New insights into the use of hydroxypropyl cellulose for drug solubility enhancement: An analytical study of sub‐molecular interactions with fenofibrate in solid state and aqueous solutions

Abstract

AbstractHydroxypropyl cellulose (HPC) is a solubility enhancer used for poorly soluble drugs, nano‐suspensions and amorphous solid dispersions (ASD). However, the underlying mechanism remains unclear. ASDs of a poorly soluble drug, fenofibrate (FEN), were analyzed using liquid nuclear magnetic resonance (NMR) and solid state NMR (ss‐NMR). Liquid NMR revealed interactions between the pyranose ring of the HPC molecule and the diphenylketone from FEN. The water accessibility of the CH3 groups in HPC and FEN is very low, they form a hydrophobic zone in aqueous solution that may sustain the drug nucleation. Moreover, ss‐NMR measurements confirmed very low drug crystallinity for HPC‐FEN ASDs. Cross‐polarization and direct polarization 13C spectra, 13C‐CPMAS and 13C‐PARIS, distinguished the most rigid and flexible portions in concordance with the ss‐NMR proton T1 and T1r relaxation results. Although HPC side chains (hydroxypropoxy) are the most flexible portions, their flexibility is moderate and high rigidity is the predominant. The ss‐NMR proton relaxation indicates a rather homogeneous distribution of the components (HPC and FEN) in the solid mixtures. The versatile NMR methodology proposed can be used to study other polymer‐drug systems and it may contribute to understand relevant functional aspects such as the rate of drug‐delivery and their stability.