacin from a 7μm poorly flowing powder to 200μm granules with excellent flow characteristics. One Pot Processing: A patented feature of the Granurex® is its ability to dry product within the same processing chamber. This unique drying method, combined with 12 bar construction, provides a true one-pot system, ideal for manufacturing highly potent and expensive pharmaceutical compounds.

Increased Batch Capacities:

The patented conical rotor plate increases batch capacities when compared to traditional rotor processors. The precision machined gap contains the product within the processing area and the peripheral spray guns are embedded into the product, which provides accurate coating with minimal spraying defects.

Maximum Process Flexibility:

Using micronized acetaminophen as the base material, the Granurex® produced both a 100 μm granulation and a 200 μm spherical bead. In both of the examples below, the APAP core material had the same initial Mean Particle Size (X50) of 40 μm³⁷.

8. TOPO Technology:

HERMES PHARMA has developed a unique technology for carrying out single pot granulation. This process requires a very small quantity of liquid to start the chain reaction. Pure water or water-ethanol mixtures are used.

TOPO Technology produces granules for tablets which at least contains one solid crystalline, an organic acid and one alkaline or alkaline earth metal carbonate that reacts with the organic acid in aqueous solution to form carbon dioxide. As a result there are no solvent residues in the finished products; granules have excellent hardness and stability. TOPO Granulator was employed for producing effervescent tablets following TOPO vacuum granulation technology, patented by Hermes Pharma. It involves granulation under vacuum to prevent uncontrolled chain reaction ¹¹.

9.Continuous Flow Technology:

This method does not require any liquid to start the chain reaction. In this case granulation is carried out in an inclined drum into which powder is fed at one end and granulate is removed at the other. The process produces granule with surface protected by inactive component that do not harm the sensitive API. CF technology can produce up to 12 tons of granules every day.

Advantages:

1. Sensitive APIs are protected.

2. Granules and effervescent become less sensitive to humidity and high temperature.

3. Granules form extremely stable products.

4. No solvent residues in the final products ⁹.

10. Thermal Adhesion Granulation Process (TAGP)

It is applicable for preparing direct tabletting formulations. TAGP is performed under low moisture content or low content of pharmaceutically acceptable solvent by subjecting a mixture containing one or more diluents and/or active ingredients; a binder; and optionally a disintegrant to heating at a temperature in the range from about 30ºC to about 130ºC in a closed system under mixing by tumble rotation until the formation of granules. This method utilizes less water or solvent than traditional wet granulation method ^38,39 It provides granules with good flow properties and binding capacity to form tablets of low friability, adequate hardness and have a high uptake capacity for active substances whose tabletting is poor.

In thermal adhesion granulation, granules are formed during mixing of the moist powder under continuous tumble rotation, as the heated powder mass flows within the container and agglomerates with the aid of the binder Drying and milling to form the desired granules are unnecessary in the present invention due to the low amount of moisture introduced to the tableting mixture⁴⁰

Another major advantage of granulating pharmaceutical products in a closed system is that it helps to minimize the generation of dust during powder processing. This technique serves to contain fine-powder active ingredients whose spread or loss from the system is not desirable due to their cost or biological activity⁴¹

CONCLUSION:

These review works mainly focus on the comparison of granulation and novel granulation techniques to produce granule. Each technique has its own advantage and disadvantages. 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.

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Received on 02.12.2015 Accepted on 08.12.2015

Asian J. Res. Pharm. Sci. 5(4): Oct.-Dec. 2015; Page 203-215

DOI: 10.5958/2231-5659.2015.00030.2

ABSTRACT: