Print Email Download Reference This Send to Kindle Reddit This
submit to reddit

Hydrochlorothiazide Immediate Release Bilayer Tablets Biology Essay

Bi-layer tablet is suitable for sequential release of two drugs in combination, separate two incompatible substances, and also for sustained release tablet in which one layer as immediate release layer as initial dose and second layer as maintenance dose. The purpose in extended release of any bi-layer tablet formulation is to separate physically or chemically incompatible ingredients and to produce repeat action or prolonged action of tablet. The aim of present work was to develop a robust formulation of bi-layer tablets of Metoprolol Succinate extended release by using methocel as polymer and Hydrochlorothiazide immediate release by using cross-carmilose-sodium as super disintegrant. Metoprolol Succinate is used in the management of hypertension, angina pectoris and heart failure in doses ranging from 25 mg to 200 mg. Hydrochlorothiazide is a first line diuretic drug of the thiazide class which inhibits the reabsorption of sodium, potassium ions in the nephron of the kidney and produces antihypertensive effect. A total number of five formulations have been taken to optimize and develop a robust and stable formulation. Wet-granulation process was used for the formulation of both layers and the final tablets were evaluated for the thickness, weight variation, hardness, friability, disintegration time, dissolution study. Among the all formulations F5 was taken as optimized formula due to its dissolution and other physical parameters with in the official specifications.

Keywords: Metoprolol Succinate , Hydrochlorothiazide, Bi-layered tablet, in vitro dissolution.

INTRODUCTION:

The scenario of pharmaceutical drug delivery is rapidly changing. Conventional pharmaceutical dosage forms are being replaced by new drug delivery systems. These new drug delivery systems are having edge over conventional ones in terms of many biopharmaceutical parameters, one such drug delivery system is combination of immediate release and extended-release drug delivery system. Bi-layer tablet is suitable for sequential release of two drugs in combination, separate two incompatible substances, and also for in which one layer as immediate release layer as initial dose and second layer as maintenance dose. Combination therapy have various advantages over monotherapy such as problem of dose dependent side effects were minimized. The combination of immediate release and extended-release drug delivery system is to ensure safety, improve the efficacy, reduce the dose frequency and ultimately result in improved patient compliance.1

Metoprolol Succinate is an antihypertensive (cardio selective b-blocker) used in the management of hypertension, angina pectoris and heart failure in doses ranging from 25 mg to 200 mg. It is a water soluble drug with bioavailability of 40-60 % and plasma half-life 3-7 hours. Hence, conventional tablet is insufficient to achieve the therapeutic plasma concentration for long duration of time and a dosage regime of twice or thrice daily is required.2 Hydrochlorothiazide is a first line diuretic drug of the thiazide class that acts by inhibiting the reabsorption of sodium, potassium ions in the nephron of the kidney. This reduces the volume of the blood, decreasing blood return to the heart and thus cardiac output and by other mechanisms. A drug having long half-life (7-14hr) doesn’t requires frequent dosing and this makes Hydrochlorothiazide an ideal candidate for an immediate release formulation, is believed to lower peripheral vascular resistance and produces antihypertensive effect.2

The use of two drugs in same formulation shows synergism effect to reduce hypertension. The object of this study was to formulate the bi-layered tablets of Metoprolol Succinate extended release and Hydrochlorothiazide immediate release by using methocel (K4M and K100M) as polymer in extended release layer and cross-carmilose-sodium as super disintegrant in immediate release layer. Metoprolol succinate is a rapidly and completely absorbed drug but plasma level achieved is highly variable after oral administration. Besides it also has relatively short elimination half-life (3 to 7 hours) then metoprolol succinate an ideal candidate for an extended release formulation.2

MATERIALS AND METHOD:

Metoprolol Succinate and Hydrochlorothiazide was received from Alkem Laboratories Limited, Taloja, Navi Mumbai. Also Povidone k-30, Starch, Lactose monohydrate was obtained from same laboratories. All other materials like Methocel (K4M and K100M), DCP Anhydrous, Brilliant blue, Cross-carmilose-sodium(Ac-Di-Sol), Xanthan gum, Sodium Stearyl Fumarate, Colloidal Anhydrous Silica(Aerosil-200) , Purified Talc and Magnesium stearate used was of analytical grade and procured from commercial sources.

Preparation of bi-layer tablets:

Metoprolol Succinate and Hydrochlorothiazide bi-layer tablets were prepared by wet granulation process according to the formula given in the table-1. Load the sifted Metoprolol Succinate, lactose monohydrate , methocel (K4M and K100M), xanthan gum in a rapid mixing granulator and add the binding agent which was previously prepared. After granulation done the lubrication with remaining ingredients. Then formed granules are subjected for compression in bi-layer machine (Kanbert). Similarly granulation of Hydrochlorothiazide layer was prepared by sifting the materials through the sieve separately. Then binding agent was prepared by dissolving starch in specified quantity of purified water. Load the sifted Hydrochlorothiazide, lactose monohydrate, DCP anhydrous, brilliant blue in a rapid mixing granulator , add the binding agent which is previously prepared. After granulation done the lubrication with remaining ingredients and subjected for compression in bi-layer machine which was specifically designed and developed for the production of quality bi-layer tablets. Metoprolol Succinate layer blend was initially pre-compressed with low hardness and Hydrochlorothiazide layer blend was compressed over it, till the desired hardness was achieved. This technology is called Bi-layered technology.

Before tablet preparation the mixture blend of all formulations were subjected to pre-formulation studies like bulk density, tapped density, compressibility index (%), hausners ratio and angle of repose.3

Evaluation of Tablets:

The prepared tablets were evaluated for various official specifications.3, 4

Thickness:

The thickness of the tablet was measured by vernier calipers scale.3

Weight variation: Twenty tablets were selected at a random and average weight was calculated. Then individual tablets were weighed and the individual weight was compared with an average weight.

Hardness:

Tablets were evaluated for hardness test using Dr.Schleuniger Pharmatron hardness tester.

Friability:

Tablets were evaluated for friability test using Roche friabilator .

In-vitro Disintegration Time:

A tablet was placed in each of the six tubes of the basket. Suspend the assembly in water maintained at a temperature of 370c ± 20c and operate the apparatus, simultaneously note the time taken to disintegrate completely by using stop watch clock.4

In-vitro drug release study:

An in-vitro drug release study was carried out by using tablet dissolution test apparatus USP type-2(paddle) at 50rpm. The dissolution medium consisted of 900ml phosphate buffer pH6.8, maintained at a temperature 370c ± 20c A sample of 5ml was withdrawn at predetermined time intervals and an equivalent amount of fresh dissolution fluid equilibrated at the same temperature was replaced, and then measure absorbance by HPLC technique.5

Study of Dissimilarity (f1) and Similarity (f2) Factors :

A statistical comparison of dissolution data was carried out using dissimilarity (f1) and similarity (f2) factors. The comparison of in vitro dissolution profiles of formulation with innovator.3,6

Stability Studies:

The effect of temperature and humidity on In vitro drug release, and Drug content of optimised formulation F5 was performed at three stability storage conditions, as per ICH guidelines (for 60 days) 40 ± 2 °C/ 75 ± 5 % RH ,30 ± 2 °C/ 75 ± 5 % RH, and 25 ± 2 °C/ 60 ± 5 % RH.

RESULTS AND DISCUSSION:

In the present study Metoprolol Succinate and Hydrochlorothiazide Bi-layered were prepared by wet granulation process by using ingredients shown in (table-1). A total number of five formulations were prepared. The values of preformulation parameters evaluated were within prescribed limit and indicated good fine flow property (table-2 and table-3). The data of evaluated tablets such as thickness, weight variation, hardness, friability, and in-vitro disintegration time, are shown in (table-4). The hardness was found to be in the range of 51 to 65 N(newton), the normal acceptance criteria for hardness are not more than 70 newton.1 The formulation F4, F5 has got hardness in the acceptable range and was consider acceptable upon comparing with the innovator product. All the formulations indicate good thickness. The friability was found to be in the range 0.002 % to 0.0045%. The normal acceptable criterion for friability is not more than 1.00%.7 The formulation F2, F3, F4 and F5 has got friability within the acceptable range. The weight variation was found to be ±1%. The normal acceptable criteria for weight variation is ±5%.8 The percentage drug release of Bi-layer tablets in F5 when compare with innovator was found to be release of Metoprolol Succinate 98.1% in 24hr and release of Hydrochlorothiazide 98.50% in 60min. The results were shown in the table-5 and table-6, While the in-vitro disintegration time of Hydrochlorothiazide layer found in the range of 3.50 to 5.34 min. Formulations F1, F2, F3, F4, and F5 are nearly matched with the disintegration time of innovator product. Among the formulation tablets of batch F5 containing Metoprolol Succinate 50mg and Hydrochlorothiazide 12.5mg per tablet is similar and equal to the innovator product in respect of all tablets properties and dissolution rate and showed good hardness, low friability, and disintegration time of 4.30min/sec. The percentage drug release for formulation F5 shows the better drug release of Metoprolol Succinate 98.1% in 24hr and release of Hydrochlorothiazide 98.50% in 60min.7

It has been observed that in the F5 dissimilarity (f1) factor was lowest (much below 15) while the similarity (f2) factor was highest (much above 50) indicating that the developed bi-layer tablet formulation has in vitro dissolution profile identical to the innovator product as shown in table-7.8

The results obtained showed no significant variation (1 to 2 %) in the drug release and uniformity of drug content. From the above results it was concluded that the formulation F5 was stable at 40 ± 2 °C and 75 ± 5 % RH, 30 ± 2 °C and 75 ± 5 % RH, 25 ± 2 °C and 60 ± 5 % RH for 60 days as shown in figure 3 and 4.9

It was concluded that Metoprolol Succinate and Hydrochlorothiazide Bi-layer tablets can be prepared successfully as it satisfies all the criteria as a Bi-layered tablet and would be alternative to the currently available conventional tablets.

Table no.1- Comparative composition profile of bilayer Tablet

FIRST LAYER (Metoprolol Succinate)

Sr.No

 

Ingredients

 

 

 

Batch no

 

 

F1 (mg/tab)

F2 (mg/tab)

F3 (mg/tab)

F4

(mg/tab)

F5

(mg/tab)

1

Metoprolol Succinate

47.5

47.5

47.5

47.5

47.5

2

Lactose monohydrate

26.50

26.50

26.50

26.50

26.50

3

Methocel (K-4M)

127

127

127

127

127

4

Methocel (K-100M)

50

60

55

50

50

5

Povidone (K-30)

9

9

9

9

9

6

Isopropyl alcohol

q.s.

q.s.

q.s.

q.s.

q.s.

7

Xanthan gum

----

10

15

30

30

8

Aerocil-200

2

2

2

2

2

9

Sodium stearyl fumarate

3

3

3

3

3

10

Purified Talc

5

5

5

5

5

SECOND LAYER (Hydrochlorothiazide)

1

Hydrochlorothiazide

12.5

12.5

12.5

12.5

12.5

2

Lactose monohydrate

87

83

84

83

83

3

DCP Anhydrous

38.5

43

40

40

40

4

Brilliant blue

3

3

3

3

3

5

Starch

1

1.5

1.5

1.5

1.5

6

Purified Water

q.s.

q.s.

q.s.

q.s.

q.s.

7

Cross carmilose sodium

5

4

6

7

7

8

Purified Talc

1.5

1.5

1.5

1.5

1.5

9

Magnesium stearate

1.5

1.5

1.5

1.5

1.5

 

Total weight (mg)

420

440

440

450

450

Table no.2

Micromeritic properties of powder blend of Metoprolol Succinate layer

Sr.

No.

Batch No.

Bulk density

(gm/cc)

Tapped density

(gm/ml)

Angle of

repose

(θ)

Compressibility

index (%)

Hausner ratio

1

F1

0.2918

0.4075

38.89

28.37

1.396

2

F2

0.3108

0.4229

36.33

26.5

1.36

3

F3

0.2949

0.3949

34.69

25.31

1.338

4

F4

0.2987

0.4083

36.77

26.82

1.366

5

F5

0.3505

0.4623

36.77

24.17

1.318

Table no.3

Micromeritic properties of powder blend of Hydrochlorothiazide layer

Sr.

No.

Batch No.

Bulk density

(gm/cc)

Tapped density

(gm/ml)

Angle of repose

(θ)

Compressibility

index (%)

Hausner ratio

1

F1

0.2749

0.4465

22.84

38.43

1.624

2

F2

0.3384

0.4769

32.71

29.041

1.409

3

F3

0.2569

0.3467

40.32

25.901

1.349

4

F4

0.2368

0.3375

38.94

29.83

1.425

5

F5

0.2648

0.3765

39.12

29.66

1.421

Table no.4

Evaluation of compressed tablets and Innovetor

Batch No.

F1

F2

F3

F4

F5

Innovetor

Thickness (mm)

4.7 ± 0.2

4.7 ± 0.2

4.5 ± 0.2

4.6 ± 0.2

4.8 ± 0.2

4.79± 0.2

Hardness (N)

51 ± 3

60± 3

65± 3

63± 3

55± 3

56± 3

Friability (%)

0.002

0.003

0.0023

0.0035

0.0045

0.0039

Weight variation (mg)

420± 1

440± 1

440± 1

450± 1

450± 1

450± 1

Uniformity of drug content (%)

100.12

101.51

100.69

103.32

100.98

100.18

TableNo.5 -In-Vitro dissolution profile of Metoprolol succinate layer

Time (hours)

%Drug release of Metoprolol succinate

F1

F2

F3

F4

F5

1

16.83 %

15.5 %

14.9 %

14.6 %

13.8%

4

39.60 %

36.6 %

36.7 %

35.4 %

34.1 %

8

59.60 %

56.1 %

57.1 %

55.0 %

54.8 %

20

92.40 %

89.0 %

92.2 %

89.4 %

88.5%

24

96.7 %

94.4 %

95.5 %

97.5%

98.1 %

Table No.6 In-Vitro dissolution profile of Hydrochlorothiazide layer

Time (min)

%Drug release of Hydrochlorothiazide

F1

F2

F3

F4

F5

5

4.10 %

3.60 %

3.80%

4.00 %

4.90 %

10

10.5 %

9.7%

10.2%

10.2%

12.1%

15

28.40%

27.70 %

29.60%

30.50%

31.0 %

30

82.40 %

84.80%

80.10%

84.60%

84.50%

45

92%

91%

93%

93%

95%

60

97%

96%

97.54%

98.43%

98.50%

Table No.7- Dissimilarity( f1) and Similarity( f2) studies results of F5

Batch No.F5

f1

f2

Metoprolol Succinate layer

4.02%

81.15%

Hydrochlorothiazide layer

1.91%

87.77%

Figure 1: Stability study at 40 ± 2 °C and 75 ± 5 % RH of Metoprolol Succinate layer.

Figure 2: Stability study at 40 ± 2 °C and 75 ± 5 % RH of Hydrochlorothiazide layer.

Print Email Download Reference This Send to Kindle Reddit This

Share This Essay

To share this essay on Reddit, Facebook, Twitter, or Google+ just click on the buttons below:

Request Removal

If you are the original writer of this essay and no longer wish to have the essay published on the UK Essays website then please click on the link below to request removal:

Request the removal of this essay.


More from UK Essays