PROGRAMAS PARA LAS ESCUELAS SECUNDARIAS

According to Iveson et al. (2001) there are three main stages of the process, as shown in Figure 2.1, which determine the wet agglomeration behaviour:

 Wetting and nucleation: wetting is the first stage of the process involving spraying the granulation liquid into a dry powder bed to form granule nuclei.

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 Consolidation and growth: where collisions are occurring between two granules, granules and feed powder, or a granule and the equipment, leading to the liquid being forced towards the surface, allowing granules to grow then coalesce.

 Attrition and breakage: the granules will break if not strong enough to withstand the agitation or compaction in the granulator during process. These three stages are occurring all together and will determine the final properties of the produced granules (Lee, 2013).

Figure ‎2.1 Schematic of granulation processes (a) Traditional view (b) Modern

approach (Iveson et al., 2001).

Wetting of the particles is necessary for nucleation, i.e. the formation of initial agglomerates. As per (Iveson et al., 2001), the nucleation rate is governed by the following:

2.4.4.1 Wetting and nucleation

This is the process of bringing a liquid binder into contact with dry powder and endeavouring to distribute this liquid consistently throughout the dry powder (Litster et al., 2004). The binder dispersion process will focus on the nucleation zone where the liquid powder and powder surface make contact to form the initial nuclei (Iveson et al., 2001). In this zone, two processes are important: firstly, nuclei formation which is the function of wetting thermodynamics and kinetics; secondly, binder dispersion or effective mixing between powder and binder (Pandeya, 2009).

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2.4.4.2 Granular growth

Granular growth takes place when materials of granular collision stick together, this process being called coalescence (Iveson et al., 2001, Litster et al., 2004). If fine materials are sticking to large granules this is frequently called layering (Ennis, 2005, Pandeya, 2009).

It starts when liquid is added to the agitated bulk powder, acting concurrently with the wetting and nucleation process, as shown in Figure 2.2. The size of the granules is determined by the nucleation condition (Ennis, 2005).

Permanent collision between two granules depends on the granular mechanical properties and availability of the liquid binder at or near the granule surface (Litster et al., 2004, Parikh, 2009).

During agitation, granules increasingly consolidate which increases the saturation of liquid pores and changes their mechanical properties (Ennis, 2005). Therefore, consolidation often has an impact on granule growth behaviour and must be considered in conjunction with it (Iveson et al., 2001).

Figure ‎2.2 Schematic showing wetting, nucleation, consolidation, and granule

growth processes (Parikh, 2009)

Granules can exist in different states of liquid saturation. These states were first described by Newitt and Conway-Jones (1958), and are shown in Figure 2.3:

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 Pendular state: particles are held together with binding liquid, which forms a liquid bridge between the particles’ contact points (Pendular bond).

 Funicular state: with an increasing quantity of liquid, the liquid bridges coalesce. Nevertheless, empty spaces are still not saturated and filled by air.

 Capillary state: occurs when a granule is saturated and all the spaces between the particles are filled with liquid and the surface liquid is drawn back into the pores under capillary action.

 Droplet state: the particles are suspended inside or at the surface of a liquid drop.

 Pseudo-droplet state: where empty spaces remain surrounded inside the droplet. This occurs in poor wetting systems.

Liquid-bound granule strength is governed by two types of force: liquid bridge and inter-particle friction. The liquid bridges can create both static surface tension forces and dynamic forces due to the liquid viscosity (Iveson et al., 2001).

Figure ‎2.3 The different states of saturation liquid-bound granules (Iveson et al.,

2001)

2.4.4.3 Breakage and attrition

There are two phenomena that describe the breakage and attrition of granules (Iveson et al., 2001) to be considered: firstly, breakage of the wet granules inside the

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granulator during the process; secondly, attrition or breakage of dried granules inside the granulator, drier or through handling.

Breakage has a significant influence on the granule-size distribution and it may be used to limit the maximum granule size or to help distribute a viscous binder, otherwise attrition leads to the creation of dust which represents a hazard to employees (Saikh, 2013).

Melt granulation

2.5

Melt granulation or the thermoplastic granulation process is widely used in the pharmaceutical manufacturing process (Walker et al., 2006). It is similar to wet granulation but the molten binder acts as a granulation fluid to form the liquid bridge between particles in the heated powder bed followed by agglomeration and consolidation (Schæfer, 2001). Granules must be left to cool at room temperature. At the end of the process, solidified binder forms bridges between the particles to produce a solid product with a granular structure (Parikh, 2009). The active ingredients should have a high melting point compared to the molten binder (Saikh, 2013).

2.5.1 Advantages

The melt granulation technique has several advantages over conventional wet granulation (Walker et al., 2006, Halle et al., 2013, Saikh, 2013):

 No solvent is involved in the process, thereby negating problems associated with in-process hydrolysis and water removal via heating;

 It is very efficient for moisture-sensitive materials, so granules can be formed without solvent;

 The process is time efficient and thereby less energy is required;

 All steps, including mixing, agglomeration and formation of solid bridges are completed in a single pot which reduces loss of materials that might otherwise occur in transferring operations;

 The process enhances the stability of hydrophilic substances which are highly degradable in the presence of moisture. The lipophilic binder coats the particles to be protected from water;

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 The process improves the dissolution rate and bioavailability, especially for poor water soluble ingredients, by forming solid dispersion (Onoue et al., 2010).

2.5.2 Disadvantages

 Heat-sensitive materials are not suitable as thermal degradation might occur during the heating process (Schæfer, 2001).

 Only a meltable binder can be used for those with a relatively low range melting point of between 50ºC-70ºC (Saikh, 2013).