carboxymethyl cellulose networks formed by gamma irradiation

ARTICLE IN PRESS Radiation Physics and Chemistry 79 (2010) 725–730

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Radiation Physics and Chemistry journal homepage: www.elsevier.com/locate/radphyschem

Swelling and drug release properties of acrylamide/carboxymethyl cellulose networks formed by gamma irradiation Horia M. Nizam El-Din a, Safaa G. Abd Alla b, Abdel Wahab M. El-Naggar b,n a b

Polymer Chemistry Department, National Center for Radiation Research and Technology, P.O. Box 29, Nasr City, Cairo, Egypt Radiation Chemistry Department, National Center for Radiation Research and Technology, P.O. Box 29, Nasr City, Cairo, Egypt

a r t i c l e in fo

abstract

Article history: Received 2 November 2009 Accepted 11 January 2010

Hydrogels based on acrylamide monomer (AM) and different ratios (5–20 wt%) of carboxymethyl cellulose (CMC) were synthesized by gamma irradiation. The hydrogels were characterized in terms of gel content, swelling and drug release characters. The effect of temperature and pH on the degree of swelling was also studied. The results showed that the gel fraction of AM/CMC hydrogels decreases greatly with increasing the contents of CMC in the initial feeding solution. The kinetic study showed that the swelling of all the hydrogels tends to reach the equilibrium state after 5 h. However, the swelling of AM/CMC hydrogels was greater than the hydrogel based on pure AM. On the other hand, it was found that the swelling of all the hydrogels changes within the temperature range 30–40 1C and within the pH range 4–8. The AM/CMC hydrogels was evaluated for the possible use in drug delivery systems. In this respect, the release properties of methylene blue indicator, as a drug model, was investigated. It was found that the percentage release from the hydrogels increase with time to reach  80% after 3 h at pH of 2 compared to  100% at pH of 8. & 2010 Published by Elsevier Ltd.

Keywords: Gamma irradiation Swelling behaviour Temperature pH Drug release

1. Introduction Natural polymers, particularly polysaccharides, have found biomedical and biotechnological applications in the field of drug delivery because they are available and more susceptible to biodegradation (Adriano et al., 2006; Wach et al., 2001). However, polysaccharides cannot be used alone due to the higher solubility in aqueous medium leading to premature release of drugs. Thus, particular attention has been paid to modify the usability of polysaccharides, especially carboxymethyl cellulose (CMC), in the preparation of responsive hydrogels by different methods. Novel semi-IPN nanocomposite hydrogel (CMC/PNIPA/Clay hydrogel) based on linear sodium carboxymethyl cellulose (CMC) and poly(N-isopropylacrylamide) (PNIPA) crosslinked by inorganic clay was prepared (Pourjavadi et al., 2007). Carboxymethyl chitosan (CMC) hydrogel beads were prepared by crosslinking with Ca2 + , in which the pH-sensitive characteristics of the beads were investigated by simulating gastrointestinal pH conditions (Liu et al., 2007). Synthesis and characterization of novel CMC-gpoly (acrylic acid-co-2-acrylamido-2-methylpropanesulfonic acid)/silica gel composite was reported (Pourjavadi et al., 2008). Composite gels were prepared by adding bentonite or its

n

Correspondence author. Tel.: + 20 2 2727413; fax: + 20 2 2749298. E-mail address: [email protected] (A.W. El-Naggar).

0969-806X/$ - see front matter & 2010 Published by Elsevier Ltd. doi:10.1016/j.radphyschem.2010.01.011

acid-activated derivative into the carboxymethyl cellulose (CMC) gel, and the resulted products were characterized by infrared spectroscopy (Li et al., 2009). Carboxymethyl cellulose (CMC)/poly(vinyl alcohol) (PVA) biocompatible blend hydrogels showed pH responsive characters (Xiao et al., 2009). A semiinterpenetrating polymer network (IPN) of carboxymethyl cellulose (CMC) and crosslinked poly(acrylic acid) (PAA) has been prepared and its water-sorption capacity has been evaluated as a function of chemical architecture of the IPN, pH, and temperature of the swelling medium (Bajpai and Mishra, 2004). Attempts have been made to crosslink carboxymethyl cellulose by ionizing radiation. It was reported that CMC has a poor efficiency of crosslinking (Balser, 1985). Radiation crosslinking of carboxymethyl cellulose (CMC) with a degree of substitution (DS) from 0.7 to 2.2 was investigated in solid-state and aqueous solutions at various irradiation doses (Fei et al., 2000; Yoshii et al., 2003). It was found that the DS and the concentration of CMC in aqueous solution had a remarkable affect on the crosslinking. Irradiation of CMC, even with a high DS, 2.2 in solid state, and a low DS, 0.7 in 10% aqueous solutions, resulted in degradation. However, it was found that irradiation of CMC (20%) with a relatively high DS, 1.32, led to crosslinking in aqueous solution, and giving the highest gel fraction. Polysaccharides such as cellulose, starch, chitin/chitosan and their water-soluble derivatives have been known as degradable type polymers under action of ionizing radiation (Wach et al., 2003). It was found that high

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concentrated (more than 10%) water-soluble polysaccharides derivatives such as carboxymethyl cellulose (CMC), carboxymethyl starch (CMS) and carboxymethyl chitin (CMCT) and carboxymethyl chitosan (CMCTS) would undergo crosslinking by radiation. It was assumed that radiation formation of hydrogels of these polysaccharides derivatives were mainly due to the mobility of side chains. Biocompatible and biodegradable hydrogels based on carboxymethyl cellulose (CMC) and poly(ethylene glycol) (PEG) was prepared as physical barriers for preventing surgical adhesions (Lee et al., 2005). Synthesis and characterization of novel gels based on carboxymethyl cellulose/acrylic acid prepared by electron beam irradiation was reported (Said et al., 2004). In the present work, hydrogels based on gamma irradiation of aqueous solutions composed essentially of acrylamide monomer (AM) and different ratios of carboxymethyl cellulose (CMC) were prepared. These hydrogels may produce materials with electrolyte properties based on the carboxyl groups of CMC and the ionized amide groups of AM. The effect of temperature and pH on the swelling behaviour in water of AM/CMC hydrogels was investigated. The possible application of AM/CMC hydrogels in the field of drug delivery taking methylene blue indicator as a drug model was also studied.

2. Experimental 2.1. Materials Carboxymethyl cellulose (CMC) used in this study was a laboratory grade chemical obtained from Aldrich Chemical Co. (Milwaukee, WI, USA), and used as received. Acrylamide monomer (AM), laboratory grade, was purchased from Merck, Germany and used without further purification. A laboratory grade of N,N’methylenebisacrylamide (MBAAm) was used as a crosslinking enhancer agent and was obtained from Aldrich Chemical Co. (Milwaukee, WI, USA). 2.2. Preparation of AM/CMC hydrogels The hydrogels were prepared by dissolving separately acrylamide monomer (AM) together with different contents of the crosslinking agent MBAAm and different ratios (5–20%) of carboxymethyl cellulose (CMC) in distilled water. The AM and CMC solutions were then mixed with continuous stirring until complete miscibility was achieved. The solutions were then poured into quick-fit tubes and the air was removed by bubbling nitrogen gas for 5 min at least. Irradiation of AM/CMC solutions to the required doses was carried out at a dose rate of 8.86 kGy/h in the 60Co gamma cell (made in Russia). 2.3. Determination of gel fraction Samples of the prepared hydrogels were accurately weighed (W0) and then extracted with distilled water using a Soxhlet system and then dried in a vacuum oven at 80 1C to a constant dry weight (W1). The gel fraction is calculated according to the following equation:
Gel fraction ð%Þ ¼ W1 =W0  100 2.4. Swelling studies Swelling study was conducted on AM/CMC hydrogels as a function of time, in which a dry weight of insoluble hydrogel (W1) was immersed in water at 25 1C for different intervals of time

durations up to 24 h. After each time interval, the sample was withdrawn and blotted on filter paper to remove excess water and weighed (wt), in which the degree of swelling is calculated according to the following equation:   Degree of swelling ð%Þ ¼ ðWt W1 Þ=W1 100 The swelling character of AM/CMC hydrogels in different external environments was also studied as a function of temperature and pH. The hydrogels were first immersed in water at 25 1C to the equilibrium state and weighed (WE). The hydrogels, in the equilibrium state, were then immersed in water at different temperatures (10–501C) and different pH values (1–8) for 24 h. After each temperature or pH, the sample was withdrawn and blotted on filter paper to remove excess water and weighed (WT) and WpH, respectively. The degree of swelling in each case is calculated as follows:
Swelling ð%Þ at temperatures ¼ WT =WE 100
Swelling ð%Þ at pH ¼ WpH =WE 100 2.5. Drug release study For the investigation of drug release properties of AM/CMC hydrogels, methylene blue (MB) was used as a model drug. Dry sample pieces (0.5 g) of hydrogels were loaded with MB by immersion into aqueous solutions of different concentrations of methyl orange (g/l) for 24 h. The release of MB from hydrogels was measured by placing the gels in a vessel containing 20 ml of different buffer solutions at a constant shaking rate. At each time interval, aliquots of 3 ml were drawn from the medium to follow the release of MB and returned into the vessel so that the solution volume is kept constant. Methylene blue release was determined by a spectrophotometeric method using a Unicam 8625 UV/ visible spectrophotometer at lmax 460 nm.

3. Results and discussion 3.1. Formation of AM/CMC hydrogels Natural polymers such as sodium alginate (AG) and carboxymethyl cellulose (CMC) often undergo oxidative degradation upon exposure to gamma irradiation. In previous work, dealt with the synthesis of hydrogels based on PVA and AG by electron beam irradiation, it was found that the gel fraction of PVA was decreased from 90% to 65% by incorporating 40% AG (Nizam ElDin et al., 2007). The reduction in gel fraction was determined to be due the existence of majority of AG in a non-crosslinked state. In the present work, methylenebisacrylamide (MBAAm) was used as a crosslinking agent to enhance the crosslinking of CMC and to avoid using higher doses, which may cause oxidative degradation to CMC component. Meanwhile, 30 kGy as a dose was chosen for making hydrogels for all studies. The use of crosslinker in situ with ionizing radiation in the preparation of hydrogels was reported in literature (Adem et al., 2009). In this work, interpenetrating networks of poly(acrylic acid) (PAAc) and poly(N-isopropylacrylamide) (PNIPAAm) were synthesized by electron beam irradiation in the presence of the crosslinker methylenebisacrylamide (MBAAm). Fig. 1(A) shows the gel fraction of AM/CMC hydrogels of different ratios formed at a dose of 30 kGy without using crosslinking agent. It can be seen that the gel fraction decreases greatly by increasing the CMC ratio. In this respect, the use of 20% of CMC in the initial feeding solutions results in a decrease of gel fraction of the hydrogels, which contains 100% of AM from 96%

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727

3000

2500

90 without crosslinking agent

80

2000

70 60 50

100/0

95/5

90/10

85/15

80/20

Swelling (%)

Gel fraction (%)

100

1500

1000 AM/CMC (100/0%) AM/CMC (95/5%) AM/CMC (90/10%)

AM/CMC ratio (%)

100

500

Gel fraction (%)

95 90

0

85

5

10

15

20

25

30

Time (h)

80

AM/CMC (100/0%) AM/CMC (95/5%) AM/CMC (90/10%)

75 70

0

0.03

0.05

0.08

Crosslinking agent (g/ g AM) Fig. 1. (A) Gel fraction (%) of PAM and AM/CMC hydrogels of different ratios, prepared by gamma irradiation at a dose of 30 kGy (without crosslinking agent); (B) gel fraction of same hydrogels, prepared by using different contents of MBAAm and at the same dose.

(Fig.1A) to 61%. When an aqueous solution of acrylamide monomer is exposed to gamma irradiation, free radicals are formed on the carbon atoms. The radiolysis products of water, especially hydroxyl free radicals, are also very effective in generating free radicals on AM monomer and CMC polymer. As shown in Fig. 1(B), the gel fraction of AM/CMC hydrogels was increased greatly by increasing the content of MBAAm. In this regard, the use of 0.08 g/g AM of MBAAm results in an increase of gel fraction of the hydrogel, which contains 10% of CMC from 70% (Fig. 1A) to 85%. This finding indicates that the crosslinking agent MBAAm enhanced the crosslinking of AM by gamma irradiation. The crosslinking enhancers during irradiation is reported, in which these materials do not directly enter into crosslinking reactions but enhance secondary reactions that lead to the formation sites (Shultz, 1985). 3.2. Swelling kinetic studies Fig. 2 shows the swelling kinetics in water at 25 1C (pH= 7) for AM and AM/CMC based hydrogels formed by gamma irradiation at a dose of 30 kGy. It can be seen that the degree of swelling of all the hydrogels increases greatly within the initial time of swelling up to 5 h. While the degree of swelling of the hydrogel based on pure AM tends to increase, with less extent, up to 24 h, the hydrogels based on AM/CMC tends to reach the equilibrium state after 5 h and up to 24 h. However, AM/CMC based hydrogels displayed higher degree of swelling than the hydrogel based on pure AM monomer. However, the degree of swelling of AM/CMC hydrogels displayed a systematic trend in accordance with composition, in which the degree of swelling increases with increasing the ratio of CMC. The higher swellability of AM/CMC hydrogel compared to that hydrogel based on pure AM may be

Fig. 2. Swelling-time dependency in water at 25 1C for the hydrogels based on pure AM and AM/CMC hydrogels formed by gamma irradiation at a dose of 30 kGy.

attributed to the higher hydrophilic character of CMC in the networks. The nature of water diffusion into AM/CMC hydrogels was determined by applying Fick’s law according to the following equation (Roy et al., 2009): F ¼ Wt =We ¼ Kt n Or ln F ¼ ln K þn ln t where Wt and We represent the amount of water absorbed by the hydrogel at time t (seconds) and at equilibrium, K is a constant characteristic of the structure of the networks and n is an exponent determines the mode of water diffusion. When ln F is plotted against ln t, it gives a straight line from which the intercept determines the constant K and the slope gives the number n. In this regard, a value of n =0.5 indicates a Fickian diffusion mechanism in which the sorption is diffusion controlled, whereas a value of 0.5 on o1 indicates an anomalous non-Fickian type diffusion and contributes to the water-sorption process. Fig. 3 shows the application of the above equation to the AM/CMC hydrogels and the calculation of the diffusion parameters are presented in Table 1. The data indicate that all the hydrogels display a non-Fickian type of diffusion. Therefore, it can be concluded that the diffusion of water into the hydrogel networks is not controlled but it depends on water sorption process, which in turn depends on the structure and pathways of water through the networks. In addition, it can be seen that the difference of n parameter for the hydrogel based on pure 100% AM and 95% AM is not as significant as that between 95% AM and 90% AM. These findings indicate the contribution of relatively higher ratios of CMC in water sorption process that creates extra water pathways. 3.3. Effect of temperature and pH on swelling The degree of swelling of previously equilibrated PAM and AM/ CMC hydrogels was investigated as a function of temperature as shown in Fig. 4. It can be seen that there are nearly no significant changes in swelling for the hydrogel based on pure 100% AM over

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the entire temperature range 10–50 1C, except the swelling tends to increase with increasing temperature. However, the swelling of AM/CMC hydrogels displayed different temperature response. Positive increase of swelling is calculated to be 50% and 16% within 10-301C temperature segment (based on swelling at 101C) for the hydrogels, contain 5 and 10% of CMC, respectively. Within 30-401C temperature segment, the swelling of same hydrogel compositions, displayed negative decrease of  15% and 19%, respectively. This behaviour of AM/CMC hydrogels can be attributed to the increasing amount of the bound fluid in hydrogels. Above 30 1C, the swelling of the hydrogels starts to decrease. The hydrogen bonding force was reduced and the bound fluid becomes non-binding fluid, free fluid, which can move out of the polymeric networks (Tomic et al., 2007). It appears that two competitive phenomena determine the swelling behaviour of hydrogels. As the temperature rises, the hydration capacity of CMC increases whereas that of PAM decreases as segments collapses (Verestiuc, et al., 2004). Fig. 5 shows the equilibrium swelling (ES) as a function of pH values for hydrogels based on pure 100% AM and AM/CMC hydrogels of different ratios. It can be seen that there is no significant change of ES within the pH range from 1.3 to 4.7. However, the effect of pH is very clear within the pH range from 4.7 to 8.0, in which it increases sharply at pH of 6.7 and then decrease abruptly at pH of 8.0. In addition, it is clear that the pHsensitivity of AM/CMC hydrogels depends largely on CMC component and it increases with increasing the CMC ratio in the

3500 3000 2500 Swelling (%)

728

2000 AM/CMC (100/0%) AM/CMC (95/5%) AM/CMC (90/10%)

1500 1000 500 0

0

10

20

30

40

50

60

Temperature (°C) Fig. 4. Effect of temperature on the equilibrium swelling for the hydrogels based on pure AM and AM/CMC hydrogels formed at a dose of 30 kGy of gamma irradiation.

3000 0.0

2500

AM/CMC (100/0%) AM/CMC (95/5%)

-0.2

AM/CMC (90/10%)

Swelling (%)

2000

ln F

-0.4

-0.6

1500

1000

AM/CMC (100/0%) AM/CMC (95/5%) AM/CMC (90/10%)

500

-0.8

0 -1.0

4.0

4.4

4.8

5.2

5.6

6.0

0

2

4

ln t Fig. 3. Plots of ln F against ln t for the hydrogels based on pure AM and AM/CMC hydrogels formed at a dose of 30 kGy of gamma irradiation.

6

8

10

pH Fig. 5. Effect of pH values on the swelling in water at 25 1C for the hydrogels based on pure AM and AM/CMC hydrogels formed at a dose of 30 kGy of gamma irradiation.

Table 1 Water diffusion and release kinetic parameters AM/CMC hydrogel composition

AM/CMC (100/0%) AM/CMC (95/5%) AM/CMC (90/10%)

Swelling diffusion kinetics

Drug release kinetic

n

pH= 2

0.43 0.39 0.29

K

0.077 0.108 0.198

pH =8

n

K

n

K

0.29 0.26 0.23

0.179 0.232 0.269

0.29 0.30 0.34

0.182 0.182 0.172

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5

729

100 pH = 2 80

3

Release (%)

Absorbance

4

2

60

AM/CMC (100/0%) AM/CMC (95/5%) AM/CMC (90/10%)

40

1 20

0 0.00

0.01

0.02

0.03

0.04

0.05

0.06

0

Methylene blue concn. (g/l)

0

1

2

3

4

Fig. 6. Absorption at lmax of 460 nm of different concentrations of methylene blue.

feed solutions. At low pH, most carboxymethyl groups in CMC are in the form of COOH. In an acidic medium, no dissociation occurs, the gel structure is devoid of charge, and collapsing is observed because of hydrogen bonding formation. As the pH of the medium increases, the carboxylic groups become ionized, and the resulting electrostatic repulsion in the network causes the hydrogel to swell. The sudden drop in ES observed at pH 8 may be due to the known sensitivity of CMC hydrogels to the presence of salts in the buffer solutions (Wach et al., 2002).

From this relation, a concentration of unknown sample can be determined. The percentage release of MB was carried out as a function of time at different pH values by 1 g of AM/CMC hydrogels and is shown in Figs. 7 and 8. It can be seen that the percentage release from the hydrogel increases with time to reach 80% after 3 h at pH of 2 compared to  100% at pH of 8. This suggests that the drug release properties of AM/CMC hydrogels are not exactly pH sensitive. This is because the release of MB from these hydrogels is close. However, at high pH value, the swelling is higher than that at pH 2, i.e. the pore size at pH 8 is much higher than that at pH 2 leading to the highest swelling of the networks and resulting in more drug release.

25

Fig. 7. Release kinetics at pH 2 of methylene blue (MB) from AM/CMC hydrogels formed by gamma irradiation at a dose of 30 kGy.

120 pH = 8 100

80 Release (%)

3.4. Drug release study To evaluate the AM/CMC hydrogels for the possible use in drug delivery systems, methylene blue (MB) indicator was used as drug model for studying the drug release behaviour. It was observed that the loading of MB has reached the equilibrium state after 3 h, after which no more MB was loaded. The release of adsorbed drug occurs after water penetrates the polymeric networks and this is followed by diffusion along the aqueous pathways. Thus, drug release is basically related to the swelling characters of hydrogels. In order to determine the release of MB, a standard curve representing the absorbance at lmax of 460 nm of different concentrations of MB was constructed as shown in Fig. 6. The relation correlating this curve is calculated to be
Absorbance ¼ concentration g=L  78:231

5 20 Time (h)

AM/CMC (100/0%) AM/CMC (95/5%)

60

AM/CMC (90/10%)

40

20

0 0

1

2

3

4

5 20

25

Time (h) Fig. 8. Release kinetics at pH 8 of methylene blue (MB) from AM/CMC hydrogels formed by gamma irradiation at a dose of 30 kGy.

The MB transport mechanism from AM/CMC hydrogels was further analyzed according to the Fick’s equation: Mt/Me =ktn, in which Mt/Me is the fraction of drug released (mg/g) at time t (min), K is a constant related to the drug release and n is the diffusion exponent describing the drug release mechanism. The application of Fick’s equation to the MB release from different compositions of AM/CMC hydrogels at different pH values is shown in Figs. 9 and 10. Table 1 shows the kinetic parameters calculated from these figures. When the content of CMC is

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0.0

synthetic/natural polymers to deliver drugs at different external conditions. Even though the presence of carboxymethyl cellulose hindered the formation of complete network structure, it is succeeded to obtain hydrogels. The results show clearly that these hydrogels possessed higher degree of swelling and that the degree of swelling was affected by temperature and pH as external conditions. The prepared hydrogel is a very good drug carrier that it is able to deliver the contained drug to anywhere but it is not a pH sensitive drug carrier. However, may be methylene blue as a drug model is not the right choice, therefore needs further investigations.

pH=2 -0.1 -0.2

ln F

-0.3 -0.4 -0.5

AM/CMC (100/0%) AM/CMC (95/5%) AM/CMC (90/10%)

References

-0.6 -0.7 4.0

4.2

4.4

4.6

4.8

5.0

5.2

5.4

ln t Fig. 9. Plots of ln F against ln t for the release of MB at pH 2 from different compositions of AM/CMC hydrogels formed by gamma irradiation at a dose of 30 kGy.

0.0

pH =8

-0.1

ln F

-0.2

-0.3

-0.4 AM (100%) AM/CMC (95/5%) AM/CMC (90/10%)

-0.5

-0.6 4.0

4.2

4.4

4.6

4.8

5.0

5.2

5.4

ln t Fig. 10. Plots of ln F against ln t for the release of MB at pH 8 from different compositions of AM/CMC hydrogels formed by gamma irradiation at a dose of 30 kGy.

increased in the feed mixture of the hydrogel, there is a decrease in n but still in the non-Fickian range. However, the values of n tend to increase with increasing the pH value indicating that the release of MB tends to be controlled in the range of CMC contents used.

4. Conclusions The present work is undertaken to explore the capability of hydrogels synthesized by gamma irradiation of mixtures of

Adem, E., Burillo, G., Bucio, E., Magan, C., Avalos-Borja, N., 2009. Characterization of interpenetrating networks of acrylic acid (AAc) and N-isopropylacrylamide (NIPAAm) synthesized by ionizing radiation. Radiat. Phys. Chem. 76, 1724–1727. Adriano, V.R., Marcos, R.G., Osvaldo, A.C., Adley, F.R., Edvani, C.M., 2006. Synthesis and characterization of pH-responsive hydrogels based on chemically modified arabic gum polysaccharide. Polymer 47, 2023–2029. Bajpai, A.K., Mishra, A., 2004. Ionizable interpenetrating polymer networks of carboxymethyl cellulose and polyacrylic acid: evaluation of water uptake. J. Appl. Polym. Sci. 9, 2054–2065. Balser, K., 1985. In: Burchard, W (Ed.), Polysaccharides. Springer, Berlin, pp. 84. Fei, B., Wach, R.A., Mitomo, H.M, Yoshii, F., Kume, T., 2000. Hydrogel of biodegradable cellulose derivatives. I. Radiation-induced crosslinking of CMC. J. Appl. Polym. Sci. 78, 278–283. Lee, J.H., Nho, Y.C., Lim, Y.M., Son, Tae-Il, 2005. Prevention of surgical adhesions with barriers of carboxymethyl cellulose and poly(ethylene glycol) hydrogels synthesized by irradiation. J. Appl. Polym. Sci. 96, 1138–1145. Li, J., Lu, J., Li, Y., 2009. Carboxymethyl cellulose/bentonite composite gels: water sorption behavior and controlled release of herbicide. J. Appl. Polym. Sci. 112, 261–268. Liu, Z., Jiao, Y., Zhang, Z., 2007. Calcium-carboxymethyl chitosan hydrogel beads for protein drug delivery system. J. Appl. Polym. Sci. 103, 3164–3168. Nizam El-Din, H.M., Abd Alla, S.G., El-Naggar, A.M., 2007. Swelling, thermal and mechanical properties of poly(vinyl alcohol)/sodium alginate hydrogels synthesized by electron beam irradiation. J. Macromol. Sci. Part A: Pure Appl. Chem. 44, 291–297. Pourjavadi, A., Zohuriaan-Mehr, M.J., Ghasempoori, S.N., Hossienzadeh, H, 2007. Synthesis and super-swelling behavior of hydrolyzed CMC-g-PAN hydrogel. J. Appl. Polym. Sci. 103, 877–883. Pourjavadi, A., Seidi, F., Salimi, H., Soleyman, R., 2008. Grafted CMC/silica gel superabsorbent composite: synthesis and investigation of swelling behavior in various media. J. Appl. Polym. Sci. 108 (5), 3281–3290. Roy, A., Bajpai, J., Bajpai, A.K., 2009. Dynamics of controlled release of chlopyrifos from swelling and eroding biopolymeric microspheres of calcium alginate and starch. Carbohydr. Polym. 76, 222–231. Said, H.M, Abd Alla, S.G., El-Naggar, A.M., 2004. Synthesis and characterization of novel gels based on carboxymethyl cellulose/acrylic acid prepared by electron beam irradiation. React. Funct. Polym. 61, 397–404. Shultz, A.R.,1985. Crosslinking with radiation. In: EPST, Ist ed., vol. 4. pp. 398–414. Tomic, S.L.J., Mic, M.M., Filipovic, J.M., Suljovrujic, E.H., 2007. Swelling and thermodynamic studies of temperature responsive 2-hydroxyethyl ethacrylate/itaconic acid copolymeric hydrogels prepared via gamma radiation. Radiat. Phys. Chem. 76, 1390–1394. Verestiuc, L., Ivanov, C., Barbu, E., Tsibouklis, J., 2004. Dual-stimuli-responsive hydrogels based on poly(N-isopropylacrylamide)/chitosan, semi-interpenetrating networks. Int. J. Pharm. 269, 185–194. Wach, R.W., Mitomo, H., Yoshii, F., Kume, T., 2001. Hydrogel of biodegradable cellulose derivatives. II. Effects of some factors on radiation-induced crosslinking of CMC. J. Appl. Polym. Sci. 81 (12), 3030–3037. Wach, R.W., Mitomo, H., Yoshii, F., Kume, T., 2002. Hydrogel of radiationinduced crosslinking hydroxypropylcellulose. Macromol. Mater. Eng. 287, 285–295. Wach, R.W, Mitomo, H, Naotsugu, N., Yoshii, F., 2003. Radiation crosslinking of carboxymethyl cellulose of various degree of substitution at high concentration in aqueous solutions of natural pH. Radiat. Phy. Chem. 68, 771. Xiao, C., Li, H, Gao, Y., 2009. Preparation of fast pH-responsive ferric carboxymethyl cellulose/poly(vinyl alcohol) double-network microparticles. Polym. Int. 58, 112–115. Yoshii, F., Long, Z., Wach, R.W., Naotsugu, N., Hiroshi, M., Tamikazu, K., 2003. Hydrogels of polysaccharide derivatives crosslinked with irradiation at pastelike condition. Ion. Radiat. Polym. 208, 320.