particle agglomeration in high shear mixers

E L S E V I E R Powder Technology 88 (1996) 197-202

POWDER TECHNOLOGY

Particle agglomeration in high shear mixers

Henning G. Kristensen Department of Pharmaceutics, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark

Received 28 October 1995; revised 6 November 1995; accepted 19 February 1996

Abstract

Agglomeration mechanisms and liquid requirements in the batch granulation of fine powders in high shear mixers are discussed. Many experiments have revealed a close correlation between the degree of liquid saturation of the agglomerates and the growth rate. The saturation degree is determined by the amount of binder liquid and the particle packing density. Its effects on the agglomerate growth can be applied in the analysis of, for example, effects of mixer scale and processing conditions on liquid requirements and the final granule size. Studies of the growth kinetics show that agglomeration of fine powders may result into uniformly sized granules of spherical shape. This can be applied in the development of modified release products.

Keywords: Agglomeration; Granulation

1. Introduct ion

In the pharmaceutical industry, high shear mixers such as the Diosna, L6dige, Fielder, Zanchetta and Moritz mixers are widely used for wet granulation purposes. Compared to fluidized bed granulators and conventional mixer granulators, wet granulation in high shear mixers is a robust process that can handle even very cohesive powders. The processing times are short and space requirements for installation are low. Industrial experiences have, however, shown that the liquid requirements are very sensitive to processing conditions and to the inevitable variations in raw material properties, in particular to the particle size distribution. Because of the inten- sive agitation, high shear mixers produce very dense granules. This may cause problems in achieving the desired rate of drug release from tablets and other dosage forms containing drug substances having a low water solubility.

Batch granulation in high shear mixers has been subject to research at the Copenhagen School of Pharmacy for more than ten years. The research has focused upon wet granulation using polymeric binder liquids and meltable binders such as polyethylene glycols (PEG) for the preparation of granula- tions intended for tablet compression as well as pelletized products, that is, uniformly sized granules of spherical or almost spherical shape, intended for the preparation of modified release products. This paper addresses our findings on the agglomeration mechanisms and liquid requirements and some aspects of the scaling-up from laboratory to production plant. More comprehensive reviews of pharmaceutical wet

0032-5910/96/$15.00 © 1996 Elsevier Science S.A. All rights reserved PIIS0032-5910(96)03123-3

granulation have been presented previously by Kristensen and Schaefer [ 1,2].

2. Agglomerate formation and growth

Fig. 1 shows the granule growth in the liquid addition phase of the wet granulation of a cohesive powder being

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Fig. 1. Granulation of calcium hydrogen phosphate (mean particle size about 10 t.tm) with a 10% m/m aqueous solution of PVP/PVA copolymer in a Fielder PMAT 25 high shear mixer. Addition of binder liquid by atomization, chopper speed 3000 rpm; I1, &: impeller speed 500 rpm; I-q, A: impeller speed 250 rpm; I1, [~: liquid flow rate 100 g/min ; &, A: liquid flow rate 300 g/min. From Holm et al. [3].

1 9 8 H.G. Kristensen / Powder Technology 88 (1996) 197-202

insoluble in the binder liquid [ 3 ]. The graph demonstrates that there is a very narrow margin between the liquid contents required to see growth and the contents giving rise to rapid, uncontrolled growth, that is, overwetting or overmassing. The granule growth rate is dependent on the impeller rotation speed or intensity of agitation, and the liquid addition rate which is interrelated with the processing time. Examination by sieving of samples taken during the process revealed that agglomeration by nucleation of primary particles proceeded even at low contents of the binder liquid where there is no sign of granule growth in terms of the mean granule size. All primary particles were nucleated at the stage where the graph shows significant growth. Growth by coalescence between agglomerates was dominant in the stage with rapid growth. This can easily be revealed by examining the agglomerates under a microscope showing all the stages of the coalescence from the agglomerates just sticking together to the stage where they are completely moulded into one, rounded agglomerate.

Fig. 1 demonstrates the characteristic features of the agglomeration of insoluble, cohesive powders in high shear mixers. The growth rate is very sensitive to the amount of liquid phase and to the processing conditions, in particular the impeller rotation speed and processing time. If the liquid addition is stopped in the stage with rapid growth, the agglomerate growth continues in the same manner as shown in the graph. The growth during wet massing is closely related to the consolidation of the agglomerates for the reasons discussed later. It is a general experience that the process is less sensitive to processing conditions when granulating materials consist of bigger particles or have a uniform particle size distribution. The agglomerates of such materials consolidate easily to their final packing density early in the process.

The growth shown in Fig. 1 can be interpreted in terms of (i) nucleation of primary particles which proceeds when there is sufficient free surface liquid to establish liquid bondings; and (ii) coalescence between agglomerates which proceeds when the agglomerates contain sufficient liquid to render them plastically deformable [4,5].

Fig. 2 shows the correlation between the degree of liquid saturation of the agglomerates and the mean granule size obtained in the wet massing phase of granulating calcium hydrogen phosphate using various binder liquids and using low, as well as high, impeller rotation speeds [ 6]. The liquid saturation expresses the volume of liquid relative to the volume of voids and pores between particles in the agglomerate [7]. In the graph, the saturation exceeds 100% due to a systematic error in the determination of the granule density by a mercury immersion method. In the measurement, the pycnometer with the test sample is evaporated to a pressure of about 1.3 kPa. The pycnometer is then filled with mercury and the pressure is increased to a fixed value, 98.4 kPa (740 mm Hg), at which the apparent granule density is measured. The procedure ensures complete wetting of the granules, but mercury will to some extent penetrate into the surface of the granules resulting in an underestimate of the granule volume

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Fig. 2. Effect of liquid saturation degree in granulating calcium hydrogen phosphate (mean particle size about 10 ~m) with aqueous binder solutions in Fielder PMAT 25 VG high shear mixer. 0: PVP K90 (3, 5, 8% m/m); O: PVP/PVA (10, 20, 30% m/m); []: HPMC E5 (3, 5, 8% m/m); rq: HPMC El5 (2, 3.5, 4.5% m/m). From Ritala et al. [6].

and, accordingly, an overestimate of the saturation degree. It has recently been shown that the saturation values given in the graph probably are overestimated by 10-15% [8].

There is apparently a good correlation between the liquid saturation degree and the mean granule size. Fig. 2 demonstrates that the agglomeration process may be very sensitive to the processing conditions. A slight change of the packing density corresponding to a change of the granule porosity of 2-3% is easily produced in the granulation of a cohesive feed by changing the processing conditions. This change of the granule porosity gives rise to a change in the saturation degree of 10% which may have a profound effect upon the mean granule size. Batch-to-batch variations of the raw material properties, in particular the particle size distribution, may accordingly give rise to variations in the growth rate and/or the liquid requirements because of the interactions between starting material properties, impeller rotation speed, processing time, amount of binder liquid and consolidation of the growing agglomerates.

Correlations similar to Fig. 2 have been found in experiments with many different materials. In experiments with lactose that is partially soluble in the binder liquid, the apparent saturation degree required to see significant growth is in the range of 30 to 60% [7]. If the liquid phase is assumed to be saturated with lactose, the estimated values of the saturation degree increase slightly. Significant growth occurs, however, well below 100% saturation. Recent experiments with PEGs that do not dissolve the lactose have shown that rapid

H. G. Kristensen / Powder Technology 88 (1996) 197-202 199

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U < U O : LOSS OF KINETIC ENERGY Fig. 3. Collision of two particles resulting in coalescence or rebound.

growth by coalescence between agglomerates requires liquid saturations of 80 to 90% [9].

Granule formation and growth are caused by collision between particles as outlined in Fig. 3. The collision may result in rebound or coalescence depending on whether a sufficient bonding strength is established by the formation of pendular liquid bondings. The required bonding strength is dependent on the mass and relative velocity of the two particles and whether the collision is purely elastic or elastic/ plastic. The smaller the particles, the higher the probability for a successful coalescence.

In the nucleation of primary particles, it is supposed that the required bonding strength is supplied by adhesion forces caused by the viscosity of free surface liquid as described by Ennis et al. [ 10]. It is well established that the liquid viscosity has a profound effect upon the adhesion forces under dynamic conditions, and that the dynamic strength of a pendular liquid bonding may exceed its static strength by many times [ 11 ]. It is difficult, however, to assess the practical implications of this effect because the pendular liquid bondings are likely to be ruptured at forces lower than the theoretical strength of the bonding. At least, viscosity is not important in agglomeration with the aqueous binder solutions normally used in pharmaceutical practice.

The bonding forces required to achieve coalescence between agglomerates consisting of many primary particles must be substantially higher than the forces needed for nucleation of the primary particles. It is very unlikely that the viscous component of the pendular liquid bridge alone can overcome the separating forces caused by the relative velocity and the masses of the two agglomerates and, thus, assimilate the kinetic energy of the colliding agglomerates. Successful coalescence requires that at least a part of the kinetic energy is assimilated by plastic deformation of the agglomerate sur- faces. When the area of contact is increased, the overall bonding strength is also increased. This means that growth by coalescence of agglomerates is supposed to proceed when

the agglomerates become highly deformable due to effects of the binder liquid [4].

The deformability of an agglomerate depends on its static compressive strength due to particle interactions and the mobile liquid bondings, see the well-known models by Rumpf and co-workers, and the ability of the agglomerate to be strained without being crushed. Studies on the compressive strength of moist samples of lactose and calcium hydrogen phosphate [5 ] have shown that at low liquid saturations the samples behave as brittle materials and have a compressive strength which is higher than the theoretical strength due to mobile liquid bondings. This is probably due to effects of particle interactions in the compressive testing. The compressive strength diminishes as the saturation degree is increased. At a certain range of saturation degree, which is dependent on the characteristics of the particle system and the particle packing density, the agglomerate strength becomes controlled entirely by mobile liquid bondings and the agglomerate becomes highly deformable.

The coalescence mechanism depicted in Fig. 3 is size dependent. According to the analysis by Ouchiyama and Tanaka [ 12] of the coalescence mechanism, there must be an upper size limit 3 beyond which coalescence is impossible due to the bending moment applied to the larger particles. It is reasonable to assume that the larger 6, the greater the probability for a successful coalescence. The following equation which was derived from the work by Ouchiyama and Tanaka presents, therefore, the physical prerequisites to growth by coalescence between agglomerates, Kristensen et al. [13]:

a 2/a =A "(A1/D)3 (1) O" c

a and A are constants for the given system. D is the diameter of the agglomerate, A I/D the normalized strain of the agglomerate caused by a stress corresponding to the compressive strength oc of the agglomerate. The numerator expresses the strain produced by the impact. The more deformable the agglomerate, the higher strain and, hence, the greater limiting agglomerate size ~ and, consequently, the higher probability for a successful coalescence, The equation demonstrate that the effect on the growth rate of an improved strain ability will overrule the counteracting effect of the strength o'c because the normalized strain in the equation is raised to its third power.

The main implication of the equation is that the rate of growth by coalescence between agglomerates is controlled primarily by the saturation degree of the agglomerate because it is the liquid saturation which controls the strain behaviour. This agrees well with the correlation presented in Fig. 2. In any stage of the agglomeration process, the liquid saturation is determined primarily by the added amount of liquid and the particle packing density in the agglomerates. The saturation degree is further influenced by increased rate of evaporation of liquid caused by the increasing temperature of the

200 H.G. Kristensen / Powder Technology 88 (1996) 197-202

agitated mass and by interactions (dissolution, absorption) between liquid and solids.

Wet granulation in high shear mixers is characterized by a significant increase of the temperature of the agitated mass, often more than 30 °C. It is a consequence of the dissipation of kinetic energy turning out into heating of the mass as outlined in Fig. 3. It is for the same reason there is a close correlation between the power consumption profile, the deformability of the agglomerates and the growth curve as demonstrated by Holm et al. [ 14].

3. Growth kinetics

Fig. 4 shows self-preserving granule size distributions obtained by wet granulation of a cohesive powder in a high shear mixer [ 15]. The size distributions fall into two classes depending on the wet massing time and, accordingly, the liquid saturation degree. These and other experiments have revealed that the granule size distributions are self-preserving and can be approximated to log-normal size distributions. In so far as the dominating growth mechanism is nucleation of primary particles, the growth can be described by random coalescence kinetics [4]. The resulting size distributions are relatively wide and adhere well to log-normal distributions as has been demonstrated in many experiments with fluidized bed granulation, for example Schaefer and Woerts [ 16], and also in experiments with high shear mixers [17]. When growth by coalescence between agglomerates becomes dominant effected by the increasing liquid saturation, the growth proceeds by the kinetics of non-random coalescence [4] where the probability for coalescence is size dependent as

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DIMENSIONLESS GRANULE SIZE Fig. 4. Self-preserving size distributions obtained by wet granulation of calcium hydrogen phosphate (mean particle size about 10/zm) with a 10% m/m aqueous solution of hydrolysed gelatine in a Fielder PMAT 25 VG mixer. ©: wet massing 0 and 3 min.; Q: wet massing 6 and 8 rain. Solid lines are log--normal distributions fitting the data; sg = 2.01 and 1.48. Based on data from Holm et al. [ 15].

described previously. Since smaller agglomerates are more susceptible to growth by coalescence than the larger agglomerates, the size distribution becomes more narrow than the distribution obtained by the nucleation mechanism.

The investigations on growth kinetics have been the basis for development of agglomeration processes intended for preparation of narrowly sized granules. Holm [18] has shown that a very high energy input produces uniformly sized agglomerates of almost spherical shape, that is a pelletized product, provided that the liquid distribution in the moistened mass can be kept very uniform and the moisture content controlled within tight limits. A major problem is that a high energy input is associated with significant densification of the agglomerates and, consequently, an increasing liquid saturation. In order to control the process and in particular to avoid uncontrolled rapid growth, the excessive surface moisture has to be removed. This can be achieved by heating and/ or ventilation of drying air during the wet massing phase as demonstrated by Holm et al. [ 15] or, presumably, by applying vacuum techniques. It is a prerequisite to the process that the mixer is equipped with a strong motor and means can be taken to avoid deposition of moist mass onto the walls of the mixer bowl [ 18,19].

4. Liquid requirements and scaling-up

This discussion of the agglomeration mechanisms shows that the amount of binder liquid required to run a wet granulation process is dependent on the packing characteristics of the feed and, in particular, whether the particle packing density changes during the process and, thereby, changes the saturation degree. The particles of a free flowing feed consolidate to the final packing density early in the process [13,20]. This means that the liquid requirements are not sensitive to changes in the processing conditions, nor to a change of the type of mixer-granulator. In the pharmaceutical industry, the feed materials are often moderate to strongly cohesive. Granulation in high shear mixers of such feed materials demonstrates the features shown in Fig. 1. It is not possible to predict the proper amount of binder liquid for which reason the industry has to apply instrumentations such as power consumption meters capable to detect the various stages of the process and its end point.

Fig. 5 shows the results of a comparison between two different laboratory scale mixers, a Fielder PMAT 25 VG and a L6dige M5G [21]. Calcium hydrogen phosphate was gran- ulated with an aqueous PVP/PVA binder solution. The graph on the left-hand side shows that the moisture content required to achieve a certain mean granule size is strongly dependent on the type of mixer as well as its operation. The reason for this becomes clear when it is compared to the graph on the right-hand side showing the consolidation of the agglomerates. The more efficient the mixer is in consolidating the granules, the less liquid is required to see growth. If the effect of the liquid saturation degree on the mean granule size is

H.G. Kristensen/Powder Technology 88 (1996) 197-202 201

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plotted, the results obtained with the two mixer granulators coincide in a graph similar to Fig. 2.

The effect of scaling-up from laboratory to production scale mixers may be interpreted on the same basis. Schaefer et al. [ 17] compared the granulation of a cohesive feed in high shear mixers available in the Danish pharmaceutical industry. They found that the laboratory scale mixers were more efficient at densifying the agglomerates than the larger scale mixers. At the same time, the loss of moisture due to evaporation was more pronounced in the smaller mixers because of a higher mass temperature produced by the agitation. It meant that the liquid requirements and the resulting granule sizes were not very sensitive to the scale of the mixer- granulator in so far as a particular type of mixer was considered.

The intensity of agitation can be expressed in terms of the relative swept volume, that is, the vertical volume swept out by the impeller blades per second divided by the volume of the mixer bowl. Comparisons between different types of high speed mixers demonstrate that there may be a significant fall in relative swept volume when scaling-up from laboratory to production scale mixers [22]. In general, this means that the scaling-up results into a less consolidated product which can have implications to the liquid requirements as well as the product performance.

The effect of polymeric binders upon the liquid requirements has also been interpreted on this basis of the saturation degree. Ritala et al. [23] showed that PVP gives rise to a more pronounced granule growth than do other polymeric binders. The effect of PVP was attributed to the surface tension of the aqueous solution being close to 70 mN/m, while aqueous solutions of cellulose derivatives have surface ten- sions of less than 50 mN/m. The high surface tension of the PVP solutions gives rise to a more pronounced consolidation of the agglomerates and, hence, a higher liquid saturation degree which explains the increased granule size, see Fig. 2.

5. Agglomeration with meltable binders

Melt granulation, or thermoplastic granulation, is an agglomeration process applying a binder material which is solid at room temperature and softens or melts at slightly elevated temperatures, usually above 50 to 60 °C. The action of the liquified binder is similar to the action of the binder liquids normally used in wet granulation processes. The binders used for thermoplastic granulation are usually PEG. Hydrophobic mcltablc substances like natural and synthetic waxes, hydrocarbons etc. may also be applied in order to achicve prolonged rclease products [24].

Schaefer et al. [9] have shown that the granule growth proceeds by the same mechanisms as by wet granulation and that the correlation between saturation degree and mean granule size holds. Experiments with calcium hydrogen phosphate showed rapid growth by coalescence at saturations slightly below 100% as is seen in wet granulation. In the case of lactose, a significant difference was observed. Melt granulation required liquid saturations of about 90%, while the wet granulation with aqueous bindcr liquids proceeds at saturations between 30 and 60%. There is no doubt that this difference is due to dissolution of lactose in the aqueous binder liquid which renders the moistened agglomerate highly deformable at the low saturation degrees.

There are, however, differences between melt and wet granulation. PEG 3000 gives rise to a more pronounced granule growth than does PEG 6000 although the latter is the more viscous binder [ 25 ]. Compared with other meltable binders, the viscosity of the molten PEGs is very high and, in case of PEG 6000, possibly too high. There is clearly a need for investigations of the effects of liquid viscosity upon agglomeration mechanisms and growth kinetics.

Experiments with different types of lactose showed that the binder requirements to achieve growth were very different comparing a-lactose monohydrate and anhydrous lactose [26]. It is supposed that melt granulation is dependent on binder-substrate interactions to a higher degree than wet

202 H.G. Kristensen / Powder Technology 88 (1996) 197-202

granulation. It is also possible that the elevated product temperatures needed to melt granulate have an effect on the growth process.

References

[ 1 ] H.G. Kristensen and T. Schaefer, Drug Dev. Ind. Pharm., 13 (1987) 803.

[2] H.G. Kristensen andT. Schaefer, inJ. Swarbrick and B. Boylan (eds.), Encyclopedia of Pharmaceutical Technology, Marcel Dekker, New York, Vol. 7, 1992, pp. 121-160.

[3] P. Holm, O. Jungersen, T. Schaefer and H.G Kristensen, Pharm. Ind., 45 (1983) 806.

[4] P.C. Kapur, Adv. Chem. Eng., 10 (1978) 55. [5] H.G. Kristensen, P. Holm and T. Schaefer, Powder Technol., 44

(1985) 227. [6] M. Ritala, P. Holm, T. Schaefer and H.G. Kristensen, Drug Dev. Ind.

Pharm., 14 (1988) 1041. [ 7] H.G. Kristensen, P. Holm, A. Jaegerskou and T. Schaefer, Pharm. Ind.,

46 (1984) 763. [8] M.O. Elema and H.G. Kristensen, Acta Pharm. Nord., 4 (1992) 233. [9] T. Schaefer, P. Holm and H.G. Kristensen, Drug Dev. Ind. Pharm., 16

(1990) 1249. [ 10] B.J. Ennis, G. Tardos and R. Pfeffer, Powder Technol., 65 (1991)

257. [11 ] F. Bowden and P.D. Tabor, The Friction and Lubrication of Solids.

Part I, Oxford University Press, Oxford, 1964, pp. 299-306,

[ 12] N. Ouchiyama and T. Tanaka, Ind. Eng. Chem. Process Des. Dev., 21 (1982) 35.

[13] H.G. Kristensen, P. Holm and T. Schaefer, Powder Technol., 44 (1985) 239.

[ 14] P. Holm, T. Schaefer and H.G. Kristensen, Powder Technol., 43 (1985) 213, 225.

[ 15] P. Holm, T. Schaefer and H.G. Kristensen, STP Pharma Sciences, 3 (1993) 286.

[ 16] T. Schaefer and O. Woerts, Arch. Pharm. Chem, Sci. Edn., 6 (1978) 1.

[ 17] T. Schaefer, H.H. Bak, A. Jaegerskou, A. Kristensen, J.R. Svensson, P. Holm and H.G. Kristensen, Pharm. Ind., 48 (1986) 1083; Pharm. Ind., 49 (1987) 297.

[18] P. Holm, Drug Dev. Pharm. Ind., 13 (1987) 1675. [19] S. Danielsen, P. Holm, T. Schaefer and H.G. Kristensen, (Niro

Atomizer Ltd.), US Patent No. 5 030 400 ( 1991 ) [20] P. Holm, O. Jungersen, T. Schaefer and H.G. Kristensen, Pharm. Ind.,

46 (1984) 97. [21] T. Schaefer, P. Holm and H.G. Kristensen, Arch. Pharm. Chem., Sci.

Edn., 14 (1986) 1. [22] T. Schaefer, Acta Pharm. Suec., 25 (1988) 205. [23] M. Ritala, O. Jungersen, O. Holm, P. Schaefer and H.G. Kristensen,

Drug Dev. lnd Pharm., 12 (1986) 1685. [24] L.J. Thomsen, T. Schaefer and H.G. Kristensen, Drug Dev. Ind.

Pharm., 20 (1994) 1179. [25] T. Schaefer, P. Holm and H.G. Kristensen, Acta Pharm. Nord., 4

(1992) 141. [26] T. Schaefer, P. Holm and H.G. Kristensen, Acta Pharm. Nord., 4

(1992) 245.

particle agglomeration in high shear mixers

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