Insights into Water-Induced Phase Separation in Itraconazole-Hydroxypropylmethyl Cellulose Spin Coated and Spray...

For amorphous solid dispersions, understanding the phase behavior of a given drug-polymer blend and factors that influence miscibility is crucial to designing an optimally performing formulation. However, it can be challenging to fully map the phase behavior of some systems, especially those produced using a cosolvent system. In this study, a comprehensive investigation of phase separation in itraconazole-hydroxypropylmethylcellulose (ITZ-HPMC) blends fabricated using solvent evaporation processes, including spin coating and spray drying, has been carried out. Phase separation was found to be driven by the presence of water, either acquired from the environment or from the solvent system. ITZ nanospecies were observed during the solvent evaporation process prior to solidification. The use of high resolution imaging techniques such as transmission electron microscopy including bright field and high angle annular dark field imaging, enabled detailed characterization of the microstructure of phase separated systems. Spectroscopic investigations suggested that drug domains contain supramolecular drug aggregates in which the nematic assembly of ITZ molecules results in the coupling of the optical transitions of ITZ monomers. Importantly, a similar pattern of behavior between drug-polymer phase in spin coated and spray dried dispersions was observed. The presence of as little as 1% water in the solvent was found to induce phase separation in the spray dried particles, which was detected using the unique photophysical properties of ITZ and fluorescence spectroscopy. The study highlights the complexity of drug-polymer phase behavior and the influence of solvent properties.