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Melt pelletization in a high shear mixer. IV. Effects of process variables in a laboratory scale mixer
European Journal of Pharmaceutical Sciences, 1 (1993) 125 - 131 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. IV. Effects of process variables in a laboratory scale mixer Torben Schaefer, Birgitte Taagegaard, Lars Juul Thomsen, H. Gjelstrup Kristensen Royal Danish School of Pharmacy, Department of Pharmaceutics, Copenhagen, Denmark (Received 10 August 1992; accepted 3 March 1993)
Abstract Melt pelletization of lactose in an 8 litre high shear mixer was examined by a factorially designed experiment. Polyethylene glycol (PEG) 3000 was used as melting binder in a concentration of 23% m/m. The load of the mixer was varied at 600, 800 and 1000 g of lactose. Effects were investigated of: massing time, impeller speed and mixer load on mean granule size and size distribution, amount of lumps, intragranular porosity, adhesion of material to the bowl, product temperature and power input. The process was found to be the most reproducible and to give rise to the optimum pellets at a mixer load of 1000 g. A lower mixer load gave rise to a larger amount of lumps. The highest impeller speed resulted in the largest and most rounded pellets. The agglomerate growth was found to be dependent on the power input.
Keywords. Polyethylene glycols; Pellets; Melt pelletization; Melt granulation; High shear mixer
Introduction
Several authors (Ford and Rubinstein, 1980; Rubinstein and Musikabhumma, 1980; McTaggart et al., 1984; Kinget and Kemel, 1985; Flanders et al., 1987; Schaefer et al., 1990) have published results of melt granulation processes in small scale mixers. Only one of these papers (Schaefer et al., 1990) deals with a process which produces granules with the characteristics of a pelletized product. The process variables which have been studied are effects of the mixer load (McTaggart et al., 1984), the impeller rotation speed (Kinget and Kemel, 1985; Schaffer et al., 1990), the massing time (Schaefer et al., 1990) and the temperature of the heating jacket (Kinget and Kemel, 1985). It is generally agreed that the impeller rotation speed is an essential process variable in melt granulation and pelletization. Like a prolonged massing time (Schaefer et al., 1990), an increase of the impeller speed gives rise to a larger mean granule size and a narrower size distribution (Kinget and Kernel, 1985; Schaefer et al., 1990). Correspondence 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.
Knowledge about the effect of the mixer load is insufficient. Experiments with melt granulation in a 15 litre mixer using four loads in the range from 1.25 to 2.75 kg showed that an increase of the load gave rise to a slightly reduced mean granule size (McTaggart et al., 1984). It was previously assumed (Schaffer, 1988) that when the mixer load is kept constant, the power input to the material depends on the impeller rotation speed and the dimensions of the impeller as expressed by the swept volume of the impeller. Nothing has been published, however, on the effect of the mixer load on the power input in a melt granulation or pelletization process. The temperature of the mass is increased due to heat developed by friction caused by the agitation. In small scale mixers, the loss of heat to the surroundings may be so appreciable that the product cannot be heated within a reasonable time to a sufficient temperature to melt the binder without the use of a heating jacket. In the melt granulation experiments carried out with heating jackets (Ford and Rubinstein, 1980; Rubinstein and Musikabhumma, 1980; Kinget and Kernel, 1985), the temperature of the jacket was 60-70°C which was above the melting point of the binder. No effect was found by varying the temperature within the range of 60-70°C (Kinget and Kernel, 1985). In these experiments, however, the
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binder was added in a molten state. There are no results reported on the effects of the jacket temperature when the binder is added in solid state. The effects of process variables on melt pelletization in a 50 litre high shear mixer were investigated in previous work (Schaefer et al., 1992a,b,c). The purpose of the present work was to investigate the effects of process variables on melt pelletization of lactose with P E G in an 8 litre mixer of the same type. Part V of this series of papers deals with a comparison of the results obtained in the 8 litre and the 50 litre mixer.
T. Sehcefer et al. / Melt pelletization in a high shear mixer, I V
cone
heating jacket impeller J
220
Experimental procedures Materials Lactose 450 mesh (c~-monohydrate lactose, D M V Veghel, Ph.Eur. quality) was used as starting material, and polyethylene glycol (PEG) 3000 (Hoechst, Germany) was used as melting binder. Although the batches of the two materials were different from those used previously (Schaefer et al., 1992a,b,c), the physical properties were similar. The geometric mean particle size of the distribution by weight of the lactose determined by a Malvern 2601Lc laser diffraction particle sizer (Malvern Instruments, U K ) was found to be 22 #m. The mean size and the size distribution were not significantly different to those of the previous batch (Schaefer et al., 1992c). The melting point of the P E G 3000 estimated by the capillary method was 60-63°C, which was the same as that of the previous batch (Schaefer et al., 1992a). The melting range was further estimated by a Perkin Elmer DSC 7 differential scanning calorimeter (Perkin Elmer, USA). A sample of about 6 mg was sealed in a 50 #1 aluminium pan and scanned between room temperature and 120°C at a heating rate of 10°C per min. The melting range was found to be 50-65°C with a peak temperature of 60°C.
mm
~"
Fig. 1. Outline of Pellmix PL 1/8 high shear mixer.
mounted to the lid of the bowl. The volume of the bowl is about 8 litre without cone and about 6.7 litre with the cone mounted. The cone was used in all the present experiments. The impeller is a two-bladed impeller of stainless steel with changeable impeller blades. Curved impeller blades were used in the present experiments. Experiments with different impeller blade construction will be described in part V of these papers. The impeller speed is continuously adjustable within the range of 0 to 1500 rpm. The power consumption of the impeller m o t o r was measured by a power consumption meter. The mixer is not equipped with a chopper. The 50 litre Pellmix mixer was equipped with a removable chopper, but the effect of the chopper was found to be inappreciable (Schaefer et al., 1992a). The temperatures of the product and of the heating jacket were measured with thermoresistance probes. The probe measuring the temperature of the product was placed in the side wall of the bowl at 53 m m from the bottom. During the process the temperatures, the power consumption and the rotation speed of the impeller were recorded.
Methods
Equipment
Mixing procedure
A laboratory scale high shear mixer (Pellmix PL 1/8, Niro A/S, Denmark) was used for the experiments. The mixer (Fig. 1) is equipped with an electrically heated jacket, which can be heated to a m a x i m u m temperature of about 120°C. The inner wall of the bowl is coated with polytetrafluoroethylene (PTFE) in order to reduce adhesion of material to the bowl. The cylindrical bowl is equipped with a removable cone, i.e. a truncated cone-shaped ring of P T F E
The load of the mixer is expressed as the amount of lactose used unless otherwise stated. The load was either 600g, 800g or 1000g. The P E G 3000 was added in a solid state. The P E G concentration was 23% m / m of the amount of lactose in all the experiments. This binder concentration was the middle concentration level used in the previous experiments (Schaefer et al., 1992a). It gave rise to pellets of an appropriate size and size distribution in the 50 litre mixer.
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T. Schcefer et al. / Melt pelletization in a high shear mixer, I V
The lactose and the binder were dry mixed at an impeller speed of 1300 rpm in order to increase the temperature to the melting point of the PEG within a reasonably short time, i.e. about 7 min. The start of the massing time was defined as this point. Two minutes after the melting point was observed on the temperature curve (Schaefer et al., 1992a), the impeller speed was lowered to either 800, 1000 or 1200 rpm. The starting temperature of the heating jacket was kept at 50°C, except in a few preliminary experiments, which are mentioned below. The relative air humidity of the room was kept at approximately 46% in all the experiments. At the end of the process, the amount of agglomerates which flowed from the bowl when tilted was weighed and then spread out in thin layers on trays in order to cool at ambient temperature (Schaefer et al., 1992a). The adhesion to the bowl was estimated as the difference between the amount of materials placed in the bowl and the amount emptied.
Since the jacket of the present mixer is not a cooling jacket, the jacket temperature cannot be kept constant during the whole process but is heated by the product, when its temperature exceeds the jacket temperature. However, the increase in jacket temperature will be slightly delayed. Preliminary experiments were carried out at starting temperatures of the heating jacket of 40, 50, 65 and 80°C. Jacket temperatures of 65 and 80°C resulted in a marked adhesion of product to the wall of the mixer bowl, and a jacket temperature of 40°C resulted in a large amount of lumps in the product. At a jacket temperature of 50°C no lumps were seen during the start of the process, and practically no adhesion of material to the wall occurred. Consequently, the starting temperature of the jacket was kept constant at 50°C in the subsequent experiments.
Granule characterization
Impeller speed
The amount of lumps larger than 2 mm was estimated as the retained fraction after vibration of the cooled agglomerates on a Jel-Fix 50 vibration sieve (J. Engelsmann AG, Germany) for about 10 seconds, until the fraction finer than 2 mm had passed. The granule size distribution was estimated by sieve analysis of a sample of about 100 g drawn by scoping from the fraction finer than 2 mm, and dgw and Sg were calculated (Schaefer et al., 1992a). The intragranular porosity and the liquid saturation of the agglomerates were estimated as previously described (Schaefer et al., 1992a).
The effect of impeller speed on the mean granule size was significant at the 0.1% level (P = 0.999) at a mixer load of 1000 g (Fig. 2). It is seen that an increase in impeller speed gives rise to a larger granule size as previously found (Kinget and Kemel, 1985; Schaefer et al., 1990, 1992a). At a mixer load of 600 g the effect of impeller speed was found to be different, since an impeller speed of 800 rpm gave rise to a larger mean granule size than impeller speeds of 1000 and 1200 rpm. These findings
Results and discussion
Jacket temperature
Experimental design Effects of massing time, impeller speed and load of the mixer were examined by a series of 66 experiments. The impeller speed was varied at three levels (800, 1000 and 1200 rpm). The load of the mixer was also varied at three levels (600, 800 and 1000 g). Massing time was varied at 6, 9 and 12 min at all the nine combinations of impeller speed and mixer load. At the low level of impeller speed combined with mixer loads of 800 and 1000 g, further experiments were carried out at massing times of 17 and 22 rain. At impeller speeds of 1000 and 1200 rpm combined with a mixer load of 1000 g, further experiments were carried out at a massing time of 17 rain. The results shown in this paper are mean values of two experiments unless otherwise stated.
1000
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10
I
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I
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I
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20
15
(rain)
Fig. 2. Effect of impeller speed on the mean granule size during massing. Mixer load: 1000 g. Impeller speed: 800 rpm (O), 1000 rpm (A), 1200 rpm (D).
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indicate that an impeller speed of 800 rpm combined with a low mixer load results in an uncontrolled agglomerate growth. At a mixer load of 800 g the effect of impeller speed was similar to the one seen in Fig. 2, but less significant (P = 0.99). Fluctuations in mean granule size were observed at 800 rpm indicating a slightly uncontrolled agglomerate growth. Similar fluctuations were seen in the amount of lumps. The effect of impeller speed on the granule size distribution (Sg) was found to be significant (P = 0.999) at a mixer load of 1000 g only. The highest impeller speed resulted in the narrowest size distribution in accordance with previous findings (Kinget and Kemel, 1985; Schaefer et al., 1990, 1992a). An analysis of variance of the results on the amount of lumps showed a significant interaction (P = 0.999) between impeller speed and massing time. At short massing times a higher impeller speed resulted in a smaller amount of lumps, because some lumps were crushed at the high speed. At prolonged massing a higher impeller speed gave rise to a larger amount of lumps due to a higher agglomerate growth rate at this speed. No clear effect of impeller speed on the intragranular porosity was found. This indicates that the densification of the agglomerates was nearly finished at the shortest massing time (6 min) used in the experiments. In accordance with previous findings (Schaefer et al., 1992a) the pellets were found to be more rounded and smoother at a higher impeller speed.
T. Schcefer et al. / Melt pelletization in a high shear mixer, I V
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/
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Fig. 3. Effect of mixer load on the mean granule size during massing. Impeller speed: 1000 rpm. Mixer load: 600 g (O), 800 g (A), 1000 g (0).
the swept volumes corresponding to impeller speeds of 800, 1000 and 1200 rpm and the energy input. The figure shows the results of each of two repeated experiments. Since the impeller speed is 1300 rpm until 2 min after the melting point, the figure shows the energy input between 2 and 12 min of massing. As can be seen, a larger swept volume results in an increased energy input, and the correlation seems to be linear at a constant mixer load. The energy input at the same swept volume is seen to be higher at a higher mixer
/
!
Mixer load
300 -
The effect of mixer load on the mean granule size was found to be significant at the 0.1% level (P = 0.999). A decrease in mixer load resulted in a larger mean granule size at all levels of impeller speed. The effect of mixer load at 1000 rpm is shown in Fig. 3. At mixer loads of 600 and 800 g the massing time could not be longer than 12 min due to formation of lumps in the product. Agglomerate growth in high shear mixers is related to the energy input from the impeller during the process, and the swept volume of the impeller is assumed to be a measure of the energy input (Schaefer, 1988). In an attempt to explain the effect of mixer load on agglomerate growth, the energy input was estimated from the power consumption curves as the area between the curve and the base line corresponding to the power consumption measured at the actual impeller speed with no material in the bowl. Fig. 4 shows the correlation between the values of
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Fig. 4. Effect of mixer load on the correlation between the swept volume of the impeller and the energy input between 2 and 12 min of massing. Massing time: 12 min. Mixer load: 600 g (O), 800 g (A),
lOOOg (~).
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T. Schaefer et al. / Melt pelletization in a high shear mixer, I V
Table 1 Effect of impeller speed and mixer load on the specificenergy input during massing after melting of the binder. Massing time: 12 min
go
800 Mixer load (g)
1000
o
~
Impeller speed (rpm) o / ~
1200
D/
80
Specific energy input (kJ/kg mass) E
600 800 1000
218 226 212
317 280 269
425 361 333
load, because a larger amount of material must be moved by the impeller. It has previously been mentioned that in practice the active part of the swept volume will be smaller than the theoretical value (Schaefer, 1988), because most of the material moves close to the wall of the bowl due to centrifugal forces. It is assumed that a larger part of the impeller blades will be in contact with the material if the mixer load is increased. It is likely, therefore, that the correlation between swept volume and energy input is independent of the mixer load, if the values of the active swept volumes could have been used instead of the theoretical ones. Since the highest energy input is seen at the mixer load which gives rise to the smallest granule size, Fig. 4 does not explain the effect of mixer load on agglomerate growth seen in Fig. 3. Table 1 shows the specific energy input during the whole wet massing phase, i.e. the energy input after the melting point was reached. The values of energy input are weight specific energy inputs obtained by dividing the energy input by the total mass of lactose and PEG. A significantly higher specific energy input is seen at decreasing mixer load at impeller speeds of 1000 and 1200 rpm. This might explain why the largest granule size is seen at the lowest mixer load in Fig. 3. However, differences in specific energy input cannot explain the effect of mixer load on granule size at 800 rpm, where other factors might contribute. This will be discussed below. It was shown in the 50 litre Pellmix mixer that the agglomerate growth during melt pelletization was reflected in the power consumption curve (Schaefer et al., 1992b). In the present mixer a good agreement between weight specific power consumption and agglomerate growth was found at an impeller speed of 1200 rpm. This indicates that the power consumption signal might be used for process control purposes in the small Pellmix mixer too. At impeller speeds of 800 and 1000 rpm, however, it is difficult to use the power consumption curve for control of agglomerate
I 0 ~
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k
r
5
Massing
t 10
S_t time(rain
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)
Fig. 5. Effect of mixer load on the product temperature during massing. Impeller speed: 1000rpm. Mixer load: 600g (O), 800g (A), 1000 g (El). growth, since the increase in power consumption was found to be slight and occurred only during the last few minutes of massing. Fig. 5 shows the effect of mixer load on the increase in product temperature during massing at 1000 rpm. It was to be expected that the highest specific energy input would result in the highest temperature, since the energy is converted into heat of friction. However, the lowest temperature is seen at a mixer load of 600 g. The reason might be that the larger specific energy input is counteracted by an increased loss of heat at lower mixer load. A similar effect of mixer load on product temperature was found at impeller speeds of 800 and 1200 rpm. The different energy input at different mixer loads was not reflected in the densification of the agglomerates, since no significant differences between the intragranular porosities were observed at the longest massing times. These final porosities were all found to be 4 5%, corresponding to liquid saturations of 95-100%. The effect of the mixer load on the granule size distribution (Sg) was found to be significant at the 1% level (P = 0.99). The lowest mixer load resulted in the narrowest size distribution, especially during the start of the wet massing phase (Fig. 6). This effect might be ascribed to the higher specific energy input at lower mixer load. The effect was unclear at an impeller speed of 1200 rpm, where large fluctuations in Sg were seen at mixer loads of 600 and 800 g. The Sg values obtained at the longest massing times were normally found to be within the range 1.3 1.4 independent of mixer load. The adhesion of material to the mixer expressed in g of material was not significantly affected by either
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T. Schcefer et al. / Melt pelletization in a high shear mixer, I V Table 2 Effect of mixer load on the reproducibility of the process expressed by the standard deviation on mean granule size, geometric standard deviation and a m o u n t of lumps
1.6
Standard deviation >
1.4 "o
1.2-
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I
[
I
J
I
I
I_
10
I
Mixer load (g)
dgw (#m)
Sg
lumps > 2mm (%)
600 800 1000
68 77 20
0.09 0.03 0.03
5.5 4.8 0.8
I
15
Massing time ( m i n )
Fig. 6. Effect of mixer load on the geometric standard deviation during massing. Impeller speed: 1000 rpm. Mixer load: 600 g (O), 800 g (A), 1000 g (El]).
mixer load, massing time or impeller speed. This indicates that most of the adhesion is due to adhesion to the lid during dry mixing. Normally the loss of material due to adhesion was about 50 g. The amount of lumps in the product is significantly affected by the mixer load (P = 0.999). Fig. 7 shows the effect of mixer load on the amount of lumps at an impeller speed of 1000 rpm. The amount of lumps is markedly larger at a mixer load of 600 g. The same effect of mixer load was seen at 800 rpm and 1200 rpm, at which the amount of lumps at the low mixer load was at the same high level. The smallest amount of lumps was generally obtained at a mixer load of 1000 g. Since the lumps occur a few minutes after melting at a load of 600 g, they are not caused by a controlled agglomerate growth. It is assumed that the movement
of the mass becomes nonhomogeneous, if the load of the mixer becomes too low, and that this might give rise to formation of lumps by an uncontrolled agglomerate growth. At the higher loads the movement of the mass is more homogeneous, and therefore a marked increase in the amount of lumps is not seen until later in the process, where the agglomerates are close to being overwetted. The effect of mixer load on the reproducibility of the process is shown in Table 2. The standard deviations are estimated by analysis of variance carried out at each mixer load on all the results obtained with the actual load. The table shows that a load of 1000 g is favourable in order to obtain a reproducible pelletization process. It was generally observed that the pellets produced at a mixer load of 1000 g were more rounded and smoother than the pellets produced at the lower mixer loads. This confirms the above-mentioned assumption that the movement of the mass is more homogeneous at a load of 1000 g.
Massing time 25
E E
20
~.o
O4 ^
~
o
0 /
15
zx
E v
10
D
5
0
5
10
15
Massing time ( m i n )
Fig. 7. Effect of mixer load on the a m o u n t of lumps during massing. Impeller speed: 1000 rpm. Mixer load: 600 g (O), 800 g (A), 1000 g (Eli).
Examples of the effect of massing time on the properties of the agglomerates are shown in the above Figures. An increased massing time gave rise to a significantly larger mean granule size, to a significantly narrower size distribution and to a significantly higher product temperature. These effects are in accordance with previous results (Schaefer et al., 1990, 1992a). The effect of massing time on the amount of lumps is unclear, because the amount of lumps is determined by a balance between crushing and growth mechanisms. Which of these mechanisms will be the dominatant one depends on the actual combination of mixer load and impeller speed. In accordance with previous findings (Schaefer et al., 1992b) an increased massing time gave rise to agglomerates which were rounder and smoother. With all the nine combinations of mixer load and
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T. Schaefer et al. / Melt pelletization in a high shear mixer, I V
impeller speed investigated, the longest massing time resulted in large agglomerates o f a n a r r o w size distribution, i.e. pellets. However, differences were observed in roundness and smoothness o f the pellets as mentioned above.
in the power c o n s u m p t i o n signal. At a speed below 1000 rpm the agglomerate growth might become less controllable, and the massing time has to be very long to obtain pellets.
Acknowledgements Conclusions The small laboratory scale high shear mixer was f o u n d to be suitable for melt pelletization with P E G , since it is able to p r o d u c e r o u n d e d pellets o f a n a r r o w size distribution at massing times between 10 and 20 min. However, the process variables are very critical. The jacket o f the mixer bowl has to be heated in order to avoid an extremely long processing time. The most suitable choice o f jacket temperature during dry mixing seems to be a temperature slightly below the melting point o f the binder. The m o v e m e n t o f the mass in the bowl has to be uniform and controlled in order to produce pellets, and the mixer load, therefore, is very critical. If the load is too low, the a m o u n t o f lumps might be extremely high, the shape of the final pellets might be irregular and the reproducibility might be poor. Since the m o v e m e n t o f the mass depends on its cohesiveness, the o p t i m u m mixer load might depend on the physical properties o f the starting materials. In the present mixer the process is negatively affected at a mixer load below approx. 1000 g of lactose 450 mesh. A high power input is a prerequisite for making pellets. It is desirable, therefore, to measure the power c o n s u m p t i o n during the process. The power input is primarily controlled by the impeller speed. The starting materials might affect the o p t i m u m impeller speed, too. W h e n lactose has to be pelletized with P E G , an impeller speed o f a b o u t 1200 rpm seems to be favourable, since this speed results in rounded pellets, and since the agglomerate growth is reflected
The Danish Medical Research Council is acknowledged for financial support to the work. Niro A t o m izer A/S, D e n m a r k , is acknowledged for the loan o f the Pellmix P L 1/8 high shear mixer.
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 Kernel, 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., 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.
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Melt pelletization in a high shear mixer. IV. Effects of process variables in a laboratory scale mixer Torben Schaefer, Birgitte Taagegaard, Lars Juul Thomsen, H. Gjelstrup Kristensen Royal Danish School of Pharmacy, Department of Pharmaceutics, Copenhagen, Denmark (Received 10 August 1992; accepted 3 March 1993)
Abstract Melt pelletization of lactose in an 8 litre high shear mixer was examined by a factorially designed experiment. Polyethylene glycol (PEG) 3000 was used as melting binder in a concentration of 23% m/m. The load of the mixer was varied at 600, 800 and 1000 g of lactose. Effects were investigated of: massing time, impeller speed and mixer load on mean granule size and size distribution, amount of lumps, intragranular porosity, adhesion of material to the bowl, product temperature and power input. The process was found to be the most reproducible and to give rise to the optimum pellets at a mixer load of 1000 g. A lower mixer load gave rise to a larger amount of lumps. The highest impeller speed resulted in the largest and most rounded pellets. The agglomerate growth was found to be dependent on the power input.
Keywords. Polyethylene glycols; Pellets; Melt pelletization; Melt granulation; High shear mixer
Introduction
Several authors (Ford and Rubinstein, 1980; Rubinstein and Musikabhumma, 1980; McTaggart et al., 1984; Kinget and Kemel, 1985; Flanders et al., 1987; Schaefer et al., 1990) have published results of melt granulation processes in small scale mixers. Only one of these papers (Schaefer et al., 1990) deals with a process which produces granules with the characteristics of a pelletized product. The process variables which have been studied are effects of the mixer load (McTaggart et al., 1984), the impeller rotation speed (Kinget and Kemel, 1985; Schaffer et al., 1990), the massing time (Schaefer et al., 1990) and the temperature of the heating jacket (Kinget and Kemel, 1985). It is generally agreed that the impeller rotation speed is an essential process variable in melt granulation and pelletization. Like a prolonged massing time (Schaefer et al., 1990), an increase of the impeller speed gives rise to a larger mean granule size and a narrower size distribution (Kinget and Kernel, 1985; Schaefer et al., 1990). Correspondence 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.
Knowledge about the effect of the mixer load is insufficient. Experiments with melt granulation in a 15 litre mixer using four loads in the range from 1.25 to 2.75 kg showed that an increase of the load gave rise to a slightly reduced mean granule size (McTaggart et al., 1984). It was previously assumed (Schaffer, 1988) that when the mixer load is kept constant, the power input to the material depends on the impeller rotation speed and the dimensions of the impeller as expressed by the swept volume of the impeller. Nothing has been published, however, on the effect of the mixer load on the power input in a melt granulation or pelletization process. The temperature of the mass is increased due to heat developed by friction caused by the agitation. In small scale mixers, the loss of heat to the surroundings may be so appreciable that the product cannot be heated within a reasonable time to a sufficient temperature to melt the binder without the use of a heating jacket. In the melt granulation experiments carried out with heating jackets (Ford and Rubinstein, 1980; Rubinstein and Musikabhumma, 1980; Kinget and Kernel, 1985), the temperature of the jacket was 60-70°C which was above the melting point of the binder. No effect was found by varying the temperature within the range of 60-70°C (Kinget and Kernel, 1985). In these experiments, however, the
126
binder was added in a molten state. There are no results reported on the effects of the jacket temperature when the binder is added in solid state. The effects of process variables on melt pelletization in a 50 litre high shear mixer were investigated in previous work (Schaefer et al., 1992a,b,c). The purpose of the present work was to investigate the effects of process variables on melt pelletization of lactose with P E G in an 8 litre mixer of the same type. Part V of this series of papers deals with a comparison of the results obtained in the 8 litre and the 50 litre mixer.
T. Sehcefer et al. / Melt pelletization in a high shear mixer, I V
cone
heating jacket impeller J
220
Experimental procedures Materials Lactose 450 mesh (c~-monohydrate lactose, D M V Veghel, Ph.Eur. quality) was used as starting material, and polyethylene glycol (PEG) 3000 (Hoechst, Germany) was used as melting binder. Although the batches of the two materials were different from those used previously (Schaefer et al., 1992a,b,c), the physical properties were similar. The geometric mean particle size of the distribution by weight of the lactose determined by a Malvern 2601Lc laser diffraction particle sizer (Malvern Instruments, U K ) was found to be 22 #m. The mean size and the size distribution were not significantly different to those of the previous batch (Schaefer et al., 1992c). The melting point of the P E G 3000 estimated by the capillary method was 60-63°C, which was the same as that of the previous batch (Schaefer et al., 1992a). The melting range was further estimated by a Perkin Elmer DSC 7 differential scanning calorimeter (Perkin Elmer, USA). A sample of about 6 mg was sealed in a 50 #1 aluminium pan and scanned between room temperature and 120°C at a heating rate of 10°C per min. The melting range was found to be 50-65°C with a peak temperature of 60°C.
mm
~"
Fig. 1. Outline of Pellmix PL 1/8 high shear mixer.
mounted to the lid of the bowl. The volume of the bowl is about 8 litre without cone and about 6.7 litre with the cone mounted. The cone was used in all the present experiments. The impeller is a two-bladed impeller of stainless steel with changeable impeller blades. Curved impeller blades were used in the present experiments. Experiments with different impeller blade construction will be described in part V of these papers. The impeller speed is continuously adjustable within the range of 0 to 1500 rpm. The power consumption of the impeller m o t o r was measured by a power consumption meter. The mixer is not equipped with a chopper. The 50 litre Pellmix mixer was equipped with a removable chopper, but the effect of the chopper was found to be inappreciable (Schaefer et al., 1992a). The temperatures of the product and of the heating jacket were measured with thermoresistance probes. The probe measuring the temperature of the product was placed in the side wall of the bowl at 53 m m from the bottom. During the process the temperatures, the power consumption and the rotation speed of the impeller were recorded.
Methods
Equipment
Mixing procedure
A laboratory scale high shear mixer (Pellmix PL 1/8, Niro A/S, Denmark) was used for the experiments. The mixer (Fig. 1) is equipped with an electrically heated jacket, which can be heated to a m a x i m u m temperature of about 120°C. The inner wall of the bowl is coated with polytetrafluoroethylene (PTFE) in order to reduce adhesion of material to the bowl. The cylindrical bowl is equipped with a removable cone, i.e. a truncated cone-shaped ring of P T F E
The load of the mixer is expressed as the amount of lactose used unless otherwise stated. The load was either 600g, 800g or 1000g. The P E G 3000 was added in a solid state. The P E G concentration was 23% m / m of the amount of lactose in all the experiments. This binder concentration was the middle concentration level used in the previous experiments (Schaefer et al., 1992a). It gave rise to pellets of an appropriate size and size distribution in the 50 litre mixer.
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T. Schcefer et al. / Melt pelletization in a high shear mixer, I V
The lactose and the binder were dry mixed at an impeller speed of 1300 rpm in order to increase the temperature to the melting point of the PEG within a reasonably short time, i.e. about 7 min. The start of the massing time was defined as this point. Two minutes after the melting point was observed on the temperature curve (Schaefer et al., 1992a), the impeller speed was lowered to either 800, 1000 or 1200 rpm. The starting temperature of the heating jacket was kept at 50°C, except in a few preliminary experiments, which are mentioned below. The relative air humidity of the room was kept at approximately 46% in all the experiments. At the end of the process, the amount of agglomerates which flowed from the bowl when tilted was weighed and then spread out in thin layers on trays in order to cool at ambient temperature (Schaefer et al., 1992a). The adhesion to the bowl was estimated as the difference between the amount of materials placed in the bowl and the amount emptied.
Since the jacket of the present mixer is not a cooling jacket, the jacket temperature cannot be kept constant during the whole process but is heated by the product, when its temperature exceeds the jacket temperature. However, the increase in jacket temperature will be slightly delayed. Preliminary experiments were carried out at starting temperatures of the heating jacket of 40, 50, 65 and 80°C. Jacket temperatures of 65 and 80°C resulted in a marked adhesion of product to the wall of the mixer bowl, and a jacket temperature of 40°C resulted in a large amount of lumps in the product. At a jacket temperature of 50°C no lumps were seen during the start of the process, and practically no adhesion of material to the wall occurred. Consequently, the starting temperature of the jacket was kept constant at 50°C in the subsequent experiments.
Granule characterization
Impeller speed
The amount of lumps larger than 2 mm was estimated as the retained fraction after vibration of the cooled agglomerates on a Jel-Fix 50 vibration sieve (J. Engelsmann AG, Germany) for about 10 seconds, until the fraction finer than 2 mm had passed. The granule size distribution was estimated by sieve analysis of a sample of about 100 g drawn by scoping from the fraction finer than 2 mm, and dgw and Sg were calculated (Schaefer et al., 1992a). The intragranular porosity and the liquid saturation of the agglomerates were estimated as previously described (Schaefer et al., 1992a).
The effect of impeller speed on the mean granule size was significant at the 0.1% level (P = 0.999) at a mixer load of 1000 g (Fig. 2). It is seen that an increase in impeller speed gives rise to a larger granule size as previously found (Kinget and Kemel, 1985; Schaefer et al., 1990, 1992a). At a mixer load of 600 g the effect of impeller speed was found to be different, since an impeller speed of 800 rpm gave rise to a larger mean granule size than impeller speeds of 1000 and 1200 rpm. These findings
Results and discussion
Jacket temperature
Experimental design Effects of massing time, impeller speed and load of the mixer were examined by a series of 66 experiments. The impeller speed was varied at three levels (800, 1000 and 1200 rpm). The load of the mixer was also varied at three levels (600, 800 and 1000 g). Massing time was varied at 6, 9 and 12 min at all the nine combinations of impeller speed and mixer load. At the low level of impeller speed combined with mixer loads of 800 and 1000 g, further experiments were carried out at massing times of 17 and 22 rain. At impeller speeds of 1000 and 1200 rpm combined with a mixer load of 1000 g, further experiments were carried out at a massing time of 17 rain. The results shown in this paper are mean values of two experiments unless otherwise stated.
1000
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Massing time
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Fig. 2. Effect of impeller speed on the mean granule size during massing. Mixer load: 1000 g. Impeller speed: 800 rpm (O), 1000 rpm (A), 1200 rpm (D).
128
indicate that an impeller speed of 800 rpm combined with a low mixer load results in an uncontrolled agglomerate growth. At a mixer load of 800 g the effect of impeller speed was similar to the one seen in Fig. 2, but less significant (P = 0.99). Fluctuations in mean granule size were observed at 800 rpm indicating a slightly uncontrolled agglomerate growth. Similar fluctuations were seen in the amount of lumps. The effect of impeller speed on the granule size distribution (Sg) was found to be significant (P = 0.999) at a mixer load of 1000 g only. The highest impeller speed resulted in the narrowest size distribution in accordance with previous findings (Kinget and Kemel, 1985; Schaefer et al., 1990, 1992a). An analysis of variance of the results on the amount of lumps showed a significant interaction (P = 0.999) between impeller speed and massing time. At short massing times a higher impeller speed resulted in a smaller amount of lumps, because some lumps were crushed at the high speed. At prolonged massing a higher impeller speed gave rise to a larger amount of lumps due to a higher agglomerate growth rate at this speed. No clear effect of impeller speed on the intragranular porosity was found. This indicates that the densification of the agglomerates was nearly finished at the shortest massing time (6 min) used in the experiments. In accordance with previous findings (Schaefer et al., 1992a) the pellets were found to be more rounded and smoother at a higher impeller speed.
T. Schcefer et al. / Melt pelletization in a high shear mixer, I V
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Messing time ( m i n )
Fig. 3. Effect of mixer load on the mean granule size during massing. Impeller speed: 1000 rpm. Mixer load: 600 g (O), 800 g (A), 1000 g (0).
the swept volumes corresponding to impeller speeds of 800, 1000 and 1200 rpm and the energy input. The figure shows the results of each of two repeated experiments. Since the impeller speed is 1300 rpm until 2 min after the melting point, the figure shows the energy input between 2 and 12 min of massing. As can be seen, a larger swept volume results in an increased energy input, and the correlation seems to be linear at a constant mixer load. The energy input at the same swept volume is seen to be higher at a higher mixer
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Mixer load
300 -
The effect of mixer load on the mean granule size was found to be significant at the 0.1% level (P = 0.999). A decrease in mixer load resulted in a larger mean granule size at all levels of impeller speed. The effect of mixer load at 1000 rpm is shown in Fig. 3. At mixer loads of 600 and 800 g the massing time could not be longer than 12 min due to formation of lumps in the product. Agglomerate growth in high shear mixers is related to the energy input from the impeller during the process, and the swept volume of the impeller is assumed to be a measure of the energy input (Schaefer, 1988). In an attempt to explain the effect of mixer load on agglomerate growth, the energy input was estimated from the power consumption curves as the area between the curve and the base line corresponding to the power consumption measured at the actual impeller speed with no material in the bowl. Fig. 4 shows the correlation between the values of
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lOOOg (~).
129
T. Schaefer et al. / Melt pelletization in a high shear mixer, I V
Table 1 Effect of impeller speed and mixer load on the specificenergy input during massing after melting of the binder. Massing time: 12 min
go
800 Mixer load (g)
1000
o
~
Impeller speed (rpm) o / ~
1200
D/
80
Specific energy input (kJ/kg mass) E
600 800 1000
218 226 212
317 280 269
425 361 333
load, because a larger amount of material must be moved by the impeller. It has previously been mentioned that in practice the active part of the swept volume will be smaller than the theoretical value (Schaefer, 1988), because most of the material moves close to the wall of the bowl due to centrifugal forces. It is assumed that a larger part of the impeller blades will be in contact with the material if the mixer load is increased. It is likely, therefore, that the correlation between swept volume and energy input is independent of the mixer load, if the values of the active swept volumes could have been used instead of the theoretical ones. Since the highest energy input is seen at the mixer load which gives rise to the smallest granule size, Fig. 4 does not explain the effect of mixer load on agglomerate growth seen in Fig. 3. Table 1 shows the specific energy input during the whole wet massing phase, i.e. the energy input after the melting point was reached. The values of energy input are weight specific energy inputs obtained by dividing the energy input by the total mass of lactose and PEG. A significantly higher specific energy input is seen at decreasing mixer load at impeller speeds of 1000 and 1200 rpm. This might explain why the largest granule size is seen at the lowest mixer load in Fig. 3. However, differences in specific energy input cannot explain the effect of mixer load on granule size at 800 rpm, where other factors might contribute. This will be discussed below. It was shown in the 50 litre Pellmix mixer that the agglomerate growth during melt pelletization was reflected in the power consumption curve (Schaefer et al., 1992b). In the present mixer a good agreement between weight specific power consumption and agglomerate growth was found at an impeller speed of 1200 rpm. This indicates that the power consumption signal might be used for process control purposes in the small Pellmix mixer too. At impeller speeds of 800 and 1000 rpm, however, it is difficult to use the power consumption curve for control of agglomerate
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i
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k
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5
Massing
t 10
S_t time(rain
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I
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)
Fig. 5. Effect of mixer load on the product temperature during massing. Impeller speed: 1000rpm. Mixer load: 600g (O), 800g (A), 1000 g (El). growth, since the increase in power consumption was found to be slight and occurred only during the last few minutes of massing. Fig. 5 shows the effect of mixer load on the increase in product temperature during massing at 1000 rpm. It was to be expected that the highest specific energy input would result in the highest temperature, since the energy is converted into heat of friction. However, the lowest temperature is seen at a mixer load of 600 g. The reason might be that the larger specific energy input is counteracted by an increased loss of heat at lower mixer load. A similar effect of mixer load on product temperature was found at impeller speeds of 800 and 1200 rpm. The different energy input at different mixer loads was not reflected in the densification of the agglomerates, since no significant differences between the intragranular porosities were observed at the longest massing times. These final porosities were all found to be 4 5%, corresponding to liquid saturations of 95-100%. The effect of the mixer load on the granule size distribution (Sg) was found to be significant at the 1% level (P = 0.99). The lowest mixer load resulted in the narrowest size distribution, especially during the start of the wet massing phase (Fig. 6). This effect might be ascribed to the higher specific energy input at lower mixer load. The effect was unclear at an impeller speed of 1200 rpm, where large fluctuations in Sg were seen at mixer loads of 600 and 800 g. The Sg values obtained at the longest massing times were normally found to be within the range 1.3 1.4 independent of mixer load. The adhesion of material to the mixer expressed in g of material was not significantly affected by either
130
T. Schcefer et al. / Melt pelletization in a high shear mixer, I V Table 2 Effect of mixer load on the reproducibility of the process expressed by the standard deviation on mean granule size, geometric standard deviation and a m o u n t of lumps
1.6
Standard deviation >
1.4 "o
1.2-
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10
I
Mixer load (g)
dgw (#m)
Sg
lumps > 2mm (%)
600 800 1000
68 77 20
0.09 0.03 0.03
5.5 4.8 0.8
I
15
Massing time ( m i n )
Fig. 6. Effect of mixer load on the geometric standard deviation during massing. Impeller speed: 1000 rpm. Mixer load: 600 g (O), 800 g (A), 1000 g (El]).
mixer load, massing time or impeller speed. This indicates that most of the adhesion is due to adhesion to the lid during dry mixing. Normally the loss of material due to adhesion was about 50 g. The amount of lumps in the product is significantly affected by the mixer load (P = 0.999). Fig. 7 shows the effect of mixer load on the amount of lumps at an impeller speed of 1000 rpm. The amount of lumps is markedly larger at a mixer load of 600 g. The same effect of mixer load was seen at 800 rpm and 1200 rpm, at which the amount of lumps at the low mixer load was at the same high level. The smallest amount of lumps was generally obtained at a mixer load of 1000 g. Since the lumps occur a few minutes after melting at a load of 600 g, they are not caused by a controlled agglomerate growth. It is assumed that the movement
of the mass becomes nonhomogeneous, if the load of the mixer becomes too low, and that this might give rise to formation of lumps by an uncontrolled agglomerate growth. At the higher loads the movement of the mass is more homogeneous, and therefore a marked increase in the amount of lumps is not seen until later in the process, where the agglomerates are close to being overwetted. The effect of mixer load on the reproducibility of the process is shown in Table 2. The standard deviations are estimated by analysis of variance carried out at each mixer load on all the results obtained with the actual load. The table shows that a load of 1000 g is favourable in order to obtain a reproducible pelletization process. It was generally observed that the pellets produced at a mixer load of 1000 g were more rounded and smoother than the pellets produced at the lower mixer loads. This confirms the above-mentioned assumption that the movement of the mass is more homogeneous at a load of 1000 g.
Massing time 25
E E
20
~.o
O4 ^
~
o
0 /
15
zx
E v
10
D
5
0
5
10
15
Massing time ( m i n )
Fig. 7. Effect of mixer load on the a m o u n t of lumps during massing. Impeller speed: 1000 rpm. Mixer load: 600 g (O), 800 g (A), 1000 g (Eli).
Examples of the effect of massing time on the properties of the agglomerates are shown in the above Figures. An increased massing time gave rise to a significantly larger mean granule size, to a significantly narrower size distribution and to a significantly higher product temperature. These effects are in accordance with previous results (Schaefer et al., 1990, 1992a). The effect of massing time on the amount of lumps is unclear, because the amount of lumps is determined by a balance between crushing and growth mechanisms. Which of these mechanisms will be the dominatant one depends on the actual combination of mixer load and impeller speed. In accordance with previous findings (Schaefer et al., 1992b) an increased massing time gave rise to agglomerates which were rounder and smoother. With all the nine combinations of mixer load and
131
T. Schaefer et al. / Melt pelletization in a high shear mixer, I V
impeller speed investigated, the longest massing time resulted in large agglomerates o f a n a r r o w size distribution, i.e. pellets. However, differences were observed in roundness and smoothness o f the pellets as mentioned above.
in the power c o n s u m p t i o n signal. At a speed below 1000 rpm the agglomerate growth might become less controllable, and the massing time has to be very long to obtain pellets.
Acknowledgements Conclusions The small laboratory scale high shear mixer was f o u n d to be suitable for melt pelletization with P E G , since it is able to p r o d u c e r o u n d e d pellets o f a n a r r o w size distribution at massing times between 10 and 20 min. However, the process variables are very critical. The jacket o f the mixer bowl has to be heated in order to avoid an extremely long processing time. The most suitable choice o f jacket temperature during dry mixing seems to be a temperature slightly below the melting point o f the binder. The m o v e m e n t o f the mass in the bowl has to be uniform and controlled in order to produce pellets, and the mixer load, therefore, is very critical. If the load is too low, the a m o u n t o f lumps might be extremely high, the shape of the final pellets might be irregular and the reproducibility might be poor. Since the m o v e m e n t o f the mass depends on its cohesiveness, the o p t i m u m mixer load might depend on the physical properties o f the starting materials. In the present mixer the process is negatively affected at a mixer load below approx. 1000 g of lactose 450 mesh. A high power input is a prerequisite for making pellets. It is desirable, therefore, to measure the power c o n s u m p t i o n during the process. The power input is primarily controlled by the impeller speed. The starting materials might affect the o p t i m u m impeller speed, too. W h e n lactose has to be pelletized with P E G , an impeller speed o f a b o u t 1200 rpm seems to be favourable, since this speed results in rounded pellets, and since the agglomerate growth is reflected
The Danish Medical Research Council is acknowledged for financial support to the work. Niro A t o m izer A/S, D e n m a r k , is acknowledged for the loan o f the Pellmix P L 1/8 high shear mixer.
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 Kernel, 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., 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.