Tabletability and compactibility of α-lactose monohydrate powders of different particle size. II: predicted relationships.

This study aimed to evaluate a material sparing method to predict tabletability and compactibility relationships. Seven α-lactose monohydrate powders with varying particle size were used as test materials. The compressibility of the powders was determined experimentally, whereas tabletability and compactibility profiles were derived both experimentally and predicted. In the prediction method, two experimental compression parameters (Kawakita b-1 and Heckel plastic stiffness) and a single tensile strength reference value were used, all necessary data obtained from a single compression experiment. For both predicted and experimental relationships, compaction and tableting parameters (performance indicators) were calculated. The correction for viscoelastic recovery was successful in generating compressibility profiles that corresponded to the series of experimental out-of-die tablet porosities. For both the tabletability and compactibility, the experimental and predicted profiles showed a high degree of similarity. Good correlations were obtained between the predicted and experimental compaction and tableting parameters. It is concluded that the hybrid prediction method is a material sparing method, which can give good approximations of tabletability and compactibility relationships. The prediction method has the potential to be included as a part of a protocol for the characterisation of the tableting performance of particulate solids.

Tabletability and compactibility of α-lactose monohydrate powders of different particle size. I. Experimental comparison.

In this paper, two types of parameters representing tabletability and compactibility profiles of a series of α-lactose monohydrate powders, ranging in particle size from approximately 3.5 to 203 µm, are derived and compared. By approximating the tabletability profiles using a three-stage model and the compactibility profiles using the Ryshkewitch-Duckworth equation, two compaction rate parameters and two compaction endpoint parameters were derived. The original median particle diameter had generally a strong effect on the tablet tensile strength and hence the tabletability and compactibility profiles. The experimental profiles were well approximated by the models used, and the compaction parameters were regarded as representative of the experimental profiles. The compaction endpoint parameters increased with decreased particle size and were controlled by the same structural feature as the compacts. The tabletability rate parameter also increased with decreased particle size and correlated well with the tabletability endpoint parameter. The compactibility rate parameter tended to increase with decreased particle size, but the effect was limited; moreover, no general correlation was obtained with the compactibility endpoint parameter. It is concluded that compactibility and tabletability parameters collectively provide a concentrated description of the compaction properties of a powder.

Atypical compaction behaviour of disordered lactose explained by a shift in type of compact fracture pattern.

The objective was to investigate tabletability and compactibility for compacts of a series of α-lactose monohydrate powders with different degree of disorder. Regarding the tabletability, the powders of high degree of disorder displayed similar behaviour that deviated markedly from the behaviour of the crystalline powders and the milled powder of modest degree of disorder. The Ryshkewitch-Duckworth equation, describing compactibility, was nearly linear for the crystalline powders, while for the disordered powders the model failed to describe the relationships, i.e. the disordered powders were characterised by a plateau in the Ryshkewitch-Duckworth plots over a relatively wide range of compact porosities. It was concluded that the difference in compaction behaviour of the milled particles compared to the crystalline powders was primarily explained by the increased particle plasticity of the disordered particles. The plateau in the Ryshkewitch-Duckworth plots obtained for the disordered powders was explained by a change in the fracture behaviour of the compacts, from an around grain to an across grain fracture pattern. This implied that the disordered particles can be described as a type of core-shell particles with an amorphous shell and a defective crystalline core.

Powder Compression Properties of Paracetamol, Paracetamol Hydrochloride, and Paracetamol Cocrystals and Coformers.

The objective was to study the relationship between crystal structure, particle deformation properties, and tablet-forming ability for the monoclinic form of paracetamol (PRA), 2 cocrystals and a salt crystal of PRA in addition to 2 coformers (oxalic acid and 4,4'-bipyridine). Thus, the structure-property-performance relationship was investigated. Analytical powder compression was used for determination of effective plasticity, as inferred from the Heckel yield pressure and the Frenning parameter, and the elastic deformation was determined from in-die tablet elastic recovery. The plasticity could not be linked to the crystal lattice structure as crystals containing zig-zag layers displayed similar plasticity as crystals containing slip planes. In addition, crystals containing slip planes displayed both high and low plasticity. The mechanical properties could not be linked to the tablet-forming ability as the tablet tensile strength, unexpectedly, displayed a tendency to reduce with increased plasticity. Furthermore, the elastic deformation could not explain the tablet-forming ability. It was concluded that no relationship between structure-property-performance for PRA and its cocrystals and salt could be established. Thus, it was indicated that to establish such a relationship, an improved knowledge of crystallographic structure and interparticle bonding during compaction is needed.

A hybrid approach to predict the relationship between tablet tensile strength and compaction pressure using analytical powder compression.

The objective was to present a hybrid approach to predict the strength-pressure relationship (SPR) of tablets using common compression parameters and a single measurement of tablet tensile strength. Experimental SPR were derived for six pharmaceutical powders with brittle and ductile properties and compared to predicted SPR based on a three-stage approach. The prediction was based on the Kawakita b-1 parameter and the in-die Heckel yield stress, an estimate of maximal tensile strength, and a parameter proportionality factor α. Three values of α were used to investigate the influence of the parameter on the SPR. The experimental SPR could satisfactorily be described by the three stage model, however for sodium bicarbonate the tensile strength plateau could not be observed experimentally. The shape of the predicted SPR was to a minor extent influenced by the Kawakita b-1 but the width of the linear region was highly influenced by α. An increased α increased the width of the linear region and thus also the maximal predicted tablet tensile strength. Furthermore, the correspondence between experimental and predicted SPR was influenced by the α value and satisfactory predictions were in general obtained for α = 4.1 indicating the predictive potential of the hybrid approach.

Effect of milling on the plastic and the elastic stiffness of lactose particles.

The purpose of this study was to investigate the effect of degree of disorder of a series of α-lactose monohydrate powders, prepared by milling for different time periods, on the plastic and the elastic stiffness of the particles. As references, a series of physical mixtures consisting of original crystalline particles and amorphous particles obtained by spray-drying was used. In addition, the effect of powder pre-storage humidity on the mechanical properties was investigated. For milled particles of a low degree of disorder, a decreased particle size increased the particle plastic stiffness. For milled particles of constant particle size, the plastic stiffness decreased with an increased degree of disorder while the elastic stiffness seemed nearly independent of the degree of disorder. The presence of moisture caused a recrystallisation of milled particles with low degree of disorder which increased their plastic stiffness. For the physical mixtures of crystalline and amorphous particles, similar relationships between plastic stiffness and amorphous content as for the milled powders were obtained. A reasonable explanation is that the nature of the milled particles is represented by a two-state system with crystalline and amorphous domains.

The influence of rolling friction on the shear behaviour of non-cohesive pharmaceutical granules--an experimental and numerical investigation.

Granule shear behaviour was investigated experimentally and numerically to evaluate the reliability of the numerical model. Additionally, parameters affecting the ensuing flow regimes - elastic quasi-static and inertial non-collisional - were highlighted. Furthermore, the influence of using the Lees-Edwards periodic boundary conditions or the standard boundary conditions was studied. Experiments were performed with microcrystalline cellulose granules of three size distributions using the FT4 powder rheometer. The numerical parameters, particle size, effective density, and particle stiffness were selected to match the experimental conditions. Experimentally, an unexpected particle size effect was evident where the resistance to shear increased with particle size. Numerically, combining rolling friction and increased shear rate enabled a transition from the inertial non-collisional to the elastic quasi-static regime at a reduced sliding friction coefficient. Presumably, this is an effect of increased particle overlap creating stronger contacts and facilitating force chain formation. Both boundary conditions provided comparable results provided a correction of system size was made, where larger systems were required for the standard boundary conditions. A satisfactory qualitative agreement between the experimentally and numerically determined yield loci emphasised the predictive capacity of the DEM. Rolling friction was in addition concluded to be an essential model parameter for obtaining an improved quantitative agreement.

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.

Flowability of surface modified pharmaceutical granules: A comparative experimental and numerical study.

Flowability - as measured by hopper discharge rate, angle of repose and Carr's index (CI) - of surface modified microcrystalline cellulose granules was investigated experimentally. Three-dimensional simulations of the granule flow were performed, using the discrete element method (DEM), including either sliding and rolling friction or sliding friction and cohesion in the model. Granule surface modification with polymer coating and lubrication was found to have a significant effect on the sliding friction coefficient. This effect was also reflected in the ensuing flow behaviour, as quantified by the experimental discharge rate and angle of repose, whereas the results for the CI were inconclusive. The numerical results demonstrated that granular flow was qualitatively different for non-cohesive and cohesive granules, occurring in the form of individual particles for the former and in larger clusters for the latter. Rolling friction and cohesion nevertheless affected the simulated discharge rate in a similar manner, producing results comparable to those observed experimentally and calculated with the Beverloo equation. The numerical results for the cohesive granules demonstrated that cohesion alone was sufficient to produce stable heaps. However, the agreement with experimental data was satisfactory only for the non-cohesive granules, demonstrating the importance of rolling friction.