Alendronate 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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C₄H₁₂NNaO₇P₂· 3H₂O 325.12

Phosphonic acid, (4-amino-1-hydroxybutylidene) bis-, monosodium salt, trihydrate;

Sodium trihydrogen (4-amino-1-hydroxybutylidene)diphosphonate, trihydrate CAS RN®: 121268-17-5; UNII: 2UY4M2U3RA.

1 DEFINITION

Alendronate Sodium contains NLT 98.0% and NMT 102.0% of alendronate sodium (C₄H₁₂NNaO₇P₂), calculated on the dried basis.

2 IDENTIFICATION 

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197M (CN 1-May-2020)

B. Identification Tests—General 〈191〉, Sodium: Meets the requirements of test A

3 ASSAY

3.1 Procedure

Buffer solution: 14.7 g/L of sodium citrate dihydrate and 7.05 g/L of anhydrous dibasic sodium phosphate. Adjust with phosphoric acid to a pH of 8.

Mobile phase: Acetonitrile, methanol, and Buffer solution (25:5:70)

Diluent: 29.4 g/L of sodium citrate dihydrate

Borate solution: 19.1 g/L of sodium borate

Solution A: 0.5 mg/mL of 9-fluorenylmethyl chloroformate in acetonitrile. [Note—Prepare this solution fresh just before use.] Standard stock solution: 0.1 mg/mL of USP Alendronate Sodium RS in Diluent

Standard solution: Transfer 5.0 mL of the Standard stock solution to a 50-mL polypropylene, screw-cap centrifuge tube containing 5 mL of Borate solution. Add 5 mL of Solution A, and shake for 30 s. Allow to stand at room temperature for 25 min. Add 25 mL of methylene chloride, and shake vigorously for 1 min. Centrifuge for 5–10 min. Use a portion of the clear upper aqueous layer.

Reagent blank: Transfer 5.0 mL of Diluent to a 50-mL polypropylene, screw-cap centrifuge tube containing 5 mL of Borate solution. Add 5 mL of Solution A, and shake for 30 s. Allow to stand at room temperature for 25 min. Add 25 mL of methylene chloride, and shake vigorously for 1 min. Centrifuge for 5–10 min. Use a portion of the clear upper aqueous layer.

Sample stock solution: 0.1 mg/mL of Alendronate Sodium in Diluent

Sample solution: Transfer 5.0 mL of the Sample stock solution to a 50-mL polypropylene, screw-cap centrifuge tube containing 5 mL of Borate solution. Add 5 mL of Solution A, and shake for 30 s. Allow to stand at room temperature for 25 min. Add 25 mL of methylene chloride, and shake vigorously for 1 min. Centrifuge for 5–10 min. Use a portion of the clear upper aqueous layer.

3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 266 nm

Column: 4.1-mm × 25-cm; packing L21

Column temperature: 35°

Flow rate: 1.2 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0% for replicate injections

3.3 Analysis

Samples: Standard solution, Reagent blank, and Sample solution

Calculate the percentage of alendronate sodium (C₄H₁₂NNaO₇P₂) in the portion of Alendronate Sodium taken:

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

r_U = peak area from the Sample solution

r_S = peak area from the Standard solution  

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

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

Acceptance criteria: 98.0%–102.0% on the dried basis

4 IMPURITIES

4.1 Organic Impurities

Buffer solution: 2.94 g/L of sodium citrate dihydrate and 1.42 g/L of anhydrous dibasic sodium phosphate. Adjust with phosphoric acid to a pH of 8 and pass through a filter of 0.5-µm or finer pore size.

Solution A: Acetonitrile and Buffer solution (3:17)

Solution B: Acetonitrile and Buffer solution (7:3)

Mobile phase: See Table 1.

Diluent and Borate solution: Proceed as directed in the Assay.

Solution C: 4 mg/mL of 9-uorenylmethyl chloroformate in acetonitrile. [Note—Prepare this solution fresh just before use.] Standard stock solution: 0.6 mg/mL of USP Alendronate Sodium RS in Diluent

Standard solution A: Transfer 5.0 mL of the Standard stock solution to a 50-mL polypropylene, screw-cap centrifuge tube containing 5 mL of Borate solution. Add 5 mL of acetonitrile and 5 mL of Solution C, and shake for 45 s. Allow to stand at room temperature for 30 min. Add 20 mL of methylene chloride, and shake vigorously for 1 min. Centrifuge for 5–10 min, and use a portion of the clear upper aqueous layer.

Standard solution B: 0.6 µg/mL of USP Alendronate Sodium RS in Diluent from Standard stock solution. Transfer 5 mL of this diluted solution (0.6 µg/mL) to a 50-mL polypropylene, screw-cap centrifuge tube containing 5 mL of Borate solution. Add 5 mL of acetonitrile and 5 mL of Solution C, and shake for 45 s. Allow to stand at room temperature for 30 min. Add 20 mL of methylene chloride, and shake vigorously for 1 min. Centrifuge for 5–10 min, and use a portion of the clear upper aqueous layer.

Reagent blank: Transfer 5.0 mL of Diluent to a 50-mL polypropylene, screw-cap centrifuge tube containing 5 mL of Borate solution. Add 5 mL of acetonitrile and 5 mL of Solution C, and shake for 45 s. Allow to stand at room temperature for 30 min. Add 20 mL of methylene chloride, and shake vigorously for 1 min. Centrifuge for 5–10 min, and use a portion of the clear upper aqueous layer.

Sample stock solution: 0.6 mg/mL of Alendronate Sodium in Diluent

Sample solution: Transfer 5.0 mL of Sample stock solution to a 50-mL polypropylene, screw-cap centrifuge tube containing 5 mL of Borate solution. Add 5 mL of acetonitrile and 5 mL of Solution C, and shake for 45 s. Allow to stand at room temperature for 30 min. Add 20 mL of methylene chloride, and shake vigorously for 1 min. Centrifuge for 5–10 min, and use a portion of the clear upper aqueous layer. Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 266 nm

Column: 4.1-mm × 25-cm; packing L21

Column temperature: 45°

Flow rate: 1.8 mL/min

Injection volume: 20 µL

Samples: Standard solution A and Standard solution B

Suitability requirements

Tailing factor: NMT 2.0 for the main peak, Standard solution A

Signal-to-noise ratio: NLT 3 for the main peak, Standard solution B

4.2 Analysis

Samples: Reagent blank and Sample solution

[Note—Disregard any peak corresponding to those obtained from the Reagent blank.] Calculate the percentage of each impurity in the portion of Alendronate Sodium taken:

Result = (r_U /r_T ) × 100

r_U = peak area of each impurity

r_T = sum of all impurity peaks and the main peak

Acceptance criteria

Individual impurities: NMT 0.1%

Total impurities: NMT 0.5%

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Sample: Dry at a pressure of NMT 5 mm of mercury at 140° to constant weight. Acceptance criteria: 16.1%–17.1%

6 ADDITIONAL REQUIREMENTS

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

USP Reference Standards 〈11〉

USP Alendronate Sodium RS