Miscibility of Amorphous Solid Dispersions: A Rheological and Solid-State NMR Spectroscopy Study

Abstract

Miscibility is critical in the prediction of stability against crystallization of amorphous solid dispersions (ASDs) in the solid state. However, currently available approaches for its determination are limited by both theoretical and practical considerations. Recently, a rheological approach guided by the polymer overlap concentration (c*) has been proposed for miscibility quantification of ASDs [J. Pharm. Sci., 112 (2023) 204-212] and shown to be useful in predicting both accelerated and long term physical stability in the absence of moisture. However, this approach can only be performed at high temperatures (slightly above the melting temperature, T_m, of drugs), and little is known about the difference in miscibility between high and low temperatures (e.g., below the glass transition temperature, T_g). Here we compare the miscibility of nifedipine (NIF)/polyvinylpyrrolidone (PVP) ASDs as determined by the rheological approach at 175°C (∼3°C above T_m of NIF) and solid state NMR (ssNMR) ¹H T₁ and T_1ρ relaxation times at -20°C (∼66°C below T_g of NIF). Our results indicate agreement between the two methods. For low molecular weight (M_w) PVP, T_1ρ measurements are more consistent with the rheological approach, while T₁ measurements are closer for relatively high M_w PVP. Our findings support the use of the c* based rheological approach for inferring miscibility of deeply cooled ASDs.

Keywords: Amorphous solid dispersions (ASDs); Miscibility; Overlap concentration (c*); Physical stability; Solid-state NMR; Viscosity.