Naproxen 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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^▲_{▲(USP 1-Aug-2024)}

C₁₄H₁₃NaO₃         252.24

2-Naphthaleneacetic acid, 6-methoxy-a-methyl-, sodium salt, (S)-;

(-)-Sodium (S)-6-methoxy-a-methyl-2-naphthaleneacetate;

^▲Sodium (S)-2-(6-Methoxynaphthalen-2-yl)propanoate _{▲(USP 1-Aug-2024)}  CAS RN^®: 26159-34-2; UNII: 9TN87S3A3C.

1 DEFINITION

Naproxen Sodium contains NLT 98.0% and NMT 102.0% of naproxen sodium (C, H, NaO), calculated on the dried basis.

2 IDENTIFICATION

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A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K or 197_{▲(USP 1-Aug-2024)}

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B. The retention time of the major peak of the Sample solution corresponds to that of the naproxen peak in the System suitability solution, as obtained in the Enantiomeric Purity Test _{▲(USP 1-Aug-2024)}

3 ASSAY

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PROCEDURE

^▲Solution A: 0.1% glacial acetic acid in water

Solution B: 0.01% glacial acetic acid in methanol

Mobile phase: See Table 1. The recommended equilibration time after the gradient is 5-10 min.

Table 1

Diluent: Methanol and water (50:50)

Standard solution: 110 µg/mL of USP Naproxen Sodium RS in Diluent

Sample solution: 110 µg/mL of Naproxen Sodium in Diluent

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 272 nm

Column: 4.6-mm x 15-cm; 3.5-µm packing L1

Column temperature: 35°

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of naproxen sodium (C₁₄H₁₃NaO₃) in the portion of Naproxen Sodium taken:

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

r_U = peak response of naproxen from the Sample solution

r_S = peak response of naproxen from the Standard solution

C_S = concentration of USP Naproxen Sodium RS in the Standard solution (µg/mL) 

C_U = concentration of Naproxen Sodium in the Sample solution (µg/mL)_{▲(USP 1-Aug-2024)}

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

4 IMPURITIES

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4.1 ORGANIC IMPURITIES

Solution A, Solution B, Mobile phase, and Diluent: Prepare as directed in the Assay.

System suitability solution: 110 µg/mL of USP Naproxen Sodium RS and 0.5 µg/mL each of USP Naproxen Related Compound K RS. USP Naproxen Related Compound A RS, and USP Naproxen Related Compound L RS in Diluent

Standard solution: 0.1 µg/mL each of USP Naproxen Sodium RS, USP Naproxen Related Compound E RS, USP Naproxen Related Compound A RS, and USP Naproxen Related Compound L. RS in Diluent

Sensitivity solution: 0.05 µg/mL each of USP Naproxen Sodium RS. USP Naproxen Related Compound A RS, USP Naproxen Related Compound L RS, and USP Naproxen Related Compound E RS in Diluent from Standard solution

Sample solution: 110 µg/mL of Naproxen Sodium in Diluent

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 240 nm

Column: 4.6-mm x 15-cm; 3.5-µm packing L1

Column temperature: 35°

Flow rate: 1 mL/min

Injection volume: 20 µL

System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution

[NOTE-See Table 2 for the relative retention times.]

Suitability requirements

Resolution: NLT 1.5 between naproxen related compound K and naproxen related compound A; NLT 2.0 between naproxen related compound L and naproxen, System suitability solution

Relative standard deviation: NMT 5.0% for each peak, Standard solution

Signal-to-noise ratio: NLT 10 for each peak, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of naproxen related compound E, naproxen related compound A, and naproxen related compound L in the portion of Naproxen Sodium taken:

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

r_U = peak response of naproxen related compound E, naproxen related compound A, or naproxen related compound L from the Sample solution

r_S = peak response of naproxen related compound E, naproxen related compound A, or naproxen related compound L from the Standard solution

C_S = concentration of USP Naproxen Related Compound E RS, USP Naproxen Related Compound A RS, or USP Naproxen Related Compound L RS in the Standard solution (µg/mL)

C_U = concentration of Naproxen Sodium in the Sample solution (µg/mL)

Calculate the percentage of naproxen related compound K and any unspecified impurity in the portion of Naproxen Sodium taken:

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

r_U = peak response of naproxen related compound K or any unspecified impurity from the Sample solution

r_S = peak response of naproxen from the Standard solution 

C_S = concentration of USP Naproxen Sodium RS in the Standard solution (µg/mL)

C_U = concentration of Naproxen Sodium in the Sample solution (µg/mL)

F = relative response factor, 0.71 for naproxen related compound K and 1.0 for unspecified impurity

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

Table 2

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4.2 LIMIT OF ▲(USP 1-AUG-2024) FREE NAPROXEN

Sample: 5.0 g

Analysis: Transfer the Sample to a separator and add 25 mL of water. Extract the solution with three 15-mL portions of chloroform. Evaporate the combined extracts on a steam bath to dryness. Dissolve the residue in 10 mL of a mixture of methanol and water (3:1), previously neutralized with 0.1 N sodium hydroxide to the phenolphthalein endpoint. Add phenolphthalein TS, and titrate with 0.10 N sodium hydroxide.

Acceptance criteria: NMT 2.2 mL is consumed (1.0%)

Add the following:

4.3 ENANTIOMERIC PURITY TEST

[NOTE-Protect solutions containing naproxen from light.]

Mobile phase: Hexane, isopropanol, acetonitrile, and glacial acetic acid (84.5: 10:5:0.5)

System suitability solution: 25 µg/mL each of USP Naproxen Sodium RS and USP Naproxen Related Compound G RS in Mobile phase

Standard solution: 1.25 µg/mL of USP Naproxen Related Compound G. RS in Mobile phase

Sample stock solution: Equivalent to 500 µg/mL of Naproxen in tetrahydrofuran prepared as follows. Dissolve 25 mg of naproxen sodium in 15 ml of water and add 1 mL of hydrochloric acid. Add 10 mL of ethyl acetate and shake well to extract the free naproxen. Separate the ethyl acetate layer and repeat the extraction with an additional 10 mL of ethyl acetate. Combine the two ethyl acetate extractions and evaporate to dryness under vacuum. Dissolve the residue in 50 mL of tetrahydrofuran.

Sample solution: Equivalent to 50 µg/mL of Naproxen in Mobile phase from Sample stock solution

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 263 nm

Column: 4.6-mm × 25-cm; 5-µm packing L102

Flow rate: 2 mL/min

Injection volume: 20 µL

Run time: NLT 1.5 times the retention time of the naproxen peak

System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for naproxen related compound G and naproxen are approximately 0.7 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 3.0 between naproxen related compound G and naproxen, System suitability solution

Relative standard deviation: NMT 2.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of naproxen related compound G in the portion of Naproxen Sodium taken:

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

r_U = peak response of naproxen related compound G from the Sample solution

r_S = peak response of naproxen related compound G from the Standard solution

C_S = concentration of USP Naproxen Related Compound G RS in the Standard solution (µg/mL)

C_U = concentration of Naproxen Sodium in the Sample solution (µg/mL)

Acceptance criteria: NMT 2.5% _{▲(USP 1-Aug-2024)}

5 SPECIFIC TESTS

Delete the following:

^▲OPTICAL ROTATION (7815), Procedures. Specific Rotation _{▲(USP 1-Aug-2024)}

Change to read:

LOSS ON DRYING (731)

Analysis: Dry in vacuum at 105° for 3 h. (ERR 1-Aug-2024

Acceptance criteria: NMT 1.0%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers.

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USP REFERENCE STANDARDS (11)

USP Naproxen Sodium RS

USP Naproxen Related Compound A RS

6-Methoxy-2-naphthoic acid.

C₁₂H₁₀O₃           202.21

USP Naproxen Related Compound E RS

(S)-Methyl 2-(6-methoxynaphthalen-2-yl)propanoate.

C₁₅H₁₆O₃            244.29

USP Naproxen Related Compound G RS

(R)-2-(6-Methoxynaphthalen-2-yl)propanoic acid.

C₁₄H₁₄O₃             230.26

USP Natroxen Related Compound K.RS

1-(6-Methoxynaphthalen-2-yl)ethanol.

C₁₃H₁₄O₂              202.25

USP Naproxen Related Compound LRS

1-(6-Methoxynaphthalen-2-yl)ethanone.

C₁₃H₁₂O₂              200.24_{▲(USP 1-Aug-2024)}