Development of Metoprolol Tartrate Sustained Release Formulations by using Modified Starches

 

T. E. Gopala Krishna Murthy, V. Akash*

Dept. of Pharmaceutics, Bapatla College of Pharmacy, Bapatla, Guntur, Andhra Pradesh, India.

*Corresponding Author E-mail: aakashvemuri999@gmail.com

 

ABSTRACT:

The present study was under taken to develop sustained release formulations for Metoprolol tartrate , a β-blocker for the treatment of Hypertension. The tablets were prepared by wet granulation technique by using modified starches as release retardant polymers. The evaluation involves 3 stages i.e. pre-compression, post compression parameters and in-vitro release kinetics assessment of tablets. The USP-II paddle method was selected to perform the dissolution test and 500ml of 6.8 pH phosphate buffer was used as dissolution medium at 50rpm at 37 C ± 0.5. The release kinetics was analyzed. All the formulations followed Peppa’s release mechanism. When the release data was plotted into korsmeyer-Peppas equation (log cumulative % of drug release Vs log time), it was observed that all formulations (F2 to F11) (formulated with modified starches) followed Anamalous (non- Fickian) type of mechanism. The in-vitro release studies revealed that the formulation F5(formulated with Potato Starch containing 1:4 drug :polymer ratio), F8(formulated with Corn Starch containing 1:3 drug :polymer ratio) and F11 formulated with Rice Starch containing 1:3 drug :polymer ratio) can be taken as ideal or optimized formulations for sustained release formulations as it fulfills all the requirements.

 

KEYWORDS: Sustained release formulations, Metoprolol  tartrate, Potato starch, Corn starch , Rice starch , Calcium starch , In-vitro release kinetics.

 

 


INTRODUCTION:

Starch is a natural, cheap, available, renewable, and biodegradable polymer produced by many plants as a source of stored energy. It is the second most abundant biomass material in nature. It is found in plant leaves, stems, roots, bulbs, nuts, stalks, crop seeds, and staple crops such as rice, corn, wheat, cassava, and potato.

 

From serving as food for man starch has been found to be effective in drying up skin lesions (dermatitis) especially where there are watery exudates consequently  starch is a major component of dusting powders, pastes and ointments meant to provide protective and healing effect on skins. Starch mucilage has also performed emollient and major base in enemas. Because of its ability to form complex with iodine, starch has been used in treating iodine poisoning. Acute diarrhea has also been effectively prevented or treated with starch based solutions due to the excellent ability of starch to take up water. In Pharmacy, starch appears indispensable; It is used as excipients in several medicines. Its traditional role as a disintegrant or diluent is giving way to the more modern role as drug carrier; the therapeutic effect of the starch-adsorbed or starch-encapsulated or starch-conjugated drug largely depends on the type of starch.

 

During recent years, starch has been taken as a new potential biomaterial for pharmaceutical applications because of the unique physicochemical and functional characteristics. Starch is composed of very small spherical or elliptical granules it is colorless, odorless with slight characteristic taste, insoluble in water and alcohol. In pharmaceutical industry, Starch is an important excipient that has been commonly employed because of its versatility and cheapness.

 

Modified starches in different forms such as Grafted, acetylated and phosphate ester derivative have been extensively evaluated for sustaining the release of drug for better patient compliances. Starch-based biodegradable polymers, in the form of microsphere or hydrogel, are suitable for drug delivery.[2,3,4]

 

Sources of starch:

starch comprises of mostly polysaccharide granules usually seperated from the fully grown grains of corn [Zea mays Linn.]; rice [Oryza sativa Linn.]; and wheat [Triticum aestivum Linn.] and from the tubers of potato [Solanum tuberosum Linn.].

 

Metoprolol tartrate is a potent, β with antihypertensive activity. It is readily absorbed from the gastrointestinal tract with oral bioavailability of about 50% and a plasma elimination half- life ranging from 3 to 4 h. Administration of Metoprolol tartrate  in a sustained release dosage form with an extended release over 20 hrs, would be more desirable as these characteristics would allow a rapid onset followed by protracted anti-hypertensive effects by maintaining the plasma concentrations of the drug well above the therapeutic concentration, thus minimizing the need for frequent administration and dose related side effects[1]

 

MATERIALS AND METHODS:

Materials:

Metoprolol tartrate is obtained as gift sample from Apogen Pharma Pvt Ltd., Bapatla. Potato starch, Corn starch, Rice starch, Magnesium stearate and Talc were procured from SD Fine chemicals Ltd .Calcium chloride and sodium hydroxide were procured from Fisher scientific. All the chemicals and reagents used in this investigation were of analytical grade.

 

Methods:

Chemical modification of Starch:

Preparation of calcium starch:[10,11,12]

Calcium starch, a new starch based polymer and to evaluate its application in controlled release (CR). Calcium starch polymer was synthesized by gelatinization of starch in the presence of sodium hydroxide and cross linking by treatment with calcium chloride. Potato starch/ Corn starch/ rice starch (5 parts) was dispersed in purified water (50 parts) to form starch slurry. Sodium hydroxide (3 parts) was dissolved in water (30 parts) and the solution was added to starch slurry, while mixing. Mixing was continued for 30 minutes to form a thick gelatinized mass. The mass formed was added to 300 mL of calcium chloride (20% w/v) solution contained in a vessel while stirring at 1000 rpm with a medium duty stirrer. The stirring was continued for 1 hour to precipitate calcium starch formed. The calcium starch formed was collected by vacuum filtration, washed repeatedly with water and dried at 80ºC. The dried polymer was powdered and passed through mesh No.100.

 

Preformulation studies on Metoprolol tartrate:

Fourier Transform Infrared Spectrophotometer (FTIR):

Metoprolol tartrate - selected excipients and mixtures were subjected to IR spectral study in order to detect the interactions between the drug and selected inactive ingredients. The drug excipients mixtures were prepared by blending the drug and excipients in 1; 1 ratio. The resulting blend was transferred into a vial and sealed properly. Such sealed vials were kept in a stability chamber and maintained at 40 ± 0.2 C, 75 ± 0.5% RH. The vials were stored for a period of 1 month. The samples were withdrawn and subjected to IR studies by KBR pellet technique.The physicochemical compatibility between metoprolol tartrate and excipients (starch, calcium starch prepare by using Potato starch ,Corn satrch, Rice starch) used in this work were carried out by subjecting to IR spectral studies by using Perkin Fourier Transform Infrared spectrophotometer, (Shelton USA). The samples were scanned within the wave length region between 3923cm-1 to 665cm-1. The spectra obtained for metoprolol tartrate and physical mixtures metoprolol tartrate blended with the selected components were compared.

 

Preparation of Metoprolol tartrate sustained release tablets by wet granulation method:[9]

Accurately weighed quantities of the drug, polymer (selected modified starches) were mixed in a polybag and then taken into a glass mortar and then wetted with isopropyl alcohol (IPA) as granulating fluid. The cohesive mass was then passed through mesh no. #24. The granules obtained were dried in a hot air oven and maintained at a temperature not more than 50 C for about 45min. Based on the drug content, granules were weighed and required quantities of talc and magnesium stearate were added and compressed into tablets with 16 station rotary tableting machine (Cadmach machinery, Ahmedabad, India) using 9mm and 12mm round punches to the required hardness.

 

Evaluation of modified release tablets:[7,8]

1)      Pre-compression parameters:

Metoprolol tartrate granules formulated with modified starches were evaluated for various pre-compression parameters like bulk density, tapped density, carr’s index and Hausner’s ratio as per the standard procedure reported in literature[7, 8]

2)      Post-compression parameters:

The formulated tablets were characterized for hardness, friability, weight variation, drug content and swelling index.

a)      Thickness of tablets was measured by using vernier calipers.

b)     Hardness and Friability was measured by using Monstanto hardness tester (Cadmach, Ahmedabad, India) and the Roche friabilator (Electro lab, Mumbai, India).

c)      Weight variation:

Twenty tablets were collected and were weighed collectively and individually. From the collective weight, average weight was calculated. The percent weight variation was calculated by using the following formulae.

% Weight variation =

                [Average weight – Individual weight]/Average weight×100

 

d) Drug content determination:

Five tablets were collected, powdered and powder containing the equivalent to 105mg of drug was dissolved in 100ml of buffer (6.8 pH phosphate). Then the solution was filtered, suitably diluted and analysed for Metoprolol tartrate by measuring the absorbance spectrophotometrically at 223nm.

 

3)      In vitro dissolution studies of formulated tablets[9]:

In vitro dissolution studies for Metoprolol tartrate sustained release tablets were performed in pH 6.8 phosphate buffer by using USP type II dissolution test apparatus with paddle stirrer, the stirring speed employed was 50rpm and the temperature was maintained at 37 ± 0.5 C. Samples were withdrawn at different time intervals and replaced with fresh dissolution medium, solutions were filtered and determined for metoprolol tartrate content by UV- Spectrophotometer at 223nm.

 

4)      Kinetic studies [16, 17]:

The in-vitro release data was subjected to zero order, first order, Higuchis, Korsemeyer- Peppas and Hixson crowell mathematical model in order to establish the drug release mechanism and kinetics of drug release from the sustained release tablets.

 

5)      Similarity factor analysis (f2):[15]:

To determine the similarity factor, in-vitro release profile of all the formulated tablets was compared with the theoretical release profile. If f2 > 50, it is considered that the products share similar drug release behaviors’. The data was analyzed by using the following formulae.

 

f2 = 50 log {1+(1/n)ƹ(Ri – Ti)2] – 0.5 × 100

 

Where n = number of time points, Ri and Ti are dissolution of reference and test products at time.

 

RESULTS AND DISCUSSION:

The Studies were under taken to study the effect of various Starches such as potato Starch, Corn Starch, Rice Starch modified as Calcium Starch on physical characters and In-vitro drug release of Metoprolol tartrate from the formulated Sustained release tablets At first we observed that the modification of the starch was done successfully by observing the disappearance of the hydroxyl peak in peaks of calcium starch by comparing the peaks of starch and calcium starch we can observe the missing peak in calcium starch which indicates the hydroxyl group.(figure 1 and figure 2) 

 

Later we can observe that there are no changes in functional groups of the metoprolol tartrate even after mixing it with the calcium starch which indicates the drug-excipient compatibility. (figure 3 to figure 6). As the Principle peaks observed were identical in the spectra of drug and spectra of various mixtures, so it was confirmed that no chemical or physical interaction exists between the drug and the excipients employed in this investigation.

 

The blend containing Metoprolol tartrate and various Calcium starches with different ratios were evaluated for micromeritic properties, and results were reported in the table 2. The observed Hausner’s ratio was found in between 1.12 to 1.23 and Carr’s index in between 9.45 to 15.71. These results are indicating that the blends are exhibiting good flow property and hence they were subjected to compression. All the formulated tablets (F1 to F11) were evaluated for thickness, hardness, friability, weight variation, drug content and the results were reported in the table 3. From the observed results all the formulated tablets found to satisfy the quality control requirements and are within limits as per IP.

 

All the formulated tablets (F1 to F11) were subjected to In vitro drug release studies and the results were shown in figure 7 to figure 9. The drug release from the all formulations with modified starches (F1 to F11) followed zero order release kinetics. The value of “n” as estimated for modified starches by linear regression of log Qt / Q vs log t of formulations (F1 to F11) was 0.79, 0.71, 0.71, 0.73, 0.74, 0.61, 0.68, 0.72, 0.71, 0.76, 0.79 respectively indicated that drug release from tablets followed Anomalous (non-fickian) diffusion. The release data observed from all the formulated tablets (F1 to F11) were compared with the theoretical release profiles given in USP. From the observed results the formulations F5, F8and F11 has similarity factor greater than 50 and satisfied all the requirements (table no: 4).

 

The formulations that are prepared with Calcium Starch from different sources and in different ratios showed different rates of drug release .The drug release observed from the formulations was found to be dependent on the amount of calcium starch present in the formulation. The drug release was found to be reduced with the concentration of calcium starch.(figures 7 to 9) it is also observed that the corn starch (F8) and rice starch (F11)  are more effective than potato starch (F4) by comparing the drug release at same concentrations (figure 10).

 

CONCLUSION:

The formulations prepared with potato starch at 1: 4 ratio, corn and rice starches at 1:3 ratios satisfied all the Quality control requirements and provided required release of metoprolol tartrate sustained release formulations.


 

 

RESULTS:

Table No 1. Composition of Metoprolol tartrate formulated with Starch and modified Starch

 

Quantity mg per tablet

Ingredients

F1

F2

F3

F4

F5

F6

F7

F8

F9

F10

F11

Metoprolol tartrate

105

105

105

105

105

105

105

105

105

105

105

Starch

100

-

-

-

-

-

-

-

-

 

 

Calcium starch(potato)

-

100

-

-

-

-

-

-

-

 

 

Calcium starch(potato)

-

-

200

-

-

-

-

-

-

 

 

Calcium starch(potato)

-

-

-

300

-

-

-

-

-

 

 

Calcium starch(potato)

-

-

-

-

400

-

-

-

-

 

 

Calcium starch(corn)

-

-

-

-

-

100

-

-

-

 

 

Calcium starch(corn)

-

-

-

-

-

-

200

-

-

 

 

Calcium starch(corn)

-

-

-

-

-

-

-

300

-

 

 

Calcium starch(rice)

-

-

-

-

-

-

-

-

100

 

 

Calcium starch(rice)

-

-

-

-

-

-

-

-

-

200

 

Calcium starch(rice)

 

 

 

 

 

 

 

 

 

 

300

Magnesium stearate

5

5

5

5

5

5

5

5

5

5

5

Talc

5

5

5

5

5

5

5

5

5

5

5

Total weight

215

215

315

415

515

215

315

415

215

315

415

 

Table No 2. Micromeritic properties observed from Metoprolol tartrate granules formulated with starch and modified starches

Formulation

Bulk density (gm /ml)

Tapped density (gm /ml)

Carr’s index (%)

Hausner’s ratio (%)

F1

0.54 ± 0.24

0.63 ± 0.19

12.73 ±  1.25

1.13 ± 0.05

F2

0.55 ± 0.36

0.62 ± 0.31

11.29 ± 1.06

1.12 ± 0.03

F3

0.51  ± 0.25

0.58 ±  0.26

12.06 ±  1.65

1.16 ± 0.05

F4

0.58  ± 0.14

0.67 ± 0.15

13.43  ± 1.41

1.15±  0.02

F5

0.52 ± 0.17

0.60 ±  0.30

13.33  ± 1.28

1.15 ± 0.06

F6

0.63 ± 0.21

0.71 ± 0.19

11.26 ± 1.21

1.12 ± 0.02

F7

0.67± 0.12

0.74  ±0.09

9.45  ± 1.63

1.23 ± 0.05

F8

0.66  ± 0.17

0.70  ± 0.24

15.71  ± 1.47

1.09 ± 0.03

F9

0.55 ±  0.15

0.64 ± 0.12

14.06  ± 1.13

1.16 ± 0.05

F10

0.54  ± 0.26

0.62 ±  0.24

12.90  ± 1.09

1.14 ± 0.02

F11

0.59  ± 0.18

0.67  ±  0.17

11.94 ±  1.29

1.13 ± 0.04

 

Table No 3. Physical characters observed from metoprolol tartrate tablets formulated with starch and modified starch

Formulation code

Hardness (kg/cm2)

Thickness (mm)

Average weight (mg)

Friability (%)

Drug content (%)

F1

4.17±0.22

4.2 ±  0.09

216.2± 0.05

0.67±0.04

97.74±0.3

F2

4.11± .36

4.5 ± 0.04

216.6± 0.03

0.69±0.05

98.1±0.5

F3

3.85± .23

4.1 ±  0.1

314.4± 0.02

0.72±0.08

97.04±0.3

F4

4.08± .17

4.3 ± 0.06

417.2 ±0.04

0.63±0.04

98.3± 0.6

F5

4.27± .27

4.5 ± 0.07

517.4± 0.03

0.84±0.07

98.7 ± 0.3

F6

4.12±0.51

4.3 ± 0.05

217± 0.05

0.72±0.03

97.1±0.4

F7

3.93± .17

3.9  ± 0.07

316 ± 0.03

0.76±0.07

96.5±0.6

F8

4.26±0.31

4.4 ± 0.03

417 ±0.07

0.81±0.04

97.3± 0.3

F9

4.3 ± 0.19

4.1 ± 0.03

214.2± 0.05

0.67±0.05

96.7±0.4

F10

4.06± .23

3.9  ± 0.06

316.4± 0.07

0.71±0.09

98.6±0.7

F11

4.23± .17

4.3 ± 0.07

416.3± 0.03

0.65±0.03

98.4± 0.3

 

 

 

 

Table No 4. Release kinetics observed from metoprolol tartrate formulated with starch and modified starches:

 

Correlation coefficient (r) value

 

 

 

Formulation code

Zero order

First order

Higuchic’s

Peppa’s

T50

f2

Diffusion Exponent n value

F1

0.9841

0.8354

0.9351

0.9816

24.6(min)

7.8

0.79

F2

0.9858

0.9212

0.9699

0.9956

4.1

28.35

0.71

F3

0.985

0.9292

0.9659

0.9962

5.6

44.05

0.71

F4

0.9798

0.8972

0.969

0.999

7.9

56.73

0.73

F5

0.9948

0.8509

0.9232

0.9751

10.6

52.23

0.74

F6

0.9624

0.949

0.9828

0.9953

4.7

33.4

0.61

F7

0.9825

0.9239

0.9925

0.9761

7.5

52.7

0.68

F8

0.9899

0.8377

0.9496

0.9924

10.2

58.32

0.72

F9

0.9852

0.9481

0.9673

0.9963

5.4

40.95

0.71

F10

0.986

0.9121

0.9644

0.9984

7.2

95

0.76

F11

0.9926

0.7153

0.9501

0.9982

10

58.7

0.79

 


 

Figure 1 FT-IR spectra of Starch.

 

 

Figure 2 FT-IR spectra of Calcium Starch.

 

 

 

Figure  3  FT - IR spectra of Metoprolol tartarate + Calcium starch (Potato).

 

Figure 4 FT - IR spectra of Metoprolol tartarate + Calcium starch (Rice).

 

 

Figure 5  FT - IR spectra of Metoprolol tartarate + Calcium starch (Corn).

 

 

Figure 6: In vitro release profiles observed from Metoprolol tartrate tablets formulated with Starch.

 

Figure 7: In vitro release profiles observed from Metoprolol tartrate tablets formulated with different ratios of  Calcium Starch prepared by using Potato Starch.

 

 

Figure 8: In vitro Release profiles observed from Metoprolol tartrate tablets formulated with different ratios of Calcium Starch prepared by using Corn Starch.

 

 

Figure 9 : In vitro Release profiles observed from Metoprolol tartrate tablets formulated with different ratios of Calcium Starch prepared by using Rice Starch.

 

Figure 10: Plots for Comparitive metoprolol release profiles observed from the tablets formulated with different types of calcium starch.

 

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Received on 13.07.2018                Modified on 26.09.2018

Accepted on 05.10.2018            © A&V Publications All right reserved

Asian J. Res. Pharm. Sci. 2018; 8(4): 241-246.

DOI: 10.5958/2231-5659.2018.00040.1