Melt pelletization in a high shear mixer. V. Effects of apparatus variables

European Journal of Pharmaceutical Sciences, 1 (1993) 133-141 0928-0987/93/$06.00 © 1993 - Elsevier Science Publishers B.V. All rights reserved

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Melt pelletization in a high shear mixer. V. Effects of apparatus variables T o r b e n Schaefer, Birgitte T a a g e g a a r d , Lars Juul T h o m s e n , H. Gjelstrup Kristensen Royal Danish School of Pharmacy, Department of Pharmaceutics, Copenhagen, Denmark (Received 10 August 1992; accepted 3 March 1993)

Abstract Effects of two different sets of impeller blades on melt pelletization of lactose with polyethylene glycol (PEG) 3000 were investigated in an 8 litre high shear mixer. Results obtained in the 8 litre mixer were compared with previous results from a 50 litre high shear mixer of the same type. In the 8 litre mixer curved impeller blades were found to give rise to a high power input and smooth pellets of a spherical shape, whereas plane impeller blades caused a lower power input and irregular agglomerates. Agglomerate growth was found to be different in mixers of different scale. This difference was primarily ascribed to differences in movement of the mass, power input and product temperature.

Keywords: Polyethylene glycols; Pellets; Melt pelletization; Melt granulation; High shear mixer

Introduction

Most of the melt granulation experiments described in the literature were carried out in small laboratory scale mixers (Ford and Rubinstein, 1980; Rubinstein and Musikabhumma, 1980; Kinget and Kemel, 1985; Schaefer et al., 1990). Only a few results of experiments with scaling-up of melt granulation processes have been published (McTaggart et al., 1984; Flanders et al., 1987). Scaling-up from a 15 litre to a 75 litre high shear mixer resulted in granulations of a similar granule size and of similar dissolution properties (McTaggart et al., 1984). A comparison of melt granulation in a 10 litre, a 60 litre and a 600 litre high shear mixer showed small granules of a similar size distribution, but the granules produced in the 10 litre scale gave rise to tablets of a lower dissolution rate than those obtained from the 60 and 600 litre scale (Flanders et al., 1987). No results on scalingup of melt pelletization processes have been published so far. A scaling-up of wet granulation processes in high shear mixers has been investigated in more detail (Schaefer et al., 1986, 1987; Schaefer, 1988). DensificaCorrespondence to: Torben Schaefer, Royal Danish School of Pharmacy, Department of Pharmaceutics, 2 Universitetsparken, DK2100 Copenhagen, Denmark. Tel.: + 45 35 37 08 50; Fax: + 45 35 37 12 77.

tion and growth of the agglomerates during the process were markedly influenced by the construction of the mixer bowl and by the size and shape of the impeller and chopper. The vertical volume swept out by the impeller blades per second was assumed to reflect the power input on the material. In order to keep the granule properties constant by scaling-up, it seems to be desirable, therefore, to keep the relative swept volume constant in mixers of different scale (Schaefer, 1988). Melt pelletization in a high shear mixer is more sensitive than melt granulation to variations in product and process variables, since the formation of pellets occurs at liquid saturations, which are near to overwetting of the agglomerates (Schaefer et al., 1990, 1992a,b). Therefore, a scaling-up of melt pelletization processes in high shear mixers is likely to be difficult. A prerequisite for a successful scaling-up is detailed knowledge of the effects of apparatus and process variables on the pelletization process in mixers of different scale. Melt pelletization of lactose with PEG in a 50 litre high shear mixer has been described in parts I - I I I of this series of papers (Schaefer et al., 1992a,b,c). Part IV dealt with the effects of process variables on melt pelletization of the same materials in an 8 litre high shear mixer of the same type (Schaefer et al., 1993). The purpose of the present work was to elucidate the effects of apparatus variables on the melt pelletization

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Fig. 1. Impeller with changeable impeller blades. Plane blades (a). Curved blades (b).

process by investigating the effects of impeller construction in the 8 litre mixer and by comparing the results obtained in the 8 litre mixer with those obtained in the 50 litre mixer.

Experimental procedures Materials Lactose 450 mesh was used as starting material and polyethylene glycol (PEG) 3000 was used as melting binder. The materials have been described previously (Schaefer et al., 1993), where it was mentioned that the batches of the two materials were not significantly different from those used in the experiments with the 50 litre mixer. It is unlikely, therefore, that the comparison between the results from the 8 litre and the 50 litre mixer is affected by the fact that different batches of the materials were used. Equipment The laboratory scale high shear mixer (Pellmix PL 1/8)

described in a previous paper (Schaefer et al., 1993) was used for the experiments. Two different sets of impeller blades were compared (Fig. 1). The angle of inclination of the plane blades (a) and of the plane part of the curved blades (b) was 40 °. The relative swept volumes and the peripheral speeds of the impeller blades in these two mixers at the impeller speeds used in the experiments are shown in Table 1. By calculation of the relative swept volume in the 8 litre mixer the swept volume was divided by the volume of the bowl with the cone mounted (Schaefer et al., 1993), i.e. the volume was set to 6.7 litre. As can be seen, the values of relative swept volume are approximately of the same size in the 8 litre and the 50 litre mixer, whereas the peripheral speed is higher in the 50 litre mixer. Methods Granule characterization The methods were the same as previously described (Schaefer et al., 1993). The amount of lumps has previously been defined either as agglomerates larger than 2 mm (Schaefer et al., 1990) or larger than 4 m m

Table 1 Relative swept volumes and peripheral speeds of the impeller blades in the 8 litre (Pellmix 1/8) and the 50 litre (Pellmix 10) high shear mixer Pellmix 1/8 Curved blades

rpm

Rel. swept volume (s

800 1000 1200

3.87 4.84 5.80

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rpm

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Periph. speed ( m . s -I )

9.0 11.3 13.6

500 600 700

3.57 4.29 5.00

13.0 15.6 18.3

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T. Schcefer et al. / Melt pelletization in a high shear mixer, V

(Schaefer et al., 1992a). The latter definition was used in the 50 litre mixer because of a high mean granule size. The former definition was more convenient in the 8 litre mixer, since the mean granule size was lower. When the amount of lumps in the 8 litre and the 50 litre mixer is compared, the values used are those of the size fraction larger than 2 mm. In order to enable a direct comparison between the two mixers, the values of dgw and Sg obtained from the previous experiments in the 50 litre mixer (Schaefer et al., 1992a,b) were recalculated on the basis of the size fraction finer than 2 mm. Therefore, the results from the 50 litre mixer, which are presented in this paper, might be slightly different from the results presented previously.

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Results and discussion

Cone Removal of the cone resulted in adhesion of 25-30% of the material to the lid of the bowl, and the rest of the product consisted primarily of large balls. Most of the adhesion occurred during dry mixing. When the cone was inserted, the adhesion to the lid was markedly reduced, and no balls were formed. The cone acts by reducing the height of the cylindrical bowl. In the 8 litre mixer the ratio between height and diameter of the bowl is 0.95 without

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Experimental design Most of the results presented in this paper stem from the series of 36 experiments in the 50 litre mixer (Schaefer et al., 1992a) and the series of 66 experiments in the 8 litre mixer (Schaefer et al., 1993). The binder concentration was kept constant at 23% m/m of the amount of lactose in all the experiments described in this paper. All the results presented here from the series in the 8 litre mixer stem from experiments with a mixer load of 1000 g. A further series of 12 experiments with the plane impeller blades was carried out in the 8 litre mixer. In these experiments the impeller speed was 1200 rpm, and the load of the mixer was 1000 g. These experimental conditions were chosen because they were found to be the optimum with the curved impeller blades (Schaefer et al., 1993). The massing time was varied at 6, 9, 12 and 17 min. These four experiments were carried out in triplicate, and the results presented are mean values of three experiments. The effect of removing the cone of the 8 litre mixer from the lid was investigated in preliminary experiments.

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cone. This ratio is reduced to 0.56 by the cone when the height is measured from the bottom to the lower part of the cone. In the 50 litre mixer the ratio between height and diameter is 0.5. This indicates that the bowl of the 8 litre mixer is too high, and that insertion of a cone is necessary to compensate for this. The moving mass is directed against the central part of the bowl by the cone, which thus results in a more convenient movement of the mass.

Impeller blades The effects of the impeller blade construction (Fig. 1) on mean granule size, granule size distribution and a m o u n t of lumps are shown in Fig. 2. As can be

136

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Fig. 3. Photographs of pellets produced with curved impeller blades. Size fraction: 500 2000 #m. Impeller speed: 1200 rpm. Massing time: 6 min (a), 17 min (b).

T. Schcefer et al. / Melt pelletization in a high shear mixer, V

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Fig. 4. Photographs of pellets produced with plane impeller blades. Size fraction: 500-2000 #m. Impeller speed: 1200 rpm. Massing time: 6 min (a), 17 min (b).

138

seen, the plane impeller blades result in a larger mean granule size, a wider size distribution and a higher amount of lumps in the product. These effects were all significant at the 1% level (P = 0.99). The Sg values obtained with the plane impeller blades are so high that it is inexpedient, if pellets are desired. Further, the curved impeller blades gave rise to a better reproducibility of the process than the plane blades. With the curved blades the standard deviations on dgw, Sg and amount of lumps were previously estimated by analysis of variance to be 20 #m, 0.03 and 0.8% (Schaefer et al., 1993). The corresponding standard deviations obtained with the plane blades were 60 #m, 0.11 and 8.4%. This poor reproducibility was the reason why the experiments with the plane blades were carried out in triplicate. The curved impeller blades gave rise to a significantly (P = 0.95) lower intragranular porosity of the agglomerates than the plane blades (cf. Fig. 9) and consequently to a higher liquid saturation. The adhesion of material to the mixer was not significantly different when the two different blades were used. The different effects of the two sets of impeller blades on the above-mentioned granule properties are reflected in the appearance of the agglomerates (Figs. 3 and 4). After 6 min of massing, the curved impeller blades produced agglomerates which are rather rounded (Fig. 3a), and the final product (Fig. 3b) consists of pellets, which are very smooth and nearly spherical. The agglomerates produced with the plane blades are of an irregular shape and a loose structure after 6 rain of massing (Fig. 4a) in accordance with the high intragranular porosity, which is observed at that time (Fig. 9). By further massing the agglomerates become denser, but after 17 min of massing the agglomerates are still of an irregular shape and rather different in size (Fig. 4b). The large differences in the effects of the two sets of impeller blades cannot be explained by differences in relative swept volume, solely, since the relative swept volumes do not differ markedly (Table 1). The specific energy input after the melting point was reached was estimated as previously described (Schaffer et al., 1993). After 17 min of massing the energy input was 515 kJ/kg mass with the curved impeller blades and 198 kJ/kg mass with the plane impeller blades. Since a high energy input from the impeller is a prerequisite for producing pellets (Schaffer et al., 1992a), the markedly lower energy input with the plane blades explains why pellets could only be produced with the curved blades. The increase in power consumption beyond the constant level observed during dry mixing was estimated as previously described (Schaefer et al., 1992b, 1993). The

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Fig. 5. Effectof impeller blades on the specificpower consumption during massing. Impeller speed: 1200 rpm. Impeller blades: plane (. . . . . ), curved ( ). power consumption curves are shown in Fig. 5. It was previously found in the 50 litre mixer and with the curved blades in the 8 litre mixer that the agglomerate growth during melt pelletization was reflected in the power consumption curves (Schaefer et al., 1992b, 1993). This is not the case in the present experiments. Although the power consumption with the plane impeller blades is markedly lower than with the curved blades, the largest mean granule size is obtained with the plane blades (Fig. 2a). The larger mean granule size with these blades is assumed to be due to an uncontrolled agglomerate growth, which results in the formation of large agglomerates (Fig. 2c). The differences in power consumption were reflected in the temperature of the product, as it was found that the temperature became markedly higher with the curved blades. It is likely that the movement of the mass within the bowl is affected by the impeller blade construction, since the similarity in relative swept volume is not reflected in the energy input. It is assumed that the inclination and the vertical height of the plane impeller blades are so low that the mass partly slides or rolls over the rotating impeller blades, i.e. the mass is partly fluidized. This results in an energy input from the impeller, which is insufficient for a proper pelletization. The curvature of the curved impeller blades is assumed to prevent the mass from being fluidized, because the curved part of the blades hits the mass more directly. Instead the curved blades might facilitate a helix-like movement of the mass, which favours the formation of pellets.

T. Schcefer et al. / Melt pelletization in a high shear mixer, V

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The results obtained with the curved impeller blades in the 8 litre mixer are used for the comparison between the 8 and the 50 litre mixer. The impeller blades in the 50 litre mixer are plane and have the same angle of inclination (40 °) as the plane blades of the 8 litre mixer. The relative mixer load expressed as g of lactose per litre mixer volume was 160 g/1 in the large mixer and 149 g/1 in the small mixer. The relative load of the small mixer was calculated on the basis of the mixer volume with the cone inserted. Since, as mentioned above, the ratio between height and diameter of the bowl is slightly larger in the small mixer, it is assumed to be reasonable that the relative load is slightly smaller in this mixer. Fig. 6 shows the effect of mixer scale on the mean granule size. It is seen that the mean granule size becomes larger in the 50 litre mixer. Especially during the last 4 min of massing the agglomerate growth rate is higher in the 50 litre mixer. The relative swept volumes are slightly higher in the 8 litre mixer (Table 1). Therefore, the differences in agglomerate growth rate cannot be explained by differences in relative swept volume. On the other hand, the peripheral speed is higher in the 50 litre mixer. The effect of peripheral speed on agglomerate growth is unknown, but the movement of the mass, and consequently the agglomerate growth, might possibly be affected by the peripheral speed.

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Massing time (rain) Fig. 7. Effect of mixer scale and impeller speed on the specific power consumption during massing. Mixer scale: 8 litre ( . . . . . . ), 50 litre (. . . . . , . . . . . . ). ImpeUer speed: 500 rpm (. . . . . i, 700 rpm (. . . . . . ), 800 rpm ( . . . . . ), 1200 rpm ( ).

The energy input in the 50 litre mixer could not be estimated from the power consumption curves, because the base power consumption with no material in the bowl was not estimated. The increase in power consumption after melting of the binder can be compared instead (Fig. 7). The marked fall in power consumption after 2 min of massing at 800 rpm is due to the fact that impeller speed is kept at 1300 rpm until 2 min after melting in all the experiments in the small mixer (Schaefer et al., 1993). It is seen that the specific power consumption is higher in the small mixer in accordance with the higher relative swept volume in this mixer. However, the higher power input is not reflected in the agglomerate growth. Differences in product temperature might possibly explain the different growth pattern between the small and the large mixer. Fig. 8 shows that the temperature is markedly higher in the 50 litre mixer. Since the specific power input is lower in this mixer, the higher product temperature is assumed to be due to a reduced loss of heat to the surroundings from a larger mixer. Some water of crystallization is observed to evaporate from the lactose when the temperature exceeds approx. 100°C, and this water might affect the agglomerate growth (Schaefer et al., 1992b). The massing time at which a marked increase in growth rate is seen in Fig. 6 is nearly coincident with the time when the product temperature exceeds 100°C. Evaporation of water of crystallization, therefore, might contribute to the larger pellets obtained in the 50 litre mixer.

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Fig. 8. Effect of mixer scale and impeller speed on the product temperature during massing. Mixer scale: 8 litre (O,A,U]), 50 litre ( O , A , I ) . Impeller speed: 500 rpm (O), 600 rpm (A), 700 rpm (11), 800 rpm (O), 1000 rpm (A), 1200 rpm (13).

Fig. 9 shows the effect of mixer scale on the intragranular porosity. In the 50 litre mixer an appreciable fall in porosity during massing is seen at 600 rpm. A similar fall was seen at 500 and 700 rpm. The change in porosity is less in the 8 litre mixer. With the curved impeller blades a slight fall in porosity occurs at 800 rpm, whereas the variations in porosity at 1200 rpm are assumed to be random. The reason for the higher densification rate in the small mixer might be the higher power input in this mixer (Fig. 7), especially during the start of massing, because the impeller speed in the small mixer is kept at 1300 rpm until 2 min after melting. At prolonged massing, however, the intra-

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Fig. 10. Effect of mixer scale and impeller speed on the amount of lumps during massing. Mixer scale: 8 litre (O,zS,E]), 50 litre ( O , A , I ) . Impeller speed: 500 rpm (O), 600 rpm (A), 700 rpm (11), 800 rpm (O), 1000 rpm (A), 1200 rpm (D).

granular porosity reaches the same low level independent of mixer size, except for agglomerates produced with the plane blades in the 8 litre mixer. The changes in porosity are reflected in the liquid saturation of the agglomerates. Since the final liquid saturations obtained from both mixers were found to be between 95 and 100%, the differences in agglomerate growth seen in Fig. 6 cannot be explained by differences in liquid saturation. The changes in amount of lumps (Fig. 10) and in granule size distribution (Fig. 11) were similar to the 2.0

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Fig. 11. Effect of mixer scale and impeller speed on the geometric standard deviation during massing. Mixer scale: 8 litre (O,/X,71), 50 litre (O,A,B). Impeller speed: 500 rpm (O), 600 rpm (A), 700 rpm (11), 800 rpm (O), 1000 rpm (A), 1200 rpm (D).

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T. Schcefer et al. / Melt pelletization in a high shear mixer, V

changes in the intragranular porosity. The lower power input in the 50 litre mixer allows the formation of loose agglomerates and lumps during the start of massing, but these lumps are crushed by further massing. The formation of these large agglomerates might explain why the mean granule size during the start of massing becomes larger in the 50 litre mixer than in the 8 litre mixer. At prolonged massing the amount of lumps becomes slightly smaller in the large mixer. The crushing of large agglomerates in this mixer results in a marked narrowing of the size distribution during massing (Fig. 11). At 600 and 700 rpm in the large mixer the final size distribution is slightly narrower than the one obtained in the small mixer.

Conclusions The dimensions of the bowl of the mixer seem to be critical, if the mixer is to be used for melt pelletization. If the bowl is too high, the vertical movement of the mass might be so high that the contact between the impeller and the mass is reduced. This will give rise to an insufficient power input to the material and will cause an irregular movement of the mass. The load of the mixer seems to be especially critical in small laboratory scale mixers (Schaefer et al., 1993). It is desirable, therefore, that such mixers are equipped with cones or other insertions, which make it possible to vary the height and volume of the bowl. The size and the shape of the impeller blades must be such that the impeller gives rise to a high energy input to the material and causes a helix-like movement of the mass. A scaling-up of the impeller is difficult. Although shape, angle of inclination and relative swept volume were the same, an impeller with plane blades was found to be unsuitable for melt pelletization in the small mixer, whereas it produced excellent pellets in the larger mixer. The relative swept volume might possibly be used for evaluation of the applicability of an impeller in a larger mixer, but not in a laboratory scale mixer. It appears easier to produce round and smooth pellets of a narrow size distribution in a large mixer. The larger amount of mass in large mixers might in itself contribute to a more appropriate movement of the mass. Evaporation of water of crystallization during the process seems to be advantageous to pelletization, although pellets can be produced at temperatures at which no evaporation of water occurs. The experiments showed that the effects of mixer construction on pellet properties are rather complex. The comparison between the two mixers, therefore,

resulted in no general rules or models for a scalingup procedure. There is a need for further studies on the effect of impeller design on power input and movement of the mass in mixers of different scale. Until then, the best way of evaluating mixer design seems to be to measure the energy input during the actual process.

Acknowledgements The Danish Medical Research Council is acknowledged for financial support to the work. Niro Atomizer A/S, Denmark, is acknowledged for the loan of the Pellmix PL 1/8 and the Pellmix 10 high shear mixers.

References Flanders, P., Dyer, G.A. and Jordan, D. (1987) The control of drug release from conventional melt granulation matrices. Drug Dev. Ind. Pharm. 13, 1001-1022. Ford, J.L. and Rubinstein, M.H. (1980) Formulation and ageing of tablets prepared from Indomethacin-Polyethylene Glycol 6000 solid dispersions. Pharm. Acta Helv. 55, 1-7. Kinget, R. and Kemel, R. (1985) Preparation and properties of granulates containing solid dispersions. Acta Pharm. Technol. 31, 57 62. McTaggart, C.M., Ganley, J.A., Sickmueller, A. and Walker, S.E. (1984) The evaluation of formulation and processing conditions of a melt granulation process. Int. J. Pharm. 19, 139 148. Rubinstein, M.H. and Musikabhumma, P. (1980) Formulation and evaluation of paracetamol 500 mg tablets produced by a new direct granulation method. Drug Dev. Ind. Pharm. 6, 451-473. Schaefer, T. (1988) Equipment for wet granulation. Acta Pharm. Suec. 25, 205-228. Schaefer, T., Bak, H.H., J~egerskou, A., Kristensen, A., Svensson, J.R., Holm, P. and Kristensen, H.G. (1986) Granulation in different types of high speed mixers. Part 1. Effects of process variables and up-scaling. Pharm. Ind. 48, 1083-1089. Schaefer, T., Bak, H.H., J~egerskou, A., Kristensen, A., Svensson, J.R., Holm, P. and Kristensen, H.G. (1987) Granulation in different types of high speed mixers. Part 2. Comparisons between mixers. Pharm. Ind. 49, 297-304. Schaefer, T., Holm, P. and Kristensen, H.G. (1990) Melt granulation in a laboratory scale high shear mixer. Drug Dev. Ind. Pharm. 16, 1249-1277. Schaefer, T., Holm, P. and Kristensen, H.G. (1992a) Melt pelletization in a high shear mixer. I. Effects of process variables and binder. Acta Pharm. Nord. 4, 133-140. Schaefer, T., Holm, P. and Kristensen, H.G. (1992b) Melt pelletization in a high shear mixer. II. Power consumption and granule growth. Acta Pharm. Nord. 4, 141-148. Schaefer, T., Holm, P. and Kristensen, H.G. (1992c) Melt pelletization in a high shear mixer. III. Effects of lactose quality. Acta Pharm. Nord. 4, 245 252. Schaefer, T., Taagegaard, B., Thomsen, L.J. and Kristensen, H.G. (1993) Melt pelletization in a high shear mixer. IV. Effects of process variables in a small laboratory scale mixer. Eur. J. Pharm. Sci. 1, 125-131.