Characterization of Grades of HPMCAS Spray Dried Dispersions of Itraconazole Based on Supersaturation Kinetics and Molecular Interactions Impacting Formulation Performance.

ABSTRACT

PURPOSE: The objective was to characterize hydroxypropyl methylcellulose acetate succinate (HMPCAS) grades L, M, and H to enhance itraconazole (ITZ) release and permeation from spray dried dispersions (SDDs), and to investigate underpinning molecular ITZ-HPMCAS interactions that differentiated grade performance. METHODS: ITZ or its SDDs were subjected to solution stabilization assessment, one-dimensional proton nuclear magnetic resonance (NMR) spectroscopy, saturation transfer difference NMR studies, small volume dissolution, solid state transformation studies, and in vitro dissolution/permeation flux studies. RESULTS: HPMCAS-L was the best performing grade overall and exhibited greatest ITZ supersaturation concentration, small volume dissolution, and in vitro dissolution/permeation flux. Meanwhile, H grade retarded ITZ precipitation to the greatest extent in solution stabilization studies and exhibited greater hydrophobic interaction with ITZ in NMR studies. However, this apparent advantage of H grade through hydrophobic interactions between drug-polymer appeared to limit overall dissolution/permeation performance of SDD. CONCLUSIONS: In vitro SDD studies and drug-polymer interaction studies provided insight into the performance of HPMCAS grades, as well as the relative contributions of various mechanisms that polymer can promote ITZ absorption from SDD.