Atomic Force Microscopy-Based Screening of Drug-Excipient Miscibility and Stability of Solid Dispersions.
ABSTRACT Purpose Development of a method to assess the drug/ polymer miscibility and stability of solid dispersions using a melt-based mixing method. Methods Amorphous fractured films are prepared and characterized with Raman Microscopy in combination with Atomic Force Microscopy to discriminate between homogenously and heterogeneously mixed drug/polymer combinations. The homogenous combinations are analyzed further for physical stability under stress conditions, such as increased humidity or temperature. Results Combinations that have the potential to form a molecular disperse mixture are identified. Their potential to phase separate is determined through imaging at molecular length scales, which results in short observation time. De-mixing is quantified by phase separation analysis, and the drug/ polymer combinations are ranked to identify the most stable combinations. Conclusions The presented results demonstrate that drug/ polymer miscibility and stability of solid dispersions, with many mechanistic details, can be analyzed with Atomic Force Microscopy. The assay allows to identify well-miscible and stable combinations within hours or a few days.
KEY WORDS amorphous formulation . raman microscopy. solid dispersion . stability prediction . AFM