PELLETIZATION TECHNIQUES

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PELLETIZATION TECHNIQUES

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PELLETIZATION TECHNIQUES NITISH R. BADGUJAR M.Pharm Industrial Pharmacy 1 E-mail - nitishrb1@gmail.com

CONTENTS :

CONTENTS 2 INTRODUCTION. ADVANTAGES OF PELLETS. TECHNIQUES. CONCLUSION. REFERENCES.

INTRODUCTION1 :

INTRODUCTION 1 3 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.

Advantages Of Pellets2 :

Advantages Of Pellets 2 4 Excellent Stability Dust free Round pellets Good flow behavior Easy to dose Compact structure Very Low hygroscopicity High bulk density Dense, uniform surface Narrow grain size distribution Low abrasion High active ingredient content possible Optimum starting shape for subsequent coating Controlled-release applications Drug absorption

TECHNIQUES3 :

TECHNIQUES 3 5 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 4 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. Mixing is a function of the P an shape, the T ilt angle, the B affle arrangement, and the R otational speed of the pan itself. 6

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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. 7

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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 8

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9 2.Solution/Suspension layering 5 A starting grain or a pellet can be presented as the starting material. The pellet is built up to the required grain size by adding the layering substance one layer at a time. Powder and binders, suspensions or solutions make suitable layering substances. The layers are densely applied due to the movement of the pellets. Thick layers can be applied to the starting grains, which, in the case of layers containing active ingredients.

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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. 10 BATCH FLUID BED SYSTEMS categorized in different manufacturing Techniques: Fluid bed coating Fluid bed coating Bottom Fluid bed coating Tangential Spray (Rotor System)

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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. 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. 11

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3.EXTRUSION-SPHERONIZATION 5,6 Extrusion–Spheronization is a multistep process involving dry mixing, wet granulation, extrusion, Spheronization, drying and screening . Variety of extruders: S crew-fed extruders, Gravity-fed extruders, and Ram extruders 12

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Screw-fed extruder: The screw rotates along the horizontal axis & hence transports the material horizontally. They may be of two types : Axial extruders : These have a die plate that is positioned axially, consist of a feeding zone, a compression zone, and an extrusion zone. (fig A) Radial extruders : The transport zone is short, and the material is extruded radially through screens mounted around the horizontal axis of the screws .(fig B) 13

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Gravity-fed extruder s: These are of two types , which differ primarily in the design of the two counter-rotating cylinders. Rotary Cylinder Extruder : One of the two counter-rotating cylinders is hollow and perforated, where as the other cylinder is solid and acts as a pressure roller. (fig A) Rotary-Gear Extruder: There are two hollow counter-rotating gear cylinders with counterbored holes. (fig B) 14

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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 15

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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 90 0 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 . 16

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CYLINDRICAL EXTRUDATE CYLINDRICAL RODS CYLINDERS WITH ROUNDED ENDS DUMBBELLS ELLIPSOIDS SPHEROIDS Shape transitions during a Spheronization process 17

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4.SPHERICAL AGGLOMERATION 7 Spherical agglomeration , or balling, is a pelletization process in which powders, on addition of an appropriate quantity of liquid ; 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 — L iquid-induced M elt-induced agglomerations. 18

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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. The 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 & 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. 19

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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. 20

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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. 21 5.SPRAY DRYING & SPRAY CONGEALING 7

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Spray Drying: 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. 22

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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. 23

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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. 24 6.MELT SPHERONIZATION 5,7

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7.CRYOPELLETIZATION 7,8,9 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 -160 0 C. 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. 25

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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 -60 0 C before drying. 26

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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. . 27 CONCLUSION

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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. Jan, S.; Goodhart, F.W. Dry Powder Layering. Pharmaceutical Pelletization Technology; Ghebre-Sellassie, I., Ed.; Marcel Dekker, Inc.: New York, 1989; 182–183. 5. Jones, D.M. Solution and Suspension Layering. Pharmaceutical Pelletization Technology; Ghebre-Sellassie, I., Ed.; Marcel Dekker, Inc.: New York, 1989; 158–159. 28 REFERENCES

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6. Hicks, D.C.; Freese, H.L. Extrusion Spheronization Equipment. Pharmaceutical Pelletization Technology; Ghebre- Sellassie, I., Ed.; Marcel Dekker, Inc.: New York, 1989; 71–100. 7. Follonier, N.; Doelker, E.; Cole, E.T. Various ways of modulating the release of diltiazem hydrochloride from hot-melt extruded sustained release pellets prepared using polymeric materials J. Control. Release , 1995, 36 , 243-50. 8.Millili, G.P.; Schwartz, J.B. The strength of microcrystalline cellulose pellets. The effect of granulating with water/ethanol mixtures. Drug Dev. Ind. Pharm., 1990, 16 , 1411-26. 9.Cheboyina, S.; O’Haver, J.; Wyandt, C.M. mathematical model to predict the size of the pellets formed in freeze pelletization techniques. Parameters affecting pellet size J. Pharm. Sci ., 2006, 95 , 167–80. 29

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Any questions ? 30