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Pelletization is defined as an agglomeration process that converts the fine powders into spherical agglomerates known as pellets. There are several methods of pelletization such as layering from liquids, layering from powders, extrusion and spheronization, balling, melt spheronization and cryopelletization (Dash et al., 2012). Extrusion/spheronization was first introduced in 1970 by Reynolds (1970). It is quickly emerged as a promising method to produce granules or pellets which is widely used in the pharmaceutical industry. Furthermore, comparison between different pelletization methods showed that high drug loading was feasible with direct pelletization via roto-processor but it was difficult to control the pellet size with this method, drug layering technique resulted in narrower particle size distribution but it cannot process with high drug loading formulation (Teng and Qiu, 2010). Thus, extrusion/spheronization was chosen as the manufacturing method for this project due to its ability to produce high drug-loaded pellets (Hileman et al., 1993; Trivedi et al., 2007) because it provides greater pellet compaction, resulting in higher drug content can be incorporated homogenously within the pellets and without excessively produced large-sized pellets as compared to the other methods mentioned above.
Extrusion/spheronization is a five-steps process, beginning with the dry mixing of ingredients, then preparation of wet mass, followed by shaping through the extrusion screen to form cylindrical extrudates (extrusion), which are subsequently broken and rounded into spherical granules (spheronization) and finally dried (Bhaskaran and Lakshmi, 2010). Dry mixing of ingredients is required prior to the addition of liquid binder to achieve homogenous powder mixture. Extrudates must be brittle enough to break into short lengths after extrusion, plastic enough to be rolled into pellets by the action of friction plate in the spheronizer and not too adhesive to prevent particle aggregation during spheronization (DukicÂ´-Ott et al., 2009).
To be exact, there are two proposed spheronization mechanisms. According to Rowe (1985), due to the particle collision caused by frictional plate, the cylinder extrudate deforms to form cylinder with rounded edges, followed by dumb-bell shape, then ellipse and finally a sphere (Figure 1). Later in time, Baert and Remon (1993) extended the idea by suggesting another mechanism (Figure 2). They proposed that a twisting mechanism will occur after the formation of cylinder with round edges and eventually broken into two distinct parts. Each part has a flat and a round side. Sometimes, the edges of the flat side will fold together like a flower forming the cavity due to the rotational and frictional forces experienced in the spheronizer (Vervaet et al., 1995).
Figure 1 Mechanism of Spheronization According to Rowe
I: cylinder; II: cylinder with rounded edges; III: dumb-bell; IV: ellipse; V: sphere
Figure 2 Mechanism of Spheronization According to Baert and Remon
I: cylinder; II: rope; III: dumb-bell; IV: sphere with a cavity outside; V: sphere
Figure 3 Chemical Structure of Ketoprofen
Ketoprofen was the drug used in this project. It is a type of non-steroidal anti-inflammatory drug (NSAID) which normally causes GI irritation in patients. The NSAID-induced GI irritation can be minimized by formulating into pellets. Carr's Index of ketoprofen obtained was 38.4% (Guerin et al., 1999) which was greater than 33% indicated a very poor powder flow (Wells and Aulton, 2007). Pellet production is desirable as it able to incorporate drugs with poor flowability.
As described above, each step in the process of extrusion/spheronization is inter-linked to each other. In order to gain a successful pelletization, the resultant formulation must exhibit an adequate degree of cohesiveness, plasticity and brittleness. Thus, pelletization aids such as microcrystalline cellulose (MCC) (Trivedi et al., 2007) or k-carrageenan (Thommes and Kleinebudde, 2006) is incorporated into the formulation to provide the desired rheological properties.
In this project, Avicel CL611 was chosen as the main excipient. It is a colloidal MCC composed of 15% sodium carboxymethylcellulose (NaCMC) (Chohan and Newton, 1996). Di Pretoro et al. (2010) had proposed that Avicel CL611 managed to hinder liquid phase migration (LPM) during extrusion and retained greater amount of water as compared to Avicel PH101 and hence it appeared as an alternative for successful pelletization. In addition, both studies done by Di Pretoro et al. (2010; 2012) showed the ability of colloidal MCC to produce pellets with â‰¥90% drug loading, where the drug used was 5-aminosalicylic acid (5-ASA). As a consequence, it facilitates the production of high drug-loaded pellets incorporating with poorly water soluble drug by providing a system with appropriate degree of rigidity and cohesiveness. Besides, Podczeck and Knight (2006) showed the inability of Avicel PH101 to work with 80% ibuprofen to produce round pellets with narrow size distribution. Thus, Avicel CL611 was chosen as the spheronization aid for ketoprofen based on the advantages suggested above.
MCC acts as a 'molecular sponge' which is able to retain large amount of water yet allowing the stored water to be squeezed out during extrusion. Water serves as a lubricant during the passage of the wetted mass through the extrusion holes. After extrusion, volume of the 'sponges' expands. Finally, these 'sponges' become more densified due to the particle collisions during spheronization and water further facilitates the pellets production (Ek and Newton, 1998). The crystallite-gel-model provides an alternative explanation for the function of MCC. During granulation and extrusion in the presence of water, MCC are thought to be broken down into smaller particles and eventually into single crystallites of colloidal sizes due to the shear forces provided. These particles are able to form a 'crystallite gel' that immobilizes the liquid binder. However, the disruption of the single crystallites is incomplete, resulting in the formation of a coherent 'gel-like' network by the crystallites and some porous particles with a high fraction of an insoluble solid phase. The process of extrusion/spheronization is only feasible with a specific range of water content which contributes to an acceptable gel strength (Kleinebudde, 1997). Both the model highlights the role of water and its distribution during pelletization besides explaining the function of MCC.
Water which "serves as a binder during wet massing, a lubricant during extrusion and a plasticiser during spheronisation" (Hileman et al., 1993) is critical to affect the pellet quality. Amount of water added must be within the threshold range for each formulation in order to obtain higher yield of pellets with desirable properties (Lustig-Gustafsson et al., 1999). Bains et al. (1991) showed that critical water content was needed for successful pellet production with 20% Avicel PH101 (80% barium sulphate; highly water insoluble drug) while wider water range applied to formulations with 40%-80% MCC. The only ratio of water: MCC resulting in successful pelletization appeared to be 1.5 for formulation with 20% MCC, whereas ratio of water: MCC of 1.0 to 1.5 can successfully be used to manufacture pellets with 50% MCC. Other than that, the amount of water needed increased with the MCC fraction in the formulations (Kleinebudde et al., 1999). Same effect will be seen with Avicel CL611 in comparison to Avicel PH101 as both of them serve as a backbone to hold the amount of water needed for appropriate degree of wet massing.
In terms of characterization, pellets should have a narrow size distribution to ensure little variation in capsule filling weight. A neither fine (<500 Âµm) nor coarse fraction (>1400 Âµm) of pellets produced is desirable. Pellet size distribution was studied rather than individual pellet size as pellets are poly-dispersal. Sousa et al. (1996) showed the increase in pellet median size with increasing amount of water added to the formulation.
Aspect ratio and circularity were investigated in this project. Pellet shape described by aspect ratio <1.2 is appropriate to ensure the capsule filling reproducibility (Rowe et al., 2005). An aspect ratio or circularity value of 1.0 corresponds to a perfect sphere (Gandhi et al., 2011). Newton et al. (1992) found that Avicel RC and CL grades unable to form spherical pellets in spite of extruding well through long dies. The finding was proven again that colloidal MCC still failed to produce round pellets due to their inelasticity although the extrudates formed had low surface impairment than Avicel PH series (Chohan and Newton, 1996).
Devereux et al. (1990) reported that an increase in density from 1.5 to 2.8g/cm3 significantly delayed the time for gastric emptying of 50% (G50) of the 1 mm pellets in both the fasted and the fed states. Furthermore, Clarke et al. (1995) performed the experiment under the same condition as Devereux et al. by comparing pellets with density of 2.0g/cm3 and 2.4g/cm3 with 1.5g/cm3. No difference in G50 was observed with pellets 1.5g/cm3 and 2.0g/cm3. This suggested that pellet density â‰¥2.4g/cm3 will lead to prolonged gastric residence times.
Generally, pellet surface tensile strength >1MPa is suitable for further coating (Kranz et al., 2009). The pellet crushing strength increased with increasing amount of water (Sousa et al., 1996). Pellets with least amount of MCC in the formulation gave a lower surface tensile strength (Sousa et al., 2002; Di Pretoro et al., 2012).
Porosity is another important characteristic to be considered as it will affect the surface tensile strength and pellet disintegration. High porosity will result in low surface tensile strength of pellets (Di Pretoro et al., 2012). Lastly, pellet disintegration is critical to determine the drug release profile. One of the limitations of MCC-based pellets was lack of disintegration and hence prolonged drug release (DukicÂ´-Ott et al., 2007), especially with poorly water soluble drug (O'Connor and Schwartz, 1985). This is due to the contraction of spheroids upon drying, resulting in pellets with low porosity (Kleinebudde, 1994). Drug diffusion across the hydrophilic matrix formed by MCC becomes the limiting step in drug dissolution. It would be problematic if an immediate drug release profile is needed for example drug with low water solubility (DukicÂ´-Ott et al., 2009). Besides, O'Connor and Schwartz (1985) produced Avicel CL611-based pellets and investigated the effect of drug: diluent ratios on the drug (theophylline) release. The results showed the direct relationship between the drug: MCC ratios and the drug release from pellets, being prolonged if the MCC level was higher.