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European Journal of Pharmaceutical Sciences 12 (2001) 297–309www.elsevier.nl / locate /ejps

Effects of interactions between powder particle size and binder viscosityon agglomerate growth mechanisms in a high shear mixer

*Anita Johansen, Torben SchæferThe Royal Danish School of Pharmacy, Department of Pharmaceutics, 2 Universitetsparken, DK-2100 Copenhagen, Denmark

Received 3 July 2000; received in revised form 5 September 2000; accepted 12 September 2000

Abstract

A study was performed in order to elucidate the effects of the interactions between powder particle size and binder viscosity on themechanisms involved in agglomerate formation and growth. Calcium carbonates having mean particle sizes in the range of 5–214 mm andpolyethylene glycols having viscosities in the range of approximately 50–100 000 mPas were melt agglomerated in a high shear mixer.Agglomerate growth by nucleation and coalescence was found to dominate when agglomerating small powder particles and binders with alow viscosity. Increasing the binder viscosity increased the formation of agglomerates by immersion of powder particles in the surface ofthe binder droplets. With a larger powder particle size, an increasing binder viscosity was necessary in order to obtain an agglomeratestrength being sufficient to avoid breakage. Due to a low agglomerate strength, a satisfying agglomeration of very large particles (214mm) could not be obtained, even with very viscous binders. The study demonstrated that the optimum agglomerate growth occurred whenthe agglomerates were of an intermediate strength causing an intermediate deformability of the agglomerates. In order to producespherical agglomerates (pellets), a low viscosity binder has to be chosen when agglomerating a powder with a small particle size, and ahigh viscosity binder must be applied in agglomeration of powders with large particles. 2001 Elsevier Science B.V. All rightsreserved.

Keywords: Melt agglomeration; High shear mixer; Binder viscosity; Powder particle size; Polyethylene glycols; Agglomerate growth mechanisms

1. Introduction is distributed on the surface of the powder particles, andformation of nuclei occurs by coalescence between the

Agglomeration is an important and established technolo- wetted particles. By the immersion mechanism, nuclei aregy in many industrial processes. However, the knowledge formed when the powder particles are captured on theof the mechanisms and kinetics involved in agglomeration surface of the binder droplets and immersed. When theis still sparse, and the need of additional research in the binder droplet size is larger than the size of the powdermatter is evident. particles, the dominating agglomerate formation mecha-

Some of the important early contributions to theory on nism will tend to be the immersion mechanism. In a highagglomeration were made by Newitt and Conway-Jones shear mixer, the binder droplet size will normally become(1958), Rumpf (1962), Capes and Danckwerts (1965), and reduced by comminution in the initial stage of the processKapur (1978). More recently, Ennis et al. (1991) de- because of the shearing forces. A low binder viscosity willveloped a new agglomeration model, and this work has enhance this size reduction of the binder droplets, as will abeen followed by several other investigations into ag- higher impeller speed. Therefore, a small initial binderglomeration mechanisms and kinetics (Knight, 1993; Kris- particle size, a low binder viscosity, and/or a high impellertensen, 1996; Iveson et al., 1996; Tardos et al., 1997; speed promote the distribution mechanism. On the otherHoornaert et al., 1998; Iveson and Litster, 1998). hand, a large initial binder particle size, a high binder

In melt agglomeration, the formation of agglomerates viscosity, and/or a low impeller speed promote the immer-can proceed by two different mechanisms (Schæfer and sion mechanism (Schæfer and Mathiesen, 1996a).Mathiesen, 1996a). By the distribution mechanism, binder The nuclei formed initially in the process might grow in

size by coalescence between nuclei. This agglomerategrowth is determined by a balance between coalescence*Corresponding author. Tel.: 145-35-306-000; fax: 145-35-306-031.

E-mail address: [email protected] (T. Schæfer). and breakage. Coalescence will be the dominant growth

0928-0987/01/$ – see front matter 2001 Elsevier Science B.V. All rights reserved.PI I : S0928-0987( 00 )00182-2

298 A. Johansen, T. Schæfer / European Journal of Pharmaceutical Sciences 12 (2001) 297 –309

mechanism if the agglomerates possess a high agglomerate Powder particles that are too large will result in a wide sizestrength (Tardos et al., 1997). If the agglomerates are too distribution and agglomerates with a non-uniform shapeweak to resist the impact and shearing forces in the mixer, due to breakage. The optimum particle size of a rawa marked agglomerate breakage will occur simultaneously material to be melt pelletized has been indicated to be inwith growth by coalescence (Knight et al., 1998; Eliasen et the size range of 20–25 mm (Schæfer et al., 1992b).al., 1998, 1999). As a result, particles and small fragments Keningley et al. (1997) have shown that to formformed by breakage might participate in the growth by a granules with calcium carbonate and silicone oils, alayering mechanism by which small particles or fragments minimum binder viscosity was required, which increasedare layered on the surface of surviving agglomerates with the size of the powder particles from 1 mPas with(Linkson et al., 1973; Eliasen et al., 1999). 8-mm particles to 1 Pas with 230-mm particles. This

The agglomerate strength becomes increased by a indicates that an interaction between powder particle sizesmaller powder particle size, a higher binder viscosity, and and binder viscosity might be important in order to controlby a densification of the agglomerates (Kristensen et al., the agglomerate growth. The present work is based on the1985a; Keningley et al., 1997). In a high shear mixer, the hypothesis that a controllable agglomerate growth isshearing forces become increased by a higher impeller attainable with powders having a small as well as a largerotation speed. Further, the shearing forces depend on the particle size by combining the powder particle size and thesize and shape of the impeller blades (Schæfer et al., binder viscosity in a way that gives rise to a suitable1993b). agglomerate strength. The purpose of this work is to test

According to Ennis et al. (1991), growth by coalescence this hypothesis by carrying out melt agglomeration experi-occurs until a critical agglomerate size has been reached. ments in a high shear mixer.This critical size becomes increased by, e.g., a smaller sizeof the powder particles /agglomerates, a higher binderviscosity, and a lower impeller speed (Ennis et al., 1991; 2. Materials and methodsTardos et al., 1997). However, at the same time a higherviscosity will reduce the growth potential by decreasing 2.1. Materialsthe deformability and the rate of densification of theagglomerates. The effect of viscosity on agglomerate Six different grades of calcium carbonate powders withgrowth will therefore depend on the balance of these two different mean particle size, manufactured from a whitecounteracting effects (Schæfer and Mathiesen, 1996c). marble, and produced by comminution and classificationAgglomerates can only resist deformation and breakage (Omya, France), were used as starting material. Poly-when below a critical agglomerate size, which depends on ethylene glycol (PEG) 1500 S, 3000 S, 6000 S, 10000 S,the externally applied energy and on the agglomerate 20000 S, or 35000 S (Hoechst, Germany) was used asstrength (Tardos et al., 1997). meltable binder. ‘S’ indicates that the PEGs are used as

Agglomeration of powders with a mean particle size flakes. Butylated hydroxyanisole (BHA) (Merck-Schuch-below approximately 10 mm has traditionally been trouble- ardt, Germany) was used as an antioxidant in order tosome and has often led to an uncontrollable agglomerate prevent thermal decomposition of the binder during thegrowth. This is because of the high liquid saturation agglomeration process (Schæfer and Mathiesen, 1996b).needed in order to obtain a sufficient deformability to The size distribution by volume of the calcium carbon-counteract for the high agglomerate strength caused by the ates was determined by a Malvern 2601Lc laser diffractioncohesiveness of the small particles (Schæfer et al., 1992b; particle sizer (Malvern Instruments, UK). The span isSchæfer, 1996a; Schæfer and Mathiesen, 1996b; Knight et calculated as the difference between the diameters at 90al., 1998). Also, the agglomeration of large powder and 10 percentage points relative to the median diameter,particles is problematic. Breakage will often dominate, and D(v;0.5).no agglomeration can occur because of a low agglomerate A Gemini 2375 Surface Area Analyzer (Micromeritics,strength (Newitt and Conway-Jones, 1958; Capes and USA) was used for the determination of the BET multi-Danckwerts, 1965). In melt agglomeration experiments, it point surface area of the calcium carbonates.has previously been shown that a powder with a mean The true density of the calcium carbonates and of theparticle size of 100 mm was unable to agglomerate solid PEGs was determined by an Accupyc 1330 gas(Thomsen, 1994). In agglomeration experiments with a displacement pycnometer (Micromeritics, USA) usingcoarse lactose monohydrate (127 mm) agglomerated with helium purge. The poured and tapped densities of thewater, weak granules were produced (Mackaplow et al., calcium carbonates were determined according to the test2000). for apparent volume (European Pharmacopoeia, 1999), and

The powder particle size is especially critical if pellets the interparticular porosities were calculated from thehave to be produced. Powder particles that are too small tapped densities.will result in oversized agglomerates and a wide agglomer- The size distributions of the PEGs were estimated byate size distribution because of an uncontrollable growth. sieve analysis with a series of 12 ASTM standard sieves in

A. Johansen, T. Schæfer / European Journal of Pharmaceutical Sciences 12 (2001) 297 –309 299

the range of 75–4000 mm. A sample of about 100 g was 75–2000 mm was vibrated by a Fritsch analysette 3sieved for 5 min at low vibration level by a Fritsch vibrator (Fritsch, Germany) for 10 min. The mass mediananalysette 3 vibrator (Fritsch, Germany). The mass median diameter and the span were calculated.diameter and the span were calculated.

The densities of molten PEGs were estimated at 70, 80,and 908C as previously described (Eliasen et al., 1998). 2.4.2. Intragranular porosity

The melting range and the peak temperature of the PEGs The intragranular porosity of the agglomerates waswere estimated by a Perkin-Elmer DSC 7 differential estimated by a mercury immersion method similar to thatscanning calorimeter (Perkin-Elmer, USA) as previously described by Strickland et al. (1956). A sample of 3–4 gdescribed (Schæfer and Mathiesen, 1996b). from the agglomerate size fraction 250–2000 mm was

The viscosities of the molten PEGs were estimated at placed in a glass pycnometer with an approximate volume70, 80, and 908C by a Rotovisco RV 12 rotation viscome- of 30 ml having a calibrated scale. Mercury was sucked upter (Haake, Germany) as previously described (Schæfer into the pycnometer by means of vacuum. The apparentand Mathiesen, 1996c). volume of the sample was estimated by displacement of

mercury after increasing the intrusion pressure to 98.7 kPa2.2. Equipment (740 mmHg). At this intrusion pressure, mercury will

penetrate into pores greater than approximately 20 mm inThe agglomeration experiments were performed in an diameter. The corrected porosity and the liquid saturation

8-l Pellmix PL 1/8 laboratory scale high shear mixer were calculated as described by Eliasen et al. (1998). The(Niro, Denmark) (Schæfer et al., 1993a). corrected porosity reflects the porosity of the wet granules

in the agglomeration phase in which the molten binder acts2.3. Mixing procedure like a liquid. All porosity analyses were performed in

duplicate.The heating jacket was preheated to 508C. Calcium The actual binder concentrations (%, m/m, of calcium

carbonate (1500 g), the amount of PEG, and 3% BHA (%, carbonate) of the fractions (250–2000 mm) were estimatedm/m, of PEG) were dry mixed at an impeller speed of indirectly from the true densities of the milled agglomerate1300 rpm. The amount of PEG (%, m/m, of calcium size fraction, determined by helium pycnometry as earliercarbonate) used was 15.5% with the 5-mm powder, 15.0% described (Schæfer and Mathiesen, 1996a). In addition, forwith the 13-mm powder, 13.5% with the 34-mm powder, a representative group of fractions, the actual binder12.0% with the 39-mm powder, 9.5% with the 80-mm concentration of the fractions was estimated from apowder, and 4.0% with the 214-mm powder. Because of quantitative determination of the calcium carbonate byformation of frictional heat caused by the impeller rotation, titration (Pharmacopoea Nordica, 1963). The two tech-the product temperature increased during mixing to a niques produced similar results, and the actual concen-temperature exceeding the melting point of the PEG. The trations of the fractions were found to be close to themelting point was observed as an inflection point on the nominal concentration. The density of the agglomerate sizerecorded product temperature curve. This inflection point fractions, therefore, was calculated from the nominal PEGwas defined as the start of massing time. Two minutes after concentration and used in the calculations of the intra-the melting point was observed on the temperature curve, granular porosity.the impeller speed was lowered to 800 rpm. After 8 min ofadditional massing time, the agglomeration procedure wasterminated. 2.4.3. Scanning electron microscopy

At the end of each experiment, the agglomerates were Photographs of agglomerate size fractions 250–2000sieved on a 4-mm Jel-Fix 50 vibration sieve (J. En- mm were taken by a scanning electron microscope (SEM)gelsmann, Germany) for about 10 s, until the fraction finer (Jeol JSM 5200, Japan).than 4 mm had passed. The agglomerates were then spreadout in thin layers on trays allowing them to cool at ambienttemperature. The adhesion of mass to the bowl was 2.4.4. Binder distribution in size fractionsestimated as previously described (Schæfer, 1996a). A sample was drawn by scooping approximately 200 g

from the cooled fraction finer than 4 mm. A series of 72.4. Agglomerate characterisation ASTM standard sieves in the range of 180–1400 mm was

vibrated by a Fritsch analysette 3 vibrator (Fritsch, Ger-2.4.1. Size distribution many) for 10 min, and the single size fractions were

The size distributions of the agglomerates were esti- collected. The actual PEG concentration of the single sizemated by sieve analysis of a sample drawn by scooping fractions was estimated by helium pycnometry as de-approximately 100 g from the cooled fraction finer than 4 scribed in Section 2.4.2. The analyses were performed inmm. A series of 14 ASTM standard sieves in the range of duplicate.


Table 1 ticles per volume will rise, the binding forces between thePhysical properties of the calcium carbonates solid particles will be higher, and the powder resistance toCalcium Particle size True Specific Inter- compaction will increase resulting in a higher interparticu-carbonate density surface particular lar porosity. This is seen in Table 1, except for the largestD(v;0.5) Span 3grade (g /cm ) area porosity

(mm) powder particle size. This probably compacts less than2(m /g) (%)expected because of its narrower size distribution (span).

Durcal 5 5 2.5 2.80 2.31 60 The solubility of calcium carbonate in PEG was found toDurcal 10 13 2.6 2.78 1.62 54

be less than 0.1% at 908C.Durcal 15 34 1.7 2.76 0.89 45The physical properties of the PEGs are shown in TableDurcal 40 39 2.4 2.74 0.75 43

Durcal 65 80 2.8 2.73 0.37 37 2. The initial median diameter and the span of the sizeDurcal 130 214 1.5 2.73 0.25 42 distribution are shown. It has been demonstrated, however,

that the particle size of the flakes becomes reduced duringdry mixing (Schæfer and Mathiesen, 1996a). The initial

2.5. Experimental design size of the molten binder droplets, therefore, will besmaller than the values in Table 2. The density of the

Six calcium carbonates of different particle size were molten PEG 35000 S could not be measured due to theagglomerated with each of six types of PEG. The experi- very high viscosity of the molten binder. The densityments were carried out in duplicate giving a total of 72 values of the molten PEGs at the final product temperatureexperiments. were estimated for each experiment by means of extrapola-

The experiments were performed in a randomized order. tion of the regression line. This value was used for theAll data presented in this paper are mean values of the calculation of the liquid saturation of the agglomerates.repeated experiments. The data were analysed for theeffect of viscosity by a one-way analysis of variance for 3.2. Binder concentrationeach calcium carbonate grade.

The binder concentration necessary for agglomerationusually becomes increased with a smaller powder particle

3. Results and discussion size (Schæfer et al., 1992b; Schæfer, 1996a; Knight et al.,1998). The binder concentration had to be varied for each

3.1. Raw material properties calcium carbonate grade and was chosen on the basis ofpreliminary experiments for each grade as the concen-

The particle properties of the calcium carbonates are tration approximately 0.5% (m/m) below the amount ofshown in Table 1. The mean particle size of the calcium PEG 3000 S resulting in overwetted agglomerates. Thecarbonate grades covers the spectrum from small and binder liquid requirement is assumed to be related to thecohesive particles (Durcal 5 and 10) to particles (Durcal surface area of the particles since the surface of the130) having a size that is similar to a usual agglomerate particles has to be wetted in order to form nuclei. Further,size. the amount of liquid necessary to obtain a liquid saturation

The true density of the calcium carbonates is slightly that is sufficient for agglomerate growth, depends on thedecreasing with a rise in powder particle size. This could packing of the particles and is supposed, therefore, to bebe due to voids within the larger particles. As to be related to the interparticular porosity (Schæfer, 1996b).expected, the specific surface area of the particles lessens Fig. 1 illustrates the correlation between the necessarywith a larger particle size. The interparticular porosity binder concentration and the specific surface area as wellreflects the compactability of the powders. For small as the interparticular porosity of the powder. Data fromparticles, the number of contact points between the par- previous melt agglomeration experiments with PEG in the

Table 2Physical properties of the PEGs

Type Median Span True Density (molten) Melting point Viscosityof diameter density

708C 808C 908C Range Peak 708C 808C 908CPEG (mm) (solid)

(g /ml) (g /ml) (g /ml) (8C) temp. (mPas) (mPas) (mPas)3(g /cm )(8C)

1500S 1075 0.8 1.224 1.085 1.076 1.068 41–47 46 66 51 383000S 1175 1.3 1.229 1.086 1.080 1.068 47–58 56 196 148 1216000S 1127 1.9 1.231 1.087 1.076 1.068 50–61 59 760 541 45410000S 897 1.5 1.228 1.087 1.077 1.070 51–62 61 3332 2415 179120000S 1340 1.4 1.231 1.089 1.081 1.072 55–63 62 24 382 19 051 13 95535000S 1284 1.1 1.229 – – – 55–65 63 137 592 105 252 76 440


illustrated by the fact that the mannitol gave rise tocorrected intragranular porosities (Schæfer, 1996b) thatwere lower than those obtained with the calcium carbon-ates of a similar interparticular porosity (Fig. 2).

Fig. 1 shows that although data on specific surface areaand interparticular porosity might be useful for a predictionof the binder liquid requirement, there is no generalcorrelation between neither the surface area nor theinterparticular porosity and the binder liquid requirement.

3.3. Intragranular porosity and liquid saturation

The corrected porosity and the liquid saturation of theagglomerates are shown in Fig. 2. No data are presentedfor the 5- and 13-mm powders agglomerated with PEG35000 S because of an insufficient agglomerate growth inthese experiments, as will be discussed in Section 3.5. Asseen in Fig. 2a, the agglomerate porosity is decreasing witha rise in powder particle size. This corresponds well to thedifferences in interparticular porosity (Table 1). Thisindicates that a decreasing particle size will still increase

Fig. 1. Relation between (a) the specific surface area and (b) the the resistance of the powder to compaction, although theinterparticular porosity and the binder liquid requirement in melt ag- densification is more pronounced in the high shear mixerglomeration experiments with different raw materials: (d) calcium

than in the tapping apparatus (Schæfer, 1996b).carbonate (present data), (m) mannitol (data from Schæfer, 1996b), (j)For the calcium carbonates of a particle size of 13 mmanhydrous lactose, and (3) anhydrous dicalcium phosphate (data from

Schæfer and Mathiesen, 1996b). and larger, the porosity is independent of the binderviscosity, but for the 5-mm powder there is a significant(P,0.0001) increase in porosity when high viscosity

same high shear mixer are included in order to evaluate binders (PEG 10000 S and 20000 S) are used. Thesewhether general correlations exist. The binder concen- findings correlate well with earlier propositions saying thattration is expressed in percent (m/v) in order to be able to a decreasing particle size as well as an increasing bindercompare raw materials with different densities.

Fig. 1a illustrates that the amount of binder per surfacearea decreases when the surface area increases. This isbecause the smaller particle size, corresponding to a largersurface area, increases the agglomerate strength thusreducing the binder liquid requirement (Schæfer, 1996b).The correlation is seen to be similar for calcium carbonateand mannitol, whereas the results obtained with anhydrouslactose and anhydrous dicalcium phosphate deviate. Thedifference in the liquid requirement of powders with asimilar specific surface area is assumed to be due todifferent surface properties, e.g., the low liquid require-ment of the anhydrous dicalcium phosphate was ascribedto surface irregularities, which caused an interlocking ofparticles reducing the need of binder liquid (Schæfer andMathiesen, 1996b).

Fig. 1b shows that, for the calcium carbonates, thecorrelation between interparticular porosity and binderconcentration is similar to that seen for the specific surfacearea, except for the 214-mm powder, which has anatypically large particle size. The binder liquid requirementfor the mannitol, at a certain interparticular porosity, is

Fig. 2. Effect of type of PEG on (a) the corrected intragranular porositymarkedly lower than that for the calcium carbonate. This is and (b) the liquid saturation of the agglomerates for different calciumbecause the densification in the high shear mixer is not carbonate particle sizes: (♦) 5 mm, (j) 13 mm, (m) 34 mm, (—) 39 mm,directly related to that in the tapping apparatus. This is (3) 80 mm, and (d) 214 mm.


viscosity decrease the consolidation rate of agglomerates agglomerates when applying a lower binder viscosity. A(Ennis et al., 1991; Iveson et al., 1996; Iveson and Litster, higher deformability creates more heat of friction.1998). The adhesion of material to the bowl varied between 1

The liquid saturation has a great influence on the and 11% (m/m) and was generally higher for the calciumagglomerate growth, and it is controlled by the amount of carbonates with a smaller powder particle size. This isbinder solution and by the intragranular porosity (Kristen- because of the higher cohesiveness of the smaller particlessen et al., 1984). Typically, when agglomerating in a high (Schæfer, 1996a). For the 5-, 80-, and 214-mm powders,shear mixer, the liquid saturation has to approach 100% in the adhesion was significantly greater (0.002,P,0.034) atorder to obtain a deformability that is sufficient for a higher viscosity, in accordance with earlier findingsagglomerate growth by coalescence (Schæfer, 1996a). It (Schæfer and Mathiesen, 1996c). However, for the inter-can be seen from Fig. 2b that when the small powder mediate powder particle sizes (the 13-, 34-, and 39-mmparticles are agglomerated with binders of a high viscosity, powders) viscosity had no significant effect on the adhe-it results in a liquid saturation well below 100%. This is a sion of mass to the bowl.consequence of the higher porosities obtained in theseexperiments. 3.5. Agglomerate growth mechanisms

The mass median agglomerate sizes obtained in the3.4. Product temperature and adhesion experiments are outlined in Fig. 4 as a function of the

binder type employed. As a consequence of the differenceThe temperature of the product rises during processing in the liquid requirement of the calcium carbonate grades,

because of a formation of heat of friction. Fig. 3 illustrates the results obtained with different grades are not directlythe temperature rise over the melting point during process- comparable. For all calcium carbonates, however, thereing. Although the formation of heat of friction might be seems to be an increase in agglomerate size with increas-supposed to depend on the cohesiveness of the powder, no ing binder viscosity until a growth optimum is reached,clear effect of particle size on the rise in product tempera- after which a further increase in binder viscosity impedesture is seen, except for the 5- and 13-mm powders the agglomerate growth. An optimum viscosity for ag-agglomerated with PEG 35000 S. For these experiments, glomeration has previously been observed in drum granu-the final product temperature is only 5–78C over the lation (Simons et al., 1993).melting point (peak temperature) of the PEG 35000 S Fig. 4 indicates that the agglomerate growth depends onbecause of the insufficient agglomerate growth mentioned the deformability of the agglomerates (Kristensen et al.,above. For the remaining experiments, the temperature rise 1985a,b). At a low binder viscosity, the agglomeratesover the melting point varies from 22 to 478C depending deform too much, and agglomerate growth is affected byon the binder used. The actual final product temperatures breakage. At a high binder viscosity, the deformability isvaried from 84 to 938C. insufficient, and this will counteract an agglomerate

The effect of type of PEG on the temperature rise is growth by coalescence. Consequently, a growth optimumsignificant (0.000,P,0.002). A lower binder viscosity is seen at an intermediate deformability. A higher agglom-gives rise to a higher temperature rise. This is in accord- erate strength will decrease the deformability (Kristensenance with previous results (Schæfer et al., 1990, 1992a) et al., 1985a,b), and the growth optimum, therefore, willand is explained by the increased deformability of the also depend on the particle size of the calcium carbonate as

will be discussed below.

Fig. 3. Effect of type of PEG on the temperature rise over the meltingpoint of the PEG during agglomeration of different calcium carbonate Fig. 4. Effect of type of PEG on the mass median diameter of theparticle sizes: (♦) 5 mm, (j) 13 mm, (m) 34 mm, (—) 39 mm, (3) 80 agglomerates for different calcium carbonate particle sizes: (♦) 5 mm,mm, and (d) 214 mm. (j) 13 mm, (m) 34 mm, (—) 39 mm, (3) 80 mm, and (d) 214 mm.


Since the agglomerate size distributions are rather high viscosity will simultaneously decrease the defor-different, the mass median diameter alone is insufficient in mability of the agglomerates, and this might counteract theorder to evaluate the agglomerate growth mechanisms. The agglomerate growth (Schæfer and Mathiesen, 1996c). Thisdiscussion of the agglomerate growth mechanisms, there- is obviously happening when PEG 10000 S or PEG 20000fore, is based upon the agglomerate size distributions. The S is employed. The deformability will be especially low inhistograms show the mean of two agglomeration experi- the experiments in Fig. 5 because of the cohesiveness ofments, and the error bars represent the range. the small particles being used. Further, the low liquid

Fig. 5 presents the agglomerate size distributions ob- saturations obtained with PEG 10000 S and PEG 20000 Stained with the calcium carbonate grade having the small- (Fig. 2b) contribute to the decelerated agglomerate growth.est particle size. It is seen that a higher binder viscosity No data are presented for PEG 35000 S owing to anincreases the agglomerate growth, until an optimum of insufficient agglomerate growth. For these experiments, thegrowth is reached with PEG 6000 S. It follows from end product consisted of a mixture of unagglomeratedcurrent theory that a higher viscosity promotes agglomer- powder particles and powder particles immersed in theate growth by coalescence (Ennis et al., 1991). However, a surface of binder particles. This is because the combination

of a cohesive powder and a highly viscous binder impedesthe distribution of binder. With the PEG 10000 S and20000 S, the viscosity is still so high that the binderdistribution becomes difficult. Therefore, a marked amountof particles below 75 mm is seen, especially with PEG20000 S, indicating the presence of unagglomerated pow-der particles.

Fig. 6 shows that spherical agglomerates (pellets) wereobtained by a combination of cohesive particles (5 mm)and a low viscosity binder. The small particle size gaverise to an agglomerate strength being sufficient to resist theforces imposed by the mixer, and the low viscosity madethe agglomerates sufficiently deformable to get properlyrounded. The spherical shape of the agglomerates indicatesthat agglomerate formation and growth occurred mainly bydistribution and coalescence.

When applying a high viscosity binder, the dominatingagglomerate formation mechanism is immersion (Fig. 7).The agglomerates are seen to be of a platelike shaperesembling the original shape of the binder flakes. Smallpowder particles can be identified on the surface of the

Fig. 6. SEM photograph of agglomerates produced with a low binderFig. 5. Effect of type of PEG on the agglomerate size distribution. viscosity and a small powder particle size. Powder particle size, 5 mm;Powder particle size, 5 mm; binder concentration, 15.5%. binder, 15.5% PEG 1500 S.


Fig. 7. SEM photograph of agglomerates produced with a high binderviscosity and a small powder particle size. Powder particle size, 5 mm;binder, 15.5% PEG 20000 S.

agglomerates. The high binder viscosity causes the poorlyrounding of these agglomerates. PEG 10000 S gave rise toagglomerates of a similar shape with the 5-mm powder.

For the 13-mm powder (Fig. 8), the agglomerate growthbecomes likewise decreased when applying a binder ofhigh viscosity (PEG 10000 S and 20000 S). As for thesmallest particle size, the 13-mm powder agglomeratedwith PEG 35000 S resulted in insufficient agglomerategrowth and unagglomerated powder. However, the dis-tribution of the PEG 10000 S and PEG 20000 S is easier inthe 13-mm powder, as indicated by only a minor content ofparticles below 75 mm. The same formation and growthmechanisms as explained for Fig. 5 are most probablyresponsible for the formation and growth in Fig. 8. Thehigh viscosity resulted in poorly rounded agglomerateswith PEG 20000 S. The lower the viscosity applied, themore rounded/spherical became the agglomerates.

When the powder particles become larger, a higherbinder viscosity is needed to give the necessary strength to Fig. 8. Effect of type of PEG on the agglomerate size distribution.the agglomerates (Keningley et al., 1997). If the agglomer- Powder particle size, 13 mm; binder concentration, 15.0%.ates do not have the sufficient strength to survive theforces imposed in the mixer, a consequence will bebreakage and comminution of the agglomerates. This is the result in weak agglomerates. As can be seen, the agglomer-explanation for the bimodal size distribution seen with the ate structure is loose, and the agglomerates are onlylowest binder viscosity, PEG 1500 S, in Fig. 9, and equally slightly densified. Also small parts of broken agglomeratesin Fig. 10 for PEG 1500 S and 3000 S, and in Fig. 11 for are present indicating that breakage is involved.PEG 1500 S, PEG 3000 S, PEG 6000 S, and PEG 10000 As for the smaller particles, an optimum binder viscosityS, i.e., the larger the particle size of the constituent can be found above which a further increase in binderparticles, the higher the binder viscosity necessary in order viscosity decreases the growth. For the 34-mm powderto avoid breakage. In this study, the impeller speed was (Fig. 9) and the 39-mm powder (Fig. 10), this optimumkept constant at an intermediate rate (800 rpm). It has to be appears with PEG 10000 S, and for the 80-mm powdermentioned, therefore, that a different impeller speed would (Fig. 11) PEG 20000 S results in the optimum growth. Themost likely have affected the balance between breakage displacement of this optimum against a higher viscosityand growth by coalescence (Eliasen et al., 1999). with a larger particle size is due to an increased de-

Fig. 12 shows that large powder particles (80 mm) formability of the agglomerates caused by a reducedagglomerated with a low viscosity binder (PEG 1500 S) agglomerate strength.


Fig. 10. Effect of type of PEG on the agglomerate size distribution.Powder particle size, 39 mm; binder concentration, 12.0%.Fig. 9. Effect of type of PEG on the agglomerate size distribution.

Powder particle size, 34 mm; binder concentration, 13.5%.

the 34-mm powder agglomerated with PEG 3000 S toThe larger powder particle sizes of the 34-, 39-, and 20000 S, the 39-mm powder with PEG 6000 S to 20000 S,

80-mm powders made it possible to obtain a uniform and the 80-mm powder with PEG 20000 S indicated thatdistribution of PEG 35000 S and consequently to form distribution and coalescence were the mechanismsagglomerates. These agglomerates were oblong and dominating in the agglomerate formation and growth.formed like the original binder flakes, indicating that Fig. 13 illustrates that the agglomerate growth of theimmersion was the dominating mechanism involved in the coarse calcium carbonate particles (214 mm) is not par-agglomerate growth. The appearance of agglomerates from ticularly affected by the binder viscosity. Only a slight


Fig. 12. SEM photograph of agglomerates produced with a low binderviscosity and a large powder particle size. Powder particle size, 80 mm;binder, 9.5% PEG 1500 S.

(Tardos et al., 1997), the agglomerate growth with the214-mm powder will occur by a layering mechanism,where small particles become layered on larger particles,combined with coalescence between the smallest particles.The particle size distribution of the 214-mm powder isrelatively narrow (cf. Table 1), and therefore the potentialfor growth by layering is limited. Fig. 14 illustrates that thelarge particle size results in a loose agglomerate structureand weak agglomerates that can easily break down. Smallparticles are seen to be layered on the largest particles.

3.6. Binder distribution

The distribution of the binder in size fractions of theagglomerates was examined for a few agglomerationexperiments (Fig. 15). It appears that for the experimentswith a small powder particle size and a low binderviscosity (Fig. 15a) and for a large powder particle size incombination with a high binder viscosity (Fig. 15d) thebinder is evenly distributed.

When a small powder particle size is agglomerated witha binder of high viscosity (Fig. 15b), the binder becomesunevenly distributed in the agglomerate size fractions,because the cohesive forces between the particles impede auniform distribution of the binder. This supports theprevious findings from Fig. 5 and indicates that a mecha-Fig. 11. Effect of type of PEG on the agglomerate size distribution.

Powder particle size, 80 mm; binder concentration, 9.5%. nism of immersion is dominating in the agglomerationprocess. Immersion results in the highest binder con-centration in the agglomerate size fraction that corresponds

increase in agglomerate size is recognized when increasing to the size of the molten binder droplets (Schæfer andthe binder viscosity up to PEG 10000 S. Further, the Mathiesen, 1996a). As more powder becomes immersed inagglomerate size is only slightly larger compared with the the droplets, the agglomerate size is growing, and theparticle size of the initial particles. The largest particles are binder concentration becomes slightly lowered.unable to form agglomerates by coalescence, because the When a large powder particle size is agglomerated withbinding forces between the particles are too weak. Since it a binder of low viscosity (Fig. 15c), the binder is also seenis much easier to bind a small particle to a large one to distribute unevenly in the agglomerate size fractions.


Fig. 14. SEM photograph of agglomerates produced with a high binderviscosity and a large powder particle size. Powder particle size, 214 mm;binder, 4.0% PEG 10000 S.

binder content (Knight et al., 1998), and partly because theweak agglomerates of the lowest binder content will growslower and easily break down. The data in Fig. 15c,

Fig. 13. Effect of type of PEG on the agglomerate size distribution.Powder particle size, 214 mm; binder concentration, 4.0%.

The agglomerates formed are weak, and only agglomerateswith a high initial binder content will be strong enough tosurvive in the mixer. These agglomerates gain additionalstrength by densification and will be able to grow in size

Fig. 15. Effect of calcium carbonate particle size and type of PEG onby coalescence. The uneven binder distribution will most binder distribution in size fractions for (a) 15.5% PEG 1500 S in 5-mmlikely be self-preserving partly because of a higher prob- powder, (b) 15.5% PEG 20000 S in 5-mm powder, (c) 9.5% PEG 1500 Sability of coalescence between agglomerates with a higher in 80-mm powder, and (d) 9.5% PEG 20000 S in 80-mm powder.


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Ennis, B.J., Tardos, G., Pfeffer, R., 1991. A microlevel-based characteri-size distributions in Fig. 11.zation of granulation phenomena. Powder Technol. 65, 257–272.

European Pharmacopoeia, 1999. 3rd ed. Council of Europe, Strasbourg,pp. 141–142.

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Iveson, S.M., Litster, J.D., Ennis, B.J., 1996. Fundamental studies ofFor small powder particles and low binder viscosities, thegranule consolidation. Part 1: Effects of binder content and binder

dominating agglomerate growth mechanisms are growth by viscosity. Powder Technol. 88, 15–20.nucleation and coalescence. When the binder viscosity Kapur, P.C., 1978. Balling and granulation. Adv. Chem. Eng. 10, 55–123.becomes very high, immersion of particles in the binder Keningley, S.T., Knight, P.C., Marson, A.D., 1997. An investigation into

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Knight, P.C., 1993. An investigation of the kinetics of granulation using aof particles on the surface of the agglomerates. If the high shear mixer. Powder Technol. 77, 159–169.powder applied has a large particle size, a high binder Knight, P.C., Instone, T., Pearson, J.M.K., Hounslow, M.J., 1998. Anviscosity is necessary in order to achieve an agglomerate investigation into the kinetics of liquid distribution and growth in high

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Powder Technol. 88, 197–202.214 mm could not be satisfactorily agglomerated, even Kristensen, H.G., Holm, P., Jægerskou, A., Schæfer, T., 1984. Granula-with a very high binder viscosity (|100 Pas at 808C). tion in high speed mixers. Part 4: Effect of liquid saturation on the

The study demonstrates that agglomerate growth is agglomeration. Pharm. Ind. 46, 763–767.Kristensen, H.G., Holm, P., Schæfer, T., 1985a. Mechanical properties offavoured by an intermediate agglomerate strength. An

moist agglomerates in relation to granulation mechanisms. Part I.intermediate strength makes the agglomerates resistant toDeformability of moist, densified agglomerates. Powder Technol. 44,

breakage and, at the same time, sufficiently deformable for 227–237.agglomerate growth by coalescence. Kristensen, H.G., Holm, P., Schæfer, T., 1985b. Mechanical properties of

The results presented in this paper verify the hypothesis moist agglomerates in relation to granulation mechanisms. Part II.Effects of particle size distribution. Powder Technol. 44, 239–247.that it will be possible to obtain a controllable agglomerate

Linkson, P.B., Glastonbury, J.R., Duffy, G.J., 1973. The mechanism ofgrowth with powders having a particle size up to 80 mm bygranule growth in wet pelletising. Trans. Inst. Chem. Eng. 51, 251–

combining the particle size and binder viscosity in order to 259.optimize the agglomerate strength. In order to produce Mackaplow, M.B., Rosen, L.A., Michaels, J.N., 2000. Effect of primarypellets, a low viscosity binder has to be chosen when the particle size on granule growth and endpoint determination in high-

shear wet granulation. Powder Technol. 108, 32–45.powder particles are small and cohesive, and a highNewitt, D.M., Conway-Jones, J.M., 1958. A contribution to the theoryviscosity binder must be applied in case of large powder

and practice of granulation. Trans. Inst. Chem. Eng. 36, 422–442.particles. This strategy can broaden the interval of powder Pharmacopoea Nordica, Editio Danica, Vol. 11, 1963, Nyt Forlag Arnoldparticle sizes being suitable for pelletization. Busck, Copenhagen, p. 128.

Rumpf, H., 1962. The strength of granules and agglomerates. In:Knepper, W.A. (Ed.), Agglomeration. Interscience Publishers, NewYork, pp. 379–418.

Acknowledgements Schæfer, T., 1996a. Melt pelletization in a high shear mixer VI.Agglomeration of a cohesive powder. Int. J. Pharm. 132, 221–230.

Schæfer, T., 1996b. Melt pelletization in a high shear mixer. X.The authors wish to thank Omya, France, for supplyingAgglomeration of binary mixtures. Int. J. Pharm. 139, 149–159.the calcium carbonates and Clariant GmbH, Germany, for

Schæfer, T., Mathiesen, C., 1996a. Melt pelletization in a high shearsupplying the PEGs. mixer. IX. Effects of binder particle size. Int. J. Pharm. 139, 139–148.

Schæfer, T., Mathiesen, C., 1996b. Melt pelletization in a high shearmixer. VII. Effects of product temperature. Int. J. Pharm. 134, 105–117.

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