The effects of cross-link density and composition on the loading and in vitro dissolution of the drug phenytoin as amorphous solid dispersions in emulsion polymerized poly( N-isopropylacrylamide) (PNIPAm) and poly( N-isopropylacrylamide- co- N, N-dimethylacrylamide) nanogels were investigated near the lower critical solution temperature (LCST). Nanogel size and particle density in phosphate buffered saline were quantified by dynamic light scattering (DLS) and viscometry experiments, while drug-nanogel interactions were revealed by cross peaks in aqueous-state nuclear Overhauser effect spectroscopy measurements. Spray-dried dispersions (SDDs) of drug-loaded PNIPAm nanogel particles ( R ≈ 43 nm) were directly visualized by cryogenic transmission electron microscopy and further quantified by small-angle X-ray scattering during in vitro dissolution. SDD dissolution profiles were highly dependent on the nanogel cross-link density and directly correlated with the state of dispersion of the drug-loaded nanogel particles. A balance between net particle hydrophobicity and hydrophilicity along with the distance in temperature from the LCST are shown to dictate the in vitro dissolution of the amorphous solid dispersions. Solubility enhancement mechanisms disclosed in this study provide essential guidance for the design of effective nanogels for oral drug delivery applications.
Keywords: N-isopropylacrylamide; cryo-TEM; drug delivery; lower critical solution temperature; nanogel; nanoparticle.