Acetaminophen, Aspirin, and Caffeine 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, Aspirin, and Caffeine Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of Acetaminophen (C₈H₉NO₂), Aspirin (C₉H₈O₄), and caffeine (C₈H₁₀N₄O₂).

2 IDENTIFICATION

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

3 ASSAY

3.1 PROCEDURE

Inject the Standard solution and the Sample solution within 8 h of preparation.

Mobile phase: Methanol, glacial acetic acid, and water (28:3:69)

Diluent: Methanol and glacial acetic acid (95:5)

Internal standard solution: 6 mg/mL of benzoic acid in methanol

Standard stock solution: 0.25 mg/mL of USP Acetaminophen RS, 0.25J' mg/mL of USP Aspirin RS, and 0.25 mg/mL of USP Caffeine RS in Diluent (J being the ratio of the labeled amount, in milligrams, of aspirin to the labeled amount, in milligrams, of acetaminophen per Tablet; and J' being the ratio of the labeled amount, in milligrams, of caffeine to the labeled amount, in milligrams, of acetaminophen per Tablet)

Standard solution: 0.1 mg/mL of USP Acetaminophen RS, 0.1J mg/mL of USP Aspirin RS, and 0.1 J' mg/mL of USP Caffeine RS in Diluent, prepared as follows. Transfer 20.0 mL of the Standard stock solution and 3.0 mL of Internal standard solution to a 50-mL volumetric flask, and dilute with Diluent to volume.

Sample stock solution: Nominally 2.5 mg/mL of acetaminophen in Diluent prepared as follows. Transfer an equivalent of 250 mg of acetaminophen, from NLT 20 finely powdered Tablets, to a 100-mL volumetric flask. Add 75 mL of Diluent, and shake by mechanical means for 30 min. Dilute with Diluent to volume.

Sample solution: Nominally 0.1 mg/mL of acetaminophen in Diluent prepared as follows. Transfer 2.0 mL of the Sample stock solution and 3.0 mL of Internal standard solution to a 50-mL volumetric flask, and dilute with Diluent to volume.

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 275 nm

Column: 4.6-mm x 10-cm; 5-µm packing L1

Column temperature: 45 ± 1°

Flow rate: 2 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

[NOTE-The relative retention times for acetaminophen, caffeine, aspirin, benzoic acid, and salicylic acid are about 0.3, 0.5, 0.8, 1.0, and 1.2, respectively.]

3.3 Suitability requirements

Resolution: NLT 1.4 between any of the analyte and internal standard peaks

Tailing factor: NMT 1.2 for each analyte peak

Relative standard deviation: NMT 2.0%

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate individually the percentage of the labeled amount of acetaminophen (C₈H₉NO₂), aspirin (C₉H₈O₄), and caffeine (C₈H₁₀N₄O₂) in the portion of Tablets taken:

Result = (R_U/R_S) x (C_S/C_U) x 100

R_U = peak response ratio of acetaminophen, aspirin, or caffeine to the internal standard from the Sample solution

R_S = peak response ratio of acetaminophen, aspirin, or caffeine to the internal standard from the Standard solution

C_S = concentration of the corresponding USP Reference Standard in the Standard solution (mg/mL)

C_U = nominal concentration of acetaminophen, aspirin, or caffeine in the Sample solution (mg/mL)

Acceptance criteria: 90.0%-110.0% of the labeled amount of acetaminophen, aspirin, and caffeine

4 PERFORMANCE TESTS

4.1 DISSOLUTION (711)

Medium: Water; 900 mL

Apparatus 2: 100 rpm

Time: 60 min

Mobile phase, Diluent, Internal standard solution, Standard stock solution, and Chromatographic system: Proceed as directed in the Assay.

Standard solution: Transfer 20.0 mL of Standard stock solution, 3.0 mL of Internal standard solution, and 20 mL of water to a 50-mL volumetric flask, and allow to stand for 30 s. Dilute with Diluent to volume. Use within 8 h.

Sample solution: Transfer 20.0 mL of a filtered portion of the solution under test to a 50-mL volumetric flask. Add 3.0 mL of Internal standard solution and 20 mL of Diluent, mix, and allow to stand for 30 s. Dilute with Diluent to volume.

Analysis: Proceed as directed for Analysis in the Assay.

Calculate individually the percentage of the labeled amount of acetaminophen (C₈H₉NO₂), aspirin (C₉H₈O₄), and caffeine (C₈H₁₀N₄O₂) dissolved:

Result = (R_U/R_S) x (C_S/C_U) x 100

R_U = peak response ratio of acetaminophen, aspirin, or caffeine to the internal standard from the Sample solution

R_S = peak response ratio of acetaminophen, aspirin, or caffeine to the internal standard from the Standard solution

C_S = concentration of the corresponding USP Reference Standard in the Standard solution (mg/mL)

C_U = nominal concentration of acetaminophen, aspirin, or caffeine in the Sample solution (mg/mL)

Tolerances: NLT 75% (Q) of the labeled amount of acetaminophen (C₈H₉NO₂), aspirin (C₉H₈O₄), and caffeine (C₈H₁₀N₄O₂) is dissolved.

4.2 UNIFORMITY OF DOSAGE UNITS (905), Content Uniformity

Meet the requirements with respect to acetaminophen, aspirin, and caffeine spect to

5 IMPURITIES

5.1 LIMIT OF SALICYLIC ACID

Mobile phase and Diluent: Prepare as directed in the Assay.

Standard solution: 0.02 mg/mL of USP Salicylic Acid RS in Diluent

Sample solution: Nominally 2.5 mg/mL of aspirin in Diluent, prepared as follows. Transfer an equivalent of 250 mg of aspirin, from NLT 20 finely powdered Tablets, to a 100-mL volumetric flask. Add 75 mL of Diluent, and shake by mechanical means for 30 min. Dilute with Diluent to volume.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 302 nm

Column: 4.6-mm × 10-cm; 5-µm packing L1

Column temperature: 45 ± 1°

Flow rate: 2 mL/min

Injection volume: 10 µL

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.6

Relative standard deviation: NMT 3.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of salicylic acid (C₇H₆O₃) relative to the labeled amount of aspirin in the portion of Tablets taken:

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

r_U = peak response of salicylic acid from the Sample solution

r_S = peak response of salicylic acid from the Standard solution

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

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

Acceptance criteria: NMT 3.0%

5.2 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 Aspirin RS

USP Caffeine RS

USP Salicylic Acid RS