Drug–polymer interactions and their effect on thermoresponsive poly(N-isopropylacrylamide) drug delivery systems

Potential interactions between model drugs (benzoates, diltiazem, cyanocobalamin, dextrans) and a thermoresponsive poly(N-isopropylacrylamide) (PNIPA) hydrogel and corresponding linear polymer were investigated. The influence of the drugs on the equilibrium swelling level of the hydrogel was examined and drug–hydrogel binding isotherms were established where appropriate. Differential scanning calorimetry (DSC) was used to investigate the influence of the drugs on the lower critical solution temperature (LCST) of the linear polymer solution. Phase solubility studies were preformed to investigate binding. Drug–polymer co-precipitated blends were also prepared and analysed by X-ray diffraction (XRD), thermal analysis and Fourier transform infrared (FT-IR) spectroscopy. Hydrophobic binding was apparent between PNIPA and the aromatic ring/ester side chain of the unionised benzoate. The effect of this binding on hydrogel swelling was clarified in terms of the influence of the binding on the LCST of the system. The drug release rates of the benzoates from the hydrogel were shown to be dependent on drug binding properties. Ionisation of the benzoate prevented such hydrophobic binding, with a weaker salting out effect apparent with sodium benzoate. Significant interactions between diltiazem, cyanocobalamin (Vitamin B12) or the dextrans and PNIPA were not apparent. High concentrations of the hydrophilic drugs did, however, interfere with the magnitude of hydrogel equilibrium swelling. Hydrophobic binding, the salting out effect and the influence of the drugs on hydrogel swelling under non-sink conditions were therefore shown to be important effects which depended on the chemical nature of the drug present.