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.     

Compression behavior of pharmaceutical powders

The compression behavior of 4 pharmaceutical powders of widely different particle size distribution and shape was studied by measuring the height of the compressed powder bed at different pressures. The data were analyzed by the Heckel equation and by the Cooper and Eaton equation. The values of the three-stage densification process, D₀, D_a, and D_b, and the material constant, K, obtained from the Heckel plots were in excellent agreement with the coefficients of the Cooper and Eaton equation. These coefficients describe two nearly independent probabilistic processes involving the filling of large holes and the filling of small pores. The results of this study suggest the usefulness of this method in studying the compression behavior of pharmaceutical powders.     

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.     

Differences between eccentric and rotary tablet machines in the evaluation of powder densification behaviour

Differences in the dynamics of powder densification between eccentric and rotary machine were pointed out by compressing at different compression pressures microcrystalline cellulose, lactose monohydrate and dicalcium phosphate dihydrate and recovering the corresponding stress/strain data in both machines equipped to monitor punches displacement and compression forces. Heckel plots were then obtained from these stress/strain data. Curves obtained in the rotary machine possess a narrower zone of linearity for the calculation of P(Y) and D(A). The effect of the different compression mechanism of the rotary machine on the shape of the Heckel plot is more noticeable in a non-deforming material such as dicalcium phosphate. The effect of the longer dwell time of the rotary machine on the porosity reduction occurring after the maximum pressure has been reached, is more noticeable in a ductile material such as microcrystalline cellulose. Heckel parameters obtained in the rotary press are in some cases different from those recovered in the eccentric machine because of the longer dwell time, machine deflection and punch tilting occurring in the rotary machine, although theoretically they could better describe the material densification in a high speed production rotary machine.     

Influence of elastic deformation of particles on Heckel analysis.

The Heckel equation is one of the most useful equations for describing the compaction properties of pharmaceutical powders. Important material properties (e.g., yield strength) of powders can be derived using Heckel analysis. Two types of Heckel analysis are in common use. One is the "out-of-die," or "zero-pressure" method, the other is the "in-die" or "at-pressure" method. Because particles undergo elastic deformation under pressure, which tends to lower the porosity of the powder bed, the "out-of-die" method describes powder consolidation and compaction more accurately than the "in-die" method. However, "in-die" Heckel analysis has been widely used because of the speed and ease of data collection. Using L-lysine monohydrochloride dihydrate as a model compound, this work analyzes quantitatively the effects of elastic deformation on the calculation of porosity of a tablet, and therefore on the Heckel analysis. The effects of a small change in porosity, epsilon, on Heckel analysis are presented mathematically. It is found that a decrease in porosity of 0.001, when the porosity is lower than 0.05, causes a significant increase in the value of -ln epsilon. Therefore, data at epsilon < 0.05 should be interpreted with caution when using Heckel analysis. Elastic deformation causes positive deviations in the Heckel plot, and therefore leads to a yield strength that is lower than the true value. The lower the elastic modulus of the powder, the greater is the deviation from the true value. Therefore, the "in-die" method gives values of yield strength that are significantly lower than the true values for most pharmaceutical powders.     

The influence of initial packing on the compression of powders

The influence of the initial packing density on the compression properties of lactose and sodium chloride has been studied. Differences in initial packing density are eliminated for both materials at relatively low pressures. The results have been analysed by the equations of Kawakita (1956), Heckel (1961), and Cooper & Eaton (1962). The constants derived from the Cooper & Eaton equation are dependent on the choice of low pressure data. The Kawakita constants are influenced by the initial packing of the powder. The Heckel treatment uses data at pressures above the point where the initial packing exerts an influence. Hence the constants are independent of the initial packing. If comparisons are to be made between processing treatments or mixtures which change the initial packing of the powder, the Heckel equation would appear to offer the most valid approach.     

The influence of initial packing on the compression of powders

The influence of the initial packing density on the compression properties of lactose and sodium chloride has been studied. Differences in initial packing density are eliminated for both materials at relatively low pressures. The results have been analysed by the equations of Kawakita (1956), Heckel (1961), and Cooper & Eaton (1962). The constants derived from the Cooper & Eaton equation are dependent on the choice of low pressure data. The Kawakita constants are influenced by the initial packing of the powder. The Heckel treatment uses data at pressures above the point where the initial packing exerts an influence. Hence the constants are independent of the initial packing. If comparisons are to be made between processing treatments or mixtures which change the initial packing of the powder, the Heckel equation would appear to offer the most valid approach.     

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.     

Capsule filling machine simulation. I. Low-force powder compression physics relevant to plug formation

The objective of this study was to simulate powder plug formation and explore the low-force powder compression physics of the process. A single-ended saw-tooth waveform was used to make powder plugs, representing no. 1 size capsules, at constant punch speeds of 1, 10, and 100 mm/sec on a tablet compaction simulator. Plugs of different heights (4, 8, and 12 mm) were made in a prelubricated die from three materials: Avicel PH 102, anhydrous lactose, and Starch 1500. The compression data were fit to Heckel's pressure-density relationship, Kawakita's pressure-volume relationship, and Shaxby-Evans's exponential relationship. Heckel analysis of this low-pressure range data revealed "apparent yield pressures" of 25-70 MPa, which were dependent upon the material type, machine speed, and plug height. Shaxby-Evans's relationship was found to hold in that the axial load transmission decreased exponentially with increased plug height/diameter ratio. A dramatic decrease in the coefficient of lubrication, R, with increase in plug height was attributed to poor axial load transmission through the length of the plug. Kawakita's pressure-volume relationship fit the plug formation data very well, and it was evident from this model (Kawakita constant, a) that Avicel PH 102 had the largest available volume for reduction. The plug formation process can be simulated using a programmable tablet compaction simulator. Overall, the data analysis demonstrated that the compression models available for tableting that were used in this study can also be applied to the powder plug formation process with appropriate interpretation.     

Formation and compression characteristics of prismatic polyhedral and thin plate-like crystals of paracetamol.

Prismatic polyhedral crystals of paracetamol were prepared by cooling an aqueous saturated solution of paracetamol from 65 to 25 degrees C. Thin plate-like crystals were prepared by adding a concentrated solution of paracetamol in hot ethanol to water at 3 degrees C. Infrared (IR), X-ray powder diffraction (XPD) and differential scanning calorimetry (DSC) studies confirmed that these two forms of crystals were structurally similar, therefore polymorphic modifications were ruled out. The crystal habit influenced the compression properties during axial compression of paracetamol at different constant rates in a compaction simulator, the Heckel plots and their associated constants being dependent on the habits. The correlation coefficient of the initial part of the Heckel plots, and also the values of strain rate sensitivity (SRS), were lower for thin plate-like crystals, indicative of greater fragmentation for the thin plate-like as compared to polyhedral crystals. Compacts made from thin plate-like crystals exhibited higher elastic recoveries and elastic energies indicating that these crystals underwent less plastic deformation during compression than the polyhedral crystals.     

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.     

Evaluation of the plug formation process of silicified microcrystalline cellulose

To investigate the powder plug formation process of silicified microcrystalline cellulose (SMCC) under compression forces consistent with automatic capsule-filling machines, a single-ended saw-tooth wave was used to make powder plugs with different heights (6, 8, 12 mm), at two different punch speeds (1 and 50 mm/s) on a tablet compaction simulator. SMCC was compared to Starch 1500, anhydrous lactose (direct tableting grade), and microcrystalline cellulose. Heckel analysis showed that 'apparent mean yield pressures' (AMYP) of all tested materials increased with an increase in the plug height and punch speed. AMYP appeared to depend on the material type and punch speed. Not all materials fit the Shaxby-Evans relationship at such low compression forces (less than 250 N). Only SMCC 90, SMCC HD90 and anhydrous lactose data fit the equation at both punch speeds. Due to poor axial load transmission, the R values of all tested materials decreased with an increase in the plug height. The experimental data fit the Kawakita equation quite well. Overall, Kawakita's b values were inversely related to AMYP values. The maximum breaking force (MBF) of a 12 mm plug formed at a punch speed of 50 mm/s correlated well with the work of compaction, except for SMCC HD90 and SMCC X, which exhibited very high MBF values. This research demonstrated that several grades of SMCC produced plugs having higher MBF than anhydrous lactose and Starch 1500 under similar compression conditions. The apparently higher compactability of these materials at low plug formation forces may be beneficial in developing direct fill formulations for automatic capsule filling machines.     

An experimental evaluation of an effective medium based compaction equation

Tablet production involves compression of free flowing powder in an enclosed cavity of defined geometry. The complexity of the powder bed system necessitates that a way be found to better understand what occurs during compression. One such approach is by means of compaction equations, of which, the Heckel and Kawakita equations are the best known. This work attempts to experimentally evaluate the applicability of the effective medium (EM) equation introduced by Frenning et al. (2009) to powder systems. Two powder types (sodium chloride and lactose monohydrate), each consisting of three size fractions (<40, 125-212 and 212-300μm) were characterised and compressed to a pressure of 500MPa. These powders were chosen because of their differing mechanical properties. An invariance which is inherent in the EM equation is exposed by varying the starting points of compression, and can yield insights into compression mechanisms. Such invariant regions were observed once plastic particle deformation started to dominate the compression behaviour, and enabled the determination of the point where particle rearrangement stops.     

The Gurnham equation in characterizing the compressibility of pharmaceutical materials

Limitations of the Heckel equation in characterizing material compression behavior have been well reported. In this work, the Gurnham equation, which was first introduced in chemical engineering, is proposed as an alternate method of evaluating the compressibility of pharmaceutical powders. The Gurnham equation was adapted for tablet compression and the estimated slope parameter c was proposed to represent material compressibility. Data from the compression of four commonly used excipients (microcrystalline cellulose, corn starch, lactose monohydrate, and dibasic calcium phosphate dihydrate) and one drug (acetaminophen) were evaluated using the Gurnham equation. Using compression data at different peak pressures, linear relationships between porosity and lnPressure of the five materials were obtained. The determined parameter c expresses the compressibility of materials. The analysis of previous experimental data, including granulations, mixtures and co-processed materials also indicates that c might be a representative parameter for material compressibility.     

Tabletting of pellet-matrix systems: ability of parameters from dynamic and kinetic models to elucidate the densification of matrix formers and of pellets

Two different types of pellets, i.e. drug-free sugar spheres, and pellets, spray-layered with crystalline theophylline and coated with Eudragit RS/RL, were tabletted each in combination with matrix-forming powder mixtures of Avicel PH200 and PEG 4000. The die fills from pellets and powder mixtures were regarded as two-compartment systems with a volume fraction of the pellets being limited to 0.52 corresponding to a cubic lattice, and the maximum degrees of densifications were adjusted related to the matrix. To data measured during single compression cycles on an instrumented eccentric tabletting machine and transformed appropriately, the Kawakita equation, the Heckel function, and a modified Weibull function were fitted, and the total work of compression was calculated. The Kawakita model fitted well systems with both types of pellets. Its parameters reflected the additional densification of the theophylline pellets separately from that of the matrix formers. The Heckel function could only be applied to systems containing non-porous sugar spheres, since the theophylline pellets underwent considerable densification and deformation. Only, when the Heckel porosity function was related to the volume fraction of the matrix, excluding the sugar spheres, the approximately linear regions for mixtures with increasing volume proportions of sugar spheres occured in comparable regions of densification. Parameters of the modified Weibull function demonstrated an increasing resistance against densification with increasing amounts of pellets. The total work of compression increased steeply with increasing volume fractions for pellets from 0.42 to 0.46 indicating, that the resistance against densification already rose when the pellets were still isolated. In conclusion, the combination of dynamic and kinetic models provides a comprehensible insight into the process of tabletting powder mixtures with pellets. Particularly, the Kawakita model was a suitable tool to differentiate the actual changes in porosity during compression from the compressibility of such complex systems.     

Evaluation of a Rotary Tablet Press Simulator as a Tool for the Characterization of Compaction Properties of Pharmaceutical Products

The Stylcam 100R, a rotary press simulator, was designed to simulate speed profiles of rotary tablet presses. Such a simulator was qualified by numerous laboratories and, actually, its ability to be used for studying the behaviour of powders under pressure should be examined. Then, the purpose of this work was to investigate the performances of the Stylcam 100R for characterizing the compaction behaviour and the tabletting properties of pharmaceutical powders. The compressibility of three pharmaceutical excipients (microcrystalline cellulose, dicalcium phosphate dihydrate and a-lactose monohydrate) was studied. Four compression speeds were used on the compaction simulator. Force-displacement cycles were associated with two energy parameters, the specific total energy (Es_tot) and the specific expansion energy (Es_exp). The mean yield pressure was calculated from Heckel’s plots obtained with the in-die method. The diametral tensile strength of compacts was measured in order to evaluate mechanical properties. To evaluate the accuracy of all these parameters, a comparative study was carried out on an eccentric instrumented press. The values of energy parameters and tensile strengths of tablets are close between the eccentric press and the compaction simulator, whatever the compression speed on the latter. The mean yield pressure values obtained using the two presses are different. Finally, the Stylcam 100R seems to be a good tool for characterising tabletting properties of powders, except for the Heckel’s model probably due to an unadapted equation of deformation and a lack of accuracy of the displacement transducers. Future improvements should allow correcting these two points.     

The Role of the Displacement-time Waveform in the Determination of Heckel Behaviour Under Dynamic Conditions in a Compaction Simulator and a Fully-instrumented Rotary Tablet Machine

Abstract— The Heckel equation has been used widely to characterize the compression behaviour of pharmaceutical powders, yet very little attention has been paid to the role of the displacement-time profile used to generate this relationship. The objective of this study was to evaluate and compare selected standard waveforms with actual and theoretical tablet press waveforms in the Heckel analysis of representative formulations under dynamic conditions in a compaction simulator and to compare such data with that determined on the same formulation using an actual fully-instrumented rotary tablet press. Increased tableting rate and different programmed displacement-time waveforms with the same gross punch-speed changed the Heckel behaviour of all formulations. The results of this study suggest the pressure-volume relationship determined during powder-bed compression is affected by the instantaneous punch-speed profile of the displacement-time waveform for all materials studied, even though they deform by different mechanisms. It appears that the instantaneous punch-speed profile of the particular displacement-time waveform is a confounding factor of Heckel analysis. Compaction simulators programmed to deliver saw-toothed displacement-time traces have the advantage of constant punch-speed and may be a better choice for characterizing a formulation by Heckel indices and the strain-rate sensitivity index. On the other hand, they also carry the liability of not being a realistic representation of tableting on a rotary tablet press.     

可压性淀粉压缩特性和成型机理的研究

以另外3种粉末为参照物,研究了可压性淀粉的压缩性和成型性。对这些性质通过分析其上冲力与最大模壁力、残余模壁力、弹性复原率的关系,应力缓和及Heckel图,并加以探讨。结果证明:可压性淀粉的良好的可压性是由于对原淀粉颗粒进行处理后,其表面性质发生变化并产生大量的非结晶区域;当其受压时表现为塑性流动而导致塑性变形,使颗粒间紧密接触并互相楔住,同时又可在颗粒间形成氢键结合,使成为坚固的压实体。     

About the use of stoichiometric hydroxyapatite in compression - incidence of manufacturing process on compressibility.

Literature concerning calcium phosphates in pharmacy exhibits the chemical diversity of the compounds available. Some excipient manufacturers offer hydroxyapatite as a direct compression excipient, but the chemical analysis of this compound usually shows a variability of the composition: the so-called materials can be hydroxyapatite or other calcium phosphates, uncalcined (i.e. with a low crystallinity) or calcined and well-crystallized hydroxyapatite. This study points out the incidence of the crystallinity of one compound (i.e. hydroxyapatite) on the mechanical properties. Stoichiometric hydroxyapatite is synthesized and compounds differing in their crystallinity, manufacturing process and particle size are manufactured. X-Ray diffraction analysis is used to investigate the chemical nature of the compounds. The mechanical study (study of the compression, diametral compressive strength, Heckel plots) highlights the negative effect of calcination on the mechanical properties. Porosity and specific surface area measurements show the effect of calcination on compaction. Uncalcined materials show bulk and mechanical properties in accordance with their use as direct compression excipients.     

A novel approach to derive a compression parameter indicating effective particle deformability

In this article, a compression parameter is derived and its physical significance discussed. Tablets were formed from two sodium chloride powders and from two sucrose powders over a wide range of compaction pressures and the tensile strength and the porosity of the tablets were determined. From these data, the novel compression parameter and the Heckel parameter were calculated. Above a lower pressure threshold, the tablet strength increased relatively linear with compaction pressure up to 300-500 MPa and thereafter, the tablet strength leveled off. From the linear region, the compression parameter was derived. The tablet porosity data obeyed reasonably the Heckel function and from the linear region, the yield strength was calculated. For all four powders, a ratio between the compression parameter and the Heckel yield strength of about 3 was obtained. It is concluded that the suggested compression parameter represents an indication of the effective deformability of particles during compression which is suggested to correlate with the hardness of the particles.