Implementing the models

This is the most widely used method for preparing pharmaceutical materials for compression. It enhances the physical characteristics of the material and affords a greater chance of producing granules which satisfy all physical requirements for compression into the desired tablets. This method is however not readily suitable for hydrolysable and/or thermolabile drugs such as antibiotics.

In a conventional massing and screening wet granulation process, the following steps are involved (Armstrong and Morton, 1979):

i. Blending of solid ingredients.

21 ii. Wetting.

iii. Granulation iv. Drying

v. Sizing

vi. Second blending

i. Blending of solid ingredients

This is an initial blending of solid ingredients and in this stage, the drug substance is mixed, if needed, with the diluent or filler. Tablets weighing much less than 50 mg are so small as to be difficult to pick up and manipulate with the fingers, yet many drug substances are active in far lower doses. Accordingly, it is necessary to dilute the drug to make a tablet of reasonable size.

The ideal diluents, which should be inert both chemically and pharmacologically, are blended in a powder mixer with the aim of producing a uniform dispersion of the drug in the filter.

ii. Wetting

The mixture of powders is now wetted and the granulating agent, usually in an aqueous solution or dispersion, is introduced at this stage. The choice of the granulating agent is governed often by the intended use of the tablet.

Though size enlargement takes place primarily with the adhesion of particles by a film of granulating agent, a second mechanism is available if the solid particles are soluble in the granulating fluid. Partial dissolution occurs, yielding a supersaturated solution of the solid, and on subsequent drying, re-crystallization occurs and the resultant crystal bridges between the particles can contribute significantly to granule strength.

The wetting stage is usually carried out in the same apparatus in which the dry powders were blended. Sufficient granulating agent is added to form a dump, coherent mass, though over-wetting should be avoided.

iii. Granulation

The damp mass is now passed through a coarse sieve (usually of mesh size 1-2 mm) to produce roughly spherical granules. This product is usually achieved by means of

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an oscillating granulator, in which a rotor, oscillating about its horizontal axis, passes the damp material through the screen. Alternatively, a comminutor, containing a number of rapidly revolving blades, may be used.

iv. Drying

The granules are now dried using either a tray drier or more usually, a fluidized bed drier to produce a coarse, free-flowing solid.

The drying temperature is about 60 ⁰C but may be reduced if thermo labile substances are present. With tray driers, air exchange is essential to prevent saturation of oven temperature with solvent vapour. By spreading the granules as thin layers on the tray and raking the layers from time to time, agglomeration of granules and migration of solutes are minimized while an even drying of granules is promoted. For large batches, granules are dried for up to 24 hours and if drying is prolonged the amount of fines increases. However, oven-dried granules have inferior compressional characteristics.

During drying, interparticulate bonds results from fusion of particles and hardening of the binding agents.

In fluidized bed drying, a means of rapid drying is offered and it has advantages enumerated below:

a. Efficient heat and mass transfer that gives high drying rates.

b. Individual particles, rather than the entire bed, are dried.

c. There is absolute control and uniformity of temperature.

d. The containers can be mobile, making handling simple, and reducing labour costs.

e. Free movement of individual particles eliminates the risk of soluble materials migrating, as may occur in static-beds.

However, certain disadvantages such as attrition of materials due to turbulence and generation of static electricity charges, including entrainment of fine particles are inherent in fluidized bed drying.

v. Sizing

The size of granules at this point will usually be considerably larger than the size required for tabletting where there is need to also ensure that a constant weight flows into

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the die of the tablet press. Hence, a communition stage followed by sieving, will normally be needed, the usual granule size for tabletting being 350-700 μm (Ansel, 1981).

vi. Second Blending

A second blending stage incorporates other important additives into the material prior to compression.

2.6.3.1 Factors Affecting Wet Granulation

Several factors have been identified to affect the physicochemical properties of granules and tablets resulting from wet granulation. These factors include:

i. The nature, volume and concentration of the binder.

ii. The particle size distribution of the starting materials.

iii. The massing time of granulation; solute migration during drying.

iv. The temperature of granulation including the quantity of granulating fluid.

Increase in granule strength has been attributed more to the quantity of granulating fluid used and the concentration of binding agent. For a given material, smaller initial particle sizes usually lead to granules of greater strength presumably due to increased occurrence of interparticulate contacts (Hunter and Ganderton, 1972). These factors are further discussed:

i. Effect of binder

The type and amount of binder added to the powder during the process of granulation affect the overall nature of the granules produced. Too much binder leads to the production of very hard tablets leading to difficulty in disintegration and dissolution of such tablets; while too little amount of binder leads to granules producing tablets that cannot withstand the hazard that tablets undergo before getting to the user.

Wells and Walker (1983) carried out a study on the effect of binder vehicle on granule and tablet properties in a model system, in which polyvinylpyrrolidone was used as a binder with acetylsalicylic acid as the medicinal agent. Using ethanol- water mixtures to produce differing drug solubilities, they found that greater drug solubility was produced by larger granules which were less friable and gave better size uniformity.

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Also, Zeiko et al (1998) did a study on the evaluation of substrate binder effects on interfacial interactions. They found that increasing the amount of binder in granules improved the adhesive interaction existing between the substrate and the binder. Their results also indicated that the mechanical properties of the tablets produced were basically determined by the physico-chemical interactions of the substrate and the binder agent.

ii. Effect of initial particle size of materials

Increasing the initial particle size of any of the components of a binary mixture leads to an increase in granule strength and generally reduces mean pore size for powders (Opakunle and Spring, 1977).

iii. Effect of massing Time

Massing time can be simply referred to as the length of time used in mixing the binder and blending it into drug powder or the time used in mixing the powders and adhesive in a dry granulation process or the time used in mixing the liquid to wet the powders even if binders are not added. It is usually carried out before screening or sieving of the dry or damp drug mass.

According to Klienebudde and Thies (2000), a study involving the melt pelletisation of a hygroscopic drug in a high shear mixer revealed that massing time is an important variable influencing mean granule size and size distribution.

iv. Effect of granulation method

Different granule characteristics have resulted from the use of different granulation methods in the production of granules from powders.

Soyeux et al (1998) compared different granule characteristics such as packing ability, particle size distribution, flow ability, granule strength and porosity, etc, between granules produced using the fluidized bed granulation method and other methods. It was discovered that the fluidized bed granulation method produced the densest packing of granules followed by the kneading method and extrusion method respectively.

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2.6.3.2 Theory and Mechanism of Moist Granulation

The addition of a granulating liquid to a mass of powder may be characterized in a series of stages described by Newitt and Conway-Jones (1958) as illustrated in Fig 2.1.

When the powder particles are wetted during the initial stage, liquid films will be formed on the surface and may combine to produce discreet liquid bridges at the point of contact. The surface tension and negative capillary pressure in such bridges provide the cohesive force and result in the pendular stage (Fig 2.1a), which has a low mechanical strength. With an increase in the liquid content, several bridges may coalesce giving rise to the funicular stage (Fig 2.1b) with a modest increase in granule strength. Eventually, as more liquid is added and the mass is kneaded to bring the particle into closer proximity, the void spaces within the granules are entirely eliminated. At this point, bonding is effected by interfacial forces at the granule surface and by negative capillary pressure throughout the interior liquid filled spaces, a condition referred to as the capillary stage (Fig 2.1c). Further addition of liquid results in the formation of droplet (Fig 2.1d) in which the particles are now held together by surface tension, however, without intragranular forces; such structures are weaker.

Thus, the capillary stage coincides with the maximum strength of well-formed granules and optimization of many granulating processes is aimed at ensuring that this state has been achieved. The granulating equipment can, for example, be equipped with torque measuring devices which sense the change in agitation power required at the capillary stage.