Action and use
Selective inhibitor of cyclic GMP-specific phosphodiesterase type V with vasodilator action; treatment of erectile dysfunction.
DEFINITION
Vardenafil Tablets contain Vardenafil Hydrochloride Trihydrate.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of vardenafil, C23H32N6O4S
95.0 to 105.0% of the stated amount.
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(1) Shake a quantity of the powdered tablets containing the equivalent of 20 mg of vardenafil in 100 mL of a solution of 1 volume of acetonitrile and 4 volumes of 0.1M hydrochloric acid and filter.
(2) 0.02% w/v of vardenafil hydrochloride EPCRS in a solution of 1 volume of acetonitrile and 4 volumes of 0.1M hydrochloric acid.
CHROMATOGRAPHIC CONDITIONS
(a) Use precoated silica gel F254 plates (Merck silica gel 60 F254 HPTLC plates are suitable).
(b) Use the mobile phase as described below.
(c) Apply 10 μL of each solution.
(d) Develop the plate to 8 cm.
(e) After removal of the plate, dry in air, and examine under ultraviolet light (254 nm).
MOBILE PHASE
1 volume each of acetone, of cyclohexane and of methanol.
CONFIRMATION
The principal spot in the chromatogram obtained with solution (1) corresponds in position and size to that in the chromatogram obtained with solution (2).
B. In the Assay, the principal peak in the chromatogram obtained with solution (1) has the same retention time as the principal peak in the chromatogram obtained with solution (2).
TESTS
Dissolution
Comply with 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 0.1M hydrochloric acid, at a temperature of 37°, as the medium.
PROCEDURE
Carry out the method for liquid chromatography, Appendix III D, using the following solutions protected from light.
(1) After 30 minutes withdraw a sample of the medium. Use the filtered dissolution medium diluted, if necessary, to obtain a solution expected to contain the equivalent of 0.00025% w/v of vardenafil.
(2) 0.00027% w/v of vardenafil hydrochloride EPCRS in 0.1M hydrochloric acid.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (5 cm × 3 mm) packed with 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 1.8 mL per minute.
(d) Use a column temperature of 40°.
(e) Use a detection wavelength of 245 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
27 volumes of acetonitrile and 73 volumes of 0.68% w/v potassium dihydrogenphosphate adjusted to pH 3.5 with orthophosphoric acid.
DETERMINATION OF CONTENT
Calculate the content of vardenafil, C23H32N6O4S, using the declared content of C23H32N6O4S, HCl, in vardenafil hydrochloride EPCRS. Each mg of vardenafil hydrochloride EPCRS is equivalent to 0.9306 mg of vardenafil.
LIMITS
The amount of vardenafil 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
Solvent A 1 volume of acetonitrile and 4 volumes of 0.1M hydrochloric acid.
(1) Disperse a quantity of powdered tablets containing the equivalent of 10 mg of vardenafil in 50 mL of solvent A with the aid of ultrasound and filter.
(2) Dilute 1 volume of solution (1) to 100 volumes with solvent A.
(3) Dilute 1 volume of solution (2) to 10 volumes with solvent A.
(4) 0.015% w/v of vardenafil for system suitability EPCRS solvent A.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 μm) (Zorbax Extend C18 is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 1.5 mL per minute.
(d) Use a column temperature of 40°.
(e) Use a detection wavelength of 245 nm.
(f) Inject 10 μL of each solution.
MOBILE PHASE
Mobile phase A: 0.08% w/v of ammonium acetate in 90 volumes of water and 10 volumes of acetonitrile.
Mobile phase B: 0.08% w/v ammonium acetate in 10 volumes of water and 90 volumes of acetonitrile.
When the chromatograms are recorded under the prescribed conditions, the relative retention times with reference to vardenafil (retention time about 8 min) are: impurity B, about 0.2; impurity 1, about 0.5; impurity 2, about 0.55; impurity A, about 0.6 and impurity C, about 1.3.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (4), the resolution between the peaks due to vardenafil and impurity A is not less than 5.0.
LIMITS
In the chromatogram obtained with solution (1):
the area of any peak due to impurity A or impurity 1 is not greater than 5 times the area of the principal peak in the chromatogram obtained with solution (3) (0.5%);
the area of any peak due to impurity 2 is not greater than 3 times the area of the principal peak in the chromatogram obtained with solution (3) (0.3%);
the area of any other secondary peak is not greater than twice the area of the principal peak in the chromatogram obtained with solution (3) (0.2%);
the sum of the areas of all secondary peaks, excluding impurities A, 1 and 2, is not greater than 1.2 times the area of the principal peak in the chromatogram obtained with solution (2) (1.2%).
Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (3) (0.1%).
Uniformity of content
Tablets containing less than 2 mg and/or less than 2% w/w of vardenafil 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.
Solvent A: 1 volume of acetonitrile and 4 volumes of 0.1M hydrochloric acid.
(1) Shake one tablet with sufficient volume of solvent A to produce a solution expected to contain 0.02% w/v of vardenafil and filter.
(2) 0.0215% w/v of vardenafil hydrochloride EPCRS in solvent A.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 μm) (Zorbax Extend C18 is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 1.5 mL per minute.
(d) Use a column temperature of 40°.
(e) Use a detection wavelength of 245 nm.
(f) Inject 10 μL of each solution.
MOBILE PHASE
Mobile phase A: 0.08% w/v of ammonium acetate in 90 volumes of water and 10 volumes of acetonitrile.
Mobile phase B: 0.08% w/v ammonium acetate in 10 volumes of water and 90 volumes of acetonitrile.
When the chromatograms are recorded under the prescribed conditions, the retention time of the vardenafil peak is about 5 minutes.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (2), the resolution between the peak due to vardenafil and impurity A is not less than 4.0.
DETERMINATION OF CONTENT
Calculate the content of vardenafil, C23H32N6O4S, using the declared content of C23H32N6O4S, in vardenafil hydrochloride EPCRS. Each mg of vardenafil hydrochloride EPCRS is equivalent to 0.9306 mg of vardenafil.
ASSAY
For tablets containing less than 2 mg and/or less than 2% w/w of vardenafil
Use the average individual results obtained in the test for Uniformity of content.
For tablets containing 2 mg or more and 2% w/w or more of vardenafil
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
Solvent A 1 volumes of acetonitrile and 4 volumes of 0.1M hydrochloric acid.
(1) Disperse a quantity of powdered tablets containing the equivalent of 10 mg of vardenafil in solvent A with the aid of ultrasound, dilute to 50 mL and filter.
(2) 0.0215% w/v of vardenafil hydrochloride EPCRS in solvent A.
(3) 0.015% w/v of vardenafil for system suitability EPCRS in solvent A.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions under Related substances may be used.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peak due to vardenafil and impurity A is not less than 5.0.
DETERMINATION OF CONTENT
Calculate the content of vardenafil, C23H32N6O4S, using the declared content of C23H32N6O4S, HCl, in vardenafil hydrochloride EPCRS. Each mg of vardenafil hydrochloride EPCRS is equivalent to 0.9306 mg of vardenafil.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed under Vardenafil Hydrochloride Trihydrate and:
1. 1-Ethyl-4-{4-ethoxy-3-[5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl]benzenesulfonyl}piperazine N1-oxide
2. 2-[2-Ethoxy-5-(piperazine-1-sulfonyl)phenyl]-5-methyl-7-propylimidazo[5,1-f][1,2,4]triazin-4(3H)-one
