Pellets

Pellets

1. PELLETS Reshma Fathima K Assistant Professor Grace College of Pharmacy, Palakkad

2. Pellets provide the development scientist with a high degree of flexibility during the design and development of oral dosage forms. They can be divided into desired dose strengths without formulation or process changes, and can also be blended to deliver incompatible bioactive agents simultaneously or particles with different release profiles at the same site or at different sites within the gastrointestinal tract.

3. Pelletization is an agglomeration process that converts fine powders or granules of bulk drugs and excipients into small, free flowing, spherical or semi spherical units, referred to as pellets. In addition, pellets have numerous therapeutic advantages over traditional single units, such as tablets and powder-filled capsules. Taken orally, pellets generally disperse freely in the gastrointestinal tract, and consequently maximize the drug absorption, minimize local irritation of the mucosa by certain irritant drugs because of the small quantity of drug available in a single pellet.

4. Advantages of pellets : They can be divided in to desired dosage strength without process or formulation changes. When pellets containing the active ingredient are in the form of suspension, capsules, or disintegrating tablets, they offer significant therapeutic advantages over single unit dosage forms They can also be blended to deliver incompatible bioactive agents. They can also be used to provide different release profile at the same or different sites in the gastrointestinal tract. Pellets offer high degree of flexibility in the design and development of oral dosage form like suspension, sachet, tablet and capsule

5. Pellets disperse freely in GI tract, maximize drug absorption, and minimize local irritation of the mucosa by certain irritant drugs. Improved flow characteristics : Spheres have excellent flow properties which can be used in automated processes or in processes where exact dosing is required, e.g. tabletting , moulding operations, capsule filling, and packaging. Coating of granules is often applied for stabilizing active ingredients in the granule or to control the release of these active ingredients. Typical applications in the pharmaceutical industry are the controlled release medicines. The easiest shape to coat is the sphere due to the absence of edges. It is also the most economical one to coat as no extra coating material is required to fill irregularities in the surface of the granules

6. Marketing : For consumer products, spheronising is sometimes only applied for improved product appearance and marketing reasons. Hardness and friability depend on the internal cohesive forces and surface characteristics. Spheronization increases the hardness and reduces the friability of granules. This will reduce the amount of fines generated during handling or transportation.

7. Disadvantages of pellets Dosing by volume rather than number and splitting into single dose units as required. Involves capsule filling which can increase the costs or tabletting which destroy film coatings on the pellets. The size of pellets varies from formulation to formulation but usually lies between 1 to 2mm.

8. Desirable properties of pellets : Uncoated pellets : Uniform spherical shape, Uniform size, Good flow properties, Reproducible packing, High strength, Low friability, Low dust, Smooth surface, Ease of coating. Once coated : Maintain all of the above properties, Have desired drug release characteristics

9. Pelletization techniques The preparation of spherical agglomerates can be approached by several techniques which can be subdivided into the basic types of systems shown in figure

10. Direct pelletizing : Means Manufacturing of pellets directly from powder. Effective process : Pellets are manufactured directly from powder with a binder or solvent, fast process. Low usage of auxiliary materials. Product advantages : Compact, round pellets - ideal for automatic dosing and even coating and Pellet diameter also obtained between 0.2 m m and 1.2 m m . Comparison : Pellets have a higher density than spray granulates and agglomerates. Process principles : Powder is mixed and moistened. A solvent or binder can also be added. The powder bed is set into a centrifugal motion. (Fluid Bed Pelletizing in the rotor). The impact and acceleration forces that occur in this process result in the formation of agglomerates , which become rounded out into uniform and dense pellets. The speed of rotation has a direct influence on the density and size of the pellets. The moist pellets are subsequently dried in the fluid bed. If required, the systems can be made inert for applications with organic solvents. Another alternative for direct pelletizing is Spray Granulation. With suitable additives, pellets can be made into tablets or used to fill capsules. The round shape is ideal for uniform coating. Pellets are good for automatic dosing

11. Powder layering Powder layering involves the deposition of successive layers of dry powder of drug or excipients or both on performed nuclei or cores with the help of a binding liquid. Because powder layering involves the simultaneous application of the liquid and dry powder, it generally requires specialized equipment. Pieces of equipments revolutionized powder layering processing as a pelletizing techniques are- tangential spray or centrifugal fluid bed granulators. In case of tangential spray the rotating disk and fluidization air provides proper mixing. With a double wall centrifugal granulator, the process is carried out in the open and closed position. With powder layering, the inner wall is closed so that simultaneous application of liquid and powder could proceed until the pellets have reached the desired size. The inner wall is then raised, and the spheres enter the drying zone. The pellets are lifted by the fluidization air up and over the inner wall back in to forming zone. The cycle is repeated until the desired residual moisture level in the pellets is achieved.

12. Fluid bed coating for layering of pellets Innovative processes for coating our products. Film coating; lipid hot melt coating, Coating of granules, pellets, tablets. Specific manipulation of the particle surface characteristics. Protection of the product against moisture, light, air. Specific manipulation of the way in which the particle dissolves the decomposition or the release of active ingredients. Process advantages: Uniform, continuous product coating. Aqueous or organic coatings can be applied. Coating and drying take place in one machine.

13. Balling technique: Balling also known as spherical agglomeration is a technique in which physical mixtures of drug and excipients are converted into spherical pellets by constant tumbling or rolling motion. Balling can be categorised into 2 types: liquid induced agglomerations and melt induced agglomerations. Balling is popularly used in fertilizer or iron ore industries, while its pharmaceutical applications are limited. In liquid induced agglomeration, liquid is introduced into the powder during or before the agggitation step. Agglomerates or nuclei are formed when powder comes in contact with the liquid phase. Melt induced agglomeration is similar to that of liquid incuded agglomeration except that here the binding material is a melt. Formulation variables such as particle size, solubility, extent of liquid saturation and viscosity of liquid phase influence the rate and extent of agglomeration

14. Extrusion spheronization In the mid-1960s extrusion, spheronization was developed as a method for pelletization . Extrusion spheronization method is regularly utilized in pharmaceutical business for the production of evenly sized pellets. Extrusion- spheronisation is a granulation process which produces dense pellets of high sphericity and have narrow size distribution. There are multiple steps associated in this technique. This method is helpful for producing granules with improved drug loading without forming excessively larger particles. This can also be utilized for obtaining oral controlled release dosage forms with the consumption of less quantity of excipients. Microcrystalline cellulose is a commonly used excipient for extrusion spheronization process. A disadvantage is reduction in the dissolution rate of drugs. This was overcome by incorporation of superdisintegrants and PEG.

15. Advantages of extrusion spheronization : Extrusion- spheronization over other techniques includes following advantages: 1.         High drug loading 2.         Incorporation of more than one active ingredient in any required ratio 3.         Physical properties of drug and excipients can be modified 4.         Spherical and smooth surfaced particles 5.         Spheres having smooth surface are a perfect base to apply the coating 6.         Enhanced flow properties 7.         Low hygroscopicity of particles 8.         Evenly sized particles 9.         Higher desnity particles 10.      Packaging of the spheres in capsules or bigger packages is convenient compared to other dosage forms like powders. 11.      Controlled drug delivery can be achieved by using suitable coating material 12.      Production of fines and dust is lowered 13.      Spheronization can improve the hardness and decreases granules friability based on the surface properties and adhesive forces

16. Extrusion spheronization consists of the following steps : i .     Process of dry blending: Dry blending/mixing for all components is made to produce a mixture of uniformly blended powder utilizing distinctive kinds of blenders such as a high shear blender, planetary blender, twin shell blender, and tumbler blender.   ii.   Process of wet massing/ granulation: Wet massing of dry powder is done to obtain an adequate dense mass for the extrusion process. This process is the same as a customary wet granulation. Generally utilized granulators are a planetary blender or the sigma cutting edge blender. Frequently planetary blender is utilized commonly for both mixing and as well as granulation activity. It is necessary to maintain the rate of evaporation of the granulating fluid, especially in case of organic solvents which tend to volatilize easily. While using high shear blender, a large quantity of energy is generated which gets transferred into the wet mass. This could result in evaporation of granulation liquid. As a precautionary step,the granulation bowl is cooled to avoid loss of solvent by evaporation. The nature of binder and granulation fluid has a significant effect on physical properties as well as release kinetics of drug from pellets prepared by extrusion/ spheronization .   

17. Process of extrusion: The mass obtained after wet granulation is subjected to pressure until the mass begins to flow. Once the mass begins to flow, it is passed through an orifice to form extrudates . The length or shape of the extrudate is determined by the geometry of the orifice, the nature of materials and the method of extrusion. The extrudate should have sufficient plasticity to turn and twist. Extrusion is carried out using either of four classes of extruders: screw, sieve and basket, roll, and ram extruders. A spheronizer is a device made up of a vertical hollow cylinder and a horizontal rotating disk/friction plate within the cylinder. Extrudates on rotating plate were broken into short segments with friction plate, due to collisions between particles and also with the wall. Spinning friction plate transfers the mechanical energy into kinetic energy to form a mechanically fluidized bed. Extrudate upon further processing will attain a spherical shape. Frictional forces increases owing to the grooved surface present on the friction plate. These grooves exist in two types of arrangement. One of the arrangement shows a cross-hatch geometry wherein the grooves form right angles while the other arrangement shows a radial geometry where the pattern is radial.   .

18. Drying process: Drying stage is required to obtain moisture content of required level in pellets. Pellets are dried at the room temperature or elevated temperatures. Equipment such as the FBD, tray driers, ovens are utilized for this purpose. Researchers examined the impact of drying method on the physical appearance and compaction qualities of spheronized granules of propyl gallate /MCC/water glue. Drying by the oven, delivered uneven and hard granules because of the improper wet powders shrinkage.   Screening process: Screening is an important process in order to obtain an particles with a uniform size distribution. Sieves of different mesh sizes are utilized. In case pellets are produced by spheronization followed by extrusion, screening is mandatory so as to stay away from pellets having higher polydispersity

19. Spray drying and congealing : Spray drying process: The drug suspension/solution is atomized into fine droplets with or without the addition of excipients, which is exposed radially to a moving steam of hot gas. The temperature of the droplets is immediately increased and fine droplets get dried, forming spherical particles.   Spray congealing process: This procedure involves formation of spherical particles by introduction of molten liquid containing drug particles which is sprayed into a cooling chamber having air at lowered temperature.  

20. Assessment of pellets Drug content It can help to determine the concentration of drug in pellets. The concentration of drug can be determined with the help of suitable UV method or HPLC method or some other suitable analytical methods.   Distribution of size: Pellets sizing is mandatory as it has a high impact on the release rate kinetics. Generally, determination of particle size is done by sieve analysis or microscopic techniques. Parameter such as the diameter of geometric mean length, and width of particle mean, ferret diameter mean applies for the determination of the distribution of particle size.  

21. The shape of pellets: There are different methods to determine the sphericity of pellets and it is very important to determine it. Determination of the deviations of the spherical geometry from a circular zone is made by the shape factor. It is determined by means of pellets projected area and their circumference. Shape factor value 1 gives perfect circular pellets projection and value of 0.6 gives good sphericity . Shape factor or roundness index must be within 1-1.2 for obtaining acceptable pellet quality. Visual examination of the pellets using stereo-microscope and light microscope is another way to decide pellets shape. Another common method is through an angle of repose to measure the flow property and pellets circularity. In this, the proportion of height produced by a heap of pellets is measured and radius is calculated by using fixed funnel. Certain amount of pellets allowed to fall from the measured height through the orifice following which the heap height and the radius is measured

22. Morphology of structure: Morphology of pellets is examined using SEM (Scanning electron microscope). Optical microscope was used for examining pellets surface microstructures. The roughness of structure can be studied using non-contracting profile laser meters.   Surface area: The surface area of pellets is controlled by the particle size, shape, porosity and roughness of pellet. It is an important parameter that has an impact on release rate of drug from the pellets.   Friability: Various process of pelletization may impact the properties of pellets. It may get chipped and result in formation of dust while coating and handling. Lower friability of pellets is required for subsequent coating. Turbula and erweka are the types of apparatus used for the determination of pellets friability.  

23. Pellets porosity: Porosity impacts the drug release from pellets as it affects drug dissolution characteristics. Mercury porosimetry can be used for quantitatively estimating pellets porosity.   Tensile strength measurement The tensile strength of pellets is usful to measure the load require to break the pellets. This is a measure of hardness of pellets.   Disintegration time: Disintegration time is one of the important test to measure the disintegration of pellets. This test is usually performed in 0.1N HCl .   In vitro dissolution studies: Commonly it is performed using USP Type-1 and USP Type-2 apparatus. They help to determine drug release pattern from the pellets