WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

Ashok Kumar et al. World Journal of Pharmacy and Pharmaceutical Sciences Research Article ISSN 2278 4357 Volume 2, Issue 5, 2789-2802.

DESIGN AND EVALUATION OF SUSTAINED RELEASE FLOATING MATRIX TABLETS OF AMOXICILLIN TRIHYDRATE
Pramoda.G, Ashok Kumar.P*, Bhoopathi.G.S,Vijaya Durga.K, Suresh V.Kulakarni Sree Siddaganga College Of Pharmacy,B.H.Road,Tumkur-572102,Karnataka,India. ABSTRACT Gastro retentive drug delivery systems of Amoxicillin trihydrate as floating tablets were prepared with the impartial to obtain site-specific drug delivery and to extend its duration of action. More over the floating system of amoxicillin will provide improved local and
*Correspondence for Author: * Ashok Kumar.P Assistant Professor, Sree Siddaganga College of Pharmacy, B.H.Road, Tumkur- 572102, Karnataka, India.. ashokkumarscp@yahoo.com

Article Received on 23 July 2013, Revised on 20 August 2013, Accepted on 16 September

systemic action in stomach. The formulations were prepared as floating matrix tablets. The drug and polymers were found to be compatible as seen by IR studies. Tablets were prepared by direct compression technique. The prepared tablets were evaluated for weight variation, hardness, friability, drug content, buoyancy and in-vitro dissolution studies. Optimized formulation of F-9 amoxicillin was found to have increased gastric residence prolonging the release of drug with 98.5% of drug release in 12 hours in vitro. The release mechanisms were explored and explained with zero order, first order, Higuchi and

Korsmeyer equations. The mechanism of drug release from optimized formulation F-9 was found to be anomalous(non-Fickian)diffusion and followed zero order kinetics. Hence gastro retentive drug delivery system of Amoxicillin trihydrate is a promising approach as it can lead to decrease in the frequency of administration and eventually lead to better patient compliance. KEY WORDS: Gastro retentive; amoxicillin; buoyancy; zero order. INTRODUCTION Amoxicillin (-amino hydroxy benzyl penicillin) is a semi synthetic antibiotic, belonging to the -Lactam family, which is effective for bacterial infection treatment, especially for Helicobacter pylori infection. Helicobacter pylori is a major causative agent of diseases such as Tonsillitis, Pneumonia, Bronchitis, Gonorrhoea, ear infections, urinary tract infection and

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skin infection. In general, it exists in the gastric mucous layer or epithelial cell surfaces. Thus, the concentration and resident time of amoxicillin in stomach should be effective for complete eradication of Helicobacter pylori. Because the conventional amoxicillin has a short resident time in stomach and may be degraded in gastric acid resulting in lesser concentration in gastric blood, the extended resident time of the antimicrobial agent is desirable to provide more effective Helicobacter pylori eradication. In order to extend the residence period, a gastro retentive system of amoxicillin based on non-effervescent mechanism has been developed. Sustained release is a kind of controlled release system that provides medication over an extended period. In other words, a sustained release system controls the drug concentration in the target tissue [1]. Due to rapid degradation of amoxicillin, a sustained release dosage form that maintains therapeutic concentration in the blood for a longer period of time is desirable. Such retention systems are important for drugs that are degraded in the intestine and drugs like antacids, antibiotics, enzymes that should act locally in the stomach [2]. Amoxicillin is usually the drug of choice within the class because it is better absorbed, following oral administration, than other beta lactam antibiotics. Since the half-life of amoxicillin is 1-1.5 hours, multiple doses are needed to maintain a constant plasma concentration for a good therapeutic response and to improve patient compliance [3]. Hydrophilic polymer matrix systems are widely used in oral controlled drug delivery because of their flexibility to obtain a desirable drug release profile, broad regulatory acceptance and cost effectiveness. The purpose of controlled release system is to maintain drug concentration in the blood or in target tissues at a desired value as long as possible. In other words, they are able to exert a control on the drug release rate and duration [4]. MATERIALS AND METHODS Materials Amoxicillin purchased from richer pharmaceuticals, Hyderabad, India. Hydroxy propyl methyl cellulose K4M; Carbomer 940p, pectin, sodium bicarbonate and Lactose, Xanthane gum, Magnesium stearate, citric acid, Talc were obtained from Narmada chemicals, Hyderabad. All other ingredients, reagents and solvents were of analytical grade.

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Ashok Kumar et al. METHODS Direct Compression

World Journal of Pharmacy and Pharmaceutical Sciences

Step1: weigh required quantity of Amoxicillin transfer in to a poly bag blend and add required quantity of polymer and then add NAHCO3,carbomer,talc blend thoroughly finally add lactose to the above mixture and blend for 15min. Step2: then add the lubricant to the above mixture; blend the mixture in a poly bag for5min. Step3: total mixture or powder was passing through sieve #60. Step4: perform the micro metric properties. Step5: Compression in concave shaped circular punches 8mm (Cadmach 16station). EVALUATION OF FLOATING TABLETS Pre-compressional Evaluation [5]: a) Bulk Density:It was expressed in gm / ml and given by Weight of granules Db = M / Vo Where, Db = Bulk density (gm/cc) M =Mass of powder (g) Vo=Bulk volume of powder (cc) b) Carrs Consolidation Index Carrs Index explains flow properties of the granules. It was expressed in percentage and given by 100

Consolidation Index =

Tapped density - Bulk density *100 Tapped density

c) Angle of Repose Angle of repose for prepared granules was determined by fixed funnel method. A funnel was fixed with its tip at a given height h above a flat horizontal surface to which a graph paper was placed. The granules were carefully poured through a funnel till the apex of the conical pile just touches the tip of the funnel. The angle of repose was then calculated using the formula Angle of Repose () = Tan-1 (Height of Pile/ Radius of the base of the pile) d) Flow rate The flow rate of the granules was determined by hopper flow rate method, in which time taken for a weighed quantity of granules to flow through an orifice was calculated. It was expressed as gm/sec.

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Post-Compressional Evaluation[6] a) Thickness and diameter The thickness and diameter of the tablets were determined by using screw gauze. Thickness of ten tablets was determined randomly. It was expressed in mm. b) Crushing strength The monsanto hardness tester was used to determine the tablet crushing strength. The tablet was held between affixed and moving jaw. Scale was adjusted to zero; load was gradually increased until the tablet fractured. The value of the load at that point gave a measure of the hardness of tablet. Hardness was expressed in Kg/ cm2. c) Friability Friability was determined using Roche Friabilator. Twenty tablets were weighed and placed in the Friabilator and then operated at 25 rpm for four minutes. The tablets were then degusted and weighed. It was expressed in percentage. The difference in the two weights is used to calculate friability.

d) Weight Variation Test Twenty tablets were weighed individually and average weight was calculated. The individual weights were then compared with average weight. The tablet passes the test if not more than two tablets fall outside the percentage limit and none of tablet differs by more than double percentage limit. e) Drug Content: Drug content was performed to check dose uniformity in the formulation. Randomly ten tablets were weighed and powdered. A quantity equivalent to 250 mg of Amoxycillin was added in to a 100 ml volumetric flask and dissolved in methanol, shaken for 10 minutes and made up the volume up to the mark and filtered. After suitable dilutions the drug content was determined by UV spectrophotometer at 272nm against blank [7]. f) Swelling index of floating tablets: The studies were carried out gravimetrically. Swelling media used for these studies were distilled water and simulated gastric fluid (pH 1.2). The prepared tablets were introduced into the swelling media. At predetermined time intervals the tablets were removed from medium, excess water was blotted with tissue paper and immediately weighed. This procedure was repeated until the tablet reached constant weight. The swelling index was calculated using following formula [8].

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Swelling index (S.I) = {(WtWo)/Wo} x 100 Where, S.I. = swelling index, Where, W1=Weight of dry tablet, W0= Weight of swollen tablet g) Buoyancy studies Buoyancy studies3were carried out in disintegration apparatus (Electrolab ED2L). About 900ml of simulated gastric fluid was transferred in to 1000 ml flask. Six tablets were placed in the apparatus and studies were carried out. h) Fourier Transform infrared spectrum (FTIR) FTIR StudiesInfrared spectra were recorded on a Shimadzu FTIR-8700 spectrophotometer. Pellets were prepared from a finely ground mixture of test sample (12 mg) anddried KBr (200300 mg) using a Quick Press and a 7 mm die set (Perkin-Elmer, USA). The various samples analysed were: (a) Amoxycillin (b) crushed and powdered tablets. The samples were scanned between 4000 and 450 cm-1 at an interval of 1.0 cm-1. In vitro release studies for floating tablets: The drug release rate was determined using USP dissolution apparatus II. Dissolution media was 900ml of simulated gastric fluid (pH 1.2) maintained at 37 0.1C and stirred at 50 rpm. Samples were withdrawn at suitable time intervals and compensated with fresh dissolution medium and assayed spectrophotometrically at 272 nm in Shimadzu U.V. spectrophotometer. Samples were assayed in triplicate [9]. RESULTS AND DISCUSSIONS Formulation of floating tablet Hydrocolloids having maximum buoyancy were selected for formulation of floating tablets. Maximum buoyancy was observed in formulations containing HPMC K4M,xanthan gum, carbopol and pectin was used. The tablet ingredients as shown in Table 1.1 Evaluation of floating tablets The tapped bulk density of the granules ranged from 0.312 to 0.391 gm/cc where as the untapped bulk density was between 0.265 to 0.335gm/cc. The percentage compressibility ranged from 12.23 to 15.87which indicated excellent flow properties. Angle of repose of the granules varied between 21004 to 24088 which also indicated excellent flow properties. Table 1.2 shows the granular properties

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Table 1.1: Composition of the Formulations (per each tablet in mg) INGREDIENTS F1 Amoxicillin Xanthan gum Carbopol 940p HPMC K4m Pectin Sodium bicarbonate Citric acid Lactose MS Talc Total weight 200 43 ------35 10 198 10 5 500 F2 200 62 ------35 10 177 10 5 500 F3 200 84 ------35 10 156 10 5 500 F4 200 --43 ----35 10 198 10 5 500 F5 200 --62 ----35 10 177 10 5 500 F6 200 --84 ----35 10 156 10 5 500 F7 200 ----43 --35 10 198 10 5 500 F8 200 ----62 --35 10 177 10 5 500 F9 200 ----84 --35 10 156 10 5 500 F10 F11 F12 200 ------43 35 10 198 10 5 500 200 ------62 35 10 177 10 5 500 200 ------84 35 10 156 10 5 500

* Quantities were taken in milligrams Table 1.2: Pre Compression Parameters Indicating Flow Properties of Blend Formulation F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 Tapped Bulk Density Density (gm/cc) (gm/cc) 0.304 0.351 0.317 0.310 0.318 0.294 0.307 0.311 0.265 0.332 0.328 0.330 0.335 0.367 0.360 0.378 0.346 0.360 0.368 0.312 0.391 0.386 0.376 0.382 Carrs Index (%) 13.39 13.12 13.88 15.87 15.02 14.72 15.48 15.06 15.08 15.02 12.23 12.30 Hausners Ratio 1.15 1.15 1.16 1.18 1.17 1.17 1.18 1.17 1.17 1.14 1.13 1.14 Angle Repose 21004 21009 21046 24088 24023 24009 24078 24056 23098 23002 24005 24024 of

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The average weight variation deviation of the formulated tablets was found to be less than 5 % which are within the limits. The hardness ranged from 5 kg/m2 to 5.4 kg/cm2. The friability ranged from 0.318 to 0.501. The mean drug content ranged from 98.15 to 98.70. Table 1.3 shows the postcompressional properties of twelve formulations. Table 1.3: Post Compression Parameters of Tablets of Batches F1 F12 Formulation F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 Average Weight (mg) 501 500 499 500 501 502 498 500 500 498 499 504 Mean Thickness (mm) 4.12 0.06 4.17 0.05 Mean Hardness (Kg/cm2) 5.1 5.4 Friability (%) 0.435 0.492 0.501 0.463 0.478 0.342 0.414 0.417 0.318 0.412 0.416 0.514 Mean % Drug Content 98.70 99.25 99.42 98.52 98.24 98.63 98.15 99.42 99.14 98.46 98.10 98.65

4.16 0.07 5.3 4.15 0.08 5.5 4.16 0.05 5.0 4.17 0.02 5.2

4.16 0.05 5.5 4.15 0.03 5.5 4.46 0.05 5.2 4.44 0.06 5.1 4.44 0.05 4.44 0.03 5..2 5.2

The values represent mean + SD; n=3 During FTIR studies it was found that floating tablets has shown almost similar peaks as that of pure drug, indicating compatibility of drug and polymers. FOURIER TRANSFORM INFRARED SPECTROSCOPY OF AMOXICILLIN 1. Amoxicillin Trihydrate

Fig. 1: FTIR Spectrum of Amoxicillin trihydrate used in the preparation of floating amoxicillin tablet www.wjpps.com 2795

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2. Amoxycillin with Carbopol

Fig. 2: FTIR Spectrum of Amoxicillin with carbopol 940

3. Amoxicillin with HPMC K4M

Fig. 3 : FTIR Spectrum of Amoxycillin with HPMC K4M 4. Amoxicillinwith Lactose

Fig.4: FTIR Spectrum of Amoxicillin Trihydrate with lactose

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5.Amoxicillin with Xanthan gum

Fig. 5: FTIR spectrum of Amoxicillin Trihydrate with Xanthan gum 6. Amoxicillin with Pectin

Fig. 6: FTIR spectrum of Amoxicillin Trihydrate with pectin Best formulation

Fig. 7: FTIR spectrum of best formulation

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Table 1.4: FT-IR reports functional group analysis Amoxicillin Trihydrate and optimised formulation
Functional Group Observed region (cm-1) (amoxicillin) 673.19 Observed region(cm-1) (Optimised formulation) 685.26 Intensity (amoxicillin) Intensity (Optimised formulation) Str Assignment (Amoxicillin) Assignment (Optimised formulation) CHdeformation CH & CH2 out of plane CH3 & CH2 Deformation C-O-H Bending NH2 scissoring C-N 879.58 876.26 Var Var 1 amines (NH-wagging)
o

CH

Str

CHdeformation

CH2

934.55

934.54

Str

Str

CH & CH2 out of plane

CH3

2972.43, 1465

2974.21, 1465.96

Med

Med

CH3 & CH2 deformation

OH

2774.72

2770.10

Str

Str

C-O-H Bending

NH

1551.41

1562.41

Med-str

Med-str

NH2 scissoring

1o amines (NH-wagging)

Table1.5 Dissolution table of formulations in 0.1N HCL

Time in hours 1hr F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

2hr

3hr

4hr

5hr

6hr

8hr -----

10hr -----

12hr -----------------

27.23 41.9

66.12 91.86 96.18 ---

22.54 35.12 50.34 63.87 77.02 96.56 18.03 27.8 37.76 51.47 64.43 78.9 -------

91.86 96.74 ---------------

37.42 61.94 94.77

24.44 35.82 49.44 70.89 85.82 95.34 19.6

32.46 50.56 65.67 78.36 89.55 96.26 -------

34.32 55.22 75.74 89.18 97.01 28.73 45.9 61.94 73.5

85.07 95.9

17.16 26.86 36.94 48.88 60.44 69.4 23.88 32.46 47.76 72.57 95.52 ---

78.54 87.31 98.5 -----------------

21.26 28.73 43.65 61.56 87.31 97.2

16.23 24.99 33.76 51.11 66.23 87.87 98.13

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Fig8: GRAPHS OF DISSOLUTION STUDIES

Fig. 8: Dissolution table of Amoxicillin trihydrate (F1-F6)

Fig. 9: Dissolution table of Amoxicillin trihydrate (F7-F12) 5.5 KINETIC MODELING OF DRUG RELEASE The regression coefficient obtained for zero kinetics was found to be (R2:0.9443 to 0.9958)when compared with those of first order kinetics(R2:0.775 to 0.999),for formulations F-2 to F-5 and F-7 to F-12,indicating that drug release from all the formulations followed zero order kinetics .Formulations F-1 and F-6 followed first order kinetics. All the formulations showed high linearity with korsmeyer equation (R2:0.9447 to 0.9988).The n values obtained from korsmeyer peppas plots ranges from (0.6600 to 0.9301) indicating that the mechanism of release of formulations (F-1 to F-12)was anomalous(non-Fickian)diffusion.

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Table1.6: kinetics of drug release from amoxicillin trihydrate floating matrix tablet.

FORMULATION ZERO ORDER R2 0.9657 F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12 0.9958 0.9567 0.9930 0.9893 0.9443 0.9688 0.9891 0.9582 0.9670 0.9736 0.971

FIRST ORDER R2 0.9990 0.7893 0.9465 0.8652 0.8946 0.9561 0.9428 0.9283 0.8684 0.7750 0.8112 0.837

HIGUCHI R2 0.9653 0.9703 0.9772 0.9748 0.9711 0.9809 0.9929 0.9983 0.991 0.9155 0.9308 0.9499

PEPPAS R2 0.9787 0.9914 0.9848 0.9898 0.9806 0.985 0.9984 0.9988 0.9897 0.9403 0.9447 0.9726

n value 0.8390 0.8045 0.7928 0.8330 0.7956 0.8300 0.6600 0.6737 0.7279 0.8649 0.8740 0.9301

Table No.1.7 Percentage drug release from optimized formulations after stability studies No. of F3 % Drug release F6 % Drug release F9 % Drug release

days 250C / 300C / 400C / 250C / 300C / 400C / 250C / 300C / 400C / 60% RH 0 15 30 45 60 75 90 96.74 96.74 96.72 96.71 96.68 96.65 96.63 65% RH 96.53 96.50 96.48 96.43 96.40 96.36 96.01 75% RH 96.24 96.21 96.18 96.14 96.11 96.08 96.01 60% RH 96.26 96.21 96.18 96.18 96.14 96.12 96.08 65% RH 96.24 96.22 96.20 96.17 96.14 96.11 96.05 75% RH 96.21 96.11 96.08 95.98 95.96 95.92 95.36 60% RH 98.50 98.48 98.42 98.35 98.28 98.24 98.04 65% RH 98.45 98.34 98.23 98.21 98.17 98.14 98.11 75% RH 98.42 98.39 98.34 98.30 98.27 98.24 98.21

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Ashok Kumar et al. CONCLUSION

World Journal of Pharmacy and Pharmaceutical Sciences

In conclusion, the effervescent based GDDS is a promising approach to achieve invitro buoyancy by using gel forming polymer, HPMC K4M. Among the various GDDS formulations studied, the formulation prepared with HPMC concentration of 20% showing buoyancy lag time of 240 sec and 12 hrs floating duration and releasing 98% of the drug in 12 hrs is considered as the ideal formulation. The dosage form can control the release, avoid dose dumping and extend the duration of action of a drug with prolonged floating time. The present study validates that amoxicillin could be successfully conveyed to provide sustained delivery and better action usingswellable polymer of HPMC K4M in 20% concentration so as to provide a better drug release. REFERENCES 1. M. George, I.V. Grass and J.R. Robinson. Sustained and controlled release drug delivery systems. Marcel Dekker(1978); New York; 124-27. 2. Cooreman MP, Krausgrill P, Hengels KJ, Local gastric and serum amoxycillin concentrations after different oral application forms. Antimicroagentschemother, 1993; 37: 1506-09. 3. Martindale. The complete drug reference Pharmaceutical press. 32nd edition, 1999 ; PP 190-91. 4. A. Arunachalam, M. Karthikeyan, Kishore Konam, Pottabathula Hari Prasad, S. Sethuraman, S.Ashutoshkumar, S.Manidipa. Floating drug delivery systems: A review, Int. J.Res.Pharm.Sci2011;2(1):76-83. 5. A.Martin, J.Swarbrick and A.Cammarata. Physical Pharmacy, 4th edition,

Philadelphia(2000); 335-38:431-32. 6. Sarwar Beg, Amit Kumar Nayak, KanchanKohli, Suryakanta Swain, MS Hasnain, Antimicrobial activity assessment of time-dependent release bilayer tablets of amoxicillin Trihydrate. Brazilian Journal of Pharmaceutical Sciences, 2012;48(2). 7. Streubel, A. Siepmann, J. Bodmeire, R. Floating matrix tablets based on low density foam powder, effect of formulations and processing parameters on drug release . Eur J Pharm Sci, 2003;vol 18: 37-45. 8. Patel VF, Patel NM. Statistical evaluation of influence of viscosity of polymer and type of filler on dipyrimadole release from floating matrix tablets. Ind J Pharm Sci,2007; Vol: 69:51-7.

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9. Vinay Pandit, Sarasija Suresh and Hemanth Joshi. Gastro retentive Drug Delivery System of Amoxycillin: Formulation And In Vitro Evaluation. International Journal of Pharma and Bio Sciences, 2010; 1(2):1-10.

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