Development and Evaluation of Self Pore Forming Osmotic Tablets of Nifedipine

 

Patel Chirag J*1, Asija Rajesh1, Asija Sangeeta1, Mangukia Dhruv K1, Patel Jaimin R1, Kanu Patel2

1Maharishi Arvind Institute of Pharmacy, Mansarovar, Jaipur, Rajasthan, India.

2K.L.E. Collage of Pharmacy, Bangalore, Karnataka, India.

 

ABSTRACT:

The aim of this study was to formulate and evaluate self pore forming osmotically controlled drug delivery system of Nifedipine. Nifedipine is a dihydropyridine acting as calcium channel blocker with an elimination half life of 2 hours, thereby requiring twice or thrice daily dosing in patients, which may lead to non-compliance. This system was formulated with an intention to achieve zero order release of Nifedipine for 12-13 hours to increase patient compliance by reducing the dosing frequency. Cellulose acetate, a film forming polymer was used with PEG 400 as plasticizer, Potassium chloride as pore forming agent and Acetone and methanol were used as solvents. Combinations of Mannitol-Sucrose, Mannitol-Lactose and Dextrose-Sucrose were used as osmotic agents. This system was developed in two stages: formulation of core tablet and coating of tablet core. Core tablets were evaluated for content uniformity, hardness and weight variation while coated tablets were evaluated for film thickness and in vitro release study. Effect of varying the concentration of pore forming agent on release rate was studied. Effect of various osmogens differing in osmotic pressure on release rate was also evaluated. Though all the formulations exhibited near zero order release, F4 gave maximum drug release at the end of 12th hour which was fairly constant at 13th hour. 

 

KEYWORDS: Nifedipine, Self pore forming osmotic tablet, Mannitol, Lactose, Sucrose.

 

INTRODUCTION:

Osmotically controlled drug delivery system provides delivery of drugs at a rate which is predictable and reproducible throughout the GI tract1. These systems are formulated such that the plasma drug concentration is maintained within the therapeutic range, thus ensuring efficacy with minimum toxic effects. This is done by regulating drug release considering the drug dose and dosing intervals2. Osmotic devices have gained much attention due to its zero order release kinetics which is unaffected by variation in pH, volume of gastric contents and other hydrodynamic conditions. These devices deliver drugs due to the difference in osmotic pressure within and outside the osmotic device. The release rate from this system is not affected by gastric pH and other hydrodynamic conditions. The release characteristic can be easily optimized by regulating the release parameters3. Elementary osmotic pump (EOP)4, first introduced by Theeuwes, is simple to prepare and releases drug at almost zero order rate. Other osmotic pump includes Rose-Nelson pump5, Higuchi-leeper pump6, ALZET osmotic pump7 and push pull osmotic pump8. Two layer push-pull, monolithic osmotic pump, two compartments and sandwiched osmotic pump were developed for drugs which have limited water solubility. These pumps however have a common disadvantage: a sophisticated laser – drilling technique to make the delivery orifice9,10. The osmotic pumps for oral administration consist of a compressed tablet core coated with a semi permeable membrane that has an orifice drilled into it. Alternately, coating solution may contain a pore forming agent.

As the core absorbs water, it compresses the drug compartment which pushes the saturated solution or suspension of drug out of tablet through one or more delivery orifices11.

 

Nifedipine is a dihydropyridine acting as calcium channel blocker. Nifedipine has quick onset and short duration of action. Nifedipine is extensively metabolized (about 60 -70% of the dose) into water soluble inactive metabolites which are excreted in urine while the remainder is excreted in faeces after metabolism. Nifedipine has half life of 2 hours and also exhibits significant fluctuations in plasma concentration12, 13. This parameter necessitates the formulation of nifedipine into modified release dosage forms that regulates the plasma concentration of the drug14, 15.In this study, an attempt was made to develop a controlled porosity osmotic pump for a poorly soluble drug (Nifedipine) without the need for complicated and expensive drilling techniques. Here, osmotic pressure was produced by osmogens and polymer swelling force worked concurrently to drive the drug out of the system through the pores. Pores are formed as pore forming agents solubilizes after exposure of the system to water16,17.

 

MATERIALS AND METHODS:

Materials:

Nifedipine was obtained as a gift sample from Ronak Pharmaceuticals pvt Ltd., Patan. Sucrose, Dextrose, Lactose, Mannitol, Micro crystalline cellulose (MCC), Poly vinyl pyrrolidone (PVP), Cellulose acetate, Talc, Magnesium stearate, Potassium chloride, Polyethylene glycol (PEG) 400, Methanol and Acetone were purchased from central drug house (P) Ltd., New Delhi.

 

Method2, 14, 18, 19, 20

Preparation of tablet core:

All the ingredients of formula for tablet core except PVP K 30, Talc and magnesium stearate were passed through sieve #85 and weighed accurately. These were than thoroughly mixed. A solution of PVP K 30 was prepared in isopropyl alcohol. Granules were prepared by wet granulation technique and were dried at 45ºC for 40 minutes. These were then passed through sieve sieve #18. Talc and magnesium stearate were mixed with dry granules and compressed into tablets using a rotary compression machine fitted with concave punches.

Coating of tablet core:

F1 formulation of tablet core was selected for the optimization of coating solution. Table 2 describes various formulations of coating solution. Acetone and Methanol were used as solvents, Cellulose acetate as polymer, potassium chloride as pore forming agent and PEG 400 as plasticizer. Coating of the core tablet was carried out in an automatic perforated coating pan by initially rotating the pan at low speed (3-5 rpm) and passing the hot air through tablet bed. Coating process was started as soon as the temperature of outlet air reached to 35ºC. Coating pan rpm was rotated at 15-20 rpm and coating solution was applied at a rate equivalent to 5-7 ml/min. coating process was continued until desired weight was gained on tablet core. For all formulations, coated tablets were dried at 50ºC for 2 hours before evaluation.

 

Evaluation

1.     Content uniformity of core tablet9, 21

Content uniformity of core tablets was determined by crushing 10 tablets in a mortar and pestle. Powder equivalent to 10 mg was weighed and transferred into a volumetric flask containing methanol. Flask was sonicated for 1 hour. Absorbance was noted against methanol as blank after suitable dilutions and drug content was calculated.

 

2. Weight variation test of core tablet14, 17, 22

Weight variation test was performed for core tablets. 20 tablets were selected at random from each formulation and were evaluated. Average weight and deviation in weight of each tablet from average was calculated.

 

3. Thickness of the coat15, 23, 24

Thickness of the film (coat) was determined by digital micrometer. Coat was peeled off from the tablet core and thickness was determined at three different points on the film. Average value was determined. 5 tablets from each formulation were tested and average was determined.

 

4. Hardness of core tablet17, 25, 26

Hardness of core tablets was determined using Monsanto hardness tester. 10 tablets from each formulation were selected at random and hardness test was performed. Average value was calculated.

 

 

Table 1: Composition of tablet core:

Ingredients

Quantity/tablet (mg)

F1

F2

F3

F4

F5

F6

F7

F8

F9

Nifedipine

30

30

30

30

30

30

30

30

30

Sucrose

70

80

75

70

80

75

-

-

-

Dextrose

80

70

75

-

-

-

-

-

-

Mannitol

-

-

-

80

70

75

70

80

75

Lactose

-

-

-

-

-

-

80

70

75

PVP K 30

16

16

16

16

16

16

16

16

16

Magnesium stearate

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5

Talc

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

1.5

 

Figure 1: In vitro release profile for F1-F9 formulations.

 

 

5. In vitro release studies16, 27, 28, 29

A tablet from each formulation was subjected to in vitro release rate studies. 900 ml of 0.1N HCl for first 2 hours followed by pH 6.8 buffer were used as dissolution medium. Temperature was maintained at 37±0.5˚C. Media was stirred at 50 rpm.  Sampling interval was 1 hour. Graphs of time versus % cumulative drug release for all formulations are shown in figure 1.

 

Table 2: composition of coating solution.

Ingredients

F1

F2

F3

F4

Cellulose acetate (mg)

5

5

5

5

PEG 400 (ml)

2

2

2

2

Potassium chloride (mg)

0.3

0.6

0.9

1.2

Acetone (ml)

85

85

85

85

Methanol (ml)

15

15

15

15

 

Table 3: optimized formula:

Ingredients

Coating solution

Tablet core

Cellulose acetate

5

-

PEG 400

2

-

Potassium chloride

0.6

-

Acetone

85

-

Methanol

15

-

Nifedipine

-

30

Mannitol

-

80

Sucrose

-

70

PVP K 30

-

16

Mg stearate

-

2.5

Talc

-

1.5

 

RESULTS:

Optimization of coating solution:

The optimized formula is mentioned in table 3. Coating resulted in a weight gain of 2.4% of the core tablet.

 

Drug content:

Drug content was uniform within each batch ranging from 96 – 103%.

 

Weight variation test:

Weight variation test and average value was determined. Individual weight of each tablet was within the limits: average weight ± 7.5%.

 

Thickness of the coating film:

Thickness of the coating film for optimized formula was found to be 0.071±0.004mm as determined by digital micrometer.

 

Hardness of the core tablets:

Average hardness of core tablets was in the range of 4-5 kg/cm2 as determined by Monsanto hardness tester.

 

In vitro release study:

In vitro release profile (figure 1and table 4) shows that release from F1to F9 exhibited near zero order release. % cumulative release from F4 was maximum and was fairly constant at 13th hour.

 

DISCUSSION:

Self pore forming osmotic tablets of Nifedipine were successfully formulated and evaluated.  All tablet core formulations coated with F2 coating solution exhibited zero order release. Release rate characteristics were studied by varying the concentration of pore forming agent (in coating solution) and varying the osmotic agents (in tablet core) in different concentration ratios.

 

Effect of level of pore former:

With an increase in concentration of pore forming agent, increase in release rate was also observed. This may be attributed to the increase in number of pores in the coating layer.

 

Effect of osmotic agent:

Release of drug is affected by the osmotic pressure. A formulation containing an osmogens with high osmotic pressure showed higher release rate and vice versa.

 

ACKNOWLEDGEMENTS:

The authors are thankful to Narendra Patel, Manager of Ronak Life Care Pvt. Ltd., Patan, India, for providing us gift sample of Nifedipine. Special thanks to Dr. Rajesh Asija and Mrs. Sangeeta Asija for providing us necessary support and facilities required for this research work. The authors also wish to acknowledge with thanks to the management of Maharishi Arvind Institute of Pharmacy, Mansarovar, Jaipur, for providing the infrastructure and facilities for our research project.

Table 4: % Cumulative drug release for F1 to F9 formulations.

Time (hour)

% Cumulative drug release

F1

F2

F3

F4

F5

F6

F7

F8

F9

0

0

0

0

0

0

0

0

0

0

1

6.84

5.87

5.35

7.79

8.35

7.11

16.37

15.87

13.85

2

13.19

14.13

12.19

15.83

15.33

14.59

28.91

32.55

26.59

3

17.69

18.32

16.99

25.11

24.91

23.22

44.59

47.19

40.74

4

25.37

24.91

24.59

33.32

32.15

30.17

62.61

65.56

61.94

5

31.43

28.59

30.35

39.91

38.76

36.99

74.53

77.58

73.49

6

38.15

36.55

35.55

47.53

47.19

44.73

88.78

89.16

86.33

7

41.12

42.95

43.12

55.64

53.93

52.87

89.25

89.87

86.97

8

48.32

50.52

47.99

63.83

62.73

61.75

-

-

-

9

53.91

56.92

54.66

73.15

72.11

70.79

-

-

-

10

61.55

63.13

60.17

79.59

80.56

77.56

-

-

-

11

67.93

70.21

66.56

87.15

86.97

85.93

-

-

-

12

73.34

77.35

71.19

94.91

91.36

93.83

-

-

-

13

80.53

84.53

77.53

95.13

92.17

94.21

-

-

-

14

88.95

89.97

86.94

-

-

-

-

-

-

15

91.32

92.11

90.45

-

-

-

-

-

-

16

91.77

92.59

91.09

-

-

-

-

-

-

 

 

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Received on 01.06.2012

Accepted on 09.07.2012        

© A&V Publication all right reserved

Research Journal of Pharmaceutical Dosage Forms and Technology. 4(4): July-Aug. 2012, 207-210