Telmisartan Raw Material Obtained From Kniss Laboratories

Published Date: 02 Nov 2017

The present was aimed at the formulation of bilayer tablets of immediate release Telmisartan and sustained release Metformin Hydrochloride. The therapy with these drugs offers a good quality of life for patients who are suffering from hypertension and Type II diabetes Mellitus.

PREFORMUALTION STUIDES

DRUG CHARACTERIZATION

Telmisartan raw material obtained from KNISS LABORATORIES was tested as per in-house specifications and the results are listed in table. 25. The drug source is identified and found complying with the specifications.

S.No

Test

Specification

Results

1.

Description

A white or slightly yellowish crystalline powder.

A white to off- white crystalline powder.

2.

Loss on drying

Not more than 0.5 % W/W

0.25% W/W.

3.

Solubility

It is practically insoluble in water and in the pH range of 3 to 9, slightly soluble in methanol, sparingly soluble in methylene chloride and strong acid (except insoluble in hydrochloric acid), and dissolves in 1M sodium hydroxide.

Complies

4.

Melting Point

261º C - 263º C

260º C - 264º C

METFORMIN

Metformin HCl raw material obtained from KNISS LABORATORIES was tested as per in-house specifications and the results are listed in table. 25. The drug source is identified and found complying with the specifications.

S.No

Test

Specification

Results

1.

Description

A white, crystalline powder; hygroscopic.

A white, needle shaped crystalline powder.

2.

Loss on drying

Not more than 0.5 % W/W

0.20 % W/W.

3.

Solubility

Freely soluble in water, soluble in ethanol, practically insoluble in chloroform and ether

Complies

4.

Melting Point

222º C - 226º C

220º C - 224º C

DRUG -EXCIPIENT COMPATIBILITY STUDY

The compatibility studies were carried out to study the possible interactions between Metformin HCL and inactive ingredients as well as Acarbose and inactive ingredients, physical mixtures of both API and excipients were prepared separately as per the ratios mentioned in table below and kept for stability at 40º C and 75% RH for one month. Samples were taken out after every 10 days and were subjected to physical and chemical compatibility tests. The physical compatibility of drug and excipients were given in table ---.

Table 8: Physical compatibility study of drug and Excipients

S.No

Drug + Excipient

Description and condition

Comments

Initial

Room temperature and 40⁰C/75% RH in days

10th

20th

30th

01.

Tel

A white to off white crystalline powder

NC

NC

NC

Compatible

02.

MH

A white, hygroscopic, crystalline powder.

NC

NC

NC

Compatible

03.

Tel + MH

White almost crystalline powder

NC

NC

NC

Compatible

04.

Lactose

White to off –white crystalline powder

NC

NC

NC

Compatible

05.

Starch

White or off -white powder

NC

NC

NC

Compatible

06.

PVP K30

White or creamy white hygroscopic powder

NC

NC

NC

Compatible

07.

SSG

White or almost white free flowing very hygroscopic powder

NC

NC

NC

Compatible

08.

Tartrazine yellow

Yellow colored crystalline powder

NC

NC

NC

Compatible

09.

Magnesium stearate

White or almost white crystalline powder

NC

NC

NC

Compatible

10.

HPMC K4M

White or creamy white powder

NC

NC

NC

Compatible

11.

HPMC K100M

White or creamy white powder

NC

NC

NC

Compatible

12.

Ethyl cellulose

Free- flowing, white colored powder

NC

NC

NC

Compatible

13.

MCC pH 102

White crystalline powder

NC

NC

NC

Compatible

14.

Talc

White or creamy white soft powder

NC

NC

NC

Compatible

15.

Tel + Lactose

White or crystalline powder

NC

NC

NC

Compatible

16.

Tel + Starch

White or crystalline powder

NC

NC

NC

Compatible

17.

Tel + PVP K 30

White or crystalline powder

NC

NC

NC

Compatible

18.

Tel + SSG

Free flowing white crystalline powder

NC

NC

NC

Compatible

19.

Tel + TY

Free flowing yellow colour powder

NC

NC

NC

Compatible

20.

Tel + Magnesium Stearate

White, crystalline powder

NC

NC

NC

Compatible

21.

MH +HPMC K4M

White, creamy white crystalline powder

NC

NC

NC

Compatible

22.

MH + HPMC K100M

White, creamy white crystalline powder

NC

NC

NC

Compatible

23.

MH + EC

White, almost white crystalline powder

NC

NC

NC

Compatible

24.

MH +MCC pH 102

White, almost white crystalline powder

NC

NC

NC

Compatible

25.

MH+ PVP K30

White, creamy white crystalline powder

NC

NC

NC

Compatible

26.

MH + Magnesium Stearate

White crystalline powder

NC

NC

NC

Compatible

27.

MH + Talc

White or creamy white powder

NC

NC

NC

Compatible

NC – No Change

The physical compatibility study was performed visually. The study implies that the drug and the excipients were physically compatible with each other as there was no change of physical parameters. The excipients which are compatible with the drug were selected for the formulation.

Chemical compatibility study

All the samples were scanned at the resolution of 4 cm-1 over the wave number region 4000-400 cm-1 using KBr disk method. This KBr disks where formed by taking Drug and KBr in a ratio of 1:100 respectively. Then this mixture was mixed well in mortar for three to five min. A very small amount of this mixture was uniformly spread and sandwich between the pellets and pressed using KBr pellet press at a pressure of 20,000 psi for 1 min. The pressure was then released and pellet was placed into the pellet holder and thus scanned in the IR region.

The results are given below the Figures

FTIR of Telmisartan

Table 9: IR Spectral Interpretation of Telmisartan

Functional group

Characteristic peak

Observed peak

Stretching

Bending

Stretching

Bending

C=O

1760-1650 cm-1

--

1666 cm-1

--

O-H (Carboxilic acids)

3500-3300 cm-1

--

3402 cm-1

--

C-H (Alkane)

2960 -2800 cm-1

--

2955 cm-1

--

C-H (Aromatic)

3150 -3020 cm-1

--

3063 cm-1

--

FTIR of Metformin Hydrochloride

Table 10: IR Spectral Interpretation of Metformin Hydrochloride

Functional group

Characteristic peak

Observed peak

Stretching

Bending

Stretching

Bending

C-N

1350-1000 cm-1

--

1057 cm-1

--

N-H

(Primary amine)

3500-3300 cm-1

1640-1500 cm-1

3294 cm-1

(2 bands)

1566 cm-1

N-H

(Secondary amine)

3300-3070 cm-1

--

3171 cm-1

--

C=N

1690 -1620 cm-1

--

1628 cm-1

--

C-H (Alkane)

2960 -2800 cm-1

--

2816 cm-1

--

FTIR of Telmisartan And Metformin Hydrochloride

Table 12: IR Spectral Interpretation of Telmisartan andMetformin Hcl

Functional group

Characteristic peak

Observed peak

Stretching

Bending

Stretching

Bending

O-H (Carboxilic acids)

3500-3300 cm-1

--

3371 cm-1

--

C-H (Aromatic)

3150 -3020 cm-1

--

2970 cm-1

--

C=O

1760-1650 cm-1

--

1697 cm-1

--

C-N

1350-1000 cm-1

--

1057 cm-1

--

N-H

(Primary amine)

3500-3300 cm-1

1640-1500 cm-1

3302 cm-1

1566 cm-1

N-H

(Secondary amine)

3300-3070 cm-1

--

3171 cm-1

--

C=N

1690 -1620 cm-1

--

1628 cm-1

--

C-H (Alkane)

2960 -2800 cm-1

--

2816 cm-1

--

FTIR Metformin Hydrochloride and HPMC K4M

Table 13: IR Spectral Interpretation of Metformin Hcl & HPMC K4M

Functional group

Characteristic peak

Observed peak

Stretching

Bending

Stretching

Bending

C-N

1350-1000 cm-1

--

1057 cm-1

--

N-H

(Primary amine)

3500-3300 cm-1

1640-1500 cm-1

3302 cm-1

1566 cm-1

N-H

(Secondary amine)

3300-3070 cm-1

--

3178 cm-1

--

C=N

1690 -1620 cm-1

--

1628 cm-1

--

C-H (Alkane)

2960 -2800 cm-1

--

2939 cm-1

--

FTIR of Metformin hydrochloride and HPMC K100M

Table 14: IR Spectral Interpretation of Metformin Hcl and HPMC K100M

Functional group

Characteristic peak

Observed peak

Stretching

Bending

Stretching

Bending

C-N

1350-1000 cm-1

--

1057 cm-1

--

N-H

(Primary amine)

3500-3300 cm-1

1640-1500 cm-1

3302 cm-1

1566 cm-1

N-H

(Secondary amine)

3300-3070 cm-1

--

3171 cm-1

--

C=N

1690 -1620 cm-1

--

1628 cm-1

--

C-H (Alkane)

2960 -2800 cm-1

--

2939 cm-1

--

FTIR of Metformin Hydrochloride and Ethyl Cellulose

Table 14: Spectral Interpretation of Metformin Hcl and Ethyl Cellulose

Functional group

Characteristic peak

Observed peak

Stretching

Bending

Stretching

Bending

C-N

1350-1000 cm-1

--

1065 cm-1

--

N-H

(Primary amine)

3500-3300 cm-1

1640-1500 cm-1

3302 cm-1

1566 cm-1

N-H

(Secondary amine)

3300-3070 cm-1

--

3171 cm-1

--

C=N

1690 -1620 cm-1

--

1628 cm-1

--

C-H (Alkane)

2960 -2800 cm-1

--

2939 cm-1

--

FTIR of Metformin hydrochloride, HPMC K4M and HPMC K100M

Table 14: IR Spectral Interpretation of Metformin Hcl, HPMC K4M and

HPMC K100M

Functional group

Characteristic peak

Observed peak

Stretching

Bending

Stretching

Bending

C-N

1350-1000 cm-1

--

1065 cm-1

--

N-H

(Primary amine)

3500-3300 cm-1

1640-1500 cm-1

3302 cm-1

1566 cm-1

N-H

(Secondary amine)

3300-3070 cm-1

--

3178 cm-1

--

C=N

1690 -1620 cm-1

--

1628 cm-1

--

C-H (Alkane)

2960 -2800 cm-1

--

2939 cm-1

--

CALIBRATION CURVE FOR TELMISARTAN

The results of calibration curve of Telmisartan is given in Table 15 and Fig ---

Table 15: Data for calibration curve of Losartan potassium in 0.1N HCl

Concentration (µg/ml)

Absorbance at λ296nm

0

0

2

0.107

4

0.223

6

0.346

8

0.453

10

0.568

Fig : Calibration Curve of Losartan potassium

It was found that the solution of Telmisartan in 0.1N HCl show linearity (R2 = 0.9997) in absorbance at concentrations of 2 -10 (μg/ml) and obey Beer Lambert Law.

CALIBRATION CURVE FOR METFORMIN HYDROCHLORIDE

The results of calibration curve of Metformin hydrochloride in 0.1N HCl and 6.8 pH phosphate buffer is given in Table 16, 17 and Fig ---

Table 16: Data for calibration curve of Metformin hydrochloride in 0.1N HCl

Concentration (µg/ml)

Absorbance at λ233nm

0

0

2

0.024

4

0.049

6

0.074

8

0.098

10

0.121

Fig : Calibration curve of Metformin hydrochloride in 0.1N HCl

It was found that the solution of Metformin hydrochloride in 0.1N HCl show linearity (R2 = 0.9998) in absorbance at concentrations of 2 -10 (μg/ml) and obey Beer Lambert Law.

Table 17: Data for calibration curve of Metformin hydrochloride in pH 6.8 Phosphate Buffer

Concentration (µg/ml)

Absorbance at λ233nm

0

0

2

0.127

4

0.259

6

0.378

8

0.506

10

0.639

Fig : Calibration curve of Metformin hydrochloride in pH 6.8 Phosphate Buffer

It was found that the solution of Metformin hydrochloride in pH 6.8 Phosphate Buffer show linearity (R2 = 0.9998) in absorbance at concentrations of 2 -10 (μg/ml) and obey Beer Lambert Law.

FOR IR FORMULATION

PRECOMPRESSION STUDY

The drug and the formulated blends are evaluated for precompression parameters. The results are given in Table 18.

Table 18 – Precompression study of drug and formulated blends

Drug and Formulation

Bulk Density g/cm3

Tapped Density g/cm3

Compressibility index (%)

Hausner’s Ratio

Angle Of Repose (Degree)

TEL

0.1253 ± 0.0095

0.2561 ± 0.0032

51.07 ±

0.5960

2.11 ± 0.0322

39⁰29’’± 0.2837

L1

0.5813 ± 0.0099

0.6944 ± 0.0079

18.56 ±

1.4040

1.24 ± 0.0416

32⁰25’’± 0.0258

L2

0.5166 ± 0.0261

0.6288 ± 0.0660

19.35 ±

1.9091

1.24 ± 0.0416

35⁰22’’ ± 0.0375

L3

0.5251 ± 0.0056

0.6756 ± 0.0660

20.36 ±

1.2933

1.35 ± 0.0657

36.33 ± 0.0804

The bulk density of the IR blends ranged from 0.51666 -0.5813 g/cm3 and the tapped density of ranged from 0.6944-0.6288 g/cm3. The compressibility index of the IR blends ranged from 18.56% 20.36% and Hausner’s ratio ranged from 1.24-1.35. The angle of repose of the IR blends ranged from 32⁰25’’ -36⁰33’’. The formulated blend shows poor flow property so wet granulation technique was used for preparing IR granules of Telmisartan.

The IR granules were evaluated for bulk density, tapped density, compressibility index, Hausner’s ratio and Angle of Repose. The results are given in the Table 19.

Table 19 – Precompression study of drug and formulated blends

Drug and Formulation

Bulk Density g/cm3

Tapped Density g/cm3

Compressibility index (%)

Hausner’s Ratio

Angle Of Repose (Degree)

L1

0.5263 ± 0.0103

0.5929 ± 0.0239

15.39 ± 1.0333

1.31 ± 0.0787

29⁰22’’ ± 0.1815

L2

0.5356 ± 0.0994

0.5551 ± 0.9121

15.31 ± 0.8995

1.28 ± 0.3512

28⁰37’’ ± 0.0412

L3

0.5006 ± 0.0912

0.5434 ± 0.0798

14.78 ± 0.08991

1.21 ± 0.0529

29⁰04’’ ± 0.0265

The bulk density of the IR granules ranged from 0.5006 -0.5356 g/cm3 and the tapped density of ranged from 0.5434-0.5929 g/cm3. The compressibility index of the IR granules ranged from 14.78%-15.31% and Hausner’s ratio ranged from 1.21-1.31. The angle of repose of the IR granules ranged from 28⁰37’’ -29⁰22’’. The granules showed good flow property.

FORMULATION DEVELOPMENT

Preparation of IR tablets of Telmisartan

Wet granulation technique was employed for the formulation of IR granules of Telmisartan.

Three formulations of immediate release layer of Telmisartan (L1, L2,L3) were prepared using super disintegrant Sodium Starch Glycolate in three different ratios. The granules were compressed using 16 Station (D tooling) tablet compression machine using 10/32 concave punches.

POST COMPRESSION STUDY FOR TABLETS

UNIFORMITY OF WEIGHT

The uniformity of weight of the formulated tablets is given in Table 20.

Table20: Uniformity of weight of the formulated tablets

Formulation

Uniformity of weight (mg)

Specified limit

175.75 – 204.25

L1

188.89 ± 0.2041

L2

185.39 ± 0.1410

L3

194.64 ± 0.1814

The tablets comply with the test for uniformity of weight.

TABLET THICKNESS AND DIAMETER

The thickness and diameter of the formulated tablets is given in table 21.

Table21: Thickness and Diameter of formulated tablets

Formulation

Thickness (mm)

Diameter (mm)

Specified limit

3.7 -4.3

7.90-8.10

L1

3.999 ±0.1140

7.969 ± 0.0198

L2

4.191 ± 0.9191

7.932 ± 0.3881

L3

4.017 ± 0.0784

7.978 ± 0.1121

The tablets have uniform thickness and diameter.

HARDNESS

The hardness of the formulated tablets is given in table 22.

Table22: Hardness of formulated tablets

Formulation

Hardness (Kg/cm2)

Specified limit

3.70- 4.30

L1

4.00 ± 0.2214

L2

3.996 ± 0.2729

L3

4.16 ± 0.1239

All the formulated tablets showed sufficient mechanical strength to resist the transportation.

FRIABILITY

The friability if the formulated tablets given in table 23.

Table23: Friability of formulated tablets

Formulation

% Friability

Specified limit

Not more than 1.0%

L1

0.129 ± 0.0130

L2

0.226 ± 0.0119

L3

0.397 ± 0.1508

The percentage friability of all the formulations was within the acceptable limits

DRUG CONTENT

The drug content of the IR tablets is given in the table 24.

Table24: Drug content of formulated IR tablets

Formulation

% Drug Content

Specified limit

90 – 110%

L1

98.641 ± 0.8040

L2

99.760 ± 0.1620

L3

98.219 ± 0.2601

Fig: Drug content of IR tablets

DISINTEGRATION TIME

The disintegration time of the IR tablets is given in the table 25.

Table25: Disintegration time of IR tablets

Formulation

Disintegration time (minutes)

L1

10.45

L2

7.05

L3

2.05

Fig: Disintegration time of IR tablets

The disintegration time of the IR tablets ranged from 10.45 to 02.05 minutes. The disintegration time of the IR tablets containing 6% sodium starch glycolate was found to have optimum disintegration time for IR tablets.

INVITRO DISSOLUTION STUDY

The Invitro dissolution of immediate release formulations of Losartan potassium is given in table 26 and fig :

Table 26: Invitro Dissolution study of Immediate release formulation of Telmisartan

Time (Minutes)

Cumulative % drug release

L1

L2

L3

0

0

0

0

5

29.76

38.98

74.29

10

39.51

47.89

80.97

15

49.51

59.97

88.11

20

61.4

65.41

91.79

25

71.94

73.97

97.49

30

80.56

83.72

98.74

35

93.44

96.75

40

95.53

98.6

45

98.89

Fig: Invitro Dissolution study of IR tablets of Telmisartan potassium

The Invitro dissolution study of IR tablets showed that 6% concentration of SSG was found to be optimum for immediate release of Telmisartan. The 2% and 4% concentration of SSG was found to be releasing the drug slowly when compared to 6% SSG. The 6% concentration of SSG released 98.45% at the end of 30mins. Therefore formulation L3was optimized and selected for final bilayer tablets.

FOR SR TABLETS

PRECOMPRESSION STUDY

The drug and the formulated blends of SR are evaluated for precompression parameters.

The results are given in the table 27.

Table 27: Precompression study of drug and formulated blends

Drug and formulation

Bulk density g/cm3

Tapped density g/cm3

Compressibility Index (%)

Hausner’s Ratio

Angle of Repose (Degree)

MH

0.4887 ± 0.1329

0.7812 ± 0.8113

37.48 ± 0.3118

1.62 ± 0.0513

43⁰37" ± 0.1503

F1

0.4072 ± 0.0690

0.5263 ± 0.0940

24.99 ± 0.6920

1.39 ± 0.0265

34⁰52" ± 0.1530

F2

0.4314 ± 0.0067

0.5426 ± 0.0962

24.29 ± 0.4628

1.37 ± 0.4628

34⁰22" ± 0.0333

F3

0.4309 ± 0.5101

0.5438 ± 0.7611

25.96 ± 0.8011

1.36 ± 0.3208

32⁰58" ± 0.1118

F4

0.4706 ± 0.0126

0.5996 ± 0.6251

25.33 ± 0.9260

1.31 ± 0.0476

35⁰33" ± 0.8018

F5

0.4676 ± 0.0233

0.5237 ± 0.0498

25.12 ± 0.9118

1.40 ± 0.1154

33⁰26" ± 0.8180

The bulk density of the SR blends ranged from 0.4072 -0.4706 g/cm3 and the tapped density of ranged from 0.5263-0.5996 g/cm3. The compressibility index of the SR blend ranged from 24.29-25.96% and Hausner’s ratio ranged from 1.26-1.28. The angle of repose of the SR blend ranged from 32⁰58’’ -35⁰33’’. The formulated blend shows poor flow property so wet granulation technique was used for preparing SR granules of Metformin hydrochloride.

The SR granules were evaluated for bulk density, tapped density, compressibility index, Hausner’s ratio and Angle of Repose. The results are given in the Table 28.

Table 28: Precompression study of sustained release granules

Drug and formulation

Bulk density g/cm3

Tapped density g/cm3

Compressibility Index (%)

Hausner’s Ratio

Angle of Repose (Degree)

F1

0.4166 ± 0.0133

0.4912 ± 0.1304

21.99 ± 0.9180

1.21 ± 0.3410

28⁰49" ± 0.2263

F2

0.4023 ± 0.4431

0.4663 ± 0.2399

24.99 ± 0.6920

1.25 ± 0.9265

28⁰01" ± 0.0208

F3

0.4212 ± 0.0053

0.4793 ± 0.1312

22.06 ± 0.0501

1.29 ± 0.0416

28⁰30’’ ± 0.0235

F4

0.4252 ± 0.0040

0.4724 ± 0.0852

23.18 ± 0.1288

1.30 ± 0.4216

27⁰15" ± 0.1255

F5

0.4176 ± 0.0056

0.4792 ± 0.0628

21.81 ± 0.5050

1.22 ± 0.0421

27⁰20" ±0.1124

The bulk density of the SR granules ranged from 0.4023 -0.4252 g/cm3 and the tapped density of ranged from 0.4663-0.4793 g/cm3. The compressibility index of the SR granules ranged from 9.80-12.85% and Hausner’s ratio ranged from 1.21-1.30. The Angle of Repose of the SR granules ranged from 27⁰20’’ -28⁰49’’. The formulated blend shows good flow property.

FORMULATION DEVELOPMENT

Wet granulation technique was employed for the formulation of SR granules of Metformin hydrochloride.

Five batches of SR granules were prepared by using hydrophilic polymers HPMC K4M and HPMC K100M in varying proportions. The formulations were compressed on a 16 station (D tooling)tablet compression machine using 18.5 × 7mm inch punches.

POST COMPRESSION STUDY

UNIFORMITY OF WEIGHT

The uniformity of weight of the formulated tablets is given in table29.

Formulation

Uniformity of weight (mg)

F1

811.40 ± 0.0016

F2

805.01 ± 0.0012

F3

804.33 ± 0.0021

F4

806.25 ± 0.1260

F5

813.05 ± 0.1121

The tablet complies with the test for uniformity of weight.

TABLET THICKNESS AND DIAMETER

The thickness and diameter of the formulated tablets is given in table30.

Table30: Thickness and Diameter of formulated tablets

Formulation

Thickness (mm)

Length

(mm)

Diameter (mm)

F1

6.515 ± 0.130

18.525 ± 0.116

7.110 ± 0.0012

F2

6.591 ± 0.120

18.510 ± 0.021

7.144 ± 0.0024

F3

6.573 ± 0.056

18.586 ± 0.512

7.133 ± 0.0015

F4

6.541 ± 0.067

18.551 ± 0.121

7.132 ± 0.0121

F5

6.548 ± 0.089

18.526 ± 0.126

7.129 ± 0.0926

The tablets have uniform thickness, length and diameter.

HARDNESS

The hardness of the formulated tablets is given in table31.

Table31: Hardness of formulated tablets

Formulation

Hardness Kg/cm2

F1

5.595 ± 0.0130

F2

6.421 ± 0.1237

F3

6.632 ± 0.1521

F4

5.916 ± 0.6671

F5

6.909 ± 0.1219

All the formulated tablets showed sufficient mechanical strength to resist the transportation.

FRIABILITY

The friability of the formulated tablets is given in table32.

Table32: Friability of formulated tablets

Formulation

Friability

F1

0.877 ± 0.0020

F2

0.008 ± 0.0031

F3

0.414 ± 0.0065

F4

0.493 ± 0.0080

F5

0.369 ± 0.0061

The percentage friability of all formulations was within the acceptable limits.

IN VITRO DISSOLUTION STUDY

The In vitro dissolution study of the formulated SR tablets is given in table33.

Table33: Invitro dissolution study of SR tablets

TIME (MINUTES)

F1

F2

F3

F4

F5

0

0 ± 0.0000

0 ±

0.0000

0 ± 0.0000

0 ± 0.0000

0 ± 0.0000

30

25.46 ± 0.0500

14.39 ± 0.1500

24.04 ± 0.0600

26.88 ± 0.0200

26.18 ± 0.0500

60

35.37 ± 0.1300

21.24 ± 0.0800

39.17 ± 0.1400

31.12 ± 0.7200

33.21 ± 0.0550

90

45.85 ± 0.0900

29.16 ± 0.7200

46.18 ± 0.4500

36.26 ± 0.1500

40.59 ± 0.3400

120

56.82 ± 0.2900

34.19 ± 0.1700

53.91 ± 0.1700

41.21 ± 0.1600

48.11 ± 0.3200

180

67.54 ± 0.5100

40.61 ± 0.1600

60.18 ± 0.4500

48.99 ± 0.0800

55.56 ± 0.5000

240

78.69 ± 0.2600

48.81 ± 0.3000

67.66 ± 0.1100

56.44 ± 0.4800

62.71 ± 0.0500

300

98.51 ± 0.2300

59.61 ± 0.6060

73.73 ± 0.1400

62.72 ± 0.3900

70.66 ± 0.5000

360

99.01 ± 0.4200

64.45 ± 0.4200

79.55 ± 0.3200

71.05 ± 0.1300

76.81 ± 0.2700

420

72.58 ± 0.0250

84.61 ± 0.1300

78.11 ± 0.2200

83.18 ± 0.2100

480

80.61 ± 0.2900

88.28 ± 0.0800

84.33 ± 0.4800

89.73 ± 0.2100

540

85.85 ± .0.9630

91.63 ± 0.2600

91.96 ± 0.3900

94.72 ± 0.2360

600

89.08 ± 0.6320

94.66 ± 0.2200

94.56 ± 0.1400

96.78 ± 0.0200

1440

95.61 ± 0.0600

98.81 ± 0.3600

96.71 ± 0.1400

98.65 ± 0.3600

fig: Invitro dissolution study of SR tablets

The results of Invitro dissolution study of SR tablets showed that the formulation F1 containing Ethyl cellulose and HPMC K4M had release the drug completely in 6 hours. The formulation F2 containing Ethyl cellulose and HPMC K100M retarded the release as the concentration of Hydrophilic polymer was high. In formulations F3 and F4 containing ethyl cellulose, HPMC K4M and HPMC K100M in different proportions the release was retarded but did not meet the IP specifications. In formulation F4 containing Ethyl cellulose, HPMC K4M and HPMC K100M in 1:1 ratio the release was sustained and it met the specifications as per IP. Based on the release formulation F4 was selected for final bilayer tablets.

FORMULATION DEVELOPMENT

PREPARATION OF BILAYER TABLETS

Optimized immediate layer of Telmisartan was prepared by wet granulation method.

Optimized sustained release layer of Metformin hydrochloride was prepared by wet granulation method

The granules were compressed on 27 (D-tooling)station bilayer tablet compression machine using 18.5 × 5 mm inch punches.

POST COMPRESSION STUDY OF BILAYER TABLETS

The compressed bilayer tablets were evaluated for following parameters and the values are given in table34.

Table34: Post Compression Study Of Bilayer Tablets

Parameters

Bilayer Tablet

Uniformity of weight (g)

1.0814

Thickness (mm)

6.60

Diameter (mm)

9.13

Hardness (kg/cm2)

7.0

Friability (%)

0.14

Drug content (simultaneous estimation method)

i)Losartan potassium

ii)Metformin hydrochloride

97.36%

95.29%

INVITRO DISSOLUTION STUDY

The Invitro dissolution of drugs in bilayer tablets is given in table 35,36 and fig 2222.

Table35: Invitro dissolution study of Losartan potassium in bilayer tablets

Time (Minutes)

% Drug Release

0

0

10

87.61

20

93.76

30

98.74

Fig: Invitro Dissolution study of Losartan potassium in bilayer tablets

Table36: Invitro dissolution study of Metformin hydrochloride in bilayer tablets

Time (Mins)

% Drug Release

0

0

30

12.02

60

25.18

90

30.02

120

33.96

180

45.05

240

53.62

300

59.07

360

65.77

420

72.35

480

81.96

540

85.44

600

91.38

Fig: Invitro Dissolution study of Metformin hydrochloride in bilayer tablets

INVITRO RELEASE KINETICS

The values obtained from invitro dissolution of Metformin hydrochloride from bilayer tablets were fitted in various kinetics models. The results are given in table37 and fig

Table37: Invitro release kinetics of bilayer tablets

Time (Mins)

% Cum

Drug Release

% Cum

Drug Remaining

Log % Cum Drug Remaining

Square

root of

time

Log

time

Log %

cum drug

release

Cube root of % drug remaining

0

0

100

2

0

0

0

4.6416

0.5

12.02

87.98

1.94438

0.7071

-0.3010

1.0799

4.4476

1

25.18

74.82

1.87402

1

0

1.4011

4.2138

1.5

30.02

69.98

1.84497

1.2247

0.1761

1.4774

4.1209

2

33.96

66.04

1.81981

1.4142

0.3010

1.5310

4.0421

3

45.05

54.95

1.73997

1.7321

0.4771

1.6537

3.8018

4

53.62

46.38

1.66633

2

0.6021

1.7293

3.5929

5

59.07

40.93

1.61204

2.2361

0.6990

1.7714

3.4463

6

65.77

34.23

1.53441

2.4495

0.7782

1.8180

3.2469

7

72.35

27.65

1.44169

2.6458

0.8451

1.8594

3.0239

8

81.96

18.04

1.25624

2.8284

0.9031

1.9136

2.6227

9

85.44

14.56

1.16316

3

0.9542

1.9317

2.4419

10

91.38

8.62

0.93551

3.1623

1

1.9609

2.0504

Fig: Zero order release kinetics

Fig: First order release kinetics

Fig :Higuchi Diffusion Kinetics

Fig: Korsmeyer Peppas Equation

Fig : Hixson crowell cube root equation

Determination of drug release mechanism of optimized bilayer tablets

The order of release was found to be first order, in which R2 value was close to 1 than the value of R2 of the zero order equation.

The n value of Korsmeyer peppas equation was found to be 0.574, from that it was concluded that the release followed non-Fickian transport.

Swelling hydration of the polymer matrix, dissolution of the drug in the polymer matrix and diffusion of the drug through the polymer matrix and surface erosion of the matrix also plays role in the drug release. The results showed that the formulation followed first order release.

Stability study

The optimized bilayer tablets were subjected to stability studies and the results are given in Table 38, 39.

Table 38: Stability study of physical parameters of the optimized formulation

Parameters

Initial

1st month

2nd month

3rd month

Uniformity of weight (mg)

Thickness (mm)

Diameter (mm)

Hardness kg/cm2)

Friability (%)

Table 39: Assay and Dissolution profile of Bilayer tablets

Time interval (month)

Drug content

Cumulative % release

Losartan potassium

Metformin hydrochloride

Losartan potassium

Metformin hydrochloride

1 month

2 month

3 month

S.No

Wave Number (cm-1)

Interpretation

01.

3371, 3294

N-H stretching vibrations (Primary amine)

02.

3171

N-H stretching vibrations (Secondary amine)

03.

2816

C-H stretching vibrations (Alkane)

04.

1566

N-H bending vibrations

05.

1057

C-N stretching vibrations

S.No

Wave Number (cm-1)

Interpretation

01.

3302

N-H stretching vibrations (Primary amine)

02.

3178

N-H stretching vibrations (Secondary amine)

03.

2970

C-H stretching vibrations (Alkane)

04.

1566

N-H bending vibrations

05.

1065

C-N stretching vibrations

S.No

Wave Number (cm-1)

Interpretation

01.

3371

OH- stretching(b) vibrations for carboxylic acids

02.

3302

N-H stretching vibrations (Primary amine)

03.

3171

N-H stretching vibrations (Secondary amine)

04.

2970

C-H stretching vibrations (Aromatic)

05.

2816

C-H stretching vibrations (Alkane)

06.

1628

C=O stretching vibrations for carboxylic acids

04.

1566

N-H bending vibrations

05.

1065

C-N stretching vibrations

S.No

Wave Number (cm-1)

Interpretation

01.

3371

OH- stretching vibrations for carboxylic acids

02.

3063

C-H stretching vibrations (Aromatic)

03.

2870

C-H stretching vibrations (Alkane)

04.

1697

C=O stretching vibrations for carboxylic acids

S.No

Wave Number (cm-1)

Interpretation

01.

3371, 3302

N-H stretching vibrations (Primary amine)

02.

3171

N-H stretching vibrations (Secondary amine)

03.

2978

C-H stretching vibrations (Alkane)

04.

1566

N-H bending vibrations

05.

1065

C-N stretching vibrations

S.No

Wave Number (cm-1)

Interpretation

01.

3371, 3302

N-H stretching vibrations (Primary amine)

02.

3171

N-H stretching vibrations (Secondary amine)

03.

2978

C-H stretching vibrations (Alkane)

04.

1628

N-H bending vibrations

05.

1065

C-N stretching vibrations