vol-3, issue-4, suppl-1, nov 2012 issn: 0976-7908 gandhi et al

Vol-3, Issue-4, Suppl-1, Nov 2012 ISSN: 0976-7908 Gandhi et al

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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 (X1) and Hydroxypropylmethyl cellulose K100M (X2) were selected as independent variables. The dependent variables were drug release at 2nd hr, 4th hr, 8th hr, 12th hr, 16th hr and 20th 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 (f2=83.86) and difference factor (f1=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 (R2=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



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



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



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 (X1) and concentration of HPMC

K100M (X2) were chosen as independent variables in Central Composite Design, while

Q2, Q4, Q8, Q12, Q16, Q20 (% 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

-1.414(-α) -1 0 +1 +1.414(+α)

HPMC K 15 M (X1) 41.72 mg 50 mg 70 mg 90 mg 98.28 mg




TABLE 2: FORMULATION OF ITOPRIDE HCl SUSTAINED RELEASE

TABLET

Ingredients (mg) FB1 FB2 FB3 FB4 FB5 FB6 FB7 FB8 FB9 FB10

Itopride HCl 150 150 150 150 150 150 150 150 150 150

HPMC K15 M 50 50 90 90 70 41.72 98.28 70 70 70

HPMC K100M 50 90 50 90 70 70 70 41.72 98.28 70

Lactose 93 53 53 13 53 81.28 24.72 81.28 24.72 53

Aerosil 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5

Mg. Stearate 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5 3.5

Total Weight(mg) 350 350 350 350 350 350 350 350 350 350

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±0.5oC 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]



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 (f2) and dissimilarity factor

(f1). 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 f2 for comparison between dissolution profiles of different samples. The similarity

factor (f2) 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 f2. The similarity factor is calculated by following formula.

( )

−

+=

−

=∑ 10011logX50 X

5.02

12

n

tttt TRw

nf …………….……. (4.7)

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 (f1).) 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.



……………………………………………………..…..(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.

f1 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 3275.24 3276.20 C-H structure of Methyl Group 2970.48 2967.58

C=O Bonding 1630.87 1633.76 C=C aromatic Structure 1607.72 1606.76 C-N aromatic Structure 1224.84 1223.87 C-O Aromatic Structure 1015.56 1014.59



500750100015002000300040001/cm

-25

0

25

50

75

100

125

150

175

200%T

3275

.24

2970

.48

2646

.42

1630

.87

1607

.72

1511

.28

1329

.00

1224

.84

1130

.32

1015

.56

992.

4193

1.65

836.

1777

0.59

694.

40

ITOPRIDE HCl

Figure 1 FT-IR Spectra of Itopride Hydrochloride

500750100015002000300040001/cm

-50

0

50

100

150

200

%T

3275.2

4

2970.4

8

2646.4

2

1630.8

716

07.

72

1511

.28

1329.0

0

1224.8

4

1130.3

2

1015.5

699

2.41

931.6

5

836.1

7770.5

9

694.4

0

3276.2

0

2967.5

8

2623.2

8 163

3.7

6 1606.7

6

1512.2

4

132

1.2

8

1223.8

7

1129.3

6

10

14.5

9992.4

1931.6

5

83

1.35

765.7

7

694.4

0

ITOPRIDE HClFORMULATION

ITOPRIDE HCl

Figure 2 FT-IR Spectra of Itopride HCl and Excipients



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 19.80 to 25.10, 11.39 to 15.22 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

FB1 21.56 0.404 0.473 15.22 1.18 FB2 23.14 0.452 0.512 14.06 1.16 FB3 25.10 0.429 0.504 14.88 1.17 FB4 24.38 0.464 0.528 12.12 1.14 FB5 22.90 0.420 0.489 14.11 1.16 FB6 22.15 0.451 0.512 11.39 1.13 FB7 19.80 0.437 0.515 15.15 1.18 FB8 20.35 0.449 0.521 13.82 1.16 FB9 20.82 0.447 0.511 12.52 1.14 FB10 23.05 0.418 0.493 15.21 1.18

TABLE 5: RESULT OF PHYSICO CHEMICAL EVALUATION OF CCD

BATCHES

Batches Hardness (kg/cm3)

Thickness (mm)

Friability (%)

Avg. Wt. (mg)

Assay (%)

FB1 6.5 ± 0.23 4.66 ±0.41 0.145 351.3 ±0.85 99.8 ±1.05

FB2 7.2 ± 0.21 4.47±0.37 0.104 352.1 ±1.11 100.2 ±0.48

FB3 7.0 ± 0.29 4.43±0.29 0.128 350.1 ±1.06 100.1 ±0.26

FB4 7.3 ± 0.22 4.57±0.31 0.059 349.9 ±1.14 98.8 ±1.05

FB5 7.5 ± 0.26 4.48±0.45 0.068 350.4 ±1.43 98.7 ±1.12

FB6 6.8 ± 0.31 4.64±0.33 0.129 350.3 ±1.21 99.3 ±1.08

FB7 7.0 ± 0.29 4.61±0.38 0.099 351.2 ±0.94 99.4 ±0.87

FB8 7.5±0.24 4.44±0.27 0.069 350.2 ±0.89 98.4 ±1.18

FB9 7.4±0.25 4.52±0.19 0.072 350.4 ±1.32 99.3 ±0.59

FB10 7.2±0.16 4.56±0.24 0.092 349.4 ±1.24 98.7 ±1.31



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 6.5-7.5 kg/cm2. 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 Q2 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.



TABLE 6: RESULT OF IN-VITRO DISSOLUTION OF CCD BATCHES FB1 TO

FB10

Time (hrs.)

Cumulative Percentage Release

FB1 FB2 FB3 FB4 FB5 FB6 FB7 FB8 FB9 FB10

0 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00 0.00

1 21.29 20.71 17.04 20.71 21.29 21.00 21.00 19.53 20.41 21.00

2 26.59 25.40 26.38 23.50 25.71 25.26 25.12 26.12 23.93 25.41

3 31.16 32.73 31.90 29.31 30.55 31.34 31.53 30.93 30.11 30.14

4 38.70 38.49 37.64 34.23 35.08 37.88 35.68 37.26 35.44 35.47

5 44.52 45.91 45.25 41.20 40.06 42.89 42.86 42.27 42.82 39.25

6 57.40 52.40 53.34 46.84 50.49 50.75 48.52 50.72 47.28 50.27

7 62.01 56.76 56.91 50.14 53.03 56.69 51.84 56.47 50.99 53.61

8 68.07 59.97 63.72 55.07 58.19 63.09 56.99 63.47 55.53 58.78

9 74.39 63.80 65.59 58.85 64.01 67.36 60.19 67.34 59.31 63.20

10 76.98 67.07 68.48 62.27 68.28 71.27 63.82 69.85 62.93 67.66

11 79.98 72.96 73.19 67.32 72.19 75.81 67.29 73.37 67.19 71.37

12 85.01 80.52 80.15 69.41 75.54 84.60 71.98 81.53 70.88 75.71

14 92.68 88.55 87.17 76.93 83.51 90.27 77.72 90.37 77.01 84.09

16 98.03 92.66 93.47 82.91 89.97 97.40 83.71 96.50 83.20 89.55

18 96.40 99.62 89.36 96.89 90.77 100.1 90.44 96.26

20 101.58 92.07 100.27 93.89 93.76 100.64

22 95.39 96.63 95.51

24 97.15 99.80 97.66



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 (Q2), 4 hour (Q4), 8 hour (Q8), 12 hour (Q12), 16 hour

(Q16) and 20 hour (Q20) 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.

Y= b0 + b1X1 + b2X2 + b12X1X2 + b11X12 + b22X2

2 …………………………..… (5.1)

Where Y is the dependent variable, b0 is the arithmetic mean response of the 10 runs, and

b1 is the estimated coefficient for the factor X1. The main effects (X1 and X2) represent

the average result of changing 1 factor at a time from its low to high values. The

interaction terms (X1X2) show how the response changes when two factors are



simultaneously changed. The polynomial terms (X12 and X2

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

FB1 -1 -1 26.59 37.8 68.07 85.01 98.03 98.03

FB2 -1 1 25.4 38.49 59.97 80.52 92.66 101.58

FB3 1 -1 26.38 37.64 63.72 80.15 93.47 99.62

FB4 1 1 23.5 34.23 55.07 69.41 82.91 92.07

FB5 0 0 25.71 35.08 58.19 75.54 89.97 100.27

FB6 -1.414 0 25.26 37.88 63.09 84.60 97.4 97.4

FB7 1.414 0 25.12 35.68 56.99 71.98 83.71 93.89

FB8 0 -1.414 26.12 37.26 63.47 81.53 96.5 100.09

FB9 0 1.414 23.93 35.44 55.53 70.88 83.2 93.76

FB10 0 0 25.41 35.47 58.78 75.71 89.55 100.64

Actual Values Coded Values

-1.414 -1 0 1 1.414



All batches contained 150 milligrams of Itopride HCl, 3.5mg Aerosil, 3.5mg magnesium stearate. X1 indicates the concentration of HPMC K15 M, X2 indicate concentration of HPMC K 100 M. Q2, Q4, Q8, Q12, Q16and .Q20 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 26.59 % and drug released after 20 hr ranging from 92.07 % to 101.58 % as shown in

Table 7. The fitted equations (full and reduced) relating the responses Q2, Q4, Q8, Q12, Q16

and Q20 to the transformed factor are shown in the Table 8. The polynomial equations can



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

Coefficients for Q2

Response(Q2)

b0 b1 b2 b12 b11 b22

FM 25.56 -0.289* -0.896 -0.423* -0.095* -0.178*

RM 25.34 - -0.896 - - -

Coefficients for Q4

Response(Q4)

b0 b1 b2 b12 b11 b22

FM 35.27 -1.00 -0.724 -0.9 0.903 0.688*

RM 36.03 -0.941 -0.662 -1.03 0.59 -

Coefficients for Q8

Response(Q8)

b0 b1 b2 b12 b11 b22

FM 58.49 -2.235 -3.497 -0.138* 1.261* 0.991*

RM 60.288 -2.235 -3.497 - - -

Coefficients for Q12

Response (Q12)

b0 b1 b2 b12 b11 b22

FM 75.63 -4.228 -3.786 -1.563* 1.713 0.671*

RM 76.39 -4.228 -3.786 - 1.468 -


Response ( Q16)

b0 b1 b2 b12 b11 b22

FM 89.76 -4.209 -4.342 -1.298* 0.789* 0.436*

RM 90.74 -4.209 -4.342 - - -


Response (Q20)

b0 b1 b2 b12 b11 b22

FM 100.455 -1.610 -1.619 -2.775 -2.02 -1.38*

RM 98.878 -1.610 -1.619 -2.775 -1.429 -

*Indicate the value is insignificant at P = > 0.05, FM= Full model, RM= Reduced model

R2 value for Q2, Q4, Q8, Q12, Q16 and Q20 are 0.900, 0.9401, 0.9269, 0.9822, 0.9704 and

0.9117 respectively indicating good correlation between dependent and independent



variables The reduced models were developed for response variables by omitting the

insignificant terms with P> 0.05. 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, b2, b12, b11 and b22 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

= 0.05. 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: Q2 = 25.6 - 0.288 X1 - 0.896 X2- 0.422 X12 - 0.095 X11 - 0.177 X22.. (5.2)

Reduced model: Q2 = 25.3 - 0.896 X2 ……...……...……..……………...…...... (5.3)

Full model: Q4 = 35.3 - 1.00 X1 - 0.724 X2 - 0.900 X12 + 0.903 X11 + 0.687 X22 .... (5.4)

Reduced model: Q4 = 36.1 - 1.00 X1 - 0.724 X2- 0.900 X12 + 0.608 X11 …….…... (5.5)

Full model: Q8 = 58.5 - 2.23 X1 - 3.50 X2 - 0.138 X12 + 1.26 X11 + 0.992 X22....... (5.6)

Reduced model: Q8 = 60.3 - 2.23 X1 - 3.50 X2………………………………...…. (5.7)

Full model: Q12 = 75.6 - 4.23 X1 - 3.79 X2 -1.56 X12+ 1.71 X11 + 0.671 X22 ….…. (5.8)

Reduced model: Q12 = 76.4 - 4.23 X1 - 3.79 X2 + 1.43 X11……………….....……. (5.9)

Full model: Q16 = 89.8 - 4.21 X1 - 4.34 X2 - 1.30 X12 + 0.789 X11 + 0.436 X22 ... (5.10)

Reduced model: Q16 = 90.7 - 4.21 X1 - 4.34 X2………………………....…...…. (5.11)

Full model: Q20 = 100 - 1.61 X1 - 1.62 X2 - 2.77 X12 - 2.02 X11 - 1.38 X22 ……. (5.12)

Reduced model: Q20 = 98.9 - 1.61 X1 - 1.62 X2- 2.77 X12 - 1.43 X11 ….....…. (5.13)



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 Q2, Q4, Q8, Q12, Q16 and Q20 it was observed that as the

level of X1 (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 X2 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 X2 has more significant negative effect than that

of factor X1 on percentage drug release. In another words, at high level of factor X2

percentage release has low value at all level of factor X1, which indicates factor X2 more

control release of drug (Figure 4).

TABLE 9: CALCULATION FOR TESTING THE MODEL IN PORTIONS

Q2 Regression FM RM

DF SS MS F R2 FCal. FCrit.

5 7.946877 1.589375 7.228681 0.9 1.735011

6.388233 1 6.420965 6.420965 21.35521 0.7274

Error FM RM

4 0.879483 0.219871 - - DF = (4,4) 8 2.405395 0.300674 - -

Q4 Regression FM RM


5 19.72864 3.945727 12.55428 0.940094 4.631475

7.708647 4 16.74499 4.186248 7.715688 0.86058



Error FM RM

4 1.257174 0.314293 - - DF = (1,4) 5 2.712816 0.542563 - -

Q8 Regression

FM RM


5 146.2934 29.25867 10.14095 0.92688 0.981358

6.591382 2 137.7991 68.89955 24.07265 0.873063

Error FM RM

4 11.5408 2.885201 - - DF = (3,4) 7 20.03505 2.86215 - -

Q12 Regression FM RM


5 280.9114 56.18228 44.08732 0.982178 4.639179 6.944272 3 269.0876 89.69588 31.80487 0.940837

Error FM RM

4 5.097364 1.274341 - - DF = (2,4) 6 16.92116 2.820193 - -

Q16 Regression

FM RM


5 302.1957 60.43914 26.24563 0.97042 1.394235 6.591382 2 292.5636 146.2818 54.34131 0.93949

Error FM RM

4 9.211309 2.302827 - - DF = (3,4) 7 18.84336 2.691908 - -

Q20 Regression

FM RM


5 92.65542 18.53108 8.264295 0.911742 3.882532

7.708647 4 83.94959 20.9874 5.937011 0.826075

Error FM RM

4 8.969227 2.242307 - - DF = (1,4) 5 17.67506 3.535011 - -

DF: degree of freedom, SS: sum of squares, MS: mean of squares, F: Fischer’s ratio, R2: regression coefficient, FM: full model, RM: reduced model.



(A) (B)

(C) (D)

(E) (F)

Figure 4 Response Surface Plot of Dependable Variables (A) Q2, (B) Q4, (C) Q8, (D) Q12, (E) Q16, (F) Q2



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 0.9233 to 0.9605

(Table 10) and zero order model regression co-efficient values were between0.9809 to

0.9950 (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 0.9921 to 0.9977 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 0.5377 to 0.6202 (Table 10) indicates non Fickian diffusion from

tablet matrix.

TABLE 10: KINETIC TREATMENT OF DISSOLUTION DATA

Formulation code

Zero order First order Higuchi model Krosmeyer model

R2 K R2 K R2 K R2 n

FB1 0.9841 5.4451 0.9427 0.0441 0.9923 28.099 0.9881 0.6116

FB2 0.9858 4.374 0.9326 0.0339 0.9959 24.991 0.9951 0.574

FB3 0.9879 4.7954 0.9255 0.0396 0.9977 26.105 0.9985 0.6202

FB4 0.9814 3.4912 0.9259 0.0276 0.9964 21.808 0.9925 0.5494

FB5 0.9898 4.3668 0.9454 0.0345 0.9943 24.808 0.9894 0.5729

FB6 0.995 5.341 0.9605 0.0442 0.9921 27.255 0.9896 0.6027

FB7 0.9825 3.5048 0.926 0.0269 0.9976 21.893 0.9952 0.5377

FB8 0.9906 4.9625 0.9451 0.0398 0.9942 26.845 0.9938 0.6087

FB9 0.9809 3.4956 0.9233 0.0273 0.9968 21.857 0.9946 0.5476

FB10 0.9899 4.3748 0.9445 0.0347 0.9945 24.854 0.9897 0.5772

K = slope, R2= 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 (f2) and dissimilarity factor (f1). The values of

similarity factor (f2) and dissimilarity factor (f1) for the batch FB7 showed maximum f2



value 77.81 and minimum f1 value was 3.45 as shown in Table 11. Hence, formulation

batch FB7 was considered as optimum batch.

TABLE 11: SIMILARITY FACTOR (F2) AND DISSIMILARITY FACTOR (F1)

FOR FB1-FB10

Batch Similarity factor (f2)

Dissimilarity factor(f1)

FB1 55.82 9.81 FB2 69.58 4.45 FB3 67.19 5.45 FB4 69.76 5.73 FB5 73.67 3.89 FB6 62.94 6.67 FB7 77.81 3.65 FB8 63.23 6.52 FB9 73.15 4.80 FB10 73.74 3.81

Stability Study

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 82.03 (Table 12) indicating good similarity

of dissolution profiles before and after stability studies.

Figure 5 Dissolution Profiles for Stability Study Of Optimized Batch FB7



TABLE 12: DISSOLUTION PROFILE FOR STABILITY STUDY OF

OPTIMIZED BATCH

Time (hr)

CPR Fresh Sample After 1

month 0 00.00 00.00 1 21.00 20.27 2 25.12 24.52 3 31.53 30.12 4 35.68 34.04 5 42.86 41.01 6 48.52 46.85 7 51.84 50.35 8 56.99 55.89 9 60.19 58.88 10 63.82 61.89 11 67.29 65.34 12 71.98 69.01 14 77.72 75.12 16 83.71 80.89 18 90.77 88.31 20 93.89 91.40 22 96.63 94.13 24 99.80 97.47 Similarity Factor(f2) 82.53

Dissimilarity factor (f1) 03.03

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.



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

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For Correspondence: Pankil A.Gandhi

Email: [email protected]

vol-3, issue-4, suppl-1, nov 2012 issn: 0976-7908 gandhi et al

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