Printed on: Wed Feb 08 2023, 11:25:37 PM(EST) Status: Currently Official on 09-Feb-2023 DocId: GUID-06F5F413-2E20-426D-B309-C1FD0C7148FB_4_en-US
Printed by: Dang Van Vu Official Date: Official as of 01-Dec-2022 Document Type: USP @2023 USPC
Do Not Distribute DOI Ref: gl84q DOI: https://doi.org/10.31003/USPNF_M19560_04_01
1
Table 1 (continued)
Codeine
Time Solution A Solution B
(min) (%) (%)
Change to read:
15 96 4
22 89 11
31 63 37
31.1 96 4
36 96 4
C18H21NO3 · H2O ▲
317.39▲ (USP 1-Dec-2022)
Morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-methoxy-17- Diluent: 0.5% (v/v) phosphoric acid in water
methyl-, monohydrate, (5α,6α)-; Standard solution: 4 mg/mL of USP Codeine Phosphate
7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan- RS in Diluent
6α-ol monohydrate CAS RN®: 6059-47-8; UNII: Sample solution: 3 mg/mL of Codeine in Diluent
Q830PW7520. Chromatographic system
Anhydrous 299.37 (See Chromatography á621ñ, System Suitability.)
CAS RN®: 76-57-3; UNII: UX6OWY2V7J. Mode: LC
Detector: UV 280 nm
Change to read: Column: 4.6-mm × 15-cm; 3-µm packing L1
Column temperature: 37°
DEFINITION Flow rate: 1.88 mL/min
al
Codeine, dried at 80° for 4 h, contains NLT Injection volume: 10 µL
▲
98.0%▲ (USP 1-Dec-2022) and NMT ▲102.0%▲ (USP 1-Dec-2022) of System suitability
codeine (C18H21NO3). Sample: Standard solution
IDENTIFICATION Suitability requirements
Tailing factor: 1.5–5.0
Change to read:
• A. SPECTROSCOPIC IDENTIFICATION TESTS á197ñ, Infrared
Spectroscopy: 197K ▲or 197A▲ (USP 1-Dec-2022)
ci Relative standard deviation: NMT 0.73%
Analysis
Samples: Standard solution and Sample solution
Calculate the percentage of codeine (C18H21NO3) in the
Standard: ▲Dissolve about 33 mg of USP Codeine portion of Codeine taken:
ffi
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 Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 100
hydroxide solution and water (50:50). Scratch the wall of
the tube with a glass rod to initiate crystallization. Cool the rU = peak response of codeine from the Sample
solution in an ice bath to obtain the crystal. [NOTE—It is solution
recommended to cool the solution for 2-3 h.] Wash the rS = peak response of codeine from the Standard
O
crystal with water and dry at 105° for 1 h.▲ (USP 1-Dec-2022) solution
Sample: ▲For codeine anhydrous, use as is; for codeine CS = concentration of USP Codeine Phosphate RS in
monohydrate, dry at 105° for 1 h.▲ (USP 1-Dec-2022) the Standard solution (mg/mL)
Acceptance criteria: Meets the requirements CU = concentration of Codeine in the Sample solution
(mg/mL)
Delete the following: Mr1 = molecular weight of codeine, 299.37
Mr2 = molecular weight of codeine phosphate,
• B. ▲SPECTROSCOPIC IDENTIFICATION TESTS á197ñ, 397.36▲ (USP 1-Dec-2022)
Ultraviolet-Visible Spectroscopy▲ (USP 1-Dec-2022)
Acceptance criteria: ▲98.0%–102.0%▲ (USP 1-Dec-2022) on the
Add the following: previously dried basis
▲
• B. The retention time of the major peak of the Sample IMPURITIES
solution corresponds to that of the Standard solution, as • RESIDUE ON IGNITION á281ñ: NMT 0.1%
obtained in the Assay.▲ (USP 1-Dec-2022)
Change to read:
ASSAY
• ORGANIC IMPURITIES
Change to read: ▲
Solution A, Solution B, Mobile phase, Diluent, Standard
• PROCEDURE solution, Sample solution, and Chromatographic
▲
Solution A: Glacial acetic acid and water (2:98). Adjust system: Proceed as directed in the Assay.
with 50% (w/v) sodium hydroxide solution to a pH of 4.5. System suitability solution: 4 mg/mL of USP Codeine
Solution B: Acetonitrile System Suitability Mixture RS in Diluent
Mobile phase: See Table 1. Sensitivity solution: 2 μg/mL of USP Codeine Phosphate RS
in Diluent
Table 1 System suitability
Samples: Standard solution, System suitability solution, and
Time Solution A Solution B Sensitivity solution
(min) (%) (%)
Suitability requirements
0 96 4 Resolution: NLT 1.5 between norcodeine and codeine,
System suitability solution
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Printed on: Wed Feb 08 2023, 11:25:37 PM(EST) Status: Currently Official on 09-Feb-2023 DocId: GUID-06F5F413-2E20-426D-B309-C1FD0C7148FB_4_en-US
Printed by: Dang Van Vu Official Date: Official as of 01-Dec-2022 Document Type: USP @2023 USPC
Do Not Distribute DOI Ref: gl84q DOI: https://doi.org/10.31003/USPNF_M19560_04_01
2
Relative standard deviation: NMT 0.73%, Standard a 7,8-Didehydro-4,5α-epoxy-3-methoxy-17-methylmorphinan-6α, 10-diol.
solution 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′-
Signal-to-noise ratio: NLT 10, Sensitivity solution
Analysis 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.
Sample: Sample solution e 4,5α-Epoxy-3,6-dimethoxy-17-methylmorphinan-6,8-diene.
Calculate the percentage of each impurity in the portion of ▲ (USP 1-Dec-2022)
Codeine taken:
Delete the following:
Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × (1/F) × 100 ▲
• LIMIT OF MORPHINE▲ (USP 1-Dec-2022)
rU = peak response of any impurity from the Sample SPECIFIC TESTS
solution
rS = peak response of codeine from the Standard Delete the following:
solution
CS = concentration of USP Codeine Phosphate RS in ▲
• MELTING RANGE OR TEMPERATURE á741ñ▲ (USP 1-Dec-2022)
the Standard solution (mg/mL) • LOSS ON DRYING á731ñ
CU = concentration of Codeine in the Sample solution Analysis: Dry at 80° for 4 h.
(mg/mL) Acceptance criteria: NMT 6.0%
Mr1 = molecular weight of codeine, 299.37
Mr2 = molecular weight of codeine phosphate, 397.36 Delete the following:
F = relative response factor (see Table 2) ▲
• READILY CARBONIZABLE SUBSTANCES TEST
Acceptance criteria: See Table 2. The reporting threshold is á271ñ▲ (USP 1-Dec-2022)
al
0.05%. ADDITIONAL REQUIREMENTS
• PACKAGING AND STORAGE: Preserve in tight, light-resistant
Table 2 containers.
Relative Relative Acceptance
Retention Response Criteria,
Morphine
Name Time
0.25
Factor
0.98
ci
NMT (%)
0.15
Change to read:
• USP REFERENCE STANDARDS á11ñ
▲
USP Codeine Phosphate RS
10-Hydroxyco-
deinea 0.40 1.12 0.15
USP Codeine System Suitability Mixture RS
Contains a mixture of the following five compounds:
ffi
14-Hydroxyco- Codeine phosphate.
deineb 0.78 0.87 0.15 Morphine: 7,8-Didehydro-4,5α-epoxy-17-
Norcodeine 0.88 0.98 0.15 methylmorphinan-3,6α-diol.
C17H19NO3 285.34
Codeine 1.00 1.00 —
Codeine N-oxide: 7,8-Didehydro-4,5α-epoxy-3-methoxy-
Codeine N-oxide 1.12 0.86 0.15 17-methylmorphinan-6α-ol N-oxide.
O
C18H21NO4 315.37
2,2′-Biscodeinec 1.15 1.42 0.15
Norcodeine: 7,8-Didehydro-4,5α-epoxy-3-
Codeinoned 1.37 0.66 0.15 methoxymorphinan-6α-ol.
Codeine methyl
C17H19NO3 285.34
ether 1.46 0.95 0.15 Codeine methyl ether: 7,8-Didehydro-4,5α-epoxy-3,6α-
dimethoxy-17-methylmorphinan.
Thebainee 1.60 4.78 0.15 C19H23NO3 313.39▲ (USP 1-Dec-2022)
Any unspecified
—
impurity 1.00 0.10
Total impurities — — 1.0
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