Edition: BP 2025 (Ph. Eur. 11.6 update)
Action and use
Angiotensin II (AT1) receptor antagonist.
DEFINITION
Candesartan Tablets contain Candesartan Cilexetil.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of candesartan cilexetil, C33H34N6O6
95.0 to 105.0% of the stated amount.
IDENTIFICATION
Shake a quantity of the powdered tablets containing 20 mg of Candesartan Cilexetil with 20 mL of water until the tablets have disintegrated and filter (a Whatman GF/C filter is suitable). Add the filter paper to 20 mL of ethyl acetate, mix with the aid of ultrasound and repeat the filtering process. Evaporate the filtrate to dryness under a stream of nitrogen. The infrared absorption spectrum of the residue, Appendix II A, is concordant with the reference spectrum of candesartan cilexetil (RS 494).
TESTS
Dissolution
For tablets containing 16 mg or less of candesartan cilexetil
Comply with the requirements in the dissolution test for tablets and capsules, Appendix XII B1.
TEST CONDITIONS
(a) Use Apparatus 2, rotating the paddle at 50 revolutions per minute.
(b) Use 900 mL of a solution containing 0.35% w/v of polysorbate 20 in phosphate buffer pH 6.5, at a temperature of 37°, as the medium.
PROCEDURE
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) After 45 minutes withdraw a sample of the medium and filter (a Acrodisc GHP 25 0.45-µm filter is suitable). Dilute the filtered medium, if necessary, with sufficient dissolution medium to produce a solution expected to contain 0.00022% w/v of Candesartan Cilexetil.
(2) 0.00022% w/v of candesartan cilexetil BPCRS in the dissolution medium.
(3) 0.00022% w/v of candesartan cilexetil for system suitability EPCRS in the dissolution medium.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 3.9 mm) packed with octadecylsilyl silica gel for chromatography (4 µm) (Nova-Pak C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 0.8 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 254 nm.
(f) Inject 20 µL of each solution.
MOBILE PHASE
1 volume of glacial acetic acid, 43 volumes of water and 57 volumes of acetonitrile.
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 impurity B is at least 4.0.
DETERMINATION OF CONTENT
Calculate the total content of candesartan cilexetil, C33H34N6O6, in the medium from the chromatograms obtained and using the declared content of C33H34N6O6 in candesartan cilexetil BPCRS.
LIMITS
The amount of candesartan cilexetil released is not less than 75% (Q) of the stated amount.
For tablets containing more than 16 mg of candesartan cilexetil
Comply with the requirements in the dissolution test for tablets and capsules, Appendix XII B1.
TEST CONDITIONS
(a) Use Apparatus 2, rotating the paddle at 50 revolutions per minute.
(b) Use 900 mL of a solution containing 0.70% w/v of polysorbate 20 in phosphate buffer pH 6.5, at a temperature of 37°, as the medium.
PROCEDURE
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) After 45 minutes withdraw a sample of the medium and filter (a 0.45-µm Acrodisc GHP 25 filter is suitable). Dilute the filtered medium, if necessary, with sufficient dissolution medium to produce a solution expected to contain 0.00022% w/v of Candesartan Cilexetil.
(2) 0.00022% w/v of candesartan cilexetil BPCRS in the dissolution medium.
(3) 0.00022% w/v of candesartan cilexetil for system suitability EPCRS in the dissolution medium.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under the Dissolution test for tablets containing 16 mg or less of candesartan cilexetil 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 impurity B is at least 4.0.
DETERMINATION OF CONTENT
Calculate the total content of candesartan cilexetil, C33H34N6O6, in the medium from the chromatograms obtained and using the declared content of C33H34N6O6 in candesartan cilexetil BPCRS.
LIMITS
The amount of candesartan cilexetil released is not less than 75% (Q) of the stated amount.
Related substance
Carry out the method for liquid chromatography, Appendix III D, using the following solutions in 60% v/v acetonitrile prepared immediately before use.
(1) To a quantity of the powdered tablets containing 20 mg of Candesartan Cilexetil, add 80 mL of 60% v/v acetonitrile and mix with the aid of ultrasound. Add sufficient 60% v/v acetonitrile to produce 100 mL and filter (a 0.45-µm PTFE filter is suitable).
(2) Dilute 1 volume of solution (1) to 100 volumes.
(3) 0.05% w/v of candesartan cilexetil for system suitability EPCRS.
(4) 0.05% w/v of candesartan cilexetil for peak identification EPCRS.
(5) 0.05% w/v of candesartan cilexetil impurity standard BPCRS.
(6) Dilute 1 volume of solution (2) to 10 volumes.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 3.9 mm) packed with octadecylsilyl silica gel for chromatography (4 µm) (Nova-Pak C18 is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 0.8 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 254 nm.
(f) Inject 20 µL of each solution.
MOBILE PHASE
Mobile phase A 1 volume of glacial acetic acid, 43 volumes of water and 57 volumes of acetonitrile.
Mobile phase B 1 volume of glacial acetic acid, 10 volumes of water and 90 volumes of acetonitrile.
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
| 0-3 | 100 | 0 | isocratic |
| 3-33 | 100→0 | 0→100 | linear gradient |
| 33-45 | 0 | 100 | isocratic |
| 45-47 | 0→100 | 100→0 | linear gradient |
| 47-55 | 100 | 0 | re-equilibration |
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to candesartan cilexetil (retention time about 10 minutes) are: impurity G, about 0.2; impurity A, about 0.3; impurity B, about 0.5; impurity C, about 0.8; impurity D, about 1.2; impurity E, about 1.5; impurity F, about 2.0; impurity H, about 3.5.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (5), the peak-to-valley ratio is at least 2.6, where Hp is the height above the baseline of the peak due to impurity D and Hv is the height above the baseline of the lowest point of the curve separating this peak from the peak due to candesartan cilexetil.
LIMITS
Use the chromatograms obtained with solutions (3) and (5) to identify the peaks due to impurities B, D and F.
Identify any peaks in the chromatogram obtained with solution (1) corresponding to impurities A, G and H using solutions (3) and (4) and multiply the area of these peaks by the corresponding correction factors: impurity A, 0.7; impurity G, 0.7; impurity H, 1.6.
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity F is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1.0%);
the area of any peak corresponding to impurity C, D or E is not greater than half the area of the principal peak in the chromatogram obtained with solution (2) (0.5% of each);
the area of any other secondary peak is not greater than twice the area of the principal peak in the chromatogram obtained with solution (6) (0.2%).
Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (6) (0.1%).
For tablets containing 16 mg or less of candesartan cilexetil
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity B is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (2.0%);
the sum of the areas of any secondary peaks, excluding the peak due to impurity B, is not greater than 3 times the area of the principal peak in the chromatogram obtained with solution (2) (3.0%).
For tablets containing more than 16 mg of candesartan cilexetil
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity B is not greater than 1.2 times the area of the principal peak in the chromatogram obtained with solution (2) (1.2%);
the sum of the areas of any secondary peaks is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (2.0%).
Uniformity of content
Tablets containing less than 2 mg and/or less than 2% w/w of candesartan cilexetil must comply with the requirements stated under Tablets using the following method of analysis.
Carry out the method for liquid chromatography, Appendix III D, using the following solutions in 60% v/v acetonitrile.
(1) Disperse one tablet in 25 mL of 60% v/v acetonitrile and mix with the aid of ultrasound for 10 minutes. Add sufficient 60% v/v acetonitrile to produce 50 mL and filter (a 0.45-µm PTFE filter is suitable). If necessary, dilute the filtrate with 60% v/v acetonitrile to produce a solution containing 0.0002% w/v of Candesartan Cilexetil.
(2) 0.0002 % w/v of candesartan cilexetil BPCRS.
(3) 0.015 % w/v of candesartan cilexetil for system suitability EPCRS.
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 impurity B is at least 4.0.
DETERMINATION OF CONTENT
Calculate the content of C33H34N6O6 in each tablet using the declared content of C33H34N6O6 in candesartan cilexetil BPCRS.
ASSAY
For tablets containing 2 mg or less and/or less than 2% w/w of candesartan cilexetil
Use the average of the individual results determined in the test for Uniformity of content.
For tablets containing more than 2 mg and 2% w/w or more of candesartan cilexetil
Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions prepared immediately before use.
(1) To a quantity of the powdered tablets containing 20 mg of Candesartan Cilexetil, add 80 mL of 60% v/v acetonitrile and mix with the aid of ultrasound for 10 minutes. Dilute to 100 mL with 60% v/v acetonitrile and filter (a 0.45-µm PTFE filter is suitable). Add sufficient 60% v/v acetonitrile to the filtrate to produce a solution containing 0.002% w/v of Candesartan Cilexetil.
(2) 0.0002% w/v of candesartan cilexetil BPCRS in 60% v/v acetonitrile.
(3) 0.015% w/v of candesartan cilexetil for system suitability EPCRS in 60% v/v acetonitrile.
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 impurity B is at least 4.0.
DETERMINATION OF CONTENT
Calculate the content of C33H34N6O6 in the tablets using the declared content of C33H34N6O6 in candesartan cilexetil BPCRS.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed under Candesartan Cilexetil.
