Mechanistic Implication for Cross-Linking in ... - ACS Publications

Biomacromolecules 2009, 10, 2515–2532

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Mechanistic Implication for Cross-Linking in Sterculia-Based Hydrogels and Their Use in GIT Drug Delivery Baljit Singh* and Nisha Sharma Department of Chemistry, Himachal Pradesh University, Shimla-171005, India Received April 24, 2009; Revised Manuscript Received June 12, 2009

Sterculia gum has been used as a therapeutic agent to cure diverticulitis. Hydrogels developed from sterculia gum to release the therapeutic agent will be double curing in action. Therefore, in the present study, an attempt has been made to synthesize novel hydrogels for the release of the model drug ciprofloxacin, a drug for diverticulitis. This paper discusses the synthesis, characterization, and in vitro release of ciprofloxacin from drug-loaded hydrogels in solutions of different pHs and simulated gastric and intestinal fluid. A non-Fickian diffusion mechanism has been observed for the release of the drug from drug-loaded hydrogels. This article also discusses the mechanistic implications of the cross-linking of sterculia gum with methacrylamide in the presence of N,N′-methylenebisacrylamide (N,N′-MBAAm) cross-linker.

1. Introduction The understanding of the mechanism for the synthesis of hydrogel could help to design the three-dimensional polymeric networks for various biomedical applications. The properties of the hydrogel, which make it favorable for use in various applications, arise mostly from its cross-linked structure, which is determined by the nature of monomers, method of preparation, and nature of the cross-linking agent. To understand the crosslinked structure of the gel, the most common approach used is to study its swelling. The release of the drug is closely related to the swelling characteristics of the hydrogels, which, in turn, are a key function of the chemical architecture of the hydrogels. The release of a water-soluble drug in the gastrointestinal tract (GIT), entrapped in a hydrogel, occurs only after water penetrates the network to swell the polymer and dissolve the drug, followed by diffusion along the aqueous pathways to the surface of the device. GIT is a site for many bacterial infections, and one such infection leads to diverticulitis. When there is erosion of the diverticular wall due to increased pressure in the gut, irritation from stool or food particles, or obstruction of the diverticular opening, inflammation and death of the intestinal lining can occur and the surrounding tissues are exposed to an overwhelming number of bacteria that are normally contained in stool in the colon. In severe cases it causes peritonitis, fistulation, and GI hemorrhage.1-3 Diverticular disease refers to the symptomatic and asymptomatic disease with an underlying pathology of colonic diverticula. Approximately 85% of patients with diverticula are believed to remain asymptomatic. Symptomatic diverticular disease is characterized by nonspecific attacks of abdominal pain without evidence of an inflammatory process. This pain typically is colicky in nature, but can be steady, and often is relieved by passing flatus or having a bowel movement.2 Diverticular disease of the colon causes symptoms, even in the absence of inflammatory diverticulitis. Predisposing factors for the formation of diverticula include a low-fiber diet and physical inactivity. Fiber supplementation may prevent progression to symptomatic disease or improve symptoms in patients without * To whom correspondence should be addressed. Tel.: +(91)1772830944. Fax: +(91)1772633014. E-mail: [email protected].

inflammation. In the majority of cases, diet based on dietary fibers relieves symptoms and lessens the need for surgery in diverticular disease.2,3 Antibiotic therapy aimed at anaerobes and gram-negative rods is the first-line treatment for diverticulitis. Systemic administration of colon drugs is associated with a number of side effects. Therefore, it needs a targeted drug delivery system to deliver the drug to the colon, which would ensure relief from these side effects along with the direct delivery of the drug to the colon in a controlled manner. Hydrogels based on polysaccharides have been considered as one of the best drug delivery systems. In most of the cases, polysaccharide-based formulations are nontoxic, safe, biocompatible, biodegradable, abundant, and colon specific.4 But, polysaccharides alone are not suitable materials to develop the drug delivery systems due to their substantial swelling and rapid enzymatic degradation in biological fluids.5 Therefore, these materials require some modifications. Graft and cross-linked copolymerization of polysaccharides with synthetic monomers is a powerful technique to modify the properties of polysaccharides and to make them advanced materials for use in drug delivery.6,7 Acetylation of potato starch has substantially retarded drug release. In this study, the average degree of acetyl substitution per glucose residue of potato starch was either 1.9 (SA DS 1.9) or 2.6 (SADS 2.6). The drug release has been controlled by the degree of substitution, because drug release from the SADS 1.9 film was faster than the corresponding release from the SADS 2.6 film.5 Grafting of acrylamide (AAm) onto guar gum showed that the grafting extent decreases with the dose rate and increases with the concentration of AAm.7 The incorporation of even 1% carrageenan (sodium salt) increases the equilibrium degree of swelling of the hydrogels of carrageenan and partially neutralized acrylic acid from 320 to 800 g/g.6 Sterculia gum and ciprofloxacin both have been used as therapeutic agents to cure diverticulitis. This article discusses the release of ciprofloxacin from a sterculia gum-based novel drug delivery system, which will have a double potential curing action. Here the double potential is due to the release of ciprofloxacin from the sterculia-based polymer matrix, which itself has therapeutic value for the same. Therefore, the brief

10.1021/bm9004645 CCC: $40.75  2009 American Chemical Society Published on Web 08/27/2009

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Biomacromolecules, Vol. 10, No. 9, 2009

Table 1. Optimum Reaction Parameters for the Synthesis of Sterculia-cl-poly(MAAm) Hydrogels Prepared at 65 °C amount of water [MAAm] [APS] sterculia [N,N′-MBAAm] uptake after 24 h S. No. (mol/L) (mmol/L) (g) (mmol/L) (per g of gel) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

0.235 0.470 0.705 0.940 1.175 0.705 0.705 0.705 0.705 0.705 0.705 0.705 0.705 0.705 0.705 0.705 0.705 0.705 0.705 0.705

4.386 4.386 4.386 4.386 4.386 4.386 8.772 13.158 17.544 21.930 21.930 21.930 21.930 21.930 21.930 21.930 21.930 21.930 21.930 21.930

1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 0.2 0.4 0.6 0.8 1.0 1.0 1.0 1.0 1.0 1.0

6.486 6.486 6.486 6.486 6.486 6.486 6.486 6.486 6.486 6.486 6.486 6.486 6.486 6.486 6.486 6.486 12.973 19.459 25.945 32.432

7.09 ( 1.80 5.22 ( 1.68 5.49 ( 2.18 3.87 ( 0.56 3.76 ( 0.38 5.49 ( 2.18 5.08 ( 1.38 4.66 ( 0.98 6.77 ( 0.52 9.67 ( 1.64 degradation degradation degradation 15.42 ( 1.01 9.67 ( 1.64 9.67 ( 1.64 12.38 ( 1.23 12.48 ( 1.56 10.88 ( 2.50 8.07 ( 0.87

Scheme 1. Graphical Representation of Structural Elements of Sterculia urens Gum

discussion of the therapeutic action of sterculia gum and ciprofloxacin will be praiseworthy. Sterculia gum has been reported as a bulk laxative due to a strong water-binding ability. It increases the faecal volume, promotes peristalsis, regulates the passage of food through the gut in people with certain long-term bowel disorders, and is effective in constipation.8,9 It is also used in diverticulitis, which is due to constipation and irritable bowel syndrome.10 Sterculia gum has reduced the average transit times from 93.4 ( 13.8 h in patients with diverticular disease to about 59.2 ( 16.1 h, thus relieving the symptoms of the same.9 Sterculia gum is a medicinally important polysaccharide that is obtained from the gummy exudates of stem bark of Sterculia urens, belonging to the family Sterculiaceae.11,12 It contains partially acetylated polysaccharides of the substituted rhamnogalacturonoglycan, with residues of D-glucuronic acid, D-galacturonic acid, Dgalactose, and L-rhamnose.13,14 On the other hand, ciprofloxacin is a broad-spectrum antibiotic that is active against both Grampositive and Gram-negative bacteria such as bacilli, including Pseudomonas aeruginosa.15 Ciprofloxacin is effective in treating bacterial infections in diverticulitis patients with upper gastrointestinal bleeding, peritonitis, and urinary tract infections.16,17 Although polysaccharide-based hydrogels have been developed much earlier, the mechanism of cross-linking the polysaccharide with various possibilities has not been reported. The present article discusses the mechanistic implications of crosslinking sterculia gum with methacrylamide by using N,N′MBAAm as cross-linker. All the mechanistic details have been

Singh and Sharma

elaborated in conjunction with the work reported in the literature. The polymeric networks were synthesized by varying the monomer, initiator, and cross-linker concentration to study the effect of these reaction parameters on the structure of polymer networks and on their swelling for the interpretation of the same. The optimum conditions were evaluated and further polymers were prepared at these conditions and were used to study the effect of the nature of swelling media on swelling. These were also used to study the release profile of the model antibiotic drug ciprofloxacin to evaluate the release mechanism.

2. Experimental Section 2.1. Materials and Method. Methacrylamide (MAAm; MerckSchuchardt, Germany), ammoniumpersulphate (APS; Qualigens Fine Chemicals Mumbai-India), and N,N′-methylenebisacrylamide (N,N′MBAAm; Sisco Research Laboratory Pvt Ltd. Mumbai-India) were used as received. Sterculia gum was obtained from a herbal medical store. Ciprofloxacin was obtained from Ranbaxy Pvt. Ltd., India. Potassium dihydrogen phosphate (KH2PO4), potassium chloride (KCl), sodium hydroxide (NaOH; Merck Specialties Pvt. Ltd. Mumbai-India); hydrochloric acid (HCl; Ranbaxy Fine Chemicals Ltd. New DelhiIndia), pancreatin (Loba Chemie Pvt. Ltd. Mumbai-India), sodium chloride (NaCl), and pepsin (SD-Fine Chemical Ltd. Mumbai-India) were used as received. 2.2. Synthesis of Sterculia-cl-poly(MAAm) Hydrogels. The polymers were prepared by free radical graft copolymerization of MAAm onto sterculia gum in the presence of cross-linker and initiator. The reaction was carried out with 1 g of sterculia gum, a definite concentration of APS, a monomer, and a cross-linker placed in a test tube at 65 °C for 2 h. The polymers were stirred for 2 h in distilled water and for 2 h in ethanol to remove the soluble fractions left in the polymers and then dried in an oven at 40 °C. These polymers were named as sterculia-cl-poly(MAAm). The optimum reaction parameters were evaluated for the synthesis of sterculia-cl-poly(MAAm) hydrogels by varying [MAAm] (from 0.235 to 1.175 mol/L), [APS] from (4.386 to 21.930 mmol/L), amount of sterculia from 0.2 to 1.0 g, and [N,N′MBAAm] (from 6.486 to 32.432 mmol/L; Table 1). These reaction parameters were evaluated on the basis of the swelling of the polymer in distilled water and the shape and structural integrity maintained by the hydrogels after a 24 h swelling. The optimum reaction conditions for the synthesis of sterculia-cl-poly(MAAm) were obtained as [MAAm] ) 0.705 mol/L, [APS] ) 21.930 mmol/L, sterculia gum ) 1.0 g, and [N,N′-MBAAm] ) 19.459 mmol/L. Further sterculia-cl-poly(MAAm) hydrogels were synthesized at the optimum reaction conditions and were used to study the swelling kinetics of hydrogels and the release dynamics of the drug from the drug-loaded hydrogels in different pH buffer solutions. 2.3. Characterization. Sterculia gum and the sterculia-cl-poly(MAAm) hydrogel were characterized by the scanning electron micrography (SEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and swelling studies. To investigate and compare the surface morphology of sterculia and sterculia-clpoly(MAAm), SEMs were taken on a ZEISS EVO 50 Microscope. FTIR were recorded in KBr pellets on a Nicolet 5700FTIR (THERMO) spectrophotometer. TGA were taken on a Perkin-Elmer (Pyris Diamond) apparatus DTA-DTG-TG in air (200 mL/min) at a heating rate of 10 °C/min. Swelling kinetics of the polymeric networks were carried out in triplicate by the gravimetric method.18 A known weight of dried hydrogels was immersed in excess distilled water for different time intervals at 37 °C. The difference in weight gave the amount of water uptake by the polymers. Swelling studies were carried out as a function of feed monomer, initiator, and cross-linker concentration used during the synthesis of hydrogels. The effect of the nature of the swelling medium was also studied. 2.4. Release Dynamics of the Model Drug. Calibration graphs were prepared in different pH solutions. The concentration of the drug

Cross-Linking in Sterculia-Based Hydrogels


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Scheme 2. Structural Representation of Sterculia urens Gum

(ciprofloxacin) in the sample solution was read from the graph as the concentration corresponding to the absorbance of the solution taken on a UV visible spectrophotometer (Cary 100 Bio, Varian). Three calibration graphs were made in distilled water, pH 2.2 buffer, and pH 7.4 buffer, respectively, at λmax 276, 277, and 271 nm, to determine the amount of drug released from the drug-loaded polymeric matrix. Buffer solutions of pH 2.2 and pH 7.4 were prepared according to the procedure reported in Pharmacopoeia of India.19 Simulated gastric fluid of pH 1.2 containing pepsin and simulated intestinal fluid of pH 6.8 containing pancreatin were prepared according to the procedure reported in United States Pharmacopeia and National Formulary, 26th edition. The loading of a drug into hydrogels was carried out by the swelling equilibrium method.18 A total of 55% loading has been observed in the samples. In vitro release studies of the drug were carried out by placing dried and loaded samples in a definite volume of releasing medium at 37 °C, and drug concentration was measured from standard curves. 2.5. Mechanism of Swelling and Drug Release from Polymer Matrix. The mechanisms of swelling and drug release have been discussed in detail in our earlier study.18 Swelling of polymers has been classified into three types of diffusion mechanisms on the basis of the relative rate of diffusion of water into the polymer matrix and the rate of polymer chain relaxation.20-23 In the case of water uptake, the weight gain, Ms, is described by eq 1

Ms ) kt

n

(1)

where k and n are constant. Normal Fickian diffusion is characterized by n ) 0.5, while Case II diffusion is characterized by n ) 1.0. When

values of the n are between 0.5-1.0, the diffusion is termed as nonFickian. Ritger and Peppas showed that the above power law expression could be used for the evaluation of drug release from hydrogels.22,23 In this case, Mt/M∞ replaces Ms in the above equation to give eq 2. For cylindrical-shaped hydrogels, the initial diffusion coefficient (Di), the average diffusion coefficient (DA), and late diffusion coefficient (DL) have been calculated from the eqs 3,4, and 5, respectively.

Mt ) ktn M∞

( )

(3)

0.049l2 t1/2

(4)

Mt DIt )4 2 M∞ πl

DA )

(2)

( )

[

0.5

Mt (-π2DLt) 8 ) 1 - 2 exp M∞ π l2

]

(5)

where Mt/M∞ is the fractional release of the drug in time t, k is the constant characteristic of the drug-polymer system, and n is the diffusion exponent characteristic of the release mechanism. Mt and M∞ are the amount of drug released at time t and at equilibrium, respectively, Di is the initial diffusion coefficient, l is the thickness of the sample, and t1/2 is the time required for 50% release of drug. The

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Scheme 3. Part 1 of 7. Mechanism for Synthesis Sterculia-cl-poly(MAAm)

values of the diffusion coefficients have been evaluated for the swelling of the polymers and for the release of the drug from the polymer.

3. Results and Discussion 3.1. Mechanism of Cross-Linking. To explain the graft and cross-linked copolymerization of poly(MAAm) onto sterculia gum, a brief discussion of the structure of sterculia gum will be praiseworthy. Sterculia gum is a partially acetylated polysaccharide that contains a rhamnogalacturonoglycan structural unit, which is shown in Schemes 1 and 2. Structurally, sterculia gum consists of two structural regions, that is, A and B. Region (A) of sterculia gum contains R-D-galactouronic acid (R-D-GalpA) and R-L-rhamnose (R-L-Rha) residue. In this chain, the galactouronic acid is linked to rhamnose through 1-2 R at one side

and through 4-1 R glycosidic linkage on the other side, and this pattern is repeated throughout the chain. β-D-Galactose (βD-Gal) and β-D-glucouronic acid (β-D-GlcA) are linked as side chains with R-D-galactouronic acid through 1-2 β linkage and 1-3 β linkage, respectively.24 The β-D-glucouronic acid side chain units generally occur singly, are attached directly to the main chain but may also be linked to the main chain via a 25,26 D-galactose residue, and are also present as the 4-O-methyl ether derivative. One half of the rhamnose units are carried at O-4 by 1,4 linkage of β-D-galactose units.8 Region (B) of sterculia gum consists of branched trisaccharide units composed of β-D-galactose and R-D-galactouronic acid that are probably not present in repetitive sequences.25 R-D-Galactouronic acid is linked through (1-4 R) and (2-1 β) glycosidic linkage to



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Scheme 3. Part 2 of 7

β-D-galactose.27 These trisaccharide units are also interrupted by the rhamnogalacturonan regions at intervals.14 The uronic acid, L-rhamnose, and D-galactose in sterculia gum have been found at the following percentages: 37.35, 22.38, and 48.27% respectively.28 The presence of three reactive hydroxyl groups on each glucan unit of cellulose makes it susceptible to get modified through free radical graft copolymerization.29,30 On the similar analogy, the initiation, propagation, and termination reactions in the case of sterculia gum can be explained. The -OH groups present in sterculia backbone are susceptible sites for the hydrogen abstraction and are active sites for graft copolymerization. There are three free hydroxyl groups present on each

galactose unit at position 2-, 3-, and 6-C and three free hydroxyl groups present on each β-D-glucouronic acid at position 2-, 3-, and 4-C. In the case of the rhamnose unit there are two hydroxyl groups present at the 3- and 4-C atoms and one free hydroxyl group present at the R-D-galactouronic acid unit (Scheme 3). The grafting and cross-linking have been generally considered to involve three steps: (1) initiation, which involves the generation of free radicals and thus the generation of reactive sites on substrate polymer through hydrogen abstraction from the polysaccharide backbone; (2) propagation, which involves the addition of monomer to the substrate reactive sites and further propagation of that monomer thus formation of macroradicals; and (3) termination in which polymeric macroradicals

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may combine to give a cross-linked product. APS is a common free radical initiator and produces sulfate anion-free radicals (SO4-•),31,32 which may react with water to produce hydroxyl radicals (-OH•).33-35 These are capable of abstracting hydrogen atom from sterculia gum backbone and, therefore, producing radical sites for grafting on the macromolecular backbone. Sulfate anion-radicals are also capable of generating free radical sites on the polysaccharide backbone,31,34 but hydroxyl radicals are more reactive than sulfate anion-radicals (SO-•).36 There are three possibilities for the generation of free radicals on sterculia backbone: abstraction of hydrogen from the -OH groups present in the sterculia gum,37,38 from the hydrogen present in the carbon skeleton,33 and from the hydrogen present in the C6 carbon of the backbone (Scheme 3, eq iii).35,39 During initiation, the -OH• radical also abstracts hydrogen from the vinyl monomer, which further reacts with oxygen and generates a peroxide free radical (Scheme 3, eqs iv and v).40 There are three possibilities for the generation of free radical sites on the sterculia backbone through three routes of hydrogen abstraction, but for convenience, in the present mechanism we are taking one possibility, that is, hydrogen abstraction from hydroxyl groups of the sterculia gum, as the initiation site. During propagation reactions, free radicals generated on the backbone and monomer will further react with monomer and give the grafted and homopolymer macroradicals, respectively.41 Due to the presence of reactive propagating radicals, the multiple branches of grafted macroradicals will form on the sterculia backbone.42 During propagation, grafting of poly(MAAm) onto sterculia gum has formed the grafted macroradicals (Scheme 3, eqs vii and viii). In the presence of the cross-linker N,N′-

MBAAm, because of its polyfunctionality, a new macroradical forms that has four reactive sites, and these sites can be linked with the radical on the sterculia gum, poly(MAAm), and sterculia-g-poly(MAAm) macroradicals. This will lead to the formation of three-dimensional networks, which were named as sterculia-cl-poly(MAAm) macroradicals (Scheme 3, eq xi).16,43 The detailed mechanism for the synthesis of sterculiacl-poly(MAAm) hydrogels is given in Scheme 3. Additionally, there are three possibilities for network formation with two sterculia-grafted methacrylamide macroradical regions, that is, A and B. In one case, the sterculia-grafted macroradical of region A of sterculia gum may cross-link with another sterculia macroradical of region A, as shown in Scheme 3, eqs x and xi, and in the second case, the sterculia of region B macroradical cross-links with another sterculia region B macroradical (Scheme 3, eq xii). The third possibility is crosslinking between the sterculia macroradical region A with the macroradical of another chain of region B (Scheme 3, eq xiii). 3.2. Characterization. 3.2.1. Scanning Electron Micrography. The surface morphology of sterculia and sterculia-clpoly(MAAm) hydrogels has been examined by SEMs, which are presented in Figure 1A and B, respectively, for sterculia and sterculia-cl-poly(MAAm) at magnifications of ×2500. It has been observed from the SEMs that sterculia has smooth and homogeneous morphology, whereas modified sterculia has structural heterogeneity. The change in surface morphology of the modified sterculia is clear from the cross-linked networks in SEMs taken at ×2500 magnification. 3.2.2. Fourier Transform Infrared Spectroscopy. FTIR spectra of sterculia and sterculia-cl-poly(MAAm) were recorded to



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study the modification of the sterculia and are presented in Figure 2a and b,respectively. From the FTIR spectrum of sterculia gum, typical absorption bands at 3441.6 (broad, s) are due to the O-H stretching vibration. Absorption peaks around 1675-1610 (i.e., 1619.2 and 1740.3-1240 cm-1) were assigned to uronic acid and the acetyl groups of sterculia gum, respectively.44 In sterculia-cl-poly(MAAm) polymers, the broad absorption band at 3430.1 cm-1 is due to the overlap stretching band of the hydroxyl groups of sterculia gum, and the N-H stretching band of the amide group of poly(MAAm) has been observed. The bands at 2997.3 and 2926 cm-1 are due to C-H asymmetric vibrations of CH3 and CH2 groups, respectively, of poly(MAAm). A peak at 1658.5 cm-1 is assigned to the CdO (amide I band) stretching vibration of the amide functional groups of modified sterculia.45 The peak at 1589.0 cm-1 is attributed to the N-H in-plane bending (amide II band), and the CH3 asymmetric deformation vibration of poly(MAAm) has been observed at 1490.4 cm-1, apart from the usual peaks in

the sterculia. Though the FTIR of the polysaccharides have very complex spectra due to their composition, after modification, the incorporation of methacrylamide into sterculia may be evident due to the appearance of two prominent peaks at 1658.5 and 1589.0 cm-1 due to amide I and II stretching. However, some peaks get overlapped with the peaks already present in the sterculia gum. 3.2.3. ThermograVimetric Analysis. The primary thermograms of sterculia gum and sterculia-cl-poly(MAAm) are presented in Figure 3. In each case, weight loss due to entrapped moisture has been ignored and initial decomposition temperature (IDT) has been taken as the temperature where the actual degradation of the polymer started. In the case of sterculia gum, initial 13.16% weight loss occurred between 24 and 100 °C, while in the case of the cross-linked polymer, 14.24% weight loss has been observed within the same temperature range. The initial weight loss can be referred to as the loss of the absorbed moisture in the polymer matrix. The initial decomposition

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temperature (IDT) has been observed at 243 and 239 °C, respectively, for sterculia and modified sterculia. Final decomposition temperatures (FDT) have been observed at 717 °C (3.72% residue) and 555 °C (2.72% residue), respectively, for sterculia and sterculia-cl-poly(MAAm) polymer. It is clear from these observations that the thermal stability of the functionalized sterculia decreases during the early stages of decomposition. This is further supported by the decomposition temperature per 10% weight loss, which is presented in the Table 2. However, at the later stages, the modification has provided some degree of stability to the polymer. A double stage decomposition mechanism has been observed from the primary thermograms of sterculia gum and the sterculia-cl-poly(MAAm) polymer. In the case of sterculia-cl-poly(MAAm) polymers, the actual decomposition started at 239 °C and at higher temperature

imidation reaction at pendant amide groups proceeds with evolution of ammonia and provides some thermal stability to the polymer chains (Scheme 4). This extra stability in the modified sterculia is reflected in a 30-60% weight loss, which is shown in Table 2. This table shows the decomposition temperature per 10% weight loss. In the case of sterculia gum, 30-60% weight loss occurred between 259 and 312 °C, whereas in modified sterculia gum, this temperature range was between 259 and 368 °C. It means that this 30% weight loss in the case of sterculia occurs with a 53 °C rise in temperature, and in the modified sterculia gum, it occurs after a 99 °C rise in temperature. These observations indicate that imidation has provided the stability in the modified sterculia gum. The second decomposition stage started at 390 °C (after a 63.60% weight loss) due to the loss of methyl groups and



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subsequent cross-linking between the residual char.46 In the latter stages thermal stability of cross-linked polymers has been improved as compared to pure sterculia gum. 3.3. Swelling Kinetics of Sterculia-cl-poly(MAAm) Hydrogels. To evaluate the optimum reaction parameters for the synthesis of the sterculia-cl-poly(MAAm) hydrogels, swelling of the polymers was taken as a function of [MAAm], [APS], and [N,N′-MBAAm]. The polymers prepared at the optimum reaction conditions were used to study the effect of pH, [NaCl], and temperature of the swelling medium on the swelling of hydrogels. 3.3.1. Swelling as a Function of Monomer Concentration. The effect of feed monomer concentration on the polymer networks was studied by taking the swelling of the hydrogels, and the results are presented in Figure 4a. The polymers were prepared by varying the [MAAm] from 0.235 to 1.175 mol/L. Swelling of polymers decreased with an increase in feed

monomer concentration. The increase in [MAAm] in the reaction system led to an increase in the network density of poly(MAAm) chains in the gel, which decreases the free volume accessibility to water molecules.47 The values of the diffusion exponent n and gel characteristic constant k have been evaluated from the slope and the intercept of the plot of ln Mt/M∞ versus ln t, and the results are presented in the Table 3. It is clear from the values of the n that the swelling of the polymer matrix prepared with different monomer concentration is occurred through Fickian diffusion mechanism. In Fickian diffusion, the rate of solvent diffusion is significantly slower than the rate of relaxation of polymeric chains, and the mechanism is diffusion controlled.48 The values of all the diffusion coefficients have shown in Table 3. The diffusion coefficients gave a measure of diffusion and mass flow of solvent to the polymeric system.49 Initial and average diffusion coefficients have been obtained higher than late diffusion

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coefficients. At the initial stages of swelling, when a glassy hydrogel is brought into contact with water, water diffuses into the hydrogel, resulting in swelling of the hydrogel with significant change in the volume of the system, and the polymeric network experiences chain relaxation with increasing macromolecular mobility. This leads to an increase in diffusion coefficients of water into the hydrogels, which is also reflected in the values of the average diffusion coefficients.50 In the later stages, after attaining the equilibrium swelling, polymer chains are fully relaxed, no further diffusion of solvent occurs, and the diffusion coefficient at this stage shows much smaller values. 3.3.2. Swelling as a Function of Initiator Concentration. To observe the effect of initiator concentration on the network structure, swelling of polymers prepared with different [APS] occurred (Figure 4b). Swelling of the polymer matrix first decreased up to feed initiator concentration of 13.158 mmol/L APS, and after that it increased. This exceptional increase in swelling after 13.158 mmol/L APS may be due to the formation of short lower molecular weight polymeric chains at higher initiator concentration, which led to the formation of lower molecular weight hydrogels. The network imperfection is higher

when the molecular weight is smaller, and this means that there are more chain ends in the networks and fewer junctions are formed between polymeric chains.51,52 Polyacrylate superabsorbents have been prepared by Chen and Zhao by in situ aqueous solution polymerization. The influence of the initiator content was investigated. They have also observed that the water absorbency increases linearly with an increase in the initiator content.52 The diffusion of solvent occurred through non-Fickian diffusion mechanism for the polymeric networks prepared at higher [APS]. This may be due to the fact that at lower concentration of initiator, long polymeric chains are formed, resulting in a loose polymeric network and low cross-linking density with larger pore size in the network. It favors the free mobility of the polymeric chains, thus resulting in a Fickian type of solvent diffusion into the polymeric hydrogel. As the concentration of initiator is increased, high cross-linking takes place, which decreases the pore size in the network, and at the same time the polymer relaxation is restricted, which results in a non-Fickian type of diffusion.53 The values of the initial and average diffusion coefficients have been obtained higher than



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Figure 1. (A) Scanning electron micrograph of sterculia gum (magnification ) ×2500). (B) Scanning electron micrograph of sterculia-cl-poly(MAAm) (magnification ) ×2500).

late diffusion coefficients, which indicate that initially the rate of swelling of the polymer matrix is higher than the latter stages of swelling. 3.3.3. Swelling as a Function of Amount of Sterculia Gum and [N,N′-MBAAm]. The polymers were not formed with lower sterculia contents, and 1 g of sterculia was taken as the optimum amount for further synthesis of polymers. Degradation of the polymers prepared with lower sterculia contents started after 270 min of swelling (Figure 4c). The concentration of crosslinker directly affects the network structure, and hence, the swelling of the hydrogels prepared with different [N,N′MBAAm] was taken (Figure 4d). Swelling first increased and then decreased with the increase in the feed cross-linker concentration during the synthesis of hydrogels. This is due to the fact that after attaining definite pore size in the polymeric network, cross-linking density starts increasing with an increase in cross-linker, resulting in a decrease in the swelling.54 A nonFickian type of diffusion mechanism occurred for the diffusion

of water molecules in the polymer matrix prepared with different cross-linker concentrations. In non-Fickian transport, both diffusion as well as polymer chain relaxation are comparable and both control the overall rate of diffusion of solvent.55 The diffusion was fast in the early stages of diffusion (Table 3). 3.3.4. Swelling as a Function of pH, [NaCl], and Temperature of the Swelling Medium. At the optimum reaction conditions, hydrogels were synthesized and were used to study the effect of pH, [NaCl] and temperature of the swelling medium and results are presented in Figure 4e, f, and g, respectively. When the effect of pH was studied, the swelling was carried out in distilled water, pH 2.2 buffer, and pH 7.4 buffer for 24 h at 37 °C. Swelling was much higher in distilled water as compared to pH 2.2 and 7.4 buffers. The swelling of the hydrogels occurred through a non-Fickian mechanism. To study the effect of salt concentration, swelling of the hydrogels was carried out in 0.9% NaCl at 37 °C and the amount of solvent uptake per gram of gel in salt solution was observed

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Figure 2. (A) FTIR spectra of sterculia gum. (B) FTIR spectra of sterculia-cl-poly(MAAm).

less as compared to the distilled water. The presence of ions in the swelling medium have a profound effect on the absorbency behavior of the hydrogels because of charge screening induced by counterions (e.g., Na+) in the medium. A similar observation has been reported by Mohamadnia et al.56 They have reported the decrease in swelling from 307 g/g to 65 g/g when hydrogels were placed in a 0.9% NaCl solution. These hydrogels were prepared by graft copolymerization of acrylonitrile (AN) onto tragacanth gum.56 The Donnan equilibrium theory attributes the

electrostatic interactions (ion swelling pressure) to the difference between the osmotic pressure of freely mobile ions in the gel and in the outer solutions. The osmotic pressure is the driving force for swelling of hydrogels. The mobile ion concentration difference between the polymer gel and the external medium increases, which, in turn, reduces the gel volume, that is, the gel shrinks and the swelling capacity decreases.57 The values of the initial, average, and late diffusion coefficients for the swelling of hydrogels are presented in Table 3. In each swelling



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Figure 3. Thermogravimetric analysis of sterculia gum and sterculia-cl-poly(MAAm). Table 2. Thermogravimetric Analysis (TGA) of Sterculia (A) and Sterculia-cl-poly(MAAm) Hydrogel (B) decomposition temp (°C) at every 10% weight loss sample

IDT (°C)

FDT (°C)

10

20

30

40

50

60

70

80

90

100

A B

243 239

717 (3.72% residue) 555 (2.72% residue)

84 80

240 225

259 259

271 278

284 313

312 368

406 410

485 459

547 527

717 555

medium, values of the initial diffusion coefficients have been observed as higher than the other coefficients. The swelling of polymers at different temperatures is presented in Figure 4g. Swelling of hydrogels in the earlier stages first increases and then decreases with an increase in the temperature of the swelling medium.47 Han and co-workers58 have also observed the decrease in swelling after 37 °C in the hydrogels prepared with lactitol polyether polyol (LPEP) and chlorinated poly(ethylene glycol) bis(carboxymethyl) ether (PEGBCOCl) hydrogels with a cross-linking ratio of (PEGBCOCl/LPEP) 3:1. At and above 37 °C, the swelling ratio decreases with increasing temperature and heating time. This suggests that greater thermal energy liberates more water molecules, which were hydrated to the polymeric hydrogel structure (De) the obtained diffusivity may be affected by the hydrogel shrinking after 2 h at 37 and 45 °C. This hydrogel shrinking may reduce the free cavity size of the hydrogels and may decrease the diffusivity above 37 °C. In another observation, the results of the swelling of the hydrogels prepared by poly(vinyl pyrrolidone), gelatin, and acrylamide indicate that the swelling ratio increases with increasing the temperature of the medium. However, on increasing the temperature of the swelling medium beyond room temperature, the hydrogel chains must have acquired complete relaxation so that with a further increase in temperature they do not loosen. As a consequence, no appreciable change in swelling behavior could be observed at a higher temperature.47 The swelling of the polymers in different temperature occurred through a non-Fickian diffusion Scheme 4. Imidation Reaction

mechanism. The values of the early diffusion coefficients were observed as being higher. 3.4. In Vitro Release Dynamics of Ciprofloxacin in pH Buffer and Simulated Fluids. In vitro release dynamics of ciprofloxacin from drug-loaded hydrogels was studied in distilled water and pH 2.2 and pH 7.4 buffers at 37 °C and the results are presented in Figure 5a. The amount of drug released from the per gram of the gel is higher in pH 2.2 than in pH 7.4 buffer. The higher release in pH2.2 buffer may be explained due to the more solubility of the ciprofloxacin hydrochloride in solution of lower pH. Swelling of the gel is higher in water (Figure 4 and 4), on the contrary drug release is less in water than buffer (Figure 5). This is due to the pH dependent solubility of ciprofloxacin which is greatly reduced between pH 5 and 9.59-61 Srinatha and co-workers62 have also observed higher release of ciprofloxacin in acidic medium from the drug loaded chitosan beads. The release of drug from the hydrogels occurred through non-Fickian diffusion mechanism indicating that the drug release is controlled by the polymer chain relaxations of the matrix as well as diffusion of the drug during solvent penetration (Figure 5.).63 As a drug molecule diffuses through a polymeric material, the polymer chains must take on new conformations consistent with the new penetrant concentration.64 The rate of diffusion of drug molecules and rate of relaxation of polymeric chains are comparable. The values of the diffusion coefficients for the release of drug from the hydrogels in different pH buffer are obtained from the Figure 5. and 5, and results are

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Singh and Sharma

Figure 4. (a) Effect of [MAAm] on swelling kinetics of sterculia-cl-poly(MAAm) hydrogels in distilled water at 37 °C. (Sterculia gum ) 1 g, [APS] ) 4.386 mmol/L, [N,N′-MBAAm] ) 6.486 mmol/L). (b) Effect of [APS] on swelling kinetics of sterculia-cl-poly(MAAm) hydrogels in distilled water at 37 °C. (Sterculia gum ) 1 g, [MAAm] ) 0.705 mol/L, [N,N′-MBAAm] ) 6.486 mmol/L). (c) Effect of amount of sterculia gum on swelling kinetics of sterculia-cl-poly(MAAm) hydrogels in distilled water at 37 °C. ([MAAm] ) 0.705 mol/L, [APS] ) 21.930 mmol/L, [N,N′-MBAAm] ) 6.486 mmol/L). (d) Effect of [N,N′-MBAAm] on swelling kinetics of sterculia-cl-poly(MAAm) hydrogels in distilled water at 37 °C. (Sterculia gum ) 1 g, [MAAm] ) 0.705 mol/L, [APS] ) 21.930 mmol/L). (e) Effect of pH on swelling kinetics of sterculia-cl-poly(MAAm) hydrogels at 37 °C. (Sterculia gum ) 1.0 g, [MAAm] ) 0.705 mol/L, [APS] ) 21.930 mmol/L, [N,N′-MBAAm] ) 19.459 mmol/L). (f) Effect of [NaCl] on swelling kinetics of sterculia-cl-poly(MAAm) hydrogels at 37 °C. (Sterculia gum ) 1.0 g, [MAAm] ) 0.705 mol/L, [APS] ) 21.930 mmol/L, [N,N′-MBAAm] ) 19.459 mmol/L). (g) Effect of temperature on swelling kinetics of sterculia-cl-poly(MAAm) hydrogels in distilled water. (Sterculia gum ) 1.0 g, [MAAm] ) 0.705 mol/L, [APS] ) 21.930 mmol/L, [N,N′-MBAAm] ) 19.459 mmol/L).



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Table 3. Results of Diffusion Exponent n, Gel Characteristic Constant k, and Various Diffusion Coefficients for the Swelling Kinetics of Sterculia-cl-poly(MAAm) Hydrogels in Different Medium at 37 °C diffusion coefficients (cm2/min) S. No.

parameter

diffusion exponent n

gel characteristic constant k × 102

initial Di × 104

average DA × 104

late time DL × 104

0.225 1.546 1.610 1.718 2.342

0.942 7.573 6.164 21.886 20.575

0.0604 0.442 0.425 0.671 0.894

1.610 5.478 15.766 11.084 10.889

6.164 12.405 25.454 17.562 17.163

0.425 1.154 3.012 1.846 1.714

5.172 10.889

10.992 17.163

0.913 1.714

10.889 10.458 20.829 19.205 21.599

17.163 18.357 24.110 24.747 30.051

1.714 1.654 2.950 2.669 3.340

20.829 13.853 17.017

24.110 21.119 26.699

2.950 2.180 2.951

20.829 13.061

24.110 21.418

2.950 2.106

7.200 5.414 6.402 20.829 14.189

14.234 10.597 10.687 24.110 20.941

1.203 0.906 0.982 2.950 2.158

Effect of [MAAm] 1 2 3 4 5

0.235 0.470 0.705 0.940 1.175

mol/L mol/L mol/L mol/L mol/L

0.303 0.296 0.320 0.215 0.215

13.335 14.859 13.062 23.659 22.387 Effect of [APS]

1 2 3 4 5

4.386 mmol/L 8.772 mmol/L 13.158 mmol/L 17.544 mmol/L 21.930 mmol/L

0.320 0.387 0.458 0.496 0.549

13.062 8.185 6.026 4.072 2.606 Effect of Amount of Sterculia Gum

1 2 3 4 5

0.2 0.4 0.6 0.8 1.0

g g g g g

0.526 0.549

2.455 2.606 Effect of [N,N′-MBAAm]

1 2 4 5

6.486 mmol/L 12.973 mmol/L 19.459 mmol/L 25.945 mmol/L 32.432 mmol/L

0.549 0.596 0.631 0.658 0.554

2.606 1.791 2.042 1.531 3.027 Effect of pH

1 2 3

distilled water pH 2.2 buffer pH 7.4 buffer

0.631 0.547 0.491

2.042 2.710 4.711 Effect of [NaCl]

1 2

distilled water 0.9% NaCl

1 2 3 4 5

22 27 32 37 42

0.631 0.528

2.042 3.016 Effect of Temperature of Swelling Medium

°C °C °C °C °C

0.685 0.690 0.672 0.631 0.575

presented in Table 4. The values obtained for initial and average diffusion coefficients are higher than the late diffusion coefficients. These values show that in the early stages, the rate of diffusion of drug from the drug loaded hydrogels was higher than the rate of diffusion in the later stages. This may be due the concentration gradient of the drug which was higher in early stages and with the passage of time this gradient goes on decreasing. This observation is very important to develop the controlled drug delivery devices. Here after maintaining certain drug concentration, the release of drug occurred in controlled manner.

0.812 0.783 1.031 2.042 2.385

In vitro release dynamics of ciprofloxacin from drug-loaded hydrogels was also studied in simulated gastic fluid (SGF) of pH 1.2 and simulated intestinal fluid (SIF) of pH 6.8. (Figure 6a). The pH of these buffers falls within the range of biological gastric and intestinal pH, respectively. It has been observed from the figure that the amount of drug released per gram of gel is higher in SGF than in SIF. This may also be based on the solubility of ciprofloxacin. The time required for 50% of the total release of the drug in SGF and SIF has been found to be 111 and 74 min (Figure 6b). The release of drug from hydrogels occurred through

Table 4. Results of Diffusion Exponent n, Gel Characteristic Constant k, and Various Diffusion Coefficients for the Release of Ciprofloxacin from Drug-Loaded Sterculia-cl-poly(MAAm) Hydrogels in Different Mediums at 37 °C diffusion coefficients (cm2/min) S. No.

drug releasing medium

diffusion exponent n

gel characteristic constant k × 102

initial Di × 104

average DA × 104

late time DL × 104

1 2 3 4 5

distilled water pH 2.2 buffer pH 7.4 buffer simulated gastric fluid (pH 1.2, containing pepsin) simulated intestinal fluid (pH 6.8, containing pancreatin)

0.60 0.58 0.65 0.44 0.70

2.350 2.404 1.538 7.477 1.793

16.038 12.815 11.343 21.321 46.710

17.032 17.607 15.431 34.240 32.332

2.416 1.925 1.631 4.918 8.0057

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Singh and Sharma

Figure 5. (a) Release profile of ciprofloxacin from drug-loaded sterculia-cl-poly(MAAm) hydrogels in different medium at 37 °C (sterculia gum ) 1.0 g, [MAAm] ) 0.705 mol/L, [APS] ) 21.930 mmol/L, [N,N′-MBAAm] ) 19.459 mmol/L). (b) Percentage of total drug release from drugloaded sterculia-cl-poly(MAAm) hydrogels in different mediums at 37 °C. (c) Plot for the evaluation of the diffusion exponent n and the gel characteristic constant k for the release of drug from drug-loaded sterculia-cl-poly(MAAm) hydrogels in different mediums at 37 °C. (d) Plot of Mt/M∞ vs t for the evaluation of initial and average diffusion coefficient (Di and DA) for the release of drug from drug-loaded sterculia-cl-poly(MAAm) hydrogels in different mediums at 37 °C. (e) Plot of ln(1 - (Mt/M∞) vs time for the evaluation of late diffusion coefficient (DL) for the release of drug from drug-loaded sterculia-cl-poly(MAAm) hydrogels in different mediums at 37 °C.

a Fickian diffusion mechanism in SGF and through a non-Fickian diffusion mechanism in SIF (Figure 6c). The values obtained for initial and average diffusion coefficients were higher than the late diffusion coefficients (Figure 6d,e, Table 4).

It is observed from the water uptake studies of the sterculiacross-linked methacrylamide that the swelling was increased in pH 7.4 solution as compare to the pH 2.2 buffer. This is due to the partial hydrolysis of -CONH2 moieties in higher pH solution. At



2531

Figure 6. (a) Release profile of ciprofloxacin from drug-loaded sterculia-cl-poly(MAAm) hydrogels in simulated gastric and intestinal fluid at 37 °C (sterculia gum ) 1.0 g, [MAAm] ) 0.705 mol/L, [APS] ) 21.930 mmol/L, [N,N′-MBAAm] ) 19.459 mMol/L). (b) Percentage of total drug release from drug-loaded sterculia-cl-poly(MAAm) hydrogels in simulated gastric and intestinal fluid at 37 °C. (c) Plot for the evaluation of the diffusion exponent n and the gel characteristic constant k for the release of drug from drug-loaded sterculia-cl-poly(MAAm) hydrogels in simulated gastric and intestinal fluid at 37 °C. (d) Plot of Mt/M∞ vs t for the evaluation of initial and average diffusion coefficient (Di and DA) for the release of drug from drug-loaded sterculia-cl-poly(MAAm) hydrogels in simulated gastric and intestinal fluid at 37 °C. (e) Plot of ln(1 - (Mt/M∞) vs time for the evaluation of late diffusion coefficient (DL) for the release of drug from drug-loaded sterculia-cl-poly(MAAm) hydrogels in simulated gastric and intestinal fluid at 37 °C.

lower pH, the -CONH2 groups do not ionize and keep the network at its collapse state. At high pH solution, these groups get partially ionize, and the charged -COO- groups repel each other and cause more swelling of the polymer. The release of water-soluble drug, entrapped in hydrogels, occurs only after water penetrates the network, swells the polymer, and dissolves the drug, followed by diffusion along the aqueous pathways to the surface of the device. The release of drug is closely related to the swelling characteristics

of the hydrogels, which, in turn, is a key function of the chemical architecture of the hydrogels. Swelling is observed more so it is proposed that this drug delivery system will be efficient for the delivery of ciprofloxacin in the colon, which cures the diverticulitis. At the same time, sterculia gum will cure constipation, which is the major cause for the diverticulitis. The release was somewhat higher at lower pH due to more solubility of the ciprofloxacin in this medium, but after 24 h, which is approximately the total transit

2532


time for a drug delivery device from the GIT tract, the total 2.146 mg of the drug release occurred from the per gram of the drugloaded hydrogels in pH 7.4 buffer. Additionally, the values of the late diffusion coefficients reflect that after maintaining a certain concentration, the release of drug occurred slowly and in a controlled manner.

4. Conclusion It is concluded from the foregone discussion that composition of hydrogels and network density is affected by the synthetic reaction parameters, which is evident from the swelling studies. The increase in feed monomer concentration and cross-linker concentration during the synthesis of polymers has increased the network density in the hydrogels, which has decreased the swelling of the hydrogels. Swelling of the polymers and release of drug from polymers occurred through a non-Fickian diffusion mechanism. In this mechanism, the rate of drug diffusion from the polymer matrix and the rate of polymer chain relaxation are comparable. Further, values of the diffusion coefficients reflect that in the early stages the rate of release of drug from the polymer was higher than the latter stages, and release of the drug has occurred in controlled manner. Hence, these hydrogels can be exploited for developing controlled and sustained drug delivery systems. It is further concluded that the release of ciprofloxacin from modified sterculia gum, which itself acts as a therapeutic agent for constipation, may act as a potential drug delivery device to cure the diverticulitis. Degradation of the polymer matrix and release of drug may exert the synergic effect, and the present drug delivery system may act with double potential to cure the diverticulitis, which is the novelty of the present work.

References and Notes (1) Terg, R.; Fassio, E.; Guevara, M.; Cartier, M.; Longo, C.; Lucero, R.; Landeira, C.; Romero, G.; Dominguez, N.; Munõz, A.; Levi, D.; Miguez, C.; Abecasis, R. J. Hepatol. 2008, 48 (5), 774–779. (2) Salzman, H.; Lillie, D. Am. Fam. Physician 2005, 72, 1229–1234. (3) Painter, N. S. Postgrad. Med. J. 1974, 50, 629–635. (4) Jain, A.; Gupta, Y.; Jain, S. K. J. Pharm. Sci. 2007, 10 (1), 86–128. (5) Tuovinen, L.; Peltonen, S.; Jarniven, K. J. Controlled Release 2003, 91, 345–354. (6) Francis, S.; Kumar, M.; Varsheny, L. Radiat. Phys. Chem. 2004, 69, 481– 486. (7) Biswal, J.; Kumar, V.; Bhardwaj, Y. K.; Goel, N. K.; Dubey, K. A.; Chaudhari, C. V.; Sabharwal, S. Radiat. Phys. Chem. 2007, 76, 1624– 1630. (8) Weiping, W. Tragacanth and karaya. In Handbook of Hydrocolloids; Philips, G. O., Williams, P. A., Eds.; Woodhead: Cambridge, 2000; pp 231-245. (9) Srivastava, G. S.; Smith, A. N.; Painter, N. S. Br. Med. J. 1976, 1, 315– 318. (10) Hopkins, S. J. Principal Drugs: An Alphabetical Guide to Modern Therapeutics, 11th ed.; Elsevier Health Science Publishers: United Kingdom, 1998; p 144. (11) Behall, K. M. AdV. Exp. Med. Biol. 1990, 270, 7–16. (12) Anderson, D. M. W.; McNab, C. G. A.; Anderson, C. G.; Braown, P. M.; Pringuer, M. A. Int. Tree Crops J. 1982, 2, 147–154. (13) Aspinall, G. O.; Nasar-ud-din, J. Chem. Soc. 1965, 2710–2720. (14) Aspinall, G. O.; Sanderson, G. R. J. Chem. Soc. C 1970, 2259–2264. (15) Greenberg, R. N.; Tra, A. D.; Marsh, P. K. Am. J. Med. 1987, 82 (4A), 266–269. (16) Hsieh, W. J.; Lin, H. C.; Hwang, S. J.; Hou, M. C.; Lee, F. Y.; Chang, F. Y.; Lee, S. D. Am. J. Gastroenterol. 2005, 93 (6), 962–966. (17) Pelaéz, N.; Pera, M.; Courtier, R.; Sańchez, J.; Gil, M. J.; Pare´s, D.; Grandea, L. Circ. Esp. 2006, 80 (6), 369–372. (18) Singh, B. Int. J. Pharm. 2007, 334, 1–14. (19) Pharmacopoeia of India., 3rd ed.; Controller of publications: Delhi, 1985; Vol II, Appendex 7, p A-142.

Singh and Sharma (20) Alfrey, T.; Gurnee, E. F.; Lloyd, W. G. J. Polym. Sci. C 1966, 12, 249– 261. (21) Peppas, N. A.; Korsmeyer, R. W. Dynamically swelling hydrogels in controlled release applications. In Hydrogels in Medicines and Pharmacy, Volume III, Properties and Applications; Peppas, N. A., Ed.; CRC Press Inc.: Boca Raton, FL, 1987; pp 118-121. (22) Ritger, P. L.; Peppas, N. A. J. Controlled Release 1987, 5, 23–36. (23) Ritger, P. L.; Peppas, N. A. J. Controlled Release 1987, 5, 37–542. (24) Yates, E. A.; Valdor, J. F.; Haslam, S. M.; Morris, H. R.; Dell, A.; Mackie, W.; Knox, J. P. Glycobiology 1996, 6 (2), 131–139. (25) Aspinall, G. O.; Khondo, L.; Williams, B. A. Can. J. Chem. 1987, 65, 2069–2076. (26) Aspinall, G. O. Pure Appl. Chem. 1967, 14, 43–55. (27) Aspinall, G. O.; Chatterjee, D.; Khondo, L. Can. J. Chem. 1984, 62, 2728– 2735. (28) Dickson, A. D.; Otterson, H.; Link, K. P. J. Am. Chem. Soc. 1930, 52, 775. (29) Ouajai, S.; Hodzic, A.; Shanks, R. A. J. Appl. Polym. Sci. 2004, 94, 2456– 2465. (30) Abdel-Razik, E. A. Polym.-Plast. Technol. Eng. 1997, 36 (6), 891–903. (31) Pourjavadi, A.; Kurdtabar, M.; Mahdavinia, G. R.; Hosseinzadeh, G. Polym. Bull. 2006, 57, 813–824. (32) Wang, L.; Xu, Y. Cellulose 2006, 13, 191–200. (33) Mondal, I. H.; Ubukata, Y. U. M.; Itoyama, K. Cellulose 2008, 15, 581– 592. (34) Yazdani-pedram, M.; Lagos, A.; Campos, N.; Retuert, J. Int. J. Polym. Mater. 1992, 18, 25–37. (35) Tapia, C.; Costa, E.; Terraza, C.; Munita, A. M.; Yazdani-Pedram, M. Pharmazie 2002, 57, 744–749. (36) Mishra, B. N.; Mehta, I. K.; Khetrapal, R. C. J. Polym. Sci., Part A: Polym. Chem. 1984, 22, 2767–2775. (37) Pourjavadi, A.; Harzandi, A. M.; Hosseinzadeh, H. Eur. Polym. J. 2004, 40, 1363–1370. (38) Pourjavadi, A.; Amini-Fazl, M. S.; Hosseinzadeh, H. Macromol. Res. 2005, 13 (1), 45–53. (39) Kele, S.; Guclu, G. Polym.-Plast. Technol. Eng. 2006, 45 (3), 365–371. (40) Zilberman, E. N. Polym. ReV. 1992, 32 (2), 235–257. (41) Mostafa, K. M. J. Appl. Sci. 2005, 5 (2), 341–346. (42) Zhang, Y.; Lam, Y. M. J. Colloid Interface Sci. 2005, 285, 80–85. (43) Dharnidharka, V. R.; Nadeau, K.; Cannon, C. L.; Harris, H. W.; Rosen, S. Am. J. Kidney Dis. 1998, 31 (4), 710–712. (44) Cerf, D. L.; Irinei, F.; Muller, G. Carbohydr. Polym. 1990, 13, 375– 386. (45) Celik, M. J. Polym. Res. 2006, 13, 427–432. (46) Akat, H.; Balcan, M. Iran. Polym. J. 2007, 16 (11), 769–774. (47) Bajpai, A. K.; Shrivastava, M. J. Macromol. Sci., Part A: Pure Appl. Chem. 2000, A37 (9), 1069–1088. (48) Lasky, R. C.; Kramer, E. J.; Hui, C. Y. Polymer 1988, 29, 1131. (49) Karadag, E.; Saraydin, D.; Guven, O. J. Appl. Polym. Sci. 1997, 66, 733– 739. (50) Siepmann, J.; Peppas, N. A. Pharm. Res. 2000, 17 (10), 1290–1298. (51) Kabiri, K.; Zohuriaan-Mehr, M. J. Iran Polym. J. 2004, 13 (5), 423– 430. (52) Chen, J.; Zhao, Y. J. Appl. Polym. Sci. 2000, 75, 808–814. (53) Zohuriaan-Mehr, M. J.; Motazedi, Z.; Kabiri, K.; Ershad-Langroudi, A. J. Macromol. Sci. Part A: Pure Appl. Chem. 2005, 42 (12), 1655–1666. (54) Buchholz, F. L. Preparation and Structure of Polyacrylates. In Absorbent Polymer Technology; Peppas, L. B., Harland, R.S., Eds.; Elsevier Publishing Company: Amsterdam, 1990; pp 23-27. (55) Satish, C. S.; Satish, K. P.; Shivakumar, H. G. Indian J. Pharm. Sci. 2006, 68 (2), 133–140. (56) Zohuriaan-Mehr, M. J.; Pourjavadi, A. J. Polym. Mater. 2003, 20, 113– 120. (57) Kim, S. J.; Shin, S. R.; Kim, N. G.; Kim, S. I. J. Macromol. Sci., Part A: Pure Appl. Chem. 2005, 42 (8), 1073–1083. (58) Han, J. H.; Krochta, J. M.; Hsieh, Y.-L.; Kurth, M. J. J. Agric. Food Chem. 2000, 48, 5658–5665. (59) Amidon, G. L.; Lennerna¨s, H.; Shah, V. P.; Crison, J. R. Pharm. Res. 1995, 12, 413–420. (60) Avdeef, A. Pharm. Pharmacol. Commun. 1998, 4, 165–178. (61) Avdeef, A.; Berger, C. M.; Brownell, C. Pharm. Res. 2000, 17, 85–89. (62) Srinatha, A.; Pandit, J. K.; Singh, S. Indian J. Pharm. Sci. 2008, 70 (1), 16–21. (63) Ekici, S.; Saraydin, D. Drug DeliVery 2004, 11, 381–388. (64) Vrentas, J. S.; Duda, L.; Huang, W. J. Macromolecules 1986, 19, 1718–1724.

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