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.     

Estimation of mixing index and contact number by spot sampling

Most of the available definitions of the mixing index, which specifies homogeneity or distribution of the composition in a solids mixture, are based on the variance of the concentration of a certain component among spot samples. However, for a solid—solid chemical reaction or any process involving contact between different solid phases, its rate is proportional to the contact points or area among particles of the different phases. Thus a definition of a microscopic and geometric mixing index based on the number of contact points appears to be of practical significance.The contact number is the number of contact points between two different types of particles for one key particles, a particle species which is selected as a reference. In this paper, the estimation of the mean contact number from spot samples is considered. An expression for estimating the contact number from spot samples is derived. Expressions for the expected value (population mean contact number) and the variance of this mean contact number are also derived. To verify these expression, random numbers with a uniform distribution are generated to simulate a binary component mixture in the completely mixed state. Results of the simulation are in reasonably good agreement with the derived expressions. The mixing index based on the mean contact number is able to indicate the homogeneity of a mixture with regular packing arrangement. In such a mixture, particles are packed either cubically or hexagonally in each layer, and therefore it is difficult to estimate the homogeneity of the mixture from the sample variance.     

The measurement of mixing efficiency of continuous mixers

A radiotracer method for testing the mixing characteristics of industrial continuous mixers in actual process conditions is described. The tracer is fed into the input of the mixer at a constant rate and the radiation in the output is measured by two properly collimated radiation detectors. The measurement yields data in the form of two time series which contain information about the radial and axial homogeneity of the tracer in the measuring point. The formulas connecting the information in the measurement data and the axial and radial concentration variation of tracer are derived by the methods of statistical mathematics. The values for experimental parameters are obtained by computer simulation of the radiation measurement geometry.The method was tested by measuring the increase of the homogeneity as a function of mixing distance in a static tube chlorine mixer in a pulp bleaching plant. Also some results obtained on another type of mixers showing the effect of pulp type on mixing are given.     

Determination of the energy consumption during the production of various concrete recipes

This article presents a report of the mixing of concrete on the laboratory scale in a single-shaft and twin-shaft mixer. For both mixers we selected five concrete recipes that cover a broad spectrum of concrete mixing techniques. The concrete recipes differ from each other amongst other things by virtue of the aggregate-sized distribution curves, water-cement ratio, flow properties, compressive strength and mixing times. The specifically volume-related application of energy - which is necessary for the homogenization of the particular recipe in the mixer - is an essential influencing variable.The comparison of the specifically volume-related application of energy is possible only if the concrete recipes possess the same homogeneity. The time curve of the homogeneity plotted against the necessary mixing time indicates the mixing efficiency, which in turn is determined by an imaging measurement process. Comprehensive mixing experiments show that the resulting application of energy, measured via the current composition, does not provide sufficient information in order to define the actual homogeneity in the mixture. A method was developed for the purpose of comparing concrete mixtures based on various recipes with the same homogeneity in relation to the specifically volume-related application of energy. The particular application of energy can be determined via the required mixing time and the power output process in terms of time.     

Sensitivity of the test risk with respect to contamination

In a framework of testing statistical hypotheses the sensitivity of the test error probabilities is studied. The Edgeworth approximations of proposed characteristics of this sensitivity are derived and specialized for the local alternative setting. Results, similar to Stein's lemma and Chernoff's theorem, describing the convergence rate of test risk sensitivity characteristic is given, too. An admissible character of contamination is also discussed.     

Continuous mixing of powder mixtures with pharmaceutical process constraints

While it would provide many advantages from many aspects, the application of continuous mixing processes to the pharmaceutical field is still in its infancy. In this paper we report results concerning the continuous mixing of nine ingredients (including three actives) that constitute a current drug. We examine these results in the light of different pharmaceutical process constraints, such as mixture quality control, time-stability of this quality, sensitivity of the process to perturbations. The apparatus is a pilot plant Gericke GCM 500 continuous mixer with three loss-in-weight feeders. A specific experimental protocol is developed to determine the homogeneity of the mixtures at the outlet of the mixer. The homogeneity of the mixtures is examined through industrial standards that would allow the product to be released on the market. The steady-state operation is first reported on, and it is demonstrated that a very acceptable mixture can be produced under certain conditions, with excellent time stability. The response of the mixer to filling sequences of two critical feeders is also quantified in terms of mixture homogeneity. It is found that it may be preferable to stop the process during these periods.     

Homogeneity control in heterogeneous materials

An analysis of the methods most suitable for ceramics technology for controlling the homogeneity of component distribution in mixtures and the distribution of the porosity (or heterogeneous components) over the article volume is made. A rather rigorous and simple method for evaluation of mixture (sample) homogeneity is suggested that is based on a hierarchic approach and statistical evaluation of the accuracy of determining the concentration of a key component in mixture samples. Translated from Steklo i Keramika, No. 1, pp. 14–17, January, 2000.     

Assessment of the mixing efficiency of solid mixtures by means of image analysis

When assessing a mixing process, mixing quality is a characteristic parameter. To determine the optimum mixing time, it is necessary to measure the mixing efficiency as a function of mixing time. Mixing efficiency is determined by a sufficient number of sample analyses after certain mixing times. The novel method of image analysis allows to rapidly determine the optimum mixing time without sampling and complex sample analysis being required. In this study the model products have different particle sizes and colors to see a difference between them in the image analysis program. Analyzing a real mixture to find chemical substitutes for all particle components is impossible. The study can help the plant engineer to mark a component of interest for finding the optimum point of stationary equilibrium. In this paper the theory for sampling and comparing multi-component mixtures by image analysis to determine the mixing efficiency will be also described and discussed.     

Assessing the homogeneity of an ordered mixture

The sample standard deviation of the content of minor component in a number of samples is the most widely used method of assessing the homogeneity of an ordered mix. A number of investigators have used thief probes to withdraw samples from a mixture. This study has demonstrated that the use of a thief can result in non-representative samples being removed from a mixer in which the mixture has undergone ordered unit segregation. Since this sampling technique has been widely used, some doubt must exist about the magnitude of values quoted in the literature for the sample standard deviation of ordered mixtures.It has been shown that producing an ordered mixture at 0 or 84% relative humidity results in significantly less segregation of the carrier particles. This finding has application as a simple method of minimizing ordered unit segregation during a mixing operation.     

Perfect powder mixtures

The ordered mixing of both crystal violet and salicylic acid in microfine form with a coarse sucrose powder results in perfect (or almost perfect) mixtures. Such mixtures have zero standard deviation for concentration of minor ingredient between samples, due to the mixing operation. The homogeneity of perfect mixtures can be defined using Buslik's concept of homogeneity. It is useful to differentiate between absolute homogeneity and relative homogeneity. Absolutely homogeneous systems have zero standard deviation above a limiting sample size. Relatively homogeneous systems have a gradually decreasing standard deviation with increasing sample size. Relative homogeneity of a system is inversely proportional to the sample weight at a fixed standard deviation. Absolute homogeneity is inversely proportional to the sample weight at which there is a discontinuity between the standard deviation of the unmixed system and a standard deviation of zero.     

Abnahme und Überwachung der Anlagen

Acceptance testing and surveillance of plant . Existing legislation require acceptance testing of the principal components of a chemical plant prior to its commissioning. As shown for a pressure vessel, this testing of a large chemical plant can only be performed effectively if the necessary concepts have been developed and the data required have been collected during the planning and construction stage. It is not sufficent to consider the components individually. Their incorporation into the plant and their mutal interaction are just as important. Acceptance testing must be preceded by a consideration of the overall safety of the plant. This does not require any new regulations. Regular surveillance ensures that the established safety level is maintained. Many surveillance measures are already stipulated during acceptance testing.     

Magnetic Ceramics: I, General Methods of Magnetic Ferrite Preparation

Various methods of preparing the technically important ferrospinels are discussed; particular attention is given to the reactivity and homogeneity of the final mixture. The reactivity and intimacy of mixing of the initial components may be improved by the use of chemical methods of comminution and mixing, viz., thermal decomposition of the mixed chemicals, chemical precipitation of the components, or ignition of the components in a fine state of division. The use of controlled partial pressures of oxygen (CO₂-CO mixtures) for the preparation of magnetite and manganese ferrite is discussed. The feasibility of the application of these methods on a commercial scale is outlined.     

A proposed universal homogeneity and mixing index

The word “homogeneous” is generally used qualitatively. A simple numerical homogeneity index is proposed suitable for expressing varying degrees of homogeneity quantitatively, namely, the negative log of the sample weight (9) required to obtain a standard deviation of 1%. The scale is universal in that a homogeneity index can be computed for heterogeneities observable only on the atomic scale (e.g. sodium chloride crystals and air) and for homogeneities observable only on the stellar scale. Values of the index, H_i, are computed for certain defined and certain theoretical mixture arrangements as follow: (a) pure hydrogen (maximum and limiting value of H_i), 23.5; (b) sodium chloride, 22.0 < H_i < 22.2; (c) air, 19.1; (d) 10% oil in water emulsion, 9.4 < H_i < 12.4; (e) a 1-g medical pill composed of 15% A and 85% B homogenized so that 99.99% of the 1-g pills are within the limits (15±1)%A, 1.2; (f) some arbitrarily defined, partially mixed industrial materials, considered as equivalent to random segregations of 1 lb., ?6.1; 1 ton, ?9.4; and (g) an approximate, order of magnitude, figure for the universe according to available scanty astronomical data, ?46.3. The index (and even more directly, its antilog) should be a useful measurement of the degree of mixing, since homogeneity is measured directly rather than indirectly as have previously used indices of degree of mixing.     

Nano-mixing of dipyridamole drug and excipient nanoparticles by sonication in liquid CO2

Nanoparticles (about 200 nm thick and 600–12000 nm long flakes) of dipyridamole, a poorly water-soluble anti-thrombosis drug, are produced by supercritical antisolvent solvent with enhanced mass transfer method. Applicability of sonication in liquid CO₂ for mixing of drug and excipient nanoparticles is demonstrated for several binary mixtures of drug and excipient. The drug particles are mixed with three different excipients: silica nanoparticles, lactose microparticles, and polyvinylpyrrolidone nanoparticles. To intimately mix at nanoscale, macro mixtures of dipyridamole and excipient particles are sonicated in liquid carbon dioxide. The effects of ultrasonic energy, amplitude, and component weight ratio are studied for the binary mixtures. Characterization of mixing is done using several methods. Scanning electron microscopy is used as a primary method for microscopic analysis. Two macroscopic effects, drug dissolution and blend homogeneity (relative standard deviation), are used to characterize mixing quality of drug/lactose mixture. Results of drug dissolution and blend homogeneity show effectiveness of the proposed mixing method for fine size particles. Material handling properties of drug/silica and lactose/silica mixtures were examined. Upon mixing, the handling properties are significantly improved as measured by compressibility index and Hausner ratio. Liquid CO₂ offers an environmentally benign media for mixing. In addition, the mixture obtained does not contain any residual solvent as compared to the sonication in organic liquids. Upon depressurization, CO₂ is easily removed from the mixture providing a facile recovery of the product.     

Effects of adhesion on mixing homogeneity part I: ordered adhesion—random adhesion

According to Hersey, adhesion of a finely powdered, monosized ingredient to a course, monosized diluent may yield ordered powder mixtures of a higher degree of homogeneity than conforming to random mixtures.However, this concept implies the adherence of an identical (or almost identical) number of the fine particles to each of the carriers (‘ordered adhesion’). If, on the contrary, a random variation of the number of adhering fines per diluent particle is assumed (‘random adhesion’), pseudorandom mixtures can be formed at best. This type of mixture shows the degree of homogeneity as well as the statistical properties of fully randomized systems.To produce ordered powder mixtures, it is thus the basic requirement that ordered but not random adhesion must be achieved during mixing. So far, no mechanism has been established that may yield ordered adhesion.     

阻火器性能测试试验系统的研制

阻火器是一种用来阻止易燃气体和易燃液体蒸气火焰蔓延的安全装置,近年来已被广泛应用在石油化工、天然气等工业领域。随着现代社会的发展,人们对于安全问题越来越重视,因此,对于阻火器的性能测试就显得必不可少。由于我国在阻火器型式试验研究方向起步较晚,目前国内尚未有阻火器性能完整的测试系统。为完善阻火器的性能测试,本文开展了阻火器性能测试试验系统的研制工作,以提高我国在这一领域的检测水平。系统能够完成试验所需的爆炸性混合气体的配置工作,气体燃烧爆炸过程中的压力、火焰速度及温度的测试工作,数据的分析处理工作。试验系统包括配气装置、传感器检测系统、数据采集装置。配气装置可以实现静态、动态混合配气的要求。传感器检测系统可完成火焰识别、温度采集、压力采集功能。数据采集装置可对数据进行处理,实时显示实验过程数据,并记录、处理试验数据。测试系统充分考虑了试验现场的安全性,测试精度完全满足阻火器型式试验的要求,且系统操作简单、方便、运行可靠,完成了多次阻爆测试和耐烧测试,其效果达到国家相关标准的要求。     

煤样黏结特性测定值影响因素分析

由于用于测定煤样黏结指数的专用无烟煤价格较高,有必要进行专用无烟煤替代品的研究.以石英砂代替专用无烟煤为添加物进行煤样的黏结指数测定实验,结果表明,不同煤种黏结指数差别较大;添加物及其掺合比对煤样黏结指数均有显著的影响.正交实验研究表明,添加物对煤样黏结指数的影响最大;添加物掺合比次之,二者为高度显著的影响因素;煤种对黏结指数的影响最小,为较显著影响因素.根据正交实验结果得出添加物及掺合比的合理选择,在此基础上,建立了以非专用无烟煤为添加物的煤样黏结指数与以专用无烟煤为添加物的煤样黏结指数之间的关系.     

Predicting the fraction of the mixing zone of a rolling bed in rotary kilns

The thermal efficiency of a rotary kiln is predominantly influenced by the amount of lateral mixing of the material bed. In this paper, the fraction of the mixing zone in the material bed is predicted for the rolling motion. For a given material, the fraction is found to depend only on three dimensionless variables—the ratio of the particle diameter to the kiln diameter, the Froude number and the filling degree. Experiments were carried out on a rotating cylinder with beans as testing material. The predicted results are in good agreement with the measurements with a maximal error of 12%. The fraction of the mixing zone is then analyzed for industrial rotary kilns. Its value is found to increase approximately linearly with increasing Froude number and the dynamic angle of repose of the material. For all investigated cases, the fraction of the mixing zone lies in the range of 20–45%. Results of this study can provide orientating values of the mixing zone fraction, which are needed to calculate the thermal efficiency of the rotary kiln.