Pellets- Industrial pharmacy

Pellets - Industrial pharmacy -I as per PCI syllabus...

1. PELLETS

2. CONTENTS Introduction formulation requirements pelletization processes and equipments for manufacture of pellet mechanism of pellet formation and growth

3. INTRODUCTION These are the small size (0.5-1.5 mm), free flowing spherical units obtained by agglomeration of fine powder or granules of bulk drugs and excipients by pelletization techniques. Pellets have low porosity (about 10%) Pellets either filled in hard gelatin capsules or compressed into disintegrating tablets. When pellets are intended for oral use, they quickly liberate their contents in the stomach and gets distributed throughout the gastrointestinal tract and produce maximal drug absorption and also minimize local irritation.

4. APPLICATION OF PELLETS l . They improved aesthetic appearance of products. 2 They offer uniformity of dose. 3. They are used to achieve controlled release rate of drugs by coating of drug pellets with different polymers. 4.Chemically incompatible products can be formulated into pellets and delivered in a single dosage form. 5.During formulation of pellets, there is no dust formation. While fine powder cause dust explosion and cause health problems.

5. 10. They reduce peak plasma fluctuations and minimize potential side effects with improved drug bioavailability. 6.Pellets have excellent flow properties in formulation development. 7.They reduce inter and intra patient variability. 8.The high bulk density of pellets plays an important role in achieving content and weight uniformity. 9. Pellets provides less risk of dose dumping. APPLICATION OF PELLETS

6. ADVANTAGES OF PELLETS 1.Improved aesthetic appearance of the product. 2.Coating of drug pellets with different polymers to achieve controlled release rate of drugs. 3.For immediate release products large surface area of the pellets enables better distribution, dissolution and absorption. 4.Chemically incompatible products can be formulated into pellets and delivered into single dosage form by encapsulating them. 5.Pellets ensures improved flow properties and flexibility in formulation, development, and manufacture.

7. DISADVANTAGES OF PELLETS 1.Preparation of pellets is a complicated and time consuming process. 2.Due to rigid nature, it is difficult to compress pellets into tablets. Therefore they are dispensed in hard gelatin capsule. 3.Specialized equipments are required for pelletization which raise manufacturing cost.  4.Due to high specific surface area per dose , more amount of coating should be given.

8. MECHANISM OF PELLET FORMATION AND GROWTH  Nucleation phase Nucleation is a stage of pelletization process in which powder particles are wetted with binder liquid. The Formation of pellet involves adhering of the solid particles or fine powders to each other due to attractive forces such as molecular forces, electrostatic forces and magnetic forces. The void spaces between the primary particles are occupied by the binder solution . This lead to the formation of three-phase -air-water-liquid nuclei system which are held together by liquid bridges that are pendular in nature.

9. Stages of Nucleation This state is referred to as pendular state because of low moisture level. The surface tension of the liquid and the negative suction pressure generated at the liquid bridges causes attraction between the powder particles. But it is due to air between the particles. PENDULAR STATE The next state in nucleation is funicular state, This is an intermediary state where air start to dispersed continuously throughout the agglomerate. FUNICULAR STATE In capillary state, all the void space in agglomerate is fully occupied by liquid. This lead to formation of strong bonds between the particles. These bonds disappear as the liquid evaporates. In this state, the liquid does not completely surround the agglomerate and cannot form nuclei. CAPILLARY STATE

10. The next state is droplet, identified when liquid completely surrounds onto the agglomerate. DROPLET The rate and the extent of nuclear formation depends upon the size of the particles, moisture content, the viscosity of the binding particles, the wettability of the substrate and the processing conditions. Coalescence phase Coalescence is defined as process of the formation of large-sized particles due to random collision of well-formed nuclei. The total mass of the system remains unchanged during this operation. But the number of nuclei is reduced. During collision, fines and particles are produce

11. The successive addition of these fines and fragments on surface of already formed nuclei is called layering. Layering is a slow growth mechanism. In this phase, the number of particles remains constant, but the total mass of nuclei in the system increases due to increasing particle size with time. The subsequent coalescence and layering continues until the number of collisions declines rapidly. This cause reduction in the rate of growth of the pellets. Layering phase Ball growth phase or Abrasion transfer phase It is the last step of pellet formation The main mechanism in the ball growth phase is the abrasion transfer. It involves the transfer of materials from one granule formed to another without any preference in either direction. This phase does not cause the change in the total number or mass of the particles.

12. Ball growth phase or Abrasion transfer phase

13. FORMULATION They are used to add bulk to products and make very small active components easy for consumer to take. They are generally water soluble or insoluble substances. The selection of filler depends on desired dose, physical property of drug and manufacturing process. Example: MCC (Micro Crystalline Cellulose), Starch, sucrose, lactose, mannitol. Fillers: They are added to bind powder and make pellet integrity. Ex. Sucrose, Starch, Hydro propyl Methyl Cellulose, Hydroxy Propyl Cellulose, Gelatin, pyrrolidone, Methyl Cellulose, Polyvinyl. Binders: They are added to reduce friction between particles and surface of equipment. Ex. Glycerin, Polyethylene Glycol, Magnesium stearate, Calcium stearate Lubricants:

14. During manufacturing pellets may develop surface charge and get attracted to each other. Separating agents promote separation of pellets into unit. Ex. Kaolin, Talc, silicon dioxide Separating agents: Ex. Alginate, cross carmellose sodium. Disintegrating agents: Ex. Citrate, Phosphate, Meglumine pH adjuster: Surfactants are added to the liquid to improve wettability by lowering the interfacial tension between the liquid and drug particles. Surfactants help to weaken the liquid bridges and results in more friable pellets. Ex. Sodium Lauryl Sulfate, Polysorbate Surfactant:

15. They not only impart plasticity onto the formulation, but also impart binding properties that are essential for pellet strength and integrity. Ex. Micro Crystalline Cellulose, Sodium Carboxy Methyl Cellulose. Spheronization enhancer: They reduces the friction between the die wall and material mix either during the compression process or in ejection phase. hey also play a significant role in smooth discharge Of the pellets from the Spheronizer Ex. Talc, starch, Magnesium stearate GIidant: They are added to possess specific release profiles in a single step. Generally, water soluble low molecular weight excipients, surfactants and disintegrants are incorporated in formulations to enhance the drug release kinetics, while water insoluble polymers, hydrophobic substances, inorganic salts, and hydrophilic polymers that swell and/or form gels are incorporated in pellets that retard release kinetics. Ex: Ethyl cellulose, Shellac, Carnauba wax  Release modifier:

16. Others: Include sweetening, coloring and flavoring agents. PELLETIZATION PROCESS Pelletization is an agglomeration process in which fine powders or granules of bulk drugs and excipients is converted into pellets. The preparation of spherical agglomerates can be approached by several techniques.

17. This is also known" as spherical agglomeration. In this Pelletization technique, the required amount of liquid is added before or during the agitation to the finely divided particles. This mass under a continuous rolling or tumbling motion in pans, discs, drums or mixers gives spherical particles. Agitation (Balling) In liquid induced agglomeration method, liquid is added to powder to obtain agglomerates while in Melt induced agglomeration binding material is in melt form. This method is mainly used in iron ore and fertilizer industry.  Types of agitation Liquid induced agglomeration Melt induced agglomeration

18. Compression: It is a pelletization process in which mixtures or blends of active ingredients and excipients are compacted by applying pressure to get pellets of definite shape and size which can be filled into capsules. Extrusion — Spheronization: This was introduced in the early 1960s. This process is commonly used in the pharmaceutical industry to make uniformly sized spheroids roughly 1 mm in diameter. It is especially useful for making dense spherical pellets of uniform size and shape with high drug loading for controlled-release oral solid dosage forms. It is a multi-step compaction process comprising of following steps. Compaction: Granulation : The process of using a liquid solution to powders involves the massing opf a mix of dry primary powder particles using a granulating fluid . The fluid contains a solvent that must be volatile. Meets all the physical requirements od compression .

19. Dry mixing: Different types of mixers like twin shell blender, high shear mixer, tumbler mixer and planetary mixer are used to get homogeneous powder dispersion . Wet Massing: This is done to produce a plastic mass for extrusion. It is similar to the conventional wet granulation method with the exception of granulation end point. The granulation end point is determined by the behavior of the wet mass during the extrusion operation. The most commonly used granulator is the Planetory mixer or Sigma blade mixer or the high shear mixer and the Horbat mixer. The planetary mixer is used systematically for mixing and granulation operations. Fluid- bed Granulator: The process is carried out continuously in a fluid-bed granulator. Spraying of a granulation solution onto the suspended particles which are then dried rapidly in the hot air stream. Advantage over traditional wet massing process : Automated, performed in one unit, thus saving costs, transfer losses and time. FBG improves the dissolution efficiency of both nimodipine and spironolactone and many other pellets based controlled release formulations.

20. Extrusion: In this process, the wet mass passes through the extruder to form rod- shaped particles of uniform diameter. The extrudate should have sufficient plasticity to deform but not so much that the extrudate particles adhere to other particles as they are rotating urmgt e sp e process. It is a process in which Spheronizer is used. In Spheronizer, the extrudate is subjected to rotate at higher speed by friction plate to break these rod shaped particle in to in to spherical particle with narrow size distribution. Spheronization:

21. STEPS OF EXTRUSTION- SPHERONIZATION

22. Hot melt extrusion It is a continuous process of converting raw material into a final product of uniform shape and density by forcing it through a die under controlled conditions HOT MELT EXTRUSION EQUIPMENT

23. The theoretical approach to understand the melt extrusion process is therefore , generally presented by dividing the process of flow into four sections . Feeding of the extruder conveying of mass ( mixing and reduction of particle size) Flow through the die Exit from the die and down stream processing The applications in the pharmaceutical industry: 1. Improving the dissolution rate and bioavailability of the drug by forming a solid dispersion or solid solution. 2.Controlling or modifying the release of the drug. 3.Masking the bitter taste of an active drug.

24. It is done to achieve the desired size distribution. Sieves are used for this purpose. Drying: Screening : It is the stage in which the pellets are dried at room temperature or at a elevated temperature in a tray dryer or in a fluidized bed dryer to retains the shape and size. In this process, drug is layered onto nonpareil or starter seeds in powder, solution or suspension form. The resulting pellet consist of an inner core region and an outer shell region of a different composition. This process is classified into two categories A. Powder layering. B. Solution or Suspension layering Layering:

25. A. Powder Layering: The first equipment used to make pellets on a commercial scale was the conventional coating pan, but it has a significant limitation, namely that the de ee of mixing is very. low and the drying process is not efficient. Therefore now a days, tangential spray granulator and a centrifugal bed granulator are used. This technique involves the deposition of successive layers of powdered drug and excipient or both on preformed cores or nucleus with the aid of a binding liquid. The binding solution and the finely milled powder are added simultaneously in a controlled manner to maintain equilibrium. In the initial steps, the drug particle is bound to the starter seeds to form the pellets using a liquid bridge from a spray binding liquid. These liquid bridges are replaced by solid bridges during solidification. This treatment leads to the formation of successive layers of a drug and the binder solution until the desired pellet size is reached.

26. Powder layer of pellets

27. B. Solution/Suspension Layering: Therefore, a conventional coating press; a centrifugal fluidized bed granulator of a Wurster coating have been successfully used to make pellets. In this technique, solution / layering of neutral pellets has been achieved by applying a novel fluidized bed technology. Hüettlin's three-component spray nozzle is a good choice as it prevents excessive spray drying or clogging of the nozzle. This technique involves the deposition of successive layers of solution and / or suspension of drug substances and binders on starter seeds, which may be inert materials or granule crystals of the same drug: In this technique, drug particles and other components are dissolved or suspended in the binding liquid. The droplets impinge on the starter seeds or cores and spread evenly when the solution or suspension is sprayed onto the nuclei. During drying, solid bridges are formed between the nuclei and the initial layer of. drug substances and. between the successive layers of drug substances or polymers. Continue this process until the desired drug or polymer layer is formed.

28. Globulation or droplet formation includes spray drying and spray congealing. In this methods, spherical pellets are produced by atomization of hot melt, solutions or suspension. Globulation or Droplet formation: A. Spray drying: It is a process in which drug entities (in or suspension) with or without excipients are sprayed into a stream of hot air to generate dry, highly spherical . It is generally used to enhance the dissolution rates and hence, bioavailability of poorly soluble drugs.

29. B. Spray Congealing or spray chilling: It is the process in which a drug is allowed to melt, disperse, or dissolve in hot melts of gums, waxes, fatty acids, etc. Then it is sprayed into an air chamber where the temperature is below the melting points of the formulation components. This technique is similar to spray drying but no source of heat is needed. This process is used to obtain spherical congealed pellets under appropriate processing conditions. This process is used to get sustained released effect.

30. It is the process in which liquid droplet is converted into solid spherical particle by using liquid nitrogen. The conventional freeze dryer is used to dry the pellets. It is used to get free flowing pellets. Cryopelletization:

31. CHARACTERIZATION OF PELLETS Pellet size and size distribution: It is determined by sieve analysis, microscopy methods like Scanning electron microscopy (SEM) and laser diffraction. Shape: The most common method of analysis is scanning electron microscopy (SEM) for qualitative and quantitative analysis .Visual inspection of pellets by microscope is also used to determine shape of pellets. Surface area : The surface area is analyzed by particle size distribution, gas adsorption (BET method- Brunauer, Emmett & Teller) and air permeability method .

32. Porosity: It is measured by mercury porosimeter. The sample introduced into the chamber, degassed, and then completely covered with mercury. Pressure is applied and the volume of mercury that penetrates into the pores is recorded. Pore radius is given by Washburn equation.  R = 2 g [cos q] / P  W here g = 480 ergs/cm3 q=1400 R = pore radius P = mercury-intrusion pressure. In-vitro Dissolution study: In this, USP I (basket) and USP Il (paddle) apparatus are used to study the release pattern of the coated pellets.

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