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Residence time distribution (RTD) modeling can aid the understanding and characterization of macro-mixing in continuous powder processing unit operations by relating observed behavior to quantitative model parameters. This article is the second part of the work done to characterize the effect of material properties on the measurement of RTDs in continuous powder processing operations. The goal of this paper is to examine the behavior of the RTD given different sets of tracer material properties. Tracer addition methods are discussed within the framework of their mathematical representation. The two most widely used RTD models in powder systems in the literature, the axial dispersion and the tank-in-series model, are presented and used to describe the experimental data. The RTD model parameters (e.g., Peclet number, number of tanks in series, and residence times) were regressed from the experimental data and compared using one-way ANOVA to determine the effects of materials properties on RTD. A model independent approach using a Multivariate Analysis of Variance (MANOVA) was also applied to compare the results with the model dependent method. Lastly, examples of how the RTD models can aid process design and understanding were described using both continuous and discrete convolution. The RTD models and their regressed coefficients were used to predict the mixing outputs of a semi-random input and the impact of disturbances on the process.

Residence time distribution (RTD) models are essential to understand process dynamics and support process monitoring and control in continuous manufacturing systems. RTD models can also be used to monitor material traceability and to isolate intermediate materials or finished products when specifications are not met. However, while pharmaceutical companies are currently making extensive use of RTD approaches, standard methods for conducting, interpreting, and using RTD results in continuous pharmaceutical manufacturing have not yet been established by regulatory authorities. This paper seeks to facilitate generating such standards. We discuss in detail the assumptions and conditions that are relevant to the proper selection of tracers for RTD experiments, and demonstrate that tracer selection can have substantial impact on RTD results. We selected seven materials with a wide range of properties as tracers and a single material as our base “blend”. The experimental results led to two major conclusions: (1) materials with different mechanical properties have dissimilar mean residence times (MRT) inside the systems and (2) blend ingredients with different mechanical properties travel at different speed inside of continuous blending systems. Results further indicated there were two critical mean residence times (MRTs): that of the tracer and that of the bulk. Matching of material properties between tracers is key in order to obtain similar MRTs using a given tracer. Differences between selected tracer and bulk material properties were found to lead to differences between the bulk space time and the tracer MRT. A set of recommendations on how to select tracer materials that would help characterize accurately the RTD of a continuous flow system are presented.

Material properties are known to have a significant impact on pharmaceutical manufacturing performance, particularly for solid product processes. Evaluating the performance of a specific material, for example an active pharmaceutical ingredient or excipient, is critical during development stages in order to determine the impact of material properties on the process. However, materials may be scarce during the early stages of process development due to high cost, unavailability, import restrictions, etc. Furthermore, research on particular active pharmaceutical ingredients may be difficult given unknown exposure limits, which may delay process development and technology transfer. The purpose of this work was to establish a methodology for finding materials with similar behavior during processing using material property measurements so that a surrogate may be found and may replace the scarce material during process development. This work presents several commercially available material property tests and emphasizes the benefits of compiling material property measurements into libraries. Twenty pharmaceutically relevant materials and seven different powder characterization tests were considered as a case study. A total of 32 measurements were collected for each of the 20 materials, leading to a dataset of 640 measurements. The material property library was utilized to find similarities between materials using two multivariate methods: principal component analysis (PCA) and hierarchical clustering. The similarities between materials were evaluated with the performance of materials on powder feeding, refilling, and continuous blending equipment. Material clusters showed similar behavior in the characterized equipment. Moreover, results from the PCA and clustering analysis were further used to evaluate the level of collinearity and similarity between characterization measurements that can be further investigated to reduce the number of measurements that need to be collected. Material property measurement clusters were established based on the collinearity of the metrics.

Impregnation of active pharmaceutical ingredients (APIs) onto porous excipients has numerous benefits for solid dosage formulations. Previous work has successfully demonstrated the manufacturing of pharmaceuticals using fluidized bed (FB) impregnation of APIs onto porous carriers and discussed its advantages (such as easy to implement, improvement of blend uniformity and dissolution kinetics, and stabilization of amorphous APIs). This study aims to develop methods for analysis of the spatial distribution of the impregnated API inside the porous excipient. An understanding of the spatial distribution of the API can be important if one wants to achieve high drug loadings. In addition, the spatial distribution of the API can impact its dissolution rate. The impregnation profile is analyzed using energy dispersive X-ray spectroscopy (EDS). Two formulations are investigated using Fenofibrate and Acetaminophen (model APIs), impregnated onto Neusilin (porous excipient). Several methods are presented for particle embedding and cutting in order to produce cross-sections for analysis. Embedding with carbon-based resins/adhesives produces cross-sections with high quality but the resins contaminate the sample with carbon and reduce the detection of trace elements. Manually cutting particles immobilized on carbon tape or inorganic-based adhesives produces cross-sections with a higher degree of roughness but improves the detection of trace elements and reduces/eliminates carbon contamination in the sample, allowing for API detection by its carbon footprint. EDS analytical results showed that for both Fenofibrate and Acetaminophen formulations examined in this work, the API profile is highly uniform (detected by both carbon and characteristic trace elements).

Purpose Lubrication is critical in pharmaceutical manufacturing of solid dosage forms. The purpose of this paper is to systematically compare and correlate the lubrication effect of two devices, a controlled shear system and a Resonant Acoustic Mixer, on the flow properties of pharmaceutical blends. Method A model formulation was selected. Full factorial designs were conducted to examine the effect of the total strain (or total energy) and the shear rate (or power) on the powder blend flow properties. Analysis of variance (ANOVA) and effect size test using omega-squared statistics were performed. Results Lubrication significantly improved the blend flowability. Mixing without magnesium stearate, or insufficient strain, resulted in more cohesive blends. The statistical analysis suggests that the shear rate had a minimal effect on the blend flow properties. The experimental results also suggest that although the two devices had comparable lubrication effects on the overall blend flowability, the changes of the interparticle forces in the lubricated blends were not identical. Conclusion This study demonstrated a scientific approach to compare different lubrication processes in an objective and reproducible manner. The findings are useful for process design, development, and transfer between different equipment types and process scales.

Binary powder mixtures with variable segregation tendencies were “mixed” in a tumbling batch blender and in a continuous convective tubular blender. The degree of homogeneity of the final blend obtained from the continuous blender was found to be much higher than that from the batch V-blender, for mixtures and blender process parameters examined in this study. A direct relationship was observed between the segregation index of mixtures and a new material property metric defined as the ratio of the median particle size and bulk density of the ingredients that constitute the mixture. Moreover, for freely flowing materials, the extent of non-homogeneity at the end of a batch blending process was found to be proportional to the segregation index of the mixture and thus consequently in relation to the material property metric. Results demonstrate the superior capability of continuous blenders compared to batch blenders in their ability to homogenize segregating mixtures.

Purpose Accurate and consistent delivery of materials by well-designed feeders ensures overall process stability. Importantly, feeding performance is strongly dependent on material flow properties. The purpose of this study is to develop a methodology that identifies predictive correlation between material flow properties and feeder performance. Method The proposed methodology includes techniques to characterize material flow properties, methods to quantify feeding performance of a loss-in-weight feeder, and predictive multivariate analysis. Two approaches to correlate feeding performance and material flow properties were examined in the study: principal component analysis, followed by similarity scoring (PCA-SS), and partial least squares regression (PLSR). Results Experimental results showed that selection of the optimal feeder screw to achieve optimum feeding performance is heavily dependent on material flow properties. Both approaches to predict feeding performance based on material properties were validated. In addition, a strong correlation between the initial feed factor of each material and its flow properties were observed. Conclusion The work presented here has demonstrated an efficient approach to correlate material properties with gravimetric feeder performance. This approach is especially powerful in the early phase of process and product development, when the amount of a material is limited.

A full factorial design of experiments was used to study the effect of blend shear strain on the compaction process, relative density and strength of pharmaceutical tablets. The powder blends were subjected to different shear strain levels (integral of shear rate with respect to time) using an ad hoc Couette shear cell. Tablets were compressed at different compaction forces using an instrumented compactor simulator, and compaction curves showing the force-displacement profiles during compaction were obtained. Although the die-fill blend porosity (initial porosity) and the minimum in-die tablet porosity (at maximum compaction) decreased significantly with shear strain, the final tablet porosity was surprisingly independent of shear strain. The increase in the in-die maximum compaction with shear strain was, in fact, compensated during post-compaction relaxation of the tables, which also increased significantly with shear strain. Therefore, tablet porosity alone was not sufficient to predict tablet tensile strength. A decrease in the ‘work of compaction’ as a function of shear strain, and an increase in the recovered elastic work was observed, which suggested weaker particle-particle bonding as the shear strain increased. For each shear strain level, the Ryskewitch Duckworth equation was a good fit to the tensile strength as a function of tablet porosity, and the obtained asymptotic tensile strength at zero porosity exhibited a 60% reduction as a function of shear strain. This was consistent with a reduced bonding efficiency as the shear strain increased.

This study presents the first investigations on the micro-mixing properties of pharmaceutical powder blends from a resonant acoustic mixer using near-infrared chemical imaging. All experiments were done in a laboratory resonant acoustic mixer (RAM). The powder blends were studied using near-infrared chemical imaging (NIR-CI). Qualitative (i.e. chemical images) and quantitative (e.g. mean diameter of aggregates) results were obtained using this analytical method. The quantitative results were correlated to the acceleration (mixing intensity) and total mixing time. Overall, the resonant acoustic mixing performance increased with increasing acceleration and mixing time. Therefore, larger aggregates of the active pharmaceutical ingredient (API) were found at lower accelerations (mixing intensity) and shorter mixing times. Mixing in the RAM efficiently reduced the overall aggregate size of the cohesive API (semi-fine APAP, ~ 45 μm) used in a common blend of filler (microcrystalline cellulose, ~ 110 μm) and lubricant (magnesium stearate, ~ 10 μm).

Purpose The purpose of this study is to develop a model for predicting the flow properties of a four-component powder mixture. Method To build the model, 22 samples were prepared using an extreme vertices mixture design. The flow properties were characterized using rotational shear cell methodology. Two additional blends were tested for external validation to illustrate model applicability. Results Cohesion was shown to be in a linear relation with unconfined yield strength and a power relation with flow factor. The special cubic model was used to build a mathematical model. Normality test of residuals showed that the regression model was more robust to predict cohesion than to use flow factor. Conclusion This QbD approach is shown to be useful for predicting flow performance and finding design space during formulation development.

Purpose The shear cell test has been widely used to characterize flow properties of powders and granular materials. The purpose of this study is to address the gap between the extensive usage of the test and the limited methods available to analyze the data, and to introduce methodologies for comparing results for different initial consolidation stresses, materials, and testing devices. Method A library of shear cell data was established. Forty-one powders were included, and each material was tested under four different initial consolidation stresses. For each initial consolidation stress, 3 sampling replicates were performed. Results A dimensionless cohesion, C*, was defined as the cohesion divided by the initial consolidation stress. By identifying a correlation between the flow function coefficient (ffc) and C*, the effects of the initial consolidation stress and the testing device were separated. In addition, by identifying a mathematical correlation between the unconfined yield strength and the cohesion, the yield loci from different initial consolidation stresses could be collapsed into a single material characteristic line, enabling one to characterize each material by a single number (the characteristic slope). This approach can be used to economically compare different materials, or different testing devices. Conclusion The proposed method augments shear cell data analysis and significantly reduces the complexity of the shear cell data.

The objective of this work was to study the granulation behavior of three different types of zirconium hydroxide, each varying in particle size and density. Different concentrations of yttrium (III) nitrate hexahydrate (Y(NO 3 ) 3 ·6H 2 O) solutions were used as a doping agent and also acted as binder. Experiments were performed using a high shear wet granulation process by adjusting two parameters, 1. liquid to solid mass ratio and 2. impeller speed, to obtain four parameter settings (referred as bounds in the paper) for a two factorial design of experiment for each powder. To understand the granule growth behavior, a regime map analysis using the growth regime map first proposed by Iveson and Litster (1998) , was carried out on the bounds. The granule growth behavior observed experimentally was compared with the regime map results. Different growth behavior was observed for different powders. Furthermore, an attempt was made to obtain a steady growth for those parameter settings that initially resulted in an induction growth. A surfactant, SDS (Sodium dodecyl sulfate), was used to improve the wetting properties of the powder and its addition to the binder solution resulted in a steady growth that is more controllable for granulation manufacturing operations compared to induction growth.

Rotating drums are encountered in numerous industrial applications, including blenders, rotary calciners, impregnators, coaters, granulators, and cement mixers. In all of these devices, the rotation of the drum is used to engender mixing of the granular material in the radial direction. Axial mixing, because of its significantly lower rate, can also have an impact on the process performance, especially when control of residence time is important. Typically, the particle dynamics in rotating drums are quantified as a function of process conditions, such as rotation speed, fill level, and cylinder size. Particle properties are also important, but previous studies have largely been limited to the effects of particle size. In this work, the quantification of the axial particle dynamics has been expanded to include the effect of bulk flow properties by studying a number of cohesive powders. Fick's second law was found to describe the axial dispersion behavior of cohesive particles. Therefore, changes in behavior can be characterized using the axial dispersion coefficient. The effect of material flow properties was found to be statistically significant; the flowability of the material (as measured using bulk flow properties) correlated significantly to the axial dispersion coefficient. Partial least squares was used to determine that 95% of the variation observed in the axial dispersion coefficient measurement can be explained using particle size, compressibility, and shear cell measurements.

Looking for a way to measure residence time distributions of an 80 micron fluidized cracking catalyst (FCC) powder, a simple measurement technique was discovered that quantifies tracer color concentration. Using a color spectrophotometer that measures percent reflectance as a function of wavelength, a calibration curve can be constructed for standard mixtures of dyed and un-dyed powder. This calibration curve can then be used to determine the color concentration of an unknown sample by measuring its reflectance. The effects of operating parameters such as dye strength, aperture size, surface roughness, sample volume and depth, and continuous flow were all evaluated. This spectrophotometric technique was found to be a quick and simple way to measure colored mixture concentrations. In addition to being ideal for residence time distribution applications, it has the potential to easily quantify mixing in any unit operation, batch or continuous.

Continuous powder processing requires accurate and consistent feed streams of the raw materials which makes loss-in-weight feeders invaluable. Periodic hopper refill of the feeders, which is needed for continuous operation, can lead to inconsistent and poor feeding performance. This paper presents both a method for measuring the feeding performance during hopper refill as well as several methods for quantifying the resultant deviations from feedrate setpoint caused by refill. The main results show that hopper fill level is the most significant factor that can be used in mitigating the deviations effects during refill. The use of discharge screens also showed a small improvement in feeding accuracy. Another potentially useful method of reducing deviations during refill is to use refilling systems that have a lower more controlled rate of refill that gently replenishes the feed hopper rather than the high rate refill of some refilling systems.

Developed to aid in the design of hoppers and silos, the shear cell is now frequently used to rank the flowability of powders relative to one another. While standards, such as ASTM D6773 and D6128, exist for shear cell tests, there are still differences between commercially available shear cell testers, such as cell geometry and size. In this work, we used two materials, a free-flowing alumina and a cohesive alumina, to compare measurements from three commercially available rotational shear cells. Results were collected and compared for cohesion, unconfined yield stress, major principal stress, pre-shear stress, flow function coefficient, bulk density, effective angle of internal friction, and the angle of internal friction. ANOVA methods were used to determine the statistical significance and relative size of each of these effects. This work has found that while, as expected, the material type has the largest effect on the shear cell results, the consolidation at which the material was tested and the tester type are also statistically significant effects. These results indicate that care should be taken when comparing the results between different shear cells.

An experimental study was performed to characterize two continuous mills for their ability to mill alumina–magnesia extrudates. The effect of mill parameters, namely, the screen aperture size, and impeller speed on the particle size distribution of the milled product was quantified for a conical screen mill and a hammer mill. In general, the conical screen mill was found to be more sensitive to changes in impeller speed compared to the hammer mill. The effect of impeller speed in case of the hammer mill was non-monotonic while the increasing speeds led to reduction in particle size in case of the cone mill, for the same screen aperture size. The effect of aperture screen size was observed to play a dominant role in dictating particle size distribution of the product material for both mills. In case of the cone mill, grated type screens exhibited higher milling capacity than round screens with equivalent apertures. Lastly, a study comparing the statistical particle size distribution parameters was performed for process design purposes. It was deduced that, if the desired particle size is greater, the comil provides a narrower particle size distributions than the hammer mill; whereas if the desired particle size is smaller, both mills exhibit similar poly-dispersity. The study provided insight into fundamental breakage mechanisms for both mill classes. Breakage in the hammer mill occurs primarily due to the impact of the hammers and large particles may often leak through the mill without sufficient breakage. Breakage in the comil is more gradual as the impeller sweeps a wide area generally ensuring sufficient breakage of particles before they exit the milling chamber.

An experimental investigation was carried out to study the mixing performance of a laboratory-scale ResonantAcoustic® Mixer (LabRAM). The first part of the study summarizes the results of a fractional factorial design of experiments used to determine the main effects of process parameters (fill level, acceleration, and blending time) on blend homogeneity. Studies were carried out for several blends having various values of particle size, cohesion and concentration of the active pharmaceutical ingredient. The second part of the study describes the LabRAM mixing performance as a function of process parameters (fill level and acceleration) and total blending time. The blend homogeneity was quantified by estimating the relative standard deviation (RSD) for low concentration of active pharmaceutical ingredient (acetaminophen, 3% w/w) and lubricant (magnesium stearate, 1% w/w) blend. Overall, the LabRAM reached the minimum blend homogeneity in as low as 30 s depending on process parameters. The temperature of the final blend increased with fill level, time and acceleration. Resonant acoustic mixing can significantly reduce blending time, making it a good candidate for improving the efficiency of powder mixing processes.

Tablet compression has great significance in the pharmaceutical industry since most of the drugs are in the tablet dosage form. The tablet press feed frame is used to fill powder into the empty dies. Die filling is one of the key steps to control final properties of tablets. Using the Discrete Element Method (DEM), a standard feed frame taken from a Manesty Betapress was simulated which represents the tableting process without the compression stage. DEM was used to understand the micro-macro dynamics of the particles inside the feed frame. Segregation behavior of a single material with a particle size distribution was investigated using this method. The DEM simulation components included 2 paddle wheel speeds (24 and 72 rpm) and 2 die disk speeds (29 and 57 rpm). Results obtained have highlighted the effect of feed frames on the powder properties. The DEM results show size segregation inside the feed frame and during the die filling stage. Velocity profiles and particle vectors show that the percolation phenomenon is the most significant segregation mechanism. Paddle wheel speed was demonstrated to be the most important factor to control particle size segregation inside the feed frame.

This paper focuses on two aspects of continuous powder mixing, namely characterizing the effects of material properties on the bulk powder flow behavior, and developing continuous blending strategies suitable for cohesive materials. The relative effects of process parameters and material properties on the bulk powder flow behavior were analyzed by performing a PLS analysis of the output parameters, including mean residence time, and axial dispersion coefficient as a function of input parameters (impeller speed, flow rate, bulk density and cohesion). The mean residence time was primarily affected by the bulk density and impeller speed, whereas the axial dispersion coefficient was affected by impeller speed and cohesion. Based on previously developed knowledge of mixing performance as a function of process parameters [1] , a design rule to select the optimal number of impeller passes based on the bulk density was proposed. Impeller speed and cohesion showed a significant interacting effect on the output variable, the axial dispersion coefficient. Increase in cohesion leads to increase in the axial dispersion coefficient at higher impeller speeds, whereas a negligible effect of cohesion on the axial dispersion coefficient was observed at lower impeller speeds. In the second part of the paper, a continuous blending methodology for blending cohesive materials was demonstrated. Considering the feeding limitations of cohesive materials, and limitations in the application of shear in the bladed continuous mixer, a combination of high shear and low shear mixing with high-shear mixing as a first step exhibited an optimal mixing strategy.

Characterization of powder consolidation and flow is important to a large number of industries that process solids. A variety of powder testers exist today, however most are application specific and results they provide are mainly qualitative. Comparison studies have been attempted previously; their main focus was whether various methods correlate, while the reasons for disagreement in the results have seldom been investigated. Among the different methods used to characterize powder flow behavior, density-based methods are some of the simplest and most popular. They are also some of the least sensitive and least reproducible. A method comparison study was performed to characterize the variability in bulk density as measured by various powder flow characterization methods. It was found that the density of the powders tested in most unconsolidated methods had a near-perfect linear correlation with one another, suggesting that there exists a critical “dilated” density value that is independent of the measurement method and can be considered a material property. The densities of the powders in consolidated states correlated poorly, especially for the methods where consolidation mechanisms were not tightly controlled (i.e. tapping). In addition, the effect of the consolidation state of the powder bed during testing on cohesion measurements was studied. The cohesion measured by shear cells at differing consolidation states and by an avalanching method, during which the powder bed is dilated, were compared. It was found that the differences in cohesion results from the shear cells tested can be attributed to differences in the powder consolidation state. Cohesion results acquired from a dilated powder bed correlate more linearly with the shear cell cohesion results at low consolidation stresses than at high consolidation stresses; further supporting the impact of the powder bed packing state on the measurement of cohesion.

Continuous powder mixing has attracted a lot of interest within the pharmaceutical industry. Much work has been done recently that targets the characterization of continuous powder mixing. In this paper, a quantitative scaling up strategy is introduced that allows the transition from lab to industrial scale. The proposed methodology is based on the variance spectrum analysis, and the residence time distribution, which are key indexes in capturing scale-up of the batch-like mixing, and scale-up of the axial mixing and motion, respectively. Our simulation results are used as preliminary guidance for scaling up different powder mixing cases.

Feed frame is a device used in rotary tablet presses to drive the powders into compression dies. It applies shear forces to the powders as they are stirred around the feed frame chambers. This study focused on understanding the particle attrition, powder properties and the flow property changes of the material processed. The results demonstrated that the impact of the feed frame and die disk on the particle size distribution (PSD) outlet depended on the initial mean particle size, the die size and the powder outlet position. It also impacted the flow properties. The scale-up effect using a feed frame for a high production tablet press shows a significant increment in powder attrition.

This review traces current applications of the residence time theory in various solid unit operations. Besides reviewing recent experimental and simulation studies in the literature, some common modeling and tracer detection techniques applied in continuous flow systems are also considered. We attempt to clarify and emphasize the influence of the residence time profile on the unit performance, which is the key in system design and performance improvement of practical unit operations. The development of predictive modeling is also an important goal in the long-term development of the residence time theory.

This paper presents a method for evaluating the steady state performance of loss-in-weight powder feeding equipment and then demonstrates the use of the method in evaluating the performance of a K-Tron KT35 loss-in-weight feeder for three pharmaceutical grade powders. The method describes in detail the experimental setup, the procedure used in collecting feedstream data, and the filtering and subsequent analysis that is needed to determine differences in the steady state feeding performance. The data stream is shown to be a complex data set that can be simplified, after applying a suggested filtering and analysis algorithm, to two quantities (average feedrate and relative standard deviation) that can be used for comparison of different feeding treatments (powder, feeder tooling, and setpoint). Through analysis of variance (ANOVA), the significance of various tooling on optimizing feeder performance can be evaluated.

A method comparison study was undertaken to characterize the effects of the formulation composition on the flow and shear properties of pharmaceutically relevant powders. Fourteen blends with various concentrations of an active ingredient, magnesium stearate as a lubricant and silica as a glidant were prepared. These blends were characterized with two very different techniques: the gravitational displacement rheometer (GDR), and a rotational shear cell. The values of GDR flow index were compared to the values of principal stresses and cohesion obtained with the shear cell. These measurements are different in that the GDR operates in the gravity-driven flow regime while the shear cell utilizes an imposed normal force, which leads to a much more pronounced powder consolidation. In spite of these differences, the study demonstrated a significant correlation between the two methods, although some discrepancies were observed due to differences in the consolidation state for each technique. This observation was confirmed by measuring compressibility of these formulations with the FT4 Powder Rheometer; the presence of a cohesive component influenced the values of the shear cell principal stresses (and therefore, the shear cell flow factor) in a non-linear manner, contributing to the discrepancies in the correlation between the flow factor and the GDR flow index. Conversely, the correlation between the shear cell cohesion parameter and the GDR flow index was significantly better, as both indices test the materials at similar degree of consolidation. The study examined the limits and the ranges of applicability of each technique, offered recommendations on applications, where the use of each method was more reliable, as well as provided reasons for the methods' failure.

An experimental investigation was carried out to study the mixing performance and flow behavior in a continuous powder mixer for a typical pharmaceutical mixture. Blender performance, characterized by the relative standard deviation (RSD) of composition of blend samples taken at the blender discharge and by the variance reduction ratio (VRR) of the blender, was measured as a function of impeller rotation rate, flow rate and blade configuration. The flow behavior in the continuous mixer was characterized using the residence time distribution (RTD) and powder hold-up measurements. To quantify the strain applied to the powder in the blender, the number of blade passes experienced by the powder in the blender was calculated using the residence time measurements. The relationship between different experimental parameters and mean residence time and mean centered variance was examined. The mixing performance was largely dominated by the material properties of the mixture, which had a larger effect than the ingredient flow rate variability contributed by the feeders. Holdup was strongly dependent on impeller rotation rate; as impeller rotation rate increased, holdup (and therefore, residence time) decreased sharply. As a result, intermediate rotation rates showed the best mixing performance. Blade configuration affected performance as well; blade patterns where some of the blades push the powder backwards improved the mixing performance.

This paper studies systematically the effect of a feed frames, a device used in rotary tablet presses to drive the powders into compression dies, on the properties of the powders entering the tablet press dies. The work focused on the effect of blend composition, feed frame parameters (blade speed, residence time), and rotary die disc parameters (die disc speed, die diameter) on the flow pattern, uniformity of die filling, applied shear, and the flow properties of pharmaceutical blends. The flow pattern suggests a stratified filling of the dies and therefore, non-uniform properties of the tablets. The amount of powder entering the dies depended on blend flow properties, feed frame speed, and dies disc speed. In addition, blend properties changed significantly as the powder flowed through the feed frame. The flowability of lubricated blends improved significantly as the number of feed frame blade passes increased, decreasing in turn the RSD of the die filling weight.

Electrostatic forces can significantly alter flow properties of granular materials and can adversely affect many industrial particulate processes in unpredictable ways. We investigate here the effect of higher order dielectric electrostatic forces, which are created by non-uniform electric fields, on the agglomeration, adhesion and flow of several granular materials, including pharmaceutical powders. We find that materials can adhere consistently and reproducibly to a metallic rod in a sufficiently strong electric field, which can be produced by either a DC source or tribocharged surfaces. These results provide a simple way to characterize material susceptibility to electrostatic agglomeration. The effect of applied non-uniform fields on the flow of grains falling from a cylindrical hopper is studied and found to significantly reduce the particle flow rate. The effects of humidity, particle size, coatings, and the grounding of equipment are also tested. Finally, contrary to common intuition, we find that grounding a metallic surface can actually exacerbate particle adhesion and agglomeration.

Heat transport through flowing particulate materials is an essential component of modern technologies such as heterogeneous catalytic reactors, high performance cryogenic insulation, construction material, and powder metallurgy. In catalyst manufacturing, heat transfer through granular media occurs in the drying and calcination stages. In this paper, we describe the use of experiments and discrete element methods to examine flow, mixing, and mass and heat transport in rotary calciners. Alumina powder (200 μm) and cylindrical silica pellets (2 mm diameter and 3 mm long), which are common support materials for catalysts, are used in our experiments. A parametric study was conducted by varying the material properties of granular material, and rotational speed of the calciner. We use the discrete element model to simulate flow, mixing, and heat transport in granular flow systems in rotary calciners. Simulations and experiments show that the rotation speed has minimal impact on heat transfer. As expected, the material with higher thermal conductivity (alumina) warms up faster in experiments and simulations. Various baffle configurations (rectangular and L-shaped flights) in the calciner and their effect on the flow and heat transfer of granular material are simulated. The average wall-particles heat transfer coefficient of the granular system is also estimated from the experimental findings.

This paper discusses how the hydrophobicity of lubricated pharmaceutical formulations is affected by process variables such as shear rate and strain. Hydrophobicity is a critical property that affects the dissolution of powder formulations, tablets and capsules as well as the performance of tablet coating and granulation operations. In this paper, hydrophobicity is measured using a modified Washburn method. Results show that, in the absence of lubricant, the hydrophobicity of powders does not change substantially as a function of shear rate or strain. However, when magnesium stearate is present (concentrations studied here range between 0.5% and 2%), hydrophobicity increases as a function of strain, shear rate and lubricant concentration. Observed changes range over several orders of magnitude, readily explaining common “overlubrication” observations of delayed drug dissolution.

The dynamics involved in powder mixing remains a topic of interest for many researchers; however the theory still remains underdeveloped. Most of the mixers are still designed and scaled up on empirical basis. In many industries, including pharmaceutical, the majority of blending is performed using “tumbling mixers”. Tumbling mixers are hollow containers which are partially loaded with materials and rotated for some number of revolutions. Some common examples include horizontal drum mixers, v-blenders, double cone blenders and bin blenders. In all these mixers while homogenization in the 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), and a central symmetry axis (spinning motion). A detailed study is conducted on mixing performance of powders and the effect of critical fundamental parameters including blender geometry, speed, fill level, presence of baffles, loading pattern, 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 efficiency 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.

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.

We study the relation between flow and electrical conductivity of multiple formulations of pharmaceutical powder blends. Ten formulations were tested, consisting of two excipient sets, two active preparations, and a variety of food-grade additives including magnesium stearate (MgSt), and ionic and conductive materials such as ascorbic acid, talc, sodium carbonate, colloidal silica and TiO2. Electrical impedance, flow index and dilation were independently measured for all of the blends, and a strong correlation was found between every pair of these three properties. The relation between flow and dilation has been observed before; we find for the first time that there is an exponential relationship between flow index or dilation and impedance. This indicates that cohesive powder behavior depends on powder electrical properties, raising the questions of whether additives such as MgSt affect friction and conductivity per se and what mechanism and phenomenon links cohesion and conductivity.

In this paper we focus on the effect of cohesion and compression speed on the outcome of the compression process for both monodisperse and polydisperse granular systems. A three dimensional discrete element model (DEM) which incorporates static and dynamic friction is used in this study to simulate die filling, and the compaction and decompaction of cohesive granular system in a confined cylindrical die similar to those used in a commercial tablet press driving the pre-compressive stage. The magnitude of the cohesive force is represented in terms of a parameter K = Fcohes/mg, where K is called the bond number and is the measure of cohesiveness. Force displacement curves are used to characterize the compression and deformation properties of the materials and are obtained by measuring the force on the upper punch and the corresponding displacements in the die. Results show that a considerable more energy is needed to compress the cohesive material as compared to free flowing materials. It is found that the time required to fill the die strongly depends on the cohesion of the material. The energy for the tableting process is directly proportional to the upper punch speed.

This paper investigates the effects of processing and equipment parameters of a ribbon blender (i.e. loading method of lubricant, fill level, blade speed and blade design) on magnesium stearate homogeneity. A core sampling technique is used to obtain at least one hundred samples per sampling event, which are extracted throughout the blender and yield a thorough characterization of the entire bed. The results presented here can be used as a guideline to develop appropriate blending processes and characterization protocols for ribbon blenders.

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.

Rotary drums are used as mixers, dryers, kilns and granulators. In all of these systems, powder cohesion deeply affects mixing and segregation, and it is critical in process scale up. In this paper, we focus on the effect of cohesion in mixing and size segregation of binary mixtures of uniform and non-uniform sizes in a partially filled rotating drum. The cohesive force between particle is simulated using a square-well potential and the numerical model is used to characterize flow and mixing properties. The model is validated by comparison to experimental images. Results show a time-dependent spatial distribution of cohesive powder that depends on the magnitude of cohesion and friction. In uniform binary systems, as cohesion increases, the rate of mixing first increases and then decreases, however for the case of non-uniform binary systems, we observe different mixing patterns depending on the relative magnitude of forces acting between particles of same/different sizes. Unlike free flowing material, for cohesive mixtures, a higher rotation speed is found to enhance mixing performance.

The flow of spherical particles in a tumbling blender is investigated using discrete element methods (DEM). Simulations are performed on a collection of particles that are mono-disperse and bi-disperse in size. The mono-disperse system is primarily used to assess the quality of mixing as a function of fill level and time. Results reveal that radial convection is faster than axial dispersion transport. This slow dispersive process hinders mixing performance in this geometry. We also find that both axial dispersion and radial convection worsen as the blender fill level is increased. This trend is corroborated by recent laboratory experiments performed in an identical geometry. Particle velocity profiles indicate that the flow is composed of two regions: i) a high velocity layer cascading atop ii) a nearly ‘solid body’ rotation region. Segregating mechanisms are investigated using bi-disperse systems, which show that small particles segregate in pockets at both extremes of the axis of rotation.

The flow dynamics of cohesive powders is investigated in rotating cylinders with an L : R ratio of 3 : 1 using experiments and DEM simulations. Flow onset and steady-state behavior are compared for free-flowing (cohesionless) dry glass beads, wet glass beads, and “dry” cohesive powders (lactose, microcrystalline cellulose). The avalanching dynamics of powders is substantially different from those observed for free-flowing or wet-cohesive glass beads. Dry cohesive powders exhibit history-dependent flow dynamics, significant dilation, aperiodic avalanche frequencies, and variable avalanche size. These behaviors also provide a route for effective characterization of cohesive forces under dilated conditions characteristic of unconfined flows.

Mixing and transport of a cohesive powder are experimentally characterized in a laboratory-scale Bohle Bin blender. The cohesive powder is a blend of Avicel, lactose, and magnesium stearate (MgSt). The effects of vessel fill level, rotational speed, mixing time, and the presence of baffles on mixing are characterized by quantifying MgSt distribution using Near Infrared (NIR) spectroscopy. Results show that the relative standard deviation (RSD) decays faster (on a per revolution basis) and further (lower plateau) at higher rotational speeds. This result indicates a dependence of mixing of cohesive materials on shear. We find that fill level has a strong impact on mixing rate; the higher the fill level, the slower the mixing. Segregated regions are observed at the center of the blender for high fill levels at low rotational speeds. The presence of baffles seems to hinder mixing; the RSD decays are slower and leveled at a higher plateau when baffles are used. Concentration profiles data shows that, at high fill levels, baffles promoted the formation of segregated region at the center of the mixer.

It is known that one of the dominant forces controlling the macroscopic motion of particles is the cohesive force due to the presence of liquid bridges between particles. In a mixing process, this force directly impacts the degree of homogeneity achievable by the system. The work presented here provides a quantitative analysis of this relationship through concurrent direct measurements of surface forces due to moisture and blending/segregation experiments. Atomic force microscopy (AFM) was employed to measure the force required to remove the AFM's cantilever from the surface of a glass bead with varying degrees of surface moisture. Corresponding blending/segregation experiments were performed using the same materials and conditions to develop a correlation between the interparticle forces due to the liquid layer and the final state of a mixing process. The extent to which greater moisture content increased the interparticle surface forces was quantified, and it was observed that segregation decreases proportionately to increases in surface forces.

In industrial practice, scale-up of granular flows in tumbling devices has been largely attempted using one of two parameters, either the vessel tangential speed (ω) or the Froude (Fr) number. In this communication, we measure surface velocities of 1.6-mm particles in half-filled rotating cylinders and find that neither ω nor Fr accurately scales changes in particle velocity with changes in vessel rotation rate, diameter, or particle size. New non-dimensional scaling criteria using a simplified model produce agreement in both the magnitude and shape of the velocity profiles. A strong dependence on both rotation rate and vessel radius is found and a small but measurable effect of particle size is also demonstrated. We find that there are two different scaling regimes that depend on whether or not the cascading layer reaches a symmetric equilibrium state. At lower rotation rates, Ω, cascading particles can reach equilibrium, and granular surface speeds scale as Ω2/3; at higher rotation rates, particle velocities scale as Ω1/2. New effects of relative particle size with respect to the cylinder diameter are also reported.

Experiments were conducted to determine the effects of rotational speed, feed rate, and angle of inclination on the mean residence time, hold-up, and axial dispersion coefficient of cylindrical zeolite catalytic pellets in a rotary calciner (kiln). Nonintrusive sampling and analysis techniques were employed to measure the residence time distribution (RTD) of tracer pellets (injected at the feed entrance) both along and at the exit of the calciner. A single-parameter continuum model was applied to the residence time distribution (RTD) data to compute the dispersion coefficient as a function of distance. It was observed that the mean residence time is strongly dependent on axial velocity, hence, inversely related to rotational speed and angle of inclination, and is not a function of feed rate up to 10% fill. Material holdup was observed to be directly related to feed rate, inversely related to rotational speed, and slightly inversely proportional to angle of inclination. The dispersion coefficient was found to be strongly dependent on rotational speed and angle of inclination, but weakly dependent on flow rate.

Experiments were conducted to determine the effects of fill level, mixing time, and use of baffles on the mixing performance of a pilot plant scale tote (bin)-blender. The binary mixture under study was free-flowing, noncohesive art sand of two colors. Mixture uniformity was evaluated by sampling the blend using core samplers with the samples quantified by image analysis. The rate of mixing was significantly affected by the degree of blender fill. Four fill levels were examined, 20% fill (fastest), 40% fill, 60% fill (optimum), and 80% fill (slowest). Top–bottom and side–side initial loading patterns were studied to determine the influence of the axial and radial mixing mechanisms with and without an internal baffle at the manufacturer's standard position. Axial mixing was found to be the rate-limiting step to achieving overall blend homogeneity. The standard baffle configuration only generated moderate enhancements in mixing. A first-order mixing model was applied to determine the mixing rate constant for the various fill levels and baffle conditions investigated.

Pharmaceutical product development and manufacturing, which is largely an exercise in particle technology, is in serious need of technical upgrading. In this article, an overview of the current state of the art is provided, along with a discussion of expected research trends and their economic and societal impacts. In particular, the anticipated role of nanotechnology is discussed in some detail.

We discuss cellular automata (CA) simulations of granular segregation in several different tumbling blenders, including simple rotating drums, V-blender shells, drums tumbling end-over-end and double-cones. In all cases, simplified CA generates data that agree surprisingly well with companion experiments. This implies that a predictive understanding of segregation mechanisms in a wide variety of problems may be achievable using relatively simple algorithms.

Experiments were conducted comparing mixing performance in a conventional double-cone blender and in a double-cone blender that was modified by means of a stationary deflector plate in order to enhance axial particle flow. Mixing performance was assessed qualitatively using a transparent mixing vessel to visualize particle mixing patterns and determine the state of homogeneity at the mixture's surface during the entire experiment. Mixing performance was also examined quantitatively by repeatedly vacuuming several layers of beads, taking a digital image of the bed after vacuuming, and using image analysis to subdivide the images into samples and determine the composition of each sample. The effect of operating conditions (rotation rate, vessel fill percentage and total number of revolutions) was examined. Mixing was quantified in terms of the standard deviation of the concentration of a tracer. The evolution of the process was accurately described by a single-parameter model that characterized axial mixing as a first order process with a characteristic rate constant. For double-cone mixers of standard design, under all operating conditions, slow flow of particles through a vertical plane of symmetry at the center of the vessel caused poor mixing performance. Insertion of a deflector plate inclined relative to this plane was very effective in enhancing mixing. The effect of the deflector was to create a convective axial flow across the center of the mixer, increasing the mixing rate by a factor of 25:1.

Granular mixing is a vital operation in food, chemical, and pharmaceutical industries. Although the tumbling blender is by far the most common device used to mix grains, surprisingly little is known about mixing or segregation in these devices. In this paper, we report the first fully three-dimensional (3D) particle dynamics simulations of granular dynamics in two standard industrial tumbling blender geometries: the double-cone and the V-blender. Simulations for both monodisperse and bidisperse (segregating) grain sizes are performed and compared with experiment. Mixing and transport patterns are studied, and we find in both tumblers that the dominant mixing mechanism, azimuthal convection, contends against the dominant bottleneck, axial dispersion. The dynamics of blending, on the other hand, differs dramatically between the two tumblers: flow in the double-cone is nearly continuous and steady, while flow in the V-blender is intermittent and consists of two very distinct processes.