High energy input, a controlled amount of liquid phase, and a uniform liquid distribution, are the prerequisites to produce pellets by wet granulation; accordingly, melt granulation in high shear mixers is likely to be appropriate for pelletization of powders insofar as the mixer can supply the required energy input. Schaefer etal. (1992a,b,c) have demonstrated that commercial qualities of calcium hydrogen phosphate and lactose can be pelletized with PEGs in a Pellmix 10 high shear mixer. The size distribution of the resulting granules had geometric standard deviations in the range 1.3 to 1.4, which compares well with the size distribution of pellets prepared by extrusion/spheronization. The resulting pellets may appear as smooth, rounded granules. Compared with wet granulation methods, melt pelletization has the advantage that the amount of binder material is easier to control because there is no evaporation during the process.
The amount of meltable binder material required to pelletize has to be adjusted to the particular feed material and to the actual process conditions. According to the work by Schaefer etal., the variation of the binder concentration that can be tolerated is less than 1-2% of the added amount of PEG. Significant deposition of the moistened mass to the walls of the mixer must be avoided in order to ensure the homogeneity of the mass (Thomsen etal., 1993a,b). In the Pellmix 10 mixer, this is achieved by a PTFE-lining of the walls of the mixer bowl. In a study on melt granulation in a 10-1 Baker Perkins mixer, Schaefer etal. (1990b) found that PEGs are especially suitable for melt granulation. Other meltable binders (stearyl alcohol, stearic acid, cetyl alcohol, glycerol monostearate) gave rise to deposition of moistened mass to the walls of the mixer bowl. Investigation of melt granulation with hydrophobic binders in a laboratory-scale Pellmix PL 1 /8 mixer has shown that the deposition of moist mass may be the determining factor in the choice of meltable binder (Thomsen etal., 1993a, b).
Effects of process variables on melt pelletization of lactose using PEGs are reported by Schaefer etal. (1993a). The authors compared the process in two different scale mixers (Schaefer etal., 1993b).
Melt pelletization in high shear mixers is a simple and rapid process compared with other methods for pelletization of powders and has the advantage of being solvent free. An additional benefit is that the pelletized product may contain up to about 85% m/m active ingredient. Melt pelletization using PEG as meltable binder renders the pellets hydrophilic. If a hydrophobic binder is used instead, the pellets may have prolonged release properties, as demonstrated by Thomsen (1994).
Figure 24 shows release profiles of pellets prepared by melt pelletization of paracetamol with a meltable binder composed of glycerol monostearate
fig. 24 Release profiles of paracetamol pellets prepared by melt pelletization using mixtures of glycerol monostearate (CMS) and microwax (MW) as meltable binder. Ratio of GMS to MW: 1:0, ■; 7:1, A, 3:1, *, 1:1, □, 1:3, *; and 1:7, x. Reproduced from Thomsen (1992).
and microcrystalline wax (a paraffin). The rate of release of paracetamol can be varied within wide limits by changing the ratio of glycerol monostearate to the wax. The mechanism of release from the matrix of binder material is diffusion controlled. A clinical study (unpublished) has shown that the matrix of glycerol monostearate and microcrystalline wax resists the gastrointestinal fluids, and that there is a close agreement between the in vivo release determined from plasma concentration profiles and the in vitro release determined by the paddle apparatus described in the European Pharmacopoeia and using a phosphate buffer of pH 6.8 as the dissolution medium.
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