Risedronate Sodium

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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C₇H₁₀NNaO₇P₂ 305.09 

C₇H₁₀NNaO₇P₂ .H₂O 323.12 

C₇H₁₀NNaO₇P₂ . 2.5 H₂O 350.13 

Phosphonic acid, [1-hydroxy-2-(3-pyridinyl)ethylidene]bis-, monosodium salt; 

Sodium trihydrogen [1-hydroxy-2-(3-pyridyl) ethylidene]diphosphonate; 

Hemi-pentahydrate CAS RN®: 329003-65-8; UNII: HU2YAQ274O. 

Monohydrate CAS RN®: 353228-19-0; UNII: F67L43UT5C. 

1 DEFINITION 

Risedronate Sodium contains one or two-and-one-half molecules of hydration. The monohydrate form contains NLT 98.0% and NMT 102.0% of risedronate sodium (C₇H₁₀NNaO₇P₂), calculated on the dried basis. The hemi-pentahydrate form contains NLT 98.0% and NMT 102.0% of risedronate sodium (C₇H₁₀NNaO₇P₂), calculated on the anhydrous basis. 

2 IDENTIFICATION 

Change to read: 

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K or 197A

B. Identification Tests—General 〈191〉, Chemical Identification Tests, Sodium: Meets the requirements of test A. [Note—Complete dissolution of the sample is achieved only after the addition of the 15% potassium carbonate.] 

Add the following: 

C. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY 

Change to read: 

Procedure 

Mobile phase: 1.8 g/L of edetate disodium in water. Adjust with 1 N sodium hydroxide to a pH of 9.5 ± 0.1. 

Standard solution: 1.0 mg/mL of USP Risedronate Sodium RS and 0.1 mg/mL of USP Risedronate Related Compound A RS in Mobile phase  

Sample solution: 1.1 mg/mL of Risedronate Sodium in Mobile phase 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 263 nm 

Column: 4.0-mm × 25-cm; 10-µm packing L48 

Flow rate: 0.8 mL/min 

Injection volume: 20 µL 

System suitability 

Sample: Standard solution 

Suitability requirements 

Resolution: NLT 2.3 between risedronate related compound A and risedronate 

Tailing factor: NMT 1.6 for the risedronate peak 

Relative standard deviation: NMT 1.0% for the risedronate peak   

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of risedronate sodium (C₇H₁₀NNaO₇P₂) in the portion of Risedronate Sodium taken:

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response of risedronate  from the Sample solution 

r_S = peak response of risedronate  from the Standard solution 

C_S = concentration of USP Risedronate Sodium RS in the Standard solution (mg/mL)  

C_U = concentration of Risedronate Sodium in the Sample solution (mg/mL) 

Acceptance criteria 

Monohydrate: 98.0%–102.0% on the dried basis 

Hemi-pentahydrate: 98.0%–102.0% on the anhydrous basis 

4 IMPURITIES 

Change to read: 

Organic Impurities, Procedure 1 

[Note—Perform both Procedure 1 and Procedure 2.] 

Mobile phase, Standard solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay. Diluted standard solution: 0.005 mg/mL of USP Risedronate Sodium RS and 0.5 µg/mL of USP Risedronate Related Compound A RS in Mobile phase from the Standard solution  

System suitability 

Samples: Standard solution and Diluted standard solution 

Suitability requirements 

Resolution: NLT 2.3 between risedronate related compound A and risedronate, Standard solution 

Tailing factor: NMT 1.6 for the risedronate peak, Standard solution 

Relative standard deviation: NMT 1.0% for the risedronate peak,   Standard solution; NMT 15% for the risedronate related compound A peak,   Diluted standard solution 

Analysis 

Samples: Sample solution and Diluted standard solution 

Calculate the percentage of each impurity in the portion of Risedronate Sodium taken: 

Result = (r_U/r_S) × (C_S/C_U) × (1/F) × 100 

r_U = peak response of each impurity from the Sample solution 

r_S = peak response of risedronate from the Diluted standard solution  

C_S = concentration of USP Risedronate Sodium RS in the Diluted standard solution (mg/mL)  

C_U = concentration of Risedronate Sodium in the Sample solution (mg/mL)

F = relative response factor (see Table 1) 

Table 1 

Acceptance criteria: The reporting threshold is 0.05%.  

Any individual impurity: NMT 0.10% 

[Note—Disregard the peak due to the sodium ion, eluting at about 1.6 min, and any peak observed in the blank.  ] Change to read: 

Organic Impurities, Procedure 2 

Mobile phase: Transfer 16.15 g of dibasic potassium phosphate and 0.46 g of edetate disodium to a 1-L beaker, and dissolve in about 400 mL of water. Add 1 vial of commercially available tetrabutylammonium dihydrogen phosphate buffered solution in methanol1 and 1 mL of hydrochloric acid. Adjust with 1 N sodium hydroxide or 1 N hydrochloric acid, as necessary, to a pH of 7.5 ± 0.1, and dilute with water to 480 mL. Add 20 mL of methanol, mix well, pass the solution through a nylon filter of 0.45-µm pore size, and degas. 

Diluent: Transfer 0.46 g of edetate disodium to a 1-L beaker, and dissolve in 500 mL of water. Adjust with 1 N sodium hydroxide to a pH of 7.5 ± 0.1. 

Standard solution: 0.005 mg/mL  of USP Risedronate Related Compound B RS in Diluent 

Diluted standard solution: 0.5 µg/mL of USP Risedronate Related Compound B RS in Diluent from the Standard solution Sample solution: 2 mg/mL of Risedronate Sodium in Diluent, using sonication if necessary 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 263 nm 

Column: 4.6-mm × 15-cm; 5-µm packing L1 

Flow rate: 1.0 mL/min 

Injection volume: 10 µL 

System suitability 

Samples: Standard solution and Diluted standard solution 

Suitability requirements 

  Tailing factor: NMT 1.5, Standard solution 

Relative standard deviation:   NMT 10%,   Diluted standard solution 

Analysis 

Samples: Standard solution and Sample solution 

[Note—Disregard any peak eluting before risedronate related compound B. The risedronate peak elutes unretained at the void volume.] Calculate the percentage of each impurity in the portion of Risedronate Sodium taken: 

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × 100 

r_U = peak response of each impurity from the Sample solution 

r_S = peak response of risedronate related compound B from the Standard solution 

C_S = concentration of USP Risedronate Related Compound B RS in the Standard solution (mg/mL) 

C_U = concentration of Risedronate Sodium in the Sample solution (mg/mL) 

M_r1 = molecular weight of risedronate related compound B as a free acid, 530.20 

M_r2 = molecular weight of risedronate related compound B as a tetrahydrate disodium salt, 646.22 

Acceptance criteria: The reporting threshold is 0.05%.  

Risedronate related compound B: NMT 0.10% 

Individual impurities: NMT 0.10% 

Total impurities: NMT 0.50%, Procedure 1 and Procedure 2 being combined. [Note—Disregard any peak observed in the blank.  (USP 1-May 2020) ] 

5 SPECIFIC TESTS 

Change to read: 

Water Determination 〈921〉  : Perform the test by direct introduction of solid sample into the titrator.   Acceptance criteria: 11.9%–13.9%; where it is labeled as a hemi-pentahydrate 

Change to read: 

Loss on Drying 

(See Thermal Analysis 〈891〉.) 

Sample: 7–15 mg of Risedronate Sodium 

Heating rate: 10°/min in a stream of nitrogen at a ow rate of about 40 mL/min 

Temperature range: Ambient temperature to 250° 

Acceptance criteria: 5.5%–7.5%; where it is labeled as a monohydrate 

6 ADDITIONAL REQUIREMENTS 

Labeling: Label to indicate whether it is the monohydrate or the hemi-pentahydrate form. 

Packaging and Storage: Preserve in well-closed containers. Store at room temperature. 

Change to read: 

USP Reference Standards 〈11〉 

USP Risedronate Sodium RS 

USP Risedronate Related Compound A RS 

[1-hydroxy-2-(2-pyridinyl)ethylidene]bis(phosphonic acid) monohydrate. 

C₇H₁₁NO₇P₂ . H₂O 301.13  

USP Risedronate Related Compound B RS 

Cyclic dimer; 

Disodium tetrahydrate salt; 

[3,6-Bis[(3-pyridinyl)methyl]-2,5-dihydroxy-2,5-dioxido-1,4,2,5-dioxadiphosphorinane-3,6-diyl]bis[phosphonic acid] disodium tetrahydrate salt. C₁₄H₁₆N₂O₁₂P₄Na₂ .4H₂O 646.22