Codeine

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 · H₂O     317.39

Morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-, monohydrate, (5α,6α)-;

7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α-ol monohydrate   CAS RN®: 6059-47-8; UNII: Q830PW7520.

Anhydrous 299.37  CAS RN®: 76-57-3; UNII: UX6OWY2V7J.

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1 DEFINITION

Codeine, dried at 80° for 4 h, contains NLT 98.0% and NMT 102.0% of codeine (C₁₈H₂₁NO₃).

2 IDENTIFICATION

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

Standard: Dissolve about 33 mg of USP Codeine Phosphate RS in about 0.5 mL of water in a suitable glass tube. Add about 0.6 mL of a mixture of 50% (w/v) sodium hydroxide solution and water (50:50). Scratch the wall of the tube with a glass rod to initiate crystallization. Cool the solution in an ice bath to obtain the crystal. [Note-It is recommended to cool the solution for 2-3 h.] Wash the crystal with water and dry at 105° for 1 h.

Sample: For codeine anhydrous, use as is; for codeine monohydrate, dry at 105° for 1 h.

Acceptance criteria: Meets the requirements

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

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

3 ASSAY

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3.1 Procedure

Solution A: Glacial acetic acid and water (2:98). Adjust with 50% (w/v) sodium hydroxide solution to a pH of 4.5.

Solution B: Acetonitrile

Mobile phase: See Table 1.

Diluent: 0.5% (v/v) phosphoric acid in water

Standard solution: 4 mg/mL of USP Codeine Phosphate RS in Diluent

Sample solution: 3 mg/mL of Codeine in Diluent

Chromatographic system

• (See Chromatography 〈621〉, System Suitability.)
• Mode: LC
• Detector: UV 280 nm
• Column: 4.6-mm × 15-cm; 3-µm packing L1
• Column temperature: 37°
• Flow rate: 1.88 mL/min
• Injection volume: 10 µL

System suitability

• Sample: Standard solution
• Suitability requirements
• Tailing factor: 1.5–5.0
• Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of codeine (C₁₈H₂₁NO₃) in the portion of Codeine taken:

Result = (r_u/r_s) × (C_s/C_u) × (M_r1/M_r2) × 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 = concentration of Codeine in the Sample solution (mg/mL)

M_r1 = molecular weight of codeine, 299.37

M_r2 = molecular weight of codeine phosphate, 397.36

Acceptance criteria: 98.0%–102.0% on the previously dried basis

4 IMPURITIES

4.1 Residue on Ignition 〈281〉: NMT 0.1%

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4.2 Organic Impurities

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

System suitability solution: 4 mg/mL of USP Codeine System Suitability Mixture RS in Diluent

Sensitivity solution: 2 μg/mL of USP Codeine Phosphate RS in Diluent

System suitability

• Samples: Standard solution, System suitability solution, and Sensitivity solution
• Suitability requirements:
• Resolution: NLT 1.5 between norcodeine and codeine, System suitability solution
• Relative standard deviation: NMT 0.73%, Standard solution
• Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Sample: Sample solution

Calculate the percentage of each impurity in the portion of Codeine taken:

Result = (r_u/r_s) × (C_s/C_u) × (M_r1/M_r2)  × (1/F) × 100

r_u = peak response of any impurity 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 = concentration of Codeine in the Sample solution (mg/mL)

M_r1 = molecular weight of codeine, 299.37

M_r2 = molecular weight of codeine phosphate, 397.36

F = relative response factor (see Table 2)

Acceptance criteria: See Table 2. The reporting threshold is 0.05%.

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,14-diol.

ᶜ Also known as codeine dimer. 4,5α:4′,5′α-Diepoxy-3,3′-dimethoxy-17,17′-dimethyl-7,7′,8,8′-tetradehydro-2,2′-bimorphinan-6α,6′α-diol.

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

ᵉ 4,5α-Epoxy-3,6α-dimethoxy-17-methylmorphinan-6,8-diene.

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4.3 Limit of Morphine

5 SPECIFIC TESTS

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Melting Range or Temperature 〈741〉

Loss on Drying 〈731〉

• Analysis: Dry at 80° for 4 h.
• Acceptance criteria: NMT 6.0%

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Readily Carbonizable Substances Test 〈271〉

6 ADDITIONAL REQUIREMENTS

6.1 Packaging and Storage

Preserve in tight, light-resistant containers.

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6.2 USP Reference Standards 〈11〉

USP Codeine Phosphate RS

USP Codeine System Suitability Mixture RS

Contains a mixture of the following five compounds:

Codeine phosphate.

Morphine: 7,8-Didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol.

C₁₇H₁₉NO₃   285.34

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

C₁₈H₂₁NO₄   315.37

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

C₁₇H₁₉NO₃   285.34

Codeine methyl ether: 7,8-Didehydro-4,5α-epoxy-3,6α-dimethoxy-17-methylmorphinan.

C₁₉H₂₃NO₃   313.39