Formulation Of Immediate Release Granules Of Telmisartan Potassium Biology Essay

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Telmisartan belongs to class II drug in BCS classification i.e. low solubility and high permeability. One of the major problems with this drug is its low solubility in biological fluids, which results into poor bioavailability after oral administration. Enhancement of solubility of Telmisartan was observed with inclusion complex of drug using βeta-Cyclodextrin as a carrier. The immediate release granules of Telmisartan (L1,L2 and L3) were prepared by wet granulation technique. Sodium Starch Glycolate (SSG) was used as a super disintegrant in (2%, 4% and 6% concentrations) to improve dissolution of the drug. The granules was compressed by 16 station (D tooling) tablet compression machine using 10/32 punches.

Table 6: Composition of immediate release granules

S.NO

INGREDIENTS

L1 (mg)

L2 (mg)

L3 (mg)

01.

Telmisartan

40.0

40.0

40.0

02.

β- Cyclodextrin

40.0

40.0

40.0

03.

Lactose

77.4

73.6

69.8

04.

Starch

20.0

20.0

20.0

05.

PVP K-30

3.8

7.6

7.6

06.

Isopropyl alcohol

q.s

q.s

q.s

07.

Sodium starch glycolate

3.8

3.8

11.4

08.

Magnesium stearte

2.0

2.0

2.0

09.

Tartrazine yellow

1.0

1.0

1.0

10.

Talc

2.0

2.0

2.0

Total weight

190.0

190.0

190.0

The immediate release tablet of Telmisartan was formulated optimized. The optimized formulation was used for the final bilayer tablets.

Telmisartan

β- Cyclodextrin

Flowchart for formulation of Telmisartan immediate release (IR) tablets

Complex formed

Dispensing & Sifting

Sifting

Sifting

Sifting

Lactose

Starch

IPA

Tartrazine yellow

Dispensing & Sifting

Sifting

Sifting

Sifting

Blended

Siftin

Immediate Release Tablets of Telmisartan

Precompression study

Wet granulated with

PVP K 30 in IPA / Dried at 60°C

Dried and mixed with SSG

Lubricated with

Magnesium stearate

Immediate release granules

Compression

Postcompression study

FORMULATION OF METFORMIN HYDROCHLORIDE SUSTAINED RELEASE TABLETS

The sustained release granules were prepared by wet granulation technique. Different polymers such as HPMC K4M, HPMC K100M and ethyl cellulose are used in different ratios. The tablets were compressed by 16 station(D-tooling) compression machine using 18.5mm(l) Ã- 7mm(w) punches. The optimized batch of sustained release of Metformin hydrochloride was then compressed with with the optimized batch of immediate release tablets to get bilayer tablets.

Table 7: composition of sustained release granules

S.NO

INGREDIENTS

F1(mg)

F2(mg)

F3(mg)

F4(mg)

F5(mg)

01.

Metformin hydrochloride

500

500

500

500

500

02.

Ethyl cellulose

24

24

24

24

24

03.

HPMC K4M

200

-

150

50

100

04.

HPMC K100M

-

200

50

150

100

05.

Microcrystalline cellulose pH102

40

40

40

40

40

06.

PVP K-30

16

16

16

16

16

07.

Isopropyl alcohol

q.s

q.s

q.s

q.s

q.s

08.

Magnesium stearate

10

10

10

10

10

09.

Talc

10

10

10

10

10

Total weight

800

800

800

800

800

Flowchart for formulation of Metformin Hydrochloride Sustained Release Tablets

Mixed with Ethyl cellulose solution and dried

Dispensed &sifted

Metformin hydrochloride

Ethyl cellulose

HPMC K4 M

HPMC K100M

Microcrystalline Cellulose

Dispensed &sifted

Mixed with Ethyl cellulose solution & Dried

Blended with HPMC K4M or HPMC K100M &MCC

Precompression study

Wet granulated with PVP K 30 in IPA & Dried

Granules were dried and lubricated with Magnesium stearate

Postcompression study

Compression

Sustained release tablets of MH

Flowchart for bilayer tablets of Losartan potassium and Metformin hydrochloride

Bilayer tablets

Compression of IR layer over SR layer

Filling of IR granules on SR layer

Single compression of SR granules

Granules fed in separate hoppers

SR granules of Metformin Hydrochloride

Optimized IR granules of Losartan potassium

POST COMPRESSION STUDIES

PHYSICAL PARAMETERS

General appearance

The general appearance of the tablets from each formulation batch was observed. The general appearance parameters are shape, color, presence or absence of ador and taste were evaluated visually.

Uniformity of Weight

Twenty tablets were selected at a random and weighed individually. The average weight was also measured. The percentage deviation of tablets was calculated and compared with the standard specifications.

Thickness and diameter

The thickness and diameter was measured to determine the uniformity of size and shape. Thickness and diameter of the tablets were measured using vernier calliper.

Hardness

Hardness is defined as the force required for breaking a tablet at diametric compression test and it is termed as tablet crushing strength. Hardness of the prepared formulations was determined using Monsanto hardness tester. It was expressed in Kg/cm2.

Friability

Friability of the prepared formulations was determined by using Roche friabiltor. Pre- weighed sample of tablets was placed in the friability tester, which was then operated for 100 revolutions, tablets were dedusted and reweighed. The friability of the tablets was calculated using the formula mentioned below.

% Friability = Initial weight of the tablets - Final weight of the tablets X 100

Final weight of the tablets

DRUG CONTENT

FOR IR TABLETS CONTAINING TELMISARTAN

Twenty tablets were selected randomly and finely grounded. An accurately weighed quantity of powder equivalent to 20 mg of Telmisartan was transferred to 100 volumetric flask and dissolved in five ml of 0.1N NaoH and the volume was made upto mark with 1.2pH hydrochloric acid buffer solution . The solution was filtered and 5 ml portion of the filtrate was further diluted with 1.2pH hydrochloric acid buffer solution in a 100ml volumetric flask. The absorbance of the resulting solution was measured at 296nm taking 1.2pH hydrochloric acid buffer solution as blank using UV-visible Spectrophotometer. The concentration was obtained from the calibration graph.

FOR SR TABLETS CONTAINING METFORMIN HYDROCHLORIDE

Twenty tablets were selected randomly, weighed and finely grounded. An accurately weighed quantity of powder equivalent to 100mg of Metformin hydrochloride was transferred to 100ml volumetric flask and shaken with 70ml of 6.8pH phosphate buffer solution for 15 minutes, then it was made upto the mark with the same buffer solution. The solution was filtered and 5ml portion of the filtrate was diluted with 6.8pH phosphate buffer solution in a 50ml volumetric flask. From the above solution 5ml portion was further diluted upto the mark with 6.8pH phosphate buffer solution in a 50ml volumetric flask. The absorbance of the resulting solution was measured at 233 nm taking 6.8pH phosphate buffer solution as blank using UV-visible Spectrophotometer. The concentration was obtained from the calibration graph.

BILAYER TABLETS OF TELMISARTAN AND METFORMIN HYDROCHLORIDE (SIMULATANEOUS EQUATION METHOD)

Simulatneous estimation of Telmisartan and Metformin hydrochloride was carried out using UV-Visible Spectrophotometer.

PROCEDURE

The following equations were used to determine the contents.

Cx = A2ay1 - A1ay2

Ax2ay1-ax1ay2

Cy = A1ax2 - A2ax1

Ax2ay1-ax1ay2

Where ax1 and ax2 = The absorptivity of drug X at λ1 and λ2 respectively.

ay1 and ay2 = The absorptivity of drug Y at λ1 and λ2 respectively.

A1 and A2 = The absorbance of sample at λ1 and λ2 respectively.

A1/ A2 and ay1/ ay2

ax1 / ax2 A1/ A2

The ratios should lie outside the range of 0.1 - 2.0 for the precise determination of X and Y drugs. This criteria is satisfied only when the λmax of the two components is reasonably dissimilar and the components should not interact chemically.

Preparation of standard stock solution of Losartan potassium

Telmisartan equivalent to 100mg was accurately weighed and dissolved by sonication with 5ml of 0.1M NaoH and kept aside for 15mins. The volume was made upto mark with 1.2 pH hydrochloric acid buffer solution in a 100ml volumetric flask. Two ml of the solution was diluted to 100ml with 1.2pH hydrochloric acid buffer solution.

Preparation of standard stock solution of Metformin hydrochloride

Metformin hydrochloride equivalent to 100mg was accurately weighed. 50ml of 0.1N HCl was added and kept in a sonicated for 10mins. The volume was made upto 100ml with 0.1N HCl. Two ml of the solution was diluted to 100ml with 0.1N HCl.

Preparation of sample solution:

Twenty tablets were accurately weighed and the average weight was calculated. The tablets were then ground to a fine powder. Powder equivalent to the Metformin hydrochloride was weighed and transferred to a 100ml standard flask. The powder was then dissolved in 0.1N HCl and sonicated. The volume was made made upto the volume with 0.1N HCl. Two ml of the solution was diluted to 100ml with 0.1N HCl. The absorbance of the resulting solution was measured at 205 nm and 233 nm respectively. The amount of both the drugs were determined.

In vitro disintegration studies for IR tablets

The disintegration time was determined using disintegration test apparatus. The tablets were placed in each of the six tubes of the basket. The assembly was suspended in 1.2pH hydrochloric acid buffer solution maintained at a temperature of 37⁰C ±2⁰C and the apparatus was switched on. The time taken to disintegrate the tablets completely was noted.

In vitro dissolution studies

For IR tablets

The release of Telmisartan was determined using Type II (paddle) dissolution apparatus under sink condition. 900ml of 1.2pH hydrochloric acid buffer solution was used as dissolution medium at a temperature of 37⁰C ±0.5⁰C. The paddle was stirred at a speed of 75 rpm. The release studies were carried out for 45 mins. The absorbance of the solution was measured at 205 nm taking 1.2pH hydrochloric acid buffer solution as blank using UV- Visible spectrophotometer.

For SR tablets

The release of Metformin hydrochlordie was determined using Type I (basket) dissolution apparatus. 1000ml of 1.2pH hydrochloric acid buffer solution was used as dissolution medium for first two hours followed by pH 6.8 phosphate buffer solution for next eight hours maintained at a temperature of 37⁰C ±0.5⁰C. The basket was rotated at a speed of 100 rpm. The release studies were carried out for ten hours. The absorbance of the solution was measured at 233 nm taking respective buffer solutions as blank using UV- Visible spectrophotometer.

For bilayer tablets

The release of bilayer tablets was determined using Type II (paddle) dissolution apparatus under sink condition. 900ml of 0.1N HCl was used as dissolution medium for first two hours followed by pH 6.8 phosphate buffer solution for next eight hours maintained at a temperature of 37⁰C ±0.5⁰C. The paddle was stirred at a speed of 100 rpm. The release studies were carried out for ten hours. The absorbance of the solution was measured at 205nm and 233 nm taking respective buffer solutions as blank using UV- Visible spectrophotometer and the calculations were done by simultaneous equation method.

Evaluation of Invitro release kinetics

To study the Invitro release kinetics of the optimized bilayer tablets, data obtained from Invitro dissolution study were plotted in various kinetic models.

Zero order equation

The zero order release kinetics can be obtained by plotting cumulative % drug released Vs time (hours). It is ideal for the formulation to have release profile of zero order to achieve pharmacological prolonged action.

C = K0t

Where K0 = Zero order constant in conc./ time

t = Time in hours

First order equation

The graph was plotted as log % cumulative drug remaining Vs time in hours.

Log C = logC0 - Kt/2.303

C0 = Initial drug concentration

K = First order constant

t = Time in hours.

Higuchi kinetics

The graph was plotted with % cumulative drug released Vs square root of time.

Q = Kt1/2

K = Constant reflecting design variable system (Differential rate constant)

t = Time in hours.

The drug release rate is inversely proportional to the square root of time.

Hixson and Crowell erosion equation

To evaluate the drug release with changes in the surface area and the diameter of particles, the data were plotted using the Hixson and Crowell erosion equation. The graph was plotted by cube root of % drug remaining Vs Time in hours.

Q01/3 - Qt1/3 = KHC X t

Qt = Amount of drug released at time t

Q0 = Initial amount of drug

KHC = Rate constant for Hixson Crowell equation

Korsmeyer - Peppas equation

To evaluate the mechanism of drug releae, it was further plotted in Peppas equation as log cumulative % of drug released Vs log time.

Mt/Mα = Ktn

Where Mt/Mα = Fraction of drug released at time t

t = Release time

K = Kinetics constant (Incorporating structural and geometric characteristics of the formulation)

N = Diffusional exponent indicative of the mechanism of drug release.

If slope (n) values is 0.5 or less, the release mechanism is "Fickian diffusion" and if 0.5<n<1 it follows "Non-Fickian diffusion" (anomalous transport). The drug release follows zero order drug release and Non-Fickian case II transport if the value is 1. For the values of n higher than 1, the mechanism of drug released is regarded as non-fickian case II transport. The model is used to analyze the release of pharmaceutical polymeric dosage forms when the release mechanism is not known or more than one type of release is involved.

Stability Study

Stability study of optimized bilayer tablets was carried out according to ICH guidelines. All the tablets were packed in blisters and kept in a humidity chamber at 40 ± 2⁰C and 75 ± 5% RH for 3 months. Samples were withdrawn at monthly intervals and analyzed for drug content, hardness and in vitro dissolution.

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