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 force/time-profiles of microcrystalline cellulose, dicalcium phosphate dihydrate and their binary mixtures-a critical consideration of experimental parameters

Compression force/time-profiles of microcrystalline cellulose and dicalcium phosphate dihydrate and mixtures thereof were compared on a modern rotary press by three different methods of compression: compression to a constant tablet weight, compression to a constant tablet height and compression from a constant filling depth. Compression was carried out at three different compression force levels. The differences obtained by analysing the area under the curve in the compression, dwell and decompression phase could be explained by differences of the in-die working density of the powders and their respective compression behaviour. From data of the compression phase as well as from the area-quotient-index obtained from the dwell time it was possible to estimate the percolation threshold of dicalcium phosphate dihydrate in a mixture with microcrystalline cellulose to ˜ 50% (w/w) corresponding to 30% (v/v).     

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.     

Adjustment of precompression force to reduce mixing-time dependence of tablet tensile strength

The dependence of tablet tensile strength on lubricant mixing time, pre- and main compression pressure was measured with microcrystalline cellulose, dicalcium phosphate dihydrate and starch 1500 on a rotary tablet machine. Loss of tablet tensile strength arising from lubricant overmixing can be substantially reduced in the case of microcrystalline cellulose by adjustment of pre- and main compression. This facility may be used in addition to or instead of reducing mixing time, or displacing lubricant by adding extra formulation components.     

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 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 < lactose < cellulose < 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.     

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.     

Three-dimensional modeling to determine properties of tableting materials on rotary machines using a rotary tableting machine simulator.

A new three-dimensional modeling technique of tableting data has been used for data measured with a rotary tableting machine simulator. The use of the tableting machine simulator is helpful in this case because a scale up or a change of equipment is easily possible. The model substances used were hydroxypropyl methylcellulose (HPMC 15.000), microcrystalline cellulose (Avicel PH 101), dicalcium phosphate dihydrate (Emcompress) and theophylline monohydrate, four very differently deforming substances. Tablets were produced by simulating a Manesty Betapress with 100 rev./min. The materials were tableted to five graded maximum relative densities (rho(rel, max)) of 0.75, 0.80, 0.85, 0.90 and 0.95. A twisted plane was fitted to the measured data and three parameters: d, the time-plasticity: e, the pressure plasticity and omega, the elastic decompression, resulted for each material at the given rho(rel, max) according to the three-dimensional tableting technique. The results show different parameter-plots for the tableting materials, allowing to differentiate between the tableting characteristics of various substances. Three-dimensional modeling of data from rotary machines is shown to be a valuable tool not only for material characterization on eccentric machines but on rotary tableting machines as well.     

A new theoretical model to characterize the densification behavior of tableting materials.

The purpose of the study was to develop a new three-dimensional model using force, time and displacement to characterize the densification behavior of tableting materials. Normalized time (x), displacement converted to ln(1/1 - D(rel)) according to Heckel (y) and force presented as pressure (z) were used to plot a graph. A twisted plane was fitted to this three-dimensional plot. This plane was characterized by three parameters d, the slope over time called 'time plasticity', e, the slope over pressure called 'pressure plasticity' and omega, the angle of rotation called 'fast elastic decompression'. These parameters were used to characterize the densification behavior of the well-known materials microcrystalline cellulose, dicalcium phosphate dihydrate, theophylline monohydrate, cellulose acetate and hydroxypropyl methylcellulose at different rho(rel, max). It could be shown that brittle, elastic and plastic compression properties could be very well distinguished and differentiated. Further on, it could be shown whether these properties were due to pressure or time. Thus this model has the prevailing advantage to characterize tableting materials in one step according to time and pressure and it is a useful tool to develop tablet formulations or new excipients.     

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.     

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.     

Influence of formulation composition and processing on the content uniformity of low-dose tablets manufactured at kilogram scale

The purpose of this study was to investigate the impact of processing, API loading, and formulation composition on the content uniformity of low-dose tablets made using direct compression (DC) and roller compaction (RC) methods at 1?kg scale. Blends of 1:1 microcrystalline cellulose/lactose or 1:1 microcrystalline cellulose/dicalcium phosphate anhydrous with active pharmaceutical ingredient (API) at loadings of 0.2, 1 and 5% were processed either by DC or RC. A statistical analysis showed that DC produced comparable content uniformity results to RC. Microcrystalline cellulose/lactose formulations had improved average potency compared to microcrystalline cellulose/dicalcium phosphate anhydrous formulations for both DC and RC. The impact of segregation in the DC blends and adhesion to equipment surfaces was assessed to aid in understanding potency trends. DC may be as suitable as RC for low-dose regime (e.g. <?1?mg) when manufacturing clinical supplies at small scale provided the API has a suitable particle size and potency loss to equipment is negligible.     

An evaluation of three-dimensional modeling of compaction cycles by analyzing the densification behavior of binary and ternary mixtures

The aim of the study is to use the 3D modeling technique of compaction cycles for analysis of binary and ternary mixtures. Three materials with very different deformation and densification characteristics [cellulose acetate (CAC), dicalcium phosphate dihydrate (EM) and theophylline monohydrate (TM)] have been tableted at graded maximum relative densities (rhorel, max) on an eccentric tableting machine. Following that, graded binary mixtures from CAC and EM have been compacted. Finally, the same ratios of CAC and EM have been tableted in a ternary mixture with 20 vol% TM. All compaction cycles have been analyzed by using different data analysis methods. Three-dimensional modeling, conventional determination of the slope of the Heckel function, determination of the elastic recovery during decompression, and calculations according to the pressure-time function were the methods of choice. The results show that the 3D model technique is able to gain the information in one step instead of three different approaches, which is an advantage for formulation development. The results show that this model enables one to better distinguish the compaction properties of mixtures and the interaction of the components in the tablet than 2D models. Furthermore, the information by 3D modeling is more precise since in the slope K of the Heckel-plot (in die) elasticity is included, and in the parameters of the pressure-time function beta and gamma plastic deformation due to pressure is included. The influence of time and pressure on the displacement can now be differentiated.     

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.     

Thermophysical Properties of Some Pharmaceutical Excipients Compressed in Tablets

Purpose. Thermophysical properties of three tableting excipients; microcrystalline cellulose, lactose and dicalcium phosphate dihydrate were observed to evaluate their ability to resist temperature induced changes in tablet form. Methods. Two thermophysical parameters, thermal diffusivity and specific heat, were measured by a pulse heating method. The materials were also evaluated by differential scanning calorimetry (DSC). Results. Microcrystalline cellulose in tablet form was found to be rather insensitive to heating and cooling treatments, even though the tablets seemed to remain in a stressed state four weeks after tableting. This stress, indicated by low temperature anomalies, was observed by the pulse method, but not by DSC. When magnesium stearate was incorporated as a lubricant within the microcrystalline cellulose powder, the thermophysical parameters indicated that the internal structure of the tablets changed with heating and cooling. Magnesium stearate eliminated the low temperature anomalies as well. The heat treatment changed the thermophysical properties of tablets made of the crystalline excipients lactose and dicalcium phosphate dihydrate, permanently causing irreversible structural changes. Conclusions. The melting of the lubricant together with enhanced stress relaxation in the structure of microcrystalline cellulose most probably caused the improved thermal diffusivity. The observed thermophysical changes with the crystalline excipients were due to changes in tablet's structure and material. The combination of methods used was found to be an accurate and reliable way to obtain useful information on the structural changes and material relaxations of intact tablets during temperature treatment and age-related changes in material properties.     

An Evaluation of Three-Dimensional Modeling of Compaction Cycles by Analyzing the Densification Behavior of Binary and Ternary Mixtures

The aim of the study is to use the 3D modeling technique of compaction cycles for analysis of binary and ternary mixtures. Three materials with very different deformation and densification characteristics [cellulose acetate (CAC), dicalcium phosphate dihydrate (EM) and theophylline monohydrate (TM)] have been tableted at graded maximum relative densities (ρ_{rel, max}) on an eccentric tableting machine. Following that, graded binary mixtures from CAC and EM have been compacted. Finally, the same ratios of CAC and EM have been tableted in a ternary mixture with 20 vol% TM. All compaction cycles have been analyzed by using different data analysis methods. Three-dimensional modeling, conventional determination of the slope of the Heckel function, determination of the elastic recovery during decompression, and calculations according to the pressure–time function were the methods of choice. The results show that the 3D model technique is able to gain the information in one step instead of three different approaches, which is an advantage for formulation development. The results show that this model enables one to better distinguish the compaction properties of mixtures and the interaction of the components in the tablet than 2D models. Furthermore, the information by 3D modeling is more precise since in the slope K of the Heckel-plot (in die) elasticity is included, and in the parameters of the pressure–time function β and γ plastic deformation due to pressure is included. The influence of time and pressure on the displacement can now be differentiated.     

Compression behavior of spray dried rice starch

Compression behaviors of spray dried rice starch (SDRS), as well as pregelatinized starch (PS), and microcrystalline cellulose (MCC) were characterized using Heckel analysis. SDRS was found to undergo plastic deformation with lower elasticity compared with PS. SDRS showed very low fragmentation tendency due to the fact that the difference between extrapolated and actual densification of its Heckel plot was low. Having aggregate sphere in shape, its densification could be initiated by deaggregation and tight packing without requiring high pressure. The above evidence explains why the compactibility of SDRS is excellent. MCC on the other hand, showed some fragmentation before undergoing plastic deformation. The fragmentation might have increased the contacts among particles which resulted in higher crushing strength of the tablets compared with that of SDRS. The slope of the Heckel plot of a mixture of each excipient and hydrochlorothiazide fairly agreed with the summation of the weight fraction of each component. The deformation of the mixture tested could be easily predicted. Since SDRS possesses both good compactibility and flowability, this new direct compression excipient has a high potential for successful tablet formulation.     

Compression behavior of formulations from Phyllanthus niruri spray dried extract

The aim of this study was to evaluate the compression behavior of Phyllanthus niruri spray dried extract as well as the influence of excipients on the properties of tablets containing a high dose (70% by weight) of this product. The effect of excipients was studied by a 22 factorial design. The factors investigated were the type of disintegrant (croscarmellose sodium and sodium starch glycolate) and the type of filler/binder (microcrystalline cellulose and dibasic dicalcium phosphate). The tablets were produced on a single punch tablet press using a constant compression force of 5000 N. The tablets formulated with microcrystalline cellulose presented a plastic behavior while the tablets containing dibasic dicalcium phosphate disclosed a fragmentary behavior. The disintegration time was significantly influenced by both factors, however, the tensile strength was only affected by the filler/binder. Additional experiments considering the influence of the compression force (2500 N and 5000 N) and the proportion of croscarmellose sodium (1.5%, 3.0% and 6.0%) on the mechanical properties of the tablets were performed by a 2 x 3 factorial design. Both factors significantly affected the tensile strength, friability and disintegration time of the tablets.     

The 3-D model: experimental testing of the parameters d, e, and omega and validation of the analysis

The aim of the study was to evaluate the parameters d, e, and omega for their significance in compression data analysis. Materials with predominantly different compression properties were used and tableting data were obtained with an instrumented eccentric and rotary tableting machine. The parameters time plasticity (d), pressure plasticity (e), and the twisting angle (omega), an indicator of fast elastic decompression, were derived by 3-D modeling. The Peak-Offset-Time, the pressure-time function parameters, the Heckel slope, normalized compaction (E2(norm)) and elastic energy (E3(norm)), and fast elastic recovery (FER), which are well known tableting parameters, were calculated from the tableting data. The plastic microhardness of the tablets was determined from using microindentation. The results revealed that d is influenced by speed, e correlates with microhardness, and omega correlates with the Elastic modulus (E). Thus, for all three 3-D model parameters an experimental basis is given. The validation showed that d correlates with the Peak-Offset-Time and the pressure-time function parameters, e correlates with the Heckel slope and E2(norm), and omega correlates with E3(norm) and FER of the tablets. The significance of the three parameters is fully given. It is no longer necessary to use two separate methods to differentiate between time- and pressure-dependent deformations.     

Effect of compaction on particle size.

Compressed tablets were prepared on a hydraulic press at several different compaction pressures by a standardized technique, using aspirin, dicalcium phosphate dihydrate, calcium phosphato-carbonate, alumina, and microcrystalline cellulose. All tablets except microcrystalline cellulose contained a cation-exchange resin as disintegrant. The particle-size spectra of the disintegrating compacts were evaluated using a particle-size counter or an air jet sieve. It is shown that compacts made from different materials but of the same initial particle-size spectra disintegrate to give particles of a considerably different size. Determination of the change in particle size produced by the compaction process provides useful insight into the nature of the compaction process.