Effect of ethylene glycol dimethacrylate on swelling and on metformin hydrochloride release behavior of chemically crosslinked pH–sensitive acrylic acid–polyvinyl alcohol hydrogel
© Akhtar et al. 2015
Received: 28 April 2015
Accepted: 27 July 2015
Published: 19 August 2015
The present work objective was to prepare and to observe the effect of ethylene glycol dimethacrylate on swelling and on drug release behavior of pH-sensitive acrylic acid–polyvinyl alcohol hydrogel.
In the present work, pH sensitive acrylic acid–polyvinyl alcohol hydrogels have been prepared by free radical polymerization technique in the presence of benzoyl peroxide as an initiator. Different crosslinker contents were used to observe its effect on swelling and on drug release. Dynamic and equilibrium swelling studies of prepared hydrogels were investigated in USP phosphate buffer solutions of pH 1.2, 5.5, 6.5 and 7.5 with constant ionic strengths. Hydrogels were evaluated for polymer volume fraction, solvent interaction parameter, molecular weight between crosslinks, number of links per polymer chain, diffusion coefficient, sol–gel fraction and porosity. To demonstrate the release pattern of the drug, zero-order, first-order, higuchi and korsmeyer-peppas models were applied. Quality and consistency of hydrogels was examined by FTIR and surface morphology of hydrogels was examined by SEM.
Decrease in swelling and in drug release was seen by increasing content of ethylene glycol dimethacrylate. A remarkable high swelling was observed at high pH indicating the potential of this hydrogel for delivery of drugs to intestine. By increasing the concentration of ethylene glycol dimethacrylate, porosity decreased. Order of release was observed first order in all cases and the mechanism was non–fickian diffusion. FTIR confirmed the formation of network. SEM results showed the incorporation of drug.
The prepared hydrogels can be suitably used for targeted drug delivery to the intestine.
Hydrogel, three–dimensional crosslinked polymeric network, can swell and collapse reversibly in response to variables such as ionic strength, pH, electric field and temperature . Hydrogels can be used as controlled release systems when they are in contact with any surface. This can happen through spaces inside the network and the matrix dissolution/disintegration effect .
Polyvinyl alcohol (PVA) is being extensively used in fields, such as: pharmaceutical (for the wound dressing systems); biomedical (as a scaffold supporting material for tissue engineering applications) and environmental (for the production of films for removal of heavy metal ions from water). Other applications comprise fuel cells, electrochemistry and agriculture. The –OH group on every second carbon atom on PVA backbone allows it to take part in many chemical crosslinking reactions, to interact with many other polymers by hydrogen bonding, and to form a hydrogel by the freeze thaw process. Excellent biocompatibility, noncarcinogenicity, biodegradability and non-toxicity are supplementary attractive properties of PVA. PVA is also useful in the pharmaceutical industries, where it is being used as a polymer for the loading/encapsulation and the subsequent release of cells, enzymes, proteins and a range of drugs .
Acrylic acid (AA) is a superabsorbent and a common pH-sensitive electrolyte. Because gels can be prepared at varying concentrations, AA based materials present huge potential for biomedical applications. They may be easily converted to a broad range of shapes and sizes. Prior to gel formation, other materials may be included into AA. AA polymers exhibit high tolerance in living cells. In addition, a glycoprotein i.e. mucin secreted locally that coats the mucosal surfaces forms hydrogen bonds with carboxylic groups of AA. AA is a fine applicant for many drug delivery routes e.g. nasal, ocular and oral due to its bioadhesive property. As, carboxylic groups of AA intermingle with different groups, attachment sites are created for a variety of therapeutics .
In the synthesis of a large number of hydrogels, crosslinkers are used, which interconnect the lineal polymeric chains establishing a three-dimensional network of chemical bonds among them. It is necessary that the polymer has certain groups in its structure that can be used as anchor points in order to form the network. The choice of crosslinker depends on the selected monomers, must have at least two reactive groups in its structure, in order to be able to crosslink different polymeric chains, normally tetrafunctional and hexafunctional compounds, such as ethylene glycol dimethacrylate (EGDMA) and 1,1,1,trimethylolpropane trimethacrylate, although other crosslinking agents have also been used such as ethylenediaminetetraacetic dianhydride and pentaerythritol triacrylate . Glutaraldehyde (GA) has been extensively used for crosslinking polymers containing hydroxyl groups . Hydrogels containing ionic network structure show pH–dependent swelling behavior .
In the present work, ethylene glycol dimethacrylate and glutaraldehyde crosslinked pH–sensitive acrylic acid–polyvinyl alcohol hydrogels were synthesized for drug delivery to intestine. Different quantities of crosslinking agent were used in order to evaluate its effects on swelling and on drug release.
Polymer used was polyvinyl alcohol (Mol.wt. 72000; degree of hydrolysis ≥98 %; Merck, Germany). The monomer used was acrylic acid (Sigma-Aldrich, Netherland). Crosslinkers used were ethylene glycol dimethacrylate (Sigma-Aldrich, Germany) and glutaraldehyde (Scharlau, Spain). Benzoyl peroxide (Fisher Scientific, UK) was used as an initiator and HCl (Fluka, Switzerland) was used as a catalyst. Distilled water was used as a solvent. Potassium dihydrogen phosphate was purchased from Merck, Germany. Metformin hydrochloride was gifted by Popular International (PVT) LTD., Karachi, Pakistan.
Synthesis of pH sensitive AA–PVA hydrogels
A list of different formulations of AA–PVA hydrogel
(g/100 g solution)
(g/100 g solution)
(g/100 g solution)
(g/100 g solution)
Buffer solutions preparation
pH 1.2, 5.5, 6.5 and 7.5 USP phosphate buffer solutions were prepared with potassium dihydrogen phosphate. 0.2 M HCl or NaOH solution was used to adjust the pH of these solutions. NaCl was used to keep the ionic strength of all the buffer solutions constant.
Dynamic and equilibrium swelling study
Wt is the swollen gel weight at time t and Wd is the dry gel initial weight. For equilibrium swelling, the swollen gels were weighed daily until they reach constant weight which took almost 2 weeks.
Network parameters of AA–PVA hydrogels
Polymer volume fraction
v p is the dried hydrogel volume and v gel is the volume in swollen state.
Solvent interaction parameter (χ)
Molecular weight between crosslinks (Mc)
where M r is the polymer repeating unit molar mass and X is the degree of crosslinking.
where n PVA and n AA are the number of moles of PVA and AA, respectively while M PVA and M AA are PVA and AA molar masses, respectively.
Number of links per polymer chain (N)
where D is the hydrogel diffusion coefficient, θ is the swelling curve linear part slope, Q eq is the equilibrium swelling ratio and h is the sample thickness before swelling.
M 1 and M 2 are the hydrogel masses before and after immersion in ethanol, respectively: ρ is the absolute ethanol density and V is the hydrogel final volume.
Loading of metformin hydrochloride into crosslinked AA–PVA hydrogels
Weighed and dried hydrogel samples were placed in 1 % w/v solution of metformin hydrochloride. Metformin hydrochloride solution was prepared by dissolving the drug in USP phosphate buffer solution of pH 7.5. After attaining the equilibrium swelling, hydrogel samples were dried first at room temperature and then in an oven at 45 °C to constant weight.
Determination of metformin hydrochloride loading
Weights of dried hydrogels before and after immersion in drug solution are Wd and WD, respectively. In the second method, drug entrapped was calculated by repeatedly extracting the weighed quantity of loaded gels using USP phosphate buffer solution (pH 7.5). Each time fresh 50 ml USP phosphate buffer solution (pH 7.5) was used until drug exhaustion. Drug concentration was determined spectrophotometrically. Drug present in all portions of the extracts was considered as the drug amount loaded. Weighed gel disk was placed in drug solution up to equilibrium swelling, in the third method. Loaded gel was weighed again after blotting with filter paper. Difference in weight before and after swelling is the weight of drug solution. Dividing the weight of drug solution with the density of drug solution gave us the volume of drug solution. So, amount of drug was easily calculated from the volume of drug solution .
Metformin release studies
The weighed hydrogel disks were immersed separately in 500 ml 0.05 M USP phosphate buffer solutions of pH 1.2, 5.5 and 7.5 at 37 °C and dissolution medium was stirred at a rate of 100 rpm for maintaining a uniform drug concentration (Dissolution apparatus, Pharmatest; PT–Dt 7, Germany). Metformin HCl release study was conducted at 218 nm up to 12 h (UV–VIS spectrophotometer, IRMECO, UV–VIS U2020) .
Analysis of drug release pattern
Mt is the mass of water absorbed at any time t; M∝ is the amount of fluid intake at equilibrium; K3 is the kinetic constant and n is the swelling exponent.
FTIR spectroscopic analysis
The crushed hydrogel samples were mixed with potassium bromide (Merck IR spectroscopy grade) in 1:100 proportions and dried at 45 °C. The mixtures were compressed to a 12 mm semitransparent disk by a pressure of 65 kN (Pressure gauge, Shimadzu) for 1 min. The FTIR spectra were recorded over the wavelength range 4,000–400 cm−1 using FTIR spectrometer (FTIR 8400 S, Shimadzu).
Scanning electron microscopy (SEM)
The morphology of AA–PVA hydrogel and drug loaded AA–PVA hydrogel was observed using scanning electron microscope JSM–6480.
Results and discussion
pH impact on swelling and on drug release behavior of AA–PVA hydrogels
Swelling coefficients (Dynamic and equilibrium) of AA–PVA hydrogels using EGDMA and GA as crosslinkers
Dynamic swelling coefficients
Equilibrium swelling coefficients
Metformin amount loaded in different samples of AA–PVA hydrogel
Amount of metformin loaded
(g/g of dry gel)
Effect of pH on dug release after 12 h drug release study
Effect of EGDMA content on swelling and on drug release behavior of AA–PVA hydrogel
Network parameters of AA–PVA hydrogels
Network parameters of AA–PVA hydrogels
Gel fraction (%)
Because of the high molar mass of the components involved, only a very small positive v 2,s value can be tolerated. The higher the value of x, weaker is the interaction between solvent and polymer, and stronger is the interaction among polymer chains. The polymer-solvent interaction parameter (x) has values that increased by increasing the content of crosslinker. For many systems, x was found to increase by increasing the polymer content for a given polymer volume fraction, smaller the value of x, greater the rate at which the free energy of the solution decreased by the solvent addition. As a result, liquids with the smallest x values are the best solvents for a polymer. When there is an increase in swelling ratio, v 2,s and x values are decreased. When there is a decrease in swelling ratio, the mesh size decreased leading to a decrease in M C and the rate of diffusion of solute would also be expected to decrease [15, 28–34].
By increasing the content of EGDMA, the gel fraction increased while the sol fraction decreased. This can be credited to the development of intermolecular crosslinks. Table 5 is elaborating the effects of EGDMA contents on the gel fraction of AA–PVA hydrogel. As by increasing crosslinker concentration, there will be more crosslinking which will ultimately increase the gel fraction [4, 8, 35–37].
Due to the porous structure, hydrogels take in more water via capillary action and transfer the drug into the pores. Table 5 is elaborating the effects of crosslinking agent on porosity. By increasing the concentration of EGDMA, porosity decreased. As a result of increased amount of EGDMA, there was an increase in crosslinking density, decrease in hydrogel mesh size which resulted in decreased porosity [4, 8, 38–40].
Drug release mechanism
When penetrant gets into the polymer network, the water soluble drug loaded in hydrogel is dissolved and drug diffusion occurs through the aqueous pathways to the surface of the device. The drug release was strongly linked to the swelling characteristics of the hydrogel which is a key parameter of structural design of the hydrogel. The method that best fits the release data was evaluated by the regression coefficient (r). Criterion for selecting the most appropriate model was based on the ideal fit indicated by the values of regression coefficient (r) near to 1.
Effect of EGDMA concentration on release kinetics of AA–PVA hydrogel at different pH
EGDMA content (% w/w)
Zero order kinetics
First order kinetics
Effect of EGDMA concentration on release mechanism of AA–PVA hydrogel
EGDMA content (%w/w)
Release exponent (n)
Order of release
Scanning electron microscopy
Chemically crosslinked pH–sensitive AA–PVA hydrogels were synthesized in the presence of EGDMA&GA as crosslinkers and proved to be a good candidate for drug delivery to intestine. By increasing the content of EGDMA, a decrease in swelling and in drug release was noted due to more crosslinking. Gel fraction was found to increase by increasing the EGDMA concentration. Porosity was found to decrease by increasing the EGDMA content. Drug release followed first order and the mechanism was non-fickian diffusion in all cases. The FTIR confirmed the formation of graft polymer. SEM image of the drug loaded hydrogel showed incorporation of drug in the hydrogel along with the voids present on the hydrogel surface. S1–S3 samples can be effectively used as carriers for targeted drug delivery to intestine.
This work was financially supported by Faculty of Pharmacy, Bahauddin Zakariya University, Multan, Pakistan.
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