Tablet Shapes Research Articles

Development of Mathematical Function Control-Based 3D Printed Tablets and Effect on Drug Release.

The application of 3D printing technology in drug delivery is often limited by the challenges of achieving precise control over drug release profiles. The goal of this study was to apply surface equations to construct 3D printed tablet models, adjust the functional parameters to obtain multiple tablet models and to correlate the model parameters with the in vitro drug release behavior. This study reports the development of 3D-printed tablets using surface geometries controlled by mathematical functions to modulate drug release. Utilizing fused deposition modeling (FDM) coupled with hot-melt extrusion (HME) technology, personalized drug delivery systems were produced using thermoplastic polymers. Different tablet shapes (T1-T5) were produced by varying the depth of the parabolic surface (b = 4, 2, 0, -2, -4mm) to assess the impact of surface curvature on drug dissolution. The T5 formulation, with the greatest surface curvature, demonstrated the fastest drug release, achieving complete release within 4h. In contrast, T1 and T2 tablets exhibited a slower release over approximately 6h. The correlation between surface area and drug release rate was confirmed, supporting the predictions of the Noyes-Whitney equation. Differential Scanning Calorimetry (DSC) and Scanning Electron Microscope (SEM) analyses verified the uniform dispersion of acetaminophen and the consistency of the internal structures, respectively. The precise control of tablet surface geometry effectively tailored drug release profiles, enhancing patient compliance and treatment efficacy. This novel approach offers significant advancements in personalized medicine by providing a highly reproducible and adaptable platform for optimizing drug delivery.

Prediction of the finished tablet coating variability in pan coaters by coupling CFD-DEM and Monte Carlo simulations: Method development and validation

We present a numerical approach to predict the long-term coating variability of tablets in pan coaters by combining coupled computational fluid dynamics-discrete element method (CFD-DEM) simulations with a Monte-Carlo method. In CFD-DEM simulations, the coater geometry, operating conditions, air flow and exact tablet shapes are directly simulated to obtain statistical distributions of tablet coating mass gain and circulation time through the spray zone. These short-term distributions (∼102 s) serve as input to a Monte Carlo (MC) method to efficiently predict the coefficient of variation in pan coaters for timescales relevant to commercial manufacture (∼104 s). These predictions achieved reasonable agreement with experimental coating thickness measurements via both the manual gauge and optical coherence tomography (OCT) from coating trials on L.B. Bohle film coaters at different scales. This method enables the application of digital tools as efficient alternatives to resource-intensive experimental trials in determining the appropriate coating process parameters.

Heat transfer studies in a rotating drum containing non-spherical particles

In chemical and pharmaceutical industries, rotating drums are commonly used as mixers, dryers, granulators, and reactors for processing particulate materials (Rutgers, 1965). Most of the earlier studies are limited to the spherical particles and have focused on understanding granular flow in drums operating under a rolling regime. However, there are numerous industrial operations in which non-spherical particles are heated in a rotating drum operating in the cascading regime. In the present work, we attempt to understand the heat transfer process between hot air and non-spherical particles in a rotating drum. Non-spherical particles, considered for the simulations, mimic pharmaceutical tablets having standard round convex (SRC) and oblong shapes. The multi-sphere approach is used to model the tablet shapes. Collisions between the tablets are captured through the interaction between candidate spheres of non-spherical particles. The focus here is to study the heat transfer between hot air and particles and the heat conduction between the particles. The effects of drum speed, particle shape, and air inlet temperature on the bed temperature distribution are investigated. Analysis of average bed temperature profiles shows that the bed temperature remains constant regardless of the drum speed but is influenced by the temperature of the incoming air. The logarithmic mean temperature is not impacted by the incoming air temperature but is influenced by particle shape. The logarithmic mean curve shows a steeper slope for SRC particles due to higher surface area-to-volume ratio and better radial mixing compared to Oblong particles

A validation of discrete-element model simulations for predicting tablet coating variability

Achieving an even coating distribution on tablets during the coating process can be challenging, not to mention the challenges of accurately measuring and quantifying inter-tablet coating variability. Computer simulations using the Discrete Element Method (DEM) provide a viable pathway towards model-predictive design of coating processes. The purpose of this study was to assess their predictivity accounting for both experimental and simulation input uncertainties. To this end, a comprehensive set of coating experiments covering various process scales, process conditions and tablet shapes were conducted. A water-soluble formulation was developed to enable rapid spectroscopic UV/VIS analysis of coating amounts on a large number of tablets. DEM predictions are found to lie within the experimentally inferred confidence intervals in all cases. A mean absolute comparison error of 0.54 % was found between model predictions of coating variability and respective sample point estimates. Among all simulation inputs the parameterization of spray area sizes is considered the most significant source for prediction errors. However, this error was found significantly smaller in magnitude compared to experimental uncertainties at larger process scales underlining the value of DEM in the design of industrial coating processes.

Tablet coating in lab-scale drum coaters: Combining DEM simulations and spray experiments to predict tablet coating

In pharmaceutical industry the coating of granulates or tablets is an essential production step, which is often realised in a rotating drum moving the tablet bed and a number of spray nozzles installed above this bed. The nozzles atomise the coating liquid through a high-velocity annular air-stream and apply steering air nozzles for producing an oval-shaped spray. The operational conditions determine the produced droplet size spectrum. The collision of the droplets with the solid particles or tablets in the drum and the resulting coating and film thickness strongly influences the product properties of granulates or tablets. In order to be able to predict the coating result, without running time-consuming lab-scale experiments, it is intended to numerically simulate the entire tablet coating process by combining Computational Fluid Dynamics (CFD), the Discrete Element Method (DEM) and the Lagrangian Parcel Concept (LPC) for simulating the spray propagation originating at the nozzle. For doing so, knowledge on the spray droplet properties produced by the two-fluid spray nozzles is indispensable. Therefore, it is necessary to characterise as a first step the local droplet size and velocity distributions in different spray cross-sections, which is the main focus of the present contribution. Such measurements are efficiently done by applying Phase Doppler Anemometry (PDA). It was found that the velocity of the spray emitted from the two-fluid nozzle exceeds almost 200 m/s and the number mean droplet diameter was well below 20 μm. In the initial spray region droplet break-up was observed whereas downstream of 50 mm a slight growth of the mean droplet size indicated further coalescence. Due to the applied pattern air, the spray flux distribution at the normally located tablet bed (i.e., 100–150 mm downstream the nozzle) has an oval shape and the mean droplet velocity still exceeds almost 50 m/s with a mean droplet diameter of about 10 μm. The cross-sectional measurements are used to provide proper inlet conditions for the spray simulations, while the other cross-sections are used for validating the computed spray expansion and dispersion. For demonstrating the effect of a real measured spray flux distribution on the tablet coating quality, additionally DEM simulations were conducted. Here, the measured spray flux data were mapped onto the temporarily evolving and moving tablet surface simulated for a lab-scale test drum by DEM. The uniformity of tablet coating (inter-tablet variability) was judged by calculating the Coefficient Of Variation (COV) for the considered different tablet shapes and operational conditions.

Influence of Solid Oral Dosage Form Characteristics on Swallowability, Visual Perception, and Handling in Older Adults.

Swallowability, visual perception, and any handling to be conducted prior to use are all influence factors on the acceptability of an oral dosage form by the patient. Knowing the dosage form preferences of older adults, as the major group of medication end users, is needed for patient-centric drug development. This study aimed at evaluating the ability of older adults to handle tablets as well as to assess the anticipated swallowability of tablets, capsules, and mini tablets based on visual perception. The randomized intervention study included 52 older adults (65 to 94 years) and 52 younger adults (19 to 36 years). Within the tested tablets, ranging from 125 mg up to 1000 mg in weight and being of different shapes, handling was not seen as the limiting factor for the decision on appropriate tablet size. However, the smallest sized tablets were rated worst. According to visual perception, the limit of acceptable tablet size was reached at around 250 mg for older adults. For younger adults, this limit was shifted to higher weights and was dependent on the tablet shape. Differences in anticipated swallowability with respect to tablet shapes were most pronounced for tablets of 500 mg and 750 mg in weight, independent of the age category. Capsules performed worse compared to tablets, while mini tablets appeared as a possible alternative dosage form to tablets of higher weight. Within the deglutition part of this study, swallowability capabilities of the same populations were assessed and have been reported previously. Comparing the present results with the swallowing capabilities of the same populations with respect to tablets, it shows adults' clear self-underestimation of their ability to swallow tablets independent of their age.

Impact of Tablet Size and Shape on the Swallowability in Older Adults.

Older adults represent the major target population for oral medications, due to the high prevalence of multimorbidity. To allow for successful pharmacological treatments, patients need to adhere to their medication and, thus, patient-centric drug products with a high level of acceptability by the end users are needed. However, knowledge on the appropriate size and shape of solid oral dosage forms, as the most commonly used dosage forms in older adults, is still scarce. A randomized intervention study was performed including 52 older adults (65 to 94 years) and 52 young adults (19 to 36 years). Each participant swallowed four coated placebo tablets differing in weight (250 to 1000 mg) and shape (oval, round, oblong) in a blinded manner on three study days. The choice of tablet dimensions allowed for a systematic comparison between different tablet sizes of the same shape, as well as between different tablet shapes. Swallowability was assessed using a questionnaire-based method. All tested tablets were swallowed by ≥80% of adults, independent of age. However, only the 250 mg oval tablet was classified as well swallowable by ≥80% of old participants. The same was true for young participants; however, they also considered the 250 mg round and the 500 mg oval tablet as well swallowable. Furthermore, swallowability was seen to influence the willingness to take a tablet on a daily basis, especially for an intake over longer time periods.

Hot-Melt Extrusion–Based Fused Deposition Modeling 3D Printing of Atorvastatin Calcium Tablets: Impact of Shape and Infill Density on Printability and Performance

The main objective of the current research was to investigate the effect of tablet shapes (heart-shaped and round tablets) and infill densities (50% and 100%) on the drug release profiles of 3D printed tablets prepared by hot-melt extrusion paired with fused deposition modeling techniques. Drug-loaded filaments of 1.5mm and 2.5mm diameters were extruded using a Process 11mm hot-melt extruder employing atorvastatin calcium as a model drug and Kollicoat® IR, Kollidon® VA64, Kollidon® 12PF, and Kolliphor® P407 as hydrophilic polymers. Filaments of Kollicoat® IR in combination with Kollidon® VA64/Kollidon® 12PF has resulted in successful printing of immediate release tablets. The mechanical properties of drug-loaded filaments were evaluated using a 3-point bend test and stiffness test. The transformation of a crystalline drug to an amorphous form and the absence of drug-polymer interactions were confirmed by differential scanning calorimetry and Fourier transform infrared spectroscopy, respectively. The effect of infill density on drug release profiles was greater than that of tablet shape. The stability of 3D printed tablets was preserved even after storage under accelerated conditions (40 ± 2°C and 75 ± 5% RH) for 6months. Thus, the 3D printing process of hot-melt extrusion paired with fused deposition modeling serves as an alternative manufacturing approach for developing patient-focused doses.

Fused Deposition Modeling as a Possible Approach for the Preparation of Orodispersible Tablets.

Additive manufacturing technologies are considered as a potential way to support individualized pharmacotherapy due to the possibility of the production of small batches of customized tablets characterized by complex structures. We designed five different shapes and analyzed the effect of the surface/mass ratio, the influence of excipients, and storage conditions on the disintegration time of tablets printed using the fused deposition modeling method. As model pharmaceutical active ingredients (APIs), we used paracetamol and domperidone, characterized by different thermal properties, classified into the various Biopharmaceutical Classification System groups. We found that the high surface/mass ratio of the designed tablet shapes together with the addition of mannitol and controlled humidity storage conditions turned out to be crucial for fast tablet’s disintegration. As a result, mean disintegration time was reduced from 5 min 46 s to 2 min 22 s, and from 11 min 43 s to 2 min 25 s for paracetamol- and domperidone-loaded tablets, respectively, fulfilling the European Pharmacopeia requirement for orodispersible tablets (ODTs). The tablet’s immediate release characteristics were confirmed during the dissolution study: over 80% of APIs were released from printlets within 15 min. Thus, this study proved the possibility of using fused deposition modeling for the preparation of ODTs.

Prediction of random packing density and flowability for non-spherical particles by deep convolutional neural networks and Discrete Element Method simulations

Non-spherical particles can be found in many industrial processes. Unfortunately, scalar shape parameters are often insufficient to predict their complex behavior. Therefore, this study used convolutional neural networks (CNN), which are able to interpret abstract shape features to derive the flow and packing behavior. For training data generation, experimentally validated Discrete Element Method simulations of silo filling and discharge were conducted. The subsequent training of the neural network was achieved with extensive input data augmentation. The CNN was then applied for the investigation of common shapes like ellipsoids or frustums for validation. The trained network showed good accordance to literature and high predictive robustness. Finally, the CNN assessed various food grains and tablet shapes. The network predicted the densest packing and best flowability for rounded lentils, whereas long rice kernels showed poor flow behavior. For pharmaceutical tablets, rounded and hexagonal shapes were predicted to yield denser packings than plain cylinders.

Impact of Tablet Shape on Drug Dissolution Rate Through Immediate Released Tablets.

Purpose: The aim of this study was to evaluate the influence of the geometric shape on the dissolution rate of the domperidone, a drug model for immediate release dosage form. In this regard, a lack of sufficient information about the effective dissolution rate of the drugs regarding their shapes has made this issue an interesting subject for researchers. Methods: For this purpose, three tablet shapes, namely flat and biconvex both in a round and oblong shapes, with different four sizes were modelled for the preparation of domperidone tablet. In vitro dissolution test was accomplished using a USP dissolution apparatus II. The drug dissolution rate was assessed by calculating various dissolution parameters; e.g., dissolution efficiency (DE), mean dissolution rate (MDR), mean dissolution time (MDT), and difference and similarity factors (f1 and f2 ). Results: Regarding the disintegration time, the larger tablets showed a faster disintegration time. When the size of the tablets was smaller, the amount of released drug was significantly decreased. In addition, #9 tablets with a flat or biconvex geometry had obvious effects on the DE values. Generally, biconvex tablets had higher DE percentage than the flat tablets. Conclusion: Noticeable differences in dissolution parameters by considering the different geometric shapes play an important role in the drug release kinetics which makes a significant effect on quick onset of action in oral administration.

Selection of a round convex tablet shape that mitigates the risk of chipping and capping based on systematic evaluation by utilizing multivariate analysis

Selecting a tablet shape that minimizes the risk of chipping and capping during manufacture is important in pharmaceutical industry. Here, the selection was performed based on systematic evaluation for the first time. Abrasion and stress relaxation time were utilized as indices of the occurrences of chipping and capping, respectively. Partial least square regression models that used tablet shape parameters to estimate the tablet's abrasion and stress relaxation time were utilized to develop response surface plots of the effect of the tablet shapes on the occurrence of chipping and capping systematically, and to identify an optimum tablet shape that is expected to have a low occurrence of chipping and capping. A verification study using commercial scale facilities proved that the optimum tablet shape had a lower occurrence of chipping and capping compared to suboptimum examples as speculated by their abrasion and stress relaxation time. The observed mathematical relationship between the tablet shapes and the occurrence of chipping and capping were consistent with the previous studies based on the comparison of limited number of tablet shapes using different formulations. Consequently, it is expected to be applicable to other formulations beyond the evaluated formulation in the present study.

Mechanism of Urea Crystal Dissolution in Water from Molecular Dynamics Simulation.

Molecular dynamics simulations are used to determine the mechanism of urea crystal dissolution in water under sink conditions. Crystals of cubic and tablet shapes are considered, and results are reported for four commonly used water models. The dissolution rates for different water models can differ considerably, but the overall dissolution mechanism remains the same. Urea dissolution occurs in three stages: a relatively fast initial stage, a slower intermediate stage, and a final stage. We show that the long intermediate stage is well described by classical rate laws, which assume that the dissolution rate is proportional to the active surface area. By carrying out simulations at different temperatures, we show that urea dissolution is an activated process, with an activation energy of ∼32 kJ mol-1. Our simulations give no indication of a significant diffusion layer, and we conclude that the detachment of molecules from the crystal is the rate-determining step for dissolution. The results we report for urea are consistent with earlier observations for the dissolution of NaCl crystals. This suggests that the three-stage mechanism and classical rate laws might apply to the dissolution of other ionic and molecular crystals.

Comparisons of Inter-tablet Coating Variability under Different Tablet Shapes and Filling Levels by Using DEM Simulations

The purpose of this paper is to investigate inter-tablet coating thickness variability based on different tablet shapes and filling levels. To achieve this goal, the Discrete Element Method (DEM) is applied, and efforts are made as following: For the first step, four different tablet shapes, referred to as Sphere, SRC (Standard Round Concave), Oval and Triangular, are built by importing three (except Sphere) CAD templates to create one or more spherical surfaces. Furthermore, a spray zone in the coating pan is presented to monitor the change of the “coating mass”, by virtue of which we calculate the inter-tablet coating variability. And to complete this work, custom contact models and properties are created to describe coating. Then, three different filling levels are added to the simulation. Eventually, the compared results are analyzed between three diverse filling degrees among tablet particles with four discrepant shapes.

Tablet Inspection and Sorting Machine

Tablets are produced in a vast quantity everyday, and which require a proper quality inspection to avoid accidental production issues. The tablet quality checking is mostly done manually which makes it an error-prone process. However, automated solutions for inspection provide much faster and accurate sorting and checking for all tablet shapes, sizes and defects. Such systems require a reliable tablet image analysis mechanism. This paper describes a low cost automated solution for tablet inspection and sorting.

Effect of geometry on drug release from 3D printed tablets

The aim of this work was to explore the feasibility of combining hot melt extrusion (HME) with 3D printing (3DP) technology, with a view to producing different shaped tablets which would be otherwise difficult to produce using traditional methods. A filament extruder was used to obtain approx. 4% paracetamol loaded filaments of polyvinyl alcohol with characteristics suitable for use in fused-deposition modelling 3DP. Five different tablet geometries were successfully 3D-printed—cube, pyramid, cylinder, sphere and torus. The printing process did not affect the stability of the drug. Drug release from the tablets was not dependent on the surface area but instead on surface area to volume ratio, indicating the influence that geometrical shape has on drug release. An erosion-mediated process controlled drug release. This work has demonstrated the potential of 3DP to manufacture tablet shapes of different geometries, many of which would be challenging to manufacture by powder compaction.

Comparisons of intra-tablet coating variability using DEM simulations, asymptotic limit models, and experiments

Discrete element method (DEM) computer simulations are used to investigate intra-tablet coating thickness variability. Two new post-processing algorithms are presented. The first algorithm uses an image-based method to track the exposure to a simulated spray of small area panels on each tablet׳s surface so that the distribution of spray exposure times over the tablet׳s surface can be determined directly from DEM data. The second algorithm predicts the asymptotic limit of intra-tablet coating uniformity. This second algorithm includes the influence of tablet orientation and shadowing when considering exposure to the spray, averaged over many tablets.The DEM simulations produce the first direct evidence that non-spherical tablets approach asymptotic intra-tablet coating variability values. The asymptotic limits are predicted well using the new asymptotic prediction model. In general, tablet caps have thicker coatings than tablet bands. Moreover, tablets that have a more elongated shape tend to have less coating on the smaller radius of curvature portions of the bands. Of particular importance in this new asymptotic modeling approach is the inclusion of shadowing effects. When shadowing is not included and only tablet orientation is considered, the predictions over-predict the asymptotic intra-tablet coating variability values and also change the observed rank order of the asymptotic values for different tablet shapes. The asymptotic intra-tablet coating variability values using the new algorithm correlate reasonably well with tablet sphericity, with increasing sphericity improving coating uniformity.This paper also presents the first attempt to directly compare experimental and simulated coating thickness distributions. The asymptotic coating thickness predictions compare well qualitatively with terahertz thickness measurements made on tablets from coating experiments. Unfortunately, only qualitative comparisons could be made due to the limited number of tablets sampled experimentally and differences in spray zone areas and flux distributions. The tablets in the experiments, however, displayed similar features as those found in the simulations.

Modelling of the break force of tablets under diametrical compression

A numerical method to predict the break force of curved faced tablets is proposed. The constitutive model and the failure criteria necessary to obtain predictions consistent with experimental data are identified. A modified Drucker-Prager cap model together with a maximum principal stress based failure criteria was found sufficient to predict the break force of tablets under diametrical compression loading. The conditions for the validity of the method were identified with reference to practical tablet shapes and failure patterns. Under these conditions the numerical procedures can be used as a practical tool to predict tablet breakage as an alternative to the empirical methods currently used in pharmaceutical product design and process development.

Effect of talc stone and chlorite-tremolite rock on ceramic tile phase composition and properties

The following processes occur in talc stone (carbonate-chlorite-talc composition) and accompanying tremolite-chlorite rocks, studied in the present work, in the temperature interval 950 – 1100°C as a result of the decomposition of talc and tremolite: dehydration (talc, tremolite, chlorite), decarbonization (dolomite, calcite, breunnerite), and formation of new crystalline phases (forsterite, enstatite, clinoenstatite, subcalcium augite). These processes, as well as the presence of an amorphous phase enriched with magnesium ions, make ceramics stronger. Larger-size little-changed grains of tremolite are an additional strength-increasing factor. Owing to their tablet and needle shapes such grains reinforce the ceramic structure.

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.