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:
Note: The solution should be used within 3 hours of preparation.
Apparatus: Paddle
Medium: 900ml of 0.1 M Hydrochloric acid,
Speed: 50 rpm
Time: 45 minutes
Limit: NLT 80% of the stated amount of Olmesartan medoxomil and Hydrochlorothiazide.
Withdraw a suitable volume of the medium and filter.
Determine by liquid chromatography.
Solvent mixture: A mixture of 50 volumes of a buffer solution prepared by dissolving 3.4 gm of potassium dihydrogen orthophosphate in 1000ml of water, adjusted to pH 2.2 with orthophosphoric acid and 50 volumes of acetonitrile.
Test solution: Dilute the filtrate, if necessary, with the dissolution medium.
Reference solution (a): Dissolve a quantity of olmesartan medoxomil reference standard in the solvent mixture 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 the solvent mixture and dilute with dissolution medium to obtain a solution having a known concentration similar to the test solution.
Reference solution (c): Dilute a volume of reference solution (a) and reference solution (b) with dissolution medium to obtain a solution having known concentration similar to the expected concentration of the test solution.
Chromatographic system:
- A stainless steel column 15cm X4.6 mm, packed with octadecylsilane bonded to porous silica (5µ),
- Mobile Phase: a mixture of 65 volumes of a buffer solution prepared by dissolving 3.4gm of potassium dihydrogen orthophosphate in 1000ml of water, adjusted to pH 2.2 with O.P.A., 30 volumes of acetonitrile and 5 volumes of methanol,
- Spectrophotometer set at 260nm,
- Injection volume: 20µl
Inject reference solution (c). The test is not valid unless the column efficiency is not less than 2500 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 (c) and the 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) Related Substances:
Determine by liquid chromatography,
Solvent mixture: A mixture of 50 volumes of a buffer solution prepared by dissolving3.4 gm of potassium dihydrogen orthophosphate in 1000ml of water, adjusted to pH 2.2 with O.P.A. and 50 volumes of acetonitrile.
Test solution: Weigh and powder 20 tablets. Disperse a quantity of powder containing 62.5mg of hydrochlorothiazide in 200.0ml volumetric flask, add about 120ml of solvent mixture and sonicate for about 30 minutes with occasional shaking. Cool the flask and make the volume with solvent mixture, mix and filter.
Reference solution: A solution containing 0.000252 per cent w/v of olmesartan medoxomil reference standard and 0.000162 per cent w/v hydrochlorothiazide reference standardin the solvent mixture.
Chromatographic system:
- A stainless steel column 15cm X4.6 mm, packed with octadecylsilane bonded to porous silica (5µ),
- Mobile Phase: A. a buffer solution prepared by dissolving 3.4gm of potassium dihydrogen orthophosphate in 1000ml of water, adjusted to pH 2.2 with O.P.A.,
- acetonitrile
- A gradient programme using the conditions given below,
- Spectrophotometer set at 230nm,
- Injection volume: 10µl
| Time
(in min.) |
Mobile phase A
(per cent v/v) |
Mobile phase B
(per cent v/v) |
| 0 | 85 | 15 |
| 7.0 | 85 | 15 |
| 25.0 | 40 | 60 |
| 30.0 | 40 | 60 |
| 35.0 | 85 | 15 |
| 45.0 | 85 | 15 |
The relative retention time with reference to hydrochlorothiazide for benzothiadiazine impurity A is about 0.7 and with reference to olmesartan medoxomil for olmesartan medoxomil impurity A is about 0.8.
Inject the reference solution. The test is not valid unless the column efficiency is not less than 2000 theoretical plates and the tailing factor not more than 2.0.
For Olmesartan Medoxomil:
Inject the test solution. In the chromatogram obtained with the test solution, the area of any peak corresponding to olmesartan impurity A is not more than 6 times the area of the principal peak in the chromatogram obtained with the reference solution (3.0 per cent). The area of any other secondary peak is not more than the area of the principal peak in the chromatogram obtained with the reference solution (0.5 per cent) and the sum of areas of all the secondary peaks excluding olmesartan is not more than 4 times the area of the principal peak in the chromatogram obtained with the reference solution (2.0 per cent)
For Hydrochlorothiazide:
Inject the test solution. In the chromatogram obtained with the test solution, the area of any peak corresponding to benzothiazide impurity A is not more than 4 times the area of the principal peak in the chromatogram obtained with the reference solution (2.0 per cent). The area of any other secondary peak is not more than 2 times the area of the principal peak in the chromatogram obtained with reference solution (1.0 per cent) and the sum of areas of all the secondary peaks excluding benzothiazide impurity A is not more than 4 times the area of the principal peak in the chromatogram obtained with the reference solution (2.0 per cent).
12.0) Assay: Determined by liquid chromatography.
Solvent mixture: A mixture of 50 volumes of a buffer solution prepared by dissolving 3.4gm of potassium dihydrogen orthophosphate in 1000ml of water, adjusted to pH 2.2 with O.P.A., 50 volumes of acetonitrile.
Test solution: Weigh and powder 20 tablets. Weigh a quantity of the powder containing 125mg of hydrochlorothiazide in to 200.0ml volumetric flask, add about 120ml of the solvent mixture and sonicate for about 30 minutes with occasional shaking. Cool the solution to room temperature and make the volume up to the mark with solvent mixture and mix. Filter the test solution with 0.45µ nylon membrane filter. Dilute 2.0ml of this solution to 50.0ml with solvent mixture.
Reference solution (a): A 0.04 per cent w/v solution of olmesartan medoxomil reference standard in the solvent mixture.
Reference solution (b): A 0.25 per cent w/v solution of hydrochlorothiazide reference standard in the solvent mixture.
Reference solution (c): Dilute a volume of reference solutions (a) and (b) with solvent mixture to obtain a solution having known concentration similar to the concentration of the test solution.
Chromatographic system:
- A stainless steel column 25cm X4.6 mm, packed with octadecylsilane bonded to porous silica (5µ),
- Mobile Phase: a mixture of 65 volumes of a buffer solution prepared by dissolving 3.4gm of potassium dihydrogen orthophosphate in 1000ml of water, adjusted to pH 2.2 with O.P.A., 30 volumes of acetonitrile and 5 volumes of methanol,
- Flow rate: 1ml per minute,
- Spectrophotometer set at 260nm,
- Injection volume: 20µl
Inject the reference solution. The test is not valid unless the column efficiency is not more than 2000 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.
Calculate the content of Hydrochlorothiazide and Olmesaratn medoxomil in the tablet.
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
