Thermodynamic analysis of compact formation; compaction, unloading, and ejection. I. Design and development of a compaction calorimeter and mechanical and thermal energy determinations of powder compaction

The aim of this investigation was to determine and evaluate the thermodynamic properties, i.e. heat, work, and internal energy change, of the compaction process by developing a 'Compaction Calorimeter'. Compaction of common excipients and acetaminophen was performed by a double-ended, constant-strain tableting waveform utilizing an instrumented 'Compaction Simulator.' A constant-strain waveform provides a specific quantity of applied compaction work. A calorimeter, built around the dies, used a metal oxide thermistor to measure the temperature of the system. A resolution of 0.0001 degrees C with a sampling time of 5 s was used to monitor the temperature. An aluminum die within a plastic insulating die, in conjunction with fiberglass punches, comprised the calorimeter. Mechanical (work) and thermal (heat) calibrations of the elastic punch deformation were performed. An energy correction method was outlined to account for system heat effects and mechanical work of the punches. Compaction simulator transducers measured upper and lower punch forces and displacements. Measurements of the effective heat capacity of the samples were performed utilizing an electrical resistance heater. Specific heat capacities of the samples were determined by differential scanning calorimetry. The calibration techniques were utilized to determine heat, work, and the change in internal energies of powder compaction. Future publications will address the thermodynamic evaluation of the tablet sub-processes of unloading and ejection.     

Comparison of the compression characteristics between new one-step dry-coated tablets (OSDRC) and dry-coated tablets (DC)

One-step dry-coated tablets (OSDRC) were prepared using materials which are generally used in pharmaceutical tablets. The radial tensile strength of OSDRC was measured for various compression pressures and core porosities before the final compression to compare with that of conventional dry-coated tablets (DC). Furthermore, stress relaxation in the compression process was investigated. Radial tensile strength and stress relaxation profiles of OSDRC were the same as those of conventional DC. X-ray computerized tomography (CT) of the tablets showed that the density distribution of both tablets was also the same. Thus, we concluded that OSDRC and conventional DC have the same compression characteristics and physical properties. The OSDRC-system was executed by the use of upper and lower punches, which had a double structure, a center punch, and an outer punch surrounding the center punch. The OSDRC process consists of three compressions to make the lower-outer layer (1st-outer layer), the core, and the whole tablet including the upper-outer and side-outer layers (2nd-outer layer). At first, the powder for the 1st-outer layer fills a space, which is made by the lower-center punch and lower-outer punch, and is pre-compressed by the upper-center punch. Then, while the upper-center punch pushes the pre-compressed 1st-outer layer, the lower-center punch is slid down. The upper-center punch is then pulled away to make a space, which is filled with the powder for the core. This is then pre-compressed by the upper-center punch. Finally, the lower-outer punch is slid downward and the powder for the 2nd-outer layer fills and surrounds the pre-compressed core/1st-outer layer completely. The core/1st-outer layer and the 2nd-outer layer complex is then compressed by the upper and lower punches in which the center punches are unified with the outer punches, respectively. This system can be assembled onto the turn table of a rotary tableting machine, and can make a dry-coated tablet in a single turn.     

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.     

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.     

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.     

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.     

Determining the compression behaviour of pharmaceutical powders from the force-distance compression profile

The force-displacement curves obtained from an eccentric tablet machine were examined in a new way. The tendency of the material for plastic deformation, fragmentation and elasticity is expressed as numerical values, which are comparable between different materials. The dependence of these numerical values on the compression pressure was modelled. The accuracy of the displacement measurement was improved by filtering out noise from the measurement data by a novel method. The plastic deformation of the material near the force maximum of the compression cycle could be seen accurately from this precise displacement data. The elastic deformation of the tablet machine was also defined very precisely from the running machine. Tablets were made with an eccentric tablet machine using fixed lower and upper punch adjustments. This ensured that the speed of the upper punch and the theoretical height of the tablets were the same for all compactions. Therefore, only the properties of the materials determined the differences in the shape of the compression curves. The test materials used were alpha-lactose monohydrate, two grades of microcrystalline cellulose, maize starch and dicalcium phosphate dihydrate. The results showed that the use of accurate displacement measurement is essential in order, to see the small variations in the shape of the force-displacement curve near the force maximum of the compression cycle, and it made it possible to dynamically calibrate the elastic deformation of the eccentric tablet machine during compression. It turned out that the numerical values obtained with the new method described the plastic, brittle and elastic properties of the tested materials satisfactorily in a wide compression pressure range.     

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.     

Bulk characterization of pharmaceutical powders by low-pressure compression II: effect of method settings and particle size

The aim of the present study was to investigate the effect of punch and die diameter, sample size, compression speed, and particle size on two low-pressure compression-derived parameters; the compressed density and the Walker w parameter. The excellent repeatability of the low-pressure compression method allowed small effects of variations in punch and die diameter and sample size to be demonstrated on a high significance level. Changing the compression speed, however, did not cause a significant effect in the compressed density, whereas a decrease in w was seen. The effect of particle size was studied by compressing and tapping different grades of calcium carbonate, lactose, and microcrystalline cellulose. The low-pressure compression-derived parameters were compared to tapped densities and to Compressibility Indexes obtained by tapping volumetry. Even though the relationship between particle size and the low-pressure compression-derived parameters appeared to be more complicated, a similar trend was observed. It was concluded that the low-pressure compression method provides a useful alternative to the more sample-consuming methods providing flow-related information.     

The effect of compression and decompression speed on the mechanical strength of compacts

The purpose of this work was to investigate the effect of punch speed on the compaction properties of pharmaceutical powders; in particular, to separate out differences between the effect of the compression and decompression events. Tablets were prepared using an integrated compaction research system. Various "sawtooth" punch profiles were followed to compare the effects of different punch speeds on the crushing strength of the resulting tablets. The loading and unloading speeds were varied independently of one another. In general, when the compression speed was equal to the decompression speed, the tablet crushing strength was observed to decrease as the punch velocity increased. When the compression speed was greater than or less than the decompression speed, the results varied, depending on the material undergoing compaction. Reduction of the unloading speed from 300 to 10 mm/sec for pregelatinized starch and microcrystalline cellulose produced a significant increase in crushing strength, whereas no significant increase in crushing strength was observed until the loading speed was reduced to 10 mm/sec. Reduction of the unloading speed had a similar effect on the direct compression (DC) ibuprofen, however, even greater improvement in the crushing strength was observed when the loading speed was reduced. No improvement in the DC acetaminophen tablets was observed when the unloading speed was reduced, however, a significant increase in crushing strength was produced when the rate of loading was reduced. This work showed that the strength of tablets can be improved and some tableting problems such as capping can be minimized or prevented by modifying the rates of loading/unloading.     

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.     

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.     

The difficulty in the assessment of the compression behaviour of powder mixtures: Double layer tablets versus arithmetic additivity rule.

The weighted arithmetic mean from values of a feature derived from the individual components is often used to calculate the theoretically expected compression behaviour of powder mixtures if no interparticulate interactions between the components occur. Alternatively, simulated and experimental double layer tablets are presented. The suitability of the various methods to serve as a reference for the assessment of the compression behaviour of powder mixtures shall be compared. Narrow and similar sieve fractions of maltitol and metamizol were mixed in various ratios of true volumes. Constant total true volumes of the single substances, powder mixtures, and layered powders of the same composition were compressed on an eccentric tabletting machine to a constant maximum geometric mean punch force. In addition, the compression of double layer tablets was mathematically simulated from the dynamic relative density-force data of the pure materials. At a given momentary force, the relative density of a simulated double layered powder bed is given by the harmonic mean of the relative density values of the pure materials weighted by their true volume fractions. The results show that the total, the net, and the expansion work change indeed almost linearly with the true volume fraction of the components in the double layer tablets, with the consequence that the plasticity index (=net work/total workx100) proceeds non-linearly. The slope of the Heckel plot 'at pressure' and the apparent mean yield pressure obtained from these Heckel data are non-linearly related to the true volume fraction. If the weighted arithmetic mean is used to analyse the compression behaviour of the powder mixtures, results are obtained which are incompatible or even contradictory between interrelated features. On the other hand, the double layer model provides a consistent evaluation. A good agreement between the results of the experimental and the simulated double layer tablets is found.     

The effect of moisture content on the compression properties of maltodextrins

The effect of moisture content on the compression properties of maltodextrin powders obtained by different degrees of hydrolysis (depolymerization) of corn starch has been studied using the yield pressure determined from the Heckel plot and the compact tensile strength measured by the diametrical compression method. An increase in the moisture content of the powder reduced the yield pressure and improved the densification for all five maltodextrins evaluated. At the same moisture level, the extent of densification which occurred during compaction was greater for maltodextrins with a lower degree of polymerization. Compacts produced by maltodextrins with a lower degree of polymerization also exhibited a greater tensile strength for a given pressure at a moisture content below 8.0%. However, further increase in moisture content resulted in a decrease in compact tensile strength for maltodextrins having a lower degree of polymerization. Despite the significant difference in compression behaviour, the five maltodextrins did not show noticeable differences in crystallinity as revealed by their x-ray powder diffraction pattern.     

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.     

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.     

粉末直接压片制备格列美脲片

目的建立格列美脲片粉末直接压片工艺。方法根据粉末直接压片工艺流程,对辅料种类、辅料规格、处方比例、混合方式等进行试验分析,选择合适的处方工艺。结果采用粉末直接压片辅料和主药与辅料以等量递增的预混芳法生产格列美脲片质量符合标准要求。结论采用粉末直接压片工艺制备格列美脲片,与湿法制粒压片工艺产品比较,质量更稳定。     

Bulk characterization of pharmaceutical powders by low-pressure compression

Low-pressure compression of pharmaceutical powders using small amounts of sample (50 mg) was evaluated as an alternative to traditional bulk powder characterization by tapping volumetry. Material parameters were extrapolated directly from the compression data and by fitting with the Walker, the Kawakita, and the Log-Exp compression models. The compression-derived material parameters were compared to the poured and tapped density and the Compressibility Index determined by tapping. The repeatability of the compression-derived parameters was generally high, supporting their potential for characterization purposes. Significant correlation was demonstrated between several of the compression and tapping-derived parameters. The discriminative power of the low-pressure compression test was discussed using the compressed density at 0.2 MPa, correlated with the tapped density, and the relative Walker coefficient, correlated with the Compressibility Index, as examples. The compressed density at 0.2 MPa and the relative Walker coefficient demonstrated excellent discriminative power, superior to the discriminative power of the correlated tapping derived parameters. The low-pressure compression test was concluded to provide a cost-effective and sensitive alternative to traditional tapping volumetry.     

The effect of stationary time of punch in the process of compression on dividing properties of scored tablets]

The significance of the stationary time of punch in the process of compression on the dividing properties of scored tablets was investigated in several tablets prepared from lactose, corn starch, hydroxypropyl starch, synthetic aluminum silicate, microcrystalline cellulose or Perfiller. The dividing strength of scored tablets was not affected by the stationary time of punch. The effect of the stationary time of punch on the coefficient of variation of divided tablet weight differed in the compacting characteristics and compaction profiles of powders. In case of tablets prepared from microcrystalline cellulose, the effect of stationary time of punch was not observed. However, in the other excipients, there existed a specific stationary time of punch to minimize the coefficient of variation of divided tablet weight. The time was different due to the change of compression pressure. The coefficient of variation of divided tablet weight showed minimum at the longer stationary time of punch when tablets were compressed at the low compression pressure, and the time showed a tendency to become short with the increase of compression pressure. These results suggested that the effect of the stationary time of punch on the coefficient of variation of divided tablet weight was concerned with the compaction structure of powders produced by the movement of punch in the process of compression.     

Understanding deformation mechanisms during powder compaction using principal component analysis of compression data

Principal component analysis (PCA) was applied to pharmaceutical powder compaction. A solid fraction parameter (SF_c/d) and a mechanical work parameter (W_c/d) representing irreversible compression behavior were determined as functions of applied load. Multivariate analysis of the compression data was carried out using PCA. The first principal component (PC1) showed loadings for the solid fraction and work values that agreed with changes in the relative significance of plastic deformation to consolidation at different pressures. The PC1 scores showed the same rank order as the relative plasticity ranking derived from the literature for common pharmaceutical materials. The utility of PC1 in understanding deformation was extended to binary mixtures using a subset of the original materials. Combinations of brittle and plastic materials were characterized using the PCA method. The relationships between PC1 scores and the weight fractions of the mixtures were typically linear showing ideal mixing in their deformation behaviors. The mixture consisting of two plastic materials was the only combination to show a consistent positive deviation from ideality. The application of PCA to solid fraction and mechanical work data appears to be an effective means of predicting deformation behavior during compaction of simple powder mixtures.