Rheological Study of Chitosan/Polyol-phosphate Systems: Influence of the Polyol Part on the Thermo-Induced Gelation Mechanism

Thermo-sensitive gelling systems, like chitosan/polyol-phosphate, are candidates with a high potential for the design of biodegradable drug delivery systems, notably for in situ forming depots. They consist of stable and low viscosity aqueous solutions, liquid at room temperature, which turn into a gel state upon an increase of temperature (e.g., after subcutaneous administration). This technology enables a sustained release of potentially encapsulated active substances. Despite these thermogelling solutions being widely studied for the development of parenteral drug delivery systems, most commonly using beta-glycerophosphate (beta-GP) as gelling agent, the mechanism inducing the gelation and the role of the polyol part in this mechanism has not been clearly elucidated. To investigate the mechanism of the gelation process, comprehensive rheological studies were performed, comparing different chitosan/polyolphosphate systems varying in the chemical structure of the polyol parts of the gelling agents. As reference, beta-GP was compared to glucose-1-phosphate (G1-P) and glucose-6-phosphate (G6-P) and to a polyol-free phosphate salt, Na2HPO4, as well. Frequency sweep experiments at different temperatures or different gelling agent concentrations, temperature, and time sweep tests were performed as complementary experimental approaches. The results disclosed significant trends with widespread implications, establishing a relationship between the chemical structure of the polyol part and the macroscopic gelling behavior of the solutions, that is, transition temperature, gelation time, and gel strength. The new results presented in this study show that increasing the size of the polyol part prevents the interactions between the chitosan chains, strongly influencing the gelling process.