Design of Stable Dual-Polymer Amorphous Solid Dispersions: Role of Thermodynamics and Kinetics

Abstract

In high-drug-loaded amorphous solid dispersions, effective stabilization requires polymers that can hinder nucleation as well as crystal growth. We hypothesized that combining two polymers with complementary stabilization mechanisms would enhance physical stability more effectively than the individual polymers. Evaluation of single-polymer systems at a polymer loading of 20% w/w showed that HPMCAS (hydroxypropyl methylcellulose acetate succinate) had the highest thermodynamic miscibility with carbamazepine (CBZ), whereas PVP (polyvinylpyrrolidone) and PVPVA (PVP/vinyl acetate) dispersions had the longest α-relaxation time. Based on these findings, ternary systems combining 80% w/w CBZ, 10% w/w HPMCAS, and 10% w/w of either PVP or PVPVA were evaluated. The ternary systems exhibited longer crystallization onset times than the corresponding single-polymer systems at the same total polymer loading. The improved stability was due to a synergistic mechanism where HPMCAS provided resistance to nucleation by increasing the activation energy barrier, while PVP/PVPVA kinetically lowered the attempt jump frequency to suppress both nucleation and crystal growth. This dual-polymer approach provided a basis for designing amorphous solid dispersions with high drug loading and improved physical stability.