Kuentz, MartinAbreu-Villela, RenataSchönenberger, MonicaCaraballo, Isidoro2018-12-142018-12-142018-120939-64111873-3441https://doi.org/10.1016/j.ejpb.2018.10.007http://hdl.handle.net/11654/26982Early 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.enSolid dispersionAmorphous drugPhase separationCrystallizationChemical imagingMultifractal analysis01A - Beitrag in wissenschaftlicher Zeitschrift122-130