The IR Spectrum of Mebeverine was found to be similar to the standard spectrum of Mebeverine. The spectrum of Mebeverine shows the functional groups at their frequencies shown in the figure no 5.
6.2 Drug - excipient compatibility study:
From the spectra of Mebeverine, physical mixture of Mebeverine and polymer, Mebeverine microspheres, it was observed that all characteristic peaks of mebeverine were present in the combination spectrum, thus indicating the compatibility of the Mebeverine and polymer. IR Spectra shown in Figure no 7, 8.
6.3 Evaluation of Preparation method:
Guar gum microspheres were prepared by emulsification method. Hardening of microspheres was performed by chemical cross linking with gluteraldehyde. The particle size of microspheres was determined using an eye piece micrometer. The mean diameter of gluteraldehyde cross-linked guar gum microspheres increased from 123.6Â±12.34Î¼m to
146.7Â±11.39Î¼m with increasing polymer concentration from 1.5 to 2.5 %. In the present study a 2% Guar gum concentration was found to be optimal, ensuring the optimal size of microspheres. The average particle size of microspheres increased with increasing polymer concentration, since at higher concentrations the polymer solution dispersed into larger droplets. At concentrations lower than the optimum the solution became less viscous and dispersed into numerous fine droplets that easily coalesced, resulting in larger microspheres. The mean particle size of microspheres decreased from 324.21Â±11.23 Î¼m to 133.32Â±64 Î¼m with increasing mixer rotational speed, from 2500rpm to 3000rpm. From the results it revealed that the average diameter of microspheres was controlled by rotational speed. The ultimate mean diameter of microspheres was determined by the size of dispersion of the polymer solution, which decreased with increasing mixer rotational speed. Results also suggested that there was a mixing rate limit for a particular polymer concentration. A higher mixing rate did not further reduce the mean diameter. The mixing speed of 3000rpm was found to be optimal for guar gum microspheres. The effect of stirring time at a particular rotational speed was also observed, and it was recorded that stirring time influenced the shape as well as size distribution of microspheres. Span 80 and Tween 80 was used to facilitate stable dispersion of polymer in oil. An optimal concentration of emulsifier was found to be 2%. Below this concentration the dispersed globules/droplets tend to fuse and forms lumps or larger globules because of insufficient lowering in interfacial tension, while above the optimal concentration no significant decrease in particle size is observed because high amount of emulsifying agent increases the viscosity of dispersion medium. An optimal concentration of cross linking agent 2ml was found to be optimal and the microspheres formed were hard, free flowing and stable.
6.4 SEM studies:
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Scanning electron microscope studies shows particles of F2 and F3 were rough surfaced. The higher magnification of the particles surface appeared as a cracks or flakes overlapped one another which confirms the quick release of the drug from the cracks shown in figure no 12(c). Hence the resultant microspheres were coated with pH sensitive polymer Eudragit S100 to make formulation F4; these coated particles were found to be almost spherical, rough surface and discrete which is shown in figure no 12(d).
6.5 Micromeritic properties:
The rheological properties like angle of repose, bulk density and tapped density of all microspheres confirms better flow and packaging properties and the values are tabulated in table no 12. Formulation F4 showed excellent flow ability represents in terms of angle of repose (<30°), Carr's index and hausner's ratio compared to F3, F2 and F1.It was observed that, increasing in the gluteraldehyde concentration results in decrease in the angle of repose values due to the extent of cross linking, in return to produce a hard free flowing spheres. Angle of repose value decreases from 28.42 to 25.90 due to coating of Eudragit S100.Carr's index and hausner's ratio of all the formulations were observed to be in the range16.4-22 and 1.14-1.28respectively, and explains the prepared spheres has good flow properties. An uncoated microsphere has shown poor flow property than coated microspheres.
6.6 Particle size:
The mean particle size of the drug loaded microspheres was performed by optical microscopy. The mean particle size of all the formulations was in the range of 123.6Â±12.34Î¼m to 146.7Â±11.39 Î¼m. The proportional increase in mean particle size of microspheres increased with the concentration of Guar gum in the formulation. This could be attributed to an increase in the relative viscosity at higher concentration of guar gum and formation of large droplets during addition of aqueous phase to oil phase. On the other hand the mean particle size of microspheres was found to be decrease with increase in the rotational speed. Microspheres with optimum shape and size were produced when agitated at 3000 rpm. With increasing agitation speed, microspheres with randomly fractured edges were produced which was due to high shear force of the blades of the agitator. When the agitation speed was kept below 2000 rpm, the guar gum solution did not disperse evenly and microspheres with irregular geometry were produced and some of them adhered to the shaft and vessel wall results in fails to produce the microspheres. the values are tabulated in table no 13.
6.7 Percentage yield:
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The total percentage yield of all the formulations was in the range of 79-85%. The yield of the formulations was varied based on the polymer concentration used. The low yield value is due to the high concentration of polymer which forms high viscous dispersion which was lost during manufacturing process.
6.7.1 Percent entrapment efficiency:
It is evident from the table that increase in guar gum concentration led to an increase in the encapsulation efficiency and this is because of increase in dispersion of the drug in the dispersed phase but further increase in the guar gum concentration led to increase in the viscosity of the medium resulting in improper dispersion of guar gum in the dispersion medium resulting in decrease in the encapsulation efficiency. So the guar gum concentration should be optimum to avoid higher viscosity and to get better encapsulation efficiency. Further, it was observed that stirring speed did not have significant effect on encapsulation efficiency. Percentage entrapment efficiency was increased from 61.4 to 67.5 due to increase in guar gum concentration. Whereas cross linking agent has no significant affect on percent entrapment efficiency.
6.7.2 Swelling studies:
Native guar gum swells 100 to 120 fold in gastric and intestinal fluids. A problem arises in its excellent swelling properties and hydrophilicity, which requires its protection in the upper part of the GI tract. Cross-linking with glutaraldehyde has been proven to decrease its swelling properties Cross-linking density increases proportionally to increases in the amount of cross linker, resulting in a corresponding reduction in solvent uptake.
As a result of cross linking with gluteraldehyde the overall swelling of polymer decreased significantly. cross linking interferes with free access of water to the guar gum hydroxyl group, which in turn reduces the swelling properties of the cross linked polymer. The cross linking of the modified guar gum formulation depended on the gluteraldehyde concentration, but the optimal concentration of the cross-linking agent was a compromise between swell ability and invitro digestion of microsphere preparation in the presence of rat caecal content.
6.8 In vitro drug release studies:
The drug release from all the formulations was summarized in the Table no 14. A comparative study of all the formulations indicates that the release of the drug from the formulations was decreased by increase in the polymer concentration and increase in the cross linking agent concentration. The guar gum microspheres were subjected to in vitro drug release rate studies in simulated gastric fluid (SGF) (pH 1.2) for 2 h and simulated intestinal fluid (SIF) (pH 6.8) for 3 h in order to investigate the capability of the formulation to withstand the physiological environment of the stomach and small intestine and subsequent time period in simulated colonic fluid (SCF) (pH 7.4) for drug release which is entrapped in the formulation.
In the formulation F1, the amount of Mebeverine HCl released during 5 h studies was found to be 33.92%, while in F2 and F3 the amount of drug releases retarded to 28.14 and 25.29 respectively, which attests the ability of the guar gum to remain intact in the physiological environment of stomach and small intestine. The little amount of the drug, which is released during 2 h release rate studies, is due to the presence of un-entrapped drug on the surface of the microspheres. It is a well established fact that as the guar gum comes in contact with the dissolution medium pH 6.8 it creates viscous gel layer around it which controls the release of the entrapped drug. No entrapped drug release was observed in stomach fluid (pH 1.2) While in colonic fluid 80% drug release was observed.
In the formulation F1, the amount of the Mebeverine HCl adsorbed on the surface of the sphere released up to 15.06% for first 2hours in SGF (pH 1.2), when it is placed in the SIF (pH 6.8) the guar gum starts swelling and creates a viscous gel layer which can release of the drug slowly, a 33.92% of the drug has been released at the end of 5hours.When it is placed in the SCF (pH 7.4) the guar gum starts dissolving and maximum amount of drug released was observed. The maximum of 96.11% of the drug release was found at the end of 9 hours.
In the formulation F2, to increase the percent entrapment efficiency of the formulation the guar gum concentration increased from 2% to 2.5%.The amount of the Mebeverine HCl adsorbed on the surface of the sphere decreased from 15.06% to 13.21%.The release for first 2hours in SGF (pH 1.2) was found 13.21%, when it is placed in the SIF (pH 6.8) the guar gum starts swelling and creates a viscous gel layer which can release of the drug slowly, a 28.14% of the drug has been released at the end of 5hours which reveals that due to increase in the concentration of the guar gum the % drug release decreased.
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In the formulation F3, in order to decrease the swelling ability of the guar gum the cross linking agent concentration increased from 1.5 to 2ml which can retard the release in GIF (pH 6.8).the release profile of F2 and F3 at the end of 5 hour clearly indicates that the gluteraldehyde slows Mebeverine HCl release from microspheres. Gluteraldehyde causes cross-linking by reacting with the hydroxyl group of galactose and the mannose unit of guar gum, thus interfering with the free access of water to the hydroxyl group of guar gum. This significantly reduces the swelling rate of the microspheres and consequently the penetration of the solvent into the microspheres. Cross linking also reduces the polymer chain mobility and decreases the solvent diffusivity. Mebeverine HCl release from cross-linked microspheres was found to be gluteraldehyde concentration-dependent. The percent cumulative release at 5 hours decreased from 28.14 to 25.29.
In the formulation F4, The most frequently encountered problem with the use of guar gum is high water solubility, which causes the partial release of drugs in the upper GIT. To prevent the release of surface adsorbed drug in the first 2 hours and also to enhance the target release, the formulation F3 has been coated with pH sensitive polymer Eudragit S100 which will degrade at pH 7 to make formulation F4. Formulation F3 can be coated with pH sensitive polymer, which dissolves at the pH of the colon. Most of the enteric polymers dissolve in the terminal ileum or at ileocaecal junction. To target the drugs specifically to colon, it is to be coated with either hydrophilic or hydrophobic polymer along with enteric polymer. At the neutral or slightly alkaline pH of the terminal ileum, the enteric coating breaks and the coating of second polymer would carry the drug to the target site. The colon is rich in harboring excellent micro flora, which can be used to the target the drug release in the colon. The formulation F4, the percent drug release for first two hours was found to be very low and in SIF (pH 6.8) at the end of 5 hour it is 17.56% which is decreased from 25.29% from uncoated formulation. When it is placed in the SCF (pH 7.4) the coated pH sensitive polymer degrades completely and the second polymer releases the drug to the target site in a controlled manner. The maximum percentage drug release at the end of 13 hours is 96.26 which is the best formulation among all the above. The percent drug release of coated and uncoated formulations was shown in figure no 18.
In the formulation F5, the ability of the most promising formulation of the guar gum microspheres to release the drug in the physiological environment of the colon was assessed by carrying out release studies in the rat caecal content release medium. In this case the cumulative drug release was significantly higher in the presence of rat caecal contents i.e. 95.77% in 13hours than in the medium without any caecal matter. This could have been due to the enzymes present in cecum (secreted by various anaerobic bacteria), which are responsible for digestion or degradation of guar gum in order to release the drug from the microspheres. When the formulation is placed in the SCF (pH 7.4) with rat caecal contents the percentage drug release increased exponentially and the maximum amount of drug released at the 13 hour. This can be shown in figure no 17.
6.9 Release kinetics:
The data from in vitro study was fitted to various kinetic models to determine the kinetics of drug release. The main models are zero order, first order, Higuchi and Korsmeyer to understand the drug release from the microspheres. The coefficients of regression and release rate constant values were computed in table no 16. However drug release was also found to be very close to zero order kinetics, indicated that the concentration was nearly independent of drug release. The corresponding plot (log cumulative percent drug release vs. time) for Korsmeyer- Peppas equation indicated a good linearity. Mechanism of drug release from formulations was determined by Korsmeyer-Peppas equation where exponent "n" indicated mechanism of drug release. From the graph it is observed that the "n" value was found to be less than 0.8 for F1 and F2 which indicates that the drug release from these formulations followed non-fickain mechanism which shows rapid swelling Where as the "n" value was found to be more than 0.8 for F3, F4 and F5 formulations which indicates that the drug release from these formulations followed case-II transport controlled by swelling and relaxation of polymer chains.