Codeine Sulfate

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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(C₁₈H₂₁NO₃)₂· H₂SO₄ · 3H₂O    750.85

(C₁₈H₂₁NO₃)₂· H₂SO₄      696.82

Morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-, (5α,6α)-, sulfate (2:1) (salt), trihydrate;

7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol sulfate (2:1) (salt) trihydrate

CAS RN®: 6854-40-6; UNII: 11QV9BS0CB.

Anhydrous CAS RN®: 1420-53-7; UNII: AVW5HY4N2E.

1 DEFINITION

Codeine Sulfate, dried at 105° for 3 h, contains NLT 98.0% and NMT 102.0% of (C₁₈H₂₁NO₃)₂· H₂SO₄.

2 IDENTIFICATION

Change to read:

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197K

Change to read:

B. Spectroscopic Identification Tests 〈197〉, Ultraviolet-Visible Spectroscopy: 197U

• Sample solution: 100 µg/mL in water
• Acceptance criteria: Absorptivities at 284 nm do not differ by more than 3.0%, calculated on the dried basis.

C. Identification Tests-General, Sulfate 〈191〉: Meets the requirements

3 ASSAY

3.1 Procedure

Buffer: Dissolve 4.0 g of potassium phosphate monobasic in 2000 mL of water, and adjust with phosphoric acid to a pH of 3.0 ± 0.1.

Solution A: 5 mM sodium heptane sulfonate in methanol and Buffer (3:7). [Note-Dissolve 1.0 g sodium heptane sulfonate for each L of Mobile phase produced, and filter.]

Solution B: 5 mM sodium heptane sulfonate in methanol and Buffer (11:9). [Note-Dissolve 1.0 g sodium heptane sulfonate for each L of Mobile phase produced, and filter.]

Diluent: Solution A

Mobile phase: See the gradient table below.

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

Sample solution: 1 mg/mL of Codeine Sulfate in Diluent

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 280 nm
• Column: 4.6-mm × 25-cm; 5-µm packing L1
• Column temperature: 40°
• Flow rate: 1.0 mL/min
• Injection size: 20 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)₂· H₂SO₄] in the portion of Codeine Sulfate taken:

Result = (r_u/r_s) × (C_s/C_u)× 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 = concentration of Codeine Sulfate in the Sample solution (mg/mL)

Acceptance criteria: 98.0%–102.0%

4 IMPURITIES

4.1 Inorganic Impurities

Residue on Ignition 〈281〉: NMT 0.1%

4.2 Organic Impurities

4.2.1 Procedure 1

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

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

Standard solution: 0.01 mg/mL of USP Codeine Sulfate RS in Diluent from Standard stock solution

Sensitivity solution: 0.5 µg/mL of USP Codeine Sulfate RS in Diluent from Standard stock solution

Sample solution: 1 mg/mL of Codeine Sulfate in Diluent

System suitability

• Samples: Standard solution and Sensitivity solution
• Suitability requirements:
• Tailing factor: NLT 0.5 and NMT 1.5, Standard solution
• Relative standard deviation: NMT 5.0%, 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 Codeine Sulfate 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 = concentration of Codeine Sulfate in the Sample solution (mg/mL)

F = relative response factor of the related compounds (see Impurity Table 1)

Acceptance criteria

Individual impurities: See Impurity Table 1.

Total impurities: NMT 1.5%.

ᵃ 7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α,10-diol.

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

ᶜ 7,8-Didehydro-4,5α-epoxy-3-methoxymorphinan-6α-ol.

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

ᵉ 7,8-Didehydro-4,5α-epoxy-3,6α-dimethoxy-17-methylmorphinan.

4.3 Procedure 2: Limit of Morphine

Analysis: Dissolve 50 mg of potassium ferricyanide in 10 mL of water, and add 1 drop of ferric chloride TS and 1 mL of a 10 mg/mL solution of Codeine Sulfate.

Acceptance criteria: No blue color is produced immediately.

5 SPECIFIC TESTS

5.1 Optical Rotation, Specific Rotation 〈781S〉

Sample solution: 20 mg/mL, in water

Acceptance criteria: −112.5° to −115.0°

5.2 Acidity

Analysis: Dissolve 500 mg in 15 mL of water, add 1 drop of methyl red TS, and titrate with 0.020 N sodium hydroxide.

Acceptance criteria: NMT 0.30 mL is required for neutralization.

5.3 Water Determination, Method III 〈921〉

Dry 500 mg at 105° for 3 h: it loses between 6.0% and 7.5% of its weight.

5.4 Readily Carbonizable Substances Test 〈271〉

Sample solution: Dissolve 10 mg in 5 mL of sulfuric acid.

Acceptance criteria: The solution has no more color than Matching Fluid S.

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers.

USP Reference Standards 〈11〉

USP Codeine Sulfate RS