Action and use
Bisphosphonate; treatment of osteoporosis, Paget’s disease.
DEFINITION
Risedronate Sodium Tablets contain Risedronate Sodium 2.5-Hydrate.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of anhydrous risedronate sodium, C7H10NNaO7P2
95.0 to 105.0% of the stated amount.
IDENTIFICATION
Shake a quantity of the powdered tablets containing 25 mg of anhydrous risedronate sodium with 10 mL of water and filter (a 0.45-μm nylon filter is suitable). Mix the filtrate with 10 mL of 0.2M copper(II) chloride and allow to stand for 10 minutes. Add 2 mL of ethanol to this solution, mix and allow to stand for 1 hour (a precipitate is produced). Filter the suspension through a Whatman No. 1 filter and wash the precipitate with 10 mL of ethanol, discarding the washings and allow the residue to dry in air. The infrared absorption spectrum of the dried residue, Appendix II A, is concordant with the reference spectrum of anhydrous risedronate sodium (RS 498).
TESTS
Dissolution
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 500 mL of water, at a temperature of 37°, as the medium.
PROCEDURE
(1) After 45 minutes withdraw a sample of the medium and filter. Use the filtered medium, diluted with water if necessary, to produce a solution containing 0.001% w/v of anhydrous risedronate sodium.
(2) 0.0012% w/v of risedronate sodium 2.5-hydrate BPCRS in water.
(3) 0.00075% w/v of risedronate impurity E EPCRS and 0.005% w/v of risedronate sodium 2.5-hydrate BPCRS in the mobile phase.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.0 mm) packed with anion exchange resin (10 μm) (Dionex Ionpac AS7 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 263 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
0.18% w/v solution of disodium edetate adjusted to pH 9.5 with 1M sodium hydroxide.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to risedronate and impurity E is at least 1.5.
DETERMINATION OF CONTENT
Calculate the total content of anhydrous risedronate sodium, C7H10NNaO7P2, in the medium from the chromatograms obtained and using the declared content of C7H10NNaO7P2, in risedronate sodium 2.5-hydrate BPCRS.
LIMITS
The amount of anhydrous risedronate sodium released is not less than 75% (Q) of the stated amount.
Related substances
A. Carry out the method for liquid chromatography, Appendix III D, using the following solutions. Prepare and store all solutions in plastic containers.
Solution A: Dissolve 0.410 g of sodium edetate, 1.7 g of dipotassium hydrogen phosphate and 1.7 g of tetrabutylammonium dihydrogen phosphate in 900 mL of water. Adjust to pH 7.5 with 1M sodium hydroxide, and dilute to 1000 mL with water.
(1) To a quantity of the powdered tablets containing 25 mg of anhydrous risedronate sodium, add 10 mL of the mobile phase and swirl for 10 minutes in a water-bath at 30° and filter (a nylon 0.45-μm filter is suitable).
(2) Dilute 1 volume of solution (1) to 100 volumes with the mobile phase. Dilute 1 volume of this solution to 10 volumes with the mobile phase.
(3) 0.001% w/v solution of risedronate impurity E EPCRS and 0.00115% w/v of risedronate sodium 2.5-hydrate BPCRS in the mobile phase.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (3 μm) (Luna C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1.0 mL per minute.
(d) Use a column temperature of 40°.
(e) Use a detection wavelength of 263 nm.
(f) Inject 20 μL of each solution.
(g) Allow the chromatography to proceed for twice the run time of risedronate.
MOBILE PHASE
10 volumes of acetonitrile and 90 volumes of solution A.
When the chromatograms are recorded under the prescribed conditions, the relative retention with reference to risedronate (retention time of about 16 minutes) of impurity E is about 0.9.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity E and risedronate is at least 3.0.
LIMITS
In the chromatogram obtained with solution (1):
the area of any secondary peak is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (0.2%);
the sum of the areas of all secondary peaks is not greater than 4 times the area of the principal peak in the chromatogram obtained with solution (2) (0.4%).
Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (2) (0.1%).
B. Carry out the method for liquid chromatography, Appendix III D, using the following solutions. Prepare and store all solutions in plastic containers.
Solution A: Dissolve 0.41 g of sodium edetate, 1.7 g of dipotassium hydrogen phosphate and 1.7 g of tetrabutylammonium dihydrogen phosphate in 900 mL of water. Adjust to pH 7.5 with 1M sodium hydroxide, and dilute to 1000 mL with water.
(1) To a quantity of the powdered tablets containing 25 mg of anhydrous risedronate sodium, add 10 mL of the mobile phase and swirl for 5 to 10 minutes in a water-bath at 30° and filter (a nylon 0.45-μm filter is suitable).
(2) Dilute 1 volume of solution (1) to 50 volumes with the mobile phase. Dilute 1 volume of this solution to 10 volumes with the mobile phase.
(3) 0.000115% w/v of risedronate sodium 2.5-hydrate BPCRS and 0.00075% w/v of risedronate impurity A EPCRS in the mobile phase.
(4) Dissolve 0.1 g of sodium chloride in the mobile phase and dilute to 10 mL with the mobile phase.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (3 μm) (Luna C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1.0 mL per minute.
(d) Use a column temperature of 40°.
(e) Use a detection wavelength of 263 nm.
(f) Inject 20 μL of each solution.
(g) Allow the chromatography to proceed for 8 times the retention time of risedronate.
MOBILE PHASE
25 volumes of acetonitrile and 75 volumes of solution A.
When the chromatograms are recorded under the prescribed conditions, the relative retention with reference to risedronate (retention time of about 4 minutes) of impurity A is about 2.2.
LIMITS
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity A is not greater than 0.5 times the area of the peak due to risedronate in the chromatogram obtained with solution (3) (0.15%);
the area of any other secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.2%);
the sum of the areas of all secondary peaks is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (0.4%).
Disregard any peak eluting before the peak due to risedronate, any peak corresponding to the peak obtained with solution (4) and any peak with an area less than half the area of the principal peak in the chromatogram obtained with solution (2) (0.1%).
ASSAY
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Mix with the aid of ultrasound 10 whole tablets with 150 mL of the mobile phase and dilute to 250 mL with the mobile phase. Filter (a nylon 0.45-μm filter is suitable) and dilute a volume of the filtrate, if necessary, with sufficient mobile phase to produce a solution containing 0.016% w/v solution of anhydrous risedronate sodium.
(2) 0.018% w/v of risedronate sodium 2.5-hydrate BPCRS in the mobile phase.
(3) 0.00075% w/v of risedronate impurity E EPCRS and 0.005% w/v of risedronate sodium 2.5-hydrate BPCRS in the mobile phase.
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 risedronate and impurity E is at least 1.5.
DETERMINATION OF CONTENT
Calculate the content of C7H10NNaO7P2, in the tablets using the declared content of C7H10NNaO7P2, in risedronate sodium 2.5-hydrate BPCRS.
LABELLING
The quantity of active ingredient is stated in terms of the equivalent amount of risedronic acid.
IMPURITIES
The impurities limited by the requirements of this monograph include those listed under Risedronate Sodium 2.5-Hydrate.
