Study on the Role of Polymers in Preventing the Crystallization of Roxadustat in an Aqueous Environment

Abstract

The use of polymers is an increasingly common approach to prevent crystallization from the supersaturated solutions for enhanced bioavailability of poorly water-soluble drugs. In this study, roxadustat (RST), a water-insoluble drug, was selected as a model substance. We quantified the effectiveness of three polymers with different types of hydrogen bonding moieties, polyvinylpyrrolidone (PVP), poly(1-vinylpyrrolidone-co-vinyl acetate) (PVPVA), and hydroxypropyl methylcellulose (HPMC), on nuclear inhibition of RST and found that the inhibitory effect was HPMC > PVPVA > PVP. In the absence of polymers, the induction time of RST in the RST supersaturated solution was 1.5 min, while in the presence of HPMC, the induction time of RST was as long as 84.5 min. Simulation by Material Studio suggested that the compatibility and bonding energy between the polymers and RST showed a strongly positive correlation with the effectiveness of polymers. The combined inhibitory effect of hydrogen bonding and hydrophobic interaction between RST and polymers were revealed by FTIR, 1H NMR spectroscopy, and nuclear Overhauser effect spectroscopy. Moreover, the obtained amorphous-state RST in RST–polymer amorphous solid dispersions achieved improved solubility than that of crystalline RST, and the dissolved amorphous RST maintained the supersaturation for 6 h in the dissolution test without the decrease in concentration due to nucleation and crystal growth.