Influence of the drug deformation behaviour on the predictability of compressibility and compactibility of binary mixtures.

Various studies investigate the predictability of the compressibility and compactibility of tablet formulations based on the behaviour of the pure materials. However, these studies are limited to a few materials so far probably because of the complexity of the powder compaction process. One approach preventing the excessive increase in complexity is the extension of the investigations from pure materials to binary powder mixtures. The focus of this study is on the predictability of the compressibility and compactibility of binary mixtures consisting of an active pharmaceutical ingredient (API) and the excipient microcrystalline cellulose. Three APIs with markedly different deformation behaviour were used. The API concentration and type are systematically varied. For all three material combinations it is found that the in-die compressibility of the binary mixtures can be precisely predicted based on the characteristic compression parameters of the raw materials using the extended in-die compression function in combination with a volume-based linear mixing rule. Since the tablet porosity (out-of-die) also follows a linear mixing rule, the predictability can be further extended using the method of Katz et al. In contrast, the influence of the API concentration on compactibility or rather on tablet tensile strength is non-linear and strongly dependent on the deformation behaviour of the API, making the predictability more difficult. Neither the approach of Reynolds et al. nor this of Kuentz and Leuenberger are able to predict the compactibility when clear deviations from a linear mixing rule appear.

The influence of particle size on the application of compression and compaction models for tableting.

The physical characteristics of raw materials determine powder compression and compaction performance as relevant in pharmaceutical processes. For instance, the influence of initial particle size on powder compression and the resulting strength of specimen are highly complex and are still not sufficiently understood. Existing studies are often limited to materials with well-defined deformation behaviour, such as purely brittle or ductile. However, the deformation behaviour of active pharmaceutical ingredients (APIs) is often more complex. In this study, the influence of initial particle size on powder compressibility and compactibility is systematically characterized by consideration of in-die compressibility, specific energies, quick elastic recovery, tablet porosity and, tensile strength for the binder microcrystalline cellulose and three APIs. The decrease of particle size leads to an increase of the resistance against compression by trend and probably to a different contribution of the acting deformation mechanisms. The compactibility is increased with decreasing particle size because of the increasing number of bonds in a cross-sectional area of the tablet, as found by the application of the model of Rumpf. Furthermore, it is found that the model of Rumpf combined with the JKR model provides a meaningful property function to estimate tablet tensile strength.

The use of X-ray microtomography to investigate the microstructure of pharmaceutical tablets: Potentials and comparison to common physical methods.

Within this study, tablets microstructure was investigated by X-ray microtomgraphy. The aim was to gain information about their microstructure, and thus, derive deeper interpretation of tablet properties (mechanical strength, component distribution) and qualified property functions. Challenges in image processing are discussed for the correct identification of solids and voids. Furthermore, XMT measurements are critically compared with complementary physical methods for characterizing active pharmaceutical ingredient (API) content and porosity and its distribution (mercury porosimetry, calculated tablet porosity, Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM)). The derived porosity by XMT is generally lower than the calculated porosity based on geometrical data due to the resolution of the XMT in relation to the pore sizes in tablets. With rising compactions stress and API concentration, deviations between the actual and the calculated API decrease. XMT showed that API clusters are present for all tablets containing >1 wt% of ibuprofen. The 3D orientation of the components is assessable by deriving cord lengths along all dimensions of the tablets. An increasing compaction stress leads to rising cord lengths, showing higher connectivity of the respective material. Its lesser extent in the z-direction illustrates the anisotropy of the compaction process. Additionally, cracks in the fabric are identified in tablets without visible macroscopic damage. Finally, the application of XMT provides valuable structural insights if its limitations are taken into account and its strengths are fostered by advanced pre- and post-processing.

How can single particle compression and nanoindentation contribute to the understanding of pharmaceutical powder compression?

The deformation behaviour of a powder and, thus, of the individual particles is a crucial parameter in powder compaction and affects powder compressibility and compactibility. The classical approach for the characterization of the deformation behaviour is the performance of powder compression experiments combined with the application of mathematical models, such as the Heckel-Model, for the derivation of characteristic compression parameters. However, the correlation of these parameters with the deformation behaviour is physically often not well understood. Single particle compression and nanoindentation enables the in-depth investigation of the deformation behaviour of particulate materials. In this study, single particle compression experiments were performed for the characterization of the deformation behaviour of common pharmaceutical excipients and active pharmaceutical ingredients (APIs) with various, irregular particle morphologies of industrial relevance and the findings are compared with the results from powder compression. The technique was found useful for the characterization and clarification of the qualitative deformation behaviour. However, the derivation of a quantitative functional relationship between single particle deformation behavior and powder compression is limited. Nanoindentation was performed as complementary technique for the characterization of the micromechanical behavior of the APIs. A linear relationship between median indentation hardness and material densification strength as characteristic parameter derived by in-die powder compression analysis is found.

Scaling Tableting Processes from Compaction Simulator to Rotary Presses-Mind the Sub-Processes.

Compaction simulators are frequently used in the formulation and process development of tablets, bringing about the advantages of flexibility, low material consumption, and high instrumentation to generate the most possible process understanding. However, their capability of resembling general aspects of rotary press compaction and their precision in simulating or mimicking sub-processes such as feeding and filling need to be systematically studied. The effect of material deformation behavior, blend composition, and feeding on tensile strength and simulation precision as compared with rotary presses of different scales is evaluated in this study. Generally, good simulation performance was found for the studied compaction simulator. Compaction profile-sensitivity was demonstrated for highly visco-plastic materials while shear-sensitivity in feeding was demonstrated for lubricated blends of ductile particles. Strategies for the compensation of both in compaction simulator experiments are presented by careful investigation of the compaction stress over time profiles and introduction of a compaction simulator-adapted shear number approach to account for differences in layout and operation mode between compaction simulator and rotary press, respectively. These approaches support the general aim of this study to provide a more straightforward determination of scaling process parameters between rotary press and compaction simulator and facilitate a quicker and more reliable process transfer.

A Mathematical Approach to Consider Solid Compressibility in the Compression of Pharmaceutical Powders.

In-die compression analysis is an effective method for the characterization of powder compressibility. However, physically unreasonable apparent solid fractions above one or apparent in-die porosities below zero are often calculated for higher compression stresses. One important reason for this is the neglect of solid compressibility and hence the assumption of a constant solid density. In this work, the solid compressibility of four pharmaceutical powders with different deformation behaviour is characterized using mercury porosimetry. The derived bulk moduli are applied for the calculation of in-die porosities. The change of in-die porosity due to the consideration of solid compressibility is for instance up to 4% for microcrystalline cellulose at a compression stress of 400 MPa and thus cannot be neglected for the calculation of in-die porosities. However, solid compressibility and further uncertainties from, for example the measured solid density and from the displacement sensors, are difficult or only partially accessible. Therefore, a mathematic term for the calculation of physically reasonable in-die porosities is introduced. This term can be used for the extension of common mathematical models, such as the models of Heckel and of Cooper & Eaton. Additionally, an extended in-die compression function is introduced to precisely describe the entire range of in-die porosity curves and to enable the successful differentiation and quantification of the compression behaviour of the investigated pharmaceutical powders.