INTRODUCTION:

Hydrogels are hydrophilic polymer networks that are able to swell and retain large amount of water without being dissolved. Hydrogels that are able respond to external stimuli are termed as smart, intelligent, stimuli responsive or environmentally sensitive hydrogels which means that they respond reversibly to slight changes in the properties of the medium. The properties can be pH, temperature, ionic strength, illumination or electric field and the responses can be observed by sudden swelling or contraction of the hydrogels. They find a number of application including in pharmaceuticals, biomedicine, bioengineering, agriculture, food industry etc.^1,2

Colon targeted delivery systems have been the focus point of formulation laboratories for the last decades because the colon is considered as suitable site for delivery of both conventional and labile molecules ^3,4 and it is also a site for some specific diseases such as ulcerative colitis, Groin’s disease, bowel cancer, some infections and constipation which require local delivery of the drugs. The colon targeted oral delivery systems require the drug to be protected during gastrointestinal (GI) transit until the dosage forms reach the colon. Various approaches have been used for oral delivery of drugs to the colon, which include time dependant delivery, pH dependant systems and delivery systems that utilize bacteria that colonize the colon or enzymes produced by these bacteria to affect drug release. But so far, the pH dependant systems have found practical application. The pH dependant systems are based on the concept that at lower pH the formation of hydrogen bonding in anionic polymers results in stabilization/ compaction of the matrix thereby preventing the release of drug, so that the active agent can bypass the stomach. To realize the above approach acrylic polymers such as Eudragit S, and cellulosics such as hydroxypropyl methylcellulose or cellulose acetate phthalate have been used in past.⁵ Because of their biocompatibility and high hydrophilicity, biopolymers such as starch, cellulose and cellulose derivatives have also been used in controlled release systems. Similarly, poly (acrylic acid) is known to be a good mucoadhesive and may increase the transit time of formulation. The polymers, composed of acrylic acid, have the ability to absorb a large amount of water and are used in many applications including ion exchange resins, personal hygiene products, membranes for hemodialysis, ultrafiltration, and controlled release devices.⁶ However, the use of either the polysaccharides or poly(acrylic acid) alone is not very effective since the swelling properties of the former are pH independent, while the latter tends to be irritant. Therefore, we intended to combine the useful properties of both the components by preparing graft copolymers. In our earlier work ⁷ we have synthesized starch – acrylic acid/ methacrylic acid graft copolymers and studied in vitro release of model drugs from tablets prepared by using these copolymers as matrix.

In present investigation we opted for synthesis of hydrogels compromising Acacia Gum (Gum Acacia) and acrylic acid. Acacia gum (Gum Acacia) is a highly branched, branch-on-branch, complex acidic hetero-polysaccharide with main chain of (1®3)-β-D-galactopyranosyl units and side chains containing L-arabinofuranosyl, L-rhamnopyranosyl, D-galactopyranosyl, and D-glucopyranosyl uronic acid units.⁸ This hydrocolloid is the most widely used natural gum in industry and extensively used in a wide range of application such as confectionery, beverage or liquid flavor emulsions, pharmaceuticals, cosmetic products, inks, etc.⁹ There are very few reports on the synthesis of hydrogels composed of gum acacia and acrylic monomers. M.J. Zohuriaan-Mehr et. al.^8,10 have synthesized hydrogel hybrids composing gum acacia and acrylamide/acrylic acid – potassium acrylate using persulphate/metabisulfite redox initiation. Here, we report on the synthesis of graft copolymer hydrogels by free radical initiated grafting of acrylic acid onto gum acacia using ceric ammonium nitrate as an initiator. Use of ceric ammonium nitrate as an initiator involves formation of radical sites onto polysaccharide backbone¹¹ and minimizes homopolymer formation.¹²

MATERIALS AND METHODS:

Acacia gum (GA) was purchased from Thomas Baker, India, Acrylic acid (AA) (Thomas Baker, India) was freshly distilled under reduced pressure before use. Ceric ammonium nitrate (CAN) (Qualigens, Germany) was dried at 110ºC for 1h. N,N–methylene bisacrylamide (MBAm) (spectrachem, India) and other chemicals were used as received.

Synthesis of hydrogel

Gum Acacia (2g) was dissolved in distilled water with constant stirring for 1h at 70ºC under nitrogen atmosphere. It was allowed to cool and ceric ammonium nitrate (0.005M in 1M HNO₃) was added over a period of 15 minutes, followed by addition of required amounts of distilled acrylic acid and crosslinker N, N–methylene bisacrylamide. The reaction was proceeded under N₂ atmosphere for 3h at 37ºC. After completion of the reaction the hydrogel was washed 2-3 times with distilled water to remove homopolymers, if any, and filtered through sintered crucible. The final product was dried under vacuum until constant weight. A series of hydrogels were prepared by varying the amount of crosslinker (0.5, 2.0 and 5.0 mole %).

IR spectral analysis

IR spectra of gum acacia (GA), poly (acrylic acid) (PAA) and the graft copolymer were taken on Perkin Elmer FTIR spectrum BS spectrophotometer using KBr pellet technique.

Swelling studies

The equilibrium swelling was measured according to a conventional ‘‘tea bag’’ method. The completely dried preweighed hydrogel sample was placed in 200 mL of distilled water and buffer solution of desired pH at 37°C, respectively. The swollen gel was taken out at regular time intervals, wiped superficially with filter paper to remove surface water, weighed, and then placed in the same bath. The mass measurements were continued until the attainment of the equilibrium. The percentage of mass swelling (SM) was determined using the following expression: ^{6, 13}

%SM =Mt - Mo x 100

Where, Mo and Mt are the initial mass and mass at different time intervals, respectively. All the experiments were carried out with three samples and the average values have been reported in the data.

RESULT AND DISCUSSIONS:

Gum acacia-based copolymer hydrogels were synthesized by free radical copolymerization of acrylic acid onto the gum. As the primary objective was to study swelling properties of the copolymer hydrogel, and the swelling characteristics are function of the degree of crosslinking, the copolymerization was carried out in the presence of varying amount, 0.5, 2.0 and 5.0 mole % of N, N–methylene bisacrylamide as the crosslinking agent.

Spectral Analysis

Figure 1 shows the FTIR spectra of the gum acacia (GA) (a), poly (acrylic acid)(PAA) (b), and GA-acrylic copolymer (c). As indicated in Figure 1(c), characteristic bands of both the gum and of the poly(acrylic acid), are present in the spectrum of hydrogel. The strong, broad peak at 3427 cm^–1 is related to the OH stretching of the carboxylic and hydroxyl groups of acrylic and polysaccharide parts. The medium peaks at 1030–1070 cm^–1 , due to stretching vibration of C–O–C and C–O–H bonds, confirm the polysaccharide structure of the hydrogel. The very sharp peak at 1717 cm^–1 is attributed to the carboxyl groups (>C=O stretching) of PAA and the IR spectra also shows a shoulder at 2179 cm^–1, which is due to the presence of the –C–N– group of the crosslinking agent (N,N–methylene bisacrylamide). Since the copolymers had already been extracted to remove the soluble contents, its FTIR analysis proved that it is not a physical mixture but chemical linkages have been formed during the free radical polymerization reaction.

Figure 1: IR spectra of (a) Gum acacia (b) poly (acrylic acid) (c) gum acacia – poly(acrylic acid) graft copolymer hydrogel.

Swelling Kinetics

The swelling characteristics of a crosslinked polymer depend not only on the hydrophilic-hydrophobic balance but also on the degree of crosslinking. The different graft copolymer prepared by varying the mole percent of crosslinking agent are listed in Table 1 along with equilibrium swelling in distilled water and media of pH 1.2 and 7.4. Also, the dynamic swelling in distilled water is shown graphically in Figure 2.

Table No:1 Gum acacia –acrylic acid graft copolymer hydrogels^a

Sr. No	Crosslinker (N,N–methylene bisacrylamide) (mole%)	Equilibrium swelling S_e
Sr. No	Crosslinker (N,N–methylene bisacrylamide) (mole%)	in distilled water	at pH 1.2	at pH 7.4
1	0.5	1010	143	1189
2	2	870	100	677.8
3	5	706	78.84	504.4

a: Gum acacia: 2g, acrylic acid: 4 ml, initiator: ceric ammonium nitrate, (0.005M in 1M HNO3), 10 ml; medium: water, total volume: 100 ml, temperature: 37˚C, time: 3h.

The data indicate that as the mole percent of the crosslinking agent increases, the equilibrium swelling (Table 1) as well as time the amount of water absorbed at different time interval (Figure 2) decreases. This may be attributed to the fact that as the mole percent of crosslinking agent increases, the number of crosslinks per unit volume increases and the chain length between the crosslinks decreases resulting in decrease in the free space available between the crosslinks and thus providing less space for accommodation of water molecules in the networks.⁷

Figure 2: Dynamic uptake of water as a function of time for GA – PAA graft copolymer hydrogels with different degrees of crosslinking.

The pH of the swelling medium plays an important role in influencing swelling behavior of hydrogels. If the hydrogel contains some ionizable groups, which can dissociate or get protonated at some suitable pH of the swelling media, then the degree of swelling of hydrogels undergoes appreciable change with external pH. Figure 3 and 4 depict the dynamic uptake of water by the hydrogels in the buffer media of pH 1.2 and 7.4, respectively, at 37°C. The hydrogel exhibits low swelling in the medium of pH 1.2, and high swelling at pH 7.4. The degree of swelling increases with time until reaches the equilibrium value. The pH dependant swelling can be attributed to the fact that when the hydrogel is allowed to swell in the media of pH 1.2, the –COOH groups present within the network remain almost nonionized, thus imparting almost nonpolyelectrolyte type behavior to the hydrogel. Moreover, there exist strong H–bonding interactions between –COOH groups of acrylic acid and hydroxyl groups of gum acacia, resulting in a compact structure that does not permit much movement of polymeric segments within the hydrogel, thereby, restricting the water uptake. However, in the medium of pH 7.4, the almost complete ionization of -COOH groups results in extensive chain relaxation due to repulsion among similarly charged –COO^– groups present along the macromolecular chains. Moreover, the ionization also causes an increase in ion osmotic pressure. These two factors are thus responsible for a higher degree of swelling in the medium of pH 7.4.

Figure 3: Dynamic uptake of water as a function of time for GA – PAA graft copolymer hydrogels with different degrees of crosslinking at pH 1.2

Figure 4: Dynamic uptake of water as a function of time for GA – PAA graft copolymer hydrogels with different degrees of crosslinking at pH 7.4

The intended application for the hydrogel was to use it as an excipient for colon targeted drug delivery. Orally administered drug has to make journey from the mouth to the colon along the gastro-intestinal tract. The pH is not constant but varies along the GI tract, and so is the residence time of the dosage form. An earlier report has indicated that the formulation enters colon between 1.75 to 3.75 h of administration.⁷ Relying on this data, we opted to expose the hydrogel for a period of 3 h at pH 1.2 and then the next 9 h in the medium of pH 7.4, thus mimicking the transition of formulation from the stomach to the colon. The results, as depicted in Figure 5, for 5 mole % of crosslinker, indicate that, the hydrogel swelled to only 20%, out of a total swelling of 420% in first 3 h in the medium of 1.2, then the remaining swelling occurred in the rest of the 9 h in the buffer medium of pH 7.4. Similar results were also obtained for other copolymer hydrogels containing the 0.5 and 2.0 mole % crosslinker. These results indicate that gum acacia – acrylic acid graft copolymers, if used, as a matrix for drug delivery would release only small amount of the drug loaded before entering colon.

Figure 5: Dynamic uptake of water as a function of time for GA – PAA graft copolymer hydrogels (* pH 1.2 and ▲ pH 7.4)

CONCLUSION:

From the results obtained in above study, it can be concluded that the graft copolymer hydrogels prepared from gum acacia and acrylic acid undergo a sharp volume phase transition with the change in pH of the swelling medium from an acid to an alkaline one, thus suggesting that diffusion of the entrapped drug will be greatly enhanced with a change in pH of the medium. The amount of crosslinker also influences the water uptake of hydrogels. Finally, the hydrogels seems to have potential to be used for colon targeted drug delivery through oral administration.

REFERENCES:

1. Hoffman AS, Hydrogels for biomedical applications, Advanced Drug Delivery Reviews, 54 (1); 2002: 3-12.

2. Peppas NA, Bures P, Leobanduny W and Ichikawa H, Hydrogels in pharmaceutical formulations European Journal of Pharmaceutics and Biopharmaceutics, 50 (1); 2000: 27-46.

3. Saffran M, Kumar GS, Savariar C, Burnham JC, Williams F and Neckers DC, A new approach to the oral administration of insulin and other peptide drugs, Science, 233 (5), 1986, 1081 – 1084.

4. Ashford M, Fell T, Targeting Drugs to the Colon: Delivery Systems for Oral Administration, Journal of Drug Targeting 2 (3) 1994: 241-257.

5. Geresh S, Gilboa Y, Korol J.P, Gdalevsky G, Voorspoels J, Remon J.P, Kost J, Preparation and characterization of bioadhesive grafted starch copolymers as platforms for controlled drug delivery, Journal Applied Polymer Science, 86, 2001: 1157 - 1162.

6. Dubey S, Bajpai S.K, Poly(methacrylamide-co-acrylic acid) hydrogels for gastrointestinal delivery of theophylline. I. Swelling characterization, Journal of Applied Polymer Science, 101 (5), 2006: 2995–3008.

7. Shaikh M.M, Lonikar S. V, Starch–acrylics graft copolymers and blends: Synthesis, characterization, and applications as matrix for drug delivery, Journal of Applied Polymer Science, 114 (5), 2009: 2893–2900.

8. Zohuriaan-Mehr, M. J.; Motazedi Z.; Kabiri, K.; Ershad Langroudi A; Allahdadi I.; Gum arabic–acrylic superabsorbing hydrogel hybrids: Studies on swelling rate and environmental responsiveness, Journal of Applied Polymer Science 102. 2006, 5667 – 5674.

9. Glicksman, M; Sand, R.E.; Gum Acacia. In Industrial Gums: Polysaccharides and Their Derivatives, 2nd Ed.; Whistler, R.L. and BeMiller, J.N., eds.; Academic Press: New York, 1973.

10. Zohuriaan-Mehr, M. J.; Motazedi Z.; Kabiri, K.; Ershad Langroudi A; , New superabsorbing hydro-gel hybrid from arabic gum and acrylic monomers, Journal of Macromolecular Science Pure Applied Chemistry, 42, 2005: 1655 – 1666.

11. Mino G. and Kaizerman S., A new method for the preparation of graft copolymers. Polymerization initiated by ceric ion redox systems, Journal of Polymer Science, 31 (122), 1958: 242 – 243.

12. Athawale V.D. and Lele V, Graft copolymerization onto starch. II. Grafting of acrylic acid and preparation of its hydrogels, Carbohydrate Polymers, 35 (1–2), 1998, 21-27.

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Received on 30.01.2014 Modified on 15.03.2014

Asian J. Research Chem. 7(4): April 2014; Page 407-411

INTRODUCTION:

Synthesis of hydrogel

Sr. No

Crosslinker (N,N–methylene bisacrylamide) (mole%)

Equilibrium swelling Se

in distilled water

at pH 1.2

at pH 7.4

1

0.5

1010

143

1189

2

2

870

100

677.8

3

5

706

78.84

504.4

CONCLUSION:

Equilibrium swelling S_e