Edition: BP 2025 (Ph. Eur. 11.6 update)
Action and use
Alpha1-adrenoceptor antagonist.
DEFINITION
Doxazosin Prolonged-release Tablets contain Doxazosin Mesilate. They are formulated so that the medicament is released over a period of several hours.
The tablets comply with the requirements stated under Tablets and with the following requirements.
PRODUCTION
A suitable dissolution test is carried out to demonstrate the appropriate release of Doxazosin Mesilate. The dissolution profile reflects the in vivo performance which in turn is compatible with the dosage schedule recommended by the manufacturer.
Risk assessment should be used to evaluate the potential for mutagenic methanesulfonate esters to be formed in the presence of low molecular weight alcohols. If a risk of methanesulfonate ester formation is identified through risk assessment, these impurities should not exceed the threshold of toxicological concern.
Content of doxazosin, C23H25N5O5
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 concordant with 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
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions prepared in solution A.
Solution A 1 volume of mobile phase B and 9 volumes of mobile phase A.
(1) Shake a quantity of powdered tablets containing the equivalent of 20 mg of doxazosin in 150 mL and mix with the aid of ultrasound. Dilute to produce 250 mL and filter (a 0.45-μm regenerated cellulose membrane filter is suitable).
(2) Dilute 1 volume of solution (1) to 200 volumes.
(3) 0.008% w/v of doxazosin impurity standard BPCRS.
(4) Dilute 1 volume of solution (2) to 5 volumes.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (12.5 cm × 4 mm) packed with base-deactivated octadecylsilyl silica gel for
chromatography (5 μm) (Licrospher RP-Select B is suitable).
(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 40°.
(e) Use a detection wavelength of 246 nm.
(f) Inject 10 μL of each solution.
MOBILE PHASE
Mobile phase A 0.15% w/v of orthophosphoric acid.
Mobile phase B 0.15% w/v of orthophosphoric acid in acetonitrile R1 .
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
| 0-5 | 90 | 10 | isocratic |
| 5-40 | 90→50 | 10→50 | linear gradient |
| 40-45 | 50 | 50 | isocratic |
| 45-46 | 50→90 | 50→10 | linear gradient |
| 46-50 | 90 | 10 | re-equilibration |
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between impurity D and impurity F is at least 4.5.
CALCULATION OF IMPURITIES
For each impurity, use the concentration of doxazosin in solution (2).
For the reporting threshold, use the concentration of doxazosin in solution (4).
Doxazosin retention time: about 32 minutes.
Relative retention: impurity G, about 0.2; impurity D, about 0.5; impurity F, about 0.7.
LIMITS
— impurity G: not more than 0.5%;
— unspecified impurities: for each impurity, not more than 0.2%;
— total impurities: not more than 1.0%;
— reporting threshold: 0.1%.
ASSAY
Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions prepared in solution B.
Solution B 0.15% w/v of orthophosphoric acid in a mixture of 1 volume acetonitrile and 9 volumes of water.
(1) Shake a quantity of powdered tablets containing the equivalent of 20 mg of doxazosin in 150 mL and mix with the aid of ultrasound. Dilute to produce 250 mL and filter (a 0.45-μm regenerated cellulose membrane filter is suitable).
(2) 0.0097% w/v of doxazosin mesilate BPCRS
(3) 0.008% w/v of doxazosin impurity standard BPCRS.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (12.5 cm x 4 mm) packed with end-capped octadecylsilyl silica gel for chromatography (5 μm) (Nucleosil 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 a column temperature of 40°.
(e) Use a detection wavelength of 246 nm.
(f) Inject 25 μL of each solution.
MOBILE PHASE
30 volumes of acetonitrile and 70 volumes of 0.05M potassium dihydrogen orthophosphate, previously adjusted to pH 6.0 with potassium hydroxide.
When the chromatograms are recorded under the prescribed conditions, the retention time of doxazosin is about 15 minutes.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between doxazosin and impurity F is at least 4.5.
DETERMINATION OF CONTENT
Calculate the content of doxazosin, C23H25N5O5, in the tablets from the chromatograms obtained and using the declared content of C23H25N5O5,CH4O3S in doxazosin mesilate BPCRS.
Each mg of C23H25N5O5,CH4O3S is equivalent to 0.8245 mg of C23H25N5O5.
LABELLING
The quantity of active ingredient is stated in terms of the equivalent amount of doxazosin.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed under Doxazosin Mesilate.
