5481-5504, 1800, IJPT-14-0203, 30.05.13, FORMULATION …Email:[email protected] ......
Transcript of 5481-5504, 1800, IJPT-14-0203, 30.05.13, FORMULATION …Email:[email protected] ......
Kotta Kranthi Kumar* et al. International Journal Of Pharmacy & Technology
IJPT | July-2013 | Vol. 5 | Issue No.2 | 5481-5504 Page 5481
ISSN: 0975-766X
CODEN: IJPTFI
Available Online through Research Article
www.ijptonline.com FORMULATION AND EVALUATION OF CLOPIDOGREL BISULFATE IMMEDIATE
RELEASE TABLETS USP 75MG
Kotta Kranthi Kumar*1, K.Sampath Kumar
2, G.Satheesh
3
Department of Pharmaceutics, S.K.U College of Pharmaceutical sciences S.K.University*1,
Anantapur,
Sri Lakshmivenkateseara Pharmacy College2 produttur, Krishnateja Pharmacy College Tirupathi
3.
Email:[email protected] Received on 02-06-2013 Accepted on 29-06-2013
Abstract
The present study relates to formulations comprising Clopidogrel, including pharmaceutically
acceptable salts thereof, which provide desired bioavailability. The aim of this study is to develop and evaluate
pharmaceutically equivalent, stable, cost effective and quality improved formulation of Clopidogrel bisulfate
immediate release tablets (at least 85% of the drug is dissolved in 30 min in each of three different aqueous media
(i.e., PH ranging from 1 to 6.8) using US pharmacopeia (USP) apparatus II at 100 rpm) and comparison of
dissolution rate of optimized formula with innovator’s product and estimation of similarity and difference
factors. In order to obtain acceptable product several trials w e r e c o n d u c t e d . Various pharmacopeia evaluations
of the formulations were conducted including weight variation, hardness, disintegration time, friability,
invitro dissolution. Final selection of formulation was done based on invitro drug release of development
formulation to that of marketed one. The optimized formulation was kept under stability conditions at 40oC ±
2oC / 75% RH conditions for 3 months as per ICH guidelines in HDPE containers and the product is to be stable
throughout the period.
Keywords: Clopidogrel bisulphate, immediate release, stability, ICH guidelines.
Introduction
Oral Drug Delivery1
Oral drug delivery is the most desirable and preferred method of administering therapeutic agents for systemic effects.
In addition oral medication is the first avenue investigated in the discovery and development of new drug entities and
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pharmaceutical formulations mainly because of patient acceptance, convenience in administration and cost effective
manufacturing process. For many drug substances, conventional immediate release formulations provide clinically
effective therapy while maintaining the required balance of pharmacokinetic and pharmacodynamic profiles with an
acceptable level of safety to the patient.
Based on desired therapeutic objectives, oral drug delivery systems may be assorted into three categories:
• Immediate- release preparations
• Controlled- release preparations
• Targeted- release preparations
Immediate Release Preparations
These preparations are primarily intended to achieve faster onset of action for drugs such as analgesics, antipyretics,
and coronary vasodilators. Other advantages include enhanced oral bioavailability through transmucosal drug delivery
and pregastric absorption, convenience in administration to dysphasic patients, especially the elderly and
bedridden and new business opportunities.
Conventional IR formulations include fast disintegrating tablets and granules that use effervescent mixtures, sodium
carbonate (sodium bicarbonate) and citric acid
(Tartaric acid) and super disintegrants such as sodium starch glycolate, Croscarmellose sodium and Crospovidone.
Current technologies in fast dispersing dosage forms include modified tableting systems, floss or shear form
technology, which employs application of centrifugal force, controlled temperature and freeze drying
Tablets: - 2-9
Tablet is solid dosage form each containing a unit dose of one or more medicaments. Tablets are solid, flat or biconvex
discs prepared by compressing a drug or mixture of drugs with or without suitable Pharmaceutical excipients tablets are
the dominant dosage forms for drug delivery, occupying two thirds of the global market. Generally, they are produced
by compressing dry powder blends consisting of a number of components with different functionalities in a die. With
advancement in technology and increase in awareness towards modification in standard tablet to achieve better
acceptability as well as bioavailability, newer and more efficient tablet dosage forms are being developed. The main
reasons behind formulation of different types of tablets are to create a delivery system that is relatively simple and in
Kotta Kranthi Kumar* et al. International Journal Of Pharmacy & Technology
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expensive to manufacture, provide the dosage form that is convenient from patient’s perspective and utilize an
approach that is unlikely to add complexity during regulatory approval process.
Immediate Release Film Coating Systems for Tablets10-13s
The pigmented and non-pigmented film coatings are used for immediate release solid dosage forms. These film
coating formulas produce attractive, elegant coatings on even the most challenging tablet surfaces and can be used in
both aqueous and organic coating procedures. An extensive selection of polymer blend formulations provides the user
with the ability to impart many beneficial features to a solid oral dosage formulation.
These benefits include
• Reduced coating process time
• Superior adhesion on difficult to coat cores
• Less stressful processing conditions for heat sensitive, friable or high drug content cores
• Sharper logo definition, even at higher weight gains
• Better gloss and smoothness compared to conventional tablets
• Improved colour stability.
Aqueous film coating is the quickest and least expensive method for enhancing the tablet appearance and unlike other
methods, will not affect dissolution or disintegration profiles. The dry-blend systems consist of polymers, plasticizers
and pigments combined in one, easy-to-use and this dry powder system which is rehydrated quickly with water. Dry
coating technology provides benefits such as improved adhesion, reduced processing times and application of the
tablet coating at wider process parameters.
The aim of present work is to formulation of Clopidogrel Bi sulphate immediate release tablet and comparable to the
marketed product which could perform therapeutically, with improved efficacy.
MATERIALS14,15
All the materials and equipments are listed in Table No:-1, 2
Table No: 1: List of Materials
Material Source
Clopidogrel bisulphate Natco Pharma Ltd.
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Microcrystalline Cellulose pH 102 Vijilak Pharma
Mannitol DC grade Signet Chemical Pvt Ltd
Low-substituted hydroxy propyl cellulose Vijilak Pharma Ltd
Croscarmellose sodium Signet Chemical Corporation Pvt Ltd
Lactose anhydrous Signet Chemical Corporation Pvt Ltd
Crospovidone / Polyplasdone XC Signet Chemical Corporation Pvt Ltd
Poly ethylene glycol 6000 Signet Chemical Corporation Pvt Ltd
L-HPC-LH-11 Signet Chemical Corporation Pvt Ltd
Hydrogenated castor oil Signet Chemical Corporation Pvt Ltd
Opadry pink32k84823 Signet Chemical Corporation Pvt Ltd
Croscarmellose sodium Signet Chemical Corporation Pvt Ltd
Table No.2: Equipment Used.
EQUIPMENT MODEL
UV-Visible Spectrophotometer Labindia UV 3000 Spectrophotometer
Digital Balance Essae model fb 3000 digital balance.
Sensitive Balance Keroy Km2 Sensitive Balance
PH
Meter Labindia Ph Analyzer
Tablet Punching Machine Cadmach single station tablet machine
Paddle Type Dissolution Apparatus Labindia Ds 800
FTIR Spectrophotometer Perkin Elmer, Japan
Hardness Tester Monsanto Ltd
Friability Apparatus Labindia Ft 1020 Tablet Friability Tester
Disintegration Apparatus Electro lab, mumbai.
Tray Dryer Sisco Tray Dryer
Hardness Tester Monsanto Hardness Tester
Experimental Session
Drug-excipient Compatibility Studies
A Compatibility study focuses on a binary mixture of drug substance and some selected excipients in a fixed ratio with
or without added moisture. The mixture stored at elevated temperatures as 40oc 75%RH, 55OC 60%RH in capped
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vials. The result of the interaction between the active drug and excipients is determined by FTIR. The objective of this
study was to determine the interactions of Clopidogrel bisulfate with Excipients in the formulation.
Drug- Excipient compatibility studies are listed in Table no:-3
Table No-3: Procedure for drug- Excipient compatibility studies.
Ingredients Ratio Initial
Colour After one
week After two
weeks After
three
weeks
After four
weeks
40 0C
75%RH
40 0C
75%RH
40 0C
75%RH
40 0C
75%RH
Clopidogrel bisulfate 1:1 White
granular
powder
White
granular
powder
White
granular
powder
White
granular
powder
White granular
powder
Clopidogrel bisulfate+ MCC 1:5 White
granular
powder
White
granular
powder
White
granular
powder
White
granular
powder
White granular
powder
Clopidogrel bisulfate+Mannitol 1:5 White
granular
powder
White
granular
powder
White
granular
powder
White
granular
powder
White granular
powder
Clopidogrel bisulfate+ L-HPMC
(LH-21) 1:1 White
granular
powder
White
granular
powder
White
granular
powder
White
granular
powder
White granular
powder
Clopidogrel bisulfate+ L-HPMC
(LH-21) 1:1 White
granular
powder
White
granular
powder
White
granular
powder
White
granular
powder
White granular
powder
Clopidogrel bisulfate+
Crospovidone 1:1 White
granular
powder
White
granular
powder
White
granular
powder
White
granular
powder
White granular
powder
Clopidogrel bisulfate+
polyethylene glycol 6000 1:0.5 White
granular
powder
White
granular
powder
White
granular
powder
White
granular
powder
White granular
powder
Clopidogrel bisulfate+ L-
Hydroxy propyl(LH-11)
1:1 White
granular
powder
White
granular
powder
White
granular
powder
White
granular
powder
White granular
powder
Clopidogrelbisulfate+Hydrogenated
castor oil 1:0.5 White
granular
powder
White
granular
powder
White
granular
powder
White
granular
powder
White granular
powder
Clopidogrel bisulfate+Opadry II
pink 32K84823 1:0.5 Pink
granular
powder
Pink
granular
powder
Pink
granular
powder
Pink
granular
powder
Pink granular
powder
Manufacturing Methods 16, 17
Pharmaceutical products are processed all over the world using the direct compressing, wet granulation or dry
granulation methods. Method is chosen depend on the ingredients individual characteristics like flow property,
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compressibility. Choosing a method requires thorough investigation of each ingredient in the formula, the combination
of ingredients, and how they work with each other. Then the proper granulation process cans be applied.
Formulation of different trial batches are listed in Table No:-4
Table no:-4: Formulation of Different Trials Batches.
S.No Composition* F1
Qty
F2
Qty
F3
Qty
F4
Qty
F5
Qty
F6
Qty
F7
Qty
F8
Qty
F9
Qty
F10
Qty
F11
Qty
F12
Qty
1. Clopidogrel bisulphate
(FORM II)
97.8 97.8 97.8 97.8 97.8 97.8 97.8 97.8 97.8 97.8 97.8 97.8
2. Microcrystalline cellulose
PH102
37.1 37.1 27.1 37.1 37.1 37.1 37.1 37.1 37.1 37 37.1 37.1
3. Mannitol DC grade 60 40 45 60 55 55 45 55 55 55 55 45
4. Low-substituted hydroxy
propyl cellulose(L-HPC) LH-21
10 3.0 15 10 15 15 15 15 15 10 10 15
5. Croscarmellose sodium 5 10 - 10 5 - 10 - 8 10 15 -
6. Lactose anhydrous - 10 15 - - 5 -
7. Crospovidone /
Polyplasdone XC
- - - 10 5 10 10 10 15 - 15 10
8. Poly ethylene glycol 6000 10 15 10 5 5 5 5 5 5 5 10 10
9. L-HPC-LH-11 10 10 5 10 10 10 10 10 13 10 10
10. Hydrogenated castor oil
(Cutina HRPH)
10 20 15 5 10 10 10 10 5 10 15
11. Opadry pink32k84823 - 7 6 - - - - 7 7 8 7
12. Purified water Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S Q.S
*The above all parameters are mentioned in mgs
Evaluation of Tablets18-37
Weight Variation Test:
This is an in process quality control test to be checked frequently (every half an hour). Corrections were made during
the compression of tablets. Any variation in the weight of tablets (for any reason) leads to either under medication or
overdose. So, every tablet in each batch should have a uniform weigh. The weight variation test was performed as per
USP. Twenty tablets were selected at random and their average weight was determined using an electronic balance.
The tablets were weighed individually and compared with average weight. The results were listed in Table no:-9
Kotta Kranthi Kumar* et al. International Journal Of Pharmacy & Technology
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Hardness Test:
Hardness (diametric crushing strength) is a force required to break the tablet across the diameter. The hardness of a
tablet is an indication of its strength. The tablet should be stable to mechanical stress during handling and
transportation. The degree of hardness varies with the different manufacturers and with the different types of tablets.
The permissible limit for hardness is 4-12 kg/cm2. The hardness of the tablets was determined by digital hardness
tester. Ten individual tablets from each trial were taken and measured individually at frequent intervals. The results
were listed in table no:5-6.
Table No- 5: Standard specifications of weight variation test.
Average weight as per USP %Difference
130 mg or less 10
More than 130 mg
through 324mg
7.5
More than 324mg 5
Table No-6: Storage Conditions in Stability Studies.
Study Storage condition Minimum time
period covered
Long term 25ºC ± 2 ºC/ 60% RH ± 5% RH 12 months
Intermediate 30ºC ± 2 ºC/ 60% RH ± 5% RH 6 months
Accelerated 40ºC ± 2 ºC/ 75% RH ± 5% RH 6 months
Table No-7: Mechanism of drug release.
Diffusion exponent (n) Overall solute diffusion mechanism
0.45 Fickian diffusion
0.45 < n < 0.89 Anomalous (non-fickian) diffusion
0.89 Case-II transport
n > 0.89 Super case-II transport
Thickness
The thickness of the tablets was determined by digital micrometer. Ten individual tablets from each trial were taken
and measured individually at frequent intervals. The results were listed in table no: 9
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Friability Test:
Friability of the tablets was determined by using Roche Friabilator (Electrolab, India). This device consists of a plastic
chamber that is set to revolve around 25 rpm for 4 minutes dropping the tablets at a distance of 6 inches with each
revolution. Friability was determined by taking 20 tablets. Tablets were weighed and placed in a Friabilator, after
specified time (4min at 25rpm) tablets were again weighed and the friability (F %) is given by the formula
F % = (1-W0 /W) ×100
Where, W0 is weight of the tablets before the test and W is the weight of the tablets after test. The results were listed
in table no:-9
Disintegration Test:
Disintegration time was measured using USP disintegration test apparatus (ED2L, Electrolab, India by using 900ml
distilled water at room temperature (37±20oC) The results were listed in table no:-9
Dissolution Test parameters
Medium: pH 2.0 HCl, pH 4.5 sodium acetate buffer, Ph 6.8 phosphate buffer
Apparatus: paddle type Speed: 50 rpm Temperature: 37±0.5°C Run time: 30 min
Dissolution Test Procedure:
6 tablets were placed in each of 6 dissolution flasks containing 900 m l of pH 2.0 HCl maintained at 37±0.5°C.
The apparatus was run for 30 minutes. A suitable volume of sample was withdrawn at regular intervals of time and
filtered through 0.45 µm membrane filter. The absorbance of the sample preparations were measured at 249 nm, using
pH 2.0 HCl as blank The results were listed in table no:-10
Similarity and Difference Factors
For each dissolution run, a mean of six determinations was recorded for marketed product. Thein vitro dissolution of
clopidogrel bisulfate immediate release tablets were prepared and matched with innovator product by calculating the
similarity and difference factors. A model independent approach was used to estimate the dissimilarity the dissolution
profile of optimized formulation (F8) with innovator’s preparation. The following equations were used for calculating f1
and f2.
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The fallowing equation given
Where
n = no of time points,
Rt = dissolution value of the reference batch at time t,
Tt=dissolution value of the test batch at same time point.
The results were listed in table no:13
Stability Studies
The design of the formal stability studies for the drug product was based on the knowledge of the behavior and
properties of the drug substance and formal stability studies on the drug substance. Specification which is list of tests,
reference to the analytical procedures and proposed acceptance criteria, including the concept of different acceptable
criteria for release and shelf life specifications, is addressed in ICH (Temperature: 40±2oC Relative humidity:
75±5% for 3 months).T he results were listed in table no:-14
When significant change occurs at any time during 6 months testing at the accelerated storage condition, additional
testing at the intermediate storage condition should be conducted and evaluated against significant change criteria.
Release Kinetics: The mathematical models are used to evaluate the kinetics and mechanism of drug release from the
tablets. The model that best fits the release data is selected based on the correlation coefficient (r) value in various
models. The model that gives high ‘r’ value is considered as the best fit of the release data.
Mathematical models are
1) Zero order release model
2) First order release model
3) Hixson-crowell release model
4) Higuchi release model
5) Korsmeyer – peppas release model
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Zero order release rate kinetics:-
To study the Zero order release kinetics the release rate data were fitted to the following equation.
F = K t
Zero order release rate kinetics:-
To study the Zero order release kinetics the release rate data were fitted to the following equation.
F = K t
Where,’F’ is the fraction of drug release,
‘K’ is the release rate constant, and‘t’ is the release time.
When the data is plotted as Cumulative percent drug released versus time, if the plot is linear then the data obeys Zero
order release kinetics, with slope equal to K.
The results are given in table.
First order kinetics:-
A First order release would be predicated by the following equation.
K t
Log C = Log Co - ----------
2.30 3
Where = Amount of drug remained at time‘t’
Co = initial amount of drug
K = First order rate constant (hr-1)
When the data is plotted as Cumulative percent drug remaining versus time yields a straight line, Indicating that the
release follows First order kinetics .The constant ‘K’ can be obtained by multiplying 2.303 with slope value.
Higuchi release model: -
To study the Higuchi release kinetics, the release rate data were fitted to the following equation.
F = K. t1/2
Where,’F’ is the amount of drug release
‘K’ is the release rate constant, and
Kotta Kranthi Kumar* et al. International Journal Of Pharmacy & Technology
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‘t’ is the release time.
When the data is plotted as Cumulative drug released Versus Square root of time, yields a straight line, indicating that
the drug was released by diffusion mechanism .The slope is equal to ‘K’.
Korsmeyer and peppas release model: - The release rate data were fitted to the following equation.
Mt / M∞ = K. t n
Where, Mt / M∞ is the fraction of the drug release,
‘K’ is the release rate constant,
‘t’ is the release time, and
‘n’ is the diffusional exponent for the drug release that is dependent on the shape of the matrix dosage form. When the
data is plotted as Log of drug released Versus log time, yields a straight line with a slope equal to ‘n’ and the, ‘K’ can
be obtained from Y-intercept.
All the results are reported in the table no: 16
Results
All the results are listed in Table No:-8-16
Summary and Conclusion
The present study was undertaken to develop Clopidogrel bisulfate immediate tablets of 75mg, comparable to the
innovators product (Plavix-sanfoi aventis). Based on the results, suitable excipients were selected for formulation
development. Various formulas of Clopidogrel bisulfate were prepared by using direct compression method. The
powder blend were subject to various physical characteristics tests such as bulk density, tapped density,
Hausner’s ratio, compressibility index and core tablets were evaluated for weight variation, hardness, thickness,
disintegration time and the results were within specification. Compatibility studies were performed and it was observed
that all the ingredients used were compatible with the drug. As Clopidogrel possess stability problem core
tablets were coated with coating suspension and were evaluated for disintegration time, assay and In-vitro release
studies. In-vitro dissolution profile of developed formula was compared with innovator’s product (Plavix) and drug
release from developed formula was found to be similar to innovator product and compared with the reference product
Kotta Kranthi Kumar* et al. International Journal Of Pharmacy & Technology
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of Plavix. The optimized batch tablets were packed in HDPE containers and performed stability studies at
40°C/75%RH. Stability samples were evaluated initially and after two months.
Table No-8: Drug Excipient compatibility studies.
Ingredients Ratio Initial
Colour After
one
Week
After two
weeks After
three
weeks
After
four
weeks
40 0C
75%RH 40
0C
75%RH 40
0C
75%RH 40
0C
75%RH
Clopidogrel bisulfate 1:1 White
granular
powder
NCC NCC NCC NCC
Clopidogrel bisulfate+ MCC 1:5 White
granular
powder
NCC NCC NCC NCC
Clopidogrel bisulfate+Mannitol 1:5 White
granular
powder
NCC NCC NCC NCC
Clopidogrel bisulfate+ L-HPMC
(LH-21) 1:1 White
granular
powder
NCC NCC NCC NCC
Clopidogrel bisulfate+
Crospovidone 1:1 White
granular
powder
NCC NCC NCC NCC
Clopidogrel bisulfate+
polyethylene glycol 6000 1:0.5 White
granular
powder
NCC NCC NCC NCC
Clopidogrel bisulfate+ L-
Hydroxy propyl(LH-11)
1:1 White
granular
powder
NCC NCC NCC NCC
Clopidogrelbisulfate+Hydrogenated
castor oil 1:0.5 White
granular
powder
NCC NCC NCC NCC
Clopidogrel bisulfate+Opadry II
pink 32K84823 1:0.5 Pink
granular
powder
NCC NCC NCC NCC
NCC-No colour change
Table No-9: Post Compression Parameters.
S.no Formulation Average
weight(mg)
Thickness Disintegration
min
Friability Assay Hardness
1 F-1 246.8 3.63±0.099 40.16 0.153±0.56 96.4±0.79 4.2±0.31
2 F-2 246.90 3.62±0.016 3.02 0.106±0.76 97.3±0.76 5.3±0.42
3 F-3 247.50 3.43±0.035 8.5 0.377±0.65 94.1±0.56 10.44±0.49
4 F-4 247.80 3.46±0.024 14.55 0.24±0.54 98.5±0.76 2.75±0.51
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5 F-5 246.70 3.48±0.029 11.5 0.17±0.86 97.4±0.87 6.09±0.24
6 F-6 246.8.55 3.47±0.053 11.2 0.28±0.76 90.3±0.79 5.46±0.32
7 F-7 246.90 3.53±0.022 12 0.23±0.45 92.4±0.67 9.45±0.59
8 F-8 247.12 3.5±0.022 10 0.5±0.56 99.8±0.56 2.9±0.47
9 F-9 245.80 3.55±0.019 5.5 0.06±0.59 98.5±0.98 9.6±0.35
10 F-10 245.32 3.54±0.016 12 0.16±0.57 98.2±0.76 7.1±0.27
11 F-11 246.9 3.53±0.02 13.02 0.4±0.45 98.3±0.45 3.5±0.13
12 F-12 247.8 3.55±0.016 13.53 0.5±0.79 97.4±0.76 4.0±0.56
All the values are expressed as mean ± S.D; No. of trails (n) =6
INFERENCE: All the formulation trials were within the specifications and F8 formulation showed appreciable results of
physical properties.
Table No:-10: Dissolution Results of Trial Batches.
S .NO TIME
(min)
F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
1. 0 0 0 0 0 0 0 0 0 0 0 0 0
2. 10 60.6 61.1 63.7 54.5 59.3 61.3 62.4 62.7 54.1 54.5 48.3 53.1
3. 15 80.2 74.3 74.1 72.3 74.3 74.5 73.6 78.8 77.8 81.2 75.7 74.3
4. 20 82.9 82.9 86.4 88.7 88.7 92.1 86.7 90.4 85.3 88.3 88.3 88.6
5. 30 95.6 96.6 94.5 91.5 91.5 96.6 91.8 99.3 90.3 90.4 90.8 98.3
Table No-11: Invitro Drug Release of Optimized Batch.
TIME
(min)
% of drug release F8
0 0
10 62.7
15 78.8
20 90.4
30 99.3
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Table No: 12: Comparative Dissolution Profile of F8 Formulation and Innovator.
TIME F8 INNOVATOR
0 0 0
10 62.7 54
15 78.8 74
20 90.4 88
30 99.3 98.3
INFERENCE: The drug content of optimized formulation was equivalent to the innovator’s product
Table No-13: Similarity and Difference Factors.
N INNOVATOR
(Rt)
F-8
(Tt)
D=(Rt-Tt) (Rt-Tt)2 f 1 f 2
0 0 0 0 0
5.15
64.29
10 54 62.7 -8.7 75.69
15 74 78.8 -4.8 23.04
20 88 90 -2 4
30 98.3 99 -0.7 0.49
Table No-14: Stability Studies of Optimized Formulation.
CONDITIONS
Sl. no Assay(%w/w) Initial 40c & 75% RH
0 Day 1 month 2month 3month
1 Optimised
formulation (F8)
100.3
99.8
99.5
99.6
2. Innovator 100 99.8 99.6 99.6
INFERENCE: The assay values are within the specifications
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Table No-15: Dissolution of Optimized Formulation and Innovator.
Time
(min)
Initial 1
st month 2
nd month 3
rd month
0 0 0 0 0
10 62.7 62.7 62.7 62.7
15 78.8 78.8 78.8 78.8
20 90.4 90.4 90.4 90.4
30 99.3 99.3 99.3 99.3
Table No-16: First Order Kinetics.
Time
(min)
% drug
release
% drug
remained
Cumulative %
drug remained
Log cumulative %drug
Remained
0 0 100 62.7
1.797267541
10 62.7 37.3 15.6
1.193124598
15 78.8 21.7 11.7
1.068185862
20 90 10 9
0.954242509
30 99 1 0 0
Drug- Excipient studies by FTIR
Fig no-1: FTIR spectra of Clopidogrel bisulfate
Kotta Kranthi Kumar* et al. International Journal Of Pharmacy & Technology
IJPT | July-2013 | Vol. 5 | Issue No.2 | 5481-5504 Page 5496
Fig No-2: FTIR spectra of Clopidogrel bisulfate + Crospovidone.
Fig No-3: FTIR spectra of Clopidogrel bisulfate+ hydrogenated castor oil.
Fig No-4: FTIR spectra of Clopidogrel bisulfate + Mannitol.
Kotta Kranthi Kumar* et al. International Journal Of Pharmacy & Technology
IJPT | July-2013 | Vol. 5 | Issue No.2 | 5481-5504 Page 5497
Fig No-5: FTIR spectra of Clopidogrel bisulfate + PEG 6000.
Fig No-6: FTIR spectra of Clopidogrel bisulfate +LH- 11.
Fig No-7: FTIR spectra of Clopidogrel bisulfate +LH 21.
Kotta Kranthi Kumar* et al. International Journal Of Pharmacy & Technology
IJPT | July-2013 | Vol. 5 | Issue No.2 | 5481-5504 Page 5498
Fig No-8: FTIR spectra of Clopidogrel bisulfate + Opadry pink.
Fig No:-9: FTIR spectra of placebo
INFERENCE: Drug Excipient stability studies showed no conformational changes in formulations and
found to stable at environmental condition as defined by ICH guidelines and there was no interaction or
physical change between the drug and Excipients. So the selected Excipients were found to be compatible with
the drug.
Fig No:-10
Kotta Kranthi Kumar* et al. International Journal Of Pharmacy & Technology
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Fig No-11: Invitro % drug release of optimized formulation in pH2.0 HCL buffer
Fig No-12: Comparison of F8 formulation with the innovator.
Fig No-13: Chromatogram of optimized formulation.
Kotta Kranthi Kumar* et al. International Journal Of Pharmacy & Technology
IJPT | July-2013 | Vol. 5 | Issue No.2 | 5481-5504 Page 5500
Fig No-14: Chromatogram of Innovator’s product.
INFERENCE: The drug content of optimized formulation was equivalent to the innovator’s product
Fig No-15: Dissolution profile of optimized batch for stability studies.
Fig No-16: First order kinetics.
INFERENCE: The optimized formulation has followed first order kinetics due to its invitro drug release was 90% in
20 min.
Kotta Kranthi Kumar* et al. International Journal Of Pharmacy & Technology
IJPT | July-2013 | Vol. 5 | Issue No.2 | 5481-5504 Page 5501
Conclusion
From the results obtained, the In-vitro dissolution profile of formula 8 was somewhat better to that of reference
product. All the stability results were found to be satisfactory. Hence the designed and developed formula of
Clopidogrel was stable. Clopidogrel bisulfate immediate release tablets developed in the present work was found to be
pharmaceutically better than the innovators product.
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Corresponding Author:
Kotta Kranthi Kumar*,
Email:[email protected]