Compaction Of Pharmaceutical Powders Research Articles

Empirical Model Variability: Developing a new global optimisation approach to populate compression and compaction mixture rules

This study systematically evaluated the predictive accuracy of common empirical models for pharmaceutical powder compaction. A dataset of nine placebo and twelve active pharmaceutical ingredient (API) loaded blend formulations (four APIs at three drug loadings) was fitted to the widely used empirical tablet compression (Gurnham, Heckel, and Kawakita) and compaction (Ryshkewitch-Duckworth and Leuenberger) models. At low API loadings (<20w/w%), all models achieved R2 above 90 % and RRMSE (relative root mean squared error) below 0.1. However, as API loads increased, overall model performance decreased, notably in the Heckel model. A parameter variability analysis identified multiple parameter pairs achieving acceptable fits. Consequently, a novel global optimization approach was developed populating arithmetic, geometric, and harmonic mixture rules for empirical tuning parameters. This method outperformed the traditional line of best fit approach. A cross validation study revealed that this method is capable of predicting tuning parameters which achieve an acceptable Goodness of Fit for new blends. Finally, with the restriction of maintaining consistent parameters for the placebo blend, the proposed method could substantially reduce the experimental requirements and API consumption for the exploration of new blends.

Prediction of Critical Quality Attributes Based on the Numerical Simulation of Stress and Strain Distributions in Pharmaceutical Tablets.

Various stresses and strains are generated on the surface and inside of pharmaceutical tablets when an external force is applied. In addition, stresses in various directions can remain on the surface and inside the tablets because they are generally prepared by compaction of pharmaceutical powders using dies and punches. As it is difficult to measure the stress and strain generation in the tablets experimentally, a numerical simulation was applied by employing a finite element method (FEM). An elastic model is often used to represent stress and strain generation after loading an external force to tablets, and the Drucker-Prager cap (DPC) model has been widely recognized for representing the remaining stress distributions during the compaction of powder to tablet form. Firstly, this article describes an FEM simulation of the stress generation on the surface of the scored tablets after loading the bending force from the back side of the tablets. Next, the FEM simulation was introduced to determine the effect of diametrical compression on the stress and strain generation in the tablets by comparing the results measured experimentally. Furthermore, the residual stresses remaining inside the tablets were simulated using FEM, in which powder compaction was represented as the DPC model. A clear difference was observed in the residual stress distributions between the flat and convex tablets. This indicates that FEM simulation is useful for achieving a science-based understanding of critical quality attributes in various types of tablets.

Comparative study between Drucker-Prager/Cap and modified Cam-Clay models for the numerical simulation of die compaction of pharmaceutical powders

Numerical simulation with finite element method is commonly used to model the process of die compaction. In pharmaceutical field, the Drucker-Prager/Cap (DPC) model is by far the most used to study the mechanical behavior of the powder. Another classical model but less used model, the modified Cam-Clay (MC-C) model, is introduced in this study. The main advantage is that the model parameters are easier to determine for MC-C model than for DPC model.The yield surface of the MC-C model is an elliptical curve. This model was compared to DPC model in order to assess its ability to describe the powder behavior in compression. Experimental tests were done to characterize the parameters of both models and the simulations were performed.The global behavior of the powder in compression was assessed from the equations of the models and the plots of compression curves. The spatial distributions of the relative density and axial stress were studied to compare the local behavior of the compact (stress concentration, areas of low/high density). The results obtained from the two models were nearly identical in the case of flat-faced punches but also when using concave-face punches. This means that the MC-C model is able to well describe the die compaction of pharmaceutical powder.

On the die compaction of powders used in pharmaceutics

Die compaction is widely used in the compaction of pharmaceutical powders (tableting). It is well known that the powder densification is a result of particle rearrangement and particle deformation. The former is considered to be the governing mechanism of densification in an initial stage of compaction and the latter is regarded as the governing mechanism in the compaction at the higher pressure range. As a more realistic assumption, one can consider that a simultaneous performance of both the rearrangement and deformation mechanisms takes place from the beginning of compaction. To mathematically formulate this assumption, a piston equation is presented where the material relative density is given as a function of the applied pressure on the powder. From the equation, it is possible to obtain the contribution of each mechanism to the material densification at each value of the applied pressure. In the continuation, the piston equation is applied to the tabletting of some pharmaceutical powders. These are the powders of Ascorbic Acid, Avicel® PH 101, Avicel® PH 301, Emcompress®, Sodium Chloride, and Tablettose® whose tableting results have been previously published in the literature. The results show the piston equation as a suitable approach to describe the tabletting of pharmaceutical powders.

An experimental investigation of temperature rise during compaction of pharmaceutical powders

During pharmaceutical powder compaction, temperature rise in the compressed powder can affect physiochemical properties of the powder, such as thermal degradation and change in crystallinity. Thus, it is of practical importance to understand the effect of process conditions and material properties on the thermal response of pharmaceutical formulations during compaction. The aim of this study was to examine the temperature rise of pharmaceutical powders during tableting, in particular, to explore how the temperature rise depends on material properties, compression speed and tablet shape. Three grades of microcrystalline cellulose (MCC) were considered: MCC Avicel pH 101, MCC Avicel pH 102 and MCC DG. These powders were compressed using a compaction simulator at various compaction speeds (10–500mm/s). Flat faced, shallow convex and normal convex tablets were produced and temperature distributions on the surface of theses tablets upon ejection were examined using an infrared thermoviewer. It was found that an increase in the compaction speed led to an increase in the average surface temperature. A higher surface temperature was induced when the powder was compressed into a tablet with larger surface curvature. This was primarily due to the increasing degree of powder deformation (i.e. the volume reduction) and the effect of interparticule/wall friction.

The role of fine particles on compaction and tensile strength of pharmaceutical powders

The role of fine particles on compaction of powders and the resultant compact was studied experimentally. Samples of powders were prepared by successively removing fine particles from microcrystalline cellulose and lactose monohydrate powders. This method of preparing samples is unique compared to previous studies on particle size distribution, and allows for a better analysis of the role of fine particles. For each sample, the role of fine particles on the initial relative density of the materials during die filling, the compaction profile, the in-die elastic recovery during unloading of compaction force, and the tensile strength of the corresponding tablet was investigated. It was found that the initial relative density during the die filling process and early phase of compaction decreased as a portion of the fine particles was reduced. However, this difference in the relative density during the early stage disappeared at higher compaction forces. The peak compaction pressure, elastic recovery, and the compact's tensile strength remained the same regardless of the amount of fine particles, when plotted as a function of the relative density. These results indicate that the fine particles affect the initial packing, but not the compaction of these powders and the tensile strength of the compacts.

The effect of punch's shape on die compaction of pharmaceutical powders

This paper investigates the compaction of pharmaceutical powders using different shapes of punches. We introduce a model of mechanical behaviour Drucker–Prager Cap (DPC), using the approach of compressible continuous media. The model parameters that are depending on the material density, were identified from experimental data and a calibration process was applied on Microcrystalline Cellulose (MCC) powder. In addition, the mathematical formulation of the boundary problem of compaction in rigid tools brings back to an optimization problem with constraint, which is solved by finite element method. The Drucker–Prager Cap model, which is implemented in Abaqus/Standard software, was employed using a user subroutine, USDFLD. Three kinds of typical pharmaceutical tablets are considered: flat-face tablet and concave face tablet with two different depths. Results of simulations of die compaction cycle as compression, decompression and ejection, reproduce the powder compaction process for the studied shaped punches. The effects of the punch's shape on the compaction process were observed on the distribution and the maximum of stress and density in the compact. Examination of the density gradient according to the shape, suggests a capping tendency, which increases with the punch depth. This study illustrates the potentiality of the FEM method, which could be used as an efficient tool to predict the density and the stress distributions into shaped compacts and to provide a diagnostic of the capping problems.

Modeling pharmaceutical compacts tensile strength based on viscoelastic properties

Abstract Although several researchers acknowledge the effects of viscoelasticity in pharmaceutical powder compaction, no models have been reported that relate compact mechanical properties to the powder viscoelastic properties. The tensile strength of a compact is largely influenced by contact area between deforming particles which depends on the viscoelastic properties and compaction variables. The objective of this research was to develop semi-mechanistic models based on viscoelastic contact area estimates, to predict tensile strength of Microcrystalline Cellulose (MCC) and Acetaminophen (APAP) compacts. Formulations with varying amounts of MCC, APAP and moisture contents corresponding to 50 and 70% RH were prepared. The powders were compressed in a Uniaxial testing machine (Instron) at a punch velocity of 2 mm/min to final pressures in the range of 12.5 to 44 MPa. The diametral tensile strength, compaction and viscoelastic properties were determined. The deformation contact area was estimated using equation by Lum and Duncan-Hewitt [22] based on the median particle size of MCC, compaction and viscoelastic properties as determined from the Maxwell model. It was found that the estimated contact area depended on the APAP composition, moisture content and on compaction pressure. The viscoelastic contact area, density and final compact tensile strength were found to increase with increasing compaction pressure, moisture content and MCC. A unified model that expresses the compact tensile strength as a function of viscoelastic contact area was successfully developed.

Modeling and Simulation of Pharmaceutical Powder Compaction

The finite element method was conducted to simulate the pharmaceutical powder compression process by using Drucker–Prager Cap model and elastic-plastic deformation theory. The effects of different friction coefficient on tablet property were systematically studied. The results show that the pressure-density curves shift towards right-hand side with slight decrease at smaller friction coefficient. The fluidity of powder remains the inverse decrease with the friction coefficient, and the density distribution changed more uniform. The maximum Mises stress becomes larger with the friction coefficient increased. The powder displacement decreases near die as the friction coefficient increasing. The research can both predict the tablet property and provide the theory reference for tablet practice production through the finite element analysis of pharmaceutical powder compaction.

A comparative study of roll compaction of free-flowing and cohesive pharmaceutical powders

Roll compaction is widely adopted as a dry granulation method in the pharmaceutical industry. The roll compaction behaviour of feed powders is primarily governed by two parameters: the maximum pressure and the nip angle. Although the maximum pressure can be measured directly using pressure sensors fitted in the rolls, it is not a trivial task to determine the nip angle, which is a measure of the size of the compaction zone and hence the degree of compression. Thus a robust approach based upon the calculation of the pressure gradient, which can be obtained directly from experiments using an instrumented roll compactor, was developed. It has been shown that the resulting nip angles are comparable to those obtained using the methods reported in literature. Nevertheless, the proposed approach has distinctive advantages including (1) it is based on the intrinsic features of slip and no-slip interactions between the powder and roll surface and (2) it is not necessary to carry out wall friction measurements that involve plates that may not be representative of the roll compactor in terms of the surface topography and surface energy. The method was evaluated by investigating the effect of roll speed for two pharmaceutical excipients with distinctive material properties: microcrystalline cellulose (MCC) and di-calcium phosphate dihydrate (DCPD). It was found that the maximum pressure and nip angle for DCPD, which is a cohesive powder, decrease sharply with increasing roll speed whereas they are essentially independent of roll speed for MCC, which is an easy flowing powder. The roll compaction behaviour of MCC–DCPD mixtures with various compositions was also investigated in order to evaluate the effect of flowability. It was found that the nip angle and maximum pressure generally increased with improved flowability of the feed powders.

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.

Book Review

Abstract Book reviewed in this article: Aqueous Two-Phase Partitioning. Physical Chemistry and Bioanalytical Applications. Boris Y. Zaslavsky. Pharmaceutical Powder Compaction Technology (Drugs and the Pharmaceutical Sciences Series/71) Edited by Göran Alderborn and Christer Nyström Physical Characterization of Pharmaceutical Solids (Drugs and the Pharmaceutical Sciences Series/70) Edited by Harry G. Brittain

Study of radial die-wall pressure changes during pharmaceutical powder compaction

Context: In tablet manufacturing, less attention is paid to the measurement of die-wall pressure than to force–displacement diagrams. Objective: Therefore, the aim of this study was to investigate radial stress change during pharmaceutical compaction. Materials and Methods: The PressterTM, a tablet-press replicator was used to characterize compaction behavior of microcrystalline cellulose (viscoelastic), calcium hydrogen phosphate dihydrate (brittle), direct compressible mannitol (plastic), pre-gelatinized starch (plastic/elastic), and spray dried lactose monohydrate (plastic/brittle) by measuring radial die-wall pressure; therefore powders were compacted at different (pre) compaction pressures as well as different speeds. Residual die-wall pressure (RDP) and maximum die-wall pressure (MDP) were measured. Various tablet physical properties were correlated to radial die-wall pressure. Results and Discussion: With increasing compaction pressure, RDP and MDP (P < 0.0001) increased for all materials, with increasing precompaction RDP decreased for plastic materials (P < 0.05), whereas with increasing speed MDP decreased for all materials (P < 0.05). During decompression, microcrystalline cellulose and pre-gelatinized starch showed higher axial relaxation, whereas mannitol and lactose showed higher radial relaxation, calcium hydrogen phosphate showed high axial and radial relaxations. Plastic and brittle materials showed increased tendencies for friction because of high radial relaxation. Conclusion: Die-wall monitoring is suggested as a valuable tool for characterizing compaction behavior of materials and detecting friction phenomena in the early stage of development.

Method of modelling the compaction behaviour of cylindrical pharmaceutical tablets

The mechanisms involved for compaction of pharmaceutical powders have become a crucial step in the development cycle for robust tablet design with required properties. Compressibility of pharmaceutical materials is measured by a force–displacement relationship which is commonly analysed using a well known method, the Heckel model. This model requires the true density and compacted powder mass value to determine the powder mean yield pressure. In this paper, we present a technique for shape modelling of pharmaceutical tablets based on the use of partial differential equations (PDEs). This work also presents an extended formulation of the PDE method to a higher dimensional space by increasing the number of parameters responsible for describing the surface in order to generate a solid tablet. Furthermore, the volume and the surface area of the parametric cylindrical tablet have been estimated numerically. Finally, the solution of the axisymmetric boundary value problem for a finite cylinder subject to a uniform axial load has been utilised in order to model the displacement components of a compressed PDE-based representation of a tablet. The Heckel plot obtained from the developed model shows that the model is capable of predicting the compaction behaviour of pharmaceutical materials since it fits the experimental data accurately.

Exceptional Events Management Applied to Roller Compaction of Pharmaceutical Powders

This study focuses on the development and implementation of an Exceptional Events Management (EEM) framework that detects, diagnoses, and mitigates exceptional events inherent to particulate processes that are prevalent in the pharmaceutical industry. The EEM framework combines several methods, including signed directed graph (SDG), qualitative trend analysis (QTA), and fast Fourier transform analysis. We discuss the efficacy of the EEM framework in detecting and diagnosing abnormal events, and demonstrate its application on roller compaction. We demonstrate that various commonly occurring exceptional events such as “no powder entering the roll region” (which includes “jamming in the nip region”), “caking of powder on rolls” and “varying moisture in powder” can be detected and diagnosed using the EEM framework. In addition, we show that the SDG-QTA approach is useful in determining the type and location of sensors that would enable better monitoring thereby improving the detection and diagnostic capabilities of our EEM framework. The developed EEM framework shows potential for facilitating the pharmaceutical transition from batch to continuous manufacturing.

Roller compaction of moist pharmaceutical powders

The compression behaviour of powders during roller compaction is dominated by a number of factors, such as process conditions (roll speed, roll gap, feeding mechanisms and feeding speed) and powder properties (particle size, shape, moisture content). The moisture content affects the powder properties, such as the flowability and cohesion, but it is not clear how the moisture content will influence the powder compression behaviour during roller compaction. In this study, the effect of moisture contents on roller compaction behaviour of microcrystalline cellulose (MCC, Avicel PH102) was investigated experimentally. MCC samples of different moisture contents were prepared by mixing as-received MCC powder with different amount of water that was sprayed onto the powder bed being agitated in a rotary mixer. The flowability of these samples were evaluated in terms of the poured angle of repose and flow functions. The moist powders were then compacted using the instrumented roller compactor developed at the University of Birmingham. The flow and compression behaviour during roller compaction and the properties of produced ribbons were examined. It has been found that, as the moisture content increases, the flowability of moist MCC powders decreases and the powder becomes more cohesive. As a consequence of non-uniform flow of powder into the compaction zone induced by the friction between powder and side cheek plates, all produced ribbons have a higher density in the middle and lower densities at the edges. For the ribbons made of powders with high moisture contents, different hydration states across the ribbon width were also identified from SEM images. Moreover, it was interesting to find that these ribbons were split into two halves. This is attributed to the reduction in the mechanical strength of moist powder compacts with high moisture contents produced at high compression pressures.

Pharmaceutical Powder Compaction and Dissolution Analytics by Laboratory Small and Wide Angle X-Ray Scattering (SWAXS)

We investigate the compaction behavior of the most usual pharmaceutical excipients mixture (placebo) contained lactose monohydrate (LmH), microcrystalline cellulose (MCC), silicum dioxyd (SiO2) and magnesium stearate (MgSt) with combined small- and wide-angle X-ray scattering (SWAXS). [...]

A study on the sensitivity of Drucker–Prager Cap model parameters during the decompression phase of powder compaction simulations

The compaction of pharmaceutical powders can be simulated using phenomenological elasto-plastic continuum models adopted from soil mechanics. These models are typically implemented in finite element codes and have been used recently to investigate the macroscopic property distributions in powders during compaction. The present study demonstrates the importance of obtaining accurate yield surface parameters for use in such models. A commercial finite element code implementing the Drucker–Prager Cap (DPC) model was used to model the compression and decompression stages of powder compaction in a tabletting operation. The parameters used in the DPC model were obtained from the literature. Although the compression stage of the process gave expected behavior, the decompression response was unrealistic for at least one set of published data. Small values for the friction and cohesion parameters resulted in a significant elastic recovery during decompression. This study demonstrates the need to obtain accurate parameter data in order to model the decompression stage of powder compaction.

A ‘granocentric’ model for random packing of jammed emulsions

The nature of the random assembly of granular particles is a fundamental and ancient problem in physics and mathematics, with practical applications in situations as different as oil extraction through porous rocks, grain storage and the manufacture of tablets from powders. To date there is no known simple underlying mechanism for granular particles analogous to crystalline ordering. A team from the Center for Soft Matter Research at New York University has measured the packing of polydisperse emulsion droplets, finding that the complexity of the global packing structure can be understood in terms of a 'granocentric' view. A statistical model based on two simple, local parameters — the available space around a particle and the ratio of contacts to neighbours — successfully predicts both the local and global characteristics of packings, including their connectivity and density. A simple underlying mechanism for the random assembly of granular particles, analogous to crystalline ordering, remains unknown. Here however, three-dimensional measurements of packings of polydisperse emulsion droplets are used to build a statistical model where the complexity of the global packing can be understood in terms of two simple, local parameters — the available space around a particle and the ratio of contacts to neighbours. Packing problems are ubiquitous1,2, ranging from oil extraction through porous rocks to grain storage in silos and the compaction of pharmaceutical powders into tablets. At a given density, particulate systems pack into a mechanically stable and amorphous jammed state3,4. Previous theoretical studies have explored a connection between this jammed state and the glass transition4,5,6,7,8, the thermodynamics of jamming9,10,11,12 and geometric modelling of random packings13,14,15. Nevertheless, a simple underlying mechanism for the random assembly of athermal particles, analogous to crystalline ordering, remains unknown. Here we use three-dimensional measurements of packings of polydisperse emulsion droplets to build a simple statistical model in which the complexity of the global packing is distilled into a local stochastic process. From the perspective of a single particle, the packing problem is reduced to the random formation of nearest neighbours, followed by a choice of contacts among them. The two key parameters in the model—the available space around a particle and the ratio of contacts to neighbours—are directly obtained from experiments. We demonstrate that this ‘granocentric’ view captures the properties of the polydisperse emulsion packing—ranging from the microscopic distributions of nearest neighbours and contacts, to local density fluctuations, to the global packing density. Application of our results to monodisperse and bidisperse systems produces quantitative agreement with previously measured trends in global density16. Our model therefore reveals a general principle of organization for random packing and may provide the foundations for a theory of jammed matter.

Temperature Evolution during Compaction of Pharmaceutical Powders

A numerical approach to the prediction of temperature evolution in tablet compaction is presented here. It is based on a coupled thermomechanical finite element analysis and a calibrated Drucker-Prager Cap model. This approach is capable of predicting transient temperatures during compaction, which cannot be assessed by experimental techniques due to inherent test limitations. Model predictions are validated with infrared (IR) temperature measurements of the top tablet surface after ejection and match well with experiments. The dependence of temperature fields on speed and degree of compaction are naturally captured. The estimated transient temperatures are maximum at the end of compaction at the center of the tablet and close to the die wall next to the powder/die interface.