Edition: BP 2025 (Ph. Eur. 11.6 update)
General Notices
NOTE: This monograph has been developed to cover unlicensed formulations.
Action and use
Thiazide diuretic.
DEFINITION
Bendroflumethiazide Oral Suspension is a suspension of Bendroflumethiazide in a suitable flavoured aqueous vehicle.
The oral suspension complies with the requirements stated under Oral Liquids and with the following requirements. Where appropriate, the oral suspension also complies with the requirements stated under Unlicensed Medicines.
Content of bendroflumethiazide, C15H14F3N3O4S2
92.5 to 105.0% of the stated amount.
Shake the oral suspension vigorously before carrying out the following tests.
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(1) Mix a quantity of the oral suspension with sufficient acetone to produce a solution containing 0.025% w/v of Bendroflumethiazide; shake for 10 minutes and filter.
(2) 0.1% w/v of bendroflumethiazide BPCRS in acetone.
CHROMATOGRAPHIC CONDITIONS
(a) Use as the coating silica gel F254 (Merck silica gel 60 F254 plates are suitable).
(b) Use the mobile phase as described below.
(c) Apply 20 μL of solution (1) and 5 μL of solution (2).
(d) Develop the plate to 15 cm.
(e) After removal of the plate, dry it in air, examine under ultraviolet light (254 nm) and then reveal the spots by Method I.
MOBILE PHASE
Ethyl acetate.
CONFIRMATION
By each method of visualisation the principal spot in the chromatogram obtained with solution (1) corresponds in position and colour to that in the chromatogram obtained with solution (2).
B. In the Assay, the retention time of the principal peak in the chromatogram obtained with solution (1) is similar to that of the principal peak in the chromatogram obtained with solution (2).
TESTS
Acidity
pH, 2.6 to 3.0, Appendix V L.
Dissolution
Complies with the requirements stated under Unlicensed Medicines, Oral Suspensions. Use a volume of the oral suspension containing one dose.
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following freshly prepared solutions. Store and inject the solutions at 4°, using a cooled autosampler.
(1) Add 30 mL of methanol to a quantity of the oral suspension containing 2.5 mg of Bendroflumethiazide and shake vigorously. Add about 10 mL of a 5% w/v solution of sodium chloride, allow to cool and add sufficient of the 5% w/v sodium chloride to produce 50 mL. Filter the resulting solution through a 0.45-μm nylon filter, discarding the first 5 mL of filtrate.
(2) Dilute 1 volume of solution (1) to 100 volumes with mobile phase A.
(3) Dilute 1 volume of solution (2) to 10 volumes with mobile phase A.
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) fitted with a stainless steel guard column (4 mm × 3 mm) packed with the same material.
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use a column temperature of 20°.
(e) Use a detection wavelength of 273 nm.
(f) Inject 10 μL of each solution.
When the chromatograms are recorded under the prescribed conditions the retention time of bendroflumethiazide is about 16.5 minutes and the relative retention of impurity A [4-amino-6-(trifluoromethyl)benzene-1,3-disulfonamide] is about 0.33.
MOBILE PHASE
Mobile phase A
4 volumes of acetonitrile and 16 volumes of water; adjust the pH of the mixture to 2.0 using orthophosphoric acid.
Mobile phase B
4 volumes of water and 6 volumes of acetonitrile; adjust the pH of the mixture to 2.0 using orthophosphoric acid.
Equilibrate the column with mobile phase A for at least 1 hour before starting the elution programme.
| 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 |
SYSTEM SUITABILITY
The following test applies only if a peak due to impurity A and a peak with a retention relative to that of bendroflumethiazide of about 0.24 are present.
The test is not valid unless, in the chromatogram obtained with solution (1), the resolution between the peak due to impurity A and the peak with a retention relative to bendroflumethiazide of about 0.24 is at least 1.5. If co-elution of these peaks occurs, re-equilibrate the column for at least 1 hour and repeat using freshly prepared mobile phase.
LIMITS
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity A is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1%);
the area of any other secondary peak is not greater than half the area of the principal peak in the chromatogram obtained with solution (2) (0.5%);
the sum of the areas of all the secondary peaks, excluding the peak due to impurity A, is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1%).
Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (3) (0.1%).
ASSAY
Carry out the method for liquid chromatography, Appendix III D, using the following freshly prepared solutions. Store and inject the solutions at 4°, using a cooled autosampler.
(1) Add 30 mL of methanol to a weighed quantity of the oral suspension containing 2.5 mg of Bendroflumethiazide and shake vigorously. Add about 10 mL of a 5% w/v solution of sodium chloride, allow to cool and add sufficient of the 5% w/v sodium chloride to produce 50 mL. Filter the resulting solution through a 0.45-μm nylon filter, discarding the first 5 mL of
filtrate.
(2) Dilute 1 volume of a 0.025% w/v solution of bendroflumethiazide BPCRS in methanol to 5 volumes with mobile phase A.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Related substances may be used.
SYSTEM SUITABILITY
The Assay is not valid unless, in the chromatogram obtained with solution (2), the symmetry factor of the peak corresponding to bendroflumethiazide is between 0.9 and 2.0.
DETERMINATION OF CONTENT
Determine the weight per mL of the oral suspension, Appendix V G, and calculate the content of C15H14F3N3O4S2 , weight in volume, using the declared content of C15H14F3N3O4S2 in bendroflumethiazide BPCRS.
STORAGE
Bendroflumethiazide Oral Suspension should be stored at a temperature of 2° to 8°.
IMPURITIES
The impurities limited by the requirements of this monograph include impurity A listed under Bendroflumethiazide.
