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INTRODUCTION WHAT ARE PELLETS? In the pharmaceutical industry, pellets can be defined as small, free-flowing, spherical particulates manufactured by the agglomeration of fine powders or granules of drug substances and excipients using appropriate processing equipment. Historically, the term pellet has been used by a number of industries to describe a variety of agglomerates produced from diverse raw materials, using different pieces of manufacturing equipment.

Advantages Of Pellets : 

Advantages Of Pellets Pellets offer a high degree of flexibility in the design and development of oral dosage forms. Pellets as drug delivery systems offer technological advantages, such as better flow properties, less friable dosage form, narrow particle size distribution, ease of coating, and uniform packing They can be divided into desired dose strengths without formulation or process changes and also can be blended to deliver incompatible bioactive agents in the gastrointestinal (GI) tract. In addition, pellets, taken orally, disperse freely in the GI tract, maximize drug absorption, minimize local irritation of the mucosa by certain irritant drugs, and reduce inter- and intrapatient variability


TECHNIQUES Powder layering Solution/Suspension layering Extrusion–Spheronization Spherical agglomeration or balling Spray congealing/ drying Cryopelletization and Melt Spheronization.

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1.POWDER LAYERING Powder layering involves the deposition of successive layers of dry powder of drug or excipients or both on preformed nuclei or cores with the help of a binding liquid. Powder layering involves the simultaneous application of the binding liquid and dry powder. The first equipment used to manufacture pellets on a commercial scale was the conventional coating pan, but it has significant limitations as pelletization equipment. The degree of mixing is very poor, and the drying process is not efficient. Mixing is a function of the Pan shape, the Tilt angle, the Baffle arrangement, and the Rotational speed of the pan itself.

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Throughout the process, it is extremely important to deliver the powder accurately at a predetermined rate and in a manner that maintains equilibrium between the binder liquid application rate and the powder delivery rate. If the powder delivery rate is not maintained at predetermined equilibrium levels, over wetting or dust generation may occur, and neither the quality nor the yield of the product can be maximized. In an ideal process, no agglomeration occurs, and the particle population at the end of the process remains the same as that of the starter seeds or cores, with the only difference being an increase in the size of the pellets and thus in the total mass in the pan.

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Other equipments used for powder layering process are: Tangential Spray granulator Centrifugal Fluid Bed granulator (A)Schematic representation of centrifugal fluid-bed equipment

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2.Solution/Suspension layering: Solution/suspension layering involves the deposition of successive layers of solutions and/or suspensions of drug substances and binders on starter seeds, which may be inert materials or crystals/granules of the same drug. Wurster coating Process: This process is particularly suitable for a controlled release of active ingredients. In the Wurster process, a complete sealing of the surface can be achieved with a low usage of coating substance. The spray nozzle is fitted in the base plate resulting in a spray pattern that is concurrent with the air feed. By using a Wurster cylinder and a base plate with different perforations, the particles to be coated are accelerated inside the Wurster tube and fed through the spray cone concurrently.

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As the particles continue travelling upwards, they dry and fall outside the Wurster tube back towards the base plate. They are guided from the outside back to the inside of the tube where they are once again accelerated by the spray. This produces an extremely even film. Particles of different sizes are evenly coated. Schematic representation of the Wurster product chamber and process. (A) product chamber, (B) partition, (C) orifice plate, (D) nozzle, and (E) expansion chamber.

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An important factor that needs to be considered when suspensions are used as opposed to solutions is the particle size of the drug. Micronized drug particles tend to provide pellets that are smooth in appearance, a property that is extremely desirable during subsequent film coating, particularly for controlled-release applications. If the particle size of the drug in the suspension is large, the amount of binder required to immobilize the particles onto the cores will be high, and, consequently, pellets of low potency are produced. The morphology of the finished pellets also tends to be rough and may adversely affect the coating process and the coated product. Moreover, because particles detach easily from the core they are being layered on owing to frictional forces, yield is usually low.


3.EXTRUSION-SPHERONIZATION Extrusion–Spheronization is a multistep process involving dry mixing, wet granulation, extrusion, Spheronization, drying and screening. Variety of extruders: Screw-fed extruders, Gravity-fed extruders, and Ram extruders

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Screw-fed extruder: The screw rotates along the horizontal axis and hence transports the material horizontally; They may be of two types: Axial screw extruders, Radial screw extruders. Axial extruders: These have a die plate that is positioned axially, consist of a feeding zone, a compression zone, and an extrusion zone. Radial extruders: The transport zone is short, and the material is extruded radially through screens mounted around the horizontal axis of the screws.

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(A)Axial extruder Screw-fed Extruders: (B)Radial screw extruder Gravity-fed Extruders: (A)Rotary-cylinder extruder (B) Rotary-gear extruder

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Gravity-fed extruders: These are of two types , which differ primarily in the design of the two counter-rotating cylinders. The Rotary Cylinder and Rotary Gear Extruders Rotary Cylinder Extruder: One of the two counter-rotating cylinders is hollow and perforated, whereas the other cylinder is solid and acts as a pressure roller. Rotary-Gear Extruder: There are two hollow counter-rotating gear cylinders with counterbored holes.

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Ram Extruders: The ram extruder is probably the oldest type of extruders; a piston displaces and forces the material through a die at the end. These extruders are preferentially used in the development phase, because they can also measure the rheological properties of formulations. Ram Extruder

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Marumerizer: It consists of a two parts: Static cylinder or stator and Rotating friction plate. A typical friction plate has a crosshatch pattern, where the grooves intersect at a 900 angle. The rotational speed of the friction plate is variable and ranges from 100 to 2000 rpm; depending on the diameter of the unit. Spheronizer friction plate with a cross-hatch pattern.

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In an extrusion–spheronization process, formulation components such as fillers, lubricants, and pH modifiers play a critical role in producing pellets with the desired attributes. Lubricants: Water and other Granulating media. Role: Lubricants are sometimes incorporated to improve processing. Fillers: Microcrystalline cellulose and lactose. Role: Regulating the water content and distribution in the granulation. In effect, it modifies the rheological properties of the formulation and imparts plasticity to the pellets. pH modifiers: Organic acids Role: Stabilize sensitive drug substances or modify the release characteristics, especially the solubility of the drug substance.

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4.SPHERICAL AGGLOMERATION Spherical agglomeration, or balling, is a pelletization process in which powders, on addition of an appropriate quantity of liquid or when subjected to high temperatures, are converted to spherical particles by a continuous rolling or tumbling action. Spherical agglomeration can be divided into two categories— Liquid-induced and Melt-induced agglomerations.

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Liquid-induced agglomeration: During liquid-induced agglomeration, liquid is added to the powder before or during the agitation step. As powders come in contact with a liquid phase, they form agglomerates or nuclei, which initially are bound together by liquid bridges. These are subsequently replaced by solid bridges, which are derived from the hardening binder or any other dissolved material within the liquid phase. The nuclei formed collide with other adjacent nuclei and coalesce to form larger nuclei or pellets. At this point, coalescence is replaced by layering, whereby small particles adhere on much larger particles and increase the size of the latter until pelletization is completed.

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Melt-induced agglomeration Melt-induced agglomeration processes are similar to liquid-induced processes except that the binding material is a melt. Therefore, the pellets are formed with the help of congealed material without having to go through the formation of solvent-based liquid bridges If the surface moisture is not optimum, some particles may undergo nucleation and coalescence at different rates and form different sizes of nuclei admixed with the larger pellets. As a result, spherical agglomeration tends to produce pellets with a wide particle size distribution.


5.SPRAY DRYING AND SPRAY CONGEALING Spray Drying and Spray Congealing, known as globulation processes, involve atomization of hot melts, solutions, or suspensions to generate spherical particles or pellets. The droplet size in both processes is kept small to maximize the rate of evaporation or congealing, and consequently the particle size of the pellets produced is usually very small.

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Spray Drying: The drug entities in solution or suspension are sprayed, with or without excipients, into a hot air stream to generate dry and highly spherical particles. As the atomized droplets come in contact with hot air, evaporation of the application medium is initiated. This drying process continues through a series of stages whereby the viscosity of the droplets constantly increases until finally almost the entire application medium is driven off and solid particles are formed. Generally, spray-dried pellets tend to be porous. Spray Dryer

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Spray Congealing: This process consists of suspending the particles in a molten coating material and pumping the resultant slurry into a spray dryer in which cold air is circulated. The slurry droplets congeal on contact with the air. The coating agents normally employed are low melting materials such as waxes. The congealing process require higher ratio of coating agents to active material than does the spray drying, because only the molten coating agent constitutes the liquid phase.


6.MELT SPHERONIZATION Melt Spheronization is a process whereby a drug substance and excipients are converted into a molten or semi molten state and subsequently shaped using appropriate equipment to provide solid spheres or pellets. The drug substance is first blended with the appropriate pharmaceutical excipients, such as polymers and waxes, and extruded at a predetermined temperature. The extrusion temperature must be high enough to melt at least one or more of the formulation components. The extrudate is cut into uniform cylindrical segments with a cutter. The segments are spheronized in a jacketed Spheronizer to generate uniformly sized pellets.

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7.CRYOPELLETIZATION Cryopelletization is a process whereby droplets of a liquid formulation are converted into solid spherical particles or pellets by using liquid nitrogen as the fixing medium. The technology, which was initially developed for lyophilization of viscous bacterial suspensions, can be used to produce drug-loaded pellets in liquid nitrogen at -1600C. The procedure permits instantaneous and uniform freezing of the processed material owing to the rapid heat transfer that occurs between the droplets and liquid nitrogen. The amount of liquid nitrogen required for manufacturing a given quantity depends on the solids content and temperature of the solution or suspension being processed.

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The equipment consists of a container equipped with: Perforated Plates A Reservoir Conveyor belt with Transport baffles Storage Container The perforated plates generate droplets that fall and freeze instantaneously as they come in contact with the liquid nitrogen below. The frozen pellets are transported out of the nitrogen bath into a storage container at -600C before drying.

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CONCLUSION Given the enormous advantages of multiparticulate systems over single-unit oral dosage forms, extensive research has focused recently on refining and optimizing existing pelletization techniques as well as on the development of novel manufacturing approaches that use innovative formulations and processing equipment.

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REFERENCES: 1. Beachgaard, H.; Nielson, G.H. Controlled Release Multiple Units and Single Unit Doses. Drug Dev. Ind. Pharm. 1978, 4, 53–67. 2. Special Delivery: Advances in Drug Therapy. The Research News; University of Michigan, 1986; 1. 3. Cimicata, L.E. How to Manufacture and Polish Smallest Pan Goods-Nonpareil Seeds. Confectioners J. 1951, 41–43. 4. Chambliss, W.C. Conventional and Specialized Coating Pans. Pharmaceutical Pelletization Technology; Ghebre- Sellassie, I., Ed.; Marcel Dekker, Inc.: New York, 1989; 16–17. 5. Jan, S.; Goodhart, F.W. Dry Powder Layering. Pharmaceutical Pelletization Technology; Ghebre-Sellassie, I., Ed.; Marcel Dekker, Inc.: New York, 1989; 182–183. 6. Jones, D.M. Solution and Suspension Layering. Pharmaceutical Pelletization Technology; Ghebre-Sellassie, I., Ed.; Marcel Dekker, Inc.: New York, 1989; 158–159.

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7. Niro-Aeromatic Product Manual Niro-Aeromatic, Inc.: Columbia, MD, 1992. 8. Hicks, D.C.; Freese, H.L. Extrusion Spheronization Equipment. Pharmaceutical Pelletization Technology; Ghebre- Sellassie, I., Ed.; Marcel Dekker, Inc.: New York, 1989; 71–100. 9. Fielden, K.E.; Newton, J.M.; Rowe, R.C. A Comparison of the Extrusion and Spheronization Behavior of Wet Powder Masses Processed by a Ram Extruder and a Cylinder Extruder. Int. J. Pharm. 1992, 81, 225–233. 10. Fielden, K.E.; Newton, J.M.; Rowe, R.C. The Effect of Lactose Particle Size on the Extrusion Properties of Microcrystalline Cellulose-Lactose Mixtures. J. Pharm. Pharmacol. 1989, 41, 217–221. 11. Dietrich, R.; Brausse, R. Erste Erfahrungen Und Validierungsversuche an Einem Neu Entwickelten GMP-Gerechten Und Instrumentierten Pharma-Extruder. Pharm. Ind. 1988,50 (10), 1179–1186. 12. Dietrich, R. Food Technology Transfers to Pellet Production. Manuf. Chem. 1989, 8, 29–33.

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