Acetaminophen and Diphenhydramine Citrate Tablets

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

1 DEFINITION

Acetaminophen and Diphenhydramine Citrate Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of acetaminophen (C₈H₉NO₂) and diphenhydramine citrate (C₁₇H₂₁NO·C₆H₈O₇).

2 IDENTIFICATION

A. The retention times of the major peaks of the Sample solution, obtained in Procedure 1: Acetaminophen and for Procedure 2:

Diphenhydramine Citrate for the Assay, relative to the retention times of the respective internal standards, correspond to those of the respective Standard solution.

3 ASSAY

Change to read:

3.1 PROCEDURE 1: ACETAMINOPHEN

Mobile phase: Methanol and water (40:60)

Diluent: Methanol and water (20:80) (USP 1-Dec-2020)

Internal standard solution: 8.0 mg/mL of USP Guaifenesin RS (USP 1-Dec-2020) in Diluent

Standard stock solution: 0.5 mg/mL of USP Acetaminophen RS, prepared as follows. Transfer 50 mg of USP Acetaminophen RS to a 100-mL volumetric flask. Dissolve in 2.5 mL of methanol, and dilute with water to volume.

Standard solution: 0.02 mg/mL of acetaminophen from Standard stock solution and 0.8 mg/mL of guaifenesin from Internal standard solution, in Mobile phase

Sample stock solution: Nominally 0.5 mg/mL of acetaminophen prepared as follows. Transfer a portion of the powder from NLT 20 finely powdered Tablets, (USP 1-Dec-2020) equivalent to an appropriate amount of acetaminophen, to a suitable volumetric flask. Add 25% of the total volume of methanol, and shake by mechanical means for 10 min. Dilute with water to volume.

Sample solution: Nominally 0.02 mg/mL of acetaminophen prepared as follows. Transfer 2.0 mL of Sample stock solution to a 50-mL volumetric flask, add 5.0 mL of Internal standard solution, and dilute with Mobile phase to volume.

3.1.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 4.6-mm x 15-cm; 5-µm packing 11

Column temperature: 35°(USP 1-Dec-2020)

Flow rate: 1 mL/min

Injection volume: 10 µL

3.1.2 System suitability

Sample: Standard solution

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

Suitability requirements

Resolution: NLT 6.0 between acetaminophen and guaifenesin (USP 1-Dec-2020)

Tailing factor: NMT 2 for the acetaminophen peak (USP 1-Dec-2020)

Relative standard deviation: NMT 2.0% (USP 1-Dec-2020) for the peak response ratios

3.1.3 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) × 100

R_U = peak response ratio of acetaminophen to the internal standard from the Sample solution

R_S = peak response ratio of acetaminophen to the internal standard 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%

3.2 PROCEDURE 2: DIPHENHYDRAMINE CITRATE

Diluent: Methanol and water (50:50) (USP 1-Dec-2020)

Mobile phase: Methanol, water, and glacial acetic acid (61:38:1) containing 1.0813 g of sodium 1-octanesulfonate in each 1000 mL of solution

Internal standard solution: 8 mg/mL of USP Xylometazoline Hydrochloride RS (USP 1-Dec-2020) in water

Standard solution: 0.38 mg/mL of USP Diphenhydramine Citrate RS and 0.8 mg/mL of USP Xylometazoline Hydrochloride RSA (USP 1-Dec-2020) from Internal standard solution in Diluent

Sample solution: Nominally 0.38 mg/mL of diphenhydramine citrate prepared as follows. Transfer a portion of the powder from NLT 20 finely powdered Tablets, (USP 1-Dec-2020) equivalent to 38 mg of diphenhydramine citrate, to a 100-mL volumetric flask. Add 65 mL of Diluent, and shake by mechanical means for 15 min. Add 5.0 mL of Internal standard solution, and dilute with Diluent to volume.

3.2.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 265 nm

Column: 3.9-mm x 30-cm; packing L1

Column temperature: 35° (USP 1-Dec-2020)

Flow rate: 1.5 mL/min

Injection volume: 50 µL

3.2.2 System suitability

Sample: Standard solution

[NOTE-The relative retention times for diphenhydramine (USP 1-Dec-2020) and xylometazoline are 0.7 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2.5 between diphenhydramine and xylometazoline (USP 1-Dec-2020)

Tailing factor: NMT 1.7 for the diphenhydramine (USP 1-Dec-2020) peak

Relative standard deviation: NMT 2.0% for the peak response ratios

3.2.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of diphenhydramine citrate (C₁₇H₂₁NO·C₆H₈O₇) in the portion of Tablets taken:

Result = (R_U/R_S) x (C_S/C_U) × 100

R_U = peak response ratio of diphenhydramine citrate to the internal standard from the Sample solution

R_S = peak response ratio of diphenhydramine citrate to the internal standard from the Standard solution

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

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

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

Change to read:

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: Water; 900 mL

Apparatus 2: 50 rpm

Time: 45 min

Analysis: Calculate the percentages of the labeled amount of acetaminophen (C₈H₉NO₂) and diphenhydramine citrate (C₁₇H₂₁NO·C₆H₈O₇) dissolved. [NOTE-Proceed using Procedure 1: Acetaminophen and Procedure 2: Diphenhydramine Citrate in the Assay. Volumetric adjustment may be needed.]

Result = (r) x C x V x (1/L) × 100

= peak response of acetaminophen or diphenhydramine from the Sample solution

s = peak response of acetaminophen or diphenhydramine from the Standard solution

= concentration of USP Acetaminophen RS or USP Diphenhydramine Citrate RS in the Standard solution (mg/mL)

V = volume of Medium, 900 mL

L = label claim of acetaminophen or diphenhydramine citrate (mg/Tablet)

Tolerances: NLT 75% (Q) of the labeled amount of acetaminophen (C₈H₉NO₂) and diphenhydramine citrate (C₁₇H₂₁NO·C₆H₈O₇) is dissolved.

Change to read:

4.2 UNIFORMITY OF DOSAGE UNITS (905), Content Uniformity

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.

Change to read:

USP REFERENCE STANDARDS (11).

USP Acetaminophen RS

USP Diphenhydramine Citrate RS