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Ž .Powder Technology 117 2001 68–82www.elsevier.comrlocaterpowtec

Growth mechanisms in melt agglomeration in high shear mixers

Torben Schæfer)

Department of Pharmaceutics, The Royal Danish School of Pharmacy, 2 UniÕersitetsparken, DK-2100 Copenhagen, Denmark

Received 10 July 2000; received in revised form 2 November 2000; accepted 15 December 2000

Abstract

This paper presents a review of factors affecting the agglomerate formation and growth mechanisms in melt agglomeration in highshear mixers. The agglomerate formation occurs either by distribution or immersion or by a combination of both mechanisms.Distribution is promoted by a low binder viscosity, by a high impeller speed, and by a small binder particle size. Effects of the liquidsaturation of the agglomerates, impeller speed, particle properties, binder viscosity, and electrostatic charging on the subsequentagglomerate growth are discussed, and experimental results are presented. The agglomerate growth becomes controlled by the balancebetween the agglomerate strength and the shearing forces. If the agglomerate strength is sufficiently high to resist the shearing forces ofthe rotating impeller, the dominant agglomerate growth mechanism will be coalescence. The shearing forces will give rise to breakage ifthe agglomerate strength is too low, and then agglomerate growth will occur by a simultaneous buildup and breakdown of agglomerates,possibly combined with growth by layering of fragments upon larger agglomerates. Provided that the liquid saturation is sufficiently high,a higher agglomerate strength is primarily caused by a higher binder viscosity, a smaller particle size, an irregular particle shape, and bydensification of the agglomerates. q 2001 Elsevier Science B.V. All rights reserved.

Keywords: Agglomerate growth mechanisms; Melt agglomeration; High shear mixers; Binder viscosity; Impeller speed

1. Introduction

Melt agglomeration is a wet agglomeration process bywhich agglomeration is obtained through the addition ofeither a molten binder liquid or a solid binder, which meltsduring the process. The product temperature has to be keptat a temperature above the melting point of the binder orwithin the melting range of the binder by external heatingof the equipment andror by a development of heat causedby friction. The agglomerates are formed by an agitation ofthe mixture, and a cooling to ambient temperature resultsin dry agglomerates due to solidification of the binder.

A binder suitable for melt agglomeration is a materialhaving a melting point typically within the range of 50–1008C. A lower melting point might cause a risk ofmelting or softening of the binder during handling andstorage of the agglomerates, whereas a higher meltingpoint might cause stability problems in case of melt ag-glomeration of heat sensitive materials, e.g. many pharma-ceuticals. Polyethylene glycols, fatty acids, fatty alcohols,

) Tel.: q45-35-30-6474; fax: q45-35-30-6030.Ž .E-mail address: [email protected] T. Schæfer .

waxes, and glycerides are examples of meltable bindersthat are applied for melt agglomeration of pharmaceuticals.

Melt agglomeration is advantageous because of thesimplicity of the process. When compared with a conven-tional wet agglomeration process, the drying step of theprocess is eliminated, and if the meltable binder is addedin a solid state, the liquid addition step is also eliminated.Further, melt agglomeration might be favourable as analternative to the use of toxic solvents for agglomeration ofwater-sensitive materials. Melt agglomeration has beenshown to be a simple way of producing pharmaceutical

w xdosage forms with prolonged release properties 1–3 sincea meltable binder that is insoluble in water will form aninsoluble matrix, from which the release rate of the drugsubstance can be controlled by varying the composition ofthe binder phase. Melt agglomeration might further beapplied in the glass industry and in fertilizer productionw x4 .

The term melt granulation is used when the processresults in agglomerates of a rather wide size distribution,typically within the range of about 0.1–2.0 mm. If thefinal agglomerates are spherical and of a narrow sizedistribution, typically within the size range of 0.5–2.0 mm,the process is called melt pelletization process, and the

0032-5910r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved.Ž .PII: S0032-5910 01 00315-1

( )T. SchæferrPowder Technology 117 2001 68–82 69

agglomerates are called pellets. Since the size, the sizedistribution, and the shape of the agglomerates normallywill change gradually during an agglomeration process, itwill not be possible to distinguish clearly between a granu-lation and a pelletization process. Thus, a melt pelletiza-tion process might be defined as a melt agglomerationprocess that is controlled in order to obtain pellets.

Melt agglomeration has been carried out in a coatingw x w x w xpan 5 , drum granulator 4,6 , blender 7,8 , and a small-

w xscale centrifugal rotating mixer 9 . Although a fluidizedbed will be very suitable for controlling the temperature,the lack of shearing forces in the process might explainwhy this method has gained no widespread application formelt agglomeration. On the other hand, the high shearingforces caused by the impeller rotation in a high shearmixer will make this equipment especially suitable formelt agglomeration. This is because the high shearingforces make it easier to obtain a uniform distribution of themolten binder and might cause so much heat of friction

w xthat an external heating of the mixer is unnecessary 10 .Contrary to other melt agglomeration methods, high shearmixers have been shown to be applicable for melt pelleti-

w xzation, e.g. Refs. 1,10 , and this is also supposed to be dueto the higher shearing forces.

The interpretation of the results of many aqueous wetagglomeration experiments is complicated by the fact thatwater evaporates during the process. Consequently, themelt agglomeration process is particularly suitable forfundamental studies of the mechanisms of agglomerateformation and growth in wet agglomeration, because noevaporation of binder liquid occurs. The aim of this paperis to give a review of factors affecting the agglomerategrowth mechanisms in melt agglomeration in high shearmixers based upon the work carried out in the laboratoryof the author.

2. Agglomerate formation

The nucleation phase of a wet agglomeration process isŽ .the initial phase where small agglomerates nuclei of a

loose structure are formed because of a formation of liquidbridges between the primary particles. Fig. 1 shows thatagglomerates can be formed by two different mechanisms.By the distribution mechanism, a distribution of the binderliquid on the surface of the primary particles will occur,and nuclei become formed by a coalescence between thewetted particles. By the immersion mechanism, nuclei areformed by immersion of primary particles being capturedin the surface of a droplet of binder liquid. Which of thesemechanisms will be the dominant one will depend on theratio between the size of the solid particles and the droplets.Distribution will be the dominant mechanism when thedroplets are smaller than the solid particles or of a similarsize, whereas immersion will dominate when the dropletsare larger than the solid particles.

The initial droplet size might be controlled by an atom-ization of the binder liquid or by a pouring procedure.When melt agglomeration occurs by an addition of a solidbinder that melts during the process, the initial droplet sizewill depend on the particle size of the solid binder. Nor-mally, the droplet size becomes reduced by comminutionin the initial stage of the process if shearing forces areactive. In a high shear mixer, therefore, the distributionmechanism will be the typical mechanism of agglomerateformation. In a conventional fluidized bed, however, theagglomerate formation has been shown to be controlled by

w xthe droplet size of the binder liquid 12–14 and conse-quently by the immersion mechanism.

By melt agglomeration in a high shear mixer, thedistribution mechanism is promoted by a small particlesize of the solid binder, by a low binder viscosity, and by ahigh impeller rotation speed. The effect of binder viscosityon agglomerate formation in an 8-l high shear mixer isillustrated in Table 1. The table shows the effects of

Ž .polyethylene glycols PEGs with different average molec-ular mass on the mean granule size expressed as the

Ž .geometric mass mean diameter d , the granule sizegw

distribution expressed as the geometric standard deviationŽ . Ž .s , and the amount of over-sized agglomerates )4 mmg

at a massing time of 1 min after the melting of the PEG.The PEGs were added in a solid state and were used as

Ž . Ž . w xFig. 1. Agglomerate formation mechanisms in melt agglomeration. a Distribution mechanism. b Immersion mechanism 11 .

( )T. SchæferrPowder Technology 117 2001 68–8270

Table 1Results of repeated experiments with different types of PEG at a massingtime of 1 min

PEG d s Agglomeratesgw gŽ . Ž .mm )4 mm %

2000 629 2.66 15.6560 2.77 12.8

3000 569 2.72 13.7548 2.78 18.7

6000 413 2.36 6.0422 2.38 5.9

8000 384 2.39 6.2373 2.41 6.4

10,000 466 2.28 3.3416 2.29 4.5

20,000 185 4.46 0.0190 4.61 0.0

w xStarting material: lactose monohydrate. Impeller speed: 1300 rpm 15 .

w xflakes of approximately the same size 11 . A highermolecular mass gives rise to a higher viscosity of the

Ž .molten PEG Table 3 . It is seen that the PEGs with thelowest viscosities cause a marked initial agglomerategrowth being reflected in a large mean granule size and alarge amount of over-sized agglomerates. This indicates agood binder distribution making a rapid agglomerategrowth by coalescence possible. With PEG 20000, only aslight initial agglomerate growth is seen because the highviscosity counteracts the binder distribution. The immer-sion mechanism, therefore, will contribute markedly to theagglomerate formation. In the case of immersion, somesurface wetness has to be generated by a densificationbefore the nuclei are able to coalesce. Therefore, the initialgrowth rate will normally be low if the immersion mecha-nism dominates. The poorer binder distribution obtainedwith the PEG 20000 results in a wider size distribution.

The effect of the binder particle size on the initialagglomerate formation has been found to interact with the

w xbinder viscosity 11 . With the PEG 3000, the PEG 6000,and the PEG 8000, the binder particle size had only aslight effect on the agglomerate formation in a high shearmixer, because the binder viscosity was so low that thedominant mechanism of agglomerate formation was distri-bution. Accordingly, other experiments in a high shearmixer showed only a minor effect of the particle size of

w xPEG 6000 on the agglomerate size 16 . In a tumbling meltgranulation process, however, the agglomerate growth wasfound to be dependent on the particle size of PEG 6000because of the lower shearing forces in that equipmentw x17 . In the high shear mixer, the agglomerates wereformed by the immersion mechanism with the highlyviscous PEG 20000. Therefore, this binder gave rise to alarger agglomerate size when it was used as flakes instead

w xof powder 11 . Further, the shape of the agglomeratesbecame plate-like with the flakes and more rounded withthe powder. With PEG 10000, the effect of the binder

particle size was similar, but less clear, indicating thatdistribution and immersion occurred simultaneously.

Fig. 2 shows that the distribution of PEG 20000 be-tween different size fractions is very inhomogeneous at 1min after melting. The binder content is very low in thesize fractions that are smaller than the initial particle sizeof the powder and the flakes, respectively. This indicatesthat practically no comminution of the molten binderdroplets has occurred, i.e. the immersion mechanism domi-nates. The binder distribution is seen to be more uniform at3 min after melting, because more of the unagglomeratedsolid particles have been captured by the molten droplets.The PEGs with lower viscosities gave rise to a binderdistribution that was much more uniform and not signifi-

w xcantly affected by the particle size of the solid binder 11 .Accordingly, a higher binder viscosity resulted in a lessuniform initial binder distribution in a tumbling melt gran-

w xulation process 18 .In the nucleation phase, the tendency for coalescence

between initial particles, or between an initial particle anda nuclei will be larger than the tendency for coalescencebetween two nuclei as the potential for agglomerate growthis inversely proportional to the size of the particlesrag-

w xglomerates 19,20 . The nucleation phase, therefore, ischaracterized by a disappearance of fines. The nucleationphase might be very short in a melt agglomeration process.This is because the solid particles become suddenly wettedwhen the melting point of the binder is reached, contraryto the more gradual wetting obtained by a pouring orpumping of binder liquid upon a solid material. The sud-den wetting might lead to a formation of large, loose

Žagglomerates within the first minute after melting Table.1 . A meltable binder having a wide melting range has

Fig. 2. Content of PEG 20000 in selected fractions of agglomeratesproduced in melt agglomeration experiments with lactose monohydrate.

Ž . Ž . w xMassing time: a 1. b 3 min 11 .


been shown to be advantageous in order to control thew xagglomerate growth 21 . After the formation, the nuclei

will normally gain so much strength by densification thatthey will be able to survive the mechanical forces acting inthe process. After that, agglomerate growth by coalescencebetween nuclei can occur.

3. Agglomerate growth

According to the agglomeration model developed byw xEnnis et al. 19 , the agglomerates will grow in size by

coalescence until a critical size has been reached. Thiscritical size becomes increased by a higher binder orgranule surface viscosity, a smaller particleragglomeratesize, a lower particle density, a lower impeller rotationspeed, a higher deformability of the particlesrag-glomerates, an increased thickness of the surface liquidlayer, and by a smoother surface of the particlesrag-

w xglomerates 19,20 . However, deformation and breakage ofthe agglomerates will occur at a certain critical size, whichdepends on the externally applied kinetic energy and on

w xthe agglomerate strength 20 . Thus, the agglomerategrowth is determined by the balance between coalescenceand breakage.

If the agglomerate strength is high, agglomerate growthby coalescence will be the dominant agglomerate growthmechanism. The agglomerate strength is affected by thechoice of raw materials, a high agglomerate strength beingprimarily caused by a small particle size, an irregularparticle shape causing interlocking, a high viscosity of thebinder liquid, and—to a certain point—by a higher liquid-to-solid ratio. Further, the agglomerate strength becomesincreased if the shearing forces give rise to densification ofthe agglomerates. In case of weak agglomerates, a markedbreakage will occur simultaneous to coalescence. Conse-quently, agglomerate growth by layering on survivingagglomerates of particles and fragments formed by break-age will also be a growth mechanism.

In a melt agglomeration process, a large amount oflarge agglomerates of a loose structure will normally beformed immediately after the melting of the binder owingto the sudden liquidification. The strength of these agglom-erates is low because of their loose structure, and they will

w xbe broken down, therefore, during massing 10,15,22 asillustrated in Fig. 3a. The rate of disappearance of theagglomerates )2 mm is seen to be higher at a higherimpeller speed due to the higher shearing forces. Thefragments will form smaller agglomerates by coalescenceas well as layering. The resulting agglomerates becomestronger by densification, and will be able to grow in sizeby coalescence. By a prolonged massing, over-sized ag-glomerates of a high strength and a spherical shape might

w xeventually be formed 15,23,24 .The agglomerate size distributions become narrower

Ž .during massing Fig. 3b due to the breakage of large

Fig. 3. Effect of massing time on the amount of agglomerates )2 mmŽ . Ž . Ž .a and the geometric standard deviation s b in melt agglomerationg

experiments with lactose monohydrate. Meltable binder: PEG 3000.Ž .Liquid-to-solid mass ratio: 0.22. Impeller speed: 500 rpm I , 600 rpm

Ž . Ž . w x` , 700 rpm ^ . Data from Ref. 10 .

agglomerates. As the agglomerate growth proceeds, thelarger agglomerates become so large that they are unableto grow further, because their size becomes equal to the

w xcritical size 19 . The smaller agglomerates are still able togrow, and this explains why the narrowing continues afterthe disappearance of the agglomerates )2 mm. A highimpeller speed promotes the narrowing.

Fig. 4 illustrates the changes in the surface structure ofthe agglomerates during massing. The surface structure isseen to be rather loose after 5 min of massing, and the

Ž .lactose particles are easily identified Fig. 4a . After 13min of massing, the surface structure has become denserŽ .Fig. 4b , because an increased amount of molten PEG hasbeen squeezed to the surface due to densification of theagglomerates. At that time, the surface plasticity has be-come so high that a marked agglomerate growth by coales-cence can occur.

3.1. Liquid saturation

The agglomerate growth by coalescence depends on theliquid saturation of the agglomerates since a higher liquidsaturation causes a higher deformability of the agglomer-


Fig. 4. SEM photographs of the surfaces of agglomerates produced fromŽ . Ž .lactose monohydrate and PEG 3000. Massing time: a 5, b 13 min.

w xLiquid-to-solid mass ratio: 0.22. Impeller speed: 700 rpm 10 .

ates and an increased thickness of the surface liquid layer.The liquid saturation is defined as the ratio of the porevolume occupied by binder liquid to the total volume ofpores and voids within the agglomerate. Fig. 5 shows thestates of liquid bridging described by Newitt and Conway-

w xJones 25 .The intragranular porosity of the agglomerates, e , can

w xbe calculated from the equation 26 :Õ yÕ rg t g

es s1y 1Ž .Õ rg t

where Õ is the volume and r the density of the granuleg g

sample including all intragranular pores and voids, and Õt

is the true volume, i.e. the volume exclusive of intragranu-lar pores and voids, and r the true density of the granulet

sample. Õ is estimated by a mercury immersion methodgw x27 , and r is calculated from r sMrÕ , where M isg g g

the mass of the granule sample.Ž .The porosity value calculated from Eq. 1 is affected

by the volume of solidified binder within the intragranular

pores and voids. In order to obtain an estimate of thepacking of the solid particles within the agglomerate whenthe binder is in the molten state, a corrected intragranularporosity, e , can be calculated:corr

1yee seq 2Ž .corr r bs

1qr ws b

where r and r are the true densities of the solid binderbs s

and the solid particles, respectively, and w is the ratio ofb

the mass of binder to the mass of solid particles. Thecorrected porosity corresponds to the pore volume of theagglomerates with the binder removed. Then the liquidsaturation is given by:

1ye w rŽ .corr b sSs 3Ž .

e rcorr bm

where r is the density of the molten binder at the actualbm

product temperature. The calculation of the correctedporosity is based on the assumption that the total volumeof binder is deposited within intragranular pores and voids,and the calculation of the liquid saturation is based on theassumption that the packing of the solid particles withinthe agglomerates is unaffected by the solidification of themolten binder during cooling. The values calculated from

Ž . Ž .Eqs. 2 and 3 are supposed, therefore, to be approximatevalues only.

The liquid saturation can be increased either by anŽ .increase in the amount of binder liquid added Fig. 5a or

Ž .by a densification of the agglomerates Fig. 5b . In prac-tice, some densification will occur during an agglomera-tion process, and the densification will usually be markedin a high shear mixer. Fig. 5a might illustrate the changestaking place by a continuous liquid addition in a low shearequipment. By melt agglomeration in a high shear mixer,no continuous addition of liquid occurs provided that themeltable binder is added in a solid state. If so, the liquidstates in melt agglomeration can be described by Fig. 5b,which illustrates that the binder liquid requirement primar-ily depends on the packing of the solid particles within the

Ž .Fig. 5. Changes in the states of liquid bridging caused by a an additionŽ .of binder liquid and b a densification of the agglomerate.


w xagglomerates 28 . The binder liquid requirement will belower, however, if the solid material is partly soluble in the

w xmeltable binder 29 .Agglomerate growth by coalescence will normally oc-

cur in the capillary state, i.e. at a liquid saturation of about80–100%. In the droplet state, the liquid saturation ex-ceeds 100%, and this will cause a risk of overwetting anduncontrollable agglomerate growth. Fig. 6 shows the corre-lation between the liquid saturation and the mean granulesize in melt agglomeration experiments with an anhydrouslactose having a mean particle diameter of 6.8 mm, i.e. acohesive powder. The liquid saturation becomes increasedby densification, and a marked increase in the mean gran-ule size is seen when the liquid saturation approaches100%. There is a correlation between the liquid saturationand the mean granule size, but this correlation depends onthe type of PEG. Since the molten PEG 6000 is moreviscous than the PEG 3000, the liquid saturation has to beslightly higher with the PEG 6000 in order to make theagglomerates sufficiently deformable for agglomerategrowth by coalescence.

The correlation seen in Fig. 6 is typical for melt ag-glomeration of a cohesive material and for aqueous wet

w xagglomeration in high shear mixers 31–34 . When non-cohesive materials are melt agglomerated, the agglomer-ates become densified to their final porosity within a fewminutes of massing, and the liquid saturation, therefore,was found to be approximately constant during most of theprocess. Nevertheless, the agglomerate growth was foundto proceed when PEGs were applied as meltable bindersw x15,28,35 , probably because the rather high viscosities ofthe PEGs increase the potential for agglomerate growth.

In order to produce large agglomerates of a sphericalshape, i.e. pellets, the deformability of the agglomeratesand consequently the liquid saturation have to be so high

Ž .Fig. 6. Correlation between liquid saturation and mean granule size dgw

in melt agglomeration experiments with anhydrous lactose. MeltableŽ . Ž .binder: PEG 3000 `,v , PEG 6000 I,B . Liquid-to-solid mass ratio:

Ž . Ž . Ž . Ž .0.26 v,B , 0.29 ` , 0.305 I . Impeller speed: 900 rpm `,I ,Ž . w x1450 rpm v,B . Data from Ref. 30 .

that the agglomerates are close to becoming overwet. Anuncontrollable growth will occur if the amount of freesurface liquid becomes too high. In an aqueous pelletiza-tion process, the agglomerate growth can be controlled byremoving the excess surface liquid by a controlled evapo-

w xration of water 36 . This will not be possible in a meltpelletization process, which is assumed, therefore, to bemore difficult to control. It was found, however, that anevaporation of water of crystallization from a lactosemonohydrate during a melt agglomeration process madethe process more controllable, probably because the sur-face wetness became reduced by absorption of binderliquid in small pores formed in the agglomerate surface

w xdue to the loss of water of crystallization 37 . Such poresare seen in the surface of the agglomerates in Fig. 4b,whereas no pores are seen in Fig. 4a because of the lowerproduct temperature caused by the shorter massing time.

3.2. Impeller rotationrshearing forces

In a high shear mixer, the shearing forces acting on thew xpowder mass depend on the inclination 16,33,34 and

w xshape 35,38–40 of the impeller blades, and on the rota-tion speed of the impeller. As mentioned above, the shear-ing forces affect the critical agglomerate size that will beobtainable considering coalescence as well as breakage.Further, the densification of the agglomerates, and conse-quently the liquid requirement, depend on the shearingforces.

Fig. 7 shows the effect of binder-to-solid mass ratio onthe mean torque measured in a small mixer torque rheome-ter containing 30 g of lactose with the impeller bladesrotating at 52 rpm. The mean torque describes the meanresistance of the mass to mixing. The equilibrium torqueprofiles are supposed to be related to the different states ofliquid saturation of the mass, a maximum in mean torquebeing reached at complete saturation in the capillary statew x42 . The mixer torque rheometer, therefore, is supposed tobe useful for predicting agglomeration properties of wetmasses in larger mixer granulators. The amount of binderliquid added immediately prior to or at the torque maxi-mum was found to be comparable to the binder liquidrequirement for aqueous wet granulationrpelletization in

w xequipment of larger scale 42,43 .As can be seen from Fig. 7, the maximum torque is

reached at a binder concentration of 36–42% for PEG3000 and at 32–36% for PEG 20000. The correspondingliquid saturations of the mass at these maximum torque

w xranges were found to be close to 100% 41 . This wasshown to be because a higher binder concentration wascompensated for by an increase in porosity, thus keepingthe liquid saturation constant at approximately 100%. Meltagglomeration of the same materials in a high shear mixershowed that concentrations of PEG 3000 higher than 24%

w xcaused overwetting 41 . This is due to the much highershearing forces in the high shear mixer causing a marked


Fig. 7. Effect of binder concentration on mean torque in melt agglomeration experiments with lactose monohydrate in a mixer torque rheometer. MeltableŽ . Ž . w xbinder: PEG 3000 powder ` , PEG 20000 powder I 41 .

densification of the agglomerates, whereas the shearingforces in the mixer torque rheometer are insufficient todensify the mass since the rather viscous binder liquidresists a densification. This indicates that the mixer torquerheometer is more suitable for predicting agglomerationproperties in case of low shear equipment and binderliquids of low viscosity.

It has been found in many melt agglomeration experi-ments in high shear mixers that a higher impeller speedgives rise to a higher agglomerate growth rate, e.g. Refs.w x26,28,44,45 . The opposite effect has been found in a fewexperiments in which an uncontrollable agglomerate growth

w xwere prevented by increasing the impeller speed 15,37,46 .w xAccording to the theory of Ennis et al. 19 , these contra-

dictory effects can be explained by the fact that a higherimpeller speed will counteract coalescence between ag-glomerates, on the other hand, a higher impeller speed willpromote coalescence by augmenting the deformability atcollisions and by increasing the densification, squeezing

w xmore liquid to the surface 47 . The latter effect seems tobe the dominant one, unless the viscosity of the binderliquid andror the impeller speed are very high.

Fig. 8a shows that the effect of impeller speed almostdisappears when the effect of the number of impellerrevolutions on mean granule size is depicted instead. Thisindicates that the effect of impeller speed is primarilyrelated to the total energy input during the process. At a

Ž .higher liquid-to-solid ratio Fig. 8b , however, an effect ofimpeller speed is seen. This is assumed to be because theeffect of impeller speed on the deformability at collisionsbetween agglomerates becomes more pronounced at thehigher liquid saturation caused by the higher liquid-to-solidratio.

After the initial breakage and densification of agglomer-ates, the further agglomerate growth has not been found tobe significantly affected by breakage and comminution ofagglomerates irrespective of the impeller speed if a PEG

w xwas applied as the meltable binder 15 . This is because thehigh viscosities of the PEGs cause a high agglomeratestrength. When a low viscosity meltable binder such asstearic acid is used, the agglomerate growth is clearlyaffected by the impeller speed because of the lower ag-

Fig. 8. Correlation between number of impeller revolutions and meanŽ .granule size d in melt agglomeration experiments with lactose mono-gw

Ž .hydrate. Meltable binder: PEG 3000. Liquid-to-solid mass ratio: a 0.22,Ž . Ž . Ž . Ž .b 0.24. Impeller speed: 500 rpm I , 600 rpm ` , 700 rpm ^ . Data

w xfrom Ref. 10 .


Fig. 9. Effect of impeller speed on the agglomerate size distribution inmelt agglomeration experiments with lactose monohydrate. Meltable

w xbinder: stearic acid 48 .

Ž .glomerate strength Fig. 9 . The agglomerate growth ispromoted by an increase in impeller speed from 200 to 400rpm since the content of agglomerates within the largersize fractions increases. A further rise in impeller speed to600 rpm results in a slight increase in the content ofagglomerates in the smaller size fractions. This becomesmore evident at higher impeller speeds at which the con-

tent of large agglomerates is seen to decrease, causing anincreasing amount of small agglomerates. This illustratesthat the agglomerate growth is appreciably affected bybreakage at a combination of a low agglomerate strengthand a high impeller speed. A similar change from amonomodal to a bimodal agglomerate size distribution dueto breakage has been observed in other melt agglomeration

w xexperiments 22 .Normally, a lower intragranular porosity is to be ex-

pected at a higher impeller speed as well as a highertemperature of the heating jacket of the mixing bowl,because densification of the agglomerates is supposed tobe eased by higher collisional forces and by a lower binder

w xviscosity 19 . As illustrated in Fig. 10, the opposite effectmight be seen when the agglomerate growth is affected bybreakage. This is because a simultaneous formation andbreakage of agglomerates result in agglomerates of a loose

w xstructure 26 . The effect of impeller speed seen in Fig. 10has been shown primarily to be an effect of producttemperature on the binder viscosity since a rise in impeller

w xspeed causes a higher product temperature 48 . This indi-cates that the higher porosity to be expected at a higherimpeller speed due to an increased breakage is counter-acted by an increased densification due to the highercollisional forces. The lower agglomerate strength causedby a higher product temperature, however, will promotebreakage and will give rise, therefore, to a higher porosity.

A higher impeller speed will normally result in morespherical agglomerates, because higher shearing forces will

w xpromote a spheronization 10,24,49 . In the experiments inFigs. 9 and 10, however, a higher impeller speed was

w xfound to result in less spherical agglomerates 48 . This ispartly because of a more pronounced breakage at higherspeed, and partly because of a lower plasticity of theagglomerate surface caused by a lower liquid saturationwhich is a consequence of the higher porosity obtained at

Ž .the higher speed Fig. 10 .

Fig. 10. Effect of impeller speed on the intragranular porosity of the sizefractions 355–2000 mm in melt agglomeration experiments with lactosemonohydrate. Meltable binder: stearic acid. Jacket temperature: 358CŽ . Ž . Ž . w xI , 608C ` , 858C ^ 48 .


3.3. Particle properties

A smaller size of the solid particles has generally beenfound to increase the liquid-to-solid ratio to be used in

w xorder to obtain a given agglomerate size 3,11,22,30,49 . Asmaller particle size will usually make the packing of theparticles more difficult, thus causing a higher interparticu-lar porosity. Since the agglomerate size depends on theliquid saturation, a higher porosity will make it necessaryto increase the liquid-to-solid ratio in order to obtain thesame liquid saturation. This is illustrated in Fig. 11, whichshows the effect of an admixture of a small amount of acoarse grade of anhydrous lactose to a fine grade. Fig. 11ashows the addition of coarse lactose results in an increaseddensification rate and a lower final porosity. Consequently,the liquid-to-solid ratio had to be lower in order to obtain a

Žsimilar liquid saturation after 17 min of massing Fig..11b . It is further seen that a higher impeller speed gives

rise to denser agglomerates when using the fine grade. Theliquid-to-solid ratio, therefore, had to be reduced from 0.29to 0.26 when the impeller speed was increased from 900 to1450 rpm in order to obtain the same liquid saturation and

Ž .Fig. 11. Effects of addition of coarse particles d s127 mm to finegwŽ .particles d s6.8 mm of anhydrous lactose on the corrected intragran-gw

Ž . Ž .ular porosity a and the liquid saturation b in melt agglomerationŽ .experiments with PEG 3000 as the meltable binder. %coarse: 0% I,^ ,

Ž . Ž . Ž . Ž .10% e , 20% = . Impeller speed: 900 rpm I,e,= , 1450 rpm ^ .Ž . Ž . Ž .Liquid-to-solid mass ratio: 0.235 = , 0.26 ^,e , 0.29 I . Data from

w xRef. 30 .

Fig. 12. Log–probability plot of cumulative weight distributions ofagglomerates produced in melt agglomeration experiments with anhy-

Ž . Ž .drous lactose. Meltable binder: a PEG 3000, b PEG 6000. MassingŽ . Ž . Ž . w xtime: 11 min = , 14 min ^ , 17 min ` 30 .

w xagglomerate growth 30 . This marked effect of impellerspeed was seen only because the solid particles were verycohesive owing to their small particle size.

Fig. 12 shows the changes in the agglomerate sizedistribution with massing time in experiments with the finegrade of the anhydrous lactose. The results indicate thatthe agglomerate growth mechanisms are dependent on the

Ž .type of PEG. With PEG 3000 Fig. 12a , the size distribu-tion becomes clearly narrowed by prolonged massing,

Ž .whereas no narrowing is seen with PEG 6000 Fig. 12b .This indicates that agglomerate growth is affected bybreakage in the experiments with PEG 3000, while break-age is insignificant with PEG 6000. The changes in sizedistribution in melt agglomeration experiments are nor-mally similar to the gradual narrowing seen in Fig. 12a.The atypical results in Fig. 12b can be ascribed to anexceptionally high agglomerate strength, which is caused


by a combination of a small particle size and a viscousbinder liquid. The fact that the PEG 3000 was applied asflakes and the PEG 6000 as a fine powder is supposed tocontribute to the higher strength obtained with PEG 6000since a smaller binder particle size might cause denseragglomerates and a more uniform binder distribution.

In case of cohesive materials, i.e. powders having amean particle size smaller than 10–20 mm, there will be arisk of an uncontrollable agglomerate growth and a forma-tion of clusters consisting of overwetted agglomeratesw x30,37 . The cohesiveness reduces the deformability of theagglomerates, and in order to make them sufficiently de-formable for agglomerate growth by coalescence, the liq-uid saturation has to be so high that the agglomeratesbecome close to being overwet.

On the other hand, if the particle size of the powderbecomes too large, the agglomerate strength might be solow that no agglomerate growth can occur, because break-age will dominate. It has been shown in melt agglomera-tion experiments that a material having a mean particle

w xsize of 100 mm was unable to agglomerate 2 . Agglomera-tion of large particles with silicone fluids in high shearmixers has been found to be possible by using a fluid of a

w xhigh viscosity to increase the agglomerate strength 50 .The effect of the size distribution of the solid particles

on agglomerate growth is supposed to be closely related tothe effect of the size distribution on the densification. Anarrower size distribution will result in a looser packing ofthe initial particles within the agglomerates. Accordingly, anarrow size distribution was found to cause weak agglom-erates in wet agglomeration experiments in a drum granu-

w xlator 51 . The present data on melt agglomeration, how-ever, do not permit an evaluation of the effect of theparticle size distribution.

The agglomerate strength is affected by the particleshape of the solid. Interlocking between particles of anirregular shape will increase the strength and might reduce

w xthe need of binder 37 . On the other hand, a roundedparticle shape will decrease the agglomerate strength. Table2 shows the effect of adding either 20% or 40% wrw ofcorn starch to an anhydrous dicalcium phosphate. Themedian particle diameter of the corn starch and the anhy-drous dicalcium phosphate was 15 and 17 mm, respec-tively. The span of the size distribution, i.e. the differencebetween the diameters at the 90% and the 10% pointsrelative to the median diameter, was found to be 1.1 forthe corn starch and 1.7 for the anhydrous dicalcium phos-phate.

Anhydrous dicalcium phosphate alone resulted in ratherw xstrong agglomerates 37 . As can be seen from Table 2, the

amount of binder liquid had to be reduced when theimpeller speed was increased in order to obtain a meangranule size of the same order of magnitude. This is inaccordance with the results in Fig. 11. With 20% of cornstarch, the narrowest size distribution is obtained at 600rpm. A higher impeller speed causes a wider size distribu-

Table 2Effects of impeller speed and content of corn starch in a mixture with

Ž . Ž .anhydrous dicalcium phosphate DCP on the mean granule size dgwŽ .and the granule size distribution s in melt agglomeration experimentsg

with PEG 3000 in an 8-l high shear mixeraRatio DCPr Impeller LrS d sgw g

Ž . Ž .starch speed wrw mmŽ .rpm

80:20 200 0.18 924 1.55400 0.17 797 1.51600 0.17 855 1.44800 0.16 885 1.66

1000 0.16 1057 1.7060:40 200 0.22 944 1.47

400 0.20 741 1.59600 0.20 865 1.55800 0.20 829 1.88

1000 0.20 933 1.99

w xMassing time: 16 min 52 .a Liquid-to-solid mass ratio.

tion due to breakage. This is ascribed to a reduced agglom-erate strength because of the narrower size distribution andthe rounded particle shape of the corn starch. With 40% ofcorn starch, 200 rpm is seen to give rise to the narrowestsize distribution. At 200, 400, and 600 rpm, the agglomer-ates were rather spherical of shape, whereas 800 and 1000rpm resulted in irregular agglomerates having a markedlywider size distribution. This indicates that a higher contentof corn starch results in a further lowering of the agglom-erate strength. A particle shape that is plate-like or needle-like might also reduce the agglomerate strength causing awider agglomerate size distribution and a less spherical

w xagglomerate shape 28 .

3.4. Binder Õiscosity

Table 3 shows the examples of viscosities of moltenbinders that have been applied for melt agglomeration inhigh shear mixers. It is seen that a wide range of binderviscosities has been used. The PEGs are especially suitablefor studies of the effect of binder viscosity since they areavailable in a large number of types having differentviscosities while their chemical properties are similar.Effects of different types of PEG on the agglomerategrowth, therefore, are ascribed to effects of viscosity. Fig.13 shows the effect of a wide range of PEGs on the meangranule size, the size distribution, and the amount ofagglomerates )4 mm in the product. It appears from Fig.13a that the PEG 6000 gives rise to the smallest agglomer-ate size, whereas the PEGs with the lower as well as thehigher viscosities cause a larger agglomerate size. Thiseffect is clearer with the anhydrous lactose than with thelactose monohydrate. The agglomerate growth is supposedto be promoted by a higher viscosity, but a higher viscositymight also counteract the growth by making the agglomer-ates less deformable and making the binder distribution

w xmore difficult 19 . These counteracting effects of binder


Table 3Ž . w xExamples of viscosities mPas of molten binders 1,15,26,48

Ž .Binder Temperature 8C

56 70 80 90

Stearic acid 12 8 6Glycerol monostearate 36 26 21Gelucire 50r13 49 39 29Stearate 6000 WL 1644 414 316 217PEG 2000 101 77 60PEG 3000 222 170 132PEG 6000 938 701 553PEG 8000 1620 1230 909PEG 10,000 4660 3560 2730PEG 20,000 26,500 19,000 14,900

viscosity explain why a minimum in mean granule size isseen with the PEG 6000. The growth-promoting effect hasbeen shown to dominate if the viscosity exceeds an uppercritical limit, which depends on the physical properties ofthe solid material, the liquid-to-solid ratio, and the impeller

w xspeed 37 . Consequently, the maximum impeller speedŽ .1500 rpm of the high shear mixer had to be applied inthe experiments in Fig. 13 in order to prevent an uncontrol-lable agglomerate growth with the PEGs of the molecular

w xmass range 6000–20000 15 . In the same mixer, theoptimum impeller speed was found to be 800–1200 rpm

w xwith PEG 3000 24,28,37 and 400–600 rpm with meltablew xbinders of a lower viscosity 1,45 .

A regression analysis of the linear correlation betweenŽ .time and log mean granule size Table 4 shows that the

Ž .initial agglomerate size expressed by a becomes smallerŽ .at a higher viscosity cf. Table 1 , because the rate of

coalescence is controlled by the distribution of the binderw x19 . When the distribution of the binder and the densifica-tion of the agglomerates are finished, however, a higherviscosity is seen to increase the agglomerate growth rate.This is in accordance with results of other melt agglomera-

w xtion experiments 18,53 .A lower viscosity gives rise to a wider size distribution

Ž .Fig. 13b and a smaller amount of agglomerates )4 mmŽ .Fig. 13c with the anhydrous lactose, whereas the oppo-site effect is seen with the lactose monohydrate. Thesefindings indicate that a breakage of agglomerates occurs,to a larger extent, at a lower viscosity with the anhydrouslactose, i.e. the agglomerate strength becomes increased bya higher viscosity. In the case of the lactose monohydrate,the agglomerate strength is sufficiently high to resistbreakage at all the binder viscosities examined, probablybecause of a smaller initial particle size of the monohy-

w xdrate 15 .The agglomerate strength becomes markedly increased

w xat a higher binder viscosity 50 . Consequently, the ag-glomerate growth will be more affected by breakage if ameltable binder having a viscosity being lower than that ofthe PEGs is applied. This is illustrated in Fig. 14, whichshows that the agglomerate size distribution might be

affected by the binder viscosity. The size distributionbecomes narrower at prolonged massing in accordancewith the results shown in Fig. 3. Further, Gelucire 50r13gives rise to a significantly wider size distribution than doPEG 3000 and Stearate 6000 WL 1644. This is because thelower viscosity of Gelucire 50r13 makes the agglomeratesmore susceptible to breakage. At prolonged massing, theagglomerates will be more able to resist breakage, becausethey gain strength by densification. Therefore, no cleareffect of binder viscosity on size distribution is seen from5 min of massing at 1500 rpm and from 15 min of massingat 1000 rpm. This indicates that densification occurs more

Ž . Ž .Fig. 13. Effect of type of PEG on the mean granule size d a , thegwŽ . Ž .geometric standard deviation s b , and the amount of agglomeratesg

Ž .)4 mm c in melt agglomeration experiments with anhydrous lactoseŽ . Ž .I and lactose monohydrate ` . Median particle size: 34 mmŽ . Ž .anhydrous lactose , 20 mm lactose monohydrate . Massing time: 12

w xmin. Impeller speed: 1500 rpm. Data from Ref. 15 .


Table 4The results of regression analysis of the linear correlation between timeŽ . Ž .t, min and log mean granule size d , mm : log d s log aq t log bgw gw

Ž .Mean viscosity a mm %rmin CorrelationŽ .mPa coefficient

2000 51 405 7.2 0.9853000 112 357 8.1 0.9916000 473 319 8.0 0.9938000 799 319 9.5 0.916

10,000 2570 284 10.3 0.96020,000 14,700 268 11.5 0.960

Time interval: 3–12 min. The percentage increase in d per minutegwŽ .%rmin is calculated on the basis of the constant b. Starting material:

w xlactose monohydrate 15 .

rapidly at the high impeller speed. In the same experi-ments, the more pronounced breakage caused by the lowerviscosity of the Gelucire 50r13 resulted in a higher intra-granular porosity since densification was counteracted bybreakage. Consequently, the liquid-to-solid volume ratiohad to be higher with Gelucire 50r13 than with PEG 3000and Stearate 6000 WL 1644 in order to obtain a liquidsaturation that was sufficiently high for agglomerate growth

w xto occur 26 . An application of glycerol monostearate asw xthe meltable binder was found by other authors 29 to

result in breakage causing a widening of the agglomeratesize distribution.

In case of a meltable binder that has a much lowerviscosity than the PEGs, e.g. stearic acid, the agglomerategrowth mechanisms will be clearly different since theagglomerate growth will be markedly dependent on thebalance between coalescence of agglomerates and break-

w x Ž .down of agglomerates 48 cf. Fig. 9 . At such a lowviscosity, crushing and layering were found to be a proba-ble growth mechanism concurrently with coalescence.

Fig. 14. Effect of type of binder and impeller speed on the geometricŽ .standard deviation s in melt agglomeration experiments with lactoseg

Ž .monohydrate. Meltable binder: Gelucire 50r13 q,I , Stearate 6000Ž . Ž . Ž .WL 1644 ^,= , PEG 3000 e,` . Impeller speed: 1000 rpm q,^,e ,Ž . w x1500 rpm I,=,` 26 .

It appears from Fig. 15 and from the results of otherw xauthors 29 that a lowering of the binder viscosity caused

by a higher temperature of the heating jacket of the mixingbowl might increase the agglomerate growth rate apprecia-bly. However, the larger thermal expansion of the binderliquid causing a higher liquid-to-solid volume ratio at ahigher product temperature will also contribute to the

w xeffect of jacket temperature 37 . PEG 6000 is seen to giverise to a smaller agglomerate growth rate than does PEG3000 in accordance with the results presented in Fig. 13.With stearic acid, the agglomerate growth was found to beextremely sensitive to even small variations in viscositycaused by minor differences in the temperature of the massw x48 . This was ascribed to the very low agglomerate strengthcaused by the very low viscosity of this binder.

The binder viscosity has also been shown to affect theagglomerate shape as illustrated in Fig. 16. The most

Ž .viscous binder PEG 20000 results in less spherical ag-glomerates, because a high viscosity will reduce the sur-

w xface plasticity of the agglomerates 15,18,26 . On the otherhand, a low viscosity might make the agglomerates sodeformable that their shape becomes elongated due to the

w xshearing forces 15 . If the viscosity is so low that apronounced breakage occurs, the agglomerate shape be-

Ž .Fig. 15. Effect of jacket temperature on the product temperature a andŽ . Ž .the mean granule size d b in melt agglomeration experiments withgw

anhydrous dicalcium phosphate. Temperature of the heating jacket: 508CŽ . Ž . Ž .I,^ , 1208C `,\ . Meltable binder: PEG 3000 I,` , PEG 6000Ž . w x^,\ 37 .


Fig. 16. SEM photographs of agglomerates produced from lactose mono-Ž . Ž .hydrate. Meltable binder: a PEG 2000, b PEG 20000. Massing time:

w x15 min. Impeller speed: 1500 rpm 15 .

comes irregular because of the continuous formation andw xbreakage of the agglomerates 48 .

3.5. Electrostatic charging

Melt agglomeration in high shear mixers provides goodconditions for generation of static electricity because of thehigh shearing and frictional forces combined with a low airhumidity within the bowl due to the non-aqueous binderliquid. Electrostatic charging might disturb the agglomer-ate growth by causing build up of material on the wall ofthe bowl. With the PEGs, the amount of adhesion to thebowl has generally been found to be low, and the PEGs,therefore, were found to be suitable for the production of

w xpellets 10,15,30 . Meltable binders that are more hy-drophobic than the PEGs were found to be less suitable for

w xpelletization due to an increased adhesion 1,46 . This isbecause a simultaneous adhesion and detachment of mate-rial will counteract a narrowing of the agglomerate sizedistribution as well as a spheronization of the agglomer-

ates. Further, a marked adhesion might result in a yield ofproduct that is unacceptably low.

Fig. 17 shows the effects of the type of binder and theair humidity of the room on the generation of static voltageduring a melt agglomeration process in a high shear mixer.The electrostatic measurements were made by means of astainless steel probe inserted into the bowl through a hole

w xon the lid 54 . Due to the elevated temperature within thebowl, the relative air humidity in the bowl was appreciablylower than that in the room. The relative air humidities of35% and 75% in the room were found to correspond toapproximately 4% and 9% in the bowl at the final tempera-ture. The highest level of static voltage is observed with

Ž .stearic acid Fig. 17c . An addition of glycerol mono-stearate to the stearic acid causes a reduction in the static

Ž .voltage Fig. 17b . PEG 3000 gives rise to low levels ofstatic voltage that are unaffected by the air humidity. Withthe stearic acid as well as the mixture of stearic acid andglycerol monostearate, a higher air humidity is seen toreduce the static voltage. The effect of air humidity isascribed to a creation of a thicker conducting moisturelayer on the particle surfaces at a higher air humidity. Theeffect of the type of binder on the electrostatic charging of

Ž .Fig. 17. Effects of type of binder and relative air humidity RH on thestatic voltage achieved during processing in melt agglomeration experi-

Ž . Ž .ments with lactose monohydrate. Meltable binder: a PEG 3000, bŽ . Ž . w xstearic acidrglycerol monostearate 20:3 , c stearic acid 54 .


the agglomerates was found to be related to the resistivityw xof the binder 54 , a high level of static voltage being

obtained with a binder of a high resistivity. Further, theresistivity of a meltable binder seems to be related to thehydrophilicity of the binder since a low resistivity wasfound with the hydrophilic PEG 3000, whereas the morehydrophobic binders glycerol monostearate and stearic acidshowed higher resistivities. Stearic acid, having the highestresistivity, was found to cause the highest amount ofadhesion in the experiments.

The results in Fig. 17 indicate that an agglomerategrowth that is less affected by adhesion can be obtained byreducing the electrostatic charging of the particles. Thiscan be done by selecting a meltable binder with a lowresistivity, by inserting a grounded probe within the mix-ing bowl, andror by performing the process at a high airhumidity.

4. Conclusions

The agglomerate growth mechanisms in melt agglomer-ation in high shear mixers are dependent on the viscosityof the meltable binder. If the meltable binder has a highviscosity, the agglomerate strength will be so high thatbreakage of agglomerates becomes insignificant and coa-lescence, therefore, will be the dominant growth mecha-nism. A binder viscosity larger than approximately 100mPas will normally cause an agglomerate strength that issufficiently high to counteract breakage, but the agglomer-ate strength depends on an interaction between binderviscosity and particle size of the solid. Agglomerate growthby coalescence is closely related to the deformability andthe surface plasticity of the agglomerates, which primarilydepend on their liquid saturation but also on the cohesive-ness of the primary particles. A higher impeller speed willincrease the agglomerate growth rate by increasing thedensification rate and consequently, the liquid saturation.Further, a higher impeller speed will promote coalescenceby augmenting the deformability at collisions betweenagglomerates.

The agglomerate growth mechanisms become morecomplex if the viscosity of the meltable binder is so lowthat the agglomerate strength becomes insufficient to resistthe shearing forces of the impeller. Then the agglomerategrowth will depend on the balance between coalescenceand breakage. Breakage will result in agglomerate frag-ments. These fragments might form new agglomerates bycoalescence or might become layered upon larger agglom-erates. At a prolonged massing, the agglomerates mightgain sufficient strength by densification, resulting in asubsequent growth by coalescence or a simultaneousgrowth and breakage might continue. A higher impellerspeed will increase breakage. If the agglomerate strength isso low that a marked breakage continues, the agglomeratesize distribution will typically become bimodal. The con-

tinuous buildup and breakdown of agglomerates will causeagglomerates having a wide size distribution, a rather highintragranular porosity, and an irregular shape.

List of symbolsdgw Geometric mass mean diameterM Mass of granulesS Liquid saturation of granulessg Geometric standard deviationÕg Volume of granulesÕt True volume of granuleswb Binder-to-solid mass ratio

Greek letterse Intragranular porosityecorr Corrected intragranular porosityr bm Density of molten binderr bs True density of solid binderrg Density of granulesrs True density of solid particlesrt True density of granules

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