Biconvex Tablets Research Articles

DEM-DDM investigation of the intra-tablet coating uniformity for tablets with different shapes

Coating uniformity is important for the quality, safety, and efficacy of tablets in the pharmaceutical industry. Among the various research methods, discrete element method (DEM) is a powerful tool for numerically investigating the coating process in particle level, increasing the understanding of coating uniformity and improving related processes. In this study, the combination of DEM and discrete droplet method (DDM) is applied for the simulation of tablet coating process, including the intra-tablet coating uniformity of differently shaped tablets. The biconvex tablets are described by multi-super-ellipsoid approach in this study. In order to obtain the coating thickness distribution on each tablet, two particle surface-based meshing methods are proposed. The proposed intra-tablet DEM-DDM coating model is subsequently verified by the qualitative comparison with both theoretical models and experimental results from other literature. Finally, the influence of tablet shape on the intra-tablet coating uniformity is investigated, including tablets with different aspect ratios and height ratios.

Effect of geometrical features on the capping behavior of biconvex tablets

Capping is a common industrial issue during the manufacturing of pharmaceutical tablets. It is influenced by both process and formulation parameters. In this work, a systematic study of the influence of the geometrical features of biconvex tablets on capping occurrence was performed on a model formulation, using a design of experiment. Capping was characterized by the pressure at which half of the produced tablets were capped. The influence of the tablet geometry was assessed by varying three parameters: the diameter (D), the band thickness (W) and the ratio between the radius of curvature (R) and the diameter, i.e. R/D. Results showed that having a large diameter, a low band thickness and a high curvature (i.e. a low R/D) favored capping occurrence. Moreover, the effects are not independent as cross-effect were detected. Finally, even for homothetic tablets (i.e. same R/D and W/D) it is shown that a large diameter increases capping occurrence. These results could be used in the future as a guideline for punch selection during tablet development.

Evaluation and Analysis of Mathematical Models of Heat-Transfer Processes Occurring Upon Application of Film Coatings on Biconvex Tablets

Evaluation and Analysis of Mathematical Models of Heat-Transfer Processes Occurring Upon Application of Film Coatings on Biconvex Tablets

On the complexity of predicting tablet capping

Predicting tablet defects, such as capping, that might occur during manufacturing, is a challenge in the pharmaceutical industry. In the literature, different parameters were presented to predict capping but no general consensus seems to have been reached yet. In this article, we chose to study a wide range of products (18 formulations, 8 of which presenting capping) to predict capping on biconvex tablets using the properties characterized on defect-free flat-faced tablets (tensile strength, solid fraction, elastic recovery, etc.), made using the same process parameters. Single parameters and predictive indices presented in the literature were evaluated on this set of formulations and were found not suitable to predict capping. A predictive model was then developed using a decision tree analysis and was found to depend only on three in-die tablet properties: the plastic energy per volume, the in-die elastic recovery and the residual die-wall pressure. This model was tested on another set of 13 formulations chosen to challenge it. The capping behavior of 29 out of the 31 formulations studied in total was well estimated using the developed model with only two products which were predicted to cap and did not. This shows the potential of the used approach in terms of risk analysis and assessment for capping occurrence.

Comparative study of discrete element modeling of tablets using multi-spheres, multi-super-ellipsoids, and polyhedrons

Discrete element method (DEM) is an effective approach to investigate non-spherical granular systems that are widely encountered in nature, industry, and our daily life. To describe the complex shapes of non-spherical particles, different particle shape representation approaches have been developed. In this paper, comparative study of modeling tablets using multi-sphere approach, multi-super-ellipsoid approach, and polyhedron approach is done to investigate the effect of different approaches. The accuracy of these approaches is testified by experiments and corresponding simulations of the packing, heap forming, and the flow in a rotating drum with two kinds of biconvex tablets firstly. Then the simulations of the flow of two kinds of biconvex tablets in a horizontal rotating drum are carried out by DEM. The simulation results are compared to discuss the effect of different approaches, which include the repose angle, the tablet orientation, the axial movement and mixing, the contact number, the percentage of the tablets reaching the free surface of the granular bed, and the computational efficiency. The results show that the simulations using multi-super-ellipsoid approach and polyhedron approach have some differences with those using multi-sphere approach.

Determination of tensile strength of shaped tablets

During early drug product development, methods for characterization of mechanical attributes are developed for flat, round tablets. However, there is a lack of understanding on how to compute the tensile strength of shaped tablets, which makes determination of the tabletability and compressibility impossible. Existing models for biconvex, round and capsule shaped tablets were analyzed. In addition, a finite element method simulation was developed to compute the tensile strength of oval tablets. It was found that the model by Shang et al. (2013) for biconvex tablets is consistent over a wide range of dimensions including flat, round tablet. A hybrid model was proposed for capsule shaped tablets based on models by Shang et al. and Pitt et al. (2013). However, models developed for capsule shaped tablets may under predict or over predict the tensile strength of oval tablets. Therefore, tensile strength of oval tablets must be separately evaluated for each tablet.

Ockham's Razor Applied on Pharmaceutical Powder Compaction Models

This investigation contains a critical survey of a collection of five well-known and often used standard models in pharmaceutical technology. The basic idea is to use the recognised Ockham's razor as a tool in search for simpler methods or explanations for these models. The study includes the indirect tensile strength of tablets, Pitt's equation for tensile strength of biconvex tablets, Adams' model for strength of agglomerates, Weibull's distribution for variability of strength measurements and Heckel's equation for compressibility. In all these cases simpler and equally valid solutions and explanations are presented and subsequently preferred rather than the original.

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.

Role of Precompression in the Mitigation of Capping: A Case Study

Capping is an important industrial problem that can arise during the manufacturing of pharmaceutical tablets. It corresponds, for biconvex tablets, to the detachment of one of the cups of the tablet during the ejection from the press or after relaxation. Solutions to this problem remain mainly empirical. Among them, precompression is widely used.One of the most popular explanation of the role of precompression in the mitigation of capping is that it increases the total time under compression. Following this interpretation, press manufacturers developped devices or machines that make it possible to maintain the pressure between precompression and main compression.In this note, we present a case study of capping. For the formulation proposed, a precompression that was maintained until the compression gave similar results as no precompression at all, i.e. capping of all the tablets. On the contrary, if the precompression was released before compression, capping stops completely. In this case, the effect of precompression is thus due to the separation of two compression events. Moreover, results prove that this separation must last long enough for the precompression to be efficient. This example shows that effect of precompression is more complex than often described in the literature.

Terahertz-Based Porosity Measurement of Pharmaceutical Tablets: a Tutorial

Porosity, one of the important quality attributes of pharmaceutical tablets, directly affects the mechanical properties, the mass transport and hence tablet disintegration, dissolution and ultimately the bioavailability of an orally administered drug. The ability to accurately and quickly monitor the porosity of tablets during manufacture or during the manufacturing process will enable a greater assurance of product quality. This tutorial systematically outlines the steps involved in the terahertz-based measurement method that can be used to quantify the porosity of a tablet within seconds in a non-destructive and non-invasive manner. The terahertz-based porosity measurement can be performed using one of the three main methods, which are (i) the zero-porosity approximation (ZPA); (ii) the traditional Bruggeman effective medium approximation (TB-EMA); and (iii) the anisotropic Bruggeman effective medium approximation (AB-EMA). By using a set of batches of flat-faced and biconvex tablets as a case study, the three main methods are compared and contrasted. Overall, frequency-domain signal processing coupled with the AB-EMA method was found to be most suitable approach in terms of accuracy and robustness when predicting the porosity of tablets over a range of complexities and geometries. This tutorial aims to concisely outline all the necessary steps, precautions and unique advantages associated with the terahertz-based porosity measurement method.

Industrial scale simulations of tablet coating using GPU based DEM: A validation study

The coating of tablets to prevent product degradation or control dissolution is a typical process in its production. Coating uniformity is critical for the quality of final product and batch acceptance. Therefore, the coating process needs to be optimized in order to achieve the desired uniformity and reduce manufacturing costs. Thus, understanding how process parameters such as spray properties, equipment geometry and tablet shape influence the coating process is critical for process optimization and approval by regulatory bodies. However this is a non-trivial task as obtaining information about the detailed processes in a tablet coater via experimental means is limited. Thus, computational modeling is the most feasible option to obtain information about the physical processes affecting the performance of tablet coaters. The most widely used computational method for such numerical modelling is the Discrete Element Method (DEM) where individual particles (tablets) are simulated. However, the computational cost of representing the typical shape of tablets is high for industrially relevant simulations. Thus tablet shape is typically approximated by simpler shapes such as spheres or multi spheres. Even with such simplifications, typical simulations take months to complete making it unfeasible for process optimization and design. In the last decade, the Graphical Processor Unit (GPU) has enabled large-scale simulations of tens of millions of spheres and millions of shaped particles using the XPS code. In this paper, we present an algorithm for modeling accurate bi-convex tablets that is tailored to the GPU. We firstly validate the algorithm and implementation against a number of experiments. Finally we perform a simulation of 20 million tablets in a drum coater to illustrate the usefulness of GPU computing for industrial coating applications. We found that the proposed method yields a good match against the lab scale experiments. For the industrial simulation the proposed method gave a more accurate result compared to the multi sphere approach while being significantly faster.

Lamination of biconvex tablets: Numerical and experimental study

Capping and lamination are common industrial problems during the manufacturing of pharmaceutical tablets. Even if they are commonly treated together, these phenomena correspond to different failure patterns of the tablet and, as a consequence, to different mechanisms of cracking. In this work, a specific case of lamination of biconvex tablets was studied. It corresponds to a breakage into two parts of the tablets along a failure plan normal to the compression direction and located approximately at the center of the tablet band.Simulation with finite element method made it possible to propose that this kind of failure is promoted by tensile stresses localized at the center of the tablet that are induced by the residual die wall pressure and the tablet shape. Moreover, these stresses are favored by a small band thickness. Experimental results confirmed these hypotheses and also showed that this kind of lamination was favored by a high compaction pressure.As the crack is formed at the center of the tablet, it may not propagate until the tablet band. Failure may thus remain undetected by external visual examination. X-ray tomography made it possible to observe central cracks inside the tablet without tablet breakage. The possibility to have such cracks inside the tablet must be considered during tablet development as, even if not detected just after compression, they could lead to tablet failure during post compaction events.

Shear strength of pharmaceutical tablets: Theoretical considerations, evaluation and relation with the capping tendency of biconvex tablets

Capping is a major industrial issue during pharmaceutical powder compression, especially in the case of biconvex tablets. Several articles proposed that capping was in fact a failure in shear. Shear strength should thus be interesting to study the capping tendency of a formulation. In this work, the ratio between the shear strength and the tensile strength obtained by diametral compression was first studied from a theoretical point of view considering different failure criteria. Then, a shear test usually performed on bilayer tablets was adapted to monolayer tablets. The shear strength obtained for 5 products, 2 of them having a known capping tendency, were compared with the strengths obtained during diametral compression test and uniaxial compression test.The results indicated that, for the formulations with a capping tendency, the ratio between the shear strength and diametral compression strength was lower than for the other products. Considering the mechanism of capping, the weakness in shear of these formulations explained their capping tendency. This was also linked with the mechanical anisotropy of the same formulations which was shown in the literature. In the cases studied in this article, the fundamental reason for the capping tendency was the anisotropic strength of the tablets.

Non-destructive Determination of Disintegration Time and Dissolution in Immediate Release Tablets by Terahertz Transmission Measurements

ABSTRACTPurposeThe aim of this study was to establish the suitability of terahertz (THz) transmission measurements to accurately measure and predict the critical quality attributes of disintegration time and the amount of active pharmaceutical ingredient (API) dissolved after 15, 20 and 25 min for commercial tablets processed at production scale.MethodsSamples of 18 batches of biconvex tablets from a production-scale design of experiments study into exploring the design space of a commercial tablet manufacturing process were used. The tablet production involved the process steps of high-shear wet granulation, fluid-bed drying and subsequent compaction. The 18 batches were produced using a 4 factor split plot design to study the effects of process changes on the disintegration time. Non-destructive and contactless terahertz transmission measurements of the whole tablets without prior sample preparation were performed to measure the effective refractive index and absorption coefficient of 6 tablets per batch.ResultsThe disintegration time (R2 = 0.86) and API dissolved after 15 min (R2 = 0.96) linearly correlates with the effective refractive index, neff, measured at terahertz frequencies. In contrast, no such correlation could be established from conventional hardness measurements. The magnitude of neff represents the optical density of the sample and thus it reflects both changes in tablet porosity as well as granule density. For the absorption coefficient, αeff, we observed a better correlation with dissolution after 20 min (R2 = 0.96) and a weaker correlation with disintegration (R2 = 0.83) compared to neff.ConclusionThe measurements of neff and αeff provide promising predictors for the disintegration and dissolution time of tablets. The high penetration power of terahertz radiation makes it possible to sample a significant volume proportion of a tablet without any prior sample preparation. Together with the short measurement time (seconds), the potential to measure content uniformity and the fact that the method requires no chemometric models this technology shows clear promise to be established as a process analyser to non-destructively predict critical quality attributes of tablets.

Noninvasive porosity measurement of biconvex tablets using terahertz pulses

Biconvex pharmaceutical microcrystalline cellulose (MCC) compacts were investigated by the detection of terahertz (THz) pulse delay in the transmission measurement mode. The dimensions of the tablets were kept as constants but the porosity was a priori known variable. It is shown that the porosity of the biconvex compact has a linear correlation with the THz pulse delay. By constructing a calibration line between these two parameters (i.e. porosity and THz pulse delay), it is possible to non-invasively detect porosity of biconvex tablets. We suggest that this preliminary study could be the starting point of in-depth future studies on the screening of porosity and related properties of real biconvex pharmaceutical tablets using terahertz sensing techniques.

Evolution of the Die-Wall Pressure during the Compression of Biconvex Tablets: Experimental Results and Comparison with FEM Simulation

Capping is a classical manufacturing problem for tablets, which is known to affect more biconvex tablets than flat-faced ones. One reason could be the development of a higher residual die-wall pressure during unloading. Unfortunately, contradictory results were published on the subject. In this work, the evolution of the die-wall pressure during the compaction of biconvex tablets was studied experimentally and using finite element method (FEM) modeling. It was compared with the case of flat-faced tablets. Experimental and numerical results showed that during the compression of biconvex tablet, a lower maximum die-wall pressure and a higher residual die-wall pressure were obtained compared with the case of flat-faced tablet. Moreover, both approaches showed, for biconvex tablets, a temporary increase of the die-wall pressure at the end of the unloading phase. FEM demonstrated that this phenomenon was due to a gradual loss of contact between the punch and the tablet from the side to the center. This complex unloading behavior causes the temporary increase of the die-wall pressure and the development of a shear stress between the convex part and the land of the tablet. This could explain the capping tendency of biconvex tablets.

PH-independent immediate release polymethacrylate formulations – an observational study

Using Eudragit® E PO (EudrE) as a polymethacrylate carrier, the aim of the study was to develop a pH-independent dosage form containing ibuprofen (IBP) as an active compound via chemical modification of the polymer (i.e. quaternization of amine function) or via the addition of dicarboxylic acids (succinic, glutaric and adipic acid) to create a pH micro-environment during dissolution. Biconvex tablets (diameter: 10 mm; height: 5 mm) were produced via hot melt extrusion and injection molding. In vitro dissolution experiments revealed that a minimum of 25% of quaternization was sufficient to partially (up to pH 5) eliminate the pH-dependent effect of the EudrE/IBP formulation. The addition of dicarboxylic acids did not alter IBP release in a pH 1 and 3 medium as the dimethyl amino groups of EudrE are already fully protonated, while in a pH 5 solvent IBP release was significantly improved (cf. from 0% to 92% release after 1 h dissolution experiments upon the addition of 20 wt.% succinic acid). Hence, both approaches resulted in a pH-independent (up to pH 5) immediate release formulation. However, the presence of a positively charged polymer induced stability issues (recrystallization of API) and the formulations containing dicarboxylic acids were classified as mechanically unstable. Hence, further research is needed to obtain a pH-independent immediate release formulation while using EudrE as a polmethacrylate carrier.

Estimation of bottle filling counts for conventional pharmaceutical tablets and capsules

A method has been developed using commonly available data for estimating the number of tablets or hard shell capsules that can be filled into bottles. The single unit volumes of conventional pharmaceutical biconvex tablets and capsules can be calculated from simple geometric relationships, which then can be used to determine the packing fraction of the units in bottles. The packing fractions of capsules and tablets studied in this work ranged from 0.53 to 0.63 and 0.56 to 0.62, respectively, and were dependent on bottle size and shape. This method can be used to assess a variety of packaging configurations computationally during drug product development.

Evaluating the effect of coating equipment on tablet film quality using terahertz pulsed imaging

In this study, terahertz pulsed imaging (TPI) was employed to investigate the effect of the coating equipment (fluid bed and drum coater) on the structure of the applied film coating and subsequent dissolution behaviour. Six tablets from every batch coated with the same delayed release coating formulation under recommended process conditions (provided by the coating polymer supplier) were mapped individually to evaluate the effect of coating device on critical coating characteristics (coating thickness, surface morphology and density). Although the traditional coating quality parameter (weight gain) indicated no differences between both batches, TPI analysis revealed a lower mean coating thickness (CT) for tablets coated in the drum coater compared to fluid bed coated tablets (p<0.05). Moreover, drum coated tablets showed a more pronounced CT variation between the two sides and the centre band of the biconvex tablets, with the CT around the centre band being 22.5% thinner than the top and bottom sides for the drum coated tablets and 12.5% thinner for fluid bed coated tablets. The TPI analysis suggested a denser coating for the drum coated tablets. Dissolution testing confirmed that the film coating density was the drug release governing factor, with faster drug release for tablets coated in the fluid bed coater (98±4% after 6h) compared to drum coated tablets (72±6% after 6h). Overall, TPI investigation revealed substantial differences in the applied film coating quality between tablets coated in the two coaters, which in turn correlated with the subsequent dissolution performance.

Discrete element method modeling of bi-convex pharmaceutical tablets: Contact detection algorithms and validation

Various algorithms have been presented in the literature for contact detection between three-dimensional bi-convex objects, such as pharmaceutical tablets. Most are approximations to true bi-convex shapes, e.g., glued spheres, sphere-intersections, sphero-cylinders, and super-ellipsoids, and others, such as the discrete function representation, are computationally expensive. In this paper, algorithms are presented for determining if two, true bi-convex tablets, or a bi-convex tablet and an infinite plane, are in contact. A bi-convex tablet has two spherical caps and a cylindrical band. In all, ten contact scenarios are examined involving all components of the tablets, i.e., caps, band, and edges. In addition to checking for contact, relations for determining the contact location, overlap, and unit normal vector for the contact are presented for use in discrete element method computer simulations. These algorithms have been validated for single and multiple tablet scenarios: (a) comparing translational and angular velocities of a single bi-convex tablet impacting a flat plane, (b) comparing the fill fractions of bi-convex tablets in a container, and (c) comparing the dynamic angle of repose of bi-convex tablets in a rotating drum.