Impact of Drug-Polymer Miscibility on Enthalpy Relaxation of Irbesartan Amorphous Solid Dispersions

Purpose Drug-polymer miscibility has been proposed to play a critical role in physical stability of amorphous solid dispersions (ASDs). The purpose of the current work was to investigate the role of drug-polymer miscibility on molecular mobility, measured as enthalpy relaxation (ER) of amorphous irbesartan (IBS) in ASDs. Methods Two polymers, i.e. polyvinylpyrrolidone K30 (PVP K30) and hydroxypropyl methylcellulose acetate succinate (HPMCAS), were used to generate ASDs with 10% w/w of the polymer. Drug-polymer miscibility was determined using melting point depression (MPD) method. Molecular mobility was assessed from ER studies at a common degree of undercooling (DOU) (T-g - 13.0 degrees C +/- 0.5 degrees C). Results IBS exhibited higher miscibility in PVP K30 as compared to HPMCAS at temperature > 140 degrees C. However, extrapolation of miscibility data to storage temperature (62 degrees C) using Flory-Huggins (F-H) theory revealed a reversal of the trend. Miscibility of IBS was found to be higher in HPMCAS (2.6%) than PVP K30 (1.3%) at 62 degrees C. Stretched relaxation time (tau(beta)) of 17.4365 h and 7.0886 h was obtained for IBS-HPMCAS and IBS-PVP K30 ASDs, respectively. Conclusion Miscibility of drug-polymer at storage temperature explained the behavior of the molecular mobility, while miscibility near the melting point provided a reverse trend. Results suggest that drug-polymer miscibility determined at temperatures higher than the storage temperature should be viewed cautiously.