Formulation and Evaluation of Oro Dispersible Tablets of Atenolol by Sublimation Method

 

Nirmala Rangu1*,  B. Chaitanya Kumari2, Ganesh Akula3, A Jaswanth4

1Department of Pharmaceutics, Surabhi Dayakar Rao College of Pharmacy, Rimmanaguda (V), Gajwel (M), Siddipet (D), Telangana – 502312 (India)

2Department of Pharmaceutics, Talla Padmavathi College of Pharmacy, karreeemabad Bodrai (V), Warangal (D), Telangana – 506012 (India)

3Department of Pharmaceutical Chemistry, Surabhi Dayakar Rao College of Pharmacy, Rimmanaguda (V), Gajwel (M), siddipet (D), Telangana – 502312 (India)

4Department of Pharmacology, Surabhi Dayakar Rao College of Pharmacy, Rimmanaguda (V), Gajwel (M), Siddipet (D), Telangana – 502312 (India)

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

 

ABSTRACT:

The present study aims to formulate and evaluate oro dispersible tablets of Atenolol, a drug that is used for the treatment of chest pain (angina) was prepared by using sublimation method and also optimize the best formulation. The study involved different excipients which were tested for their compatibility with Atenolol by the FT-IR studies. Based on the results of FT-IR studies, majority of the excipients were found to be compatible with Atenolol which were used for the preparation of Atenolol oral disintegrating tablets. Oral disintegrating tablets of Atenolol were prepared by direct compression method by the addition of subliming agents. Twelve batches (H1-H12) of oral disintegrating tablets of Atenolol were prepared by using Subliming agents like Ammonium Carbonate, Camphor, Thymol and Menthol in variable concentrations along with other excipients for the development of optimized formulation. All the formulations were subjected to evaluation studies of weight variation, hardness, friability, drug content, Wetting time, in-vitro disintegration, in vitro-dissolution studies and are found to be within the limits.

 

KEY WORDS: Oro dispersible tablet (ODT), Atenolol, Direct compression, Sublimation Method, Anti angina activity.

 

 


INTRODUCTION:

Most of the oral pharmaceutical dosage forms like conventional tablets and capsules are formulated to be swallowed or chewed. As a result children, bedridden patients and elderly patients have difficulty in swallowing these dosage forms. To overcome this drawback novel drug delivery systems like orally disintegrating tablets have been developed which disintegrate/dissolve/ disperse in saliva within few seconds without water. United States of America Food and Drug Administration (USFDA) define ODT as “A solid dosage form containing medicinal substances or active ingredient which disintegrates rapidly usually within a matter of seconds when placed upon a      tongue” [1].

 

The principal benefits of ODT include meliorated patient compliance, improved bioavailability, rapid onset of action, pain avoidance, consumption without water, pregastric absorption, versatility, and economical [2-4]. Pre gastric absorption is the major capital advantage of the ODTs, which avoids hepatic first-pass metabolism of the drugs.[5]

 

Atenolol is a β1-blocker used to treat chest pain (angina) and high blood pressure. It is also used after an acute heart attack to improve survival. High blood pressure reduction helps prevent strokes, heart attacks and kidney problems. This drug works by blocking the action of certain natural chemicals in your body such as epinephrine on the heart and blood vessels. This result in a lowering of the heart rate, blood pressure, and strain on the heart. This medication may also be used for irregular heartbeats, heart failure, migraine headache prevention, tremors.

 

The main objective of the study was undertaken for formulation and evaluation of oral dispersible tablets of atenolol by direct compression technique. In the present work, an attempt was made to formulate atenolol or dispersible tablet using sublimation method. The fundamental principle used in the development of the fast dissolving tablet is to maximize its pore structure.

 

MATERIALS AND METHODS:

The active pharmaceutical ingredient—Atenolol was procured from Litaka Pharmaceuticals, Pune. The other excipients such as Ammonium bicarbonate, Camphor, Menthol, Thymol, Micro crystalline cellulose, and Talc were procured from SD Fine Chemicals, Mumbai. Aspartame and Sodium Stearyl Fumarate were purchased from DMV, Fonterra excipients, India. Directly compressible Mannitol was purchased from Roquette Chemicals, France.

 

Standard calibration curve for Atenolol in pH 1.2 buffer:

100 mg of atenolol was dissolved in small amount of pH 1.2 buffer and the volume was made up to 100 ml using the same, which is called as stock-I solution. 1 ml of the above solution is diluted to 100 ml in another volumetric flask, which is called as Stock-II solution. From this stock-II solution serial dilutions were made to obtain solutions of the drug in the concentration ranging from 2, 4, 6, 8, 10, 12, 14, 16, 18 and 20 µg/ml. The absorbance of the solutions was measured at 224.2 nm using Elico Double beam UV-visible spectrophotometer. A graph of concentration vs. absorbance was plotted.

 

Drug-excipient interaction studies:

Fourier Transform Infrared (FTIR) Spectroscopy studies were used for the evaluation of physicochemical compatibility and interactions, which helps in the prediction of interaction of the drug with polymers. Positive interactions sometimes have a beneficial effect as far as desired release parameters are concerned. Therefore, in the present studies Atenolol with the given polymers were analyzed for compatibility studies. The spectra were shown in figure 2 - 6.

 

Pre-compression studies [6]

All the physical parameters namely, angle of repose, bulk density, compressibility index and Hausner’s ratio were performed and the results were shown in table 2.

 

1. Angle of Repose:

It is the maximum angle possible between the surface of a pile of powder and the horizontal plane. Angle of Repose was determined by the funnel method. Accurately weighed powder blend was taken in the funnel. Height of the funnel was adjusted in such a way the tip of the funnel just touched the apex of the powder blend. Powder blend was allowed to flow through the funnel freely on to the surface. Diameter of the powder cone was measured and angle of repose was calculated using the given formula.

 

                     h

θ= tan -1 (--------)

                     r

 

2. Bulk density:

It is the ratio of total mass of powder to the bulk volume of powder. Required quantity of powder blend was transferred in 100 ml graduated cylinder and the bulk density was calculated by using the formula given below.

                       Weight of Powder

Bulk Density = ---------------------

                              Bulk Volume

 

3. Tapped density:

It is the ratio of total mass of powder to the tapped volume of powder. Required quantity of powder blend was transferred in 100 ml graduated cylinder which was operated for fixed number of taps until the powder bed volume has reached a minimum Tapped density using the was calculated by formula given below.

                           Weight of Powder

Tapped Density = ---------------------

                          Tapped Volume

 

4. Compressibility Index:

It is a simple test to evaluate bulk and tapped density of a powder .The formula for Carr’s index is as below:

 

                             Tapped Density - Bulk Density

Tapped Density = -----------------------------------  X 100

                               Tapped Density 

 

5. Hausner’s Ratio:

Hausner’s Ratio is a number that is correlated to the flow ability of a powder.

 

 

 

                              Tapped Density

Housner's Ratio = -------------------------

                               Bulk  Density 

 

Formulation of Orodispersible Tablets of Atenolol:

Specified quantity of atenolol and other excipient according to formulae given in the table 1 were weighed and passed through 60 # screen prior to mixing.  All the materials were transferred to mortar and triturated till it was mixed uniformly. The resulting powder mixture was compressed into tablets using single punch tablet machine. The tablets were dried at 60şC in oven till constant weight was obtained.[7]


 

Table –1: Different Formulations of Atenolol using addition of subliming agent

Sr. No.

Name of the chemical used

Quantity used in mg

H1

H2

H3

H4

H5

H6

H7

H8

H9

H10

H11

H12

1

Atenolol

25

25

25

25

25

25

25

25

25

25

25

25

2

Ammonium Bicarbonate

7.5

15

22.5

---

---

---

---

---

---

---

---

---

3

Camphor

---

---

---

7.5

15

22.5

---

---

---

---

---

---

4

Menthol

---

---

---

---

---

---

7.5

15

22.5

---

---

---

5

Thymol

---

---

---

---

---

---

---

---

---

7.5

15

22.5

7

Avicel pH 102

30

30

30

30

30

30

30

30

30

30

30

30

8

Aspartame

6

6

6

6

6

6

6

6

6

6

6

6

9

Sodium stearyl fumarate

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

10

Talc

3

3

3

3

3

3

3

3

3

3

3

3

11

Mannitol Directly compressible

77

69.5

62

77

69.5

62

77

69.5

62

77

69.5

62

 


Post Compression Studies [8,9]

1. Weight Variation:

20 tablets were selected and weighed collectively and individually. From the collective weight, average weight was calculated. Each tablet weight was then compared with average weight to assure whether it was within permissible limits or not. Not more than two of the individual weights deviated from the average weight by more than 7.5% for 150 mg tablets and none by more than double that percentage.

 

2. Hardness test:

Hardness of the tablet was determined by using the Monsanto hardness tester-Mumbai. The lower plunger was placed in contact with the tablet and a zero reading was taken. The plunger was then forced against a spring by turning a threaded bolt until the tablet fractured. As the spring was compressed a pointer rides along a gauge in the barrel to indicate the force.

 

3. Friability test:

This test is performed to evaluate the ability of tablets to withstand abrasion in packing, handling and transporting. Initial weight of 20 tablets is taken and these are placed in the Roche friabilator, rotating at 100rpm for 4min. The tablets are then taken out, de dusted and was weighed. The difference in the weight is noted and expressed as percentage.

 

4. Wetting Time:

Circular tissue papers were placed in a Petri dish containing water. The prepared tablet was then carefully placed. The time required for water to reach the upper surface of the tablets and to get completely wet was noted as the wetting time. Wetting time was recorded using a stopwatch.

 

5. Content Uniformity:

At random 20 tablets were weighed and powdered. The powder equivalent to 25 mg was weighed accurately and dissolved in 100ml of 0.1 N HCl. The solution was shaken thoroughly. The un dissolved matter was removed by filtration through Whatmann No.41 filter paper.  Then dilute the solution to obtain 10µg solution. The absorbance of the diluted solutions was measured at 224.2 nm by spectrophotometric method. The concentration of the drug was computed from the standard curve of the atenolol in 0.1 N HCl.

 

6. In- Vitro Disintegration Time:

In- vitro disintegration time was measured by dropping a tablet in a beaker containing phosphate buffer PH 1.2. Tablets from each formulation were randomly selected and in vitro dispersion time was performed. All these studies were performed and the results were shown in table 3.

7. In-vitro drug release studies:

In-vitro drug release studies were carried out by using Electrolab TDT-08L USP-type II dissolution apparatus 900 ml of Phosphate buffer (pH 1.2) was placed in the dissolution flask maintained at a temperature of 37±0.50C.One tablet was placed in the flask of the dissolution apparatus and was operated to run up to 60mins at 50 rpm. At definite time intervals, 5 ml of dissolution medium was withdrawn, filtered and again replaced with 5 ml of fresh medium. Suitable dilutions were done with dissolution medium and were analyzed spectrophotometrically at λmax is 224.2 nm using a UV-spectrophotometer. The in-vitro drug release of ODT tablets of Atenolol were shown in table 4 and graphically in fig 7-10. The comparative profile of best formulation (H6) with marketed tablet was shown in fig 11.

 

RESULTS AND DISCUSSIONS:

FT-IR Studies:

To study the presence of interactions between the active pharmaceutical ingredient and the selected polymers, FT-IR studies were undertaken. The FT-IR spectra are shown in Figure 2 to 6.

 

 

 


 

 

Fig 1: Standard calibration curve

 

 

 

Fig 2. I.R. Specturm of atenolol (pure drug)

 

 

Fig 3. I.R. Specturm of Atenolol with Ammonium Carbonate

 

 

Fig 4. I.R. Specturm of Atenolol with Camphor

 

Fig 5. I.R. Specturm of Atenolol with Thymol

 

 

Fig 6 I.R. Specturm of Atenolol with Menthol

 

Table 2. Pre Compression parameters of Atenolol tablet formulation

Code of formu lations

Parameters

Angle of Repose (o)*

Bulk Density (g/ml)*

Tapped Density (g/ml)*

Carrs

Index. (%)*

Hausner ratio*

Total Porosity (%)*

H1

26.62 ± 0.057

0.3830 ±0.006

0.4681 ±0.020

18.12 ± 1.15

1.20 ± 0.023

18.10 ± 1.15

H2

27.71 ± 0.245

0.3830 ±0.006

0.4562 ±0.020

15.94 ± 1.28

1.18 ± 0.04

15.95 ± 1.23

H3

27.11 ± 0.193

0.4554 ±0.009

0.5478 ±0.027

14.14 ± 1.67

1.19 ± 0.026

14.30 ± 1.55

H4

29.51 ± 0.378

0.4190 ±0.016

0.5005 ±0.020

16.27 ± 1.81

1.19 ± 0.026

16.26 ± 1.81

H5

25.33 ± 0.238

0.3750±0.013

0.4446 ±0.016

15.58 ± 1.12

1.17 ± 0.030

15.88 ± 1.08

H6

26.65 ± 0.057

0.4444±0.015

0.5478 ±0.027

14.30 ± 1.55

1.19 ± 0.026

14.14 ± 1.67

H7

25.27 ± 0.041

0.4055 ±0.016

0.4933 ±0.011

16.98 ± 1.86

1.20 ± 0.045

16.98 ± 1.87

H8

29.60 ± 0.296

0.4138 ±0.014

0.4933 ±0.011

16.12 ± 1.61

1.19 ± 0.026

16.06 ± 1.56

H9

27.53 ± 0.323

0.3750±0.010

0.4443 ±0.015

15.58 ± 1.08

1.17 ± 0.03

15.62 ± 1.12

H10

25.65 ± 0.212

0.3956 ±0.011

0.4803 ±0.019

17.57 ± 1.12

1.21 ± 0.032

17.59 ± 1.10

H11

29.30±0.228

0.4554±0.009

0.5478±0.027

14.3 ± 1.55

1.19 ± 0.026

14.14 ± 1.67

H12

28.40 ± 0.049

0.4190±0.016

0.5005±0.020

16.27 ± 1.81

1.19 ± 0.026

16.26 ± 1.81

* n=3 , Mean ± SD

 

Table 3. Post Compression Parameters of ODT of Atenolol

Formulations

Parameters

Weight variation test (%)*

Friability

(%)

Hardness

(kg/cm2)*

Thickenss

(mm)*

Disintegration Time (sec)*

Wetting Time (sec)*

Drug Content

(%)*

H1

152.25±1.87

0.525

3.66±0.28

2.47±0.06

64.33±1.52

62±1.64

100.88±1.28

H2

150.85±1.66

0.395

3.50±0.50

2.28±0.01

56.66±1.52

49±0.79

99.41±0.88

H3

150.5±0.74

0.650

3.66±0.28

2.26±0.05

41.66±1.52

32±1.00

98.23±0.50

H4

152.75±0.46

0.658

3.00±0.50

2.31±0.01

49.33±1.08

36±0.58

101.17±0.77

H5

153.8±0.61

0.394

3.16±0.28

2.32±0.02

24±1.73

23.66±0.52

98.82±1.34

H6

149.4±0.43

0.524

3.16±0.28

2.44±0.01

18±1.00

19.33±0.52

99.70±1.63

H7

148.3±1.16

0.657

2.83±0.28

2.29±0.02

49.33±1.52

42.66±1.15

98.72±1.77

H8

148.75±0.42

0.661

2.66±0.28

2.37±0.03

44.33±0.51

40±0.60

99.21±0.16

H9

152.15±0.31

0.795

2.66±0.28

2.82±0.16

24.66±1.52

25±1.64

98.33±0.61

H10

149.55±1.28

0.527

2.83±0.57

2.43±0.02

65±1.64

62±1.60

101.17±0.77

H11

151.70±0.50

0.780

2.83±0.28

2.36±0.05

51±1.00

48±1.52

99.11±1.06

H12

151.2±0.96

0.652

2.66±0.28

2.44±0.05

34.33±1.21

32±1.73

98.82±1.06

* n=3 Mean ± SD

Table 4. In Vitro Drug Release data for Atenolol Formulations H1- H12 and Marketed product

Time (Min)

H1

H2

H3

H4

H5

H6

H7

H8

H9

H10

H11

H12

MARKETED

TABLET

0.5

5.13

5.68

9.11

20.21

42.91

48.55

16.23

11.18

39.23

8.54

22.08

32.85

31.92

1

20

22.07

69.43

65.5

79.36

96.95

47.22

47.22

74.75

50.75

46.22

70.04

69.98

1.5

61.03

67.26

83.23

76.55

94.84

95.57

70.24

69.43

81.85

67.24

72.62

76.59

76.45

2

92.71

93.1

93.88

88.95

93.85

94.39

75.42

76.33

88.36

74.03

80.94

80.75

80.54

2.5

93.29

94.87

92.9

94.76

93.05

93.8

81.99

83.63

96.25

78.68

86.48

87.89

87.56

3

95.24

93.88

92.31

93.79

92.26

92.82

86.17

95.07

94.28

84.3

89.84

95.63

89.83

3.5

93.1

93.29

91.12

93.02

91.07

92.03

94.92

94.08

93.88

90.31

94.39

94.64

91.64

4

92.51

92.11

90.33

92.63

90.28

90.07

90.15

92.9

93.1

93.79

93.4

93.65

90.65

4.5

91.35

90.93

89.54

91.86

89.48

89.28

88.35

91.52

92.31

92.63

92.41

92.46

91.46

5

90.99

90.14

88.95

90.89

88.89

88.49

86.76

90.73

91.32

91.47

91.03

91.86

91.86

 


 

Fig 7. In-vitro drug release profiles of ODT of Atenolol (H1-H3)

 

 

Fig 8. In-vitro drug release profiles of ODT of Atenolol (H4-H6)

 

Fig 9. In-vitro drug release profiles of ODT of Atenolol (H7-H9)

 

Fig 10. In-vitro drug release profiles of ODT of Atenolol (H10-H12)

 

Fig 11. Comparative in-vitro drug release profile of best formulation (H6) With marketed product

 

CONCLUSION:

Suitable analytical method based on UV-Visible spectrophotometer was developed for Atenolol. λmax of 224.2 nm was identified by using phosphate buffer solution, pH 1.2 From the FT-IR spectra, the interference was verified and found that Atenolol did not interfere with the excipients used. Precompression studies of atenolol were performed. Oral Disintegrating tablets of atenolol were successfully prepared using Ammonium Carbonate, Camphor, Thymol and Menthol by using direct compression method. Post compression parameters like general appearance, weight variation, hardness, friability, in-vitro dispersion and wetting time indicate that values were within permissible limit for all formulations. In-vitro drug release study was carried out and based on the results, H-6 formulation was identified as best amongst all the other formulations and its release was found to be 96.95% within 1min. and  it showed a constant release up to 3 min. The best formulation (H6) showed linearity when compared with marketed product. On the basis of the results, the formulation containing camphor was considered as ideal among all other formulations used for the development of atenolol tablets.

 

REFERENCES:

1.     Rangasamy Manivannan. Oral disintegrating tablets: A future Compaction Publication. International Journal of Pharmaceutical Research and Development 2009; 1: 1-10.

2.     Ibrahim HK, El-Setouhy DA. Valsartan orodispersible tablets: formulation, in vitro/in vivo characterization. AAPS PharmSciTech 2010;11: 189-96.

3.     Revathi S, Moulali SK, Dhanaraju MD. Formulation and evaluation of orodispersible valsartan tablets. Pharm Lett. 2015; 7: 315-24.

4.     Rewar S, Singh C, Bansal B, Pareek R, Sharma A. Oral dispersible tablets: An overview; development, technologies and evaluation. Int J Res Dev Pharm Life Sci. 2014; 3: 1223-35.

5.     Deshpande K, Ganesh N. Orodispersible tablets: an overview of formulation and technology. Int J Pharma Biol Sci. 2011; 2: 726-34.

6.     L Lachman, HA Liberman, Joseph L Kani G. The Theory and Practice of Industrial Pharmacy. Varghese publishing house. Bombay. 1990; 3rd Edition: p. 315-317.

7.     Patel B, Patel JK, Rajput G, Thakor R. Formulation and evaluation of tablets of cinnarizine. Journal of pharmacy research. 2009; 2(3):510-13.

8.     L Lachman, HA Liberman, Joseph L Kani G. The Theory and Practice of Industrial Pharmacy. Verghese Publication House. Bombay. 1990; 3rd Edition: p. 171-193.

9.     Jeevanandham S , Dhachinamoorthi D, Chandrashekhar KB, Muthukumaran M, Sriram N. Formulation and evaluation of naproxen sodium orodispersible tablets- A sublimation technique. Asian journal of pharmaceutics. 2010; 4(1):48-51.

 

 

 

 

 

 

 

 

 

 

 

 

Received on 19.12.2017          Accepted on 28.01.2018         

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2018; 8 (1):01-07 .

DOI:  10.5958/2231-5713.2018.00001.6