Edition: BP 2025 (Ph. Eur. 11.6 update)
General Notices
Action and use
Thiazide diuretic.
DEFINITION
Bendroflumethiazide Tablets contain Bendroflumethiazide.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of bendroflumethiazide, C15H14F3N3O4S2
95.0 to 105.0% of the stated amount.
IDENTIFICATION
In the Assay, record the UV spectrum of the principal peak in the chromatograms obtained with solutions (1) and (2) with a diode array detector in the range of 210 to 400 nm.
The UV spectrum of the principal peak in the chromatogram obtained with solution (1) is similar to that of the peak in the chromatogram obtained with solution (2);
the retention time of the principal peak in the chromatogram obtained with solution (1) is similar to that of the peak in the chromatogram obtained with solution (2).
TESTS
Dissolution
Comply with the requirements in the dissolution test for tablets and capsules, Appendix XII B1.
TEST CONDITIONS
(a) Use Apparatus 1, rotating the basket at 50 revolutions per minute.
(b) Use 900 mL of 0.005M sodium hydroxide, at a temperature of 37°, as the medium.
PROCEDURE
Carry out the method for liquid chromatography, Appendix III D, using the following solutions prepared immediately before use.
(1) After 45 minutes withdraw a sample of the medium, filter (a polyethylene filter is suitable) and dilute the filtrate with sufficient of the dissolution medium, if necessary, to produce a solution expected to contain 0.00028% w/v of Bendroflumethiazide.
(2) 0.028% w/v of bendroflumethiazide BPCRS in methanol. Dilute 1 volume to 100 volumes with the dissolution medium.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (10 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (3.5 μm) (SunFire C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 273 nm.
(f) Inject 10 μL of each solution.
MOBILE PHASE
40 volumes of acetonitrile and 60 volumes of water, adjusted to pH 2.0 with orthophosphoric acid.
When the chromatograms are recorded under the prescribed conditions the retention time of bendroflumethiazide is about 8 minutes.
DETERMINATION OF CONTENT
Calculate the total content of bendroflumethiazide, C15H14F3N3O4S2, in the medium from the chromatograms obtained and using the declared content of C15H14F3N3O4S2 in bendroflumethiazide BPCRS.
LIMITS
The amount of bendroflumethiazide released is not less than 75% (Q) of the stated amount.
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions in mobile phase A. Protect the solutions from light.
(1) Shake a quantity of powdered tablets containing 12.5 mg of Bendroflumethiazide with 15 mL of methanol, dilute to 25 mL with mobile phase A and filter through a 0.45-μm nylon filter.
(2) Dilute 1 volume of solution (1) to 200 volumes.
(3) 0.5% w/v of bendroflumethiazide BPCRS and 0.005% w/v of bendroflumethiazide impurity A EPCRS in methanol. Dilute 1 volume to 10 volumes with mobile phase A.
(4) Dilute 1 volume of solution (2) to 5 volumes.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (10 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (3.5 μm) (Waters SunFire C18 is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 273 nm.
(f) Inject 10 μL of each solution.
MOBILE PHASE
Mobile phase A 20 volumes of acetonitrile and 80 volumes of water, adjusted to pH 2.0 with orthophosphoric acid.
Mobile phase B 40 volumes of water and 60 volumes of acetonitrile, adjusted to pH 2.0 with orthophosphoric acid.
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
| 0-10 | 100 | 0 | isocratic |
| 10-14 | 100→0 | 0→100 | linear gradient |
| 14-18 | 0 | 100 | isocratic |
| 18-22 | 0→100 | 100→0 | linear gradient |
| 22-28 | 100 | 0 | re-equilibration |
When the chromatograms are recorded under the prescribed conditions, the relative retention with reference bendroflumethiazide (retention time about 16 minutes) is: impurity A, about 0.4.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity A and bendroflumethiazide is at least 40.
LIMITS
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity A is not greater than 0.8 times the area of the principal peak in the chromatogram obtained with solution (2) (0.4%);
the area of any other secondary peak is not greater than 0.4 times the area of the principal peak in the chromatogram obtained with solution (2) (0.2%);
the sum of the areas of any secondary peaks is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.5%).
Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (4) (0.1%).
ASSAY
Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions. Protect the solutions from light.
(1) Shake a quantity of powdered tablets containing 12.5 mg of Bendroflumethiazide with 30 mL of methanol and dilute to 50 mL with the mobile phase. Dilute 1 volume to 50 volumes with the mobile phase and filter through a 0.45-μm nylon filter.
(2) 0.005% w/v of bendroflumethiazide BPCRS in methanol. Dilute 1 volume to 10 volumes with the mobile phase.
(3) 0.005% w/v of bendroflumethiazide BPCRS and 0.0005% w/v of bendroflumethiazide impurity A EPCRS in methanol. Dilute 1 volume to 10 volumes with the mobile phase.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Dissolution may be used.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity A and bendroflumethiazide is at least 15.
DETERMINATION OF CONTENT
Calculate the content of bendroflumethiazide, C15H14F3N3O4S2, in the tablets from the chromatograms obtained and using the declared content of C15H14F3N3O4S2 in bendroflumethaizide BPCRS.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed under Bendroflumethiazide.
