Codeine Phosphate

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·H₃PO₄·½H₂O 406.37

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

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

CAS RN®: 41444-62-6

Anhydrous CAS RN®: 52-28-8

1 DEFINITION

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Codeine Phosphate contains NLT 98.0% and NMT 102.0% of codeine phosphate (C₁₈H₂₁NO₃·H₃PO₄), calculated on the anhydrous basis.

2 IDENTIFICATION

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

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

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C.

Analysis: Neutralize 20 mg/mL of Codeine Phosphate in water with 6 N ammonium hydroxide and add silver nitrate TS.

Acceptance criteria: A yellow precipitate of silver phosphate is formed, and it is soluble in 2 N nitric acid and 6 N ammonium hydroxide.

3 ASSAY

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3.1 Procedure

Solution A: 2% acetic acid in water. 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: 4 mg/mL of Codeine Phosphate in Diluent

Chromatographic system

(See Chromatography (621), System Suitability.)

• Mode: LC
• Detector: UV 280 nm
• Column: 4.6-mm × 15-cm; 3.0-µm packing L1
• Column temperature: 37°C
• Flow rate: 1.88 mL/min
• Injection volume: 10 µL

System suitability

• Sample: Standard solution
• Suitability requirements
• Tailing factor: 0.8-3.0
• Relative standard deviation: NMT 0.73%

Analysis

Calculate the percentage of codeine phosphate (C₁₈H₂₁NO₃·H₃PO₄) in the portion of Codeine Phosphate taken:

Result = (r_u/r_s) × (C_s/C_u) × 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 Phosphate in the Sample solution (mg/mL)

Acceptance criteria: 98.0%-102.0% on the anhydrous basis

4 IMPURITIES

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4.1 LIMIT OF MORPHINE

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

Acceptance criteria: No blue color is produced immediately 

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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.

Sensitivity solution: 0.002 mg/mL of USP Codeine Phosphate RS in Diluent

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

System suitability

• Samples: Standard solution, Sensitivity solution, and System suitability 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 Phosphate taken:

Result = (r_u/r_T) × (1/F) × 100

r_u = peak response of each impurity from the Sample solution

r_T = peak response of codeine from the Sample solution

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 7,7′,8,8′-Tetradehydro-4,5α:4′,5′α-diepoxy-3,3′-dimethoxy-17,17′-dimethyl-2,2′-bimorphinanyl-6α,6′α-diol.

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

e 6,7,8,14-Tetradehydro-4,5α-epoxy-3,6-dimethoxy-17-methylmorphinan.

5 SPECIFIC TESTS

5.1 Acidity

Sample: 100 mg of Codeine Phosphate

Titrant: 0.010 N sodium hydroxide

Analysis: Dissolve the Sample in 20 mL of water, and titrate with Titrant to a pH of 5.4, using a pH meter.

Acceptance criteria: NMT 1.0 mL of Titrant is required.

5.2 Water Determination 〈921〉, Method I: NMT 3.0%

5.3 Chloride

Sample solution: 10 mg/mL of Codeine Phosphate in water

Analysis: Acidify 10 mL of Sample solution with nitric acid and add a few drops of silver nitrate TS.

Acceptance criteria: No opalescence is produced immediately.

5.4 Sulfate

Sample solution: 10 mg/mL of Codeine Phosphate in water

Analysis: To 10 mL of the Sample solution add a few drops of barium chloride TS.

Acceptance criteria: No turbidity is produced immediately.

6 ADDITIONAL REQUIREMENTS

6.1 Packaging and Storage

Preserve in tight, light-resistant containers. Store up to 40°C as permitted by the manufacturer.

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6.2 USP Reference Standards 〈11〉

USP Codeine Phosphate RS

USP Codeine System Suitability Mixture RS (contains codeine phosphate hemihydrate, morphine, codeine N-oxide, norcodeine, and codeine methyl ether).

It contains codeine phosphate hemihydrate, morphine, codeine N-oxide, norcodeine, and codeine methyl ether.

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   315.36

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