Mutual Impact of Phase Separation/Crystallization and Water Sorption in Amorphous Solid Dispersions.

The molecular integration of poorly water soluble active pharmaceutical ingredients (APIs) in a suitable polymeric matrix is a possible approach to enhance the dissolution behavior and solubility of these APIs. Like all newly developed pharmaceutical formulations, these formulations (often denoted as amorphous solid dispersions (ASDs)) need to undergo storage stability tests at defined relative humidity (RH) and temperature conditions. In a previous work ( Int. J. Pharm. 2017 ; 532 , 635 - 646 ), it was shown that thermodynamic modeling can be successfully used to predict the long-term stability of ASDs against API crystallization and moisture-induced amorphous-amorphous phase separation (MIAPS). This work in turn demonstrates the prediction of water sorption in ASDs accounting for the potential occurrence of API crystallization and MIAPS. The water sorption and phase behavior of ASDs containing the APIs felodipine and ibuprofen incorporated in three different hydrophilic polymers poly(vinylpyrrolidone), poly(vinyl acetate), and poly(vinylpyrrolidone-co-vinyl acetate) at the conditions 25 °C/60% RH and 40 °C/75% RH were predicted using the perturbed-chain statistical-associating fluid theory (PC-SAFT). The predictions were successfully validated via two-year-lasting water sorption experiments. It was shown that crystallization of the API and MIAPS on the one hand and water sorption in the ASDs on the other hand dramatically influence each other and that this behavior can even be quantitatively predicted by PC-SAFT, which already provides valuable insights at early stages of formulation development.