Every single step in the process of pelletization by extru-

sion/spheronization affects the properties of the resulting pellets. Pharmaceutical scientists originally directed their focus to extrusion, spheronization and drying which can be seen from the literature. Only a few authors reported investigations concerning the impact of the granulation step. Baert et al. investigated ternary mixtures of microcrystalline cellulose (MCC), a drug substitute and water on a planetary mixer and a high-shear mixer. Granulation time on the high-shear mixer was then varied. Granulation in the high shear mixer resulted in higher extrusion forces for the same composition blends. But these results were not further evaluated. Increasing granulation time also resulted in higher extrusion forces, but this was attributed exclusively to an increased loss of water. Vervaet and Remon worked inter alia on the influence of granulation time, mixing speed and type of mixing arm of a planetary mixer on the quality of pellets made of MCC, ibuprofen and water. They concluded that the extrusion step superimposed the effect of variations in granulation. These experiences show that studies on the isolated influence of the granulation process have to be performed under the following conditions. Firstly, the changes in granulation have to be distinct enough to result in perceptible effects. Secondly, the subsequent steps that can influence the product also have to be chosen carefully. Additional excessive treatment of the granules that would level existing differences should be avoided. The aim of this study was to meet those requirements by the utilization of suitable equipment. For that purpose a planetary mixer and a high-shear mixer were used as well as a twin-screw extruder with two different screw designs for granulation. Extrusion was performed on a rotary ring die press, an intrument which is known to work with less compression force and shear rate than other extruders. The resulting pellets were evaluated with regard to their size, shape, porosity, release behaviour and other properties. Experimental Materials Pellets were prepared from a binary mixture of paracetamol (Rhodapap dense and fine powder, Rhone Poulenc, Frankfurt, Germany) and MCC (Avicel PH 101, FMC, Cork, Ireland) at a ratio of 20 : 80. Demineralized water was used as granulation liquid. Table 1 summarises the characterization of excipients. Pellet Preparation Granulation: After sufficient blending the dry excipients were granulated with demineralized water by four different procedures. A planetary mixer (A200, Hobart GmbH, Offenburg, Germany) was used for low shear granulation (G1). Granulation liquid was added manually over 45 s. High shear granulation was performed on a SP1 (G2) (AeromaticFielder, Eastleigh, UK). A previously described twin-screw extruder (Berstorff ZE 25318 D, Berstorff GmbH, Hannover, Germany) was used for granulation by removing the die plate and collecting the exceeding material. The screws were assembled without (G3) and with mixing and kneading elements (G4) again in order to apply different amounts of shear (Fig. 1) . For details see Table 2. The moisture content (MC) of granules was measured for two samples per batch and was calculated by the loss of drying at 105 °C for 24 h on dry base (m/m). Calculations of the formulations were based on dry substances. Extrusion/Spheronization/Drying: Extrusion and spheronization of all granules was performed on a rotary ring die press PP-127 and a RM-300 spheronizer (Schlüter Maschinenfabrik GmbH & Co. KG, Neustadt a. Rbge., Germany). Process conditions were kept constant for all trials as described. The shear stress exerted on the granule and the compression of the granule was adjusted by the width of the gap between press roll and ring March 1999 Chem. Pharm. Bull. 47(3) 405—412 (1999) 405