2019-09-06, Abreu-Villela, Renata, Kuentz, Martin

Pharmaceutical formulations are complex systems consisting of active pharmaceutical ingredient(s) and a number of excipients selected to provide the intended performance of the product. The understanding of materials' properties and technological processes is a requirement for building quality into pharmaceutical products. Such understanding is gained mostly from empirical correlations of material and process factors with quality attributes of the final product. However, it seems also important to gain knowledge based on mechanistic considerations. Promising is here to study morphological and/or topological characteristics of particles and their aggregates. These geometric aspects must be taken into account to better understand how product attributes emerge from raw materials, which includes, for example, mechanical tablet properties, disintegration or dissolution behavior. Regulatory agencies worldwide are promoting the use of physical models in pharmaceutics to design quality into a final product. This review deals with pharmaceutical applications of theoretical models, focusing on percolation theory, fractal, and multifractal geometry. The use of these so-called fractal approaches improves the understanding of different aspects in the development of solid dosage forms, for example by identifying critical drug and excipient concentrations, as well as to study effects of heterogeneity on dosage form performance. The aim is to link micro- and macrostructure to the emerging quality attributes of the pharmaceutical solid dosage forms as a strategy to enhance mechanistic understanding and to advance pharmaceutical development and manufacturing processes.

2018-12, Kuentz, Martin, Abreu-Villela, Renata, Schönenberger, Monica, Caraballo, Isidoro

Early stages of crystallization from amorphous solid dispersion (ASD) are typically not detected by means of standard methods like powder X-ray diffraction (XRPD). The aim of this study is therefore to evaluate if fractal analysis based on energy dispersive X-ray imaging can provide the means to identify early signs of physical instability. ASDs of the poorly water-soluble compound, felodipine (FEL) were prepared by solvent evaporation using different grades of HPMCAS, at 50 wt% drug loading. Samples were stored at accelerated conditions of 40 °C. Scanning electron microscopy equipped with an energy-dispersive X-ray spectroscopy (SEM-EDS) was used for elemental mapping of tablet surfaces. Comparative data were generated with a standard XRPD and with more sensitive methods for detection of early instability, i.e. laser scanning confocal microscopy (LSM) and atomic force microscopy (AFM). The SEM-EDS identified changes of drug-rich domains that were confirmed by LSM and AFM. Early changes in drug clusters were also revealed by a multifractal analysis that indicated a beginning phase separation and drug crystallization. Therefore, the presented fractal cluster analysis based on chemical imaging bears much promise as a new method to detect early signs of physical instability in ASD, which is of great relevance for pharmaceutical development.

2018, Abreu-Villela, Renata, Adler, Camille, Caraballo, Isidoro, Kuentz, Martin

Much contemporary research of poorly water-soluble drugs focuses on amorphous solid dispersions (SDs) for oral drug delivery. Recently, a multifractal formalism has been introduced to describe the distribution of an inorganic carrier in SDs. The present work attempts to directly image model drugs by means of scanning electron microscopy and energy dispersive X-ray spectroscopy. The compounds amlodipine, felodipine, glyburide, and indomethacine, which include halogens to enable sufficient scattering in energy dispersive X-ray spectroscopy, were employed to prepare SDs with hydroxypropyl methylcellulose acetate succinate (HPMCAS) by using a microwave method. Following chemical imaging, it was demonstrated that drug distribution was best described by multifractals, which was clearly superior to a monofractal assumption. The obtained fractal dimensions were influenced by drug loading and it was possible to detect microstructural changes upon addition of the plasticizer urea. Accordingly, the multifractal approach bears much potential to better explore the analytical results of chemical formulation imaging. Insights can be gained from the microstructural organization of SDs, which is interesting to further study formulation and process factors as well as physical stability.