Solventless-mixing layering using a high shear mixer for preparing drug pellets: A feasibility study using acetaminophen

Our aim was to investigate the feasibility of mechanical-mixing layering using a high shear mixer, which can produce drug pellets by simply mixing drug crystals and inactive seed particles without the need for solvents or binders. Acetaminophen crystals and microcrystalline cellulose spheres were mechanically mixed using various impeller speeds and the resulting composite particles were characterized. Acetaminophen particles were separated from the spheres using a low impeller speed and deposited on the surface of the spheres at a higher impeller speed. The diameter of the acetaminophen crystals in the composite particles decreased as the impeller speed increased, due to increased collision impact between the spheres. The correlation between drug content and drug particle diameter in the composites indicates that acetaminophen particles were layered on the cellulose spheres due to their pulverization during the mixing treatment. We examined additional mixing treatments to enhance drug loading: after mechanically mixing acetaminophen crystals and cellulose spheres, fresh acetaminophen crystals were added and mechanically mixed with the composite particles. Additional mixing increased the loading of acetaminophen particles without lowering the layering efficiency. In conclusion, mechanical-mixing layering can be accomplished using a high shear mixer.     

Mixing assessment of non-cohesive particles in a paddle mixer through experiments and discrete element method (DEM)

In this study the mixing kinetics and flow patterns of non-cohesive, monodisperse, spherical particles in a horizontal paddle blender were investigated using experiments, statistical analysis and discrete element method (DEM). EDEM 2.7 commercial software was used as the DEM solver. The experiment and simulation results were found to be in a good agreement. The calibrated DEM model was then utilized to examine the effects of the impeller rotational speed, vessel fill level and particle loading arrangement on the overall mixing quality quantified by the relative standard deviation (RSD) mixing index. The simulation results revealed as the impeller rotational speed was increased from 10?RPM to 40?RPM, generally a better degree of mixing was reached for all particle loading arrangements and vessel fill levels. As the impeller rotational speed was increased further from 40?RPM to 70?RPM the mixing quality was affected, for a vessel fill level of 60% and irrespective of the particle loading arrangement. Increasing the vessel fill level from 40% to 60% enhanced the mixing performance when impeller rotational speed of 40?RPM and 70?RPM were used. However, the mixing quality was independent of vessel fill level for almost all simulation cases when 10?RPM was applied, regardless of the particle loading arrangement. Furthermore, it was concluded that the particle loading arrangement did not have a considerable effect on the mixing index. ANOVA showed that impeller rotational speed had the strongest influence on the mixing quality, followed by the quadratic effect of impeller rotational speed, and lastly the vessel fill level. The granular temperature data indicated that increasing the impeller rotational speed from 10?RPM to 70?RPM resulted in higher granular temperature values. By evaluating the diffusivity coefficient and Peclet number, it was concluded that the dominant mixing mechanism in the current mixing system was diffusion.     

DEM simulation for optimal design of powder mixing in a ribbon mixer

A ribbon mixer is often employed in powder mixing in a wide range of engineering fields. The structure of the ribbon mixer is extremely complicated. This structure makes it difficult to understand the mixing mechanism by experimental approaches due to problems related to accurate sampling. At present, the mixing mechanism in the ribbon mixer is empirically identified as convection, despite a lack of precise assessment. Additionally, experimental investigations to find the optimal design of the ribbon mixer have not been sufficiently conducted because of its prohibitive cost. As such, there is a lack of sufficient discussion concerning the design for better mixing in the ribbon mixer. Numerical technologies represent a promising approach for solving the aforementioned problems. Significant improvements in computer hardware have enabled numerical models such as the discrete element method (DEM) to be positively employed in powder mixing. In the current study, an identification approach is developed for convective mixing, and besides, the study explores an effective parameter for better mixing in the ribbon mixer using the DEM. A swept volume measurement approach due to paddle movement is newly developed to identify the main mixing mechanism as convection. Sensitivity analyses are performed to find an effective parameter for better mixing. Through the sensitive analyses, the blade width is indicated as an important factor for achieving better mixing. Moreover, this study shows that the relationship between the swept volume and mixing index remains, even if the paddle width changes. Thus, the swept volume measurement method is revealed as useful for identifying the mechanism as convection in the ribbon mixer. Thus, not only novel finding regarding the blade width for better mixing but also the development of an approach for identifying convective mixing in the ribbon mixer is presented herein. Incidentally, convection being the dominant mechanism is consistent with the novel finding regarding blade width achieving better mixing.     

Flow of granular materials in a bladed mixer: Effect of particle properties and process parameters on impeller torque and power consumption

The torque and power needed to drive an impeller are important quantities that can indicate flow behavior and can be used to control processes, especially mixing and granulation in the pharmaceutical industry. In this study, experiments were conducted on monodisperse spherical glass beads flowing in a cylindrical bladed mixer agitated by an impeller. The impeller torque was measured using a rotating platform and a data recording device, and the power draw for the motor driving the impeller was measured using a power meter. The effect of various impeller blade designs and material properties on the torque and power were investigated as a function of the impeller blade rotation rate. It was found that the torque exerted on a granular bed and the power consumption were a strong function of the impeller blade configuration, the position of the blades in a deep granular bed, the fill height of the glass beads, and the size and friction coefficient of the particles. It was observed that the time-averaged torque and power consumption for different particle sizes qualitatively scaled with particle diameter. A scale-up relationship for a deep granular bed was developed: the time-averaged torque and average adjusted power consumption scaled with square of the material fill height.     

DEM study on identification of mixing mechanisms in a pot blender

A pot blender with both blending and storage capabilities offers an advantage over a conventional rotating drum. However, the mixing mechanism of the pot blender is extremely complicated because the pot blender rotates and swings simultaneously. Owing to the lack of systematic investigations, the mixing mechanism of the pot blender has not been fully elucidated. In this study, we clarify the mixing mechanism of the pot blender by using the discrete element method. Simulation results reveal that the main mixing mechanism is convective mixing in the rotational direction and shear mixing in the axial direction. Moreover, the mixing performance is unaffected by particle density, whereas the velocity gradient in the axial direction, which mainly determines the axial mixing performance, is affected by the particle filling ratio. Considering the relationship between the variance of axial particle velocity and granular temperature, the filling ratio is shown to significantly influence the mixing efficiency in the pot blender. In addition, the dependency of shear and diffusive mixing on Lacey’s mixing index in the pot blender is newly clarified. Consequently, this study demonstrates essential insights into the mixing mechanism of the pot blender and the pot blender as an effective industrial mixer.     

Numerical simulation of solid-liquid mixing characteristics in a stirred tank with fractal impellers

The hydrodynamics of solid-liquid mixing process in a stirred tank with four pitched-blade impellers, fractal 1 impellers, and fractal 2 impellers were investigated using computational fluid dynamics (CFD) simulation. An Eulerian-Eulerian approach, standard k-ε turbulence model, and multiple reference frames (MRF) technique were employed to simulate the solid-liquid two-phase flow, turbulent flow, and impeller rotation, respectively. The effects of impeller speed, impeller type, impeller spacing, impeller blade tilt angle, impeller blade shape, solid particle size and initial solid particle loading on the solid particle suspension quality were investigated. Results showed that the homogenous degree of solid-liquid system increased with the increase of impeller speed. The impeller spacing of T5/6 and T and impeller blade tilt angle of 60° and 45° were appropriate for the solid-liquid suspension process. Fractal shape impeller was more efficient than jagged shape impeller in solid-liquid mixing process. Larger particle diameter and higher initial solid particle loading resulted in less homogenous distribution of solid particles. It was found that fractal impeller could improve the solid particle suspension quality compared with four pitched-blade impeller under the same power consumption, increasingly so with the fractal iteration number of fractal impeller. Moreover, fractal impeller reduced the size of impeller trailing vortex and consumed less power consumption compared with four pitched-blade impeller at the same impeller speed, and the more the number of fractal iteration, the higher the impeller energy utilization rate of fractal impeller.     

Scale-up and flow behavior of cohesive granular material in a four-bladed mixer: effect of system and particle size

Flow of cohesive granular materials with different moisture contents was examined in a four-bladed mixer via the discrete element method (DEM). Firstly, the mixer diameter (D) was increased while keeping the particle diameter (d) constant. It was observed that when the mixer diameter to the particle diameter ratio (D/d) was larger than a certain critical size (D/d ≥ 75), granular flow behaviors and mixing kinetics followed simple scaling relations. For D/d ≥ 75, flow patterns and mixing kinetics were found to be independent of system size, and velocities of particles scaled linearly with the tip speed of the impeller blades and particle diffusivities scaled with the tip speed of the blades and mixer diameter. These results suggest that past a certain system size the flow and mixing of cohesive particles in large-scale units can be predicted from smaller systems. Secondly, system size was kept constant and particle diameter was changed and it was observed that by keeping the Bond number constant (by changing the level of cohesion) the flow behavior and mixing patterns did not change, showing that larger particles can be used to simulate flow of smaller cohesive particles in a bladed mixer by matching the Bond numbers.     

A Comparison of Free-Flowing, Segregating and Non-Free-Flowing, Cohesive Mixing Systems in Assessing the Performance of a Modified V-Shaped Solids Mixer

The performance of a modified V-shaped solids mixer, i.e., uneven leg or offset angle, has been reassessed by using a binary cohesive mixture, made up of 1% sodium salicylate and 99% microcry stalline cellulose, as the mixing system. The performance of the mixer was defined in terms of relative standard deviation from the measured mean. The results generated from the present study were compared with the previously published data generated by using a free-flow mixing system. It appears in the present study that the free-flowing, segregating materials may be used as a mixing model to predict the trend of the performance of a modified V-shaped blender for the non-free-flowing, cohesive materials. However, in the equilibrium state, the non-free-flowing, cohesive mixture has much better quality of the mix than that of the free-flowing, segregating system in terms of the scale and intensity of segregation.     

Optimization of a microfluidic mixer for studying protein folding kinetics

We have applied an optimization method in conjunction with numerical simulations to minimize the mixing time of a microfluidic mixer developed for protein folding studies. The optimization method uses a semideterministic algorithm to find the global minimum of the mixing time by varying the mixer geometry and flow conditions. We describe the minimization problem and constraints and give a brief overview of the optimization algorithm. We present results of the optimization, including the optimized geometry and parameter sensitivities, and we demonstrate the improvement in mixing performance with experiments using microfabricated mixers. The dye-quenching experiments of the original and optimized mixer designs show respective mixing times of 7 and 4 mus, a 40% reduction. The new design also provides more uniform mixing across streamlines that enter the mixer. The optimized mixer is the fastest reported continuous flow mixer for protein folding.     

An Experimental and Numerical Study of Transversal Dispersion of Granular Material on a Vibrating Conveyor

The mixing of thin granular layers transported on the surface of an oscillating trough is experimentally and numerically examined. The particle dispersion was experimentally quantified by an image processing system recording the growth of the mixing layer thickness of two differently colored but otherwise identical sand particle streams along the longitudinal position within the transporting channel. Granular flow and dispersion on the vibrating conveyor were studied numerically based on a three-dimensional discrete element code. Both experiments and simulations were used to derive quantities characterizing the transversal dispersion. The mixing was found to be directly proportional to the vertical acceleration of the conveyor and inversely proportional to the mass flow of the transported material. Keeping the above-mentioned parameters constant, the dispersion increases with increasing mean particle diameter. When performing the experiments with materials of different mean particle diameters and tuning the mass flow to achieve the same level of dimensionless bed height, the magnitude of the dispersion coefficient remains constant, as was also confirmed by the numerical simulation.     

Investigations at an industrial scale on granule and tablet attributes in high shear rapid mixer granulator

Particle agglomeration by granulation was a very ubiquitous operation that finds applications in various industries such as pharmaceutical, food, chemical, fertilizer, etc. Among many granulators, the high shear rapid mixer granulator (RMG) was a very commonly used wet granulator in pharmaceutical industry. The wet granulation process was sensitive to the process parameters and the input product variables. The flow pattern, fill ratio, cohesive forces, velocities, and the kinetic energy of the particles have impact on the granular and the tablet properties. In this work, solid dosage formulation integrated with the RMG process has been studied at an industrial scale. The total formulation of the tablet was kept constant and the impact of various critical operating and process parameters of RMG viz., impeller design, impeller speed, batch size, binder concentration, and binder type on granule and tablet attributes has been studied and analyzed. The optimal set of process parameters to achieve the desired granular and tablet attributes viz., bulk density, compressibility (Carr index) flow properties (Hausner ratio), particle size distribution, texture, tablet hardness, dissolution, and disintegration times were found in the study.     

Effects of Mixer and Mixing Time on the Pharmaceutical Properties of Theophylline Tablets Containing Various Kinds of Lactose as Diluents

Effect of mixing time on the flowability, compressibility, tablet hardness and dissolution of theophylline tablets was investigated using two types of mixers, i.e., twin-shell and high-speed mixers. Theophylline, three kinds of lactose ($aL-monohydrate, β-anhydrate and spray-dried product), disintegrator and magnesium stearate were mixed, and tablets were compressed. While the particles mixed with magnesium stearate by the high speed mixer were coated with magnesium stearate, those mixed by the twin-shell mixer formed an ordered mixture. The dissolution differed depending on the mixing time and method.     

Dispersion and re-agglomeration of graphite nanoplates in polypropylene melts under controlled flow conditions

The kinetics of GnP dispersion in polypropylene melt was studied using a prototype small scale modular extensional mixer. Its modular nature enabled the sequential application of a mixing step, melt relaxation, and a second mixing step. The latter could reproduce the flow conditions on the first mixing step, or generate milder flow conditions. The effect of these sequences of flow constraints upon GnP dispersion along the mixer length was studied for composites with 2 and 10 wt.% GnP. The samples collected along the first mixing zone showed a gradual decrease of number and size of GnP agglomerates, at a rate that was independent of the flow conditions imposed to the melt, but dependent on composition. The relaxation zone induced GnP re-agglomeration, and the application of a second mixing step caused variable dispersion results that were largely dependent on the hydrodynamic stresses generated.     

Instrumentation of a Vertical High Shear Mixer with a Motor Slip Monitoring Device

The main impeller shaft of a vertical high shear mixer was instrumented with a device which measures motor slip and displays its output in percent horsepower. Response was proportional to mixer load. A warm-up period was required to minimize variability in output. High speed impeller operation showed more consistency in response than low speed impeller operation. During the granulation process of the different test systems, a typical response profile showed a change in percent horsepower as the binder solution was added followed by a plateauing at about the proposed optimum mixing time. Additional studies to correlate this observation with granulation physical and compression characteristics are necessary     

基于三维实体造型的搅拌器叶轮结构反求及其抗磨性能

 某污水处理厂的潜水搅拌器叶轮磨损严重，且叶轮备件需从国外进口。为了解决该叶轮的抗磨损问题，实现备件的国产化，基于反求工程设计理论，应用三坐标测量机、Surfacer软件和Pro/E软件获得原叶轮的三维实体造型，所获得的叶轮实体造型与原型有较高精度的一致。应用叶轮实体造型，完成叶轮模具的制造、叶轮的抗磨损研究和备件的国产化工作。新叶轮已应用于该污水处理厂，并通过了现场生产运行试验。试验结果表明：叶轮的搅拌和推进效果很好，运行3个月后无磨损情况发生，经济效益和社会效益显著。     

Numerical analysis of similarities of particle behavior in high shear mixer granulators with different vessel sizes

This paper deals with the numerical analysis of kinematic and dynamic similarities of particle behavior in high shear mixer granulators with different vessel sizes. The three-dimensional particle motion in high shear mixer granulators with four different vessel sizes was calculated using a discrete element method (DEM). The geometrically similar mixer granulators equipped with a flat-shaped impeller blade were used as simulated mixer granulators.Kinematic and dynamic similarities of particle behavior in various vessel sizes under a constant normalized agitation power were numerically analyzed. In various vessel sizes, dynamic similarity expressed by the particle collision energy was confirmed under a constant normalized agitation power, while kinematic similarity expressed by the particle velocity was not confirmed. These results indicate that the dynamic similarity should be maintained for successful scale-up of high shear mixer granulators.     

Discrete element simulation for mixing performances and power consumption in a twin-blade planetary mixer with non-cohesive particles

The present study aims to characterize the mixing performances and power consumption of a twin-blade planetary mixer with non-cohesive particles through the discrete element method (DEM). A DEM model used for simulating the particle flow and mixing kinetics of the mixer was experimentally verified. The particle velocity and mixing mechanism are elaborated quantitatively, indicating that particle mixing is realized under the combined actions of radial, circumferential and vertical circulations, and some local collisions and mergers. Increasing the absolute speed N and the speed ratio i promotes the radial circulation, while the tangential and vertical circulations are strengthened with the increase of N and the decrease of i. The mixing time required for the homogeneous state decreases, and the power consumption increases as N increases and i decreases. Thus, increasing N and decreasing i can improve the mixing performance but require more energy to reach the homogeneous state. Also, the mixing performance shows a strong correlation with the swept volume of blades, which proves that the dominant mixing mechanism of the mixer is convection.     

Dispersion of clusters of nanoscale silica particles using batch rotor-stators

Nanoparticle powders added into a liquid medium form structures which are much larger than the primary particle size (aggregates and agglomerates)-typically of the order of 10’s of microns. An important process step is therefore the deagglomeration of these clusters to achieve as fine a dispersion as possible. This paper reports the findings of a study on the dispersion of hydrophilic fumed silica nanoparticle clusters, Aerosil 200 V, in water using two batch rotor-stators: MICCRA D-9 and VMI. The MICCRA D-9 head consists of a set of teeth for the stator and another for the rotor, whereas the VMI has a stator with slots and a rotor which consists of a 4-bladed impeller attached to an outer set of teeth. The dispersion process, studied at different power input values and over a range of concentrations (1, 5, 10 wt.%), was monitored through the evolution of PSD. Erosion was found to be the dominant breakage mechanism irrespective of operating conditions or rotor-stator type. The smallest attainable size was also found to be independent of the power input or the design of the rotor-stator. Break up kinetics increased upon the increase of power input, and this also depended on the rotor-stator design. With MICCRA D-9 which has smaller openings on both the stator and rotor, the break up rate was faster. Increasing the particle concentration decreased break up kinetics. It could also be shown that operating at high concentrations can still be beneficial as the break up rate is higher when assessed on the basis of specific power input per mass of solids.     

Dry mixing of cathode composite powder for all-solid-state batteries using a high-shear mixer

All-solid-state lithium-ion batteries (ASSLIBs) are promising candidates for next-generation batteries because of their various attractive properties. The uniform mixing of active materials (AMs) and solid electrolytes (SEs) is important for high-performance ASSLIBs. However, most AMs and SEs have poor flowability owing to their small particle size, which makes it difficult to uniformly mix the AM and SE particles. This study is focused on a high-shear mixer (HSM) as a scalable method to uniformly mix the AM and SE particles. The objective of this study is to determine the optimal operating conditions for HSM and its effectiveness in AM-SE mixing. The higher rotating speed of the chopper caused uniform SE dispersion by deagglomerating the SE particles and improving the adhesion of SE onto the AM particles, affording an electrode with well-balanced electrical/ionic conductivity and lower internal resistance. The ASSLIB with this electrode exhibited lower electrode polarization and excellent rate and cycle performance. Additionally, it has been demonstrated that the HSM could lead to a more uniform SE dispersion than conventional lab-scale mixing methods, resulting in significantly improved battery performance. Moreover, insights into the process-homogeneity-performance relations have been obtained.     

Instrumentation of a Vertical High Shear Mixer with a Motor Slip Monitoring Device

Abstract

The main impeller shaft of a vertical high shear mixer was instrumented with a device which measures motor slip and displays its output in percent horsepower. Response was proportional to mixer load. A warm-up period was required to minimize variability in output. High speed impeller operation showed more consistency in response than low speed impeller operation. During the granulation process of the different test systems, a typical response profile showed a change in percent horsepower as the binder solution was added followed by a plateauing at about the proposed optimum mixing time. Additional studies to correlate this observation with granulation physical and compression characteristics are necessary