Formulation and Optimization of Natural Polysaccharide Hydrogel Microbeads of Aceclofenac Sodium for Oral Controlled Drug Delivery

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2.2.7 Process Variables and Process Optimization

The following process variables were investigated, i.e. concentration of SA, concentration calcium chloride, curing time, stirring speed and drying condition. The different batches thus produced were analyzed for size, shape, ease of preparation, drug content and drug release. It was found that optimum concentration of SA[1:10], Calcium chloride [4%], cross-linking time [2h], Stirring time-2000 rpm could influence the microbeads size, average diameter, recovery, encapsulation efficiency, size distribution swelling behavior and the release characteristics

A different batch [F11-F16] of microbeads was then prepared by using the optimized process variables and then only changes the concentration of GG and LBG coating polymers. The final formulations were subjected to several characterization studies.

2.2.8 Preparation of Alginate –Guar Gum Microbeads

To 50ml of deionized water, GG was added and stirred with the electric stirrer to form mucilage. Then SA (2%w/v) was added to form uniform dispersion. Weighed quantity of aceclofenac sodium (200mg) was added and homogenized for 5min. The resulting dispersion was dropped through syringe with needle into 100ml of 4%w/v aqueous calcium chloride solution and stirred at 200rpm for 2h. After stirring the formed beads were separated by filtration, washed with distilled water, dried at 80⁰C for 2h in an oven ^[16].

2.2.9 Preparation of Alginate-locust Bean Gum Microbeads

To 50ml of deionized water, LBG was added and stirred with electric stirrer to form mucilage. Then SA (2%w/v) was added to form homogenous dispersion. Weighed quantity of aceclofenac sodium (200mg) was added and homogenized for 5min. The resulting dispersion was dropped through syringe with needle into 100mL of 4%w/v aqueous calcium chloride solution and stirred at 2000rpm. After stirring for 2h the formed beads were separated by filtration, washed with distilled water, dried at 80⁰C for 2h in an oven ^[17].

3. Characterizations and Evaluation of Microbeads

3.1 Measurement of Micromeritic Properties of Microbeads

The flow properties were investigated by measuring the angle of repose of drug loaded microbeads using fixed-base cone method. Microbeads were allowed to fall freely through a funnel fixed at 1cm above the horizontal flat surface until the apex of the conical pile just touches to the tip of the funnel. The height and diameter of the cone was measured and angle of repose was calculated by using the following formula ^[18]. Each experiment was carried out in triplicate [n=3].

θ=tan -1(h/r)

h=cone height, r= radius of circular base formed by the microbeads on the ground.

The bulk and tapped densities were measured in a 10ml graduated cylinder as a measure of packability of the microbeads. The sample contained in the measuring cylinder was tapped mechanically by means of constant velocity rotating cam. The initial bulk volume and final tapped volume were noted from which, their respective densities were calculated.

Compressibility index or Carr’s index value of microbeads was computed according to the following equation:

Corr’s index (%) = [(Tapped density-Bulk density) / Tapped density] x100

Hausner’s ratio of microbeads was determined by comparing the tapped density to the bulk density by using the equation:

Hausner’s ratio= Tapped density / Bulk density

3.2 Particle Size Analysis

The particle sizes of both placebo and drug loaded formulations were measured by an optical microscope fitted with an ocular and stage micrometer and particle size distribution was calculated. The Olympus model (SZX-12) having resolution of 30xs was used for this purpose. The instrument was calibrated at 1unit of eyepiece micrometer was equal to 1/30mm (33.33µm). In all measurements at least 100 particles in five different fields were examined ^[19]. Each experiment was carried out in triplicate.

3.3 Scanning Electron Microscopy Analysis (SEM)

The shape and surface characteristics were determined by scanning electron microscopy (model-JSM, 35CF, jeol, Japan) using gold sputter technique. The vacuum dried particles were coated to 200 Ao thicknesses with gold palladium using prior to microscopy. A working distance of 20nm, a tilt of zero-degree and accelerating voltage of 15kv were the operating parameters. Photographs were taken within a range of 50-500 magnifications.

3.4 Drug Entrapment Efficiency (DEE)

Aceclofenac sodium content in the microbeads was estimated by a UV-spectrophotometrically. Accurately weighed 100mg of drug loaded microbeads were suspended in 100ml of phosphate buffer pH 7.2±0.1. The resulting solution was kept for 24 hrs. Next day it was stirred for 15min. The solution was filtered, after suitable dilution, Aceclofenac sodium content in the filtrate was analyzed at 275nm using Shimadzu 1201 UV-Visible spectrophotometer. The obtained absorbance was plotted on the standard curve to get the exact concentration of the entrapped drug. Calculating this concentration with dilution factor we get the percentage of actual drug encapsulated in microbeads ^[20]. The drug entrapment efficiency was determined using following relationship;

% Drug Entrapment Efficiency = [Actual drug content /Theoretical drug content] x 100

3.5 Swelling Properties

The swelling properties of the drug loaded microbeads were determined in various pH range ( i.e. 1.2, 4.8, and 6.8 buffer solutions) Thirty dried microbeads were placed in a small beaker to which 100ml of buffer solutions was added and then allowed to swell at 37⁰C. After 2h interval, the equilibrium swollen beads were observed and measured by Optical microscopy (Olympus model SZX-12). The magnitude of swelling was presented by the ratio of the mean diameter of swelling beads to the mean diameter of the dried beads before the test ^[21]. Swelling ratio was determined from the following relation.

Swelling ratio= [(Mean diameter at time t-initial diameter) / initial diameter of beads)] X100

3.6 In-vitro Drug Release Studies

The release profiles of Aceclofenac sodium from microbeads were examined in three different buffer solutions to mimic the various physiological GI-tracts. The media of pH 1.2 was representing the gastric condition; pH 6.8 was a compromise condition between pH of the gastric and small intestine and pH 7.2, which is simulated intestinal fluid. The dissolution process was carried out by using USP XIII rotating basket apparatus (Micro labs, Mumbai, India). The drug loaded microbeads (equivalent to 200mg of aceclofenac sodium) filled in empty capsule shells were put into the basket rotated at a constant speed at 75rpm and maintained temperature 37⁰C. The 900 mL of the dissolution medium, pH 1.2 containing 2% SLS and the test was done for 2h. At the end of 2h continued the test with changing the dissolution media with pH 6.8 buffer solution up to 6h and pH 7.2 phosphate buffers up to the end of 24h. At scheduled time intervals, the sample (5mL) was withdrawn and replaced with same volume of fresh medium. The withdraw sample were filtered through a 0.45µm membrane filter and after appropriate dilution, then estimated for aceclofenac sodium concentration at 275nm using Shimadzu 1201 UV-Visible spectrophotometer ^[22]. Finally, corresponding drug content in the samples was calculated from the calibration curve of aceclofenac sodium to determine the drug release pattern.

3.7 Stability Studies of Microbeads

After determining the drug content, the optimized drug- loaded microbeads were charged for the accelerated stability studies according to ICH guidelines ^[23]. To assess long-term stability, accurately weighed drug loaded microbeads equivalent to 200mg of aceclofenac sodium were filled into a hard gelatin capsules manually and sealed in a aluminum packaging coated inside with polyethylene. The studies were performed at 40 ±2⁰C and 75±5% relative humidity (RH) in the desiccators with saturated salt solution for up to 6 months. A visual inspection, drug content, in-vitro drug release was conducted every 15 days for the entire period of stability study.

4. Results and Discussions

Side effects, mainly at the gastric level are well known, following oral administration of NSAIDs. Therefore the efforts of many researchers have been concerned to solve these problems, through a variety of techniques of protection of the gastric mucosa or alternatively to prevent the NSAID release in this gastric region. In this paper we evaluate the potential utility of the natural material such as SA along with GG, and LBG as coating polymers to inhibiting the release of aceclofenac sodium in the gastric environment and minimize drug related adverse effects.

4.1 Preformulation Studies
4.1.1 Saturation Solubility Studies

The available data on solubility profile of aceclofenac sodium indicated that the drug is freely soluble in acetone and practically insoluble in water. The results of the solubility study and the influence of sink conditions are summarized in Table 1. The results showed, that there was a significant increase in solubility with increasing pH. The addition of different concentrations of SLS in 0.1N HCl significantly increased up to 0.487mg/ml. A dissolution study of dosage forms necessitates modifications in the dissolution medium to increase the solubility of practically insoluble drugs. Aceclofenac sodium is a weak acid; the solubility of aceclofenac sodium in HCl was very less compared with distilled water. However, the addition of surfactant is a reasonable approach for solubilizing such drugs, because various surfactants are present in the GI-fluid. Saturation solubility of aceclofenac sodium in different media increased with an increase in buffer pH as well as with an increase in surfactant concentration. The significant increase is attributed to the micellar solubilization by SLS. Aceclofenac sodium showed sufficient solubility in 0.1N HCl with 2%w/v of SLS which was adequate to maintain sink condition and was selected as the dissolution medium for in-vitro drug release studies. The solubility of aceclofenac sodium in calcium chloride was found to be 0.96±1.54 mg/mL The solubility of aceclofenac sodium was more in 1%w/v of calcium chloride solution than in double-distilled water, which induces certain amount of drug release, when prolonged exposés of the beads in curing medium during the manufacturing process.

4.1.2 FT-IR Spectroscopic Analysis

The molecular interactions of aceclofenac sodium, SA, GG and LBG in the microbeads were investigated using FTIR spectroscopy. The characteristic absorption peaks of pure aceclofenac sodium were obtained 3276.5, 2915.5, 1716.5, 1589.3, 1279.6 and 749.4cm^-1 corresponding to NH- stretching, C=O stretching of –COO and –COOH group respectively.(Figure 1 a) The characteristic absorption peaks SA powder showed peaks around 3077.15, 2914.98, 1615.34, 1359.60 and 754.05 cm^-1 reflective of O–H, C-H, COO− (asymmetric), COO− (symmetric), and C–O–C stretching respectively.(Figure 1 b) The cross-linking process of SA with calcium caused an obvious shift to higher wave numbers and a decrease in the intensity of COO− stretching peaks. Additionally, a change to lower wave numbers and a decrease in the intensity of the C–O–C stretching peak of SA was observed. This indicated the presence of an ionic bond between the calcium ion and the carboxyl groups of SA and partial covalent bonding between the calcium and oxygen atoms of the ether groups. (24) The physical mixture SA powder and aceclofenac sodium characteristic peaks were obtained at 2820.28, 1591.72, 1384.91, 1102.03 and 766.4cm^-1caused a shift in the O–H, COO− (asymmetric), and COO− (symmetric) stretching peaks to lower wave numbers,(Figure 1 c) suggesting that a molecular interaction between SA and aceclofenac was formed due to hydrogen bonding and electrostatic force. Further, characteristic IR peaks of Guar gum shows around 3078.18, 2836.84, 1628.19, 1503.56 and 718.81 cm^-1 and physical mixture of aceclofenac and GG 30556.97, 2940.01, 1708.99, 1509.35 and 761.24 cm^-1.(Figure 1 d, e) On other hand, the characteristic IR-peaks of LBG observed around at 3186.4, 2915.6, 1705.6, 1528.4 and 774.5 cm^-1 and physical mixture of drug obtained at 3124.2, 2856.5, 1710.8, 1538.2 and 774.5 cm^-1 (Figure 1 f, g) The IR spectra of the drug and polymer combination were compared with the spectra of the pure drug and individual polymer spectra. The peaks showed at 2916.5, 1589.3 1279.6, and 749.4cm^-1 as major peaks for drug are presents in all physical mixture of drug and polymer that confirms the drug was molecularly dispersed in the polymer without any interaction.

4.1.3 Differential Scanning Calorimetry (DSC)

DSC is a well-established method often used as a qualitative technique to characterize physical and chemical changes in either enthalpy or heat capacity of a crystalline drug in the polymer matrix during the manufacturing process. The thermal behavior of the pure aceclofenac sodium, drug loaded SA, SA-GG, and SA-LBG microbeads was characterized using DSC, as shown in Figure 2. The thermogram of pure aceclofenac showed a sharp endothermic peak at 158.50⁰C followed by corresponding meting point. (Figure 2 a] However, the drug-loaded SA microbeads showed a sharp endothermic peak at 193.5^oC. However, the DSC thermogram of drug loaded SA-GG and SA-LBG microbeads were observed at 189.50C and 195.60C respectively. It can clearly suggested the drug loaded microbeads containing SA, SA-GG and SA-LBG showed an increase in the exothermic peak temperature (Figure 2 b, c, d) and improves the thermal stability of the alginate beads. The extra obvious peak of the drug (158.5⁰C) was not observed in any type of the prepared microbeads containing the drug. There was no appreciable change in the melting endothermic peak of the physical mixture as compared to pure drug. It may indicate that there are no changes in thermal behavior of drug and also the drug was molecularly dispersed in different hydrogel matrix.

4.1.4 X-Ray Powder Diffractometry (X-RD)

The X-ray powder diffraction patterns of pure drug are compared with drug-loaded microbeads. The XRD scan of plain aceclofenac showed sharp intense peaks of crystallinity (Figure 3 a); whereas the XRD pattern of the drug-loaded microbeads exhibited halo pattern with less intense and more denser peaks compared to plain aceclofenac indicating the decrease in crystallinity or partial amorphization of the drug in the microbeads (Figure 3 b).. The intensity of the aceclofenac peaks at 14.47, 24.87, 26.26 and 29.95 and 36.55⁰C (2 θ), CA microbeads (F3) at 16.29, 39.23, 43.76⁰C (2 θ), CA-GG microbeads (F12) shows at 14.06, 16.65 45.65⁰C (2 θ), and CA-LBG microbeads (F15) 13.98, 16.76, 44.32⁰C (2 θ) was calculated using D8 TOOLS software. The calculated percentage relative crystallinity value for pure aceclofenac was 92.40% and that of formulations containing SA (F3), GG (F12) and LBG (F15) was 89.25, 83.09 and 81.32 respectively.(Figure 3 b, c, d) This is possibly due to the decrease in the degree of crystallinity of the drug following dispersal in the polymer matrix.

Figure 1. FT-IR Spectra a) Pure aceclofenac sodium b) Sodium alginate c) Guar gum d) Locust bean gum e) Physical mixture of aceclofenac sodium and sodium alginate f) Physical mixture of aceclofenac sodium and Guar gum g) Physical mixture of aceclofenac sodium and Locust bean gum.

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Figure 2. DSC Thermo-grams a) Pure aceclofenac sodium b) CA drug loaded microbeads (F3) c) CA-GG drug loaded microbeads (F12) d) CA-LBG drug loaded microbeads (F15)

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Figure 3. X-Ray diffraction patterns of a) Pure aceclofenac sodium b) CA drug loaded microbeads (F3) c) CA-GG drug loaded microbeads (F12) d) CA-LBG drug loaded microbeads (F15)

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4.2 Characterization and Evaluation of Microbeads

The total percentage yields of drug-loaded microbeads obtained were in the range between 72.40 to 88.30%w/w. It was observed that increasing the SA, GG and LBG in the formulation significantly lower the product yield, due to the formation of high viscous polymer dispersion which may be lost during manufacturing process. Further observation, while increasing in the concentration of calcium chloride and long curing time slightly increased the percent of yield.

4.2.1 Measurement of Micromeritic Properties

The rheological parameters like angle of repose, bulk density and tapped density of all microbeads confirms better flow and packaging properties. All the formulations showed excellent flowability represent in terms of angle of repose (<40⁰)²⁰. Here, too, the sodium alginate concentration has a significant positive effect on the angle of repose. (Table 3) Particle size increased with increase in the concentration of SA, GG and LBG resulted in a decrease angle. However, higher calcium chloride concentration influenced the formation of smaller beads because of shrinkage and showed an increased angle of repose. (Table 3) Bulk and tapped density of beads showed good acceptable range indicates that have good packability. The density of the beads increases as the concentration of the GG and LBG increases suggesting that the beads formed at high polymer concentration are more compact and less porous than those prepared with SA alone.(Table 3) Carr’s index, and Hausner’s ratio explains the formulated microbeads had excellent compressibility and good flow properties.(Table 3) The improvement of flow properties suggest that the microbeads can be easily handled during processing.

4.2.2 Particle Size Analysis

The mean particle sizes of drug loaded microbeads were performed by Optical microscopy, and mean particle sizes of the SA formulations (F1-F5) of microbeads were obtained in the range between 596.45±1.04 to 880±1.23 (Table 2). It was found that the particle size distribution was within a narrow size but the mean particle size was different among the formulations. The results indicated that the proportional increase in the mean particle size of microbeads increased with the amount of sodium alginate in the formulations. This could be attributed to an increase in relative viscosity at higher concentration of SA and formation of large droplets during addition of polymer solution to the gelling agent. On the other hand which increases in the concentration of GG, and LBG coating polymers the mean particle size was found to decreases in the range 708.37±1.21, 748.92±0.45, 768.78±0.22 due to the formation of dense matrix with SA and covers irregular pores and wrinkles present on the surface of SA microbeads and influences the sphericity, smooth surface of the microbeads. Further, the concentration of calcium chloride increases would significantly decreases the mean particle size of microbeads obtained in the range 746.60±0.73, 734.10±0.54, 724.40±0.34, 703.55±0.75, 688.56±1.25 (Table 2). It has been stated that when a drop of alginate solution comes in contact with calcium ions, gelation occurs instantaneously. As Ca⁺² ions, penetrates into interior of droplets, water is squeezed out of the interior of droplets resulting in contraction of beads ^[25]. The size of the spherical matrix could easily be controlled by varying the stirring speed and cross-linking time of the system.(Results are not mentioned)

Table 2. Effect of drug-polymer ratio, Concentration of calcium chloride, GG and LBG on physical characteristics of drug loaded microbeads

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Table 3. Micromeritic Properties of Drug-Loaded Microbeads

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4.2.3 Scanning Electron Microscopy Analysis (SEM)

The SEM photomicrographs are shown in Figure 4; concentration of SA influences the surface morphology of CA beads at higher concentration SA formed discrete and spherical shape with a rough outer surface and visible large wrinkles have a sandy appearance because of the surface-associated crystals of drug. Addition of GG and LBG alters morphological regularity due to formation of smooth surface; uniform sphericity and formation of thick coat on outer surface of the CA beads followed by complete entrapment of drug into interior polymer network (Figure 4 c, d).

Figure 4. SEM Photographs magnification 200X at 10kv a) Pure aceclofenac sodium b) CA drug-loaded microbeads (F3) c) CA-GG drug loaded microbeads (F12) d) CA-LBG drug-loaded microbeads (F15)

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4.2.4 Drug Entrapment Efficiency (DEE)

Actual drug concentration in the microbeads was evaluated and found to be in the range 56.20±0.50 to 76.30±0.54mg/100mg. (Table 2). The polymer SA concentration increases consequently the actual drug loading high due to increase in hydrophobicity, leading to better precipitation of polymer at the boundary phase of the droplets. On other hand, actual drug content in CA-GG and CA-LBG was determined and observed in range 60.45±0.68 to 76.30±0.54/100mg. (Table 2) Increasing the concentration of GG and LBG coating polymers influences higher drug content in the microbeads may be formation of thick surface and decreases loss of drug in the curing medium.

As showed in Table 2, by increasing the drug-polymer ratio concentration from 1:5, 1:7.5, 1:10, 1:12.5 and 1:15 w/w, and fixed other variables constant the drug entrapment efficiencies were found to in the range 63.24±0.66, to 98.90±0.86.(F1-F5) The drug entrapment efficiencies increased progressively with increasing the concentration of sodium alginate resulting in the formation of larger beads entrapping the greater amount of the drug This may be attributed to the greater availability of active calcium binding sites in the polymeric chains and, consequently, the greater degree of cross-linking as the amount of sodium alginate increased. Increasing calcium chloride concentration from 1-5%w/v the drug entrapment efficiencies were found to be in the range 83.30±0.75 to 93.30±0.2. (F6-F10) From the results, it is obvious that increasing calcium chloride concentration produced beads with higher levels of Ca ²⁺ions. Consequently, the cross-linking of the polymer and compactness of the formed insoluble dense matrices also increased, resulting in more drug entrapment in the microbeads. On other hand further increase in the concentration of calcium chloride above (5%w/v) did not enhance the drug loading. This could be due to possible saturation of calcium binding sites in the guluronic acid chain, preventing further Ca²⁺ions entrapment and, hence, cross-linking was not altered with higher concentration of calcium chloride solution ^[26]. Increasing in the concentrations of GG and LBG in CA beads the drug entrapment efficiency progressively increases and were found 92.95±1.19, 94.56±1.34, 98.89±0.98 (F11-F13) and 94.90±1.22, 96.70±1.06, 99.75±0.87 (F14-F16) respectively. It may be the formation of dense matrix and also insoluble aceclofenac uniformly encapsulate within the hydrophilic helix of SA-GG, SA-LBG interpenetrating polymer net-work.

4.2.5 Swelling Properties

The swelling ratio of the CA (F1-F5) formulated by increasing in the concentration of sodium alginate was observed under pH 1.2 acidic buffer, pH 4.8 and 6.8 phosphate buffers up to 4h. Under acidic conditions swelling of calcium alginate beads occurs scarcely.The low swelling in acidic media pH 1.2 was probably due to proton-calcium ion exchange forming insoluble alginic acid regions and followed by solvent penetration into the gel network ^[27]. Under neutral conditions the beads will swell and the drug release depends on the swelling and erosion process. Being a polyelectrolyte, alginate can exhibit swelling properties that are sensitive to the pH, ionic strength and ionic composition of the medium (28). The equilibrium swelling studies showed, with increase in the SA concentration, swelling of beads was significantly increased in pH 4.8 and pH 6.8 at the end of 4h (Figure 5 a ). It has been reported that the swelling can be enhanced by the presence of phosphate ions in higher pH which displaces the Ca²⁺ ions within the beads. The swelling behavior of the formulations (F6-F10) curing with increase in the concentration of calcium chloride produces the beads with higher levels of Ca²⁺ ions that could reduce the swelling of the beads in acidic medium but slightly increases due to ionic exchange between the phosphate ions in the buffer and higher level of Ca²⁺ ions within the beads.(Figure 5 b) The water uptake behavior of CA-GG and CA-LBG bipolymeric beads (F11-F16) was also studied. The beads swelled to less in simulating gastric fluid (SGF) of pH 1.2 in 4h.(Figure 5 c d) On transferring the beads into higher pH the swelling was significantly enhanced due to degradation of galactan and mannan units combined through glycosidic linkages of the polysaccharide with phosphate ions of the buffer solution ^[29]. The overall results suggest that the dried beads swell slightly in the stomach. When they are subsequently transferred to upper intestine, the particles are begin to swell and diffuse formation of thick diffusion layer and they behave as matrices for sustained release of incorporated drug but they are subjected to erosion in the lower intestine.

4.2.6 In-vitro Drug Release Studies

Aceclofenac sodium release from formulated microbeads have been performed in different media, either in simulated gastric fluid (SGF) pH 1.2 for initial 2h, mixed phosphate buffer pH6.8 for the period up to 6h and simulated intestinal (SIF) pH 7.2 at end of 12h studies. The aceclofenac sodium being slightly soluble in water and showed very poor solubility in the buffer media as result of which we had to use 2%w/v SLS in the media to aid the dissolution of the drug. The drug release from CA beads was pH dependent, all the formulations showed negligible drug release in acidic pH 1.2 (<5%w/w) may be due to the stability of polymers at lower pHs and conversion of Ca-alginate to the insoluble alginic acid to formed tightening of the gel mesh work. In other hand, the polymer is eroded at alkaline pH and the contents are released in a sustained manner by both diffusion and slow erosion of polymer matrix ^[30]

The effect of drug-polymer ratio on aceclofenac sodium release from different batches of microbeads is shown in Figure 6 a. Formulations F1 to F5 were showed the percentage of drug release in pH 6.8 buffer media at the end of 6h was 80.74, 76.38, 69.28, 68.01, and 63.23. Moreover, at the end of 12hr in pH 7.2 phosphate buffer solution the percentage of drug released in the range 98.54, 94.61, 90.63, 88.04, and 85.06 respectively. As the drug-polymer ratio increased, the release rate of aceclofenac sodium from the microbeads decreased. The slower in the release rate can be explained by the increase in the extent for swelling and the gel layer thickness that acted as a barrier for the penetration medium thereby retarding the diffusion of drug from the swollen alginate beads. However, the steady state release was achieved after an initial lag time and it was directly proportional to the concentration of sodium alginate. The first phase might be for the negligible dissociation of alginate beads in phosphate buffer mainly based on drug diffusion through the small pores and cracks. The second phase exhibited a burst-like release pattern, which was accompanied by alginate disintegration ^[31].

The effect of cross-linking agent on aceclofenac sodium release from different batches of microbeads is shown in Figure 6 b. The percentage of drug release from the formulations F6 to F10 was observed in pH 6.8 buffer solution at the end 6hr 76.15, 72.37, 64.66, 60.80, 57.72 and at the end of 12hr in pH 7.2 phosphate buffer media was 94.20, 91.84, 88.44, 84.26, and 81.25 respectively. The results indicate that rate and extent of drug release decreased significantly with increase of concentration of calcium chloride, because sodium alginate as a linear copolymer consisting of β (1→4) mannuronic acid and α (1→4) L-guluronic acid residues; a tight junction is formed between the residues of alginate with calcium ions. However, in case of higher calcium chloride concentration due to increased surface roughness and porosity and also poor entry of dissolution medium into the polymer matrix may be delayed drug release ^[32].

The effect of GG concentration on release of aceclofenac is shown in Figure 6 c; the percentage of drug release from F11 to 13 in pH 6.8 buffer solutions was observed in the range 78.25, 70.57 65.36 and at the end of 12hr in pH 7.2 phosphate buffer media was 92.24, 82.36, 79.28 respectively. The influence of LBG concentration on drug release from F14-F16 in pH 6.8 buffers at 6h and in pH 7.2 phosphate buffer medium at the end of 12h was observed 76.35, 69.75, 64.86 and 88.16, 81.12, 76.65 respectively.(Figure 6 d) The results explain that the initial burst release of CA was reduced by increasing the coating polymer concentration of GG and LBG resulting better entrapment efficiency, as discussed earlier and formation of diffusional bridges due to swelling of hydrophilic linkage in pH 6.8 buffer. On other hand, the optimum release of drug observed in pH 7.2 phosphate buffers due to relaxation of polymer net-work at higher pH level followed by erosion process shows near to zero-order kinetics.

4.2.7 Kinetics of Drug Release

The in-vitro dissolution data were analyzed by different kinetic models in order to find out the n- value, which describes the drug release mechanism (Table 4). The values of correlation (r) were calculated and were found to be more linear for first-order release as compared to zero order. Cumulative % drug release was analyzed using PCP DissoV2.08 software. The kinetic data was best fitted to Korsmeyer and Peppa’s model and good regression co-efficient was observed ^[33]. The values of diffusion co-efficient ranged between n=0.6448 and 1.6988 indicating the drug release from the microbeads followed by Zero-order and super case-II transport mechanism controlled by swelling and relaxation of polymer chains.

Table 4: Study of various kinetic models on In-vitro drug release of CA, CA-GG and CA-LBG microbeads of aceclofenac sodium

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