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

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<ul><li><p>Pharmaceutical Development and Technology, 12:371380, 2007 Copyright Informa Healthcare USA, Inc.ISSN: 1083-7450 print / 1097-9867 onlineDOI: 10.1080/10837450701369311 </p><p>371</p><p>LPDT</p><p>Impact of a Non-meltable Additive on Melt Agglomeration with a Hydrophobic Meltable Binder in High-Shear Mixer</p><p>Non-meltable Additive Effects in Melt AgglomerationWai See Cheong and Paul Wan Sia HengDepartment of Pharmacy, Faculty of Science, National University of Singapore, Singapore </p><p>Tin Wui WongParticle Design Research Group, Faculty of Pharmacy, Universiti Teknologi MARA, Shah Alam, Selangor, Malaysia</p><p>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.</p><p>Keywords frictional forces, melt agglomeration, non-meltableadditive, surface tension</p><p>INTRODUCTION</p><p>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</p><p>the non-meltable solid particles by liquid bridges and sub-sequently solid bridges on its resolidification on cooling.</p><p>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]</p><p>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</p><p>Received 3 October 2006, Accepted 12 February 2007.Address correspondence to Paul Wan Sia Heng, Department</p><p>of Pharmacy, Faculty of Science, National University ofSingapore, 18 Science Drive 4, Singapore 117543;</p><p>Phar</p><p>mac</p><p>eutic</p><p>al D</p><p>evel</p><p>opm</p><p>ent a</p><p>nd T</p><p>echn</p><p>olog</p><p>y D</p><p>ownl</p><p>oade</p><p>d fr</p><p>om in</p><p>form</p><p>ahea</p><p>lthca</p><p>re.c</p><p>om b</p><p>y U</p><p>nive</p><p>rsity</p><p> of </p><p>Uls</p><p>ter </p><p>at J</p><p>orda</p><p>nsto</p><p>wn </p><p>on 1</p><p>1/13</p><p>/14</p><p>For </p><p>pers</p><p>onal</p><p> use</p><p> onl</p><p>y.</p></li><li><p>372 W.S. Cheong et al.</p><p>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.</p><p>EXPERIMENTAL</p><p>Materials</p><p>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.</p><p>Agglomeration Procedure</p><p>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]</p><p>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.</p><p>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 &gt; 0.05).</p><p>Characterization of Melt Agglomerates</p><p>Size and Size Distribution</p><p>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.</p><p>Crushing Strength</p><p>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.</p><p>Intra-Agglomerate Pore Size and Size Distribution</p><p>The pore size and size distribution of melt agglomerateswithin the size fraction of 250 2800 m were determined</p><p>Phar</p><p>mac</p><p>eutic</p><p>al D</p><p>evel</p><p>opm</p><p>ent a</p><p>nd T</p><p>echn</p><p>olog</p><p>y D</p><p>ownl</p><p>oade</p><p>d fr</p><p>om in</p><p>form</p><p>ahea</p><p>lthca</p><p>re.c</p><p>om b</p><p>y U</p><p>nive</p><p>rsity</p><p> of </p><p>Uls</p><p>ter </p><p>at J</p><p>orda</p><p>nsto</p><p>wn </p><p>on 1</p><p>1/13</p><p>/14</p><p>For </p><p>pers</p><p>onal</p><p> use</p><p> onl</p><p>y.</p></li><li><p>Non-meltable Additive Effects in Melt Agglomeration 373</p><p>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 averaged. The plot of cumulative differen-tial specific intrusion volume against pore diameter wasused to characterize the pore size and size distribution ofmelt agglomerates.</p><p>Drug Release Study</p><p>Drug release study was performed on melt agglomer-ates of size fraction between 1000 and 1400 m by usingthe USP Apparatus 2 with the paddle rotating at 50 rpm(Optimal DT-1, Optimal Control Inc., USA). The dissolu-tion medium was 900 mL of USP simulated gastric fluidwith 0.05% w/v polysorbate 20 added and was maintainedat 37.0 0.5C. At predetermined intervals, 5-mL aliquotswere withdrawn from each dissolution vessel, filtered, andanalyzed for chlorpheniramine maleate spectrophotometri-cally at 264.8 nm (UV-1201; Shimadzu, Japan). The per-centage of drug released was calculated with respect to thedrug content of the melt agglomerates. The drug contentwas expressed as the amount of drug in a unit weight ofmelt agglomerates. It was determined by subjecting thesame sample of melt agglomerates from the drug releasestudy to heating at 80C to destroy the matrices by melt-ing, then, on cooling, 5-mL aliquots were withdrawn, fil-tered, and assayed as mentioned.</p><p>Characterization of Molten HCO</p><p>The surface tension, viscosity, and contact angle ofthe molten HCO, with and without the addition of magne-sium stearate, were characterized at 80C, which repre-sented the intermediate temperature for median andmaximum product temperatures encountered during meltagglomeration. The molten HCO was a clear yellow liq-uid. The addition of magnesium stearate, in the range of03% w/w, with respect to the weight of HCO, broughtabout a turbid suspension due to insolubility of magne-sium salt in the molten HCO. The formed suspension wascontinuously stirred by using a magnetic stirrer and wasused for characterization without prior filtration. Therange of 03% w/w magnesium stearate in HCO was cho-sen because of the concentration ranges of magnesiumstearate, with respect to the total weight of processingmaterial, were equivalent to 02.78, 02.63, and 02.50%w/w magnesium stearate, with respect to 18, 19, and 20%w/w HCO used in the melt agglomeration runs. The meth-ods for surface tension and viscosity were the same as pre-viously described.[16] For contact angle, a lactose powder</p><p>bed containing 4.3% w/w chlorpheniramine maleate wasdetermined at 80 2C by the Washburn liquid penetra-tion method.[16,18] The contact angle of molten HCO, ,was calculated by using Equation (1)[19]:</p><p>where l is the length of liquid penetration in time t, Land are the surface tension and viscosity of the penetrat-ing liquid, respectively, and r is the effective pore size. was obtained from the gradient of the linear plot of l2 ver-sus t by least-square approximation method with r esti-mated by using Equation (2)[20]:</p><p>where is the particle shape factor, which was assumed tobe unity in the present study, and d32 is the surface meanparticle diameter of a sphere. The surface mean particlediameters of lactose and chlorpheniramine maleate were7.89 and 10.91 m, respectively, determined by a laserdiffraction particle sizer. The surface mean particle diame-ter of the powder mixture was calculated by the propor-tional method based on the fractional weight of lactose andchlorpheniramine maleate. is the porosity of the powderbed and was calculated from the apparent porosity (app)and tapped porosity (tap) of the powder mixture usingEquation (3)[20]:</p><p>where app and tap were determined from the apparent andtapped densities of the powder mixture and pycnometricdensity values of lactose and chlorpherinaramine maleate.The apparent and tapped densities were determined on thebasis of the weight and volume of the powder mixture fill-ing the tube prior to and after tapping to a constant vol-ume. Pycnometric density values of lactose andchlorpheniramine maleate were 1.5394 and 1.2848 g/cm3,respectively, determined by using a gas displacement pyc-nometer (PYY-14; Quantachrome Instrument, USA) withhelium purge. Duplicates of contact angle measurementwere carried out for each batch of sample, and the resultswere averaged.</p><p>Characterization of Tensile Strength of Re-Solidified Molten HCO</p><p>Samples of resolidifed molten HCO containing 03%w/w magnesium stearate were prepared by melting theHCO or mixture of HCO and magnesium stearate and then</p><p>lr tL2</p><p>2= </p><p> cos (1)</p><p>r = ( )</p><p>d323 1</p><p>(2)</p><p> = +( )tap app tap1 (3)</p><p>Phar</p><p>mac</p><p>eutic</p><p>al D</p><p>evel</p><p>opm</p><p>ent a</p><p>nd T</p><p>echn</p><p>olog</p><p>y D</p><p>ownl</p><p>oade</p><p>d fr</p><p>om in</p><p>form</p><p>ahea</p><p>lthca</p><p>re.c</p><p>om b</p><p>y U</p><p>nive</p><p>rsity</p><p> of </p><p>Uls</p><p>ter </p><p>at J</p><p>orda</p><p>nsto</p><p>wn </p><p>on 1</p><p>1/13</p><p>/14</p><p>For </p><p>pers</p><p>onal</p><p> use</p><p> onl</p><p>y.</p></li><li><p>374 W.S. Cheong et al.</p><p>pouring into a cylindrical mould (9.5 mm in internal diam-eter and 6 mm in depth) and cooled to ambient tempera-ture. The cooled samples had an average weight of 406 3.6 mg. Samples were conditioned at 22 2C and 55%relative humidity for at least 24 hr prior to tensile strengthmeasurement. The tensile strength of each sample wasdetermined by using the cone penetration breakingstrength method as described by Chee et al.[21] A uniaxialpenetration load was applied from a conical tip onto theaxial surface of the sample. The maximum load (N)required to break each sample was recorded from theforce-time profiles. A total of 10 measurements were car-ried out for each batch of samples, and the results wereaveraged.</p><p>Characterization of Solid Powder</p><p>The flow properties of the preagglomeration powdermixtures of lactose and drug, with and without the addi-tion of magnesium stearate, were assessed by using tap-ping analysis and Hausner ratio (ratio of tapped densityto poured density of powder mixture) and Carrs index(difference between tapped and poured densities relativeto tapped den...</p></li></ul>