Article pubs.acs.org/Langmuir

Correlation Study of Structural Parameters of Bioadhesive Polymers in Designing a Tunable Drug Delivery System Baljit Singh* and Vikrant Sharma Department of Chemistry, Himachal Pradesh University, Shimla 171005, India

ABSTRACT: Keeping in view the importance of network structure in designing tunable drug delivery devices, in the present work, correlation between structural parameters and drug release profile has been determined for polysaccharide gum based polymers. These polymers have been characterized by SEMs, FTIR, 13C NMR, XRD, TGA/DTA/DTG, DSC, and swelling studies. The mechanical, biocompatible, and mucoadhesive properties of polymers have also been determined. The polymer network parameters such as polymer volume fraction in the swollen state, Flory−Huggins interaction parameter, molecular weight of the polymer chain between two cross-links, cross-link density, and mesh size have been evaluated. Different kinetic models have been applied for the drug release profile of the antifungal drug fluconazole. The swelling and drug release occurred through a non-Fickian diffusion mechanism and a release profile best fitted in the Higuchi square root model. The polymers have been observed as non-thrombogenic, hemo-compatible, and mucoadhesive in nature and may be used in slow drug delivery applications to oral mucosa. infections.7,8 Conventional formulations are associated with some drawbacks, and hence, there is necessity to develop the mucoadhesive controlled drug delivery system to provide its prolonged release required within the therapeutic concentration.9 The polysaccharide tragacanth gum (TG) is a dried gummy exudation obtained from the branches of genus Astragalus (family Leguminosae). It is generally recognized as safe (GRAS) by the Food and Drug Administration (FDA).10 TG has been used in various pharmaceutical and food applications as a suspending agent/emulsifying agent.11 It is also used in toothpastes and mouthwash to reduce the adhesion of Streptococcus mutans to teeth. It is a biodegradable and biocompatible biopolymer which is non-allergenic, nonmutagenic, non-teratogenic, and non-carcinogenic.12 TG is a complex, highly branched, heterogeneous polysaccharide which consists of two fractions named as tragacanthic acid (or bassorin) and arabinogalactan (or tragacanthin).10 It has been used as a mucoadhesive drug delivery system for penicillin to the oral mucosa.13 It exhibited a considerable potency for

1. INTRODUCTION Design of drug delivery systems is as important as the design of new drug molecules. Polymer based drug delivery devices are effective in enhancing drug targeting specificity, lowering systemic drug toxicity, and providing protection for drug against biochemical degradation. Polymeric hydrogels specially based on polysaccharides have attracted considerable attention as an excellent candidate for controlled release of therapeutic agents.1−3 The properties of hydrogels which make them suitable for various biomedical applications are dependent on their cross-linked structure, which is influenced by the concentration of monomers and cross-linker used during synthesis. The diffusion of drug from hydrogels can be controlled by tailoring the cross-linked network structure.4 In order to understand the cross-linked structure of the hydrogels, the most common approach is to study their swelling behavior.5 Once this information is obtained, the gel can be manipulated by varying the mesh size to enable diffusion of drug in a controlled manner.6 In the present work, a correlation study of structural parameters of newly explored tragacanth gum (TG)− polyvinylpyrrolidone (PVP) based polymeric hydrogels has been carried out to design the tunable drug delivery system for fluconazole. It is an antifungal agent, and it has been reported for the treatment of oral candidiasis, along with other mucosal © 2014 American Chemical Society

Received: April 22, 2014 Revised: June 9, 2014 Published: June 25, 2014 8580

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wound healing.14 It has good compatibility with synthetic polymer like PVP, to form polymeric blends.15 TG and PVA based nanofibers showed an antibacterial property against Gram-negative bacteria.16 Amoxicillin loaded TG based mucoadhesive tablets are developed to overcome limitations like low biological half-life and high dosing frequency. The higher gelling ability of TG has the potential for sustaining and controlling the release of water-soluble drugs.17 On the other hand, PVP is a non-toxic and biocompatible polymer and has a remarkable tolerance to the body due to its polypeptide-like structure.18,19 Additionally, its mucoadhesive and non-immunogenic nature makes it a material of choice for the mucosal drug delivery applications.20 Antifungal drug loaded PVP based mucoadhesive polymers have been developed to increase the contact time of drug with the vaginal mucosa for the treatment for vaginal candidasis.21 In view of the above, the present study is an attempt to prepare the mucoadhesive biocompatible tragacanth gum−PVP based polymers meant for site specific delivery of drug fluconazole to oral infections. These polymers have been characterized with scanning electron micrographs (SEMs), Fourier transform infrared spectroscopy (FTIR), solid state 13C NMR spectroscopy, X-ray diffraction study (XRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), gel strength, mucoadhesion, blood compatibility, and swelling studies. The effect of reaction parameters and nature of swelling medium on swelling and various network parameters such as the polymer volume fraction in the swollen state (ϕ), molecular weight of the polymer chain between two neighboring cross-links (M̅ c), Flory−Huggins interaction parameter (χ), cross-link density (ρ), and mesh size (ξ) were studied. The swelling of hydrogels has been carried out in solutions of different pH’s, temperatures, and salt concentrations. This article also discusses the swelling and drug release mechanism.

2.3. Characterizations. The polymers were characterized by scanning electron micrographs (SEMs), Fourier transform infrared spectroscopy (FTIR), solid state 13C NMR spectroscopy, X-ray diffraction study (XRD), thermogravimetric analysis (TGA), differential thermal analysis (DTA), differential thermogravimetry (DTG), differential scanning calorimetry (DSC), gel strength, and swelling studies. SEMs were taken on an FEI SEM Quanta 256, Model D9393 (Singapore). Scanning electron micrographs were obtained by scanning the surface of samples with a high energy beam of electrons (5−20 kV). A focused beam of high energy electrons was used to generate a variety of signals at the surface of solid specimens. These electrons interacted with atoms of the sample and have produced the signal which has revealed the information about surface morphology, chemical composition, crystalline structure, and orientation of materials. The SEM images of tragacanth gum, PVP, and dried TGcl-PVP hydrogels were taken at high vacuum pressure ((1.42−0.571) × 10−5 Torr) using a high energy beam of electrons (5−20 kV), while the SEM images of swelled TG-cl-PVP hydrogels were taken at low vacuum pressure (0.293 Torr) in environmental mode. All SEM images were taken on carbon tape without using any staining or coating at 2000× magnification. FTIR spectra of polymers were recorded in KBr pellets on a Nicolet 5700FTIR THERMO (USA). XRD measurements of polymers were made using a PAN-analytical X’Pert Pro powder diffraction system (The Netherlands). The solid state 13C NMR was carried out on a BRUKER DSX-300 solid state NMR spectrometer. The spectrophotometer was operated at a magnetic field of 7.0 T and at a frequency of 75.4 MHz for 13C. TGA, DTA, and DTG were carried out on an EXSTAR TG/DTA 6300 thermal analyzer. These thermograms were obtained in the range 20−800 °C under air atmosphere at a 10 °C/ min heating rate. DSC scans of the powdered samples were recorded on a NETZSCH DSC 204 (USA). All samples were weighed (3−5 mg) and heated at a scanning rate of 10 °C/min under dry nitrogen flow (50 mL/min) in the 25−300 °C temperature range using an empty pan sealed as a reference. The gel strength of hydrogels was measured by a texture analyzer (TA.XT plus Stable Micro system, U.K.) with a 5 kg load cell. Each test was carried out in triplicate. After a trigger force of 5 g is attained, the probe then proceeds to penetrate into the gel to a depth of 5 mm. At this depth, the maximum force reading (i.e., the resistance to penetration) is obtained and translated as the “gel strength” of the sample. The resistance of the hydrogels to penetration and withdrawal of the cylindrical probe with a diameter of 10 mm (P/10) was measured. The pretest speed was set up at 1.0 mm/s, the test speed at 0.5 mm/s, and the post-test speed at 1.0 m/s and the penetration depth was 5 mm, with a fixed strain of 10% being imposed with an acquisition rate of 200 points/s. Swelling studies of the polymers were carried out by the gravimetric method in triplicate.22 2.4. Drug Release Studies. The release profile of the model drug fluconazole from the drug loaded hydrogels was determined in distilled water, pH 2.2 buffer, and pH 7.4 buffer. Preparation of buffer solution, calibration curves, drug loading, drug release, and preparation of reagents have been discussed elsewhere.22 The calibration curves of fluconazole were prepared in distilled water, pH 2.2 buffer, and pH 7.4 buffer solution at λmax = 260 nm. The loading of a drug into the hydrogels was carried out by the swelling equilibrium method. In vitro release studies of the drug were carried out by placing dried and drug loaded sample in a definite volume of releasing medium for 30 min at 37 °C, and then, sample was transferred to the fresh releasing medium. The process was repeated for 300 min, and finally, polymers are removed after 24 h. The release of drug from the polymer samples was measured from the calibration graphs which were prepared on the UV−visible spectrophotometer (Cary 100 Bio, Varian). All of the studies were carried out in triplicate. 2.5. Mechanism of Swelling and Drug Release. The mechanism of swelling and drug release has been determined by using eq 1. The values of the diffusion exponent “n” and various diffusion coefficients have been evaluated.22−24

2. EXPERIMENTAL SECTION 2.1. Materials and Methods. Polyvinylpyrrolidone (PVP, K 90, molecular weight ∼360 000) was obtained from Sigma-Aldrich (USA), N,N′-methylenebis(acrylamide) (NN-MBA), and ammonium persulfate (APS) were obtained from Qualigens Fine Chemicals MumbaiIndia, tragacanth gum (TG) was obtained from Loba Chemie (Mumbai, India), and fluconazole was obtained from CIPLA Ltd., Roorkee-India. All of the materials were used as received. 2.2. Preparation of TG-cl-PVP Hydrogels. The polymerization reaction was carried out with a definite concentration of tragacanth gum, PVP, initiator (APS), and cross-linker (NN-MBA), taken in the aqueous reaction system in a beaker. The reaction mixture was stirred for 3 h to get a homogeneous reaction mixture, and then, a polymerization reaction was carried out for 2 h at 65 °C temperature in a water bath. After completion of reaction, polymer was then stirred in distilled water to remove the soluble fractions and then it was dried in an oven at 40 °C until the constant weight was obtained. These polymers were named as (TG-cl-PVP) polymers/hydrogels. The optimum reaction parameters for synthesis of hydrogels were evaluated by varying [PVP] from 1 to 7% (w/v) and [NN-MBA] from 0.0130 to 0.0649 mol/L at constant [TG] (6% w/v) and [APS] 0.0263 mol/L. The optimum reaction conditions for the synthesis of hydrogels were obtained as [TG] = 6% (w/v), [PVP] = 4% (w/v), [NN-MBA] = 0.0259 mol/L, [APS] = 0.0263 mol/L. These conditions were determined on the basis of swelling of the hydrogels and surface consistency maintained by hydrogels after 24 h of swelling. At the optimum reaction parameters, further polymers were synthesized and were used to determine the swelling, drug release, and other properties such as blood compatibility, gel strength, and mucoadhesion. 8581

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Mt = kt n M∞

(TA.XT Stable micro System, U.K.) with a 5 kg load cell equipped with a mucoadhesive holder. The polymers were attached to a cylindrical probe (P/10) by double-sided adhesive tape. The tissue was equilibrated in simulated intestinal fluid for 15 min at 37 °C before placing it onto the holder stage of the mucoadhesive holder. The probe with the polymer attached was then moved downward (pre-test speed 0.5 mm/s) to contact with goat large intestine at different contact forces (from 0.1 to 0.5 N) and maintained for different contact times (from 60 to 300 s), and the probe was subsequently withdrawn at a specific test speed (test speed 0.1 mm/s). The trigger force and data acquisition rate were set as 0.03 N and 400 points/s, respectively. The maximum force required to separate the probe from the goat mucosa (i.e., maximum detachment force, Fmax in N) could be directly recorded in the instrument, and the total amount of force involved in the probe withdrawal from the tissue (work of adhesion, Wad) was then calculated from the area under the force versus distance curve in N mm. In order to confirm the reproducibility and validity of the obtained data, measurements were carried out in triplicate.

(1)

where Mt/M∞ is 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 parameters of release kinetics from the drug loaded polymer have been determined by using t/Ct = α + βt, where Ct is the amount of drug released at time t, β = 1/Cmax is the inverse of the maximum amount of released drug, α = 1/(Cmax)2krel = 1/r0 is the inverse of the initial release rate, and krel is the constant of the kinetics of release.25 Different kinetic models were applied to drug release data obtained for release of drug from loaded hydrogels in different media. To find out the mechanism of drug release from hydrogels, the data was applied in different in vitro release kinetics models, i.e., zero order, first order, Higuchi square root law, Korsmeyer−Peppas, and Hixson−Crowell cube root models.26,27 2.6. Determination of Network Parameters. The most important parameters used to characterize network structure are the polymer volume fraction in the swollen state (ϕ), molecular weight of the polymer chain between two neighboring cross-links (M̅ c), Flory− Huggins interaction parameter (χ), cross-link density (ρ), and mesh size (ξ), and they were determined by the swelling equilibrium method.28 Due to the random nature of the polymerization process, only average values of M̅ c can be calculated, which is a measure of the degree of cross-linking of the polymer, regardless of the nature (physical or chemical) of cross-linking, and has been studied by a number of techniques (the equilibrium swelling theory and the rubber elasticity theory). However, one of the most popular techniques to calculate M̅ c is to study the swelling of polymer in a solvent.29 The average molecular weight between cross-links (M̅ c) is related to the density of intermolecular bonds. The higher the density of cross-links, the lower the M̅ c value. Since the density of cross-links is reaction parameter dependent, the value of M̅ c is closely linked with the concentration of synthetic reaction parameters.30 In order to calculate the M̅ c values, the Flory−Rehner equation in the following form was used (eq 2).31−33

M̅ c = − dPvm,1ϕ1/3[ln(1 − ϕ) + ϕ + χϕ2]−1

3. RESULTS AND DISCUSSION 3.1. Characterizations. 3.1.1. Scanning Electron Micrographs (SEMs) of Polymers. SEM images show that the tragacanth gum polysaccharide and PVP have a smooth and homogeneous morphology, whereas cross-linked polymer has shown structural heterogeneity (Figure 1). The cross-linked

(2) 3

Here, vm,1 is the molar volume of the swelling agent (18.1 cm /mol for water), χ is the Flory−Huggins interaction parameter, and ϕ is the polymer volume fraction in the swollen state, which is a measure of the amount of fluid imbibed and retained by the hydrogel. 2.7. Blood-Compatibility Studies of Polymers. The hemocompatibility was evaluated according to the International Standard Organization (ISO) (ISO10993-4, 1999), and the two categories of blood interactions were studied: thrombogenicity and hemolytic potential.34 Thrombogenicity was evaluated by determining the weight of thrombus formation on polymeric surfaces, and it was carried out by the gravimetric method.35 The thrombose percentage is calculated as follows:

Figure 1. SEMs of (a) tragacanth gum, (b) PVP, (c) dried, and (d) swelled TG-cl-PVP hydrogels.

⎡ Mass of test sample − Mass of ( −)control ⎤ Thrombose (%) = ⎢ ⎥ ⎣ Mass of (+ )control − Mass of (− )control ⎦

networks have been observed in the SEMs of the dry as well as swelled forms of the hydrogels. SEMs of dry and swelled hydrogels have shown pores in their polymer networks. Pores of hydrogels are opened in the swollen state as compared to the dry state. These pores in hydrogels are the regions for water permeation and interaction sites of external stimuli with the hydrophilic groups of polymeric networks.37 The sizes of pores in SEM images of swelled hydrogels are observed to be less than 20 μm with irregular geometry, as shown in the scale of the photograph. 3.1.2. FTIR Spectra of Polymers. In the case of FTIR spectra of TG-cl-PVP hydrogels (Figure 2), a broad band at 3404.7 cm−1 has been observed due to hydrogen bonding of functional moieties present in TG and PVP. Besides the presence of other

× 100 The hemolytic potential was determined according to the procedure reported in American Society for Testing and Materials (ASTM).36 The hemoglobin released by hemolysis was measured by the optical densities (ODs) of the supernatants at 540 nm using a UV−visible spectrophotometer. The percentage of hemolytic index (%) was calculated as follows: Haemolytic Index ⎡ ⎤ (OD of sample − OD of negative control) ⎥ × 100 =⎢ ⎣ (OD of positive control − OD of negative control) ⎦ 2.8. Mucoadhesion Studies of Polymers. Mucoadhesion studies of the polymers were carried out using a texture analyzer 8582

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Figure 2. FTIR spectra of (a) tragacanth gum, (b) PVP, and (c) TG-cl-PVP hydrogels.

bands appearing in FTIR of TG, the presence of absorption bands at 1655.2 cm−1 (due to the CO group of PVP), 1292.7 cm−1 (due to CN stretching vibrations of the NVP ring), and 665.9 cm−1 (due to OCN deformation, amide IV band) showed incorporation of PVP into a composite polymer matrix. In the cross-linked polymer matrix, the decrease in intensity and shift in band due to OH stretching vibration (at 3404.7 cm−1) as compared with TG has been observed. This may be due to a decrease in the number of free hydroxyl groups due to crosslinking and grafting of PVP.38 A similar observation has been observed by Kaity and co-workers39 in the case of a locust bean gum−PVA based polymer matrix. Additionally, the shift in the carbonyl peak of TG from 1727 to 1736 cm−1 is also attributed to the concomitant disruption of some intramolecular hydrogen bonding in TG after grafting of PVP. 3.1.3. XRD Studies of Polymers. The results of XRD studies showed a broad peak of less intensity (characteristic amorphous peak) along with a small sharp peak for TG, which may be due to the microcrystalline structure of natural polysaccharide. In the case of PVP, there is no crystalline region in its X-ray diffractogram and two broad peaks (at 2θ equal to 11 and 22°) of less intensity showed the amorphous nature of PVP (Figure 3). In the case of the TG-cl-PVP polymer matrix, also a broad amorphous peak (at 2θ equal to 20.5°) of low intensity is present, which indicates that cross-linked polymers do not show a considerable peak of crystallinity and are amorphous in nature. The amorphous nature of hydrogels may be due to grafting of PVP chains, which restricted any long- or shortrange regular pattern in polymeric samples. Mishra and coworkers38 have also observed a decrease in the crystallinity of pectin polysaccharide on blending with PVP. 3.1.4. 13C NMR Spectroscopy of Polymers. The results of solid state 13C NMR spectra of TG, PVP, and TG-cl-PVP polymers are shown in Figure 4. In the case of TG, peaks at 18−22 ppm (due to 1 and 2 °C of polysaccharide), at 73.1 ppm (due to COH), at 104.5 ppm (due to the anomeric carbon atom of polysaccharide), and at 174.9 ppm (due to COOH

Figure 3. XRD spectra of (a) tragacanth gum, (b) PVP, and (c) TG-clPVP hydrogels.

groups of the galacturonic acid chain present in TG) have been observed,40 while, in the case of PVP, six resonance peaks at 178.012, 44.168, 38.0, 32.820, and 19.501 ppm of the pyrrolidonyl ring and at 178.012 ppm due to the carbonyl carbon (C-6) have been observed.41,42 In the case of crosslinked polymer, peaks at 18.829 (CH3), 21.233 (CH2), 43.688 (C-2 and C-3 of PVP), 71.311 (COH), 104.163 (anomeric carbon of TG), and 177.477 ppm (COOH groups of galacturonic acid and CO of PVP) have been observed. The presence of peaks at the chemical shift of 32.05, 36.457, and 43.688 ppm in polymer matrix may be due to grafting of 8583

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95.2 °C is observed, because of the presence of residual moisture present in PVP.46 In the case of a cross-linked polymer matrix, a broad endotherm centered at 85.8 °C with a heat of fusion of 425 J/g is observed with a glass transition state in the temperature range 180−191 °C (ΔCp = 0.353 J/(g K)). The lower-temperature endotherm between 40 and 120 °C (at 85.8 °C) is attributed to the evolution of unbound water from the polymer matrix.47 The presence of a glass transition state in the DSC curve of the cross-linked polymer matrix showed the modification of TG with PVP. This increase in Tg of the polymer matrix, as compared to PVP, may be attributed to the presence of intermolecular hydrogen bonding between TG ( OH) and PVP (CO)38 and showed a good miscibility of TG and PVP polymeric chains.48 3.2. Swelling Studies. Swelling is controlled by the crosslink density which is further dependent on the reaction conditions, and in the present work, the effect of [PVP] and [NN-MBA] on the structure of the polymeric networks has been studied by taking the swelling of the hydrogels. The swelling behavior of hydrogels prepared with different [PVP] was studied, and the results are presented in Table 1. Hydrogels were not formed with low [PVP] (i.e., with 1 and 2%). The swelling of hydrogels first increased with increased [PVP] up to 4% and thereafter decreased due to increase in cross-linking density after attaining an optimum value.49 The swelling followed a non-Fickian diffusion mechanism. The effect of cross-linker concentration on swelling showed that swelling generally decreased with an increase in [NN-MBA], which again could be explained on the basis of an increase in crosslinking density and decrease in porosity.50 A non-Fickian diffusion mechanism is followed during swelling. The effect of different pH’s of the swelling medium showed that swelling has been more observed in pH 2.2 buffer as compared to the pH 7.4 buffer for an unknown reason. In the case of the salt effect on swelling, the results showed a decrease in swelling in 0.9% NaCl solution as compared to the distilled water due to exosmosis. Swelling of the hydrogel increased with an increase in temperature of the swelling medium due to an increase in the diffusion rate of the solvent (Table 1). 3.3. Effect of Feed [PVP] and [NN-MBA] on Network Parameters of Hydrogels. In order to study the effect of feed [PVP] and [NN-MBA] on the network structure of TG-cl-PVP hydrogels, various network parameters such as polymer volume fraction in the swollen state (ϕ), molecular weight of the polymer chain between two neighboring cross-links (M̅ c), Flory−Huggins interaction parameter (χ), cross-link density (ρ), and mesh size (ξ) were determined as a function of feed [PVP] and [NN-MBA] (Table 2). M̅ c and ξ values of hydrogels generally decreased with an increase in feed [PVP]. The values of cross-link density (ρ) increased with an increase in [PVP]. The increase in the polymer content in the reaction mixture has increased the effective cross-link density in hydrogels and decreased the pore size.51 A decrease in the values of ξ and M̅ c has been observed with an increase in [NN-MBA]. The increase in the cross-link density (ρ) (from 1.68044 × 10−5 to 4.92768 × 10−5) of hydrogels has been observed with an increase in cross-linker concentration from 0.0130 to 0.0649 mol/L during the polymerization reaction (Table 2). As the cross-linker concentration increases in the reaction system, the probability of forming cross-links in the system also increases and this favors faster gelation. This led to the decrease in flexibility of macromolecular chains, which makes the network chains stiffer.

Figure 4. Solid state 13C NMR spectra of (a) tragacanth gum, (b) PVP, and (c) TG-cl-PVP hydrogels.

PVP onto TG. Appearance of a lesser intensity peak with a downfield shift of (COH) of TG at 80.926 ppm in polymer matrix may be due to the participation of some C OH groups of TG in grafting/cross-linking.43 3.1.5. TGA, DTA, and DTG of Polymers. The results of thermal analysis are shown in Figure 5. The thermal degradation temperature showed an initial 9.4% weight loss in the cross-linked polymer matrix due to removal of bounded water of the hydrogel matrix observed below 100 °C. Initial and final decomposition were observed at 207 and 593 °C, respectively. The three-stage decomposition was found at 207, 311, and 465 °C (residue left = 29.8%) with a gradual decrease in weight. DTA curves showed endothermic peaks at 77.6 °C. Additionally, the exothermic peaks of hydrogels (346 and 508 °C) have suggested exothermic polymeric degradation. From the DTG analysis of polymers, it is observed that the rate of decomposition was at a slower rate as compared to the polysaccharide backbone and hence modification of PVP has induced some degree of thermal stability to the gum. 3.1.6. DSC Analysis of Polymers. DSC curves of TG, PVP, and TG-cl-PVP hydrogels are shown in Figure 6. The broad endothermic peak at 88.6 °C with a heat of fusion of 449.2 J/g indicated the amorphous nature of TG.44 This broad peak appears due to dehydration of hydrophilic functional groups present in the gum,45 and a glass transition temperature (Tg) has not been observed. However, in the case of PVP, the glass transition state started at 177 °C and ended at 184 °C with a ΔCp value of 0.170 J/(g K). A broad endotherm centered at 8584

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Figure 5. TGA, DTA, and DTG of (a) tragacanth gum, (b) PVP, and (c) TG-cl-PVP hydrogels.

network parameters of hydrogels have been observed as compared to distilled water (Table 2). The cross-link density (ρ) and ϕ values of hydrogels increased in salt solution. These results may be due to the fact that, when salt is added to the system, ions (Na+) diffuse from the solution into the network. The overall concentration of mobile ions (H+ and Na+) in the gel is still higher than before, but the difference between ion concentrations inside and outside is reduced. Consequently, the driving force for swelling decreases gradually with an increase in salt concentration.54 With an increase in the temperature of the swelling medium, ϕ and ρ values of network parameters of hydrogels decreased and corresponding ξ and M̅ c values of the polymer network increased. The χ values of the polymers have been observed as nearly 0.5 for all cases in swelling of hydrogels in different natures of swelling medium (Table 2). Kulkarni et al.33 have also studied the effect of temperature on the network structure of sodium alginate beads and observed an increase in M̅ c values with an increase in temperature. Overall, the reaction parameters such as PVP/NN-MBA concentration and nature

It resulted in poor chain relaxation and is responsible for a decrease in swelling of hydrogels.52 Bajpai and Giri50 have also observed similar trends for ρ and M̅ c values of carboxymethyl cellulose (CMC) based hydrogels, in the case of the effect of [NN-MBA]. The χ value increased with an increase in feed [NN-MBA]. This means that interaction between polymer and water decreases and polymer−polymer chains increase, which leads to a decrease in pore size and swelling.53 3.4. Effect of the Nature of the Swelling Medium on Network Parameters of Hydrogels. To study the influence of the nature of the swelling medium (i.e., pH, salt concentration, and temperature) on the network structure of TG-cl-PVP hydrogels, network parameters were evaluated. The decreases in mesh size (ξ) (from 28.314 to 21.712 nm) and M̅ c values (from 31 857.286 to 27 260.890 g/mol) have been observed with a change in pH of the swelling medium from pH 2.2 to pH 7.4 (Table 2). These trends may be due to more swelling of hydrogels in pH 2.2 buffer solution. In pH 7.4 buffer, the χ value has been observed more as compared to pH 2.2 buffer. In salt solution, decreases in ξ and M̅ c values of 8585

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Figure 6. DSC analysis of (a) tragacanth gum, (b) PVP, and (c) TG-cl-PVP hydrogels.

solubility of fluconazole in pH 2.2 buffer may be responsible for these trends.55 The increase in the pore size of the polymer matrix in pH 2.2 buffer facilitated the dissolution of entrapped drug and led to more release of soluble drug (Table 2). Thus, network parameters of hydrogels can be correlated with the drug release and the desired rate of drug release can be obtained by tailoring the network structure of polymers. Knowledge of the network structure of polymers in media of different pH’s could be a useful tool for designing tunable drug delivery devices.56 Drug release followed a non-Fickian diffusion mechanism where the rates of drug diffusion and polymeric chain relaxation are comparable. Diffusion of fluconazole has been found higher in later stages than earlier ones. These results show release of loaded drug without any initial burst for a long period, and hence, these hydrogels can be used for slow drug delivery systems. The kinetic parameters calculated and results are presented in Table 3. It is clear from this table that the Cmax values are almost the same for pH 2.2 and pH 7.4 buffer, whereas the initial release rate (r0) and the constant of kinetics of drug release were higher in pH 2.2 as compared to pH 7.4 buffer. The rate of drug release and amount of total release have been influenced by the cross-link density and pore size of hydrogels in the releasing medium. Fluconazole released more in pH 2.2 buffer at a higher rate as compared to pH 7.4 buffer due to the

of the swelling medium have influenced the network structure of hydrogels. 3.5. Gel Strength of Polymers. The gel strength of hydrogels in pH 2.2 buffer, distilled water, and pH 7.4 buffer are 62.677 ± 9.5, 42.388 ± 5.5, and 170.766 ± 14.8 g cm, respectively. The higher values of the gel strength in pH 7.4 buffer may be due to less swelling of hydrogels as compared to the pH 2.2 buffer. These results are further substantiated with the results of the cross-linking density of the hydrogels. The cross-link density has been observed more in pH 7.4 buffer (3.76594 × 10−5 mol/cm3) as compared to pH 2.2 buffer (3.22259 × 10−5 mol/cm3). The cross-linking density is one of the most important factors that affect gel fraction, gel strength/ mechanical properties, and swelling of hydrogels. Hydrogels swell in a swelling medium until the osmotic forces that help to extend to the polymer network are balanced by the elastic forces from the stretched segments of the network polymer, which is inversely proportional to swelling of hydrogels.37 The optimum value of the mechanical strength is necessary to maintain hydrogel integrity to prevent the hydrogel degradation and thereafter burst drug release immediately. 3.6. Drug Release Studies. It has been observed from the release profile of fluconazole in different pH media that release occurred more in pH 2.2 buffer than pH 7.4 buffer solution (Figure 7). Both more swelling of hydrogels and more 8586

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Table 1. Results of Diffusion Exponent “n”, Gel Characteristic Constant “k”, and Various Diffusion Coefficients for the Swelling Kinetics of TG-cl-PVP Hydrogels diffusion coefficients (cm2/min) parameters

swelling (g/g of gel)

diffusion exponent “n”

7.684 8.756 8.170 8.056 7.858

± ± ± ± ±

0.501 0.361 0.549 0.320 0.232

0.750 0.715 0.697 0.707 0.694

11.275 9.089 8.756 7.652 8.789

± ± ± ± ±

0.170 0.129 0.361 0.015 0.021

0.689 0.688 0.715 0.648 0.654

9.848 5.214 9.089 8.118

± ± ± ±

0.082 0.108 0.129 0.063

0.770 0.626 0.688 0.701

7.247 ± 0.188 9.089 ± 0.129 10.630 ± 0.185

0.694 0.688 0.648

3 4 5 6 7 0.0130 0.0259 0.0389 0.0519 0.0649 pH 2.2 buffer pH 7.4 buffer D.W. 0.9% NaCl 27 °C 37 °C 47 °C

gel characteristic constant “k” × 10

3

Variation of [PVP] (% w/v) 5.933 6.989 7.702 7.341 8.120 Variation of [NN-MBA] (mol/L) 7.936 8.122 6.989 10.271 10.463 Swelling Medium 5.816 18.379 8.122 8.800 Temperature 7.254 8.122 9.359

initial Di × 105

average DA × 105

late time DL × 105

3.570 4.000 5.428 5.880 6.463

2.542 2.922 4.003 4.258 4.684

3.653 4.423 5.781 6.163 6.732

3.317 3.871 4.000 4.668 5.227

2.506 2.908 2.922 3.663 3.959

3.593 4.164 4.223 5.121 5.542

4.717 6.048 3.871 3.760

3.142 4.797 2.908 2.759

4.462 5.682 4.164 3.711

3.572 3.871 3.357

2.661 2.908 2.716

4.004 4.164 3.930

Table 2. Network Parameters of TG-cl-PVP Hydrogels as a Function of Different Variations S.No.

parameters

density (dp) (g/cm3)

volume fraction (ϕ)

slope (dϕ/dT)

Flory−Huggins interaction parameter (χ)

mol. wt. between two cross-links (M̅ c) (g/mol)

cross-link density (ρ × 105) (mol/cm3)

mesh size ξ (nm)

41 112.131 38 949.414 35 809.419 38 337.949 33 120.810

2.574 66 2.620 04 2.817 39 2.780 40 3.459 58

30.152 30.183 28.252 29.592 27.898

61 930.708 36 946.645 38 949.414 29 485.725 19 027.805

1.680 44 2.778 68 2.620 04 3.301 22 4.927 68

41.344 29.783 30.183 24.879 20.593

31 857.286

3.222 59

28.314

3 4 5 6 7

1.05850 1.02049 1.00889 1.06595 1.14584

± ± ± ± ±

0.071 0.033 0.041 0.022 0.093

0.108 84 0.100 05 0.107 55 0.103 68 0.099 36

6 7 8 9 10

0.0130 0.0259 0.0389 0.0519 0.0649

1.04071 1.02663 1.02049 0.97339 0.93763

± ± ± ± ±

0.041 0.016 0.033 0.024 0.039

0.078 05 0.096 21 0.100 05 0.117 67 0.107 57

11

1.02663 ± 0.016

0.089 66

1.02663 ± 0.016

0.157 39

−0.002 75

0.544 69

27 260.890

3.765 94

21.712

1.02663 ± 0.016

0.096 21

−0.001 75

0.509 89

36 946.645

2.778 68

29.783

14

pH 2.2 buffer pH 7.4 buffer distilled water 0.9% NaCl

Effect of [PVP] (% w/v) −0.002 18 0.520 64 −0.001 94 0.514 47 −0.002 07 0.518 50 −0.001 97 0.515 73 −0.001 58 0.506 48 Effect of [NN-MBA] (mol/L) −0.001 70 0.506 25 −0.001 75 0.509 89 −0.001 94 0.514 47 −0.002 13 0.521 97 −0.001 44 0.502 62 Effect of Swelling Medium −0.001 40 0.499 93

1.02663 ± 0.016

0.107 09

−0.001 68

26 486.840

3.876 00

24.333

15 16 17

27 °C 37 °C 47 °C

1.02663 ± 0.016 1.02663 ± 0.016 1.02663 ± 0.016

0.118 12 0.096 21 0.083 12

20 923.678 36 946.645 56 447.924

4.906 55 2.778 68 1.818 75

20.932 29.783 38.652

1 2 3 4 5

12 13

0.509 84 Effect of Temperature −0.001 75 0.512 06 −0.001 75 0.509 89 −0.001 75 0.508 95

layer becomes exhausted of the drug; the next inner layer begins to be depleted by dissolution and diffusion through the polymer matrix to the releasing medium. Thus, the interface between the region containing dispersed drug and the releasing medium moves into the interior as a front.38 In our earlier study, the swelling and release of amoxicillin from the drug loaded TG-cl-poly(AAc) hydrogels has been more observed in pH 7.4 buffer as compared to pH 2.2.57 However, in the

greater cross-link density of hydrogels in basic buffer. While the different release models applied to the release profile of the drug, it has been found that release of the drug fluconazole from the drug loaded TG-cl-PVP hydrogels is best fitted in the Higuchi model with the highest value of regression coefficients (R2) (Table 3). Hence, the release pattern is described by the Higuchi model, where it is assumed that loaded drug dissolves first from the outer layer of the polymeric device, when this 8587

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release medium

0.998 25, 0.001 25 0.999 05, 0.038 26 0.999 62, 0.048 39 0.996 33, 0.005 41 0.973 42, 0.001 79 12.830 118.389 168.07 0.539

4.191

0.997 31, 0.001 03 0.999 68, 0.042 45 0.999 71, 0.043 59 0.997 73, 0.004 08 0.978 43, 0.001 84 10.873 120.009 5.102 153.37 0.504

0.993 17, 0.000 96 0.998 64, 0.045 74 0.998 81, 0.041 42 0.998 21, 0.003 76 0.968 18, 0.001 74 10.185 145.843 5.163 168.07 0.488

pH 2.2 buffer distilled water pH 7.4 buffer

Hixson−Crowell R2, kHC (min−1/3) Korsmeyer−Peppas R2, kKP (min−n) Higuchi R2, kH (min−1/2) first order R2, k1 (min−1) zero order R2, k0 (min−1) diffusion coeff icients (cm2/min) Di × 105 initial release rate, r0 × 102 (mg L−1 s−1) constant of the kinetics of release, krel × 105 (s−n)

present case, TG-cl-PVP hydrogels showed a higher degree of swelling as compared to TG-cl-poly(AAc) hydrogels. Swelling changed from 11.275 ± 0.170 to 7.652 ± 0.015 g/g of gel on increasing cross-linker concentration (from 0.0130 to 0.0519 mol/L) in TG-cl-PVP hydrogels, while in an earlier case the effect of change was less observed (i.e., from 4.083 ± 0.053 to 2.710 ± 0.085 g/g of gel) for the same variation. Swelling and drug release have occurred through a non-Fickian diffusion mechanism in both cases. The release profile of loaded drug was best fitted in a first order model in the case of TG-clpoly(AAc) hydrogels, while it is the Higuchi model in TG-clPVP hydrogels. 3.7. Thrombogenicity and Hemolytic Potential of Polymers. The results of thrombogenicity studies of TG-clPVP hydrogels showed that the weight of clot formed and thrombose percentage for polymers are 0.343 ± 0.006 g/2 mL of citrated blood and 78.02 ± 1.45%, respectively. It has been observed that clot formation was lower in the case of polymers than in the positive control (0.434 ± 0.005 g), and the polymers are classified as non-thrombogenic materials.35 Thrombogenic character is a desirable property of any material used for biomedical applications which evaluate its tissue and blood compatibility. At the same time, this material should not promote hemolysis and should be non-hemolytic in nature. In the present case, the hemolytic index (%) for these polymers has been found to be 0.51 ± 0.04%. From the results, it has been observed that TG-cl-PVP hydrogels have a hemolytic percentage less than 2% and are considered to be nonhemolytic in nature. According to ASTM F 756-00, materials can be classified in three different categories according to their hemolytic index (hemolysis %).36 Materials with a hemolytic index over 5% are considered hemolytic, while between 5 and 2% they are slightly hemolytic and below 2% they are considered as non-hemolytic in nature.34 3.8. Mucoadhesion Studies of Polymers. To study the effect of contact force and contact time on the mucoadhesion property of hydrogels with an intestinal mucus membrane, the peak detachment force (Fmax) and work of adhesion (Wad) were calculated at different contact forces and contact times. The results of Fmax with different contact forces of 0.1, 0.2, 0.3, 0.4,

maximum amount of released drug, Cmax (mg L−1)

Figure 7. Release profile of fluconazole from drug loaded TG-cl-PVP hydrogels in different media at 37 °C.

diffusion exponent “n”

Table 3. Results of Diffusion Exponent “n”, Diffusion Coefficients, Release Kinetic Parameters, and Different Models for the Release of Fluconazole from Drug Loaded TG-clPVP Hydrogels

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and 0.5 N are (22.320 ± 3.4), (11.442 ± 3.1), (14.867 ± 3.1), (32.012 ± 6.3), and (17.728 ± 0.9) × 10−3 N and with different contact times of 60, 120, 180, 240, and 300 s are (32.012 ± 6.3), (33.311 ± 6.9), (52.450 ± 7.1), (53.241 ± 4.4), and (52.055 ± 0.9) × 10−3 N, respectively. The Fmax value first increased with an increase in contact force up to 0.4 N (except 0.1 N) and then decreased at a higher contact force (0.5 N) held for 60 s of contact time. A similar trend has been obtained for the work of adhesion. With an increase in contact time (from 60 to 300 s) for a fixed contact force (i.e., 0.4 N), both Fmax amd Wad values generally increased. A longer contact time and faster probe speed not only gave better reproducibility of results but also gave better sensitivities for both parameters measured. On the other hand, a certain level of contact force has been found essential for achieving good bioadhesion, above which there is no further contribution to the bioadhesion. The maximum force of adhesion (Fmax) of (53.241 ± 4.4) × 103 N and work of adhesion (Wad) of (112.448 ± 1.5) × 103 N mm have been observed for adhesion of TG-cl-PVP hydrogels with an intestinal mucus membrane at 0.4 N contact force for 240 s contact time. Polymers having Fmax of this range were reported as potential bioadhesive polymers for a GI-mucoadhesive drug delivery system. The mucoadhesive strength of polymers with a mucosal membrane depends upon the availability of adhesive sites of natural polymer with mucin which tends to increase in bond strength of adhesion. Polymer swelling permits a mechanical entanglement by exposing the bioadhesive sites for hydrogen bonding and/or electrostatic interaction between the polymer and the mucous network. All of these factors are correlated with the strength of the bonds formed between the polymeric matrix and mucosal membrane during the contact time. An ondansetron loaded PEG and lactose based delivery system has ∼130 g (i.e., 1.3 N) of adhesive force with buccal mucosa and prolonged in vitro release and reported as a transmucosal drug delivery system which bypasses the presystemic metabolism of loaded drug.58 It is reported that a fluconazole loaded compressed disc of gum cordia polysaccharide has provided good bioadhesion and extended release of drug for 24 h.59 Overall, the newly explored polymer matrix showed sufficient mucoadhesion, biocompatibility, and mechanical strength and could be exploited as a slow drug delivery system for site specific drug delivery for an extended period. This will give more effective treatment of diseases associated with infection of mucous membrane.7 However, it is pertinent to mention here that both of the materials used in the hydrogels (i.e., tragacanth gum and PVP) have been reported as biodegradable. Fermentation of tragacanth gum by the anaerobic bacteria of the human colon has been reported, and enzymatic degradation of tragacanth gum to galactose, arabinose, xylose, and rhamnose units has been established.60,61 On the other hand, the molecular structure of PVP is similar to proteins and it contains a γ-lactam ring. It has been subjected to attack by γ-lactamase (an enzyme) produced by the microorganisms in an aqueous aerobic environment to study the biodegradation. The results proved the biodegradability of the PVP.62 Further, PVP based hydrogels have also been observed as biodegradable and have been proposed as material for biomedical devices.63

strength of the hydrogels. Swelling decreased with an increase in [NN-MBA]. The cross-link density increased and the mesh size decreased with an increase in [PVP] and [NN-MBA]. The swelling and release of drug occurred through a non-Fickian diffusion mechanism. It has been found that the drug release profile best fit in the Higuchi model. The rate of diffusion of fluconazole from drug loaded hydrogels was higher in later stages as compared to initial stages, which indicates a continuous release of loaded drug without any initial burst. Further, a correlation has been observed between structural parameters of hydrogels and the drug release profile, which indicates that a tunable drug delivery system can be designed by tailoring the network structure of desired characteristics and properties. These hydrogels have been observed as nonthrombogenic, hemo-compatible, and mucoadhesive in nature and could be utilize for developing slow mucoadhesive drug delivery systems.

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Phone: +(91) 1772830944. Fax: +(91)1772633014. Notes

The authors declare no competing financial interest.

■

REFERENCES

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