Formulation Development and In vitro Evaluation of Floating Tablets of Lafutidine by Employing Effervescent Technology

 

N. M. Vageesh1*, Ramya Sri Sura2, K Gulijar Begum2, B Swathi2

1St. Johns College of Pharmaceutical Sciences, Yerakota, Yemmiganur, Kurnool (Dist), Andhra Pradesh

2Department of Pharmaceutics, OU Ph. D Scholar, Osmania University, Hyderabad

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

 

ABSTRACT:

In the present research work gastro retentive floating matrix formulation of Lafutidine by using various polymers were developed. Initially analytical method development was done for the drug molecule. Absorption maxima was determined based on that calibration curve was developed by using different concentrations. Gas generating agent sodium bicarbonate concentration was optimized. Then the formulation was developed by using different concentrations of polymers Xanthan gum, guar gum and Sodium Alginate as polymeric substances. The formulation blend was subjected to various preformualation studies, flow properties and all the formulations were found to be good indicating that the powder blend has good flow properties. Among all the formulations Only Xanthan gum, Sodium Alginate highest concentrations (60 mg) retards the drug release upto 12 hours and the drug release 96. 25%, 95. 81% respectively. In this Xanthan gum releases the more drug release when compared to Sodium alginate. So F3 Formulation considered as optimized formulation. Optimised formulation F3 was kept for release kinetic studies. From the above graphs, it was evident that the formulation F3 was followed the Peppas release mechanism.

 

KEY WORDS: Lafutidine, Xanthan gum, Guar Gum and Sodium Alginate, Floating tablets.

 

 

 


1. INTRODUCTION:

Oral delivery of drugs is the most preferable route of drug delivery. Oral route is considered most natural, uncomplicated, convenient and safe due to its ease of administration, patient compliance and flexibility in formulation and cost-effective manufacturing process 1.

 

Many of the drug delivery systems, available in the market are oral drug delivery type systems Pharmaceutical products designed for oral delivery are mainly immediate release type or conventional drug delivery systems, which are designed for immediate release of drug for rapid absorption. These immediate release dosage forms have some limitations such as:

 

1. 1 Controlled Drug Delivery Systems:

Controlled drug delivery systems have been developed which are capable of controlling the rate of drug delivery, sustaining the duration of therapeutic activity and/or targeting the delivery of drug to a tissue.

 

 


DRUG PROFILE:

Drug

:

Lafutidine

Synonym

:

Protecadin

Drug category

:

Histamine H-receptor antagonist

Treatment of peptic ulcer and gastro-oesophageal reflux disease (GORD)

Structure

:

Chemical name/ Nomenclature / IUPAC Name

:

2-(furan-2-ylmethylsulfinyl)-N-[(Z)-4-[4-(piperidin-1-ylmethyl) pyridin-2-yl] oxybut-2-enyl] acetamide

Molecular Formula

:

C22H29N3O4S

Weight

:

431. 54 gm/mole.

PHYSICOCHEMICAL PROPERTIES:

Storage Conditions

:

store at room temperature

Dosage

:

10 mg of Lafutidine, twice daily,

PHARMACOKINETIC PROPERTIES:

Half-life

:

1. 92 ± 0. 94 hrs

Absorption

:

Absorbed after oral administration. rapidly absorbed in the GIT.

Protein binding

:

88 %

Metabolism

:

Hepatic by CYP2D6 and CYP3A4 enzymes

Excretion

:

Excreted through urine 

 

 


METHODOLOGY:

Analytical method development:

a)       Determination of absorption maxima:

A solution containing the concentration 10 µg/ mL drug was prepared in 0. 1N HCL UV spectrum was taken using Double beam UV/VIS spectrophotometer. The solution was scanned in the range of 200 – 400 nm.

 

b)       Preparation calibration curve:

10mg Lafutidine pure drug was dissolved in 10ml of methanol (stock solution1) from stock solution1 1ml of solution was taken and made up with10ml of 0. 1N HCL (100μg/ml). From this 1ml was taken and made up with 10 ml of 0. 1N HCL (10μg/ml). The above solution was subsequently diluted with 0. 1N HCL to obtain series of dilutions Containing 2, 4, 6, 8, 10 µg /ml of per ml of solution. The absorbance of the above dilutions was measured at 236 nm by using UV-Spectrophotometer taking 0. 1N HCL as blank. Then a graph was plotted by taking Concentration on X-Axis and Absorbance on Y-Axis which gives a straight-line Linearity of standard curve was assessed from the square of correlation coefficient (R2) which determined by least-square linear regression analysis.

 

Drug – Excipient compatibility studies:

Fourier Transform Infrared (FTIR) spectroscopy (11-15):

The compatibility between the pure drug and excipients was detected by FTIR spectra obtained on Bruker FTIR Germany (Alpha T). The solid powder sample directly place on yellow crystal which was made up of ZnSe. The spectra were recorded over the wave number of 4000 cm-1 to 550 cm-1.

 

Pre formulation parameters:

The quality of tablet, once formulated by rule, is generally dictated by the quality of physicochemical properties of blends. There are many formulations and process variables involved in mixing and all these can affect the characteristics of blends produced. The various characteristics of blends tested as per Pharmacopoeia.

 

Angle of repose (16-20):

The frictional force in a loose powder can be measured by the angle of repose. It is defined as, the maximum angle possible between the surface of the pile of the powder and the horizontal plane. If more powder is added to the pile, it slides down the sides of the pile until the mutual friction of the particles producing a surface angle, is in equilibrium with the gravitational force. The fixed funnel method was employed to measure the angle of repose.

 

Table: 1. Angle of Repose values (as per USP)

Angle of Repose

Nature of Flow

<25

Excellent

25-30

Good

30-40

Passable

>40

Very poor

 

Bulk density (21-26):

Density is defined as weight per unit volume. Bulk density, is defined as the mass of the powder divided by the bulk volume and is expressed as gm/cm3. The bulk density of a powder primarily depends on particle size distribution, particle shape and the tendency of particles to adhere together. Bulk density is very important in the size of containers needed for handling, shipping, and storage of raw material and blend. It is also important in size blending equipment. 10 gm powder blend was sieved and introduced into a dry 20 ml cylinder, without compacting. The powder was carefully leveled without compacting and the unsettled apparent volume, Vo, was read.

 

Tapped density:

After carrying out the procedure as given in the measurement of bulk density the cylinder containing the sample was tapped using a suitable mechanical tapped density tester that provides 100 drops per minute and this was repeated until difference between succeeding measurement is less than 2 % and then tapped volume, V measured, to the nearest graduated unit. The tapped density was calculated, in gm per L, using the formula:

 

Measures of powder compressibility:

The Compressibility Index (Carr’s Index) is a measure of the propensity of a powder to be compressed. It is determined from the bulk and tapped densities. In theory, the less compressible a material the more flowable it is. As such, it is measures of the relative importance of interparticulate interactions. In a free- flowing powder, such interactions are generally less significant, and the bulk and tapped densities will be closer in value.

 

For poorer flowing materials, there are frequently greater interparticle interactions, and a greater difference between the bulk and tapped densities will be observed. These differences are reflected in the Compressibility Index which is calculated using the following formulas:

 

 

Table 2. Carr’s index value (as per USP)

Carr’s index

Properties

5 – 15

Excellent

12 – 16

Good

18 – 21

Fair to Passable

2 – 35

Poor

33 – 38

Very Poor

>40

Very Very Poor

Formulation development of floating Tablets:

For optimization of sodium bicarbonate concentration, granules were prepared by direct compression method.

 

Procedure for direct compression method:

1)       Drug and all other ingredients were individually passed through sieve no ą 60.

2)       All the ingredients were mixed thoroughly by triturating up to 15 min.

3)       The powder mixture was lubricated with talc.

4)       The tablets were prepared by using direct compression method by using 7mm punch.

 

Optimization of Sodium bicarbonate:

Sodium bicarbonate was employed as effervescent gas generating agent. It helps the formulation to float. Various concentrations of sodium bicarbonate were employed; floating lag time and floating duration were observed. Based on the concentration of sodium bicarbonate was finalised and preceded for further formulations.

 

Table 3: Optimization sodium bicarbonate concentration

Ingredients

DO1

DO2

DO3

Lafutidine

20

20

20

Xanthan Gum

60

60

60

NaHCO3

5

7. 5

10

Citric Acid

7. 5

7. 5

7. 5

Mg. Stearate

3

3

3

Aerosil

3

3

3

MCC pH 102

Q. S

Q. S

Q. S

Total weight

250

250

250

All the quantities were in mg.

 

Based on the floating lag time and floating duration the concentration of sodium bicarbonate was optimized.

 

 


 

Table 4. Formulation composition for Floating tablets

Ingredients

F1

F2

F3

F4

F5

F6

F7

F8

F9

Lafutidine

20

20

20

20

20

20

20

20

20

Xanthan gum

20

40

60

-

-

-

-

-

-

Guar gum

-

-

-

20

40

60

-

-

-

Sodium Alginate

-

-

-

-

-

-

20

40

60

Sodium bi Carbonate

7. 5

7. 5

7. 5

7. 5

7. 5

7. 5

7. 5

7. 5

7. 5

Citric acid

7. 5

7. 5

7. 5

7. 5

7. 5

7. 5

7. 5

7. 5

7. 5

MCC

Q. S

Q. S

Q. S

Q. S

Q. S

Q. S

Q. S

Q. S

Q. S

Aerosil

3

3

3

3

3

3

3

3

3

Magnesium Stearate

3

3

3

3

3

3

3

3

3

Total tablet

250

250

250

250

250

250

250

250

250

All the quantities were in mg

 


Evaluation of post compression parameters for prepared Tablets:

The designed compression tablets were studied for their physicochemical properties like weight variation, hardness, thickness, friability and drug content.

 

Weight variation test:

To study the weight variation, twenty tablets were taken and their weight was determined individually and collectively on a digital weighing balance. The average weight of one tablet was determined from the collective weight. The weight variation test would be a satisfactory method of deter mining the drug content uniformity. Not more than two of the individual weights deviate from the average weight by more than the percentage shown in the following table and none deviate by more than twice the percentage (27-30). The mean and deviation were determined. The percent deviation was calculated using the following formula.

 

Table 5. Pharmacopoeial specifications for tablet weight variation

Average weight of tablet (mg) (I. P)

Average weight of tablet (mg)

(U. S. P)

Maximum percentage difference allowed

Less than 80

Less than 130

10

80-250

130-324

7. 5

More than

More than 324

5

 

Hardness:

Hardness of tablet is defined as the force applied across the diameter of the tablet in order to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under condition of storage transformation and handling before usage depends on its hardness. For each formulation, the hardness of three tablets was determined using Monsanto hardness tester and the average is calculated and presented with deviation.

 

Thickness:

Tablet thickness is an important characteristic in reproducing appearance. Tablet thickness is an important characteristic in reproducing appearance. Average thickness for core and coated tablets is calculated and presented with deviation.

 

Friability:

It is measured of mechanical strength of tablets. Roche friabilator was used to determine the friability by following procedure. Pre-weighed tablets were placed in the friabilator. The tablets were rotated at 25 rpm for 4 minutes (100 rotations). At the end of test, the tablets were re- weighed, and loss in the weight of tablet is the measure of friability and is expressed in percentage as

 

Determination of drug content:

Both compression-coated tablets of were tested for their drug content. Ten tablets were finely powdered quantities of the powder equivalent to one tablet weight of Lafutidine were accurately weighed, transferred to a 100ml volumetric flask containing 50 ml water and were allowed to stand to ensure complete solubility of the drug. The mixture was made up to volume with water. The solution was suitably diluted and the absorption was determined by UV –Visible spectrophotometer. The drug concentration was calculated from the calibration curve.

 

In vitro Buoyancy studies:

The in vitro buoyancy was determined by floating lag time, and total floating time. (As per the method described by Rosa et al) The tablets were placed in a 100ml beaker containing 0. 1N HCl. The time required for the tablet to rise to the surface and float was determined as floating lag time (FLT) and duration of time the tablet constantly floats on the dissolution medium was noted as Total Floating Time respectively (TFT).

 

In vitro drug release studies:

Dissolution parameters:

Apparatus               --           USP-II, Paddle Method

Dissolution Medium  -- 0. 1 N HCL

RPM       --             50

Sampling intervals (hrs)  --0. 5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 11, 12

Temperature --     37°C + 0. 5°C

 

As the preparation was for floating drug release given through oral route of administration, different receptors fluids are used for evaluation the dissolution profile.

 

Procedure:

900ml of 0. 1 HCL was placed in vessel and the USP apparatus –II (Paddle Method) was assembled. The medium was allowed to equilibrate to temp of 37°C + 0. 5°c. Tablet was placed in the vessel and the vessel was covered the apparatus was operated for 12 hours and then the medium 0. 1 N HCL was taken and process was continued from 0 to 12 hrs at 50 rpm. At definite time intervals of 5 ml of the receptors fluid was withdrawn, filtered and again 5ml receptor fluid was replaced. Suitable dilutions were done with media and analyzed by spectrophotometrically at 236 nm using UV-spectrophotometer.

 

Application of Release Rate Kinetics to Dissolution Data:

Various models were tested for explaining the kinetics of drug release. To analyze the mechanism of the drug release rate kinetics of the dosage form, the obtained data were fitted into zero-order, first order, Higuchi, and Korsmeyer-Peppas release model.

 

 

Zero order release rate kinetics:

To study the zero–order release kinetics the release rate data are fitted to the following equation.

 

RESULTS AND DISCUSSION (34-35):

Analytical Method:

a. Determination of absorption maxima:

The standard curve is based on the spectrophotometry. The maximum absorption was observed at 236 nm.

 

b. calibration curve:

Graphs of Lafutidine was taken in 0. 1N HCl (pH 1. 2)

 

Table 6: Observations for graph of Lafutidine in 0. 1N HCL

Concentration [µg/mL]

Absorbance

0

0

5

0. 162

10

0. 346

15

0. 548

20

0. 732

25

0. 926

 

Standard graph of Lafutidine was plotted as per the procedure in experimental method and its linearity is shown in Table and Fig. The standard graph of Lafutidine showed good linearity with R2 of 0. 999, which indicates that it obeys “Beer- Lamberts” law.

 

Fig 1: Standard graph of Lafutidine in 0. 1N HCL


 

8. 2. Drug – Excipient compatibility studies

Fourier Transform-Infrared Spectroscopy:

 

Figure 2. FTIR Spectrum of pure drug

 

Fig 3. FTIR Spectrum of optimized formulation

Table 7. Pre-formulation parameters of blend

Formulation Code

Angle of Repose

Bulk density (gm/mL)

Tapped density (gm/mL)

Carr’s index (%)

Hausner’s Ratio

F1

24. 58°

0. 510

0. 610

21. 32

0. 112

F2

29. 67°

0. 421

0. 621

28. 26

0. 056

F3

30. 90°

0. 458

0. 581

25. 90

0. 078

F4

28. 15°

0. 561

0. 632

21. 78

0. 141

F5

23. 13°

0. 541

0. 642

18. 45

0. 098

F6

25. 41°

0. 483

0. 587

26. 53

0. 088

F7

30. 89°

0. 463

0. 591

24. 67

0. 110

F8

31. 23°

0. 437

0. 623

28. 78

0. 121

F9

24. 34°

0. 521

0. 632

17. 32

0. 146

 

 


There was no disappearance of any characteristics peak in the FTIR spectrum of drug and the polymers used. This shows that there is no chemical interaction between the drug and the polymers used. The presence of peaks at the expected range confirms that the materials taken for the study are genuine and there were no possible interactions.

Lafutidine are also present in the physical mixture, which indicates that there is no interaction between drug and the polymers, which confirms the stability of the drug.

 

Tablet powder blend was subjected to various pre-formulation parameters. The angle of repose values indicates that the powder blend has good flow properties. The bulk density of all the formulations was found to be in the range of 0.421 to 0.561 (gm/ml) showing that the powder has good flow properties. The tapped density of all the formulations was found to be in the range of        0.581 to 0.642 showing the powder has good flow properties. The compressibility index of all the formulations was found to be below 18 which shows that the powder has good flow properties. All the formulations has shown the hausners ratio ranging between 0 to 0.146 indicating the powder has good flow properties.

 

Optimization of sodium bicarbonate concentration:

Three formulations were prepared with varying concentrations of sodium bicarbonate by direct compression method to compare the floating buoyancy in between direct compression method. The formulation containing sodium bicarbonate in 7.5 mg concentration showed less floating lag time in wet granulation method and the tablet was in floating condition for more than 12 hours.

 

Quality Control Parameters For tablets:

Tablet quality control tests such as weight variation, hardness, and friability, thickness, Drug content and drug release studies were performed for floating tablets.

 

Fig 4 Dissolution data of Lafutidine Floating tablets containing Xanthan Gum


 

Table 8. In vitro quality control parameters

Formulation codes

Average Weight (mg)

Hardness (kg/cm2)

Friability (%loss)

Thickness (mm)

Drug content (%)

Floating lag time (Seconds)

Total Floating Time (Hrs)

F1

249. 3

5. 5

0. 43

3. 0

99. 12

25 s

>12 hrs

F2

249. 6

6. 0

0. 45

2. 9

98. 34

35 s

>10 hrs

F3

249. 7

5. 5

0. 67

3. 1

100. 12

56 s

>18 hrs

F4

248. 3

5. 5

0. 45

3. 2

101. 34

75 s

>20 hrs

F5

247. 5

6. 0

0. 78

3. 0

98. 12

60 s

>20 hrs

F6

249. 2

5. 5

0. 87

2. 9

99. 45

80 s

>24 hrs

F7

251. 6

5. 5

0. 65

3. 0

100. 43

35 s

>12 hrs

F8

250. 7

6. 0

0. 32

2. 9

101. 91

30 s

>12 hrs

F9

250. 1

5. 5

0. 74

2. 8

100. 12

38 s

>12 hrs

All the parameters for tablets such as weight variation, friability, hardness, thickness, drug content was found to be within limits.

 

In Vitro Drug Release Studies:

Table No 9. Dissolution data of Floating Tablets

Time (hr)

F1

F2

F3

F4

F5

F6

F7

F8

F9

0

0

0

0

0

0

0

0

0

0

0. 5

20. 28

19. 31

18. 57

21. 26

20. 38

22. 24

19. 16

18. 18

19. 83

1

39. 34

37. 85

35. 85

38. 32

38. 46

36. 84

21. 32

29. 26

21. 31

2

54. 52

46. 32

41. 31

44. 24

50. 15

46. 23

36. 44

33. 23

26. 92

3

76. 38

59. 51

54. 32

51. 76

62. 43

53. 58

44. 33

39. 68

34. 39

4

92. 62

63. 62

65. 71

58. 82

79. 32

64. 32

57. 67

48. 95

46. 41

5

96. 78

78. 91

68. 92

80. 42

85. 16

82. 27

67. 52

50. 36

51. 75

6

99. 86

84. 89

73. 53

92. 72

89. 11

96. 32

70. 14

60. 32

63. 81

7

90. 32

77. 21

98. 22

94. 74

97. 92

75. 56

76. 41

74. 57

8

93. 57

82. 31

99. 21

83. 54

83. 23

78. 81

9

98. 18

84. 85

99. 83

86. 18

83. 75

10

90. 67

 

98. 69

87. 32

11

94. 31

 

 

93. 05

12

96. 25

 

 

95. 81

 


 

Fig 5 Dissolution data of Lafutidine Floating tablets containing Guar Gum

 

Fig 6 Dissolution data of Lafutidine Floating tablets containing Sodium Alginate

 

Fig 7. Dissolution data of Lafutidine Floating tablets All Formulations (F1-F9)

 

From the dissolution data it was evident that the formulations prepared with Guar Gum as polymer were retarded the drug release Less than 12 hours.

 

Whereas the formulations prepared with higher concentration of Xanthan gum retarded the drug release up to 12 hours in the concentration 60 mg. In lower concentrations, the polymer was unable to retard the drug release upto 12 hours.

 

Fig 8 : Zero order release kinetics

The formulations prepared with Sodium alginate gum showed good retardation capacity of drug release (95. 81%) up to 12 hours in concentration 60 mg whereas Less concentrations (20 mg, 40 mg) not retard the drug release up to 12 hours. Hence, they were not considered.

 

Fig 9. Higuchi release kinetics

 

Fig 10. Kors mayer peppas release kinetics


 

Application of Release Rate Kinetics to Dissolution Data for optimised formulation:

Table No 10. Application kinetics for optimised formulation

Cumulative (%) release

Q

Time

(t)

 root

 (t)

 log

(%) release

log

(t)

log (%) remain

 release rate

(cumuli-tive % release / t)

1/cum% release

Peppas

Log q/100

% drug remaining

Q01/3

Qt1/3

Q01/3-qt1/3

0

0

0

 

 

2. 000

 

 

 

100

4. 642

4. 642

0. 000

18. 57

0. 5

0. 707

1. 269

-0. 301

1. 911

37. 140

0. 0539

-0. 731

81. 43

4. 642

4. 334

0. 307

35. 85

1

1. 000

1. 554

0. 000

1. 807

35. 850

0. 0279

-0. 446

64. 15

4. 642

4. 003

0. 638

41. 31

2

1. 414

1. 616

0. 301

1. 769

20. 655

0. 0242

-0. 384

58. 69

4. 642

3. 886

0. 755

54. 32

3

1. 732

1. 735

0. 477

1. 660

18. 107

0. 0184

-0. 265

45. 68

4. 642

3. 575

1. 067

65. 71

4

2. 000

1. 818

0. 602

1. 535

16. 428

0. 0152

-0. 182

34. 29

4. 642

3. 249

1. 393

68. 92

5

2. 236

1. 838

0. 699

1. 492

13. 784

0. 0145

-0. 162

31. 08

4. 642

3. 144

1. 498

73. 53

6

2. 449

1. 866

0. 778

1. 423

12. 255

0. 0136

-0. 134

26. 47

4. 642

2. 980

1. 661

77. 21

7

2. 646

1. 888

0. 845

1. 358

11. 030

0. 0130

-0. 112

22. 79

4. 642

2. 835

1. 806

82. 31

8

2. 828

1. 915

0. 903

1. 248

10. 289

0. 0121

-0. 085

17. 69

4. 642

2. 606

2. 036

84. 85

9

3. 000

1. 929

0. 954

1. 180

9. 428

0. 0118

-0. 071

15. 15

4. 642

2. 474

2. 167

90. 67

10

3. 162

1. 957

1. 000

0. 970

9. 067

0. 0110

-0. 043

9. 33

4. 642

2. 105

2. 536

94. 31

11

3. 317

1. 975

1. 041

0. 755

8. 574

0. 0106

-0. 025

5. 69

4. 642

1. 785

2. 856

96. 25

12

3. 464

1. 983

1. 079

0. 574

8. 021

0. 0104

-0. 017

3. 75

4. 642

1. 554

3. 088

 


 

Fig 11. First order release kinetics

Optimised formulation F3 was kept for release kinetic studies. From the above graphs it was evident that the formulation F3 was followed Peppas release mechanism.

 

CONCLUSION:

Development of Gastro retentive floating drug delivery of Lafutidine tablets is to provide the drug action up to 12 hours. Gastro retentive floating tablets were prepared by direct compression method using various polymers like Xanthan gum, guar gum and Sodium Alginate. The formulated gastro retentive floating tablets were evaluated for different parameters such as drug excipient compatibility studies, weight variation, thickness, hardness, content uniformity, In vitro Buoyancy studies, In vitro drug release studies performed in 0. 1N HCL for 12 hrs and the data was subjected to zero order, first order, Higuchi release kinetics and Karsmayer Peppas graph. FTIR studies concluded that there was no interaction between drug and excipients. The physico-chemical properties of all the formulations prepared with different polymers Xanthan gum, guar gum and Sodium Alginate were shown to be within limits. Quality control parameters for tablets such as weight variation, Hardness, Friability, thickness, drug content and floating lag time were found to be within limits. In-vitro drug release studies were carried out for all prepared formulation and from that concluded F3 formulation has shown good results. Finally concluded release kinetics to optimized formulation (F3) has followed Peppas release kinetics. Present study concludes that gastro retentive floating system may be a suitable method for Lafutidine administration.

 

ACKNOWLEDGEMENT:

I take this opportunity to express my deep sense of gratitude to all teaching and non-teaching staff of St. Johns College of Pharmaceutical Sciences, Yerakota, Yemmiganur, Kurnool (Dist), Andhra Pradesh India for his encouragement, guidance and inspiration to write this article and also thankfull to Sura Lab, Hyderabad, Telangana for providing necessary facilities for research work.

 

CONFLICTS OF INTEREST:

The authors declare that there are no conflicts of interest.

 

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Received on 20.05.2017          Accepted on 19.08.2017        

© Asian Pharma Press All Right Reserved

Asian J. Pharm. Res. 2017; 7(3): 189-197.

DOI:  10.5958/2231-5691.2017.00029.6