Exploring biorelevant conditions and release profiles of ritonavir from HPMCAS-based amorphous solid dispersions

Abstract

Development of a release test for amorphous solid dispersions (ASDs) that is in vivo predictive is essential to identify optimally performing formulations early in development. For ASDs containing an enteric polymer, consideration of buffer properties is essential. Herein, release rates of hydroxypropyl methyl cellulose acetate succinate (HPMCAS) and ritonavir from ASDs with a 20% drug loading were compared in phosphate and bicarbonate buffers with different molarities, at pH 6.5. The bioaccessibility of ritonavir from the ASD in the tiny-TIM apparatus was also evaluated and compared to that of the crystalline drug. The surface pH at the dissolving solid: solution interface was evaluated using a pH-sensitive fluorescence probe for HPMCAS and ASD compacts in phosphate and bicarbonate buffers. Drug and polymer were found to release congruently in all buffer systems, indicating that the polymer controlled the drug release. Release was slowest in 10 mM bicarbonate buffer, and much faster in phosphate buffers with molarities typically used in release testing (20-50 mM). Release from the 10 mM bicarbonate buffer was matched in a 5 mM phosphate buffer. The surface pH of HPMCAS and HPMCAS:ritonavir ASDs was found to be lower than the bulk solution pH, where surface pH differences largely explained release rate differences seen in the different buffer systems. Ritonavir was highly bioaccessible from the ASD, as assessed by the tiny-TIM system, and much less bioaccessible when crystalline drug was used. The observations highlight the need for continued development of biorelevant assays tailored for ASD formulation assessment.