granulation Granulation is the process in which primary

granulation Granulation is the process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Pharmaceutical granules typically have a size range between 0. 2 and 4. 0 mm, depending on their subsequent use. In the majority of cases this will be in the production of tablets or capsules, when granules will be made as an intermediate product and have a typical size range between 0. 2 and 0. 5 mm,

reasons for granulation To prevent segregation of the constituents of the powder mix Segregation is due to differences in the size or density of the components of the mix, the smaller and/or denser particles concentrating at the base of a container with the larger and/or less dense ones above them. An ideal granulation will contain all the constituents of the mix in the correct proportion in each granule, and segregation of the ingredients will not occur

Powder Granules Granulation sieving Segregated Powder Monosized Granules

It is also important to control the particle size distribution of the granules because, although the individual components may not segregate, if there is a wide size distribution the granules themselves may segregate. If this occurs in the hoppers of capsule-filling machines or tablet machines, products with large weight variations will result. This is because these machines fill by volume rather than weight, and if different regions in the hopper contain granules of different sizes (and hence bulk density), a given volume in each region will contain a different weight of granules. This will lead to an unacceptable distribution of the drug content within the batch of finished product.

To improve the flow properties of the mix Many powders, because of their small size, irregular shape or surface characteristics, are cohesive and do not flow well. Poor flow will often result in a wide weight variation within the final product owing to variable fill of tablet dies etc. Granules produced from such a cohesive system will be larger and more isodiametric, both factors contributing to improved flow properties.

To improve the compaction characteristics of the mixture Some powders are difficult to compact even if a readily compactable adhesive is included in the mix, but granules of the same formulation are often more easily compacted and produce stronger tablets. This is associated with the distribution of the adhesive within the granule. Often solute migration occurring during the postgranulation drying stage results in a binder-rich outer layer to the granules. This in turn leads to direct binder–binder bonding, which assists the consolidation of weakly bonding materials.

Reduce the hazard of toxic dust powders The granulation of toxic materials will reduce the hazard associated with the generation of toxic dust that may arise when handling powders. Suitable precautions must be taken to ensure that such dust is not a hazard during the granulation process. Thus granules should be non-friable and have a suitable mechanical strength.

Reduce the hazard of hygroscopic powder adhesion Materials which are slightly hygroscopic may adhere and form a cake if stored as a powder. Granulation may reduce this hazard, as the granules will be able to absorb some moisture and yet retain their flowability because of their size. More convenient for storage Because granules are denser than the powder mix, they occupy less volume per unit weight. They are therefore more convenient for storage or shipment.

methods of granulation Granulation methods can be divided into two types: wet methods, which use a liquid in the process, dry methods in which no liquid is used. In a suitable formulation a number of different excipients will be needed in addition to the drug. Diluents, to produce a unit dose weight of suitable size, 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. Adhesives in the form of a dry powder may also be added, particularly if dry granulation is employed. These ingredients will be mixed before granulation.

dry granulation In the dry methods of granulation the primary powder particles are q Granulation: (aggregation) under high pressure without the use of a liquid using one of the following processes. v Using Sluggers: large tablet compacts (known as a slug) is produced in a heavy-duty tabletting press (a process known as sluggin’) v or using Roller compactors the powder is squeezed between two rollers to produce a sheet of material ( roller compaction). q Milling: the intermediate products are broken using a suitable milling technique to produce granular material, which is usually sieved to separate the desired size fraction. The unused fine material may be reworked to avoid waste.

roller compactors Alexanderwerk Roller compactor

Hutt Roller compactor

Advantages of dry granulation: q Avoids heat–temperature combinations that might cause degradation of the product. q This dry method may be used for drugs which are sensitive to moisture.

Wet granulation Ø Wet granulation involves the massing of a mix of dry primary powder particles using a granulating fluid. Ø The fluid contains a solvent which must be volatile so that it can be removed by drying, and be non-toxic. Ø The granulation liquid may be used alone or, more usually, as a solvent containing a dissolved adhesive (binding agent) which is used to ensure particle adhesion once the granule is dry. Ø In the traditional wet granulation method the wet mass is forced through a sieve to produce wet granules which are then dried. A subsequent screening stage breaks agglomerates of granules and removes the fine material, which can than be recycled.

v Typical liquids include water, ethanol and isopropanol, either alone or in combination. The primary advantages of water are that: it is non-flammable, which means that expensive safety precautions not be taken. Water is commonly used for economical reasons. disadvantages of water as a solvent are that: It may adversely affect drug stability, causing drug hydrolysis. It needs a longer drying time than do organic solvents, that increases the length of the process and again may affect stability because of the extended exposure to heat. v Organic solvents are used when water-sensitive drugs are processed, as an alternative to dry granulation, or when a rapid drying time is required.

effect of granulation method on granule structure The properties of the granules are influenced by the manufacturing process. The method and conditions of granulation affect intergranular and intragranular pore structure by changing the degree of packing within the granules. üPrecompressed granules (dry granulation), consisting of compressed drug and binder particles, are held together by simple bonding during compaction. üGranules prepared by wet massing (wet granulation), consist of intact drug particles held together in a sponge-like matrix of binder. üFluidized-bed 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. üWith spray-dried systems the granules consist of spherical particles composed of an outer shell and an inner core of particles.

Wet granulators There are many types of granulator used in the pharmaceutical industry for wet granulation. Shear granulators High-speed mixer/granulators Fluidized-bed granulators Spray-driers Spheronizers /Pelletizers Rotor granulators

Shear granulators Powder mixing in a separate operation using suitable mixing equipment. A planetary mixer is used for wet massing of the powders With some formulations, such as those containing two or three ingredients in equal quantities, it is suitable to mix powder in the Mixing arm Mixing bowl planetary mixer. The mixed powders are fed into the bowl of the planetary mixer and granulating liquid is added as the paddle of the mixer agitates the powders. Planetary Mixer

The moist mass has been transferred Rotor to a granulator, as oscillating granulator. The rotor bars of the granulator oscillate and force the moist mass Sieve through the sieve screen, the size of which determines the granule size. Oscillating Granulator The mass should be sufficiently moist to form discrete granules when sieved. If excess liquid is added, string (filament) of material will be formed and if the mix is too dry the mass will be sieved as powder and granules will not be formed.

The granules can be collected on trays and transferred to a drying oven. Tray drying has three major disadvantages: 1. The drying time is long. 2. Dissolved material can migrate to the upper surface of granules’ bed, as the solvent is only removed from the upper surface of the bed on the tray. 3. Granules may aggregate owing to bridge formation at the points of contact of the granules. To deaggregate the granules and remix them, a sieving stage is necessary after drying.

An alternative method is to dry the granules using a fluidized-bed drier. This is quicker and, as it keeps the individual granules separated during drying, it reduces the problems of aggregation and intergranular solute migration, thereby reducing the need for a sieving stage after drying.

Advantages of Shear granulation process: ü The process is not very sensitive to changes in the characteristics of the granule ingredients (e. g. surface area variations in different batches of an excipient) üThe end-point of the massing process can often be determined by examination. The disadvantages of Shear granulation process: ü Long duration ü the need for several pieces of equipment ü The high material losses because of the transfer stages.

The granulator has a stainless steel mixing bowl containing a three-bladed main impeller, which revolves in the horizontal plane, and a three-bladed auxiliary chopper (breaker blade) which revolves either in the vertical or the horizontal plane. ch op pe r High-speed mixer/granulators

The unmixed dry powders are placed in the bowl and mixed by the rotating impeller for a few minutes. Granulating liquid is then added via a port in the lid of the granulator while the impeller is turning. The granulating fluid is mixed into the powders by the impeller. 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. Once a granule has been produced, the granular product is discharged, passing through a wire mesh which breaks up any large aggregates, into the bowl of a fluidized-bed drier.

Advantages of High-speed mixer/granulation: Mixing and granulation are all performed within a few minutes in the same piece of equipment. Disadvantages of High-speed mixer/granulation: Ø The process needs to be controlled with care as the granulation progresses so rapidly that a usable granule can be transformed very quickly into an unusable, overmassed system. Thus it is often necessary to use a suitable monitoring system to indicate the end of the granulation process, i. e. when a granule of the desired properties has been attained. Ø The process is also sensitive to variations in raw materials, but this may be minimized by using a suitable end-point monitor.

Fluidized-bed granulator Air outlet Exhaust filter Spray nozzle Product container Air inlet Air filter Granulating liquid glatt

fluidized-bed granulator (glatt) The powder particles are Air outlet fluidized in a stream of air. Granulation fluid is pumped Exhaust filter from a reservoir and sprayed from a nozzle on to the bed of powders. Heated and filtered air is blown through the bed of unmixed powders to fluidize the particles and mix the powders. Spray nozzle Product container Air inlet Air filter Granulating liquid

The fluid causes the primary powder particles to adhere when the droplets and powders collide. Air outlet Escape of material from the granulation chamber is prevented by exhaust filters, which are Exhaust filter periodically agitated to reintroduce the collected material into the fluidized bed. Spray nozzle Sufficient liquid is sprayed to Product produce granules of the required container size, at which point the spray is turned off but the fluidizing air continued. The wet granules are then dried in the heated fluidizing air stream. Air inlet Air filter Granulating liquid

Advantages of fluidized-bed granulation All the granulation processes, which require separate equipment in the conventional method, are performed in one unit, saving labour costs, transfer losses and time. The process can be automated once the conditions affecting the granulation have been optimized. Disadvantages of fluidized-bed granulation The equipment is expensive. Optimization of process parameters affecting granulation needs extensive development work.

Spray-driers Granular product is made from a solution or a suspension rather than initially dry primary powder particles. suspension The resultant granules are free-flowing hollow spheres and the distribution of the screen binder in such granules results in good compaction properties. Fluidization air

Spray-drying can convert hard elastic materials into more ductile ones. The primary advantages of the process are the short drying time suspension and the minimal exposure of the product to heat owing to the short residence time in the drying screen chamber. This means that little deterioration of heat-sensitive materials takes place. Fluidization air

Spheronizers /Pelletizers 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. A commonly used process involves: v Separation of wet massing. v Extrusion of this wet mass into rod-shaped granules and subsequent spheronization of these granules.

Advantages of granulation using Extrusion/spheronization process is used to make uniformly sized spherical particles. It is used primarily to produce multiparticulates for controlled drug release applications. The major advantage over other methods of producing drug loaded spheres or pellets is the ability to incorporat high levels of active ingredients without producing excessively large particles (minimal excipients). Ideal flow behaviour and dosability Compact structure Low hygroscopicity High bulk density

The main steps of the process are: 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 to achieve the desired narrow size distribution.

Extrusion Schematic representation of production extruder

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.

Rotor granulation In the Freund granulator, the powder mixture is added to the bowl and wetted with granulating liquid from a spray. The base plate rotates at high speed and centrifugal force keeps the moist mass at the edges of the rotor.

The velocity difference between the rotor and the static walls, combined with the upward flow of air around the rotor plate, causes the mass to move in a toroidal motion, resulting in the formation of isolated spherical pellets. The spheres are dried by the heated inlet air from the air chamber, which acts as a positive pressure seal during granulation.

Process principle Powder is mixed and moistened and the powder bed set into 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 and are then dried.

Principle of the powder layering process Using this technique it is possible to continue the process and coat the pellets by spraying coating solution on to the rotating dried pellets. In layered pellets can be produced by using uncoated pellets as nuclei in a second granulation with a powder mix of a second ingredient or ingredients.

granulation mechanisms To form granules, sufficiently strong bonds must be formed between powder particles so that they adhere and prevent breakdown of the granule to powder during handling. There are four primary bonding mechanisms between particles: 1. Adhesion and cohesion forces in the immobile liquid films between individual primary powder particles. 2. Interfacial forces in mobile liquid films within the granules. 3. The formation of solid bridges after solvent evaporation. 4. Attractive forces between solid particles.

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.

particle size and shape. The particle size of a granulation is known to affect the average tablet weight, disintegration time, granule friability, granulation flowability and the ding rate kinetics of wet granulations.

surface area. The surface area of the drug has a significant effect upon dissolution rate. An inverse relationship normally exists between particle size and surface area; Methods for determining surface area of solid particles are gas adsorption and air permeability. In gas adsorption method, the amount of gas that is adsorbed onto the powder to form a monolayer is measured and then used to calculate the surface area of the powder sample. Air permeability, the rate at which air permeates a bed of powder, is used to calculate the surface area of the powder sample.

density. q Granule density may influence compressibility, tablet porosity and dissolution. q Dense, hard granules may require higher compressible loads to produce a cohesive compact. q The higher compression load, increase the tablet disintegration and drug dissolution times. Even if the tablets disintegrate readily, the harder, denser granules may dissolve less readily.

q Methods used to determine granule density involve the use of a pycnometer. q Where, the intrusion fluid is mercury, and in the other, it is a solvent of low surface tension (e. g. , benzene) in which the granules are not soluble. q These pycnometer methods depends on the ability of the intrusion fluids to penetrate the pores of the granules. Density is calculated from the volume of intrusion fluid displaced in the pycnometer by a given mass of granulation

strength and friability. A granule is an aggregation of component particles that is held together by bonds of finite strength. The strength of a wet granule is due to the surface tension of liquid and capillary forces. These forces are responsible for initial agglomeration of the wet powder. Upon drying, the granule has strong bonds resulting from fusion or recrystallization of particles and curing of the adhesive or binder.

Measurements of granule strength estimate the magnitude of attractive forces that hold the granule together. The resultant strength of a granule depends on base material, the kind amount of granulating agent used and the granulating equipment used. Granule strength and friability are important, as they affect changes in particle size distribution of granulations, and compressibility into cohesive tablets.

Methods used for measuring granule strength are: Compression strength. Where a granule is placed between anvils, and the force required to break the granule is measured. Friability measurements. measuring the tendency of granules to break into smaller pieces when subjected to disturbing forces.

flow properties. Flow properties of a material result from many surface forces: (1)frictional forces, (2) surface tension forces, (3) mechanical forces caused by interlocking of particles of irregular shape, (4) electrostatic forces, (5) cohesive or van der Waals forces. They can affect granule properties such as: particle size, particle size distribution, particle shape, surface texture or roughness, surface energy, and surface area.

With fine powders (<150µm), the magnitude of the frictional and van der Waals forces are predominate. For larger particles (>150µm) such as granules produced by a wet granulation, frictional forces are predominate over van der Waals forces. Flow measur the effect of all the interparticulate forces acting at once. Two methods are used: (1) angle of repose, (2) hopper flow rate measurements.

compaction The process of compacting powder or granule materials to form a tablet is complex, owing to the numerous internal events that act simultaneously. The basic tool that has been developed for studying the compression process is the tablet press. Tablet presses are instrumented by affixing transducers to measure the forces applied during the compression process. The signals produced by the transducer system are monitored by computer.

Effervescent salts are granules or coarse to very coarse powders containing a medicinal agent in a dry mixture usually composed of sodium bicarbonate, citric acid, and tartaric acid. When added to water, the acids and base react to liberate carbon dioxide, resulting in effervescence. The resulting carbonated solution masks the usually saline or undesirable taste of the medicinal agent present.

A good effervescent blend consists of both citric acid and tartaric acid (1 : 2 ratio), since the former is rather sticky to manipulate and the latter produces a chalky, friable granule. Citric Acid 3 Na. HC 03 + C 6 H 8 O 7. H 2 O 3 x 84 4 H 20 + 3 C 02 + Na 3 C 6 H 5 O 7 210 = X = 1. 2 g One gram of citric acid (MW = 210) reacts with 1. 2 g of sodium bicarbonate (MW = 84)

Tartaric Acid 2 Na. HC 03 + C 4 H 606 2 x 84 2 H 20 + 2 C 02 -+ Na 2 C 4 H 4 O 6 150 = X = 2. 24 g Since it is desired to use a 1: 2 ratio of critic acid to tartaric acid, two grams of tartaric acid (MW = 150) reacts with 2. 24 g of sodium bicarbonate.

From the above, it has been calculated that 1. 2 g and 2. 24 g of sodium bicarbonate is required to react with 1 + 2 g of the citric : tartaric acid combination. Since it is desired to leave a small amount of the acids unreacted to enhance palatability and taste, 2. 24 g + 1. 2 g= 3. 44 g, only 3. 4 g of sodium bicarbonate will be utilized. Therefore, the ratio of the effervescent ingredients is 1 : 2 : 3. 4 for the citric acid : tartaric acid : sodium bicarbonate.

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