Acetaminophen, Diphenhydramine Hydrochloride, and Pseudoephedrine Hydrochloride 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

Acetaminophen, Diphenhydramine Hydrochloride, and Pseudoephedrine Hydrochloride Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of Acetaminophen (C₈H₉NO₂), diphenhydramine hydrochloride (C₁₇H₂₁NO·HCI), 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 diphenhydramine peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay for Diphenhydramine Hydrochloride.

C. 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

Solution A: Transfer 6.8 g of monobasic potassium phosphate to a 1000-mL volumetric flask, and add water to dissolve. Add 2.0 mL of triethylamine, and dilute with water to volume. Adjust with phosphoric acid to a pH of 4.0.

Diluent: Acetonitrile and Solution A (11:89)

Mobile phase: Acetonitrile and Solution A (6:94)

Standard solution: 25 µg/mL of USP Acetaminophen RS, 12.5 µg/mL of USP Diphenhydramine Hydrochloride RS, and 30 µg/mL of USP Pseudoephedrine Hydrochloride RS in Diluent

Sample stock solution: Nominally 5 mg/mL of acetaminophen in Diluent prepared as follows. Transfer an amount nominally equivalent to 500 mg of acetaminophen from NLT 20 finely powdered Tablets to a 100-mL volumetric flask, add 75 mL of Diluent, shake, and sonicate for 15 min. Dilute with Diluent to volume.

Sample solution: Nominally 25 µg/mL of acetaminophen from the Sample stock solution in Diluent

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm x 15-cm; packing L10

Flow rate: 2 mL/min

Injection volume: 20 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0 for the acetaminophen, diphenhydramine, and pseudoephedrine peaks

Relative standard deviation: NMT 2.0% determined from the acetaminophen, diphenhydramine hydrochloride, and pseudoephedrine hydrochloride responses for replicate injections

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of acetaminophen (C₈H₉NO₂) in the portion of Tablets 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 (µg/mL)

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

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

3.2 DIPHENHYDRAMINE HYDROCHLORIDE

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

Sample stock solution: Nominally 0.125 mg/mL of diphenhydramine hydrochloride in Diluent prepared as follows. Transfer an amount nominally equivalent to 12.5 mg of diphenhydramine hydrochloride from a portion of finely powdered Tablets (NLT 20) to a 100-mL volumetric flask, add 75 mL of Diluent, and sonicate for 15 min. Dilute with Diluent to volume.

Sample solution: Nominally 12.5 µg/mL of diphenhydramine hydrochloride from the Sample stock solution in Diluent

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of diphenhydramine hydrochloride (C₁₇H₂₁NO·HCI) in the portion of Tablets taken:

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

r_U = peak response of diphenhydramine from the Sample solution

r_S = peak response of diphenhydramine from the Standard solution

C_S = concentration of USP Diphenhydramine Hydrochloride RS in the Standard solution (µg/mL)

C_U = nominal concentration of diphenhydramine hydrochloride in the Sample solution (µg/mL)

Acceptance criteria: 90.0%-110.0% of the labeled amount of diphenhydramine hydrochloride (C₁₇H₂₁NO·HCI)

3.3 PSEUDOEPHEDRINE HYDROCHLORIDE

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

Sample stock solution: Nominally 0.3 mg/mL of pseudoephedrine hydrochloride in Diluent prepared as follows. Transfer an amount nominally equivalent to 30 mg of pseudoephedrine hydrochloride from a portion of finely powdered Tablets (NLT 20) to a 100-mL volumetric flask, add 75 mL of Diluent, and sonicate for 15 min. Dilute with Diluent to volume.

Sample solution: Nominally 30 µg/mL of pseudoephedrine hydrochloride from the Sample stock solution in Diluent

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of pseudoephedrine hydrochloride (C₁₀H₁₅NO·HCI) in the portion of Tablets 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 (µg/mL)

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

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

4 PERFORMANCE TESTS

4.1 DISSOLUTION (711), Procedure, Apparatus 1 and Apparatus 2. Immediate-Release Dosage Forms, Procedure for a pooled sample for immediate-release dosage forms

Medium: pH 5.8 phosphate buffer (see Reagents, Indicators, and Solutions-Buffer Solutions); 900 mL

Apparatus 2: 50 rpm

Time: 45 min

Solution A, Diluent, Mobile phase, Standard solution, and Chromatographic system: Proceed as directed in the Assay for Acetaminophen.

Sample solution A: Combine equal volumes of the filtered solutions, and use the pooled sample.

Sample solution B: Transfer 5.0 mL of Sample solution A to a 100-mL volumetric flask. Dilute with Mobile phase to volume.

Analysis: Using Sample solution A and the Standard solution, and making any necessary volumetric adjustments, proceed as directed in the Assay for Diphenhydramine Hydrochloride and the Assay for Pseudoephedrine Hydrochloride, and determine the percentage of the labeled amount of diphenhydramine hydrochloride (C₁₇H₂₁NO·HCI) and pseudoephedrine hydrochloride (C₁₀H₁₅NO·HCI) dissolved. Using Sample solution B and the Standard solution, and making any necessary volumetric adjustments, proceed as directed in the Assay for Acetaminophen, and determine the percentage of the labeled amount of acetaminophen (C₈H₉NO₂) dissolved.

Tolerances: NLT 75% (Q) of the labeled amount of acetaminophen (C₈H₉NO₂), diphenhydramine hydrochloride (C₁₇H₂₁NO·HCI), and pseudoephedrine hydrochloride (C₁₀H₁₅NO·HCI) is dissolved.

For Tablets labeled as chewable

Medium: pH 5.8 phosphate buffer (see Reagents, Indicators, and Solutions-Buffer Solutions); 900 mL

Apparatus 2: 75 rpm

Time: 45 min

Tolerances: NLT 75% (Q) of the labeled amount of acetaminophen (C₈H₉NO₂), diphenhydramine hydrochloride (C₁₇H₂₁NO·HCI), and pseudoephedrine hydrochloride (C₁₀H₁₅NO·HCI) is dissolved.

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

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

6 ADDITIONAL REQUIREMENTS

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

USP REFERENCE STANDARDS (11)

USP Acetaminophen RS

USP Diphenhydramine Hydrochloride RS

USP Pseudoephedrine Hydrochloride RS