Codeine Sulfate
(C18H21NO3)2·H2SO4·3H2O 750.85
(C18H21NO3)2·H2SO4 696.82
Morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-, (5
,6)-, sulfate (2:1) (salt), trihydrate;
7,8-Didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol sulfate (2:1) (salt) trihydrate
[6854-40-6].
Anhydrous[1420-53-7].
(koe' deen sul' fate).
(C18H21NO3)2·H2SO4·3H2O 750.85
(C18H21NO3)2·H2SO4 696.82
Morphinan-6-ol, 7,8-didehydro-4,5-epoxy-3-methoxy-17-methyl-, (5
,6)-, sulfate (2:1) (salt), trihydrate;
7,8-Didehydro-4,5
-epoxy-3-methoxy-17-methylmorphinan-6-ol sulfate (2:1) (salt) trihydrate
[6854-40-6].Anhydrous
[1420-53-7].DEFINITION
Codeine Sulfate, dried at 105
for 3 h, contains NLT 98.0% and NMT 102.0% of (C18H21NO3)2·H2SO4.
for 3 h, contains NLT 98.0% and NMT 102.0% of (C18H21NO3)2·H2SO4.IDENTIFICATION
• B. Ultraviolet Absorption 
197U
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
191:
Meets the requirements
ASSAY
• 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.
| Time (min) |
Solution A (%) |
Solution B (%) |
|---|---|---|
| 0 | 100 | 0 |
| 16 | 0 | 100 |
| 16.5 | 100 | 0 |
| 24 | 100 | 0 |
Standard solution:
1 mg/mL of USP Codeine Sulfate RS in Diluent
Sample solution:
1 mg/mL of Codeine Sulfate in Diluent
Chromatographic system
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 = (rU/rS) × (CS/CU) × 100
| rU | = | = peak area of codeine sulfate from the Sample solution |
| rS | = | = peak area of codeine sulfate from the Standard solution |
| CS | = | = concentration of USP Codeine Sulfate RS in the Standard solution (mg/mL) |
| CU | = | = concentration of Codeine Sulfate in the Sample solution (mg/mL) |
Acceptance criteria:
98.0%–102.0%
IMPURITIES
Inorganic Impurities
• Residue on Ignition 281:
NMT 0.1%
281:
NMT 0.1%
Organic Impurities
• 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 = (rU/rS) × (CS/CU) × (1/F) × 100
| rU | = | = peak response of each individual impurity from the Sample solution |
| rS | = | = peak response of codeine sulfate from the Standard solution |
| CS | = | = concentration of USP Codeine Sulfate RS in the Standard solution (mg/mL) |
| CU | = | = 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%.
Impurity Table 1
| Name | Relative Retention Time |
Relative Response Factor |
Acceptance Criteria NMT (%) |
|---|---|---|---|
| 10-Hydroxycodeinea | 0.81 | 1.35 | 0.15 |
| Codeine-N-oxideb | 0.90 | 1.0 | 0.15 |
| Codeine sulfate | 1.00 | — | — |
| Norcodeinec | 1.09 | 1.0 | 0.15 |
| Codeinoned | 1.16 | 1.0 | 0.15 |
| Codeine methyl ethere | 1.34 | 1.0 | 1.0 |
| Individual unspecified impurities |
— | — | 0.10 |
|
a
7,8-Didehydro-4,5
-epoxy-3-methoxy-17-methylmorphinan-6,10-diol.
b
7,8-Didehydro-4,5
-epoxy-3-methoxy-17-methylmorphinan-6-ol N-oxide.
c
7,8-Didehydro-4,5
-epoxy-3-methoxymorphinan-6-ol.
d
7,8-Didehydro-4,5
-epoxy-3-methoxy-17-methylmorphinan-6-one.
e
7,8-Didehydro-4,5
-epoxy-3,6-dimethoxy-17-methylmorphinan.
|
|||
• 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.
SPECIFIC TESTS
• Optical Rotation, Specific Rotation 781S
781S
Sample solution:
20 mg/mL, in water
Acceptance criteria:
112.5 to 115.0
112.5 to 115.0
• 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.
• Water Determination, Method III 921:
Dry 500 mg at 105 for 3 h: it loses between 6.0% and 7.5% of its weight.
921:
Dry 500 mg at 105 for 3 h: it loses between 6.0% and 7.5% of its weight.
• Readily Carbonizable Substances Test 271
271
Sample solution:
Dissolve 10 mg in 5 mL of sulfuric acid.
Acceptance criteria:
The solution has no more color than Matching Fluid S.
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight, light-resistant containers.
• USP Reference Standards 11
11
USP Codeine Sulfate RS 
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Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Clydewyn M. Anthony, Ph.D.
Senior Scientific Liaison 1-301-816-8139 |
(SM22010) Monographs - Small Molecules 2 |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP35–NF30 Page 2760
Pharmacopeial Forum: Volume No. 36(4) Page 909