Formulation and In Vitro Characterisation of Capecitabine Gastro Retentive Floating Tablets

 

Dasari Nirmala*, Lakshmi Durga, M. Sudhakar

Department of Pharmaceutics, Malla Reddy College of Pharmacy, Maisammaguda, Dhulapally, Secunderabad -500100 Telangana State India

*Corresponding Author E-mail: dasarinirmala1980@gmail.com

 

ABSTRACT:

In the present study was carried out with an objective of preparation and in vitro characterization of Capecitabine gastro retentive floating tablets by using various natural polymers (xantan gum, karaya gum and guar gum) the floating tablets were based on effervescent approach using sodium bicarbonate a gas generating agent. Tablets were prepared by direct compression method. Gas generating agent sodium bicarbonate concentration was optimized. Then the formulation was developed by using different concentrations of polymers Xanthan gum, guar gum and Karaya Gum as polymeric substances. The formulation blend was subjected to various preformualation studies, flow properties and all the formulations were found to be good indicating that the powder blend has good flow properties. The results of in vitro release studies showed that the drug release profile should be sustained as increasing the concentration of polymers. The formulations prepared with Karaya Gum as polymer was retarded the drug release more than12 hours. The formulations prepared with guar gum were also retarded the drug release up to 12 hours. The formulations prepared with xanthan gum showed very less retardation capacity hence they were not considered. Among all the formulations F6 formulation was optimized formulation 96.32% of drug release up to 12 hours. The optimized formulation dissolution data was subjected to release kinetics, from the release kinetics data it was evident that the formulation followed zero order mechanism of drug release. The present study shows that polymers like xanthan gum, guar gum and karaya gum with sodium bicarbonate as a gas generating agent can be used to develop sustained release floating tablets of capecitabine.

 

KEYWORDS: Capecitabine, Xanthan gum, guar gum and Karaya Gum, Floating Tablets.

 

 


INTRODUCTION:

Oral rout of administration is the most convenient and widely used method of drug administration, and the development of stomach specific oral controlled-release drug delivery systems is a challenging job due to the variation of pH in different segments of the gastrointestinal tract, the fluctuation in gastric emptying time and the difficulty of localizing an oral delivery system in a selected region of the gastrointestinal tract.

 

Rapid gastrointestinal transit can prevent the absorption of complete drug in the absorption zone and reduce the efficacy of the administered dose since the majority of drugs are absorbed in stomach or the upper part of small intestine. To overcome the above discussed issues, many types of oral controlled drug delivery systems having prolonged gastric residence times have been reported such as: floating drug dosage systems (FDDS), swelling or expanding system, mucoadhesive systems, modified-shape systems, high-density systems and other delayed gastric emptying devices.

 

FDDS have lower density than gastric fluids and thus remain buoyant in the stomach fluid without affecting the gastric emptying for a prolonged period of time. While the system is floating in the gastric fluid, the drug is released slowly from the system at a desired rate. Materials used for FDDS include carbon dioxide gas-forming agents (carbonate or bicarbonate compounds), highly swellable hydrocolloids and light mineral oils. Multiple unit systems and floating systems prepared by solvent evaporation methods have also been developed. Capecitabine, 5′-deoxy-5-fluoro-N-((pentyloxy) carbonyl)-cytidine, is a fluoropyrimidine carbamate which has an antineoplastic activity. This chemical is a prodrug of 5′-deoxy-5-fluorouridine (5′-DFUR), which is enzymatically converted in vivo to 5-fluorouracil (5-FU). Important problems of Capecitabine as to the current clinical treatment are a short half-life and its rapid metabolism in the liver. Therefore, the administration of high doses of Capecitabine leads to some undesirable side effects1. All these problems can be resolved using sustained release. Based on previous research, since the advantages of these systems are to achieve the therapeutic concentration, the desired drug release rate prolonged drug release and reduction of the repeating dosage. Many of these problems can be resolved if sustained release is done. Sustained release (SR) tablets of anticancer drugs could not only provide an optimum plasma concentration with less frequent administration but also help decrease the side effects of conventional dosage forms, such as GIT problems. This could increase the safe administration and improve patient compliance2.

 

MATERIALS AND METHODS:

Capecitabine gift sample from Mylan pharmaceutical, Hyderabad (Telangana, India) Xanthan Gum, Guar Gum, Karaya Gum PVP K30, NaHCO3 Citric Acid, Mg. Stearate, Talc and MCC PH 102 were obtained from S.D fine chemicals Mumbai.

 

Drug–Excipient compatibility studies:

Fourier Transform Infrared (FTIR) spectroscopy:

To find the physical and chemical interactions or compatability between drug and excipients. Fourier transform spectra of physical mixture drug and excipients were recorded using FT IR instrument .3

 

Preparation of Capecitabine floating tablets:

Floating tablets were formulated with different types and ratios of polymers using the direct compression method, and then tablets were compressed directly by rotary tablet press4. Capecitabine was mixed with different polymers (Xanthan Gum, Guar Gum, and Karaya Gum) as a control releasing agent. NaHCO3 Citric Acid to extend floating time. PVP K30 acts as binding agent. All other ingredients were individually passed through sieve no ¹ 60.All the ingredients were mixed thoroughly by triturating up to 15 min.The powder mixture was lubricated with talc and magnesium stearate. Then compressed using 7 mm punch. In this study, 9 formulations were designed with 150mg of Capecitabine, and the different ratios of polymers are as shown in Table 1


Table 1: Formulation composition for Capecitabine Floating tablets

Formulation Code

F1

F2

F3

F4

F5

F6

F7

F8

F9

Capecitabine

150

150

150

150

150

150

150

150

150

Xanthan Gum

37.5

75

150

-

-

-

-

-

-

Guar Gum

-

-

-

37.5

75

150

-

-

-

Karaya Gum

-

-

-

-

-

-

37.5

75

150

PVP K30

7.5

7.5

7.5

7.5

7.5

7.5

7.5

7.5

7.5

NaHCO3

15

15

15

15

15

15

15

15

15

Citric Acid

7.5

7.5

7.5

7.5

7.5

7.5

7.5

7.5

7.5

Mg. Stearate

3

3

3

3

3

3

3

3

3

Talc

3

3

3

3

3

3

3

3

3

MCC PH 102

Q.S

Q.S

Q.S

Q.S

Q.S

Q.S

Q.S

Q.S

Q.S

Total weight (mg)

300

300

300

300

300

300

300

300

300

 


Evaluation of capecitabine gastrorentive floating tablets:

The designed compression tablets were studied for their physicochemical properties like weight variation, hardness, thickness, friability and drug content.

 

Weight variation test5:

To study the weight variation, twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight. The mean and deviation were determined. The percent deviation was calculated using the following form.

% Deviation = (Individual weight–Average weight / Average weight) × 100

 

Hardness:

For each formulation, the hardness of three tablets was determined using Monsanto hardness tester and the average is calculated6.

 

Thickness:

Thickness and diameter of tablets were measured using a calibrated dial caliper. Three tablets of each formulation were picked randomly and dimensions determined. It is expressed in mm and standard deviation was also calculated.

Friability:

It is measured of mechanical strength of tablets. Roche friabilator was used to determine the friability by following procedure. Pre weighed 10 tablets were placed in the friabilator. The tablets were rotated at 25 rpm for 4 minutes (100 rotations). At the end of test, the tablets were re- weighed, and loss in the weight of tablet is the measure of friability and is expressed in percentage as

 

% Friability = [(W1-W2) / W1] × 100

 

Where,

W1 = Initial weight of tablets

W2 = Weight of the tablets after testing

 

Determination of drug content:

To evaluate the drug content through a uniformity test, 10 tablets of each formulation were crushed and suspended in 0.N HCL to remove the Capecitabine from the tablets. After 24 hours, media were filtrated and measured by a UV spectrophotometer (Shimadzu 1601) at 214nm

 

In vitro Buoyancy studies:

The in vitro buoyancy was determined by floating lag time, and total floating time. The tablets were placed in a 100ml beaker containing 0.1N HCL. The time required for the tablet to rise to the surface and float was determined as floating lag time (FLT) and duration of time the tablet constantly floats on the dissolution medium was noted as Total Floating Time respectively (TFT).

 

In vitro drug release studies:

A dissolution test was performed for 12 hours using the Lab India (UV-3000) dissolution apparatus Each vessel contained 900 mL of 0.1 N HCL; the paddle apparatus with 50 rpm speed was also used, while the temperature was kept stable at 37°C. Every two hours till 24 hours, 5 mL of media was withdrawn and measured by UV spectrophotometer at 214 nm (Shimadzu 1601). Furthermore, 10 mL of 0.1 N HCL was replaced to keep the volume stable 7

 

Application of Release Rate Kinetics to Dissolution Data8:

Various models were tested for explaining the kinetics of drug release. To analyze the mechanism of the drug release rate kinetics of the dosage form, the obtained data were fitted into zero-order, first order, Higuchi, and Korsmeyer-Peppas release model.

 

Zero order release rate kinetics:

To study the zero–order release kinetics the release rate data are fitted to the following equation.

 

F = Ko t

 

Where, ‘F’ is the drug release at time‘t’, and ‘Ko’ is the zero order release rate constant. The plot of % drug release versus time is linear.

 

First order release rate kinetics:

The release rate data are fitted to the following equation

Log (100-F) = kt

 

A plot of log cumulative percent of drug remaining to be released vs. time is plotted then it gives first order release.

 

Higuchi release model:

To study the Higuchi release kinetics, the release rate data were fitted to the following equation.

 

F = k t1/2

 

Where, ‘k’ is the Higuchi constant.

In higuchi model, a plot of % drug release versus square root of time is linear.

 

Korsmeyer and Peppas release model:

The mechanism of drug release was evaluated by plotting the log percentage of drug released versus log time according to Korsmeyer- Peppas equation. The exponent ‘n’ indicates the mechanism of drug release calculated through the slope of the straight Line.

 

Mt/ M = K tn

 

Where, Mt/ M is fraction of drug released at time ‘t’, k represents a constant, and ‘n’ is the diffusional exponent, which characterizes the type of release mechanism during the dissolution process. For non-Fickian release, the value of n falls between 0.5 and 1.0; while in case of Fickian diffusion, n = 0.5; for zero-order release (case I I transport), n=1; and for supercase II transport, n > 1. In this model, a plot of log (Mt/ M) versus log (time) is linear.

 

RESULTS AND DISCUSSIONS:

Drug–Excipient compatability studies of capecitabine floating tablets:

Fourier Transform-Infrared Spectroscopy:

 

Figure No 1: FTIR Spectrum of pure drug (capecitabine)

 

Fig No 2: FTIR Spectrum of optimised formulation

 

FT-IR Spectrum of pure drug (Capecitabine) and mixture are presented in the fig no 1, and 2 respectively. Pure drug has shown sharp characteristic band at 1398, 78 and 634 cm-1 due to carbonyl group, C-H bending and C-C bending respectively. It was observed that there was no change in these main bands due to the presence of excipients. FT-IR studies revealed that there is no physical and chemical interaction between drug and excipients.

 

 

 


Table No 2: Post compression Parameters of capecitabine Floating tablets

Formulation codes

Average Weight (mg)

Hardness (kg/cm2)

Friability (%loss)

Thickness (mm)

Drug content (%)

Floating lag time

(min)

Total Floating Time(Hrs)

F1

300.4

5.1

0.61

3.3

98.42

5.5

4

F2

301.2

5.2

0.58

3.2

99.65

4.2

6

F3

299.3

5.5

0.45

3.4

99.12

5.0

12

F4

299.8

5.1

0.61

3.3

98.42

5.1

6

F5

298.6

5.3

0.59

3.5

99.65

4.0

8

F6

300.4

5.5

0.65

3.4

99.12

3.2

12

F7

301.6

5.3

0.62

3.6

98.16

4.5

5

F8

298.2

5.2

0.59

3.4

98.11

3.6

12

F9

297.5

5.4

0.60

3.3

98.25

4.7

12

 


Hardness for all the formulations were in range of 5.1 to 5.4 kg/cm2, it indicated that all the formulations possess sufficient mechanical strength. Weight variation was found to be within IP limits. Friability values were found to be less than 1% indicated that within the IP limits. Floating lag time was found to be 3.2 to 5.5 minutes. Total floating time was found to be minimum 4 hours maximum 12 hours. Thickness of all the formulations were found to be 3.3 to 3.6mm. drug content of the all the formulations were found to be 98.11% to 99.65%.

 

In Vitro Drug Release Studies:

 

Fig No 3: Dissolution profile of Capecitabine Floating tablets containing Xantham Gum

 

Fig 4: Dissolution profile of Capecitabine Floating tablets containing Guar Gum

 

Fig No 5: Dissolution data of Capecitabine Floating tablets containing Karaya Gum

From the dissolution studies it was evident that the formulations prepared with Karaya Gum as polymer were retarded the drug release more than 12 hours. Whereas the formulations prepared with higher concentration of guar gum retarded the drug release up to 12 hours in the concentration 150 mg. In lower concentrations the polymer was unable to retard the drug release.

 

The formulations prepared with xantham gum showed very less retardation capacity hence they were not considered. Hence from the above dissolution data it was concluded that F6 formulation was considered as optimized formulation because good drug release (96.32%) in 12 hours.

 

Release rate kinetics was applied to optimised formulation (F6) has followed Zero order kinetics.

 

Conclusion: Gastro retentive floating tablets of capecitabine were prepared by direct compression method using various various polymers like Xantham gum, guar gum and Karaya Gum. All the parameters were satisfactory. Hence present study concludes that gastro retentive floating system may be a suitable method for Capecitabine administration.

 


 

Application of Release Rate Kinetics for optimised formulation:

Table no 3: Application kinetics for optimised formulation

Cumula-tive (%) release q

Time (t)

 root

(t)

Log (%) release

Log (t)

Log (%)

remain

 release rate (cumulative % release / t)

1/cum% release

Peppas log q/100

% drug remaining

Q01/3

Qt1/3

Q01/3-qt1/3

0

0

0

 

 

2.000

 

 

 

100

4.642

4.642

0.000

10.49

0.5

0.707

1.021

-0.301

1.952

20.980

0.0953

-0.979

89.51

4.642

4.473

0.168

17.63

1

1.000

1.246

0.000

1.916

17.630

0.0567

-0.754

82.37

4.642

4.351

0.291

26.55

2

1.414

1.424

0.301

1.866

13.275

0.0377

-0.576

73.45

4.642

4.188

0.454

32.84

3

1.732

1.516

0.477

1.827

10.947

0.0305

-0.484

67.16

4.642

4.065

0.577

39.39

4

2.000

1.595

0.602

1.783

9.848

0.0254

-0.405

60.61

4.642

3.928

0.713

44.71

5

2.236

1.650

0.699

1.743

8.942

0.0224

-0.350

55.29

4.642

3.810

0.832

53.05

6

2.449

1.725

0.778

1.672

8.842

0.0189

-0.275

46.95

4.642

3.608

1.034

60.87

7

2.646

1.784

0.845

1.593

8.696

0.0164

-0.216

39.13

4.642

3.395

1.247

67.02

8

2.828

1.826

0.903

1.518

8.378

0.0149

-0.174

32.98

4.642

3.207

1.435

74.15

9

3.000

1.870

0.954

1.412

8.239

0.0135

-0.130

25.85

4.642

2.957

1.685

79.24

10

3.162

1.899

1.000

1.317

7.924

0.0126

-0.101

20.76

4.642

2.748

1.893

87.54

11

3.317

1.942

1.041

1.096

7.958

0.0114

-0.058

12.46

4.642

2.318

2.323

96.32

12

3.464

1.984

1.000

0.566

8.027

0.0104

-0.016

3.68

4.642

1.544

3.098

 


CONCLUSION:

From the above results and discussion, it can be concluded that the floating tablets of capecitabine using natural polymers stable and best formulation is F6 formulation is considered as optimized formulation because good drug release (96.32%) in 12 hours. Hence preparation of floating tablets of Capecitabine with natural polymers is successful.

 

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Received on 25.06.2019            Accepted on 21.07.2019           

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2019; 9(3):154-158.

DOI: 10.5958/2231-5713.2019.00026.6