Acetaminophen and Codeine Phosphate Capsules

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 Capsules contain NLT 90.0% and NMT 110.0% of the labeled amount of acetaminophen (C₈H₉NO₂) and codeine phosphate (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 portion of Capsule contents, equivalent to 12 mg of codeine phosphate, to a separator. Add 5 mL of water, 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.

2.1 Chromatographic system

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

Adsorbent: 0.25-mm layer of chromatographic silica gel mixture

Application volume: 10 µL

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

2.2 Analysis

Samples: Standard solution and Sample solution

Allow the spots to dry after applying each sample to the adsorbent. Develop the chromatogram in the Developing solvent system until the solvent front has moved three-fourths of the length of the plate. Remove the plate from the developing chamber, mark the solvent front, and allow the solvent to evaporate. Locate the spots on the plate by examination under short-wavelength UV light.

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

3 ASSAY

3.1 PROCEDURE

Solution A: Dissolve 2.04 g of monobasic potassium phosphate in 950 mL of water. Add 2 mL of triethylamine, adjust with phosphoric acid to a pH of 2.35, and dilute with water to 1000 mL.

Mobile phase: Methanol and Solution A (8:92)

Codeine phosphate standard stock solution: 0.3 mg/mL of USP Codeine Phosphate RS in Mobile phase

Standard solution: 0.3 mg/mL of USP Acetaminophen RS and 0.3J mg/mL of codeine phosphate in Mobile phase, prepared as follows.

Transfer an appropriate amount of USP Acetaminophen RS and a suitable volume (multiplied by J) of Codeine phosphate standard stock solution (J being the ratio of the labeled amount, in mg, of codeine phosphate to that of acetaminophen) to a suitable volumetric flask.

Dilute with Mobile phase to volume.

Sample stock solution: Nominally 3.0 mg/mL of acetaminophen and 3.0J mg/mL of codeine phosphate (equivalent to 2.93J mg/mL of anhydrous codeine phosphate) in Mobile phase, prepared as follows. Transfer a portion of the combined contents, equivalent to 300 mg of acetaminophen, from NLT 20 Capsules, to a 100-mL volumetric flask. Add 75 mL of Mobile phase, and sonicate for 10 min. Dilute with

Mobile phase to volume.

Sample solution: Dilute 5.0 mL of the Sample stock solution with Mobile phase to 50 mL, and pass a portion through a filter of 1-µm pore size.

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 214 nm

Column: 4.6-mm x 25-cm; 5-µm packing L1

Flow rate: 1.5 mL/min

Injection volume: 30 µL

3.3 System suitability

Sample: Standard solution

Suitability requirements

Resolution: NLT 2.0 between acetaminophen and codeine

Relative standard deviation: NMT 2.0% for acetaminophen; NMT 3.0% for codeine

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of acetaminophen (C₈H₉NO₂) in the portion of Capsules 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)

Calculate the percentage of the labeled amount of codeine phosphate (C₁₈H₂₁NO₃·H₃PO₄·½H₂O) in the portion of Capsules 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 in the Sample solution (mg/mL)

M_r1 = molecular weight of codeine phosphate, 406.37

M_r2 = molecular weight of anhydrous codeine phosphate, 397.37

3.5 Acceptance criteria

Acetaminophen: 90.0%-110.0%

Codeine phosphate: 90.0%-110.0%

4 PERFORMANCE TESTS

4.1 DISSOLUTION (711)

Medium: 0.01 N hydrochloric acid; 900 mL

Apparatus 2: 50 rpm

Time: 30 min

Analysis: Determine the percentage of the labeled amount of acetaminophen (C₈H₉NO₂) and codeine phosphate (C₁₈H₂₁NO₃·H₃PO₄·½H₂O) dissolved by using the method set forth in the Assay, except use 0.01 N hydrochloric acid to prepare the Codeine phosphate standard stock solution, and make any other necessary volumetric adjustments.

Tolerances: NLT 75% (Q) of the labeled amount of acetaminophen (C₈H₉NO₂) and codeine phosphate (C₁₈H₂₁NO₃·H₃PO₄·½H₂O) is dissolved.

Change to read:

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements (CN 1-Aug-2023)

4.2.1 Procedure for content uniformity

Solution A, Mobile phase, Codeine phosphate standard stock solution, Standard solution, Chromatographic system, and System suitability: Proceed as directed in the Assay.

Sample stock solution: Transfer the contents of 1 Capsule to a 100-mL volumetric flask. Add 75 mL of Mobile phase, and sonicate for 10 min. Dilute with Mobile phase to volume.

Sample solution: Dilute 5.0 mL of the Sample stock solution with Mobile phase to 50 mL, and pass a portion through a suitable filter of 1-µm pore size.

4.2.2 Analysis

Samples: Standard solution and Sample solution

Calculate the quantity, in mg, of acetaminophen (C₈H₉NO₂) in the Capsule taken:

Result = (r_U/r_S) x C_S x F

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)

F = dilution volume, 1000 mL

Calculate the quantity, in mg, of codeine phosphate (C₁₈H₂₁NO₃·H₃PO₄·½H₂O) in the Capsule taken:

Result = (r_U/r_S) x C_S x (M_r1/M_r2) x F

r_U = peak response of codeine from the Sample solution U

r_S = peak response of codeine from the Standard solution

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

M_r1 = molecular weight of codeine phosphate, 406.37

M_r2 = molecular weight of anhydrous codeine phosphate, 397.37

F = dilution volume, 1000 mL

5 IMPURITIES

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

6 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