investigation of melt agglomeration process with a hydrophobic binder in combination with sucrose...

European Journal of Pharmaceutical Sciences 19 (2003) 381–393www.elsevier.com/ locate/ejps

I nvestigation of melt agglomeration process with a hydrophobic binder incombination with sucrose stearate

*Paul Wan Sia Heng , Tin Wui Wong, Wai See CheongDepartment of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543,Singapore

Received 18 November 2002; received in revised form 24 April 2003; accepted 12 May 2003

Abstract

The melt agglomeration process of lactose powder with hydrogenated cottonseed oil (HCO) as the hydrophobic meltable binder wasinvestigated by studying the physicochemical properties of molten HCO modified by sucrose stearates S170, S770 and S1570. The size,size distribution, micromeritic and adhesion properties of agglomerates as well as surface tension, contact angle, viscosity and specificvolume of molten HCO, with and without sucrose stearates, were examined. The viscosity, specific volume and surface tension of moltenHCO were found to be modified to varying extents by sucrose stearates which are available in different HLB values and melt properties.The growth of melt agglomerates was promoted predominantly by an increase in viscosity, an increase in specific volume or a decrease insurface tension of the molten binding liquid. The agglomerate growth propensity was higher with an increase in inter-particulate bindingstrength, agglomerate surface wetness and extent of agglomerate consolidation which enhanced the liquid migration from agglomeratecore to periphery leading to an increased surface plasticity for coalescence. The inclusion of high concentrations of completely meltablesucrose stearate S170 greatly induced the growth of agglomerates through increased specific volume and viscosity of the molten bindingliquid. On the other hand, the inclusion of incompletely meltable sucrose stearates S770 and S1570 promoted the agglomeration mainlyvia the reduction in surface tension of the molten binding liquid with declining agglomerate growth propensity at high sucrose stearateconcentrations. In addition to being an agglomeration modifier, sucrose stearate demonstrated anti-adherent property in meltagglomeration process. The properties of molten HCO and melt agglomerates were dependent on the type and concentration of sucrosestearate added. 2003 Elsevier B.V. All rights reserved.

Keywords: Hydrophobic meltable binder; Melt agglomeration; Specific volume; Sucrose stearate; Surface tension; Viscosity

1 . Introduction binders that are hydrophobic in nature, prolonged-releasesolid dosage forms can be designed and tailored to the

Melt agglomeration in a high shear mixer is a one-pot needs of the therapeutic regimen (Thomsen et al., 1994;process that has gained interest in the pharmaceuticalEvrard and Delattre, 1996; Zhou et al., 1996; Voinovich etindustry especially over the past decade. The processal., 2000).involves the addition of a meltable binder to the solid bulk The mechanism of melt agglomeration is similar to thatmaterial, either in the form of a solid which melts during of wet agglomeration. It involves processes of wetting andthe process or directly in the form of a molten liquid. The nucleation, consolidation and growth as well as attritionmolten liquid acts as a binding liquid which results in the and breakage except that the formation and growth of meltaggregation of solid bulk material into agglomerates, in the agglomerates are not complicated by binding liquid losspresence of impeller agitation. Melt agglomeration offers via evaporation during the agglomeration process. Thethe advantages of not using both aqueous and organic processes of wet agglomeration are governed by capillary,solvents for agglomeration. Consequently, the drying phase frictional and viscous forces (Iveson et al., 2001). Theis eliminated and the total processing time becomes capillary forces aid agglomerate consolidation by pullingshorter. Through an appropriate selection of meltable the solid particles together but resist agglomerate dilation.

On the other hand, the viscous and frictional forces resistboth consolidation and dilation of solid particle assembly.*Corresponding author. Tel.:165-6874-2930; fax:165-6775-2265.

E-mail address: [email protected](P.W.S. Heng). The capillary, frictional and viscous forces of an agglome-

0928-0987/03/$ – see front matter 2003 Elsevier B.V. All rights reserved.doi:10.1016/S0928-0987(03)00138-6

mailto:[email protected]

382 P.W.S. Heng et al. / European Journal of Pharmaceutical Sciences 19 (2003) 381–393

ration are affected by the physicochemical properties of a ates S770 and S1570 contain higher proportion of monoes-binding liquid, namely surface tension, contact angle and ters of stearic acid. They were not completely meltedviscosity. In melt agglomeration process, the viscosity of within the temperature range of 60–1108C, which en-molten binding liquid has largely been examined as the compassed the maximum processing temperature encoun-core characteristic of meltable binders which has a strong tered during the melt agglomeration experiments, a tem-bearing on the formation and growth of melt agglomerates perature below 1058C. Sucrose stearates S770 and S1570(Schæfer and Mathiesen, 1996; Keningley et al., 1997; only formed semisolids above their softening temperatures.Wong et al., 1999; Thies and Kleinebudde, 2001). Hydro- Among the sucrose stearates, sucrose stearate S1570 wasphobic meltable binders have low viscosity values, typical- the least meltable additive. The meltability of sucrosely ranging from 8 to 49 mPa s at the melting temperatures stearate was related to the degree of esterification ofbetween 70 to 908C (Thomsen et al., 1994). It was sucrose molecule by stearic acid. The availability of areported that the melt agglomerates produced were suscep- larger proportion of unesterified sucrose molecules wastible to breakdown due to low viscous strength of the translated to a stronger intermolecular interaction viamolten binding liquid (Eliasen et al., 1999). Nonetheless, hydrogen bonding between the adjacent hydroxyl groupsthe agglomerative capability of hydrophobic meltable and thus a lower meltability within the temperature rangebinders could not be entirely related to the viscosity values studied. The physicochemical properties of sucrose stear-of the molten binding liquid (Thomsen et al., 1994). ates are summarized inTable 1.

In the search of hydrophobic meltable binders suitablefor use in melt agglomeration, it is therefore imperative to 2 .2. Equipmenthave a better understanding of the complex influences ofsurface tension, contact angle and viscosity of molten A laboratory-scale vertical high shear mixer (PMA-1binding liquid on the formation and growth processes of Processor, Aeromatic-Fielder, UK) was used as previouslymelt agglomerates. Melt agglomeration is an ideal model described (Heng et al., 2000). A two-bladed, bottom-for elucidation of an agglomeration process. The physico- driven impeller with curved blade tips was used. Through-chemical properties of a molten binding liquid are unaf- out the process of melt agglomeration, the product tem-fected by an evaporation process and potentially modifi- perature, impeller current consumption and impeller speedable with an additive. The present study investigated the were captured using a data acquisition system (PCI-melt agglomeration process with hydrogenated cottonseed 20089W-1, Burr-Brown, USA). Typical profiles of theoil (HCO) as a model hydrophobic meltable binder using product temperature and impeller current consumption as asucrose stearates as an additive. The formation and growth function of processing time are shown inFig. 1.processes of melt agglomerates, in association with thephysicochemical properties of molten HCO modified by 2 .3. Agglomeration proceduresucrose stearates S170, S770 and S1570, were examined.

All experiments were carried out under an ambienttemperature of 2262 8C and a relative humidity of

2 . Materials and methods 5065%. Unless otherwise stated, a load of lactose (1.3 kg)

2 .1. Materials

T able 1Crystalline a-lactose monohydrate (Pharmatose 450M, Physicochemical properties of sucrose stearates

DMV, The Netherlands) was used as the solid bulkSucrose stearate type

material with HCO (Sterotex NF, Abitec, USA) as theS170 S770 S1570hydrophobic meltable binder. The median particle diame-

a,bHLB 1 7 15ters of lactose and HCO were 23 and 81mm, respectively,bEster composition (%)with corresponding spans of 1.83 and 1.38 (LS230 with

Monoester 0 40 70dry powder feeder, Coulter, USA). The melting range ofDi-, tri-, polyesters 100 60 30

HCO was 49–648C (DSC-50, Shimadzu, Japan). Sucrose Median particle diameter (mm) 148 33 47stearates S170, S770 and S1570 (Ryoto Sugar Ester,Span 2.35 2.82 2.53

Melting/softening temperatures (8C)Mitsubishi Chemical, Japan) were used as the additive.Range 52–64 45–54 47–54Sucrose stearate is a non-ionic surfactant containing suc-Peak 60 48 49rose as the polar head and fatty acid as the non-polar tail.

Physical appearance above melting/ Liquid Semisolid SemisolidcThe fatty acids are derived from vegetable oils which softening temperature range

contain 70% of stearic acid. Sucrose stearate S170 com- a Hydrophilic–lipophilic balance.prises mainly of polyesters of stearic acid. Sucrose stearate b Information obtained from product brochure, Ryoto Sugar Ester,S170 was completely meltable and transformed into a Mitsubishi Chemical, Japan.

cmolten liquid at temperature above 608C. Sucrose stear- Visual observation by heating the sucrose stearates up to 1108C.

P.W.S. Heng et al. / European Journal of Pharmaceutical Sciences 19 (2003) 381–393 383

amount of adhesion within the processing chamber wascalculated as:

adhesion (%)

initial total load (g)2 final load harvested (g)]]]]]]]]]]]]]5 3 100%

initial total load (g)

(1)

All batches of melt agglomerates were subjected tophysical characterization unless otherwise stated. Dupli-cates were carried out for each batch of agglomerates andthe results averaged.

2 .4. Characterization of agglomerates

2 .4.1. Size analysisFig. 1. Typical profiles of product temperature (—) and impeller currentThe agglomerates from each run were randomly dividedconsumption (—) as a function of processing time in a melt agglomera-

tion process. Sucrose stearate type: S770; sucrose stearate concentration:using a spinning riffler (PT, Retsch, Germany). A sample2% (w/w). of about 170 g was sized using a series of 12 sieves

(Endecott, UK) within the aperture size range of 90–3350mm and vibrated by means of a sieve shaker (VS1000,with HCO at 14% (w/w), expressed as the weight per-Retsch, Germany). Size fractions above 710mm werecentage of lactose, was used for melt agglomeration.vibrated at an amplitude of 1 mm for 15 min while the restSucrose stearate at concentration of 0, 0.5, 0.75, 1, 2, 5 andwere vibrated at the same amplitude for an additional 2010% (w/w), expressed as the weight percentage of HCO,min. The mass median diameter and span of agglomerateswas added as an additive. All materials were transferredwere calculated. The mass median diameter was defined asinto the processing chamber and mixed at an impelleragglomerate size corresponding to 50th weight percentilespeed of 500 rpm for 5 min. After 5 min, the impeller(X ) of the cumulative agglomerate size distribution. The50speed was raised to 1300 rpm. The high impeller speedspan was computed based on Eq. (2):produced shear friction that enabled the product tempera-

ture to rise to the melting point of HCO and/or sucrose X 2X90 10]]]span5 (2)stearates within 3 to 4 min. The onset of melting was X50

detected by an inflection point on the profile of impellerwhereX andX are the diameters corresponding to 90thcurrent consumption against processing time (Fig. 1). The 90 10

and 10th weight percentiles of the cumulative agglomeratepre-melt processing time was taken from the start of highsize distribution, respectively. The amounts of oversizedshear mixing at 1300 rpm to the onset of melting. At 2 minagglomerate and fines were expressed as the weightafter onset of melting, the impeller speed was adjusted topercentage of sieve fraction larger than 2800mm and1200 rpm and was maintained for 7 min. The extendedsmaller than 250mm, respectively. For runs with excessiveperiod of processing after the onset of melting was definedgrowth, quenched cakes were harvested. The quenchedas post-melt distribution phase. Following the post-meltcakes were large agglomerates with no suitable sieve candistribution phase, the impeller speed was reduced to 400be used for size characterization. Therefore, a caliper wasrpm and continued for a specified time of which wasused to measure the dimensions of the agglomerates. Thetermed as post-melt massing phase. The post-melt process-average value of the maximum and minimum diameters ofing condition was divided into two phases as it was foundeach agglomerate was determined. At least a quarter orto be suitable for melt agglomeration of lactose using HCOmore of the quenched cake fraction was subjected toas the meltable binder in a high shear mixer (Zhu, 2000).manual size and weight determination. The mass medianFor each formulation, the melt agglomeration was carrieddiameters of these agglomerates were estimated based onout using three different post-melt massing times: 0, 20,the weights and averaged diameters of the agglomerates.and 50 min. The jacket temperature was set at 608C

throughout the experiments. The post-melt product tem-peratures were consistently higher than the melting point 2 .4.2. Intra-agglomerate pore size and size distributionof HCO and/or sucrose stearates, ranging between 65 and The pore size and size distribution of agglomerates1058C. Upon completion of each run, the agglomerates within the size fractions of 250–2000mm were determinedwere collected, spread in thin layers on stainless steel using a mercury intrusion porosimeter (Poresizer 9320,trays, and allowed to cool to ambient temperature. The Micromeritics, USA), similar to that described byWong etweight of agglomerates harvested was determined. Theal. (2000). Intrusion pressures between 3 to 5000 p.s.i.a.


were used (1 p.s.i.56894.76 Pa). The plot of differential g cosurtL2 ]]]specific intrusion volume against pore diameter was used l 5 (3)2hto characterize the pore size and size distribution of

wherel is the length of liquid penetration in timet, g andagglomerates. L

h are the surface tension and viscosity of the penetratingliquid, respectively, andr is the capillary radius. The

2 .5. Characterization of molten HCO and binary molten contact angle between the solid and the liquid,u, was2mixtures of HCO and sucrose stearates calculated based on the slope of the linear plot ofl vs. t

by least-square approximation method andr was calcu-The surface tension, contact angle, viscosity and specific lated based on Eq. (4) (Maejima et al., 1992):

volume of the molten HCO, with and without sucrose2´stearates, were characterized. For mixtures of HCO and ]]]]r 5 (4)

(12´) ? S rwsucrose stearates, the molten liquid fraction of the mixtureswas examined. Visible non-molten fractions of sucrose where ´ is the porosity of the powder bed and wasstearates S770 and S1570 were excluded from the bulk ofcalculated from the weight and volume of the lactosemolten HCO during characterization. The term ‘‘molten filling the tube,S andr are the specific surface area andwliquid’’ or ‘‘molten binding liquid’’ is used interchangeably density of lactose powder, respectively.S was 1.053w

2with reference to molten HCO or binary mixture of molten m /g, based on the BET surface area determined by aHCO and molten fractions of sucrose stearates. The surface area analyzer (SA3100, Coulter) andr was 1.542

3characterizations of surface tension, viscosity, contact g/cm , determined by a gas displacement pycnometerangle and specific volume of molten liquid were conducted (AccuPyc 1330, Micromeritics) with helium purge.at 808C as it represented the most probable producttemperature encountered during the melt agglomeration2 .5.3. Viscosityprocess. Typically, the median product temperature at The viscosity of molten liquid was determined atpost-melt phases of all experiments had an average value8060.28C using a rotation viscometer (Rheostress 1,of 77.066.88C. The product temperature of the melt ThermoHaake, Germany). The viscosity values were ob-agglomeration process was not appreciably affected by tained using sensor system Z10 DIN at a shear rate of 600

21type and concentration of sucrose stearates added except ats . At least triplicates were carried out for each batch of10% (w/w) sucrose stearates S170 and S770. molten liquid and the results averaged.

2 .5.4. Specific volume2 .5.1. Surface tensionThe specific volume of molten liquid was determined atThe surface tension of molten liquid was determined at

8060.28C by weighing a known volume of molten liquid8060.38C using the Wilhelmy plate method (Rosano,in a 50-ml volumetric flask. The specific volume of moltenRoller Smith, USA). A correction factor due to the thermalliquid was defined as the quotient of volume to weight ofexpansion of plate was included in the calculation ofthe molten liquid. The determination of specific volumesurface tension. A total of six replicates were carried outwas carried out in triplicates and the results averaged. Afor each batch of molten liquid and the results averaged.correction factor due to the thermal expansion of volu-metric flask was included in all calculation of specific

2 .5.2. Contact angle volume.The contact angle of molten liquid over the lactose

powder bed was determined at 8062 8C by the Washburnliquid penetration method, similar to that ofKiesvaara and 3 . Results and discussionYliruusi (1993).Lactose powder was packed into a sampletube (250 mm311 mm I.D.) using a tapping apparatus Fig. 2 shows the physical appearance of melt agglomer-(STAV 2003, Jel, Germany) and the opening of the tube ates produced with meltable binder HCO in combinationwas sealed with a sintered glass disc (average pore size, with sucrose stearates S170, S770 and S1570. The formed160–200mm) to prevent the leakage of powder particles. agglomerates were discrete in appearance.Fig. 3 shows theThe tube was placed horizontally and connected to the effects of sucrose stearates on the size and size distributionmolten liquid reservoir via a silicone tubing with an of melt agglomerates produced. The size distribution of theinternal diameter of 8 mm. The length of molten liquid melt agglomerates did not consistently conform to a logpenetrated across the lactose powder bed was measured at normal distribution. It was not appropriate to characterizeregular intervals. At least duplicates were carried out for the size and size distribution of these agglomerates basedeach batch of molten liquid and the results averaged. The on geometric weight mean diameter and geometric stan-contact angle of molten liquid on lactose powder bed was dard deviation as previously described (Heng et al.,calculated using Eq. (3) (Washburn, 1921): 1999a,b). Instead, agglomeration model-independent mass


post-melt massing phases of 20 or 50 min were introduced.The growth propensity of melt agglomerates containingsucrose stearate S770 or S1570 was sensitive to lowconcentrations of sucrose stearate but such sensitivitydeclined when high concentrations of sucrose stearateswere concerned. Apparently, the propensity of melt ag-glomerate growth containing high concentrations of suc-rose stearate S170, S770 or S1570 was not entirelypredictable from runs using low concentrations of sucrosestearates.

3 .1. Agglomerative property

3 .1.1. Sucrose stearate S170At less than 2% (w/w), sucrose stearate S170 gave rise

to a less marked agglomerate growth, unlike sucrosestearates S770 and S1570. The agglomerates producedusing sucrose stearate S170 had a high percentage of finesand practically no oversized agglomerates (Fig. 4). Never-theless, a further increase in the concentration of sucrosestearate S170 gave rise to a marked increase in theagglomerate size, formation of oversized agglomerates andreduction in the percentage of fines. Uncontrollable growthof melt agglomerates was encountered when 10% (w/w)sucrose stearate S170 was used particularly in experimentscarried out with an additional post-melt massing phase of20 and 50 min, respectively. In these experiments,quenched cakes were collected. The cakes were oversizedagglomerates with extremely large mass median diameters,about 18 and 26 mm in agglomeration with 20 and 50 minof post-melt massing time, respectively.

During the melt agglomeration process, sucrose stearateS170 melted completely and participated as an additionalmolten binding liquid. Previous experiment with low-mo-lecular-weight polyethylene glycol showed that the growthof melt agglomerates was sensitive to the changes inbinder concentration (Wong et al., 2000). An increase inbinder concentration by 1% (w/w) resulted in a markedincrease in the size of agglomerates produced. Nonethe-Fig. 2. Physical appearance of melt agglomerates (sieve fraction 710–less, the contribution of molten sucrose stearate S170 to1000mm) produced using HCO in combination with sucrose stearates (a)melt agglomeration could not be merely explained by theS170, (b) S770 and (c) S1570. Sucrose stearate concentration: 2% (w/w);

post-melt massing time: 20 min. difference in the total volume of molten binding liquid. Inruns using a mixture of HCO and 10% (w/w) sucrose

median diameter and span were used for characterization stearate S170, the total molten liquid volume was higherof size and size distribution of the agglomerates. by 1.5% (v/w) than that of HCO alone and this caused the

Generally, the size of the melt agglomerates became formation of quenched cakes. However, a deliberatelarger with an increase in the concentration of sucrose increase in the concentration of HCO from 14 to 20%stearates (Fig. 3). Interestingly, the agglomerate growth (w/w), equivalent to an increase in total molten liquidpropensity of powder mass containing sucrose stearate volume by 7% (v/w), did not lead to the formation ofS170 was distinctly lower than those of sucrose stearates quenched cakes. The increased volume of HCO onlyS770 and S1570 at 2% (w/w) or less sucrose stearates. resulted in the size of agglomerates to increase from 178 toNonetheless, at sucrose stearate concentrations greater than 1311mm with the formation of 4 to 10% of oversized2% (w/w), sucrose stearate S170 brought about a greater agglomerates. This indicated that there were other charac-extent of melt agglomerate growth than those of sucrose teristics of sucrose stearate S170 which modified thestearates S770 and S1570, particularly when additional properties of the molten binding liquid and had a signifi-


Fig. 3. Effects of sucrose stearates on the size and size distribution of melt agglomerates produced using post-melt massing time of (a) 0 min, (b) 20 minand (c) 50 min. Sucrose stearate type: (s) S170, (h) S770 and (3) S1570.

cant role on the formation and growth processes of melt interface of molten HCO giving the molten liquid a loweragglomerates. surface tension. With high concentrations of sucrose stear-

The surface tension of molten HCO was reduced by the ate S170 added, the excess sucrose stearate moleculesaddition of sucrose stearate S170 up to 2% (w/w) [Fig.5a, immersed in the bulk phase were able to interact with theiranalysis of variance (ANOVA):P,0.05]. Further addition counterparts located at the interface of molten HCO andof sucrose stearate S170 resulted in a slight increase in air. Thus, a correspondingly higher surface tension wassurface tension values but these values remained lower developed above 2% (w/w) sucrose stearate S170. None-than that of molten HCO alone (Fig. 5a, ANOVA: P, theless, the contact angle of molten HCO was not sig-0.05). Sucrose stearate S170 is hydrophobic (HLB51), nificantly affected by the presence of sucrose stearate S170completely meltable and miscible with the molten HCO. at all concentrations studied (Fig. 5b, ANOVA: P.0.05).As a surfactant, sucrose stearate S170 can orientate at the This was not unexpected as the surface tension of molten


Fig. 4. Effects of sucrose stearates on the oversized agglomerate and fine formation of melt agglomeration process using post-melt massing time of (a)0min, (b) 20 min and (c) 50 min. Sucrose stearate type: (s) S170, (h) S770 and (3) S1570.

HCO was only marginally affected by the sucrose stearate cules via the hydrogen bonding in addition to that ofS170 molecules. Both HCO and sucrose stearate S170 are hydrophobic interaction. The summative effect was thatmainly constituted by polyesters of stearic acid. They have the viscosity of molten HCO was raised upon the additionsimilar chemical compositions and hydrophobicity. Conse- of sucrose stearate S170.quently, the interfacial properties of molten HCO were not Table 2shows the Pearson correlation coefficient valuesmarkedly influenced by the sucrose stearate S170. The between the physical properties of molten HCO containingbulk viscosity of molten HCO, on the other hand, was various concentrations of sucrose stearate S170 and thesignificantly raised particularly when 10% (w/w) sucrose size of melt agglomerates produced after 0, 20 and 50 minstearate S170 was added (Fig. 5c, ANOVA: P,0.05). At of post-melt massing, respectively. The size of melthigh concentrations of sucrose stearate S170, the sucrose agglomerates produced was significantly correlated to thestearate molecules might be interacting with HCO mole- volume and viscosity of the molten binding liquid but was


not significantly related to the surface tension and contactangle of the same liquid. Generally, the growth of meltagglomerates was promoted by an addition of sucrosestearate S170 which was translated to a large volume ofmolten binding liquid of a higher viscosity. The growthprocess of melt agglomerates prepared using a low viscosi-ty binder (below 50 mPa s) was especially sensitive tosmall changes in the binder viscosity, within the range of afew mPa s (Eliasen et al., 1999). Typically, a smallincrease in the viscosity of a molten binding liquid greatlyenhanced the binding strength and growth propensity ofagglomerates.Fig. 6 shows that the specific averageimpeller current consumption recorded during the post-melt distribution phase increased with an increase in theconcentration of sucrose stearate S170 (ANOVA:P,

0.05). The impeller current consumption was an indirectmeasurement of the rheological property of the powdermass (Cliff, 1990; Lin and Peck, 1995).

Fig. 5. Profiles of (a) surface tension, (b) contact angle and (c) viscosityof molten HCO with 0 to 10% (w/w) sucrose stearate added. Sucrose

Fig. 6. Specific average impeller current consumption at post-meltstearate type: (s) S170, (h) S770 and (3) S1570.distribution phase of melt agglomeration process as a function of sucrosestearate concentration. Sucrose stearate type: (s) S170, (h) S770 and(3) S1570.

T able 2Pearson correlation coefficient values between the size of melt agglomerates produced using various sucrose stearates and post-melt massing times and thephysical properties of molten HCO with 0 to 10% (w/w) sucrose stearate added

Sucrose stearate Post-melt massing Physical properties of molten HCO with 0 to 10% (w/w) sucrose stearatetype time (min)

ST CA VIS VOLa aS170 0 0.0401 0.3003 0.9408 0.9806a a20 0.1248 0.1293 0.9094 0.9050a a50 0.1238 0.1222 0.8934 0.8867

a aS770 0 20.6351 20.0049 0.8876 –a a20 20.6713 20.0056 0.8873 –a a50 20.8641 20.2602 0.6866 –

aS1570 0 20.8141 0.3690 20.4104 –a20 20.8259 0.4866 20.5600 –a50 20.8820 0.3917 20.5090 –

ST: Surface tension; CA: contact angle; VIS: viscosity; VOL: volume of molten binding liquid.a P,0.05. Level of significance was set at 0.05.


A rise in specific impeller current consumption reflectedan increase in viscosity of the processing mass. The meltagglomerates possessed a higher level of viscous strengthwhen high concentrations of sucrose stearate S170 wereadded. They could survive the impact of high speedimpeller rotation and thus had a better possibility forfurther agglomerate growth.

During a melt agglomeration, the molten binding liquidwas squeezed from the agglomerate core towards theperiphery by consolidation action of the impeller impactleading to an increased surface plasticity and propensity ofagglomerate growth by coalescence (Wong et al., 2000).The deformability of agglomerates may be similarlyenhanced by increasing the liquid to solid ratio of the meltagglomerates. As a result, an increase in the volume ofmolten binding liquid in association with increased sucrosestearate S170 concentration led to a higher propensity ofmelt agglomeration. The introduction of post-melt massingphase augmented agglomerate densification and moltenbinding liquid migration, which in turn led to a greaterpropensity of agglomerate growth.

Fig. 7 shows the pore size and size distribution of meltagglomerates prepared using various concentrations ofsucrose stearate S170 and post-melt massing times. Themode of pore size distribution of the melt agglomeratesranged from approximately 1 to 10mm. Unlike meltagglomerates containing polyethylene glycol 3000 as themeltable binder (Wong et al., 2000), the majority of poresin lactose–HCO–sucrose stearate S170 melt agglomerateswere larger than 1mm. There was no substantial increasein the population of submicron pores even at longer post-

Fig. 7. Effects of (a) sucrose stearate concentration and (b) post-meltmelt massing time or using higher concentration of sucrose massing time on pore size and size distribution of melt agglomeratesstearate S170. Instead, the population of micropores produced using mixtures of HCO and sucrose stearate S170. (a) Sucrosebecame lesser with an increase in concentration of sucrosestearate concentration: (s) 2% (w/w), (h) 5% (w/w) and (3) 10%

(w/w); post-melt massing time: 0 min. (b) Post-melt massing time: (s) 0stearate S170 or post-melt massing time. The melt agglom-min, (h) 20 min and (3) 50 min; sucrose stearate concentration: 2%erates were denser with an increase in volume and(w/w).

viscosity of molten binding liquid as well as prolongedconsolidation action by the impeller rotation. The formedagglomerates were expected to be stronger and survived agglomeration was accompanied by an increase in the spanthe impeller impact. With a large volume of molten of agglomerates (Fig. 3a). This implied that the distributionbinding liquid of a higher viscosity, the growth of melt of molten HCO and/or sucrose stearates might beagglomerates eventually became uncontrollable with pro- inhomogeneous. The agglomerates richer in HCO and/orlonged massing phase. sucrose stearates had the tendency to grow larger, whereas

smaller agglomerates were formed from aggregates in3 .1.2. Sucrose stearates S770 and S1570 which the relative contents of HCO and/or sucrose stear-

At 2% (w/w) or less sucrose stearates, both sucrose ates were lower. The heterogeneity of molten HCO and/orstearates S770 and S1570 promoted a marked agglomerate sucrose stearates distribution can be reduced by an intro-growth (Fig. 3). However, the growth potential of agglom- duction of a post-melt massing phase. With the intro-erates diminished with a further increase in the con- duction of a massing phase, the oversized agglomeratescentration of sucrose stearates. There was significantly less formed during the post-melt distribution phase wereexcessive agglomerate growth when high concentrations of broken down into smaller fragments (Fig. 4). Thesesucrose stearates S770 and S1570 were employed in fragments could grow into larger entities via coalescencecontrast to those of sucrose stearate S170. with the other agglomerates or layering onto the pre-

In the absence of post-melt massing phase, the growth of formed agglomerates. Through breakage, coalescence andmelt agglomerates was notably promoted by low con- layering, the molten HCO and/or sucrose stearates can becentrations of sucrose stearates S770 and S1570 but the redistributed. A more homogeneous agglomerate growth


process was promoted and this was evidenced by a the contact angle of molten HCO upon the addition ofreduction in the span of agglomerates. sucrose stearates S770 and S1570 might be ascribed to

Unlike sucrose stearate S170, both sucrose stearates preferential adsorption of sucrose stearate molecules ontoS770 and S1570 were not completely molten and remained the surfaces of the lactose particles during the measure-as semisolids at the elevated temperatures. The non-molten ment of contact angle by the liquid penetration methodfractions of sucrose stearates S770 and S1570 were (Buckton, 1990; Prestidge and Tsatouhas, 2000). This leddispersible in the bulk of molten HCO with stirring. It had to changes ing and g which in turn negated theL SL

been reported that a soften semisolid could act as a binder reduction in contact angle values. Overall, the molten HCO(McTaggart et al., 1984; Evrard et al., 1999). The local containing sucrose stearate S1570 appeared to have highermelting zone on the surface of a semisolid could promote contact angle values than that of sucrose stearate S770.particle aggregation and subsequently agglomerate growth. This was not impossible as sucrose stearate S1570 is moreHowever, in the present study, a further increase in the hydrophilic, less meltable and present in smaller amount inconcentration of sucrose stearates beyond 2% (w/w) the molten HCO than sucrose stearate S770.resulted in diminishing growth potential of melt agglomer- The viscosity of molten HCO was affected differentlyates. Thus, a rise in the content of semisolid sucrose by the sucrose stearates S770 and S1570. Sucrose stearatestearates beyond 2% (w/w) did not necessarily translate to S770 significantly gave rise to a higher viscosity par-an enhanced particle binding propensity and agglomerate ticularly at 10% (w/w) HCO (Fig. 5c,ANOVA: P,0.05).growth. It was concluded that other characteristics of On the other hand, there was insignificant increase in thesucrose stearates S770 and S1570 might have negated the viscosity of molten HCO with sucrose stearate S1570role of semisolid sucrose stearates to act as a binder. added (Fig. 5c,ANOVA: P.0.05). Unlike sucrose stearate

Sucrose stearates S770 and S1570 are mainly composed S170, sucrose stearate S770 affected the viscosity ofof mono- and diesters of stearic acid and sucrose mole- molten HCO via a different mode as the latter was morecules. They had a larger proportion of hydroxyl groups hydrophilic and less miscible with the molten HCO. Thewhich are unesterified with stearic acid than the sucrose increase in viscosity of molten HCO in conjunction withstearate S170. As a result, sucrose stearates S770 and the use of sucrose stearate S770 was probably due to theS1570 are relatively more hydrophilic in nature and have formation of a dispersed mixture of molten sucrose stearatehigher HLB values (Table 1). The interfacial property of S770 and HCO instead of forming a miscible moltenmolten HCO, namely surface tension, was significantly solution. Sucrose stearate S1570 is less meltable thanreduced by the addition of sucrose stearates S770 and sucrose stearate S770. The fraction of molten sucroseS1570, owing to the latter’s hydrophilic nature and prefer- stearate S1570 present in the HCO was smaller than that ofence for adsorption at the interface of molten HCO and air sucrose stearate S770. The net effect was that no observ-(Fig. 5a,ANOVA: P,0.05). Generally, the surface tension able rise in the viscosity of molten HCO when sucroseof molten HCO was lower with an increase in con- stearate S1570 was added.centration of sucrose stearates added. The surface tension Sucrose stearates S770 and S1570 were not completelyof molten liquid containing HCO and sucrose stearate molten within the processing temperatures encounteredS770 was lower than that of HCO with sucrose stearate during the melt agglomeration experiments. The availabili-S1570, albeit sucrose stearate S770 was less hydrophilic ty of molten sucrose stearates S770 and S1570 fractionsand had a lower HLB value. One reason might be that was low at elevated temperatures up to 1108C, making thesucrose stearate S1570, being the least meltable additive, volumetric determination of these molten sucrose stearateprovided a lesser amount of molten sucrose stearate fractions practically difficult to be carried out. Hence, themolecules necessary for reduction of the surface tension of Pearson correlations of the size of melt agglomerates withmolten HCO. the physical properties of molten HCO containing sucrose

Unexpectedly, both sucrose stearates S770 and S1570 stearates S770 and S1570 were analyzed without consider-did not bring about marked changes to the contact angle of ing the aspect of total molten binding liquid volume. It wasmolten HCO over lactose particles (Fig. 5b, ANOVA: undeniable that the growth profiles of melt agglomeratesP.0.05) despite their ability to reduceg of molten HCO. might be affected by the presence of molten sucroseL

Based on Young’s equation: stearates S770 and S1570 through an increase in thevolume of molten liquid, but the additional increase in the

g 2g volume of molten liquid contributed by molten sucroseS SL21 ]]]u 5 cos ? (5)S D stearates S770 and S1570 was relatively low within thegL

sucrose stearate concentration range employed in thewhereg , g andg are the solid surface tension, liquid present study. It was foreseeable that the effects of sucroseS L SL

surface tension, and interfacial tension between solid and stearates S770 and S1570 on melt agglomeration wouldliquid, respectively, andu is the contact angle, a decrease mainly be manifested through the modification of thein g would result in smalleru and improved wetting physical properties of molten HCO and thus its agglomera-L

property, in a system withu ,908. The lack of changes in tive property.


The size of melt agglomerates produced was correlatedsignificantly with the surface tension of molten HCOcontaining sucrose stearates S770 and S1570, respectively,as well as the viscosity of molten mixture of HCO andsucrose stearate S770 (Table 2). At low concentrations ofsucrose stearates S770 and S1570, a marked reduction inthe surface tension of molten HCO was accompanied by asharp rise in the size of the formed agglomerates. Thisclearly indicated that reduced inter-particulate tensionpromoted particle rearrangement and consolidation, withthe molten binding liquid being squeezed from the core tothe surfaces of agglomerates and enabled agglomeratedeformation and growth by coalescence (Iveson andLitster, 1998). With increasing concentration of sucrosestearates from 2 to 10% (w/w), the growth propensity ofmelt agglomerates was gradually diminished. This phe-nomenon could be ascribed to a limited change in thesurface tension of molten HCO with high concentrations ofsucrose stearates. At high concentrations of sucrose stear-ates, the extent of consolidation of melt agglomerates wasnot markedly enhanced and the population of pores in meltagglomerates was not substantially reduced (Fig. 8).Hence, the formation and growth processes of melt ag-glomerates became self-limiting.

In melt agglomeration process employing sucrose stear-ate S770, a rise in the viscosity of molten binding liquidwas not accompanied by an equivalent increase in thevolume of molten binding liquid as in the case of sucrosestearate S170, and this further complicated the inclinationfor agglomerate growth. The viscous strength and growthpropensity of melt agglomerates were expected to be high

Fig. 8. Pore size and size distribution of melt agglomerates producedwith an increase in the concentration of sucrose stearateusing mixtures of HCO and sucrose stearates (a) S770 and (b) S1570,S770, as illustrated by the profile of specific averagerespectively. Sucrose stearate concentration: (s) 2% (w/w), (h) 5%

impeller current consumption of the melt agglomeration (w/w) and (3) 10% (w/w); post-melt massing time: 0 min.process (Fig. 6, ANOVA: P,0.05). Nonetheless, thevolume of molten binding liquid migrating from core tosurfaces of agglomerates was not markedly increased with come of a melt agglomeration was more likely a complexan increase in the concentration of sucrose stearate S770. interplay between the physical properties of the moltenThe propensity of liquid migration under consolidation was mixture of HCO and sucrose stearate. The surface tension,negated by a gain in viscosity of the molten binding liquid. viscosity and contact angle of molten binding liquid wereThe melt agglomerates were not sufficiently deformed for characterized without the consideration of the intriguinggrowth by coalescence. The summative effect was an effects of the non-molten fractions of sucrose stearatesincrease in the span of melt agglomerates produced using S770 and S1570. It was envisaged that the non-moltenprolonged post-melt massing phase owing to inefficient fractions of sucrose stearates S770 and S1570 wereredistribution of molten binding liquid (Fig. 3c). In the contributive to the melt agglomerate growth. Nevertheless,case of sucrose stearate S1570, the magnitude of the such contribution was considered minimal as a variation inspecific average impeller current consumption was rela- the semisolid binder content between 18.75 to 50% (w/w)tively low and independent of the concentration of sucrose brought about a less drastic change in agglomerationstearate (Fig. 6, ANOVA: P.0.05). The formation and (McTaggart et al., 1984) than that of employing complete-growth processes of melt agglomerates prepared using ly meltable binder such as polyethylene glycol (Wong etsucrose stearate S1570 were mainly governed by theal., 2000).surface tension values of the molten binding liquid.

Experimentally, the melt agglomerates prepared using 3 .2. Anti-adherent propertysucrose stearates S770 and S1570 had similar growthprofiles, despite vast differences in the physical properties During the melt agglomeration process, the use of HCOof molten HCO modified by sucrose stearates. The out- alone as the meltable binder led to a substantial material


adhesion onto the processing chamber. Typically, 16 to marginal, owing to limited changes in the surface tension20% (w/w) HCO resulted in varying extents of material of the molten binding liquid and limited rise in the volumeadhesion, between 25 to 35%, of which was translated to a of molten binding liquid at the agglomerate surfaceslow product yield. Melt agglomeration using 14% (w/w) needed for agglomerate deformation and growth.HCO, on the other hand, gave rise to a markedly lower In addition to being an agglomeration modifier, sucrosepercentage of adhesion at 6.360.8%. However, the formed stearates promoted the growth of agglomerates without theproduct was mainly consisted of fine particles. In conjunc- excessive build-up of material adhesion onto the surfacestion with the use of HCO at a reduced concentration, of processing chamber. The melt agglomeration processsucrose stearates may be employed to promote the growth with a hydrophobic binder can be affected by sucroseof melt agglomerates without the build-up of material stearate through the modification of the properties of theadhesion. The amount of adhesion was consistently low, molten binding liquid. The properties of melt agglomeratesranging from 4.661.5 to 3.360.7 and 2.961.0% in melt can be adjusted via an interplay between type and con-agglomeration employing 14% (w/w) HCO with sucrose centration of sucrose stearate.stearates S170, S770 and S1570, respectively, with theamount of adhesion being lower with an increase in theconcentration of sucrose stearate. The effectiveness ofA cknowledgementssucrose stearates as an anti-adherent was largely related totheir surfactant property of which increased the surface The authors would like to thank Mitsubishi Chemical,polarity of molten HCO, thereby reducing the extent of Japan for supplying the sucrose stearates used in thishydrophobic interaction between the molten HCO and research.hydrophobic PTFE-lined chamber surfaces.

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investigation of melt agglomeration process with a hydrophobic binder in combination with sucrose...

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