Continuous Powder Mixing Research Articles

Determination of steady-state for continuous powder mixing: Analysis of mixture properties and signal processing

Continuous powder mixing offers many advantages over batch processes, but its industrial implementation requires control of transient phases due to startup or variations in operating conditions. Detecting the steady-state by observing the mixture properties, obtained through in-line analysis of the mixture composition, is challenging due to the significant fluctuations in these properties. However, there is no quantitative method for identifying the steady-state for continuous powder mixing. We therefore propose in this work a methodology for steady-state detection by comparing several methods of mixture property analysis and signal processing. We show that conventional methods of mixture property analysis cannot reliably and accurately detect steady-state. We conclude that the best methodology is to perform signal processing on the content of the key component in the mixture. To do this, the signal of the content of the key component is first smoothed by the Savitzky-Golay filter. Then, the standard deviation of the filtered signal is compared with a tuning parameter to detect the beginning of steady-state. This method could be used to determine the mixing conditions leading to the smallest startup time, hence avoiding costly waste.

Development of a high-fidelity digital twin using the discrete element method for a continuous direct compression process. Part 2. Validation of calibration workflow

This paper is the second in a series of two that describes the application of discrete element method (DEM) and reduced order modeling to predict the effect of disturbances in the concentration of drug substance at the inlet of a continuous powder mixer on the concentration of the drug substance at the outlet of the mixer. In the companion publication, small-scale material characterization tests, a careful DEM parameter calibration and DEM simulations of the manufacturing process were used to develop a reliable RTD models. In the current work, the same calibration workflow was employed to evaluate the predictive ability of the resulting reduced-order model for an extended design space. DEM simulations were extrapolated using a relay race method and the cumulative RTD was accurately parameterized using the n-CSTR model. By performing experiments and simulations, a calibrated DEM model predicted the response of a continuous powder mixer to step changes in the inlet concentration of an API. Thus, carefully calibrated DEM models was used to guide and reduce experimental work and to establish an adequate control strategy. In addition, a further reduction in the computational effort was obtained by using the relay race method to extrapolate results. The predicted RTD curves were then parameterized to develop reduced order models and used to simulate the process in a matter of seconds. Overall, a control strategy evaluation tool based on high-fidelity DEM simulations was developed using material-sparing small-scale characterization tests.

Dry Battery Electrode Manufacturing Enabled By Continuous Powder Mixing

Lithium-Ion Battery electrode manufacturing is a cost- and energy-intensive process that usually relies on the use of a hazardous and expensive solvent, N-methyl-2-pyrrolidone (NMP), for cathodes. After coating the battery-slurry to a current collector, the solvent needs to be evaporated to obtain a porous electrode suitable for the use in a Lithium-Ion Battery. The solvent is a processing material and unwanted in the final product. In fact, solvent residues can fuel parasitic side-reactions within the battery cell and hence deteriorate battery lifetime and safety. The utilization of NMP in battery production plants demands costly labor protection and explosion safety measurements during mixing and coating and necessitates a highly energy and floor-space demanding drying step using thermic drying ovens of up to 100 meters.[1] For ecological and economic reasons, NMP is not emitted in large-scale production facilities, but condensed and recycled by distillation. The NMP-recovery system adds additional floor space and energy demand to the production site. The drying and solvent recovery can account for up to 39% of the total energy demand of a Lithium-Ion Battery Cell production and therefore produce significant CO2 emissions.[2] A solvent-free, dry electrode manufacturing that eliminates the use of solvents hence reduces the floor space, energy demand and cost of a production plant and eases safety and environmental concerns. Different approaches have been reported in the literature to put dry coating into practice,[3],[4] yet most strategies, for example spray coating or brush coating, lack of a feasible implementation into large scale production. In contrast, a dry coating approach that is sometimes referred to as the Maxwell-Process is, according to media reports, currently installed at Tesla’s Gigafactories in Berlin and Austin.[5] In fact, a publicly available teardown of a Tesla 4680 battery cell hints that a dry coated anode could already be used in commercial vehicles.[6] Compared to the state-of-the-art electrode manufacturing process, dry coating requires different polymeric binder systems that form spiderweb-like structures of fine fibrils connecting the electrochemical active particles and the conductive additive particles. PTFE is highly suitable since it is stable towards typical electrolytes and cathode materials and is known to easily form fibrils. These properties are also utilized to produce expanded PTFE membranes like Gore-Tex. The fibril-network in the battery context is primarily formed by a high-shear dry mixing process. The powder mixture is then compressed to a free-standing electrode film (powder-to-film) by a heated rolling mill (calender) and the resulting film is ultimately laminated to a current collector foil (film-to-foil). We demonstrate that a twin screw-extruder can be used to tune the degree of binder-fibrillation during dry-mixing of NMC-based cathode mixtures. Extrusion based mixing allows to use powder mixtures with little amounts of PTFE binder (1 wt%) to produce self-supporting, free-standing cathode films and, ultimately, battery electrodes with high flexibility and sufficient mechanical stability. We show a superior rate-performance and cycling-stability of single-layer pouch cells with dry-coated cathodes compared to cells with wet coated reference electrodes of likewise composition and electrode design. Possible causes for the improved performance focusing on microstructural electrode properties are discussed.[1] Westphal, Bastian G.; Kwade, Arno (2018): Critical electrode properties and drying conditions causing component segregation in graphitic anodes for lithium-ion batteries. In: Journal of Energy Storage 18, S. 509–517.[2] Erik Emilsson, Lisbeth Dahllöf (2019): Lithium-Ion Vehicle Battery Production. IVL Swedish Environmental Research Institute.[3] Duffner, Fabian; Kronemeyer, Niklas; Tübke, Jens; Leker, Jens; Winter, Martin; Schmuch, Richard (2021): Post-lithium-ion battery cell production and its compatibility with lithium-ion cell production infrastructure. In: Nat Energy 6 (2), S. 123–134.[4] Verdier, Nina; Foran, Gabrielle; Lepage, David; Prébé, Arnaud; Aymé-Perrot, David; Dollé, Mickaël (2021): Challenges in Solvent-Free Methods for Manufacturing Electrodes and Electrolytes for Lithium-Based Batteries. In: Polymers 13 (3).[5] https://www.tagesspiegel.de/berlin/tesla-coup-mit-giga-berlin-neue-technologie-soll-wasserverbrauch-minimieren/27244032.html[6] https://www.youtube.com/watch?v=8WPPBhqeekw Figure 1

Assessing residence time distributions and hold-up mass in continuous powder blending using discrete element method

Continuous manufacturing of pharmaceutical products can improve process efficiency and quality assurance. The propagation of material through continuous manufacturing processes can be characterized by residence time distributions (RTDs). Conventional parameter-fitted RTD models rely extensively on experimental measurements that are often expensive and limited to available observation methods and instruments. This limitation can be compensated by discrete element method (DEM) simulations. This work evaluates the predictive capabilities of DEM modeling for a continuous powder mixing process. First, the developed DEM model was validated using experimentally measured RTDs. Then, the effects of the mass flow rate, blender element pattern, and blender speed on mean residence time and hold-up mass were studied. The simulation results showed that the mean residence time increased linearly with increasing number of mixing elements but decreased with increasing mass flow rate and blender speed. The hold-up mass increased with increasing mass flow rate and number of mixing elements but decreased with increasing blender speed. The work successfully demonstrated the capability of the DEM model in improving our understanding regarding the impacts of the blender operating conditions on the RTD and hold-up mass as well as in supporting the assessment of control strategies for continuous blending processes.

Dry Powder Mixing Is Feasible in Continuous Twin Screw Extruder: Towards Lean Extrusion Process for Oral Solid Dosage Manufacturing.

Using discrete element method (DEM) modeling and near-infrared (NIR) spectroscopy, the feasibility of powder mixing in the initial pre-melting zones of a twin screw extruder using two independent feeders was studied. Previous work in the pharmaceutical and food industry has focused on mixing when materials are melted or on material homogeneity at the extruder's output. Depending on the formulation, ensuring a fully blended formulation prior to melting may be desired. Experiments were conducted using a Coperion ZSK-18 extruder to evaluate if blend uniformity can be achieved by exploring screw configuration, screw speed, and powder feed rate. As powder exited the extruder and deposited on a conveyor belt, an in-line NIR spectrophotometer measured spectra of material. Chemometric-based models predicted unknown concentrations to evaluate if blend uniformity was achieved. Using the EDEM software, Hertz-Mindlin contact model, and dimensions of the extruder, DEM simulations complemented the experimental work. The DEM computational models provided understanding of mixing patterns inside the extruder at particle scale and helped select the screw configuration before doing experimentation. The simulations showed good axial mixing for all the screw configurations studied, while good cross (radial) mixing was only observed for the screw configuration with 90-degree kneading elements. Therefore, the screw configuration with two 90-degree kneading elements was chosen for the experimental study. The RTD profiles when using a screw configuration with only conveying screw elements are comparable to a plug flow reactor (PFR), while the profiles when using kneading elements are more comparable to an ideal continuous stirred tank reactor (CSTR). For the screw configuration with 90 degrees kneading elements, the mean residence time (MRT) decreases with an increase in the screw speed. Experimental NIR spectra showed that concentrations can be predicted with an error of 2%. It was demonstrated that the twin screw extruder can provide proper dry powder mixing of two powder feed streams based on a unit dose scale, enabling continuous powder mixing prior to the melting zone in the extruder for the formulation studied with a cohesive API. This setup may also work for other types of formulations. These studies can help in developing lean hot melt as well as wet extrusion/granulation processes using twin screw extruders for the continuous manufacturing of oral solid dosage products.

Continuous mixing technology: Validation of a DEM model

Continuous powder mixing is an important technology used in the development and manufacturing of solid oral dosage forms. Since critical quality attributes of the final product greatly depend on the performance of the mixing step, an analysis of such a process using the Discrete Element Method (DEM) is of crucial importance. On one hand, the number of expensive experimental runs can be reduced dramatically. On the other hand, numerical simulations can provide information that is very difficult to obtain experimentally. In order to apply such a simulation technology in product development and to replace experimental runs, an intensive model validation step is required. This paper presents a DEM model of the vertical continuous mixing device termed CMT (continuous mixing technology) and an extensive validation workflow. First, a cohesive contact model was calibrated in two small-scale characterization experiments: a compression test with spring-back and a shear cell test. An improved, quicker calibration procedure utilizing the previously calibrated contact models is presented. The calibration procedure is able to differentiate between the blend properties caused by different API particle sizes in the same formulation. Second, DEM simulations of the CMT were carried out to determine the residence time distribution (RTD) of the material inside the mixer. After that, the predicted RTDs were compared with the results of tracer spike experiments conducted with two blend material properties at two mass throughputs of 15 kg/h and 30 kg/h. Additionally, three hold-up masses (500, 730 and 850 g) and three impeller speeds (400, 440 and 650 rpms) were considered. Finally, both RTD datasets from DEM and tracer experiments were used to predict the damping behavior of incoming feeder fluctuations and the funnel of maximum duration and magnitude of incoming deviations that do not require a control action. The results for both tools in terms of enabling a control strategy (the fluctuation damping and the funnel plot) are in excellent agreement, indicating that DEM simulations are well suited to replace process-scale tracer spike experiments to determine the RTD.

Continuous Mixing Technology: Characterization of a Vertical Mixer Using Residence Time Distribution.

Continuous powder mixing technology (CMT) application during continuous direct compression has emerged as a leading technology used in the development and manufacture of solid oral dosage forms. The critical quality attributes of the final product are heavily dependent on the performance of the mixing step as the quality of mixing directly influences the drug product quality attributes. This study investigates the impact of blend material properties (bulk density, API particle size distribution) and process parameters (process throughput, hold up mass and impeller speed) on the mixing performance. Mixing of the blend was characterized using the Residence Time Distribution (RTD) of the process by trending the outlet stream of the mixer using a near-infrared (NIR) probe after the injection of a small mass of tracer at the inlet stream. The outcomes of this study show that the RTDs of the mixer with throughput ranging between 15 and 30kg/h; impeller speed ranging between 400 and 600rpm and hold up mass (HUM) ranging between 500 and 850g can be described by a series of two ideal Continuous Stirred Tank Reactors (CSTRs) with different volumes, and correspondingly, different mean residence times. It is also observed that the mixing is mainly occurring in the lower chamber of the CMT and the normalized RTDs of the mixer are similar across the range of process conditions and material attributes studied. The results also showed that the formulation blend with different API particle sizes and bulk properties, like bulk density and flowability, provide insignificant impact on the mixing performance. The CMT allows independent selection of target set points for HUM, impeller rotational speed and line throughput and it shows great robustness and flexibility for continuous blending in solid oral dose manufacturing.

Determination of Residence Time Distribution in a Continuous Powder Mixing Process With Supervised and Unsupervised Modeling of In-line Near Infrared (NIR) Spectroscopic Data.

Successful implementation of continuous manufacturing processes requires robust methods to assess and control product quality in a real-time mode. In this study, the residence time distribution of a continuous powder mixing process was investigated via pulse tracer experiments using near infrared spectroscopy for tracer detection in an in-line mode. The residence time distribution was modeled by applying the continuous stirred tank reactor in series model for achieving the tracer (paracetamol) concentration profiles. Partial least squares discriminant analysis and principal component analysis of the near infrared spectroscopy data were applied to investigate both supervised and unsupervised chemometric modeling approaches. Additionally, the mean residence time for three powder systems was measured with different process settings. It was found that a significant change in the mean residence time occurred when comparing powder systems with different flowability and mixing process settings. This study also confirmed that the partial least squares discriminant analysis applied as a supervised chemometric model enabled an efficient and fast estimate of the mean residence time based on pulse tracer experiments.

Facile synthesis of micro-sized Ni–Al alloy powders through low-temperature chemical alloying

Micro-sized Ni–Al alloy powders were synthesized using different quantities of Ni and Al powders as well as AlCl3 as an activator in a quartz batch reactor at ≤773 K. This method, named low-temperature chemical alloying (LTCA), which allows Al atoms to diffuse into micro-sized nickel particles mediated by aluminum chloride (chemical promotor), is distinct from conventional processes, such as cast-and-crush, and gas atomization. As-synthesized Ni–Al alloys were characterized using different analytical techniques that included X-ray diffraction (XRD), particle size analysis, and field emission scanning electron microscopy in conjunction with energy dispersive X-ray spectroscopy (FESEM-EDS), to confirm the formation of alloy phases, such as Ni3Al, NiAl, Ni2Al3, and NiAl3. The analytical results showed that the crystalline phase compositions of the Ni–Al alloys were highly dependent upon the initial amounts of Ni and Al powders employed at the given alloying conditions (alloying temperature, 773 K; alloying time, 20 h; amount of AlCl3, 1.2 wt%). As a result of the thermal treatment of Ni–Al powder mixtures with the Al contents of (5, 15, 30, and 50) wt.% under continuous powder mixing by rotation, each powder was found to have (i) Ni solid solution + Ni3Al, (ii) Ni3Al, (iii) NiAl, and (iv) Ni2Al3 + NiAl3 phases, respectively, corresponding to the equilibrium states of the Ni–Al phase diagram. The cross-sectional analyses showed that the alloy structures of the heat-treated powders exist in a single-phase or core-shell form, depending on the number of crystalline phase compositions predicted from the phase diagram. In particular, the Ni–50 wt% Al powder has a unique Ni2Al3@NiAl3 core-shell structure. We further evaluate the performance of the as-developed Ni–Al alloy powders as oxidation-resistant materials and template materials for high-surface area (∼60 m2/gcat) nickel catalysts.

Powder flow and mixing in a continuous mixer operating in either transitory or steady-state regimes: Mesoscopic Markov chain models

Continuous powder mixing is gaining interest in the industrial community concerned with more and more functional powder products. The understanding of powder flow and mixing/segregation of particles as well as their translation into models that can be used in process monitoring and control is a major issue. In the present work, we describe the development of different mesoscopic Markov chain models that are based on interconnected compartments or cells delimited in the mixing chamber. The general structure of the chain allows the derivation of either homogeneous or non-homogeneous markovian models, for which transition probabilities are state-dependent.The models can be adapted to simulate variations of outflow rate, outlet mixture composition, hold-up weights and the distribution of these at the level of the compartments, during processing, including stationary and transitory phases. This is applied to a Gericke 500 GCM® continuous mixer for either pure powders or their mixtures, in the latter case through the consideration of a Markov chain for each component. The models are fed by independent experiments that allow for the determination of the probabilities and the rules governing their change with the processing step, in particular during the transitory regimes. Agreement is found between model calculation and experimental data for a wide range of configurations. The models can catch the variations of hold-up weights and internal or outlet flow rates at any rotational stirrer's speed during mixer start and steady state. They can reproduce the variations of the outflow rate, and therefore mixture composition, when dealing with a mixture of two components. This is also presented for two nominal compositions.Conclusions are drawn in terms of process monitoring and control. It gives insights for process intensification, in particular for mixer design and the feeding configuration.

Detailed modeling and process design of an advanced continuous powder mixer

A vertical in-line continuous powder mixing device (CMT – Continuous Mixing Technology) has been modelled with the discrete element method (DEM) utilizing a calibrated cohesive contact model. The vertical design of the mixing device allows independent control of mean residence time (MRT) and shear rate. The hold-up mass and outlet flow are controlled by an exit valve, located at the bottom of the in-line mixer. A virtual design of experiments (DoE) of DEM simulations has been performed and parameters such as particle velocities, powder bed shape, residence time distribution (RTD), travel distance, and mixing quality are evaluated for the complete operating space. The RTD of the DEM model has been validated with tracer experiments. The resulting RTD has been fitted with an analytical form (generalized cascade of n continuous stirred tank reactors) and utilized to study the downstream response of the continuous mixing device to upstream fluctuations in the inlet material stream. The results indicate a high mixing quality and good filtering properties across the operating space. However, the combination of low hold-up mass and high impeller speeds leads to a reduced filtering capability and wider exit valve openings, indicating a less desirable operating point.

A dimensionless analysis of residence time distributions for continuous powder mixing

For continuous manufacturing of pharmaceuticals, understanding the dynamics of how a material flows through the process is critical with respect to the development of a control strategy for product quality assurance. Such understanding of the process dynamics can be obtained by characterization of the residence time distribution (RTD). The RTD for a process is not fixed and can vary due to changes in operating conditions or physiochemical properties of the blend. As such the RTD needs to be evaluated over the range of operating condition that can impact process dynamics (e.g. throughput, impeller rotation rate etc.). In this paper, we demonstrate that the dimensionless RTD (normalized with respect to the mean residence time) is invariant with throughput and impeller rotation rates under certain conditions for the two continuous direct compression processes. We present a case study to illustrate the utility of this relationship for predicting the process dynamics at different operating conditions (i.e., throughputs) and evaluating the impact of variations in the process dynamics on the control strategy for a continuous direct compression process.

Continuous powder mixing of segregating mixtures under steady and unsteady state regimes: Homogeneity assessment by real-time on-line image analysis

Continuous powder processes, such as continuous powder mixing, are more than ever envisioned as a viable alternative to batch equipment, in various industries such as pharmaceuticals, specialty chemicals (zeolites, SiC), bio-renewables or food. In the present work we have implemented an on-line image analysis set-up that is able to capture all the images of the particles at the outlet of a continuous pilot-scale mixer. This allows the determination of the homogeneity of mixtures of two different compositions, as well as the analysis of their evolution during steady-state and transitory regimes. The importance of a proper definition of the scale of scrutiny of the mixture is emphasized by providing homogeneity results obtained at four different scales. Evidence of segregation by percolation giving rise to the enrichment of the mixer's bed with fine particles is given and commented. The impact of the stirrer's rotational speed on the quality of the mixtures, as provided by the coefficient of variation CV, is reported. Up to 20Hz, CV's are extremely high, while above 30Hz, the influence of the impeller speed is much weaker. Finally, the influence of impeller speed's step perturbations is measured and commented. Due to the size – segregation phenomenon inside the mixer, negative steps are deeply detrimental to the mixing process. On the contrary, positive steps can be absorbed by the equipment without degradation of the quality of the mixtures.

Diminished segregation in continuous powder mixing

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.

Effects of processing parameters and blade patterns on continuous pharmaceutical powder mixing

The present study summarizes the experimental characterization of a new continuous powder mixer (GCG-70 by Glatt®) using common pharmaceutical ingredients. The powder hold-up and residence time distribution were used to characterize the bulk behavior of the mixer as a function of impeller rotational speed, total throughput (mass flow rate) and blade configuration. The relative standard deviation (RSD), calculated from samples taken at the outlet of the blender, was used to characterize its mixing performance. The hold-up and the mean residence time decreased with increasing impeller rotational speed. The mean centered variance and the number of blade passes increased with increasing impeller rotational speed. The effect of the blade configuration on the mixing dynamics diminished as the rotation rate increased. The hold-up and mean residence time were sensitive enough to demonstrate the effects of blade configurations. The mixing performance, depending on the processing parameters, was found to be between 5% and 10% RSD for 5% w/w active pharmaceutical ingredient (API), and <3% for 30% w/w API. These results showed improvements in the mixing performance when compared to studies of other continuous mixers using similar materials and analytical techniques for quantification.

Continuous feeding of low-dose APIs via periodic micro dosing

Precise and effective feeding of small powder quantities remains a challenge in many fields, including pharmaceutical development and production. This paper demonstrates that a simple feeding principle can be applied to accomplish stable micro feeding (<100mg/s) and describes a gravimetric powder feeding system with a vibratory sieve mounted on a chute. Feeding was induced via vertical vibrations that can be adjusted within a broad range of frequencies and amplitudes. The feeding system was studied using different frequencies, amplitudes, sieves and powder properties. Feeding was characterized by means of a dynamic scale and high-speed camera recordings. The feeding system provided effective powder feeding even in a range of 1–2mg/s. It was shown that powder properties require special attention when the vibratory sieve-chute system operates at higher feed rates (or feeding times >30min), i.e., feeding at a higher throughput.A combination of discrete element method (DEM) simulations and compartment population balance model (PBM) was used to incorporate the proposed micro feed system into a continuous powder mixer (Gerike GCM250; Gerike Holding LTD., Regensdorf, Switzerland). It illustrates how oscillating feeding rates (the latter is a characteristic of the studied micro feeding system) affect the content uniformity of low dose blends, i.e., powder mixtures with a relatively low fraction of active pharmaceutical ingredient.

Effects of powder flow properties and shear environment on the performance of continuous mixing of pharmaceutical powders

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. The Gericke mixer was found to be a poor micro-mixer/de-lumper, whereas the Comil was found to be a good micro-mixer and poor macro-mixer. Integrated system with Comil first provided the best possible mixing performance. • Residence time was primarily affected by bulk density and impeller speed. • Axial dispersion was primarily affected by cohesion and impeller speed. • High-shear before low-shear mixing exhibited an optimal continuous mixing strategy.

Development of a methodology to estimate error in the on-line measurements of blend uniformity in a continuous powder mixing process

Abstract In this paper, a multi-point fiber optic based NIR system was implemented to monitor API concentration at the discharge of a continuous mixer. The sample size being interrogated by NIR was determined by measuring the velocity of the powder on the chute, which allowed selection of the number of scans to be averaged. A methodology was developed that allows quantification of the error associated with the in-line measurements. Comparison of in-line and off-line measurements was made at equivalent sample sizes. Mathematical model fitting for the in-line as well as off-line data revealed that the contribution of the analytical method error was negligible. A baseline RSD of 0.02 in the in-line measurements persists because of the inherent non-uniform nature of powder material. These results are useful towards achieving Real-Time-Release (RTR) of continuously manufactured drug product.

Mathematical Development and Comparison of a Hybrid PBM-DEM Description of a Continuous Powder Mixing Process

This paper describes the development of a multidimensional population balance model (PBM) which can account for the dynamics of a continuous powder mixing/blending process. The PBM can incorporate the important design and process conditions and determine their effects on the various critical quality attributes (CQAs) accordingly. The important parameters considered in this study are blender dimensions and presence of noise in the inlet streams. The blender dynamics have been captured in terms of composition of the ingredients, (relative standard deviation) RSD, and (residence time distribution) RTD. PBM interacts with discrete element modeling (DEM) via one-way coupling which forms a basic framework for hybrid modeling. The results thus obtained have been compared against a full DEM simulation which is a more fundamental particle-level model that elucidates the dynamics of the mixing process. Results show good qualitative agreement which lends credence to the use of coupled PBM as an effective tool in control and optimization of mixing process due to its relatively fewer computational requirements compared to DEM.

Transitory powder flow dynamics during emptying of a continuous mixer

This article investigates the emptying process of a continuous powder mixer, from both experimental and modelling points of view. The apparatus used in this work is a pilot scale commercial mixer Gericke GCM500, for which a specific experimental protocol has been developed to determine the hold up in the mixer and the real outflow. We demonstrate that the dynamics of the process is governed by the rotational speed of the stirrer, as it fixes characteristic values of the hold-up weight, such as a threshold hold-up weight. This is integrated into a Markov chain matrix representation that can predict the evolution of the hold-up weight, as well as that of the outflow rate during emptying the mixer. Depending on the advancement of the process, the Markov chain must be considered as non-homogeneous. The comparison of model results with experimental data not used in the estimation procedure of the parameters contributes to validating the viability of this model. In particular, we report results obtained when emptying the mixer at variable rotational speed, through step changes.