Pelletization is a size enlargement process by which fine powders are converted into uniformly sized granules, preferably of spherical shape. Pellets for pharmaceutical purposes range in size, typically, from 0.5 to 1.5 mm, and are produced primarily for oral dosage forms with gastro-resistant or prolonged release properties. As drug delivery systems become more sophisticated, the role of pellets in the design and development of dosage forms is increasing.
Methods commonly used for pelletization of drug formulations are layering of drug substances from liquids or powders on inert spheres in coating pans or fluidized bed granulators, and extrusion/spheronization of moist, plasticized masses (Ghebre-Selassie, 1989). Wet-granulation in fluidized beds of the rotary type is a relatively new technique which seems to offer a great potential for pelletization purposes (Goodhart, 1989). Little attention has been paid to pelletization by wet granulation techniques although there is the possibility of a simple, one-step process with a short processing time in high shear mixers (Holm, 1987; D'Alonzo etal., 1990; Zhang etal., 1990).
Holm (1987) showed that wet granulation in a high shear mixer may result in narrowly sized and rounded granules provided that a high energy input is applied and that the amount of binder liquid is carefully controlled. He used a Fielder PMAT 25 mixer equipped with an impeller which allowed the blade angle to be varied. A high blade angle (40°) gave rise to a high power consumption and, hence, a high energy input resulting in rounded
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Fig. 17 The intragranular porosity of calcium hydrogen phosphate granulated with a 10% m/m solution of hydrolysed gelatine in water in a Fielder PMAT 25 high shear mixer; impeller blade angle 30° and impeller speed 400 r.p.m. Temperature of heating jacket: 12°C, O; 45°C, • . Reproduced with permission from Holm et al. (1993), 5TP Pharma. Science 3, 286-293. Editions de Sante, France.
granules of uniform size. In order to ensure a uniform liquid distribution in the agitated mass, the walls of the mixer bowl were covered by a poly-tetrafluoroethylene (PTFE) tape in order to avoid deposition of the moistened powder.
Figure 15 shows that granulation of calcium hydrogen phosphate should result in a product with a geometric standard deviation of about 1.5. Experimental values are, however, greater because of the presence of larger granules. As growth by coalescence is size dependent, it should be possible to reduce the content of the larger agglomerates by reducing the amount of free surface liquid on the agglomerates, thereby delaying the growth of larger agglomerates. Holm etal. (1993) have recently shown that this can be done by drying in the wet massing stage. In this work, air was blown through the agitated mass, but it is likely that the same result can be achieved by vacuum techniques.
Figure 17 shows the change in granule porosity during wet massing in two series of experiments performed with cooling and heating, respectively, of the mantle of the mixer bowl. The graph demonstrates that the intra-granular porosity of the agglomerates is affected by the product temperature. It shows that less liquid is required to achieve growth by the coalescence mechanism when the mantle is heated and, consequently, more liquid has to be removed by drying in order to delay the growth of larger agglomerates.
Figure 18 shows that the rate of removal of water from the product in the wet massing phase influences the geometric standard deviation. Holm etal. (1993) calculated the rate at which free liquid was supplied to the agglomerate surfaces because of densification. In experiments with a cooled mantle, the rate was about lOgmin-1, while in the experiment with a heated mantle, the rate was 40gmin_1. The calculations compare well with Fig. 18 showing that the most narrow size distributions were obtained when water was removed at a rate equal to that derived from densifying the agglomerates. The effect of the product temperature on the size dispersion is in agreement with equation 12 which predicts that the compressive strength of the denser agglomerates counteracts the growth rate. The resulting granules, with a geometric standard deviation of about 1.5, were approximately spherical.
The results shown in Fig. 18 describe the pelletization of a cohesive powder without addition of plasticizing agents. The plasticizing effect required to round the agglomerates is supplied entirely by the free surface liquid and supported by the high intensity of agitation. It is a prerequisite to the process that the rate by which the solvent is removed is adjusted carefully to the rate by which it is forced to the agglomerate surface by consolidation.
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