Hydrate formation in polymer-based pharmaceutical formulations

Abstract

Amorphous solid dispersions (ASD) are state-of-the art enabling formulations for poorly water-soluble active pharmaceutical ingredients (APIs). Depending on the relative humidity (RH), temperature, and API content, ASDs are often metastable against crystallization of the API or even against the formation of API hydrates in the ASD. Knowing the conditions at which API crystals or API hydrate formation may occur in ASDs therefore is an important prerequisite for developing a suitable formulation strategy for APIs. ASDs containing hydrate-forming APIs (carbamazepine/polyvinylpyrrolidone, carbamazepine/hydroxypropylmethylcellulose acetate succinate, and theophylline/polyvinylpyrrolidone) were investigated in this work. The influence of polymer type, RH, API content, and water sorption on the ASD stability was determined via phase diagrams predicted using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). These predictions were successfully validated by long-term stability tests at 295 K and 0%, 58%, 76%, 86%, and 93% RH. Hydrate crystals are formed above their critical RH. Thus, ASDs with carbamazepine (critical RH 65% at 295 K) as well as theophylline (critical RH 58% RH) showed hydrate crystals at 76%, 86% and 93% RH, no matter which polymer was used for preparing the ASD.