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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..
ashokkumarscp@yahoo.com
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Ashok Kumar et al. World Journal of Pharmacy and Pharmaceutical Sciences
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. World Journal of Pharmacy and Pharmaceutical Sciences
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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Ashok Kumar et al. World Journal of Pharmacy and Pharmaceutical Sciences
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.
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2. Cooreman MP, Krausgrill P, Hengels KJ, Local gastric and serum amoxycillin
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3. Martindale. The complete drug reference Pharmaceutical press. 32nd edition, 1999 ; PP
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4. A. Arunachalam, M. Karthikeyan, Kishore Konam, Pottabathula Hari Prasad, S.
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6. Sarwar Beg, Amit Kumar Nayak, KanchanKohli, Suryakanta Swain, MS Hasnain,
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9. Vinay Pandit, Sarasija Suresh and Hemanth Joshi. Gastro retentive Drug Delivery System
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