Codeine Sulfate 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

Codeine Sulfate Oral Solution contains NLT 93.0% and NMT 105.0% of the labeled amount of codeine sulfate [(C₁₈H₂₁NO₃)·H₂SO₄].

2 IDENTIFICATION

2.1 A. The retention time of the codeine peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

2.2 B. Thin-Layer Chromatography

Diluent: Methanol and water (25:75)

Standard solution: 1 mg/mL of USP Codeine Sulfate RS in Diluent

Sample solution: 1 mg/mL of codeine sulfate in Diluent

Chromatographic system

• Mode: TLC
• Adsorbent: 0.25-mm layer of chromatographic silica gel mixture
• Application volume: 10 µL
• Developing solvent system: Methanol, ethyl acetate, water, and ammonium hydroxide (135:85:1:0.5)

Analysis

Samples: Standard solution and Sample solution

Develop the plate until the solvent front has moved about three-fourths of the length of the plate, mark the front, and allow to evaporate. Place the plate in an iodine chamber and visualize for NLT 5 min.

Acceptance criteria: The principal spot from the Sample solution corresponds in R value to that from the Standard solution

3 ASSAY

3.1 Procedure

[Note-Solutions are stable for 4 days at room temperature when stored in amber glassware.]

Buffer: 0.02 M ammonium acetate. Dissolve 1.54 g of ammonium acetate in 1 L of water, and adjust with glacial acetic acid to a pH of 4.2 ± 0.1.

Solution A: Dissolve 1.71 g of sodium decanesulfonic acid in 1 L of methanol and Buffer mixture (33:67). Pass through a filter of 0.45-µm pore size.

Solution B: Dissolve 1.71 g of sodium decanesulfonic acid in 1 L of methanol and Buffer mixture (63:37). Pass through a filter of 0.45-µm pore size.

Mobile phase: See Table 1.

Diluent: Methanol and water (25:75)

Standard solution: 1.2 mg/mL of USP Codeine Sulfate RS in Diluent. Prepare by adding 70% of the flask volume of Diluent, and sonicate to dissolve. Dilute with Diluent to volume.

Sample solution: 1.2 mg/mL of codeine sulfate in Diluent, prepared by adding 70% of the flask volume of Diluent, then swirling, and letting it sit for 10 min. Dilute with Diluent to volume.

Chromatographic system

• (See Chromatography (621), System Suitability.)
• Mode: LC
• Detector: UV 280 nm
• Column: 4.6-mm × 15-cm; 3.5-µm packing L1
• Column temperature: 40 ± 2"
• Flow rate: 1.2 mL/min
• Injection volume: 30 µL

System suitability

• Sample: Standard solution
• Suitability requirements
• Tailing factor: NMT 2.0
• Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of codeine sulfate [(C₁₈H₂₁NO₃)·H₂SO₄] in each mL of Oral Solution taken:

Result = (r_u/r_s) × (C_s/C_u) × 100

r_u = peak response from the Sample solution

r_s= peak response from the Standard solution

C_s = concentration of USP Codeine Sulfate RS in the Standard solution (mg/mL)

C_u = nominal concentration of codeine sulfate in the Sample solution (mg/mL)

Acceptance criteria: 93.0%–105.0%

4 IMPURITIES

4.1 ORGANIC IMPURITIES

Buffer, Solution A, Solution B, Mobile phase, Diluent, Standard solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

Sensitivity solution: 0.6 µg/mL of USP Codeine Sulfate RS in Diluent from the Standard solution

System suitability

• Samples: Standard solution and Sensitivity solution
• Suitability requirements
• Relative standard deviation: NMT 2.0%, Standard solution
• Tailing factor: NMT 2.0, Standard solution
• Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each individual impurity in the portion of Oral Solution taken:

(r_u/r_s) × (C_s/C_u) × 100

r_u = response of each individual impurity from the Sample solution

r_s = response of codeine sulfate in the Standard solution

C_s = concentration of USP Codeine Sulfate RS in the Standard solution (mg/mL)

C_u = nominal concentration of codeine sulfate in the Sample solution (mg/mL)

Acceptance criteria

Individual impurities: See Table 2. Disregard any peak less than 0.05%.

a 7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol N-oxide.

b 7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-one.

5 SPECIFIC TESTS

MICROBIAL ENUMERATION TESTS (61) and TESTS FOR SPECIFIED MICROORGANISMS (62): The total aerobic microbial count does not exceed 102 cfu/mL. The total yeasts and molds count does not exceed 20 cfu/mL. It meets the requirements of the test for absence of Escherichia coli.

PH (791): 2.8-3.8

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Store at controlled room temperature in a well-sealed container.

USP REFERENCE STANDARDS (11)

USP Codeine Sulfate RS