Growth mechanisms in melt agglomeration in high shear mixers

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<ul><li><p> .Powder Technology 117 2001 6882www.elsevier.comrlocaterpowtec</p><p>Growth mechanisms in melt agglomeration in high shear mixersTorben Schfer)</p><p>Department of Pharmaceutics, The Royal Danish School of Pharmacy, 2 Uniersitetsparken, DK-2100 Copenhagen, DenmarkReceived 10 July 2000; received in revised form 2 November 2000; accepted 15 December 2000</p><p>Abstract</p><p>This paper presents a review of factors affecting the agglomerate formation and growth mechanisms in melt agglomeration in highshear mixers. The agglomerate formation occurs either by distribution or immersion or by a combination of both mechanisms.Distribution is promoted by a low binder viscosity, by a high impeller speed, and by a small binder particle size. Effects of the liquidsaturation of the agglomerates, impeller speed, particle properties, binder viscosity, and electrostatic charging on the subsequentagglomerate growth are discussed, and experimental results are presented. The agglomerate growth becomes controlled by the balancebetween the agglomerate strength and the shearing forces. If the agglomerate strength is sufficiently high to resist the shearing forces ofthe rotating impeller, the dominant agglomerate growth mechanism will be coalescence. The shearing forces will give rise to breakage ifthe agglomerate strength is too low, and then agglomerate growth will occur by a simultaneous buildup and breakdown of agglomerates,possibly combined with growth by layering of fragments upon larger agglomerates. Provided that the liquid saturation is sufficiently high,a higher agglomerate strength is primarily caused by a higher binder viscosity, a smaller particle size, an irregular particle shape, and bydensification of the agglomerates. q 2001 Elsevier Science B.V. All rights reserved.</p><p>Keywords: Agglomerate growth mechanisms; Melt agglomeration; High shear mixers; Binder viscosity; Impeller speed</p><p>1. Introduction</p><p>Melt agglomeration is a wet agglomeration process bywhich agglomeration is obtained through the addition ofeither a molten binder liquid or a solid binder, which meltsduring the process. The product temperature has to be keptat a temperature above the melting point of the binder orwithin the melting range of the binder by external heatingof the equipment andror by a development of heat causedby friction. The agglomerates are formed by an agitation ofthe mixture, and a cooling to ambient temperature resultsin dry agglomerates due to solidification of the binder.</p><p>A binder suitable for melt agglomeration is a materialhaving a melting point typically within the range of 501008C. A lower melting point might cause a risk ofmelting or softening of the binder during handling andstorage of the agglomerates, whereas a higher meltingpoint might cause stability problems in case of melt ag-glomeration of heat sensitive materials, e.g. many pharma-ceuticals. Polyethylene glycols, fatty acids, fatty alcohols,</p><p>) Tel.: q45-35-30-6474; fax: q45-35-30-6030. .E-mail address: ts@mail.dfh.dk T. Schfer .</p><p>waxes, and glycerides are examples of meltable bindersthat are applied for melt agglomeration of pharmaceuticals.</p><p>Melt agglomeration is advantageous because of thesimplicity of the process. When compared with a conven-tional wet agglomeration process, the drying step of theprocess is eliminated, and if the meltable binder is addedin a solid state, the liquid addition step is also eliminated.Further, melt agglomeration might be favourable as analternative to the use of toxic solvents for agglomeration ofwater-sensitive materials. Melt agglomeration has beenshown to be a simple way of producing pharmaceutical</p><p>w xdosage forms with prolonged release properties 13 sincea meltable binder that is insoluble in water will form aninsoluble matrix, from which the release rate of the drugsubstance can be controlled by varying the composition ofthe binder phase. Melt agglomeration might further beapplied in the glass industry and in fertilizer productionw x4 .</p><p>The term melt granulation is used when the processresults in agglomerates of a rather wide size distribution,typically within the range of about 0.12.0 mm. If thefinal agglomerates are spherical and of a narrow sizedistribution, typically within the size range of 0.52.0 mm,the process is called melt pelletization process, and the</p><p>0032-5910r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. .PII: S0032-5910 01 00315-1</p></li><li><p>( )T. SchferrPowder Technology 117 2001 6882 69</p><p>agglomerates are called pellets. Since the size, the sizedistribution, and the shape of the agglomerates normallywill change gradually during an agglomeration process, itwill not be possible to distinguish clearly between a granu-lation and a pelletization process. Thus, a melt pelletiza-tion process might be defined as a melt agglomerationprocess that is controlled in order to obtain pellets.</p><p>Melt agglomeration has been carried out in a coatingw x w x w xpan 5 , drum granulator 4,6 , blender 7,8 , and a small-</p><p>w xscale centrifugal rotating mixer 9 . Although a fluidizedbed will be very suitable for controlling the temperature,the lack of shearing forces in the process might explainwhy this method has gained no widespread application formelt agglomeration. On the other hand, the high shearingforces caused by the impeller rotation in a high shearmixer will make this equipment especially suitable formelt agglomeration. This is because the high shearingforces make it easier to obtain a uniform distribution of themolten binder and might cause so much heat of friction</p><p>w xthat an external heating of the mixer is unnecessary 10 .Contrary to other melt agglomeration methods, high shearmixers have been shown to be applicable for melt pelleti-</p><p>w xzation, e.g. Refs. 1,10 , and this is also supposed to be dueto the higher shearing forces.</p><p>The interpretation of the results of many aqueous wetagglomeration experiments is complicated by the fact thatwater evaporates during the process. Consequently, themelt agglomeration process is particularly suitable forfundamental studies of the mechanisms of agglomerateformation and growth in wet agglomeration, because noevaporation of binder liquid occurs. The aim of this paperis to give a review of factors affecting the agglomerategrowth mechanisms in melt agglomeration in high shearmixers based upon the work carried out in the laboratoryof the author.</p><p>2. Agglomerate formation</p><p>The nucleation phase of a wet agglomeration process is .the initial phase where small agglomerates nuclei of a</p><p>loose structure are formed because of a formation of liquidbridges between the primary particles. Fig. 1 shows thatagglomerates can be formed by two different mechanisms.By the distribution mechanism, a distribution of the binderliquid on the surface of the primary particles will occur,and nuclei become formed by a coalescence between thewetted particles. By the immersion mechanism, nuclei areformed by immersion of primary particles being capturedin the surface of a droplet of binder liquid. Which of thesemechanisms will be the dominant one will depend on theratio between the size of the solid particles and the droplets.Distribution will be the dominant mechanism when thedroplets are smaller than the solid particles or of a similarsize, whereas immersion will dominate when the dropletsare larger than the solid particles.</p><p>The initial droplet size might be controlled by an atom-ization of the binder liquid or by a pouring procedure.When melt agglomeration occurs by an addition of a solidbinder that melts during the process, the initial droplet sizewill depend on the particle size of the solid binder. Nor-mally, the droplet size becomes reduced by comminutionin the initial stage of the process if shearing forces areactive. In a high shear mixer, therefore, the distributionmechanism will be the typical mechanism of agglomerateformation. In a conventional fluidized bed, however, theagglomerate formation has been shown to be controlled by</p><p>w xthe droplet size of the binder liquid 1214 and conse-quently by the immersion mechanism.</p><p>By melt agglomeration in a high shear mixer, thedistribution mechanism is promoted by a small particlesize of the solid binder, by a low binder viscosity, and by ahigh impeller rotation speed. The effect of binder viscosityon agglomerate formation in an 8-l high shear mixer isillustrated in Table 1. The table shows the effects of</p><p> .polyethylene glycols PEGs with different average molec-ular mass on the mean granule size expressed as the</p><p> .geometric mass mean diameter d , the granule sizegwdistribution expressed as the geometric standard deviation . .s , and the amount of over-sized agglomerates )4 mmgat a massing time of 1 min after the melting of the PEG.The PEGs were added in a solid state and were used as</p><p> . . w xFig. 1. Agglomerate formation mechanisms in melt agglomeration. a Distribution mechanism. b Immersion mechanism 11 .</p></li><li><p>( )T. SchferrPowder Technology 117 2001 688270</p><p>Table 1Results of repeated experiments with different types of PEG at a massingtime of 1 minPEG d s Agglomeratesgw g</p><p> . .mm )4 mm %</p><p>2000 629 2.66 15.6560 2.77 12.8</p><p>3000 569 2.72 13.7548 2.78 18.7</p><p>6000 413 2.36 6.0422 2.38 5.9</p><p>8000 384 2.39 6.2373 2.41 6.4</p><p>10,000 466 2.28 3.3416 2.29 4.5</p><p>20,000 185 4.46 0.0190 4.61 0.0</p><p>w xStarting material: lactose monohydrate. Impeller speed: 1300 rpm 15 .</p><p>w xflakes of approximately the same size 11 . A highermolecular mass gives rise to a higher viscosity of the</p><p> .molten PEG Table 3 . It is seen that the PEGs with thelowest viscosities cause a marked initial agglomerategrowth being reflected in a large mean granule size and alarge amount of over-sized agglomerates. This indicates agood binder distribution making a rapid agglomerategrowth by coalescence possible. With PEG 20000, only aslight initial agglomerate growth is seen because the highviscosity counteracts the binder distribution. The immer-sion mechanism, therefore, will contribute markedly to theagglomerate formation. In the case of immersion, somesurface wetness has to be generated by a densificationbefore the nuclei are able to coalesce. Therefore, the initialgrowth rate will normally be low if the immersion mecha-nism dominates. The poorer binder distribution obtainedwith the PEG 20000 results in a wider size distribution.</p><p>The effect of the binder particle size on the initialagglomerate formation has been found to interact with the</p><p>w xbinder viscosity 11 . With the PEG 3000, the PEG 6000,and the PEG 8000, the binder particle size had only aslight effect on the agglomerate formation in a high shearmixer, because the binder viscosity was so low that thedominant mechanism of agglomerate formation was distri-bution. Accordingly, other experiments in a high shearmixer showed only a minor effect of the particle size of</p><p>w xPEG 6000 on the agglomerate size 16 . In a tumbling meltgranulation process, however, the agglomerate growth wasfound to be dependent on the particle size of PEG 6000because of the lower shearing forces in that equipmentw x17 . In the high shear mixer, the agglomerates wereformed by the immersion mechanism with the highlyviscous PEG 20000. Therefore, this binder gave rise to alarger agglomerate size when it was used as flakes instead</p><p>w xof powder 11 . Further, the shape of the agglomeratesbecame plate-like with the flakes and more rounded withthe powder. With PEG 10000, the effect of the binder</p><p>particle size was similar, but less clear, indicating thatdistribution and immersion occurred simultaneously.</p><p>Fig. 2 shows that the distribution of PEG 20000 be-tween different size fractions is very inhomogeneous at 1min after melting. The binder content is very low in thesize fractions that are smaller than the initial particle sizeof the powder and the flakes, respectively. This indicatesthat practically no comminution of the molten binderdroplets has occurred, i.e. the immersion mechanism domi-nates. The binder distribution is seen to be more uniform at3 min after melting, because more of the unagglomeratedsolid particles have been captured by the molten droplets.The PEGs with lower viscosities gave rise to a binderdistribution that was much more uniform and not signifi-</p><p>w xcantly affected by the particle size of the solid binder 11 .Accordingly, a higher binder viscosity resulted in a lessuniform initial binder distribution in a tumbling melt gran-</p><p>w xulation process 18 .In the nucleation phase, the tendency for coalescence</p><p>between initial particles, or between an initial particle anda nuclei will be larger than the tendency for coalescencebetween two nuclei as the potential for agglomerate growthis inversely proportional to the size of the particlesrag-</p><p>w xglomerates 19,20 . The nucleation phase, therefore, ischaracterized by a disappearance of fines. The nucleationphase might be very short in a melt agglomeration process.This is because the solid particles become suddenly wettedwhen the melting point of the binder is reached, contraryto the more gradual wetting obtained by a pouring orpumping of binder liquid upon a solid material. The sud-den wetting might lead to a formation of large, loose</p><p>agglomerates within the first minute after melting Table.1 . A meltable binder having a wide melting range has</p><p>Fig. 2. Content of PEG 20000 in selected fractions of agglomeratesproduced in melt agglomeration experiments with lactose monohydrate.</p><p> . . w xMassing time: a 1. b 3 min 11 .</p></li><li><p>( )T. SchferrPowder Technology 117 2001 6882 71</p><p>been shown to be advantageous in order to control thew xagglomerate growth 21 . After the formation, the nuclei</p><p>will normally gain so much strength by densification thatthey will be able to survive the mechanical forces acting inthe process. After that, agglomerate growth by coalescencebetween nuclei can occur.</p><p>3. Agglomerate growth</p><p>According to the agglomeration model developed byw xEnnis et al. 19 , the agglomerates will grow in size by</p><p>coalescence until a critical size has been reached. Thiscritical size becomes increased by a higher binder orgranule surface viscosity, a smaller particleragglomeratesize, a lower particle density, a lower impeller rotationspeed, a higher deformability of the particlesrag-glomerates, an increased thickness of the surface liquidlayer, and by a smoother surface of the particlesrag-</p><p>w xglomerates 19,20 . However, deformation and breakage ofthe agglomerates will occur at a certain critical size, whichdepends on the externally applied kinetic energy and on</p><p>w xthe agglomerate strength 20 . Thus, the agglomerategrowth is determined by the balance between coalescenceand breakage.</p><p>If the agglomerate strength is high, agglomerate growthby coalescence will be the dominant agglomerate growthmechanism. The agglomerate strength is affected by thechoice of raw materials, a high agglomerate strength beingprimarily caused by a small particle size, an irregularparticle shape causing interlocking, a high viscosity of thebinder liquid, andto a certain pointby a higher liquid-to-solid ratio. Further, the agglomer...</p></li></ul>