Formulation and Evaluation of Floating Tablets of Cefixime trihydrate

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The objective of the present work is to fabricate a new strategy to develop a buoyant gastric dosage form of Cefixime Trihydrate and to study its release kinetics, so as to establish the control release of drug.

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FORMULATION AND EVALUATIONS OF GASTRO RETENTIVE FLOATING TABLETS OF CEFIXIME TRIHYDRATE SUPERVISOR: SUBMITTED BY: Dr. K.S Rathore Miss PINKY GUPTA Associate Professor Enrolment No.06/14029 Department of Pharmaceutics B.N. Institute of Pharmaceutical Sciences Udaipur B.N. INSTITUTE OF PHARMACEUTICAL SCIENCES 1

AIM AND OBJECTIVES :

AIM AND OBJECTIVES The objective of the present work is to fabricate a new strategy to develop a buoyant gastric dosage form of Cefixime Trihydrate and to study its release kinetics, so as to establish the control release of drug. The success of the strategy depends on selection of the appropriate delivery system and the potential candidate. Such type of dosage form are designed to complement the pharmaceutical activity of the medicament in order to achieve better selectivity and longer duration of action. This study will involve designing and evaluation of floating drug delivery system of Cefixime Trihydrate along with the comparison of release kinetics of drug by using different drug release modifiers. 2

RESEARCH ENVISAGED :

RESEARCH ENVISAGED Introduction Literature Survey Analysis of Drug: Infra red spectroscopy (IR) Differential scanning calorimetry (DSC) Calibration curve Selection of polymers and excipients Preparation of dosage form Characterization: Evaluation of Powder Blend of Cefixime Angle of repose Bulk density Tapped density Compressibility index Hausner’s ratio Evaluation of Tablet Parameters : Tablet hardness Friability Weight variation Thickness/diameter Swelling index Floating or buoyancy test Uniformity of drug content In vitro dissolution studies Kinetic analysis of dissolution data Results and Discussion Summary and Conclusion References   3

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S.NO. INGREDIENTS F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 1 Cefixime 200 200 200 200 200 200 200 200 200 200 200 200 2 Gaur Gum 80 100 120 0 0 0 0 0 0 0 0 0 3 Sodium CMC 0 0 0 80 100 120 0 0 0 0 0 0 4 HPMC K 4M 0 0 0 0 0 0 80 100 120 0 0 0 5 HPMC K 100M 0 0 0 0 0 0 0 0 0 80 100 120 6 Sodium Bicarbonate 100 100 100 100 100 100 100 100 100 100 100 100 7 Sodium Alginate 40 40 40 40 40 40 40 40 40 40 40 40 8 PVP K 30 20 20 20 20 20 20 20 20 20 20 20 20 9 Magnesium Sterate 15 15 15 15 15 15 15 15 15 15 15 15 10 Lactose 45 25 5 45 25 5 45 25 5 45 25 5 Composition of Cefixime Floating Tablets FORMULATION All tablets contain 200 mg of Cefixime Trihydrate and net weight of tablet is 500mg (all quantities are in milligrams) 4

RESULTS AND DISCUSSION :

RESULTS AND DISCUSSION DRUG ANALYSIS Description : Drug was observed for its general appearance and was found to be light yellow crystalline powder with pungent odour . Melting point : Melting point was determined by using melting point apparatus and it was found to be in the range of 220-224°C. pH : pH was found to be 3.1 Partition coefficient: Was found to be 0.12 5

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S . No . Concentration (µg/ml) Absorbance (288nm) 1 1 0.074 2 2 0.102 3 3 0.146 4 4 0.188 5 5 0.242 6 6 0.282 7 7 0.318 8 8 0.383 9 9 0.425 10 10 0.477 Calibration Curve In Simulated Gastric Fluid (pH 1.2) UV Spectroscopy 6

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IR Spectra of Pure Cefixime Trihydrate IR Spectra of Cefixime +Gaur Gum 7

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IR Spectra of Cefixime + HPMCK100M IR Spectra of Cefixime + HPMCK4M 8

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IR Spectra of Cefixime + Sodium CMC 9 IR Interpretations S . No . FUNCTIONAL GROUP IR ABSORBANCE (cm - 1 ) 1. C-H str. (aliphatic) 2900-2980 (2943,2978) 2. C-H str. (aromatic) 3040-3010 (3052) 3. C=O str. 1725-1700 (1739) 4. C-N str. 1250-1335 (1269,1332) 5. C-H band. 675-900 (658,689,742,804) 6. C-O str. 1050-1260 (1089,1226) 7. C-S str. 1200-1100 (1226) 8. N-H str. (primary) 3398-3381 (3290) 9. C-OH (bonded) 3550-3450 (3566,3533,3423) 10. C-C str. (aromatic ring) 1400-1560 (1541)

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Differential Scanning Calorimetry of Cefixime Trihydrate 10

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Polymer Formulation Code Angle of Repose (θ) Bulk Density (gm/cm 3 ) Tapped Density (gm/cm 3 ) Carr's Index (%) Hausner's Ratio (HR)   Gaur Gum   F1 23.64 0.3199 0.381 16.0367 1.1910 F2 24.45 0.3487 0.4021 13.2803 1.1531 F3 24.75 0.3219 0.3762 14.4338 1.1687   Sodium CMC   F4 24,20 0.3333 0.4166 19.9952 1.2499 F5 26.76 0.3061 0.3658 16.3204 1.1950 F6 21.36 0.3191 0.375 14.9067 1.1752   HPMC K4M   F7 23.14 0.314 0.3659 14.1842 1.1653 F8 21.65 0.2883 0.341 15.4545 1.1828 F9 22.75 0.2824 0.328 13.9024 1.1615   HPMCK100M   F10 21.32 0.3467 0.3994 13.1948 1.1520 F11 21.51 0.3389 0.4091 17.1596 1.2071 F12 22.26 0.3326 0.3798 12.4276 1.1419 Parameters Evaluated for Cefixime Trihydrate Parameters Evaluated for Powder Blend of Cefixime FLOW PROPERTIES 11 Drug Angle Of Repose (θ) Bulk Density (gm/cm 3 ) Tapped Density (gm/cm 3 ) Carr's Index (%) Hausner's Ratio (HR) Cefixime Trihydrate 34.25 0.48 0.74 35.1351 1.5417

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F o r m u l a tion Weight Variation (mg ) Drug content (%) Hardness (Kg/cm2) Friability (%) Diameter (mm) Thickness (mm) F1 505.00±1.36 98.62±0.18 6.02±0.32 0.260 8.22±0.32 4.12±0.32 F 2 502.00±0.56 99.34±0.54 6.04±0.49 0.380 8.17±0.53 4.11±0.33 F3 498.00±0.18 99.66±0.86 5.94±0.24 0.310 8.35±0.44 4.12±0.34 F 4 503.00±1.37 98.67±0.19 6.05±0.33 0.367 8.42±0.33 4.14±0.35 F5 502.00±0.57 99.38±0.55 6.06±0.50 0.392 8.18±0.39 4.13±0.36 F6 498.00±0.19 99.69±0.87 5.98±0.25 0.417 8.48±0.65 4.14±0.37 F7 506.00±1.38 98.65±0.20 6.02±0.34 0.260 8.46±0.34 4.12±0.38 F8 503.00±0.58 99.37±0.56 6.04±0.51 0.224 8.50±0.37 4.13±0.39 F9 499.00±0.20 99.64±0.88 5.97±0.26 0.159 8.35±0.46 4.12±0.40 F10 504.00±1.39 99.66±0.21 6.07±0.35 0.193 8.27±0.38 4.09±0.41 F11 500.00±0.59 98.38±0.57 6.08±0.52 0.227 8.99±0.36 4.11±0.42 F12 501.00±0.21 99.56±0.89 5.99±0.27 0.261 8.36±0.77 4.10±0.43 Post Compression Parameters 12

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Time F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 1 40.74 51.53 69.98 86.8 96.3 98.45 41.26 52.56 72.59 68.25 72.5 96.5 2 87.67 98.67 123.3 99.98 103.45 124.3 88.56 99.56 125.6 142.5 156.2 182 3 107 119.6 146.76 109.45 138.77 136.4 109.6 121.6 149.5 185.6 172 215.6 4 128.6 143.3 197.2 128.43 132 165.54 139.25 142.6 198.5 216.2 235 265.5 6 195.45 215 235.3 187.43 179.54 183 199.56 215.3 236.5 246.5 276.3 299.3 8 218.7 234.2 284.76 205.3 213.89 264.12 221.5 236.5 286.5 296.5 301.5 345.2 10 153 163.6 170.3 148 155.7 168.8 156 166.5 172.5 185.2 174.6 168.2 12 124.1 140.8 149 120.67 141.3 147.4 126.3 142.5 152 115 126 136.5 Percent Swelling Index 13

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Formulation Floating Lag Time(sec) Total Floating Time(min) F1 69 >720 F2 74 >720 F3 80 >720 F4 89 >720 F5 94 >720 F6 105 >720 F7 41 >720 F8 47 >720 F9 52 >720 F10 49 >720 F11 55 >720 F12 61 >720 Floating Properties 14

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Time (hr) Sqrt . Of Time (hr1/2) F1 F2 Cum% Drug Release F9 F10 F11 F12 F3 F4 F5 F6 F7 F8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1.000 25.64 20.2 24.82 20.11 21.98 21.11 31.33 25.74 23.36 20.36 25.64 20.31 2 1.414 34.46 25.72 30.74 25.64 27.75 24.63 38.8 31.91 30.85 29.45 30.86 26.53 3 1.732 42.58 35.3 37.41 34.86 35.46 32.89 45.39 40.05 38.78 34.51 35.36 33.97 4 2.000 50.61 42.78 45.62 40.36 41.43 38.43 52.99 47.6 45.39 39.9 42.71 41.44 5 2.236 59.52 49.97 51.87 45.71 46.86 44.79 58.6 54.66 52.9 44.42 48.6 48.51 6 2.449 65.69 56.02 59.67 51.6 55.68 50.56 64.32 58.35 57.29 51.33 54.86 53.79 7 2.646 71.96 64.82 66.11 54.86 59.86 53.86 71.1 63.01 63.46 58.54 58.65 57.33 8 2.828 79.33 71.96 71.86 59.98 67.65 60.65 77.56 70.51 70.52 65.43 65.5 64.45 9 3.000 84.38 78.28 76.91 72.5 73.54 66.5 82.88 76.23 75.79 74.66 71.67 70.63 10 3.162 84.65 79.84 79.69 76.67 75.877 73.78 87.98 82.85 81.12 78.21 79.19 80.54 12 3.464 85.53 84.76 83.63 84.14 84.14 83.14 94.71 90.33 89.3 89.33 86.52 86.94 16 4.000 85.43 85.57 85.46 85.93 85.57 82.36 94.37 88.43 90.59 90.82 87.69 87.89 20 4.472 86.34 86.77 87.68 86.67 85.48 82.96 95.51 88.94 90.79 91.65 89.84 89.98 24 4.899 89.72 87.01 87.73 86.82 85.01 81.93 95.91 89.44 91.94 91.05 90.27 90.8 Invitro Dissolution Studies ZERO ORDER RELEASE KINETICS 15

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Time (hr) F1 F2 F3 Log Cum % Drug Retained F9 F10 F11 F12 F4 F5 F6 F7 F8 0 2 2 2 2 2 2 2 2 2 2 2 2 1 1.8713 1.9020 1.8761 1.9024 1.8922 1.8970 1.8367 1.8707 1.8844 1.9011 1.8713 1.9014 2 1.8165 1.8708 1.8404 1.8713 1.8588 1.8771 1.7867 1.8330 1.8397 1.8484 1.8397 1.866 3 1.7590 1.8109 1.7965 1.8138 1.8098 1.8267 1.7372 1.7777 1.7868 1.8161 1.8105 1.8197 4 1.6936 1.7575 1.7354 1.7755 1.7676 1.7893 1.672 1.7193 1.7372 1.7788 1.7580 1.7676 5 1.6072 1.6992 1.6824 1.7347 1.7254 1.7420 1.617 1.6564 1.6730 1.7449 1.7109 1.7117 6 1.5354 1.6432 1.6056 1.6848 1.6466 1.6940 1.5524 1.6196 1.6305 1.6872 1.6545 1.6647 7 1.4477 1.5462 1.5300 1.6545 1.6035 1.6640 1.4608 1.5680 1.5627 1.6176 1.6164 1.6301 8 1.3153 1.4477 1.4493 1.6022 1.5098 1.5949 1.3510 1.4696 1.4695 1.5386 1.5378 1.550 9 1.1936 1.3368 1.3634 1.4393 1.4225 1.5250 1.2335 1.3760 1.3839 1.4038 1.4522 1.4679 10 1.1861 1.3044 1.3077 1.3679 1.3824 1.4186 1.0799 1.2342 1.2760 1.3382 1.3182 1.2891 12 1.1604 1.1829 1.2140 1.2003 1.2003 1.2268 0.7234 0.9854 1.0293 1.0281 1.129 1.1159 16 1.1634 1.1592 1.1625 1.1482 1.1592 1.2464 0.7505 1.0633 0.9735 0.9628 1.0902 1.0831 20 1.1354 1.1215 1.0906 1.1243 1.1619 1.231 0.6522 1.0437 0.9642 0.9216 1.0068 1.0008 24 1.0119 1.1136 1.0888 1.1199 1.1758 1.2569 0.6117 1.0236 0.9063 0.9518 0.9881 0.9637 FIRST ORDER RELEASE KINETICS 17

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Time (hr) Sqrt . Of Time (hr1/2) F1 F2 F3 Cum% Drug Release F9 F10 F11 F12 F4 F5 F6 F7 F8 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1.000 25.64 20.2 24.82 20.11 21.98 21.11 31.33 25.74 23.36 20.36 25.64 20.31 2 1.414 34.46 25.72 30.74 25.64 27.75 24.63 38.8 31.91 30.85 29.45 30.86 26.53 3 1.732 42.58 35.3 37.41 34.86 35.46 32.89 45.39 40.05 38.78 34.51 35.36 33.97 4 2.000 50.61 42.78 45.62 40.36 41.43 38.43 52.99 47.6 45.39 39.9 42.71 41.44 5 2.236 59.52 49.97 51.87 45.71 46.86 44.79 58.6 54.66 52.9 44.42 48.6 48.51 6 2.449 65.69 56.02 59.67 51.6 55.68 50.56 64.32 58.35 57.29 51.33 54.86 53.79 7 2.646 71.96 64.82 66.11 54.86 59.86 53.86 71.1 63.01 63.46 58.54 58.65 57.33 8 2.828 79.33 71.96 71.86 59.98 67.65 60.65 77.56 70.51 70.52 65.43 65.5 64.45 9 3.000 84.38 78.28 76.91 72.5 73.54 66.5 82.88 76.23 75.79 74.66 71.67 70.63 10 3.162 84.65 79.84 79.69 76.67 75.877 73.78 87.98 82.85 81.12 78.21 79.19 80.54 12 3.464 85.53 84.76 83.63 84.14 84.14 83.14 94.71 90.33 85.3 89.33 86.52 86.94 16 4.000 85.43 85.57 85.46 85.93 85.57 82.36 94.37 88.43 88.79 90.82 87.69 87.89 20 4.472 86.34 86.77 87.68 86.67 85.48 82.96 95.51 88.94 88.94 91.65 89.84 89.98 24 4.899 89.72 87.01 87.73 86.82 85.01 81.93 95.91 89.44 89.04 91.05 90.27 90.8 HIGUCHI MODEL RELEASE KINETICS 19

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Time (hr) Log Time F1 F2 F3 Log % Drug Release F9 F10 F11 F12 F4 F5 F6 F7 F8 1 0.000 1.457 1.305 1.339 1.303 1.342 1.324 1.496 1.411 1.368 1.309 1.409 1.308 2 0.301 1.562 1.410 1.473 1.409 1.443 1.391 1.589 1.504 1.489 1.469 1.489 1.424 3 0.477 1.629 1.548 1.573 1.542 1.550 1.517 1.657 1.603 1.589 1.538 1.549 1.531 4 0.602 1.704 1.631 1.659 1.606 1.617 1.585 1.724 1.678 1.657 1.601 1.631 1.617 5 0.699 1.775 1.699 1.715 1.660 1.671 1.651 1.768 1.738 1.723 1.648 1.687 1.686 6 0.778 1.817 1.748 1.776 1.713 1.746 1.704 1.808 1.766 1.758 1.710 1.739 1.731 7 0.845 1.857 1.812 1.820 1.739 1.777 1.731 1.852 1.799 1.803 1.767 1.768 1.758 8 0.903 1.899 1.857 1.856 1.778 1.830 1.783 1.890 1.848 1.848 1.816 1.816 1.809 9 0.954 1.926 1.903 1.903 1.860 1.867 1.823 1.918 1.882 1.880 1.873 1.855 1.849 10 1.000 1.960 1.945 1.937 1.885 1.880 1.868 1.944 1.918 1.909 1.907 1.893 1.890 12 1.079 1.956 1.942 1.931 1.925 1.925 1.920 1.976 1.956 1.946 1.945 1.943 1.924 16 1.204 1.949 1.930 1.922 1.935 1.927 1.910 1.965 1.949 1.938 1.935 1.932 1.910 20 1.301 1.937 1.921 1.913 1.925 1.918 1.899 1.958 1.935 1.929 1.925 1.923 1.899 24 1.380 1.925 1.910 1.902 1.918 1.909 1.891 1.948 1.927 1.917 1.918 1.909 1.891 KORSMEYER PEPPAS MODEL RELEASE KINETICS 21

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Kinetic Model Parameters F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 Zero Order Slope (k) 3.10 3.25 3.38 3.50 3.42 3.32 3.42 3.32 3.50 3.68 3.45 3.60 Intercept 30.77 31.79 31.53 30.52 30.55 30.65 26.39 26.00 26.34 25.56 25.99 25.87 R 2 0.91 0.92 0.94 0.941 0.95 0.92 0.984 0.981 0.975 0.96 0.965 0.97 First Order Slope (k/2.303) 0.02 0.02 0.02 0.02 0.02 0.02 0.03 0.03 0.03 0.02 0.02 0.02 Slope (k) 0.05 0.05 0.05 0.05 0.05 0.05 0.07 0.06 0.06 0.05 0.05 0.05 Intercept 1.58 1.58 1.58 1.50 1.50 1.51 1.58 1.58 1.57 1.57 1.57 1.57 R 2 0.92 0.91 0.924 0.94 0.93 0.95 0.956 0.961 0.951 0.96 0.974 0.968 Higuchi Model Slope (k) 19.63 19.63 19.61 19.63 19.65 19.64 20.11 21.44 20.13 21.12 21.20 21.03 Intercept 7.91 7.92 7.90 4.88 4.92 4.94 6.68 6.72 6.69 1.78 1.79 1.78 R 2 0.92 0.94 0.92 0.93 0.92 0.94 0.93 0.93 0.95 0.94 0.96 0.94 Korsmeyer Peppas Model Slope (n) 0.59 0.56 0.57 0.59 0.61 0.66 0.75 0.79 0.81 0.84 0.86 0.85 Intercept ( log k) 1.31 1.41 1.37 1.36 1.38 1.31 1.41 1.40 1.37 1.32 1.34 1.37 k 20.31 25.60 23.54 22.87 23.87 20.39 25.87 24.98 23.22 20.76 21.87 23.66 R 2 0.89 0.85 0.90 0.94 0.96 0.967 0.98 0.96 0.969 0.971 0.959 0.94 Kinetic Modelling Of Dissolution Data 23

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SUMMARY AND CONCLUSION Floating tablets of Cefixime were prepared by using various natural and semi synthetic polymers such as Guar Gum, Sodium CMC, HPMC K4M and HPMC K100M. The prepared tablets exhibited satisfactory physico -chemical characteristics. All the prepared batches showed good in vitro buoyancy studies and continuous till 24 hours. All the prepared tablet formulations were found to be free from capping and chipping. Infrared Spectroscopy studies indicated that there were no drug excipients interactions in the prepared formulations. The in vitro dissolution profile of all prepared formulations of GFDDS were found to extend the drug release over a period of 12-16 hrs and the drug release decrease with the decrease in polymer concentration. Release of Cefixime from GFDDS follows Zero order kinetics. When drug release data were fitted to Korsmeyer Equation value of slope ‘n ’ (0.51-0.86) indicate that the drug release follow Non Fickian Mechanism. Comparing all the formulations of GFDDS showed that the formulation F7 was found most suitable for preparing gastro retentive tablet of Cefixime Trihydrate. 24

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25 THANK YOU