Naproxen Sodium and Pseudoephedrine Hydrochloride Extended- Release Tablets

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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1 DEFINITION

Naproxen Sodium and Pseudoephedrine Hydrochloride Extended-Release Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of naproxen sodium (C₁₄H₁₃NaO₃) and pseudoephedrine hydrochloride (C₁₄H₁₅NO · HCI).

2 IDENTIFICATION

A. The retention times of the naproxen and pseudoephedrine peaks of the Sample solution correspond to those of the Standard solution, as obtained in the Assay.

B. The UV absorption spectra of the naproxen and pseudoephedrine peaks of the Sample solution exhibit maxima and minima at the same wavelengths as those of the corresponding peaks of the Standard solution, as obtained in the Assay.

3 ASSAY

PROCEDURE

Buffer: Dissolve 400 mg of sodium lauryl sulfate in 1 L of water. Add 5 mL of triethylamine and adjust with glacial acetic acid to a pH of 4.1.

Mobile phase: Acetonitrile, methanol, and Buffer (25:25:50)

Standard solution: 0.22 mg/mL of USP Naproxen Sodium RS and 0.12 mg/mL of USP Pseudoephedrine Hydrochloride RS in methanol

Sample stock solution: Nominally 2.2 mg/mL of naproxen sodium and 1.2 mg/mL of pseudoephedrine hydrochloride in methanol prepared as follows. Transfer NLT 5 whole Tablets to an appropriate volumetric flask, add 70% of the final volume of methanol, and shake to disintegrate the Tablets. Sonicate for 30 min with intermittent shaking. Allow the solution to cool to room temperature and dilute with methanol to volume. Centrifuge 10 mL of the solution for 10 min, and use the clear supernatant to prepare the Sample solution.

Sample solution: Nominally 0.22 mg/mL of naproxen sodium and 0.12 mg/mL of pseudoephedrine hydrochloride in methanol from the Sample stock solution. Pass a portion of the solution through a suitable filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 257 nm. For Identification B, use a diode array detector in the range of 200-400 nm.

Column: 4.6-mm x 25-cm; 5-µm packing L1

Flow rate: 1.0 mL/min

Injection volume: 10 µL

Run time: NLT 6 times the retention time of pseudoephedrine

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for the naproxen and pseudoephedrine peaks

Relative standard deviation: NMT 2.0% for the naproxen and pseudoephedrine peaks

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of naproxen sodium (C₁₄H₁₃NaO₃) and pseudoephedrine hydrochloride (C₁₄H₁₅NO · HCI) in the portion of Tablets taken:

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

r_U = peak response of naproxen or pseudoephedrine from the Sample solution

r_S = peak response of naproxen or pseudoephedrine from the Standard solution

C_S = concentration of USP Naproxen Sodium RS or USP Pseudoephedrine Hydrochloride RS in the Standard solution (mg/mL)

C_U = nominal concentration of naproxen sodium or pseudoephedrine hydrochloride in the Sample solution (mg/mL) 

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

Change to read:

4.1 DISSOLUTION (711)

4.1.1 Test 1

Medium: 0.01% ^▲sodium dodecyl sulfate _{▲(RB 1-Sep-2024)} in water, degassed; 900 mL

Apparatus 1: 75 rpm

Times

Naproxen sodium: 1 h

Pseudoephedrine hydrochloride: 1, 3, and 8 h

Buffer: Add 5 mL of triethylamine to 1 L of 0.4 g/L of ^▲sodium dodecyl sulfate _{▲(RB 1-Sep-2024)} in water. Adjust with glacial acetic acid to a pH of 4.1.

Mobile phase: Acetonitrile, methanol, and Buffer (25:25:50)

Standard stock solution: 1.22 mg/mL of USP Naproxen Sodium RS and 0.66 mg/mL of USP Pseudoephedrine Hydrochloride RS in methanol

Standard solution: 0.24 mg/mL of USP Naproxen Sodium RS and 0.13 mg/mL of USP Pseudoephedrine Hydrochloride RS in Medium from the Standard stock solution

Sample solution: At the times specified, withdraw 10 mL of the solution under test, and pass through a suitable filter of 0.45-µm pore size. Replace the aliquots withdrawn for analysis with equal volumes of fresh portions of Medium maintained at 37°.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 257 nm

Column: 4.6-mm x 25-cm; 5-µm packing L1

Flow rate: 1.5 mL/min

Injection volume: 40 µL

Run time: NLT 2.5 times the retention time of pseudoephedrine

System suitability

Sample: Standard solution

[NOTE-The relative retention times for pseudoephedrine and naproxen are 0.5 and 1.0, respectively.]

Suitability requirements

Tailing factor: NMT 2.0 for the naproxen and pseudoephedrine peaks

Relative standard deviation: NMT 2.0% for the naproxen and pseudoephedrine peaks

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage (Q) of the labeled amount of naproxen sodium (C₁₄H₁₃NaO₃) dissolved: 

                         Result = (r_U/r_S) × C_S x V x (1/L) × 100

r_U = peak response of naproxen from the Sample solution

r_S = speak response of naproxen from the Standard solution

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

V = volume of Medium, 900 mL

L = label claim of naproxen sodium (mg/Tablet)

Calculate the concentration (C_i), in mg/mL, of pseudoephedrine hydrochloride (C₁₄H₁₅NO · HCI) in the sample withdrawn from the vessel at each time point (i):

                         Result_i = (r_U/r_S) × C_S

r_U = peak response of pseudoephedrine from the Sample solution

r_S = peak response of pseudoephedrine from the Standard solution 

C_S = concentration of USP Pseudoephedrine Hydrochloride RS in the Standard solution (mg/mL)

Calculate the percentage of the labeled amount of pseudoephedrine hydrochloride (C₁₄H₁₅NO · HCI) dissolved at each time point (1):

                         Result₁ = C₁ x V x (1/L) x 100

                         Result₂ =  [(C₂ x V)+ (C₁ x V_S)] x (1/L) x 100

                         Result₃ = {(C₃ x V) + [(C₂ + C₁) x V_S)} x (1/L) x 100

C_i = concentration of pseudoephedrine hydrochloride in Medium in the portion of the sample withdrawn at each time point (i) (mg/mL)

V = volume of Medium, 900 mL

L = label claim of pseudoephedrine hydrochloride (mg/Tablet)

V_S = volume of the Sample solution withdrawn from the Medium (mL) 

Tolerances

Naproxen sodium: NLT 80% (Q) of the labeled amount of naproxen sodium (C₁₄H₁₃NaO₃) is dissolved.

Pseudoephedrine hydrochloride: See Table 1.

Table 1

The percentages of the labeled amount of pseudoephedrine hydrochloride (C₁₄H₁₅NO · HCI) dissolved at the times specified conform to Dissolution (711). Acceptance Table 2.

4.1.2 Test 2: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: 0.01% ^▲sodium dodecyl sulfate _{▲(RB 1-Sep-2024)} in water; 900 mL

Apparatus 1: 75 rpm

Times

Naproxen sodium: 1 h

Pseudoephedrine hydrochloride: 1, 3, and 8 h

Solution A: Dissolve 6.8 g of monobasic potassium phosphate in 1 L of water. Adjust with phosphoric acid to a pH of 4.0.

Solution B: Acetonitrile

Mobile phase: See Table 2.

Table 2

Standard solution: 0.24 mg/mL of USP Naproxen Sodium RS and 0.13 mg/mL of USP Pseudoephedrine Hydrochloride RS prepared as follows. Dissolve suitable quantities of USP Naproxen Sodium RS and USP Pseudoephedrine Hydrochloride RS with 2% of the final volume of methanol and sonicate if necessary. Dilute with Medium to volume.

Sample solution: At the times specified, withdraw 10 mL of the solution under test, and pass through a suitable filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm for the pseudoephedrine peak (before relative retention time of 0.5 in relation to the naproxen peak); UV 290 nm for the naproxen peak (at relative retention time of 0.5 and after relative retention time of 0.5 in relation to the naproxen peak)

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

Column temperature: 30°

Flow rate: 1.6 mL/min

Injection volume: 30 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for the naproxen and pseudoephedrine peaks

Relative standard deviation: NMT 2.0% for the naproxen and pseudoephedrine peaks

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage (Q) of the labeled amount of naproxen sodium (C₁₄H₁₃NaO₃) dissolved:

                         Result = (r_U/r_S) × C_S x V x (1/L) x 100 

r_U = peak response of naproxen from the Sample solution

r_S = peak response of naproxen from the Standard solution s

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

V = volume of Medium, 900 mL

L = label claim of naproxen sodium (mg/Tablet)

Calculate the concentration (C_i), in mg/mL, of pseudoephedrine hydrochloride (C₁₄H₁₅NO · HCI) in the sample withdrawn from the vessel at each time point (i):

                         Result = (r_U/r_S) × C_S

r_U = peak response of pseudoephedrine from the Sample solution

r_S = peak response of pseudoephedrine from the Standard solution

C_S = concentration of USP Pseudoephedrine Hydrochloride RS in the Standard solution (mg/mL)

Calculate the percentage of the labeled amount of pseudoephedrine hydrochloride (C₁₄H₁₅NO · HCI) dissolved at each time point (1):

                         Result₁ = C₁ x V x (1/L) x 100

                         Result₂ = {[C₂ x (V - V_S)] + (C₁ x V_S)) x (1/L) x 100

                         Result₃ = ((C₃ x [V - (2 x V_S)] + [(C₂ + C₁) x V_S) x (1/L) x 100

C_i = concentration of pseudoephedrine hydrochloride in Medium in the portion of the sample withdrawn at each time point (i) (mg/mL) 

V = volume of Medium, 900 mL

L = label claim of pseudoephedrine hydrochloride (mg/Tablet)

V_S = volume of the Sample solution withdrawn from the vessel, 10 mL

Tolerances

Naproxen sodium: NLT 80% (Q) of the labeled amount of naproxen sodium (C₁₄H₁₃NaO₃) is dissolved. 13

Pseudoephedrine hydrochloride: See Table 3.

Table 3

The percentages of the labeled amount of pseudoephedrine hydrochloride (C₁₄H₁₅NO · HCI) dissolved at the times specified conform to Dissolution (711), Acceptance Table 2.

4.1.3 Test 3: If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

Medium: 0.01% sodium dodecyl sulfate in water (Dissolve 0.1 g of sodium dodecyl sulfate in 1 L of water.); 900 mL, deaerated, if necessary

Apparatus 1: 75 rpm

Times

Naproxen sodium: 45 min

Pseudoephedrine hydrochloride: 1, 3, and 8 h

Solution A: Acetonitrile and water (45:55)

Mobile phase: Dissolve 2.5 g of dioctyl sodium sulfosuccinate and 1.0 mL of phosphoric acid in 1 L of Solution A. Adjust with ammonia water, 25 percent or phosphoric acid to a pH of 3.0.

Standard stock solution A: 0.62 mg/mL of USP Naproxen Sodium RS in Medium. Sonicate to dissolve, if necessary.

Standard stock solution B: 0.56 mg/mL of USP Pseudoephedrine Hydrochloride RS in Medium. Sonicate to dissolve, if necessary.

Standard solution: 0.124 mg/mL of USP Naproxen Sodium RS and 0.0672 mg/mL of USP Pseudoephedrine Hydrochloride RS from Standard stock solution A and Standard stock solution B in Medium

Sample solution: At the specified time points, withdraw a suitable volume of the solution under test. Pass through a suitable filter, discarding an appropriate volume of filtrate so that a consistent result can be obtained. Dilute 5 mL of the filtrate with Medium to 10 mL.

Replace the portion removed from the solution under test with the same volume of Medium.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 257 nm for naproxen; UV 215 nm for pseudoephedrine

Column: 4.6-mm x 25-cm; 5-µm packing L11

Column temperature: 30°

Flow rate: 1.2 mL/min.

Injection volume: 10 µL

Run time: NLT 1.7 times the retention time of naproxen

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: 0.8-2.0 for naproxen and pseudoephedrine

Relative standard deviation: NMT 2.0% for naproxen and pseudoephedrine

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of naproxen sodium (C₁₄H₁₃NaO₃) dissolved: 13

                         Result = (r_U/r_S) × C_S x V x D x (1/L) x 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 (mg/mL) 

V = volume of Medium, 900 mL 

D = dilution factor for the Sample solution

L = label claim of naproxen sodium (mg/Tablet)

Calculate the concentration (C), in mg/mL, of pseudoephedrine hydrochloride (C₁₄H₁₅NO · HCI) in the sample withdrawn from the vessel at each time point (i):

                         Result = (r_U/r_S) × C_S x D

r_U = peak response of pseudoephedrine from the Sample solution

r_S = peak response of pseudoephedrine from the Standard solution

C_S = concentration of USP Pseudoephedrine Hydrochloride RS in the Standard solution (mg/mL)

D = dilution factor for the Sample solution

Calculate the percentage of the labeled amount of pseudoephedrine hydrochloride (C₁₄H₁₅NO · HCI) dissolved at each time point (1):

                         Result₁ = C₁ x V x (1/L) x 100

                         Result₂ =  [(C₂ x V)+ (C₁ x V_S)] x (1/L) x 100

                         Result₃ = {(C₃ x V) + [(C₂ + C₁) x V_S)} x (1/L) x 100

C_i = concentration of pseudoephedrine hydrochloride in Medium in the portion of the sample withdrawn at each time point (i) (mg/mL)

V = volume of Medium, 900 mL

L = label claim of pseudoephedrine hydrochloride (mg/Tablet)

V_S = volume of the solution under test withdrawn at each time and replaced with Medium (mL) 

Tolerances

Naproxen sodium: NLT 80% (Q) of the labeled amount of naproxen sodium (C₁₄H₁₃NaO₃) is dissolved.

Pseudoephedrine hydrochloride: See Table 4.

Table 4

The percentages of the labeled amount of pseudoephedrine hydrochloride (C₁₄H₁₅NO · HCI) dissolved at the times specified conform to Dissolution (711), Acceptance Table 2-._{▲(RB 1-Sep-2024)}

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

Change to read:

ORGANIC IMPURITIES

5.1 Naproxen sodium related impurities

Mobile phase: Acetonitrile, water, and glacial acetic acid (50:50:1)

Diluent: Acetonitrile and water (90:10)

System suitability solution: 3.1 mg/mL of USP Naproxen Sodium RS and 8 µg/mL each of USP Naproxen Related Compound K RS and USP

Naproxen Related Compound L RS in Diluent

Standard solution: 0.006 mg/mL of USP Naproxen Sodium RS in Diluent

Sample solution: Nominally 3.1 mg/mL of naproxen sodium in Diluent prepared as follows. Transfer a suitable amount of naproxen sodium from NLT 20 finely powdered Tablets to an appropriate volumetric flask, add 70% of the final volume of Diluent, and sonicate for 20 min with intermittent shaking. Allow the solution to cool to room temperature and dilute with Diluent to volume. Pass a portion of the solution through a suitable filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 260 nm

Column: 4.6-mm x 25-cm; 5-µm packing L1

Flow rate: 1.0 mL/min

Injection volume: 10 µL

Run time: NLT 5.6 times the retention time of naproxen

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 2 between naproxen related compound K and naproxen; NLT 2 between naproxen and naproxen related compound L, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each naproxen sodium related impurity in the portion of Tablets taken:

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

r_U = peak response of each naproxen related 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 (mg/mL)

C_U = nominal concentration of naproxen sodium in the Sample solution (mg/mL)

F = relative response factor (see ^▲Table 5 _{▲(RB 1-Sep-2024)})

Acceptance criteria: See ^▲Table 5.

Table 5 _{▲(RB 1-Sep-2024)}

^a Methyl 2-(6-methoxynaphthalen-2-yl)propionate.

^b Isopropyl 2-(6-methoxynaphthalen-2-yl)propionate.

^c Exclude pseudoephedrine related peaks before the relative retention time of 0.4.

5.2 Pseudoephedrine hydrochloride related impurities

Solution A: 5 mL/L of triethylamine in water. Adjust with phosphoric acid to a pH of 3.0.

Solution B: Acetonitrile and water (90:10)

Mobile phase: See ^▲Table 6.

Table 6 _{▲(RB 1-Sep-2024)}

Diluent: 5 mL/L of triethylamine in water. Adjust with phosphoric acid to a pH of 6.8.

System suitability solution: 0.5 mg/mL of USP Pseudoephedrine Hydrochloride RS and 1.5 µg/mL of USP Ephedrine Hydrochloride RS in Diluent

Standard solution: 0.001 mg/mL of USP Pseudoephedrine Hydrochloride RS in Diluent

Sample solution: Nominally 0.5 mg/mL of pseudoephedrine hydrochloride in Diluent prepared as follows. Transfer a suitable amount of pseudoephedrine hydrochloride from NLT 20 finely powdered Tablets to an appropriate volumetric flask, add 70% of the total volume of Diluent, and sonicate for 30 min with intermittent shaking. Allow the solution to cool to room temperature and dilute with Diluent to volume. Centrifuge a portion of the solution for 10 min. Pass a portion of the solution through a suitable filter of 0.45-µm pore size.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm x 25-cm; 5-µm packing L1

Flow rate: 1.0 mL/min

Injection volume: 20 µL

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 1.5 between ephedrine and pseudoephedrine, System suitability solution

Relative standard deviation: NMT 5.0%, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each pseudoephedrine hydrochloride related impurity in the portion of Tablets taken:

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

r_U = peak response of each pseudoephedrine hydrochloride related impurity from the Sample solution 

r_S = peak response of pseudoephedrine from the Standard solution

C_S = concentration of USP Pseudoephedrine Hydrochloride RS in the Standard solution (mg/mL)

C_U = nominal concentration of pseudoephedrine hydrochloride in the Sample solution (mg/mL)

F = relative response factor (see ^▲Table 7_{▲(RB 1-Sep-2024))}

Acceptance criteria: See ^▲Table 7.

Table 7 _{▲(RB 1-Sep-2024)}

^a (1R,2S)-2-Amino-1-phenylpropan-1-ol hydrochloride.

^b (1S,2S)-2-Amino-1-phenylpropan-1-ol hydrochloride.

^c Exclude naproxen related peaks after a relative retention time of 1.8 and blank peaks before a relative retention time of 0.2.

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in a dry place. Store at controlled room temperature.

LABELING: When more than one Dissolution test is given, the labeling states the Dissolution test used only if Test 1 is not used.

USP REFERENCE STANDARDS (11)

USP Ephedrine Hydrochloride RS

(1R,2S)-2-(Methylamino)-1-phenylpropan-1-ol hydrochloride.

C₁₀H₁₅NO · HCI          201.69

USP Naproxen Sodium RS

USP Naproxen 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            200.23

USP Pseudoephedrine Hydrochloride RS