Formulation and Development of a Compression coated, matrix based, tablet of Verapamil HCl using design of experiments

 

Subhashis Debnath1*, C Shashank1, M. Niranjan Babu1, R Suresh Kumar2

1Department of Pharmaceutics, Seven Hills College of Pharmacy, Tirupati-517561, A.P, India.

2Department of Pharmaceutics, J S S College of Pharmacy, Ooty-643001, A.P, India

*Corresponding Author E-mail: shcp7@yahoo.com

 

ABSTRACT:

Compression coating provides a unique platform for formulating modified release products in a way the dosage form can successfully be targeted to localize the release of the drug in any desired portion of the GIT without the additional step of film coating.  The current work focuses on the development and optimization of modified release Verapamil Hydrochloride tablets using compression coating. The effect of various concentrations of different grades HPMC polymers, like, K4M, K15M and K100M on the release profile was studied in DOE environment. The results of the DOE provide an optimized range of the three polymers which could potentially give the targeted release profile for all drugs which have solubility profiles similar to Verapamil HCl. Three batches of optimized formulation were loaded on to accelerated stability studies at 400 C/75% RH in HDPE containers and the 3 months stability data indicates that there is no significant change in either the potency of the dosage form or its in vitro dissolution profile.

 

KEY WORDS: Verapamil, DOE, HPMC, formulation.

 

 


INTRODUCTION:

Most conventional oral drug products, such as tablets and capsules, are formulated to release the active drug immediately after oral administration, to obtain rapid and complete systemic drug absorption. Such immediate-release products result in relatively rapid drug absorption and onset of accompanying pharmacodynamic effects. However, after absorption of the drug from the dosage form is complete, plasma drug concentrations decline according to the drug's pharmacokinetic profile.

 

Eventually, plasma drug concentrations fall below the minimum effective plasma concentration (MEC), resulting in loss of therapeutic activity. Before this point is reached, another dose is usually given if a sustained therapeutic effect is desired. An alternative to administering another dose is to use a dosage form that will provide sustained drug release, and therefore maintain plasma drug concentrations, beyond what is typically seen using immediate-release dosage forms. In recent years, various modified-release drug products have been developed to control the release rate of the drug and/or the time for drug release [1,2].

 

Verapamil HCl is a calcium channel blocker used in the treatment of several cardiovascular disorders, particularly angina pectoris, supraventricular tachycardia and hypertension. It is established that 90% of verapamil HCl is absorbed following its oral administration and then it reaches maximum plasma concentration within 1- 2 hours. However, due to first pass effect it has low bioavailability (10-20%). It has short half- life of 4 hours, so dosing frequency is high. The physicochemical properties of verapamil HCl and its short half life make its suitable candidate for preparation of compression coated, matrix based, controlled release system [3,4].

 

The objective of the project is to design and formulate compression coated tablets for verapamil HCl and to run a 33 DOE for studying the effect of the combination of polymers of 3 different viscosity grades of HPMC and to perform accelerated stability study for optimized lab batch [5].

 

MATERIAL AND METHODS:

Verapamil HCl was obtained as a gift sample from Panxin Biochem Co Ltd,China. HPMC K15M and HPMCK4M were obtained as a gift sample from DOW Chemicals, USA. HPMCK100M was obtained as gift sample from Colorcon Asia Pacific Pvt. Ltd.  All other chemicals were of analytical reagent grade and were used as received.

 

Formulation and Development:

Compressed coated tablet contains immediate release (IR) core tablet and extended release coat. A 33 DOE for studying the effect of the combination of polymers of 3 different viscosity grades of HPMC were performed on the extended release coat. Composition of the IR core tablet is given in the Table 1. IR core tablets were prepared by direct compression method [3,6].

 

Table 1: Verapamil IR Core Formula

Materials

Weights (in mg)

Verapamil

100

PVP k30

03

Magnesium stearate

01

Aerosil

01

Total

105

 

Optimization of Verapamil HCl Formulation using 33 full factorial designs:

The three factors viz. HPMCK4M, HPMC K15M and HPMCK100M were varied, as required by the experimental design, and the factor levels suitably coded. Quantity of filler (MCC) was adjusted so as to keep the tablet weight constant (900 mg). Levels of polymers were decided based on the inactive ingredient database and listed in the Table 2. Twenty-seven various formulations have been designed by the software were listed in Table 3. The design was developed using the DOE PRO EXL software[2,3-5].

 

Table 2: Polymer levels

HPMC

L %

M %

H %

K 4M

7

11

15

K 15M

7

11

15

K 100M

7

11

15

 

Table 3:  DOE Formulations

S. NO/HPMC GRADE

K4M

K15M

K100M

1

L

H

H

2

L

H

M

3

L

H

L

4

L

M

H

5

L

M

M

6

L

M

L

7

L

L

H

8

L

L

M

9

L

L

L

10

M

H

H

11

M

H

M

12

M

H

L

13

M

M

H

14

M

M

M

15

M

M

L

16

M

L

H

17

M

L

M

18

M

L

L

19

H

H

H

20

H

H

M

21

H

H

L

22

H

M

H

23

H

M

M

24

H

M

L

25

H

L

H

26

H

L

M

27

H

L

L

 

In vitro Drug Release Studies:

The in vitro drug release study was performed for the formulated tablets using USP Type II dissolution apparatus under the following conditions.

 

Dissolution test parameters:

Medium                                             :              900ml of 01.N HCl

Rotation speed                   :              50 rpm

Temperature                       :              37±0.5ºC

Sampling Volume              :              5ml

 

At predetermined time intervals samples (5 ml) were collected and replenished with same volume of fresh media. The drug content in the samples was estimated using UV-spectrophotometer. 5 ml sample was withdrawn at each time point, and absorbance was measured at 271nm [3,6,7].

 

Table 4: Composition of F optimized formula

Name of the Ingredient

F1 (in mg)

F2 (in mg)

F3 (in mg)

Verapamil HCl

100

100

100

Lactose

300

300

300

MCC

232

223.2

216

PVP K30

14.5%

14.8%

15%

HPMC K4M

7%

7.3%

7.5%

HPMC K 15M

8%

8.5%

9%

HPMC K100M

20

20

20

Mg. St

8

8

8

Aerosol

4

4

4

Total

900

900

900

 

F optimum Formulations:

The F optima formula was scaled up to 1000 tablets. Fig 1 shows different parts of the prepared compressed coated tablet of Verapamil HCl. Based on all the dissolution studies performed on all the 27 different formulations the following optimized formulations were designed and compositions of the F1, F2 and F3 were given in Table 4. The dissolution tests were performed based on the above-mentioned procedure [5,7,8].

 

Stability Study:

For all the pharmaceutical dosage forms it is important to determine the stability of the dosage form. This will include storage at exaggerated temperature conditions, with the necessary extrapolations to ensure the product will, over its designed shelf life, provide medication for absorption at the same rate as when originally formulated. The design of the formal stability studies for the drug product should be based on the knowledge of the behavior and properties of the drug substance and formal stability studies on the drug substance. Specification which is list of tests, reference to the analytical procedures and proposed acceptance criteria, including the concept of different acceptable criteria for release and shelf life specifications, is addressed in ICH guidelines.

·        These tablets were filled in HDPE container at 30’s count, the cap was induction sealed.

·        The containers were incubated at 40 º/75% RH

·        The samples were withdrawn at 1M, 2M and 3M time intervals and analyzed for % drug content and dissolution profile in pH 0.1N buffer.

·        The data is compiled and compared with the initial values for % drug content and dissolution profile

 

RESULT AND DISCUSSIONS:

The effect of concentrations of the 3 polymers was studied in DOE enviroment by using a 33 expermimental design. The mean dissolution value at each time point was considerd as the measurable parameter and the DOE was separately run for each time point. This gives the idea of the effect of combination of polymers on both the rate as well as the extent of dissolution. In the following tables Y1, Y2 and Y3 are the 3 different mean % drug release. Y bar is the average mean % drug release and S is the standard deviation. Table 5 to 9 shows the mean % drug release of various 27 formulations at different time intervals. Fig 2 to 21 shows the Y-hat Contour Plot and Y-hat Surface Plot for the mean % dissolution profile for the different composition of the polymers at different time periods.  The values of the Mean % Drug Release v/s time for all 27 experimental runs were fed into the DOE PROEXEL software. Mean % Drug Release at release at each time point (2, 4, 8, 10 and 16 hours) was considered as the variables and the DOE was run at each of these time points. The data which came out of the soft ware indicates the following optimized range of polymer concentration was tabulated in Table 10. This indicates that when Verapamil ER tablets are formulated using polymer ratios within the above-mentioned design space; the formulation will always be within the dissolution specification. Any change outside this range may result in the failure of the dissolution profile. The results of in vitro dissolution studies have been given in Table 11 and the release profile in fig 22.

 


 

Table 5: DOE for 2 hours

Factor

A

B

C

2 HR % of drug releases

Row #

K4 M

K15 M

K100 M

Y1

Y2

Y3

Y bar

S

1

15

15

15

4.5

5

5.5

5

0.5

2

15

15

11

3

3.5

3.9

3.466667

0.450925

3

15

15

7

3

3.2

4

3.4

0.52915

4

15

11

15

4.4

4.8

4.5

4.566667

0.208167

5

15

11

11

6.2

6.6

6.6

6.466667

0.23094

6

15

11

7

12.8

11

12.8

12.2

1.03923

7

15

7

15

6

8

7

7

1

8

15

7

11

11

12.2

12.9

12.03333

0.960902

9

15

7

7

6

7

6.5

6.5

0.5

10

11

15

15

2.4

2.4

2.3

2.366667

0.057735

11

11

15

11

6

5.5

5.8

5.766667

0.251661

12

11

15

7

3.3

3.3

3.4

3.333333

0.057735

13

11

11

15

7.3

7.4

7.4

7.366667

0.057735

14

11

11

11

6

5.4

6.1

5.833333

0.378594

15

11

11

7

2.4

2.5

2.8

2.566667

0.208167

16

11

7

15

3.8

3.8

4

3.866667

0.11547

17

11

7

11

5.1

5.2

5.1

5.133333

0.057735

18

11

7

7

4

4.1

4.2

4.1

0.1

19

7

15

15

8

8

8.1

8.033333

0.057735

20

7

15

11

14

13

13

13.33333

0.57735

21

7

15

7

5.7

5.7

5.4

5.6

0.173205

22

7

11

15

6.1

6.2

6

6.1

0.1

23

7

11

11

4.1

4.2

4

4.1

0.1

24

7

11

7

4.3

4.4

4.5

4.4

0.1

25

7

7

15

4.7

4.6

4

4.433333

0.378594

26

7

7

11

4.8

4.4

4.9

4.7

0.264575

27

7

7

7

14.1

14.8

14.4

14.43333

0.351188

Table 6: DOE for 4 hr

Factor

A

B

C

4 HR % of drug release

Row #

K4 M

K15 M

K 100 M

Y1

Y2

Y3

Y bar

S

1

15

15

15

4.8

5

4.5

4.766667

0.251661

2

15

15

11

3.8

3.7

4

3.833333

0.152753

3

15

15

7

3.8

3.8

3.5

3.7

0.173205

4

15

11

15

9

8.6

8.6

8.733333

0.23094

5

15

11

11

8.5

8.4

8.7

8.533333

0.152753

6

15

11

7

21

20

21

20.66667

0.57735

7

15

7

15

11

11.7

12

11.56667

0.51316

8

15

7

11

40.23

40

40

40.07667

0.132791

9

15

7

7

14

14

14

14

0

10

11

15

15

4.5

4.7

4.5

4.566667

0.11547

11

11

15

11

6.3

6.2

6.2

6.233333

0.057735

12

11

15

7

5.7

5.6

5.8

5.7

0.1

13

11

11

15

8

8.5

8.5

8.333333

0.288675

14

11

11

11

7.5

7

7.8

7.433333

0.404145

15

11

11

7

4.8

4.7

4.6

4.7

0.1

16

11

7

15

5.5

6

6

5.833333

0.288675

17

11

7

11

5.8

6

5.9

5.9

0.1

18

11

7

7

11.235

10.8

11

11.01167

0.217735

19

7

15

15

14

13

13.586

13.52867

0.502459

20

7

15

11

28

28

28.12

28.04

0.069282

21

7

15

7

6.26

6.9

6.4

6.52

0.336452

22

7

11

15

12.36

12.5

12.8

12.55333

0.224796

23

7

11

11

9

8.9

9.23

9.043333

0.169214

24

7

11

7

6.35

7

7.5

6.95

0.576628

25

7

7

15

5.5

5.5

5.6

5.533333

0.057735

26

7

7

11

5.9

5.8

5.68

5.793333

0.110151

27

7

7

7

24

24.5

25

24.5

0.5

 

 

 

Table 7: DOE for 8 hr

Factor

A

B

C

8 HR % of drug release

Row #

K4 M

K15M

K100 M

Y1

Y2

Y3

Y bar

S

1

15

15

15

6.5

6

6.2

6.233333

0.251661

2

15

15

11

8.2

8.1

8.3

8.2

0.1

3

15

15

7

12

12.1

12.1

12.06667

0.057735

4

15

11

15

15

16

16.2

15.73333

0.64291

5

15

11

11

32

30.6

31

31.2

0.72111

6

15

11

7

59

58

57.2

58.06667

0.90185

7

15

7

15

26

27.5

27

26.83333

0.763763

8

15

7

11

70

70

71

70.33333

0.57735

9

15

7

7

22

21

22

21.66667

0.57735

10

11

15

15

26

25.3

25

25.43333

0.51316

11

11

15

11

22

21

22

21.66667

0.57735

12

11

15

7

30.2

30

31

30.4

0.52915

13

11

11

15

36.5

35

35.6

35.7

0.754983

14

11

11

11

9

10

11

10

1

15

11

11

7

24

25.3

26

25.1

1.014889

16

11

7

15

14

15

16

15

1

17

11

7

11

21

22

23

22

1

18

11

7

7

51

50

51.25

50.75

0.661438

19

7

15

15

22

23

24

23

1

20

7

15

11

56.5

55

55

55.5

0.866025

21

7

15

7

23.1

33

32.2

29.43333

5.499394

22

7

11

15

51

50

52

51

1

23

7

11

11

28

27.3

26

27.1

1.014889

24

7

11

7

16

15.8

16

15.93333

0.11547

25

7

7

15

11

10.4

10.5

10.63333

0.321455

26

7

7

11

11

11.8

12

11.6

0.52915

27

7

7

7

56.2

54.9

56

55.7

0.7

 

 

 

Table 8: DOE for 10 hr

Factor

A

B

C

10 HR % of drug releases

Row #

K4 M

K15 M

K100 M

Y1

Y2

Y3

Y bar

S

1

15

15

15

24

25

25

24.66667

0.57735

2

15

15

11

24

24

25

24.33333

0.57735

3

15

15

7

29.2

28

26

27.73333

1.616581

4

15

11

15

31.2

32

33

32.06667

0.90185

5

15

11

11

46.3

45

46

45.76667

0.680686

6

15

11

7

87.3

87.8

89

88.03333

0.873689

7

15

7

15

43.2

42

43

42.73333

0.64291

8

15

7

11

91

90

92

91

1

9

15

7

7

31

30

32

31

1

10

11

15

15

45

44

45

44.66667

0.57735

11

11

15

11

41.1

41

42

41.36667

0.550757

12

11

15

7

54.2

53

54

53.73333

0.64291

13

11

11

15

54

53

53.5

53.5

0.5

14

11

11

11

25.2

26.2

28

26.46667

1.41892

15

11

11

7

43.2

44

45

44.06667

0.90185

16

11

7

15

32.4

33

34

33.13333

0.80829

17

11

7

11

39.2

38

39.5

38.9

0.793725

18

11

7

7

72.3

71.4

72.2

71.96667

0.493288

19

7

15

15

43

42

23.2

36.06667

11.15407

20

7

15

11

73.2

72

73

72.73333

0.64291

21

7

15

7

58

56

57

57

1

22

7

11

15

69

69.2

70

69.4

0.52915

23

7

11

11

46

45

45.6

45.53333

0.503322

24

7

11

7

36

35

36

35.66667

0.57735

25

7

7

15

25

26

26.5

25.83333

0.763763

26

7

7

11

27.2

26

27

26.73333

0.64291

27

7

7

7

90

89

90.1

89.7

0.608276

 

 

 

Table 9: DOE for 16 hr

Factor

A

B

C

16 hr

% of drug release

Row #

k4 m

k15 m

k100 m

Y1

Y2

Y3

Y bar

S

1

15

15

15

45

46

47.2

46.06667

1.101514

2

15

15

11

68

66.8

67

67.26667

0.64291

3

15

15

7

71.2

70.8

72

71.33333

0.61101

4

15

11

15

68

66

67

67

1

5

15

11

11

74

75

75.8

74.93333

0.90185

6

15

11

7

100

100

100

100

0

7

15

7

15

77

76

78

77

1

8

15

7

11

100

100

100

100

0

9

15

7

7

51.2

50

51

50.73333

0.64291

10

11

15

15

73

74

74.5

73.83333

0.763763

11

11

15

11

71.2

70

72

71.06667

1.006645

12

11

15

7

75.3

75.4

75.8

75.5

0.264575

13

11

11

15

74

75

76

75

1

14

11

11

11

65.5

64

66

65.16667

1.040833

15

11

11

7

73.8

74

75

74.26667

0.64291

16

11

7

15

67.9

67

68

67.63333

0.550757

17

11

7

11

74.3

75

76

75.1

0.8544

18

11

7

7

100

99.1

96.6

98.56667

1.761628

19

7

15

15

57

56

58

57

1

20

7

15

11

82.1

81

82

81.7

0.608276

21

7

15

7

79.9

79

80

79.63333

0.550757

22

7

11

15

96

95.3

97

96.1

0.8544

23

7

11

11

76

75

74

75

1

24

7

11

7

71

70

71.2

70.73333

0.64291

25

7

7

15

59

58

59

58.66667

0.57735

26

7

7

11

61.3

60

32

51.1

16.55385

27

7

7

7

100

100

100

100

0

 

 


Table 10: Data generated by the software indicating the optimized range of polymer concentration

HPMC Grade

Low level (%)

High level (%)

K4M

14.5

15

K15M

7

7.5

K100M

8

9

 

Table 11: Dissolution Studies for F Optimum Formulations

TIME

(Hours)

% of drug release

F1

F2

F3

0

0

0

0

2

9

7

6.2

4

27

24.8

23

8

75

77

74

10

85.4

84

88

16

93

94

96

 

Fig. 1: Prepared Compression Coated Tablet of Verapamil HCl

 

Fig. 2: Y-hat Contour Plot K4 M vs K15 M

 

Fig. 3: Y-hat Contour Plot K4 M vs K100 M

 

Fig. 4: Y-hat Contour Plot K15 M vs K100 M

 

Fig. 5: Y-hat Surface Plot K15 M vs K100 M

 

Fig.6: Y-hat Contour Plot K4 M vs K15 M

 

Fig. 7: Y-hat Contour Plot K4 M vs K100 M

 

Fig. 8: Y-hat Contour Plot K15 M vs K100 M

 

Fig. 9: Y-hat Surface Plot K15 M vs K100 M

 

Fig. 10: Y-hat Contour Plot K4 M vs K15 M

 

Fig. 11: Y-hat Contour Plot K4 M vs K100 M

 

Fig. 12: Y-hat Contour Plot K15 M vs K100 M

 

Fig. 13: Y-hat Surface Plot K15M vs K100 M

 

Fig.14: Y-hat Contour Plot K4M vs K15 M

 

Fig. 15: Y-hat Contour Plot K4M vs K100 M

 

Fig. 16: Y-hat Contour Plot K15M vs K100 M

 

Fig. 17: Y-hat Surface Plot K15 M vs K100 M

 

Fig. 18: Y-hat Contour Plot K4 M vs K15 M

 

Fig. 19: Y-hat Contour Plot K4 M vs K100 M

 

Fig. 20: Y-hat Contour Plot K15 M vs K100 M

 

Fig. 21: Y-hat Surface Plot k15 M vs k100 M

 

Fig. 22: Comparison of % of drug release for various F optimized formulations and innovator product

 

Stability Testing:

During stability studies, % drug content and dissolution studies were performed at 0, 30, 60 and 90 days. As can be seen from Table 12, these parameters were slightly increased with respect to time but the changes in the observed parameters were not found to be statistically significant. Stability studies at 40±20C and 75±5% RH predicted a lower release of the drug from the tablet at the end of 90 days.

 

Table 12: Assay and dissolution test studies of the tablets stored at 40±20C and 75±5% RH.

S.N0

TIME (MONTHS)

0

1M

2M

3M

Assay (% drug content) (95% to 105%)

99.76

98.54

98.74

97.49

Dissolution -Mean % Drug Release at different time intervals

Time (hours)

Mean % Drug Release

0

1M

2M

3M

0

0

0

0

0

2 (NMT 15%)

6

6.89

7.32

8.5

4 (10 to 40%)

27

29.57

26.51

24.57

8 (45 to 85%)

75

68.54

71.77

77.45

10 (60 to 95%)

85

83.47

88.30

86.71

16(NLT 80% Q)

95

100.12

96.55

93.40

DISCUSSION:

The current work focuses on the development and optimization of modified release Verapamil tablets using the compression coating platform. The effect of the concentration and viscosity grades of combination of HPMC polymers K4M, K15M and K100M on the release profile was studied in DOE environment. The 27 experiments (33) which were designed by the DOE soft ware throws up a narrow optimum range for each of these 3 polymers within which the formulation may always match the desired drug release. Three batches of 1000 tablets each were fabricated and packed in HDPE containers (30s count). After the initial evaluation, the containers were induction sealed and incubated in 40 C/75% RH accelerated stability condition. Sampling was done at 1M, 2M and 3M interval. The samples were analyzed for drug content and dissolution profiling. The stability data indicates that the values are within acceptable range indicating that the product is stable.

 

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Received on 08.05.2017       Accepted on 30.07.2017     

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Tech.  2017; 7 (3): 117-126.

DOI: 10.5958/2231-5713.2017.00020.4