Codeine Sulfate 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

Codeine Sulfate Tablets contain NLT 93.0% and NMT 107.0% of the labeled amount of codeine sulfate trihydrate [(C₁₈H₂₁NO₃)₂· H₂SO₄ · 3H₂O].

2 IDENTIFICATION

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

2.2 B.

Standard solution and Sample solution: Proceed as directed in the Assay.

Analysis: Inject 2 µL each of the Standard solution and the Sample solution using the Chromatographic system in the Assay.

Acceptance criteria: The spectrum of the codeine peak of the Sample solution exhibits maxima and minima at the same wavelengths as those of the corresponding peaks of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 Procedure

Solution A: Acetonitrile and 0.1% ammonium hydroxide (1.0 mL of concentrated ammonium hydroxide and 1000 mL of water) (1:19)

Solution B: Acetonitrile and 0.1% ammonium hydroxide (9:11)

Mobile phase: See Table 1.

[Note-The Standard solution and Sample solution, for the degradation products, are stable for 4 days when stored at room temperature in amber vials.]

Diluent: 0.5% phosphoric acid (5 mL of concentrated phosphoric acid and 1000 mL of water)

Standard solution: 1.2 mg/mL of USP Codeine Sulfate RS in Diluent

Sample solution: Nominally 1.2 mg/mL of codeine sulfate trihydrate in Diluent. Dissolve 20 Tablets in 80% of the flask volume of Diluent and sonicate for 15–30 min with occasional swirling before diluting with Diluent to volume.

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 282 nm. For Identification test B, use a diode-array detector in the range of 210–400 nm.
• Column: 4.6-mm × 15-cm; 3-µm packing L1
• Column temperature: 40°
• Flow rate: 1.2 mL/min
• Injection volume: 40 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 the labeled amount of codeine sulfate trihydrate [(C₁₈H₂₁NO₃)₂· H₂SO₄ · 3H₂O] in the portion of Tablets taken:

Result = (r_u/r_s) × (C_s/C_u) × (M_r1/M_r2) × 100

r_u = peak area of codeine sulfate from the Sample solution

r_s = peak area of codeine sulfate 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 trihydrate in the Sample solution (mg/mL)

M_r1 = molecular weight of codeine sulfate trihydrate, 750.85

M_r2 = molecular weight of codeine sulfate, anhydrous, 696.81

Acceptance criteria: 93.0%–107.0%

4 PERFORMANCE TESTS

4.1 Dissolution 〈711〉

Medium: Water; 500 mL

Apparatus 2: 25 rpm

Time: 45 min

Detector: UV maxima at about 284 nm

Cell: 1 cm

Blank: Medium

Standard solution: USP Codeine Sulfate RS in Medium

Sample solution: Pass a portion of the solution under test through a suitable filter of 0.8-µm pore size.

Tolerances: NLT 75% (Q) of the labeled amount of codeine sulfate trihydrate [(C₁₈H₂₁NO₃)₂· H₂SO₄ · 3H₂O] is dissolved.

4.2 Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

5.1 Organic Impurities

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 from the Standard solution in Diluent

System suitability

• Samples: Standard solution and Sensitivity solution
• Suitability requirements
• Tailing factor: NMT 2.0, Standard solution
• Relative standard deviation: 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 Tablets taken:

Result = (r_u/r_s) × (C_s/C_u) × (1/F) × 100

r_u = peak response of each individual impurity from the Sample solution

r_s = peak response of codeine sulfate 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 trihydrate in the Sample solution (mg/mL)

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. Disregard any impurity 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.

6 ADDITIONAL REQUIREMENTS

6.1 Packaging and Storage

Preserve in well-closed containers. Store at controlled room temperature. Protect from moisture and light.

6.2 USP Reference Standards 〈11〉

USP Codeine Sulfate RS