Experimental study of the mixing kinetics of binary pharmaceutical powder mixtures in a laboratory hoop mixer

As increasingly commented by the literature during the last 5 years, estimating the homogeneity of a powder mixture and following powder mixing processes is not a simple task. In this paper, we present the development and statistical validation of a sampling methodology for defining the number of samples required to provide a reasonable estimation of the homogeneity attained in a laboratory scale tumbler mixer. This method is then used to follow the mixing kinetics of a dilute binary powder mixture in a hoop mixer. Special attention is paid to the statistical meaning of the values obtained and the influence of the physical characteristics such as particle size and shape. The role of the particle shape of the majority powder is particularly emphasised and it is quantitatively demonstrated that spherical particles are harder to mix and more ready to segregate than particles with irregular shapes. The different mixing mechanisms at play are identified; the practical limits of use of such tumbler mixers with pharmaceutical powders are discussed.     

Influence of stirrer type on mixture homogeneity in continuous powder mixing: A model case and a pharmaceutical case

Continuous powder mixers offer a viable alternative to batch processes, but have received very little attention in scientific literature and in the industrial world. Mixer design is still very empirical and is not based on assessed methodologies. In this paper, we report experiments that aimed to compare two very different types of stirrers for a pilot-scale continuous powder mixer, and for two types of mixtures: a model mixture and a real pharmaceutical mixture. The first stirrer A is of the frame type with inclined paddles and internal transporting screw, the other stirrer B is of the shaft type with paddles mounted on it. Results are first presented from the viewpoint of bulk powder flow by hold-up determination and correlation with operating conditions. General relationships are derived which show that the mobile B leads to higher hold-ups, which may be an important drawback. The study of mixture homogeneity globally confirms these findings, especially in a dense phase flow regime. In the fluidised regime, where the stirrer B can be used, attention is drawn to the negative effect of excessive rotational speeds on the quality of the mixtures.     

Evaluation of powder mixing operation during batch production: Application to operational qualification procedure in the pharmaceutical industry

Powder mixing is an important operation routinely used in many industries, including pharmaceuticals. The quality of products depends on certain operating conditions, such as the equipment, technical parameters and formulation. In this work, an operational qualification of powder mixing during large scale production in a pharmaceutical industry was performed. A simple and practical protocol was followed. Using a V-blender and dry powder mixing, the operation was tested to illustrate the effect of mixing time on the homogeneity of the drug in the mixture, demonstrating that this parameter can be used as a secure parameter to control this pharmaceutical operation on a large scale during batch production and using an off-line monitoring technique.     

Characterization of continuous convective powder mixing processes

The Process Analytical Technology (PAT) initiative has encouraged the development of new technology to improve upon the current manufacturing paradigm. As a result substantial attention has recently focused on continuous processing due to the ability to control disturbances online, avoiding the loss of processing materials and enabling effective process scale-up. In this paper, a pharmaceutical formulation is blended using a continuous flow “high shear” mixer utilizing different operating and design parameters. The mixing efficiency is characterized by extracting samples at the discharge of the blender, and analyzing them using Near Infrared Spectroscopy to determine compositional distribution. Operational conditions such as the inclination angle of the mixer and impeller rotation rate were investigated and showed to affect the mean residence time. The effects of mixer angle, agitation speed, number of blades, blade angle, number of passes through the mixer on the mixing performance of a powder continuous convective mixer are also examined and shown to affect mixing performance whereas the cohesive properties of the material did not significantly affect the mixing operation.     

Numerical simulation of mixing process in T-shaped and DT-shaped micromixers

Recently, numerous studies have been done on the micro- and nano-scale equipment because of their importance and wide range of application. Micromixers are among the equipment in which two or more fluids are mixed and have applications in the processes, such as chemical synthesis. In this research, a numerical investigation using finite volume approach is done on mixing two incompressible fluids in 3D mixers with T- and double-T-(DT) shaped geometries in the range of Reynolds numbers 75–400. One of the important parameters for the quantitative analysis of the mixing performance of micromixers is the mixing index. So, the effects of different geometries, Reynolds number and channel length on this parameter are studied. The results show that, at different Reynolds numbers, the mixing index of fluids in the DT-shaped channel with 90° is less than the corresponding one in T-shaped mixers because changing the flow regime occurs at higher Reynolds numbers in the DT-shaped channels. The amount of mixing index increases by decreasing the angle of branches in the DT-shaped channel. It is observed that the mixing index of fluids increases along the channel, which tends to a constant value far away from the inlet.     

Effects of rotation rate, mixing angle, and cohesion in two continuous powder mixers—A statistical approach

In this paper we examine the effect of rotation rate, mixing angle, and cohesion on the powder residence time and the content uniformity of the blend exiting from two continuous powder mixers. In addition, differences in mixing performance between the two blenders are examined. Analysis of variance is used to determine significance of main effects and their interactions. The results show that the effect of powder cohesion is scale-dependent, having a significant effect in the larger mixer. The overall rotation rate was the least influential parameter in terms of content uniformity. The residence time is significantly affected by both rotation rate and mixing angle.     

粉末涂料的邦定生产技术

介绍了国内外邦定设备及生产工艺,对存在的问题进行了分析并给出了以下改进措施:加入w=0.1%～0.2%的粉体改进剂以提高上粉率,将温度控制在邦定工艺温度段以延长处理时间,筛分邦定工艺处理后的物料,结块时切断电源后手工清理等.     

Numerical investigation of coarse powder and air flow in an electrostatic powder coating process

The work presented here reports on the numerical simulation of an electrostatic powder coating process that uses a commercial computational fluid dynamic code, FLUENT v6.1. The purpose of this study was to understand the gas and particle flow fields inside a coating booth under given operating conditions and the effect of particle sizes on its trajectories and the final coating quality. The air and powder particle flows in a coating booth were modeled as a three-dimensional turbulent continuous gas flow with solid particles as a discrete phase. The continuous gas flow was calculated by solving Navier-Stokes equations including the standard k − ε turbulence model with non-equilibrium wall function and the discrete phase was modeled based on the Langrangian approach. Since the solid phase volumetric fraction was less than 0.1%, the effect of particle-particle interaction on particle trajectories was not taken into account. In addition to drag force and gravity, the electrostatic force including the effect of space charge due to the free ions was considered in the equation of motion and implemented using user defined scalars and functions. The governing equations were solved using the second order upwind scheme. Information was provided on the particle trajectories with respect to the particle diameters that could be used to develop suitable operating conditions for the use of fine powders in a powder coating process.     

基于递推部分最小二乘自适应质量监控策略及其在橡胶混炼过程中的应用

提出一种新的基于递推部分最小二乘（RPLS）算法的自适应在线质量监控策略。利用隐变量选择算法,根据实时采集的现场数据,在不增加计算和存储容量的基础上递推更新RPLS过程监测模型,进而更新Qα控制限,从而使RPLS自适应质量监控系统具有强时变跟踪特性,能够有效克服传统监测算法Qα无法反映系统时变性的缺点,大大降低了监控系统的误报率和漏报率,提高监控系统性能。并根据橡胶混炼过程特点,将此方法运用于该时变间歇过程质量监控中,取得了满意效果。     

Analysis of pharmaceutical powder compaction using multiplicative hyperelasto-plastic theory

Single-ended compaction of lactose powder is investigated numerically within the framework of multiplicative hyperelasto-plastic theory. In keeping with previous work in the pharmaceutical field, a slightly modified Drucker-Prager Cap model is described and used in the simulations. Coulomb friction is included on all interfaces. Our results indicate that simulations of this type may be useful not only to determine density and stress distributions within tablets, as has been done hitherto, but also may provide indications of circumstances under which the tableting operation fails due to capping.     

双转子连续混炼机混炼过程和原理的研究

研究了双转子连续混炼机的混炼过程和混炼原理,并建立了混合过程的数学和物理模型。研究结果表明,转子组合（螺棱交汇区的长度）、转子转速、螺棱顶部与混炼腔内壁之间的间隙、嵌入块形状和卸料门开启度是影响混合过程的主要参数。     

优化炼胶工艺改善胎面气孔率

Φ250冷喂料螺杆挤出机,挤出的工艺优点是胎面更换规格、尺寸比较容易,劳动生产率高。由于胎面规格种类多,在挤出过程中经常出现半成品表面不平滑、尺寸和质量波动较大的问题,特别是胶部件内部气孔较多,气孔率有时达到7%以上,导致挤出半成品无法使用,返回率较高,影响正常生产。气孔的存在会影响成品轮胎的耐磨性能,且易出现崩花、掉块和花纹沟裂等质量问题。本文通过增加胎面胶的混炼段数以提高炭黑分散度,来改善胎面胶的气孔率。     

Periodic section modeling of convective continuous powder mixing processes

This study aims to develop a general model of the convective continuous mixing process. The main idea is that continuous mixing can be considered as a combination of powder flow and mixing processes. Although powder flow is characterized by the residence time distribution (RTD), powder mixing can be described by a batch mixing process simulated in one periodic section of the continuous mixer. By characterizing the two processes separately, we can calculate the number of sections required to achieve certain homogeneity. In this study, continuous mixing is simulated using the discrete element method, and segregating and non‐segregating mixing cases are tested to investigate the applicability of the model. Results show satisfactory predictions by the model, which is able to characterize the continuous mixing performance of both mixing cases. On the basis of this study, we were also able to suggest a novel method in design and control of continuous powder mixing systems. © 2011 American Institute of Chemical Engineers AIChE J , 2012     

物料无桨混合过程数值模拟

目前物料混合主要采用有桨混合方式,该方法容易使物料受到较大摩擦作用。为了解决这一问题,本文对无桨滚筒混合工艺过程进行探索研究。采用离散元软件EDEM模拟无桨滚筒对两种物料的混合过程,分析混合过程中物料的运动特征,通过定义颗粒混合均匀性指数来定量表征混合均匀程度,分析了不同填料（10000~20000个颗粒）和转速（7~22r/min）对混料均匀性的影响规律,并对物料受力情况进行了定量分析。研究结果表明：在无桨滚筒混料过程中,可以实现对两种物料的混合,且随着转速提高,物料能较快达到均匀。在混合过程中物料受力呈波动式变化,其中最大受力小于0.6N,稳定在0.1~0.35N;物料受力平均值小于0.015N,稳定在0.005~0.01N;最大受力是平均受力值的20~30倍;且随着填料和滚筒转速增加,物料的受力略有增加。     

Scheduling of cracking production process with feedstocks and energy constraints

This paper addresses the short-term scheduling problem for the ethylene cracking process with feedstocks and energy constraints. The cracking production of ethylene is a process with units that have decaying performance, requiring periodic cleanup to restore their performance. Under the condition of limited feedstocks, the production operating mode of the cracking furnaces is to keep yields constant by continuously increasing the coil temperature. We present a hybrid MINLP/GDP formulation based on continuous-time representation for the scheduling problem over a finite time horizon. In order to solve the proposed model, which is reformulated as an MINLP model, an improved outer approximation algorithm with multi-generation cuts and problem-dependent integer cuts are developed to solve real large-scale problems. Numerical examples are presented to illustrate the application of the model. Based on analyzing the optimal solution and sensitivity of the model, some conclusions are obtained to provide useful suggestions for real cracking process production.     

Lubrication of pharmaceutical powder/wall interfaces and electrostatic effects

The lubrication of powder/wall interfaces was investigated by tracking the evolution of the torque response during wall friction tests. A FT4 rheometer was employed to conduct this study. Two types of surfaces, borosilicate and Delrin, and 3 commercially-available pharmaceutical excipients, xylitol, microcrystalline cellulose and dicalcium phosphate dihydrate, lubricated or not with magnesium stearate, were tested. Two levels of relative humidity (RH), 20% and 60%, at which the powders were stabilized were used. The results showed that wall friction behaviors and, consequently, wall lubrication trends were strongly dependent on the nature of both the surfaces and powders. However, unexpected high data variability was obtained during the wall friction tests with non-lubricated powders sheared with a borosilicate surface at 20% RH. This variability was not observed when magnesium stearate was present in the powder formulations or when the tests were conducted at 60% RH. A particular effort was made to understand the possible causes of this variability. The results with non-lubricated MCC indicate that variability is reduced when the borosilicate surface is ionized at − 20 kV prior to the wall friction tests, while with the same treatment on non-lubricated xylitol did not produce a similar effect. Thus, contrary to the so far prevailing belief in the literature, this preliminary study proves that electrostatic phenomena can, at least partially, explain the reported variability.     

Development of a tribolelectric procedure for the measurement of mixing and drying in a vibrated fluidized bed

Fluidization of fine, pharmaceutical powders makes them easier to dry, coat and mix. Fine powders, however, are difficult to fluidize well with gas flow only. Vibration can often help achieve smooth fluidization at a lower gas flow. The objective of the present study was, thus, to develop reliable and quick experimental methods to characterize mixing and drying in vibrated fluidized beds of fine powders.Effective mixing is critical in many industrial applications and, in gas-solid fluidized beds, requires gas velocities greater than the minimum bubbling velocity (U_mb). There are a number of techniques available for determining U_mb. However, they often are impossible or impractical to use in an industrial application. A new measurement technique involving the use of triboelectric probes was developed. Signal characteristics obtained from sophisticated signal analysis were used to identify the minimum bubbling velocities. These predictions corresponded well with the values obtained from more traditional laboratory methods such as the bed pressure gradient.In a fluidized bed, particles hitting a metal probe will generate a small triboelectric current. Triboelectric probes are able to detect rapid changes in particle surface properties. Surface properties of the particles were modified by wetting the particles in a low shear mixer. This change was detected by triboelectric probes at various locations inserted throughout the bed. The water adsorbed on the particles will begin to evaporate when exposed to the gas stream and the surface properties of the particles will gradually return to their original dry state. The triboelectric probes were able to monitor this drying process. The effects of vibration amplitude on the mixing and drying rate of the bed were also determined.     

Impact of agitated drying on the powder properties of an active pharmaceutical ingredient

In this study, the impact of agitated drying on the physical and bulk powder properties of an active pharmaceutical ingredient (API) is presented. The effects of different agitated drying conditions such as agitation rate, drying temperature, drying time pre-agitation, drying time during agitation and number of solvent wash cycles on the bulk density, millability, flow and specific surface area is reported. The crystal morphology is altered from fibrous needles to agglomerates when switching from tray to agitated drying. An increase in bulk density and specific surface area was evident when using agitated drying compared to tray drying as hard coarse granules were produced with an increase in the number of fine particles < 10 μm. The bulk density was found to increase with an increase in agitation speed, drying time and number of solvent wash cycles used during filtration. Controlling both fine and coarse particle size of the granules for this API during agitated drying was difficult to achieve due to the fibrous crystal habit. However, the increase in the bulk density observed has the potential to facilitate improvements in the ease of drug product development. In the case of this system further particle size control was required through the use of dry milling.     

回转干馏炉内二组元颗粒混合机理及混合度分析

采用非等径二组元颗粒,用圆形滚筒模拟回转干馏炉,研究回转干馏炉转速对颗粒径向混合的影响。以滚筒径向颗粒Lacey指数作为混合指数,对5种不同转速下滚筒侧表面颗粒的混合指数与混合机理进行研究,对比分析了混合指数的变化趋势。结果表明：在圆形滚筒混合器内1/6填充率、倾角为0°的情况下,在转速为13.3 r/min时混合度优于其它转速,以对流混合与扩散混合为主;通过对混合质量与混合机理综合分析,得颗粒混合呈现“双振荡趋势”。