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08855, Blender Acetaminophen powder Some er. I with respect to two axes: a horizontal axis (tumbling motion), and a central symmetry axis (spinning is conducted on mixing performance of powders and the effect of critical in a metall the long ativel type isthetumblingblender,wheregrainsowby device, mixing and segregation mechanisms in these devices are not micronized Acetaminophen. We use extensive sampling to character- Powder Technology 196 (2009) 17 Contents lists available at ScienceDirect Powder Technology s fully understood and the design of blending equipment is largely based on empirical methods. Tumblers are the most common batch mixersinindustry,andalsonduseinmyriadofapplicationasdryers, kilns, coaters, mills and granulators 48.Whilefree-owing materials in rotating drums have been extensively studied 9,10, cohesive granular ows in these systems are still not completely understood. Little is known about the effect of fundamental param- ize mixing by tracking the evolution of Acetaminophen homogeneity using a Near Infrared spectroscopy detection method. After materials and methods are described in Section 2, results are presented in Section 3, followed by conclusions and recommendations, which are presented in Section 4. eters such as blender geometry, speed, ll lev loading pattern and axis of rotation on cohesive powders or the scaling requirements However,conventionaltumblers,rotating all share an important characteristic: while Corresponding author. Tel.: +1732 445 3357; fax: +1 E-mail address: (F.J. Muzzio). 0032-5910/$ see front matter 2009 Elsevier B.V. All doi:10.1016/j.powtec.2009.06.008 acombinationofgravity is a very common rotation on the mixing performance of a free-owing matrix of Fast Flo lactose and Avicel 102, containing a moderately cohesive API, and vessel rotation. Although the tumbling blender 1. Introduction Particle blending is a required step spanning the ceramic, food, glass, pharmaceuticals industries. Despite mixing (or perhaps because of it), compar mechanisms involved 13. A common and axis of rotation. In this work Acetaminophen is used as the active pharmaceutical ingredient and the formulation contains commonly used excipients such as Avicel and Lactose. The mixing efciency is characterized by extracting samples after pre-determined number of revolutions, and analyzing them using Near Infrared Spectroscopy to determine compositional distribution. Results show the importance of process variables including the axis of rotation on homogeneity of powder blends. 2009 Elsevier B.V. All rights reserved. variety of applications urgical, polymers, and history of dry solids y little is knownof the of batch industrial mixer direction of rotation is fast, mediated by a convective mixing process, mixing in the horizontal (axial) direction, driven by a dispersive process, is often much slower. In this paper, we experimentally investigate a new tumbling mixer that rotates with respect to two axes: a horizontal axis (tumbling motion),andacentral symmetryaxis(spinningmotion).We examine the effects of ll level, mixing time, loading pattern and axis of Relative standard deviation NIR fundamental parameters including blender geometry, speed, ll level, presence of bafes, loading pattern, Mixer motion). A detailed study Comparing mixing performance of uniaxial Amit Mehrotra, Fernando J. Muzzio Department of Chemical and Biochemical Engineering, Rutgers University, Piscataway, NJ, abstractarticle info Article history: Received 17 February 2009 Received in revised form 30 May 2009 Accepted 14 June 2009 Available online 27 June 2009 Keywords: Powder mixing Cohesion The dynamics involved in theory still remains underdeve In many industries, including mixers”. Tumbling mixers are some number of revolutions. cone blenders and bin blenders. mediated by a convective mixing process, is often much slow journal homepage: www.el el, presence of bafes, mixing performance of of the devices. aroundahorizontalaxis, homogenization in the 732 445 2581. rights reserved. and biaxial bin blenders United States mixing remains a topic of interest for many researchers; however the loped. Most of the mixers are still designed and scaled up on empirical basis. pharmaceutical, the majority of blending is performed using “tumbling hollow containers which are partially loaded with materials and rotated for common examples include horizontal drum mixers, v-blenders, double In all these mixers while homogenization in the direction of rotation is fast, process, mixing in the horizontal (axial) direction, driven by a dispersive n this paper, we experimentally investigate a new tumbling mixer that rotates /locate/powtec 2. Materials and methods The materials used in the study are listed in Table 1, along with their size and morphology. Acetaminophen is blended with com- monly used excipientsand is used as a tracer toevaluate the degree of homogeneity achieved as a function of number of revolutions. Acetaminophen is one of the drugs most widely used in mixing studies, and Avicel and Lactose are commonly used pharmaceutical The experimental plan used in this study is as follows: Fill level: blender 160% Fill level: blender 260%, 70%, 80% Loading pattern: blender 1 sideside loading,topbottom loading Loading pattern: blender 2 sideside loading,topbottom loading Speed: blender 115 rpm, 20 rpm, 25 rpm Speed: blender 2 rotational/spinning:15/7.5 rpm, 20/10 rpm, 30/15 rpm Sampling time: blender 1, blender 27.5,15, 30, 60,120 revolutions 3. Results The homogeneity index used is the RSD, where C is the concentration of each individual sample, C _ is the average concentra- tion of all samples and n is the total number of samples obtained at a given sampling time. RSD = S C ; where S = n P C 2 P C 2 nn 1 s We examine the effect of ll level on mixing performance. 2 A. Mehrotra, F.J. Muzzio / Powder Technology 196 (2009) 17 excipients. Intheinterestof brevitytheirSEMimagesarenotincluded in this paper, but can be found in “Handbook of Pharmaceutical excipients”. 2.1. Near infrared spectroscopy Acetaminophen homogeneity was quantied using near infrared spectroscopy. A calibration curve was constructed for a powder mixturecontaining(inaverage)35% avicelPH102,62% lactose and3% acetaminophen. Near infrared (NIR) spectroscopy can be a useful tool to characterize acetaminophen. Samples are prepared by keeping the ratio of Avicel to lactose randomized in order to minimize effects of imperfect blending of excipients during the actual experiments on the accuracy of the results. The Rapid Content Analyzer instrument manufactured by FOSS NIR Systems (Silver Spring, MD) and Vision software (version 2.1) is used for the analysis. The samples are prepared byweighing 1 g of mixture into separate optical scintillation vials; (Kimble Glass Inc. Vineland, NJ) using a balance with an accuracyof0.01mg.Near-IRspectraarecollectedbyscanninginthe range 11162482 nm in the reectance mode. Partial least square (PLS) regression is used in calibration model development using the second derivative mathematical pretreatment to minimize the particle size effects. As shown in Fig. 1, excellent agreement is achieved between the calibrated and predicted values. 2.2. Binblendersusedinthisstudy:uni-axialblender(Blender1),bi-axial blender (Blender 2) Due to its widespread use, a cylindrical blender 1 with a capacity of 30 L is chosen as a reference blender in the study. As shown in Fig. 2, this blender has a circular cross section and tapers at the bottom.Itcanbeusedwithorwithoutbafes,whicharemountedon a removable lid. In this study all the experiments are conducted without the use of bafes. Mixing performance in this device is used to provide a base-line for evaluating the mixing performance of a newly developed blender 2 with a capacity of 40 L, which is also cylindrical, in order to determine theeffectofdualaxisof rotation on mixing performance. The blender shown in Fig. 2(b) has two axis of rotation.Thespinningrateofprecessionrelativetothecentralaxisof symmetryisgearedtobehalfofthatoftherateofrotationaroundthe horizontal axis. 2.3. Experimental method Two types of initial powder loading used in the experiments: top bottom loading and sideloading, which are schematically repre- Table 1 Materials studied in this paper. Name Size and morphology Vendor, City, State Fast-Flo Lactose 100 , spherical Foremost farms, Newark, NJ Avicel PH 102 Microcrystalline cellulose 90 , needle-like FMC, Rothschild, WI Acetaminophen 40 , needle-like Mallinckrodt, St Louis, MO sented in Fig. 3. To avoid agglomeration, the API, acetaminophen, was delumped prior to loading it into the blender by passing it through a 35meshscreen.Inordertocharacterizemixingperformance,agroove sampler was used to extract samples from the blenders at 7.5,15, 30, 60, 120 revolutions. The thief was carefully inserted in the bin, and a corewas extractedateachpointof insertion (each “stab”) minimizing perturbation to the powder bed remaining in the blender. Approxi- mately 7 samples are taken from each thief stab, and a total of ve stabs are used at each sampling time, as shown in Fig. 4 so a total of 35 samples are taken at each sampling point. Previously there have been studies on the effect of ll level in the Bohle bin blender, Gallay bin blender and V-blender and double cone blender 1113. All the aforementioned blenders have only one axis of rotation, therefore the objective of this study is to examine how dual axis impact mixing performances at high ll levels. To avoid repetition, studies for ll level are not conducted for bin blender 1. Results available from a previous study using MgSt as a tracer showed that mixing in a uni-axial blender slowed down quite dramatically as the ll level exceeded 70%. Moreover, results for acetaminophen can be assumed to be similar to those obtained in previous work by Muzzio et al. 11,13, for a single axis rectangular bin blender 11, which have shown that even after few hundred revolutions homo- geneity achieved with a 80% ll level is very poor as compared to 60% ll level. To examine the effect of ll level in a dual axis blender, experi- ments were performed in blender 2 with the top-bottom loading pattern for a rotational speed of 15 rpm and with spinning speed of 7.5rpm.Thelllevelsexaminedare60%,70%and80%respectivelyand samples are taken after 7.5,15, 30, 60,120 revolutions. Typical results are shown in Fig. 5, which shows the RSD vs. number of blender revolutions. As expected for non-agglomerating materials, the curves Fig.1. Near Infrared (NIR) spectroscopy validation curve. The equation used to predict acetaminophen concentration is validated by testing samples with known amounts of acetaminophen concentration. The y axis represents the concentration calculated from the equation and the x axis represents the actual concentration. Thus a perfectly straight line at 45 would represent the best calibration model. Each point on the graph represents a single sample. The concentration of acetaminophen examined here ranges from 0 to 8%. Fig. 2. Pictorial representation of (a) bin blender 1 and (b) bin blender 2 showing the corresponding axis of rotation. Fig.3.Schematicoftheloadingpatternusedinthestudy.Intopbottomloading,AvicelisloadedrstintotheblenderfollowedbyLactoseontopofitandnallyAcetaminophenisuniformly sieved over. In sideside loading avicel is placed at the bottom and then Acetaminophen is only sieved only in half part of the blender and is sandwiched between lactose and Avicel. Fig. 4. (a) Thief sampler (b) top view of the sampling position scheme. Fig. 5. Mixing curves for different ll levels in blender 2. The RSD of acetaminophen is plotted as a function of number of revolutions. The loading pattern in top-bottom and the blender rotational speed is 15 rpm with spinning speed of 7.5 rpm. 3A. Mehrotra, F.J. Muzzio / Powder Technology 196 (2009) 17 d 4 A. Mehrotra, F.J. Muzzio / Powder Technology 196 (2009) 17 show a rapidly decaying region. The slope of the curves in this region, in semi-logarithmiccoordinates, is used todene the mixing rate. The curves then level off to a plateau that indicates the maximum degree of homogeneity that is achievable in the blender for a give material. Similar to previous studies with other tumbling blenders we ob- servethatblendingperformanceisadverselyaffectedbyincreasingll levels. As shown in Fig. 5, the curve for 80% ll performs more poorly thanthosefor60%and70%ll;aslllevelincreases,RSDcurvesdecay moreslowly,signifyingaslowermixingprocess.However,theeffectis not as pronounced as in other bin blenders and after about only 100 revolutions, the same plateau (the same asymptotic blend homo- geneity) is achieved for all three ll levels. Next, the effect of rotational speed is investigated in the blender 1 Fig. 6. Mixing curves for top-bottom loading experiments with 60% ll level. RSD is plotte blender 1, while solid lines represent data points from the blender 2. with one axis of rotation and is compared to the blender 2 with dual rotation axis. Experiments were conducted for both blenders with top-bottom and side-side loading. Experiments were performed at Fig.7.Mixingcurvesforsidesideloadingexperimentswith60%lllevel.RSDisplottedasafunction while solid lines represent data points from the blender 2. 60% ll level and the rotation speeds considered for blender 1 are 15 rpm, 20 rpm and 25 rpm respectively. As shown in Figs. 6 and 7, whenplottedasafunctionofblenderrevolutions,thereisnotmuchof an effect of rotation speed on the homogeneity index (RSD) of acetaminophen at 60% ll level. It is observed that mixing perfor- manceat20rpmand25rpmisslightlybetterthanat15rpm,however the differences in the performance of the blender under different speeds areprobably toosmall to be signicant. RSD curves decay with the same slope, indicating similar mixing rates. In the study reported here, thell level is only 60%, and all the rotational speeds areenough to achieve homogenization. The aforementioned studies were con- ducted at 85% ll level. For such a high ll level, at low speeds, a stagnant core is known to occur at the center of many blenders, as a function of number of revolutions. Dotted lines correspond to experiments in the requiring higher shear stress per unit volume to achieve homogeniza- tion. Moreover, the ow properties of MgSt are known to be strongly different than those of most materials, and are known to have a deep ofnumberofrevolutions.Dottedlinescorrespondtoexperimentsintheblender1, t 15 5A. Mehrotra, F.J. Muzzio / Powder Technology 196 (2009) 17 impacton theow properties of the mixture as awhole. Furthermore, MgSt is famously known to be a shear sensitive material. Thus an expectation that lubricated and unlubricated blends would show similar behavior with respect to shear is probably unwarranted. Subsequently, experiments were performed using the blender 2 at three rotation speeds: 15 rpm, 20 rpm and 30 rpm, and as explained before, the corresponding spinning speeds were 7.5 rpm,10 rpm and 15rpm.Filllevelconsideredforbothside-sideandtop-bottomloading was 60%. Again, it was observed that varying rotation and spinning speeds didnotmakemuchdifferenceinmixingrate.AsshowninFigs.6and7, mixing curves for blender 2 vary only slightly with rotation speed. For the top-bottom loading pattern it appears that mixing improves slightly whenrotation speedisincreased(theplateauisslightlylower for higher rotation speeds, indicating an improvement in the levels of asymptotic homogeneity), but no signicant changes with speed are observed in side-side loading pattern. Fig.8.Comparisonbetweenthemixingcurvesoftheblender2andtheblender1fortopbottom while solid lines represent data points from the blender 2. Experiments are performed a The blending performance of both blenders is compared at different rotation speeds for both side-side and top-bottom loading patterns. To make a fair comparison, the ll level was kept as 60% for Fig. 9. A typical mixing plot, with RSD plotted against number of revolutions. both blenders, a condition for which both blenders achieve effective mixing at long enough times. Due to geometric similarity of the two blenders, this comparison help evaluate the effect of spin (rotation withrespecttothecentralsymmetryaxis)onmixingperformance. As shown in Fig. 6, the mixing curves for the blender 2 lie belowthose for the blender 1 for each rotation rate, indicating faster mixing. Note that the nal RSD asymptote reached for both blenders is also different, with the blender 2 showing a lower asymptote (better nal mixed state,presumablyduetoalessereffectof theslowmixingmodeinthe horizontal direction) than blender 1. Similar results were obtained for the side-side loading pattern, as displayed in Fig. 7. The RSD curves for the blender 1 for all the three rotation rates lie above the blender 2. It is therefore conrmed that spinning a blender in direction perpendicular to the rotation axis helps in enhancing mixture homogeneity; however, for the materials examined here, the rotation rate does not have much effect on mixing performance. andsidesideloadingpattern.Dottedlinescorrespondtoexperimentsintheblender1, rpm with 60% ll level. Finally,acomparisonismadebetweenthetwoloadingpatternsfor bothblenders.Again,to achievea faircomparison,allexperimentsare performed at 15 rpm and 60% ll level. As evident in Fig. 8, in both The two solid lines emphasize on the two distinctive mixing regimes. blenders topbottom loading gives a more rapid decay of the RSD, indicating faster homogenization as compared to sideside loading studies14, tocapturethe evolution of the RSD inpowder systems. In this model, an exponential curve decaying towards a plateau is tted Fig.10. Mixing performance was evaluated at three differe