Formulation Development and Evaluation of Clopidogrel FDT

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Iranian Journal of Pharmaceutical Sciences 2016: 12 2: 61-74 Original Article Formulation Development and Evaluation of Clopidogrel Fast Dissolving Tablets Gunda Raghavendra Kumar a J.N.Suresh Kumar a V.Satyanarayana b G.Swarupa Rani c B.Satya Prasad d a Department of Pharmaceutics Narasaraopeta Institute of Pharmaceutical Sciences Narasaraopet Guntur Dt Andhra Pradesh India-522601. b Department of Pharmacy Practice Narasaraopeta Institute of Pharmaceutical Sciences Narasaraopet Guntur Dt Andhra Pradesh India-522601. c Department of Pharmacology Narasaraopeta Institute of Pharmaceutical Sciences Narasaraopet Guntur Dt Andhra Pradesh India-522601. d Department of Pharmaceutical Analysis Narasaraopeta Institute of Pharmaceutical Sciences Narasaraopet Guntur Dt Andhra Pradesh India-522601. Abstract The main objective of the present research work is to formulate the Clopidogrel Fast Dissolving tablets. Clopidogrel an antiplatelet drug belongs to BCS Class-II and used to control Heart attack Hypertension by inhibiting Platelet activation and aggregation .The Fast Dissolving tablets of Clopidogrel were prepared employing different concentrations of Crospovidone and Croscarmellose sodium in different combinations as a Superdisintegrant by Direct Compression technique using 3 2 factorial design. The concentration of Crospovidone and Croscarmellose sodium was selected as independent variables X 1 and X 2 respectively whereas wetting time Disintegration time t 50 t 90 were selected as dependent variables. Totally nine formulations were designed and evaluated for hardness friability thickness Assay Wetting time Disintegration time and in-vitro drug release. From the Results it was concluded that all the formulation were found to be with in the Pharmacopoeial limits and the in-vitro dissolution profiles of all formulations were fitted into different Kinetic models the statistical parameters like intercept a slope b and regression coefficient r were calculated. Polynomial equations were developed for Wetting time Disintegration time t 50 t 90 . Validity of developed polynomial equations was verified by designing 2 check point formulations C 1 C 2 . According to SUPAC guidelines the formulation F 5 containing combination of 15 Crospovidone and 15 Croscarmellose is the most similar formulation similarity factor f 2 91.3936 dissimilarity factor f 1 1.203 No significant difference t -0.00062 to marketed product PLAVIX-75. The selected formulation F 1 follows First order Higuchi’s kinetics mechanism of drug release found to be Fickian Diffusion n 0.226. Keywords : Clopidogrel 3 2 Factorial Design super disintegrants Crospovidone croscarmellose Sodium Wetting Time Disintegration Time Fickian Diffusion.

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Kumar G R et al / IJPS 2016 12 2: 61-74 62 1. Introduction Researchers throughout the world are focusing intensively on the methods for the development of new drug delivery systems to enhance patient’s compliance. Fast dissolving tablets become an emerging trend in the pharmaceutical industry. Fast dissolving tablets are ideal for all types of people including for people who have swallowing difficulties pediatric geriatric and bedridden patients. It is also for active patients who are busy travelling and may not have access to water. Fast dissolving tablets are also known as oro dispersible tablets mouth-dissolving tablets orally disintegrating tablets melt-in mouth tablets rapimelts porous tablets quick dissolving etc. Many drugs have the potentials to be made into oro dispersible tablets. They vary from analgesics to neuroleptics and anti- psychotic drugs. However only a small percentage of them are researched on and some have been manufactured and marketed. Fast-dissolving drug-delivery systems were initially developed in the late 1970s as an alternative to tablets capsules and syrups for pediatric and geriatric patients who experiences difficulties in swallowing traditional oral solid-dosage forms 1. The speed of solubility of drug affects the rate of absorption of the drug. The faster the drug dissolve into solution quicker the absorption and onset of clinical effect. They should readily dissolve or disintegrate in the saliva generally within 60 seconds. Some drugs are absorbed from the mouth pharynx and esophagus as the saliva passes down into the stomach. The significance of oro dispersible dosage forms are progressively being recognized in both industry and academics 2 3.The small volume of saliva is usually sufficient to result in tablet disintegration in the oral cavity. The medication can then be absorbed partially or entirely into the systemic circulation from blood vessels in the sublingual mucosa or it can be swallowed as a solution to be absorbed from the gastrointestinal tract. The sublingual route usually produces a faster onset of action than orally ingested tablets and the portion absorbed through the sublingual blood vessels bypasses the hepatic first-pass metabolic processes 4. The performance of ODT depends on the technology used in their manufacture. The orally disintegrating property of the tablet is attributable to a quick intake of water into the tablet matrix which creates porous structures and result in rapid disintegration. Hence the basic approaches to develop ODT include maximizing the porous structure of the tablet matrix incorporating the appropriate disintegrating agent and using highly water soluble excipients in the formulation. Orally disintegrating tablets are formulated by utilizing several processes which differ in their methodologies and the Corresponding Author: Raghavendra Kumar Gunda Department of Pharmaceutics Narasaraopeta Institute of Pharmaceutical Sciences Narasaraopet Guntur Dt Andhra Pradesh India-522601. Tel: +91-9666705894 E-Mail: Cite this article as: Kumar G R Kumar J.N.S Satyanarayana V Swarupa Rani G Prasad B.S Formulation Development and Evaluation of Clopidogrel Fast Dissolving Tablets.Iranian Journal of Pharmaceutical Sciences 2016 12 2: 61-74.

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Clopidogrel fast dissolving tablets 63 ODTs formed vary in various properties such as mechanical strength of tablet taste and mouth feel swallowability drug dissolution in saliva bioavailability and stability. Various processes employed in formulating ODTs include Freeze-Drying or Lyophilization cotton candy process molding spray drying mass extrusion and compaction wet granulation dry granulation direct compression 5. In the present study the direct compression method was adopted to manufacture the ODT tablets since it is very simple and do not require any sophisticated equipment’s. The direct compression represents the simplest and most cost effective tablet manufacturing technique. ODT by direct compression technique is a simple approach of drug delivery systems that proved to be rational in the pharmaceutical arena for its ease compliance faster production avoid hydrolytic or oxidative reactions occurred during processing of dosage forms. 1.1. Drug Profile and Rationality for Experimental Design Clopidogrel a weak base known chemically as Methyl S- α- 2chlorophenyl- 67-dihydrothieno32-cpyridine-54H- acetate sulfate 1:1.It is practically insoluble in water at neutral pH freely soluble in aqueous buffer at pH 1 and in methanol sparingly soluble in methylene chloride and practically insoluble in ethyl ether 6.Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y12 class of ADP receptors on platelets. The blockade of inhibits platelet aggregation by blocking activation of the glycoprotein IIb/IIIa pathway. Platelet inhibition can be demonstrated 2 h after a single dose of oral Clopidogrel but the onset of action is slow so that a loading-dose of 300-mg is followed by 75 mg once daily.The active metabolite has an elimination half-life of about six hours and acts by forming a disulfide bridge with the platelet ADP receptor 7-10. According to the biopharmaceutics classification system BCS Clopidogrel is categorized as a class II agent poorly water soluble and highly permeable its solubility is very low i.e. 0.0099 mg/ml and has very low bioavailability 6. Oral bioavailability of clopidogrel is very low less than 50 due to poor water solubility.Hence the drug is selected for formulating Fast Dissolving Tablets by Direct compression method. It is an important issue is to design an optimized formulation with an appropriate dissolution rate in a short time period and minimum trials. Many statistical experimental designs have been recognized as useful techniques to optimize the process variables. For this purpose response surface methodology RSM utilizing a polynomial equation has been widely used. Different types of RSM designs include 3-level factorial design central composite design CCD Box- Behnken design and D-optimal design. Response surface methodology RSM is used when only a few significant factors are involved in experimental optimization. The

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Kumar G R et al / IJPS 2016 12 2: 61-74 64 technique requires less experimentation and time thus proving to be far more effective and cost-effective than the conventional methods of formulating sustained release dosage forms 11-14. Hence an attempt is made in this research work to formulate Fast Dissolving Tablets of Clopidogrel using Crospovidone and Croscarmellose sodium. Instead of normal and trial method a standard statistical tool design of experiments is employed to study the effect of formulation variables on the release properties. Large scale production needs more simplicity in the formulation with economic and cheapest dosage form. The Fast Dissolving tablets formulation by direct compression method is most acceptable in large scale production. A 3 2 full factorial design was employed to systematically study the drug release profile. A 3 2 full factorial design was employed to investigate the effect of two independent variables factors i.e the amounts of Crospovidone and Croscarmellose on the dependent variables i.e. Disintegration time Wetting Time t 50 t 90 Time taken to release 50 90 respectively 2. Materials and Methods Materials used in this study were obtained from the different sources. Clopidogrel was a gift sample from Dr.Reddy’s Laboratories Hyderabad India. Avicel pH-101 Crospovidone Croscarmellose were procured from Loba ChemiePvt.Ltd Mumbai. Other excipients such as Magnesium Stearate and talc were procured from S.D. Fine Chem. Ltd. Mumbai. 2.1. Formulation Development of Clopidogrel Fast Dissolving Tablets The factorial design is a technique that allows identification of factors involved in a process and assesses their relative importance. In addition any interaction between factors chosen can be identified. Construction of a factorial design involves the selection of parameters and the choice of responses 15. A selected three level two factor experimental design 3 2 factorial design describe the proportion in which the independent variables Crospovidone and Croscarmellose sodium were used in formulation of Clopidogrel Fast Dissolving Tablets. The time required for 50 t 50 90 t 90 drug dissolution Disintegration Time and Wetting Time were selected as dependent variables. Significance terms were chosen at 95 confidence interval p0.05 for Final Equations. Polynomial equations were developed for t 50 t 90 Disintegration Time and Wetting Time step-wise backward Linear Regression Analysis. The three levels of factor X 1 Crospovidone at a concentration of 7.5 10.0 15three levels of factor X 2 Croscarmellose at a concentration of 7.5 10.0 15. with respect to average weight of Tablet i.e200 mg were taken as the rationale for the design of the Clopidogrel Fast Dissolving tablet formulation. Totally nine Clopidogrel Fast Dissolving tablet formulations were prepared employing

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Clopidogrel fast dissolving tablets 65 selected combinations of the two factors i.e X1 X 2 as per 3 2 Factorial and evaluated to find out the significance of combined effects of X1 X 2 to select the best combination and the concentration required to achieve the desired Fast release/ Dissolution of drug by providing large Surface area and Improved Solubility from the dosage form. 2.2. Preparation of Clopidogrel Fast Dissolving Tablets Clopidogrel Tablets were prepared by direct compression method. The composition of each tablet is shown in Table No 2. The drug diluents and superdisitegrants were passed through sieve 40. All the above ingredients were properly mixed together in a poly-bag. Talc and Magnesium stearate were passed through mesh 80 mixed and blended with initial mixture in a poly-bag. The powder blend was compressed into tablets on a 8 station rotary punch tableting machine minipress using 8 mm circular punches and same hardness was used for the required number tablets. Compressed tablets were examined as per official standards and unofficial tests. Tablets were packaged in well closed light resistance and moisture proof containers. 2.2.1. Experimental Design Experimental design utilized in present investigation for the optimization of Superdisintegrant concentration such as concentration of Crospovidone was taken as X 1 and concentration of Croscarmellose sodium was taken as X 2 . Experimental design was given in the Table 1. Three levels for the Concentration of Crospovidone were selected and coded as -1 7.5 010.0 +115. Three levels for the Concentration of Croscarmellose sodium were selected and coded as -1 7.5 010.0 +115. Formulae for all the experimental batches were given in Table 2 16. 2.3. Evaluation of Clopidogrel Fast Dissolving Tablets 2.3.1. Hardness The hardness of the tablets was tested by diametric compression using a Monsanto Hardness Tester. A tablet hardness of about 2- 4 Kg/cm 2 is considered adequate for mechanical stability 17. 2.3.2. Friability The friability of the tablets was measured in a Roche friabilator Camp-bell Electronics Mumbai. 20 Tablets were taken and weighed and also initial weight was noted W 0 Table 1. Experimental design layout. Formulation Code X 1 X 2 F 1 1 1 F 2 1 0 F 3 1 -1 F 4 0 1 F 5 0 0 F 6 0 -1 F 7 -1 1 F 8 -1 0 F 9 -1 -1 C 1 -0.5 -0.5 C 2 +0.5 +0.5

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Kumar G R et al / IJPS 2016 12 2: 61-74 66 dedusted in a drum for a fixed time 100 revolutions in a Roche Friabilator and they were weighed W again. Percentage friability was calculated from the loss in weight as given in equation as below. The weight loss should not be more than 1 17. Friability Initial weight- Final weight / Initial weight x 100 2.3.3. Content Uniformity In this test 20 tablets were randomly selected and the percent drug content was determined. The tablets contained not less than 85 or not more than 115 100±15 of the labeled drug content can be considered as the test passed 17. 2.3.4. Assay Drug content was determined by weighing randomly selected tablets pulverizing to a fine powder. The powder equivalent to 100 mg Clopidogrel was weighed and dissolved in 10 ml of Distilled water in volumetric flask the volume was adjusted to 100 ml with Phosphate buffer pH 6.8 and the solution was filtered. An aliquot of 1.0 ml of solution was diluted to 10 ml Phosphate buffer pH 6.8 in separate volumetric flask. The drug content was determined spectrophotometrically at 324 nm 6. 2.3.5. Thickness Thickness of the all tablet formulations were measured using vernier calipers by placing tablet between two arms of the vernier calipers 17. 2.3.4. Wetting Time To measure wetting time of the tablet a piece of tissue paper folded twice was placed in a small petri dish Internal Diameter is 6.5 cm containing 5 ml of Distilled water. A tablet placed on the paper and the time for complete wetting of the tablet was measured in seconds 18-19. 2.3.5. In-vitro Dissolution Study The in-vitro dissolution study for the Clopidogrel Fast Dissolving tablets were carried out in USP XXIII type-II dissolution test apparatus Paddle type using 900 ml of Phosphate buffer pH 6.8 as dissolution medium at 50 rpm and temperature 37±0.5°C. At predetermined time intervals 5 ml of the samples were withdrawn by means of a syringe fitted with a pre-filter the volume withdrawn at each interval was replaced with the same quantity of fresh dissolution medium. The resultant samples were analyzed for the presence of the drug release by measuring the absorbance at 324 nm using UV Visible spectrophotometer after suitable dilutions. The determinations were performed in triplicate n3 6. 2.3.6. Disintegration Test Disintegration of fast disintegrating tablets is achieved in the mouth owing to the action of saliva however amount of saliva in the mouth is limited and no tablet disintegration test was found in USP and IP to simulate in vivo conditions. A modified method was used to determine disintegration time of the tablets. A cylindrical vessel was used in which 10 mesh

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Clopidogrel fast dissolving tablets 67 screen was placed in such way that only 2 ml of disintegrating or dissolution medium would be placed below the sieve. To determine disintegration time 6 ml of Sorenson’s buffer pH 6.8 was placed inside the vessel in such way that 4 ml of the media was below the sieve and 2 ml above the sieve. Tablet was placed on the sieve and the whole assembly was then placed on a shaker. The time at which all the particles pass through the sieve was taken as a disintegration time of the tablet. Six tablets were chosen randomly from the composite samples and the average value was determined. 2.3.7. Kinetic Modeling of Drug Release The dissolution profile of all the formulations was fitted in to zero-order first- order Higuchi and Korsmeyer-peppas models to ascertain the kinetic modeling of drug release 21-24. 3. Results and Discussion Fast Dissolving tablets of Clopidogrel were prepared and optimized by 3 2 factorial design in order to select the best combination of different Superdisintegrants Crospovidone Croscarmellose sodium and also to achieve the desired rapid release of drug from the dosage formby Disintegrating quickly. The two factorial parameters involved in the development of formulations are quantity of Crospovidone Croscarmellose sodium as independent variables X 1 X 2 and in vitro dissolution parameters such as t 50 t 90 wetting time and disintegrating time as dependent variables . Totally nine formulations were prepared using 3 levels of 2 factors and all the formulations containing 100 mg of Clopidogrel were prepared as a Fast Dissolving tablet dosage form by Direct Compression technique as per the formulae given in Table 2. All the prepared tablets were evaluated for Table 2. Formulae for the preparation of Clopidogrel fast dissolving tablets as per experimental design. Name of Ingredients Quantity of Ingredients per each Tablet mg F 1 F 2 F 3 F 4 F 5 F 6 F 7 F 8 F 9 Clopidogrel 75 75 75 75 75 75 75 75 75 Avicel pH-101 71 76 81 76 81 86 81 86 91 Crospovidone 25 25 25 20 20 20 15 15 15 Croscarmellose sodium 25 20 15 25 20 15 25 20 15 Magnesium Stearate 2 2 2 2 2 2 2 2 2 Talc 2 2 2 2 2 2 2 2 2 Total Weight 200 200 200 200 200 200 200 200 200

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Kumar G R et al / IJPS 2016 12 2: 61-74 68 different post compression parameters drug content mean hardness friability mean thickness Weight variation as per official methods and results are given in Table 3. The hardness of tablets was in the range of 3.175±0.13-3.375±0.15 Kg/cm 2 . Weight loss in the friability test was not more than 0.67. Drug content of prepared tablets was within Table 3. Post-compression parameters for the formulations. S.No Formulati on Code Hardness kg/cm 2 Thickne ss mm Friabilit y Weight Variation mg Drug Content Wetting Time sec Disinte gration Time sec 1 F 1 3.375±0.15 4.79±0.1 4 0.6±0.2 200.71±0.9 99.86±0.25 20.59±1. 4 10±1.4 2 F 2 3.29±0.14 4.825±0. 16 0.66±0.3 201.48±1.9 99.69±0.70 20.66±1. 5 11±1.5 3 F 3 3.29±0.15 4.76±0.1 5 0.64±0.1 200.69±1.1 99.68±0.50 22.91±1. 7 11±1.7 4 F 4 3.275±0.15 4.765±0. 10 0.64±0.2 200.57±2.2 99.78±0.40 22.50±1. 3 11±1.3 5 F 5 3.175±0.13 4.8±0.12 0.54±0.3 201.50±1.1 99.61±0.90 22.58±1. 4 12±1.4 6 F 6 3.18±0.15 4.735±0. 11 0.67±0.0 4 201.06±2.0 99.60±0.70 24.23±1. 6 13±1.6 7 F 7 3.378±0.16 4.715±0. 12 0.63±0.3 200.50±1.4 99.20±0.25 22.32±1. 3 11±1.3 8 F 8 3.275±0.14 4.75±0.1 2 0.54±0.4 199.70±0.3 99.03±0.70 22.40±1. 35 12±.1.4 9 F 9 3.28±0.16 4.685±0. 11 0.64±0.4 200.47±0.9 99.03±0.5 24.65±1. 6 13±1.6 Figure1. Comparative zero order plots for formulation f 1 -f 9.

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Clopidogrel fast dissolving tablets 69 acceptance range only. The wetting time of tablets was in the range of 20.59±1.4- 24.65±1.6 sec. The disintegration time of tablets was in the range of 10±1.4-13±1.6 sec. Results for all Post-compression parameters were tabulated or shown in table 3. In-vitro dissolution studies were performed for prepared tablets using Phosphate buffer pH 6.8 as a dissolution media at 50 rpm and temperature 37±0.5°C. The In-vitro dissolution profiles of tablets are shown in figure 1 and wetting time chart disintegration time charts were shown in figure 2-3 respectively.The dissolution parameters are given in Table 4. Cumulative Drug release of factorial design formulations F 1 -F 9 at 1 Hr was found to be in the range of 94.95-97.145 . From the result it reveals that the release rate was higher for formulations containing high level of Crospovidone/Croscarmellose sodium compared with other formulations containing Lower level due to high concentration of Superdisintegrant in combination showing various disintegration mechanism such as wicking and swelling etc more compared with lower concentration and alone drug may release rapidly and shows improved bioavailability. Therefore required release of drug can be obtained by Figure 2.Wetting time chartfor formulation F 1 -F 9 . Figure 3. Disintegration time chart for formulation F 1 -F 9 .

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Kumar G R et al / IJPS 2016 12 2: 61-74 70 manipulating the composition of Crospovidone and Croscarmellose sodium. Variation was observed in the wetting time disintegrating time t 50 and t 90 due to formulation variables. Formulation F 1 containing 25 mg of Crospovidone 25 mg of Croscarmellose sodium showed promising dissolution parameter wetting time 20.59±1.4sec disintegrating time 10±1.4sec t 50 11.070min t90 36.785 min. The difference in burst effect of the initial time is a result of the difference in the concentration of Superdisintegrants mixtures. This reveals that increased concentration of superdisintegrants resulted in a corresponding decrease in the wetting Time which might be due to the result of wicking and other possible disintegrating mechanisms. Disintegration time is directly proportional to wetting time. The In -vitro dissolution data of Clopidogrel Fast Dissolving formulations was subjected to goodness of fit test by linear regression analysis according to zero order and first order kinetic equations Higuchi’s and Korsmeyer-Peppas models to assess the mechanism of drug release. The results of linear regression analysis including regression coefficients are summarized in Table 4. It was observed from the above that dissolution of all the tablets followed first order kinetics with co-efficient of determination R 2 values in the range of 0.932-0.956. The values of r of factorial formulations for Higuchi’s equation was found to be in the range of 0.909-0.934 which shows that the dissolution data fitted well to Higuchi’s square root of time equation confirming the release followed diffusion mechanism. Kinetic data also treated for Peppas equation the slope n values ranges from 0.210-0.260 that shows Fickian diffusion mechanism. Polynomial equations were derived for wetting time disintegrating time Table 4. Regression analysis data of 3 2 factorial design formulations of Clopidogrel fast dissolving tablets. S.NO Formulation Code KINETIC PARAMETERS ZERO ORDER FIRST ORDER HIGUCHI KORSMEYER- PEPPAS a b r a b r a b r a b r 1 F 1 37.423 1.510 0.759 1.767 0.027 0.955 16.579 13.263 0.914 0.226 1.405 0.866 2 F 2 36.744 1.511 0.765 1.771 0.026 0.955 16.094 13.227 0.917 0.230 1.406 0.867 3 F 3 35.625 1.509 0.774 1.794 0.025 0.956 15.386 13.118 0.923 0.239 1.408 0.870 4 F 4 37.516 1.500 0.756 1.753 0.026 0.948 16.691 13.202 0.912 0.219 1.401 0.865 5 F 5 36.838 1.501 0.762 1.759 0.025 0.947 16.205 13.166 0.916 0.224 1.402 0.866 6 F 6 35.718 1.499 0.771 1.782 0.024 0.950 15.498 13.057 0.921 0.232 1.403 0.869 7 F 7 37.441 1.478 0.752 1.739 0.024 0.932 16.795 13.038 0.909 0.210 1.392 0.865 8 F 8 36.762 1.479 0.758 1.748 0.023 0.933 16.310 13.001 0.913 0.215 1.393 0.867 9 F 9 33.450 1.514 0.794 1.832 0.024 0.959 13.919 12.989 0.934 0.260 1.415 0.875 10 MP 37.363 1.513 0.759 1.744 0.026 0.946 16.399 13.307 0.915 0.223 1.404 0.861 F 1 to F 9 are factorial formulations r-correlation coefficient a-Intercept b-Slope and MP-Marketed Product.

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Clopidogrel fast dissolving tablets 71 t 50 and t 90 values by backward stepwise linear regression analysis using PCP Disso software and response surface plots were constructed using SIGMAPLOT V13 software. The response surface plots were shown in figure 4-7 for wetting time disintegrating time t 50 and t 90 using X 1 and X 2 on both the axes respectively. The dissolution data Kinetic parameters of factorial formulations F 1 to F 9 are shown in Table 5. Polynomial equation for 3² full factorial designs is given in Equation Y b 0 +b 1 X 1 +b 2 X 2 +b 12 X 1 X 2 +b 11 X 1 ²+b 22 X 2 ²… Where Y is dependent variable b 0 arithmetic mean response of nine batches and b 1 estimated co-efficient for factor X 1 . The main effects X 1 and X 2 represent the average result of changing one factor at a time from its low to high value. The interaction term X 1 X 2 shows how the response changes when two factors are simultaneously changed. The polynomial terms X 1 ² and X 2 ² are included to investigate non-linearity. Validity of derived equations was verified by preparing two check point formulations of intermediate concentration C 1 C 2 . The equations for Wetting time disintegrating time t 50 and t 90 developed as follows. Y 1 22.538-0.808X 1 -1.063X 2 +0.0025X 1 X 2 - 0.808 X 1 2 +0.986X 2 2 for Wetting time Figure 4. Response Surface plot for Wetting Time. Figure 5. Response surface plot for disintegration time. Figure 6. Response Surface plot for t 50 . Figure 7. Response Surface plot for t 90 .

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Kumar G R et al / IJPS 2016 12 2: 61-74 72 Y 2 11.556-0.667X 1 -0.833X 2 +0.25 X 1 X 2 - 0.667 X 1 2 -0.167 X 2 2 for Disintegration time Y 3 12.16-0.617X 1 -0.328X 2 -0.256 X 1 X 2 +0.104 X 1 2 -0.125 X 2 2 for t 50 Y 4 40.393-2.050X 1 -1.09X 2 -0.851 X 1 X 2 +0.345 X 1 2 -0.418 X 2 2 for t 90 The positive sign for co-efficient of X 1 in Y 1 Y 2 Y 3 and Y 4 equations indicates that as the concentration of Crospovidone decreases wetting time disintegrating time t 50 and t 90 value increases. In other words the data demonstrate that both X 1 amount of Crospovidone and X 2 amount of Croscarmellose sodium affect the time required for drug release Wetting time disintegrating time t 50 and t 90 . From the results it can be concluded that an increase in the amount of the Superdisintegrant leads to decrease in disintegration time of the dosage form and drug release pattern may be changed by appropriate selection of the X 1 and X 2 levels. The dissolution parameters for predicted from the polynomial equations derived and those actual observed from experimental results are summarized in table 6. The closeness of predicted and observed values for wetting time disintegrating time t 50 and t 90 indicates validity of derived equations Table 5. Dissolution parameters of Clopidogrel fast dissolving tablets 3² full factorial design batches. S.NO FORMULATION CODE KINETIC PARAMETERS t1/2 Min t90 Min WTSec DTSec 1 F 1 11.070 36.785 20.59 10 2 F 2 11.570 38.446 20.66 11 3 F 3 12.081 40.144 22.91 11 4 F 4 11.610 38.579 22.50 11 5 F 5 12.068 40.103 22.58 12 6 F 6 12.581 41.807 24.23 13 7 F 7 12.677 42.126 22.32 11 8 F 8 13.081 43.467 22.40 12 9 F 9 12.664 42.083 24.65 13 10 MP 11.573 38.457 18.98 10 Table 6. Dissolution parameters for predicted and observed values for check point formulations. FORMULATION CODE PREDICTED VALUE ACTUAL OBSERVED VALUE WTSec DTSec t 50 min t 90 min WTSec DTSec t 50 min t 90 min C 1 23.509 12.16 12.560 41.732 23.619 12.28 12.652 41.898 C 2 21.638 10.66 11.614 38.592 21.690 10.93 11.721 39.012

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Clopidogrel fast dissolving tablets 73 for dependent variables. The response surface plots were presented to show the effects of X 1 and X 2 on wetting time disintegrating time t 50 and t 90. The final best Optimized formulation F 5 is compared with marketed product PLAVIX-75 shows similarity factor f 2 and 91.3936 difference factor f 1 1.203 There is no significant difference in drug release becauset cal 0.05. 4. Conclusion The present research work envisages the applicability of Superdisintegrants such as Crospovidone and Croscarmellose sodium in the design and development of Fast Dissolving tablet formulations of Clopidogrel utilizing the 3 2 factorial design. From the results it was clearly understood that as the concentration of Superdisintegrant increases the release rate of drug was RAPID Improved Solubility and both of these Superdisintegrants can be used in combination since do not interact with the drug which may be more helpful in achieving the desired fast dissolving of the dosage form for rapid action and improved bioavailability. The optimized formulation followed Higuchi’s kinetics while the drug release mechanism was found to be Fickian diffusion first order release type. On the basis of evaluation parameters the optimized formulation F 1 may be used for the effective management of Acute Coronary Syndrome ACS Hypertension Heart Attack and Stroke. This may improve the patient compliance by showing rapid action via disintegration without difficulty in swallowing and side effects which will ultimately improve the therapeutic outcome. We could be able to minimize the per oral cost of the formulation. Acknowledgements The author would like to thank Management Principal Teaching Non- teaching Staff of Narasaraopeta Institute of Pharmaceutical Sciences Narasaraopet Guntur D.t A.P. India for providing support for successful completion of research work. References 1 K Kavitha KumuthaSubramaniam BoeyJiaHui K. Santhi SA Dhanaraj and M Rupesh Kumar. Potential Drug Candidates for Fast Dissolving Drug Delivery - A Review. Research Journal of Pharmaceutical Biological and Chemical Sciences 2013 44: 1510-1526. 2 Sehgal P Gupta R Umesh Kumar S Chaturvedi A Gulati A Sharma M. Fast Dissolving Tablets: A New Venture in Drug Delivery Am. J. Pharm Tech Res. 2012 24: 252-279. 3 MdNehal S Garima G Pramod KS. Fast Dissolving Tablets: Preparation Characterization and Evaluation: An Overview International Journal of Pharmaceutical Sciences Review and Research 2010 42: 87-96. 4 David E Armen H. T Ethrin J Aand April W. Armstrong.Principles of pharmacology. Thepathophysiologic basis of drug therapy. Wolters Kluwer India Pvt. Ltd New Delhi 2008 2 nd edition pp. 815. 5 Rajeev soni Galividyasagar. Design and development of quick dissolving tablet Containing loratadine by direct compression methodInternational Journal of Pharmaceutical Chemical and Biological Sciences 2013 33: 771-800. 6 R. RedyaNaik AishwaryaMadikanti T.Sunitha NusrathYasmeen P.S. Malathi D. Vijay kumarGummadiSridharbabu SujathaRamavath S.SrinuNaik. Formulation and evaluation of oral

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Kumar G R et al / IJPS 2016 12 2: 61-74 74 dispersible tablets of clopidogrel bi sulfate by solid dispersion method. Indo American Journal of Pharmaceutical Research 2014 47: 3152-3162. 7 Hardik Jain VimalArora Jitendra Gupta Anil Bhandari Formula Optimization of Immediate Release Tablet of Clopidogrel Bisulphate Free From Surface Irregularities International Journal of Pharmaceutical Sciences and Research 2011 Vol. 212: 3243-3246. 8 K. Rama KoteswaraRao K. Rajya Lakshmi. Design development and evaluation of Clopidogrel bisulfate floating tablets International Journal of Pharmaceutical Investigation 201441: 19-26. 9 Sanjeeva Yarkala1 Sivakumar A and Sameer G. Navalgund Physico-chemical Studies on Stability of Clopidogrel Tablet Formulations International Journal of Pharma and Bio Sciences 2012 34: 433 – 439. 10 SreeGiri Prasad. B Tamilselvan A Siva Subramanian. N. Formulation and Evaluation of Clopidogrel Bisulfate Immediate Release Tablets. Journal of Global Trends in Pharmaceutical Sciences 201454: 2154 – 2166. 11 M.A.Shende R.P.Marathe S.B. Khetmalas P. N. Dhabale.Studies on development of Sustained release Diltiazem hydrochloride matrices through jackfruit mucilage. IntJ of pharmpharma sci2014 6 7: 72-78. 12 Swarbrick J Boylan JC. Optimization techniques in formulation and processing Encyclopedia of Pharmaceutical technology. New York:Marcel Dekker1994. p. 70. 13 Montgomery DC. Introduction to factorial deigns. Design and Analysis of Experiments. 5th ed. Wiley India Pvt.Ltd:New Delhi2004. p. 170-217. 14 Schwartz BJ Connor RE.Optimization technique in pharmaceutical formulations and processing. J Drugs and Pharm Sciin Modern Pharmaceutics 1996 723:727-54. 15 A. A. Kharia s. N. Hiremath a. K. Singhai K. Omray and S. K. Jain Design and optimization of floating drug delivery system of acyclovir . Indian J. Pharm. Sci.2010 72 5: 599-606. 16 Raghavendra Kumar Gunda J. N. Suresh Kumar Ch Ajay Babu and M. V. AnjaneyuluFormulation development and evaluation of lamotrigine sustained release tablets using 32 factorial design. International Journal of Pharmaceutical Sciences and Research 2015 64: 1746-1752. 17 Raghavendra Kumar Gunda. Formulation development and evaluation of rosiglitazone maleate sustained release tablets using 32 factorial design. International J of PharmTech Research 2015 84: 713-724. 18 NG RaghavendraRao UpendraKulkarni. Development of Carbamazepine Fast Dissolving Tablets: Effect of Functionality of Hydrophillic Carriers on Solid Dispersion Technique Asian Journal of Pharmaceutical and Clinical Resear ch 2010 32:114-117. 19 Shiv Shankar Hardenia G.N. Darwhekar ShaileshSharmaandAnuHardenia. Designing and Pharmaceutical Evaluation of Fast Dissolving Tablet of Fexofenadine Using CoprocessedSuperdisintegrants International Journal of Pharmaceutical Sciences and Research 2014 Vol. 5 7: 3018-3030. 20 Raghavendra Kumar Gunda J. N. Suresh Kumar. Formulation Development and Evaluation of Carbamazepine Fast Dissolving Tablets Journal of Pharmacy Research 2016 10 5:216-225. 21 K.P.R.chowdaryOptimization of valsartan tablet formulation by 23 factorial design Journal of Global Trends in Pharmaceutical Sciences 2014 Volume 511374-1379 . 22 Notari RE. Biopharmaceutics and clinical pharmacokinetics. 4th ed. New York: Marcel Dekker Inc 1987 6-21. 23 Higuchi TMechanism of sustained-action medication. Theoretical analysis of rate of release of solid drugs dispersed in solid matrices. J Pharm Sci.1963 51:1145-9. 24 Peppas NA. Analysis of fickian and non-fickian drug release from polymers Pharm ActaHelv1985 60:110-1.

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