Design and Development of Fast Dissolving Tablets of Terbutaline Sulphate by using Various Polymers

 

Gupta Manoj1, Goyal Rupendra Kumar2*, Rai Vishnu Kant3

1Sun Institute of Pharmaceutical Education and Research, Lahar, Bhind (M.P.) India

2SOS in Pharmaceutical Sciences, Jiwaji University, Gwalior (M.P.), India

3Shri R.N.S. College of Pharmacy, Gormi, Bhind (M.P.), India

*Corresponding Author E-mail: goyalrk09@gmail.com

 

ABSTRACT:

Difficulty in swallowing leads to non-compliance and subsequently leading to ineffective therapy. New era is an era of novel drug delivery system. Formulation research is oriented towards increasing safety and efficacy of existing drug molecule through novel concept of drug delivery and these target can be achieved by formulating drug with suitable polymer or polymers combination. Terbutaline Sulphate is a beta-2 agonist and has action similar to that of Isoproterenol. The basic aim of this formulation was to decrease the onset time of the drug by decreasing the disintegration time of the tablet by formulating fast dissolving tablet. In the present study fast dissolving tablets of Terbutaline Sulphate was prepared by using of various polymers. The tablets were prepared by direct compression technique. The prepared tablets were evaluated for general appearance, hardness, weight variation, friability, in-vitro disintegration time. In vitro disintegration time studies showed a drug release up to 91 to 98% in 3 min. that was found to be better than a commercial product (86%) in 1 hrs. The formulation were subjected to stability testing for two months at accelerated condition result revealed that no significance change in formulation of final batch.

 

KEYWORDS: Terbutaline Sulphate, direct compression, polymers.

 


INTRODUCTION:

Most commonly employed oral dosage forms are tablets and capsules. Compressed tablets are most widely used dosage form for a number of reasons. They are convenient, easy to use, less expensive, temper proof, easy to pack and ship and more stable than other oral dosage forms. Also tablet lend themselves to certain special release profile products such as enteric or delayed release products1.

 

Over a decade, the demand for the development of fast dissolving tablets has enormously increased as it has a significant impact on patient compliance. Fast dissolving tablets offer an advantage for populations who have difficulty in swallowing. It has been reported that dysphagia2 is common among all the age groups and more specific with the pediatric, geriatric population along with institutionalized patients and patients with nausea, vomiting and motion sickness complications3.  Fast dissolving tablets with a good taste and flavor increase the acceptability of bitter drugs by various group of the population..

Terbutaline sulfate is a selective β-adrenergic agonist bronchodilator. Chemically, it is ()-a-[(tert-butylamino) methyl]-3,5dihydroxy benzyl alcohol sulfate. It is an effective agent in the treatment of bronchospasm in bronchial asthma and chronic bronchitis4.  However, the oral bioavailability is poor, with only 14.8% of the dose reaching systemic circulation due to extensive first pass metabolism.

 

Hence, an attempt was made for preparation of fast dissolving tablets of model bronchodilator terbutaline sulfate with an aim of reducing the lag time and providing faster onset of action to relieve the acute asthmatic effect immediately.This object can be achieved by using the suitable disintegrating agent(s).

 

The proper choice of disintegrants and the optimum concentration of the same is critical factor in the design and development of fast dissolving tablets. These super disintegrants are polymers which are cross linked and have the capability to swell in contact with aqueous medium. As the superdisintegrants swell they increase the diameter of the tablet and help in overcoming the binding force of the binder and the compaction force used in the formulation of the tablet which held together the granules. In this work we have tried to formulate a mouth dissolving dosage form of Terbutaline Sulphate by varying the concentration of superdisintegrants [Crospovidone (CRP), Sodium starch glycolate(SSG) and Croscarmellose Sodium (CCS)] so as to know at which concentration it is most effective.


Table 1 :Formulation of fast dissolving tablet of terbutaline sulfate by using single super disintegrants

Formulation ingradients

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

F11

Terbutaline sulphate

5

5

5

5

5

5

5

5

5

5

5

Sodium starch glycolate(SSG)

2

4

6

8

---

---

---

---

---

---

---

Croscarmellose Sodium (CCS)

---

---

---

---

2

4

6

8

---

---

---

Crospovidone (CRP)

---

---

---

---

---

---

---

---

2

4

6

Sodium Saccharin

0.2

0.2

0.2

0.2

0.2

0.2

0.2

0.2

0.2

0.2

0.2

Flavors

2

2

2

2

2

2

2

2

2

2

2

Talc

2

2

2

2

2

2

2

2

2

2

2

Magnesium Stearate

1

1

1

1

1

1

1

1

1

1

1

Mannitol

10

10

10

10

10

10

10

10

10

10

10

MCC

qs

qs

qs

qs

qs

qs

qs

qs

qs

qs

qs

Total

100

100

100

100

100

100

100

100

100

100

100

 

Table 1 :Formulation of fast dissolving tablet of terbutaline sulfate by using single super disintegrants

Formulation ingradients

F12

F13

F14

F15

F16

F17

F18

F19

F20

F21

F22

Terbutaline sulphate

5

5

5

5

5

5

5

5

5

5

5

Sodium starch glycolate(SSG)

---

10

12

14

----

---

---

---

---

---

2

Croscarmellose Sodium (CCS)

---

---

---

---

10

12

14

---

---

---

2

Crospovidone (CRP)

8

---

---

---

---

---

---

10

12

14

2

Sodium Saccharin

0.2

0.2

0.2

0.2

0.2

0.2

0.2

0.2

0.2

0.2

0.2

Flavors

2

2

2

2

2

2

2

2

2

2

2

Talc

2

2

2

2

2

2

2

2

2

2

2

Magnesium Stearate

1

1

1

1

1

1

1

1

1

1

1

Mannitol

10

10

10

10

10

10

10

10

10

10

10

MCC

qs

qs

qs

qs

qs

qs

qs

qs

qs

qs

qs

Total

100

100

100

100

100

100

100

100

100

100

100

 

Table 2 :Evaluation of the fast dissolving tablet of terbutaline sulfate formulated with Crospovidone (CRP) and combination of three (F22)

Formulation properties

F9

F10

F11

F12

F19

F20

F21

F22

Weight Variation

Pass

Pass

Pass

Pass

Pass

Pass

Pass

Pass

Hardness (kg/cm2)

3.2

3.5

3.0

2.8

3.2

3.5

3.0

3.2

Friability (%)

0.62

0.48

0.56

0.54

0.58

0.59

0.56

0.56

Uniformity of Content (%)

99.98

95.80

97.65

98.25

95.65

97.56

98.56

99.45

Water Absorption Ratio (%)

74.6

75.3

76.2

74.3

76.2

77.3

76.4

71.1

Wetting Time (Sec)

15

18

21

15

20

13

18

15

Disintegration Time In Vitro(Sec)

140

170

50

60

50

30

35

44

 


MATERIALS AND METHODS:

Terbutaline sulfate was procured from Jayco Chemical Industries( Thane, Mumbai). Crospovidone (CRP), Sodium starch glycolate(SSG) and Croscarmellose Sodium (CCS) were obtained from Micro Labs, Bangalore, India. Microcrystalline Cellulose was obtained from Shrusti Pharmaceuticals, Bangalore, Mannitol from Loba Chemicals, Mumbai, Magnesium stearate and Purified Talc were obtained from S.D Fine chemicals, Mumbai, India. All other reagents used were of analytical grade.

 

Preparation of the fast dissolving tablet of terbutaline sulfate

The superdisintegrants Explotab(SSG), Ac-Di-Sol(CCS) and Polyplasdone XL(CRP) in varying concentrations (2,4,6,8,10,12,14%) were used to prepare the tablets. All the ingredients [Table 1] were passed through sieve no. 40 and mixed in geometric progression in a dry and clean mortar for 25 min. The mixed blend of excipients was compressed into tablets using 6.93 mm flat beveldeged punches in an 8 station rotary tablet machine5 (Rimek).

 

Formulation Development and Evaluation of the tablets

To optimize the parameters which is related to the formation of terbutaline sulphate FDDTs. DT of different formulation is shown in (Table2, 3, 4), formulation were designed using higher and lower level of superdisintegrant. SSG, CRP, CCS were used as superdisintegrant, Microcrystaline Cellulose(MCC) used as diluent, which is also superdisintegrant. Tablets were prepared by direct compression techniques.

 

The prepared fast dissolving tablets were evaluated for thickness, hardness 6 (Monsanto hardness tester), friability 7 (Roche friabilator), drug content,8,9 wetting time, water-absorption ratio10 and in vitro disintegration time. The in vitro dissolution studies of fast dissolving tablets were performed using a type-II apparatus as specified in the United State Pharmacopoeia at 50 rpm (Electro Lab, Mumbai, India) and Sorenson's buffer (pH 6.2), 650 ml was used as dissolution medium. Temperature of the dissolution medium was maintained at 37 0.5C. An aliquot of the dissolution medium was withdrawn at a specific time interval and it was filtered. Absorption of the filtered solution was checked by UV spectroscopy (Shimadzu-1700, Japan) at 276.6 nm and the drug content was determined from the standard calibration curve. Dissolution rate was studied for all designed formulations and the conventional tablet. 11

 

RESULT AND DISCUSSION:

The present investigation was undertaken to fabricate and evaluate fast dissolving tablets of terbutaline sulfate by the direct compression method comparing with the conventional tablet. Superdisintegrants at different concentration levels (2, 4, 6, 8,10 and 14% w/w) were used to assist disintegration. Bulk densities of various formulations varied between 0.55 and 0.58 g/cm 3 .


Table 3 :Evaluation of the fast dissolving tablet of terbutaline sulfate formulated with Croscarmellose Sodium (CCS)

Formulation ingradients

F5

F6

F7

F8

F16

F17

F18

Weight Variation

Pass

Pass

Pass

Pass

Pass

Pass

Pass

Hardness (kg/cm2)

3.2

3.5

3.0

2.8

3.2

3.5

3.0

Friability (%)

0.82

0.61

0.63

0.61

0.63

0.61

0.62

Uniformity of Content (%)

99.22

100.01

99.87

99.12

97.51

98.32

98.65

Water Absorption Ratio (%)

70.2

71.6

74.3

76.1

78.2

74.5

70.1

Wetting Time (Sec)

22

20

18

14

15

14

16

Disintegration Time In vitro(Sec)

58

63

35

80

90

55

40

 

Table 4 :Evaluation of the fast dissolving tablet of terbutaline sulfate formulated withSodium starch glycolate(SSG)

Formulation ingradients

F1

F2

F3

F4

F13

F14

F15

Weight Variation

Pass

Pass

Pass

Pass

Pass

Pass

Pass

Hardness (kg/cm2)

3.5

2.8

2.9

2.8

3.2

3.2

3.4

Friability (%)

0.65

0.63

0.61

0.62

0.67

0.65

0.64

Uniformity of Content (%)

98.63

99.31

98.63

98.97

97.51

98.32

98.65

Water Absorption Ratio (%)

71.6

74.3

76.5

78.6

77.8

79.8

81.5

Wetting Time (Sec)

20

18

16

11

17

18

22

Disintegration Time In Vitro(Sec)

180

60

60

50

80

120

150

 

Figure 1: Comparisons of Disintegration Time of various drug formulations of batch F1 to F22

 

Table 5 :In vitro dissolution profile of formulations with Crospovidone (CRP), combination of three (F22) and the conventional tablet (% release)

Time (min)

1

2

3

4

5

10

F9

31.76

55.94

75.08

81.20

99.84

100.00

F10

50.29

66.73

78.05

84.20

99.95

100.00

F11

74.11

77.58

83.73

90.12

99.11

100.00

F12

71.47

77.55

83.70

95.20

98.88

100.00

F19

63.52

69.53

78.23

81.73

93.20

99.53

F20

74.11

85.52

91.76

95.05

99.11

100.00

F21

76.76

80.26

87.73

94.02

99.08

100.00

F22

66.17

77.55

86.29

98.91

100.00

100.00

Conventional Tablet

14.02

16.96

24.98

29.64

33.72

48.95

 


The angle of repose and the compressibility values varied from 21 to 23 and 9.44 to 13.16%, respectively. From these values, it was evident that these blends had excellent flow properties. Physical parameters conformed to the requirements. Weight variation was found within the specification of the USP limits. Average weight of 20 tablets of all 22 formulations was found in the range of 98.9-100.7 mg.


Table 6 :In vitro dissolution profile of formulations with Croscarmellose Sodium (CCS) and the conventional tablet(% release)

Time (min)

1

2

3

4

5

10

F5

60.88

74.79

86.20

95.08

98.76

99.82

F6

50.29

66.73

78.05

94.79

95.82

99.50

F7

68.82

77.52

86.02

95.14

100.00

100.00

F8

34.41

49.35

82.98

86.54

99.83

100.00

F16

50.29

66.73

78.05

84.20

89.11

96.61

F17

71.47

82.85

89.70

96.34

98.94

100.00

F18

68.82

74.88

91.58

99.96

100.00

100.00

Conventional Tablet

14.02

16.96

24.98

29.64

33.72

48.95

 

Table 7 :In vitro dissolution profile of formulations with Sodium starch glycolate(SSG), and the conventional tablet(% release)

Time (min)

1

2

3

4

5

10

F1

52.81

61.46

70.02

81.40

98.25

99.31

F2

55.65

64.14

86.02

92.26

98.55

100.00

F3

55.59

66.79

88.71

92.32

98.62

100.00

F4

58.24

69.47

88.76

92.38

100.00

100.00

F13

42.35

48.12

80.41

91.88

95.53

96.56

F14

60.88

72.14

80.88

84.41

99.8

100.00

F15

52.94

64.11

75.41

84.17

99.71

100.00

Conventional Tablet

14.02

16.96

24.98

29.64

33.72

48.95

 


Hardness and friability of all the tablet formulations were observed in the range of 2.8-3.5 kg/cm 2 and 0.48- 0.82%, respectively. Wetting time and water absorption ratio were found in the range of 11-22 s and 70.1-81.5%, respectively. Drug content of all the formulations was found in the range of 95.65-100.01%[Table 2,3,4] .

 

The in vitro disintegration time was rapid with Polyplasdone XL containing batches (30 sec) [Table 2] followed by Ac-Di-Sol containing batches(35 sec) [Table 3] and delayed with Explotab containing batches (50 sec) [Table 4]. The rapid disintegration may be due to the rapid uptake of water from the medium, swelling and burst effect . Polyplasdone XL exhibit high capillary action and pronounced hydration with a little tendency to gel formation disintegrate rapidly.

 

In vitro dissolution studies of various formulations at different time intervals are reported in [Table 5,6,7]. The Polyplasdone XL formulation showed the maximum dissolution rate of 91.76% drug release in 3 min[Table 5]. Ac-Di-Sol containing tablets released more than 91.58% of the drug in 3 min and Explotab formulations released more than 88.76% of the drug in 3 min. This shows that the effectiveness of superdisintegrants was in the order of Polyplasdone XL > Ac-Di-Sol > Explotab. The comparative reduction in the drug dissolution rate by Explotab was possibly due to the lack of binding force during direct compression. When the combination of three superdisintegrant used the DT is also decreased then single use of each. At lower concentration 2 %, Batch F22 [Table 2] DT is 44 sec. From the overall observations, formulation F20 containing 12% w/w Polyplasdone XL was considered to be the best formulation, which releases up to 91.76% of the drug in 3 min. The in vitro drug release profile F20 was compared with conventional tablet. The conventional tablet released only 24.98% of the drug in 3 min whereas the F20 formulation released up to 91.76%.

 

It can be conclusively inferred that the fast dissolving tablet of terbutaline sulfate with 12% w/w Polyplasdone XL as the superdisintegrant is an alternative to and better than the conventional tablet dosage form used in the management of asthma.

 

CONCLUSION:

In the work under taken an attempt was made to explore the use of terbutaline sulphate with superdisintegrant in the formulation of FDDT. The purpose was to enhance patient compliance and provide rapid onset of action. That were obtained by direct compression method. Then subjected to evaluation studies for the parameter like general appearance, thickness, hardness, weight variation, friability, in-vitro DT. In vitro DT studies showed a drug release up to 91 to 98% in 3 min. that was found to be better than a commercial product (86%) in 1 hrs. The formulation were subjected to stability testing for two months at accelerated condition result revealed that no significance change in formulation of final batch.

 

Formulations tested for the entire official test for tablets and were found to be within limits. Thus it can be concluded that FDDTs can be prepared with a view of obtaining faster action of drug and would be advantageous in comparison to the currently available conventional forms.

 

We are able to achieve our objective of preparing FDDT of terbutaline sulphate with minimum excipients and simple method of manufacture. The techniques adopted was found to be economical and industrial feasible. Terbutaline sulphate being a water-soluble drug would be readily available in dissolved form for rapid oral uptake. The rapid dissolving concept in case of Terbutaline sulphate could be of a great importance in relieving acute asthmatic attack. It can also be concluded that CRP and CCS are better disintegrant for formulation of FDDTs of Terbutaline sulphate.

 

Nowadays these tablets are gaining more importance in industry targeting pediatrics, geriatrics and all age group. The basic approach followed by all the currently available techniques engaged in the formulation of mouth dissolving tablet (MDT) is to maximize the porous structure of the tablet matrix and incorporate super disintegrating agent in to optimum concentration so as to achieve rapid DT and instantaneous dissolve of the tablet along with good taste masking properties and excellent mechanical strength. The availability of various technology and multiple advantages of FDDT will surely increase its popularity in the near future.

 

REFERENCES:

1.       Lieberman HA, Lachman L and Schwartz JB. Pharmaceutical dosage forms. Tablets. Vol. 1. Second edition. Marcel Dekker Inc. USA: p. 285-286

2.       Lindgren S, Janzon L. Dysphagia: Prevalence of swallowing complaints and clinical finding. Med Clin North Am. 1993; 77: 3-5.

3.       Sastry SV, Nyshadham JR, Fix JA. Recent technological advances in oral drug delivery: A review. Pharm Sci Technol Today. 2000;3:138-45.

4.       Bradley JU, Lawrence ML. Drugs used in the treatment of asthma. In: Hardman JG, Lee E, editors. Goodman and Gilman's: The Pharmacological basis of therapeutics. 10 th ed. NewYork: The Mc Graw-Hill Companies; 2001. p. 735.

5.       Kucherkar BS, Badhan AC, Mahajan HS. Mouth dissolving tablets of salbutamol sulphate: A novel drug delivery system. Indian Drugs. 2004;41:592-8.

6.       Banker GS, Anderson NR. In: Lachman L, Liberman HA, Kanig JL, editors. The theory and Practice of industrial pharmacy. 3 rd ed. Mumbai: Varghese Publishing House; 1987. p. 297.

7.       Indian Pharmacopoeia. Vol. 2. Delhi: The Controller of Publications; 1996. p. A-80.

8.       Arias MJ, Gines JM, Moyano JR, Perez-Martinez JI, Rabasco AM. Influence of preparation method of solid dispersions on dissolution rate: Study of triammterene-D- mannitol system. Int J Pharm. 1995;123:25-31.

9.       Yunxia B, Sunada H, Yonezawa Y, Danjo K. Evaluation of rapid disintegrating tablets prepared by direct compression method. Drug Dev Ind Pharm. 1999;25:571.

10.     Chaudhari PD, Chaudhari SP, Kolhe SR, Dave KV, More DM. Formulation and evaluation of fast dissolving tablet of famotidine. Indian Drugs. 2005;42:641-9.

11.     Kuchekar BS, Arumugam V. Fast dissolving tablets. Indian J Pharm Edu. 2001;35:150.

 

 

 

Received on 09.10.2012 Modified on 20.10.2012

Accepted on 24.10.2012 RJPT All right reserved

Research J. Pharm. and Tech. 5(11): Nov. 2012; Page 1433-1437