Investigation of Phase Mixing in Amorphous Solid Dispersions of AMG 517 in HPMC-AS Using DSC, Solid-State NMR, and Solution Calorimetry.

Intimate phase mixing between the drug and the polymer is considered a prerequisite to achieve good physical stability for amorphous solid dispersions. In this article, spray dried amorphous dispersions (ASDs) of AMG 517 and HPMC-as were studied by differential scanning calorimetry (DSC), solid-state NMR (SSNMR), and solution calorimetry. DSC analysis showed a weakly asymmetric (ΔTg ≈ 13.5) system with a single glass transition for blends of different compositions indicating phase mixing. The Tg-composition data was modeled using the BKCV equation to accommodate the observed negative deviation from ideality. Proton spin–lattice relaxation times in the laboratory and rotating frames (1H T1 and T1ρ), as measured by SSNMR, were consistent with the observation that the components of the dispersion were in intimate contact over a 10–20 nm length scale. Based on the heat of mixing calculated from solution calorimetry and the entropy of mixing calculated from the Flory–Huggins theory, the free energy of mixing w...