Vol-3, Issue-4, Suppl-1, Nov 2012 ISSN: Gandhi et al PHARMA SCIENCE MONITOR

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1 PHARMA SCIENCE MONITOR AN INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES FORMULATION AND EVALUATION OF SUSTAINED RELEASE TABLET OF ITOPRIDE HYDROCHLORIDE BY USING CENTRAL COMPOSITE DESIGN Pankil A. Gandhi *, Mukesh R. Patel, Kanu R. Patel, Alpesh D. Patel, Natubhai M. Patel Shri B.M.Shah College of Pharmaceutical Education and Research, Modasa. ABSTRACT The aim of present investigation was undertaken with the objective of formulating once a day delivery of sustained release tablet of Itopride hydrochloride. Itopride hydrochloride is highly water soluble prokinetic drug. Hydroxypropylmethylcellulose K15M and K100M were used as a matrix forming agents to control the release of drug. The formulation of Itopride hydrochloride matrix forming tablet was developed by using Central composite design. The concentrations of Hydroxypropylmethylcellulose K15M (X 1 ) and Hydroxypropylmethyl cellulose K100M (X 2 ) were selected as independent variables. The dependent variables were drug release at 2 nd hr, 4 th hr, 8 th hr, 12 th hr, 16 th hr and 20 th hr. Tablets were evaluated for in vitro dissolution, friability, hardness, drug content and weight variation. Dissolution data were fitted to various models to ascertain kinetic of drug release. Response surface plot, regression analysis and analysis of variance were performed for dependent variables. There was no incompatibility observed between the drug and excipients used in the formulation of matrix tablets. In vitro drug release study showed that batch FB7 was found to be optimized as it had almost identical dissolution profile with innovator by similarity factor (f 2 =83.86) and difference factor (f 1 =3.65). Optimized batch FB7 shows good tablet properties like hardness, thickness, friability and assay. The dissolution of batch FB7 can be described by zero order kinetics (R 2 =0.9825) with anomalous (non-fickian) diffusion as a release mechanism (n=0.5377). Stability study of optimized batch FB7 was conducted at accelerated conditions for one month and it was found to be stable. Keywords: Central Composite Design, Hydroxypropylmethylcellulose, Itopride hydrochloride, Prokinetic drug, Sustained release. INTRODUCTION Oral route is the most preferred route for administration of drugs. Tablets are the most popular oral formulations available in the market and preferred by the patients and physicians alike. In long-term therapy for the treatment of chronic disease conditions, conventional formulations are required to be administered in multiple doses, and therefore have several disadvantages [1].Sustained release tablet formulations are much desirable and preferred for such therapy because they offer better patient compliance, maintain uniform drug levels, reduce dose and side effects, and increase safety margin for IC Value

2 high-potency drugs. [2] Oral drug delivery continues to rise in popularity as formulation scientists look for ways to control drug release and improve patient convenience. However, developing oral sustained release tablets for water soluble drugs with constant release rate has always been a challenge to the pharmaceutical technologist. Most of these water soluble drugs if not formulated properly, may readily release the drug at a faster rate and produce a toxic concentration of drug on oral administration [3]. Hence, it is a challenging task to formulate a suitable tablet dosage form for prolonged delivery of highly water soluble drugs. The most commonly used method of modulating the drug release is to include it in a matrix system [4]. Diffusion controlled polymeric matrix devices have been widely used as drug delivery systems owing to their flexibility to obtain a desirable drug release profile, cost effectiveness and broad regulatory acceptance. [5] Many polymers have been used in the formulation of matrix based sustained release drug delivery systems. Reports were found on the use of hydrophilic polymers like hydroxypropylmethylcellulose (HPMC), sodiumcarboxymethylcellulose. [6] carbopols [7] for the preparation of sustained release (SR) formulations of different drugs. HPMC, a semisynthetic derivative of cellulose, is a swellable hydrophilic polymer. It contains methoxyl and hydroxypropyl substituents on its b-o-glucopyranosyl ring backbone, which makes it very resistant to changes in ph or ionic content of the dissolution medium [8]. At ph values from 2 to 13, HPMC is relatively stable and the SR matrix formulations of any drug prepared using HPMC can show ph independent drug release if the drug has ph independent drug solubility [9]. A number of reports appear in the literature on the utility of Hydroxypropylmethylcellulose in the design of oral controlled release tablets. [10-12] It is very suitable to use as a retardant material in SR matrix tablets, as it is nontoxic and easy to handle. [13] Matrix tablets prepared using HPMC on contact with aqueous fluids gets hydrated to form a viscous gel layer through which drug will be released by diffusion and/or by erosion of the matrix [14]. Itopride, a novel prokinetic agent is unique and different from the available prokinetics because of its dual mode of action and lack of significant drug interaction potential. Itopride is a newly developed prokinetic agent, which enhances gastric motility through both antidopaminergic and anti-acetylcholinesterasic actions. [15] Cisapride and IC Value

3 Metoclopramide have been reported to have a modest prokinetic effect. The main side effects of Metoclopramide are extra pyramidal such as dystonic reactions [16].Cisapride has the potential to cause QT prolongation on ECG, thus predisposing to cardiac arrhythmias and its use has been restricted by the USFDA. Mosapride too belongs to the same group and although its side effects are not well documented, it has drug interaction potential similar to that observed with Cisapride. Thus, a prokinetic drug like Itopride, by virtue of its efficacy and tolerability could be considered as a drug of first choice. [17, 18] Itopride is used in the treatment of gastrointestinal symptoms caused by reduced gastrointestinal motility, like feeling of gastric fullness, upper abdominal pain, anorexia, heartburn, nausea and vomiting, non-ulcer dyspepsia or chronic gastritis. Itopride hydrochloride, a novel prokinetic agent is best candidate for GERD. Central Composite design has been used to optimize the concentration of different component in the formulation of sustained release tablet. In this design, 2 factors were evaluated by using combination of different concentrations of polymer. MATERIALS AND METHODS MATERIALS: Itopride hydrochloride was received as a gift sample from Cadila Healthcare ltd, Ahmedabad India. Hydroxypropylmethylcellulose (HPMC) K15M and K100M were received as gift sample from Colorcon Asia Pvt Ltd, Goa. Lactose, Magnesium stearate, Aerosil and other reagents were purchased from Crystal chemicals, Himmatnagar, Gujarat, India. All other chemicals and reagents were of analytical grades. METHODS Preparation of matrix tablets The matrix tablets of itopride hydrochloride were prepared by employing hydrophilic polymers from synthetic (hydroxypropyl methylcellulose with different viscosity grades) in combination by direct compression method using 10mm concave-faced punch of 10 station Rimek compression machine. For the preparation of tablets previously sieved ingredients are mixed by using the well closed plastic bottle for 20 min. Magnesium stearate and Aerosil were added to above mixture as flow promoters and mixed for 10 IC Value

4 min. In all formulations the amount of itopride hydrochloride was kept constant at 150mg. Experimental design: A Central Composite Design was employed in the present study. In this design 2 factors were evaluated, each at 5 levels and experimental trials were performed for 10 possible combinations. The concentration of HPMC K 15M (X 1 ) and concentration of HPMC K100M (X 2 ) were chosen as independent variables in Central Composite Design, while Q 2, Q 4, Q 8, Q 12, Q 16, Q 20 (% drug release after 4, 8, 12, 16, 20 hours respectively) were taken as dependent variables. The coding of variables and composition of Central Composite design batches (FB1-FB10) is shown in Table 1 and Table 2. The matrix tablets of itopride hydrochloride were evaluated for precompression parameters such as angle of repose, % compressibility index, Hausner s ratio and postcompression parameters such as hardness (Monsanto hardness tester), weight variation, content uniformity, percentage friability (Roche friabilator), thickness (vernier caliper). Drug content of matrix tablets was determined by weighing and finely grinding 10 tablets of each batch. Aliquot of this powder equivalent to 150 mg of itopride hydrochloride was accurately weighed, suspended in approximately 50 ml of phosphate buffer ph 6.8 and shaken for 15 min. final volume was adjusted to 100 ml with phosphate buffer and filtered. The suitable dilutions were made and absorbance recorded at 258 nm. Statistical treatment was carried out to CCD batches using statistical software. TABLE 1: CODING OF VARIABLES Central Composite Design Factors Level (-α) (+α) HPMC K 15 M (X 1 ) mg 50 mg 70 mg 90 mg mg HPMC K 100 M (X 2 ) mg 50 mg 70 mg 90 mg mg IC Value

5 TABLE 2: FORMULATION OF ITOPRIDE HCl SUSTAINED RELEASE TABLET Ingredients (mg) FB1 FB2 FB3 FB4 FB5 FB6 FB7 FB8 FB9 FB10 Itopride HCl HPMC K15 M HPMC K100M Lactose Aerosil Mg. Stearate Total Weight(mg) Characterization of Matrix tablet: Drug-polymer-excipient compatibility studies: This was confirmed by carrying out by Infrared light absorption scanning spectroscopy (IR) studies. Infra-red spectra of pure drug and mixture of formulation were recorded by dispersion of drug and mixture of formulation in suitable solvent (KBr) using Fourier Transform Infrared Spectrophotometer. The spectra were recorded over the number range of 4000 to 500cm-1. In vitro Dissolution study [19] In vitro dissolution studies for the prepared matrix tablets were conducted for a period of 20 hours using USP type-ii (Paddle) dissolution apparatus (Electro lab, Mumbai.) at 37±0.5 o C and 50 rpm speed using ph 1.2 buffer for initially 2 hrs and phosphate buffer of ph 6-8 for remaining hours as a dissolution medium. At predetermined interval of time, 10 ml of sample was withdrawn from the dissolution medium and replaced with fresh medium to maintain the volume constant. After filtration and appropriate dilution, the sample solutions were analyzed at 258 nm for itopride hydrochloride by a UV-Visible spectrophotometer. The amount of drug present in the samples was calculated. All the release studies were conducted in triplicate and the mean values were plotted versus time with standard deviation less than three indicating reproducibility of results. Kinetics of drug release [20] IC Value

6 The dissolution profile of all the batches was fitted to various models such as zero order, first-order, Higuchi, Korsmeyer and Peppas to ascertain the kinetic modeling of drug release. To ascertain the release property of formulation. Statistical Analysis [21] : The statistical analysis of the CCD batches was performed by multiple regression analysis using Microsoft Excel. To demonstrate graphically the influence of each factor on responses, the response surface plots were generated using Sigma Plot software Version 8.0, (Jandel Scientific Software, San Rafael, CA). The P < 0.05 was considered to be significant. Comparison of Dissolution Profiles For Selection of Optimum Batch The developed optimized tablet formulation was compared with Innovator formulations for in-vitro release profile. The in-vitro release profile of optimized formulation was compared with marketed formulations for similarity factor (f 2 ) and dissimilarity factor (f 1 ). The similarity factor (f2) was defined by CDER, FDA and EMEA as the logarithmic reciprocal square root transformation of one plus the mean squared difference in percent dissolved between the test and the reference products. Moore and Flanner give the model independent mathematical approach for calculating a similarity factor f 2 for comparison between dissolution profiles of different samples. The similarity factor (f 2 ) given by SUPAC guidelines for modified release dosage form was used as a basis to compare dissolution profile. The dissolution profiles of products were compared using f 2. The similarity factor is calculated by following formula. 0.5 n 2 f = X log 1 ( ) w t R t T t X (4.7) n t = 1 Where, n = No. of time points Rt = The reference profile at the time point t Tt = The test profile at the same point The dissimilarity factor (f 1 ).) calculates the percentage difference between two profiles i.e. Innovator product dissolution profile & test sample dissolution profile at each sampling points and corresponds to a relative error measure between the two profiles. IC Value

7 ....(4.8) Where, = Absolute difference of % drug released at each time points between reference product & test product. R = % drug released of test product at each time points. f 1 value should be less than15 ideally it should be as close as possible to 0. Stability Study [22] Stability testing of drug products begins as a part of drug discovery and ends with demise of compound or commercial product. FDA and ICH specifies the guidelines for stability testing of new drug products, as a technical requirement for registration of pharmaceuticals for human use. The samples of optimized batch were kept at 40 C and 75% RH for one month in HDPE bottle. Then samples were withdrawn and analyzed for physical evaluation, assay and dissolution. RESULTS AND DISCUSSION Drug-polymer-excipient compatibility studies: The Itopride HCl exhibits peak due to different functional groups. It was observed that there were no changes in these main peaks in the FTIR spectra of a drug and mixture of drug and polymers (Figure 1-2, Table 3). Hence, it was concluded that no physical or chemical interactions of Itopride HCl with HPMC K15M, HPMC K100M and other excipients. TABLE 3: COMPARISON OF VIBRATION FREQUENCY OF FTIR SPECTRA OF ITOPRIDE HCl (PURE DRUG) AND FORMULATION Functional Group Frequency Pure Drug Formulation NH Asymmetric Structure C-H structure of Methyl Group C=O Bonding C=C aromatic Structure C-N aromatic Structure C-O Aromatic Structure IC Value

8 200 %T ITOPRIDE HCl 200 %T Figure 1 FT-IR Spectra of Itopride Hydrochloride ITOPRIDE HCl FORMULATION 500 1/cm ITOPRIDE HCl Figure 2 FT-IR Spectra of Itopride HCl and Excipients /cm IC Value

9 Evaluation of pre and post compression parameters of Tablet All the batches were evaluated for pre and post compression parameters and found within acceptable limits. The results of angle of repose, compressibility index, hausner s ratio ranged from to 25.10, to and 1.13 to 1.18 respectively. TABLE 4: RESULT OF PRE-COMPRESSION PARAMETERS OF CCD BATCHES Formulation Code Angle of Repose ( o ) Bulk Density (gm/ml) Tapped Density (gm/ml) Carr s Index (%) Hausner s Ratio FB FB FB FB FB FB FB FB FB FB TABLE 5: RESULT OF PHYSICO CHEMICAL EVALUATION OF CCD BATCHES Batches Hardness (kg/cm 3 ) Thickness (mm) Friability (%) Avg. Wt. (mg) Assay (%) FB1 6.5 ± ± ± ±1.05 FB2 7.2 ± ± ± ±0.48 FB3 7.0 ± ± ± ±0.26 FB4 7.3 ± ± ± ±1.05 FB5 7.5 ± ± ± ±1.12 FB6 6.8 ± ± ± ±1.08 FB7 7.0 ± ± ± ±0.87 FB8 7.5± ± ± ±1.18 FB9 7.4± ± ± ±0.59 FB10 7.2± ± ± ± IC Value

10 The results of angle of repose (<30) indicate good flow properties of the powder. It was further supported by lower compressibility index value that was less than 15.5%. (Table 4). Hardness of the prepared tablets was found in range of kg/cm 2. All the tablet formulations showed acceptable properties and complied with the specifications for weight variation (5%), drug content (98%-102%) and friability (< 1%). All batches showed tablet thickness in range of 4.44 to 4.66 mm as shown in Table 5. In vitro Dissolution study The results of in-vitro dissolution study of CCD batches FB1 to FB10 which was shown in the Table 6 and comparative dissolution profile was shown in Figure 3. The drug release profiles were characterized by an initial burst effect Q 2 i.e. initial 25-30% drug release required in 2 hrs. The biphasic release is often observed from hydrophilic matrix systems. As the release rate limiting polymer like HPMC changes from a glassy state to rubbery state, a gel structure is formed around the tablet matrix, which considerably decreases the release rate of drug since the drug has to diffuse through this gel barrier into bulk phase. The strength of the gel depends on the chemical structure and molecular size of the polymer. It is known that higher viscosity grade polymer i.e HPMC K100M hydrates at faster and therefore, it is capable of forming gel structure quickly than a low viscosity grade HPMC K15M polymer. The drug release is significantly dependent on the proportion and type of the polymer used. HPMC K15M was responsible for initial burst effect and HPMC K100M was used to sustained drug release. CCD batches formulated using combination of HPMC K15M and HPMC K100M of Itopride HCl were evaluated for dissolution study (table 6). It was observed that the polymer concentration has the significant effect on the drug release profile. Decreased rate of drug release was observed with increase of the concentration of polymers Release of drug from the polymer matrix takes place after swelling of polymer and as the amount of polymer in the formulation increases the swelling time also increases thereby decreasing the drug release. IC Value

11 Time (hrs.) TABLE 6: RESULT OF IN-VITRO DISSOLUTION OF CCD BATCHES FB1 TO FB10 Cumulative Percentage Release FB1 FB2 FB3 FB4 FB5 FB6 FB7 FB8 FB9 FB IC Value

12 Figure 3 Comparative Dissolution Profiles of FB1-FB10 Results of Central Composite design The independent variables selected in Central Composite design were Cumulative percent release (CPR) of drug at 2 hour (Q 2 ), 4 hour (Q 4 ), 8 hour (Q 8 ), 12 hour (Q 12 ), 16 hour (Q 16 ) and 20 hour (Q 20 ) to study the effect of independent variables X1 and X2. The results of dependable variables of all FB1 to FB10 batches were displayed in Table 7. A statistical model incorporating interactive and poly nominal terms was used to evaluate the responses. 2 Y= b 0 + b 1 X 1 + b 2 X 2 + b 12 X 1 X 2 + b 11 X 1 + b 22 X (5.1) Where Y is the dependent variable, b 0 is the arithmetic mean response of the 10 runs, and b 1 is the estimated coefficient for the factor X 1. The main effects (X 1 and X 2 ) represent the average result of changing 1 factor at a time from its low to high values. The interaction terms (X 1 X 2 ) show how the response changes when two factors are IC Value

13 simultaneously changed. The polynomial terms (X 2 1 and X 2 2 ) are included to investigate nonlinearity. TABLE 7: FORMULATION AND RESULT OF DEPENDENT VARIABLES FOR CCD BATCHES Batch Code Variable Levels in Coded Form Q2 Q4 Q8 Q12 Q16 Q20 X1 X2 FB FB FB FB FB FB FB FB FB FB Actual Values Coded Values HPMC K 15 M (X 1 ) mg 50 mg 70 mg 90 mg mg HPMC K 100 M (X 2 ) mg 50 mg 70 mg 90 mg mg All batches contained 150 milligrams of Itopride HCl, 3.5mg Aerosil, 3.5mg magnesium stearate. X 1 indicates the concentration of HPMC K15 M, X 2 indicate concentration of HPMC K 100 M. Q 2, Q 4, Q 8, Q 12, Q 16 and.q 20 indicate percentage drug released after 2, 4, 8, 12, 16 and 20 hours respectively. The dissolution profile for 10 batches showed an initial 1 hr release ranging from 23.5 % to % and drug released after 20 hr ranging from % to % as shown in Table 7. The fitted equations (full and reduced) relating the responses Q 2, Q 4, Q 8, Q 12, Q 16 and Q 20 to the transformed factor are shown in the Table 8. The polynomial equations can IC Value

14 be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries (i.e., negative or positive). Table 9 shows the results of analysis of variance (ANOVA), which was performed to identify insignificant factors. TABLE 8: SUMMARY OF RESULTS OF REGRESSION ANALYSIS Response (Q 2 ) Response (Q 4 ) Response (Q 8 ) Coefficients for Q 2 b 0 b 1 b 2 b 12 b 11 b 22 FM * * * * RM Coefficients for Q 4 b 0 b 1 b 2 b 12 b 11 b 22 FM * RM Coefficients for Q 8 b 0 b 1 b 2 b 12 b 11 b 22 FM * 1.261* 0.991* RM Coefficients for Q12 Response b 0 b 1 b 2 b 12 b 11 b 22 (Q12) FM * * RM Coefficients for Q16 Response b 0 b 1 b 2 b 12 b 11 b 22 ( Q 16 ) FM * 0.789* 0.436* RM Coefficients for Q20 Response b 0 b 1 b 2 b 12 b 11 b 22 (Q20) FM * RM *Indicate the value is insignificant at P = > 0.05, FM= Full model, RM= Reduced model R 2 value for Q 2, Q 4, Q 8, Q 12, Q 16 and Q 20 are 0.900, , , , and respectively indicating good correlation between dependent and independent IC Value

15 variables The reduced models were developed for response variables by omitting the insignificant terms with P> The terms with P<0.05 were considered statistically significance and retained in the reduced model. The coefficients for full and reduced models for response variables are shown in Table 8. Full and reduced model The full model was developed by using the coefficients. The significance level of coefficients b1, b 2, b 12, b 11 and b 22 were checked. These coefficients were found to be significant at p<0.05, hence they were retained in the reduced model if They were found to be significant at p>0.05, hence they were omitted from the full model to generate the reduced model. The results of statistical analysis are shown in table 8. The reduced model was tested in portions to determine whether the omitted coefficients contribute significant information for the prediction of dependent variable or not. The results for testing the model in portions are shown in table 9. To calculate the F-value and critical F-value for α = Since the calculated F-value is less than critical F-value, it may be concluded that the omitted coefficients do not contribute significantly to the prediction of dependent variable and therefore can be omitted from the full model. Full Model and reduce model equation for dependent variables. Full model: Q 2 = X X X X X 22.. (5.2) Reduced model: Q 2 = X (5.3) Full model: Q 4 = X X X X X (5.4) Reduced model: Q 4 = X X X X (5.5) Full model: Q 8 = X X X X X (5.6) Reduced model: Q 8 = X X (5.7) Full model: Q 12 = X X X X X 22.. (5.8) Reduced model: Q 12 = X X X (5.9) Full model: Q 16 = X X X X X (5.10) Reduced model: Q 16 = X X (5.11) Full model: Q20 = X X X X X 22. (5.12) Reduced model: Q20 = X X X X (5.13) IC Value

16 From the reduced model generated for all dependent variables, it can be concluded that negative sign of both factor indicate that increase in amount of HPMC K15M and HPMC K100M decrease in drug release. Also concluded that negative sign for interaction term indicate that both polymer in combination decrease the drug release and positive sign for interaction term indicate that both polymer in combination increase in the drug release for that variable. Response Surface Plot From the response surface plot of Q 2, Q 4, Q 8, Q 12, Q 16 and Q 20 it was observed that as the level of X 1 (HPMC K 15M) and X2 (HPMC K 15M) were changed from low to high there was significant decrease in release of drug from matrix due to increase in the concentration of HPMC K 100M in the matrix formulation and HPMC changes from a glassy state to rubbery state, a gel structure is formed around the tablet matrix, which considerably decreases the release rate of drug since the drug has to diffuse through this gel barrier into bulk phase. HPMC K100M hydrates at faster and therefore forming gel structure quickly. HPMC K15M was responsible for initial burst effect and HPMC K100M was used to sustained drug release. At high level of X 2 the percentage release of Itopride HCl was low. From the results, it can be concluded that both the independent variables have negative effect and factor X 2 has more significant negative effect than that of factor X 1 on percentage drug release. In another words, at high level of factor X 2 percentage release has low value at all level of factor X 1, which indicates factor X 2 more control release of drug (Figure 4). TABLE 9: CALCULATION FOR TESTING THE MODEL IN PORTIONS Regression FM RM Error FM RM Regression FM RM Q2 DF SS MS F R 2 F Cal. F Crit DF = (4,4) Q4 DF SS MS F R 2 F Cal. F Crit IC Value

17 Error FM RM Regression FM RM Error FM RM Regression FM RM Error FM RM Regression FM RM Error FM RM Regression FM RM Error FM DF = (1,4) Q8 DF SS MS F R 2 F Cal. F Crit DF = (3,4) Q12 DF SS MS F R 2 F Cal. F Crit DF = (2,4) Q16 DF SS MS F R 2 F Cal. F Crit DF = (3,4) Q20 DF SS MS F R 2 F Cal. F Crit DF = (1,4) RM DF: degree of freedom, SS: sum of squares, MS: mean of squares, F: Fischer s ratio, R 2 : regression coefficient, FM: full model, RM: reduced model. IC Value

18 (A) (B) (C) (D) (E) Figure 4 Response Surface Plot of Dependable Variables (A) Q 2, (B) Q 4, (C) Q 8, (D) Q 12, (E) Q 16, (F) Q 2 (F) IC Value

19 Kinetics of Drug Release In order to elucidate the release mechanism the dissolution data were fitted in to different kinetic models zero order, First order, Higuchi model and Krosmeyer model. When data fitted into first order model regression co-efficient values were between to (Table 10) and zero order model regression co-efficient values were between to (Table 10) which suggests that rate of release from tablet matrix was followed zero order kinetics. The data fitted with higuchi model with their regression co-efficient values between to indicating the release of drug from tablet matrix was diffusion controlled. To know precisely whether Fickian or non-fickian diffusion was existing, the data was fitted in to krosmeyer model with their diffusion exponent (n) values ranging between to (Table 10) indicates non Fickian diffusion from tablet matrix. Formulation code TABLE 10: KINETIC TREATMENT OF DISSOLUTION DATA Zero order First order Higuchi model Krosmeyer model R 2 K R 2 K R 2 K R 2 n FB FB FB FB FB FB FB FB FB FB K = slope, R 2 = Square of correlation coefficient, n= diffusion exponent Selection of Optimized Batch: Central Composite Design batches dissolution profile compare with innovator dissolution profile by calculating similarity factor (f 2 ) and dissimilarity factor (f 1 ). The values of similarity factor (f 2 ) and dissimilarity factor (f 1 ) for the batch FB7 showed maximum f 2 IC Value

20 value and minimum f 1 value was 3.45 as shown in Table 11. Hence, formulation batch FB7 was considered as optimum batch. TABLE 11: SIMILARITY FACTOR (F 2 ) AND DISSIMILARITY FACTOR (F 1 ) Stability Study FOR FB1-FB10 Batch Similarity factor (f 2 ) Dissimilarity factor(f 1 ) FB FB FB FB FB FB FB FB FB FB In order to determine the change in In-Vitro release profile on storage, stability study of formulation FB7 was carried out at 40 C in a humidity jar having 75 % RH. Samples evaluated after one month showed no change in In-Vitro drug release pattern as shown in Table 12. The value of similarity factor was (Table 12) indicating good similarity of dissolution profiles before and after stability studies. Figure 5 Dissolution Profiles for Stability Study Of Optimized Batch FB7 IC Value

21 TABLE 12: DISSOLUTION PROFILE FOR STABILITY STUDY OF OPTIMIZED BATCH Time (hr) CPR Fresh Sample After 1 month Similarity Factor(f 2 ) Dissimilarity factor (f 1 ) CONCLUSION The CCD was used to find out the effect of independent variables on the dependant variables. The result of CCD revealed that the HPMC K15M and HPMC K100M have significant effect on the drug release at 2, 4, 8, 12, 16 and 20 hour. The observed independent variables were found to be very close to predicted values of optimized formulation. The formulation FB7 dissolution profile was found to be very close to innovator dissolution profile with similarity factor (77.81) which demonstrates the feasibility of the optimization procedure in successful development of sustained release tablets containing Itopride HCl by using HPMC K15M and HPMC K100M. IC Value

22 ACKNOWLEDGEMENTS Authors are thankful to Zydus Healthcare, Ahmedabad (India) for providing gift sample of Itopride Hydrochloride. Authors also wish to thank Shri B.M.Shah College of Pharmaceutical Education and Research, Modasa for providing all the required laboratory facilities REFERENCES: 1. Chien YW, Novel Drug Delivery System, ed. by Chien YW, Marcel Dekker, New York, USA;1992: Vyas SP, Khar RK, Controlled Drug Delivery: Concepts and Advances, Vallabh Prakashan, Delhi; 2002: Saleh MA, Yellela SR, Srinivas SP and Satyanaryana V, In Vitro and In Vivo Evaluation of Guar Gum Matrix Tablets for Oral Controlled Release of Watersoluble Diltiazem Hydrochloride, AAPS PharmSciTech; 2005: 6 (1): E14-E Salsa T, Veiga F, Pina ME. Oral controlled-release dosage forms. Cellulose ether polymers in hydrophilic matrices, Drug Dev Ind Pharm; 1997: 23: Tiwari SB, Murthy TK, Pai MR, Mehta PR and Chowdary PB, Controlled Release Formulation of Tramadol Hydrochloride Using Hydrophilic and Hydrophobic Matrix System, AAPS PharmSciTech; 2003: 4 (3): Ranga RK, Padmalatha DK, Buri B, Drug Dev. Ind. Pharm ;1988: 14: Rao R, Sindhura G and Saha RN, Design and in Vitro Evaluation of Zidovudine Oral Controlled Release Tablets Prepared Using Hydroxypropyl Methyl cellulose, Chem. Pharm. Bull.; 2008: 56(4): Rao R, Sindhura G and Saha RN, Design and in Vitro Evaluation of Zidovudine Oral Controlled Release Tablets Prepared Using Hydroxypropyl Methyl cellulose, Chem. Pharm. Bull.; 2008: 56(4): Marcos BP, Ford JL, Armstrong DJ, Elliott PN, Rostron C, Hogan JE, J. Pharm. Sci.; 1996: 85: Saravanan M., Kalakonda SN and Kettavarampalayam SG, HydroxypropylMethyl cellulose Based Cephalexin Extended Release Tablets: Influence of Tablet IC Value

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24 19. Ulla SN, Roy A, Kulkarni M Formulation and Evaluation of Sustained Release Matrix Tablets of Lornoxicam, International Journal of Drug Development & Research; 2011: 3(1): Mandal U, Gowda V, Ghosh A, Selvan S, Formulation and Optimization of Sustained Release Matrix Tablet of Metformin HC1 500 mg Using Response Surface Methodology, yakugaku Zasshi; 2007: 127(8): Rao PB and Gandhi P, Formulation and Evaluation of Mucoadhesive Buccal Drug Delivery System of Metoprolol Tartrate by Using Central Composite Design, RGUHS Journal of Pharmaceutical Sciences; 2011: 1(2): ICH guideline Q1A- Q1F, For Correspondence: Pankil A.Gandhi pankilpharma01@yahoo.com IC Value