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The Pharma Innovation Journal 2014; 3(8): 20-28

ISSN: 2277- 7695

TPI 2014; 3(8): 20-28 © 2013 TPI

www.thepharmajournal.com Received: 06-09-2014 Accepted: 22-09-2014

Viral Kanzariya Sigma institute of pharmacy, Vadodara, Gujarat, India.

Falguni Sharma Sigma institute of pharmacy, Vadodara, Gujarat, India.

Hitesh Jain Sigma institute of pharmacy, Vadodara, Gujarat, India.

Umesh Upadhyay Sigma institute of pharmacy, Vadodara, Gujarat, India.

Crrespondence: Viral Kanzariya Sigma institute of pharmacy, Vadodara, Gujarat, India.

Formulation development and evaluation of floating tablet of Cinnarizine for an effective management of

motion sickness

Viral Kanzariya, Falguni Sharma, Hitesh Jain, Umesh Upadhyay

AbstractObjectives: The objective of the present study is to formulate the Gastro-retentive floating tablets containing cinnarizine, which would remain in stomach and/or upper part of GIT for prolonged period of time in a view to maximize solubility of drug which is necessary for its absorption.

Experimental Work: The floating tablets of Cinnarizine were prepared by direct compression method using Polyox WSR 303 in various concentrations and NaHCO3 as an effervescent agent. 32 factorial design was carried out. The factorial batches were formed by taking concentrations of Polyox WSR 303 and Sodium bicarbonate as independent variables and floating lag time and % CDR as dependent factors. The formulations were evaluated for hardness, friability, weight variation, swelling index, floating lag time, floating time, % CDR etc. From the formulated factorial batches, S3 batch containing 22% Polyox WSR 303 and 15% sodium bicarbonate showed the lowest lag time of 24.22±0.88 sec and the highest % CDR at 12th hr of 98.69%.

Conclusion: From the results obtained, it was concluded that the optimized formulation containing Polyox WSR 303 and sodium bicarbonate shows better swelling properties with desired drug release properties and floating behaviour. Hence Polyox WSR 303 is a potential polymer candidate for formulation of sustained release floating effervescent tablets.

Keywords: Gastro-retentive floating tablets, Cinnarizine, Polyox WSR 303, Sustained release floating effervescent tablets, swelling index, optimization.

1. Introduction Oral ingestion has long been the most convenient, versatile and commonly employed route of drug delivery due to its advantages like ease of administration, high patient compliance, least sterility constraints and flexibility in the design of the dosage form [1, 2]. More than 50% of the drug delivery systems available in the market are oral drug delivery systems. Although tremendous advances have been seen in oral controlled drug delivery system during last two decades. This approach is be deal with several physiological difficulties such as inability to restrain and locate the controlled drug delivery system within the desired region of the gastrointestinal tract (GIT) due to variable gastric emptying and motility [3, 4]. Controlled- release drug delivery systems (CRDDS) provide drug release at a predetermined, predictable and controlled rate. Controlled- release drug delivery system is capable of achieving the benefits like maintenance of optimum therapeutic drug concentration in blood with predictable and reproducible release rates for extended time period; enhancement of activity of duration for short half- life drugs; elimination of side effects; reducing frequency of dosing and wastage of drugs; optimized therapy and better patient compliances [5, 6]. Cinnarizine is absorbed from the gastrointestinal tract, peak plasma concentrations occurring 2 to 4 hours after oral doses. It undergoes metabolism and has a half-life of 3 to 6 hours [7, 8]. So it makes cinnarizine the best candidate for GRDDs drug delivery. The objective of the present study is to formulate the Gastro-retentive floating tablets containing Cinnarizine, which would remain in stomach and/or upper part of GIT for prolonged period of time in a view to maximize solubility of drug which is necessary for its absorption [9, 10]. The tablets were prepared by varying concentrations of swelling polymer Polyox WSR 303 and Sodium bicarbonate as an effervescent agent. 32 statistical design was applied and further optimization was done.

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The Pharma Innovation Journal 2. Materials and Methods Cinnarizine was obtained as a gift sample from Elite pharmaceuticals, Ahmedabad. Polyox WSR 303 was obtained as a gift sample from Colorcon Asia Pvt. Ltd. All other ingredients used were of analytical grade. 2.1 Drug-Excipient interaction study using Fourier Transform Infra-Red (FTIR) spectroscopy Infrared spectrophotometry (IR) (Shimadzu-8400) is a useful analytical technique utilized to check the chemical interaction between the drug & other excipients used in the formulation. One milligram of the sample was powdered & intimately mixed with 10 mg of dry powdered potassium bromide. The powdered mixture was taken in a diffuse reflectance sampler & the spectrum was recorded by scanning in the wavelength region of 3500-500 cm-1 in an FTIR spectrophotometer .The IR spectrum of the drug was compared with that of the physical mixture to check for any possible drug-excipients interaction. 2.2 Preparation of Floating Tablets All the ingredients were accurately weighed and passed through mesh 60#. In order to mix the ingredients thoroughly drug & polymer were blended and geometrically in a mortar and pestle for 15 minutes then magnesium stearate, sodium bicarbonate, talc, PVP k-30, dicalcium phosphate and magnesium stearate were mixed one by one. After thoroughly

mixing the ingredients, the powder was blend was passed through 44# sieve and compressed on rotary tablet punching machine. (Made-Krishna Engineering). 2.2.1 Factorial Design [11, 12] A 32 full factorial design was used in the present study to obtain optimized formulation. In this design, 2 factors were evaluated, each at 3 levels and experimental trials were performed at all 9 possible combinations. The amount of Polyox WSR 303(X1) and sodium bicarbonate (X2) were selected as independent variables (factor). The lag time (Y1) and % drug release (Y2) at 12th hr were selected as dependent variables (responses). The responses were recorded & analysis of the data was carried out using ANOVA in DESIGN-EXPERT 8.0.7.1 demo version software (STAT-EASE).The polynomial equation generated by this experimental design is as follows: Y= B0+ B1X1+ B2X2+ B12X1X2+ B11X12+ B22X2+ E Where, B0 = Intercept B1 and B2 = Co-efficient of X1 and X2 variable B12 = Co-efficient of interaction B11 and B22 = Co-efficient of quadratic terms X1 and X2 = Variables E = Error

Table 1: Coded values & Actual values of the Independent Variables

Independent variables(Factors) Coded values Actual values Low Medium High Low Medium High Polyox WSR 303(%)

(X1) -1 0 +1 22 25 28

Sodium Bicarbonate (%) (X2)

-1 0 +1 5 10 15

Table 2: Composition of the formulations in terms of coded and Actual value

Run Coded values Actual values

Batch code X1 X2

Polyox WSR 303 (X1)

Sodium bicarbonate

(X2) S1 -1 -1 22 5 S2 -1 0 22 10 S3 -1 +1 22 15 S4 0 -1 25 5 S5 0 0 25 10 S6 0 +1 25 15 S7 +1 -1 28 5 S8 +1 0 28 10 S9 +1 +1 28 15

2.3 Evaluation Parameters 2.3.1 Hardness [13, 14] The tablet hardness is defined as the force required break a tablet in a diametric compression test. To perform this test, a tablet was placed between two anvils, force was applied to the anvils & the crushing strength that just caused the tablet to break was recorded. The hardness was measured using Pfizer tester. It is expressed in Kg/cm2.

2.3.2 Friability Test [15, 16] The friability of the tablets was determined using Roche friabilator. It is expressed in percentage (%). Approximately 6.5 g (Wo) of dedusted tablets were subjected to 100 free falls of 6 inches in a rotating drum & are then reweighed (W). The friability is given by F= (1 – Wo/W) × 100 2.3.3 Weight Variation Test [17, 18] Twenty tablets were weighed individually, average weight was calculated & individual tablet weights were compared to the average weight. The tablets met the USP test if no more than 2 tablets are outside the percentage limit & if no tablet differs by more than two times the percentage limit. 2.3.4 Lag Time [19, 20] The In vitro buoyancy was determined by the lag time. The tablets were placed in a 100 ml beaker containing 0.1 N HCl. The time required for a tablet to rise to the surface for floating was determined as the lag time. 2.3.5 Floating Time [20, 21] The tablets were placed in a 100 ml glass beaker containing 0.1 N HCl. The time for which the tablet remained floating on the

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The Pharma Innovation Journal surface of medium was determined as floating time. 2.3.6 Swelling Index [22, 23] For each formulation, one tablet was weighed and placed in a beaker containing 200 ml of distilled water. After each hour the tablet was removed from beaker and weighed again up to 8 hours. The percentage weight gain by the tablet was calculated by using the formula. Swelling index (S.I) = {(Wt‐Wo)/Wo} x 100 Where, S.I. = swelling index Wt = Weight of tablet at time t Wo = Weight of tablet before immersion. 2.3.7 Drug Content [24, 25] Ten tablets were weighed and average weight was calculated. All the 10 tablets were crushed in a mortar. The powder equivalent to 10 mg was accurately weighed, dissolved in 5 ml of Methanol & made upto 100 ml of 0.1 N HCl. The volumetric flask was then shaken for approximately 20 minutes. The solution was filtered & 1 ml of filtrate was diluted to 10 ml using 0.1 N HCl. Absorbance was measured at 253.5 nm using 0.1 N HCl as a blank. The amount of drug present in one tablet was calculated. 2.3.8. In-vitro Dissolution Studies [26] The dissolution was performed by using a USP XXII paddle apparatus. The dissolution was performed using 900 ml of 0.1 N HCl solutions at 37 ± 0.5 ºC temperature & at 50 rpm. At

every 1 hour interval, samples of 5 ml were withdrawn from the dissolution medium & that amount was replaced with fresh medium to maintain the volume constant. The absorbance of the solutions was measured at 253.5 nm for Cinnarizine using UV- Visible double beam spectrophotometer. 2.3.9 Stability Study [27] A study is carried out to assess the stability of cinnarizine floating tablet. The optimized formulation was subjected to the accelerated stability studies according to ICH guidelines (40±2 ºC and 75±5% RH) for a period of 3 months in a stability chamber. Samples were evaluated at 1st and 90th day for drug content and In-vitro drug release. 2.3.10 Evaluation of Factorial Design by Check Point Batch Two optimum checkpoints were selected based on the criteria from optimum formulation to validate the chosen experimental design and polynomial equations. The formulations corresponding to these checkpoints were prepared and evaluated for various response properties. The coded values of the check point batch from the overlay plot were subjected to analysis in MS Excel and the regression equation was derived. The coded values of X1 and X2 are replaced with the x in regression equation and the check point formulation batch was obtained as shown in the below given table. Subsequently, the resultant experimental data of response properties were quantitatively compared with that of their predicted values. Also, linear regression plots between observed & predicted values of the response properties were drawn using MS Excel forcing the line through origin.

Table 3: Formulation of check point batches

Parameters Coded Values Actual Values CP1 CP2 CP1 CP2 Polyox WSR 303 (%) -1.34 -1.69 20.98 19.96

Sodium Bicarbonate (%) -0.19 -0.85 9.05 5.75 3. Result and Discussions 3.1 Drug-Excipient interaction study of FTIR spectroscopy

Fig 1: FTIR spectra of Cinnarizin

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The Pharma Innovation Journal

Fig 2: FTIR spectra of mixture of Cinnarizine & Polyox WSR 303

The FTIR spectrums of Cinnarizine and its mixture with Polyox WSR 303 showed no interaction. 3.2 Evaluation of Floating Tablets

Table 4: Post-Compression Parameters of Formulations (S1-S9)

Formulation Hardness* (Kg/Cm2)

(n=3)

Friability (%)

Weight variation(mg) (n=20)

Drug Content (%) (n=10)

S1 3.44±0.12 0.28 401.22±0.68 98.57±0.63 S2 3.63±0.16 0.24 399.21±0.34 99.82±0.52 S3 3.87±0.21 0.21 400.89±1.01 99.32±1.12 S4 4.20±0.20 0.16 399.71±0.54 98.94±1.31 S5 4.34±0.18 0.14 398.71±1.21 99.81±1.18 S6 4.40±0.10 0.13 399.45±1.35 99.74±0.58 S7 4.43±0.19 0.10 400.5±0.32 99.65±1.02 S8 4.39±0.26 0.11 400.72±1.45 98.56±1.14 S9 4.49±0.79 0.10 399.97±1.11 99.57±0.87

* The values represent mean ± S.D.

Table 5: In-vitro buoyancy and floating time of Formulations (S1-S9)

Formulations Lag time(sec) Floating time(hrs)

S1 31.12±1.01 >12

S2 28.74±0.79 >12

S3 24.22±0.88 >12

S4 48.18±1.32 >12

S5 42.11±1.65 >12

S6 36.39±2.03 >12

S7 59.48±1.11 >12

S8 50.48±1.25 >12

S9 39.40±1.79 >12

* The values represent mean ± S.D.

(a)

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The Pharma Innovation Journal

(b) (c) (d)

Fig 3: Images (a-d) of tablet for floating and buoyancy of the optimized batch

In-vitro dissolution of Formulation of S1-S9

Fig 4: A plot of % cdr vs time of formulations (S1-S9)

3.3 Treatment of Dissolution Data with Different kinetic Models

Table 6: Dissolution data treatment of Formulation S3

Release Mechanism Zero Order First

Order Higuchi Korsmeyer-Peppas Hixson- Crowell

Values R2 Slope R2 Slope R2 Slope R2 Slope n R2 Slope S3 0.983 5.720 0.917 0.038 0.997 26.59 0.996 0.443 0.443 0.945 0.118

The R2 value indicated best fit model for particular formulations. The best fit model of the formulation S3 was found to be Higuchi. The diffusion exponent ‘n’ value was

found to be less than 0.5 for the formulation S3 indicating Fickian mechanism.

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The Pharma Innovation Journal 3.4 Data Analysis The responses were recorded & analysis of the data was carried out using ANOVA in DESIGN-EXPERT 8.0.7.1 demo version

software (STAT-EASE). The individual parameters were evaluated using F test.

Table 7: Design summary

Formulations Factor 1 (X1): Polyox

WSR 303 (%)

Factor 2(X2): Sodium Bicarbonate

(%)

Response 1 Lag Time (Seconds)

Response 2 %CDR at 12th hr (Hours)

S1 22 5 31.12 91.23 S2 22 10 28.74 95.12 S3 22 15 24.22 98.69 S4 25 5 48.18 84.49 S5 25 10 42.11 85.12 S6 25 15 36.39 89.60 S7 28 5 59.48 74.36 S8 28 10 50.48 77.51 S9 28 15 39.40 82.25

Design-Expert® SoftwareFactor Coding: ActualLag time

Design Points59.74

24.23

X1 = A: Polyox WSR 303X2 = B: Sodium Bicarbonate

-1.00 -0.50 0.00 0.50 1.00

-1.00

-0.50

0.00

0.50

1.00Lag time

A: Polyox WSR 303

B: S

odiu

m B

icar

bona

te 30

40

50

Fig 5: Contour plot showing the effect of Polyox WSR 303 & Sodium Bicarbonate on lag time

Design-Expert® SoftwareFactor Coding: ActualLag time

Design points above predicted valueDesign points below predicted value59.74

24.23

X1 = A: Polyox WSR 303X2 = B: Sodium Bicarbonate

-1.00

-0.50

0.00

0.50

1.00

-1.00

-0.50

0.00

0.50

1.00

20

30

40

50

60

70

Lag

tim

e

A: Polyox WSR 303 B: Sodium Bicarbonate

Fig 6: Response surface plot (3D) showing the effect of Polyox WSR 303 & Sodium Bicarbonate on lag time

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The Pharma Innovation Journal Design-Expert® SoftwareFactor Coding: Actual% CDR

Design Points98.69

74.36

X1 = A: Polyox WSR 303X2 = B: Sodium Bicarbonate

-1.00 -0.50 0.00 0.50 1.00

-1.00

-0.50

0.00

0.50

1.00% CDR

A: Polyox WSR 303

B: S

odiu

m B

icar

bona

te

80

8590

95

Fig 7: Contour plot showing the effect of Polyox WSR 303 & Sodium Bicarbonate on % CDR at 12th hr

Design-Expert® SoftwareFactor Coding: Actual% CDR

Design points above predicted valueDesign points below predicted value98.69

74.36

X1 = A: Polyox WSR 303X2 = B: Sodium Bicarbonate

-1.00

-0.50

0.00

0.50

1.00

-1.00

-0.50

0.00

0.50

1.00

70

75

80

85

90

95

100

% C

DR

A: Polyox WSR 303 B: Sodium Bicarbonate

Fig 8: Response surface plot (3D) showing the effect of Polyox WSR 303 & Sodium Bicarbonate on % CDR at 12th hr

Design-Expert® SoftwareFactor Coding: ActualOverlay Plot

Lag time% CDR

Design Points

X1 = A: Polyox WSR 303X2 = B: Sodium Bicarbonate

-2.00 -1.50 -1.00 -0.50 0.00

-1.00

-0.50

0.00

0.50

1.00Overlay Plot

A: Polyox WSR 303

B: S

odiu

m B

icar

bona

te

Lag time: 25.000 % CDR: 95.000% CDR: 100.000

Lag time: 27.591% CDR: 96.875X1 -1.34X2 -0.19

Lag time: 28.654% CDR: 98.409X1 -1.69X2 -0.85

Fig 9: Overlay plot of Polyox WSR 303 & Sodium Bicarbonate

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The Pharma Innovation Journal 3.5 Comparison between observed and predicted result of check point batch

Table 8: Evaluation of tablets by check point batch

Formulations Parameters Predicted Values Obtained Values % Error

CP1 Lag Time (Sec) 27.59 28.40 2.85 % CDR at 12 hr 96.87 95.44 1.49

CP2 Lag Time (Sec) 28.65 29.55 3.15 % CDR at 12 hr 98.40 97.48 0.93 Observed values were found to be closer to predicted values obtained from the check point batch. It was observed that there

was no significant difference between observed and predicted values.

Table 9: Stability study of optimized formulation (S3)

Parameters* Initially After 3 months % CDR at 12th hr 98.69 97.94

Drug content 99.32±1.12 98.55±0.74

Fig 10: Stability Studies of Formulation S3

4. Conclusion The floating tablets of Cinnarizine were formulated by direct compression using various Polyox WSR 303 and sodium bicarbonate as an effervescent agent. The formulations were evaluated for various parameters like Hardness, Friability, Weight variation, Floating lag time, Floating time, swelling index etc. From the results obtained, it was concluded that the optimized formulation containing Polyox WSR 303 and sodium bicarbonate shows better swelling properties with desired drug release properties and floating behaviour. Hence Polyox WSR 303 is a potential polymer candidate for formulation of sustained release floating effervescent tablets.

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