Preparation and characterization of pH‐sensitive hydrogels based on chitosan,itaconic acid and methacrylic acid

Novel pH‐sensitive hydrogels based on chitosan, itaconic acid and methacrylic acid were prepared in two steps. Chitosan was first ionically crosslinked with itaconic acid, after which a free radical polymerization and crosslinking of the chitosan/itaconic acid network was performed by adding methacrylic acid and a crosslinker in order to achieve better mechanical properties and tunable swelling. The samples were characterized using Fourier transform infrared spectroscopy, scanning electron microscopy, thermogravimetric analysis, X‐ray diffraction, dynamic mechanical analysis and the swelling ratios of the hydrogels at various pH values (2.0–8.0). The hydrogel composition is found to have a great impact on the hydrogel structure, mechanical and thermal properties, morphology and swelling kinetics. The highly porous morphology of the gels is probably connected with the bulky chitosan/itaconic acid network which reduces the degree of crosslinking in the second step of the synthesis due to steric hindrances. The gels demonstrate substantial change in buffer absorbency with change of pH, low for acid buffers and the higher for pH values above 6 where the swelling is considerably slow, thus suggesting their strong candidature for use as oral drug‐delivery systems in the lower parts of the gastrointestinal tract and for drugs that require longer release times. Copyright © 2010 Society of Chemical Industry     

Synthesis and swelling properties of pH‐sensitive hydrogels based on chitosan and poly(methacrylic acid) semi‐interpenetrating polymer network

A novel semi‐interpenetrating polymer network (semi‐IPN) hydrogel composed of chitosan and poly(methacrylic acid) was synthesized using formaldehyde as a crosslinker. The amount of crosslinker was searched and optimized. The structure of the hydogel was investigated by Fourier transform infrared (FTIR) spectroscopy. The spectrum shows that a structure of polyelectrolyte complex exists in the hydrogel. The effects of pH, ionic strength, and inorganic salt on the swelling behaviors of the hydrogel were studied. The results indicate the hydrogel has excellent pH sensitivity in the range of pH 1.40 to 4.50, pH reversible response between pH 1.80 and 6.80, and ionic strength reversible response between ionic strength 0.2 and 2.0M. The results also show that the hydrogel has a bit higher swelling capacity in a mix solution of calcium chloride (CaCl₂) and hydrochloric acid (HCl) solution than in a mix solution of sodium chloride (NaCl) and HCl. These results were further confirmed through morphological change measured by scanning electron microscope (SEM). © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 98: 1720–1726, 2005     

Synthesis of pH‐ and temperature‐responsive chitosan‐graft‐poly[2‐(N,N‐dimethylamino) ethyl methacrylate] copolymer and gold nanoparticle stabilization by its micelles

Novel pH‐ and temperature‐responsive chitosan‐graft‐poly[2‐(N,N‐dimethylamino)ethyl methacrylate] (chitosan‐g‐PDMAEMA) copolymers were successfully synthesized by homogeneous atom transfer radical polymerization (ATRP) under mild conditions. Chitosan macroinitiator was prepared by phthaloylation of amino groups of chitosan and subsequent acylation of hydroxyl groups of chitosan with 2‐bromoisobutyryl bromide. The copolymers were obtained by ATRP of 2‐(N,N‐dimethylamino)ethyl methacrylate and they can self‐assemble into stable micelles in water. Hybrid micelles with a PDMAEMA corona incorporating gold nanoparticles (Au NPs) were prepared in situ via the reduction of HAuCl₄ with NaBH₄. The pH and temperature responses of the copolymer micelles and hybrid micelles were characterized using UV‐visible spectroscopy and dynamic laser light scattering. The morphology of the micelles was observed using transmission electron microscopy and atomic force microscopy. The PDMAEMA corona of the micelles acts as the ‘nanoreactor’ and the ‘anchor’ for the in situ formation and stabilization of Au NPs. Therefore, the spatial distribution of Au NPs within the micelles can be tuned by varying the temperature and pH value. Copyright © 2010 Society of Chemical Industry     

Swelling behavior of pH‐ and temperature‐sensitive copolymers containing 2‐hydroxy‐ethyl methacrylate and N‐vinyl‐2‐pyrrolidone crosslinked with new crosslinkers

Copolymers of 2‐hydroxyethyl methacrylate (HEMA) and N‐vinyl‐2‐pyrrolidone (VP) and homopolymers of HEMA and VP were crosslinked in the presence of different mol% of melamine trimethacrylamide (MMAm) and melamine triacrylamide (MAAm) as crosslinkers by bulk radical polymerization. The resultant xerogels were characterized by extracting the soluble fractions and measuring the equilibrium water content. Lower critical solution transition temperatures (LCST) were measured by DSC. The properties of crosslinked HEMA and VP copolymers, VP and HEMA series were evaluated in terms of compositional drift of polymerization, heterogeneous crosslinking, and chemical structure of the relevant components. Soluble fractions of the crosslinked networks were reduced by varying the MAAm and MMAm concentrations. The influence of environmental conditions such as temperature and pH on the swelling behavior of these polymeric gels was investigated. The swelling behaviors of the resulting gels show pH sensitivity. This behavior is explained on the basis that amide groups of VP or crosslinkers could be hydrolyzed to form negatively charged carboxylate ion groups in the produced networks in response to an external pH variation. Copyright © 2004 Society of Chemical Industry     

Synthesis and characterization of fast responsive thermo‐ and pH‐sensitive poly[(N,N‐diethylacrylamide)‐co‐(acrylic acid)] hydrogels

BACKGROUND: A considerable amount of research has been focused on smart hydrogels that can respond to external environmental stimuli, especially temperature and pH. In this study, fast responsive thermo‐ and pH‐sensitive poly[(N,N‐diethylacrylamide)‐co‐(acrylic acid)] hydrogels were prepared by free radical copolymerization in aqueous solution using poly(ethylene glycol) (PEG) as a pore‐forming agent. RESULTS: Swelling studies showed that the hydrogels produced had both temperature and pH sensitivity. The deswelling kinetics at high temperature demonstrated that the shrinking rates were influenced by the addition of the pore‐forming agent and the amount of acrylic acid in the initial total monomers. The deswelling curves in low‐buffer solutions had two stages. Pulsatile swelling studies indicated that the PEG‐modified hydrogels were superior to the normal ones. These different swelling properties were further confirmed by the results of scanning electron microscopy. CONCLUSION: Such fast responsive thermo‐ and pH‐sensitive hydrogels are expected to be useful in biomedical fields for stimuli‐responsive drug delivery systems. Copyright © 2008 Society of Chemical Industry     

Swelling characteristics of thermo‐ sensitive poly[(2‐diethylaminoethyl methacrylate)‐co‐(N,N‐dimethylacrylamide)] porous hydrogels

Temperature‐sensitive poly[(2‐diethylaminoethyl methacrylate)‐co‐(N,N‐dimethylacrylamide)] [P(DEAEMA‐co‐DMAAm)] hydrogels with five different DMAAm contents were synthesized with and without the addition of sodium carbonate as porosity generator. The synthesized hydrogels were characterized with dry gel density measurements, scanning electron microscopy observation and the determination of swelling ratio. The influence of the pore‐forming agent and content of DMAAm on swelling ratio and network parameters such as polymer–solvent interaction parameter (χ), average molecular mass between crosslinks (M?_c) and mesh size (ζ) of the cryogels are reported and discussed. The swelling and deswelling rates of the porous hydrogels are much faster than for the same type of hydrogels prepared via conventional methods. At a temperature below the volume phase transition temperature, the macroporous hydrogels also absorbed larger amounts water compared to that of conventional hydrogels and showed obviously higher equilibrated swelling ratios in aqueous medium. In particular, the unique macroporous structure provided numerous water channels for water diffusion in or out of the matrix and, therefore, an improved response rate to the external temperature changes during the deswelling and swelling processes. These properties are attributed to the macroporous and regularly arranged network of the porous hydrogels. Scanning electron micrographs reveal that the macroporous network structure of the hydrogels can be adjusted by applying porosity generation methods during the polymerization reaction. Copyright © 2007 Society of Chemical Industry     

β‐cyclodextrin/poly(vinyl alcohol) hydrogels containing phenylpropionic acid and naphthylamine: dual pH‐sensitive release

Hydrogel composed of β‐cyclodextrin (β‐CD) and poly(vinyl alcohol) was prepared in a strong alkaline condition using epichlorohydrin as a crosslinker. Phenylpropionic acid (PPA) and naphthylamine (NA) were loaded in the cavities of β‐CD residues to endow the hydrogel with a dual pH‐sensitive characteristic. In release experiments using fluorescein isothiocyanate‐dextran (FITC‐dextran) as a dye, PPA/NA‐loaded hydrogel exhibited an extensive release not only in acidic conditions (e.g. pH 3.0) but also in alkaline conditions (e.g. pH 9.0). PPA and NA will be highly ionized at the alkaline and the acidic pH and they could promote swelling of the hydrogel, causing an extensive release at those pH values. However, the release was suppressed at mid pH values (e.g. pH 5.0 and pH 7.4), possibly due to the formation of salt bridges between PPA^? and NA⁺. In fact, the degree of swelling at mid pH was lower than that observed at strong acidic pH and alkaline pH. According to SEM images, the pore size and the texture compactness of hydrogels which had been subjected to swelling at different pH values could also account for the dual pH‐sensitive releases. The hydrogels exhibited dual pH sensitivities in terms of FITC‐dextran release and swelling. These hydrogels might be used as a pH‐sensitive vehicle for water‐soluble drugs. © 2013 Society of Chemical Industry     

Thermosensitive Poly[(2‐(diethylamino)ethyl methacrylate)‐co‐(N,N‐dimethylacrylamide)] Cryogels Prepared by a Two‐Step Polymerization Method

Summary: Temperature‐sensitive P(DEAEMA‐co‐DMAAm) cryogels with five different DMAAm contents were synthesized via a two‐step polymerization method, the initial polymerization being conducted for various times at 22 °C, followed by polymerization at ?26 °C for 24 h. The influence of the first‐step time and the content of DMAAm on the swelling ratio and network parameters such as the polymer/solvent interaction parameter, the average molecular mass between crosslinks, and the mesh size of the cryogels were reported and discussed. The swelling studies indicated that the swelling increased in the following order: 22C45 > 22C30 > 22C15 > 22C0. The cryogels exhibited swelling/deswelling transitions (reentrant phenomena) in water depending on temperature. These properties were attributed to the macroporous and regularly arranged network of the cryogels. Scanning electron microscope graphs reveal that the macroporous network structure of the cryogels can be adjusted by applying a two‐step polymerization.

Chemical structure of the P(DEAEMA‐co‐DMAAm) cryogels.     

Synthesis and properties of electrically‐sensitive poly(acrylic acid‐co‐acetoacetoxy ethyl methacrylate) gels

A series of electric field sensitive copolymer P(AA‐co‐AAEM) gels of acrylic acid (AA) with acetoacetoxy ethyl methacrylate (AAEM) were prepared by free‐radical copolymerization, with N,N′‐methylene bisacrylamide (MBAAm) and ammounium persulfate (APS) as crosslinking agent and initiator, respectively. The structures and properties of the gels were tunable by changing the monomer feed weighty ratio (R) (R = W_AAEM/(W_AAEM + W_AA) of AAEM and AA. The influences of the NaCl concentration and pH buffer solutions on the equilibrium swelling ratios of the gels were studied in detail. It is shown that both NaCl concentration and pH value of the buffer solution affect the swelling properties of the P(AA‐co‐AAEM) gels greatly. Moreover, the gel deswelling behavior induced by a direct current electric field was investigated and an excellent electric‐sensitivity was found. Among all the samples, the gel with monomer feed weighty ratio (R) = 0.1479 showed the best electrical contraction properties. On the basis of the experimental results, the mechanism of the electricity‐induced deswelling behavior was presented. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008     

Bioerodible hydrogels based on 2‐hydroxyethyl methacrylate: Synthesis and characterization

Biocompatible polymers with specific shape and tailored hydrogel properties were obtained by polymerization of mixtures of 2‐hydroxyethyl methacrylate (HEMA) with 1–8 wt % ethylene glycol dimethacrylate (EGDMA) or tetra(ethylene glycol) diacrylate (TEGDA) as crosslinking agents, by using a redox initiator. Introduction of charged positive and negative groups was easily achieved by direct polymerization of appropriate monomer mixtures and by chemical transformation of preformed hydrogels. Investigation of the swelling behavior of the prepared hydrogels evidenced an appreciable dependence on both solvent type and polymer chemical structure. Additionally, the solvation process resulted in being controlled by solvent diffusion, according to a Fickian II mechanism. The presence of several types of water with different melting behavior was observed in fully swollen hydrogels. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 85: 2729–2741, 2002     

Fast, multi-responsive microgels based on photo-crosslinkable poly(2-(dimethylamino)ethyl methacrylate)

Multi-responsive microgels based on poly(2-(N,N-dimethylamino)ethyl methacrylate) were developed and their properties were investigated. The primary goal of this research was to speed up the stimulus-response time of the hydrogels to a level usable for actuator applications, by reducing the diffusion distance of water. The gels were prepared by a UV induced photodimerization of a copolymer of 2-(dimethylamino)ethyl methacrylate and 4-cinnamoyl-phenyl methacrylate. Patterning studies showed that these materials can be used as photo-resist materials with high resolution at short exposure times. They showed lower critical solution temperature behavior in water, as well as pH dependent solubility and swelling ratios. While 1 mm thick gels showed response times to temperature and pH-changes of several hours, Si-supported microgels of 300 nm thickness had response times in the range of only a few seconds. The copolymer was prepared by free radical copolymerization, and the reactivity ratios were determined with the extended Kelen Tudos method. Spin-coating of this copolymer on Si supports and subsequent UV-irradiation yielded microgels of variable thickness (200 nm-15 μm), which was determined by confocal scanning laser microscopy. Surface plasmon resonance spectroscopy measurements demonstrated the fast, stimuli-responsive swelling behavior, while differential scanning calorimetry gave insight into the morphology of the networks.     

Swelling and drug release profile of poly(2‐ethyl‐2‐oxazoline)‐based hydrogels prepared by gamma radiation‐induced copolymerization

Poly(2‐ethyl‐2‐oxazoline) and acrylic acid were copolymerized in different compositions using γ‐rays‐induced polymerization and cross‐linking to obtain a series of pH‐sensitive hydrogels. The preparation parameters that may affect the copolymerization process such as the feed solution composition and irradiation dose were optimized. Swelling characteristics of the obtained polymeric hydrogels were evaluated. The results show the significant effects of the hydrogel composition, soaking time, and pH on the swelling equilibrium. The diffusion parameters obtained at pH 1 and 7 show the possibility of using the prepared hydrogels in the field of colon‐specific drug delivery systems. Ibuprofen as a model drug was loaded into (poly(2‐ethyl‐2‐oxazoline)/acrylic acid) copolymer hydrogel to investigate their drug release behavior at different pH values. © 2011 Wiley Periodicals, Inc. J Appl Polym Sci, 2011     

Synthesis and characterization of poly[4‐(2‐thiazolylazo)phenyl methacrylate]‐co‐poly(methyl methacrylate)

A new methacrylic monomer, 4‐(2‐thiazolylazo)phenylmethacrylate (TPMA) was synthesized. Copolymerization of the monomer with methyl methacrylate (MMA) was carried out by free radical polymerization in THF solution at 70 ± 0.5°C, using azobisisobutyronitrile (AIBN) as an initiator. The monomer TPMA and the copolymer poly(TPMA‐co‐MMA) were characterized by Fourier transform infrared (FTIR), ¹H nuclear magnetic resonance (NMR), and elemental analysis methods. The polydispersity index of the copolymer was determined using gel permeation chromatography (GPC). Thermogravimetric analysis (TGA) of the copolymer performed in nitrogen revealed that the copolymer was stable to 270°C. The glass transition temperature (T_g) of the copolymer was higher than that of PMMA. The copolymer with a pendent aromatic heterocyclic group can be dissolved in common organic solvents and shows a good film‐forming ability. Both the monomer TPMA and the copolymer poly (TPMA‐co‐MMA) have bright colors: orange and yellow, respectively. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 103: 2152–2157, 2007     

A novel approach for albumin determination in aqueous media by using temperature‐ and pH‐sensitive N‐isopropylacrylamide‐co‐N‐[3‐(dimethylamino)‐propyl]methacrylamide random copolymers

Random copolymers of N‐isopropylacrylamide (NIPA) and N‐[3‐(dimethylamino)propyl]methacrylamide (DMAPM) were synthesized by solution polymerization using azobisizobutyronitrile as the initiator in 1,4‐dioxane at 60°C. NIPA‐co‐DMAPM copolymer exhibited both temperature and pH sensitivity. Thermally reversible phase transitions were observed both in the acidic and the alkaline pH regions for copolymers produced with different DMAPM/NIPA feed ratios. The pH dependency of the lower critical solution temperature (LCST) was stronger for copolymers produced with higher DMAPM feed concentrations. NIPA‐co‐DMAPM random copolymer was also sensitive to the albumin concentration. In the presence of albumin, thermally irreversible phase transitions were observed in slightly acidic and neutral media. However, reversible transitions were obtained in aqueous media containing albumin at basic pH. The phase‐transition temperature of NIPA‐co‐DMAPM copolymer significantly decreased with increasing albumin concentration at both acidic and alkaline pH values. This behavior was explained by albumin binding onto the copolymer chains by means of H‐bond formation between the dimethylamino groups of the copolymer and the carboxyl groups of albumin. For a certain range of albumin concentration, the phase‐transition temperature exhibited a linear decrease with increasing albumin concentration. By utilizing this behavior, a simple albumin assay was developed. The results indicated that NIPA‐co‐DMAPM copolymer could be utilized as a new reagent for the determination of albumin concentration in the aqueous medium. The proposed method was valid for the albumin concentration range of 0–4000 μg/mL. The protein concentrations commonly utilized in biotechnological studies fall in the range of the proposed method. © 2002 Wiley Periodicals, Inc. J Appl Polym Sci 84: 2060–2071, 2002; DOI 10.1002/app.10503     

Synthesis and characteristics of semi‐interpenetrating polymer network hydrogels based on chitosan and poly(hydroxy ethyl methacrylate)

Semi‐interpenetrating polymer networks (semi‐IPNs), composed of chitosan and poly(hydroxy ethyl methacrylate) hydrogels, were prepared and the effects of various pH, temperatures, and an electric‐field on the swollen hydrogels were investigated. The swelling kinetics increased rapidly, reaching equilibrium within 60 min. Semi‐IPN hydrogels exhibited relatively high swelling ratios, 150～350%. The swelling ratio increased when the pH of the buffer was below pH 7 as a result of the dissociation of ionic bonds. Semi‐IPN hydrogels showed electroresponsiveness by shrinking when an electric field was applied. © 2005 Wiley Periodicals, Inc. J Appl Polym Sci 96: 86–92, 2005     

Thermo‐ and pH‐responsive microgels for controlled release of insulin

Microgel particles were prepared, made of hydroxypropylcellulose‐graft‐(acrylic acid) (HPC‐g‐AA) and acrylic acid(AA). The particles undergo reversible volume phase transitions in response to both pH and temperature changes while keeping the inherent properties of PAA and HPC‐g‐AA. Dynamic light scattering measurements reveal that the average hydrodynamic radius and hydrodynamic radius distributions of the microgel particles depend on temperature and pH. The microgels exhibit excellent pH sensitivity and a higher swelling ratio at higher pH in aqueous solution. In vitro release study shows that the amount of insulin released from the microgels is less at pH = 1.2 than at pH = 6.8. The results indicate that the resultant microgels seem to be of great potential for intelligent oral drug delivery. Copyright © 2012 Society of Chemical Industry     

Study of novel biodegradable thermo‐sensitive hydrogels of methoxy‐poly(ethylene glycol)‐block‐polyester diblock copolymers

A series of biodegradable thermo‐sensitive hydrogels were synthesized by ring‐opening polymerization of methoxy‐poly(ethylene glycol) (mPEG) and various ester monomers, i.e. D ,L ‐lactide, glycolide, β‐propiolactone, δ‐valerolactone and ε‐caprolactone. The copolymers were characterized using ¹H NMR spectroscopy and gel permeation chromatography. The micelle properties were also measured. The results indicated that the diblock copolymers formed nano‐micelles at low concentrations in aqueous phase. The lower critical solution temperatures of the diblock copolymers were above 35 °C at 1 wt%. As the temperature increased above room temperature, the diblock copolymer solutions underwent a sol‐to‐gel phase transition, which was manifested in viscosity increases, indicative of the formation of a gel. The mPEG–polyester diblock copolymer solutions exhibited sol‐gel transition behavior as a function of temperature and polymer concentration. Copyright © 2010 Society of Chemical Industry