Chemistry and Ionization of HPMCAS Influences the Dissolution and Solution-Mediated Crystallization of Posaconazole Amorphous Solid Dispersions.

Abstract

Hydroxypropyl methyl cellulose acetate succinate (HPMCAS) is one of the polymers of choice in formulating amorphous solid dispersions (ASDs) and helps to sustain high levels of drug supersaturation by delaying drug crystallization. Herein, the impact of HPMCAS chemistry on the solution crystallization kinetics of a fast-crystallizing lipophilic drug, posaconazole (PCZ), from the aqueous bulk phase and the drug-rich phase generated by liquid-liquid phase separation (LLPS), was studied. Three grades of HPMCAS: L, M, and H, which differ in the degree of acetyl and succinoyl substitution (A/S ratio), were compared. The influence of the polymers on the nucleation induction time, and LLPS concentration of PCZ, as well as the size, ζ-potential and composition of the nano-sized drug-rich phase was determined. An increase in the nucleation induction time was observed with an increase in the polymer A/S ratio. A blue shift in the fluorescence emission spectrum of PCZ suggested a greater extent of interaction between PCZ and HPMCAS with an increase in the A/S ratio. More polymer partitioning into the drug-rich phase was also observed with an increase in the A/S ratio, resulting in smaller droplets. A greater extent of ionization of HPMCAS upon increasing the pH from 5.5 to 7.5 decreased the hydrophobicity of the polymer resulting in shorter nucleation induction times. The phase behavior of PCZ in ASD release studies was consistent with these observations, where the shortest duration of supersaturation was observed with the L grade. Although the H grade provided the best inhibition of crystallization, complete release was only observed at higher pH. HPMCAS grade thus influences the kinetics of PCZ crystallization following release from an ASD, as well as the extent of release at physiologically relevant pH conditions. This study provides insights into the role of HPMCAS chemistry and ionization as factors influencing its ability to act as a crystallization inhibitor.