Pamidronate Disodium

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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C₃H₉NNa₂O₇P₂·5H20 369.11

Phosphonic acid, (3-amino-1-hydroxypropylidene)bis-, disodium salt, pentahydrate;

Disodium dihydrogen (3-amino-1-hydroxypropylidene)diphosphonate, pentahydrate CAS RN^®: 109552-15-0; UNII: 8742T8ZQZA.

Anhydrous

C₃H₉NNa₂O₇P₂ 279.03 CAS RN^®: 57248-88-1; UNII: C7S8VWP5DH.

1 DEFINITION

Pamidronate Disodium contains NLT 98.0% and NMT 102.0% of Pamidronate Disodium (C₃H₉NNa₂O₇P₂), calculated on the anhydrous basis.

2 IDENTIFICATION

Change to read:

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K or 197A (USP 1-Aug-2022)

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

C. IDENTIFICATION TESTS-GENERAL (191), Chemical Identification Tests, Sodium: Meets the requirements

3 ASSAY

Change to read:

3.1 PROCEDURE

Mobile phase: 0.47 mL of formic acid, anhydrous in 2500 mL of water. Adjust with 2 N sodium hydroxide to a pH of 3.5. [NOTE-The small amounts of formic acid have a strong influence on the retention times.]

Standard solution: 2.0 mg/mL of USP Pamidronate Disodium RS in water

Sample solution: 2.0 mg/mL of Pamidronate Disodium in water

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: Refractive index

Column: 4.6-mm x 10-cm; packing L23. [NOTE-It is required to saturate the column for at least 12 h before starting analysis.] (USP 1-Aug-2022)

Column temperature: 35°

Flow rate: 1 mL/min

Injection volume: 100 µL

3.3 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: 0.3-1.2

Relative standard deviation: NMT 2.0%

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of pamidronate disodium (C₃H₉NNa₂O₇P₂) in the portion of Pamidronate Disodium taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response of pamidronate from the Sample solution

r_S = peak response of pamidronate from the Standard solution

C_S = concentration of USP Pamidronate Disodium RS in the Standard solution (mg/mL)

C_U = concentration of Pamidronate Disodium in the Sample solution (mg/mL)

Acceptance criteria: 98.0%-102.0% on the anhydrous basis

4 IMPURITIES

Change to read:

4.1 ORGANIC IMPURITIES, PROCEDURE 1

Buffer: 2.94 g/L of sodium citrate dihydrate and 1.42 g/L of anhydrous dibasic sodium phosphate in water. Adjust with phosphoric acid to a pH of 8.0.

Solution A: Acetonitrile and Buffer (15:85)

Solution B: Acetonitrile and Buffer (70:30)

Mobile phase: See Table 1.

Table 1

Diluent: 29.4 g/L of sodium citrate dihydrate in water

Derivatizing reagent solution: 4.0 mg/mL of 9-fluorenylmethyl chloroformate in acetonitrile. [NOTE-Prepare fresh prior to use.]

Borate solution: 19.1 mg/mL of sodium borate in water

Standard stock solution: 0.6 µg/mL of USP Pamidronate Disodium RS in Diluent

Standard solution: 0.15 µg/mL of USP Pamidronate Disodium RS from the Standard stock solution as follows. Transfer 5.0 mL of Standard stock solution into a 50-mL polypropylene screw-cap centrifuge tube containing about 5.0 mL of Borate solution and 5.0 mL of acetonitrile. Add 5.0 mL of Derivatizing reagent solution and shake for 45 s. Allow the solution to stand at room temperature for 30 min. Add 20 mL of methylene chloride and shake for 1 min. Centrifuge for 5-10 min and use a portion of the clear supernatant layer.

Sensitivity stock solution: 0.3 µg/mL of USP Pamidronate Disodium RS in Diluent, from the Standard stock solution

Sensitivity solution: 0.075 µg/mL of USP Pamidronate Disodium RS from the Sensitivity stock solution as follows. Transfer 5.0 mL of Sensitivity stock solution into a 50-mL polypropylene screw-cap centrifuge tube containing about 5.0 mL of Borate solution and 5.0 mL of acetonitrile. Add 5.0 mL of Derivatizing reagent solution and shake for 45 s. Allow the solution to stand at room temperature for 30 min. Add 20 mL of methylene chloride and shake for 1 min. Centrifuge for 5-10 min and use a portion of the clear supernatant layer.

Sample stock solution: 0.6 mg/mL of Pamidronate Disodium in Diluent

Sample solution: 0.15 mg/mL of Pamidronate Disodium from the Sample stock solution as follows. Transfer 5.0 mL of the Sample stock solution into a 50-mL polypropylene screw-cap centrifuge tube containing about 5.0 mL of Borate solution and 5.0 mL of acetonitrile. Add 5.0 mL of Derivatizing reagent solution and shake for 45 s. Allow the solution to stand at room temperature for 30 min. Add 20 mL of methylene chloride and shake for 1 min. Centrifuge for 5-10 min and use a portion of the clear supernatant layer.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 266 nm

Column: 4.1-mm x 25-cm; 5-µm packing L21

Column temperature: 45°

Flow rate: 1.8 mL/min

Injection volume: 50 µL

System suitability

Samples: Standard solution and Sensitivity solution

Suitability requirements

Relative standard deviation: NMT 10.0%, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Pamidronate Disodium taken:

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

r_U = peak response of each impurity from the Sample solution

r_S = peak response of pamidronate disodium from the Standard solution

C_S = concentration of USP Pamidronate Disodium RS in the Standard solution (mg/mL)

C_U = concentration of Pamidronate Disodium in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.

Table 2

^a 3-Aminopropanoic acid.

^b Including phosphate and phosphite.

Change to read:

4.2 ORGANIC IMPURITIES, PROCEDURE 2: PHOSPHATE AND PHOSPHITE

Mobile phase, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

Standard stock solution 1: 0.3 mg/mL of USP Phosphoric Acid RS (USP 1-Aug-2022) in water

Standard stock solution 2: 0.25 mg/mL of phosphorous acid in water

Standard solution: 12.0 µg/mL of USP Phosphoric Acid RS and 10.0 µg/mL of phosphorous acid from Standard stock solution 1 and Standard stock solution 2 in water

System suitability

Sample: Standard solution

[NOTE-The elution order is phosphate, followed by phosphite.]

Suitability requirements

Resolution: NLT 2.5 between phosphate and phosphite

Relative standard deviation: NMT 10.0% for phosphate and NMT 20.0% for phosphite

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of phosphate as orthophosphoric acid in the portion of Pamidronate Disodium taken:

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

r_U = peak response of phosphate from the Sample solution

r_S = peak response of phosphate from the Standard solution

C_S = concentration of USP Phosphoric Acid RS in the Standard solution (mg/mL)

C_U = concentration of Pamidronate Disodium in the Sample solution (mg/mL)

Calculate the percentage of phosphite as phosphorous acid in the portion of Pamidronate Disodium taken:

Result = (r_U/r_S) x (C_S/C_U) x 100

r_U = peak response of phosphite from the Sample solution

r_S = peak response of phosphite from the Standard solution

C_S = concentration of phosphorous acid in the Standard solution (mg/mL)

C_U = concentration of Pamidronate Disodium in the Sample solution (mg/mL)

Acceptance criteria

Phosphate: NMT 0.50%

Phosphite: NMT 0.50%

Total phosphate and phosphite: NMT 0.50%

Total other impurities (excluding beta alanine, phosphate, and phosphite): NMT 0.50%

5 SPECIFIC TESTS

5.1 CLARITY AND COLOR OF SOLUTION

Sample solution 1: 20 mg/mL of Pamidronate Disodium in water with gentle warming. Allow to cool to room temperature.

Sample solution 2: 40 mg/mL of Pamidronate Disodium in 2 N sodium hydroxide with gentle warming. Allow to cool to room temperature.

Instrumental conditions

Mode: UV-Vis

Analytical wavelength: 420 nm

Path length: 4 cm

Blank: Water (Sample solution 1) and 2 N sodium hydroxide (Sample solution 2)

Analysis

Samples: Sample solution 1 and Sample solution 2

Examine Sample solution 1 and Sample solution 2.

Acceptance criteria: The solutions are clear. The absorbance of each solution is NMT 0.10.

5.2 PH (791)

7.8-8.8, in a solution (1 in 100)

Add the following:

5.3 BACTERIAL ENDOTOXINS TEST (85)

Where the label states that pamidronate disodium must be subjected to further processing during the preparation of injectable dosage forms, the level of bacterial endotoxin is such that the requirement in the relevant dosage form monograph(s) in which pamidronate disodium is used can be met. (USP 1-Aug-2022)

5.4 MICROBIAL ENUMERATION TESTS (61) and TESTS FOR SPECIFIED MICROORGANISMS (62)

The total aerobic microbial count does not exceed 1000 cfu/g, and the total combined yeasts and molds count does not exceed 100 cfu/g.

5.5 WATER DETERMINATION (921), Method I

23.0%-25.5%

6 ADDITIONAL REQUIREMENTS

6.1 PACKAGING AND STORAGE

Preserve in tight containers. Store at a temperature not exceeding 30°.

Add the following:

6.2 LABELING

Where Pamidronate Disodium must be subjected to further processing during the preparation of injectable dosage forms to ensure acceptable levels of bacterial endotoxins, it is so labeled. (USP 1-Aug-2022)

Change to read:

6.3 USP REFERENCE STANDARDS (11)

(USP 1-Aug-2022)

USP Pamidronate Disodium RS

USP Phosphoric Acid RSA (USP 1-Aug-2022)