Formulation and Evaluation of Floating tablet of Metronidazole for eradication of Helicobacter pylori

 

Sandhya Chandrakar, Kushagra Nagori, Mukesh Sharma, Sujata Gupta, Harsha Solanki, Kalyani Dewangan, Garima Sharma, Vandana Devi Sahu, Manisha Majumdar, D. K. Tripathi, Amit Alexander, Ajazuddin*

Rungta College of Pharmaceutical Sciences and Research, Kurud Road Kohka, Bhilai, CG, India, 490024

*Corresponding Author E-mail: ajazuddin@rungta.ac.in

 

ABSTRACT:

Metronidazole is widely used antimicrobial drug against Gram-negative and Gram-positive anaerobic bacteria.  Floating drug delivery systems (FDDS) offer a number of applications for drugs having poor bioavailability because of narrow absorption window in the upper part of gastrointestinal tract. It was used for preparing floating dosage forms that are designed to retain in the stomach for a long time and have developed as a drug delivery system for better eradication of Helicobacter Pylori in peptic ulcer diseases. In the present study hydroxy propyl methyl cellulose (HPMC) and micro crystalline cellulose (MCC) are used in different concentrations and sodium bicarbonate was used as effervescent agent.  Five formulations (F1-F5) were prepared and evaluated for various physicochemical parameters like hardness, friability, floating ability and drug release profiles and were found to be within range. In general, these systems can float in the gastric conditions and control the drug release from the tablets. Formulation was optimized on the basis of different tablet properties and drug release pattern in invitro release profile.  In this study it was confirmed that the formulations containing polymer like HPMC K15M and MCC showed better floating properties.

 

KEYWORDS: Metronidazole, floating, polymer, HPMC, MCC.

 

 

INTRODUCTION:

Floating drug delivery systems (FDDS) offer a number of applications for drugs having poor bioavailability because of narrow absorption window in the upper part of gastrointestinal tract (1,2).  The gastric retention of the dosage form in the stomach depends upon various factors like pH, size of the dosage form, food intake, and biological factors which include age, body mass index, gender, posture, and diseased states. Out of all available gastro retentive systems floating tablets, floating beads, floating granules and floating microspheres have gained major importance in the formulation development more recently (3,4).

 

Floating delivery systems seem to offer a greater safety for clinical uses than other approaches. Various dosage forms like tablets, capsules, beads, microparticles, pellets, granules have been evaluated for floating systems (5,6). Over the past decade the use of biodegradable polymers for development of sustained drug delivery systems has increased dramatically. Synthetic polymers offer greater advantages than natural ones, wherein they can be tailored to develop a wide range of properties. However, there is a trend to restrict the use of synthetic polymers in pharmaceutical formulations since processing techniques of these polymers are based on organic solvents (7,8). Various approaches ranging from coated tablets and gels to biodegradable microparticles and osmotic system have been used to sustain the drug release from dosage forms(9,10). Metronidazole, chemically 2-(2-methyl-5-nitro-1Himidazol-1-yl) ethanol, is a nitroimidazole antibiotic medication used particularly for anaerobic bacteria and protozoa. Metronidazole is an antibiotic, amebicide, and antiprotozoal. It is the drug of choice for first episodes of mild-to-moderate Clostridium difficile infection. Metronidazole is indicated for the treatment of Helicobacter pylori eradication therapy, as part of a multidrug regimen in peptic ulcer disease (11,12). In the present study, Metronidazole floating tablets were prepared to increase the gastric residence time and absorption of drug through gastric mucosa and to decrease the dose frequency. The prepared tablets were evaluated for their floating properties and in-vitro drug release.

 

MATERIAL AND METHOD:

The chemicals used in this study were pure drug Metronidazole and polymers like HPMC K15M (Jubilant life science limited), carbopol 934 (Loba chemie),  other excipients like Micro crystalline cellulose,  magnesium stearate, talc, sodium bicarbonate (Loba chemie).

 

Preparation of calibration curve of Metronidazole in 0.1 N HCl

Preparation of 0.1N HCl solution

To produce 0.1N HCl  take 9.8 ml of concentrated HCl and diluted with distilled water and make up the volume up to 1000 ml.

 

Preparation of standard stock solution

The stock solution (100µg/ml) of metronidazole was prepared by dissolving accurately about 10mg of drug in small amount of methanol and the volume was making up to 100ml with 0.1N HCl to prepare standard stock solution.

 

Determination of λmax

Calibration curve of metronidazole was prepared with 0.1N HCl and the  λmax was found to be 274.6 nm.

 

Preparation of calibration curve

From the stock solution of metronidazole, a series of dilutions ranging from 2-10 µg/ml were prepared. Absorbance of these solutions was measured at 274.6 nm wavelength and calibration curve was plotted between concentration and absorbance UV-Visible (Spectrophotometer- Shimadzu UV-1800). The maximum absorbance of metronidazole was observed at 274-277nm respectively.

 

Preparation of Floating matrix tablets by direct compression method

Accurately weighed quantities of polymer like HPMC and MCC were taken in a mortar and mixed thoroughly, to this mixture required quantity of metronidazole was added and mixed slightly with pestle, after that  accurately weighed quantity of sodium bicarbonate was taken separately in a mortar and powdered with pestle.  The powder is passed through sieve #40 and mixed with the drug blend which is also passed through sieve #40.  The whole mixture was collected in a plastic bag and mixed for 3 minutes. To this mixture magnesium stearate was added and mixed for 5 minutes, later Talc was added and mixed for 2 minutes. The mixture was compressed into tablets (Tablet Compression machine Shakti).

 

Characterization of tablets for physicochemical parameters

The prepared Metronidazole floating tablets were evaluated for their physicochemical parameters like hardness, friability and drug content.

 

Tablet weight variation

Every individual tablet in a batch should be in uniform weight and weight variation within permissible limits. Twenty tablets were randomly selected and accurately weighted using an electronic balance. The results are expressed as mean values of 20 determinations.

 

Hardness

The hardness of tablets is defined as “the force required in breaking a tablet” and it is determined using Monsanto hardness testing apparatus.

The tablet is placed vertically in the tester and the force required to break the tablet is measured.

 

Friability

The friability of tablets was measured in a Roche friabilator. 20 tablets of known weight (Wo) were taken in a drum for a fixed time (100 revolutions) and weight (W) again. Percentage friability was calculated from the loss in weight as given in equation below. The weight loss should not be more than 1% w/w.15

 

% friability = (Wo-W)/Wo X 100

 

 

Table 1: Formulation table

Ingredients

Quantity in mg (F1)

Quantity in mg (F2)

Quantity in mg (F3)

Quantity in mg (F4)

Quantity in mg (F5)

Metronidazole

10

10

10

10

10

HPMC K15 M

10

15

--

--

--

MCC

33.77

28.29

33.77

37.7

28.29

NaHCO3

5.4

5.4

5.4

5.4

5.4

Mg stearate

0.3

0.3

0.3

0.3

0.3

Talc

0.6

0.5

0.6

0.5

0.5

Carbopol 934

--

--

10

6

15

Total wt.

60

60

60

60

60

In vitro floating lag time13

The in vitro buoyancy was determined by floating lag time. The tablets were placed in a 100 ml beaker containing 0.1N HCl. The media was kept in stagnant condition and the temperature was maintained at 370C. The time required for the tablet to rise to the surface and float was determined as floating lag time.

 

In vitro floating duration time

The floating capacity of the tablets was determined using USP Dissolution apparatus II containing 900ml of simulated gastric fluid. The time interval between introduction of the tablet in to the dissolution medium and its buoyancy to the dissolution medium was taken as buoyancy lag time and for which time the tablet constantly floats on the surface of the medium was observed visually and taken as floating duration.

 

In vitro drug release14

The release of Metronidazole from floating tablets was determined by using Dissolution apparatus (ELECTROLAB TDT- 08L. The dissolution test was performed using 900 ml 0.1N HCl solution at 37 ± 0.5oC temperature and at 50 rpm. At specified time intervals, samples of 1 ml were withdrawn from the dissolution medium and that amount was replaced with fresh medium to maintain the volume constant. The samples were filtered and diluted to a suitable concentration with 0.1 N HCl.  The absorbance of the diluted samples was measured at 274nm for Metronidazole by using UV Visible spectrophotometer. The percentage drug release was calculated using an equation obtained from standard curve.

 

Characterization of drug in Floating tablets:

FTIR studies were conducted for characterization of drug in tablets of selected optimized formulation. The floating tablets were compressed and powdered. The pelletized powder along with KBr was used for FTIR studies. The IR spectra were recorded using Fourier Transform Infrared spectrophotometer. The IR spectra of pure Metronidazole and pelletized powder of tablets were taken, interpreted and compared with each other.

 

RESULTS AND DISCUSSION:

 

Figure 1: Standard calibration curve of metronidazole in 0.1 N HCl

 

Calibration curve of Metronidazole was prepared in 0.1N HCl. The slope of the graph was found to be 0.042 and intercept with -0.004 with regression coefficient   R2 = 0.999.

 

FTIR spectrum of Metronidazole

The FTIR spectroscopy was performed for identification of pure drug and drug excipient compatibility study. The spectra obtained in figure no. 2 from the FTIR spectrophotometer in the range of 4000-500 cm-1 is of pure drug and that in figure no. 3 is drug with excipients which showed similar/almost similar peaks as that of pure drug i.e. for C-H, C=C, C=N stretching. This indicates no modification and interaction between drug and excipients.

 

 

Figure 2: FTIR spectra of metronidazole, mtronidazole +excipients and excipients

 

Table 4:  Evaluation of different formulations of extended release Metronidazole tablet:

Formulation

Hardness (kg/cm3 )

Friability (%)

Drug content (%)

F1

5

0.197

92

F2

5

0.265

90

F3

5.8

0.294

85

F4

6

0.186

82

F5

5.8

0.301

87

Table 5: Comparative in-vitro dissolution study of different formulations of Metronidazole floating tablet:

Time in hrs.

(F1)

(F2)

(F3)

(F4)

F(5)

0

0

0

0

0

0

0.16

40.21

21.06

9.57

5.74

6.57

0.33

40.41

28.72

15.31

11.48

14.31

0.5

47.87

36.38

17.23

15.31

16.23

0.66

51.7

42.12

21.06

22.97

20.06

0.83

59.36

47.87

30.63

28.72

32.63

1

67.06

51.7

32.55

34.46

33.55

1.16

70.85

61.27

37.43

40.46

35.43

1.33

74.6

67.02

40.45

49.43

41.45

1.5

80.42

70.85

46.86

55.53

44.86

2

84.25

78.5

52.65

59.77

54.65

2.5

88.05

82.34

65.48

63.35

66.48

3

93.82

86.17

76.59

67.13

74.59

3.5

97.65

93.82

84.25

72.65

82.25

4

97.66

97.65

86.55

78.43

83.55

4.5

--

--

86.76

78.45

81.76

 

 

 

Figure 3: Comparative in-vitro dissolution study of different test formulations of Metronidazole floating  tablets .

 

 

Table 6: Floating lag time and floating duration

Formulation

Floating lag time (sec)

Floating duration time

F1

12 sec.

7hrs

F2

8 sec.

7hrs

F3

60 sec

15min

F4

300 sec

5min

F5

--

0min.

 

RESULT AND DISCUSSION:

Floating tablets of metronidazole were developed to increase the gastric residence time of the drug, so that they can be retained in stomach for longer time and help in controlled release of drug and absorption of drug through gastric mucosa and to decrease the dose frequency. The punched tablets of different formulation were also subjected to several evaluation parameters like tablet hardness, friability, dissolution study, etc. which is shown in table no. 4. The hardness of tablets ranged between 4-7 which indicated good mechanical strength and ability to withstand physical pressure and stress. The friability was between 0.186 to 0.301 which is within limits and shows good resistance of tablets to mechanical stress. The percent drug content of tablets was within permissible limits i.e. 82% to 92%.  The prepared floating tablets were also evaluated  for their floating properties and in-vitro drug release. The drug release profile of all the formulation was given in table 5 and figure 3. Based on the results from in-vitro floating studies the formulations F1 and F2 containing polymer like HPMC K15M and MCC was selected as best formulation with optimum floating properties.

 

ACKNOWLEDGMENT:

The authors want to acknowledge the management and library of Rungta College of Pharmaceutical Sciences and Research, Kohka-Kurud road Bhilai, for providing necessary infrastructure and literature for the compilation of the work.

 

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Received on 04.05.2016          Modified on 03.06.2016

Accepted on 18.06.2016        © RJPT All right reserved

Research J. Pharm. and Tech. 2016; 9(7):870-874.

DOI: 10.5958/0974-360X.2016.00165.7