Acetaminophen, Dextromethorphan Hydrobromide, Doxylamine Succinate, and Pseudoephedrine Hydrochloride Oral Solution

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

Acetaminophen, Dextromethorphan Hydrobromide, Doxylamine Succinate, and Pseudoephedrine Hydrochloride Oral Solution contains NLT 90.0% and NMT 110.0% of the labeled amount of Acetaminophen (C₈H₉NO₂), dextromethorphan hydrobromide (C₁₈H₂₅NO·HBr·H₂O), doxylamine succinate (C₁₇H₂₂N₂O·C₄H₆O₄), and pseudoephedrine hydrochloride (C₁₀H₁₅NO·HCI).

2 IDENTIFICATION

A. The retention time of the acetaminophen peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay for Acetaminophen.

B. The retention time of the dextromethorphan peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay for Dextromethorphan Hydrobromide.

C. The retention time of the doxylamine peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay for Doxylamine Succinate.

D. The retention time of the pseudoephedrine peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay for Pseudoephedrine Hydrochloride.

3 ASSAY

3.1 ACETAMINOPHEN

Mobile phase: Methanol and water (45:55)

Standard solution: 0.2 mg/mL of USP Acetaminophen RS in Mobile phase

Sample solution: Nominally 0.2 mg/mL of acetaminophen from a volume of Oral Solution in Mobile phase prepared as follows. Dilute a volume of Oral Solution, equivalent to about 200 mg of acetaminophen, in Mobile phase.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

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

Flow rate: 1 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for the acetaminophen peak

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of acetaminophen (C₈H₉NO₂) in the portion of Oral Solution taken:

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

r_U = peak response of acetaminophen from the Sample solution

r_S = peak response of acetaminophen from the Standard solution

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

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

Acceptance criteria: 90.0%-110.0% of the labeled amount of acetaminophen (C₈H₉NO₂)

3.2 DEXTROMETHORPHAN HYDROBROMIDE

Solution A: 6.8 g/L of monobasic potassium phosphate in water

Mobile phase: Acetonitrile and Solution A (45:55)

Standard solution: 0.1 mg/mL of USP Dextromethorphan Hydrobromide RS, 0.04 mg/mL of USP Doxylamine Succinate RS, and 0.2 mg/mL of USP Pseudoephedrine Hydrochloride RS in Mobile phase

Sample solution: Nominally 0.1 mg/mL of dextromethorphan hydrobromide from a volume of Oral Solution in Mobile phase prepared as follows. Dilute a volume of Oral Solution, equivalent to about 5 mg of dextromethorphan hydrobromide, in Mobile phase.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm x 25-cm; packing L9

Flow rate: 2.5 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

[NOTE-The relative retention times for pseudoephedrine, dextromethorphan, and doxylamine are 0.38, 0.65, and 1.0, respectively.]

Suitability requirements

Tailing factor: NMT 2.5 for the dextromethorphan, doxylamine, and pseudoephedrine peaks

Relative standard deviation: NMT 2.0% for dextromethorphan, doxylamine, and pseudoephedrine

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of dextromethorphan hydrobromide (C₁₈H₂₅NO·HBr·H₂O) in the portion of Oral Solution taken:

Result = (r_U/r_S) x (C_S/C_U) x (M_r1/M_r2) x 100

r_U = peak response of dextromethorphan from the Sample solution

r_S = peak response of dextromethorphan from the Standard solution

C_S = concentration of USP Dextromethorphan Hydrobromide RS in the Standard solution (mg/mL)

C_U = nominal concentration of dextromethorphan hydrobromide in the Sample solution (mg/mL)

M_r1 = molecular weight of dextromethorphan hydrobromide monohydrate, 370.32

M_r2 = molecular weight of anhydrous dextromethorphan hydrobromide, 352.32

Acceptance criteria: 90.0%-110.0% of the labeled amount of dextromethorphan hydrobromide (C₁₈H₂₅NO·HBr·H₂O)

3.3 DOXYLAMINE SUCCINATE

Solution A, Mobile phase, Standard solution, Chromatographic system, and System suitability: Proceed as directed in the Assay for Dextromethorphan Hydrobromide.

Sample solution: Nominally 0.04 mg/mL of doxylamine succinate from a volume of Oral Solution in Mobile phase prepared as follows. Dilute a volume of Oral Solution, equivalent to about 2 mg of doxylamine succinate, in Mobile phase.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of doxylamine succinate (C₁₇H₂₂N₂O·C₄H₆O₄) in the portion of Oral Solution taken:

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

r_U = peak response of doxylamine from the Sample solution

r_S = peak response of doxylamine from the Standard solution

C_S = concentration of USP Doxylamine Succinate RS in the Standard solution (mg/mL)

C_U = nominal concentration of doxylamine succinate in the Sample solution (mg/mL)

Acceptance criteria: 90.0%-110.0% of the labeled amount of doxylamine succinate (C₁₇H₂₂N₂O·C₄H₆O₄)

3.4 PSEUDOEPHEDRINE HYDROCHLORIDE

Solution A, Mobile phase, Standard solution, Chromatographic system, and System suitability: Proceed as directed in the Assay for Dextromethorphan Hydrobromide.

Sample solution: Nominally 0.2 mg/mL of pseudoephedrine hydrochloride from a volume of Oral Solution in Mobile phase prepared as follows. Dilute a volume of Oral Solution, equivalent to about 10 mg of pseudoephedrine hydrochloride, in Mobile phase.

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of pseudoephedrine hydrochloride (C₁₀H₁₅NO·HCI) in the portion of Oral Solution taken:

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

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)

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

Acceptance criteria: 90.0%-110.0% of the labeled amount of pseudoephedrine hydrochloride (C₁₀H₁₅NO·HCI)

4 PERFORMANCE TESTS

4.1 UNIFORMITY OF DOSAGE UNITS (905)

For single-unit containers

Acceptance criteria: Meets the requirements

4.2 DELIVERABLE VOLUME (698)

For multiple-unit containers

Acceptance criteria: Meets the requirements

5 IMPURITIES

4-AMINOPHENOL IN ACETAMINOPHEN-CONTAINING DRUG PRODUCTS (227): Meets the requirements

6 SPECIFIC TESTS

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

The total bacterial count does not exceed 100 cfu/g, the total combined molds and yeasts count does not exceed 10 cfu/g, and it meets the requirements of the tests for absence of Salmonella species and Escherichia coli.

6.2 PH (791)

4.5-6.3

6.3 ALCOHOL DETERMINATION (611), Method II(if present)

90.0%-110.0% of the labeled amount of alcohol (C₂H₅OH)

7 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight containers, and store at controlled room temperature.

USP REFERENCE STANDARDS (11).

USP Acetaminophen RS

USP Dextromethorphan Hydrobromide RS

USP Doxylamine Succinate RS

USP Pseudoephedrine Hydrochloride RS