Compressibility and tablet forming ability of bimodal granule mixtures: Experiments and DEM simulations.

Compressibility and tablet forming ability (compactibility) of bimodal mixtures of differently sized granules formed from microcrystalline cellulose were studied experimentally and numerically with the discrete element method (DEM). Compression data was analysed using the Kawakita equation. A multi-body contact law that accounts for contact dependence resulting from plastic incompressibility/geometric hardening was used in the DEM simulations. The experimental Kawakita a and 1/b parameters both depended non-monotonically on composition (weight fraction of large particles). For the a parameter, this dependence was explained by variations in the porosity of the initial granule beds; for the 1/b parameter, other factors were found to be of importance as well. The numerical results generally compared favourably with the experiments, demonstrating the usefulness of the DEM at high relative densities, provided that a suitable multi-particle contact model is used. For all mixtures, the tensile strength of the formed tablets increased with increasing applied pressure. The tensile strength generally decreased with increasing fraction of large particle, and this decrease was more rapid for large differences in particle size. A possible interpretation of these findings was proposed, in terms of differences in lateral support of small particles in the vicinity of large particles.

Powder compression mechanics of spray-dried lactose nanocomposites.

The aim of this study was to investigate the structural impact of the nanofiller incorporation on the powder compression mechanics of spray-dried lactose. The lactose was co-spray-dried with three different nanofillers, that is, cellulose nanocrystals, sodium montmorillonite and fumed silica, which led to lower micron-sized nanocomposite particles with varying structure and morphology. The powder compression mechanics of the nanocomposites and physical mixtures of the neat spray-dried components were evaluated by a rational evaluation method with compression analysis as a tool, using the Kawakita equation and the Shapiro-Konopicky-Heckel equation. Particle rearrangement dominated the initial compression profiles due to the small particle size of the materials. The strong contribution of particle rearrangement in the materials with fumed silica continued throughout the whole compression profile, which prohibited an in-depth material characterization. However, the lactose/cellulose nanocrystals and the lactose/sodium montmorillonite nanocomposites demonstrated high yield pressure compared with the physical mixtures indicating increased particle hardness upon composite formation. This increase has likely to do with a reinforcement of the nanocomposite particles by skeleton formation of the nanoparticles. In summary, the rational evaluation of mechanical properties done by applying powder compression analysis proved to be a valuable tool for mechanical evaluation for this type of spray-dried composite materials, unless they demonstrate particle rearrangement throughout the whole compression profile.

The granule porosity controls the loss of compactibility for both dry- and wet-processed cellulose granules but at different rate.

The aim of this study was to investigate the role of porosity on the compression behavior and tablet tensile strength for granules produced by a dry granulation procedure. Microcrystalline cellulose was used as a typical pharmaceutical excipient and a comparison was made with the effect of granule porosity on the compression behavior and tablet tensile strength of wet-processed granules of the same composition. Both the wet and dry granulation process caused a loss in compactibility of the material that was controlled by the granule porosity up to a critical point of porosity and friability. Above this threshold value of porosity, the granules nearly collapsed completely into primary particles during compression. In these cases, the micro-structure and tensile strength of the formed tablets resembled that of tablets formed from the original ungranulated powder.

A comparison between two powder compaction parameters of plasticity: the effective medium A parameter and the Heckel 1/K parameter.

The purpose of the research was to introduce a procedure to derive a powder compression parameter (EM A) representing particle yield stress using an effective medium equation and to compare the EM A parameter with the Heckel compression parameter (1/K). 16 pharmaceutical powders, including drugs and excipients, were compressed in a materials testing instrument and powder compression profiles were derived using the EM and Heckel equations. The compression profiles thus obtained could be sub-divided into regions among which one region was approximately linear and from this region, the compression parameters EM A and 1/K were calculated. A linear relationship between the EM A parameter and the 1/K parameter was obtained with a strong correlation. The slope of the plot was close to 1 (0.84) and the intercept of the plot was small in comparison to the range of parameter values obtained. The relationship between the theoretical EM A parameter and the 1/K parameter supports the interpretation of the empirical Heckel parameter as being a measure of yield stress. It is concluded that the combination of Heckel and EM equations represents a suitable procedure to derive a value of particle plasticity from powder compression data.

The degree of compression of spherical granular solids controls the evolution of microstructure and bond probability during compaction.

The effect of degree of compression on the evolution of tablet microstructure and bond probability during compression of granular solids has been studied. Microcrystalline cellulose pellets of low (about 11%) and of high (about 32%) porosity were used. Tablets were compacted at 50, 100 and 150 MPa applied pressures and the degree of compression and the tensile strength of the tablets determined. The tablets were subjected to mercury intrusion measurements and from the pore size distributions, a void diameter and the porosities of the voids and the intra-granular pores were calculated. The pore size distributions of the tablets had peaks associated with the voids and the intra-granular pores. The void and intra-granular porosities of the tablets were dependent on the original pellet porosity while the total tablet porosity was independent. The separation distance between pellets was generally lower for tablets formed from high porosity pellets and the void size related linearly to the degree of compression. Tensile strength of tablets was higher for tablets of high porosity pellets and a scaled tablet tensile strength related linearly to the degree of compression above a percolation threshold. In conclusion, the degree of compression controlled the separation distance and the probability of forming bonds between pellets in the tablet.

A protocol for the classification of powder compression characteristics.

In this paper, a structured protocol for powder compression analysis as a test to assess the mechanical properties of particles in a formulation development programme is presented. First, the sequence of classification steps of the protocol is described, and secondly, the protocol is illustrated using compression data of six powders of two model substances, sodium chloride and mannitol. From powder compression data, a set of compression variables are derived, and by using critical values of these variables, the stages expressed during the compression of the powders are identified and the powders are classified into groups with respect to the expression of particle rearrangement, particle fragmentation and particle plastic deformation during compression. It is concluded that the proposed protocol could, in a satisfactorily way, describe and distinguish between the powders regarding their compression behaviour. Hence, the protocol could be a valuable tool for the formulation scientist to comprehensively assess important functionality-related characteristics of drugs and excipients.

Degree of compression as a potential process control tool of tablet tensile strength.

The current view on the development and manufacturing of pharmaceutical preparations points towards improved control tools that can be implemented in pharmaceutical manufacturing as a means to better control end product properties. The objective of this paper was to investigate the relationship between tablet tensile strength and the degree of bed compression in order to evaluate the suitability of assessing the straining of the powder bed during tableting as a process control tool of tablet tensile strength. Microcrystalline cellulose was used as powder raw material and subjected to wet granulation by different procedures to create agglomerates of different physical and compression properties. The produced agglomerates thus showed a large variation in compressibility and compactibility. However, in terms of the relationship between the degree of compression and the tablet tensile strength, all agglomerates gathered reasonably around a single general relationship. The degree of compression hence appears to be a potential valuable process control tool of the tablet tensile strength that may enable the use of an adaptive tableting process with improved product quality consistency.

A statistical approach to evaluate the potential use of compression parameters for classification of pharmaceutical powder materials.

The current work aims to investigate whether a multivariate statistical approach could reveal latent structures in compression data and group powders with respect to their compression behavior in a way that is consistent with an earlier proposed classification system. Seventeen pharmaceutically relevant materials, exhibiting a wide range of mechanical properties, were used as supplied, compressed, and parameters from three commonly used powder compression models (Kawakita parameters a and b(-1), the rearrangement index ab, the Shapiro f parameter and Heckel P(y)) were retrieved. Multivariate analysis of the compression parameters was done with a Principal Component Analysis (PCA). It was found that the latent structures could be divided into three main parts; the most variation was found in the direction associated with particle rearrangement, second largest variation was found in the direction described by the particle fragmentation propensity, and the least variation was found in the direction associated with the plasticity of the particles. This work demonstrates that a combination of the selected compression parameters could be utilized to find relevant differences in compression behavior for a wide range of materials, and that this information can be presented in an efficient way by applying multivariate data analysis techniques.

On the physical interpretation of the initial bending of a Shapiro-Konopicky-Heckel compression profile.

The relationship between the natural logarithm of the tablet porosity and the applied pressure is used to describe the compression behavior of a powder. Such a relationship, here referred to as a Shapiro-Konopicky-Heckel (SKH) profile, is usually divided into three regions, of which the first often is non-linear. The objective of this work was to address the question of the mechanisms controlling the compression and the bending of the first region of a SKH profile for dense particles. In this paper, the first region was described by the Shapiro General Compression Equation, from which a compression parameter was derived as a measure of the bending. The results indicate that for powders undergoing significant particle rearrangement at low applied pressures, the particle rearrangement is the major cause for the initial bending of the SKH profile. For powders showing limited particle rearrangement, the initial bending is mainly caused by the change in particle diameter due to particle fragmentation. It is concluded that the evaluation of the first region of a SKH profile in terms of bending may be used to assess particle fragmentation. The SKH profile could hence be a useful tool to describe powder compression behavior in terms of particle fragmentation and particle deformation from one single compression analysis.