Alen Damiani, Milan Decorte, Martin Purino, Wim Dehaen, Guy Van den Mooter
This study investigates how the degree of substitution (DS) governs the behaviour of polysaccharide-based materials relevant for oral drug delivery, using pullulan acetate (PA) as a model system. A PA library with controlled DS (0.1-2.8) was synthesised via acetylation with acetyl chloride to enable systematic evaluation of structure-property relationships, including physicochemical properties, enzymatic accessibility, and drug-release performance. Structural and functional characterisation was performed using spectroscopic and thermal techniques, while solubility and compressibility were assessed through solvent screening and Heckel analysis, respectively. Enzymatic degradability was evaluated using pullulanase type I as a simplified model to probe polymer accessibility, and drug-release behaviour was studied using indomethacin-loaded PA/HPMC matrix tablets, with comparison to conventional EC/HPMC systems. The results revealed strong DS-dependent behaviour. Increasing DS induced a transition from hydrophilic to hydrophobic properties, accompanied by a decrease in Tg. Enzymatic degradation was observed only for low-DS materials, indicating a threshold around DS ≈ 0.5, above which enzymatic accessibility was suppressed. PA/HPMC matrix tablets exhibited tuneable sustained-release profiles, with drug release governed by the DS of the polymer. Kinetic modelling suggested that drug release is governed by a combination of diffusion and polymer relaxation mechanisms, with their relative contributions depending on DS and HPMC content. These findings demonstrate that controlled variation of DS enables systematic tuning of both enzymatic behaviour and drug-release performance in polysaccharides. In addition, PAs provide a useful model system for studying DS-dependent structure-property relationships and demonstrate potential for use in sustained oral drug delivery applications.