Industrial Pharmacy II 3rd Lecture Size Enlargement PDF

Industrial Pharmacy II 3rd lecture size enlargement  SIZE ENLARGEMENT (Agglomeration) Definition: A process whereby small particles are gathered into larger ones in which the original particles can still be identified. Reasons for Size Enlargement: Improve...

Industrial Pharmacy II 3rd lecture size enlargement  SIZE ENLARGEMENT (Agglomeration) Definition: A process whereby small particles are gathered into larger ones in which the original particles can still be identified. Reasons for Size Enlargement: Improve flow Densify materials Improve content uniformity Improve compression characteristics Control the rate of drug release. Facilitate metering or volume dispensing Decrease dust generation and reduce employee exposure to drug products. Improve the appearance of the tablet. 2  Granulation It is the process of collecting particles together and converting fine or coarse particles into physically stronger and larger agglomerates by creating bonds between them. Bonds are formed by compression or by using a binding agent. Granulation methods 1. Wet granulation 2. Dry granulation 3  The effectiveness of granulation depends on the following properties : i) Particle size of the drug and excipients ii) Type of binder (strong or weak) iii) Volume of binder (less or more) iv) Wet massing time (less or more) v) Amount of shear applied to distribute drug, binder, and moisture. vi) Drying rate (Hydrate formation and polymorphism). 4  Types of granulation 1- Dry Granulation Dry granulation involves granule formation without using a liquid solution as the product may be sensitive to moisture and heat. In this process, dry powder particles may be brought together mechanically by compression into slugs or by roller compression to obtain flakes. 2- Wet Granulation It involves the addition of a liquid solution (with or without binder) to powders, to form a wet mass or it forms granules by adding the powder together with an adhesive, instead of by compaction. The wet mass is dried and then sized to obtain granules. The liquid added binds the moist powder particles by a combination of capillary and viscous forces in the wet state. 5  Formation of Granule 1- Nucleation & growth process. ❖ At first, the binder solution droplet touches the particle nucleus; capillary force and binder flocculation provide strength 2- Growth of the nuclei: by layering through contact and adhesion; or by nuclei agglomeration. 3- Rubbing between granules make granules’ surface smooth 6 Steps involved in the wet granulation 1- The active ingredient and excipients are weighed and mixed. 2- The wet granulate is prepared by adding the liquid binder– adhesive to the powder blend and mix thoroughly. 3- Screening the damp mass through a mesh to form pellets or granules. 4- Dry the granules through a conventional tray dryer or fluid-bed dryer. 5- After the granules are dried, they are passed through a screen of a smaller size than the one used for the wet mass to create granules of uniform size. 7  Disadvantages of wet granulation 1. It is not used with heat and/or moisture–sensitive material. 2. Migration of color (water–soluble colors). 3. Cost is high because of long procedures and the use number of expensive equipment. 4. It is more time-consuming, especially the wetting and drying steps. 5. Material loss during processing due to the transfer of materials from one unit operation to another. 8  I-Wet granulation Methods 1) High-shear mixture granulation 2) Fluid bed granulation 3) Extrusion and Spheronization 4) Spray drying 9  1. High-shear mixture granulation High shear mixture has been widely used for blending and granulation. Blending and wet massing is accompanied by high mechanical agitation by an impeller and a chopper. Mixing, densification, and agglomeration are achieved through shear and compaction force exerted by the impeller. The mixer consists of a mixing bowl, a three- bladed impeller, & an auxiliary chopper.  Mixing bowl can be jacketed for heating or cooling the contents in the bowl, by circulating hot or cool liquid or steam through the jacket. Chopper is used to break down the wet mass to produce granules. The rotation speed of the chopper ranges from 1000 to 3000 rpm. Impeller is employed to mix the dry powder & spread the granulating fluid. The impeller normally rotates at a speed ranging from 100 to 500 rpm. 11 12 13 14 Diosna Mixer Granulator 15  High-Shear Wet-Granulation Process 1. Loading all the ingredients into the mixing bowl. 2. Mixing dry ingredients with the rotating impeller at moderate speed for a few minutes. 3. Addition of a liquid binder into the powder mixture, while the impeller is running at a low speed. 4. Wet massing is formed by running the impeller at a high speed. The chopper is usually switched on when the moist mass is formed, as its function is to break up the wet mass to produce a bed of granular material. 5. Removal of the resulting wet granules, drying them. 6. Sieving the dried granules. 16  High-Shear Wet-Granulation Process Advantages Disadvantages i) The mixing, massing, and 1) Mechanical degradation granulation are all performed could take place in the case of within a few minutes in the fragile particles. same piece of equipment 2) Due to increasing ii) Less amount of liquid temperature chemical binders required compared degradation of thermo-labile with the fluid bed. material could be resulted. iii) Highly cohesive material 3) Over wetting of granules can be granulated. can lead to large-size lumps formation. 17 18  2. Fluid bed granulation Fluid bed granulation is a process by which granules are produced in a single piece of equipment by spraying a binder solution onto a fluidized powder bed. An upward stream of hot air is used to fluidize & dry the powder & granule bed. 19  2. Fluid bed granulation Advantages Disadvantages 1) It reduces dust formation 1) Fluid Bed cleaning is during processing, thus labor-intensive and time- improving housekeeping. consuming. 2) It reduces product loss. 2) Difficulty in assuring 3) It improves worker safety. reproducibility. 4) Finer, more free-flowing, & more homogenous granules, It is unsuitable for heat- which, after compression, sensitive materials. produce stronger & faster disintegration of tablets 20 Fluidized bed granulator 21 22  3. Extrusion and Spheronization It is a multiple-step process capable of making uniform- sized spherical particles. It is primarily used as a method to produce multi- particulates for controlled release applications. The most common application of the process is to produce spherical pellets for controlled drug release. 23  Process Description: 1. Dry mixing of ingredients to achieve a homogenous powder dispersion; 2. Wet massing to produce a sufficiently plastic wet mass; 3. Extrusion to form rod-shaped particles of uniform diameter; 4. Spheronization to round off these rods into spherical particles; 5. Drying to achieve the desired final moisture content; 6. Screening (optional) to achieve the desired narrow size distribution. 24 Screw-feed extruders (axial or end-plate, dome and radial) 25 Spheronization This is carried out in a relatively simple piece of apparatus. The working part consists of a bowl with fixed side walls and a rapidly rotating bottom plate or disc. The rounding of the extrudate into spheres is dependent on frictional forces generated by particle-particle and particle-equipment collisions. The bottom disc has a grooved surface to increase these forces. 26 The transition from rods to spheres during spheronization occurs in various stages as follows: The diagram shows a transition from cylindrical particles (a) into cylindrical particles with rounded edges (b), then dumbbells (c), to ellipsoids (d), and finally spheres (e). 27 28 Advantages: i) Ability to incorporate higher levels of active components without producing excessively larger particles. ii) Applicable to both immediate and controlled-release dosage forms. iii) It is more efficient than other techniques for producing spheres. iv) Therefore, it is used when the desired particle properties are essential & cannot be produced using more conventional techniques. 29  4. Spray drying granulation o It’s used for the conversion of a liquid, slurry, or low- viscosity paste to a dry solid (free-flowing hollow spheres) in a single step. o So spray drying is a suitable process for the production of directly compressible excipients such as lactose, microcrystalline cellulose, & mannitol. 30  Process Description: a) Atomization of a liquid feed into fine droplets. b) Spray droplets mix with a heated gas stream. c) Dried particles are produced by the evaporation of the liquid from the droplets. d) Separation of the dried powder from the gas stream & collection of these powders in a chamber. Advantages: i) Rapid process ii) Ability to be operated continuously iii) Suitable for heat sensitive product 31 Spray drying granulation 32  II. Dry granulation Dry granulation operations do not use moisture or heat to process powders into densified granules Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules. This process is often used when the product to be granulated is sensitive to moisture and heat. 33 34  A- Slugging Steps in dry granulation: i) Milling of drugs and excipients ii) Mixing of milled powders iii) Compression into large, hard tablets to make slug iv) Screening of slugs. The slugging process is still used today by only a few manufacturing firms that have old pharmaceutical formulation processes. 35  B- Roller Compaction (Chilsonator) This technology is well suited for dry granulation in the area of modern development of active pharmaceutical ingredients in pharmaceutical plants. 36  Process Description a) The powder is fed down between the rollers from the hopper which contains a spiral screw. b) The screw serves to maintain a constant flow of the powder into the compaction rolls. c) The pressure between the rolls is regulated by hydraulic means. d) The product obtained is in the form of compressed sheets which can be broken up into granules of the desired size. N.B. Therefore, materials that normally require slugging two or more times can be granulated by a single pass through the “chilsonator” 37 Advantages of dry granulation 1. It is used for heat sensitive and/or moisture-sensitive material. 2. It improves the disintegration of tablets. Disintegration is usually more rapid 3. It improves the solubility of materials tending to float. 4. No- migration of active ingredients or colors. 5. It is of particular value in preparing effervescent tablets since the dried acid and alkali remain fully dry and active until the tablet is immersed in water when used. 6. It uses less equipment and space. 7. It eliminates the need for binder solution, heavy mixing equipment, and time-consuming drying step required for wet granulation. Uses: 1. For moisture-sensitive material 2. For heat-sensitive material 3. For improved disintegration since powder particles are not bonded together by a binder. 38  Disadvantages of dry granulation i) It requires a specialized heavy-duty tablet press to form a slug. ii) It does not permit uniform color distribution as can be achieved with wet granulation where the dye can be incorporated into binder liquid. iii) The process tends to create more dust than wet granulation, increasing the potential contamination. 39 40