The bending strength of tablets with a breaking line--Comparison of the results of an elastic and a "brittle cracking" finite element model with experimental findings.

The aim of this work was to ascertain the influence of the position of the breaking line of bevel-edged tablets in a three-point bending test. Two different brands of commercially available, flat-round, bevel-edged tablets with a single central breaking line were studied. Breaking line positions tested, relative to the upper loading roll, were 0°, 22.5°, 45°, 67.5° and 90°. The breaking line faced either up- or downwards during the test. The practical results were compared with FEM results simulating similar test configurations. Tablets failed mainly across the failure plane, resulting in two tablet halves. An exception to this was found for tablets where the breaking line faced down and was positioned at an angle of 22.5° relative to the loading plane. Here the crack followed the breaking line in the centre of the tablets and only diverged towards the loading plane position at the edges of the tablets. The breaking line facing upwards resulted in a significantly higher tensile strength of the tablets compared to it facing downwards. However, with one exception, the orientation of the breaking line relative to the loading plane appeared not to affect the tensile strength values. A fully elastic FEM model indicated that both the position of the breaking line relative to the loading plane and as to whether the breaking line faced up- or downwards during the bending test would result in considerably different failure loads during practical experiments. The results also suggested that regardless of the breaking line position, when it is facing down crack propagation should start at the outer edges propagating towards the midpoint of the discs until failure occurs. Failure should hence always result in equal tablet halves, whereby the failure plane should coincide with the loading plane. Neither predictions fully reflected the practical behaviour of the tablets. Using a brittle cracking FEM model significantly larger tensile stresses for tablets with the breaking line positioned downwards at 0° or 22.5° relative to the loading plane were still predicted, but the differences between model and experimental values was greatly reduced. The remaining differences are more likely due to the inadequacy of the equation available to calculate the experimental tensile strength values. This equation cannot account for the presence of a breaking line and overestimates the thickness of the loading plane by the depth of the breaking line when in 0° or 22.5° position. If the depth of the breaking line is taken into account, the model predictions and the experimental findings are comparable. Also, in the brittle cracking FEM simulations the predicted crack propagation patterns were similar to those found in the experiments, and the model stress distributions across the lower surfaces were much more homogeneous and streamlined parallel to the loading plane. The brittle cracking model hence reflected the practicalities of the bending test more closely. The findings suggested that with the breaking line facing down fracture should always start in the centre of a tablet at its lower surface, initiated by the breaking line. Due to simultaneous development of larger stresses along the y-axis the tablet should still break into two equal halves along the loading plane, unless the position of the breaking line relative to the loading plane was 22.5°. In this case the tablet would fail by a mixed process, whereby failure would occur mainly along the breaking line, but due to simultaneous crack formation at the lower surface close to the bevel edge parallel to the loading plane the final breaking pattern would deviate from the breaking line about half-way from its centre, as seen in the practical experiments.

Theoretical investigations into the influence of the position of a breaking line on the tensile failure of flat, round, bevel-edged tablets using finite element methodology (FEM) and its practical relevance for industrial tablet strength testing.

Flat, round tablets may have a breaking ("score") line. Pharmacopoeial tablet breaking load tests are diametral in their design, and industrially used breaking load testers often have automatic tablet feeding systems, which position the tablets between the loading platens of the machine with the breaking lines in random orientation to the applied load. The aim of this work was to ascertain the influence of the position of the breaking line in a diametral compression test using finite element methodology (FEM) and to compare the theoretical results with practical findings using commercially produced bevel-edged, scored tablets. Breaking line test positions at an angle of 0°, 22.5°, 45°, 67.5° and 90° relative to the loading plane were studied. FEM results obtained for fully elastic and elasto-plastic tablets were fairly similar, but they highlighted large differences in stress distributions depending on the position of the breaking line. The stress values at failure were predicted to be similar for tablets tested at an angle of 45° or above, whereas at lower test angles the predicted breaking loads were up to three times larger. The stress distributions suggested that not all breaking line angles would result in clean tensile failure. Practical results, however, did not confirm the differences in the predicted breaking loads, but they confirmed differences in the way tablets broke. The results suggest that it is not advisable to convert breaking loads obtained on scored tablets into tablet tensile strength values, and comparisons between different tablets or batches should carefully consider the orientation of the breaking line with respect to the loading plane, as the failure mechanisms appear to vary.

Investigations into the tensile failure of doubly-convex cylindrical tablets under diametral loading using finite element methodology.

In the literature various solutions exist for the calculation of the diametral compression tensile strength of doubly-convex tablets and each approach is based on experimental data obtained from single materials (gypsum, microcrystalline cellulose) only. The solutions are represented by complex equations and further differ for elastic and elasto-plastic behaviour of the compacts. The aim of this work was to develop a general equation that is applicable independently of deformation behaviour and which is based on simple tablet dimensions such as diameter and total tablet thickness only. With the help of 3D-FEM analysis the tensile failure stress of doubly-convex tables with central cylinder to total tablet thickness ratios W/D between 0.06 and 0.50 and face-curvature ratios D/R between 0.25 and 1.85 were evaluated. Both elastic and elasto-plastic deformation behaviour were considered. The results of 80 individual simulations were combined and showed that the tensile failure stress σt of doubly-convex tablets can be calculated from σt=(2P/πDW)(W/T)=2P/πDT with P being the failure load, D the diameter, W the central cylinder thickness, and T the total thickness of the tablet. This equation converts into the standard Brazilian equation (σt=2P/πDW) when W equals T, i.e. is equally valid for flat cylindrical tablets. In practice, the use of this new equation removes the need for complex measurements of tablet dimensions, because it only requires values for diameter and total tablet thickness. It also allows setting of standards for the mechanical strength of doubly-convex tablets. The new equation holds both for elastic and elasto-plastic deformation behaviour of the tablets under load. It is valid for all combinations of W/D-ratios between 0.06 and 0.50 with D/R-ratios between 0.00 and 1.85 except for W/D=0.50 in combination with D/R-ratios of 1.85 and 1.43 and for W/D-ratios of 0.40 and 0.30 in combination with D/R=1.85. FEM-analysis indicated a tendency to failure by capping or even more complex failure patterns in these exceptional cases. The FEM-results further indicated that in general W/D-ratios between 0.15 and 0.20 are favourable when the overall size and shape of the tablets is modified to give maximum tablet tensile strength. However, the maximum tensile stress of doubly-convex tablets will never exceed that of a flat-face cylindrical tablet of similar W/D-ratio. The lowest tensile stress depends on the W/D-ratio. For the thinnest central cylinder thickness, this minimum stress occurs at D/R=0.50; for W/D-ratios between 0.10 and 0.20 the D/R-ratio for the minimum tensile stress increases to 0.67, and for all other central cylinder thicknesses the minimum tensile stress is found at D/R=1.00.

The filling of powdered herbs into two-piece hard capsules using hydrogenated cotton seed oil as lubricant.

The aim of this work was to investigate the plug formation and filling properties of powdered herbal leaves using hydrogenated cotton seed oil as an alternative lubricant. In a first step, unlubricated and lubricated herbal powders were studied on a small scale using a plug simulator, and low-force compression physics and parameterization techniques were used to narrow down the range in which the optimum amount of lubricant required would be found. In a second step these results were complemented with investigations into the flow properties of the powders based on packing (tapping) experiments to establish the final optimum lubricant concentration. Finally, capsule filling of the optimum formulations was undertaken using an instrumented tamp filling machine. This work has shown that hydrogenated cotton seed oil can be used advantageously for the lubrication of herbal leaf powders. Stickiness as observed with magnesium stearate did not occur, and the optimum lubricant concentration was found to be less than that required for magnesium stearate. In this work, lubricant concentrations of 1% or less hydrogenated cotton seed oil were required to fill herbal powders into capsules on the instrumented tamp-filling machine. It was found that in principle all powders could be filled successfully, but that for some powders the use of higher compression settings was disadvantageous. Relationships between the particle size distributions of the powders, their flow and consolidation as well as their filling properties could be identified by multivariate statistical analysis. The work has demonstrated that a combination of the identification of plug formation and powder flow properties is helpful in establishing the optimum lubricant concentration required using a small quantity of powder and a powder plug simulator. On an automated tamp-filling machine, these optimum formulations produced satisfactory capsules in terms of coefficient of fill weight variability and capsule weight.

Methods for the practical determination of the mechanical strength of tablets--from empiricism to science.

This review aims to awake an interest in the determination of the tensile strength of tablets of various shapes using a variety of direct and indirect test methods. The United States Pharmacopoeia monograph 1217 (USP35/NF30, 2011) has provided a very good approach to the experimental determination of and standards for the mechanical strength of tablets. Building on this monograph, it is hoped that the detailed account of the various methods provided in this review will encourage industrial and academic scientists involved in the development and manufacture of tablet formulations to take a step forward and determine the tensile strength of tablets, even if these are not simply flat disc-shaped or rectangular. To date there are a considerable number of valid test configurations and stress equations available, catering for many of the various shapes of tablets on the market. The determination of the tensile strength of tablets should hence replace the sole determination of a breaking force, because tensile strength values are more comparable and suggestions for minimum and/or maximum values are available. The review also identifies the gaps that require urgent filling. There is also a need for further analysis using, for example, Finite Element Method, to provide correct stress solutions for tablets of differing shapes, but this also requires practical experiments to find the best loading conditions, and theoretical stress solutions should be verified with practical experiments.

The influence of plate design on the properties of pellets produced by extrusion and spheronization.

The aim of this work was to produce pellets using a standard formulation by means of extrusion and spheronization. Three different spheroniser friction plate patterns (i.e. cross-hatch, radial, striated edge pattern) have been used in order to investigate whether the plate pattern affects physical properties of the pellets such as pellet size distribution, yield, shape, mechanical strength, density and drug dissolution. Extrusion was performed with a screen extruder and the screen size was varied to determine whether the extrudate produced could affect the physical properties of pellets. The plate load was also varied. Diclofenac sodium was chosen as a model drug. The pattern of the friction plate used in the spheronization of extrudates affected the properties of the pellets. Yield values varied by up to 20%, and for an otherwise optimised formulation the use of a striated edge plate appeared advantageous in this respect. However, these pellets had a reduced mechanical strength despite their lower porosity, which might be disadvantageous. In addition, other factors such as the amount of extrudate loaded into the spheroniser, the maintenance of a constant moisture content within the spheroniser and the size of the extruder screen influenced these findings significantly. The only physical property of the pellets that did not respond to the various changes in the manufacturing process of the pellets is the pellet shape, which remained spherical. The dissolution of the drug appeared to be related to the median pellet size and was only marginally affected by changes in the spheronization process.

Theoretical and experimental investigations into the delamination tendencies of bilayer tablets.

Delamination is one major problem in the production of layered tablets, yet there is little knowledge about the physical reasons for this to occur. The aim of this work was to explore the theoretical influence of thermal stresses and strains that can develop during tabletting and to devise an experimental method that can be used to detect delamination tendencies in bilayered tablets. Theoretical considerations have shown that thermal stresses due to development of heat during powder compaction can result in delamination, and this effect is the more pronounced the larger the Young's modulus for the individual layer materials is. Elastic mismatch further enhances delamination tendencies. Experiments on mixed powder beams showed that there is only limited adhesion between particle surfaces of a model drug (acetylsalicylic acid) and model excipient (lactose monohydrate), indicative of limited adhesion between similar interfaces in layered tablets. A three-point bending test was developed to determine the far field stress intensity factor for bilayered compacts. Under the test conditions employed, lactose monohydrate behaved as a brittle material, whereas acetylsalicylic acid demonstrated ductility, which resulted in considerable differences in the far field stress intensity factor values, depending on whether the excipient or the drug formed the downward facing layer during the bending test. Ductile phase toughening was observed when the drug formed the downward facing layer, and hence for bilayer tablets made from these two powders lactose monohydrate must form the downward facing layer during the test. Using the correct test configuration the far field stress intensity factor correctly predicted practically observed delamination between the two material layers. Hence, the proposed fracture mechanics approach could become a formulation tool in the development of bilayered tablets.

The tensile strength of bilayered tablets made from different grades of microcrystalline cellulose.

The aim of this work was to determine the tensile strength of bilayered tablets made from different grades of microcrystalline cellulose. While these grades are chemically identical, they differ significantly in their particle size distribution and in their mechanical properties such as Young's modulus of elasticity. Tablets were produced in the shape of beams of similar dimensions using uniaxial compression, and solid beams made from one material only were compared with bilayered beams made from various combinations of powders. It was found that in the production of layered tablets it is important for the purpose of quality assurance and control that the upper and lower layer of the compact can be identified. Otherwise, tensile strength measurements will result in large variability depending on which layer faces upwards during the test. Both particle size and Young's modulus of elasticity influenced the overall strength of layered tablets. If the material forming the lower layer was more elastic, then the beam strength was reduced due to tension introduced into the system, acting especially at the layer interface and potentially causing partial or complete delamination. Larger differences in the particle size of the materials forming the tablet layers resulted in an overall reduced compact tensile strength.

Assessment of the in-vivo drug release from pellets film-coated with a dispersion of high amylose starch and ethylcellulose for potential colon delivery.

OBJECTIVES: The aim of this study was to test the ability of a colon targeting system comprising pellets film-coated with a dispersion of high amylose starch (Hylon VII) and ethylcellulose (Surelease) (1 : 2 w/w) to deliver a model drug (5-aminosalicylic acid; 5-ASA) in vivo into the colon of rabbits. An uncoated pellet formulation was used as a control. METHODS: Six New Zealand female rabbits, approximately 2 kg, were randomly divided into two groups. Pellet formulations containing 50 mg/kg of 5-ASA were filled into hard gelatin capsules size 4, and were administered orally using a cannula. The rabbits were fasted for 12 h before, and throughout, the study but had free access to water. Blood samples were collected, through a catheter inserted into the marginal vein of the ear, at pre-determined times and the plasma analysed by a validated HPLC method with fluorescence detection. RESULTS: Analysis of the 5-ASA plasma levels following administration of the uncoated pellets showed a C(max) of 2.38 +/- 0.49 microg/ml at 2 h post administration confirming that this system released the drug at an unspecific site, most likely in the rabbits' stomach and proximal small intestine. On the other hand, the coated formulation showed a delayed drug absorption (C(max) 0.22 +/- 0.19 microg/ml and t(max) of 8 h), suggesting that the coating is able to prevent drug release in the stomach and small intestine, but allowing drug release in the colon. The coated pellets were retrieved from the rabbits' faeces after the 24-h study. They had a drug content of < 40%, suggesting that the film-coating had been digested by the bacterial amylases of the colon and the drug was released specifically in the colon of the rabbits. CONCLUSIONS: Results from this study showed that the proposed drug delivery system has the potential to deliver drugs specifically into the colon.

Influence of the coating formulation on enzymatic digestibility and drug release from 5-aminosalicylic acid pellets coated with mixtures of high-amylose starch and Surelease intended for colon-specific drug delivery.

BACKGROUND: Colon-specific delivery of drugs can be achieved with dosage forms coated with biopolymers that are metabolized selectively by the colonic microflora and yet resistant to enzymatic digestion in the small intestine. AIM: The aim of this study was to study the influence of formulation factors on the performance of mixed films from high-amylose starches and Surelease((R)), applied using a spray-coating process, as potential colon-specific delivery devices. METHODS: 5-Aminosalicylic acid-loaded pellets were prepared by an extrusion-spheronization process and film coated with mixtures of the starches and Surelease((R)). Optimization of the coating formulation, that is, starch-to-Surelease((R)) ratio, film-coating thickness, and type of starch, was undertaken first in enzyme-free media resembling the conditions in the stomach and small intestine. The effect of curing of the film coating on the drug release profile upon storage was also evaluated. Optimized coating formulations were further assessed for enzymatic digestibility using artificial gastric and intestinal juices containing commercially available pepsin and pancreatin or alpha-amylase from hog pancreas, respectively. Finally, drug release was assessed in fluid-simulating conditions in the colon (SCF) containing Bacillus licheniformis alpha-amylase. RESULTS: Film coatings comprising high-amylose starches and Surelease((R)) in a ratio of 1:2 (w/w) and film thickness of approximately 45 microm were able to withstand the chemical and enzymatic environment of the upper gastrointestinal tract, in particular, resisted degradation by the pancreatic alpha-amylases. Stability of the coatings during storage was achieved with additional curing. In SCF, these coatings were susceptible to enzymatic degradation. CONCLUSIONS: This study showed that high amylose starch-mixed films can be successfully used as colon-specific delivery devices. The preparation of the coating dispersions described is simple and rapid, without the need to extract the amylose component of starch.

The influence of non-ionic surfactants on the rheological properties of drug/microcrystalline cellulose/water mixtures and their use in the preparation and drug release performance of pellets prepared by extrusion/spheronization.

The influence of adding two concentrations (5 and 25%) of non-ionic surfactants, one hydrophilic and the other hydrophobic, plus mixtures of equal parts of the two, on the rheological properties of a mixture of equal parts of microcrystalline cellulose and ibuprofen with water has been assessed by capillary rheometry. The mixtures were also used to form pellets by extrusion/spheronization and their in vitro dissolution in simulated intestinal fluid was measured. As with previous rheological studies of these types of pastes, the flow was non-Newtonian (shear thinning). Other rheological parameters were determined in terms of die entry angles, extensional flow and elastic parameters of recoverable shear and compliance. By comparisons with previous studies with the model drug, it was found that it was these latter parameters that were indicative of the ability of the formulations to produce satisfactory pellets. The experiments also identified that the level of surfactant as opposed to the type of surfactant determined the rheological properties of the wet mass. All the formulations were able to produce round pellets with a narrow size distribution, whereby their median size increased with the concentration of the surfactant. The 25% level of each of the surfactant formulations provided a rapid release of the drug (100% within 30min), but the 5% level and the mixed surfactant formulations provided lower drug release profiles.

Starch-based coatings for colon-specific drug delivery. Part I: the influence of heat treatment on the physico-chemical properties of high amylose maize starches.

In this study, the changes in the physico-chemical properties of different high amylose maize starches, i.e., Hylon VII, Hylon V and IM-DS acetate starch, were studied prior and after heat treatment used in the preparation of film coatings (WO 2008/012573 A1). Characterisation of the unprocessed maize starches was carried out with regard to the outer particle morphology, particle size distribution, specific surface area, moisture content, apparent particle density, swelling, polarised light microscopy, Fourier Transform Infrared (FT-IR), X-ray powder diffraction and modulated Differential Scanning Calorimetry (mDSC). Pure amylopectin and low amylopectin samples (LAPS) were also used to aid the interpretation of the results. The effect of heat processing was evaluated in terms of degree of crystallinity, FT-IR and mDSC. Enzymatic digestibility of both processed and unprocessed maize starches was estimated qualitatively using various alpha-amylases resembling those present under in vivo conditions. A significant decrease in the degree of crystallinity of the dried samples after processing was observed, in particular for amylopectin. Only LAPS and Hylon VII samples showed differences in their thermal behaviour upon heat treatment, thus suggesting that a minimum amount of amylose is required for an effect to be detectable. High amylose starches maintained a well-ordered arrangement of their macromolecular chains, as was seen by X-ray and FT-IR studies. This effect could be explained by a formation of retrograded forms of the starches. The retrograded starches were found to be less digestible by various types of amylase, in particular those found in the upper intestines, indicating that the formation of a butanol complex as claimed elsewhere is not essential in the preparation of colon delivery devices.

The rheological properties of modified microcrystalline cellulose containing high levels of model drugs.

The rheological properties of different types of microcrystalline cellulose (MCC) mixed with model drugs and water have been evaluated to identify the influence of sodium carboxymethylcellulose (SCMC) added to the cellulose during preparation. A ram extruder was used as a capillary rheometer. The mixtures consisted of 20% spheronizing agent (standard grade MCC or modified types with 6% or 8% of low viscosity grade SCMC) and 80% of ascorbic acid, ibuprofen or lactose monohydrate. The introduction of SCMC changed all rheological parameters assessed. It produced more rigid systems, requiring more stress to induce and maintain flow. Degree of non-Newtonian flow, angle of convergence, extensional viscosity, yield and die land shear stress at zero velocity, and static wall friction were increased, but recoverable shear and compliance were decreased. The presence of SCMC did not remove the influence of the type of drug. The mixture of ibuprofen and standard MCC had the lowest values for shear stress as a function of the rate of shear, extensional viscosity, and angle of convergence, but the highest values for recoverable shear and compliance. The findings indicate that the system has insufficient rigidity to form pellets.

The gastric emptying of food as measured by gamma-scintigraphy and electrical impedance tomography (EIT) and its influence on the gastric emptying of tablets of different dimensions.

A study in human volunteers has been designed to evaluate the influence of different food regimes on the gastric emptying of 3 mm and 10 mm diameter tablets. Dextrose and beef drinks were used as liquid food; a mixture of minced beef and mashed potato (shepherd's pie) was used as a solid meal. The gastric emptying of these foods was monitored simultaneously with electrical impedance tomography (EIT) and gamma-scintigraphy (GS), and was quantified in terms of the time before gastric emptying started, the lag time, the mean gastric residence time (MGRT) and its variance (VGRT), and the time for complete emptying. The gastric emptying time of the tablets was established by monitoring the position of the tablets, which had been labelled with suitable radio isotopes, by GS. The two systems for monitoring gastric emptying of the foods did not provide equivalent results: times obtained with EIT were generally shorter than those obtained with GS for the liquid foods, but were longer for the solid meal. There was only a slight difference in the emptying times of the two liquid foods, whereas values for MGRT, VGRT and the time for complete emptying were considerably longer for the solid meal. In nearly all instances the tablets emptied after the foods had emptied completely from the stomach. Gastric emptying times were longer for the 3 mm tablets than the 10 mm tablets, whatever food they were taken with. The difference between the median emptying times was significant when the meal was either a dextrose solution or a beef drink, but not when the meal was shepherd's pie. The increase in gastric emptying time of tablets induced by solid food was greater than that associated with the differences in tablet size. By providing a protocol that did not allow the administration of further food until after the tablets had emptied from the stomach, no tablet emptying times exceeded 6 h.

The determination of the mechanical strength of tablets of different shapes.

The aim of the study was to investigate the influence of the platen design, on the evaluation of the mechanical strength of tablets of different shapes in terms of the potential of ensuring reproducible failure mechanisms and deriving their tensile strength. Tablets which were circular, square or hexagonal in shape were prepared at a range of formation pressures each from microcrystalline cellulose (Avicel PH102), a direct compression anhydrous beta-lactose (DCL 21) and dicalcium phosphate dihydrate (Emcompress) with a reciprocating single punch tablet machine. The mechanical strength of the tablets has been determined with a three-point bending test and by applying a diametral load across the edges of the tablets with platens of different designs. Many of the tablets tested in three-point bending did not fail in tension. However, with platens to which semi-circular rods of radius 3.0mm were attached and vertically aligned, a test procedure was provided with which a wide range of tablets tested failed in tension, i.e., split into two halves. Where this occurred it was possible to calculate the tensile strength from the breaking load. Although the value of the tensile strength obtained with such platens was generally lower than that obtained for circular tablets when flat platens were used, the ability to be able to use this new configuration for all the tablet shapes provided a practical system for a range of tablet shapes. The tablets of the three shapes tested here were found to have equivalent values for the tensile strength when formed at the same compaction pressure for the three materials tested.

Evaluation of the role of pores during strength testing in compacts made from different particle size fractions of sucrose.

The purpose of this study was to investigate the role of pores in the fracture of circular compacts and to predict compact properties and critical crack lengths. Four different particle size fractions of sucrose, ranging from 20 to 500 microm, were compressed into circular discs (i.e. flat tablets) and rectangular beam specimens of porosity between 30 and 14%. Modelling of the relationship between the tensile strength of the circular discs and the compact porosity indicated extensive fragmentation during compaction for particles in the size range of 250-500 microm, accompanied by a change in densification mechanism for very coarse particles (355-500 microm). When determining the critical stress intensity factor from rectangular single edge notched beam specimens by 3-point bending, an apparent influence of particle size on the values could be seen, whereby here the results indicated that the critical particle size for fragmentation to occur is about 20-40 microm. It was possible to predict the critical stress intensity factor of the compacts from the median pore size and the tensile strength of the circular disc specimens by interpolation of the critical crack length for propagation to occur. The results indicated that for sucrose compacts regardless of their porosity, the pores themselves acted as stress concentrators, not as sharp cracks. For sucrose compacts, crack propagation hence proceeds most likely along grain boundaries.