Inter-tablet coating variability: Tablet residence time variability

This paper investigates inter-tablet coating variability, specifically, the variability of tablet residence times within the spray zone of a horizontal coating pan. Results from experiments, discrete element method (DEM) computer simulations, and an analytical model developed to describe the coating mass distribution are presented.The simulations indicate that the coefficient of variation of tablet residence times, and subsequently, of coating mass, decreases with time following a power law relation. The theoretical model demonstrates that the coefficient of variation of residence time for a randomly mixed tablet bed is inversely proportional to the square root of the number of coating “trials”. DEM simulations show that during each pan revolution, tablets in the spray zone remain in a quasi-segregated state from tablets located outside the spray zone for some time period termed Δt_seg. Increasing the pan's Froude number, the spray zone aspect ratio, and the tablet-tablet and tablet-pan friction coefficient all act to decrease Δt_seg, leading to more uniform residence times and less inter-tablet coating variability for a given operating time. The relationship between Δt_seg and tablet load is more complex due changes in bed dynamics. In addition to the variability studies, a model is developed that relates coating fraction, effective mass flow rate, Δt_seg, and the desired coating mass to the allowable fraction of tablets with a coating mass lying outside of a specified range of coating masses.     

Intra-particle coating variability: Analysis and Monte-Carlo simulations

An analytical model is presented that describes the intra-particle coating variability of a single particle by a uniform spray. For uniformly random orientations, the film thickness coefficient of variation is proportional to the number of coating trials raised to the ?1/2 power, and thus the coefficient of variation asymptotes to zero as the number of coating trials increases. However, if the particle has a preferred orientation while in the spray zone, the limiting value of the coefficient of variation is non-zero. Monte-Carlo simulations of a single particle subject to a coating spray are also presented and verify the theoretical model. Finally, analysis of discrete element method (DEM) computer simulations of spheres in a rotating, circular drum without baffles show that a sphere passing through the “spray zone” has an orientation corresponding to a preferred rotation from the sphere's orientation during its last past through the spray zone. Although the intra-particle coefficient of variation for orientations exhibiting this effect still asymptote to zero over time, the rate at which this occurs is smaller than that for uniformly random orientations.     

Study of tablet-coating parameters for a pan coater through video imaging and Monte Carlo simulation

The movement of tablets in a pan coater and the exposure of different surfaces of tablets for deposition of coatings by spray-coating have been studied by video imaging and Monte Carlo simulation techniques. A representative variety of tablets of different shapes and sizes were used at different pan loads and at various pan speeds. A single “tracer” tablet was used to track the motion of tablets and coating variables such as circulation time, surface time, projected surface area and surface velocity of a tablet were determined from the video imaging experiments. The coating uniformity is described in terms of the coating variation from tablet to tablet CV(tt) and a new parameter CV(st) the coating variation on a single tablet. The effect of shape of tablets on coating uniformity was analyzed by introducing a “sphericity” of tablet (φ_s) into the CV models. The methodology, new models and the analysis developed here incorporating the additional parameters will help users to optimize the coating process in pan-coating operations.     

Inter-tablet coating variability: Residence times in a horizontal pan coater

This paper investigates inter-tablet coating variability, specifically, tablet residence times within the spray zone. Discrete element method computer simulations, experiments, and analytical investigations are performed to measure the residence time per pass, the circulation time, and appearance frequency of spherical shaped tablets for a range of pan speeds and tablet loads. In addition, the fractional residence time, defined as the ratio of time spent by a tablet in the spray zone to the total coating time, is measured. The average fractional residence time (averaged over all the tablets in the bed) is found to be equal to the ratio of the time-averaged number of tablets exposed to the spray to the total number of tablets in the pan, a result that is consistent with analyses. The average fractional residence time is observed to be independent of pan speed and total coating time. Furthermore, the fractional residence time is shown to be related to the residence time per pass and circulation time per pass. Appearance frequency is defined as the number of appearances a tablet makes in the spray zone per pan rotation. Simulations and analyses show that appearance frequency decreases with increasing pan speed. Circulation time per pass for a tablet is defined as the average time between successive appearances in the spray zone and residence time per pass is defined as the average time spent in the spray zone per pass. These various measures are all related, but from the standpoint of developing an analytical model for coating variability, fractional residence time is a more useful and intuitive parameter as it determines the fraction of total run time that a tablet spends in the spray. This paper concentrates on determining average fractional residence times and residence time per pass, while the inter-tablet variability is more closely related to the standard deviation of the fractional residence time.     

DEM simulation of continuous tablet coating: Effects of tablet shape and fill level on inter-tablet coating variability

Tablet coating is a common pharmaceutical technique of applying a thin polymer-based film to a tablet or a granule containing active pharmaceutical ingredients (APIs). Inter- and intra-tablet variability of film coating is a critical issue in the production of solid oral dosage forms. In fact, inhomogeneity in the coating thickness can lead to significant variations in the delivery rate of active pharmaceutical ingredients and compromise the functional attributes of the tablet film. Although attempts have been made to use numerical approaches to analyze this complex problem, at present the uniformity of coating thickness is difficult to predict without expensive experimental work.The aim of this work is to analyze and understand the effects of tablet form and fill volume on the intra-tablet coating variability in a semi-continuous coating device. To this end, the Discrete Element Method was used to numerically reproduce the tablet motion inside a chamber of the coating pan. First, the material attributes of a sample placebo tablet were experimentally quantified in detail. Thereafter, three different tablet shapes, namely bi-convex, oval, and round, were modeled by means of the “glued spheres” method. The effect of three different fill volumes was then analyzed in terms of RT of the tablets under the coating spray, leading to a quantification of the intra-tablet coating variability for each particle shape. A detailed analysis of the tablets' velocities, both translational and rotational, on top of the tablet bed is presented. These results help to understand the dynamical behavior of the tablets under a spray gun that is essential for a satisfactory intra-tablet coating homogeneity. Finally, the various behaviors observed during the numerical simulations were addressed through a detailed analysis of the tablets' flow on the bed in terms of mean velocities and granular temperatures. The aim of this work is to demonstrate how a numerical simulation may be used for the development and design of continuous pharmaceutical tablet coating processes.     

Local analysis of the tablet coating process: Impact of operation conditions on film quality

Spray coating is frequently used in the pharmaceutical industry to control the release of the active pharmaceutical ingredient of a tablet or to mask its taste. The uniformity of the coating is of significant importance, as the coating usually has critical functional properties. However, coating uniformity is difficult to predict without significant experimental work, and even advanced particle simulations need to be augmented by CFD models to fully describe the coating uniformity on a single tablet.In this study we analyze the coating process by using detailed computational fluid dynamics (CFD) multiphase spray simulations. The impact and the deposition of droplets on tablets with different shape, as well as the production and evolution of the liquid film on the surface of the tablets are numerically modeled. Spray droplets are simulated with a Discrete Droplets Method (DDM) Euler–Lagrange approach. Models for multi-component evaporation and particle/wall interaction are taken into account. The wall film is treated with a two-dimensional model incorporating submodels for interfacial shear force, film evaporation and heat transfer between film, solid wall and gas phase. Our simulations show how different physical parameters of the coating spray affect the coating process on a single tablet. For example, we analyze for the first time the deposition behavior of the droplets on the tablet. The outcome of our work provides a deeper understanding of the local interaction between the spray and the tablet bed, allowing a step forward in the design, scale-up, optimization and operation of industrial coating devices. Furthermore, it may serve as a basis for the combination with state-of-the-art DEM particle simulation tools.     

Effect of speed, loading and spray pattern on coating variability in a pan coater

A computational study using the discrete element method was performed to study the effect of pan speed, fill level and the design of the spray pattern on the coating variability of tablets coated in a rotating pan. The method simulates the movement of tablets in the pan and calculates the residence time of each tablet inside the spray zone, which is directly related to the amount of coating received by the tablet. The computational method was experimentally validated using a Laser Induced Breakdown Spectroscopy based analytical method. The simulations showed that the axial mixing was the most critical parameter affecting the coating variability. Although axial mixing was found to be better at higher pan speed, it did not affect the coating variability significantly. Lower variability was obtained when a 100% fill level was used as compared to 67% fill. Four spray patterns were used, two idealized (full surface spray and a symmetric band spray) and two realistic (5-ellipse and 5-circular spray guns). The full and band spray showed similar results while the ellipse and circular patterns were similar to each other (and much worse than the other two patterns) at all speeds and fill levels.     

Scaling inter‐tablet coating variability in a horizontal rotating drum

This study investigates how the drum‐to‐particle diameter ratio (D/d) affects the surface speed and interparticle coating variability in geometrically similar coaters. Discrete element method simulations were used to model particle movement in different‐sized, cylindrical drums with identical particle diameters, Froude numbers, fill volume fractions, and spray characteristics. The dimensionless streamwise surface speed profiles become increasingly symmetric as D/d increases, with the maximum speed increasing with D/d. The relationship between the maximum dimensionless speed and D/d is fit well with a power‐law expression. Interparticle coating variability decreases with the square root of the number of drum revolutions after a sufficiently large number of drum revolutions. Increasing D/d increases, in a logarithmic manner, the number of drum revolutions required to reach a given degree of coating variability. A similar logarithmic coating variability trend was observed in simulations using almond‐shaped pharmaceutical tablets, suggesting that the trend is independent of tablet shape. © 2017 American Institute of Chemical Engineers AIChE J, 63: 3743–3755, 2017     

Monte Carlo simulations to determine coating uniformity in a Wurster fluidized bed coating process

This paper presents a coating model to predict the mass coating uniformity in a Wurster fluid bed coater using a Monte Carlo method. The velocity and voidage data obtained using imaging techniques on the same Wurster coater are used as inputs to the model. The semi-circular Wurster fluid bed used in this work was 22.9 cm in diameter. A batch of 3.6 kg tablets was used to conduct coating experiments and the coating weight gain distribution results were compared to predictions from the simulation. The model rigorously considers the sheltering effect of particles as they move in the spray zone. Good agreement was obtained when comparing the results with an analytical model.Spray shape and orientation of discretization were found to play an important role in predicting the coating uniformity. A simple spray experiment in a particle-free bed showed that the direction of spray material, in general, was vertically upward. Simulation results confirmed that an upward cylindrical spray model gives better agreement with experimental results compared to a solid cone spray model. Finally, the model was used to predict the changes in coating uniformity with bed operating conditions such as gas velocity and gap height. A wider coating distribution was found for the case with the lower gas velocity and gap height.     

颗粒形状对包衣设备内药片颗粒运动特性影响的数值模拟

为研究颗粒形状对包衣设备内药片颗粒运动特性的影响,基于离散单元法及自行编写的喷雾区颗粒检测算法,采用数值模拟的方法对五种不同形状(棒状、长椭球、扁椭球、双凸形和球形)的药片颗粒在包衣设备内的运动行为规律进行了研究。分析了颗粒形状对颗粒系统的能量、床面颗粒平动速度、颗粒温度及颗粒流在喷雾区域停留时间的分布及其相对标准差的影响。结果表明,颗粒形状对颗粒的平均动能、颗粒床面速度、颗粒温度、喷雾区域停留时间分布及颗粒间包衣均匀性有重要影响。除双凸形颗粒系统外,对于其他四种形状的颗粒系统,随着颗粒球形度增大,颗粒系统具有的动能、床面速度和颗粒温度均呈减小趋势。除棒状颗粒系统外,对于其余四种形状的颗粒系统,随着颗粒球形度增大,颗粒系统在包衣喷雾区域内平均停留时间减小,平均停留时间的相对标准差增大,包衣均匀性变差。与球形颗粒系统相比,非球形颗粒系统的包衣均匀性更好;药片颗粒形状对包衣设备内颗粒运动特性及颗粒之间的包衣均匀性有重要影响。     

Modelling of pharmaceutical tablet swelling and dissolution using discrete element method

This work presents a novel use of the Discrete Element Method (DEM) combined with inter-particle mass transfer in order to simulate polymer swelling and dissolution. Each particle can absorb water and swell, pushing on its neighbours and causing an overall expansion. Once the disentanglement threshold is reached, the polymer dissolves and the particle reduces in size. This paper applies DEM to simulate the radial swelling and dissolution of cylindrical tablets. The method was validated against exact numerical solution of the same system to assess the accuracy of the DEM simulations for different DEM particle sizes. Parametric studies were done to assess the impact of physical parameters – namely the concentration-dependent diffusion coefficient of water through the polymer, the dissolution rate constant of the polymer and the disentanglement threshold of the polymer – on the radial expansion of the tablet. It was found that different settings of the concentration-dependent water diffusion coefficient function could produce similar radial expansion curves but with different internal concentration profiles. Increasing the dissolution rate constant or decreasing the disentanglement threshold of the polymer caused a reduction in the maximum radius of tablet. Lastly, ATR-FTIR spectroscopic imaging was used to obtain chemical images of a pure hydroxy-propyl methylcellulose (HPMC) tablet swelling and dissolving. The model was optimised to match both the HPMC tablet radius and the concentration profiles over time.     

Ibuprofen release from porous hydroxyapatite tablets

The present study investigated drug release profiles from porous hydroxyapatite [Ca₅(PO₄)₃OH, HAP] tablets. HAP tablets prepared synthetically and porous structure was generated via microemulsion after sintering at 700 °C. The influence of tablet's microemulsion concentration on drug release profiles from sintered porous tablets was investigated by using ibuprofen (C₁₃H₁₈O₂) as model drug.A numerical approach based on Fick's second diffusion law was used to investigate drug release kinetics from porous HAP tablets. Via this equation, diffusion coefficients were calculated for each tablet and compared. Drug release from the tablets was influenced by the porosity and tortuosity of the porous network. The drug release from porous HAP tablets was increased by microemulsion concentration. It is possible to obtain HAP based drug delivery system which has different drug release behavior by controlling microemulsion concentration in tablets before sintering.     

In situ, near real-time acquisition of particle motion in rotating pan coating equipment using imaging techniques

The uniformity of coating applied to large particles and tablets in rotating-drum coating devices is of significant interest to the Pharmaceutical Industry, especially when the coating contains active material or provides a sustained release barrier for drug transport in a functional coat. The purpose of this research was to quantify parameters that characterize the movement of tablets through the region where they receive maximum coating. The three parameters of greatest interest are (1) circulation time (τ_circ), (2) surface exposure time (τ_surf) and (3) surface area of the tablet projected toward the spray source (nozzle) during each pass through the spray zone (A_tab). In order to measure these parameters, a digital imaging system was developed and implemented to analyze images of the surface of the tumbling tablet bed in near real-time.The drum rotation rate was varied between 6 and 12 rpm, at two different drum fills of 1/8 and 1/4. Three tablet sizes, 6.3, 7.9 and 10.4 mm, were used. The circulation time was found to vary from 2.9 to 15.5 s and the surface time from 0.06 to 0.2 s. Decreasing trends for circulation and surface times were observed with increasing drum speeds, drum loadings, and tablet size. A_tab and surface velocities were also estimated for the movement of tablets through the spray zone in the rotating drum. The axial dispersion coefficient was estimated from random walk theory. It was found to lie in the range of 0.2×10^-3- for the conditions studied and was found to increase with increasing drum speed.     

Understanding granular mixing to enhance coating performance in a pan coater: Experiments and simulations

The knowledge of the particle flow and mixing in a pan coater is critical to optimize the design and operation of coating equipment. Mixing is an important but poorly understood aspect of coating of pharmaceutical dosage forms (tablets). Our study focuses on the fundamental mechanisms of granular flow and mixing and their relationship to the coating performance. A quantitative method is developed and validated to characterize the mixing process throughout the mixing vessel. This method is used to establish a baseline determination of mixing homogeneity as a function of various mixing conditions. White and red non-pareils of 5–6 mesh size are loaded in the ellipsoid pan coater to check the effect of initial loading (side–side and front–back), fill level, orientation of the vessel and the vessel speed on granular mixing. Video-imaging and discrete-pocket samplers are used to quantify mixing and to finally estimate the optimal operating conditions. DEM (Discrete Element Method) based numerical model was also developed to study the effect of granular mixing in a pan coater. When the axis of rotation of the mixer is horizontal (no tilt), slower axial dispersion is observed in both the experiments and simulations, than the radial convection. However, tilt enhances axial mixing, and faster axial mixing is seen for higher tilt angles from the horizontal. The speed of the rotating vessel has a nominal effect on the rate of mixing in a coating pan, as observed from the experimental and simulation studies. Moreover, fill level has no significant effect on the rate of mixing. Coating experiments are performed in the pan coater where white non-pareils being coated by spraying Opadry II solution. DEM simulation of coating is performed with post processing particle dynamics data. The effects of various operational and spray parameters are determined on the coating performance. Optimal coating performance is attained at an optimal mixing condition.     

Matched asymptotic solutions of the coalescence-redispersion model for unmixed feed stream plug flow reactors

Matched asymptotic expansions are given for the first moments of the concentration distribution function of Curl's coalescence-redispersion population balance model when mixing is faster than reaction. The physical situation considered is an unmixed feed stream tubular reactor with a plug flow residence time distribution in which the single reaction A + nB → P occurs. The asymptotic expansions lead to analytical expressions for species conversion in such reactors and thus obviate the need for numerically tedious Monte Carlo simulations. It is also demonstrated that the perturbation technique applies in a straightforward manner to situations with competing reactions and that the analytical calculations compare favourably with Monte Carlo simulations.     

Investigating the effect of shape on particle segregation using a Monte Carlo simulation

A Monte Carlo simulation has been used to investigate the segregation potential of a range of particulate systems under conditions in which the particles undergo high amplitude low frequency shaking. These systems involve a wide range of binary powder mixtures in which complex particle shapes have been investigated, including plates and rods which represent the real world materials encountered in pharmaceutical systems such as those which include crystalline components. Previous simulations on the segregation propensity of systems with different shapes were limited to spheres and spherocylinders, with relatively low vibrational amplitude drops. A commercial computer application for particle packing—called MacroPac—has been successfully employed here, as it has been able to model systems that are more complex where the shape variation is much wider. These simulations apply to the case of macroscopic particles, in the absence of air resistance and inter-particle forces. For non-spherical shapes, an ‘effective size’ which relates to the radius of gyration of the particles is determined. Our studies indicate that with high amplitude low frequency shaking, in a mixture of particles with different shapes but with equal volumes, the particles with the larger ‘effective size’, which tend to have a lower packing fraction, segregate to the top.     

Contact detection algorithms for DEM simulations of tablet-shaped particles

The shape of standard round tablet was represented by using the intersection of three spherical surfaces. Using this model, the contact criteria for tablet-flat surface and tablet-tablet contact were developed and were applied for tablet-tablet contact using a DEM simulation implemented in Matlab™ code. In addition, a high-speed digital imaging system was used to capture the images of one tablet hitting another fixed tablet anchored to a flat surface. Comparison of angular velocity showed good agreement between simulation and experimental results. The simulations were compared with alternative multi-sphere representations for the shape of the tablet and the results showed that the simulation times for 66- and 178-sphere representations were much larger than that for the tablet simulations. In addition, the simulation results for all the multi-sphere representations were significantly different from those of the tablet simulation.