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  • Pharmaceutical Development and Technology, 12:371380, 2007 Copyright Informa Healthcare USA, Inc.ISSN: 1083-7450 print / 1097-9867 onlineDOI: 10.1080/10837450701369311

    371

    LPDT

    Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer

    Non-meltable Additive Effects in Melt AgglomerationWai See Cheong and Paul Wan Sia HengDepartment of Pharmacy, Faculty of Science, National University of Singapore, Singapore

    Tin Wui WongParticle Design Research Group, Faculty of Pharmacy, Universiti Teknologi MARA, Shah Alam, Selangor, Malaysia

    The present study aims to investigate the behavior of meltagglomeration with a low-viscosity hydrophobic meltable binderby using a non-meltable additive. The size, crushing strength,and pore size distribution of resultant agglomerates, the rheologi-cal, surface tension, and wetting properties of the molten binder,as well as, the flow characteristics of preagglomeration powderblend were determined. The use of additive showed contradic-tory agglomerate growth-promoting and -retarding effects on themolten binder surface tension and the interparticulate frictionalforces. Critical concentration effects of additive corresponded tothreshold transition of agglomeration-promoting to -retardingbehavior were discussed.

    Keywords frictional forces, melt agglomeration, non-meltableadditive, surface tension

    INTRODUCTION

    Melt agglomeration in a high-shear mixer is a viableprocess to produce granules or pellets that can be directlyfilled into capsules or compressed into tablets. The corefeature of melt agglomeration is that the process uses amolten liquid as the binder for solid particles. The moltenliquid is obtained through heating of a solid substance,which melts between 50 and 90C. The molten liquid binds

    the non-meltable solid particles by liquid bridges and sub-sequently solid bridges on its resolidification on cooling.

    Examples of meltable binders include polyethyleneglycols, fatty acids, fatty alcohols, triglycerides, andwaxes.[112] The polyethylene glycols are relatively morewidely studied because of their good particle-bindingcapability as well as their low adhesiveness onto the pro-cessing chamber that produced melt agglomerates withrelatively narrow size distributions.[2] The hydrophobicmeltable binders have been explored particularly for thedevelopment of sustained-release formulations.[712] Themelt agglomerates prepared with hydrophobic meltablebinders have a high tendency to break and shatter underthe impact of the impeller because these meltable bindershad generally low-viscosity values of less than 50 mPas inthe temperature range between 60 and 90C.[8,13] Never-theless, it was indicated that the agglomerative capabilityof hydrophobic meltable binders could not be entirelyascribed to their viscosity profiles.[8]

    Practically, the sciences of melt agglomeration usinglow-viscosity hydrophobic meltable binders are lessunderstood than those of polyethylene glycols. In accor-dance to Ennis et al.[14] and Rumpf,[15] the viscosity, liquidsaturation, surface tension, and spreading property of thebinding liquid are important parameters controlling thestrength and growth profiles of agglomerates. In meltagglomeration using a low-viscosity hydrophobic meltablebinder, it was previously found by our laboratory that thegrowth of melt agglomerates was promoted by increasedinterparticulate binding strength, agglomerate surface wet-ness, and agglomerate density through modification in thebinding liquids viscosity, surface tension, as well as spe-cific molten volume with the use of meltable or partiallymeltable additive, sucrose stearate.[16] In conjunction withthe need to understand further the processes of melt

    Received 3 October 2006, Accepted 12 February 2007.Address correspondence to Paul Wan Sia Heng, Department

    of Pharmacy, Faculty of Science, National University ofSingapore, 18 Science Drive 4, Singapore 117543; E-mail:phapaulh@nus.edu.sg

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  • 372 W.S. Cheong et al.

    agglomeration, the present investigation aims to reinforcethe findings on the behavior of melt agglomeration with alow-viscosity hydrophobic meltable binder via the use of anon-meltable additive.

    EXPERIMENTAL

    Materials

    Crystalline -lactose monohydrate (Pharmatose450M, DMV, The Netherlands) was used as the solid fillerwith hydrogenated cottonseed oil (HCO; Sterotex NF,Abitec, USA) as the hydrophobic meltable binder similarto previously described.[16] Magnesium stearate (Produc-tos Metalest, Spain) was used as a non-meltable additivewithout further processing. The magnesium stearate had amelting range between 101 and 119C (DSC-50;Shimadzu, Japan). The median volume particle diameterand span of magnesium stearate were 20 m and 3.17,respectively. The span was calculated as the differencebetween the 90th and 10th percentiles of the cumulativesize distribution relative to the median diameter. Chlor-pheniramine maleate (Merck, Singapore) was selected as amodel drug of high water solubility. The median volumeparticle diameter of chlorpheniramine maleate wasreduced to 30 m with a corresponding span of 2.47 byusing a pin mill (ZM 1000; Retsch, Germany) prior to use.

    Agglomeration Procedure

    Melt agglomerates were prepared by using a 10-Lvertical high-shear mixer (PMA-1 Processor, Aeromatic-Fielder, UK) equipped with online product temperature,impeller current consumption, and impeller speed record-ing as previously described.[16]

    The total amount of processing material for each meltagglomeration run was kept at 1.2 kg, with a fixed amountof 3.33% w/w chlorpheniramine maleate, HCO variedbetween 18 and 20% w/w and magnesium stearate,between 0 and 0.5% w/w, expressed as the total weightpercentage of processing material. The melt agglomera-tion process was preceded with a premixing of the pow-ders at 500 rpm for 5 min, following by a mixing at 1200rpm to produce shear friction to melt the HCO withinabout 4 to 5 min. At 5 min after the onset of melting,which was detected as an inflection point on the impellercurrent consumption against processing time, the impellerspeed was adjusted to 400 rpm, and the mixing was con-tinued for another 10 min. On completion of each run, themelt agglomerates were collected, spread in thin layers ontrays, and allowed to cool to ambient temperature.

    The weight of melt agglomerates harvested was deter-mined at the end of each run, and the amount of wet massadhesion was calculated as the weight percentage of unre-coverable material from the initial load. Duplicates werecarried out for each formulation, and the results were aver-aged. Throughout all experiments, the jacket temperaturewas set at 60C. The average median and maximum prod-uct temperatures were 74.4 1.6 and 87.8 0.7C,respectively. There was no marked difference in the pro-files of product temperatures among all batches of meltagglomeration runs (ANOVA: p > 0.05).

    Characterization of Melt Agglomerates

    Size and Size Distribution

    The melt agglomerates from each run were randomlysubdivided by using a spinning riffler (PT; Retsch,Germany) into eight samples of 120140 g each. A samplewas sized by using a series of 12 sieves (Endecott, UK) ona square root progression from 90 to 4000 m on a sieveshaker (VS1000; Retsch, Germany) within a predeter-mined time interval. The weight percentage of meltagglomerates retained on each sieve was calculated. Theagglomerate size was represented by the mass mediandiameter defined as the diameter at 50th weight percentileof the cumulative agglomerate size distribution. The sizedistribution of melt agglomerates was represented by thespan and was calculated as the difference between 90thand 10th percentiles of the cumulative agglomerate sizedistribution relative to the mass median diameter. Theamounts of fines and lumps were expressed as the weightpercentage of sieve fraction smaller than 250 m andlarger than 2800 m, respectively.

    Crushing Strength

    The crushing strength measurement of melt agglom-erates was carried out by using a tensile tester (EZ test-500N; Shimadzu, Japan) mounted with a 500 N capacityload cell. An agglomerate, randomly sampled from meltagglomerates in the size range of 10001400 m, wascrushed diametrically between two platens driven at a rateof 3 mm/min, and the maximum load (N) required to crusheach agglomerate was recorded from the force-time pro-file. A total of 50 measurements were carried out for eachbatch of melt agglomerates, and the results were averaged.

    Intra-Agglomerate Pore Size and Size Distribution

    The pore size and size distribution of melt agglomerateswithin the size fraction of 250 2800 m were determined

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  • Non-meltable Additive Effects in Melt Agglomeration 373

    by using a mercury intrusion porosimeter (Poresizer 9320;Micromeritics, USA), similar to that described by Wonget al.[17] Intrusion pressures between 5 and 5000 psia wereused. The experiments were carried out in duplicates, andthe results were

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