Granulation Lecture 5 PDF

SOLID DOSAGE FORMS GRANULATION LECTURE 5 By Maha Mostafa Ghalwash Department of Pharmaceutics &Drug Manufacturing 1  Granules : are powders agglomerated to produce larger free flowing particles which may have overall dimensions greater than 1000 µm. (between 0.2...

SOLID DOSAGE FORMS GRANULATION LECTURE 5 By Maha Mostafa Ghalwash Department of Pharmaceutics &Drug Manufacturing 1  Granules : are powders agglomerated to produce larger free flowing particles which may have overall dimensions greater than 1000 µm. (between 0.2 and 4.0 mm) depending on their subsequent use 2 INTRODUCTION 3 Steps: 1. Initial dry mixing of powdered ingredients (to achieve uniform distribution of each ingredient through the mix.). 2. Granulation. 3. Packed (used as dosage form) or mixed with other excipients prior to tablet compaction or capsule filling). Reasons for the powder granulation :- 1. Prevent segregation 2. Improve flow properties of the mix. 3. Improve compaction characteristics of the mix. 4. Other reasons. 4 4 1. Prevent segregation of the constituents of the powder mix Segregation (demixing) is due to: 1. Differences in size. 2. Differences in density of the components of the mix. 3. Electrostatic charge due to constant friction among the mixed particles. Similar charges repel particles from each others. N.B. The smaller &/or more dense particles at the base of the container & The larger &/or less dense ones above them. Ideal granulation : each granule will contain all the constituents of the mix. in the same proportion. 5 It is important to control particle size distribution of the granules, why? Because although the individual components may not segregate, if there is a wide size distribution the granules themselves may segregate. 6 2. To improve flow properties of the mix Powders may be cohesive & don’t flow well due to their small size, irregular shape or surface characteristics Poor flow will often result in a wide weight variation within the final product owing to variable fill of tablet dies etc. Granules will be More isodiametric larger Improved flow properties 7 7 3. To improve the compaction characteristics of the mix Applied to powders which are difficult to compact (even if compactable adhesive (binder) is included in the mix). Granules of the same formulation are easily compacted and produce stronger tablets. This is associated with the distribution of the adhesive within the granule and depends on the method used to produce the granule. 8 8 4. Other reasons 1. Granulation of toxic materials to reduce toxic dust that may arise during handling powders. 2.Control the rate of the drug release 3. Improve the appearance of the tablet. 4. Densify the material (Granules occupy less volume per unit weight, they are more convenient for storage or shipment. 9 9  Different excipients used in granulation In a suitable formulation a number of different excipients will be needed in addition to the drug Diluents 1. to increase the bulk volume of powder 2. increase the size of the tablet. E.g. lactose. Disintegrating agents: which are added to aid the break-up of the granule when it reaches a liquid medium, e.g. on ingestion by the patient. E.g. starch. Adhesives: in the form of a dry powder may also be added, particularly if dry granulation is employed. E.g. gum & gelatin. 10 10 The ideal characteristics of granules include : 11 1.Spherical 2.Shape, smaller particle size distribution with sufficient fines to fill void spaces between granules, 3. Uniform distribution , 4.Good flow 5.Adequate moisture (between 1-2%), 6.Good compressibility and 7.Sufficient hardness. 11 As with any type of formulation, the goal is to Obtain the desired drug product with the fewest necessary processing steps and The lowest cost. For solid dosage drugs, that means using the granulation (method required) that provides a tablet with the desired properties (appearance, uniformity, drug-release profile) using the least number / quantity of excipients possible and as rapidly as possible 12  Granulation method Wet granulation Dry granulation Direct Compression Crystallization method 13  Methods of granulation Wet granulation Important 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 mixing thoroughly. 3.Screening the damp mass through a mesh to form pellets or granules. 4. Drying the granules. A conventional tray-dryer or fluid bed dryer are most commonly used. 5. After the granules are dried, they are passed through a screen of smaller size than the one used for the wet mass to create granules of uniform size. 14  The fluid contains a solvent which must be volatile so that it can be removed by drying, and be non-toxic. Typical liquids include water, ethanol and isopropanol, either alone or in combination. The granulation liquid maybe used alone or, more usually, as a solvent containing a dissolved adhesive (also referred to as a binder or binding agent} which is used to ensure particle adhesion once the granule is dry. 15  Water commonly used for economical and ecological reasons. The primary advantage of water is that it is (non- flammable, nontoxic, Adour less and tasteless). disadvantages of using water as a solvent are that 1. it may adversely affect drug stability, causing hydrolysis of susceptible products, 2. it needs a longer drying time than do organic solvents. This increases the length of the process and again may affect stability because of the extended exposure to heat. 16 17  Wet granulation methods 1) High shear granulation 2) Rotary granulator 3) Fluid bed granulation 4) Extrusion - Spheronization 5) Spray drying granulation 14 18  1- High shear granulation High shear granulation is a shaping process for granulation that has been enhanced for application in the pharmaceutical industry. A binder liquid is fed to the powder particles in a closed container with blending tools and a chopper. the particles are set into movement by an impeller rotating, the rotating part of a centrifugal pump, or other machine designed to move a fluid by rotation. at a high speed (Approx. 50- 100 rpm). After the wet mass is produced, the granules are wet sieved, dried and sieved again. The liquid amount is critical, because the process is susceptible for over-wetting, which leads to uncontrollable agglomerate growth. 19 20 21 High shear mixture granulation Advantages 1) Short processing time 2) Lesser amount of liquid binders required compared with fluid bed granulation. 3) Highly cohesive material can be granulated. Disadvantages 1) Mechanical degradation could take place in case of fragile particles. 2) Due to increase in temperature chemical degradation of thermo-labile material could be resulted. 3) Over wetting of granules can leads to large size lumps formation 22 23  2- Rotary granulator rolling drum granulator is one of the most widely used granulating equipment devices in which the size enlargement is achieved by collisions in a bed of moist particles undergoing rolling motion. 24  3- Fluid bed granulation The fluid bed granulation process (also known as agglomeration) it involves suspending particles in an air stream and spraying a liquid from the top of the system down onto the fluidized bed (top-down spray). Particles in the path of the spray get slightly wet and become sticky. granules are similar to those prepared by the wet granulation but possess greater porosity and the granule surface is covered by a film of binding agent. Note Fluidization is the operation by which the fine solid particles are transferred into fluid through contact with air or gas. 26 Advantages of Fluid bed granulation 1)It reduces dust formation during processing, thus improves housekeeping. 2)It reduces product loss. 3)It improves worker safety. Disadvantages of Fluid bed granulation 1)The Fluid Bed cleaning is effort labor-intensive and time consuming. 2)Difficulty of assuring reproducibility. 3)It is unsuitable for heat sensitive materials 27  4- Extrusion – Spheronization For some applications it may be desirable to have a dense, spherical pellet of the type difficult to produce with the previous equipments.Such pellets are used for controlled drug release.. Process Description: 1. 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. 28 29 30 Spheronization ❑ The function of spheronization is to round off the rods produced by extrusion into spherical particles. ❑ This is carried out in Spheronizer which 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. 31 Advantages: 1) Ability to incorporate higher levels of active components without producing excessively larger particles (minimal excipients) 2) Applicable to both immediate and to produce multi-particulates for controlled drug release dosage form. 3) It’s more efficient than other techniques for producing spheres, 4) Ideal flow behavior and dose-ability 5) Compact structure 6) Low hygroscopicity 7) High bulk density Disadvantages This process is more labor & time intensive than other commonly used granulation techniques. 32  5- Spray drying granulation 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. Granules produced are extremely consistent in terms of particle size, bulk density & compaction behavior. So spray drying a suitable process for the production of directly compressible excipients such as lactose, microcrystalline cellulose, & mannitol. 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. 33 34 35 Advantages: 1. Rapid process 2. Ability to be operated continuously 3. Reduces overall cost by avoiding labor intensive drying and granulation steps. 4. Offers minimal product handling and operator exposure to dust. 5. Suitable for heat sensitive product 36 Advantages of wet granulation 1. Cohesiveness and compressibility of the powder are improved. 2. It is used for high dosage drugs with weak compressibility. 3. It ensures better content uniformity, especially for soluble small doses drugs to avoid non-uniformity of mixing which occur if direct compression is used. 4. The colorant is dissolved in the solvent and distributed uniformly, but in direct compression, there is no uniform distribution of the color. 5. Wet granulation process prevent segregation and separation of particles leading to reduced intra- and inter-batch variability.. 6. The process may improve the dissolution rate of poorly soluble drugs by imparting hydrophilic properties to the surface of the granules. 37 Disadvantages of wet granulation 1.It is not used with heat and /or moisture – sensitive material. 2. Migration of color (water – soluble colors) and this can be overcome by using color lakes. 3. Cost is high because of long procedures and use number of expensive equipment's. 4. It is more time consuming especially the wetting and drying steps (it takes about 2 days) 5. It increase the incompatibility between ingredients 38  Disadvantages of wet granulation (cont.) 19 6. It requires a large area with temperature and humidity control as it require many steps. 7. Material loss during processing due to the transfer of materials from one unit operation to another. 8. The presence of moisture may cause an increase in particle size and may cause modification of crystal structure so increase disintegration time which lead to decrease of dissolution of drugs. 39 Despite all these limitations, the manufacture of tablet using wet granulation still used due to the following reasons: a. Availability of extensive data on manufacture of existing products by wet granulation. This has made pharmaceutical companies reluctant to adopt new techniques except there exist a compelling reason to do that. b. Experience over the years in formulation has also shown that wet granulated granules and tablets assure good content uniformity. c. The drying process can be control to produce granules with the desired moisture content. 40  Dry granulation Do not use moisture or heat to process powders into densified granules Create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules (agglomerates). This process is often used when the product to be granulate is sensitive to moisture and heat. Dry granulation methods Slugging Roller Compaction 41  Dry granulation In dry granulation process the powder mixture is compressed without the use of heat and solvent 42  When to choose Dry Granulation Method??? The drug dose is too high For heat sensitive drugs Moisture sensitive drugs 43  Slugging Steps in dry granulation (Slugging) : 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 formulation processes. 44 45 Granulation Properties The process variables involved in the granulation steps ( ❑ Formulation ingredients and their concentrations, ❑ The type of granulating equipment and processing conditions employed) can affect the characteristics of the granulations produced. ❑ Particle Size and Shape. ❑ Surface Area. ❑ Density. ❑ Strength and Friability. ❑ Flow Properties. ❑ Compaction. 46 47  Roller Compaction (Chilsonator) This technology is well suited for dry granulation in the area of modern development of active pharmaceutical ingredients in pharmaceutical plants. Process Description a) The powder is fed down between the rollers from the hopper which contains a spiral auger (screw). b) The screw serve to de-aerate the powder and maintain a constant flow of the powder into the compaction rolls. c) The pressure between the nips of 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 those normally require slugging two or more times can be granulated by a single pass through the “Chilsonator” 48 49 Chilsonator 50 Advantages of dry granulation 1.It is used for heat sensitive and/or moisture sensitive material. 2. It improves the disintegration of tablet. Disintegration is usually more rapid, since the disintegration power of starch is not diminished by the presence of adhesives used in moist granulation. 3. It improves the solubility of materials tending to float. 4. No- migration of active ingredients or colors. 5. It is of the 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's and space. 7. It eliminates the need for binder solution, heavy mixing equipment and time-consuming drying step required for wet granulation 51 Disadvantages of dry granulation i) It requires a specialized heavy-duty tablet press to form slug ii) It does not permit uniform colour 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. 52  Granulation by Crystallization This method exploits the presence of crystallization water in the active material. It is rarely used 53 Advanced granulation methods Steam Granulation: This process is a modification of the conventional wet granulation.(steam is used instead of water) Melt granulation (use molten binder). Moisture activated dry granulation (use moisture absorbent materials) Freeze granulation (spraying powder suspension into liquid nitrogen). Thermal adhesion granulation process (mixing with tumble rotation at 130 co ) 54 55 56 1. Choose the correct answer 1. We can improve powder flowability by which of the following a. Decreasing particle size b. Granulation c. Addition of Talc d. b and c e. a and c 2. All of the following are true about granulation except: a. Decrease the bulk density b. Improve flowability c. Controlling the rate of drug release d. Improve the appearance of the product. 57 3-The more efficient method than other techniques for producing spheres particles in granulation is a. Spray drying b) Fluid bed c)Extrusion d) High shear mixture 4-For heat sensitive and/or moisture sensitive material it is better to used a)Wet granulation b)High shear mixture granulation c- Dry granulation d-- Flid bed granulation 5-What ingredients are necessary for wet granulation manufacturing? a. Binder b)Diluent c)Surfactant d)Emulsifier 58