Naproxen

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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C₁₄H₁₄O₃        230.26

2-Naphthaleneacetic acid, 6-methoxy-α-methyl-, (S)-.

(+)-(S)-6-Methoxy-a-methyl-2-naphthaleneacetic acid CAS RN^®: 22204-53-1; UNII: 57Y76R9ATQ.

Change to read:

1 DEFINITION

Naproxen contains ^▲NLT 98.0% and NMT 102.0% _{▲(USP 1-Aug-2024)} of naproxen (C₁₄H₁₄O₃), 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: Acetonitrile and water (50:50)

Standard solution: 0.1 mg/mL of USP Naproxen RS in Diluent

Sample solution: 0.1 mg/mL of Naproxen 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 (C₁₄H₁₄O₃) in the portion of Naproxen 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 RS in the Standard solution (mg/mL) 

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

_{▲(USP 1-Aug-2024).}

Acceptance criteria: ^▲98.0%-102.0% _{▲(USP 1-Aug-2024)} 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: 100 µg/mL of USP Naproxen 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 RS. USP Naproxen Related Compound A RS, USP Naproxen Related Compound L RS. and USP Naproxen Related Compound E RS in Diluent

Sensitivity solution: 0.05 µg/mL each of USP Naproxen 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: 100 µg/mL of Naproxen 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 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 in the Sample solution (µg/mL)

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

                         Result = (r_U/r_S) × (C_S/C_U) × (1/F) × 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 RS in the Standard solution (µg/mL)

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

F = relative response factor, 0.64 for naproxen related compound K and 1.0 for unspecified impurity

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

Table 2

Add the following:

4.2 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 stock solution: 250 µg/mL each of USP Naproxen RS and USP Naproxen Related Compound G RS in tetrahydrofuran

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

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

Sample stock solution: 500 µg/ml. of Naproxen in tetrahydrofuran

Sample solution: 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 x 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 naproxen

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 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 in the Sample solution (µg/mL)

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

5 SPECIFIC TESTS

Delete the following:

^▲OPTICAL ROTATION (781S), Procedures. Specific Rotation _{▲(USP 1-Aug-2024)}

LOSS ON DRYING (731)

Analysis: Dry at 105" for 3 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers.

Change to read:

USP REFERENCE STANDARDS (11)

USP Naproxen RS

USP Naproxen Related Compound A RS

6-Methoxy-2-naphthoic acid.

C₁₂H₁₀O₃             202.21

USP Nagroxen Related Compound ERS

(S)-Methyl 2-(6-methoxynaphthalen-2-yl)propanos

C₁₅H₁₆O₃               244.29

USP Naproxen Related Compound G.RS

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

C₁₄H₁₄O₃               230.26

USP Naproxen Related Compound K RS

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

C₁₃H₁₄O₂               202.25

USP Naproxen Related Compound L.RS

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

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