Synthesis and characterization of thermoresponsive polymers, hydrogels and microgels, based on poly(N-substituted acrylamides)

Abstract

Stimuli-responsive polymers have the unique property of undergoing a reversible phase transition. This property has attracted much interest for their application in the field of medicine and biotechnology, such as drug delivery systems. Linear polymers of the poly(N-substituted acrylamides) family and their three-dimensional macroscopic (hydrogels) or microscopic (microgels) networks demonstrate such a phase transition behavior. In particular, polymers of this family have the ability to respond to external stimuli, such as temperature and are characterized by a critical solution temperature (CST). The aim of the present thesis was the synthesis and investigation of the thermoprecipitation of the above mentioned linear polymers and their three-dimensional forms. Polymers that are having a similar or even higher phase transition temperature than that of the well-established poly(N-isopropylacrylamide) is becoming increasingly attractive since they increase the range of applications even further. Optimization of their thermoresponsive behavior could be obtained by changing the surrounding environmental conditions, such as addition of salts, solvents or copolymerization. Polymers with different thermosensitivity depending on the chemical structure of the backbone, such as poly (N-isopropylacrylamide), poly (N,N'-diethylacrylamide), poly (N-ethyl,N-methylacrylamide) and poly (N-pyrrolidinoacrylamide), were synthesized by chain transfer and anionic polymerization and characterized by a variety of experimental techniques. Using N,N-methylenebisacrylamide as crosslinking agent, macro- and microscopic network structures of poly (N-isopropylacrylamide) and poly (N,N'-diethylacrylamide) were obtained by free radical polymerization and surfactant-free emulsion polymerization, respectively. The synthesis of thermosensitive polymers was mainly manipulated taking the behavior of oligomeric poly (N-isopropylacrylamide) as reference. An influence of the polymerization method and in some cases of the molecular weight and tacticity on the CST was observed. Copolymerization of poly (N-isopropylacrylamide) with a more hydrophilic comonomer, shifted the CST to higher values. Co-solutes and co-solvents influence the thermoprecipitation of linear thermosensitive polymers from aqueous solution. A salting-out effect was noticed when inorganic salts, except for potassium iodide, were presented in the polymer aqueous solution. Contrary to the effects observed upon the addition of simple salts as additives, the chemistry of the investigated polymers was of direct consequence for the effect of a given solvent. Also, the strength of the observed effect was related not only to the size but also the structure of the hydrophobic domain of the solvent molecule. Despite the presence of chemical crosslinks, similarity was found between the phase transition of hydrogels with the corresponding linear polymers. Synthesis conditions seem to influence the macroscopic gel structure. Gel structure and crosslinking density showed partly an influence to the characteristic properties of the hydrogels, namely swelling ratio, reswelling and deswelling kinetics. In the presence of salts, certain parallels can be drawn to the effect observed on the phase transition of thermosensitive hydrogels in comparison with the one on polymers. Solute permeation and pore size characterization of the two gels were investigated using dextran molecules and their molecular weight cut off was estimated to be close to 70 kDa. For the purpose of drug loading experiments, insulin and BSA were chosen as model drugs with the insulin showing higher percentage of ingress. Release experiments from the gel networks at 37°C, a temperature higher than the CST of the gels, were also realized using insulin as model drug. Between the gels, different release profiles were obtained attributed to their different hydrophobicity. The invention of small sized thermosensitive microgels is of great interest due to their fast kinetic response. Between the polymerization processes the stirring rates were varied and an effect on the particle size was noticed; increasing stirring rate, the average particle diameter decreases. Small particles presented in the microgel solution, indicate the continuation of nucleation process and therefore the necessity for longer polymerization time.