Bendrofluazide

Bendroflumethiazide

Bendrofluazide is (3RS)-3-benzyl-6-(trifluoromethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide.

Bendrofluazidecontains not less than 98.0 per cent and not more than 102.0 per cent of C15H14F3N3O4S2, calculated on the dried basis.

Category.  Diuretic.

Dose. Initially, 5-10 mg in the morning, daily or on alternate days; maintenance dose 5-10 mg one to three times weekly.

Description. A white or almost white, crystalline powder.

Identification

2. Determine by infrared absorption spectrophotometry (2.4.6). Compare the spectrum with that obtained withbendrofluazideRS or with the reference spectrum of bendrofluazide.

Tests

Related substances. Determine by liquid chromatography (2.4.14).

Buffer solution. Dissolve 2 g of citric acid monohydrate in 1000 ml of water,

Solvent mixture. 40 volumes of methanol and 60 volumes of buffer solution.

Test solution. Dissolve 10 mg of the substance under examination in the solvent mixture and dilute to 50.0 ml with the solvent mixture. 

Reference solution (a). Dissolve 2 mg of bendrofluazide impurity A RS (4-amino-6-(trifluoromethyl) benzene-1,3-disulfonamide) and 2.5 mg of altizide RS in the solvent mixture and dilute to 10.0 ml with the solvent mixture. Mix 1.0 ml of this solution with 1.0 ml of the test solution and dilute to 100.0 ml with the solvent mixture.

Reference solution (b). Dilute 1.0 ml of the test solution to 100.0 ml with the solvent mixture. Dilute 1.0 ml of this solution to 10.0 ml with the solvent mixture.

Chromatographic system

     –   a stainless steel column  15 cm x 3.0 mm, packed with octadecylsilane bonded to porous silica or ceramic microparticles (5 µm),

     –   mobile phase: a mixture of 15 volumes of tetrahydrofuran , 25 volumes of methanol and 60 volumes of buffer solution,

–   column temperature: 40°,

     –   flow rate: 0.8 ml per minute,

     –   spectrophotometer set at 273 nm,

     –   injection volume: 20 µl.

Name                                                                                     Relative

                                                                                                retention time      

bendrofluazide                                                                     8.0

bendrofluazide impurity A                                                0.2                         

altizide                                                                   0.5

Inject  reference solution (a). The test is not valid unless the resolution between the peaks due to bendrofluazide

and altizide is not less than 10.0.

Inject reference solution (b) and the test solution.Run the chromatogram at least twice the retention time of the principal peak.In the chromatogram obtained with the test solution, the area of any peak corresponding to bendrofluazide impurity A is not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.1 per cent).  The area of any other secondary peak is not more than  the area of the principal peak in the chromatogram obtained with reference solution (b) (0.1 per cent). The sum of areas of all the secondary peaks is not more than twice the area of the principal peak in the chromatogram obtained with reference solution (b) (0.2 per cent). Ignore any peak with an area less than 0.5 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 1.0 g.

Loss on drying (2.4.19).  Not more than 0.5 per cent, determined on 1.0 g by drying in an oven at 105°.

Assay. Dissolve 0.15 g in 50.0 ml of dimethyl sulphoxide. Titrate with 0.1 M tetrabutylammonium hydroxide in 2-propanol, determining the end point potentiometrically (2.4.25). Read the volumes added between the two points of inflection. Carry out a blank titration.

1.0 ml of 0.1 M tetrabutylammonium hydroxide in 2-propanol  is equivalent to 0.02107 g of C₁₅H₁₄F₃N₃O₄S₂.