Acetaminophen and Codeine Phosphate Oral Suspension

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 Suspension is a suspension of Acetaminophen and Codeine Phosphate in a suitable aqueous vehicle. It 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 solution correspond to those of the Standard solution, as obtained in the Assay.

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 Suspension, 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.

Chromatographic system

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

Adsorbent: 0.25-mm layer of chromatographic silica gel mixture

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

Application volume: 10 µL

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 short-wavelength UV light.

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 PROCEDURE

Diluent: Methanol and 0.01 N sodium hydroxide (30:70)

Mobile phase: Dissolve 4.9 g of monobasic potassium phosphate in 900 mL of water, adjust with phosphoric acid to a pH of 3.9, and add 216 mg of sodium 1-octanesulfonate. Add 100 mL of acetonitrile, and filter.

Codeine phosphate standard stock solution: 0.5 mg/mL of USP Codeine Phosphate RS in Diluent

Standard stock solution: Transfer a quantity of 5 mg of USP Acetaminophen RS (J being the ratio of the labeled amount, in mg, of acetaminophen to the labeled amount, in mg, of codeine phosphate hemihydrate) and 10.0 mL of Codeine phosphate standard stock solution to a 100-mL volumetric flask. Dissolve in and dilute with Diluent to volume.

System suitability stock solution: 0.02 mg/mL of sodium benzoate and 0.03 mg/mL of methylparaben in Diluent

System suitability solution: Transfer 10.0 mL of the System suitability stock solution to a 50-mL volumetric flask, add 10.0 mL of Standard stock solution, and dilute with Mobile phase to volume.

Standard solution: 0.01 mg/mL of USP Codeine Phosphate RS and 0.01J mg/mL of USP Acetaminophen RS in Mobile phase. Prepare by diluting 10.0 mL of the Standard stock solution with Mobile phase to 50 mL in a volumetric flask.

Sample stock solution: Nominally 0.5 mg/mL of acetaminophen and 0.5 mg/mL of codeine phosphate hemihydrate in Diluent prepared as follows. Transfer a measured volume of well-mixed Oral Suspension, equivalent to 50 mg of acetaminophen, to a 100-mL volumetric flask. Add 50 mL of Diluent, and mix by mechanical means for 30 min. Dilute with Diluent to volume. Foaming may be minimized by adding a few drops of acetonitrile before diluting with Diluent to volume. Centrifuge a portion of this mixture.

Sample solution: Dilute 10.0 mL of the clear supernatant from the Sample stock solution with Mobile phase to 50 mL in a volumetric flask.

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm x 15-cm; 5-µm packing L11

Flow rate: 2 mL/min

Injection volume: 20 µL

3.3 System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for acetaminophen, benzoate, codeine, and methylparaben are about 0.25, 0.5, 1.0, and 1.3, respectively.]

Suitability requirements

Resolution: NLT 2 between each pair of adjacent peaks, System suitability solution

Tailing factor: NMT 2 for each analyte peak, Standard solution

Relative standard deviation: NMT 2.0%, Standard solution

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of acetaminophen (C₈H₉NO₂) in the portion of Oral Suspension 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%

Calculate the percentage of the labeled amount of codeine phosphate hemihydrate (C₁₈H₂₁NO₃·H₃PO₄·½H₂O) in the portion of Oral Suspension taken:

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

r_U = peak response of codeine from the Sample solution

r_S = peak response of codeine 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 hemihydrate 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

7 ADDITIONAL REQUIREMENTS

7.1 PACKAGING AND STORAGE

Preserve in tight, light-resistant containers, and store at controlled room temperature.

7.2 USP REFERENCE STANDARDS (11)

USP Acetaminophen RS

USP Codeine Phosphate RS