1.0) Description: Visual
2.0) Average Weight: Check weight of 20 tablets at randomly and calculate the average weight by formula.
Average weight (mg) = wt of 20 tablets (gm) x 1000
20
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 to calculate the percentage of deviation.
Deviation (%) = Weight of each tablet – Average weight x 100
Average weight
| Average weight of tablets | Percentage deviation |
| 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 (c).
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:
Diameter and thickness are determined by vernier calliper 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 6.5 g. 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.
% Friability = W1 – W2 X 100
W1
W1= Initial weight W2= Final weight
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. If obviously cracked, chipped or broken tablets are present in the sample after tumbling, the sample fails the test.
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;
Apparatus: Paddle
Speed: 75 rpm
Time: 30 min.
For Hydrochlorothiazide:
Medium: 900 ml of 0.1M Hydrochloric acid
Appratus: Basket
Speed: 100 rpm
Time: 30 min.
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.
- 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.
Formula:
Area of test
—————– X STD Dilution X Test Dilution X Potency of STD X 100
Area of STD
Limit: N.L.T. 85% of the stated amount of Telmisartan and Hydrochlorothiazide.
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) Related Substances:
Determine by liquid chromatography, as described under assay with the following modifications.
Reference solution (d): A 0.000125 per cent w/v solution of 4-Amino-6-chloro-1,3-benzenedisulphonamide reference standard ( benzothiadiazine impurity A reference standard) in the solvent mixture and further dilute with a solution prepared by diluting equal volumes of mobile phase A and mobile phase B to obtain a final concentration of 0.00005 per cent w/v.
Reference solution (e): A solution containing 0.016 per cent w/v of Telmisartan reference standard and 0.005 per cent w/v hydrochlorothiazide reference standard in the solvent mixture. Dilute 1.0ml of this solution and 2.0ml of reference solution (a) to 100.0ml with the solvent mixture and further dilute 1.0ml of this solution to 5.0 ml with a solution prepared by diluting equal volumes of mobile phase A and mobile phase B.
Inject reference solution (c) and (e). The test is not valid unless the resolution between the peaks due to hydrochlorothiazide and benzothiadiazine impurity A in the chromatogram obtained with reference solution (c) is not less than 2. And the relative standards deviation for replicate injections for both peaks of Telmisartan and hydrochlorothiazide is the chromatogram obtained with reference solution (c) is not more than 2.0 per cent. The signal to noise ratio for the Telmisartan, hydrochlorothiazide and benzothiadiazine impurity A peak in the chromatogram obtained with reference solution (c) is not less than 3.0.
Inject reference solution (c), (d) and the test solution. In the chromatogram obtained with the test solution, the area of any peak corresponding to benzothiadiazine impurity A is not more than 6.4 times the area of the benzothiadiazine impurity A peak in the chromatogram obtained with reference solution (d) (1.0 per cent), the area of any individual secondary peak due to Telmisartan is not more than 0.005 times the area of the Telmisartan peak in the chromatogram obtained with reference solution (c) (0.5 per cent), the area of any individual secondary peak due to hydrochlorothiazide is not more than 0.002 times the area of the hydrochlorothiazide peak in the chromatogram obtained with reference solution (c) (0.2 per cent). The sum of area of all secondary peak is due to Telmisartan is not more than 0.002 times the area of the Telmisartan peak in the chromatogram obtained with reference solution (c) (0.2 per cent). The sum of areas of all the secondary peaks due to hydrochlorothiazide is not more than 0.02 times the area of the hydrochlorothiazide peak in the chromatogram obtained with reference solution (c) (2.0 per cent).
12.0) Assay: Determined by liquid chromatography.
Solvent mixture: 0.005 M Methanolic solution of sodium hydroxide
Note: To prevent heat from degrading the sample, do not extend the sonication time and also maintain the bath temperature at a temperature not exceeding 22° by adding ice.
Test solution: Weigh and disperse 10 intact Tablets into a suitable volumetric flask, add 0.1 N sodium hydroxide solution (5% of the total volume of the flask), and shake until the Tablets have completely disintegrated. Add methanol (80% of the total volume of the flask). Sonicate for 10 min and stir vigorously for 30 min. Allow to cool to room temperature, dilute with methanol to obtain a solution containing 0.16per cent w/v of Telmisartan. Centrifuge a portion of the solution at 4000 rpm and use clear supernatant liquid. Dilute 1.0ml of this solution to 5.0 ml with a solution prepared by diluting equal volumes of mobile phase A and mobile phase B.
Reference solution (a): A 0.0025 per cent w/v solution of benzothiadiazine impurity A reference standard in the solvent mixture.
Reference solution (b): A solution containing 0.16 per cent w/v of Telmisartan reference standard, 0.05 per cent w/v of hydrochlorothiazide reference standard and 0.0025 per cent w/v of benzothiadiazine impurity A reference standard in the solvent mixture.
Reference solution (c): Diluting reference solution (b) with a solution prepared by diluting equal volumes of mobile phase A and mobile phase B to obtained a solution containing 0.032 per cent w/v of Telmisartan reference standard, 0.01 per cent w/v of hydrochlorothiazide reference standard and 0.0005 per cent w/v of benzothiadiazine impurity A reference standard.
Chromatographic system:
- A stainless steel column 12.5 cm X 4.0 mm, packed with octadecylsilane bonded to porous silica (5µ),
- Column Temperature: 40°
- Mobile Phase: A. a buffer solution prepared by dissolving 2.0 gm of ammonium dihydrogen orthophosphate in 1000ml of water, adjusted to pH 3.0 with diluted phosphoric acid.
- a mixture of equal volumes of methanol and acetonitrile,
- Flow rate: 1.2 ml per minute
- A gradient programme using the conditions given below,
- Spectrophotometer set at 270 nm for hydrochlorothiazide and 298 nm for Telmisartan,
- Injection volume: 10 µl
Mobile phase: see the gradient table below
| Time
( in Minute) |
Mobile phase A
(per cent v/v) |
Mobile phase B
(per cent v/v) |
| 0 | 85 | 15 |
| 3.50 | 85 | 15 |
| 3.51 | 45 | 55 |
| 7.70 | 45 | 55 |
| 7.71 | 20 | 80 |
| 12.0 | 20 | 80 |
| 12.1 | 85 | 15 |
| 15.5 | 85 | 15 |
Inject reference solution (c). The test is not valid unless the resolution between the peaks due to hydrochlorothiazide and benzothiadiazine impurity A is not less than 2.0 and the relative standard deviation for replicate injections for both the peaks of telmisartan and hydrochlorothiazide is not more than 2.0 per cent.
Inject reference solution (c) and the test solution.
Calculate the content of Hydrochlorothiazide and Telmisartan in the tablet.
Acceptance criteria: 95.0%-105.0%
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: Milligram
ml: Milliliter
STD: Standard
inHg: Inch of Mercury
rpm: Rotations per minute
CFU: Colony forming unit
w/v: Weight/volume
