DESIGN AND CHARACTERISATION OF GLIMEPIRIDE AND

PIOGLITAZONE BILAYERED TABLETS

Thesis submitted to
FACULTY OF PHARMACY
JNTU
IN PARTIAL FULFILLMENT FOR THE AWARD OF THE
DEGREE OF
MASTER OF PHARMACY
IN
PHARMACEUTICS
Submitted by
K.GIRIDHAR
B.Pharm
121J1SO304

Under the guidance of

GUIDE
Dr.D RAMAKRISHNA
M.phram. Ph D
PRINCIPAL

SUSHRUT INSTITUTE OF PHARMACY

HYDERABAD
2012-2014
1
CONTENT

 Introduction
 Objective
 Drug profile
 Plan of work
 Experimental methodology
 Results and Discussion
 Conclusion
 References

2
INTRODUCTION

3
DureDasTM technology

Bilayer tableting technology.

Tailored release rate of two drug components.

Immediate release and modified release components in one tablet

Two different CR formulations combined

4
Advantages

• Dual release tablet

• Elegance to the product
 Administration of fixed dose combinations of different APIs
 Suitable for Mucoadhesive delivery system and gastro-retentive
drug delivery
 Allows for synergistic combination
 Monotherapy prevented
 Objectionable odour and bitter taste can be masked by coating
technique
 Patient convenience is improved

5
Objective

To formulate and evaluate bilayer tablets containing

Pioglitazone hydrochloride and Glimepiride for sustained
release.

6
Criteria for Drug Selection:

PIOGLITAZONE HCl
Biological half life : 3-7 hours
Treatment of Type II diabetes mellitus
Water soluble

GLIMEPIRIDE
Biological half life : 5 hours
Treatment of Type II diabetes mellitus
Water insoluble

7
DRUG PROFILE

8
Name: Pioglitazone HCl

IUPAC name:5-[4-[2-(5-Ethyl-2-pyridinyl) ethoxy]benzyl] thiazolidine-2, 4-

dione.
Molecular weight: 392.90
State: solid
Half-life: 3-7 hr
λ max: 269nm
Solubility: water soluble
Mechanism of action
Pioglitazone acts as an agonist at peroxisome proliferator activated receptors
(PPAR) in target tissues for insulin action such as adipose tissue, skeletal
muscle and liver.
Dosage: 15, 30 and 45 mg

9
Name: Glimepiride

IUPAC name: (1–[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]

phenyl] sulfonyl]-3-(trans-4-methylcyclohexyl) urea
Molecular weight: 490.62
State: solid
Half-life: 5 hr
λ max: 229nm
Solubility: Glimepiride is insoluble in water. But partially soluble in methanol,
ethanol, acetone, and completely soluble in DMF.
Mechanism of action
Glimepiride acts as an insulin secretagogue. It lowers blood sugar by stimulating the
release of insulin by pancreatic beta cells and by inducing increased activity of
intracellular insulin receptors.
Absorption: Glimepiride is completely (100%) absorbed from the GI tract.
Dosage: 1mg, 2mg, 4mg and 8mg.
10
Plan of work
 Literature review
 Selection of drug and excipients
 Drug-Excipient compatibility studies by FT-IR spectroscopy and DSC.
 Determination of λmax
 Standard graph preparation in 0.1N HCl and pH 7.4 PBS
 Preparation and evaluation of immediate release layer tablets
 Preparation and evaluation of sustained release layer tablets
 Preparation and evaluation of Bilayer tablets
 Kinetics of drug release
 Stability studies

11
EXPERIMENTAL METHODOLOGY

12
Materials

Drugs : Pioglitazone HCl

Glimepiride

IR layer superdisintegrants:
Sodium starch glycolate
Polyplasdone XL10
Crosscarmellose sodium

SR layer Polymers :
Xathan gum
Sodium alginate
Hypromellose

13
INSTRUMENTS USED

S.NO Name of instrument Manufacturing company

1 Tablet dissolution apparatus Lab India DS8000.

2 UV-VIS spectrophotometer Lab India UV3000, Mumbai.

3 Balance Indian equipment corporation Pvt.Ltd,

Mumbai.

4 Roche friabilator Indian equipment corporation Pvt.ltd.

Mumbai.

5 Monsanto hardness tester Cintex

6 Electronic weighing balance Contech

7 Thickness measurement apparatus Mitutoyo, Hyderabad.

(Screw guage)

8 Multi station punch tablet compression Manesty

machine

14
Formulation of immediate release layer

MATERIALS USE

PIOGLITAZONE HCl Drug (ANTIDIABETIC)

MCC Diluent

SODIUM STARCH GLYCOLATE Super disintegrant

POLYPLASDONE XL10
(CROSSPOVIDONE)
CROSS CARMELLOSE SODIUM

AEROSIL Flow promotor

MAGNESIUM STEARATE Lubricant

15
Formulation of Pioglitazone HCl immediate release layer using sodium starch
glycolate

Ingredients F1(mg) F2(mg) F3(mg) F4(mg)

Pioglitazone HCl 30 30 30 30

MCC 66.25 64.25 62.25 60.25

Sodium starch glycolate 2 4 6 8

Aerosil 0.25 0.25 0.25 0.25

Magnesium stearate 1.5 1.5 1.5 1.5

Total 100 100 100 100

16
Formulation of Pioglitazone HCl immediate release layer using polyplasdone XL 10

Ingredients F5(mg) F6(mg) F7(mg) F8(mg)

Pioglitazone HCl 30 30 30 30

MCC 66.25 64.25 62.25 60.25

Polyplasdone xl 10 2 4 6 8

Aerosil 0.25 0.25 0.25 0.25

Magnesium stearate 1.5 1.5 1.5 1.5

Total 100 100 100 100

17
Formulation of Pioglitazone HCl immediate release layer using
croscarmellose sodium

Ingredients F9(mg) F10(mg) F11(mg) F12(mg)

Pioglitazone HCl 30 30 30 30

MCC 66.25 64.25 62.25 60.25

Croscarmellose sodium 2 4 6 8

Aerosil 0.25 0.25 0.25 0.25

Magnesium stearate 1.5 1.5 1.5 1.5

Total 100 100 100 100

18
Immediate release layer (Direct compression)

WEIGHING
Drug, Super disintegrant , Microcrystalline
cellulose, Magnesium stearate and Aerosil
were weighed

SIEVING
All ingrediants were separately
passed through the mesh 60

MIXING

LUBRICATION
Addition of magnesium stearate
and aerosil

COMPRESSION
Using 6mm punches
19
Formulation of sustained release layer

MATERIALS USE

GLIMEPIRIDE Drug (ANTIDIABETIC)

MANNITOL Diluent

XANTHAN GUM Polymer

SODIUM ALGINATE
HYPROMELLOSE

AEROSIL Flow promotor

MAGNESIUM STEARATE Lubricant

20
Formulation of Glimepiride sustained release layer using Xanthan gum

Ingredients F13(mg) F14(mg) F15(mg) F16(mg) F17(mg)

Glimepiride 4 4 4 4 4

Mannitol 74.25 69.25 64.25 59.25 54.25

Xanthan gum 20 25 30 35 40

Aerosil 0.25 0.25 0.25 0.25 0.25

Magnesium stearate 1.5 1.5 1.5 1.5 1.5

Total 100 100 100 100 100

Formulation of Glimepiride sustained release layer using Sodium alginate

Ingredients F18(mg) F19(mg) F20(mg) F21(mg) F22(mg)

Glimepiride 4 4 4 4 4

Mannitol 74.25 69.25 64.25 59.25 54.25

Sodium alginate 20 25 30 35 40

Aerosil 0.25 0.25 0.25 0.25 0.25

Magnesium stearate 1.5 1.5 1.5 1.5 1.5

Total 100 100 100 100 100

22
Formulation of Glimepiride sustained release layer using Hypromellose

Ingredients F23(mg) F24(mg) F25(mg) F26(mg) F27(mg)

Glimepiride 4 4 4 4 4

Mannitol 74.25 69.25 64.25 59.25 54.25

Hypromellose 20 25 30 35 40

Aerosil 0.25 0.25 0.25 0.25 0.25

Magnesium stearate 1.5 1.5 1.5 1.5 1.5

Total 100 100 100 100 100

23
Sustained release layer (Direct compression)

WEIGHING
Drug, polymer, Mannitol
Magnesium stearate and Aerosil were weighed

SIEVING
All ingredients were separately
passed through the mesh 60

MIXING

LUBRICATION
Addition of Magnesium
stearate and Aerosil

COMPRESSION
Using 6mm punches

24
Compression cycle of bi-layer tablet

25
 EVALUATION STUDIES

 PREFORMULATION STUDIES:
• Determination of λmax and standard graph of Pioglitazone HCl
and Glimepiride.
• Drug-Excipient compatibility study by FTIR-Spectroscopy and
DSC.

 EVALUATION PARAMETERS:
I.PRECOMPRESSION PARAMETERS
1. Flow properties
Bulk density
Tapped density
Carr's index
Hausner's ratio
Angle of Repose

26
II. POST COMPRESSION PARAMETERS

2.Weight variation

3. Hardness

4. Thickness

5. Friability

6. Drug content

7. In vitro Dissolution studies

27
In-vitro drug release studies

Apparatus used : USP dissolution apparatus II

[paddle type]

Dissolution medium : 0.1N HCl (2hours)

pH 7.4PBS (10hours)

Rotation speed : 50 rpm

Volume of medium : 900ml

Temperature : 37±0.50c

Sample volume : 5ml

Analytical method : UV-Visible spectrophotometry

28
RESULTS AND DISCUSSION

29
Determination of λmax of Pioglitazone HCl and Glimepiride

Test Solution : Stock solution of Pioglitazone HCl in 0.1N HCl (10µg/ml)

Stock solution of Glimepiride in pH 7.4 PBS (10µg/ml)

Blank : 0.1N HCl for Pioglitazone HCl

pH7.4 PBS for Glimepiride

Scanning range : 200-400nm

Instrument : Double beam UV-Visible Spectrophotometer

30
Absorption maxima of Pioglitazone HCl in 0.1N HCl

31
Absorption maxima of Glimepiride in 0.1N HCl

32
Absorption maxima of Glimepiride in pH 7.4 PBS

33
Preparation of Standard Graph of Pioglitazone HCl in 0.1N HCl

1
Concentration Absorbance
y = 0.0158x
0.9
R² = 0.9949
0.8
0 0
0.7

Absorbance
10 0.138 0.6

0.5
20 0.353
0.4

30 0.440 0.3

0.2
40 0.610
0.1

50 0.806 0
0 10 20 30 40 50 60 70

60 0.950 Concetration( µg/ml)

34
Preparation of Standard Graph of Glimepiride in 0.1N HCl

Concentration Absorbance 1.2

y = 0.0316x
0 0 R² = 0.9983
1

Absorbance
5 0.182 0.8

10 0.327 0.6

15 0.456 0.4

20 0.634 0.2

25 0.781 0
0 20 40
30 0.954 Concentration (µg/ml)
35
Preparation of Standard Graph of Glimepiride in pH 7.4 PBS

Concentration Absorbance 0.9

y = 0.0274x
0.8 R² = 0.9974
0 0
0.7

5 0.165 0.6

Absorbance
0.5
10 0.290
0.4
15 0.423 0.3

0.2
20 0.547
0.1
25 0.675 0
0 10 20 30 40
30 0.817 Concentration(µg/ml)

36
Flow properties of powder (immediate release layer)

Batch Bulk density Tapped density Carr’s Hausner’s ratio Angle of

code (gm/ml) (gm/ml) index (%) repose
F1 0.378 0.416 9.09 1.10 29.3
F2 0.373 0.431 13.43 1.15 30.9
F3 0.390 0.446 12.50 1.14 27.1
F4 0.403 0.454 11.29 1.12 32.5
F5 0.384 0.423 9.23 1.10 32.9
F6 0.396 0.463 14.28 1.16 30.9
F7 0.378 0.431 12.12 1.13 27.8
F8 0.373 0.409 8.95 1.09 33.7
F9 0.390 0.438 10.93 1.12 27.2
F10 0.403 0.463 12.90 1.14 31.6
F11 0.416 0.446 6.60 1.07 32.9
F12 0.384 0.454 15.38 1.18 30.9

37
Evaluation of physical properties of tablets (immediate release layer)

Batch Weight variation Hardness Thickness Friability Drug content

code (mg) (kg/cm2) (mm) (%) (%)
F1 101.5 3.8 3.09 0.44 95.7
F2 102.3 4.1 3.02 0.36 93.2
F3 102.7 3.9 3.22 0.43 99.2
F4 103.5 4.0 3.15 0.29 95.3
F5 101.5 4.3 3.09 0.60 82.7
F6 102.4 4.4 3.18 0.48 94.8
F7 101.2 3.7 3.13 0.69 87.3
F8 103.1 4.3 3.29 0.49 93.2
F9 100.7 4.5 3.15 0.30 85.6
F10 101.6 4.2 3.21 0.29 89.0
F11 102.4 4.4 3.12 0.19 91.9
F12 103.2 4.1 3.16 0.29 96.1

38
Flow properties of powder (sustained release layer)
Batch code Bulk density Tapped density Carr’s index Hausner’s Angle of
(gm/ml) (gm/ml) (%) ratio repose
F13 0.409 0.480 14.75 1.17 29.6
F14 0.416 0.471 11.66 1.13 31.5
F15 0.431 0.500 13.79 1.16 30.6
F16 0.438 0.490 10.52 1.11 31.7
F17 0.423 0.467 9.32 1.10 27.5
F18 0.396 0.446 11.11 1.12 27.8
F19 0.403 0.438 8.06 1.08 27.5
F20 0.409 0.454 9.83 1.10 28.2
F21 0.390 0.446 12.50 1.14 31.6
F22 0.384 0.431 10.76 1.12 28.9
F23 0.462 0.531 12.96 1.14 25.9
F24 0.454 0.531 14.54 1.17 28.9
F25 0.480 0.555 13.46 1.15 32.7
F26 0.490 0.543 9.80 1.10 28.3
F27 0.462 0.520 11.11 1.12 33.9
39
Evaluation of physical properties of tablets (sustained release layer)

Batch Weight variation Hardness Thickness Friability Drug content

code (mg) (kg/cm2) (mm) (%) (%)
F13 101.4 5.7 3.21 0.44 95.8
F14 100.8 5.9 3.14 0.36 98.5
F15 100.9 5.8 3.19 0.19 90.3
F16 102.3 6.2 3.25 0.26 88.5
F17 101.2 6.4 3.23 0.15 93.9
F18 100.3 5.7 3.09 0.34 87.5
F19 102.5 5.6 3.25 0.20 88.3
F20 101.3 5.9 3.06 0.24 99.4
F21 103.2 6.2 3.24 0.19 93.7
F22 102.1 6.6 3.13 0.20 81.7
F23 101.5 5.8 3.34 0.48 95.8
F24 100.4 6.3 3.21 0.23 92.1
F25 103.5 6.2 3.19 0.44 86.7
F26 101.3 6.4 3.14 0.15 90.3
F27 100.3 6.5 3.26 0.19 93.0
40
In vitro release data of Immediate release layer of Pioglitazone HCl
TIME F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11 F12
(min)

0 0 0 0 0 0 0 0 0 0 0 0 0

5 11.07 16.99 19.66 22.72 18.90 24.43 27.68 30.35 17.75 20.42 22.33 25.96

10 24.24 28.25 33.03 38.37 32.07 33.98 41.24 45.25 32.07 33.60 37.23 43.53

15 40.09 43.14 46.96 51.35 43.34 49.06 58.80 64.72 41.43 45.05 47.35 50.97

20 54.79 58.99 62.43 67.01 56.51 60.71 73.31 83.05 55.94 58.42 62.05 66.25

25 62.81 66.82 70.64 78.08 68.16 75.79 88.78 99.09 66.63 72.55 78.28 81.71

30 75.60 79.42 85.53 88.97 82.29 91.45 97.94 78.66 86.29 92.79 96.80

41
In vitro release profile of Immediate release layer of Pioglitazone HCl
formulated with sodium starch glycolate

42
In vitro release profile of Immediate release layer of Pioglitazone HCl
formulated with polyplasdone XL 10

43
In vitro release profile of Immediate release layer of Pioglitazone HCl
formulated with crosscarmellose sodium

44
Cummulative Percent Drug Release for sustained release layer of Glimepiride
formulated with Xathan gum

TIME(hrs) F13 F14 F15 F16 F17

0 0 0 0 0 0

1 16.51 14.03 9.90 6.60 5.78

2 28.07 29.72 15.68 11.56 9.92

3 49.54 38.80 26.42 18.99 15.68

4 61.92 51.19 32.20 25.59 21.46
5 75.96 60.27 39.63 36.33 27.24
6 87.52 69.36 47.06 45.41 34.68
7 99.08 77.61 53.67 53.67 40.46
8 86.70 60.27 61.10 47.06
9 98.26 75.14 66.88 54.49
10 81.74 71.83 61.29
11 92.48 77.61 68.53
12 98.17 83.39 74.31
45
In vitro release profile of sustained release layer of Glimepiride formulated
with Xanthan gum (F13-F17)

46
Cummulative Percent Drug Release for sustained release layer of
Glimepiride formulated with Sodium alginate

TIME(hrs) F18 F19 F20 F21 F22

0 0 0 0 0 0

1 18.99 15.68 12.38 10.73 7.43

2 40.46 29.72 20.64 18.99 14.03

3 56.14 44.58 31.37 26.42 21.46

4 78.44 59.45 42.11 37.98 27.24
5 98.83 71.83 53.67 48.71 34.68
6 84.22 61.10 59.45 41.28
7 98.67 69.36 65.23 53.67
8 78.44 71.01 59.45
9 89.17 78.44 68.53
10 97.43 85.87 75.14
11 93.30 80.92
12 99.58 86.70
47
In vitro release profile of sustained release layer of Glimepiride formulated
with Sodium alginate (F18-F22)

48
Cummulative Percent Drug Release for sustained release layer of
Glimepiride formulated with Hypromellose

TIME(hrs) F23 F24 F25 F26 F27

0 0 0 0 0 0

1 10.02 8.59 7.87 5.01 3.57

2 18.61 17.18 12.88 9.30 8.59

3 23.94 23.94 16.51 14.03 12.38

4 30.55 32.20 22.29 17.34 15.68
5 42.93 40.46 26.42 22.29 20.64
6 51.19 47.06 31.37 26.42 23.94
7 64.40 58.62 38.80 31.37 29.72
8 70.18 71.83 49.54 34.68 33.85
9 83.39 79.27 61.10 43.76 40.46
10 97.27 85.87 73.48 50.36 44.58
11 90.00 78.44 61.92 49.54
12 98.59 84.22 72.66 54.49
49
In vitro release profile of sustained release layer of Glimepiride
formulated with Hypromellose (F23-F27)

50
Physical properties of bilayer tablet (F28)

Batch Weight Hardness Thickness Friability Drug content

code variation (kg/cm2) (mm) (%)
(mg)

Pioglt Glim

F28 202.6 6.3 4.14 0.15 96.6 93.9

(F8+F24)

51
In vitro dissolution of bilayer tablet (Optimized formulation)

Immediate release layer Sustained release layer

Time(min) F28 Time (hr) F28

0 0 0 0
1 7.15
5 22.91
2 15.03
10 38.75
3 23.94
15 57.27
4 30.55
20 76.94
5 39.63
25 98.70
6 47.89
7 59.45
8 71.83
9 80.09
10 87.52
11 91.65
12 98.01
52
In vitro release profile of bilayer tablet
Immediate release layer Sustained release layer

120
120

100
100

80
80
%
%
c 60
c 60
d
d
r
r
40
40

20 20

0 0
0 5 10 15 20 25 30 0 2 4 6 8 10 12 14
Time(min) Time(hr)

53
COMPARASION OF OPTIMISED FORMULATION (F28) AND MARKETED
FORMULATION (DUETACT)

In Vitro Drug Release

TIME DUETACT F28

DUETACT
Time (PioglitazoneHCL) (min) (Glimepiride) (Glimepiride)
F28
(min) (PioglitazoneHCL) 0 0 0
0 0 0 5 7.15 1.43
5 11.83 22.91 10 11.45 2.86
10 23.67 38.75 15 15.46 4.29
15 36.27 57.27 20 22.91 5.72
20 46.58 76.94 30 32.93 7.15
25 56.89 98.70 45 60.14 8.59
30 67.97 60 75.89 10.02
45 98.51 90 95.22 11.45

54
In vitro release profile

55
Stability studies
PHYSICO CHEMICAL CHARACTERISTICS OF OPTIMIZED FORMULATION
STORED AT 40 ± 2ºC /75 ± 5%

F28 0 Days 30days 60days 90 Days

Friability 0.28 0.34 0.39 0.47
Hardness 6.37 6.19 6.11 6.02
Physical change No No No No
% C D R (25min) 98.89 97.65 96.38 96.15
% C D R (12hr) 98.94 98.03 97.06 96.73

DRUG CONTENT ANALYSIS STORED AT 40 ± 2ºC /75 ± 5%

Drug content Pioglitazone in Glimepiride in Glimepiride in pH

0.1NHCL 0.1NHCL 7.4PBS
0 Days 98.89 97.86 95.29
90 Days 97.18 96.32 95.16

56
CONCLUSION
 Bilayered tablets of Glimepiride (SR layer) and Pioglitazone HCl (IR layer)
were formulated successfully using Xanthan gum, Sodium alginate and
Hypromellose for Glimepiride SR layer and SSG, polyplasdone XL10 and
CCS for Pioglitzone HCl IR layer.
 Immediate release layer and sustained release layer blend showed good flow
properties and post compressional parameter values were with in the limits.
 Dissolution studies showed that formulation F-24 containing Hypromellose is
ideally suitable for sustained release (12hr) and F8 containing polyplasdone
XL 10 is suitable for immediate release (25min).
 Dissolution studies of Optimized formulation (F28) was compared with
conventional marketed product in in vitro dissolution and it was concluded that
F28 showed faster release in case of Pioglitazone layer in 25min and showed
more extended release in case of Glimepiride layer in 12hrs.
 The prepared tablets met the objective and increased the patient compliance.

57
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