Amorphous solid dispersions have been widely used as an effective formulation strategy in the oral delivery of poorly soluble drugs. However, one of the main challenges in the development of amorphous drugs is to maintain their physical stability. The underlying mechanism of amorphous drugs crystallized in polymeric matrices is still poorly understood. Herein, we report the phenomenon of polymer enrichment at the crystal-liquid interface during the crystallization of griseofulvin (GSF) containing poly(ethylene oxide) (PEO). Confocal Raman microscopy, scanning electron microscope (SEM), and energy-dispersive X-ray spectroscopy (EDS) are employed to reveal the heterogeneous distribution of GSF and PEO at the crystal growth front. The concentration of PEO in the polymer-rich phase at the crystal-liquid interface is determined by Raman spectroscopic analysis. At a given temperature, the crystal growth rates of GSF initially increase with increasing the PEO loading in the bulk and then reach a plateau at high polymer loadings. We propose that the crystal growth rates of GSF are predominantly controlled by the local concentration of PEO at the growth front rather than the overall bulk concentration. This study provides the direct evidence of physical mechanisms that contributes to the local phase separation occurred at the crystal-liquid interface, which governs the kinetics of crystal growth in amorphous solid dispersions. These results are important for understanding the crystallization behavior of amorphous solid dispersions and beneficial for the rational design of robust amorphous formulations.
Keywords: crystal growth; griseofulvin; interface; phase separation; poly(ethylene oxide).