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Ashok Kumar et al. World Journal of Pharmacy and Pharmaceutical Sciences

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

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

*Correspondence for

Author: * Ashok Kumar.P

Assistant Professor,

Sree Siddaganga College of

Pharmacy, B.H.Road,

Tumkur- 572102, Karnataka,

India..

[email protected]

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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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METHODS

Direct Compression

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 =density Tapped

density Bulk -density Tapped *100

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 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12

Amoxicillin 200 200 200 200 200 200 200 200 200 200 200 200

Xanthan gum 43 62 84 --- --- --- --- --- --- --- --- ---

Carbopol 940p --- --- --- 43 62 84 --- --- --- --- --- ---

HPMC K4m --- --- --- --- --- --- 43 62 84 --- --- ---

Pectin --- --- --- --- --- --- --- --- --- 43 62 84

Sodium bicarbonate 35 35 35 35 35 35 35 35 35

35

35

35

Citric acid 10 10 10 10 10 10 10 10 10 10 10 10

Lactose 198 177 156 198 177 156 198 177 156 198 177 156

MS 10 10 10 10 10 10 10 10 10 10 10 10

Talc 5 5 5 5 5 5 5 5 5 5 5 5

Total weight 500 500 500 500 500 500 500 500 500 500 500 500

* Quantities were taken in milligrams

Table 1.2: Pre Compression Parameters Indicating Flow Properties of Blend

Formulation Bulk Density (gm/cc)

Tapped Density (gm/cc)

Carrs Index (%)

Hausners Ratio

Angle of Repose

F1 0.304 0.351 13.39 1.15 21004

F2 0.317 0.367 13.12 1.15 21009

F3 0.310 0.360 13.88 1.16 21046

F4 0.318 0.378 15.87 1.18 24088

F5 0.294 0.346 15.02 1.17 24023

F6 0.307 0.360 14.72 1.17 24009

F7 0.311 0.368 15.48 1.18 24078

F8 0.265 0.312 15.06 1.17 24056

F9 0.332 0.391 15.08 1.17 23098

F10 0.328 0.386 15.02 1.14 23002

F11 0.330 0.376 12.23 1.13 24005

F12 0.335 0.382 12.30 1.14 24024

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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 Average Weight (mg)

Mean Thickness (mm)

Mean Hardness (Kg/cm2)

Friability (%)

Mean % Drug Content

F1 501 4.12 0.06 5.1 0.435 98.70

F2 500 4.17 0.05 5.4 0.492 99.25

F3 499 4.16 0.07 5.3 0.501 99.42

F4 500 4.15 0.08 5.5 0.463 98.52

F5 501 4.16 0.05 5.0 0.478 98.24

F6 502 4.17 0.02 5.2 0.342 98.63

F7 498 4.16 0.05 5.5 0.414 98.15

F8 500 4.15 0.03 5.5 0.417 99.42

F9 500 4.46 0.05 5.2 0.318 99.14

F10 498 4.44 0.06 5.1 0.412 98.46

F11 499 4.44 0.05 5..2 0.416 98.10

F12 504 4.44 0.03 5.2 0.514 98.65

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

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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

Table1.5 Dissolution table of formulations in 0.1N HCL

Time in hours 1hr 2hr 3hr 4hr 5hr 6hr 8hr 10hr 12hr

F1 27.23 41.9 66.12 91.86 96.18 --- --- --- ---

F2 22.54 35.12 50.34 63.87 77.02 96.56 --- --- ---

F3 18.03 27.8 37.76 51.47 64.43 78.9 91.86 96.74 ---

F4 37.42 61.94 94.77 --- --- --- --- --- ---

F5 24.44 35.82 49.44 70.89 85.82 95.34 --- --- ---

F6 19.6 32.46 50.56 65.67 78.36 89.55 96.26 --- ---

F7 34.32 55.22 75.74 89.18 97.01 --- --- --- ---

F8 28.73 45.9 61.94 73.5 85.07 95.9 --- --- ---

F9 17.16 26.86 36.94 48.88 60.44 69.4 78.54 87.31 98.5

F10 23.88 32.46 47.76 72.57 95.52 --- --- --- ---

F11 21.26 28.73 43.65 61.56 87.31 97.2 --- --- ---

F12 16.23 24.99 33.76 51.11 66.23 87.87 98.13 --- ---

Functional Group

Observed region (cm-1) (amoxicillin)

Observed region(cm-1) (Optimised formulation)

Intensity (amoxicillin)

Intensity (Optimised formulation)

Assignment (Amoxicillin)

Assignment (Optimised formulation)

CH 673.19 685.26 Str Str CH-

deformation

CH-

deformation

CH2 934.55 934.54 Str Str CH & CH2

out of plane

CH & CH2

out of plane

CH3 2972.43, 1465 2974.21,

1465.96

Med Med CH3 & CH2

deformation

CH3 & CH2

Deformation

OH 2774.72 2770.10 Str Str C-O-H

Bending

C-O-H

Bending

NH 1551.41 1562.41 Med-str Med-str NH2 scissoring NH2

scissoring

C-N 879.58 876.26 Var Var 1o amines

(NH-wagging)

1o amines

(NH-wagging)

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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

FIRST ORDER R2

HIGUCHI R2

PEPPAS R2 n value

F1 0.9657 0.9990 0.9653 0.9787 0.8390

F2 0.9958 0.7893 0.9703 0.9914 0.8045

F3 0.9567 0.9465 0.9772 0.9848 0.7928

F4 0.9930 0.8652 0.9748 0.9898 0.8330

F5 0.9893 0.8946 0.9711 0.9806 0.7956

F6 0.9443 0.9561 0.9809 0.985 0.8300

F7 0.9688 0.9428 0.9929 0.9984 0.6600

F8 0.9891 0.9283 0.9983 0.9988 0.6737

F9 0.9582 0.8684 0.991 0.9897 0.7279

F10 0.9670 0.7750 0.9155 0.9403 0.8649

F11 0.9736 0.8112 0.9308 0.9447 0.8740

F12 0.971 0.837 0.9499 0.9726 0.9301

Table No.1.7 Percentage drug release from optimized formulations after stability

studies

No.

of

days

F3 F6 F9

% Drug release % Drug release % Drug release

250C /

60%

RH

300C /

65%

RH

400C /

75%

RH

250C /

60%

RH

300C /

65%

RH

400C /

75%

RH

250C /

60%

RH

300C /

65%

RH

400C /

75%

RH

0 96.74 96.53 96.24 96.26 96.24 96.21 98.50 98.45 98.42

15 96.74 96.50 96.21 96.21 96.22 96.11 98.48 98.34 98.39

30 96.72 96.48 96.18 96.18 96.20 96.08 98.42 98.23 98.34

45 96.71 96.43 96.14 96.18 96.17 95.98 98.35 98.21 98.30

60 96.68 96.40 96.11 96.14 96.14 95.96 98.28 98.17 98.27

75 96.65 96.36 96.08 96.12 96.11 95.92 98.24 98.14 98.24

90 96.63 96.01 96.01 96.08 96.05 95.36 98.04 98.11 98.21

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CONCLUSION

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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