Search

Pharmaceutical tablet quality is tightly controlled to ensure the patient’s safety. Though the tableting process is a well-known and accepted approach, process understanding is frequently built upon long-time experience of the operators. This is also true for the first step in tableting, the die filling where the powder is fed from the hopper through a force feeding system into the rotating dies of the turret. The current study considers a three-chambered force feeder of a FETTE 1200i, with the focus to evaluate the influence of the paddle wheel shape, which may either be of cylindrical or cuboid shaped blades, on tablet quality. A numerical approach utilizing the discrete element method allowed to compute the powder transfer in the tablet press which helps in identifying the optimal paddle wheel shape configuration. For instance, at a low turret – high paddle wheel speed, the cylindrical configuration revealed highest quality with respect to tablet mass, tablet mass variation, and content uniformity. In contrast, the cuboid configuration indicated better quality at a high turret – low paddle wheel speed. In addition, the detailed analysis of macroscopic and microscopic powder flow phenomena within the force feeder was performed which improves general process understanding in pharmaceutical development.

In the present work, the discrete element method (DEM) is used to investigate the behaviour of Rosin-Rammler (R-R) particle size distribution (PSD) during hopper discharge. The study attempts to identify mass flow rate (MFR) and segregation as a function of spread parameter (PSD width) and location parameter, which includes detailed analysis of bulk density, segregation and velocity profile of particles. The applicability of the widely used Beverloo correlation for prediction of MFR for studied R-R PSDs is also investigated. The results show that, (1) MFR increases as PSD width (at fixed location parameter) increases, whereas MFR decreases with increase in location parameter at fixed PSD width; (2) the studied R-R PSDs exhibit a monotonic trend of flow bulk density and MFR with respect to PSD width and location parameter; (3) the effect of PSD width on overall segregation is found to be more than the location parameter; (4) the velocity profiles for considered R-R PSDs vary along the height of hopper, but remain uniform in shape and follow a pure parabolic increase from the hopper wall; (5) DEM flow rate prediction shows a good agreement with the Beverloo correlation by applying the concept of flow bulk density.

The combined approach of quality by design (QbD) framework and discrete element method (DEM) is applied to force feeding process within the tableting machine to assess the influence of potential critical process conditions (CPPs) and critical material attributes (CMAs) on tablet quality. The numerical model considers the three paddled force feeder of a FETTE 1200i tableting machine. The influence of the selected potential CPPs: turret speed and paddle wheels speed and CMAs: API dose strength, inter-particle cohesion, and particle-wall friction on the critical quality attributes (CQAs) tablet mass, tablet mass variation, and content uniformity are evaluated by using a fractional-factorial screening design. In addition to the CQAs, the DEM provides the opportunity to shed light on the powder flow phenomena within the force feeder thus an understanding on the impact of the paddle wheels on powder over-lubrication and particle attrition is provided. Such a combined approach of QbD and DEM helps in identifying the significance of selected CPPs and CMAs and thereby to generate the design space providing an optimal tablet quality.

An Artificial Neural Network (ANN) was developed to predict the mass discharge rate from conical hoppers. By employing Discrete Element Method (DEM), numerically simulated flow rate data from different internal angles (20°–80°) hoppers were used to train the model. Multi-component particle systems (binary and ternary) were simulated and mass discharge rate was estimated by varying different parameters such as hopper internal angle, bulk density, mean diameter, coefficient of friction (particle-particle and particle-wall) and coefficient of restitution (particle-particle and particle-wall). The training of ANN was accomplished by feed forward back propagation algorithm. For validation of ANN model, the authors carried out 22 experimental tests on different mixtures (having different mean diameter) of spherical glass beads from different angle conical hoppers (60° and 80°). It was found that mass discharge rate predicted by the developed neural network model is in a good agreement with the experimental discharge rate. Percentage error predicted by ANN model was less than ±13%. Furthermore, the developed ANN model was also compared with existing correlations and showed a good agreement.

The optimization of operating conditions is vital for cell culture process development. In the present study, the pilot-scale single-use bioreactor XcellerexTM XDR-200, which is typically used in cell culture scale-up, is investigated. This unbaffled reactor is equipped with an off-centered, bottom mounted impeller, and has a maximum working volume of 200 L. The flow field for this sparsely investigated bioreactor configuration is studied with computational fluid dynamics. Moreover, numerical simulations of the mixing time and the volumetric oxygen mass transfer coefficient for seven different test conditions are validated against experimental data. Mixing times across all tested conditions are found to remain below 30 s, and the volumetric oxygen mass transfer coefficient is between 2.0 to 20.0 h−1, which is a typical range for animal cell culture processes. These values of the oxygen transfer coefficient are found for as low as 0.004 to 0.125 L L−1 min−1 sparging rates with the microporous sparger. The hydrodynamic stress remains below critical values for cell damage for all conditions investigated. Vortex formation is suppressed in the bioreactor even though it is unbaffled due to off-centered impeller. Across the test conditions, the highest investigated impeller speed of 200 rpm is the most favorable due to fast mixing and high oxygen transfer.

The die filing process within a lab-scale rotary tablet press is simulated using the Discrete Element Method (DEM). Powder is transferred from a gravity feeder (comprising of a cylindrical pipe, an inclined chute, and a rectangular box) into rotating dies. Spherical shape micro-crystalline cellulose particles serve as an experimental pendant to measure the particle size distribution (PSD) and to calibrate the micro-mechanical material properties entering in the DEM calculations. At first, the die filling process of the particles having poly-dispersity in size is explored by analyzing the basic metrics such as tablet mass, tablet mass variation, and mass flow rate. Particle size segregation is investigated by computing the PSD development in different locations of the feeding system and in the filled dies. In addition, particles’ velocity and coloring analysis (both qualitative and quantitative) are performed. Results show that different zones of the system are involved in various powder flow phenomena constituting varying particle size segregation causes. Next, the micro-mechanical properties, namely inter-particle cohesion, particle-particle and particle-wall friction, are varied one at a time to shed light on their influence on the particle size segregation and tablet quality. Finally, the influence of different material properties on various metrics are compared with each other providing a guide towards formulation optimization resulting in optimal tableting process performance.

The study presents the die filling process of pharmaceutical powders using high-speed camera imaging. The objectives are to qualitatively visualize and to quantify the powder flow. A model die filling system with a shoe for powder storage and a moving die underneath the shoe was designed. The die filling process is captured through a high-speed camera and the images allow flow type identification and flow rate calculation. Correlations are generated to predict the fill ratios and flow rates based on particle size data, which could help in process understanding and optimization of die filling.

The focus of this study is to establish a characterization method determining the powder flowability in context of tableting. At first, flowability of different materials is measured using the ring shear tester, and its prediction from particle size is established. Next, the model die-filling system is presented which is a modified version of previous studies. Using this system, flowability of different materials is measured at varying die speeds. A new curve fit to assess die fill ratio vs die speed is suggested improving predictability, and a novel flowability metric, "Die Fill Index" (DFI), is derived. The DFI is appropriate to describe flowability for most of the tested materials, and sensitivity of a material with respect to tableting speed. A correlation is generated predicting DFI from particle size. Additionally, it is shown that model die filling is the preferable method to assess flowability for tableting compared to ring shear tester.

Vibration is often utilized as a means of initiating and/or controlling flow from hopper in industries dealing with powder/granular materials such as packing, conveying, etc. The effect of horizontal vibration on gravity flow of granular material from conical hopper is modeled using the discrete element method. Material considered in this study includes glass beads of diameter ranging between 0.7 mm and 2.0 mm. The flow dynamics and segregation of material are analyzed for different mixtures characterized based on mass percentage of smaller particles (fines) and multi-component mixtures (binary and ternary) at different vibration parameters. The study includes the influence of vibration frequency, acceleration amplitude, fines percentage, diameter ratio and mixture components on segregation and mass flow rate during vibratory hopper discharge. The extent of segregation is calculated by means of mass fraction of fines inside hopper for different operating conditions. The numerical results indicate that the increase in vibration acceleration at a fixed frequency results into increased mass flow rate and there exists acceleration amplitude beyond which segregation is predominant. Mixture components play significant role in segregation behaviour and binary mixture suffers more segregation as compared to ternary mixture. The spatial distribution of the velocity profile indicates that different mixtures behave differently at a particular vibration conditions. The phenomena like sieving or percolation are also observed based on the analysis of top view simulation snap shots.

The die filling process within a lab-scale rotary tablet press is simulated using the Discrete Element Method (DEM). The particle motion is captured as particles travel from the gravity feeder consisting of a chute connected to the shoe represented by a rectangular box to the dies/cavities of the turret. The particles fill the dies mostly due to gravity. The process conditions such as die table speed, die diameter as well as the material characteristics e.g. cohesion, coefficient of friction, coefficient of restitution, etc. influence the die filling process. The process conditions and material characteristics are systematically investigated by varying one of those parameters at a time while keeping other conditions constant. Eventually process conditions as well as material properties were changed simultaneously to analyze interaction relationships. The results give both qualitative (powder flow pattern from the feeder to the dies) and quantitative (tablet mass variation, mass flow rate etc.) insights into the die filling process. The numerical results indicate that faster die table speeds and smaller die diameters give rise to lower tablet mass with a significantly increased mass variation, which would eventually increase the challenges in meeting the specifications. On the other hand, cohesion between the particles significantly reduces the tablet mass and increases the mass variation. The influence of particle-wall friction coefficient on the particle rearrangement is analyzed both qualitatively and quantitatively, which shows that increasing the particle-wall friction reduces the dead zones within the shoe. The coefficient of restitution does not exhibit any influence on the die filling which may be attributed to the very confined space of the feeding system. Eventually this study emphasizes the importance of tablet blend characterization prior to tableting and provides operators with optimal process parameters and material attributes to ensure a high tableting process performance.

This paper presents a combined experimental and numerical study of the evaporation and solid layer formation of single bi-component mannitol–water droplets in hot air. Experimentally, the process of droplet evaporation and drying is studied in a custom-built acoustic levitator. The experimental results are compared with numerical simulations of spherically symmetric bi-component droplets in an unsteady, one-dimensional configuration. The model includes evaporation and solid layer formation. This approach enables the comparison of the temporal variation of the droplet size and the porosity, which are related to the final particle sizes. The study is performed for various drying conditions and initial droplet sizes as well as compositions of the droplets. The objective of this paper is the derivation and validation of a suitable model to predict the properties of spray-dried mannitol particles, depending on their drying conditions. A design of experiments (DoE) is used to define suitable drying conditions and to analyze the results. The study includes initial droplet diameters varying from 350 μm to 550 μm and initial mannitol mass fractions in water droplets ranging from 5% to 15%. The surrounding air temperature is varied from 80 °C to 120 °C. Additionally, different relative humidity of the surrounding air between 1% and 7.5% is studied. Based on the DoE, correlations for results from both experiments and simulations including the temporal evolution of the droplet surface area and the final particle size are derived and discussed. Major influences are identified that dominate particle drying characteristics.

The effect of process parameters on the droplet drying process, which is crucial for tailor-made particle designs in spray drying processes, was investigated. Because of the challenging observability in spray towers single droplet experiments were carried out using acoustic levitation. The influence of the air humidity on the particle and solid layer formation of single mannitol-water droplets and temperature profiles of the complete drying process were experimentally determined. Also, the influence of the air humidity on the solid layer formation and the droplet temperature evolution was investigated.

The effect of particle size enlargement and blender geometry down-scaling on the blend uniformity (BU) was evaluated by Discrete Element Method (DEM) to predict the blending performance of a binary granular mixture. Three 10 kg blending experiments differentiated by the physical properties specifically particle size were performed as reference for DEM simulations. The segregation behavior observed during the diffusion blending was common for all blends, while the sample BU, i.e., standard deviation of active ingredient content % was different among the three blends reflecting segregation due to the particle size differences between the components. Quantitative prediction of the sample BU probability density distribution in reality based on the DEM simulation results was successfully demonstrated. The average root mean square error normalized by the mean of the mean sample BU in the blends was 0.228. Beside the ratio of blender container to particle size, total number of particles in the blender and the number of particles in a sample were confirmed critical for the blending performance. These in-silico experiments through DEM simulations would help in setting a design space with respect to the particle size and in a broader sense with respect to the physical properties in general.

A mathematical model to describe the evaporation and drying behavior of a single quiescent spherical bi-component droplet containing evaporating liquid and dissolved solid substance is developed with primary focus on the application of this model to study the evaporation and drying of a droplet of polymer (Polyvinylpyrrolidone – PVP) in water and Mannitol in water. The water evaporation rate is computed using a convective two-film model with modifications to account for solid layer formation. The non-ideality effect induced by the presence of PVP or Mannitol on vapor pressure of water is accounted through the calculation of activity coefficient of water in either system. The problem under consideration is governed by the continuity (diffusion) and energy equations, which are solved using a finite difference method. The effect of drying conditions such as gas velocity, temperature, and relative humidity on evaporation and drying rate is studied. It is concluded that the present model effectively captures the initial stages of single droplet drying.

The study concerns the modeling and simulation of gas-droplet and droplet-droplet interactions on spray dynamics and droplet size distribution in turbulent spray flows where the spray is described in an Eulerian framework. The primary focus is to develop a suitable mathematical model that can describe the underlying physics including the polydispersion of the spray, evaporation, drag, coalescence, and interaction with the convective gas flow. This is achieved by applying the direct quadrature method of moments, which is extended to account for evaporation, drag force and coalescence by implementing well-established standard models available in literature. The model is developed and formulated in three-dimensional physical space, whereas the computations are carried out in a one-dimensional geometric configuration since the reference experimental setup is only one-dimensional. A water spray carried by nitrogen was injected through a hollow cone nozzle into a cylindrical spray chamber. The results reveal that evaporation and coalescence have a significant effect on the droplet size distribution whereas the droplet velocity is influenced by drag force as anticipated. Computational and experimental results agree very well when coalescence is considered.

This contribution concerns the development of an integral model to describe spray drying processes, including droplet interactions, evaporation, and particle formation. Spray modeling requires the knowledge of single-droplet evaporation and drying, which constitutes the first part of this chapter, and then sprays are considered. Single-droplet drying in hot air below and above the boiling temperature is modeled, where the latter may lead to particle expansion and rupture and healing of the particle crust. For single droplets of mannitol and polyvinylpyrrolidone (PVP) solutions in water, the final particle characteristics are computed for different drying conditions such as the initial droplet diameter and initial solute mass fraction, and for the drying temperature and the air humidity. For mannitol-water droplets, the normalized surface reduction rate during the water evaporation appears to be mainly dependent on the initial droplet diameter and the drying temperature, whereas the final particle size depends on all studied parameters as well as on their correlations. Furthermore, an integral model for spray evaporation and interaction is presented. The spray process is modeled using Williams’ spray equation, which is solved with the direct quadrature method of moments (DQMOM). The spray and the gas strongly interact, and the equations for the liquid and the gas phase are coupled. The commonly used spray equation and the DQMOM formulation are extended to account for the variation of the droplet temperature. The numerical results with the new models are compared with the discrete droplet model (DDM) and with experimental data from G. Brenn, TU Graz, Austria. Both models show very good agreement with the experimental data, where the DQMOM method tops the DDM in terms of computational efficiency.

Dry powder inhalation as commonly used in the local therapy of asthma or chronic obstructive pulmonary disease (COPD) is a very effective route of drug delivery. The system of small cohesive drug particles attached to the surface of large carriers with particle sizes >50 μm is successfully applied to numerous marketed products. The performance of these blends is based on the particle properties of both carriers and drug particles and is usually linked to the Fine Particle Fraction (FPF), which represents the fraction of drug particles with an aerodynamic diameter of 1–5 μm, which triggers the desired effect in the lung. Mannitol, which was chosen as an alternative carrier to the market-leading α-lactose monohydrate as it is highly crystalline in contrast to lactose even after spray drying, was prepared by spray drying to generate carrier particles at a range of 50–90 μm with various morphologies. This project was first aiming at the examination of the drying kinetics of bicomponent mannitol water droplets. It could be shown that high drying temperatures cause deep indentations and increasingly rough surface structures, while low drying temperatures result in spherical particles with rough surfaces at very low drying temperatures and smoother ones when increasing temperatures. Low rotation speeds and high mass fractions increase the particle size. Further particle properties like porosity, breaking strength or flowability were related accordingly. A defined set of mannitol batches was further selected for interactive powder blends with a micronised and spray dried quality of the model drug SBS. Particle–particle interactions were then investigated by correlating carrier properties to the resulting FPF. Particle shape was found to hinder the detachment of drug particles. Rough structures dried at the lowest drying temperatures were preferred for micronised drug particles, whereas spherical drug particles were preferably detached from smoother surfaces. This effect could be related to the drug size as only the detachment of the smallest drug particles (

This paper presents a combined experimental and numerical study of the evaporation and solid layer formation of a single bi-component mannitol-water droplet in air. For spherically symmetric droplets, the problem is described mathematically by the unsteady, one-dimensional conservation equations of mass and energy. The effect of the formation of a solid layer at the droplet surface on the droplet evaporation and thermal diffusion rate is included in the present approach. The simulations are validated by comparison with experiments using acoustically levitated droplets. The study includes initial droplet diameters varying from 350 to 450 μm, gas temperatures ranging from 80 to 120 °C, and the initial mannitol mass fraction inside the droplet varies from 0.05 to 0.15. The numerical results are analyzed to identify the occurrence of solid layer formation, and the temporal evolutions of both the droplet size and mass are presented. A parameter study of the initial gas temperature, the initial droplet size, and the initial mannitol mass fraction inside the droplet on droplet evaporation and solid layer formation is presented. The present model accurately captures the initial stages of droplet drying under all conditions investigated.Copyright © 2014 by ASME