Formulation and Evaluation of Fast Dissolving Tablet of Montelukast by using Co-processed Excipients

 

Kuldeep Kumar*, Himansu Chopra, Gyanendra Kumar Sharma

Rajiv Academy for Pharmacy, N.H. #2, Mathura Delhi Road, P.O. Chhatikara Mathura-281001(U.P) India

*Corresponding Author E-mail: kuldeepcpmt@gmail.com, h_chopra22@yahoo.com

 

ABSTRACT:

The current research work was aimed with an objective of formulation development of fast dissolving tablet of montelukast by using co-processed excipient and to evaluate the effect of co-processed excipient over physical mixture of same excipients. The co-processed excipients were developed by using solvent evaporation method. The sodium starch glycolate and mannitol were selected for co-processing. The co-processed mixture of excipient was used to develop montelukast tablet by direct compression method in different ratio. The developed formulation were evaluated for hardness, friability, weight variation, drug content, thickness, disintegration time, wetting time and in-vitro drug release. All batches showed weight variation within Pharmaceutical limit. Hardness was found within range of 2.96±0.5 to 3.37±0.2 kg/cm2. Wetting time was found in between 26±02 sec to 116±3.51 sec. Disintegration time was found to be in between 32±01 to 120±01 sec. On the basis of this statistical analysis of data it was concluded that formulation F8 can be selected at optimized formulation after analysis of in-vitro drug release and other characteristics. The in vitro release of drug was more in formulations prepared with co-processed excipient in comparison to their physical mixture.

 

KEYWORDS: Co-processed, Fast Dissolving, Excipients, Mannitol.

 

 

 

1. INTRODUCTION:

The oral route is most popular routes to ease intake, avoid pain, versatility and, most relevantly, patient compliance. This problem is more apparent when drinking water is not easily available to the patient taking medicine. It also have advantage as solid oral delivery system don’t need sterile conditions so it is less expensive to produce.1 In the recent past survey, new methods for the manufacture of mouth dissolving tablets (MDTs) have been discovered, which can reduce disintegration time, amaze mouth feeling and good taste masking. MDT manufacturing technologies include innovation and improvement of technologies such as freeze drying, sublimation, tablet molding, direct compression, spray drying, cotton candy procedure, as well as their advantages and disadvantages. These methods depend on the basic concept of booming porosity or the use of water-soluble superdisintegrants and excipients.2

 

 

Most of the formulations (> 70 percent) contain greater concentration of excipients than the active drug. Single component excipients do not always provide the required performance in the formulation of the active component, Therefore, a multi-component excipient scheme such as excipient co-processing needs to be developed to enhance formulation efficiency.3 A combination of two or more compendial or non-compendial excipients is a co-processed excipient used to alter their physical characteristics that cannot be accomplished by simple physical mixing without any chemical change.4 In this we coprocess Sodium starch glycolate and Mannitol  by varying in their concentration.

 

Montelukast is a leukotriene receptor antagonist used in chronic asthma and in bronchospasm. The present research involves the development and evaluation of Fast dissolving tablet of montelukast by using co-processed excipients containing Sodium starch glycolate and mannitol was studied.

 

2. MATERIALS AND METHODS:

2.1 Materials:

Montelukast was acquired from Ultra Drugs Pvt. Ltd. Baddi. Sodium Starch glycolate and Mannitol were acquired from Qualigens fine chemicals New Delhi. Microcrystalline cellulose, saccharin sodium and magnesium stearate were acquired from S.D fine chemical Ltd., Mumbai. Talc was acquired from Arora pharmaceuticals Ltd, New Delhi.

 

2.2 Methods:

2.2.1 Melting Point Determination:

By using capillary tube method the temperature at which powder was converted to liquid was recorded as melting point.

 

2.2.2 Solubility study:

In solubility study, four different solvents were used as water, ethanol, methanol and petroleum ether.1ml solvents were collected in a 10ml flask and the weight of drug to be dissolved is 100mg. In volumetric flask little amount of drugs were added and check the solubility. Powder form of drug has been added step by step to the extent of dissolution. The mass that was added was recorded. Each step may take several hours to complete the dissolution. When some particles remained in suspension, the last step was identified.

 

2.2.3 Partition Coefficient:

10ml octanol and 10ml phosphate buffer were pulled in a volumetric flask and 20mg of drugs was added in this solvents mixture, shake the mixture for 1 hour and stand this mixture in separating funnel for 48 hours at room temperature. Two layers were separate out and concentration of drug was calculated by using UV Spectroscopy.

 

2.2.4 Determination of Montelukast λmax:

The stock solution of Montelukast has been prepared by dissolution, accurately 10mg of Montelukast in methanol, in a 100ml volumetric flask to obtain a concentration of 100µg/ml.

 

PBS 6.8 pH phosphate buffer was made with mixing 0.2M potassium dihydrogen phosphate along with 0.2M NaOH, to maintain the volume distilled water was added and make up the volume to 1000ml.

 

2.2.5 Fourier Transform Infra-Red Spectroscopy Spectroscopy (FTIR):

FTIR study of drug and excipient was performed by Attenuated total reflectance (ATR) technique. A very small quantity of drug/excipient was kept in a diamond-shaped sample cell consist of Kbr. Take IR spectra of drug/excipient under IR range 4000-500 cm-1.

 

2.3 Formulation design:

Preparation of Co-processed excipients:

The Co-processed excipients were prepared by solvent evaporation technique using isopropyl alcohol, varying the concentration of SSG (2%, 4%, 6%, and 8%). In 10 ml isopropyl alcohol SSG and mannitol was mix and stirring continuously till most of ethanol evaporated. Then put this mixture in an oven at 50°C temperature about 20 min for evaporation of solvent. After this, all ingredients were mix in a mortar pestle and triturate and stored in airtight container till further use.

 

Preparation of Fast dissolving tablet by using direct compression method:

All formulations were prepared following direct compression method with single hand punching machine Total nine formulations were prepared by varying in quantity of ingredients, in which four batches were prepared by using co-processed ingredients.

 

 

Table 1: Composition of FDT of Montelukast

Name of Ingredients

Quantity in mg/ tablet

2%

4%

6%

8%

F1(CP)

F2

F3

F4(CP)

F5

F6(CP)

F7

F8(CP)

F9

Montelukast

10

10

10

10

10

10

10

10

10

CP (SSG+Mannitol)

100

-

-

100

-

100

-

100

-

SSG

-

3.6

-

-

7.2

-

10.8

-

14.4

Mannitol

-

96.4

100

-

92.8

-

89.2

-

85.6

MCC

66.4

66.4

66.4

66.4

66.4

66.4

66.4

66.4

66.4

Magnesium stearate

1.8

1.8

1.8

1.8

1.8

1.8

1.8

1.8

1.8

Talc

1.8

1.8

1.8

1.8

1.8

1.8

1.8

1.8

1.8

Total

180

180

180

180

180

180

180

180

180

 

 

2.4 Evaluation of prepared mouth dissolving tablets

I) Pre-Compression Parameters:

1. Bulk Density5:

The Bulk density of powder was measured by weighed an accurate mass of powder and transferred it in to a 50 ml measuring cylinder after this Bulk volume was measured. The cylinder was kept from a height of 2.5cm on a wooden surface. The keeping was continued until no existing volume changes were obtained (Until a steady volume) and Calculated as

Bulk Density= Powder Mass / Powder Volume

 

2. Tapped volume5:

It is the ratio of the total powder mass to the tapped powder volume.It was evaluated several times (about 100) by tapping the powder, and the pressed volume was observed.From this tapped density computed by the formula given below

 

DT= M / VT

Where,

DT= Tapped density,

M= Powder Weight in grams,

VT=Tapped volume of powder

 

3. Compressibility index and Hausner ratio5,6:

The powder was taken in a measuring cylinder, and bulk volume was noted down. Then it was tapped note the tapped volume. From that Carr’s index was calculated as follows-

 

CI=DT-DB / DTX100

 

Where,

DT=Powder Tapped density,

DB=Powder Bulk density. It is expressed in "percentage."

 

4. Hausner Ratio:

The ratio of the tapped density to the bulk density is hausner ratio. The formula calculates it as follows

 

Hausner ratio= DT/DB

 

Where,

DT= Tapped density,

DB=Bulk density.

 

II) Post-Compression parameters:

1. Hardness test5:

Durability has been determined using Monsanto Hardness Tester. Tablets hardness expressed in kg/cm2. Three tablets were chosen from each batch and assessed for hardness. Average value was determined with standard deviation.

 

2. Friability test5,7:

Roche friabilator was used for friability determination. It consists of a plastic chamber that revolves at 25rpm. The friability is expressed in %. Note the tablets initial weight individually (W initial).Tablets are placed in chamber and revolves 25rpm and they are subjected to fall from height of six inches in friabilator for approx 100 revolution. Then check the tablet weight (W final) and observe any difference in weight before the tablet and the processing of friabilator.

 

       Initial weight – Final weight

% Friabillity = -------------------------------------- x 100

    Initial weight

 

3. Drug content8:

In drug content, weigh and crush 20 tablets to make powder. Weigh precisely the powder amount equivalent to approximately 10mg of Montelukast was transferred to a standard 100ml flask and volume made up with 0.5% SLS in water. The solution was shaken slowly and filtered with what man filter paper to remove un-dissolved matter.

 

4. Uniformity of thickness5:

Vernier caliper was used to measure the thickness of the tablets. Six tablets were randomly selected for thickness. The extent to which each tablet's thickness deviated from the original value of ±5 percent was determined.

 

5. Wetting time of tablets9:

A piece of tissue paper was folded twice in a tiny Petri dish with 10 ml of water (internal diameter-6.5), a tablet was positioned on paper and the total wetting time was evaluated.

 

6. In vitro disintegration time5:

Tablets were measured for In vitro disintegration time using disintegration assembly. As per I.P, there was 6 basket tubes in each tubes put one tablet and one disk in each tube and start the assembly. PH 6.8 was used as an immersion liquid at 37° ± 02°C. Increase and reduce the assembly by 30cycles/minute. Measured and recorded the time observed for tablet's complete disintegration.

 

7. In vitro dissolution studies10:

Drug release was assessed using a USP type II dissolution device,100 rpm, maintained at 37±0.5 °C in the 900ml Ph 6.8 phosphate buffer, at continuous intervals 5ml sample was withdrawn and replaced with same volume of (37±0.5°C) fresh dissolution media. The samples collected have been filtered and analyzed, the amount of Montelukast was determined spectrophotometrically at 340nm.

 

3. RESULT AND DISCUSSION:

3.1 Determination of Melting Point:

The melting point of Montelukast was found to be 110°C.

 

3.2 Solubility study:

It was found to be freely soluble in Ethanol, Methanol and slightly soluble in water.

 

3.3 Partition coefficient:

The absorbance of drug in buffer layer was found to be 0.317. The partition coefficient was found to be 0.0033.

 

3.4 Determination of Montelukast λmax

A) UV spectroscopy:

The spectra of Montelukast were constructed between 200 to 400nm and wavelength maximum of drug was found equal to 340 nm.

 

B) Construction of calibration curve of Montelukast

Table 2: UV Absorbance of Drug solutions

Sr. No.

Concentration (mcg/ml)

Absorbance

0

0

0

1

2

0.121

2

4

0.221

3

6

0.295

4

8

0.368

5

10

0.455

 

Figure 1: Calibration curve of Montelukast

 

3. 5 IR Spectroscopy:

Excipient compatibility studies were carried out using Fourier Transform Infra Red spectroscopy to establish or rules out any possible interaction of Sodium starch glycolate with mannitol.

 

The FT-IR spectra of the coprocessed excipient were compared with the FT-IR spectra of pure compound. The results are shown in below figures, indicating that there is no significant shift in the IR values; hence it may conclude that there is no chemical interaction between SSG and mannitol.

 

A) Montelukast:

Figure 2: IR Spectra of Montelukast

 

B) Sodium starch glycolate (SSG):

 

Figure 3: IR Spectra of SSG

 

C) Mannitol:

 

Figure 4: IR Spectra of Mannitol

 

D) SSG + Mannitol (Co-processed):

 

Figure 5: IR Spectra of co-processed excipients (SSG + Mannitol)

 

DISCUSSION:

The precompression evaluation like tapped density, bulk density, Carr’s index, Hausner’s ratio and angle of repose was calculated for all formulation.

 

The bulk density was found in the range of 0.43to 0.56 gm/cm3, tapped density was found in the range of 0.57 to 0.75 gm/cm3. Compressibility index was observed in the range of 15.15 to 34.0 which indicate good flowability and compressibility of the powder blend. Hausner’s ratio results in the range of 1.17 to 1.52, which showed different pattern of flow properties of formulated batches.

 

The post compression parameter of formulated tablets showed promising results which comply the pharmacopeial limits also. The tablets weight variation was in the range of 0.72 to 1.1% which reveals good control of weight of tablets by the powder blend. The tablets hardness was found in the range of 2.96±0.5 to 3.37±0.45 kg/cm2. Which reveal good mechanical properties of formulated tablet. The thickness of tablets was in the range of 3.0±0.1 to 3.8±0.1 nm. The friability of all batches was found less than 1%. The drug content of different batches was found in the range of 97.82±0.52 to 99.65±0.03%. The wetting time was found in the range of 26±2 to 116±3.51 second.

 

Table 3: Results of Pre-compression parameters-

Formulation code

Bulk Density (gm/cm3)

Tapped Density (gm/cm3)

Carr’ s index (CI) %

Hausner’ s Ratio

Angle of Repose (ᶿ)

F1(CP)

0.50

0.62

19.35

1.24

26.00±0.70

F2

0.51

0.74

31.0

1.45

22.01±0.54

F3

0.48

0.73

34.0

1.52

24.70±0.98

F4(CP)

0.52

0.63

17.46

1.21

28.46±0.64

F5

0.54

0.75

28.0

1.38

23.72±0.16

F6(CP)

0.50

0.59

16.25

1.18

28.12±0.67

F7

0.51

0.68

25.0

1.33

30.12±1.14

F8(CP)

0.56

0.66

15.15

1.17

29.14±0.36

F9

0.43

0.57

24.56

1.32

28.12±0.65

 

Table 4: Result of the post-compression parameter-

Formulation code

Weight variation % deviation

Hardness

(Kg/cm2)

Thickness (mm)

Friability

(%)

Drug content

(%)

Wetting time(sec)

Disintegration time (Sec)

F1(CP)

0.94

3.11±0.05

3.1±0.02

0.68±0.005

98.06±0.05

40±2

50.3±1.52

F2

0.85

3.32±0.02

3.4±0.02

0.65±0.01

98.55±0.03

46±2

82±2

F3

1.08

3.35±0.05

3±0.1

0.58±0.011

97.82±0.52

116±3.51

120±1

F4(CP)

0.80

3.09±0.03

3.36±0.25

0.69±0.005

99.45±0.02

34.3±1.52

42.3±2.08

F5

0.72

3.37±0.45

3.8±0.09

0.55±0.01

99.36±0.02

39.3±1.52

48.3±1.52

F6(CP)

0.58

2.960±0.5

3.03±0.1

0.59±0.011

99.64±0.71

29.3±2.52

36±2

F7

1.1

3.2±0.015

3.23±0.57

0.59±0.023

99.65±0.03

37.3±1.15

45±3

F8(CP)

0.96

3.19±0.005

3.8±0.1

0.60±0.011

99.45±0.02

26±2

32±1

F9

0.85

3.37±0.02

3.6±0.40

0.69±0.01

99.65±0.03

32±2.08

39.3±3.05

 

IN vitro Dissolution studies:

 

Table 5: Result of cumulative % drug release of FDT of Montelukast formulation

Time (min)

5

10

20

30

40

50

60

F 1 (CP)

20.33±0.68

34.86±1.497

45.8±1.053

57.86±1.46

65.43±0.70

73.5±0.70

82.4±0.80

F2

18.5±0.45

31.16±1.05

43.03±1.68

51.56±0.83

61.56±1.51

68.36±1.38

76.9±1.90

F3

14.03±0.86

22.7±1.21

30.96±1.70

42.43±1.20

51.5±0.88

62.46±0.90

72.03±1.07

F4(CP)

24.83±0.95

41.7±1.5

55.23±1.05

68.43±1.07

81.76±1.07

87.33±0.8

91.36±1.2

F5

20.96±1.68

36.43±1.07

52.36±2.08

62.73±1.35

75.3±1.37

81.23±1.00

88.3±0.80

F6(CP)

28.46±1.22

45.6±1.07

61.63±0.8

72.6±0.7

85.43±1.00

91.66±0.75

91.66±0.25

F7

23.36±0.51

35.9±0.95

47.43±0.05

61.8±0.6

73.26±0.80

82.5±1.1

93.53±1.2

F8(CP)

32.73±0.70

48.8±0.87

65.5±0.98

76±0.2

92.06±1.05

97.0±1.02

98.76±0.51

F9

30.46±0.94

44.46±0.83

60.23±0.90

73.16±0.55

88.16±0.75

92.76±1.01

97.4±0.62

 

 

Figure 6: Cumulative % Drug Release of FDT of Montelukast

 

 

 

 

4. CONCLUSION:

The fast dissolving tablets of montelukast were developed by using co-processed excipients. The excipient was selected after extension literature search. The formulations developed with co-processed excipients were compared with formulations having physical mixture of excipients and with formulations which do not have such excipients. The in-vitro drug release studies 60min (USP dissolution rate test apparatus II, 100rpm, 37±0.5°C) using 6.8 pH phosphate buffer as a dissolution medium (900ml) for next 60 mins. The drug release was found to be 98.76% over a period of 60min. The data was analyzed for different evaluation parameters. It was concluded based on the analysis that formulations prepared with co-processed excipients showed better characteristics in comparison to other formulations. Further formulations F8 was considered as optimized formulation based on the dissolution and other characteristics.

 

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Received on 23.06.2019           Modified on 11.08.2019

Accepted on 10.09.2019         © RJPT All right reserved

Research J. Pharm. and Tech. 2019; 12(11): 5543-5548.

DOI: 10.5958/0974-360X.2019.00961.2