Action and use
Purine nucleoside analogue; antiviral (herpesviruses).
DEFINITION
Valaciclovir Tablets contain Valaciclovir Hydrochloride or Valaciclovir Hydrochloride Hydrate.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of valaciclovir, C13H20N6O4
95.0 to 105.0% of the stated amount.
IDENTIFICATION
Shake a quantity of the powdered tablets containing the equivalent of 50 mg of valaciclovir with 20 mL of methanol, filter (Whatman GF/C is suitable), evaporate the filtrate and dry the residue at 60° for 1 hour. The infrared absorption spectrum of the residue, Appendix II A, is concordant with the reference spectrum of Valaciclovir Hydrochloride (RS 481).
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.
(1) After 45 minutes withdraw a 10-mL sample of the medium and filter using a 0.45-μm filter. Dilute with sufficient 0.1M hydrochloric acid, if necessary, to contain the equivalent of 0.00278% w/v of valaciclovir.
(2) 0.0031% w/v of valaciclovir hydrochloride BPCRS in the dissolution medium.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (5 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 μm).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 2 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 254 nm.
(f) Inject 10 μL of each solution.
MOBILE PHASE
5 volumes of acetonitrile and 95 volumes of 0.1% v/v orthophosphoric acid in water.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (2), the symmetry factor is not greater than 2.
DETERMINATION OF CONTENT
Calculate the content of C13H20N6O4 in the medium using the declared content of C13H20N6O4 in valaciclovir hydrochloride BPCRS.
LIMITS
The amount of valaciclovir 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 0.1% v/v of orthophosphoric acid in water.
(1) Shake a quantity of the powdered tablets containing the equivalent of 2.5 g of valaciclovir in 600 mL of 0.1M hydrochloric acid with the aid of ultrasound for 10 minutes. Allow to cool and dilute to 1000 mL with 0.1M hydrochloric acid. Dilute 4 mL of the resulting solution to 100 mL with solvent A, mix, filter through a 0.45-μm glass fibre filter (Whatman Uniprep is suitable) and use the filtrate.
(2) Dilute 1 volume of solution (1) to 100 volumes.
(3) Dilute 1 volume of solution (2) to 10 volumes.
(4) Mix, with the aid of ultrasound 10 mL of a solution containing 0.004% w/v of aciclovir BPCRS in 0.1M hydrochloric acid with 300 mL of a 0.0166% w/v solution of valaciclovir hydrochloride BPCRS in solvent A and dilute to 500 mL with
solvent A.
(5) 0.01% w/v of valaciclovir impurity standard BPCRS.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.0 mm) packed with silica gel for chromatography, crown ether (5 μm) (Diacel Chiral Phase Crownpack CR (+) is suitable).
b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 0.75 mL per minute.
(d) Use a column temperature of 10°.
(e) Use a detection wavelength of 254 nm.
(f) Inject 10 μL of each solution.
(g) Inject solution (1) and continue the chromatography for twice the retention time of valaiciclovir.
MOBILE PHASE
1 volume of methanol and 19 volumes of 0.1% v/v orthophosphoric acid in water.
When the chromatograms are recorded under the prescribed conditions, the retention times relative to valaciclovir (about 4.5 minutes) are: aciclovir, about 0.5; impurity R, about 0.8; impurity I, about 1.5.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (5):
the symmetry factor of the peak due to valaciclovir is not greater than 2;
the resolution between the peaks due to impurity R and valaciclovir is at least 1.3.
LIMITS
Identify any peak corresponding to aciclovir using the chromatogram obtained with solution (4) and multiply the area of this peak by a correction factor of 0.7.
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity R is not greater than 3 times the area of peak due to valaciclovir in the chromatogram obtained with solution (2) (3.0%);
the area of any peak corresponding to aciclovir (impurity B) is not greater than twice the area of the peak due to valaciclovir in the chromatogram obtained with solution (2) (2.0%);
the area of any peak corresponding to impurity I is not greater than half the area of peak due to valaciclovir in the chromatogram obtained with solution (2) (0.5%);
the area of any other secondary peak is not greater than the area of the peak due to valaciclovir in the chromatogram obtained with solution (3) (0.1%);
the sum of the areas of any secondary peaks is not greater than 5.5 times the area of the peak due to valaciclovir in the chromatogram obtained with solution (2) (5.5%).
Disregard any peak with an area less than 0.5 times the area of the peak due to valaciclovir in the chromatogram obtained with solution (3) (0.05%).
ASSAY
Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
Solvent A: 0.1% v/v orthophosphoric acid in water.
(1) Shake a quantity of the powdered tablets containing the equivalent of 2.5 g of valaciclovir in 600 mL of 0.1M hydrochloric acid with the aid of ultrasound for 10 minutes. Allow to cool and dilute to 1000 mL with 0.1M hydrochloric acid.
Dilute 4 mL to 100 mL with solvent A, mix, filter through a 0.45-μm glass fibre filter (Whatman Uniprep is suitable) and use the filtrate.
(2) 0.011% w/v of valaciclovir hydrochloride BPCRS in solvent A.
(3) Mix, with the aid of ultrasound 10 mL of a solution containing 0.004% w/v of aciclovir BPCRS in 0.1M hydrochloric acid with 300 mL of a 0.0166% w/v solution of valaciclovir hydrochloride BPCRS in solvent A and dilute to 500 mL with solvent A.
(4) 0.01% w/v of valaciclovir impurity standard BPCRS.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Related substances may be used.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (4):
the symmetry factor of the peak due to valaciclovir is not greater than 2;
the resolution between the peaks due to impurity R and valaciclovir is at least 1.3.
DETERMINATION OF CONTENT
Calculate the content of C13H20N6O4 in the tablets using the declared content of C13H20N6O4 in valaciclovir hydrochloride BPCRS.
LABELLING
The quantity of active ingredient is stated in terms of the equivalent amount of valaciclovir.
IMPURITIES
The impurities limited by the requirements of this monograph include impurities A, B, I and R listed under Valaciclovir Hydrochloride.
