Metoprolol Succinate And Hydrochlorothiazide Bilayer Tablets

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ABSTRACT: 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 aim of present work was to develop a robust formulation of Bi-layer tablets of Metoprolol Succinate Extended Release and Hydrochlorothiazide Immediate Release using methocel as polymer and Cross-carmilose-sodium as super disintegrant respectively in two layers. The drug product developed to reduce Hypertension. 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. 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. Among the formulations of tablets, formulation -5 was taken as optimized formula due to its dissolution and other physical parameters in the official specifications.

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KEYWORDS: Metoprolol-Succinate , Hydrochlorothiazide, Bi-layered

tablet,compatability, 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 (Aithal KS et al., 1996; Akihiko I. et al 1996). 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. The primary objective is 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 (Fausett H. et al 2002).

Now a day's various developed and developing countries move towards combination therapy for treatment of various diseases and disorders requiring long term therapy such as hypertension and diabetes. Combination therapies have various advantages over monotherapy such as problem of dose dependent side effects minimized. A low-dose combination of two different agent reduces the dose-related risk, the addition of one agent may counteract some deleterious effects of the other. The term Bi-layered tablets refers to tablet containing subunits that may be either the same or different.Bi-layered tablets allows for designing and modulating the dissolution and release characteristics and they are prepared with one layer of drug for immediate release while second layer designed to release drug latter, either as second dose or in an extended release manner (Podczeck F. et al., 2008; Aithal KS et al., 1996). This study shows how to formulate the Bi-layered tablets of Metoprolol Succinate Extended Release and Hydrochlorothiazide Immediate Release by using methocel (K4M and K100M) as polymer and Cross-carmilose-sodium as super disintegrant respectively in two layers (Siepmann J. et al 2001; Fausett H. et al 2002). 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 . 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, is believed to lower peripheral vascular resistance and produces antihypertensive effect . 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 and Cross-carmilose-sodium as super disintegrant respectively in two layers. Bi-layer tablet is suitable for sequential release of two drugs in combination, separate two incompatible substances. Bi-layer tablets are preferred when the release profiles of the drugs are different from one another (Rajabi AR. et al 2004; Lauretta M. et al., 1999; Huber HE et al.,1996 ).

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Main objective to develop bi-layer tablet of Hydrochlorothiazide (immediate release layer) and Metoprolol Succinate (extended release layer) to avoid chemical incompatibility between Hydrochlorothiazide and Metoprolol Succinate.

Bi-layer tablets are prepared with one layer of drug for immediate release with second layer design to release drug, later, either as second dose or in an extended release manner. 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 (Vyas SP. Et al 2002). 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. 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 (Huber HE et al., 1996).

Materials and Methods

Materials

Metoprolol Succinate, Hydrochlorothiazide, Povidone k-30, Starch, Lactose monohydrate 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 was received from Alkem Laboratories Limited, Taloja, Navi Mumbai.

Methods

Analysis of Innovator Product

Innovator product (METO-ER-HT 50) was analysed to evaluate its physical parameters and drug release profile so that the formulation being developed can be compared. Further, this will facilitate calculation of the dissimilarity (f1) and similarity (f2) dissolution factor.

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 and 2. Up to five formulations are prepared. Granulation of first Metoprolol Succinate layer is prepared by sifting the materials shown in table-1, through the sieve separately. Then binding agent is prepared by dissolving Povidone k-30 in specified quantity of Isopropyl Alcohol. Load the sifted Metoprolol Succinate, Lactose monohydrate, Methocel (K4M and K100M), Xanthan gum, in a rapid mixing granulator, add the binding agent which is previously prepared (Aithal KS et al., 1996). After granulation done the lubrication with remaining ingredients shown in table 1, then formed granules subjected for compression in bi-layer machine. Similarly granulation of Hydrochlorothiazide layer is prepared by sifting the materials shown in table-2, through the sieve separately. Then binding agent is 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 shown in table 2, then formed granules subjected for compression in bi-layer machine which is specifically designed and developed for the production of quality Bi-layer tablets. Metoprolol Succinate layer blend is initially pre-compressed with low hardness and Hydrochlorothiazide layer blend is compressed over it, till the desired hardness is achieved (Birringer N. et al 2005). This technology is called Bi-layered technology. Before tablet preparation the mixture blend of all formulations are subjected to pre-formulation studies like bulk density, tapped density, compressibility index (%), hausners ratio and angle of repose.

Compatibility Study

The study to evaluate compatibility of drug, polymers and other excipients under experimental conditions is an important prerequisite before actual formulation is initiated in order to confirm that the drug does not react with the polymers and excipients and affect the shelf stability of product. Differential scanning calorimetry (DSC) study was conducted to identify compatibility between drugs and excipients (Wells J.I. et al 1988).

Evaluation of Tablets

The prepared tablets can be evaluated for various official and non-official specifications ( Rahman Z et al., 2006 ;Chinam N.P. et al., 2007).

Thickness

The thickness of the tablet is measured by vernier calipers scale. Thickness of the tablet related to the tablet hardness and can be used an initial control parameter.

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 and Friability

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Tablets were evaluated for hardness and friability test using Dr.Schleuniger Pharmatron hardness tester and Roche friabilator respectively.

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 (Huber HE et al.,1996).

In-vitro drug release study

An in-vitro drug release study was carried out 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 (Lauretta M. et al., 1999).

Calculation of Dissimilarity (f1) and Similarity (f2) Factor

Dissimilarity factor (f1)

It was calculated in the comparison with reference or with the innovator product to know the dissimilarity.

∑ Rt - Tt

f1= ---------------- 100

∑ Rt

The dissimilarity factor (f1) should be always less than 15 (f1<15)

Similarity factor (f2)

The similarity factor (f2) was defined as the logarithmic reciprocal square root transformation of one plus the mean squared difference in percent dissolved between the test and the reference products. This was calculated to compare the test with reference release profiles.

1

f2 = 50 - log10 - - 100

1+ 1/n - ∑ (Rt - Tt) 2

Where, n= numbers of sampling points

The similarity factor (f2) should be always greater than 50 (f2>50)

Mathematical Modeling of In Vitro Dissolution: (Drug Release Models)

Drug release mechanisms and kinetics are the two important characteristics of a drug delivery system in describing drug dissolution profile such as zero-order, first order, Higuchi, Hixson-Crowell and Korsmeyer-Peppas models were used (Notari RE 2005; Varma VS. et al 2004).

Stability Studies:

Stability of a drug has been defined as the ability of a particular formulation, in a specific container, to remain within its physical, chemical, therapeutic and toxicological specifications. The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and enables recommended storage conditions, retest periods and shelf lives to be established. stability studies were carried out at 40 ± 2 oC/ 75 ± 5 % RH, 30 ± 2 oC/ 75 ± 5 % RH and 25 ± 2 oC/ 60 ± 5 % RH for a specific time period up to 60 days for developed formulation F5 as per ICH guideline.

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 and innovator such as thickness, weight variation, hardness, friability, and uniformity of drug content 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. The formulation F4 and 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%. 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 criterion for weight variation is ±5% all parameters are shown in table 4. 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. The comparative dissolution profile of both layer are shown in the figure 4 and 5. 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 for immediate release layer. 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 ( Reynolds JEF., et al., 1982)

DSC thermogram of Metoprolol Succinate shows sharp endothermic peak at 138.8°C and Hydrochlorothiazide shows sharp endothermic peak at 272.22°C indicating the melting point of stable crystalline drug. However, the DSC thermograms of tablet Formulation F5 shows sharp endothermic peak at 133.03°C and 272.22°C respectively. These thermograms indicate that was no significant changes in melting point, peak shape, area and peak location were found. Therefore, this study revealed that there was no interaction between the drugs, polymers and other excipients as shown in figure 1 to 3.

It has been observed that in the formulation 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.

Release rates obtained from the optimised formulations B.NoF5 were subjected to kinetic treatment to understand the drug release behaviour. The data were grouped according to five modes of data treatment as follows-

1. Cumulative percent drug released v/s time (zero order release kinetics)

2. Log cumulative percent drug retained v/s time (first order release kinetics)

3. Cumulative percent drug released v/s square root of time (Higuchi model of

drug release kinetics)

4. Cube root of percent drug remaining v/s time (Hixson-Crowell cube root law)

5. Log cumulative percent drug release v/s log time (Korsmeyer-Peppas drug

release kinetics) The results of kinetic treatment are given in table 8 and figure 6 to 7.

The results obtained showed no significant variation (1 to 2 %) in the drug release and uniformity of drug content. From this 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 table 9 and 10.

From above all results 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 1 Comparative composition profile of bi-layer 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)

11

Hydrochlorothiazide

12.5

12.5

12.5

12.5

12.5

12

Lactose monohydrate

87

83

84

83

83

13

DCP Anhydrous

38.5

43

40

40

40

14

Brilliant blue

3

3

3

3

3

15

Starch

1

1.5

1.5

1.5

1.5

16

Purified Water

q.s.

q.s.

q.s.

q.s.

q.s.

17

Cross carmilose sodium

5

4

6

7

7

18

Purified Talc

1.5

1.5

1.5

1.5

1.5

19

Magnesium stearate

1.5

1.5

1.5

1.5

1.5

 

Total weight (mg)

420

440

440

450

450

Table 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 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 4 Evaluation of compressed tablets and Innovator.

Batch No.

F1

F2

F3

F4

F5

Innovator

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

Table 5 In-Vitro dissolution profile of Metoprolol succinate layer of

compressed tablets and innovator.

Time (hours)

%Drug release of Metoprolol succinate

F1

F2

F3

F4

F5

Innovator

1

16.83 %

15.5 %

14.9 %

14.6 %

13.8%

12.6 %

4

39.60 %

36.6 %

36.7 %

35.4 %

34.1 %

31.02 %

8

59.60 %

56.1 %

57.1 %

55.0 %

54.8 %

47.70 %

20

92.40 %

89.0 %

92.2 %

89.4 %

88.5%

83.60 %

24

96.7 %

94.4 %

95.5 %

97.5%

98.1 %

96.70 %

Table 6 In-Vitro dissolution profile of Hydrochlorothiazide layer of compressed

tablets and innovator.

Time (min)

%Drug release of Hydrochlorothiazide

F1

F2

F3

F4

F5

Innovator

5

4.10 %

3.60 %

3.80%

4.00 %

4.90 %

4.80 %

10

10.5 %

9.7%

10.2%

10.2%

12.1%

11.2 %

15

28.40%

27.70 %

29.60%

30.50%

31.0 %

30.70 %

30

82.40 %

84.80%

80.10%

84.60%

84.50%

81.30 %

45

92%

91%

93%

93%

95%

94%

60

97%

96%

97.54%

98.43%

98.50%

97.9%

Table 7 Dissimilarity( f1) and Similarity( f2) studies results of formulation F5.

Batch No.F5

f1

f2

Metoprolol Succinate layer

4.02%

81.15%

Hydrochlorothiazide layer

1.91%

87.77%

Table 8 R2 values of different mathematical models (batch F5).

Batch No.F5

Zero order

First order

Higuchi

model

Hixson-Crowell

Korsmeyer-Peppas

Best fit

model

ER layer

0.952

0.181

0.995

0.146

0.761

Higuchi

model

IR layer

0.949

0.068

0.845

0.072

0.985

Korsmeyer-Peppas

Table 9 Stability study at 40 ± 2 °C/ 75 ± 5 % RH of Metoprolol Succinate layer.

Time

(days)

Condition

Drug release (%)

Uniformity of drug content

1hr.

4hr.

8hr.

20hr

24hr.

0

Initial

13.2

28.5

52.8

93.4

98.2

100.99 %

15

40 ±2 °C and 75 ±5 % RH

12.6

28.5

52.3

93.8

99.1

103.21 %

30

40 ±2 °C and 75 ±5 % RH

11.5

28.4

52.9

93.2

99.5

102.10 %

45

40 ±2 °C and 75 ±5 % RH

12.9

28.9

52.6

93.5

99.0

100.99 %

60

40 ±2 °C and 75 ±5 % RH

11.9

28.2

52.6

93.4

98.9

99.36 %

Table 10 Stability study at 40 ± 2 °C/ 75 ± 5 % RH of Hydrochlorothiazide layer.

Time

(days)

Condition

Drug release (%)

Uniformity of drug content

5

min

10

min

15

min

30

min

45

min

60

min

0

Initial

4

10.4

30.4

81.2

93.6

98.9

99.99 %

15

40 ±2 °C and 75 ±5 % RH

4.2

10.5

30.6

83.4

94.5

98.9

101.29 %

30

40 ±2 °C and 75 ±5 % RH

3.9

10.8

30.3

83.5

93.4

98.9

102.37 %

45

40 ±2 °C and 75 ±5 % RH

4.4

10.4

30.8

84.6

94.8

98.7

99.88 %

60

40 ±2 °C and 75 ±5 % RH

4.1

10.6

30.6

83.6

94.9

99.1

103.87

Fig. 1 DSC thermogram of pure Metoprolol Succinate.

Fig. 2 DSC thermogram of pure Hydrochlorothiazide.

Fig. 3 DSC thermogram of Tablet formulation F5.

Fig. 4 Comparative in vitro dissolution profile of ER layer.

Fig. 5 Comparative in vitro dissolution profile of IR layer.

Fig. 6 Different mathematical models of ER layer for B.No.F5.

Fig. 7 Different mathematical models of IR layer for B.No.F5.

Acknowledgements:

The authors are thankful to Alkem Laboratories Limited, Taloja, Navi Mumbai. Also thankful to the management and staff of The Erode College Of Pharmacy And Research Institute, Erode, Tamil Nadu.