Full Text Article

Transcription

Full Text Article

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES
Sharma et al.
World Journal of Pharmacy and Pharmaceutical Sciences
Volume 3, Issue 2, 1499-1512.
Research Article
ISSN 2278 – 4357
FORMULATION AND STABILITY STUDIES OF AMOXYCILLIN AND
POTASSIUM CLAVULANATE CHEWABLE TABLET
Monika Sharma1*, Jugaldas Chudasama2, Prabhu Narayan2, and Pratap Singh
Rathore, Ashok Kumar Sharma.
1
Arya College of Pharmacy, Kukas, Jaipur, Delhi Road, Rajasthan(302028). India.
2
Article Received on
02 December 2013,
Revised on 28 December
2013,
Accepted on 29 January
2014
*Correspondence for
Medicef Pharma, Jharmajri, Baddi (H.P.), India.
ABSTRACT
Amoxycillin/Clavulanic acid or co-amoxiclave is a combination
antibiotic consisting of amoxycillin trihydrate, a β-lactam antibiotic,
and potassium clavulanate, a β-lactamase inhibitor. This combination
results in an antibiotic with an increased spectrum of action and
restored efficacy against amoxycillin-resistant bacteria that produce β-
Author:
Monika Sharma
lactamase. 10 formulation of the amoxycillin and potassium
Arya College of Pharmacy,
clavulanate chewable tablet are formed with increasing or decreasing
Kukas, Jaipur, Delhi Road,
the conc. of disintegrant and diluents. These formulations are formed,
Rajasthan(302028). India.
evaluated and study accelerated stability studies for the best
formulation .Accelerated stability studies of amoxycillin and potassium
clavulanate chewable tablet was performed as per ICH guidelines. Various parameters are
analyzed including description, assay, dissolution, water content, and microbiological quality.
These parameters were evaluated at 0 month, 1 month, 2 month, 3 month and 6 month
intervals.
Keywords: Amoxycillin Trihydrate, Potassium Clavulanate, Accelerated stability studies,
Chewable tablet, Dissolution study.
INTRODUCTION
The oral route of drug administration is the most important method of administering drug for
systemic effects. Drugs that are administered orally, solid oral dosage forms represent the
preferred class of product. Tablet and capsules represent unit dosage forms in which usual
dose of drug has been accurately placed. Chewable tablets are intended to be chewed in the
www.wjpps.com
Vol 3, Issue 2, 2014.
1499
Sharma et al.
mouth prior to swallowing and are not intended to be swallowed intact. Selection of the
appropriate excipients to perform a specific function in a tablet formulation such as
disintegration or lubrication can be critical to achieving acceptable manufacturing.
Sweeteners are both naturally occurring and synthetic are one type of functional excipients
commonly used in chewable tablet formulations to mask unpleasant tastes and facilitate
pediatric dosing. (I)
Stability Studies
Stability is defined as the capacity of a drug substances or drug product to remain within the
established specification to maintain its identity, strength, and quality, purity throughout the
retest or expiration date period. Stability of a pharmaceutical preparation can be defined as
“the capability of a particular formulation (dosage form or drug product) in a specific
container – closure system to remain within its physical, chemical, microbiological,
therapeutic and toxicological specification throughout its shelf life. Stability testing is a
routine procedure performed at various stages of product development.
The purpose of the stability testing is to provide evidence how quality varies with time under
influence of temperature, humidity, light. Establish the re-test period of the drug substances.
Pack selected for stability studies should be the marketed / proposed to be marketed pack, or
simulate the actual pack used for storage and distribution. If the product in more than one
pack stability studies of each of the pack is necessary. To demonstrate the consistency and
skill of production and packing of drug substances or drug product for quality, batch after
batch, in a standard manufacturing process. (II)
MATERIAL AND METHOD
Materials
API: Amoxycillin Trihydrate & Potassium Clavulanate by DSM Sinochem Pharma.
Excipients: Microcrystalline cellulose by Mingtai chem. Cells co. Ltd.
Croscarmellose sodium by Base Chemicals, Magnesium stearate by Suzong Chemicals,
Aspartame by Biocon Ltd and Aerosil by Wacker.
Solvents
and
reagents:
Methanol
For
HPLC,
Water
was
double
distilled.
METHOD
Preformulation Studies
Identification of API by HPLC method
The assay of Amoxycillin and Clavulanic acid was carried out using HPLC Method.
www.wjpps.com
Vol 3, Issue 2, 2014.
1500
Sharma et al.
Table I: Identification of amoxycillin and potassium clavulanate by high performance
liquid chromatography method.
Column type
Flow rate
Detection
Column oven
temp.
Injection
volume
C18 type
1.5 ml/min
220nm,
U.V detector
25° C
20 ml
Fig1:Standard curve of Amoxycillin Trihydrate Fig 2:Standard Curve of sample of Amoxycillin
Figure 3: Standard Curve of Potassium Clavulanate Figure 4:Curve of Sample of Pot.Clavulanate
Figure 5: Standard Curve of Mixture of Amoxycillin & Potassium Clavulanate
www.wjpps.com
Vol 3, Issue 2, 2014.
1501
Sharma et al.
Figure 6: Curve of Mixture of Amoxycillin & Potassium Clavulanate.
Precompression Studies (Evaluation of granules)
Bulk density: A 10 g quantity each of the powder samples was, placed into a clean 50 ml
measuring cylinder and the volume, V0 (bulk volume), occupied by each of the samples
without tapping was noted. The bulk density was expressed in grams per milliliter (g/ml). (IX)
Tapped density: A 50 ml measuring cylinder was filled with 10 gm quantity of powder. The
cylinder was tapped 500 times on a hard table top and tapped volume, V500 were recorded.
The experiment was repeated in triplicates.(9)
Carr’s index: The Carr’s compressibility index was calculated by calculating the tapped and
bulk density using the 100 ml measuring cylinder. Compressibility is calculated by the
formula.
Carr’s index (%) = (Tapped density – Poured density)
x
100
Tapped density
A Carr’s index greater than 25 is considered to be an indication of poor flowability, and
below 15, of good flowability.
Hausner’s ratio: Hausner’s ratio is the ratio of the tapped density to bulk density. (XII)
Angle of repose
The angle of repose is a relatively simple technique for estimation of the flow property of a
powder. Powders with low angle of repose are free flowing and those with a high angle of
repose are poorly flowing powders.10 gm of granules were passed through funnel and the
pile was formed. The angle of repose was calculated by using the formula. (V)
Angle of Repose (Θ) = Tan-1 Height /Radius
www.wjpps.com
Vol 3, Issue 2, 2014.
1502
Sharma et al.
Table II : Pre-compression studies
S.No.
1
2
3
4
5
Test
F1
F2
F3
Bulk
0.46 0.48 0.47
density(gm/ml)
Tapped
0.43 0.52 0.53
density(gm/ml)
12.53 10.77 13.53
Carr’s index
Hausner’s
1.14 1.13 1.14
ratio
Angle of
21.4 22.5 21.34
repose(degrees)
F4
F5
F6
F7
F8
F9
F10
0.49
0.47
0.46
0.46
0.45
0.47
0.46
0.52
0.54
0.54
0.53
0.54
0.54
0.53
9.77 13.24 13.26 13.53 15.88 14.75 13.08
1.11
1.24
1.14
1.15
1.14
1.15
1.16
22.1
22.3
22.4
22.5
22.7
22.6
22.6
Formulation of Chewable Tablet
Ten different formulations of Amoxycillin and Potassium Clavulanate (625mg) chewable
tablets were prepared and were coded as F1-F10. Various concentration of binder MCC was
used in decreasing order to maintain the release of drug from dosage form. Similarly,
different concentration of disintegrant, Croscarmellose Sodium was used but in increasing
order. Magnesium Stearate was used as a lubricant and talcum was used as anti adherent.
Aspartame was used as sweetener while Strawberry was used as flavoring agent.
Dry Granulation Method
Raw material  weighing  screening  mixing  slugging  milling  screening 
mixing  compression  stability studies.
Procedure
Amoxycillin and potassium clavulanate was sifting with the help of sifter. In dry blending the
sifted material was load in the octagonal blender & mix for 15 min. Then compact the tablet
by roll compactor at the temp.23-25.pass the compacted material through oscillatory
granulator through 2.5 mm screens. Sift the milled material of previous step through 18 s.s
mesh. After sifting dry the granular power in vaccum try dryer for 2 hrs at 60 c .temp. And
vaccum at 710±10 mm Hg. Then sift the pot. Clavulanate through sifter fitted with sieve
30.after sifting load the drying material in the octagonal blender and add potassium
clavulanate, Aerosil & magnesium stearate mix for 30 min. Then compressed the tablet by
using the station D tooling machine for formulation of amoxycillin and potassium
clavulanate.
www.wjpps.com
Vol 3, Issue 2, 2014.
1503
Sharma et al.
Table III: Sifting process of API & excipients
S. No. NAME OF MATERIAL
Amoxycillin Trihydrate
Potassium Clavulanate
3.
Micro crystalline Cellulose
4.
Croscarmellose sodium
5.
Colloidal anhydrous silica
6.
Talcum
7.
Magnesium Stearate
SIEVE NO.
18
30
30
30
30
60
30
Table IV: Composition of all formulations f1-f10.
Name of Raw
Material
F1
(mg)
F2
(mg)
F3
(mg)
F4
(mg)
F5
(mg)
F6
(mg)
F7
(mg)
F8
(mg)
F9
(mg)
F10
(mg)
Amoxycillin
trihydrate
Potassium
Clavulanate
575
575
575
575
575
575
575
575
575
575
304
304
304
304
304
304
304
304
304
304
03.
MCC
27.32
27.32
27.32
27.32
27.3
2
26.3
2
25.32
24.32
23.32
22.32
04.
Croscarmellose
sodium
51
52
53
54
55
55
55
55
55
55
Talcum
1
1
1
1
1
1
1
1
1
1
06.
Colloidal
anhydrous silica
25
23
22
21
20
27
28
29
30
31
07.
Magnesium
Stearate
6.60
6.60
6.60
6.60
6.60
6.60
6.60
6.60
6.60
6.60
Aspartame
27
27
27
27
27
27
27
27
27
27
Strawberry
14
14
14
14
14
14
14
14
14
14
S. No.
01.
02.
05.
08.
09.
Evaluation of tablet
Hardness
The force required to break a tablet along its diameter by applying compression loading. A
tablet is placed between two anvils, force is applied to the anvils, & the crushing strength that
just causes the tablet to break is recorded (in kg). Hence, Hardness is thus sometimes termed
the tablet crushing strength. It lies in between 6-10 kg.
www.wjpps.com
Vol 3, Issue 2, 2014.
1504
Sharma et al.
Friability (attrition resistance test)
It also used for the tablet strength. Friability test is performed to assess the effect of friction
and mechanical shock, which may often cause tablet to chip, cap, laminate or break. (XI)
Thickness, width, length
These were checked by vernier caliper. Five tablets were randomly selected for the
determination of thickness and diameter with the help of vernier caliper.
Disintegration Time
Disintegration test was carried out by using Disintegration test apparatus. One tablet is placed
in each tube, and the basket rack was positioned in a 1-litre beaker of water, at 37°C ±2°C. A
standard motor-driven device is used to move the basket assembly containing the tablets up
and down through a distance of 5 to 6 cm at a frequency of 28 to 32 cycles per minutes. The
time taken for the tablet to disintegrate completely was noted. (X)
Figure 7: Disintegration time of F1-F10 formulation.
Table V: Post-compression study
TEST
F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
Avg.Wt (mg)
1027
1030.2
1030.3
1031.2
1028
1031
1030
1030
1030.8
1030.2
Hardness(Kg/cm3)
5
4
5
6
7
6
5
5
6
7
Friability (%)
0.16
0.17
0.15
0.15
0.16
0.18
0.19
0.20
0.19
0.20
Length(mm)
19.31
19.30
19.31
19.31
19.32
19.30
19.31
19.30
19.32
19.31
Thickness(mm)
6.7
6.8
6.8
6.7
6.8
6.7
6.7
6.8
6.8
6.7
Width(mm)
Disintegration
9.2
04:56
9.2
04.52
9.1
04.51
9.1
04.52
9.2
04.50
9.2
04.51
9.1
03.58
9.2
03.55
9.2
03.51
9.1
03.19
time(Mts)
ERH (%)
0.05
0.06
0.07
0.06
0.07
0.07
0.07
0.07
0.08
0.08
www.wjpps.com
Vol 3, Issue 2, 2014.
1505
Sharma et al.
Assay
Amoxycillin
95.09
98.29
98.78
98.74
98.85
98.92
99.16
99.37
99.42
99.59
Pot. Clav.
97.00
98.20
98.59
98.85
99.95
99.97
99.20
99.36
99.59
99.70
In-vitro release studies
The amoxycillin and potassium clavulanate release study of chewable tablet was determined
by using dissolution IInd type apparatus. All the parameters of the dissolution were set using
900ml water at 37± 0.5c temperature and at 75 rpm and add one tablet in each six dissolution
vessel. The dissolution apparatus was immediately started ,5ml of the sample were withdrawn
at the time interval of 10,20,30 and 45 min from each dissolution vessel and the amount was
maintain with the fresh medium after each sample withdrawal. The solution was filtered with
the suitable membrane filter and filled in to vials and determines their % release at HPLC. (II)
Table VI: Dissolution study of f1-f10 formulation.
AFTER
20MIN. (%)
Amoxycillin
Pot. Clav.
Amoxycillin
Pot. Clav.
Amoxycillin
Pot. Clav.
Amoxycillin
Pot. Clav.
AFTER
10MIN.
(%)
30.596
52.127
55.491
56.589
60.633
58.177
65.644
68.173
61.971
63.555
68.379
69.470
68.038
68.332
67.188
75.255
65.907
74.411
74.303
77.720
75.732
78.361
75.576
77.802
70.198
75.618
75.945
78.101
78.042
79.622
80.267
82.150
Amoxycillin
Pot. Clav.
Amoxycillin
Pot. Clav.
Amoxycillin
Pot. Clav.
Amoxycillin
Pot. Clav.
Amoxycillin
Pot. Clav.
Amoxycillin
Pot. Clav.
72.290
72.581
72.910
73.044
78.929
78.521
78.799
79.123
79.024
79.445
80.109
85.762
88.214
90.099
89.237
92.788
92.951
93.029
94.797
95.042
95.587
96.545
97.548
98.069
89.708
92.104
91.927
93.249
93.851
95.435
95.667
96.139
97.190
97.228
98.526
98.124
90.122
93.703
94.829
95.379
95.364
96.398
97.632
97.732
98.455
98.744
99.666
99.015
FORMULATIONS
F1
F2
F3
F4
F5
F6
F7
F8
F9
F10
AFTER
30MIN. (%)
AFTER
45MIN. (%)
Note: Pot. Clav. = Potassium Clavulanate
www.wjpps.com
Vol 3, Issue 2, 2014.
1506
Sharma et al.
Figure 8: In -Vitro Dissolution of Amoxycillin
Figure 9: In Vitro Dissolution of Potassium Clavulanate
Stability Study
The effect of temperature and humidity on the physical and chemical characteristics of the
amoxycillin and potassium clavulanate chewable tablet was evaluated as per ICH guidelines.
(VIII)
Table VII: Storage condition as per ICH guideline
Storage condition
Temperature
Relative Humidity
Accelerated study
40±2C
75±5% RH
Table VIII: Stability study plan
S. NO
1
2
3
4
5
www.wjpps.com
Test Interval in month
(accelerated stability)
0
1
2
3
6
Vol 3, Issue 2, 2014.
Parameter to be analyzed
I
I
I
I,II
I,II
1507
Sharma et al.
Table IX: Parameter to be analyzed
Category
Test
I
Description,
Average
weight,
Dissolution,
Assay,
Moisture content, Water activity
Dissolution profile
II
Table
X:
Shows
accelerated
stability
data
for
amoxycillin
and
pot.
clavulanate chewable tablet.
Product
name
: Amoxycillin & Potassium
ChewableTablets 625 mg
Label claim
Each Chewable Tablet Contains:
Amoxycillin Trihydrate IP eq. to. Amoxycillin
: 500 mg
Storage
Potassium Clavulanate Diluted IP eq. to Condition
Clavulanic Acid
125 mg
Parameter
01 Month
02 Months
03 Months
06 Months
Complies
Complies
Complies
Complies
Complies
Complies
1031.21mg
Complies
1032.30mg
NMT 4:40
min
Complies
1031.15mg
NMT 4:45
min
Complies
1030.17mg
NMT 4:40
min
Complies
1032.26mg
MNT 4:50
min
Dissolution
NLT 90.0% of
claim in 45
minutes.
Clav: Min98.58%, Max99.81%
Amoxy: Min98.45%, Max99.69%
Clav:99.51
%
Amoxy:99.
14%
Clav:98.87
%
Amoxy:98.
63%
Clav:98.38
%
Amoxy:98.
04%
Clav:97.92
%
Amoxy97.74%
Water
Not more than 10
% w/w
7.71%w/w
7.06%w/w
7.70%w/w
7.79%w/w
7.86%
141cfu/g
Nil
Absent
137cfu/g
Nil
Absent
138cfu/g
Nil
Absent
133cfu/g
Nil
Absent
136cfu/g
Nil
Absent
Identification
Average Weight
Disintegration
Time
Microbiological
Quality
Total Bacterial
Count
Total Fungal
Count
E. coli
NMT 5min.
NMT 4:35 min
Temp. 40 
: 2C and RH
755%
Initial
Description
Specification
White colored,
elongated,
biconvex, and
Free from any
obvious defects.
To meet the test.
1030 mg + 2%
Clavulanate
Not more than
1000 cfu/g
Not More than
100 cfu/g
Should be absent.
www.wjpps.com
Vol 3, Issue 2, 2014.
1508
Sharma et al.
Assay
Each Chewable
tablet Contains
Amoxycillin
Trihydrate IP eq.
to. Amoxycillin
500 mg
Potassium
Clavulanate
Diluted IP eq. to
Clavulanic Acid
125 mg
90% to 120%
99.14%
98.92%
98.45%
98.14%
97.73%
90% to 120%
99.23%
99.08%
98.95%
98.45%
97.91%
Figure 10: Comparative DPs for zero month and 3 month accelerated data
Figure 11: Comparative DPs for Zero month and 6 month accelerated data.
RESULTS
Preformulation studies
Solubility

Amoxycillin was slightly soluble in water, methanol and ethanol.

Potassium Clavulanate was freely soluble in water and methanol.
www.wjpps.com
Vol 3, Issue 2, 2014.
1509
Sharma et al.
Identification of API by HPLC
Identified successfully by HPLC. The retention time of Standard curve and test curve were
same.

Amoxycillin: RT of standard Amoxycillin was 2.060 and RT of test was also
2.06(fig.1&2).

Potassium clavulanate: RT of standard and test of potassium clavulanate was also nearly
same respectively. 1.924, 1.928(fig.3&4).

The RT of mixture of Amoxycillin & Potassium Clavulanate standard was 4.082 & 2.143
and RT of test was 4.082 & 2.143(fig.5&6).
Flow Properties
Flow properties of granules were determined successfully. All results were in limits.
Hausner’s ratio was found to be in limit -1.11to1.24. And angle of repose was found to be 21
to 21.7.
Carr’s index- It was found to be in limit-9 to 15.
Evaluation of tablet

Tablet evaluations were lies in the limit. The average weight of tablet shows the value in
limit in between 1025-1032.

All the result of the tablet evaluation are lies in the limit and they are shows in the table
no-V.

The % releases of batch f1-f5 were 70 to 80 % and from batch f6-f10 was in the limit of
90 to 100 %.

Batch f10 shows the best result as compare to the all formulation.F10 formulation shows
the amoxycillin value 99.67 and potassium clavulanate was 99.12.then f10 was used for
the accelerated stability studies.

Accelerated stability studies data of the f10 formulation was shown in the table X.
CONCLUSION
It was concluded that Amoxycillin & Potassium Clavulanate Chewable tablet can be
formulated and the % release of batch F1-F4 was found to be failed i.e., 70.19% to 82.15%
only and from batch F6-F10 was within the limit of 90-100%. The % release of batch F10
was found to be best i.e., 99.67% of Amoxycillin & 99.02% of Potassium Clavulanate was
released in 45 minutes. The best formulation i.e., F10 was kept for accelerated stability
www.wjpps.com
Vol 3, Issue 2, 2014.
1510
Sharma et al.
studies as per ICH guidelines and was evaluated for various parameters such as description,
assay, dissolution, water content at 1 month, 2 month, 3 month, 6 month intervals at
accelerated condition (40C±2C/75%, RH±5%RH). All the parameters were satisfactory thus,
the formulated chewable tablet was found to be stable.
ACKNOWLEDGEMENT
I express my heartfelt thank to Mr. Jugaldas Chudasama, M.Pharm, (Plant head), Mr. Vijay
Aggarwal, (M.D.) & Mr. Prabhu Narayan Yadav, (Q.A. Execeutive), Medicef Pharma,
Baddi(H.P.),For providing me research facilities to carry out my work and whose inspiring
support, valuable suggestions and guidance made me to complete this project successfully.
I express my deep sense of gratitude and thank my guide, Mr. Ashok Kumar Sharma,
Lecturer, Department of Pharmaceutics, and Mr. Pratap Singh Rathore associate professor in
Arya College of Pharmacy, Kukas, Jaipur (raj).
REFERENCE
I.
Priyanka, Kumar B. Pragati, “Formulation development and evaluation of Montelukast
and sodium chewable tablet”, page no-35.
II.
Ravouru Nagaraju1, Rajesh Kaza2*, “Stability evaluation of amoxycillin and potassium
Clavulanate tablets USP by accelerated studies”, 5 (3) 201-214, 2008.
III.
Bajaj Sanjay, Singla Dinesh and Shakuja Neha, “Stability of Pharmaceutical Product”,
Journal of applied pharmaceutical science, 02 (03); 2012: 129-138
IV.
Kumar N. Amurnth , Rajan V.S.Thiruvengada, Cheety C Madhusudana , “A review on
Stability Studies overview”,1(3),2011,106-111.
V.
Jagdale Swati , Gattani Mahesh, Bhavsar Dhaval, Kuchekar Bhanudas, Chabukswar
Aniruddha, “Formulation and evaluation of chewable tablet of Levamisole”,Vol-1, Issue3, 282-289, 2010.
VI.
Patil Jaydev, V Vishwajith, V Gopal, “Formulation and evaluation of chewable tablets
containing non-sedating antihistamine”, Journal of pharmaceutical science,1(3),2012,112117.
VII.
Olowosulu A.K, Oyi Avosuahi, Isah A.B., Ibrahim M.A., “Formulation and Evaluation of
Novel Co-Processed Excipients of Maize Starch and Acacia Gum for Direct Compression
Tableting”, International Journal of Pharmaceutical Research and Innovation, Vol. 2: 3945, 2011.
www.wjpps.com
Vol 3, Issue 2, 2014.
1511
Sharma et al.
VIII.
World Health Organization, WHO Technical Report Series, No. 953, 2009, Annex-2,
Stability Testing of Active Pharmaceutical Ingredient.
IX.
Kalvimoorthi* .V, ThamizhMozhi M, Rajasekaran. M and Karthi .J, “Formulation and InVitro Evaluation of Amoxycillin Clavulanate Potassium Tablet”, International Journal of
Analytical, Pharmaceutical and Biomedical Sciences, 1, (3), 2012.
X.
Anusha V., Palanichamy S. Sugumar M., Rajesh*, Parasakthi N., Godwin raja das T.,
Ramasubramaniyan P. and Thanga thirupathi A. “Formulation and Characterization of
Albendazole Chewable Tablets”, Pelagia Research Library, Der Pharmacia Sinica, 2012,
3 (2):211-216.
XI.
Pacharane Sharad, Jadhav K.R., and Kadam V.J,“Formulation and development of
Extended Released Tablet of Lamotrigine”, International Journal of Pharma and Bio
Sciences.
www.wjpps.com
Vol 3, Issue 2, 2014.
1512

Full Text Article

Transcription

Similar documents

Call 1-888-4PPA-NOW

PDF - Issue 0215 - The Medicine Maker

Pharmacy Daily for 250712

Sangaku--Japanese Mathematics and Art in the 18 ,19 and 20

chemistry - Bank Soalan SPM

Goldberg Variations

Patient Care Process Faculty of Pharmacy and Pharmaceutical

PDF

sample report

DRUG DESCRIPTION - Pharma Consult Website

December 2010

Pharmaceutical Marketing