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Publikation Early stages of drug crystallization from amorphous solid dispersion via fractal analysis based on chemical imaging(Elsevier, 12/2018) Kuentz, Martin; Abreu-Villela, Renata; Schönenberger, Monica; Caraballo, IsidoroEarly 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.01A - Beitrag in wissenschaftlicher ZeitschriftPublikation Glass-forming ability of compounds in marketed amorphous drug products(Elsevier, 03/2017) Wyttenbach, Nicole; Kuentz, MartinThis note is about the glass-forming ability (GFA) of drugs marketed as amorphous solid dispersions or as pure amorphous compounds. A thermoanalytical method was complemented with an in silico study, which made use of molecular properties that were identified earlier as being relevant for GFA. Thus, molar volume together with effective numbers of torsional bonds and hydrogen bonding were used to map drugs that are as amorphous products on the market either as solid dispersion of without co-processed carrier as amorphous drug in a solid dosage form. Differential scanning calorimetry experiments showed that most compounds were stable glass formers (GFs) (class III) followed by so-called unstable GFs (class II) and finally, only vemurafenib was found in class I with increased crystallization propensity. The in silico results, however showed that all drugs were either clearly in the chemical space expected for GFs or they were borderline to the region that holds for high crystallization tendency. Interestingly, the pure amorphous compounds scattered in a very confined region of the molecular predictors. These findings can guide amorphous product development of future drug candidates. Based on the compound location in the given chemical space, amorphous formulation opportunities can be balanced against the risks of physical instability upon storage.01A - Beitrag in wissenschaftlicher Zeitschrift