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Synthesis and Characterization of Poly(hydroxyethyl methacrylate-co-methacrylic acid) Cross Linked Polymeric Network for the Delivery of Analgesic Agent.

Byline: Haroon Rashid, Mahmood Ahmad, Muhammad Usman Minhas, Muhammad Sohail and Muhammad Fakhruddin Aamir

Summary: Objective of the study was to synthesize a chemically cross-linked poly(hydroxyethylmethacrylate-co-methacrylic acid) hydrogel [p(HEMA-co-MAA hydrogel)] for pH-responsive, controlled drug delivery of Flurbiprofen. pH-sensitive hydrogel drug delivery system was synthesized with the help of poly hydroxyethyl methacrylate (HEMA) and methacrylic acid (MAA) by using ethylene glycol dimethacrylate (EGDMA) as crosslinker. The monomers (HEMA and MAA) were successfully cross linked through free radical polymerization process, initiated by benzoyl peroxide in an aqueous medium. All formulations were loaded with Flurbiprofen as a model drug and evaluated at pH 1.2 and pH 7.4 to investigate pH-responsive nature of the system.

Fourier transform infrared spectroscopy (FTIR) was performed to confirm the cross-linking of copolymer while thermo gravimetric analysis (TGA) and differential scanning calorimetry (DSC) were performed to evaluate the thermal stability of the system. Swelling studies and in-vitro release studies were carried out to evaluate pH-responsive nature of the hydrogels. FTIR confirmed that monomers were successfully cross-linked to form a copolymer. Hydrogel system showed less swelling at lower pH while at higher pH, it showed higher swelling, releasing drug in the same fashion. It was concluded that a stable hydrogel network was chemically cross- linked showing pH-responsive nature and thus, synthesized p(HEMA-co-MAA) hydrogels can be successfully employed as potential candidate for controlled drug delivery.

Keywords: Hydrogel, pH-sensitive, p(HEMA-co-MAA), Swelling, Crosslink, Flurbiprofen.


Hydrogel is a complex network having three dimensional arrangement of different polymers /monomers which can absorb water [15] from 10% to thousands times of their dry weight due to hydrophilic nature of different functional groups present in the respective polymers [68]. It is an established fact that different polymeric networks are present inside hydrogels having hydrophilic nature which can easily dissolve in an aqueous environment. To restrict hydrogels from dissolution, different cross linkers are added in order to maintain its mechanical integrity [911]. These cross linkers act through chemical and physical means to synthesize hydrogels after transformation of covalent bonding forces and physical interactions [12]. Dissolution of this network is being restricted by different physical interactions between polymeric arrangements which can be rattled easily by any change in the physical conditions. Due to this property, these are called as reversible hydrogels [6, 11, 13].

With the passage of time, hydrogels have been revolutionized to become one of the promising drug delivery carriers for controlled drug delivery [14, 15]. They have been reported to release drug at predetermined rate for sustained period of time at spatial location [16, 17]. Smart hydrogels are being used to carry out the same purpose by triggering drug release with the help of certain stimuli in which sensor properties of the polymers undergo into phase transitions in response to different environmental conditions [18]. These stimuli may include pH, temperature, light, electric field, ions, sound etc. [14].

HEMA is a synthetic monomer, being known, for its high mechanical strength and resistance to the chemical and microbiological degradation. Different ionic monomers can be integrated into it to achieve significant changes in its swelling properties and drug release by promoting pH-sensitivity [19]. Due to its biocompatible nature, it has been implied in drug delivery, implants, cell immobilization and contact lenses [20].

Flurbiprofen is a propionic acid derivative of non-steroidal anti-inflammatory pharmacological agents' class and being indicated in different clinical inflammatory states, pain and arthritis conditions. Due to its plasma half-life of 3-6 hours, it is frequently administered [21, 22]. This frequent administration leads to different systemic gastric side effects due to absorbance at upper gastrointestinal region [23].

This research work is aimed at synthesizing HEMA based hydrogels for the controlled release of non-steroidal anti-inflammatory model drug Flurbiprofen. For the same purpose, HEMA was copolymerized with methacrylic acid by crosslinking with EGDMA to synthesize p(HEMA-co-MAA) hydrogels for pH-sensitive triggering of drug as well as site-specific targeting for masking of Flurbiprofen from gastric side effects. In this work, copolymerization process has been optimized with suitable proportion of monomers with benzoyl peroxide as initiator to introduce copolymeric network for controlled delivery of Flurbiprofen.

A simplified process has been developed that is modification of previously reported methods. Previously, HEMA and MAA combination has been used to prepare cross linked structures with various synthesis processes in different ratios [24-31] while in this study HEMA/MAA combination is crosslinked with a simplified procedure and optimized for loading of less water soluble drug Flurbiprofen. The developed networks have advantages of controlled and pH sensitive drug release that would be contributory work to solve problems related with oral administration of this commonly analgesic agent.



Both the monomers used in this preparation, 2-hydroxyethylmethacrylate and methacrylic acid, were purchased from Merck, Germany. According to the manufacturer, HEMA was being stabilized with hydroquinone monoethyl ether for synthetic purpose. EGDMA and benzoyl peroxide were obtained from Sigma-Aldrich UK and Flurbiprofen was received as a kind gift from Global Pharmaceuticals Pvt. Ltd., Pakistan. All the chemicals used, were of analytical grade while deionized water, being used in the process, was distilled in Pharmaceutics Research Lab., the Islamia University of Bahawalpur.

Method of preparation

Copolymeric network of p(HEMA-co- MAA) was synthesized through free radical polymerization process. Measured quantity of HEMA (10 g/100 g) was diluted with deionized distilled water and was stirred at room temperature. Benzoyl peroxide was dissolved in methacrylic acid at a concentration of 1% of methacrylic acid. Both solutions were mixed homogeneously and EGDMA (0.1 mol% of methacrylic acid) was added finally to initiate crosslinking. After stirring of solution, it was carefully transferred to pyrex glass tubes having 16 mm internal diameter and 150 mm length. Dissolved oxygen was being removed from the final polymeric solution by introduction of nitrogen gas stream acting as free radial scavenger and glass tubes were then placed in the water bath.

Temperature of water bath was gradually increased to avoid bubble formation by sequential manner, in a way that reaction mixtures were kept for 4 hours at 55C, for 6 hours at 60C and for 12 hours at 65C. Glass tubes were taken out of the water bath followed by cooling at room temperature. Hydrogels were then cut into discs (8mm in length) and were washed by 50% v/v ethanol-water mixture to remove any unreacted monomer, initiator or cross linker. Discs were then air dried at room temperature for 24 hours and subsequently for 7 days in vacuum oven. Chemical structure of monomers, crosslinkers and their presumptive resultant structure is listed in Table-1.


Fourier Transform Infrared Spectroscopy (FTIR)

In the present study, attenuated total reflectance (ATR) technology along with OPUS data collection software was executed to encompass fourier transform infrared (FTIR) spectra of the required sample employing Bruker FTIR (Tensor 27 series, Germany). The samples evaluated were HEMA, methacrylic acid, EGDMA, p(HEMA-co- MAA) polymer, Flurbiprofen and Flurbiprofen loaded HEMA based polymer. Samples in solid/liquid form were placed individually on pike miracle ATR cell covering the ZnSe crystal surface, followed by rotation of assembly to form compact mass. Empty cell plate scan was taken before analysis of any sample whose spectra was recorded by the above procedure and scanned in a range of 4000 cm-1 650 cm-1.

Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) p(HEMA-co-MAA) discs were first crushed and then sieved through mesh no. 40. 0.5-5 mg of sample was taken in aluminum crucible of size 45 l for TGA and heated from 25-500C at a rate of 20C/min under 20 ml/min stream of N2 purge. Similarly for DSC, 0.5-3 mg of sample was placed on aluminum lid and was analyzed from 0-400C at heating rate of 20C/min.

Table-1: Chemical structure of monomers, crosslinker and presumptive crosslinked structure of synthesized hydrogels

###Monomer/Polymer###Abbreviation###Chemical Structure

###Hydroxyethyl methacrylate###HEMA

###Methacrylic acid###MAA

Ethylene glycol di-methacrylate###EGDMA

Crosslinked poly(hydroxyethyl###p(HEMA-co-

methacrylate-co-methacrylic acid)###MAA)

Swelling Ratios

Dynamic swelling and equilibrium swelling ratios of p(HEMA-co-MAA) hydrogel were determined by using 100 ml 0.1M HCl of pH 1.2 and 100 ml 0.2M phosphate buffer solution having pH 7.4. Dried discs of hydrogels were weighed on microbalance before immersing in the above mentioned solutions to swell at room temperature. Swelling readings were taken at different time intervals till its equilibrium swelling mass. At every interval, excess of water was removed with bloating paper. Dynamic swelling ratio was measured with the following equation [32].


where Wh shows swollen gel's weight at time t while Wd shows initial weight of dried hydrogel disc.

Swelling ratios were recorded throughout a week regularly till discs achieved constant weight. Equilibrium swelling ratio was then figured out with the following equations [32].


where Md represents weight of dried hydrogel, Ms represents swelling at any time interval while Meq shows the weight of hydrogel at equilibrium swelling time.

Drug loading

Flurbiprofen is poorly water soluble drug but it shows higher solubility in buffered solution [33]. p(HEMA-co-MAA) hydrogels were loaded by diffusion process in Flurbiprofen solution (0.5%) in phosphate buffer having pH 7.4. Discs were kept in the drug solution for 72 hours before they were taken out and washed with distilled water in order to remove any excess drug. Drying of loaded discs was carried out at room temperature followed by drying at 40C in vacuum oven. Percent of drug loaded in hydrogel disc was determined by the following method [34]:

Total drug quantity = WD Wd (4)

While, percent of drug loaded was evaluated as following [35]:


Wd is the weight of dried hydrogel before loading.

Drug release studies

Drug release from Flurbiprofen loaded HEMA-co-methacrylic acid hydrogel discs was assessed by specifications of United States Pharmacopeia (USP), dissolution apparatus type paddle method (Curio; DL-0609) and UV-Visible spectrophotometer (UV- 1601, Shimadzu). Hydrogels discs were immersed in two separate 900 ml dissolution media consisting of 0.1M HCl having pH 1.2 and 0.2M phosphate buffer having pH 7.4. Stirring of medium was set at paddle's rotation speed of 50 rpm while temperature was maintained at 37C 0.5C. 5 ml solution was extracted out at different time intervals and replaced through fresh 5ml medium at each interval to maintain the volume and sink condition. Flurbiprofen release was then evaluated through UV-Visible spectrophotometer at 247 nm. In Vitro release studies were performed in triplicate.

Release kinetics

Different models were applied to analyze the release kinetics of p(HEMA-co-MAA) hydrogels through different formulas as under:

Zero order release kinetic model,


First order release kinetic model,


Higuchi release kinetic model,


Hixon-Crowell release kinetic model,


Korsmeyer-Peppas release kinetic model,


Surface Morphology

Scanning electron microscopy Quanta 400 SEM (FEI Company, Cambridge, UK) has been used to study the surface morphology of hydrogel networks. Optimum sized dried discs were prepared to fix on a double-adhesive tape stuck to an aluminum stub. The stubs were coated with gold to a thickness of ~300 A under an argon atmosphere using a gold sputter module in a high-vacuum evaporator. Samples were randomly scanned and photomicrographs were recorded at different magnification levels to reveal surface morphology.

Results and discussion

Physical shape of the hydrogels

p(HEMA-co-MAA) copolymeric network chains were synthesized by crosslinking HEMA and methacrylic acid to form stable networks with milky white colored hydrogels through free radical polymerization process. Milky white color was changed to transparent one after drying phase. Stability and mechanical strength of the crosslinked hydrogels was confirmed when it retained its physical shape after swelling and drug loading process, showing no signs of disintegration.

Structural analysis by FTIR

HEMA spectrum gives characteristic peak of C=O at 1717 cm-1, observed as doublet spectral peak due to intra- and intermolecular hydrogen bonding while peak at 1636 cm-1 due to absorption indicates C=C methacrylate vibration as shown in Fig. 1. 1440-1470 cm-1 range displays asymmetrical methyl bending (CH3) while a sharp peak at 1163cm-1 is attributed to C-O absorption band. Methacrylic acid spectrum shows asymmetric stretching of methyl C-H bond by giving peak at 2987 cm-1. Another Peak at 1698 cm-1 shows stretching vibration band of C=O showing carboxylic acid group while peak at 1636 cm-1 shows stretching of C=C group.

Weak stretching band of carboxylate ion is represented by peak in a range of 1430-1460cm-1. The resultant crosslinked polymer of p(HEMA/MMA) display peaks, which were different to the individual monomers (HEMA and methacrylic acid). A peak at 1721 cm-1 shows absorption band of carbonyl group (C=O) indicating esterification between HEMA and methacrylic acid while a peak at 1163 cm-1 shows stretching of C-O-C group. This resultant spectrum thus reveals cross linking of HEMA and methacrylic acid. Flurbiprofen shows characteristic peak at 1696.19 cm-1 in native position while after loading in p(HEMA-co-MAA) hydrogels it shows peak at 1698.76 cm-1 due to carbonyl stretching vibration band. Similarly, it shows hydroxyl group stretching through peaks ranging from 2828.44 cm-1 to 2999.34 cm-1 while shows hydrogen bonding from 1700 cm-1 to 3050 cm-1.

It is also depicted from the FTIR spectrum of drug loaded p(HEMA-co-MAA) hydrogels that there is no sign of interaction between polymer and drug, showing stable crosslinked network.

Thermal Analysis

Thermal behavior of synthesized hydrogel was evaluated by TGA and DSC to determine the thermal stability. TGA thermogram of p(HEMA-co- MAA), as given in Fig. 2, shows degradation in three different stages. In the first phase, mass loss of about 8 % occurs which can be attributed to the evaporation of water molecules. In second stage, first endothermic peak occurs at round about 220C and ends at 390C. A sharp kink at 400C represents the third and final decomposition stage with a curve ranging from 400C to 450C and a mass loss of about 60%. These high temperature degradation depicts high stability behavior of p(HEMA-co-MAA) hydrogels.

DSC thermogram, as given in Fig. 3, shows first endothermic peak at 75C which is being attributed to the initial loss of water molecules. Decomposition starts at 200C i.e. melting temperature and ends at 450C which is similar to the TGA thermogram. Thermal analysis of p(HEMA-co- MAA) indicates a strong and stable network for the controlled delivery of pharmacological agents to the body sites.

Swelling studies

Fig. 4 represents dynamic swelling index of p(HEMA-co-MAA) hydrogels at pH 1.2 and pH 7.4 with respect to time. p(HEMA-co-MAA) hydrogels showed pH dependant swelling behavior as significant difference was observed in swelling coefficient values of the hydrogel formulation with respect to time as shown in Fig. 4. It was observed that synthesized hydrogels were in collapsed state at pH 1.2 while it swelled to highest degree at pH 7.4. Elaborating characteristics of the p(HEMA-co-MAA) hydrogels, HEMA contributed to the main interactive part with water through its hydrophilic pendent groups. Fig. 4 also confirmed the variable ionization of carboxylic functional groups (correlated with methacrylic acid) with increase in pH as equilibrium and dynamic swelling ratios were found high in phosphate buffer solution with a pH 7.4 as compared to its swelling ratios in 0.1M HCl with pH 1.2.

These higher swelling ratios at higher pH as compared to lower pH shows greater ionization and functional group's electrostatic repulsion of the above synthesized anionic pH sensitive hydrogels at higher pH. It also verifies that pKa of hydrogels is higher than pH 1.2 which plays an important role in the ionization of any species. From this pH dependant swelling behavior, we can interpret that the above synthesized hydrogel remains a potential candidate for pH responsive drug delivery system because it can exhibit an excellent biological on-off mechanism due to the environmental change in physiological media.

Drug loading and in-vitro drug release behavior

Flurbiprofen was used as a model drug for loading into p(HEMA-co-MAA) hydrogels. Flurbiprofen is an NSAID that causes gastric problems that's why it was incorporated in pH sensitive hydrogels to minimize its gastric side effects. Drug loading was calculated as 69.739 mg/g of a hydrogel disc. Fig. 5 shows the Flurbiprofen release rate from p(HEMA-co-MAA) hydrogels with respect to time. Significant difference was observed in the amount of drug released from p(HEMA-co- MAA) hydrogels at two different pH.

There is a clear depiction of less Flurbiprofen release at pH 1.2 as compared to pH 7.4 since only 16.260% drug was released at pH 1.2 while 100% drug release was observed at pH 7.4 after 24 hours of in-vitro release study. The main reason behind this significant difference in release can be attributed to swelling behavior of hydrogels which showed that drug loaded hydrogel disc was in collapsed state at pH 1.2 while at pH 7.4, it swelled significantly releasing drug through diffusion process. It has been observed that pH was the main factor in drug release behavior of p(HEMA-co-MAA) hydrogels. Stomach pH ranges from pH 1.2-2.0 while small intestine pH is round about 7.0, that's why p(HEMA-co-MAA) hydrogels can act as a promising pH sensitive drug delivery system for the delivery of Flurbiprofen.

Release kinetics models

p(HEMA-co-MAA) hydrogels were subjected to different release kinetic models including zero order, first order, Higuchi model and Korsmeyer Peppas model as shown in Table-2. It was found that p(HEMA-co-MAA) hydrogels followed zero order release pattern as it showed greater agreement with regression co-efficient (R2) of 0.937. Higuchi model displayed a linear fit towards the regression line having R2 of 0.996, showing the release behavior of synthesized hydrogels adjusted to the matrix system [16].

Korsmeyer Peppas method is another comprehensive model to explain and discuss the release kinetics of controlled release formulations being represented by "n" which is release exponent and classifies the mode of transport exhibited by the system. According to this model, when "n = 0.5", then system follows fickian diffusion, when "n greater than 0.5 and less than 1.0", system follows non-fickian diffusion, when "n = 1.0" shows case II transport while "n greater than 1.0" follows super case transport mechanism. p(HEMA-co-MAA) hydrogels followed the nonfickian diffusion behavior as "n" value is 0.621, showing both diffusional and relaxational release behavior where relaxational behavior is due to change from glassy to rubbery nature and stresses formed during swelling mechanism [39].

Surface Properties

Crosslinked polymeric hydrogel samples were scanned under SEM to evaluate its surface characteristics. SEM images of copolymeric structure have been shown in Fig. 6. p(HEMA-co-MAA) hydrogels samples showed less porous structure and dense mass. These properties support the high crosslinking between two monomers HEMA and MAA made it highly dense and stable network.

!!Table-2: Drug release kinetic models of p(HEMA-co- MAA) hydrogels. Batch Code P(HEMA-c0-MAA) hydrogels k0 3.454Zero order R2 0.937First order k1 0.032 R2 0.779 kH 19.96Higuchi R2 0.996Hixon Crowel KHC 0.086 R2 0.841 N 0.621Korsmeyer Peppas R2 0.981


Chemically crosslinked p(HEMA-co-MAA) hydrogel was successfully synthesized through free radical polymerization process. pH dependent swelling behavior and pH-sensitive in-vitro drug release studies confirm the pH responsive nature of the above mentioned hydrogels. Another major advantage of such hydrogel system is the use of HEMA which is being known for its biocompatible nature. Hence, p(HEMA-co-MAA) hydrogel drug delivery system remains a potential candidate for controlled release of different pharmacological agents.


Authors are pleased to express their gratitude for the Islamia University of Bahawalpur to provide financial support.


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Date:Oct 31, 2015
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