Formulation Optimization and Evaluation of Immediate Release Tablet of Telmisartan

 

Sonali S. Jaiswal*, Dr. Shashikant D. Barhate

Shree Sureshdada Jain Institute of Pharmaceutical Education and Research, Jamner.

*Corresponding Author E-mail: sonalijaiswal9050@gmail.com

 

ABSTRACT:

Telmisartan is an angiotensin-II receptor antagonist used in the treatment of hypertension. The goal of this research work was to develop the formulation as immediate release tablet of telmisartan by using the superdisintegrants by design of experiments. The FTIR study revealed that there was no interaction between drug and polymer and combination can be safely prepared. Tablets were prepared by using direct compression method. Tablets were evaluated for hardness, thickness, weight variation, disintegration time, drug content, friability and in vitro drug release. All the physical parameters were in acceptable limit of pharmacopoeial specification. A Central Composite Design (CCD) was selected to optimize the formulation B6 which showed the in-vitro drug release 97.16% at 30 min. The two factors croscarmellose sodium and microcrystalline cellulose were varied as required by the experimental design. A composition was selected as optimized formulation (N1), which was compared with the conventional tablet (10% MCC) formulation, while difference (F1) factor and similarity (F2) factor found to be 6.96 and 60.5 respectively. The optimized formulation (N1) was showed in- vitro drug release of 97.74% at the end of 30 minutes, while disintegration time of the tablet was showed 19 sec comparison to other formulations. Further the drug release of immediate release tablets was compared with the drug release profile of conventional tablet which was prepared by using 10% micro crystalline cellulose (MCC) as disintegrating agent.

 

KEYWORDS: Telmisartan, Hypertension, Optimization, Central composite design, Croscarmellose sodium, Direct compression.

 

 


INTRODUCTION:

Oral administration is the most popular and successful route for systemic effects due to its ease of ingestion, pain avoidance, versatility and most importantly patient compliance. Immediate release tablets are those which disintegrate rapidly and get dissolved to release the medicaments.

 

Immediate release may be provided for an appropriate pharmaceutically acceptable diluent or carrier, which diluent or carrier does not prolong to an appreciable extent, the rate of drug release and/or absorption. Release term includes the provision (or presentation) of drug from the formulation to the gastrointestinal tract, to body tissues and/or into systemic circulation. For gastrointestinal tract release, the release is under pH conditions such as pH=1 to 3, especially at, or about, pH=1.

 

Immediate release drug delivery is suitable for drugs having long biological half-life, high bioavailability, lower clearance and lower elimination half-life. But main requirement for immediate release dosage form is poor solubility of the drug and need the immediate action of drug to treat undesirable imperfection or disease.

 

Hypertension is sustained elevation of resting systolic BP (≥ 130 mm Hg), diastolic BP (≥ 80 mm Hg), or both. The basic explanation is that blood pressure is elevated when there is increased cardiac output plus increased peripheral vascular resistance. The most common hypertensive urgency is a rapid unexplained rise in BP in a patient with chronic essential hypertension.

 

Telmisartan is an angiotensin II receptor antagonist used mainly for the treatment of hypertension. Angiotensin II receptor blockers (ARBs) help relax your blood vessels, which lowers your blood pressure and makes it easier for your heart to pump blood. Telmisartan is BCS class II drug, which has low solubility and high permeability. It has oral bioavailability about 67% and having biological half life upto 24 hours.

 

The aim these study was to develop, optimize the immediate release tablets of telmisartan and increase the drug release.

 

MATERIALS AND METHODS:

Materials:

Telmisartan received as a gift sample from Glenmark Pharmaceuticals, India. Sodium starch glycolate, crospovidone, Croscarmellose sodium and other excipients were received from from S.D. Fine Chem. Ltd., Mumbai.

 

Methods:

Preparation of immediate release tablet4:

Immediate release tablets were prepared by direct compression method as per given in table 1. All the materials were passed through the sieve #60 separately to ensure the uniformity in particle size. Telmisartan, MCC, aspartame and superdisintegrant (CCS, CP, SSG) were mixed. Magnesium stearate and talc were added to blend and mixed properly before compression of tablet. The above lubricated blend was compressed by using 9 mm round punches with desired hardness. Similarly the conventional tablets of telmisartan were also prepared by omitting super disintegrants and changing the concentrations of micro crystalline cellulose (Formulation B7). The formulation design of both immediate release and conventional tablets were given in table 1.

 

Table 1: Formulation of Preliminary Trial Batches of Telmisartan tablet:

Ingredient

Batches

B1

B2

B3

B4

B5

B6

B7

Telmisartan

40

40

40

40

40

40

40

SSG

5

12.5

-

-

-

-

-

CP

-

-

5

12.5

-

-

-

CCS

-

-

-

-

5

12.5

-

MCC

112.5

112.5

112.5

112.5

112.5

112.5

25

Mannitol

85

77.5

85

77.5

85

77.5

177.5

Aspartame

2.5

2.5

2.5

2.5

2.5

2.5

2.5

Mg. Stearate

2.5

2.5

2.5

2.5

2.5

2.5

2.5

Talc

2.5

2.5

2.5

2.5

2.5

2.5

2.5

Total (mg)

250

250

250

250

250

250

250

 

Experimental design [5]:

The central composite design was employed to systematically study the drug release profile to investigate the effect of two independent variables (factors), i.e the amounts of Croscarmellose sodium (X1) and Microcrystalline cellulose (X2) on the dependent variables, i.e. Percentage Drug Release (Y1), Disintegration time (Y2) and Friability (Y3). All analysis were performed by using the Design-Expert® 7.1.5 Software.

 

Table 2: Factor Combination as per Experimental Design

Batches

Croscarmellose Sodium (X1)

Microcrystalline Cellulose (X2)

N1

0

4

0

45

N2

0

4

52.07

N3

+1

5

+1

50

N4

+1

5

-1

40

N5

-1

3

-1

40

N6

5.41

0

45

N7

-1

3

+1

50

N8

0

4

37.93

N9

2.59

0

45

 


 

Table 3: Formulation Composition of Optimized Batches of Immediate Release Tablet of Telmisartan.

Ingredient

Batches

N1

N2

N3

N4

N5

N6

N7

N8

N9

Telmisartan

40

40

40

40

40

40

40

40

40

CCS

10

10

12.5

12.5

7.5

13.525

7.5

10

6.475

MCC

112.5

130.175

125

100

100

112.5

125

94.825

112.5

Mannitol

80

62.325

65

90

95

76.475

70

97.675

83.525

Aspartame

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5

Magnesium Stearate

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5

Talc

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5

2.5

Total (mg)

250

250

250

250

250

250

250

250

250

MCC: microcrystalline cellulose, CCS: crosscarmellose sodium


 

 

Preformulation parameters:

Calibration curve of telmisartan6:

It was measured by using UV spectrophotometer (Shimadzu, 1800). For this 100 mg of the drug was dissolved in 100 ml of 0.1 N HCL and shaken for complete dissolve. Then it was filtered and dilution was done in such a way that the resultant sample were made of 2, 4, 6, 8, 10 and 12 μg/ml and was analysed under UV spectrophotometer (Shimadzu, 1800) at the λmax 228 nm. The calibration curve of telmisartan showed in figure 1.

 

Drug Excipients Interaction study7:

The compatibility of the drug and excipients under experimental conditions is important prerequisite before formulation. It is therefore necessary to confirm that the drug does not react with the excipients under experimental conditions and not affecting the shelf life of product or any other unwanted effects on the formulation. The physical mixture of drug and excipients were used for determination of infrared spectrum. The FTIR spectrum of pure drug and physical mixture of drug and polymer are given in figure 2 and 3 respectively.

 

Differential scanning calorimetry8:

The thermal analysis can be used to investigate and predict any physicochemical interactions between components in a formulation and can therefore be applied to the selection of suitable chemically compatible excipients. The melting point was also determined by DSC. Drug and excipients in the ratio 1:1 were analyzed for DSC. The DSC spectrum of pure telmisartan were shown in figure 4 and the DSC spectrum of mixture of telmisartan with CCS, CP and SSG were shown in figure 5 respectively.

 

Evaluation of tablet9, 10, 11, 12:

Pre-compression parameters of optimized batches:

The powder blend of the formulations are subjected to pre-compression parameters such as bulk density, tapped density, carrs index, Hausner’s ratio and angle of repose to determine the nature of its flow and its compressibility nature.

 

Post-compression parameters of optimized batches:

The various post compression evaluation parameters such as thickness, hardness, weight variation, friability, drug content, wetting time, disintegration time and in-vitro drug dissolution studies were performed on the developed formulations as per the standard procedure.

 

For each formulation hardness was determined using the Monsanto hardness tester by taking 6 tablets. Friability was determined by using Roche friabilator. The thickness of the tablets was determined by using vernier caliper for the 6 tablets and average was taken. Weight Variation was determined by taking 20 tablets of each formulation was weighed using an electronic balance and the test was performed according to the official method. Drug Content was determined by taking 6 tablets and triturated and weighed 100 mg equivalent drug in 100 ml volumetric flask containing 0.1 N HCl and then the concentration was determined spectrophotometrically by measuring the absorbance at 228 nm. Disintegration time for tablets was performed using disintegration testing apparatus by using 0.1 N HCl maintained at 37±0.5°C.

 

In vitro dissolution studies:

Drug release of tablets was studied by using USP type-II apparatus at 75 rpm using 900ml of 0.1 N HCl as dissolution medium maintained at 37±0.5°C. A 5 ml was withdrawn at specific time intervals and same volume of fresh medium was replaced. From the withdrawn samples, the 1 ml sample were diluted upto 10 ml with 0.1 N HCl, filtered and analyzed on UV spectrophotometer at 228 nm using 0.1 N HCl as a blank and percentage drug release was calculated.


 

RESULTS AND DISCUSSION:

Preformulation parameters:

Fig 1: Calibration curve of telmisartan Drug Excipients Interaction study

 

Figure 2: FTIR spectrum of Telmisartan (pure drug)

 

Figure 3: FTIR spectrum of drug along with polymer

 

Figure 4: DSC of Telmisartan                                                               Figure 5: DSC overlay of drug with polymers

 

Evaluation of optimized batch of immediate release tablet of telmisartan

Table 4: Pre-compression parameter of optimized batches

Batches

Bulk Density

(gm/ml)

Tapped Density

(gm/ml)

Carr's Index

(%)

Hausner's Ratio

Angle of Repose (θ)

N1

0.48±0.005

0.57±0.012

17.27 ± 0.56

1.20 ± 0.037

28.23 ± 0.70

N2

0.46±0.011

0.58±0.012

20.02 ± 0.88

1.24 ± 0.012

28.87 ± 0.68

N3

0.47±0.015

0.56±0.004

17.13 ± 0.73

1.21 ± 0.046

26.28 ± 0.65

N4

0.46±0.005

0.57±0.009

19.17 ± 0.75

1.25 ± 0.019

28.93 ± 0.59

N5

0.47±0.011

0.57±0.012

17.96 ± 0.56

1.22 ± 0.042

27.50 ± 0.68

N6

0.47±0.005

0.58±0.008

19.54 ± 0.68

1.24 ± 0.014

29.00 ± 0.48

N7

0.48±0.005

0.58±0.008

17.81 ± 0.74

1.22 ± 0.009

27.36 ± 0.82

N8

0.47±0.011

0.57±0.004

18.50 ± 0.86

1.23 ± 0.012

25.84 ± 0.17

N9

0.47±0.011

0.58±0.008

19.03 ± 0.71

1.21 ± 0.005

28.24 ± 0.20

 

Table 5: Post-compression parameters of optimized batches

Batches

Thickness

(mm)

Hardness

(kg)

Weight Variation (mg)

Friability

(%)

Drug Content

(%)

Disintegration Time (sec)

N1

4.48±0.03

4.73 ± 0.64

249.0±0.83

0.69 ± 0.32

97.65±1.82

19 ± 0.28

N2

4.53±0.02

4.49 ± 0.59

249.0±0.82

0.56 ± 0.33

99.51±1.80

23 ± 0.26

N3

4.46±0.02

4.66 ± 0.57

248.0±0.82

0.56 ± 0.24

97.43±1.28

23 ± 0.26

N4

4.53±0.01

4.76 ± 0.68

249.67±0.47

0.63 ± 0.34

98.65±1.28

21 ± 0.33

N5

4.51±0.01

4.73 ± 0.46

250.67±2.04

0.65 ± 0.07

98.54±1.81

21 ± 0.09

N6

4.49±0.02

4.86 ± 0.70

249.33±1.24

0.65 ± 0.05

98.12±1.19

22 ± 0.19

N7

4.95±0.02

4.91 ± 0.64

248.33±0.94

0.58 ± 0.32

98.12±1.19

20 ± 0.28

N8

4.52±0.04

4.56 ± 0.58

250.33±1.24

0.56 ± 0.41

97.65±1.82

24 ± 0.32

N9

4.46±0.04

0.45 ± 0.65

249.33±2.05

0.57 ± 0.08

99.61±0.94

22 ± 0.21

 

In-Vitro Drug Release of Optimized Batches of Immediate Release Tablet of Telmisartan

Table 6: In-Vitro Drug Release of Optimized Batches of Immediate Release Tablet of Telmisartan and conventional formulation (Reference formulation- B7)

Time

(Min)

Batches

N1

N2

N3

N4

N5

N6

N7

N8

N9

B7

0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

0.0

5

51.22

48.37

55.02

50.74

50.27

52.64

47.42

53.12

54.07

48.37

10

65.93

64.51

75.90

74.00

53.59

74.48

64.03

72.58

74.00

56.44

15

82.55

80.65

85.87

81.12

66.88

83.02

82.55

83.50

81.12

78.75

30

97.74

95.36

92.52

96.31

85.02

91.09

96.79

88.24

89.67

91.09

45

101.06

97.74

95.52

100.11

93.46

94.89

98.69

95.84

99.64

98.21

60

106.28

99.64

100.59

104.38

99.63

99.16

100.59

98.69

99.68

99.08

 


 

Figure 6: Comparative study of % Drug Release of Reference Batch (B7) and Optimized Batch N1

 

The two factors croscarmellose sodium and microcrystalline cellulose were determined as the critical material attributes from preliminary studies and varied as required by the experimental design. The screened factors of overlay plot were incorporated into a suitable experimental design to optimize the process formulation. Design Expert® version 7.1.5 software was used to generate a mathematical model for each response parameter and the subsequent statistical analysis.

Regression Equations for the quadratic model: In-vitro % drug release

% Drug release (Y1) = + 97.74 + 1.38 X1+ 2.51 X2 -4.39 X1X2 - 3.41 X12 - 2.70 X22

 

The results of multiple linear regression analysis showed that the coefficients X1 and X2 bear a positive sign. Therefore, increasing the concentration of superdisintegrant the dissolution rate increases.

 

ANOVA for response surface Quadratic Model:

ANOVA for Y1 (% Drug Release)

Source

DF

Sum of Square

Mean Square

F value

P value

Model

Residual

Cor Total

5

7

12

259.61

8.44

268.05

51.92

1.21

-

43.08

-

-

0.0001- significant

 

 

 

 

 

 

 

 

Graphical Representation: plot for dissolution:

 

Figure 7: Contour graph for dissolution surface           

 

 

Figure 8: Three dimensional response

 

Regression Equations for the quadratic model: Disintegration Time:

Disintegration Time (Y2) = + 19.00 + 0.37 X1 -0.052 X2 + 0.75 X1X2 + 1.13 X12 + 1.88 X22

the results of multiple linear regression analysis showed that the coefficients X1 and X2 bear a negative sign. Therefore increase in the concentration of X1 and X2 is expected to decrease the disintegration time.

 

ANOVA for response surface Quadratic Model

ANOVA for Y2 (Disintegration Time)

Source

DF

Sum of Square

Mean Square

F value

P value

Model

Residual

Cor Total

5

7

12

33.34

6.35

39.69

6.67

0.91

-

7.35

-

-

0.0104- significant

 

Graphical Representation: plot for Disintegration Time:

 

Figure 9: Contour graph for disintegration Time surface

 

Figure 10: Three dimensional response

 

ANOVA for response surface Quadratic Model

ANOVA for Y3 (Friability)

Source

DF

Sum of Square

Mean Square

F value

P value

Model

Residual

Cor Total

5

7

12

0.033

6.181E-003

0.040

6.678E-003

8.831E-004

-

7.56

-

-

0.0096- significant

 

 

Graphical Representation: plot for Friability

 

Figure 11: Contour graph for friability

 

 

Figure 12: Three dimensional response surface

 

 

Figure 13: Response Surface Contour Graph Showing Desirability at of CCS(X1)= 4% and MCC (X2)= 45% Response Surface Contour Graph Showing Desirability at of CCS(X1)= 4% and MCC (X2)= 4

 

 

Figure 14: 3-D Surface Graph Showing Desirability at of CCS(X1) = 4% and MCC (X2)= 45%

 

 

Figure 15: Overlay Plot Showing Compositions for Optimized Formulation

 

CONCLUSION:

The Drug- excipients compatibility studies showed that the polymer used in the formulations has no interaction with the drug. The melting point of pure telmisartan was carried out by using melting point apparatus and it was found to be 268°C – 270°C and it matches with standard value. It was also confirmed by DSC and melting point was found to be 269.65°C. The sharp DSC peak showed that the drug was pure. The precompression and postcompression parameters were showed satisfactory results. The quantitative interaction effect of independent variables on the % drug release, disintegration time and friability were predicated by using polynomial equations. The quadratic model was found to be satisfactory for dictating the relationships between independent variables and response variables.

Among all optimized formulation, batch N1 containing concentration of superdisintegrant CCS (4%) and MCC (45%) was found to be optimized for formulation of immediate release tablet of telmisartan. It showed 97.74% drug release in 30 min, with disintegration time 19 sec respectively. The F1 and F2 values were found to be 6.96 and 60.5 respectively.

 

Finally it was concluded that the optimized concentration of CCS and MCC can be used to formulate immediate release tablet of telmisartan.

 

ACKNOWLEDGEMENTS:

Authors are thankful to Glenmark Pharmaceuticals and S.D. Fine Chem. Ltd. for providing drug and excipients to carry out these research work successfully. I am thankful to Principal Dr. S. D. Barhate for providing institutional facility to carry out research work successfully.

 

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Received on 21.06.2019            Modified on 18.07.2019

Accepted on 10.08.2019            © A&V Publications All right reserved

Asian J. Res. Pharm. Sci. 2019; 9(3):167-173.

DOI: 10.5958/2231-5659.2019.00026.2