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Ž . Powder Technology 108 2000 32–45 www.elsevier.comrlocaterpowtec Effect of primary particle size on granule growth and endpoint determination in high-shear wet granulation Michael B. Mackaplow 1 , Lawrence A. Rosen ) , James N. Michaels Merck & Co., Inc., WP78A-31, P.O. Box 4, West Point, PA 19486-0004, USA Received 12 October 1998; accepted 30 August 1999 Abstract The effect of primary particle size on granule growth and endpoint determination during high-shear wet granulation was investigated. Ž . Three different grades of lactose monohydrate, having different volume mean particle sizes 39, 84, and 127 mm , were granulated with water in a 25-l high-shear mixer. Increasing primary particle size results in larger, less porous wet granules. This is consistent with the expectation that both the capillary and viscous interparticle forces decrease with increasing primary particle size, and the resulting granules become more deformable. Increasing the volume of granulating liquid reduces the porosity, but has only a minor influence on wet granule size. In contrast, the apparent dry granule size increases markedly with increasing granulating liquid. Changes in the impeller torque correlated reasonably well with changes in the wet granule size distribution, although torque is not a state function of wet granule size. It is also influenced by primary particle size and the chaotic nature of wall build-up and collapse. Impeller torque correlated poorly with apparent dry granule size. This is because of the changing nature of interparticle forces upon drying. Thus, understanding the relationship between impeller torque and dry granule size requires understanding both wet and dry granule interparticle forces and how they are influenced by pore saturation and primary particle size. One needs to be keenly aware of these limitations if using impeller torque to determine granulation endpoint. q 2000 Elsevier Science S.A. All rights reserved. Keywords: Agglomeration; Granulation; Mixers; Particle size; Power curves 1. Introduction Wet granulation is a unit operation in which fine pow- ders are agglomerated by mixing them with a liquid. It is used in a number of industries and employs various types wx of equipment 1 . In the pharmaceutical industry, wet granulation is used to combine active drugs and inert excipients into granules that have good flow and tabletting properties. This is commonly done in high-shear granula- tors, a class of mixers that use a rapidly rotating impeller to granulate with typical process times on the order of minutes. Because of its industrial importance, many studies have attempted to understand the effect of processing conditions ) Corresponding author. Tel.: q1-215-652-8925; fax: q1-215-652- 2132; e-mail: larry_[email protected] 1 Abbott Laboratories, Department 4P8, Bldg. A4r4, 1401 Sheridan Rd., North Chicago, IL 60064-6235, USA. and solid and liquid properties on the granule properties w x 2–39 . Although much has been learned, fundamental understanding has been encumbered by the fact that the dynamics of solid–liquid granular systems are poorly un- derstood. As a result, wet granulation processes are gener- ally empirically designed. Theoretical analyses of granulation have focused on capillary and viscous interparticle fluid forces and granule wx deformability. Newitt and Conway-Jones 2 noted that increases in liquid saturation enhance the capillary cohe- sive forces and increase granule deformability. These ef- fects increase the probability that two colliding granules w x will coalesce 2,40,41 , and hence agglomeration proceeds w x w x further 8,10,12,18,25,34 . In contrast, Ennis et al. 42 argued that viscous forces control agglomeration kinetics. They assumed two colliding particles will coalesce if the kinetic energy of their collision can be dissipated by the flow of binder between the particles. It follows that gran- ules will grow only until reaching a critical size that 0032-5910r00r$ - see front matter q 2000 Elsevier Science S.A. All rights reserved. Ž . PII: S0032-5910 99 00203-X

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Ž .Powder Technology 108 2000 32–45www.elsevier.comrlocaterpowtec

Effect of primary particle size on granule growth and endpointdetermination in high-shear wet granulation

Michael B. Mackaplow 1, Lawrence A. Rosen ), James N. MichaelsMerck & Co., Inc., WP78A-31, P.O. Box 4, West Point, PA 19486-0004, USA

Received 12 October 1998; accepted 30 August 1999

Abstract

The effect of primary particle size on granule growth and endpoint determination during high-shear wet granulation was investigated.Ž .Three different grades of lactose monohydrate, having different volume mean particle sizes 39, 84, and 127 mm , were granulated with

water in a 25-l high-shear mixer. Increasing primary particle size results in larger, less porous wet granules. This is consistent with theexpectation that both the capillary and viscous interparticle forces decrease with increasing primary particle size, and the resultinggranules become more deformable. Increasing the volume of granulating liquid reduces the porosity, but has only a minor influence onwet granule size. In contrast, the apparent dry granule size increases markedly with increasing granulating liquid. Changes in the impellertorque correlated reasonably well with changes in the wet granule size distribution, although torque is not a state function of wet granulesize. It is also influenced by primary particle size and the chaotic nature of wall build-up and collapse. Impeller torque correlated poorlywith apparent dry granule size. This is because of the changing nature of interparticle forces upon drying. Thus, understanding therelationship between impeller torque and dry granule size requires understanding both wet and dry granule interparticle forces and howthey are influenced by pore saturation and primary particle size. One needs to be keenly aware of these limitations if using impeller torqueto determine granulation endpoint. q 2000 Elsevier Science S.A. All rights reserved.

Keywords: Agglomeration; Granulation; Mixers; Particle size; Power curves

1. Introduction

Wet granulation is a unit operation in which fine pow-ders are agglomerated by mixing them with a liquid. It isused in a number of industries and employs various types

w xof equipment 1 . In the pharmaceutical industry, wetgranulation is used to combine active drugs and inertexcipients into granules that have good flow and tablettingproperties. This is commonly done in high-shear granula-tors, a class of mixers that use a rapidly rotating impellerto granulate with typical process times on the order ofminutes.

Because of its industrial importance, many studies haveattempted to understand the effect of processing conditions

) Corresponding author. Tel.: q1-215-652-8925; fax: q1-215-652-2132; e-mail: [email protected]

1 Abbott Laboratories, Department 4P8, Bldg. A4r4, 1401 SheridanRd., North Chicago, IL 60064-6235, USA.

and solid and liquid properties on the granule propertiesw x2–39 . Although much has been learned, fundamentalunderstanding has been encumbered by the fact that thedynamics of solid–liquid granular systems are poorly un-derstood. As a result, wet granulation processes are gener-ally empirically designed.

Theoretical analyses of granulation have focused oncapillary and viscous interparticle fluid forces and granule

w xdeformability. Newitt and Conway-Jones 2 noted thatincreases in liquid saturation enhance the capillary cohe-sive forces and increase granule deformability. These ef-fects increase the probability that two colliding granules

w xwill coalesce 2,40,41 , and hence agglomeration proceedsw x w xfurther 8,10,12,18,25,34 . In contrast, Ennis et al. 42

argued that viscous forces control agglomeration kinetics.They assumed two colliding particles will coalesce if thekinetic energy of their collision can be dissipated by theflow of binder between the particles. It follows that gran-ules will grow only until reaching a critical size that

0032-5910r00r$ - see front matter q 2000 Elsevier Science S.A. All rights reserved.Ž .PII: S0032-5910 99 00203-X

( )M.B. Mackaplow et al.rPowder Technology 108 2000 32–45 33

Fig. 1. Cumulative particle size distribution of lactose monohydrategrades F, M, and C.

depends on the amount of binder and its viscosity. Unlikeprevious work, this model quantitatively predicted theeffect of material and process variables. However, themodel assumes that the granules are non-deformable, andthis is questionable for agglomerates of more than a fewparticles. In order to account for granule deformability,

w xAdetayo et al. 43 proposed that, after the initial viscous-dissipation controlled growth stage, coalescence takes placeprimarily among larger, more deformable granules. More

w xrecently, Iveson and Litster 39 proposed a ‘‘growth regimemap’’ for liquid-bound granules that suggests that capil-lary, viscous, and frictional forces may all be important,

w xwith the particular balance being system-dependent 37,38 .To compensate for the limited ability to model and

control granulation processes, high-shear processes aresometimes ‘‘controlled’’ by monitoring the power or torque

wrequired to rotate the mixing blade 4,5,9,12,18,26,28,44–x49 . Granulation is terminated once the power or torque

reaches a level experimentally determined to produce gran-

ules with desirable properties. The lack of fundamentalunderstanding dictates that such control algorithms areempirically developed for each material–process combina-tion.

In an effort to increase the fundamental understandingof high shear granulation, we have investigated the effectof feed material particle size. In the pharmaceutical indus-try, the tablet formulator must choose from a number ofcommercially available powder grades. Even after thegrade is specified, the particle size will often vary withinsome broadly defined specification. Thus, it is important tounderstand the effect of particle size on granulation kinet-ics and granule properties. In order to study particle sizeeffects in a manner that is amenable to fundamental under-standing, we use a two-component system in which lactoseis granulated with water. Lactose is used extensively as atablet diluent. We use three standard grades of lactosehaving widely differing mean particle sizes.

We have measured the impeller torque and powerŽcurves, wet granule properties size distribution, porosity,

. Žand pore saturation , and dry granule properties size dis-.tribution and porosity as a function of the amount of

liquid added. Previous investigations have related impellertorque and power to dry granule properties, since the drygranules are more directly related to the tablet product.However, few studies have analyzed both the wet and dry

w xgranules 15 , and, we are unaware of any that havemeasured all of these entities for the same system. Webelieve that understanding granulation requires characteri-zation of the wet granules, because the granule growthkinetics and the impeller torque and power are determinedby the properties of the wet, not the dry, granules. Therelationship between the wet and dry granule size distribu-tion depends on how the interparticle forces change duringdrying. Thus, to better understand granulation, we examinehow the wet and dry granule properties vary with primaryparticle size and granule liquid saturation.

Table 1Mass of liquid in samples taken from the granulator at various times. Values shown are relative to the theoretical amounts based on the total amount ofliquid added to the granulator. Each timergrade combination sampled in triplicate

Time Theoretical Lactose gradeŽ .min moisture

F M CŽ .m rmliquid dry solidŽ .% Mean Max Min Mean Max Min Mean Max Min

Ž . Ž . Ž . Ž . Ž . Ž . Ž . Ž . Ž .% % % % % % % % %

Granulation2 3.4 104 119 91 95 105 89 98 102 924 6.9 94 99 89 95 100 92 92 94 906 10.3 101 110 96 101 103 100 95 96 94

10 17.1 98 99 98 101 104 98 101 102 100

Wall build-up2 3.4 186 381 86 96 110 89 87 89 844 6.9 73 88 65 100 131 80 151 330 516 10.3 71 88 59 99 113 90 81 94 60

10 17.1 72 76 70 86 88 85 78 88 69

( )M.B. Mackaplow et al.rPowder Technology 108 2000 32–4534

2. Experimental

2.1. Materials

Three grades of lactose monohydrate, designated FŽ . Ž . Ž .‘‘Fine’’ , M ‘‘Medium’’ , and C ‘‘Coarse’’ , were gran-ulated with water. Grades F and M were supplied by

Ž .Foremost Farms USA Baraboo, WI ; grade C was sup-Ž .plied by Sheffield Products Norwich, NY . Their volume

mean particle diameters, as determined by a MicrotracŽSRA150 particle size analyzer Leeds & Northrup, St.

.Petersburg, FL were 39, 84, and 127 mm, respectively.The cumulative volume distributions are shown in Fig. 1.True densities of the three grades were measured with a

ŽQuantachrome Ultrapycnometer 1000 Boynton Beach,

. 3FL , and found to be 1.54"0.01 grcm , in good agree-ment with the published value for lactose monohydratew x52 . The tap densities of the three grades were 0.87"0.01,0.93"0.02, 0.92"0.02 grcm3, respectively. The close-ness of these values is important since different tap densi-ties imply different particle packing efficiencies, which can

w xindependently affect granule properties 2,3,50 .

2.2. Granulation procedure

Granulation was performed using 7 kg of lactose in aŽPharmaMATRIX PMA25 25-l mixer Aeromatic-Fielder,

.Hampshire, UK . A plexiglass top was used during manyof the experiments, allowing us to observe the progressionof the granulation. The impeller and chopper speeds were

Ž . Ž . Ž .Fig. 2. Effect of wet massing on wet granule size distribution: a lactose Fq10.3% water, b lactose Mq10.3% water, c lactose Cq17.1% water. InŽ . Ž . Ž .a and b , the error bars represent the low and high values of the three samples. In c , only one sample was tested.

( )M.B. Mackaplow et al.rPowder Technology 108 2000 32–45 35

Ž .Fig. 2 continued .

set at 250 and 3000 rpm, respectively. The mixer wasinstrumented to record both the indirect torque exerted on

Žand the power supplied to the impeller Specialty Measure-.ments, Whitehouse, NJ . Although impeller power is more

commonly measured than torque in industrial practice, itmay be less sensitive to changes in the wet mass. Powermay also be influenced by bearing wear and other changes

w xin the efficiency of the drive system 28,44,49–51 . Thepower and torque signals were recorded using a personal

Žcomputer running LabTech Notebook Laboratory Tech-.nologies, Wilmington, MA . The signals were smoothed

by averaging over 1-s increments.The dry powder was mixed for 2 min followed by the

continuous addition of water into the agitating mix. Waterwas delivered as a finely dispersed spray at a rate of 120

Žmlrmin using a Watson 505S Peristaltic pump Watson-.Marlow, Wilmington, MA and a TeeJet 800067 spray

Ž .nozzle Spraying Systems, Wheaton, IL . Mixing and liq-uid addition were continued until the specified time andthen both were terminated simultaneously. The granulatorwas opened and samples were taken from the top of thegranulation bed. Previous studies using similar equipmenthave shown that the mixing is sufficiently good that thegranule properties are independent of vertical location in

w xthe bed 15 . For the experiments in which the effect ofwet massing was studied, the granulator was reclosed andmixing was continued without further liquid addition fortwo additional minutes before resampling. This was re-peated for three to four cycles. Water at 158C was circu-

Žlated CFT33 Refrigerated Circulator, Neslab, Newiston,.NH in a jacket around the mixing bowl in order to

w xminimize viscous heating of the wet mass 6,8,28,34 . Thisallowed the wet mass temperatures to be maintained be-tween 188C and 318C for all experiments, reducing evapo-

w xrative water losses 18 and minimizing changes in lactosew xsolubility over the course of the granulation 52 .

2.3. Wet and dry granule analysis

In order to determine the amount of water in the wetmass, 3–7 g samples were taken and immediately placedin air-tight containers. Three samples were taken from thefree-flowing granulation at angular positions separated by;1208. Similar samples were taken from the wall build-up.Moisture content was determined from weight loss ondrying at 758C for approximately 24 h, which was suffi-cient to remove all water added to the lactose duringgranulation, without removing the water of hydration.

The wet granules were too deformable and adhesive tosieve. For this reason, we measured the size distribution offrozen granules. Three 50–80 g samples were taken fromthe granulator and immediately placed into beakers ofliquid nitrogen. Sieving was accomplished by first pouringthe liquid nitrogen from the beaker through the 7-in.sieves, in order to cool them, and then pouring the frozengranules onto the topmost sieve. The sieves were placed on

Ža CSC Scientific Shaker, Catalog a18480 CSC Scientific,.Fairfax, VA at a moderate amplitude for 90 s. Similar

‘‘frozen sieve’’ techniques have been used previouslyw x38,53 .

One may ask if immersion in liquid nitrogen alters thewet granule size distribution. We performed two experi-ments to test this. First, after sieving, the granules wereallowed to thaw, and then placed again in liquid nitrogenand resieved. This cycle was repeated four times. If thefreezing process causes agglomeration, then we wouldexpect the mean size to increase with each successivecycle. The mean size actually decreased slightly with eachcycle, probably due to attrition during the sieving. Itappears, therefore, that any agglomeration due to freezing

Ž .of surface water is too weak to survive 1 the particlecollisions resulting from the boiling action when the wet

Ž .granules are immersed in the liquid nitrogen, andror 2

( )M.B. Mackaplow et al.rPowder Technology 108 2000 32–4536

the subsequent sieving. In another experiment, dry lactosepowder was poured into liquid nitrogen and sieved by thesame method used for the wet granules. In this case, therewas much less boiling action and very weak powder flocsformed. These generally did not survive the sieving opera-tion, and almost certainly would not if placed with frozen‘‘real’’ granules in the sieve. Thus, we conclude that ourmethod of size determination for the frozen granules doesnot induce agglomeration and gives a good estimate of thesize of the agglomerates in the wet granulation.

We note that some of our initial experiments used 3-in.Ž .sieves, smaller 10–20 g samples, and a different sieve

agitation method. The latter consisted of placing the sievestack on a tap densitometer for 500 taps while gentlyswinging the train around its base and tapping it on theside with a hammer. Although the smaller sample sizes led

to larger uncertainties, a direct comparison of the twomethods showed that they yielded similar results. We notein the results when this latter method was used.

For dry granule size analysis, three 50–80 g samples ofthe wet granulation were loaded into trays to a depth ofapproximately 1 in. and dried at 508C using ambient air in

Ža Fisher Scientific 600 Series Isotemp Oven Pittsburgh,.PA . The samples were sieved through 7-in. screens using

the same CSC sieve shaker used in the frozen wet granulesizing. For dry sizing, the shaker was operated at moderateamplitude for 10 min.

Dried granule porosities were measured by mercuryw xpycnometry 5,8,14,20,30,54 using specially constructed

3 Žglass cells with a volume of 30–40 cm A.A. Pesce Glass,.Chadds Ford, PA . Approximately 10 g of granulation was

loosely packed into these large diameter cells, taking care

Fig. 3. Wet granule size distribution as a function of liquid addition time. Times of 2, 4, 6, and 10 min of liquid addition correspond to 3.4%, 6.9%, 10.2%,Ž . Ž . Ž .and 17.1% mass waterrmass lactose, respectively. a lactose F, b lactose M, and c lactose C.

( )M.B. Mackaplow et al.rPowder Technology 108 2000 32–45 37

Ž .Fig. 3 continued .

not to crush the large granules. The samples were evacu-ated to ca. 1 mm Hg and subsequently filled with mercury

Ž .to 155 mm Hg 3 psia . At this subatmospheric pressure,taking into account the static pressure associated with theheight of the mercury column below the sample, intrusionis restricted to pore radii greater than 50–60 mm. Thischoice was based on scanning electron microscopy andlow pressure porosimetry, which indicated that this was areasonable estimate of the largest granule pores. Thus, thefilling operation intrudes mercury into extragranular porespace, with minimal intrusion into the granules. The fillpressure of 150 mm was also used by Hunter and Gander-

w xton 20 in their early study of lactose granule porosity.The use of higher fill pressures, i.e., 1 atm, is likely toresult in low estimates of granule porosity.

The mass of mercury that filled the extragranular voidvolume was determined from the difference in cell weightbefore and after filling. The mercury volume was calcu-lated from the mass of mercury assuming a density of13.534 grcm3. The granule apparent volume is then thedifference between the empty cell volume and the addedmercury volume. The apparent density r D is equal to thegranule mass divided by the granule apparent volume. Theapparent density was determined in duplicate for eachgranulation.

The dry granule porosity, ´ D, was determined from thedry granule apparent density, r D, and the pure lactosedensity, r ,lactose

´ D s1yr Drr 1Ž .lactose

If we assume that the liquid phase in the granules wasw xsaturated with lactose 13 and that drying does not cause

significant changes in the granule pore structure, we can

estimate the wet granule total porosity, ´W, and fractionalsaturation of the pore space, ´Wr´ W, usingL

´W s´ D qsA 1y´ D 2Ž . Ž .´Wr´ W s 1y´ D 1qs Ar rr r´W 3Ž . Ž . Ž . Ž .L lactose sat water

Ž .where sssolubility of lactose in water; Asxr lyx ;xsmass fraction of granules that are liquid, as determinedvia drying; r sdensity of lactose saturated water.sat water

At the temperature range in the granulator, s and rsatw x 3were approximately 0.2 grg 52 and 1.076 grcmwater

w x55 , respectively.

3. Results

3.1. Moisture distribution in wet mass

Table 1 shows the mass of unbound water in samplestaken from the granulator at various times and locations.For samples taken from the granulation, the values werevery close to the theoretical amounts. The mean andstandard deviation of the samples were 97.9% and 6.3%,respectively. No single sample varied by more than 19%from theoretical. The homogeneity of the liquid distribu-tion in high-shear lactose granulations is consistent with

w xthe results of Holm et al. 7 . Although there is insufficientdata to draw a firm conclusion, the results suggest that thehomogeneity increases over time, consistent with the re-

w xsults of Holm et al. 6 .In contrast, the moisture in the wall build-up is much

less homogeneously distributed. The mean and standarddeviation of the samples were 98.3% and 65.5%, respec-tively. Two wall samples, presumably near the spray noz-zle, had over three times the theoretical moisture content.

( )M.B. Mackaplow et al.rPowder Technology 108 2000 32–4538

If these samples are removed from the analysis, the meanand standard deviation are 82.8% and 16.2%, respectively.The fact that the wall build-up is not constantly mixingwith the rest of the wet mass accounts for the non-uniformliquid distribution. There is no clear effect of changingprimary particle size on the moisture distribution.

3.2. Effect of wet massing

Fig. 2a–c shows three representative histograms of theeffect of wet massing time on the wet granule size distribu-tions. Wet massing is defined as continued impeller andchopper motion after liquid addition has ceased. The threefigures correspond to wet massing fine, medium, andcoarse lactose after the mass additions of 10.3%, 10.3%,and 17.1% water, respectively. Size distributions were

measured with the 3-in. sieves as described in Section 2.3.These data show no consistent growth or attrition of thegranules during wet massing times up to 10 min. Hence,under the granulating conditions used in our experiments,liquid is rapidly incorporated into the lactose granules, sothat wet-massing does not significantly change the granulesize. This observation is consistent with previous investiga-tions which have shown that under granulating conditionssimilar to ours lactose granule growth is quasi-steadyw x Ž7,10,17,18 although this would not necessarily be the

.case at higher liquid addition rates .

3.3. Effect of granulation timer total liquid addition

ŽBecause granule growth is quasi-steady see Section.3.2 , no wet massing was performed. Since water was

Fig. 4. Apparent dry granule size distribution as a function of liquid addition time. Times of 2, 4, 6, and 10 min of liquid addition correspond to 3.4%,Ž . Ž . Ž .6.9%, 10.2%, and 17.1% mass waterrmass lactose, respectively. a lactose F, b lactose M, and c lactose C.

( )M.B. Mackaplow et al.rPowder Technology 108 2000 32–45 39

Ž .Fig. 4 continued .

Fig. 5. Porosity of dry granules as measured by low pressure, mercury pycnometry method discussed in Section 2.3. Error bars are 80% confidenceintervals based on Student’s t-distribution.

Fig. 6. Pore saturation of wet granules as calculated from dry granule pore saturation and method discussed in Section 2.3. Error bars are 80% confidenceintervals based on Student’s t-distribution.

( )M.B. Mackaplow et al.rPowder Technology 108 2000 32–4540

Fig. 7. Typical granulation impeller power and torque curve. Granulationof lactose M. Two minutes dry mix followed by 6 min of liquid addition.Data collection began a few seconds before the mixer was turned on andcontinued for a few seconds after it was turned off.

added at a constant rate, total liquid addition is directlyproportional to granulation time.

3.3.1. Wet granule size distributionFig. 3a–c shows the wet granule size distributions

produced by the fine, medium, and coarse grades of lac-tose, respectively, after granulating for 2, 4, 6, and 10 min.Liquid addition and mixing were stopped simultaneously.The four times corresponded to total water mass additionsof 3.4%, 6.9%, 10.2%, and 17.1%. For all three grades oflactose, the granulation becomes coarser with increasingliquid addition. During the period from 4 to 10 min, largegranules increase at the expense of small granules, whilethe middle size fractions do not change significantly. Un-der all granulating conditions, there are few granules

Fig. 8. Curves of the torque exerted on the mixer blade as a function of water addition time during wet granulation. The impeller was started at timesy2Ž . Ž . Ž .min. Water addition commenced at times0. Granulation material a lactose F, b lactose M, c lactose C.

( )M.B. Mackaplow et al.rPowder Technology 108 2000 32–45 41

Ž .Fig. 8 continued .

smaller than 1 mm. These results are consistent with thew xkinetic theory of Ennis et al. 42 which predicts that small

granules will agglomerate preferentially due to the lowerviscous Stokes number.

More interesting than the effect of binder volume is thelarge influence of primary particle size on wet granulesize. The coarse lactose C has the largest granule size at allprocess conditions, and it was observed that granulationsmade with grade C tended to form lumps in the early

Ž .stages of granulation t-2 min . Grade M generally gavecoarser granules than grade F, but at short times thedifferences between the two grades were relatively small.

3.3.2. Apparent dry granule size distributionThe size of the dry granules depends on the drying

process and the sizing method. A vigorous drying method,such as fluidized bed drying, will produce relatively small,strong granules — because only the strongest dry interpar-ticle bonds survive the processing. In contrast, tray dryingwill produce larger, weaker granules, since stationary gran-ules do not suffer attrition, and the weaker interparticlebonds survive. Sizing methods such as sieving may alsoreduce the granule size, depending on the stresses experi-enced by the granules.

For these reasons, it is appropriate to use the terminol-ogy apparent dry granule size, since the measured size is aconvolution of the wet granule size, wet and dry granulestrength, and the stresses experienced during drying andsizing. There are no standard methods for drying andsizing granules, so the concept of absolute dry granule sizeis meaningless. In this work, the apparent dry granule sizerefers to the size of granules after tray drying and moder-ate amplitude sieving, as discussed in Section 2.3. Ourmethods are typical of those used to dry and size pharma-ceutical granules.

Fig. 4 shows the apparent dry granule size distributions.Apparent dry granule size increases strongly with theamount of granulating liquid, consistent with previous

w xinvestigations 8,10,12,18,25,34 . At all but the largestgranulating fluid volume, these distributions show no con-sistent variation with primary particle size. This is qualita-tively different than the behavior exhibited by the wetgranule size distributions. For lactose grades F and M, theapparent granule size distribution at the highest liquidaddition level is reasonably close to the wet granule size

Ž .distribution Fig. 3 . For grade C, the dry granule size issignificantly finer than wet granule size at all liquid addi-tion levels.

3.3.3. Granule porosity and pore saturationFig. 5 shows that the dry granule porosity decreases

with both the amount of granulating liquid and increasingprimary particle size. These findings are consistent withprevious studies when relatively inviscid granulating flu-

w xids, such as water, have been used 12,14,17,20 .Because of the relatively low solubility of lactose in

water at our granulating temperatures, the calculated wetgranule porosities are approximately equal to the dry gran-

Ž .ule porosities. This follows from Eq. 2 , noting that theproduct sA<1 in all our experiments. Fig. 6 shows the

Ž .wet granule pore saturations calculated from Eq. 3 . Be-cause of decreasing total porosities, pore saturation in-creases with increasing primary particle size.

3.4. Impeller torque and power curÕes

For all of our granulations, the impeller torque andpower curves had very similar shapes. An example isshown in Fig. 7. This suggests that, despite the limitationsof power measurement discussed in Section 2.2, power

( )M.B. Mackaplow et al.rPowder Technology 108 2000 32–4542

was a reasonable approximation to impeller torque for oursystem. For brevity, we present only the torque profiles.

Fig. 8 shows the torque profiles for all three grades oflactose. Liquid was added continuously for 22 min, whichwas sufficiently long to observe the granulation changefrom a dry powder to a liquid-like suspension. Each plotshows two of these profiles to illustrate their reproducibil-ity. In addition, we have superimposed a single granulationexperiment torque curve on each chart. For each grade, theprofiles display similar magnitudes and regions of in-crease, plateau, decrease, and noise. However, there isquantitative variation in these features.

The torque magnitude, noise level, and duration of theplateau region are all affected by particle size. In particu-lar, the duration of the plateau region increases withparticle size, whereas the plateau magnitude decreases.The amount of noise decreases with increasing primaryparticle size. Lactose F shows that the noise occurs consis-tently before and after the plateau region. Observations ofthe granulation suggested that wall build-up became moresevere with decreasing primary particle size and that thenoise for lactose F before the plateau region correspondedto a periodic build-up and collapse of material from thewalls. The large torque drop after the plateau corresponded

w xto large build-ups on the impeller and wall 17,18,46 . As aresult, the impeller no longer moved through a viscousmass, but instead rotated a few chunks of attached materialwhile a large stagnant mass stuck to the sides. The noisemay correspond to large chunks moving from the impeller

w xto the wall, or visa versa 18 . For all three grades ofmaterial, the noise and subsequent power decrease near theend of the experiments corresponded to many granuleslarger than 10 cm forming and an inhomogeneous distribu-tion of material in the granulator due to massive wallbuild-up. After this, the material became an overwet paste.

Ž .Fig. 9. Difference between granulation and dry mix ts0 torque. Databased on the two full curves for each grade of lactose presented in thefigure. To reduce the effect of noise, the values in the figure are averagedover a 20-s window surrounding the time of interest. The times0 torque,just before liquid addition begins, is used for the dry mix value. Errorbars denote range.

Torque increment is the granulation torque minus thedry mix, times0, value. It is sometimes used to monitorgranulation progression as an alternative to absolute torque.For our system, torque increment was more sensitive thanabsolute torque to primary particle size. This is becauseabsolute torque was not significantly different for wetlactose M and C, but lactose C had a higher dry mix torquereading. Using the two complete torque curves for eachgrade, Fig. 9 shows the ‘‘torque increment’’ at variousliquid addition times. At 2 min, there is no effect ofprimary particle size. However, for all times beyond this,lactose C yields the smallest torque increment. At 6 and 10min, lactose F has the highest torque increment.

4. Discussion

This study shows that the lactose wet granule sizedistribution depends on the primary particle size and theamount of water added during granulation. The apparentdry granule size distribution also depends on these twoparameters. However, compared to the wet granules, thedry size is less sensitive to primary particle size and moresensitive to the amount of added water. In order to recon-cile these apparently conflicting observations, it is neces-sary to consider the forces that hold wet and dry granulestogether.

The addition of liquid to the agitated dry powder pro-vides the cohesive forces required for agglomerationw x56,58 . Fundamental treatments of interparticle liquidforces have focused on two-particle bridges expected topredominate at low liquid levels, viz. for pore saturationsless than ca. 10%. However, the results can be qualita-tively extended to multiparticle bridges that become preva-lent at higher saturations. In the following discussion weassume that, for a given pore saturation, the volume of aliquid bridge is proportional to the third power of primary

Ž 3.particle size d . This scaling is consistent with analysesof liquid bridges formed between two spherical particlesw x2 . The scaling can also be deduced if we assume that theliquid bridges will form around particle–particle contacts,and the number of these contacts per unit volume isproportional to 1rd3. Then the added liquid V will beliq

distributed into bridges of average volume;V d3. ThisliqŽ .picture should be valid as long as: 1 wetting and mixing

are sufficiently good to eliminate the memory of the initialŽ .drop size; and 2 the surfaces of different sized primary

particles are comparably smooth so that all the addedliquid is available to form interparticle bridges. Underthese conditions, granules formed from coarser powderswill have larger, but fewer, liquid bridges.

We consider first how the amount of liquid addedduring granulation affects the interparticle forces. Studiesof wet granule strength suggest that interparticle friction is

( )M.B. Mackaplow et al.rPowder Technology 108 2000 32–45 43

w xreduced as pore saturation increases 41,49 . Both capillaryw x w x57 and viscous forces 59 are relatively insensitive tobridge volume for pore saturations above 5%–10%. Themaximum extensability of a bridge, viz. the distance that itcan be stretched before rupture, increases weakly with

1r3 w xbridge volume, ;V 57 . Since we expect bridgeb

volume to be directly proportional to V , it follows thatliq

the maximum bridge extensability is a relatively weakfunction of the amount of liquid added.

Our experiments showed that wet granule size increaseswith increasing volume of granulating liquid. At low satu-rations, the liquid forms bridges between primary particles.Increases in V reduce the interparticle friction, makingliq

the granules more deformable, promoting growth by coa-w xlescence 49 . The concomitant increases in capillary and

viscous forces provide sufficient cohesive strength to pre-vent the granules from breaking apart during collisionswith other granules. We observed small yet significantchanges in the size distribution for added liquid levelsbetween 6.9% and 17.1%. During this period, the finesŽ .-1 mm are incorporated into the granules, with littlechange in the coarse part of the size distribution. The

Ž .added liquid promotes granule densification Fig. 5 , butfurther growth of the largest granules is minimal.

Primary particle size exerts a greater influence on inter-particle forces than added liquid volume. Assuming thegeometric similarity discussed earlier, the liquid bridgecapillary force is proportional to primary particle size, d.

w xThe lubrication analysis by Ennis et al. 59 shows that theviscous bridge force is also ;d. Since the number ofbridges per unit cross-sectional area varies as 1rd2, thetotal cohesive force in a granule varies as 1rd. Thisscaling holds irrespective of which fluid force predomi-nates. The 1rd scaling is consistent with studies showingthat as primary particle size increases, wet granule strength

w xdecreases 2,3,15 . It is also consistent with experimentsshowing that as primary particle size increases, binder

w x w xliquid viscosity 36,43 and surface tension 3 must in-crease to maintain wet granule strength. Since the viscousand capillary forces are directly proportional to viscosityand surface tension, respectively, these quantities mustincrease in order to offset the effect of particle size.

While the cohesive forces decrease with increasingparticle size, the maximum bridge extensability actuallyincreases with primary particle size. This follows from theway extensability scales with bridge volume. Since maxi-

1r3 w x 3mum extensability ;V 57 , and V ;d , extensabilityb b

increases linearly with primary particle size. Thus, asprimary particle size increases, the wet granules becomeboth weaker and more deformable. This was found experi-

w xmentally by Iveson and Litster 37,38 using agglomeratesof glass beads.

As primary particle size increases, growth is morew xlikely to occur via a crushing and layering mechanism 3 .

Granules comprised of large primary particles will berelatively weak. Within a granulation, the large granules

will be stronger than the small granules by virtue of theirlarger cross-sectional area. The large granules tend tocrush the small granules. Crushing releases liquid bindertrapped within the small granules, which promotes granula-tion of the fragments, often with the crushing granule. Thenet effect of this process is to enhance the rate of granula-tion and increase the granule size.

Increasing the lactose primary size resulted in an in-crease in the wet granule size for most levels of liquid

Ž .addition Fig. 3 . The coarse C grade rapidly produced ahigh percentage of large granules. Granules made fromlactose C should be most deformable, which favors growthby coalescence. The crushing and layering mechanismwould also explain the rapid growth of grade C, as well asthe preferential granulation of fines that appears to beoccurring for all grades between 6.9% and 17.1% addedwater.

The forces holding dry granules together are very dif-ferent than those for wet granules. For the lactoserwatersystem, the most important bonding mechanism is ex-pected to be solid bridges formed by the recrystallizationof dissolved lactose.

The apparent size of the dry granules increases stronglywith the volume of liquid added. This is presumably due tothe increased number andror volume of recrystallizedlactose bridges created during drying. The effect of pri-mary particle size is more complicated and requires addi-tional study.

Our measured porosities are generally higher than thosereported in the literature for similar systems. For example,for lactose similar to grade M, granulated for the equiva-

w xlent of 6 min, Schaefer et al. 17 reported a porosity of22%. This compares with our value of 56%. We believethis discrepancy is due to the lower intrusion pressure usedin this study, as discussed in Section 3.3. This hypothesis

w xis supported by the data of Juppo and Yliruusi 14 whogranulated with lactose similar to grade F, used a lowmercury intrusion pressure, and reported porosities similarto ours.

Additionally, the granule porosities are generally higherthan the ungranulated lactose porosities inferred from thelactose tap densities. The latter range from 40% to 43%, as

Ž .can be calculated from Eq. 1 and the tap densitiespresented in Section 3.1. This is consistent with the factthat we observed an expansion of the powder bed, relativeto the bed volume during the dry mix, upon the initialaddition of water. Subsequent water addition slowly com-pacted the bed.

This study highlights the complicated relationship be-tween impeller torque, granule size, and primary particlesize. For each lactose grade, impeller torque increased withincreasing wet granule size in the early stages of granula-tion. In all cases, a plateau in the torque profile wasobserved at intermediate granulation times, and the dura-tion of this plateau increased with increasing primary

Ž .particle size Fig. 9 . In this constant-torque regime, gran-

( )M.B. Mackaplow et al.rPowder Technology 108 2000 32–4544

ules were densified and the mean granule size continued toincrease slowly due to preferential granulation of the fines.The torque increment was observed to decrease monotoni-

Ž .cally with primary particle size Fig. 9 .For each lactose grade, the torque profiles exhibit sig-

nificant degrees of irreproducibility. Part of this variabilityis due to wall build-up and failure, which are inherentlychaotic. The importance of wall build-up is expected to

w xdepend on granulator scale 17,28,34 , binder propertiesw x45 , and primary particle size, as illustrated by the differ-

Ž .ence in noise in the torque profiles Fig. 9 . In general, wetgranular materials cannot be treated as continuous mediaw x60 , and this results in a randomness in the system dynam-ics that is discernible on the length and time scales ofinterest.

Our results point to several serious difficulties withusing impeller torque or power measurements to monitorgranulation. First, torque and power are not simple statefunctions of wet granule size, but also depend on primaryparticle size and wet granule porosity. Secondly, the chaoticnature of wall build-up and collapse affects the curves inways not related to intrinsic granule properties. Finally, therelationship between torque and ultimate dry granule sizeis problematic, since the latter depends on dry granulestrength and the forces the granules experience duringpost-granule processing. One needs to be keenly aware ofthese limitations if using impeller torquerpower to deter-mine granulation endpoint.

5. Conclusion

Primary particle size did not have a measurable effecton either the distribution of liquid in the granulator or itsrate of incorporation into granules. For all lactose grades,the liquid was homogeneously distributed in the wet granu-lation, but not in the wall build-up. The latter is due topoor mixing and emphasizes the importance of minimizingwall build-up in order to produce granules with uniformcomposition. Granule growth was quasi-steady, suggestingthat wet massing is unnecessary in systems where theresistance to intragranule primary particle rearrangement issmall.

In contrast, primary particle size had a strong effect ongranule growth rate, granule porosity, and wet granule sizedistribution. At identical process conditions, coarser pow-ders yielded larger, less porous wet granules. This reflectschanges in the strength of the liquid bridges betweenprimary particles, which is predicted to scale with thereciprocal of the primary particle size. Thus, larger pri-mary particles produce weaker, more deformable wet gran-ules, favoring growth by coalescence andror crushing andlayering.

The apparent dry granule size increased strongly withthe volume of granulating water added. This is presumably

due to the increased size and number of recrystallizedlactose bridges holding the dried lactose particles together.

Impeller torque and power profiles were also sensitiveto the primary particle size of the lactose. The profileswere influenced by the wet granule size distribution, andthe amount of material that adhered to the granulator wall.Since granule size was changed significantly by drying andsieving, torque and power was, at best, an indirect indica-tor of dry granule size distribution.

Acknowledgements

The authors would like to acknowledge Dr. James Zegaand Dr. Susan Ashley for helpful discussions concerningthe direction of our study. Dr. John P. Elder used thermalanalysis to determine the appropriate drying temperaturefor lactose monohydrate. We also acknowledge the MerckManufacturing Division for providing a graduate fellow-ship and post-doctoral research position to MBM.

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