Convex Tablets Research Articles

Prediction of Critical Quality Attributes Based on the Numerical Simulation of Stress and Strain Distributions in Pharmaceutical Tablets.

Various stresses and strains are generated on the surface and inside of pharmaceutical tablets when an external force is applied. In addition, stresses in various directions can remain on the surface and inside the tablets because they are generally prepared by compaction of pharmaceutical powders using dies and punches. As it is difficult to measure the stress and strain generation in the tablets experimentally, a numerical simulation was applied by employing a finite element method (FEM). An elastic model is often used to represent stress and strain generation after loading an external force to tablets, and the Drucker-Prager cap (DPC) model has been widely recognized for representing the remaining stress distributions during the compaction of powder to tablet form. Firstly, this article describes an FEM simulation of the stress generation on the surface of the scored tablets after loading the bending force from the back side of the tablets. Next, the FEM simulation was introduced to determine the effect of diametrical compression on the stress and strain generation in the tablets by comparing the results measured experimentally. Furthermore, the residual stresses remaining inside the tablets were simulated using FEM, in which powder compaction was represented as the DPC model. A clear difference was observed in the residual stress distributions between the flat and convex tablets. This indicates that FEM simulation is useful for achieving a science-based understanding of critical quality attributes in various types of tablets.

Enhanced in-situ liquid transport investigation setup for pharmaceutical tablet disintegration analysis using terahertz radiation

The disintegration process of pharmaceutical solid dosage forms commences on contact with the dissolution medium and continues with subsequent spontaneous imbibition of the medium in the tablet matrix. Identifying the location of the liquid front in situ during imbibition, therefore, plays a significant role in understanding and modelling the disintegration process. Terahertz pulsed imaging (TPI) technology can be used to investigate this process by its ability to penetrate and identify the liquid front in pharmaceutical tablets. However, previous studies were limited to samples suitable for a flow cell environment, i.e. flat cylindrical disk shapes; thus, most commercial tablets could only be measured with prior destructive sample preparation. This study presents a new experimental setup named open immersion to measure a wide range of pharmaceutical tablets in their intact form. Besides, a series of data processing techniques to extract subtle features of the advancing liquid front are designed and utilised, effectively increasing the maximum thickness of tablets that can be analysed. We used the new method and successfully measured the liquid ingress profiles for a set of oval convex tablets prepared from a complex eroding immediate-release formulation.

Lamination of Pharmaceutical Tablets: Classification and Influence of Process Parameters

Lamination is a common industrial problem during the production of pharmaceutical tablets. It corresponds to a failure of the tablet in one or several planes parallel to the surface and passing through the tablet band. But different kinds of lamination exist, and a classification of the different cases is proposed in this work. Type 1 corresponds to a multiple fracture caused by air entrapment. Type 2 occurs because of the shear stresses developing when the tablet goes out of the die. Type 3, which is limited to convex tablets, is due to a tensile stress developing at the center of the tablet at the end of the unloading that further propagates toward the band. One case of each type was studied experimentally in order to test three solutions classically used at the industrial level: slowing down the press, using a precompression and using a tapered die. Results shows that, in coherence with the proposed mechanisms, lamination type 1 can be mitigated by slowing down the press or using a precompression. For type 2, only the tapered die solution stopped lamination. None of the solutions completely solved lamination type 3. Nevertheless, the use of a tapered die decreased the severity of the problem avoiding the propagation of the crack until the surface.

Prediction of tablet characteristics based on sparse modeling for residual stresses simulated by the finite element method incorporating Drucker-Prager cap model

Effects of residual stresses on the mechanical characteristics of tablets such as tensile strength (TS) and disintegration time (DT) were investigated. The residual stresses were simulated using the finite element method (FEM), in which the powder compaction was represented by a Drucker-Prager cap (DPC) model under unconstrained condition. As model tablet formulations, we employed powder mixtures comprising various quantities of lactose (LAC), corn starch (CS), and microcrystalline cellulose (MCC). Key parameters of DPC model were well predicted as a function of quantity ratio of LAC, CS, and MCC. A clear difference was observed in the residual stress distributions between the flat and convex tablets. Strong stresses remained in the convex tablets, while they were rather weak in the flat tablets. For a sparse modeling, an elastic-net (ENET) regression was employed to identify specific stress sites in the tablets. Consequently, the ENET regression revealed specific significant sites in the tablet affecting the TS and DT values. Both quantity and direction of the remaining stresses acting at specific sites close to the die wall were crucial in the convex tablets to predict the TS and DT values; however, no such tendency was seen in the flat tablet.

Co-Processed Excipients for Dispersible Tablets-Part 1: Manufacturability.

Co-processed excipients may enhance functionality and reduce drawbacks of traditional excipients for the manufacture of tablets on a commercial scale. The following study aimed to characterise a range of co-processed excipients that may prove suitable for dispersible tablet formulations prepared by direct compression. Co-processed excipients were lubricated and compressed into 10.5-mm convex tablets using a Phoenix compaction simulator. Compression profiles were generated by varying the compression force applied to the formulation and the prepared tablets were characterised for hardness, friability, disintegration and fineness of dispersion. Our data indicates that CombiLac, F-Melt type C and SmartEx QD100 were the top 3 most suitable out of 16 co-processed excipients under the conditions evaluated. They exhibited good flow properties (Carr's index ˂20), excellent tabletability (tensile strength > 3.0MPa at 0.85 solid fraction), very low friability (< 1% after 15min), rapid disintegration times (27-49s) and produced dispersions of ideal fineness (< 250μm). Other co-processed excipients (including F-Melt type M, Ludiflash, MicroceLac, Pharmaburst 500 and Avicel HFE-102) may be appropriate for dispersible tablets produced by direct compression providing the identified disintegration and dispersion risks were mitigated prior to commercialisation. This indicates that robust dispersible tablets which disintegrate rapidly could be manufactured from a range of co-processed excipients.

Quantification of lubrication and particle size distribution effects on tensile strength and stiffness of tablets

We adopt a Quality by Design (QbD) paradigm to better control the mechanical properties of tablets. To this end, the effect of particle size distribution, lubricant concentration, and mixing time on the tensile strength and elastic modulus of tablets is studied. Two grades of lactose, monohydrate and spray-dried, are selected. Tablets are compressed to different relative densities ranging from 0.8 to 0.94 using an instrumented compaction simulator. We propose a general model, which predicts the elastic modulus and tensile strength envelope that a specific powder can obtain based on its lubrication sensitivity for different particle size distributions. This is possible by introducing a new dimensionless parameter in the existing tensile strength and elastic modulus relationships with relative density. A wide range of lubrication conditions is explored and a predictable model is calibrated. The mechanical properties of lactose monohydrate tablets are noticeably dependent on particle size, unlike spray-dried lactose where little to almost no sensitivity to particle size is observed. The model is designed in a general fashion that can capture mechanical quality attributes in response to different lubrication conditions and particle size, and it can be extended to powders than undergo different deformation mechanisms, complex mixtures, and doubly convex tablets. Therefore, the model can be used to map the achievable design space of any given formulation.

An experimental investigation of temperature rise during compaction of pharmaceutical powders

During pharmaceutical powder compaction, temperature rise in the compressed powder can affect physiochemical properties of the powder, such as thermal degradation and change in crystallinity. Thus, it is of practical importance to understand the effect of process conditions and material properties on the thermal response of pharmaceutical formulations during compaction. The aim of this study was to examine the temperature rise of pharmaceutical powders during tableting, in particular, to explore how the temperature rise depends on material properties, compression speed and tablet shape. Three grades of microcrystalline cellulose (MCC) were considered: MCC Avicel pH 101, MCC Avicel pH 102 and MCC DG. These powders were compressed using a compaction simulator at various compaction speeds (10–500mm/s). Flat faced, shallow convex and normal convex tablets were produced and temperature distributions on the surface of theses tablets upon ejection were examined using an infrared thermoviewer. It was found that an increase in the compaction speed led to an increase in the average surface temperature. A higher surface temperature was induced when the powder was compressed into a tablet with larger surface curvature. This was primarily due to the increasing degree of powder deformation (i.e. the volume reduction) and the effect of interparticule/wall friction.

Finite element analysis of thermomechanical behaviour of powders during tabletting

In the current paper, a systematic finite element (FE) analysis of the thermo-mechanical behaviour of pharmaceutical powders during die compaction is performed using the FE solver ABAQUS. The transformation of irreversible compression work to heat during compaction is considered, so is the energy dissipated by the particle–particle friction, and die-wall friction. Die compaction with various shaped punches to produce flat-face (FF), shallow convex (SC) and standard convex (STC) tablets at different compression speeds are then analysed. Evolutions of density and temperature distributions during compaction are examined. The effect of die wall friction on thermo-mechanical behaviours is also explored. It is shown that the punch shape, the compression speed and die-wall friction significantly affect the thermo-mechanical behaviour. The maximum temperature and temperature distribution of the compressed powder changes dramatically when different shaped punches are used. The maximum temperature of the tablet upon ejection can be reduced by decreasing the die-wall friction or the compression speed.

General and mechanistic optimal relationships for tensile strength of doubly convex tablets under diametrical compression

We propose a general framework for determining optimal relationships for tensile strength of doubly convex tablets under diametrical compression. This approach is based on the observation that tensile strength is directly proportional to the breaking force and inversely proportional to a non-linear function of geometric parameters and materials properties. This generalization reduces to the analytical expression commonly used for flat faced tablets, i.e., Hertz solution, and to the empirical relationship currently used in the pharmaceutical industry for convex-faced tablets, i.e., Pitt's equation. Under proper parametrization, optimal tensile strength relationship can be determined from experimental results by minimizing a figure of merit of choice. This optimization is performed under the first-order approximation that a flat faced tablet and a doubly curved tablet have the same tensile strength if they have the same relative density and are made of the same powder, under equivalent manufacturing conditions. Furthermore, we provide a set of recommendations and best practices for assessing the performance of optimal tensile strength relationships in general. Based on these guidelines, we identify two new models, namely the general and mechanistic models, which are effective and predictive alternatives to the tensile strength relationship currently used in the pharmaceutical industry.

Numerical investigation into the influence of the punch shape on the mechanical behavior of pharmaceutical powders during compaction

During the production of pharmaceutical tablets using powder compaction, certain common problems can occur, such as sticking, tearing, cutting, and lamination. In the past, the compressibility of the powder was calculated only along the axis of the device; consequently, critical areas of the material throughout the volume could not be identified. Therefore, finite element method (FEM) can be used to predict these defects in conjunction with the use of an appropriate constitutive model. This article summarizes the current research in the field of powder compaction, describes the Drucker–Prager Cap model calibration procedure and its implementation in FEM, and also examines the mechanical behavior of powder during compaction. In addition, the mechanical behavior of pharmaceutical powders in relation to changes in friction at the wall of the system is examined, and the dependence of lubrication effect on the geometry of the compaction space is also investigated. The influence of friction on the compaction process for the flat-face, flat-face radius edge, and standard convex tablets is examined while highlighting how the effects of friction change depending on the shape of these tablets.

Impact of Alternative Solid State Forms and Specific Surface Area of High-Dose, Hydrophilic Active Pharmaceutical Ingredients on Tabletability

In order to investigate the effect of using different solid state forms and specific surface area (TBET) of active pharmaceutical ingredients on tabletability and dissolution performance, the mono- and dihydrated crystalline forms of chlorothiazide sodium and chlorothiazide potassium (CTZK) salts were compared to alternative anhydrous and amorphous forms, as well as to amorphous microparticles of chlorothiazide sodium and potassium which were produced by spray drying and had a large specific surface area. The tablet hardness and tensile strength, porosity, and specific surface area of single-component, convex tablets prepared at different compression pressures were characterized. Results confirmed the complexity of the compressibility mechanisms. In general it may be concluded that factors such as solid-state form (crystalline vs amorphous), type of hydration (presence of interstitial molecules of water, dehydrates), or specific surface area of the material have a direct impact on the tabletability of the powder. It was observed that, for powders of the same solid state form, those with a larger specific surface area compacted well, and better than powders of a lower surface area, even at relatively low compression pressures. Compacts prepared at lower compression pressures from high surface area porous microparticles presented the shortest times to dissolve, when compared with compacts made of equivalent materials, which had to be compressed at higher compression pressures in order to obtain satisfactory compacts. Therefore, materials composed of nanoparticulate microparticles (NPMPs) may be considered as suitable for direct compaction and possibly for inclusion in tablet formulations as bulking agents, APIs, carriers, or binders due to their good compactibility performance.

Swellable elementary osmotic pump (SEOP): An effective device for delivery of poorly water-soluble drugs

A new type of elementary osmotic pump (EOP) tablet for efficient delivery of poorly water-soluble/practically insoluble drugs has been designed. Drug release from the system, called swellable elementary osmotic pump (SEOP), is through a delivery orifice in the form of a very fine dispersion ready for dissolution and absorption. SEOP tablets were prepared by compressing the mixture of micronized drug and excipients into convex tablets. Factors affecting the release of drug from the SEOP tablets containing a poorly water-soluble drug, indomethacin, have been explored. The release behaviour of indomethacin from different formulations of this dosage form was studied at pH 6.8 for a period of 24 h. The formulations were compared based on four comparative parameters, namely, D 24h (total release after 24 h), t L (lag time), RSQ zero ( R square of zero order equation) and D% zero (percentage deviation from zero order kinetics). The drug release profile from osmotic devices showed that the type of polymer in the core formulation can markedly affect the drug release. The results showed that concentration of wetting agent in the core formulation was a very important parameter in D 24h and release pattern of indomethacin from SEOP system. Increasing the amount of wetting agent to an optimum level (60 mg) significantly increased D 24h and improved zero order release pattern of indomethacin. Increasing concentration of caster oil (hydrophobic) in the semipermeable membrane of the device or hydrophilic plasticizer (glycerin) in coating formulation markedly increased t L and decreased D 24h. The results also demonstrated that aperture size is a critical parameter and should be optimized for each SEOP system. Optimum aperture diameter for the formulations studied here was determined to be 650 μm for zero order release pattern. t L and D% zero were dramatically decreased whereas D 24h and RSQ zero increased with increasing the aperture size to optimum level. This study also revealed that optimization of semipermeable membrane thickness is very important for approaching zero order kinetics.

Numerical and experimental investigation of capping mechanisms during pharmaceutical tablet compaction

Capping is a common problem in the pharmaceutical tabletting process in which catastrophic failure of the powder compact can occur. It is of great interest to the pharmaceutical industry to understand the fundamental reasons why capping occurs and how it can be avoided. Recently, a combined numerical and experimental study on pharmaceutical powder compaction revealed that cone capping, which is a typical failure mechanism during the production of flat-faced cylindrical tablets using powders of low tensile strength, is due to the formation of a narrow band with localised, intensive shear stresses running from the top edge towards the bottom centre of the tablet [C.Y. Wu, O. Ruddy, A.C. Bentham, B.C. Hancock, S.M. Best, J.A. Elliott, Modelling the mechanical behaviour of pharmaceutical powders during compaction, Powder Technology, 152 (2005)107–117.]. In this paper, the results of further studies are reported in an attempt to explore possible methods to alleviate the propensity for tablets to cap. These methods have been systematically investigated using finite element methods (FEM), and include using lubrication to reduce the die-wall friction, employing different tooling kinematics (speeds and compression profiles), making tablets with different thicknesses, and making convex tablets using punches with curved surfaces. It has been found that none of these methods could avoid the development of intensive shear bands during unloading, which implies that capping cannot necessarily be avoided using these methods. In addition, physical experiments using a compaction simulator have also been carried out, in particular, for making convex tablets with different curvatures. The tablets produced were examined using X-ray microtomography (XMT), from which the failure patterns were identified and found to be in very good agreement with the numerical analysis. The combination of experimental and numerical studies has demonstrated that: (i) capping takes place during the decompression (unloading) phase, and (ii) the intensive shear bands formed during decompression are responsible for the occurrence of capping.

Liquid boundary movements in cylindrical and convex hydrophobic matrix tablets: Effects on tablet cracking and drug release

The aim of this study was to investigate liquid penetration into both cylindrical and convex hydrophobic matrix tablets and to relate the changes in tablet structure to drug release. Starch acetate with degree of substitution of 2.7 was used as a hydrophobic matrix former and anhydrous caffeine as a freely soluble model drug. Phenolred was used as a colouring agent to enhance the visual detection of the liquid boundary movements, which were examined in axial and radial directions for both types of tablets. The tablets started to expand during the dissolution, resulting in cracking as the liquid boundary penetrated into tablet. The cracking influences drug release by shortening the diffusion path and decreasing the tortuosity. The liquid boundaries proceed differently in cylindrical and convex tablets, this being attributable to differences in pore structure and density distribution. Cylindrical tablets are quite homogeneous in terms of density, but convex tablets have more porous areas at the domes of the tablet.

Analysis of tablet compaction. II. Finite element analysis of density distributions in convex tablets

A Drucker‐Prager/cap constitutive model, where the elastic and plastic model parameters are expressed as a function of relative density (RD), was presented in a companion article17 together with experimental calibration procedures. Here, we examine the RD distribution in curved‐faced tablets with special reference to the die wall lubrication conditions. The compaction of powders is examined using finite element analysis, which involves the following factors: constitutive behavior of powder, friction between powder and tooling, geometry of die and punches, sequence of punch motions, and initial conditions that result from die fill. The predictions of the model are validated using experimental RD maps. It is shown that different die wall lubrication conditions induce opposite density distribution trends in identical tablets (weight, height, and material). The importance of the internal tablet structure is illustrated with respect to break force, failure mode, and friability: it is demonstrated that for a given average tablet density the break force and failure mode are not unique. Also, tablet regions having lower density locally have higher propensity for damage. The applicability of finite element analysis for optimizations of formulation design, process development, tablet image, and tool design is discussed.

Influence of the punch diameter and curvature on the yield pressure of MCC-compacts during Heckel analysis

The volume reduction behaviour of powders has been quantified by means of the 'in-die' yield pressure (YP) using Heckel analysis. However, because different YPs are reported for the same material, the experimental conditions influencing this material-constant were investigated. Silicified microcrystalline cellulose was compressed into flat-faced and convex tablets using a compaction simulator instrumented with load and displacement transducers. During compression, upper and lower punch force and displacement data were recorded and corrected for punch deformation. A symmetrical triangle wave compression profile was used and the instantaneous punch velocity was kept constant (5mm/s). Individual tablet height and weight were used for Heckel analysis. The influence of the 'effective compression pressure' (P(EFF)) (ranging from 10 to 350 MPa), punch diameter (PD) (4, 9.5 and 12 mm) and filling depth (FD) (4.5, 7.5 and 10.5mm) on YP was statistically evaluated using Response Surface Modelling software. A quadratic surface response equation, describing the relationship between P(EFF), PD, FD and YP, was proposed for concave (Adj R(2): 0.8424; S.D.: 14.60 MPa) and flat-faced (Adj R(2): 0.8409; S.D.: 4.49 MPa) punches. YP and tensile strength were mainly determined by P(EFF), irrespective of punch curvature. FD and PD had only a minor influence on the YP, although more pronounced for the concave punches. The method used resulted in reproducible P(EFF) and tensile strength values and the flat-faced tablets showed less weight variation. Flat-faced punches are preferred over punches with a concave surface when investigating the volume reduction behaviour of a powder by means of Heckel analysis and the experimental parameters should be reported.

Finite element analysis of diffusional drug release from complex matrix systems.: II. Factors influencing release kinetics

This work concentrated on the analysis of several factors influencing the kinetics of diffusional drug release from complex matrix devices, such as convex tablets and rings, into a finite volume. These factors include initial drug concentration distribution, anisotropic matrix, and time- and concentration-dependent diffusion coefficients. The individual and comprehensive effects of these factors on the release kinetics were investigated by the finite element method. Errors introduced by neglecting drug diffusion through the ends or edges of cylindrical devices were estimated by comparison of the 1-D models with the 2-D cylinder model. The influence of side-wall coating on the accuracy of the prediction of release profiles by the 1-D slab model for cylindrical devices was studied using various coating materials of different permeabilities. The analyses carried out in this work could assist the design of the complex matrix systems required for controlled drug release.

Punch Geometry and Formulation Considerations in Reducing Tablet Friability and Their Effect on In Vitro Dissolution

The tablet friability resulting from formulation variations was studied under controlled granulation moisture content and tablet crushing strength. Tablets made with lactose were more friable than tablets made with microcrystalline cellulose. Replacement of 0.5% magnesium stearate with 0.5% stearic acid in the formula reduced tablet friability, whereas the combination of 0.5% stearic acid and up to 0.25% magnesium stearate did not increase tablet friability, decrease drug dissolution rate, or increase tablet-to-tablet variability in dissolution. Tablets compressed with extra deep concave punches resulted in lower friability compared with tablets compressed with standard concave or deep concave punches. The friabilities of the standard convex and deep convex tablets were similar, indicating that a critical level of punch tip curvature was important in reducing tablet friability. The dissolution rate was not affected by the punch tip geometry, but the tablet-to-tablet dissolution variability at the 0.5% stearic acid level for the extra deep convex tablets was higher compared with the standard convex tablets.