Introduction Compared to single-unit dosage forms, oral multiparticulate drug-delivery systems (e.g.

pellets, granules) offer biopharmaceutical advantages in terms of a more even and predictable distribution and transportation in the gastrointestinal tract. There are different types of pelletization and granulation techniques available to prepare drug loaded spherical particles or granules. Multiparticulate dosage forms are receiving a great deal of attention as alternative system for oral drug delivery. The present review outlines the recent findings on the manufacturing and evaluation of spherical pellets published over the past decade. The techniques namely extrusionspheronization, hot melt extrusion, freeze pelletization, cryopelletization have been discussed along with parameters affecting pelletization. Evaluation of quality of the pellets is discussed with reference to the size distribution, shape, surface morphology, specific surface area, friability, tensile strength, density, porosity, disintegration time and in vitro dissolution studies of pellets. What are pellets? Pellets are small particles typically created by compressing an original material. They are uniform, usually spherical forms in which the drug is administered. They are usually encapsulated as shown and used in pharmaceuticals.

Rationale of Pelletization Pellets are of great interest to the pharmaceutical industry for a variety of reasons 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 forms, 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. Types of Pelletization:
1) Extrusion-spheronization 2) Hot melt extrusion 3) Freeze pelletization 4) Cryopelletization

Extrusion Spheronization Spheronization, marumerization, pelletization and micropelletization all mean the same thing. The manufacture of products in small spheres (spheroids) is used in pharmaceutical and related industries. Within each batch, the spheroids are of regular shape and size and are quite dense. The products produced by these processes can be called spheroids, spheres, micro-spheres, pellets, micro-pellets or pharmaceutical pellets. All these terms refer to the same thing. The size range is normally from about 0.8 mm to about 1.5 mm in diameter although smaller and larger are possible they are less common. Granulation normally refers to the manufacture of irregularly shaped particles with a large size range included within the batch. Granulated materials are generally less dense. Extrusion spheronization is a multiple process of wet mass extrusion followed by spheronization to produce uniform size spherical particles, called as spheroids, pellets, beads or matrix pellets depending upon the material as well as process used for extrusion spheronization. Extrusion Spheronization has been used in agrochemicals, detergent additives, sweeteners, food and now it is used in pharmaceuticals.

It is more labor intensive than other granulation method, but it is useful when uniform spherical shape, uniform size, good flow properties, reproducibility in packing, high strength, low friability and smooth surface of granules is desired. Extrusion spheronization process has gained worldwide attention because it is a simple and fast processing technology. Any pharmaceutical products utilize pellets or beads as a drug delivery system can be effectively produced by the extrusion spheronization process. Wet mass extrusion and spheronization is established method for the production of spherical pellets, and are coated effectively to achieve controlled release product. Steps of extrusion spheronization Extrusion spheronization follows mainly five steps, that is mixing or blending, extrusion, spheronization, coating and finally drying, which can be explained/described as:

Dry mixing of ingredient to achieve a homogenous powder dispersion Wet massing to produce a sufficient plastic wet mass
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Amount of granulating fluid and uniform dispersion of fluid are the two factors which play an important role in preparation of wet mass as optimum plasticity and cohesiveness directly affect the final production of pellets.

Extrusion to form rod shaped particles of uniform diameter The wet metered mass is placed into the extruder where it is continuously formed into cylindrical rods of uniform size and shape. The wet mass is forced through dies and shaped into small cylindrical particles with uniform diameter. The extrudate particles break at similar lengths under their own weight. Thus the extruder must have enough plasticity to deform but not so much that the extruded particles adhere to other particles when collected or rolled in the spheronizer.

Fig: Extruder (external view and internal schematic diagram)

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Based upon the type of feed mechanism used to transfer the mass towards the die, extruders are divided into three classes: o Screw feed extruder [axial or end plate, dome or radial] o Feed extruder [cylindrical roll, gear roll, radial]
o

Piston feed extrude [ram] (generally utilized for experimental development)

The primary extrusion variables are: o The feed rate of the wet mass o The diameter of the die o The length of the die o Water content of the wet mass

Spheronization to round off these rod shaped particles into spherical particles with narrow size distribution. This process is carried out in a relatively simple apparatus. The working part consists of a bowl having fixed side walls, with a rapidly rotating bottom plate or disc.
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Here, the extrudates are spheronized or rotated at higher speed by friction plate that breaks the rod shaped particles into smaller particles and rounded them to form spheres.

The size of the spheroids is mainly depending upon the diameter of circular die that modifies the diameter of cylindrical rods produced in extrusion stage.

Fig: Spheronizer (external view and internal schematic diagram)

Drying to achieve the desired final moisture content This is often the final step in the process. Drying can be accomplished in any dryer that can be used for conventional wet granulations, including tray dryers and fluidized-bed dryers.

Screening (optional) to obtain desired narrow size distribution of spheres/pellets For screening, normal sieves are used to achieve the desired narrow size distribution. If the previous steps are done carefully, this step is not necessary.

Advantages of extrusion spheronization The pellets or beads produced by the extrusion spheronization offer the following advantages over conventional drug delivery system:

It Produces spheroids with high drug loading capacity of active ingredient without producing extensively large particles.

It produces particles of uniform size and consistent smooth surface, with narrow size distribution and good flow properties.

Successful coating is applied to spheroid because of its spherical shape and low surface area to volume ratio.

Pellets composed of different drugs can be blended and formulated in single unit dosage form that facilitates delivery of two or more chemically compatible or incompatible drug at the same or different site in GI tract.

Pellets are frequently used in controlled release delivery system as it facilitates free dispersion of spheroids in the GI tract and offer flexibility for further modification.

It improves the safety and efficiency of active ingredient. It helps to increase bioavailability of drugs by controlling or modifying the release rate of drugs.

It is also possible to prepare a sustained release pellets without coating of the pellets.

Disadvantages of extrusion spheronization It is more labor intensive than other Pelletization techniques and therefore should be considered when the other methods are not satisfactory or when it is important to produce spheres. Despite this, it is the most widely used process of Pelletization because spheres are the most common type of pellets. Applications of extrusion spheronization: Extrusion spheronization is primarily used for the production of multiparticulates for oral controlled drug delivery system. Extrusion spheronization is widely utilized in formulation of sustained release, controlled release delivery system. Hot Melt Extrusion Researchers have investigated a new modified method for preparing matrix pellets for controlled release drug delivery system to overcome the disadvantages associated with wet mass extrusion and spheronization process which is called as a Hot Melt Extrusion (HME) method where a thermal agent softens or gets melted during the process to obtain matrix pellets. HME consists of thermal agent or polymer, an active ingredient, release modifying agents, bulking agents and processing agents.

Procedure: Hot melt extrusion is classified as the molten system under control and semisolid viscous system, in former case heat is applied to material in order to control its viscosity and enable it to flow through the die, while the latter case is a multiphase concentrated dispersion where high solid content portion is mixed with liquid phase. Hot melt extrusion equipment consists of an extruder, auxiliary equipment for downstream processing and monitoring tool for performance and product quality evaluation. HME process is divided in four sections that are: 1) Feeding of extruder
2) Conveying of mass[mixing and reduction of particle size]

3) Flow through the die

4) Exit from the die and downstream processing

In hot melt extrusion process, extrusion

channel is conventionally divided into three sections

that are feed zone, transition zone, and metering zone. The monitor and controlling parameter in HME are barrel temperature, feed rate, screw speed, motor load and melt pressure. Extruder consist of two rotating screw inside a stationary cylindrical barrel. And an endplate die connected to the end of barrel determines the shape of extruded products. Applications of HME: HME has been widely used technique in plastic industries and now it is used in pharmaceutical industries for formulation of sustained release, controlled release and transdermal as well as transmucosal drug delivery system.
1) Hot melt extrusion technpology was used to produce sustained release pellets of diltiazem

HCl, using polymers such as ethyl cellulose. The resulting pellets exhibited smooth surface, low porosity and showed slow drug release
2) A transdermal patch was made by using Killion melt extruder for HPMC films employing

PEG 8000.
3) A ram extruder was made to prepare a fast release dosage form with uniform shape and

density, containing carbamazepine as poorly soluble model drug and PEG 4000 as a

hydrophilic carrier and low melting binder. The evaluation studies revealed that the extruded mixture of equal composition exhibited more rapid release than simple physical mixture.
4) Controlled release theophylline pellets were prepared by hot melt extrusion method using

eudragit preparation 4135 F, microcrystalline cellulose and poly ethylene glycol 8000 powder. The evaluation studies showed that pellet follows diffusion controlled drug release which is influenced by polymer swelling and pH dependent dissolusio.
5) Sustained release matrix tablets of chlorpheniramine maleate were prepared by hot melt

extrusion method, the evaluation studies revealed that drug release was controlled by erosion of matrix and the diffusion of drug took place through swollen gel layer at surface of the tablet. Advantages of HME: The HME offers following advantage over a wet mass extrusion and spheronization method, and are as follows: It is a simple, efficient, continuous process that requires fewer processing stages. HME is continuous process as it does not require a lengthy drying stage since it does not involve addition of water or other solvent. The absence of water may prevent drug degradation as many drugs are unstable in presence of water. It produces a spherical shape pellets with narrow range particle size distribution. Reduce the loss of coating material during the coating process associated with wet mass extrusion process. It is a convenient technology for preparation of solid dispersion and solid solution for delivery of poorly soluble drug as it offers a advantage of solvent free formulation of solid dispersion. It helps to mask the bitter taste of the active ingredient.

Poorly compatible materials can be incorporated into tablets produced by cutting an extruded rod.

Pharmaceutical grade polymer which is functional at low temperature and its selection depends on drug polymer miscibility, polymer stability, and function of final dosage form.

It maintains the thermal stability of drug as well as excepients.

Freeze Pelletization: Freeze Pelletization is a new technique that can be used in the preparation of immediate and controlled release matrix pellets. Procedure In this study, a novel method for producing pellets was developed. Immediate release pellets are prepared with hydrophilic solids and controlled release pellets are prepared using a mixture of hydrophilic and hydrophobic solids. Effect of drug loading on pellet properties was studied. Particle size distribution was carried out by sieve analysis. An evaluation of the surface morphology of the pellets was conducted using microscopy. Release studies were conducted in 900 ml of nanopure water using USP apparatus I at a rotation speed of 100rpm. Samples were taken at predetermined time intervals and amount of drug released was analyzed by UV-VIS spectrophotometer. Goodness of fit of release data was tested with various mathematical models. Pellets were found to be spherical and non-porous. Particle size analysis showed that pellets were in a very narrow size range. Applications of freeze pelletization The Freeze pelletization technique is a novel method for producing immediate and controlled release pellets. Advantages of freeze pelletization It is a simple and inexpensive. The bioavailability of the pellets from this technique was greater than when using other methods.

It is a reproducible technique for producing pellets with varying properties.

Cryopelletization

Fig: Cryo Pelletizer Procedure: In a device for the cryogenic pelletization of liquids, the process is done by dripping the liquids into a coolant having a temperature sufficiently cold to solidify the drops. Then a device including a liquid container mounted above a coolant reservoir and a dripping unit at the bottom of the container. The dripping unit including an inner disk is disposed towards the interior of the container. It contains an outer disk against an inner disk, the outer disk being disposed towards the coolant reservoir. The flow openings in the inner and outer disks are alignable with each other to permit liquid reservoir, means for rotating one of the disks with respect to the other of the disks to adjust the effective size of the flow openings by adjusting their degree of alignment. The improvement is the that nozzle-like drip-off elements are mounted in the flow openings of the outer disk, and the elements are detachably mounted to comprise the replaceable insert elements. Applications: Cryo-pelletizing can be applied in the production stream in some of the following ways:

as an intermediate holding step for long-term storage to enable ultra-fast freeze drying to halt a fermentation reaction as part of a separation/purification process or as a finishing step

Advantages of cryopelletization: It is very easy to handle. It produces free-flowing pellet forms. It offers ultra-fast thawing for consistent and fast reconstitution eliminating the need to freeze in block form which is difficult to handle. Disadvantages: It is inconsistent in freezing and thawing cycles and requires additional labour. Overall Applications of Pelletization: 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, etc., few reports have described the masking of unpleasant taste without lowering of bioavailability especially for oral products. 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. Sustained release 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 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

Different types of polymers are utilized for coating of different drugs to enable the sustained release/controlled release rate of drugs.

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. Varying dosage without 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 without reformulating the product. Conclusion Today extrusion spheronization (wet mass extrusion) and melt extrusion spheronization represents an efficient pathway for novel drug delivery system. The potential of this technology is lies in the scope for different oral controlled delivery systems including oral and topical delivery systems. Because of its simple design, high efficiency of producing spheres and fast processing, extrusion spheronization has found a special position in pharmaceutical industry and especially in case of production of multiparticulate oral controlled release dosage forms. Pellet formation by this technique produces more spherical pellets and offers more advantages than other pelletization process. In addition, hot melt extrusion method has provided a new platform to produce spherical particles of drugs which are not stable or having compatibility problem in presence of solvents.