Candesartan Cilexetil

C33H34N6O6                                                          Mol. Wt. 610.7

Candesartan Cilexetil is (±)-1-Hydroxyethyl 2-ethoxy-1-[p-(o-1H -tetrazol-5-ylphenyl)benzyl]-7-benzimidazolecarboxylate, cyclohexyl carbonate (ester).

Candesartan Cilexetil contains not less than 98.7 per cent and not more than 101.0 per cent of C33H34N6O6 ,calculated on the anhydrous basis.

Category. Angiotensin II receptor Antagonist.

Dose. Usually 8 mg daily, with a maximum dose of 16 mg.

Description. A white to off-white powder.

Identification

2. Determine by infrared absorption spectrophotometry (2.4.6). Compare the spectrum with that obtained withcandesartan cilexetilRS or with the reference spectrum of candesartan cilexetil. If the spectra obtained show differences, dissolve the substance under examination and the reference substance separately in alcohol.

[ NOTE: Heating the solution may be necessary for complete dissolution.] Cool the solution in an ice bath, filter the crystals, and dry at 105°.

1. In the Related substances, the principal peak in the chromatogram obtained with the test solution corresponds to the peak in the chromatogram obtained with the reference solution.

Tests

Related substances.  Determine by liquid chromatography (2.4.14).

Solvent mixture.  A mixture of 60 volumes of acetonitrile and 40 volumes of water.

Test solution. Dissolve 20 mg of the substance under examination in 50.0 ml of the solvent mixture.

Reference solution (a). A 0.004 per cent w/v solution of candesartan cilexetil RS and 0.0125 per cent w/v solution of acenaphthene in the solvent mixture.

Reference solution (b). A 0.0004 per cent w/v solution of candesartan cilexetil RS in the solvent mixture.

Chromatographic system

     –   a stainless steel column 15 cm x 3.9 mm, packed with octadecylsilane bonded to porous silica (4 µm),

–         mobile phase: A.  a mixture of 57 volumes of acetonitrile, 1 volume of glacial acetic acid and 43 volumes of water.

1. a mixture of 90 volumes of acetonitrile 1 volume of glacial acetic acid and 10 volumes of water.

     –   a gradient programme using the conditions given below,

     –   flow rate: 0.8 ml per minute,

     –   spectrophotometer set at 254 nm,

     –   injection volume: 10 µl.

              Time           Mobile phase A          Mobile phase B

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

                  0                         100                                  0

                30                          0                                  100

[NOTE- Equilibration for about 10 minute may be necessary between injections.]

Name                                              Relative                        

                                                    retention time                  

Ethyl candesartan A1                       0.4                        

Desethyl candesartan cilexetil B2  0.5                        

Candesartan Cilexetil                                  1.0                        

N 2-Ethyl candesartan cilexetil C³ 2.0                        

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

2 ±1-(Cyclohexyloxycarbonyloxy)ethyl 1-{[2-(1H -tetrazol-5-yl)biphenyl-4-yl]methyl}-2-oxobenzimidazole-7-carboxylate.

3 ±1-(Cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-{[2-(N-ethyl-tetrazol-5-yl) biphenyl-4-yl]methyl}benzimidazole-7-carboxylate.

[NOTE: The mobile phase used for testing system suitability is 100 per cent solution A in an isocratic mode.]

Inject reference solution (a). The test is not valid unless the resolution between candesartan cilexetil and   acenaphthene is not less than 5.0 and the tailing factor is due to candesartan cilexetil is not more than 1.5 and the relative standard deviation for replicate injections is not more than 3.0 per cent. 

Inject reference solution (b) and the test solution. In the chromatogram obtained with the test solution, the area of any peak due to ethyl candesartan is not more than 0.2 times the area of the principal peak in the chromatogram obtained with the reference solution (b) (0.2 per cent), the area of any peak due to desethyl candesartan cilexetil is not more than 0.3 times the area of the principal peak in the chromatogram obtained with the reference solution (b) (0.3 per cent) and the area of any peak due to N 2-ethyl candesartan cilexetil is not more than 0.2 times the area of the principal peak in the chromatogram obtained with the reference solution (b) (0.2 per cent). The area of any secondary peak is not more than 0.1 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.1 per cent). The sum of the areas of all the secondary peaks is not more than 0.6 times the area of the principal peak in the chromatogram obtained with the reference solution (b) (0.6 per cent). Ignore any peak with an area less than 0.05 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05 per cent).

Sulphated ash (2.3.18). Not more than 0.1 per cent, determined on 1 g.

Water (2.3.43). Not more than 0.3 per cent.

Assay.  Dissolve 0.833g  in a 100 ml of glacial acetic acid. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.4.25). Carry out a blank titration.

1 ml of 0.1 M perchloric acid is equivalent to 0.06107 g of C33H34N6O6.

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