Time-dependent phase separation of amorphous solid dispersions: Implications for accelerated stability studies

Abstract

Freshly prepared amorphous solid dispersions (ASDs) may not be in an equilibrium mixed state, as high-temperatures and/or solvents are generally used during their preparation. In this study, tolbutamide (TLB) and acetaminophen (AAP) were transformed into ASDs using hydroxypropylmethylcellulose acetate succinate, Eudragit E100 (E100), Soluplus, and Kollidon VA64 using the melt-quench method to observe their phase stability at 5, 25, 40, and 60 °C. Time-dependent phase separation was observed for all the drug and excipient combinations under all investigated storage conditions. The phase separation of the E100/TLB and Soluplus/TLB ASDs was faster under high-temperature storage conditions, whereas the opposite trend was observed with the other ASDs. In the above-mentioned stability studies, phase separation kinetics of the E100/TLB and Soluplus/TLB ASDs appeared to be dominated by molecular mobility due to the low glass transition temperature (Tg) of both the drug and polymer, whereas departure from equilibrium was a dominating factor for the other ASDs. The Tg of the mixed phase just after preparation could be used as an indicator for predicting phase separation after long-term storage, as the mixing ratio calculated from the Tg was in agreement with that after storage for certain ASDs.