Review on a novel approach in Recent Advances of granulation techniques and technologies

 

Gowripattapu Sridevi¹*, Vasanthi Korangi², S. Madhavi Latha¹

Aditya Pharmacy College, Surampalem, Andhra Pradesh, India-533437

Jawaharlal Nehru Technological University Kakinada 533004.

 

ABSTRACT:

Granulation refers to the act or process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. It is the process of collecting particles together by creating bonds between them. Bonds are formed by compression or by using a binding agent. Granulation is extensively used in the manufacturing of tablets and pellets. Pharmaceutical granules typically have a size range between 0.2 and 4.0 mm, depending on their subsequent use. After granulation the granules will either be packed or they may be mixed with other excipients prior to tablet compaction or capsule filling. Granules are produced to enhance the uniformity of the API in the final product, to increase the density of the blend so that it occupies less volume per unit weight for better storage and shipment, to facilitate metering or volumetric dispensing, to reduce dust during granulation process to reduce toxic exposure and process-related hazards, and to improve the appearance of the production. This review focuses on the recent progress in the granulation techniques and technologies. This review gives an overview of these with a short description about each development along with its significance and limitations.

 

 

INTRODUCTION:

In the pharmaceutical industry, granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. It is the process of collecting particles together by creating bonds between them. Bonds are formed by compression or by using a binding agent. Granulation is extensively used in the manufacturing of tablets and pellets^[1]. 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.

 

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 ^[2].Granules are produced to enhance the uniformity of the API in the final product, to increase the density of the blend so that it occupies less volume per unit weight for better storage and shipment, to facilitate metering or volumetric dispensing, to reduce dust during granulation process to reduce toxic exposure and process-related hazards, and to improve the appearance of the production. ^[3]

 

OBJECTIVE OF THE STUDY:

The main objective of the present study is to this review focuses on the recent progress in the granulation techniques and technologies.

 

Ideal characteristics of granules:

The ideal characteristics of granules include spherical shape, smaller particle size distribution with sufficient fines to fill void spaces between granules, adequate moisture (between 1-2%), good flow, good compressibility and sufficient hardness. The effectiveness of granulation depends on the following properties.^[4]

 

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).

 

Method of granulation methods:

Generally there are 2 methods of granulation wet and dry.

 

Dry granulation methods:

The primary advantages of dry granulation are its simplicity and low cost. There are three common methods.

 

Direct compression:

This method simply combines the drug-substance powder with the excipients powders in a blender. The blend then moves directly to a tablet press or capsule filling machine.

 

Slugging:

In this method, poor-flowing blends are compressed using a rotary tablet press fitted with a die much larger than the die used to make the final tablet, forming “slugs.” Slugs are typically 1 inch in diameter or larger, and there is little attention paid to weight variation or compression properties. Instead, the objective is to make the slug as hard as possible. Next, the slugs pass through a mill, join additional excipients in a blender, and are transferred to a tablet press or capsule filling machine. Occasionally, products require double slugging to densify the mixture enough to obtain the desired flow properties.

 

Roller compaction:

In this method, typically used with moisture-sensitive drug substances and formulations with poor flow characteristics, the material flows between two rollers that compact it. The rollers come in a variety of designs so the formulator can produce compacts of the correct hardness. The compacts are subsequently milled, blended, and made into tablets or filled into capsules. In addition to its ability to process poor-flowing and moisture- sensitive materials, roller compaction entails low labor costs and can be adapted for continuous production. ^[5]

 

Steps involved in the dry granulation ^[6]

·         Milling of drugs and excipients

·         Mixing of milled powders

·         Compression into large, hard tablets to make slug

·         Screening of slugs

·         Mixing with lubricant and disintegrating agent

 

Disadvantages:

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.

 

Wet granulation methods:

Wet granulation methods introduce a fluid onto a shearing mass of fine powders contained in a vessel. Wet granulation equipment includes low-shear and high-shear mixers, fluid-bed processors, rotating drums, and pan mixers. Successfully agglomerating primary particles requires controlling the adhesion forces between particles. It’s these forces that encourage agglomerates to form and grow and that determine whether the agglomerates have sufficient mechanical strength. The rheology of the particles before they’re agglomerated is sometimes also critical to rearranging them in a way that permits densification of the agglomerate and development of an agglomerate structure that suits end-use requirements. ^[7]

 

Steps involved in the wet granulation:^[8]

·         Mixing of the drugs and excipients

·         Preparation of binder solution

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

·         Coarse screening of wet mass using a suitable sieve (6-12 screens)

·         Drying of moist granules.

·         Screening of dry granules through a suitable sieve (14-20 screens)

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

 

Disadvantages:

Process is expensive because of labor, space, time, special equipment and energy requirement,

Multiple processing steps involved in the process add complexity, Loss of material during various stages of processing, Moisture sensitive and thermo labile drugs are poor candidates.

 

Advances in granulation theory:

Many researchers have used empirical methods to study how the material properties of the granulating powder and how the process conditions influence the granulation process. Recent studies, however, emphasize the influence of material properties and the particle wetting mechanism. Iverson et al. presented an excellent review of the wet granulation process. ^[9] Other researchers have added to our understanding of the traditional granulation process ^[10] and proposed a more modern approach^[11]. Three fundamental sets of rate processes within the granulation process that are important in determining wet granulation behavior:

1. Wetting and nucleation 2.Consolidation and growth 3. Breakage and attrition.

 

Iverson and co-authors also cited other work that describes the current thinking about granule growth^[12-13]. In the wetting and nucleation stage, the powder is strongly influenced by the spray rate or distribution of the binding fluid and by the properties of the powders. In the consolidation and growth stage, partially wetted particles and large nuclei coalesce to form granules and develop internal void age, also known as granule porosity. In the breakage and attrition stage, the granules that are inherently weak or that developed flaws during drying are particularly susceptible to attrition. Schaefer and Matheson proposed two different mechanisms that cause nucleation in a high-shear mixer: distribution and immersion ^[14].

 

Distribution mechanism:

This occurs in cases where the binder droplets are small. They coat the primary particles, and the wetted particles coalesce to form initial granules. Low-viscosity binders and high-speed impellers promote the occurrence of this mechanism ^[15].

 

Fig. 1: Nuclei formation mechanisms (adapted from Schaefer and Matheson)

 

Immersion mechanism:

This occurs when binder droplets engulf the primary particles. It commonly occurs when binder viscosity is high and impeller speed is low. Ennis proposed a model to describe the influence of viscosity on granule growth when wet-surface granules coalesce ^[16]. In this model, when two granules collide, a viscous liquid layer surrounding the granules dissipates the impact energy. If the impact energy is high and the viscous liquid layer cannot dissipate all the energy, the granule rebounds instead of adhering. If all the energy is absorbed, however, the granules stick together. This explains why granules formed in a high-shear mixer are denser than those formed in a fluid-bed granulator: The granules deform during processing in proportion to the intensity of bed agitation. Where large granule deformation occurs during granule collisions, granule growth and consolidation follows ^[17]. See Figure 2. Rather than “sticking” together as often occurs in the low-deformability environment of fluid beds, high-shear mixers “smash the granules together. In short, high-agitation, high deformation processes generally produce denser granules than low-agitation, low-deformation processes. The breakage mechanism is strongly influenced by material properties and bond strength, and any granule breakage mechanism that causes a continuous exchange of primary particles promotes granule homogeneity. Breakage in a high-shear mixer is of significant importance. There are various forms of breakage, including cleavage of particles and particle surface attrition, in which granules are chipped when they collide with other particles, vessel walls, or the impeller.

 

Fig. 2: The rate processes of agitate granulation, which include powder wetting, granule growth and consolidation, and granule attrition, combine to control granule size and porosity. These rate processes may be influenced by changes to the formulation or the granulation process.

 

Recent progress in dry granulation method:

Dry granulation could be achieved either by roller compaction or by slugging. There has not been much progress in the dry granulation technique and technology in comparison to wet granulation, except for one important innovation known as pneumatic dry granulation technology developed by Atacama Lab soy (Helsinki, Finland), which is described below. ^[18]

 

Pneumatic Dry Granulation (PDG):

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 flow ability and compressibility. ^[18-19]. 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 and are either returned to the roller compactor for immediate reprocessing (recycling or recirculation process) or placed in a container for reprocessing later to achieve the granules of desired size. ^[19-20]. The schematic diagram of this process is represented as Fig. 3. 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 flow ability could be achieved even at lower roll compaction forces (lower solid fractions) compared to usual roller compaction. ^[21].  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 a major issue regarding this technology.

 

Fig. 3: Schematic diagram of pneumatic dry granulation

 

 

Advantages of PDG Technology:

The PDG Technology has a number of advantages to support the above claims including the following: 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, and 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. ^[22-23].

 

 

Recent progress in wet granulation:

Wet granulation is the widely used technique and the granules are produced by wet massing of the excipients and API with granulation liquid with or without binder. The steps involved in conventional wet granulation technique could be seen in Fig. 4. Wet granulation has witnessed various technical and technological innovations such as steam granulation, moisture-activated dry granulation or moist granulation, thermal adhesion granulation, melt granulation, freeze granulation, foamed binder or foam granulation, and reverse wet granulation.

 

Reverse wet granulation:

Reverse wet granulation or reverse-phase wet granulation is a new development in the wet granulation technique that involves the immersion of the dry powder formulation into the binder liquid followed by controlled breakage to form granules ^[24]. According to this invention, the binder solution was prepared initially and the dry powder excipients were added to the binder solution under mixing in granulator. Alternatively, the drug was mixed with a solution of hydrophilic polymer and/or binder to form a drug-polymer/binder slurry as a granulating fluid. Granules were then formed by immersing a mixture of other dry excipients into the drug polymer/binder slurry. The resulted wet granules were milled after drying. The granules produced by this process were found to have good flow and handling characteristics like those produced with wet granulation process. In addition, tablets formed from these granules eroded more uniformly during dissolution testing as compared to usual wet granulation technique. The schematic diagram of this process is presented in Fig. 5. Controlled breakage was proposed to be the predominant granule formation mechanisms in reverse wet granulation technique. ^[25-26].

 

Fig.4: Schematic diagram of conventional wet granulation

 

 

Advantages:

It is purported that this technique improves the dissolution characteristics of the poorly water-soluble drugs by allowing uniform distribution of the binder that acts as a wetting agent and enable adequate wetting of the drug substance during granulation. It also increases the chances of adequate and uniform contact between the drug and hydrophilic polymer for better dissolution. These improved granule characteristics result in even erosion of tablets during dissolution. The advantages of this technique over conventional wet granulation include small and spherical-shaped granules with improved flow properties, uniform wetting and erosion of the granules. This technique could be suitable for poorly water-soluble drugs because of the intimate association between a drug and the polymer. However, this technique produced granules with a greater mass mean diameter and lower intragranular porosity when compared to the conventional wet granulation at lower binder concentrations.

Steam Granulation:

In steam granulation as a new wet granulation technique, water steam is used as binder instead of traditional liquid water as granulation liquid.13 Fig. 6 shows the schematic diagram of steam granulation. 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. 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 ^[27].  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.

 

 

Fig 5. Schematic diagram of steam granulation

Advantages:

Higher distribution uniformity, higher diffusion rate into powders, steam granules are more spherical and 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. Equipment such as high-shear mixer coupled with a steam generator would be enough for this technique. However, this method requires high energy inputs for steam generation. Besides, this process is not suitable for all binders and is sensitive to thermo labile drugs. The granules produced by this process have higher dissolution rate due to increased surface area of the granules compared to conventional wet granulation process ^[28-29].

 

Moisture-Activated Dry Granulation (MADG):

This technique is a variation of conventional wet granulation technique. It uses very little water to activate a binder and initiate agglomeration ^[30]. This technique involves two steps,

1) Wet agglomeration of the powder particles, and

2) Moisture absorption or distribution.

 

Agglomeration is facilitated by adding a small amount of water, usually less than 5% (1-4% preferably), to the mixture of drug, binder and other excipients. The two steps of this MADG are presented in Fig.6 Agglomeration takes place when the granulating fluid (water) activates the binder. Once the agglomeration is achieved, moisture-absorbing material such as microcrystalline cellulose, silicon dioxide, etc. is added to facilitate the absorption of excess moisture. The moisture absorbents absorb the moisture from the agglomerates, resulting in moisture redistribution within the powder mixture, leading to relatively dry granule mixture. During this moisture redistribution process, some of the agglomerates remain intact in size without change, while some larger agglomerates may break leading to more uniform particle size distribution. It does not require an expensive drying step ^[31-36].^. The process does not lead to larger lumps formation since the amount of water used is very small compared to usual wet granulation. The particle size of the agglomerates is mainly accounted to be in the range of 150-500μm. This technique is also known as “moist granulation technique” leading to confusions with the use of appropriate terminology. Some authors believe that dry granulation involves the use of a roller compaction or a slugging step followed by milling to obtain granules. However, this technique did not use either of those steps. The technique is the same and this review uses the terminology “Moisture-Activated Dry Granulation (MADG)” coined by the inventors of this technique in 1987. FMC Biopolymer has introduced two new excipients 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 benefits. ^[37]. 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. 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 ^[38]. Avicel HFE-102 is a new, proprietary co-spray dried MCC/mannitol high functionality binding excipients for direct compression. The co-spray drying added extra benefits to the excipients 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 tablet. ^[39].

 

Fig. 6. Schematic diagram of moisture-activated dry granulation

Advantages:

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.

 

However, this technique could not be used for the preparation of granules that require high drug load and for moisture sensitive drugs and hygroscopic drugs due to stability and processing problems associated with these types of drugs. A high-shear mixer coupled with a sprayer would be suitable equipment for the MADG process. An ideal machine should be equipped with efficient impellers, blades, and choppers to allow good mass movement and proper mixing of the granulation mass ^[40-43].

Thermal Adhesion Granulation (TAG):

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 ⁴⁴. This is clearly presented in Fig as a schematic diagram. 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 excipients 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. Granules of the required particle size can be obtained after cooling and sieving ^[44-45]. 

 

Advantages:

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, provides granules with better particle size, good flow properties, high tensile strength that could be directly compressed into tablets with adequate hardness and low friability, it helps to minimize the generation of dust during powder processing

 

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 thermo labile drugs ^[45-47]. 

 

Fig. 7. Schematic diagram of thermal adhesion granulation

 

Melt granulation:

Melt granulation or thermoplastic granulation is a technique that facilitates the agglomeration of powder particles using melt able binders, which melts or softens at relatively low temperature (50–90 °C) ^[48].   Fig. represents the schematic diagram of melt granulation. Cooling of the agglomerated powder and the consequent solidification of the molten or soften binder complete the granulation process ^[49-50].   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. 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 ^[51-53].   Melt granulation is an appropriate alternative to other wet granulation techniques which are used for water sensitive materials ^[54].   Moreover, in comparison with the conventional wet granulation process, it proposes several advantages ^[55].  

Requirements of melt granulation:

·         Generally, an amount of 10–30% w/w of meltable binder, with respect to that of fine solid particles, is used.

·         A Meltable binder suitable for melt a granulation has a melting point typically within the range of 50– 100_C.

·         Hydrophilic Meltable binders are used to prepare immediate-release dosage forms while the hydrophobic Meltable binders are preferred for prolonged-release formulations.

·         The melting point of fine solid particles should be at least 20°C higher than that of the maximum processing temperature.

 

Meltable binders:

·         It must be solid at room temperature and melt between 40 and 80°C,

·         Its physical and chemical stability

·         Its hydrophilic-lipophilic balance (HLB) to ensure the correct release of the active substance.

·         There are two type of Meltable binder

1) Hydrophilic Meltable binders

2) Hydrophobic Meltable binder

 

Advantages:

Neither solvent nor water used, Fewer processing steps needed thus time consuming drying steps eliminated, Uniform dispersion of fine particle occurs, Good stability at varying pH and moisture levels, Safe application in humans due to their non-swellable and water insoluble nature ^[55]. 

 

Efficiently applied in order to enhance the stability of moisture sensitive drug and further to    improve the poor physical properties of the drug substance ^[56].While the absence of water excludes the wetting and drying phases, making the entire process less energy- and time-consuming. The major drawback of this process is the need of high temperature during the process, which can cause degradation and/or oxidative instability of the ingredients, especially of the thermo labile drugs. Hydrophilic or hydrophobic. The equipments that could be used for melt granulation are high-shear mixer and fluidized bed granulator ^[57-60].   Interest in melt granulation has increased in recent years, owing to the numerous advantages of this technique over conventional wet granulation process.

 

Fig. 8. Schematic diagram of melt granulation

 

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 ^[61].   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. The above-mentioned steps are depicted as schematic diagram in figure 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.  This technology could be useful for the preparation of granules that needs to be prepared from suspensions whose particle size and homogeneity need to be preserved. Eventually, re-dispersible parenteral formulations, nonmaterial’s, solid self-emulsifying drug delivery systems, etc. could benefit from this technology given its ability to maintain size and homogeneity. The suspension quality always determines and reflects the granule quality in terms of homogeneity. In pharmaceutical industry, the low-temperature and soft freeze drying has vital advantage to minimize damage of organic compounds and improve stability and/or solubility. According to Powder Pro AB, compared with spray drying, freeze granulation obviously produces protein particles with light and porous characteristics, and making powders with superior aerosol performance due to favorable aerodynamic properties ^[61-63]. 

 

Advantages:

Besides, high degree of granule homogeneity, FG offers several other advantages: ^[64].  

 

Control of granule density by the solids content of the suspension, Mild drying prevents serious oxidation of non-oxides and metals, No cavities in the granules, no wastage of material, Small (50–100 ml suspension) as well as large granule quantities can be produced to equal quality, Easy clean of the equipment (latex binder can be used).

Organic solvents with suitable freezing point (-25 to +10 °C) can be used, water as medium is preferred in this process, which could be a limiting criteria given the poor solubility of various drugs and processing excipients. Originally, this process was developed by Swedish Ceramic Institute in the late 1980. Currently, Powder Pro AB, the spinoff company (year 2000) from Swedish Ceramic Institute, develops, manufactures, markets, and sells equipment for freeze granulation.

 

Fig. 9. Schematic diagram of freeze granulation

 

Foam 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. Fig. shows the schematic diagram of this technology. 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^[65]. 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. The surface area and volume of the foamed binder/water are phenomenally high compared to the sprayed water. This technology exploits the characteristics of the foamed binder to successfully improve the distribution of binder onto the powder particles, even at a binder amount lower than that required in the conventional spray granulation method. Besides, the sprayed liquid droplets have a low spread-to-soak ratio, which means they tend to soak into powders and cause over wetting rather than spreading on the surface of the particles, requiring high levels of water and binder, and eventually drying to remove excess water. On the contrary, foamed binders have a high spread- to-soak ratio, and because of this the binders are coated onto the particles rather than soaked, leading to less amount of binder and more consistent binder distribution. These factors improve the reproducibility and shorten the processing time. Most importantly, this technology eliminates the spray nozzles and its related processing variables and clogging problems^[66]. In addition to the above-mentioned advantages, this technology would prove useful for high potent/low dose drug formulations due to its ability to distribute drugs evenly.

 

Advantages:

No spray nozzle is used, Improve process robustness, Less water required for granulation, Time efficient drying, Uniform distribution of binder, No over wetting.

 

Standard equipment such as high/low shear mixer, fluid bed granulator, etc. could be used for this technology in association with a foam generator. Although this technology merits in myriad ways, further understanding of foam quality, process parameters, equipment, flow patterns, mixing behavior, etc. needs to be explored. Besides, the regulatory approval would be a huge hurdle that needs to be overcome ^[67-69].

 

Fig. 10. Schematic diagram of foam granulation

 

Concluding Remarks:

Technical and technological innovations that improve and ease existing processes could contribute to improved process ability and quality of the product formulations in addition to a substantial impact on the product development, time and economy. During the formulation development, each drug substance poses a unique challenge that must be taken into consideration at the process selection stage by the formulation development scientists. Each technique has its own merits and limitations, and the type of technique and technology selection requires thorough knowledge of physicochemical properties of the drug, excipients, required flow and release properties, etc. in addition to the granulation techniques and technologies itself. Here we are mainly focusing on different types of granulation technique. Advanced Granulation techniques like Steam Granulation, Melt/Thermoplastic Granulation, Moisture Activated Dry Granulation (MADG), Moist Granulation Technique (MGT), Thermal Adhesion Granulation Process (TAGP), Foam Granulation selected depends on drug and excipients.

 

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