Candesartan Cilexetil Tablets

Candesartan Cilexetil Tablets contain not less than 90.0 per cent and not more than 110.0 per cent of the stated amount of candesartan cilexetil C33H34N6O₆.

Usual strength. 4 mg,8 mg, 16 mg.

Identification

1. In the Assay, the principal peak in the chromatogram obtained with the test solution corresponds to the peak in the chromatogram obtained with the reference solution.
2. When examined in the range of 200 nm to 400 nm (2.4.7), a 0.08 per cent w/v solution in a mixture of 70 volumes ofacetonitrileand 30 volumes of water shows an absorption maxima and minima as that of reference solution prepared in the similar manner as test solution.

Tests

Dissolution (2.5.2).

Apparatus No. 1,

Medium. 900 ml of 0.35 per cent w/v solution of  polysorbate 20 in 0.05 M phosphate buffer pH 6.5.

Speed and time. 50 rpm and 45 minutes.

Withdraw a suitable volume of the medium and filter.

Determine by liquid chromatography (2.4.14).

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

Reference solution. A solution containing 0.00045 per cent w/v of candesartan cilexetil RS in acetonitrile with the aid of ultrasound.

Chromatographic system

     –   a stainless steel column 15 cm x 4.6 mm, packed with octylsilane bonded to porous silica (5 µm),

     –   mobile phase: a mixture of  550 volumes of acetonitrile, 1 volume of trifluoroacetic acid and 450 volumes of water.

     –   flow rate: 1.5 ml per minute,

     –   spectrophotometer set at 254 nm,

     –   injection volume: 50 µl.

Inject the reference solution. The test is not valid unless the tailing factor is not more than 2.0 and the relative standard deviation is not more than 2.0 per cent.

Inject the reference solution and the test solution.

6. Not less than 80 per cent of the stated amount of C33H34N6O₆.

Related substances. Determine by liquid chromatography (2.4.14).

Test solution. Weigh and powder 20 tablets. Disperse a quantity of powder containing 50 mg of candesartan cilexetil with 30 ml of acetonitrile and ultrasound for 15 minutes with intermittent shaking in cold water and dilute to 50.0 ml with the acetonitrile and filter.

Reference solution (a). A solution containing 0.005 per cent w/v each of  candesartan cilexetil impurity A RS , candesartan cilexetil impurity B RS, candesartan cilexetil impurity D RS and candesartan cilexetil impurity F RS in acetonitrile.

Reference solution (b). A solution containing 0.01 per cent w/v of  candesartan cilexetil RS in acetonitrile.

Reference solution (c). A solution containing 0.05 per cent w/v of  candesartan cilexetil impurity G RS in methanol.

Reference solution (d). A solution containing 0.00015 per cent w/v each of  candesartan cilexetil impurity A RS , candesartan cilexetil impurity B RS, candesartan cilexetil impurity D RS and candesartan cilexetil impurity F RS  and 0.0001 per cent w/v of candesartan cilexetil RS, 0.0005 per cent w/v of candesartan cilexetil impurity G RS from reference solution (a), (b) and (c) in acetonitrile.

Reference solution (e). A solution containing 0.0001 per cent w/v of candesartan cilexetil RS in acetonitrile from reference solution (b).

Chromatographic system

     –   a stainless steel column 10 cm x 4.6 mm, packed with octadecylsilane bonded to porous silica (3.5 µm),

     –   mobile phase:            A. a mixture of 10 volumes of acetonitrile, 0.1 volume of trifluoroacetic acid and 90 volumes of water,

1.            a mixture of 90 volumes of acetonitrile, 0.1 volume of trifluoroacetic acid and 10 volumes of water,

     –   a gradient programme using the conditions given below,

     –   flow rate: 1 ml per minute,

     –   spectrophotometer set at 254 nm,

     –   injection volume: 10 µl.

              Time           Mobile Phase A          Mobile Phase B

           (in min.)         (per cent w/v)              (per cent v/v)

                  0                          65                                  35

                30                          5                                   95

                45                          5                                   95

                50                         65                                  35

                55                         65                                  35

Name                                                              Relative                 Correction

                                                                       retention time                factor

Candesartan Cilexetil impurity  G1                             0.17                         0.8

Candesartan Cilexetil impurity A2*                              0.46                        0.9

Candesartan Cilexetil impurity B3                              0.77                           ---

Candesartan Cilexetil                                      1.0                             ---               

Candesartan Cilexetil impurity D4                  1.15                            ---

Candesartan Cilexetil impurity F5                 1.47                             1.1

1 1-{[2’-(1H -Tetrazol-5-yl)biphenyl-4-yl]methyl}-2-ethoxybenzimidazole-7-carboxylic acid,

2 Ethyl 1-{[2’-(1H -tetrazol-5-yl)biphenyl-4-yl]methyl}-2-ethoxybenzimidazole-7-carboxylate,

3 1-(Cyclohexyloxycarbonyloxy)ethyl 1-{[2’-(1H -tetrazol-5-yl)biphenyl-4-yl]methyl}-2-hydroxybenzimidazole-7-carboxylate,

41-{[(Cyclohexyloxy)carbonyl]oxy}ethyl3-({2’-(2-ethyl-1H -tetrazol-5-yl)-[1,1’-biphenyl]-4-yl}methyl)-2-oxo-2,3-dihydro-1H -benzimidazole-4-carboxylate,

51-(Cyclohexyloxycarbonyloxy)ethyl2-ethoxy-1-{[2’-(2-ethyltetrazol-5-yl)biphenyl-4-yl]methyl}benzimidazole-7-carboxylate.613-O-decladinosylazithromycin,

* It is a Process related  impurity not included in total impurities.

Inject reference solution (d) and (e). The test is not valid unless the resolution between candesartan cilexetil impurity B and candesartan cilexetil peaks is not less than 5.0 obtained with reference solution (d),the tailing factor is not more than 2.0 obtained with reference solution (e) and the relative standard deviation is not more than 10 per cent obtained with reference solution (e).

Inject reference solution (e) and the test solution. In the chromatogram obtained with the test solution, the area of any peak due to candesartan cilexetil impurity G is not more than 10 times the area of the principal peak in the chromatogram obtained with the reference solution (e) 
(1.0 per cent), the area of any peak due to candesartan cilexetil impurity B is not more than 15 times the area of the principal peak in the chromatogram obtained with the reference solution (e) 
(1.5 per cent), the area of any peak due to candesartan cilexetil impurity D is not more than 5 times the area of the principal peak in the chromatogram obtained with the reference solution (e) 
(0.5 per cent) and the area of any peak due to candesartan cilexetil impurity F is not more than 15 times the area of the principal peak in the chromatogram obtained with the reference solution (e) 
(1.5 per cent). The area of any other secondary peak is not more than twice the area of the principal peak in the chromatogram obtained with the reference solution (e) (0.2 per cent) and the sum of areas of all the secondary peaks is not more than 30 times the area of the principal peak in the chromatogram obtained with reference solution (e) (3.0 per cent).

Uniformity of content. Complies with the test stated under tablets.

Determine by liquid chromatography (2.4.14) as described under Assay using the following solutions.

Test solution. Disperse 1 tablet with sufficient quantity of the solvent mixture with the aid of the ultrasound to obtain a solution containing 0.04 per cent w/v of candesartan cilexetil.

Reference solution. A solution containing 0.04 per cent w/v of candesartan cilexetil RS in the solvent mixture. 

Other tests. Comply with the tests stated under Tablets.

Assay. Determine by liquid chromatography (2.4.14),     

Solvent mixture: a mixture of 70 volumes of acetonitrile and 30 volumes of water.                

Test solution. Disperse whole 5 tablets containing 20 mg of candesartan cilexetil  with about 20 ml of solvent mixture and ultrasound for 25 minutes with intermittent shaking. Allow to cool and dilute to 25.0 ml with solvent mixture and filter.

Reference solution. A 0.8 per cent w/v solution of candesartan cilexetil RS  in the solvent mixture, sonication may be necessary for complete dissolution.

Chromatographic system

     –   a stainless steel column 15 cm x 4.6 mm, packed with octylsilane bonded to porous silica (5 µm),

     –   mobile phase: a mixture of  55 volumes of acetonitrile, 0.1 volume of trifluoroacetic acid and 45 volumes of water.

     –   flow rate: 1.5 ml per minute,

     –   spectrophotometer set at 282 nm,

     –   injection volume: 10 µl.

Inject the reference solution. The test is not valid unless 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 the reference solution and the test solution.

Calculate the content of C33H34N6O₆.

Storage. Store protected from light and moisture at a temperature not exceeding 30º.