Acetaminophen and Codeine Phosphate 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 and Codeine Phosphate Oral Solution contains NLT 90.0% and NMT 110.0% of the labeled amount of acetaminophen (C₈H₉NO₂) and codeine phosphate hemihydrate (C₁₈H₂₁NO₃·H₃PO₄·½H₂O).

2 IDENTIFICATION

A. The retention times of the major peaks of the Sample solutions correspond to those of the Standard solutions, as obtained in the Assays for Acetaminophen and Codeine Phosphate.

B. THIN-LAYER CHROMATOGRAPHY

Standard solution: 12 mg/mL each of USP Acetaminophen RS and USP Codeine Phosphate RS in methanol

Sample solution: Transfer a volume of Oral Solution, equivalent to 12 mg of codeine phosphate, to a separator. Add 1 mL of ammonium hydroxide and 5 mL of methylene chloride. Shake for 1 min, and allow the layers to separate. Use the clear lower layer.

Developing solvent system: Methanol and ammonium hydroxide (49:1)

2.1 Chromatographic system

(See Chromatography (621), Thin-Layer Chromatography.)

Mode: TLC

Adsorbent: 0.25-mm layer of chromatographic silica gel mixture

Application volume: 10 µL

2.2 Analysis

Samples: Standard solution and Sample solution

Develop the chromatogram in the Developing solvent system until the solvent front has moved three-fourths of the length of the plate.

Locate the spots on the plate by examination under

Acceptance criteria: The R, values of the two principal spots of the Sample solution correspond to those of the Standard solution.

3 ASSAY

3.1 ACETAMINOPHEN

Mobile phase: Methanol and water (3:7)

Standard solution: 0.48 mg/mL of USP Acetaminophen RS in Mobile phase

Sample solution: Nominally 0.48 mg/mL of acetaminophen in Mobile phase, prepared by adding a volume of Oral Solution, equivalent to 120 mg of acetaminophen, to a 250-mL volumetric flask. Dilute with Mobile phase to volume.

3.1.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 280 nm

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

Flow rate: 2 mL/min

Injection volume: 10 µL

3.1.2 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

3.1.3 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) × 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%

3.2 CODEINE PHOSPHATE

Mobile phase: Dissolve 4.44 g of Docusate sodium in 1000 mL of a mixture of methanol, tetrahydrofuran, phosphoric acid, and water

Diluent: Methanol and water (3:7)

(600:40:1:360) with stirring, and pass through a membrane filter of 0.45-µm or finer pore size.

Standard solution: 0.12 mg/mL of USP Codeine Phosphate RS in Diluent

Sample solution: Nominally 0.12 mg/mL of codeine phosphate hemihydrate in Diluent, prepared by adding a volume of Oral Solution, equivalent to 12 mg of codeine phosphate hemihydrate, to a 100-mL volumetric flask. Dilute with Diluent to volume.

3.2.1 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 280 nm

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

Flow rate: 1.5 mL/min

Injection volume: 10 µL

3.2.2 System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 3.0%

3.2.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of codeine phosphate hemihydrate (C₁₈H₂₁NO₃·H₃PO₄·½H₂O) 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 codeine phosphate from the Sample solution

r_S = peak response of codeine phosphate from the Standard solution

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

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

M_r1 = molecular weight of codeine phosphate hemihydrate, 406.37

M_r2 = molecular weight of anhydrous codeine phosphate, 397.37

Acceptance criteria: 90.0%-110.0%

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

PH (791): 4.0-6.1

ALCOHOL DETERMINATION (611), Method II (if present): 90.0%-120.0% of the labeled quantity of alcohol (C₂H₅OH), acetone being used as the internal standard

7 ADDITIONAL REQUIREMENTS

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

USP REFERENCE STANDARDS (11)

USP Acetaminophen RS

USP Codeine Phosphate RS