Investigating the Correlation between Miscibility and Physical Stability of Amorphous Solid Dispersions Using Fluorescence-Based Techniques.

Abstract

The purpose of this study was to investigate the feasibility of using a fluorescence-based technique to evaluate drug-polymer miscibility and to probe the correlation between miscibility and physical stability of amorphous solid dispersions (ASDs). Indomethacin-hydroxypropyl methylcellulose (IDM-HPMC), indomethacin-hydroxypropyl methylcellulose acetate succinate, and indomethacin-polyvinylpyrrolidone (IDM-PVP) were used as model systems. The miscibility of the IDM-polymer systems was evaluated by fluorescence spectroscopy, fluorescence imaging, differential scanning calorimetry (DSC), and infrared (IR) spectroscopy. The physical stability of IDM-polymer ASDs stored at 40 °C was evaluated using fluorescence imaging and X-ray diffraction (XRD). The experimentally determined miscibility limit of IDM with the polymers was 50-60%, 20-30%, and 70-80% drug loading for HPMC, HPMCAS, and PVP, respectively. The X-ray results showed that for IDM-HPMC ASDs, samples with a drug loading of less than 50% were maintained in amorphous form during the study period, while samples with drug loadings higher than 50% crystallized within 15 days. For IDM-HPMCAS ASDs, samples with drug loading less than 30% remained amorphous, while samples with drug loadings higher than 30% crystallized within 10 days. IDM-PVP ASDs were found to be resistant to crystallization for all compositions. Thus, a good correlation was observed between phase separation and reduced physical stability, suggesting that miscibility is indeed an important ASDs characteristic. In addition, fluorescence-based techniques show promise in the evaluation of drug-polymer miscibility.