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.     

Punch velocities during the compaction process

Velocities achieved by the upper punch of an eccentric tablet press during compaction have been compared with those predicted by equations describing the movement of the punch in an empty die. Up to the point of maximum punch penetration, actual speeds are invariably less than the predicted speed, the magnitude of the deceleration being determined by the machine speed and applied force. As the punch withdraws from the die, its speed can exceed that predicted on theoretical grounds, due to the elastic expansion of the tablet assisting punch ejection.     

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.     

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.     

Tablet compression force measurement using strain gauges

An instrumented tableting machine yields some of the most significant information about the compressional and ejectional forces involved in the tableting operation. A number of versions of instrumented tablet presses are commercially available but tend to be very expensive to be used widely in academic institutions. The present project involving the instrumentation of a single punch tableting machine (Manesty, Model F3) was undertaken to propose a low cost alternative to researchers in the area of product development. This paper deals with the measurement of the compression force using strain gauges mounted in two different configurations: upper punch and lower pin. Good linearity between applied force and measured strain was observed.     

The influence of crystal form on the radial stress transmission characteristics of pharmaceutical materials.

Various crystal forms of sulphathiazole, barbitone and aspirin were compressed in a single-punch tablet machine instrumented to monitor axially applied and radially transmitted forces, and upper punch movement. The changes in radial stress during the compression cycle depended upon the polymorphic form of the compressed material. The results were rationalized in terms of the degree of plastic flow/crushing that occurred with each material, and the degree to which the final compact underwent elastic compression. It is postulated that the reduction in the transition temperature of polymorphic forms of sulphathiazole and barbitone and the polymorphic transition of sulphathiazole Form II was due to the production of dislocations in the crystal and the crystals at crystal boundaries formed in the compressed materials.     

Influence of compression pressure and die-wall pressure on tablet sticking

An eccentric-type tablet machine fitted with 8-mm-diameter flat-faced punches was used to measure the forces of upper and lower punches, die-wall pressure, tablet ejection force, and scraper pressure (SCR), a type of shear stress, to evaluate sticking behavior. The shear stress between the surfaces of the tablet and lower punch was determined using an SCR detection system. Mean surface roughness (R(a)) of tablets, measured by laser scanning microscopy, was used to estimate the magnitude of sticking. Tablet tensile strength tended to increase with compression pressure, which is consistent with previous reports. SCR decreased with increasing compression pressure for samples at all formulations (i.e., for different kinds and percentages of lubricant). R(a) associated with sticking increased with SCR, indicating that the adhesive force between the particles of the tablet surface and the lower punch surface plays an important role in sticking. Multiple linear regression analysis with SCR as the response variable was conducted. Upper and lower punch force, die-wall pressure, tablet ejection force, SCR, percentage of lubricant, and tensile strength of tablet were selected as explanatory variables. Results of this analysis indicate that the incidence of sticking decreased when either the lower punch force or die-wall pressure increased, where, of these two, increasing the lower punch force had a stronger effect on decreasing SCR.     

A New Method of Estimating Volume During Powder Compaction and the Work of Compaction on a Rotary Tablet Press from Measurements of Applied Vertical Force

Abstract— The volume per unit mass of a powder bed, V', during compaction on a rotary tablet press has been expressed as a function of pressure, P using a modification of Kawakita's equation: V = (V'_o –V')P'/(P+P')+V', where V'_o, V and P' constitute a set of unique values for a given powder or powder mix under specified tableting conditions. The volume, V, is determined from the machine deformation constant which is the relationship between applied vertical force and the deformation of the tablet press and the punches. An iterative method is described which allows the determination of V'_o, V' and P' from the slope and intercept of V vs 1/(P+P') where all values are evaluated at peak pressure. By substituting these values into the equation, the volume of a given powder bed during compaction up to peak pressure can be accurately predicted from the pressure vs time curve. This method of estimating volume and hence punch displacement, is much simpler than an earlier analytical method which was derived from direct measurements of punch displacement under running conditions. Since volume is an explicit function of pressure, the work of compaction is also a function of pressure. Estimates of the work of compaction are in good agreement with values calculated using our previous method. Values of V'_o, V' and P' are reported for 35 pharmaceutical materials and could be incorporated into a database library of drugs and tableting excipients. This database could then be used for the quality control of incoming raw materials (batch to batch assessment) and for the comparison of materials from alternative sources. The experimental methodology and method of calculation should, in principle, be applicable to any rotary tablet press and together with other tableting parameters (such as compression time, peak offset time, decompression time, elastic recovery and work of compaction) would provide a simple, inexpensive method for the in process validation of tablet compression.     

Characterization of particle deformation during compression measured by confocal laser scanning microscopy

Direct compression of riboflavin sodium phosphate tablets was studied by confocal laser scanning microscopy (CLSM). The technique is non-invasive and generates three-dimensional (3D) images. Tablets of 1% riboflavin sodium phosphate with two grades of microcrystalline cellulose (MCC) were individually compressed at compression forces of 1.0 and 26.8 kN. The behaviour and deformation of drug particles on the upper and lower surfaces of the tablets were studied under compression forces. Even at the lower compression force, distinct recrystallized areas in the riboflavin sodium phosphate particles were observed in both Avicel PH-101 and Avicel PH-102 tablets. At the higher compression force, the recrystallization of riboflavin sodium phosphate was more extensive on the upper surface of the Avicel PH-102 tablet than the Avicel PH-101 tablet. The plastic deformation properties of both MCC grades reduced the fragmentation of riboflavin sodium phosphate particles. When compressed with MCC, riboflavin sodium phosphate behaved as a plastic material. The riboflavin sodium phosphate particles were more tightly bound on the upper surface of the tablet than on the lower surface, and this could also be clearly distinguished by CLSM. Drug deformation could not be visualized by other techniques. Confocal laser scanning microscopy provides valuable information on the internal mechanisms of direct compression of tablets.     

Energy relations in compression of polymeric materials and granulations

In tablet compression, a force, F, is exerted on a punch penetrating into a tablet die. For a stationary bottom punch, the force on the upper punch is a function, F = f(x), of penetration and this value was previously determined empirically. Since differential energy is force, f(x), multiplied by distance, dx, the integral of f(x)dx between limits should give the energy input into the tablet. The integral yields an expression where energy input is a linear function of the logarithm of the maximally applied pressure, F*, a fact substantiated by the data presented.     

Effects of temperature and pressure during compression on polymorphic transformation and crushing strength of chlorpropamide tablets.

The effects of temperature on the polymorphic transformation of chlorpropamide during compression and on the physical properties of the tablet have been investigated. A heater and liquid nitrogen pool were mounted on the die of a single punch eccentric tableting machine, and the die temperature was controlled by a thermocontroller. A tableting machine with two load cells (upper and lower punches) and a non-contact displacement transducer were used to measure compression stress, distance and energy. The X-ray diffraction profiles of the deagglomerated compressed sample powder were measured to calculate the polymorphic content. The amount of form C transformed from form A at 45 degrees C was about twice that at 0 degree C with the same compression energy. The amount of form A transformed from form C by compression at 45 degrees C was almost the same as that at 0 degree C. This suggests that the mechanochemical effect of form A depended on the compression temperature, but that of form C was independent of temperature. The crushing strength of tablets of form A was about twice that of form C, even at the same porosity. The plots of log (crushing strength of tablet) against porosity of form A tablets compressed at 0 and 45 degrees C were linear with the same slope; the slope for form C tablets compressed at 45 degrees C was less than that at 0 degree C.     

The repeated compression of powders

Powders were subjected to repeated compression in a tablet press, the ejection mechanism of which had been disconnected. The force detected at the upper punch was found to change with successive compressions, the magnitude of the change being dependent on the powder, the compressive force and the interval between compressions. Repeated compression also caused a change in tablet crushing strength. With compression intervals of 1.2 s, all substances showed an significant increase in strength. With longer time intervals, the increase was reduced and in some cases, a diminution in strength occurred.     

Effects of true density, compacted mass, compression speed, and punch deformation on the mean yield pressure.

Compressibility properties of pharmaceutical materials are widely characterized by measuring the volume reduction of a powder column under pressure. Experimental data are commonly analyzed using the Heckel model from which powder deformation mechanisms are determined using mean yield pressure (Py). Several studies from the literature have shown the effects of operating conditions on the determination of Py and have pointed out the limitations of this model. The Heckel model requires true density and compacted mass values to determine Py from force-displacement data. It is likely that experimental errors will be introduced when measuring the true density and compacted mass. This study investigates the effects of true density and compacted mass on Py. Materials having different particle deformation mechanisms are studied. Punch displacement and applied pressure are measured for each material at two compression speeds. For each material, three different true density and compacted mass values are utilized to evaluate their effect on Py. The calculated variation of Py reaches 20%. This study demonstrates that the errors in measuring true density and compacted mass have a greater effect on Py than the errors incurred from not correcting the displacement measurements due to punch elasticity.     

Mechanical characterization of pharmaceutical solids: a comparison between rheological tests performed under static and dynamic porosity conditions.

The aim of this work was to verify how and to what extent rheological tests, carried out under dynamic (Heckel) and static (creep, stress/strain) porosity conditions, may serve as a valuable complement to the classic Heckel tests in the characterization of viscoelastic and densification properties of solid materials for pharmaceutical use. Six different modified (pregelatinized) starches were compressed in a rotary tablet machine equipped to measure force and punch displacement. Tablets were obtained using flat-faced 6mm diameter punches at different compression pressures. Compression cycles performed at the maximal pressure of 200MPa were used to build the Heckel plots. Ejected tablets at the 10%, 20%, 30%, and 40% porosity levels were used for the stress/strain and creep tests. Parameters obtained with both types of tests were consistent with each other. In particular, among the six starches, lower viscosity values corresponded to lower P(Y) values, and lower elastic modulus values corresponded to lower elastic recovery of the tablet. Mechanical properties of materials can be better characterized if viscoelastic tests performed under dynamic porosity conditions (Heckel analysis) are supported by classical viscoelastic tests carried out under conditions of static porosity.     

Comparison of calculated and experimentally determined punch displacement on a rotary tablet press using both Manesty and IPT punches

An indirect method of calculating punch displacement on a rotary tablet press from measurements of the change in punch force with the turret position was in good agreement with direct measurements of punch displacement made using a linear variable displacement transducer (LVDT)-slip ring system. The direct measurements were made during the compaction of three direct compression agents using Manesty punches. However, the agreement between calculated and experimentally determined punch displacements was unsatisfactory when IPT punches were used. The IPT punches have a much flatter punch head profile than the Manesty punches. Due to this difference, the analytic equation does not accurately describe the dynamics of the press under normal operating conditions. Terms in the analytic equation, determined originally under static conditions, were re-evaluated under dynamic conditions for both sets of tooling using the LVDT-slip ring system. Excellent agreement for both IPT and Manesty punches was found between punch displacement calculated using the revised analytic equation and direct experimental measurements. Punch displacements determined from punch head profile and machine geometry only, without taking machine deformations into account, were shown to differ widely from the calculated and experimental values.     

Disintegrating efficiency of croscarmellose sodium in a direct compression formulation

The efficiency of croscarmellose sodium (Ac-Di-Sol®) in a direct compression formulation containing a poorly water soluble drug (albumin tanate) at high dosage was investigated. An experimental design with two variables, applied pressure and concentration of Ac-Di-Sol®, allowed the evaluation of microstructural, mechanical and disintegration properties of the tablets. Tablet properties evaluated were affected by both variables, while compression parameters were essentially dependent on applied pressure. The disintegration process was correlated with the densification behaviour, analysed by means of Heckel plots and force-displacement curves, and tablet microstructure, measured by using a mercury porosimeter. The shortest disintegration time was found for mixtures more prone to plastic deformation and densification at same level of applied pressure. These mixtures also revealed a finer pore structure. However, mixtures with higher yield pressures (i.e. less prone to plastic deformation) showed longer disintegration times and coarse pore structure. The different rearrangement of disintegrant particles in powder mixture is suggested to explain the dominant effect of the disintegrant bonding mechanism presented at a given mixture composition. According to our results, consolidation mechanism and microstructure analysis should be performed while optimizing disintegration response in tablets formulated with a disintegrant mainly acting by swelling mechanism.     

The tabletting machine as an analytical instrument: qualification of the tabletting machine and the instrumentation with respect to the determination of punch separation and validation of the calibration procedures.

The quality of the determination of punch separation in an eccentric tabletting machine equipped with two inductive displacement transducers was carefully investigated, since this tabletting machine is used as an 'analytical instrument' for the evaluation of the compression behaviour of pharmaceutical materials. For a quasistatic calibration procedure using gauge blocks, the repeatability under standard conditions and the robustness against variations in machine settings, installation conditions, equipment and methods were examined. The readings during calibration can be easily influenced by machine parameters as a result of deficiencies in the construction of the machine and in the mode of instrumentation. The poor plane-parallelism of the punch faces has a further negative effect on the accuracy of punch separation. In addition, the response at loading to lower and higher forces as during calibration was investigated. While at loading up to 100 N, the response of the system to the gauge blocks is systematically influenced by punch separation, for slow manually applied punch-to-punch loading up to 16.5 kN at a broad range of penetration depths, no significant effects were observed in the region of interest for tabletting. To get an indication of the transferability of the calibration and the determination of punch deformation to normal operating conditions, the lateral tilting of the punches during dynamic idle runs, punch-to-punch loading, and compression of microcrystalline cellulose was analyzed. A transfer of the response derived from punch-to-punch compression to tabletting conditions seems to be possible, although this must be questioned on grounds of theoretical considerations. From all the experiments performed, a total error of about +/- 30 microns must be assessed for the determination of punch separation.     

Time-dependent deformation of some direct compression excipients.

Three techniques were used to compare the time-dependent deformation of microfine cellulose (Elcema G250), anhydrous lactose, dicalcium phosphate dihydrate (Emcompress), modified starch (Sta-Rx 1500) and sodium chloride. (1) In stress-relaxation experiments using a reciprocating tablet machine, none of the materials behaved as a Maxwell body in contrast to recent published work (David & Augsburger, 1977). Possible reasons for this disagreement are discussed. (2) Heckel plots showed that increasing the time for which a material was under compression (contact times of 0.17 and 10 s) had no effect on dicalcium phosphate compacts but increased the consolidation of other materials in the rank order sodium chloride less than lactose less than cellulose less than starch. (3) Deformation tests on preformed compacts were carried out in diametral compression by loading compacts to 75% of their breaking force at four different strain rates between 0.05 and 6.5 mm min-1. The deformation of Sta-Rx compacts was time-dependent. Sodium chloride compacts exhibited brittle behaviour in the diametral compression test and in the 10 s contact time experiment. This was apparently due to work-hardening, following the extensive plastic deformation of crystals during compaction as indicated by the stress relaxation results.     

Time-dependent Densification Behaviour of Cyclodextrins

Understanding of volume reduction mechanisms is a valuable aid in the development of robust cyclodextrin tablet formulations. The particle and powder properties of α-, β-, γ-and hydroxypropyl (HP) -β-cyclodextrins and their behaviour under compression were examined. The cyclodextrins studied showed big differences in particle-size distribution and particle shape. The highest densification on tapping was found for cyclodextrins having the smallest particle size. Cyclodextrins were compressed using single-sided saw-tooth displacement-time profiles at rates of 3 and 300 mm s^?1 with a compaction simulator. The densification of the powders was examined by Heckel treatment, using the tablet-indie and ejected-tablet methods. The cyclodextrins were denser at the beginning of the tableting process (at low pressures) if high rather than low velocity was used. Ranking according to their tendency toward total deformation and permanent plastic deformation was: HP-β-cyclodextrin > β-cyclodextrin > γ-cyclodextrin > α-cyclodextrin. The ranking order in strain-rate sensitivity (SRS) of total deformation was HP-β-cyclodextrin γ-cyclodextrin ≥ α-cyclodextrin ≥ β-cyclodextrin. On the basis of the yield pressure values and the Heckel plot profiles, all the cyclodextrins were highly prone to plastic deformation. Cyclodextrins showed time-dependent consolidation behaviour manifested as increased yield pressure with decreased contact time. A ratio was defined between the SRS of fast elastic recovery and total elastic recovery. The two materials with high ratios, HP-β-cyclodextrin and β-cyclodextrin, were especially prone to fast elastic recovery with increasing punch velocities; γ-cyclodextrin and α-cyclodextrin had low values and were less prone. On the basis of this parameter it might be possible to categorize pharmaceutical materials according to capping tendency.     

Calorimetric analysis of powder compression: I. Design and development of a compression calorimeter

The heat of compression and work of compression of three common pharmaceutical excipients (Avicel PH-101, anhydrous lactose, and Starch 1500) were determined using experimental instrumentation of original design. The heat of compression was independently determined using two different temperature sensors: a tungsten wire temperature sensor positioned within the powder sample and a two-thermistor system positioned behind thin metal plates in the lower surface of the upper punch. The effective heat capacity of the sample when contained within the punch and die apparatus was determined by a simultaneous heating and compression method. An energy correction method was used to account for system heat effects. Upper and lower punch force transducers and a displacement transducer were used to determine the work of compression. In the materials studied, exothermic powder compression subprocesses outweighed the endothermic subprocesses and an overall net exotherm was observed. The rank orders of the heats of compression determined from the in-sample and in-punch temperature sensors were in agreement. This instrumentation and approach, while still being developed, is proposed as a discriminating method to characterize and quantitate fundamental powder compression behavior.