Development of New Shaped Punch to Predict Scale‐up Issue in Tableting Process

Scale‐up issues in the tableting process, such as capping, sticking, or differences in tablet thickness, are often observed at the commercial production scale. A new shaped punch, named the size adjusted for scale‐up (SAS) punch, was created to estimate scale‐up issues seen between laboratory scale and commercial scale tableting processes. The SAS punch's head shape was designed to replicate the total compression time of a laboratory tableting machine to that of a commercial tableting machine. Three different lubricated blends were compressed into tablets using a laboratory tableting machine equipped with SAS punches, and any differences in tablet thickness or capping phenomenon were observed. It was found that the new shaped punch could be used to replicate scale‐up issues observed in the commercial tableting machine. The SAS punch was shown to be a useful tool to estimate scale‐up issues in the tableting process. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:235–240, 2014     

Calculation of punch displacement and work of powder compaction on a rotary tablet press

To calculate the work of compaction during tableting it is necessary to have accurate values of force and punch displacement. The direct measurement of punch displacement on a rotary press is both costly and complicated but calculated displacements will be in considerable error unless deflections in the press during compression, are taken into account. By analysing the physical restraints imposed on the punches during tablet compression, an expression for punch displacement was derived. From preliminary measurements made on the table press of machine deflections and punch displacement under static conditions, the terms of this expression were evaluated for dynamic conditions. This analytic solution was then used to determine the true punch displacement and work of compaction from direct measurements of vertical force and turret position.     

Development of a New Punch Head Shape to Replicate Scale-Up Issues on a Laboratory Tablet Press III: Replicating Sticking Phenomenon Using the SAS Punch and Evaluation by Checking the Tablet Surface Using 3-D Laser Scanning Microscope

Sticking is a common observation in the scale-up stage on the punch tip using a commercial tableting machine. The difference in the total compression time between a laboratory tableting machine and a commercial one is considered one of the main root causes of scale-up issues in the tableting processes. The proposed “Size Adjusted for Scale-up punch” can be used to adjust the consolidation and dwell times for commercial tableting machine. As a result, the sticking phenomenon is able to be replicated at the pilot scale stage. As reported in this article, the quantification of sticking was done using a 3-D laser scanning microscope to check the tablet surface. It was shown that the sticking area decreased with the addition of magnesium stearate in the formulation, but the sticking depth was not affected by the additional amount of magnesium stearate. It is proposed that the use of a 3-D laser scanning microscope can be applied to evaluate sticking as a process analytical technology tool, and so sticking can be monitored continuously without stopping the machine.     

A novel method for the detection of sticking of tablets.

The purpose of this work was to develop an instrumented upper punch to measure the adhesion force which occurs when the punch detaches itself from the upper surface of the tablet after compression. A specially designed adhesion force sensor instrumented with semiconductor strain gauges was inserted into an upper punch with a 25-mm punch face diameter suitable for a Korsch EK II eccentric press. Sorbitol, microencapsulated acetylsalicylic acid (ASA), and a formulation of a new active ingredient resulted in characteristic pull-off signals, providing a quantitative measure of the adhesion force. With "sticking-free" substances such as microcrystalline cellulose, tension signals could not be obtained; only Starch 1500 showed small adhesion force signals that indicated a sticking tendency. The compression force had a specific influence on the extent of the adhesion force; increasing the compression force caused an increase (sorbitol) or a decrease (ASA) of the adhesion force signals due to the plastic and elastic behavior of the substances. Depending on running time, ASA showed an increase in the adhesion force, reaching a plateau after 150 tablets. The addition of lubricants such as magnesium stearate resulted in smaller adhesion forces. The instrumented upper punch is a new helpful tool for the quantification of sticking and a valuable instrument in the development of formulations.     

Granule size distribution of tablets

The purpose of this study was to determine the variation in the granule size distribution in a die of an eccentric tableting machine. Theophylline anhydrate and α‐lactose monohydrate were granulated with an aqueous solution of polyvinylpyrrolidone, using an instrumented fluid bed granulator. The granules were tabletted, using an instrumented eccentric tableting machine. Punch forces were recorded and tablets were collected in order during the tableting process. Powder samples, which had the same mass as the tablets, were also collected from the die for particle size determination. The particle size distribution was measured, using a spatial filtering technique. In addition, the segregation of microcrystalline cellulose pellets during tableting was analyzed. The particle size distribution changed dramatically during the tableting process, due to a segregation phenomenon. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2061–2069, 2010     

Influence of tableting on the enzymatic activity of different alpha-amylases using various excipients.

The purpose of the study was to show the influence of compression pressure on the enzymatic activity of different types of alpha-amylases and to analyze the loss of activity of alpha-amylase in mixtures with different excipients. Following that, the properties of excipients used for tableting enzymes were evaluated. Tablets were produced on an instrumented single punch tableting machine. The pure amylases were tableted with increasing graded compaction pressures. Mixtures were tableted to different maximum relative densities, rho(rel,max). The remaining enzymatic activity of the alpha-amylase in the tablets was determined by the starch iodine reaction. The results show a difference between different types of alpha-amylase depending on their origin and additives. Enzymatic inactivation occurs for the pure materials at all pressures used. It is initiated during and continues after compaction. It can be inhibited by freezing the tablets. Another possibility is to tablet the enzyme in a mixture with excipients, which prevent inactivation by softly embedding the enzyme. One example which even stabilizes alpha-amylase at high volume reduction is kappa-carrageenan. In conclusion, enzymatic inactivation can be markedly reduced when excipients are used for tableting, which require little compaction pressure and are able to release the mechanical stress in the form of expansion.     

Compression physics in the formulation development of tablets

The advantages of high-precision dosing, manufacturing efficiency, and patient compliance make tablets the most popular dosage forms. Compaction, an essential manufacturing step in the manufacture of tablets, includes compression (i.e., volume reduction and particle rearrangement), and consolidation (i.e., interparticulate bond formation). The success of the compaction process depends not only on the physico-technical properties of drugs and excipients, especially their deformation behavior, but also on the choice of instrument settings with respect to rate and magnitude of force transfer. This review discusses various properties of drugs and excipients, such as moisture content, particle size and distribution, polymorphism, amorphism, crystal habit, hydration state, and lubricant and binder level of the blend that have an influence on compaction. Tableting speed and pre/main compression force profile, also have a bearing on the quality of the final tablet. Mechanistic aspects of tableting can be studied using, instrumented punches/dies, instrumented tableting machines, and compaction simulators. These have potential application in pharmaceutical research and development, such as studying basic compaction mechanism, process variables, scale-up parameters, trouble shooting problem batches, creating compaction data bank, and fingerprinting of new active pharmaceutical ingredients (APIs) or excipients. Also, the mathematical equations used to describe compaction events have been covered. These equations describe density-pressure relationships that predict the pressures required for achieving an optimum density. This understanding has found active application in solving the analytical problems related to tableting such as capping, lamination, picking, sticking, etc. Mathematical models, force-time, force-distance, and die-wall force parameters of tableting are used to describe work of compaction, elasticity' plasticity, and time dependent deformation behavior of pharmaceuticals. Various indices of tableting performance such as the bonding index, brittle fracture index, and strain index can be used to predict compaction related problems. Compaction related physico-technical properties of commonly used tableting excipients have been reviewed with emphasis on selecting suitable combination to minimize tableting problems. Specialized tools such as co-processing of API and excipients can be used to improve their functionality.     

The tabletting machine as an analytical instrument: consequences of uncertainties in punch force and punch separation data on some parameters describing the course of the tabletting process.

The influence of the uncertainties involved in the measurement of punch forces and punch separation in an eccentric tableting machine on the validity of the analytical results was evaluated using six direct compression excipients. The analytical parameters considered were the maximum upper punch pressure, the minimum punch separation, the maximum relative density, the contact time, the area quotient according to Emschermann and Müller, the Weibull and Heckel parameters, as well as the total, expansion and apparent net work. The measuring uncertainties were divided into between-run deviations (BD) and within-run deviations (WD), which are constant and variable, respectively, during a tableting event. Both types of uncertainties were expressed as simple error limits. The effects of the measuring BD's were calculated by adding them to the force and displacement data and then computing the analytical parameters in the conventional way. The estimation of the effects of the measuring WD's needs special methods for each parameter. Their validation showed that they were in most cases able to include the true effects of some exemplary selected errors but tend to overestimate them. From the sum of the confidence interval (CI) of a mean parameter value from repeated tableting experiments, the confidence interval with respect to curve fitting, the BD and the WD of the analytical results, the total deviation (TD) of the results was obtained, which provides a worst case measure of the uncertainties. The TD makes a differentiation between materials with similar tableting behaviour impossible in many cases, thus providing too low a selectivity. The best case uncertainties account for the difference in the response of the data to be compared to the measuring errors. The uncertainty decreases considerably under best case conditions. However, the best case intervals predicted from the worst case limits are not generally valid. Thus, besides the TD, only the CI's remain for the assessment of the analytical results. However, in the presence of systematic errors the statistical analysis cannot assure the correctness of the conclusions drawn with the degree of certainty supposed, even if the systematic measuring errors are the same for the data to be compared.     

Influence of crystal hydration on the mechanical properties of sodium naproxen.

The aim of this work is to establish a correlation between water uptake by anhydrous sodium naproxen (ASN) at two different relative humidities and modifications in tableting and densification behaviour under hydration. Water uptake was evaluated at different relative humidities. Models for the hydration kinetics of ASN at 55% and 86%, corresponding to the formation of the dihydrated and tetrahydrated forms, respectively, were evaluated assuming Eyring's dependence on temperature. Tabletability, compressibility, compactibility, and densification behaviour were determined using an instrumented single punch tablet machine. Kinetic data are consistent with a model where water molecules enter the crystal preferentially along hydrophilic tunnels existing in the crystal structure and corresponding to the propionate side chain. Water inclusion perturbs the crystallographic structure, causing slight structural changes according to the amount and associated to an increase in entropy. The interposition of water molecules between sodium naproxen molecules weakens intermolecular bonds, and these sites can behave like sliding planes under compression. Such structural changes may explain the improved compression behaviour and modified densification propensity mechanism. Kinetic data describing the water hydration mechanism of ASN explain in an original way the improved tableting and densification properties under hydration.     

The influence of engravings on the sticking of tablets. Investigations with an instrumented upper punch.

The purpose of this study was to investigate the influence of engravings on the sticking of tablets. Therefore, an instrumented upper punch capable of measuring the pull-off force, which occurs when the punch detaches itself from the upper surface of a tablet, was equipped with small cones of different angles between the punch face and the cones' lateral face. The cones could be screwed into a threaded hole at the center of the punch face. The adhesion forces of two formulations known to stick to engravings during production increased with a greater steepness of the cones' lateral face. With microencapsulated acetylsalicylic acid, no quantitative differences could be found between the adhesion forces obtained with plain and modified punch faces, indicating that the sticking behavior of the substance was not affected by shear forces. Starch 1500 showed higher adhesion force signals in comparison to those obtained with a plain punch face. Microcrystalline cellulose, which gave no adhesion force signals with a plain punch face and did not stick to the cones, showed distinct pull-off signals. The instrumented upper punch equipped with shear cones is a valuable instrument for detecting the adhesion caused by engravings and is therefore a helpful tool for tablet formulation development and the design optimization of tablet identification.     

The Influence of Engravings on the Sticking of Tablets. Investigations with an Instrumented Upper Punch

The purpose of this study was to investigate the influence of engravings on the sticking of tablets. Therefore, an instrumented upper punch capable of measuring the pull-off force, which occurs when the punch detaches itself from the upper surface of a tablet, was equipped with small cones of different angles between the punch face and the cones’ lateral face. The cones could be screwed into a threaded hole at the center of the punch face. The adhesion forces of two formulations known to stick to engravings during production increased with a greater steepness of the cones’ lateral face. With microencapsulated acetylsalicylic acid, no quantitative differences could be found between the adhesion forces obtained with plain and modified punch faces, indicating that the sticking behavior of the substance was not affected by shear forces. Starch 1500® showed higher adhesion force signals in comparison to those obtained with a plain punch face. Microcrystalline cellulose, which gave no adhesion force signals with a plain punch face and did not stick to the cones, showed distinct pull-off signals. The instrumented upper punch equipped with shear cones is a valuable instrument for detecting the adhesion caused by engravings and is therefore a helpful tool for tablet formulation development and the design optimization of tablet identification.     

Compactibility characterization of granular pectin for tableting operation using a compaction simulator

Pectin has great potential as a tableting excipient and drug carrier to the colon. It is a non-toxic, soluble polysaccharide which passes through the stomach and small intestine with limited digestion, but is totally metabolized by the colonic microflora. In the past, drug–pectin matrices coated with pH-dependent polymers have been investigated for possible drug delivery to the colon. Although many scientists have used pectin, its feasibility in terms of tablet manufacturability with a high-speed machine has never been evaluated. In this report compactibility of different pectin types (low and high methoxylated) for large-scale tableting operation have been evaluated. The compactibility behavior of granular pectins were studied by a compaction simulator. It was found that pectin on its own does not produce tablets of acceptable quality even at a punch velocity as low as 20 rpm (e.g. low tensile strengths, capping and lamination irrespective of applied compression force). Heckel plots were constructed and changes in porosity at different compaction pressures and punch velocities were determined. Yield pressures for the pectin at a maximum punch velocity of 50 and 250 mm/s were 200 and 213 MPa, respectively. Such close values indicate that this material primarily consolidates by fragmentation with little plastic deformation. This was further evidenced from a low strain rate sensitivity value (SRS=6.1%) for high methoxylated pectin. The high apparent porosity of 13.8% at 160 MPa shows significant resistance to densification, and compacts underwent substantial elastic recovery (18–25%) during decompression and ejection. These findings suggest that pectin is hard, rigid and poorly compactible. To improve tabletability of pectin, a 50/50 binary mixture with microcrystalline cellulose was evaluated and excellent compacts were produced at all compaction rates and pressures. It is concluded that frequent structural failures observed in both pectin types are due to lack of plastic deformation, poor compactibility and high elastic recovery.     

The application of photoelastic techniques to a rotary tabletting machine

Powders have been compacted on a rotary tabletting machine, using a Perspex die mounted above the die table, with an extended lower punch and a shortened upper punch. By high speed cine photography in polarized light, the fringes due to the radial stress in the die wall were recorded during compaction. At the same time, the upper and lower punch forces were monitored by instrumented pressure rollers coupled to a recording oscilloscope. The total information thus obtained was sufficient to enable compression cycles to be determined for the first time on a rotary machine.     

A modified pressure wheel for the instrumentation of rotary tabletting machines

IN any research into tabletting processes, it is necessary to know the force applied at the punch so that the tabletting pressure may be calculated. Much work has been done using single punch machines having strain gauges bonded to the shank of the punch (Higuchi, Nelson & Busse, 1954; Shotton & Ganderton, 1960). High-speed rotary machines require additional sophistication to enable useful results to be obtained, and there are two methods known. The first is that used by Shotton, Deer & Ganderton (1963). The resistance of strain gauges near the punch tips was used to control the frequency of an oscillator, and the signal was transmitted from the rotary part of the machine to a stationary aerial by radio emission. Thus the difficulty of providing a slip ring connection to the strain gauges was circumvented. However, because the radio transmitter took up space normally occupied by punches, it was difficult to obtain readings from more than one pair of punches, and impossible to obtain readings from all. In the second method (Knoechel, Sperry & others, 1967), strain gauges were placed on the compression screws interposed between the arm holding the movable axis of the pressure wheel and the spring used to adjust the compression force applied. Deflection, measured by the strain gauges, was proportional to the force applied to the punch. Since the gauges were stationary, their output could easily be displayed on a cathode ray oscilloscope, and the pressure to each punch recorded as its head passed under the pressure wheel.     

Modeling of adhesion in tablet compression. II. Compaction studies using a compaction simulator and an instrumented tablet press

Adhesion problems are usually not identified until prolonged compression runs are studied near the end of the drug development process. During tablet manufacturing, adhesion problems encountered are usually addressed by statistically designed experiments based on experience. It would be a significant benefit for the pharmaceutical industry if adhesion problems could be identified early in drug development based on molecular considerations of the drug substance and/or prototype formulations. Drug substance-punch face interactions were reported in the first of the articles in this series, and focused on the elucidation of adhesion problems in tablet compression. It was hypothesized that the intermolecular interactions between drug molecules and the punch face was the first step (or criterion) in the adhesion process, and that the rank order of adhesion during tablet compression should correspond with the rank order of these energies of interaction. That is, the interaction between the molecular structure of the drug and the metal surface determines the primary interaction event or relative potential for adhesion, while the mechanical processes and/or lubrication effects may subsequently impact the extent of adhesion. Molecular simulations and atomic force microscopy were used to establish the rank order of the work of adhesion of a series of profen compounds. The results predicted that the relative degree of drug substance-punch face adhesion should decrease in the order of ketoprofen > ibuprofen > flurbiprofen. In this study, the authors investigated whether the rank order of the work of adhesion established on the molecular level and interparticulate level holds true in the tableting environment by measuring tablet take-off force, ejection force, and visual observation of the punch surfaces for both pure drug compacts and formulated tablets. The compaction simulator was used for pure profen compacts, while the instrumented tablet press for formulated tablets. Due to the inability to extract the adhesion force component from the total ejection force measurement, tablet ejection force was not used as a criterion to judge the adhesion behavior of the model compounds. The criteria used for judgement of punch face adhesion were tablet take-off force and visual observation of the punch faces. The rank order of adhesion for both pure drug and formulated tablets was determined to follow the order of ketoprofen > ibuprofen > flurbiprofen. The effect of run time on adhesion behavior was also investigated. Therefore, the rank order of the punch-face adhesion tendencies for the series of profen compounds was determined, and found to agree with the data from the predictive methods reported in the first article.     

Evaluation of the compaction of sulfathiazole polymorphs

The aim of this study was to relate the tableting performance assessed by an instrumented tableting machine to the mechanical properties measured by nanoindentation. Three different polymorphic forms of sulfathiazole were prepared by recrystallization, and the density and X-ray powder diffraction patterns were measured and compared with theoretical density and simulated powder patterns, respectively. Tablets were prepared using a series of applied pressures, and the results were subjected to energy analysis, three dimensional (3D) modeling, and the traditional Heckel analysis. With these approaches, form I was found to be consistently the most brittle material, but the subtle differences between forms II and III were only revealed by 3D modeling. The rank order of the crushing force was found to be I is congruent to II < III. From nanoindentation, form III was found to be much harder than forms I and II, and III also had a much higher Young's modulus. The energy calculations of the nanoindentation curves showed that form III was distinct from forms I and II, which is consistent with the presence of slip planes that are only present in form III. However, in this system, there was little correspondence between the macroscopic and microscopic measurements, and thus particle-particle interactions may to be of paramount importance.     

Timing relationships among maxima of punch and die-wall stress and punch displacement during compaction of viscoelastic solids

The times of occurrence of maxima in punch stress, die-wall stress, and punch displacement in instrumented rotary tablet machines are shown to be noncoincidental for compacts exhibiting viscoelastic behavior. Equations are presented which characterize materials behaving as Kelvin solids in either or both distortion and dilation. These equations explicitly relate the timing of stress maxima to punch strain and strain rate. Typical effects are illustrated by data obtained for Avicel PH 101, Klucel, and mannitol. Punch stress maxima are shown to significantly precede the time of maximum punch insertion into the die for viscoelastic materials compacted at rates typical of production. Die-wall stress maxima occur after punch stress maxima due to internal rate-limited processes.     

Brittle fracture propensity measurements on ‘tablet-sized’ cylindrical compacts

The brittle fracture propensity test which was originally designed for large, square compacts with a central hole has been modified and extended to compacts of ‘tablet-sized’ dimensions. This allows a brittle fracture propensity (BFP) index to be measured at strain rates and conditions approaching those normally used in tableting. The BFP indices for microcrystalline cellulose, Tablettose and heavy magnesium carbonate were evaluated at punch velocities of 3.33 and 200 mm s^?1 and found to be in good agreement with the results of previous workers.     

The effect of punch tilting in evaluating powder densification in a rotary tablet machine

The effect of punch tilting on the mechanism of punch penetration in the die of a rotary tablet machine during the compression cycle was evaluated by installing four displacement transducers on one station of a rotary machine. Two transducers were symmetrically positioned beside the upper punch in the upper turret, and the other two transducers were similarly placed beside the lower punch in the lower turret. Microcrystalline cellulose and dicalcium phosphate dihydrate were compressed at 5, 10, 15 and 20 kN using two different machine speeds, in order to quantify the effect of punch tilting in the evaluation of punch penetration. These compression data served to construct the powder bed reduction curves, from which it was possible to establish that punch tilting is directly proportional to the compression force used. Tilting is maximal at the beginning of the dwell time, disappears at half dwell time, and reaches a new maximum at the end of the dwell time. In latter case, tilting occurred in the direction opposite that of the first maximum. The impact of tilting in powder densification behaviour, evaluated through the construction of Heckel plots, depends on the compression force used in the analysis. Heckel plots are as distorted as the compression force is elevated. Consequently, the calculated Heckel parameters differ from the real values. Unless a very low compression force is used, a proper Heckel analysis can be performed in a rotary machine only if it is fitted with a device that includes the effect of punch tilting in the evaluation of punch penetration.     

A study of powder adhesion to metal surfaces during compression of effervescent pharmaceutical tablets

Effervescent tablets were produced using four different formulations containing citric and/or tartaric acid and sodium bicarbonate with povidone and macrogol 6000. The same formulations were prepared with the addition of 1% sucrose ester powder. The adhesion of each formulation to the metal faces of tableting machine punch tips was determined using electron microscopy, surface roughness measurements and quantification of punch weight variations during tablet production. The basic formulations were inherently adhesive and produced tablets with a weak, porous structure which were qualitatively and quantitatively rougher than conventional, non-effervescent compressed tablets. Both formulations containing tartaric acid produced tablets with a lower surface roughness and with less tendency to stick to tablet punch faces than the two formulations containing citric acid alone. The addition of a water-soluble sucrose ester had a beneficial effect especially on the formulations with inherently high adhesive tendencies.