Polyelectrolyte Copolymer Hydrogels: Synthesis, Characterisation and Drug Delivery System Based on 2-Acrylamido-2-Methyl-1-Propane Sulphonic Acid

Abstract

The literature on polymer gels and hydrogels since the beginning of last century has been reviewed, and the properties of polymers and gels based on 2-acrylamido-2-methylpropanesulphonic acid (AMPS) summarized. Copolymer gels were synthesised, using gamma radiation initiation, from aqueous solutions of the comonomers acrylamide and AMPS. The progress of copolymerisation and crosslinking was followed by measuring the viscosity of reaction mixtures that had been irradiated for different times and hence had received different doses. The variation of viscosity with dose has been interpreted in terms of main chain growth and the onset of crosslinking and gelation. It was observed that the viscosity of irradiated reaction mixtures decreased substantially on standing at ambient temperature. That behaviour has been attributed to breaking of non-permanent bonds formed during irradiation and subsequently broken over the ageing period. The environmental responsiveness of the gels formed by gamma radiation initiation was assessed by observation of the volume phase transition triggered by increasing the proportion of acetone in aqueous acetone media in which the gels were immersed. Free-radical copolymerisation of aqueous solutions of comonomer AMPS and Nisopropylacrylamide (NIPA) was initiated with ammonium persulphate at 70°C. Reaction times that varied with comonomer mixture composition gave a series of copolymers corresponding to low conversion. The copolymer composition data set was used in conjunction with the Kelen-Tϋdos and Finemann-Ross methods, assuming the terminal model to be valid, to give the monomer reactivity ratios r(AMPS)=0.24 and r(NIPA)=1.12. The reactivity ratios show that copolymers made from comonomer mixtures with more than 25 mol% AMPS consist of relatively short monomer sequences. The dependence of glass transition temperature on copolymer composition was determined using differential scanning calorimetry and the experimental data compared with Tg predicted from the Fox equation. High-field (400 MHz) 1H-NMR spectroscopy was used to probe the early stages of polymerisation and gelation at 70°C in a D2O solution of AMPS and NIPA, crosslinker N,N1-methylenebisacrylamide (MBAA) and poly(ethylene glycol) (PEG). The change in signal intensity of vinyl protons of the monomers and crosslinkers, and the methylene proton signals from PEG were recorded as a function of reaction time. The relative initial rates of reactant consumption showed that the crosslinking monomer was consumed more rapidly than either AMPS or NIPA, so that crosslinking of the copolymer chains took place predominantly in the early stages of copolymer chain growth. The PEG signal was found to be invariant with time, confirming that PEG did not participate in the polymerization reaction but acted as the linear interpenetrating component in semi-interpenetrating network gels. The kinetics of gel formation and other rheological properties of copolymer and SIPN pregel solutions were analysed using parallel plate rheometry. The variation of shear moduli and other rheological parameters during reaction under dynamic shear was interpreted in terms of chain growth and crosslinking reactions. In relation to the sol-gel transition, viscosity, tan(δ), G' and G" were used to assess the kinetics of gelation. The densities of copolymer and SIPN dried gels were measured for a range of copolymer chain compositions and found to be similar in magnitude (within about 10%) for gels with the same copolymer chain composition. The surface morphology of both types of gel, in dried form, was examined using scanning electron microscopy. The swelling ratio of SIPN gels in water was found, in general, to be proportional to the AMPS content of the copolymer chains. The influence of initiator and crosslinker concentrations in the pregel solutions on the rheological properties of gels was investigated in detail. G', G", tan(δ) and critical strain were correlated to initiator concentration, but the crosslink density of the gel was essentially independent of initiator concentration. As expected, the effect of crosslinker concentration, hence crosslink density in the gels, on rheological properties, was significant. With increasing crosslinker concentration, the critical strain (at gel rupture) and tan(δ) decreased markedly. The surface roughness of dried gels also decreased with increasing crosslinker concentration. Effects of comonomer mixture and copolymer chain composition for copolymer and SIPN systems on the initiation temperature of pregel solutions and rheological properties of gels were compared. A feature of the data is that the copolymer gels exhibited much larger values of G' and G" than the corresponding SIPN gels, whereas the SIPN gels had larger equilibrium storage modulus (G'e), indicating that stronger covalent or physical crosslinks may exist in the SIPN gels. Copolymer and SIPN gels examined at constant frequency and shear stress exhibited a phase transition associated with the water in the gels. Both types of gels were found to have an ice-dominant structure at -6°C with G' smaller than that of ice at -5°C, and there was an ice phase to gel phase transition induced by shear strain at -6°C, which was not found in gels at -4°C. Temperature-time effects on gel formation kinetics and post-gel properties were determined and appear to be correlated to rates of gel formation as well as the final gel microstructure. As expected, the induction time for gel formation is greater at lower reaction temperature, and PEG enhances this effect and reduces the viscosity compared to the corresponding PEG-free system. The post gel microstructure has been examined in terms of G', angular frequency, reaction temperature and time. The most significant effect is that increasing reaction temperature for a fixed time builds a more complete gel network. Creep and stress relaxation of gels were investigated. Both copolymer and SIPN gels show a high degree of elasticity, and at specific frequencies the gels behave as ideal elastic solids. SIPN and copolymer gels were characterized using spectroscopic, thermal and morphological techniques (DSC, TG, FTIR, XPS, XRD and SEM). Interactions between PEG and copolymer network were found to markedly influence the properties of SIPNs. Thermal analysis revealed that the PEG component of the SIPNs showed melting behaviour that was similar to that of pure PEG, but modified by interactions between PEG and the copolymer network. Composition and temperature effects on thermal and morphological properties were investigated in detail. Protonation of a substantial proportion of the amide groups in the dried SIPN gets was detected by X-ray photoelectron spectroscopy, and mainly attributed to proton transfer from the sulphonic acid groups of AMPS units to the amide groups of NIPA units. Sodium diclofenac was used as a model drug in design of a drug encapsulation/release system based on use of PEG/poly(AMPS-co-NIPA) SIPN hydrogels. The thermal stability of the drug and the SIPN gel used for its encapsulation was determined as a prerequisite to the development of a direct drug loading technique whereby the drug was encapsulated during accelerated formation of the SIPN matrix in a suspension polymerisation system at 100°C. Direct loading of the drug was found to be superior, in terms of the distribution of the drug in the gel matrix, to the conventional diffusion loading technique. Drug release in pH7.4 phosphate buffer solutions and in pHl.0 simulated gastrointestinal liquid was determined as a function of time.