Mechanism Based on Formation, Closure and Overgrowth of Pores Describing Zero-Order Release from Polylactide Films

The use of drug delivery systems requires an understanding of the release kinetic patterns of an encapsulated drug or a model compound. In this work, the zero-order release of the pH-sensitive nitroxide radical 5,5-dimethyl-4-dimethylamino-2-ethyl-2-(4-pyridyl)-2,5-dihydroimidazole-1-oxyl (DPI) from poly-D,L-lactide (PDLLA) films into aqueous buffer solution was studied with continuous-wave electron paramagnetic resonance spectroscopy (EPR). The EPR method allowed for quantifying the DPI release kinetics from PDLLA films and analyzing rotational mobility and the concentration of the spin probe inside the films during their swelling and degradation. The EPR data were globally analyzed within the previously proposed phenomenological diffusion model based on the processes of pores formation and overgrowth in polyester films. The interaction between the doubly protonated DPI cation, formed in acid media inside the polymer pores, and the counterions of (oligo)lactic acid is proposed. Such interaction leads to the formation of bulk DPI-containing paramagnetic aggregates which make the release kinetics diffusion-controlled. This is in contrast to the pore-formation control observed for the standard spin probe 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxide (TEMPOL). Therefore, the release rate depends on the thickness of the film and the size and the charge of the dopant. Keywords: poly-D,L-lactide films; spin probes; electron paramagnetic resonance; mechanism of drug release; mathematical model of the release kinetics; zero-order release.