STP FOR TELMISARTAN, AMLODIPINE AND HYDROCHLOROTHIAZIDE TABLETS

1.0) Description: Visual

2.0) Average Weight: Check weight of 20 tablets at randomly and calculate the average weight by formula :  wt of 20 tablets (gm) x 1000 / 20. found avg. wt in mg

3.0)                  Uniformity of weight:

Weigh 20 tablets selected at random and calculate the average weight. Not more than two of the individual weights deviate from the average weight by more than the percentage shown in table.

Tablets were weighed individually and the percentage of deviation of its weight from the average weight was determined for each tablet. Formula for calculate the percentage of deviation = (experimental weight – theoretical weight)    x 100%

Theoretical weight

 Average weight of tablets Percentage deviation More than 80mg but Less than 250mg 7.5% 250mg or More 5%

4.0)      Identification Test:

In the assay, the principal peaks in the chromatogram obtained with the test solution corresponds to the principal peaks in the chromatogram obtained with reference solution.

5.0)      Hardness:

The standard method used for tablet hardness testing is compression testing. The tablet is placed between two jaws that crush the tablet. The machine measures the force applied to the tablet and detects when it fractures. Although compressive force is applied to the tablet, along the diameter of the tablet at right angles to the applied force.

6.0)      Disintegration Time

Unless otherwise stated in the individual monograph, introduce one tablet into each tube and add a disc to each tube. The assembly is suspended in the liquid medium in a suitable vessel, preferably a 1-litre beaker. The volume of liquid is such that the wire mesh at its highest point is at least 15mm below the surface of the liquid, and at its lower point is at least 25mm above the bottom of the beaker. At no time should the top of the basket-rack assembly become submerged. There is a thermostatic arrangement for heating the liquid and maintaining the temperature at 37±2°.

If 1 or 2 tablets fail to disintegrate, repeat the test on 12 additional tablets; not less than 16 of the total of 18 tablets tested disintegrate.

If the tablets adhere to the disc and the preparation under examination fails to comply, repeat the test omitting the disc. The preparation complies with the test if all the tablets in the repeat test disintegrate.

7.0)      Dimension of Tablet:

Length, breadth and thickness are determined by vernier in mm

8.0)      Friability:

The test is applicable to compressed tablets and is intended to determine the physical strength of tablets. Tablets with a unit weight equal to or less than 650 mg, take a sample of whole tablets corresponding as near as possible to 6.5g. For tablets with a unit weight of more than 650mg, take a sample of 10 whole tablets. The tablets should be carefully dedusted prior to testing. Accurately weigh the tablet sample, and place the tablets in the drum. Rotate the drum 100 times and remove the tablets. Remove any loose dust from the tablets as before, and accurately weigh.

The test is run only once unless the results are difficult to interpret or if the weight loss is greater than the target value, in which case, the test is repeated twice and the mean of the three tests is determined.

Formula: initial wt. – after friability wt. x100 / initial wt.

A maximum loss of weight (From a single test or from the mean of three tests) not greater than 1.0 percent is acceptable for most tablets.

9.0)      Dissolution:

For Telmisartan:

Medium: 900 ml of Buffer (PH7.5 Phosphate buffer): prepared 13.61 g/l of Potassium Dihydrogen phosphate in water. Adjust with 2M Sodium Hydroxide to a PH of 7.5;

Speed: 75 rpm

Time: 30min.

For Hydrochlorothiazide:

Medium: 900ml of 0.1M Hydrochloric acid

Speed: 100 rpm

Time: 30min.

Limit: NLT 85% of the stated amount of telmisartan and hydrochlorothiazide.

Withdraw a suitable volume of the medium and filter.

Determine by liquid chromatography.

Test solution: Dilute the filtrate, if necessary, with the dissolution medium.

Reference solution (a): Dissolve a quantity of telmisartan reference standard in minimum quantity of methanol and dilute with dissolution medium to obtain a solution having a known concentration similar to the test solution.

Reference solution (b): Dissolve a quantity of hydrochlorothiazide reference standard in minimum quantity of methanol and dilute with dissolution medium to obtain a solution having a known concentration similar to the test solution.

Chromatographic system:

• A stainless steel column 6cm X3.0mm, packed with octadecylsilane bonded to porous silica (5µ),
• Column Temperature: 40°
• Mobile Phase: A. a buffer solution prepared by dissolving 5.0 gm of ammonium dihydrogen orthophosphate in 1000ml of water, adjusted to pH 3.0 with diluted phosphoric acid.
1. Acetonitrile
• A gradient programme using the conditions given below,
• Spectrophotometer set at 270nm for hydrochlorothiazide and 298 nm for telmisartan,
• Injection volume: 4µl

Mobile phase: Set the gradient table below:

The relative retention time with reference to telmisartan for hydrochlorothiazide is about 0.33.

Inject reference solution (a) and (b). The test is not valid unless the tailing factor for each peak is not more than 2.5 and the relative standard deviation for replicate injections for each peak is not more than 2.0 per cent.

 Time ( in Minute) Mobile phase A (per cent v/v) Mobile phase B (per cent v/v) Flow rate (ml per minute) 0 85 15 0.6 1.50 85 15 0.6 1.51 60 40 0.6 5.00 60 40 0.6 5.01 20 80 1.0 6.20 20 80 1.0 6.21 85 15 0.6 9.70 85 15 0.6

Inject reference solution (a) and (b) and the test solution.

Calculate the percentage of telmisartan or hydrochlorothiazide dissolved.

For Amlodipine:

Medium: 500 ml of 0.01 M HCl

Speed: 75 rpm

Time: 45min.

Limit: NLT 80% of the stated amount of Amlodipine.

Withdraw a suitable volume of the medium and filter, rejecting the first few ml of the filtrate.

Test solution: Use filtrate, dilute if necessary, with the dissolution medium.

Reference solution: A solution of amlodipine besylate reference standard containing 0.02 per cent w/v of amlodipine in methanol. Dilute this solution with dissolution medium to obtain a solution having a known concentration similar to the test solution.

Chromatographic system:

• A stainless steel column 15cm X4.6mm, packed with endcapped octadecylsilane bonded to porous silica (5µ),
• Column Temperature: 40°
• Mobile Phase: a mixture of 60 volumes of a buffer slution prepared by dissolving 2.72gm potassium dihydrogen orthophosphate in 1000ml of water and adjusted to pH 2.4 with O.P.A. and 40 volumes of acetonitrile
• Flow rate: 1ml per minute
• Spectrophotometer set at 237nm for hydrochlorothiazide and 298 nm for telmisartan,
• Injection volume: 10µl
• Inject reference solution. The test is not valid unless the column efficiency is not less than 1500 theoretical plates, the tailing factor is not more than 2.0 and the relative standard deviation for replicate injections is not more than 2.0 per cent.
• Inject reference solution and test solution.

10.0)    Leak test:

The apparatus is used to test for the integrity of packed strips, blisters and Alu-Alu Blister pack containing tablets. Ensure apparatus bath is filled with purified water upto mark indicated and add 0.5% crystal violet solution in water. Samples are placed into the desiccators and the lid is placed in position. The pump starts to produce a vacuum 15inHg inside the desiccators and the vacuum is held for 1 minute. The sample remains at the required vacuum level for given time interval buzzer will sound after time is over and will cut off the vacuum pump. As the package is immersed in a colored dye solution the venting of the desiccators will allow any holes to be penetrated by the dye and the contents of the flexible packaging will also be stained with the same coloring material.

Examine all the strips for any leakage by opening the pockets manually. If anyone pocket shows evidence of leakage, reject the sample, stop the Blister / Strip machine and immediately take corrective action.

11.0)    Assay: Determined by liquid chromatography.

Test solution: Weigh and powder 20 tablets. Weigh sample equivalent to 10mg of amlodipine in 100ml volumetric flask. Add 20ml of methanol in it and dissolve m sonication and shaking. Make up the volumetric with methanol. Stirr the test solution for 10 minutes. Filter and dilute 2ml of it to 25ml with mobile phase.

Reference solution of amlodipine: Weigh 64mg of amlodipine besilate reference standard into 25 ml volumetric flask and add in methanol to dissolve. Make up the volume up to mark. Reference solution: Weigh 80mg of telmisartan reference standard and 25 mg of Hydrochlorothiazide reference standard in 100ml of volumetric flask. Add 20ml of methanol to dissolve the standard. Add 5ml of Amlodipine reference solution to it. Dissolve and make up the volume up to the mark. Dilute 2ml to 25ml in moblie phase.

Chromatographic system:

• A stainless steel column 25cm X4.6mm, packed with octadecylsilane bonded to porous silica (5µ),
• Mobile Phase: Buffer: Acetonitrile (600:400)

[Buffer: 6.8 gmKH2PO4→1000ml pH 3]

• Flow rate: 1.2ml per minute
• Spectrophotometer set at 238 nm,
• Injection volume: 20µl

Inject the reference solution and test solution.

Calculate the content of Amlodipine, Telmisartan and Hydrochlorothiazide in tablet.

Formula: Amlodipine

Area of Test       STD Wt.(mg)       5                 2              100             25       Potency

—————-X—————X—————-X——–X————–X———X———X Avg.wt.

Area of STD          25                     100              25      Test Wt.(mg)     2          100

Formula;Telmisatan & Hydrochlorothiazide

Area of Test        STD Wt.(mg)       2           100                  25       Potency

——————–X—————-X——–X————–X———X———X   Avg.wt.

Area of STD                100              25      Test Wt.(mg)     2          100

Acceptance criteria: 90.0%-110.0%

13.0)    MICROBIOLOGICAL PURITY

Perform the test according to requirements of IP,

Total aerobic Microbial count (TAMC): NMT 103 CFU/g

Total combined yeasts/Moulds count (TYMC): NMT 102 CFU/g

Pathogens: in 1gm drug.

Escherichia Coli – Should be absent

Pseudomonas aeroginosa – Should be absent

Salmonella – Should be absent

Staphylococcus aureus– Should be absent

Abbreviations:

Wt.: Weight

mg: Miligram

ml: Milileter

STD: Standard

inHg: Inch of Mercury

rpm: Rounds per minute

CFU: Colony forming unit

O.P.A.: Orthophosphoric acid

w/v: Weight/volume

HCl: Hydrochloric acid

Avg.: Average weight