Phase Behavior of Drug-Hydroxypropyl Methylcellulose Amorphous Solid Dispersions Produced from Various Solvent Systems: Mechanistic Understanding of the Role of Polymer using Experimental and Theoretical Methods.

The vast majority of studies evaluating amorphous solid dispersions (ASDs) utilize solvent evaporation techniques as the preparation method. However, the impact of the solvent/cosolvent system properties on the polymer conformation and the phase behavior of the resultant drug/polymer blends is poorly understood. Herein, we investigate the influence of solvent properties on the phase behavior of ASDs containing itraconazole (ITZ) and hydroxypropylmethyl cellulose (HPMC) prepared using spin coating from binary/ternary cosolvent systems containing alkyl alcohols, dichloromethane (DCM), and water. The compatibility of the polymer with the cosolvent system was probed using high-resolution imaging techniques supported by molecular dynamics simulations. Solvent evaporation and evaporation rate profiles were tracked gravimetrically to understand the impact of the solvent composition on the evaporation process. Short-chain alcohols, including methanol (MeOH) and ethanol (EtOH), were found to induce drug-polymer demixing in the presence of water, with EtOH being less sensitive to moisture than MeOH owing to its ability to form an azeotrope with water. In contrast, water-induced mixing was observed when higher alcohols, including n-propanol (PrOH) and n-butanol (BuOH), were used as a cosolvent, due to the improved solubility of HPMC in the higher alcohols in the presence of water. Isopropanol (IPA) produced phase separated ASDs under wet and dry conditions with an increase in miscibility with faster evaporation rates in the presence of water. This solvent-triggered phase behavior highlights the importance of conducting a thorough screening of various solvents prior to the preparation of ASDs via solvent evaporation approaches such as spray drying.