Pharmaceutical Micropellets : An Overview

Abstract

The major target of Pharmaceutical Sciences is to design a successful and suitable dosage forms for effective therapy, considering individual patient needs and compliance. Development of new technology or development of new dosage form using the existing technology is growing in importance and attracting increased interest, as they are specifically effective at a comparably low dose. Pellets falling in the size range of 1-1000μm are of great interest in the pharmaceutical industry for a variety of reasons which are not only offer flexibility in dosage form design and development, but are also utilized to improve the safety and efficacy of bioactive agents. The most important factor responsible for the proliferation of pelletized products is the popularity of controlled release technology in the delivery of drugs. Moreover, controlled release pellets are less susceptible to dose dumping than the reservoir-type single unit formulations. In case of oral products these pellets solve difficult taste-masking problems, disperse freely in the gastro intestinal tract, invariably maximize drug absorption, reduce peak plasma fluctuations and minimize potential side effects without appreciably lowering drug bioavailability, and also reduce variations in gastric emptying rate and overall transit time, thus, intra and inter subject variability of plasma profiles, which are common with single unit regimens, are minimized. An even more exciting area of application is the use of micropellets for subcutaneous and intramuscular administration and has a tremendous potential as depot formulations using biodegradable polymers. The pelletisation technology can be used to manufacture a broad range of pellet sizes and very small pellets down to 50µm containing drug loads of <95% achievable. This technology delivers almost perfectly spherical particles exhibiting a very narrow particle size distribution and excellent flow properties. In order to design and develop a suitable dosage form, the mechanisms and effective parameters need to be understood and clarified. Therefore, we review the importance and rationale of pharmaceutical development and production of drug pellets, possible formulation variables and aids during the pellets formulation, technologies involved in the fabrication of pellets, various mechanisms involved in the formation of pellets, characterization and application of the pellets and also discussed the results of recent researches on the pharmaceutical drug pellets.

Key words: Micropellets, oral delivery, controlled release, biomaterials.

1.1.0 Introduction

1.1.1 Micropellet technology - Historical development

The microparticles or microspheres, microcapsules, micropellets have been used for different purposes in pharmaceuticals which are falling in the size range of 1-1000μm solid particles. Various industries have routinely utilized pelletization processes since the turn of the century to manufacture particles with defined sizes and shapes, in response to a desire to sustain the release of drugs over extended period of time. A major breakthrough occurred in 1949 when a pharmaceutical scientist at Smith Kline & French (SKF) realized the potential application of candy seeds in sustained release preparations and embarked on the development of tiny drug pellets that could be loaded in capsules². Not only was the process directly applicable to drug candidates, but also the candy seeds or nonpareils, upon drugs were layered, with or with out sustaining material. However, it was the major success of the long acting cold remedy that partially fueled a renewed interest in the development of extended release pelletization products¹.

In 1964, a new pelletization technique that provided sustained release pellets ranging in size between 0.25 – 2.0 mm was patented by SKF. At the same time, the Marumerizer or Spheronizer was commercially introduced^2,3. This new machine was developed in Japan and could produce large quantity of spherical pellets in a relatively short time. The marumizer and variations of it were subsequently patented in the US. The process is capable of producing pellets containing more than 90% active pharmaceuticals, provided that the physicochemical properties of the drug and other formulation constituents are optimum. Direct pharmaceutical application of the process for the development of pellets was first published in the literature in the early 1970s and the process has been the subject of intensive research ever since^4,5,6.

1.1.2 Rationale for pelletization

Pellets are of great interest to the pharmaceutical industry for a variety of reasons^7,8 and these products not only offers flexibility in dosage form design and development, but also utilized to improve the safety and efficacy of bioactive agents. However, the single most important factor responsible for the proliferation of pelletized products is the popularity of controlled release technology in the delivery of drugs. When the pellets containing active ingredient are administered in-vivo in the form of suspensions, capsules, or disintegrating tablets, they offer significant therapeutic advantages over single unit dosage forms⁹, since pellets disperse freely in the GIT, they invariably maximize drug absorption, reduce peak plasma fluctuations and minimize potential side effects without appreciably lowering drug bioavailability.

In case of oral products micropellets solve difficult taste-masking problems¹⁰ while maintaining a high degree of bioavailability due to smaller in size (10 - 600 µm) furthermore, because of the special design of the manufacturing process; dust fractions which could cause taste problems are absent in micropellets. Pellets also reduce variations in gastric emptying rate and overall transit time, thus, intra- and inter subject variability of plasma profiles, which are common with single unit regimens, are minimized.

Another advantage of pellets over single-unit dosage forms is that high local concentrations of bioactive agents, which may inherently be irritative or anesthetic, can be avoided¹¹. When formulated as modified release dosage forms, pellets are less susceptible to dose dumping than the reservoir-type single unit formulations.

Micropellets technology delivers almost perfectly spherical particles exhibiting a very narrow particle size distribution and excellent flow properties and these are characterized by a smooth surface free of dust and thus provide optimal conditions for subsequent film coating¹. Controlled release pellets are manufactured either to deliver the bioactive agent at a specific site within the GIT or to sustain the action of drugs over an extended period of time. While these results have been traditionally achieved through the application of a functional coating material, at times the core pellets themselves have been modified to provide the desired effect. This further enhances the role of pellets in oral dosage form development.

Pellets also provide the pharmaceutical scientist with tremendous flexibility during the development of oral dosage forms. Pellets composed of different drug entities can be blended and formulated in a single dosage form. This approach has numerous advantages. It allows the combined delivery of two or more bioactive agents; they may or may not be chemically compatible, at the same site or at different sites with in the GIT.  It also permits the combination of pellets of different release rates of the same drug in a single dosage form¹². In addition, pellets have an enough surface area-to-volume ratio and provide an ideal shape for the application of film coatings. As pellets flow and pack freely, it is not difficult to obtain uniform and reproducible fill weights in capsules, provided that the size and densities are favorable. Pellets can also be made attractive due to the various shades of color that can easily be imparted to them during manufacturing process. As the application of pellets in the development of oral dosage forms increases¹³, so does our understanding of the basic principles governing pellet formation and growth. Critical process and formation variables are being systematically evaluated and characterized. Consequently, general processing conditions are being adapted to fit to specific manufacturing needs. Due to their unique properties and flexibility of manufacturing involved, pellets are expected to continue to play a major role in the fabrication of solid dosage forms. Many generic companies have already shown an interest in micropellets for the development of superior line extensions of existing products that suffer from taste-masking problems. The antibiotic market also provides a target for this technology and a blockbuster macrolide antibiotic was recently introduced into the market as micropellet formulation.

An even more exciting area of application is the use of micropellets for subcutaneous and intramuscular administration¹⁴. The excellent reproducibility and homogeneity of the particle size and the round shape and smooth surface of the particles make micropellets with sizes smaller than 200 µm a perfect match for powder injectors. Micropellets have a tremendous potential as depot formulations. In sterile dosage form technology only suspensions of (lipophilic) drug particles and micro particles using biodegradable polymers are used as depot principles. Micropellets that use parenterally acceptable polymers ensure that the entire slow release strategies¹⁵ normally used for solid dosage forms can now be made available for sterile products. Drug substance particles can either be coated with biodegradable polymers or embedded in a polymer matrix. Using these approaches, release profiles ranging from days to months and even pulsed release can be obtained at wish. The full impact of systematically agglomerated spherical units or pellets in oral dosage form design and performance was not realized until the early 1950s, when attempts were made to develop extended release products. Since then, the manufacture of pellets has been the subject of intensive research, in terms of both innovative formulations and processing equipment. Traditionally, the word “pellet” had been used to describe a variety of systematically produced, geometrically defined agglomerates obtained from diverse starting materials utilizing different processing conditions. Pelletization is an agglomeration process that converts fine powders or granules of bulk drugs and excipients in to small, free flowing, spherical or semi-spherical units, referred to as pellets^16,17. New Micropellet Technology has opened new avenues in Pharmaceutical Development and Production.

1.1.3 Why Pellets?

Pellets have varied applications in a number of industries and an innovative use of its could achieve maximum profitability. Some of the few instances where smooth surfaced uniform pellets are being successfully used highlighted below:

• Improved aesthetic appearance of products.
• Coating of drug pellets with different polymers to achieve controlled release rate of drugs.
• For immediate release products larger surface area of pellets enables better distribution, dissolution and absorption¹⁸.
• Chemically incompatible products can be formulated into pellets and delivered in a single dosage form by encapsulating them^19,20.
• This technique is used to avoid powder dusting in chemical industries.
• Varied applications are possible e.g., Sustained release detergent powder, milkshake pellets.
• Pellets ensure improved flow properties and flexibility in formulation development and manufacture.
• The coating material may be colored with a dye material so that the beads of different coating thickness will be darker in color and distinguishable from those having fewer coats and the beads or granules of different thickness of coatings are blended together in the desired proportions to give the desired effect.

The thickness of the coat over the drug pellets ensures the rate at which the drug/contents are released from the coated particles. A smooth surface of the pellet provides uniform coating thickness on each pellet and it is effective in dosage form development.

2.1.0 Formulation variables

Excipients may vary widely in their chemical composition and physical properties and are classified mainly in terms of their functional role during the development and manufacture of dosage forms. The physicochemical properties of both excipients and drugs are crucial to the successful development of pelletized products and should be thoroughly examined. Therefore, conventional preformulation screening-involving compatibility and stability of the drug in combination with a variety of excipients-should be performed in the same manner as is done in any solid-dosage form development sequence²¹.

 The major factors that must be considered when determining the type of pelletization process include the intended dose and the physicochemical properties of the drug^22,23, such as solubility, pKa and particle size. However, the selection of appropriate excipients also deserves equal consideration, this is because it is usually the excipients that bring about the formation of pellets of suitable strength and integrity. The excipients not only affect the interplay between the physical (natural) and mechanical forces during pellet formation, but also influence the growth mechanisms of the pellets manufactured by the various processes. Consequently, pellet hardness, friability, size, shape, and dissolution characteristics depend, to a great extent, on the properties of the excipients employed.

2.1.1 Formulation aids

2.1.1a Binders / agglomeration inducers / bridging agents

Binders are adhesive materials²⁴ that are incorporated in pellet formulations to bind powders and maintain pellet integrity and it may be added as a solution than the dry form, although application via solution is more efficient than dry mixing followed by liquid addition. When applied as solution form, binders are dissolved/dispersed in organic or aqueous solvent, however the latter is most preferred and commonly used system in pelletization. Choice of binders may differ from formulation to formulation and it is depending on the process and physicochemical properties of the drug. The mechanism of action of the binder is that initially it forms liquid bridge that holds the particles together; but as the liquid evaporates the precipitating and hardening binder takes over as the main bonding force and the soluble constituents may also crystallize and contribute to the bonding mechanisms.

In powder layering, the drug is layered on the surface of the starter material with the help of binders. Sequential layering of binder and the drug allows the formation and growth of pellets²⁵. In the suspension and solution layering and spray-drying process, the binder is intimately mixed as suspension or solution form with the drug to provide a fairly cohesive mixture. After drying, pellets of appreciable strength are obtained and they are held together mainly by solid bridges formed from the hardening binder and crystallized soluble substances.  

The binders are commonly used in the range of 2-10%w/w or v/v and should be optimized so that the pellets are durable and not friable and yet to maintain the other desirable properties of the pellets, such as releasing the drug at the intended rate²⁶.

2.1.1b Separating agents

Separating agents are materials that adsorb on the surface and promote the separation of pellets into distinct units during a pelletization process²⁷ which are incorporated initially in the formulation or externally during processing to avoid some problems such as pellets may tend to attract one another due to surface charge development during the process, binding the pellets together leads to the formation of aggregates due to subsequent addition of binding agents, and agglomeration of pellets due to the wetness of the surface of the pellets coupled with the local concentration of the binding agents. The amount of separating agent required varies with the type of formulation and the manufacturing process and they are also used in dry form during spheronisation to prevent adhesion of the spheres to the friction plate and the cylindrical wall of the Spheronizer.

2.1.1c pH adjusters

The pH adjusters²⁸ are substances that are incorporated in pellet formulations to influence the microenvironment of drug molecules for a variety of reasons. Generally acid-labile compounds are protected from the acidic region of the GIT by the application of an enteric coating. Buffer systems may also be added to the core formulation to maintain the pH to the core in a favorable range for drug stability. In addition, buffer systems^29,30 may be included in pellet formulations to enhance the dissolution rates of drugs whose solubilities are influenced by changes in the pH for which the dosage form is exposed as it transverses in the GIT and this is particularly true with pellets whose release rates are membrane-controlled and the solubility of the drug plays a major role in determining the rate of release. Therefore, buffer systems are incorporated in pellet formulations to adjust the solubility of drugs to fit a particular process.

2.1.1d Surfactants

Commonly surfactants are used for the same reason that they are used in conventional solid dosage forms. In most pelletization processes, the initial formation and subsequent growth of pellets depends, to some extent, on the liquid bridges that hold the primary particles together, it is therefore, important that the liquid (water in most cases) wets the particles effectively. Surfactants are added to the liquid to improve wettability by lowering the interfacial tension between the liquid and drug particles. Surfactants tend to weaken the liquid bridges and make the pellets friable. In extreme cases, excess fines would be produced. Therefore, addition of surfactants in pellet formulations should be avoided unless it is absolutely essential for the production of pellets that possess specific properties^1,2.

2.1.1e Spheronization enhancers

Spheronization enhancers are formulation aids that improve the production of spherical pellets, mainly during spheronization and balling. These are not only confers plasticity on the formulation, but also impart binding properties that are essential for pellet strength and integrity.

2.1.1f Release modifiers

The main thrust of pelletization process is to manufacture spherical drug cores that will be subsequently coated in a separate step with some sort of a functional membrane or it is also possible to prepare pellet cores that inherently possess specific release profiles in a single step which can be achieved by the incorporation of release modifiers along with drug during the core formulation. Due to the diversity of chemical composition and physical properties of release modifiers, pellet formulations that provide a multitude of release profiles could be designed. Generally, water soluble low molecular weight substances, surfactants and disintegrants may be incorporated in formulations to enhance the release rate of drugs, while water insoluble polymers, hydrophobic substances, inorganic salts, and hydrophilic polymers that swell and/or form gels are incorporated in pellets to retard release rates³¹.

2.1.1g Lubricants

In pelletization process, lubricants are rarely used especially where high-speed rotary equipments are utilized. However, during compression and Extrusion-Spheronization, lubricants may play a crucial role in the successful manufacture of pellets. They are used to reduce the friction between the die wall and powder mix during the compression and ejection phase. They may also aid in the smooth discharge of the pellets from the Spheronizer^2,32.

2.2.0 Process variables

2.2.1 Stirring speed

Stirring operation can be performed using paddle devices which will disperse the precipitate of the drug and the balling could be done by using another type of device i.e, magnetic stirrer. Optimum stirring speed is to be maintained till the entire process to get almost narrow sized pellets. High stirring speed makes spherical crystallization worse because of destruction of crystal agglomerates and lower stirring speed reduces the possibility of obtaining spherical crystals^33,34.

2.2.2 Solvent-nonsolvent

It is very important to select a suitable solvent (good solvent) for a drug exhibiting good solubility and stability; infact a very concentrated solution of drug could increase the densification of the material during the crystallization process. In nonsolvent (poorsolvent), in which drug is less soluble, an appropriate densification will never be reached and spherical crystals would never be formed. Nonsolvent, in which the drug produces precipitation due to good and poor solvent freely miscibles and interaction (bonding force) between the solvents are stronger than the drug interaction with good solvent^1,34.

2.2.3 Temperature

To optimize spherical crystal formation, especially, coated pellets using polymers, special attention has to be given to the difference between the solution temperature T1 and the nonsolvent temperature T₂ (∆T = T₁ – T₂). The reduced temperature is preferred when hydrophilic polymers are used as coating material for drug micropellet formulations³⁵.

2.2.4 Viscosity

The good solvent and poor solvent viscosity has a slight influence in the formation of spherical micropellets in terms of its size. Low viscosity of the medium produces narrow size distribution than the one with high viscosity³⁴.

3.1.0 Techniques to produce micropellets

Pellets range in size, typically, between 10 – 1000µm, though other sizes could be prepared, depending on the processing technologies employed. The reproducibility of pellet size distribution, surface area, smoothness and density of the pellet in addition to reproducibility of morphological properties of the pellets, should become the criteria by which a suitable process be selected.

3.1.1 Spherical agglomeration / pelletization / balling

Spherical- agglomeration / pelletisation / balling is a pelletization technique, in which powders (crystalline, amorphous etc.) are converted into spherical agglomerates / pellets by a continuous rolling or tumbling action using suitable solvent systems and processing conditions. This system was traditionally used to separate or recover fine solids dispersed in a liquid suspension by the addition of a third liquid/binder which is capable of forming small liquid bridges that holds the particles together.

Spherical agglomeration / pelletization can be divided into two categories – liquid induced and melt induced. Liquid induced agglomeration / pelletization technique- a quasi-saturated solution of drug in a good solvent is poured in to a poor solvent and both good and poor solvents are freely miscible and interaction (bonding forces) between the solvents is stronger than drug interaction with the good solvent, crystals precipitate immediately and form agglomerate or nuclei, which initially are bound together by liquid bridges. These liquid bridges between the crystals are due to capillary negative pressure and interfacial tension between the interfaces of solid and liquid³⁶. These are replaced by solid bridges by the addition of bridging liquid³⁴ (isopropyl alcohol) / binder or any other dissolved material within the liquid phase. The nuclei formed collide with other adjacent nuclei and coalesce to form large nuclei or pellets. The coalescence process continues until a condition arises in which bonding forces are overcome by breaking forces. If the surface moisture is not optimum, some particles may undergo nucleation and coalescence at different rates and form different size of nuclei admixed with the larger pellets. This process is called ‘Spherical agglomeration’³⁷. When the interaction between the drug and the good solvent is stronger than that of the good and poor solvents, the good solvent drug solution is dispersed in the poor solvent, producing quasi emulsion droplets, even if the solvents are normally miscible. This is due to an increase in the interfacial tension between the good and poor solvents. Then the good solvent gradually diffuses out of the emulsion droplet in to the outer poor solvent phase. The counter-diffusion of the poor solvent into the droplet induces the crystallization of the drug within the droplet due to decreasing solubility of the drug in the droplet containing the poor solvent. This process is called ‘Emulsion solvent diffusion’³⁸. The rate and extent of agglomerate formation depends on the formulation variables such as particle size and solubility of the powder, the degree of liquid saturation, equipment, temperature, agitation speed and the viscosity of the medium.

A microchannel (MC) emulsification technique^39-41 have been used for preparing gelatin beads by preparing water-in-oil (W/O) and oil-in-water (O/W) emulsions of gelatin solution as disperse phase with Iso-octane containing 5%w/w Tetraglycerin con-densed ricinoleic acid ester as continuous phase and the primary emulsion temperature was then lowered to 5°C by rapid air cooling and stirring to completely solidify the droplets of the disperse phase. The gelatin beads were separated by suction filtration, washed quickly with hexane pre cooled to 5°C, and finally dried to get the narrow sized beads.

3.1.2 Pelletisation by Fluid Bed System

The major advantage is that all the operations from mixing to bead formation, bead drying and bead coating can all be done in a single machine. Uniform spherical pellets are formed using Tangential Spray Attachment⁴² or Roto-Processor attachment in the fluid bed system and the top-spray / bottom spray attachment can be used for making granules / coating respectively. Further development of the process resulted in equipment capable of continuous manufacture of pellets with particle sizes between 10 and 600 µm with striking homogeneity. Micropellets are manufactured in a continuous fashion by means of an adapted fluidized bed process combined with a fractionation device to yield mechanically stable pellets⁴³. Direct spraying of the drug solution or suspension into an empty drying chamber maintained at a raised temperature results in finely dispersed starter seeds for further granulation being formed. Selection of proper drying conditions can ensure that the seeds can be maintained in a fluidized bed and serve as nuclei for the droplets with drug in solution or suspension which is continuously sprayed into the chamber. Careful control of the spraying conditions will lead to a very well controlled growth of the particle size of granulates. With the use of a zigzag fractionating device operating at conditions, which ensure that only particles with defined size and density can leave the chamber, very homogeneous micro particles can be harvested in a continuous fashion.

3.1.3 Roto processor for drug loading, pellet coating and tablet coating

In roto processor, specially designed baffles, bottom plate, low speed rotation, enables it to coat pellets and tablets, and it can also be used for drug loading. High controlled speed of rotation enables pellet formation by this principle⁴⁴.

3.1.3a Process Description

Fluid bed rotor process by principle is a horizontal Wurster process which utilizes the main features like concurrent spraying below the product bed without premature droplet evaporation, high kinetic energy inside the product that is created by the rotating disc, and regular statistical exposure of the particles to the spray nozzle by means of a defined disc rotation speed.

The fluid bed processing is not limited to film coating only, but permits a number of process versions. Unlike the Wurster process the rotor is not suited for the film coating of powder, due to the higher kinetical energy produced by the centrifugal forces of the fast rotating disc.

3.1.4 Pelletisation by Extrusion and Spher'oidisation

The Extrusion and Spher'oidisation process was first introduced to the pharmaceutical industry in 1964 with the invension of the marumerizer. Since then, significant improvements have been made to the machine, and currently well-designed marumerizers of different sizes are commercially available. The process involves first making extrudes from the powder material and then converting extrudes into beads using the spheroidizer⁴⁵. The powder material could be any kind of powder (drug powder, ayurvedic powder, food ingredient powder, detergent powder, nuclear powder etc), beads as fine as 0.6mm can be made. The extrusions can be made using two types of Extruders:

1.Die-roller design extruder

2.Twin Screw Extruder

Depending on the application a suitable extruder is suggested to the client. In some cases by selection of proper excipients and by controlling other variable parameters similar spherical granules can be produced using either of the techniques. Depending on the formulations one of the processes may be more appropriate than the other and the choice of the appropriate equipment should be done only after conducting appropriate trials using both the techniques⁴⁶.

3.1.5 Pelletisation by Coating Pan Technique

Coating pan technique is a very conventional method used for making uniform pellets. However, it is very labor oriented and time consuming. The resultant pellets do not have a smooth surface, which is required for uniform coating of the same; hence the extrusion spher'oidization process gains importance.

3.1.5a Coating

In this era when the implications of GATT are on the anvil different molecules and differential formulations have become a necessity. Differential release patterns, aesthetic appeals have become the order of the day⁴⁷. In order to achieve the same the coating of the pellets and particles with relevant polymers plays a very important role. Coating can be done in solid drug layering machine which is an open system or by using the fluid bed technology. The various techniques used for the manufacture of micropellets of some drugs are shown in Table 1.

4.1.0 Mechanism of pellet formation and growth

One of the most significant properties of pellets is their ability to withstand the mechanical forces that act on them during the manufacturing process and the subsequent conditioning and/or coating and handling. If the pellets lack sufficient mechanical strength, they may disintegrate completely or wear down in size due to frictional forces. The ability to withstand the mechanical forces becomes pronounced during a coating operation, particularly in fluid bed equipment where pellets are in constant motion and rub against each other and against the walls of the instrument. It is absolutely essential, therefore, that pellets possess sufficient strength to overcome any appreciable abrasion during agitation². The role that pellet strength plays during the development of high-quality products has been well recognized. There are number of procedures to evaluate and various theoretical and mathematical expressions designed to explain the strength of pellets, mechanism of pellet formation and growth and the fundamental bonding forces that determine the strength of pellets during any pelletization process^48,49.

4.1.1 Bonding forces

The strength of pellets depends on the physical forces that bond the primary particles together. Initially, mechanical forces, such as tumbling, kneading, agitating, extruding, rolling, and compressing are needed to bring individual particles in contact with one another, these physical forces are also responsible for the inherent strength of other types of agglomerated particles⁴⁹.

4.1.1a Attraction between solid particles

Attractive forces are short-range forces that cause solid particles to adhere to each other only if they are brought close together, their effectiveness diminishes dramatically as the size of the particles or interparticle-distance increases⁵⁰. Therefore, the significance of attractive forces in the overall mechanism of agglomerate bonding is not only play a crucial role in the binding of the final product but they initially hold and orient the particles in a contact region long enough for stronger forces to take over.

4.1.1b Interfacial forces and capillary pressure in movable liquid surfaces

In any wet agglomeration process, it is the liquid phase in the system that initially generates the cohesive forces between particles. Therefore, the amount and type of solvent present at any given time is very critical in determining the strength of the final product (Figure 1.1). The solvent could be added prior to or during the agglomeration step. When the solvent is added initially, part of the void space in a randomly packed material is filled with the liquid to form discrete lens-like rings at the contact and coordination points between particles forming the agglomerates^39,40. During the agglomeration process, when the ratio of the liquid to the void volume is low and air is the continuous phase, is known as the pendular state (Fig 1.1A) Mutual attraction of particles is brought about by the surface tension of the liquid and the negative suction pressure generated at the liquid bridges. The forces that bond the particles are, therefore, derived from the interfacial tension at the liquid-gas interface. The capillary state is reached when all the void space within the agglomerate is completely filled with the liquid (Fig 1.1C). The quantity of liquid, however, is not sufficient enough to surround the agglomerate. Since the liquid extends up to the edges of the pores at the surface, a concave meniscus, which creates a negative capillary pressure, develops at the surface of the agglomerate and gives rise to bonding forces. Capillary pressure and interfacial forces create strong bonds between particles, which disappear once the liquid evaporates⁵¹.

In between the pendular and capillary states exists an intermediate state known as funicular state (Fig 1.1B). In the funicular state, as in the pendular state, liquid bridges containing gas and pores filled with liquid are present and the cohesive strength of the agglomerate is attributed to the bonding forces exerted by the pendular bridges and capillary suction pressure. In the droplet state liquid completely envelopes the agglomerates (Fig 1.1D) and the primary particles are held together only by the surface tension of the droplet⁵². There is no interparticle capillary bonding and the concave surfaces observed with the capillary state are replaced by the convex surfaces of the liquid droplets. Thus, the strength of the droplet is dependent only on the surface tension of the liquid used⁵³.  

4.1.1c Adhesional and Cohesional forces

Many viscous binders harden during the agglomeration process and form solid bridges (Figure 1.2). Thin-adsorption layers are also immobile and can form strong bonds between adjacent particles by either smoothing out surface roughness or increasing the interparticle contact area or by decreasing the effective interparticle distance and allowing the intermolecular attractive forces to participate in the bonding mechanism² (Fig 1.2A). The areas of contact of adsorption layers increase appreciably when the solid particles are subjected to a high pressure like compression and produce high bonding forces.

4.1.1d Solid bridges

The above methods described the forces that initially bond the primary particles together; it is the solid bridges that largely determine the strength of the final cured or dried product, formed by different mechanisms (Fig. 1.2B) such as:- 

1.Crystallization of the dissolved substances, as the dissolving medium evaporates, the dissolved substance may be identical to the bonded particles in nature or it may be the solid component of the binding liquid.

2.  Hardening binders are commonly used in the form of solutions to agglomerate primary particles. Upon curing, these binders harden and form bridges that owe their strength to the properties of the binder substance itself, the forces of adhesion between the binder and particles and /or the physicochemical characteristics of the particles forming the agglomerate⁵⁴.

Substances that melts on the input of energy tend to solidify when cooled, and invariably form strong, solid bridges between particles. The strength and extent of the bridges formed can be either small or large depending on the chemical composition of the molten material and the other constituent of the agglomerate.

Sintering and chemical reaction mechanism by which the solid bridge formation is not common in the pharmaceutical industry.

The most common solid-bonding mechanisms that are usually encountered during the manufacture of drug pellets are hardening of binders, crystallization of solutes during the curing or drying stage of the pelletization process and melting and subsequent cooling of pellet components that may occur during compression, extrusion or spray congealing.

4.1.1e Mechanical Interlocking

Mechanical Interlocking of particles may occur during the agitation and compression of fibrous, flat-shaped and bulky particles (Fig 1.2C). It is probably a minor contributor to pellet strength. However, it can provide sufficient mechanical strength.   

4.1.2 Elementary growth mechanisms

It is essential that the fundamental mechanisms of pellet formation and growth are clearly understood in order to optimize any pelletization process. On the basis of various theories, techniques and experimental reports, a formal representation of the elementary growth mechanisms of pellet formation is shown in (Fig 1.3). These mechanism known as nucleation, coalescence, abrasion transfer and layering, are believed to constitute a complete set of elementary events, which, directly or indirectly influence the growth and formation of pellets during manufacture⁴⁹.

4.1.2a Nucleation

It is a growth mechanism in which primary particles are drawn together to form three-phase air-water-solid nuclei (Fig 1.3A). The particles are held together by liquid bridges, which are pendular in nature. The liquid is either added to the primary particles at once in a carefully controlled manner or sprayed slowly onto a mass of dry powder to produce moist nuclei. An important feature of nucleation is that both the mass and nature of the nuclei in the system changes as a function of time⁵⁵. 

4.1.2b Coalescence

The formation of large sized particles following random collision of well-formed nuclei is known as coalescence (Fig 1.3B). Successful collisions occur only if the nuclei have a slight excess of surface moisture, if it is not so, the nuclei cannot deform and coalesce easily unless subjected to significant mechanical pressure. In coalescence, the total mass of the system does not change, although the number of nuclei is progressively reduced.

4.1.2c Layering

Layering⁵⁶ is a growth mechanism that describes the successive deposition of materials on already formed nuclei (Fig 1.3C). The material deposited over the nuclei may be dry or moist and the growth rate is always slow, since a small amount of material is added to the growing nuclei at any given time. Although the number of particles remains same, the particle size increases uniformly as a function of time, thereby increasing the total mass in the system.

4.1.2d Abrasion transfer

Abrasion transfer involves the transfer of material from one particle to another without any preference in either direction (Fig 1.3D). It is therefore, apparent that the situation does not result in a change in the total number or mass of the particles. The particles, however, undergo a continuous change in size as long as the conditions that lead to the transfer of material persist.

4.1.2e Size reduction

There are three size reduction mechanisms that have an indirect effect on the elementary growth mechanisms, particularly layering, and to some extent coalescence. Well-formed particles may undergo size reduction due to attrition, breakage and shatter. If the particles have sufficient surface plasticity, however, they may coalesce to form larger particles upon collision.

4.1.3 Pellet formation and growth

Depending on the type of equipment and process selected for pellet formation and growth may occur in a number of ways. The following methods describe the systematic formation of pellets during the various pelletization processes in terms of the bonding forces and the elementary growth mechanisms.

4.1.3a Balling

This technique is not popular in the pharmaceutical industry as a pelletization process, probably due to the constraints of particle size distribution and content uniformity. Work in this area is expected to continue. It is appropriate, therefore, to examine the various phases of pellet growth in a drum, pan, or disc pelletizer. The first phase, known as the nucleation region, involves the random collision and subsequent coalescence of the primary particles to provide well-formed nuclei⁵⁷. The sizes of the nuclei depend on the sizes of the primary particles, the moisture content, the viscosity of the binding liquid, and the wettability of the substance. Followed by the transition region where particles collide with each other and coalesce in a preferential molten, or where smaller particles are crushed and layered on large particles. This mechanism in this region is, therefore, size dependent, fines that are produced through attrition or crushing are picked up by large pellets. Production of fines and subsequent coalescence and layering continues until a time is reached when the number of favorable collisions declines rapidly, thereby leading to a reduction in the rate of growth of the pellets. At this point, the third phase, known as the ball growth region, is reached. In this region surface abrasion becomes marked; as a result, layering becomes the predominant mechanism of growth i.e., spherical agglomeration (Figure 1.4) or emulsion solvent diffusion (Figure 1.5). During the process, the tumbling action in the pelletizers allows the particles to re-orientate themselves and form dense pellets of appreciable strength. The strength of the uncured pellets is directly related to the surface tension of the binding liquid which in turn affects the suction potential that develops into the pellets⁵⁸.

4.1.3b Drug Layering

Pelletization by layering involves the deposition of successive layers of drug moieties from solution, suspension, or dry powder of preformed nuclei, which may be crystals or granules of the same material or inert starter seeds.

In solution/suspension layering, the drug particles are dissolved or suspended in the binding liquid, a hardening binder may or may not be added in the binding liquid. Once this formulation is sprayed, the droplets, which owe their existence to the surface tension of the liquid, spread out on the nuclei, and drying follows. Spreading depends on the droplet wetting characteristics, the wettability of the material, and the thermodynamics. As the liquid evaporates, the dissolved substances crystallize out. On further evaporation, these crystals and the particles they are initially suspended in the binding liquid are drawn toward each other and toward the starter seeds by capillary forces. This leads to the formation of solid bridges among the particles. Strength of the solid bond depends on the properties of the binder, other additives in the formulation and the active ingredient. This phenomenon of spraying and drying and the subsequent formation of solid bridges, is repeated until the desired size of pellet is achieved.  In powder layering, liquid saturation is low and irrespective of the solubility of the active in the binding liquid, complete dissolution does not occur. Typically, a binder solution is first sprayed onto the nuclei, followed by the addition of powder⁵⁹. The moist nuclei tumble in the rotating pan or disc, pick up powder particles, and form layers of small particles that adhere to each other and the nuclei by means of capillary forces developed in the liquid phase. As additional binding liquid is sprayed, layering of more powder on the nuclei continues until the desired pellet sizes are achieved. On drying, the binder and other dissolved substances crystallize out and the liquid bridges are partially replaced by solid bridges.

4.1.3c Compaction (Extrusion-Spheronization)

Compaction is a form of pressure agglomeration, in which drug particles or granules are forced together with or with out formulation aids by a mechanical force to generate pellets of well defined shapes and sizes. The pelletization process can be subdivided into compression and extrusion.

In the first stage of compression, particles that are pretreated through the blending or wet granulation followed by drying, rearranges themselves to form a closely packed mass, during this process, particles retain most of their properties. At high pressures, increased interparticle contact is observed. Mechanical interlocking is the only bonding mechanism that does not involve any forces and is expected to contribute very little to the physical strength of the pellet⁵². On cooling, the molten material forms very strong solid bridges, tapped moisture, albeit insignificant may also contribute to bonding through capillary forces.

In the second stage, the granulation is then put into the extruder to produce high-density extrudates. These extrudates are bonded together by capillary forces, solid bridges formed due to loss of moisture, mechanical interlocking and to some extent, molecular forces. These extrudates are finally converted to pellets on spheronization. During the process, the moisture is forced out from the pellet interior into the outside and imparts plasticity to the pellet surface. The surface plasticity, coupled with the concurrent tumbling of the particles in the spheronizer, allows the formation of spherical pellets.

4.1.3d Globulation

It is a process where hot melts, solutions, or suspensions are atomized to generate spherical particles or pellets⁶⁰. In globulation, atomization produces solid particles directly from the liquid phase through evaporation or cooling and subsequent solidification of hot melts, solution and suspension. During spray drying, the atomized droplets are contacted by a hot gas stream and evaporation of the liquid is initiated, which involves simultaneous heat- and mass transfer and depends on the temperature, humidity, and transport properties of the air surrounding the droplet. As more and more liquid evaporates, surface saturation conditions are reached and formation of solid begins. These particles are initially held together by capillary forces developed by the liquid phase and are gradually replaced by solid bridges. Continuation of the process leads to the formation of a porous layer or crust on the surface of the droplets and thickness of the crust increases through both evaporation and subsequent crystallization of the dissolved material that may include active drug, hardening binder or any other excipients which have solubility in the binding liquid. The rate controlling mechanism is the diffusion of the liquid through the expanding crust, followed by convective transport from the surface of the shell. In cross-linking technique, the polymer is rigidized by chemical reaction with the cross linking agents such as aldehydes⁶¹, calcium chloride⁶², etc.   

During spray congealing, the atomized droplets are cooled below the melting point of the vehicle. The particles are held together by solid bonds formed from the congealed melts. Due to the absence of solvent evaporation during most spray congealing processes, the particles are generally nonporous and strong and remain intact upon agitation. The processing conditions play a very significant role in the development of good quality pellets, it is the physical forces that first bond the primary particles together and initiate the pelletization process⁶³. The propensity and strength of these physical forces depend to a large extend, upon the physicochemical properties of the formulation components. Therefore the physical forces coupled with the elementary growth mechanisms ultimately determine the strength and performance of pellets and should be taken into account during the design and development of pellet dosage forms.        

5.1.0 Characterization of micropellets

The equipment, process variables and formulation considerations are the major parameters in the manufacture of pellets and the reproducibility of particle-size distribution, surface area, density and hardness of pellets, in addition to reproducibility of morphologic properties, should become the criteria by which formulation, equipment, and process are selected.

5.1.1 Particle size distribution

Pellets are invariably uncoated or coated for aesthetics, enteric release, taste masking, stability, or controlled release. In order to achieve any of these desired end-product performances, it is necessary to determine the amount of coating required to produce the desired film thickness and/or coverage. Since particle size directly affects the surface area and, consequently, the amount of coating necessary for the desired coverage. It is advantageous to use the largest particle size for the substrate that may provide the desired end-product performance, but it is essential that particle size distribution should be as narrow as possible for several reasons such as;

1. It will ensure minimum variation in coating thickness throughout the batch of pellets, hence, uniform performance of pellets within the batch.
2. During capsule filling operations or the compression of pellets into tablets, segregation may occur if the particle-size distribution is too wide, leading to variations in the content uniformity and/or dosage form performance.
3. It facilitates blending process if blending of different types of pellets or different batches of pellets is required.

5.1.1a Sieving

It is the most widely used method for measuring particle size distribution of pellets, because it is inexpensive, simple and rapid with little variation among formulators⁶⁴. The procedure involves the mechanical shaking of a sample through a series of successively smaller sieves and weighing of the portion of the sample retained on each sieve. Sieve loading, type of motion (vibratory or tap), intensity and duration of agitation are some of the critical variables that need to be standardized in size analysis. The disadvantage of sieve analysis includes inability of sieves to detect variations in the shape of particles i.e., a longer needle-shape particle may pass through a screen opening that is smaller than its length, hence, particle-size data may be misleading.

5.1.1b Microscopy

The other method of particle size analysis is microscopy, which provides a direct method for determining particle size distribution of pellets. In case of optical microscopy, the diameter of pellets can be measured either by using calibrated micrometers or with the help of eyepieces with grids of circles and squares. In either case, the magnification is determined by the use of calibrated stage micrometer since the magnification is not equal to the product of the nominal magnification of the objective and the eyepiece. The average particle diameters of the gelatin microbeads were determined by averaging the values of more than 200 diameters of gelatin microbeads measured from pictures taken with the microscope video system⁴⁰.

5.1.1c Scanning Electron Microscopy

Scanning electron microscope can be employed to keep a permanent record by means of photograph and, in most cases, a micron bar, used for reference, can be imprinted on these photographs. The pellets first need to be sputter-coated with gold or gold-palladium to improve conductivity. Generally, a 70 Aº- thick film of conductive material is applied with an average grain size of 20-30 Aº. The coating time ranges between 1 to 4 min. Several parameters need to be optimized and kept constant such as acceleration voltage, angle of tilt, and working distance when comparison among specimens is conducted.  Increase in working distance and acceleration voltage provides increased depth of field. Since the perceived particle size and shape is dependent on the angle of specimen tilt, the later should be standardized before making comparative testing. Stereovisualization (stereopsis) of specimens is frequently necessary to avoid misinterpretation about structural features and special relationships². Steromicrograph pairs can be obtained by tilting the electron beam or by shifting, rotating, or tilting the specimen between successive exposures. In addition to the perceptual advantages associated with stereopsis, a stereo pair may also contain information equivalent to a two-fold increase over that found in a single micrograph. Both types of microscopic techniques are tedious, since a large number of particles need to be measured individually in order to create a size frequency distribution plot. In addition, considerable variation among the generated data is possible among operators. However, they provide valuable information, such as presence of aggregates that may not be detected by the sieve analysis.

5.1.2 Surface area

Surface area of pellets is obviously controlled by particle size, shape, porosity and surface roughness. However, it does not account for the contributions to surface area arising from other morphologic characteristics, such as porosity, roughness and shape of pellets. Because of the thickness of the film applied to pellets in a sustained-release type dosage form dictates the rate at which drug is released from the coated pellets, the reproducibility of the surface area to be covered from batch to batch cannot be overemphasized⁶⁵.

There are three methods of measuring surface area of pellets.

5.1.2a Mathematical calculations

A spherical pellet, which is smooth and dense, has minimum surface area per unit volume and can be characterized by its diameter. Since surface area is equal to πr2. True density measurements can also be used to determine the specific surface area.

5.1.2b Gas adsorption

In this technique, the volume of nitrogen that is adsorbed by the substrate contained in an evacuated glass bulb is determined at various pressures, and the results are interpreted using a linear plot of the BET equation for the adsorption of nitrogen on a substrate.

5.1.2c Air permeability

The simple instrumentation and the speed which determinations can be ensured that, permeability methods are widely used pharmaceutically for specific surface determinations, especially when the aim is to control batch-to-batch variations. A commercially available, instrument is the Fisher sub-sieve sizer, principle resistance to the flow of a fluid-such as air-through a plug of compacted material, is the surface area of the material. Since the flow rate through the plug or bed is also affected by the degree of compression of material, the applicability of air-permeability methods for pellets is questionable. In this study, specific surface area can be calculated based on the sieve analysis data of uncoated drug granules. Subsequently surface area measurements were utilized to estimate the desired dissolution rate profile by generating a standard plot of percentage drug release versus the amount of polymer applied per unit surface area of raw material. Based on these curves and the surface area of a batch of granules, a desired dissolution rate profile can be obtained.

5.1.3 Porosity

Porosity of pellets can affect the capillary action of the dissolved drug and consequently, influence the rate of release of drugs from the pellets; it also affects film deposition and formation during coating. The process can be analyzed, qualitatively by scanning electron microscopy and, quantitatively by mercury intrusion pressure. Pore radius is given by Washburn equation; 

 R = 2 γ [cos θ] / P

Where

γ = 480 ergs/cm3,                    θ = 140º

r = pore radius,                        p = mercury-intrusion pressure

The determination of the pore-size distribution by mercury porosimetry is a well-established practice and various factors should be considered for the practical applicability and reproducibility of the method⁶⁶.

5.1.4 Density

Density of pellets^66,67 can be affected by changes in the formulation and/or process, and consequently may affect other processes or factors such as

1. Mostly pellets are filled into hard gelatin capsules volumetrically, if the density of pellets vary significantly from batch-to-batch, the potency of the finished capsule also varies.
2. Any significant variation in the density of pellets will affect the batch size determinations in the coating equipment.
3. If mixing of different types of pellets or different batches of pellets are necessary prior to filling them into capsules or prior to tabletting, it is advisable and may be necessary not only to have similar densities but also reproducible density from batch to batch.

The bulk density of pellets can be measured by using an automated tapper, while the true density of pellets can be determined by an air-comparison pycnometer or by solvent displacement method. Bulk density is indicative of the packing properties of particles and as such, is greatly influenced by the diameter of spherical seeds or pellets. Similar seeds or pellets provide higher bulk densities mainly due to small intraparticle porosities. True density indicates the extent of densification or compactness of substances and is therefore, influenced by the diameter of spherical pellets to a lesser extent. The effect of density on the gastric residence time is not quite clear, however, recent studies conclude that pellets of different densities, given to healthy subjects, did not show significant differences in gastric emptying.

5.1.5 Hardness and Friability

It is necessary to attain acceptable hardness and friability of pellets that can withstand handling, shipping, storage and other processing, such as coating^17,68. Variation in the formulation and/or process of pellets, as well as variability in the raw material, can potentially result in significant variations in the hardness and/or friability of pellets. Hardness measurements for pellets may not be determined accurately. However, instruments such as the Kahl pellet-hardness tester provide relative hardness values, and a friabilator may be employed for generating the friability index.

A wide variety of techniques are available for testing (i) the susceptibility of particles to attrition, (ii) the sources of attrition, and (iii) the mechanisms that causes breakdown. It may be a more realistic indication of friability if the technique used simulates the environment that pellets may be exposed to. For example, pellets may be placed in a pan or fluid bed equipment for a predetermined time period and the weight loss measured in order to determine its friability. Alternatively, pellets may be placed in a friabilator-with or without abrasive agents such as steel balls and rotated for a predetermined interval of time and rotational speed.

It is evident that reproducibility of particle-size distribution, surface area, density, hardness, and friability, in addition to reproducibility of morphologic properties, should become the criteria by which a formulation and process for manufacturing pellets is selected. 

5.1.6 Thermal analysis

Differential scanning calorimetry (DSC) and Differential thermal analysis (DTA) measures⁶⁹ the heat loss or gain resulting from physical or chemical change within a sample as a function of temperature. Examples of endothermic (heat absorbing) processes are fusion (agglomeration, coalescence etc.), boiling, sublimation, vaporization, desolvation, solid-solid transitions, and chemical degradation. Crystallization and degradation are usually exothermic processes. Quantitative measurements of these processes have many applications in preformulation studies including purity, polymorphism, solvation, degradation, and excipient compatibility. A sharp symmetric melting endotherm indicates relative purity, whereas broad, asymmetric curves suggest impurities or more than one thermal process. Thermal gravimetric analysis (TGA) measures changes in sample weight as a function of time (isothermal) or temperature. Desolvation and decomposition processes are frequently monitored by TGA. DSC and TGA analysis can also be used to quantitate the presence of a solvated species with in a bulk drug sample⁷⁰.

5.1.7 X-ray diffraction – Crystalinity

An important technique for establishing the batch-to-batch reproducibility of a crystalline form is X-ray powder diffractions. Random orientation of a crystal lattice in a powder sample curves the X-rays to scatter in a reproducible pattern of peak intensities at distinct angles (θ) relative to the incident beam. Each diffraction pattern is characteristic of a specific crystalline lattice for a given compound⁷¹.

6.1.0 Applications 

6.1.1 Taste masking

Micropellets are ideal for products where perfect abatement of taste is required. Although various technique have been utilized to mask the bitter taste of a drug such as the addition of sweetners and flavours, filling in capsules, coating with water insoluble polymers or pH dependent soluble polymers, complexing with ion-exchange resins, microencapsulation with various polymers, compelxing with cyclodextrins and chemical modifications such as the use of insoluble prodrugs, few reports have described the masking of unpleasant taste without lowering of bioavailability especially for oral products. The micropelletization technique solves difficult taste masking problems⁷² while maintaining a high degree of bioavailability due to their high surface area, especially for oral products. Furthermore, because of the special design of the manufacturing process, dust fractions that representing an uncoated fragments which could cause taste problems are absent in micropellets. Many products, such as antibiotics (clarithromycin, roxithromycin and cephelexin) and anti-inflammatory drugs with a prohibitively bitter taste, can now be formulated in products with high patient compliance, thus markedly increasing the sales potential of the product.

6.1.2 Immediate release

Administering drugs in pellet form leads to an increased surface area as compared to traditional compressed tablets and capsules. This would considerably reduce the time required for disintegration and have the potential for use in rapidly dispersible tablets.

6.1.3 Sustained release

The pellet form provides a smoother absorption profile⁷³ from the gastrointestinal tract as the beads pass gradually through the stomach in to the small intestine at a steady rate. Pellets are being increasingly used in the manufacture of sustained release dosage form of drugs. The advantages of the dosage form is well known and some examples are given below

• Extend day time and night time activity of the drugs,
• Potential for reduced incidence of side effects,
• Reduced dosage frequency of dosage forms,
• Increased patient compliance, patients who are required to take 2 or more doses of formulation a day are thought to be less likely to forget a dose then if they are required to take 3 or 4 times a day,
• Potential lower daily cost to patient due to fewer dosage units,
• In contrast the whole tablet is released at once in to the small intestine as the stomach empties itself, and
• Different type of polymers e.g. carboxymethylcellulose, ethylcellulose, Eudragit etc., are utilized for coating of different drugs to enable the sustained release/controlled release rate of drugs.

Pellets ensure improved flow properties and flexibility in formulation development and manufacture^74,75. If the pellet surface is smoother it allows thin or thick coat of the polymer on the surface of the pellets. The thickness of the coat determines the rate at which the drug is released from the coated pellets. The coating material may be colored with a dye materials so that the beads of different coating thickness will be darker in colour and distinguishable from those having fewer coating. It is widely used for frequently administered drugs having a half-life of 0.5-2 hr. The excellent reproducibility and homogeneity of the particle size and the round shape and smooth surface of the particles makes micropellets with sizes smaller than 200mm a perfect match for powder injections.

In addition, the very high drug substance load level of the micropellets promotes lower injection volumes⁷⁶, thus increasing patient acceptance. Many drug substances, e.g. neuroleptics, peptides, hormones, therapeutic proteins; vaccines etc. in need of slow release formulations are product candidates for this technology. Micropellets have thus opened a new dimension in parenteral depot technologies. Drug substance particles can either be coated with biodegradable polymers or embedded in a polymer matrix. Using these approaches, release profiles ranging from days to months and even pulsed release can be obtained at wish.

The release rate of drugs from the polymer coat can be modified using various concentration of plasticizer and influence of pH. Even if they are useful as drugs, the necessity of frequent injection makes them inconvenient and often causes pain and trouble to patients.

6.1.4 Chemically incompatible products

At times such ingredients are required to be delivered in a single dose. In the compressed tablet dosage form separate tablets would have to be administered, but the pellets can be administered in a single capsule.

6.1.5 Varying dosage with out reformulation

Pellets have excellent flow properties, due to this, they can be conveniently used for filling capsules and the manufacturer can vary the dosage by varying the capsule size with out reformulating the product.

7.1.0 Conclusion

Pelletization technology has revolutionized the pharma research with its wide range of applications which includes immediate and sustained release oral, parenteral, subcutaneous products. Moreover, an improvement of physical properties of drug such as solubility, dissolution, flow property, wettability, and packability which holds key part during processing or formulation of pharmaceuticals. Different formulation techniques are available for the economic production of pellets depending upon the physicochemical properties of the drugs and the simple methods for the characterization resolves the regulatory requirements. The recent pharma products outcome using this technology indicates there is start of this technology once again and this would bring the highest profile in pharma industry for the production of novel drug delivery systems economically.  

Acknowledgement

Author is thankful to The Management, Chitkara College of Pharmacy, The Director, Central Indian Pharmacopoeia Laboratory, Ghaziabad (India), and Director, Arbro Pharmaceuticals Testing House, Delhi(India) for providing facilities, advice and encouragement during this work.

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Figure 1.1 Liquid saturation in a spherical assembly of particles.
(A) Pendular state (B) Funicular state (C) Capillary state (D) Droplet state

Figure 1.2 Formal representation of (A). Thin adsorption layer (B). Solid bridges (C). Mechanical interlocking.

Figure 1.3 Pellet growth mechanisms (A) Nucleation (B) Coalescence (C) Layering and (D) Abrasion transfer.

Figure 1.4 Pellet growth mechanisms- (spherical agglomeration)

Figure 1.5 Pellet growth mechanisms- (emulsion solvent diffusion)

Table 1. Studies on drug micropellets and various techniques used for the formulation.

S.No	Studies performed	Techniques used	Drugs used	References
1.	Encapsulation of Water-insoluble Drug by a Cross-linking Technique: Effect of Process and Formulation Variables on Encapsulation Efficiency, Particle Size, and In-Vitro Dissolution Rate	Cross linking	Ibuprofen	69
2.	Preparation of kangfuxin colon targeting micropellets	Fluidized bed coating	Kangfuxin	77
3.	Entrapment of andrographolide in cross-linked alginate pellets: I. Formulation and evaluation of associated release kinetics	Ionotropic gelation	Andrographolide	78
4.	Investigation of the release of aspirin from spray congealed micropellets	Spray congealing	Aspirin	79
5.	Preparation and evaluation of lansoprazole floating micropellets	Emulsion solvent diffusion	Lansoprazole	80
6.	Study on preparation of glycyrrhiza total flavones effective components sustained release pellets and its properties	Extrusion-Spheronisation	Glycyrrhiza total flavones	81
7.	Effect of thermal curing of the ethyl cellulose film on the rapidity of the release of diclofenac sodium from pellets	Coating	Diclofenac Sodium	82
8.	Novel micropelletization Technique: Highly Improved Dissolution, Wettability and Micromeritic Behavior of Domperidone	Solvent diffusion	Domperidone	34
9.	The effect of polymeric dispersion type on the release of diclofenac sodium from coated pellets	Roto-agglomeration	Diclofenac Sodium	83
10.	Pellets preparation by the drug layering technique in a rotary processor	Drug layering by rotary process	Dummy beads	84
11.	Application of computer image analysis for characterization of pellet	-	Sugar pellets	85

About Authors:

Prabakaran. L
Department of Pharmaceutics, Chitkara College of Pharmacy, Chandigarh–Patiala Highway, Rajpura, Dist. Patiala, Punjab, India. Pin 140401
Address for correspondence: Email: prabakar75@gmail.com, Ph.: 09216273429, 09865747026.

Prushothaman. M
Rao’s College of Pharnacy, Chemudugunta-Post, Nellore, Andra Pradesh, India. Pin 524004

Sriganesan P
Department of Pharmaceutical sciences, Mahatma Gandhi University, Kottayam, Kerala-9, India.