Synthesis of Biodegradable Gum ghatti Based Poly(methacrylic acid

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Synthesis of Biodegradable Gum ghatti Based Poly(methacrylic acid-aniline) Conducting IPN Hydrogel for Controlled Release of Amoxicillin Trihydrate Kashma Sharma,† Vijay Kumar,*,† B. S. Kaith,‡ Sudipta Som,† Vinod Kumar,† Anurag Pandey,† S. Kalia,§ and H. C. Swart*,† †

Department of Physics, University of the Free State, P. O. Box 339, Bloemfontein ZA9300, South Africa Department of Chemistry, Dr. B. R. Ambedkar National Institute of Technology, Jalandhar, Punjab 144011, India § Department of Chemistry, Bahra University, Waknaghat (Shimla Hills) 173234, District Solan, Himachal Pradesh, India ‡

S Supporting Information *

ABSTRACT: Gum ghatti-graf t-poly(methacrylic acid-aniline) interpenetrating network (IPN) hydrogel was prepared by a twostep aqueous polymerization method. First, poly(methacrylic acid) (poly(MAA)) chains were graft co-polymerized onto a Gum ghatti (Gg) backbone via free radical polymerization. Different reaction conditions were optimized in order to incorporate maximum water uptake capacity of the synthesized hydrogel. The synthesized hydrogel network showed a pH-dependent swelling behavior. Second, aniline (ANI) monomer was penetrated through the preformed Gg-g-poly(MAA) network by simple oxidative polymerization method. The homogeneity and distribution of different ions of the cross-linked hydrogels were investigated by the time-of-flight−secondary-ion mass spectrometry chemical imaging technique, and a correlation analysis by color overlay and scatter plot technique. The resulting cross-linked hydrogels’ structure, morphology, and thermal behavior were investigated. Biodegradation studies of the cross-linked hydrogel samples were carried out by composting soil test for a period of 60 days. The evidence for biodegradability has been confirmed by carrying out the scanning electron microscopy technique. The release profiles of the hydrogel networks were investigated through amoxicillin trihydrate model drug under different pH conditions at 37 °C. Drug release through the Gg-g-poly(MAA) matrix was found to show non-Fickian behavior at pH 2.2 and 7.0, whereas, a Fickian mechanism was exhibited at pH 9.2. On the other hand, Gg-g-poly(MAA-IPN-ANI) matrix exhibited Fickian behavior at each pH media. The hydrogel networks showed less release in acidic and neutral media than in basic media, suggesting that hydrogels may be suitable drug carriers for colon specific controlled release of drug delivery in the lower gastrointestinal tract.

1. INTRODUCTION Colon specific drug delivery refers to targeted delivery of drugs into the lower gastrointestinal tract (GT), which occurs mainly in the colon area.1,2 The localized treatment of many stomach infections becomes easier if we are able to develop colon site specific antibiotic release.3,4 The conventional methods are not much useful as they have drawbacks such as poor permeability of the antibiotics across the mucus membrane and availability of subtherapeutic antibiotic concentrations in the target area after administration from conventional tablets or capsules.5,6 Second, the contact time of antibiotic and infectious bacteria needs to be sufficiently long for successful eradication of bacteria from the gastric mucosa, which is possible only by a gastroretentive drug delivery system.5,6 Amoxicillin is used in the treatment of peptic ulcer for the eradication of Helicobacter pylori (H. pylori) bacterium that is found in the gastric mucous layer of the stomach. The usual dose given to an ulcer patient is 0.75 or 1.00 g twice daily or 500 mg three times daily.7,8 The lower and higher doses prove ineffective due to lower contact time.9 To overcome some of these problems, a stimuli-responsive hydrogels based drug delivery system that localizes the antibiotic at the site of infection to achieve bactericidal concentrations would be desirable.10,11 Recently, stimuli-responsive hydrogels based on natural polymers have attracted great attention due to their ability to © XXXX American Chemical Society

dramatically change their volume and other properties in response to small changes to various stimuli such as temperature, pH, and certain chemicals.12 They have been widely used in biomedical fields due to their outstanding properties such hydrophilicity, biocompatibility, biodegradability, and excellent water uptake capacity.13−16 The efficacy to uptake aquatic fluids is due to the presence of functional groups such as -NH2, -COOH, and -OH.14 To date, extensive studies have been conducted on hydrogels synthesized under different reaction conditions to fulfill the ever-increasing needs of pharmaceutical and medical industries.17−27 For quite a long time, superabsorbent hydrogels have also been explored as primary materials for colon specific drug release.28−30 Hydrogels based on natural polysaccharides have been used as a tool for site specific drug delivery to the lower and upper gastrointestinal (GI) track of the body under acidic and basic conditions.5 Various researchers have developed freeze-dried chitosan based hydrogels as a controlled release system for antibiotic delivery.3,31,32 Received: November 13, 2014 Revised: January 11, 2015 Accepted: January 30, 2015

A

DOI: 10.1021/ie5044743 Ind. Eng. Chem. Res. XXXX, XXX, XXX−XXX

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Industrial & Engineering Chemistry Research Table 1. Optimized Process Parameters for the Synthesis of Gg-g-poly(MAA) and Gg-g-poly(MAA-IPN-ANI)a optimized reaction parameters sample code Gg-g-poly(MAA) Gg-g-poly(MAA-IPN-ANI) a b

APS × 10−1 mol L−1 0.131 0.131

pH 7 7

time (min) 180 180

solvent (mL)

monomer × 10−1 mol L−3 −3

0.236 × 10 0.219 × 10−3b

12 12

MBA × 10−1 mol L−1

temp (°C)

mean %G

mean %S

±SD

±SE

0.324 0.324

60 60

34.9 25.94

967.2 979.1

38.9 34.8

22.5 20.1

Where the number of replication = 3, M = mean, ±SD = standard deviation, ±SE = standard error of mean.b, and %S = percentage swelling. Aniline.

Gum ghatti (G. ghatti, Gg) is a natural water-soluble polysaccharide originating from India, and the main species is Anogeissus latiofolia.33 It has excellent properties such as high solubility, pH stability, nontoxicity, and gelling characteristics. The chemical composition of gums derived from different species of Gg has been studied by various workers.33 Research efforts in this area are directed toward the grafting and network formation of Gg with different vinyl monomers and conducting polymers under variable synthetic conditions so that devices with improved property profile could be developed.34−39 Since the chemical structures of polysaccharides include functional groups such as -OH, -NH2, -CONH2, -COOH, and -SO3 therefore, they can be activated and derivatized as per requirement. Thus, such superabsorbent materials can be explored as sorbents for removing and separating toxic heavy metal ions and dyes from industrial effluents along with some other industrially important applications such as sustained drug release in biomedicals and pharmaceuticals.28,35,38 To the best of our literature knowledge, it is hard to find studies of the drug delivery aspects for crosslinked hydrogel based on Gg so far. In the present study, we have developed biodegradable hydrogels based on Gg via free radical co-polymerization. The synthesized hydrogels with optimized process parameters were characterized in detail using different techniques. The biodegradation profile of synthesized hydrogels under soil composting condition has been investigated and discussed. The release profile of the prepared hydrogels using amoxicillin trihydrate as a model drug has been studied and evaluated kinetically.

%G =

WS − Wd × 100 Wd

(2)

where Wf is the weight of the functionalized polymer and Wb is the weight of the polymer backbone. The replications carried out for the reproducibility of the results were done in triplicate, and the statistical analysis of the results was performed using the standard software package of Microsoft Excel. Arithmetic means, standard error, and standard deviations were calculated. Statistical results of the optimum %S are depicted in Table 1. A comparison of the percentage swelling and percentage grafting of the cross-linked hydrogels based on Gg prepared under different reaction conditions is given in Table S1 (Supporting Information). It is clear from the table that the %S and %G varied with synthesis conditions. 2.2. Characterization. X-ray studies were carried out on a Philips (Model PW 1830) X-ray diffractometer, using nickelfiltered Cu Kα radiation and scanned from 15 to 50° at a scan speed of 2°/min. The characteristic functional groups of the G. ghatti and its corresponding structures were analyzed by Nicolet 6700 Fourier transformed infrared (FTIR) spectrophotometer. Thermal gravimetric analysis (TGA) curves were taken by a TGA/SDTA 851e instrument (Mettler Toledo) in argon atmosphere at a heating rate of 10 °C/min. Scanning electron microscopic (SEM) images were obtained using a JEOL JSM6490LV microscope at 25 kV after being covered with a thin layer (∼20 nm) of sputtered gold. For time-of-flight−secondary-ion mass spectrometry (TOF-SIMS) analysis, a pulsed 30 keV Bi+ primary ion beam, operated at a direct current (DC) of 1 pA, and pulse repetition rate of 10 kHz (100 μs) were used to acquire chemical images of the hydrogels in the negative secondary-ion polarities. Moreover, the O+ with 1 kV and DC current of 250 nA was used as a sputter gun. The analytical field-of-view was 100 μm × 100 μm with a 512 × 512 pixel2 digital raster. The current−voltage measurements were made on compressed circular pellets (mass ∼ 0.2 g; diameter = 8 mm; thickness = 1 ± 0.07 mm; pressure = 8 tons/cm2) by a two-probe method using a Keithley source meter (Model 2400). UV−visible spectroscopy was carried out using PerkinElmer Lambda 950 UV−vis spectrophotometer. 2.3. Biodegradability Test. Test samples were studied for biodegradability through composting method following the standard procedure reported elsewhere.40 The degree of degradation at each stage was determined by evaluating the change in physical appearance, morphology, and percentage weight loss. The degree of degradation was estimated from the weight loss of the cross-linked hydrogels based on the following equation:34,37

2. EXPERIMENTAL SECTION 2.1. Synthesis of Gg-g-poly(MAA-IPN-ANI) Hydrogel. The preparation of the Gg-g-poly(MAA-IPN-ANI) (MAA = methylacrylic acid, IPN = interpenetrating network, and ANI = aniline) conducting hydrogel is a two-step process. The superabsorbent based on Gg and MAA was prepared via free radical co-polymerization using N,N′-methylenebisacrylamide (MBA) and ammonium peroxydisulfate (APS) as a cross-linkerinitiator system. Various reaction parameters such as monomer concentration, initiator concentration, cross-linker concentration, polymerization time, amount of solvent, pH, and reaction temperature were optimized to get the maximum percentage of swelling (%S). A set of Gg-g-poly(MAA-IPN-ANI) conducting hydrogels was also prepared following a technique that has been reported previously.36 Details of the reaction scheme were reported in our previous work.36 Percent graft yield (%G) and percent swelling (%S) were calculated according to the equations given as follows:36 %S =

Wf − Wb × 100 Wb

Bs =

(1)

where Ws is the weight of the swollen hydrogel and Wd is the weight of the dry hydrogel.

Wi − Wf × 100 Wi

(3)

where Wi is the initial weight of the cross-linked hydrogels and Wf represents the weight after 6 days. B


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Industrial & Engineering Chemistry Research Mt D = 4 2i M∞ πl

2.4. Drug Loading and Release Studies. Drug loading into the hydrogels matrix can be achieved by two methods: one by incorporating the drug during the polymerization process or second by absorbing the drug after the formation of cross-linked hydrogel network by incubating them in the drug solution.41 The former method entraps the drug within the matrix whereas in the latter case gel is swelled in the drug solutions until equilibrium is reached. Test samples were loaded for drug delivery study through the second method. Saturated aqueous solution (1000 ppm) of drug (amoxicillin trihydrate) was prepared in double distilled water, and the wavelength for maximum absorption by the drug was noted using a UV−vis spectrophotometer. In 100 mL saturated aqueous solution of the drug, 1.0 g of the semi-IPNs and IPNs (10 mm × 10 mm × 10 mm) was immersed for 24 h and the drug was allowed to imbibe inside the swollen matrix. The drug loaded matrices were taken out, wiped, and dried at 50 °C in a vacuum oven. The calibration curve was prepared for absorbance versus drug concentration. The drug loaded hydrogel matrices were placed in different pH media to carry out drug release behavior. The drug release experiment was performed at 37 °C in order to ascertain the stomach specific or colon specific release behavior of the candidate polymer under different pH conditions varying from acidic to basic. The concentration of the drug released in different pH media was determined by using the UV− visible spectrophotometer after every 2 h interval. The release kinetics was also studied for drug release interval. The release of drugs through the synthesized polymer matrix was found to exhibit different behavior in different pH media with respect to the time interval and was observed to show sustained drug release. 2.5. Mathematical Analysis of Drug Release Behavior. Drug release behavior of the cross-linked hydrogels was studied with a mathematical model reported earlier in the literature.16,28,41 The empirical equation has been used to explain the drug release behavior in different pH from the synthesized device. The empirical equation used to describe the liquid uptake which is the weight gain (Ms) can be considered as Ms = kt n

Here Di is the initial diffusion coefficient, Mt/M∞ is the fractional release, Mt and M∞ are the drug release at time t and at equilibrium, and l is the thickness of the sample. The average diffusion coefficient can be calculated from the following equation:28 DA =

0.049l 2 t 1/2

(7)

where t1/2 is the time required for 50% release of the drug. The later diffusion coefficient can be calculated from the given equation: ⎛ −π 2D ⎞ ⎛8⎞ Mt = 1 − ⎜ 2 ⎟ exp⎜ 2 t ⎟ ⎝π ⎠ M∞ ⎝ l ⎠

(8)

The slope of the plot between ln(1 − (Mt/M∞)) and time t has been used for the evaluation of the later diffusion coefficient, DL, as per eq 9.

⎛ slope l 2 ⎞ ⎟ DL = ⎜ ⎝ 8 ⎠

(9)

These equations give the results of the diffusion coefficient of drug release behavior.

3. RESULTS AND DISCUSSION 3.1. TOF-SIMS Analysis. The main goal of the present study was to evaluate the use of ToF-SIMS to study the homogeneity, distribution, and arrangement of the different ions of Gg and their cross-linked hydrogels as well as to confirm the formation of cross-linked networks. The TOF-SIMS chemical imaging technique was employed, and a correlation analysis by color overlay and scatter plot technique was used. As shown in Figure 1, the positive ions chemical images of Gg were taken in an area of 500 × 500 μm2, and CH3+, CH2+, OH+, and CO+ ions were observed. The distribution of these ions was studied separately as well as an overlay was made. All possible combinations were studied, and it was observed that Gg showed faintly distribution of OH+ and CO+ ions. However, CH3+ and CH2+ ions were found in high concentration and show dominance in chemical imaging as clearly seen from Figure 1. The TOF-SIMS images of Gg-g-poly(MAA) and Gg-g-poly(MAA-IPN-ANI) hydrogels were taken in an area of 100 × 100 μm2. After graft copolymerization with MAA, the concentration of all ions was increased significantly as expected. The poly(MAA) is expected to have OH+, CO+, CH3+, and CH2+ ions. The vibration band observed in the region of 1700−1725 cm−1 is due to carboxylic acid stretching vibration of MAA.39 It has been observed that the concentration of CO+ ions was increased as shown in Figure 2. The chemical images and overlay shows the uniform distribution of all ions on the surface of the backbone and confirm the formation of graft co-polymer based on Gg and MAA. The TOFSIMS images of Gg-g-poly(MAA-IPN-ANI) are shown in Figure 3. CH2+, CH+, and NH+ ions are observed in the images. These ions are distributed in the measured area, but some higher concentration CH2+ and CH+ areas in the overlays are visible. The NH+ ions are also observed in the studied area for Gg-g-poly(MAA-IPN-ANI), which may point to the grafting of polyaniline chains on the semiIPN matrix. The peak observed at 690 cm−1 in the FTIR spectrum of Gg-g-poly(MAA-IPN-ANI) is due to C−H out-of-plane bending

(4)

where k and n are constants. Drug release from the swelled samples can be evaluated using the power law equation.28,42 When Ms is replaced with Mt/M∞, the modified expression is as follows: Mt = kt n M∞

(6)

(5)

where Mt/M∞ represent the fractional release of 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. The n value is used to predict different release mechanisms.16 n ≤ 0.45 indicates Fickian diffusion, in which the rate of diffusion is less than that of relaxation and release is primarily controlled by the diffusion process. The value of n in the range of 0.45 < n < 0.89 indicates the mechanism is non-Fickian diffusion or anomalous diffusion, where the diffusion and relaxation rates are comparable and drug release depends on both diffusion and erosion of the matrix. When n > 0.89, the major mechanism of drug release is case II diffusion, where release is mainly controlled by the polymer relaxation process.16,28 The slope and intercept of the plot between Mt/M∞ and ln t give the values of n and k. Fick’s law was used to describe the diffusion process. The initial, average, and later diffusion coefficients were calculated from the following equations:28 C


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Industrial & Engineering Chemistry Research

Figure 1. ToF-SIMS images of Gum ghatti.

Figure 2. ToF-SIMS images of Gg-g-poly(MAA).

3.2. FTIR Spectroscopy. FTIR spectra of Gg, Gg-gpoly(MAA), and Gg-g-poly(MAA-IPN-ANI) have been shown

of single substituted benzene rings. These results are in good agreement with the FTIR analysis. D


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Figure 3. ToF-SIMS images of Gg-g-poly(MAA-IPN-ANI).

substituted benzene rings (region VI in Figure 4). The shifting and formation of new bands supported the formation of Gg-gpoly(MAA-IPN-ANI) hydrogel. 3.3. Current−Voltage Characteristics. The room temperature current−voltage characteristics of Gg-g-poly(MAAIPN-ANI) hydrogel network doped with HCl at different concentrations is shown in Figure 5. The linear response of the

Figure 4. FTIR spectra of Gum ghatti based cross-linked hydrogels.

in Figure 4. The Gg spectrum showed a broad absorption band between 3200 and 3500 cm−1 indicating the presence of -OH stretching vibration of the carbohydrate (region I in Figure 4).35,39 The bands observed in the region 2800−3000 cm−1 refer to the -CH stretching vibrations (region II in Figure 4). The peaks at 1612 and 1420 cm−1 are related to the presence of −CO stretching of a carbonyl group (region III in Figure 4) and C−C bending vibration (region IV in Figure 4). A band at 1032 cm−1 showed C−O−C stretching vibration (region V in Figure 4).35,39 After the cross-linking with MAA, the absorption spectrum showed additional peaks from the backbone. The vibration band observed in the region of 1700−1725 cm−1 is assigned to carboxylic acid, and the characteristic vibration modes at ca. 1174 cm−1 are attributed to N−Q−N (Q represents a quinone ring). FTIR spectrum of Gg-g-poly(MAA-IPN-ANI) showed the characteristic peaks of PANI, as well as Gg-g-poly(MAA).37,39 The characteristic peak at 1570 cm−1 is assigned to the CC stretching modes of the quinoid ring in the PANI backbone. The peak at 1498 cm−1 corresponds to CC stretching modes of the benzoid ring in the polyaniline backbone, and the peak at 690 cm−1 is ascribed to C−H out-of-plane bending of single

Figure 5. Current−voltage characteristics of Gg-g-poly(MAA-IPN-ANI).

data shows that the cross-linked polymer networks obey Ohm’s law. The increase in current has been found with an increase in HCl concentration up to 2.0 N, and further increase in dopant concentration results in a decreased current value. The increase in the current values with an increasing HCl concentration may be due to the enhancement of charge carriers on the surface of PANI chains.44 On the other hand, the dropped current at high concentration of HCl is probably due to the overprotonation of PANI chains causing a decrease in the delocalization of charge over the length of PANI. The decrease in the delocalization of charge carriers hampers the movement of the charge carriers between the valence band and the conduction band and results in a low current.35 3.4. X-ray Diffraction Studies. XRD patterns of Gg, Gg-gpoly(MAA), and Gg-g-poly(MAA-IPN-ANI) hydrogels were recorded and have been shown in Figure 6. A broad peak at 2θ = 19.74° is the characteristic of Gg, which reflected a partial E


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in significant weight loss of 57.21%, 38.1%, and 27.7% in the case of Gg, Gg-g-poly(MAA), and Gg-g-poly(MAA-IPN-ANI) at a temperature range of 200−400 °C, respectively. However, further increase in decomposition temperature resulted in a slow rate of weight loss in the case of Gg and Gg-g-poly(MAA). Gg, Gg-g-poly(MAA), and Gg-g-poly(MAA-IPN-ANI) showed 28.1%, 33%, and 45% weight loss between 400 and 600 °C. The subsequent weight loss at higher temperature may be due to the degradation of the samples.37 Although IDT of Gg-g-poly(MAAIPN-ANI) is higher than Gg-g-poly(MAA), but residual left is high in case of Gg-poly(MAA). So the cross-linked hydrogels were found to be thermally more stable than the backbone. On the other hand, Gg-g-poly(MAA) hydrogels have higher thermal stability than that of the Gg-g-poly(MAA-IPN-ANI). This may be due to maximum percentage grafting found in the case of Gg-g-poly(MAA) as compared with Gg-g-poly(MAA-IPN-ANI). Second, polyaniline is not very stable; it gets degraded easily in higher temperature which also leads to its less thermally stable character. 3.6. Biodegradation Studies of the Gg-g-poly(MAA) and Gg-g-poly(MAA-IPN-ANI) Hydrogel Polymers. The ability of hydrogels based on different materials to degrade under both aerobic and anaerobic conditions is considered to be the most prominent properties of these materials.45 Many techniques have been used to modify the physical and chemical properties of natural polymers with different monomers suited for various industrial applications.45 The biodegradability studies of the cross-linked hydrogels were examined using the soil composting method. It is well reported for biobased polymers that the process of biodegradation typically begins with the backbone polymer. The variation of percentage weight loss of hydrogels on degradation time under compositing soil condition has been depicted in Table S3 (Supporting Information). It can be seen in Supporting Information Table S3 that the weight of the cross-linked hydrogels decreased continuously with the passage of time and the weight loss was lower in the early days than in the later days of biodegradation. The Gg-g-poly(MAA) and Gg-g-poly(MAA-IPN-ANI) hydrogels were found to be 80−90% degraded after the composting method. The degradation of polymers depends on several factors, e.g., pH, oxygen content, temperature, availability of mineral nutrients, and humidity, which are responsible for the growth of microorganisms.40,45 The percentage weight loss calculation is found to be an important method employed to check the biodegradation rate of materials. The degradation rate of Gg-gpoly(MAA-IPN-ANI) in the composting soil test was faster than Gg-g-poly(MAA). The Gg-g-poly(MAA) lost 78.2% weight after 60 days. On the other hand, a Gg-g-poly(MAA-IPN-ANI) sample was readily mineralized by the microorganism, reaching a maximum degree of 92.7% after 60 days. The rate of degradation was found to be 1.3 mg/day in the case of Gg-g-poly(MAA), while 1.54 mg/day was the case of Gg-g-poly(MAA-IPN-ANI). Degradation of the hydrogels can be attributed to breakage of cross-linked poly(MAA) chains and polyaniline chains due to bacterial attack and hydrolysis through bacterial digestion process.34 It was found that Gg-g-poly(MAA) has a high percentage grafting due to the breaking of covalent bonds, which takes more time and thus results in less degradation as compared to the Gg-g-poly(MAA-IPN-ANI) (Table 1).37 The weight loss was dominant in Gg-g-poly(MAA-IPN-ANI) as compared to Gg-g-poly(MAA). This may be because polyaniline is not stable in nature; it gets degraded in moistened condition and leaves a way behind for the entry of a microbes battery in the

Figure 6. X-ray diffraction patterns of Gum ghatti based cross-linked hydrogels.

crystalline nature with dominant amorphous phase.37 Gg-gpoly(MAA) showed a different XRD pattern with a significantly shifted and reduced main peak from the pure Gg that confirmed the formation of cross-linked hydrogel. The reduction in the peak intensity reflected that cross-linked hydrogel became more amorphous. This might be due to the fact that with cross-linking the surface becomes rougher because polymerized chains attached randomly on the surface. On the other hand, Gg-gpoly(MAA-IPN-ANI) showed a slightly shifted and enhanced main peak as compared to Gg-g-poly(MAA). The cross-linking between Gg and MAA decreases the crystalline behavior of the Gg, whereas the cross-linking between Gg-g-poly(MAA) and aniline increases the crystalline behavior. 3.5. Thermal Behavior. TGA thermograms of G. ghatti and cross-linked hydrogels are shown in Figure 7. It is clear from the figure that a two-stage decomposition process is found for all of

Figure 7. TGA spectra of raw and grafted samples.

the samples. The degradation trends in all of the samples are similar, but the residue left behind after decomposition is different for each sample. The initial decomposition temperature (IDT), final decomposition temperature (FDT), percentage weight losses at different temperature intervals, and residue left in the case of Gg and their cross-linked hydrogels have been summarized in Table S2 (Supporting Information). In the case of Gg, Gg-g-poly(MAA), and Gg-g-poly(MAA-IPN-ANI) initial weight loss was found to be 13.7%, 5.8%, and 7.3% at 100−200 °C, respectively. It is probably due to the removal of moisture and loss of volatile components up to about 200 °C.37 However, beyond this temperature decomposition of the samples resulted F


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Industrial & Engineering Chemistry Research matrix.34,37 This causes deep and fast penetration of bacteria that cause more breakage, and destruction of superabsorbent results in more weight loss. Degraded samples of the cross-linked hydrogels were also characterized by SEM analysis. Figure 8 shows the SEM images of

Gg-g-poly(MAA) and Gg-g-poly(MAA-IPN-ANI) was found to be 59% and 82%, respectively. The drug loading was found more in Gg-g-poly(MAA-IPN-ANI) as compared to Gg-g-poly(MAA). The synthesized Gg-g-poly(MAA) hydrogel has a cross-linked structure and less pores, which inhibit the absorption of drug molecules. However, after interpenetration of polyaniline chains inside the Gg-g-poly(MAA) matrix creates voids on the surface and thus leads to the easy loading of the drug molecules into the matrix. Synthesized cross-linked hydrogels were found to swell constantly as a function of time; they were observed to be suitable devices for drug release mechanism. The release of amoxicillin trihydrate through loaded Gg-g-poly(MAA) and Gg-g-poly(MAA-IPN-ANI) hydrogels in the medium at different pH was carried out at λmax = 228 nm in triplicates. Various pH solutions of 2.2, 7.0, and 9.2 were used as releasing media in the present study. A controlled drug delivery system has many advantages over the conventional drug release methods such as keeping a constant level of drug compound in the blood with minimum fluctuations. Controlled release of drugs leads to expected and reproducible release rates over a long period of time which protect the bioactive compound from premature decay. This also leads to less side effects as well as lowering the wastage of drug and frequent dosing. Controlled drug release can be achieved by various systems; the drug dose levels in the blood plasma depend on the amount of drug released from the device.46 The effect of pH on amoxicillin trihydrate release behavior through Gg-g-poly(MAA) and Gg-g-poly(MAA-IPN-ANI) has been studied as shown in Figures 9 and 10, respectively. The diffusion exponent, gel characteristic constants, and diffusion coefficients for the release of amoxicillin trihydrate through loaded cross-linked hydrogels has been studied and given in Table 2. Figure 9a shows the amoxicilin trihydrate release patterns of Gg-g-poly(MAA) at different pH values. It is clear from Table 2 that Gg-g-poly(MAA) exhibits a 104 ppm initial release of amoxicillin trihydrate at 2 h intervals in basic medium with initial diffusion value of 3.2 × 10−5 cm2 h−1 followed by 103.8 ppm release at neutral media with Di = 3.0 × 10−5 cm2 h−1 and 61 ppm in acidic medium with Di = 2.9 × 10−5 cm2 h−1. The final release of the drug at the interval of 14 h was found to be 202 ppm in the case of neutral medium with later diffusion value of 4.14 × 10−6 cm2 h−1 followed by 226 ppm in alkaline medium (DL = 4.65 × 10−6 cm2 h−1) and 169 ppm in acidic medium with DL = 2.88 × 10−6 cm2 h−1. The release of amoxicillin trihydrate was found to increase with an increase in pH. It was due to the fact that at lower pH -COO− groups are shielded by H+ ions screening effect, resulting in the collapsed state of the polymer matrix,28,41 whereas at higher pH these partially ionized -COO− groups are least shielded and maximum repulsions between different polymeric chains exist resulting in larger swelling of the matrix with increased fluid intake and hence increased drug diffusion. The drug release was also found to be dependent on time. At the start, the drug release slowly kept on increasing with an increase in the time interval and the maximum equilibrium was attained with a constant rate of drug release. This could be due to the fact that in the beginning the drug loaded polymer matrix slowly swells under different pH media allowing slow diffusion of drug which further increases with an increase in swelling until equilibrium is reached.41 It is also clear from Table 2 that Gg-g-poly(MAA-IPN-ANI) showed initial release of 216 ppm at pH 9.2 with initial diffusion value of 2.9 × 10−5 cm2 h−1, whereas it showed 203 ppm at pH 7.0 (Di = 3.1 × 10−5 cm2 h−1) and 182 ppm at pH 2.4 (Di = 3.0 × 10−5 cm2 h−1) was observed. On the other hand final release of

Figure 8. SEMs images of synthesized cross-linked hydrogels (a) Gg-gpoly(MAA) before biodegradation; (b) Gg-g-poly(MAA-IPN-ANI) before biodegradation; (c) Gg-g-poly(MAA) biodegradation stage I; (d) Gg-g-poly(MAA-IPN-ANI) biodegradation stage I; (e) Gg-g-poly(MAA) biodegradation stage II; (f) Gg-g-poly(MAA-IPN-ANI) biodegradation stage II using compositing soil method.

the cross-linked hydrogels before and after degradation. In the case of Gg smooth surface morphology was observed,35 whereas poly(MAA) grafted Gg showed whisker-like morphology with a rough agglomerated surface (Figure 8a). On the other hand, Gg-gpoly(MAA-IPN-ANI) showed a layered type surface morphology (Figure 8b). Before the degradation, only small cracks and pores were observed on the surface of cross-linked hydrogels. But, after incubation in the composting soil, the cross-linked hydrogels showed a rough surface; pores and cracks were different on the surface and obvious inside the hydrogel, which reflects that the cross-linked hydrogels may degrade simultaneously in the bulk and on the surface (Figure 8c,d). The rough surface porosity increased and the surface became heterogeneous at the later stage of biodegradation because of the breakage of the surface of crosslinked hydrogel which might be due to the degradation of Gg and MAA by the fungal and bacterial species commonly found in the soil that are responsible for degradation (Figure 8e,f).34,37,40,45 The enhanced degradation at this stage might be due to detachment of cross-linked chains from the surface of the backbone. Thus, it can be concluded from the morphological studies that the cross-linked networks of Gg-g-poly(MAA) and Gg-g-poly(MAA-IPN-ANI) were degraded in the composting soil test. 3.7. Drug Delivery Studies. Amoxicillin trihydrate was selected as a model drug. Drug loading efficiency of G


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Figure 9. Effect of pH on amoxicillin trihydrate release behavior through Gg-g-poly(MAA): (a) concentration vs time, (b) ln(1 − Mt/M∞) vs time, (c) Mt/M∞ vs t1/2, and (d) ln Mt/M∞ vs ln t.

Figure 10. Effect of pH on amoxicillin trihydrate release behavior through Gg-g-poly(MAA-IPN-ANI): (a) concentration vs time, (b) ln(1 − Mt/M∞) vs time, (c) Mt/M∞ vs t1/2, and (c) ln Mt/M∞ vs ln t.

drug at the interval of 14 h was found to be maximum at pH 9.2 with 598 ppm having later a diffusion value of 3.6 × 10−6 cm2 h−1, followed by the release of 516 ppm at neutral medium with DL = 4.14 × 10−6 cm2 h−1 and 478 ppm drug release at pH 2.4 (DL = 3.55 × 10−6 cm2 h−1). The results so obtained can be explained on the basis that, at lower pH value, the -COOH and -CONH2

groups present in the Gg-g-poly(MAA-IPN-ANI) chain tend to remain in an isolated state due to ion screening effect, which gets decreased with an increase in pH leading to more volume capacity for fluid uptake and greater diffusion of drug. The value of n points out that the release of entrapped drug from the Gg-g-poly(MAA) in different release media with pH 2.4 and H


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Table 2. Diffusion Exponent, n, Gel Characteristic Constant, k, and Diffusion Coefficient of Amoxicillin Trihydrate Release Behavior through Loaded Cross-linked Hydrogels at Different pH diffusion coefficient (cm2 h‑1)

drug release (ppm) samples

pH

initial

final

n

Gg-g-poly(MAA)

2.4 7.0 9.2 2.4 7.0 9.2

61 82 104 182 203 216

169 202 226 478 516 598

0.56 0.46 0.34 0.44 0.41 0.37

Gg-g-poly(MAA-IPN-ANI)

−2

k × 10 3.5 8.3 12.4 5.9 6.3 3.3

pH 7.0 occurs through a non-Fickian diffusion process.16 However, a Fickian type mechanism was observed at pH 9.2. On the other hand, Gg-g-poly(MAA-IPN-ANI) exhibited a Fickian type mechanism for the drug release at each pH.16 It has also been observed that values of DL are less than that of Di indicating faster release of drugs at early stages as compared to that of later stages. Thus, it can be said that the synthesized hydrogels can be used in the fabrication of controlled drug delivery devices where quick release of the drug is desired initially and sustained release thereafter.28,41 Further, it was found that the hydrogels are reliable drug delivery devices for colon specific drug delivery as the drugs were found to be released to a greater extent in alkaline medium as compared to acidic and neutral media.28

■

DL × 10−6

mechanism

2.9 3.0 3.2 3.0 3.1 2.9

2.4 2.8 3.47 2.4 2.8 2.4

2.88 4.14 4.65 3.55 4.14 3.6

non-Fickian non-Fickian Fickian Fickian Fickian Fickian

REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

Tables listing comparison of the percentage swelling and percentage grafting of the cross-linked hydrogels, TGA data of Gum ghatti, Gg-g-poly(MAA), and Gg-g-poly(MAA-IPN-ANI), and results of biodegredation studies of Gg-g-poly(MAA) and Gg-g-poly(MAA-IPN-ANI). This material is available free of charge via the Internet at http://pubs.acs.org.

■

DA × 10−4

National Research Foundation of South Africa. The University of the Free State Cluster program is also acknowledged for financial support.

4. CONCLUSION Biodegradable hydrogels based on Gg with MAA and ANI was successfully synthesized using a free radical co-polymerization. The grafting has been confirmed by TOF-SIMS and FTIR spectroscopic techniques. The thermal stability of the crosslinked hydrogels was much higher than that of Gg. The percentage degradation of Gg-g-poly(MAA-IPN-ANI) is higher than that of Gg-g-poly(MAA) in the composting soil test. The release of amoxicillin trihydrate from the drug loaded hydrogels has been observed more in pH 9.2 as compared to pH 2.4 and pH 7. Further, these hydrogels can be used in the fabrication of controlled drug delivery devices where quick release of the drug is desired initially and sustained release thereafter.

■

Di × 10−5

AUTHOR INFORMATION

Corresponding Authors

*(V.K.) Tel.: +27-849774899. Fax: +27-514013507. E-mail: vijays_phy@rediffmail.com. *(H.C.S.) Tel.: +27-849774899. Fax: +27-514013507. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS The research is supported by the South African Research Chairs Initiative of the Department of Science and Technology and I


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Synthesis of Biodegradable Gum ghatti Based Poly(methacrylic acid

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