Insight into the State Evolution of Norfloxacin as a Function of Drug Concentration in Norfloxacin-Vinylpyrrolidone/Hydroxypropyl Methylcellulose/Hydroxypropyl Methylcellulose Phthalate Solid Dispersions

摘要

The purpose of this study was to investigate the state evolution of norfloxacin (NFX) as a function of drug content in solid dispersions (SDs) with three pharmaceutical polymers, including vinylpyrrolidone (PVP), hydroxypropyl methylcellulose (HPMC), and hydroxypropyl methylcellulose phthalate (HPMCP) by identifying the presence of specific intermolecular interactions within the formulation. The state of NFX was determined by powder X-ray diffraction and fluorescence spectroscopy. It was found that with the increase of drug loading, three states, namely, the amorphous NFX, hydrated transitional phase of NFX, and anhydrous crystalline NFX, were observed in turn. To reveal the underlying mechanism, X-ray photoelectron spectroscopy, Fourier transform infrared spectroscopy, thermogravimetric analysis, differential scanning calorimetry, variable temperature X-ray diffraction, and molecular modeling were employed. The results indicate a possible model of drug state evolution that the conversion from an amorphous to a hydrated state is likely caused by the domination of NFX self-protonation over NFX-polymer hydrogen bonding or ionic interaction, while the transformation to an anhydrous crystalline state is due to the dehydration effect resulting from increasing NFX-NFX aggregation. Furthermore, possible interaction patterns were delineated, and we also demonstrated a new mechanism of the formation of hydrated transitional NFX. The molecular insight into the drug state evolution provided here can be useful for the rational design of drug/polymer SDs.