Codeine Sulfate Tablets
DEFINITION
Codeine Sulfate Tablets contain NLT 93.0% and NMT 107.0% of the labeled amount of (C18H21NO3)2·H2SO4·3H2O.
IDENTIFICATION
•  A. Infrared Absorption 197K
Standard solution:  50 mg of USP Codeine Sulfate RS dissolved in 15 mL of water, then rendered alkaline with 6 N ammonium hydroxide and extracted with several 10-mL portions of chloroform, followed by evaporation of the combined chloroform extracts on a steam bath to dryness, drying at 80 for 4 h
Sample solution:  Digest an equivalent to 50 mg of codeine sulfate, from finely powdered Tablets, with 15 mL of water and 5 mL of 2 N sulfuric acid for 1 h. Filter, if necessary, and wash any undissolved residue with a few mL of water. Render the filtrate alkaline with 6 N ammonium hydroxide, extract with several small portions of chloroform, and evaporate the chloroform solution on a steam bath to dryness, drying at 80 for 4 h.
•  B. Identification Tests—General, Sulfate 191: A filtered solution of Tablets meets the requirements.
ASSAY
•  Procedure
Diluent:  0.5% of phosphoric acid (5 mL of concentrated phosphoric acid and 1000 mL of water)
Solution A:  Acetonitrile and 0.1% ammonium hydroxide (1.0 mL of concentrated ammonium hydroxide and 1000 mL of water) (1:19)
Solution B:  Acetonitrile and 0.1% ammonium hydroxide (9:11)
Mobile phase:  See the gradient table below.
Time
(min)
Solution A
(%)
Solution B
(%)
0 100 0
40 0 100
41 100 0
50 100 0
[Note—The Standard and Sample solutions, for the degradation products, are stable for 4 days when stored at room temperature in amber vials. ]
Standard solution:  1.2 mg/mL of USP Codeine Sulfate RS in Diluent
Sensitivity solution:  0.6 µg/mL of USP Codeine Sulfate RS from the Standard solution in Diluent
Sample solution:  1.2 mg/mL of codeine sulfate in Diluent. [Note—Dissolve 20 Tablets in 80% of the flask volume of Diluent, and sonicate for 15–30 min with occasional swirling before diluting with Diluent to volume. ]
Chromatographic system 
Mode:  LC
Detector:  UV 282 nm
Column:  4.6-mm × 15-cm; 3-µm packing L1
Column temperature:  40
Flow rate:  1.2 mL/min
Injection size:  40 µL
System suitability 
Samples:  Standard solution and Sensitivity solution
Suitability requirements 
Relative standard deviation:  NMT 2.0%, Standard solution
Tailing factor:  NMT 2.0, Standard solution
Column efficiency:  NLT 10,000 theoretical plates, Standard solution
Signal-to-noise ratio:  NLT 10, Sensitivity solution
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of (C18H21NO3)2·H2SO4·3H2O in the portion of Tablets taken:
Result = (rU/rS) × (CS/CU) × (Mr1/Mr2) × 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)
Mr1== molecular weight of codeine sulfate, trihydrate, 750.87
Mr2== molecular weight of codeine sulfate, anhydrous, 696.82
Acceptance criteria:  93.0%–107.0%
PERFORMANCE TESTS
•  Dissolution 711
Medium:  Water; 500 mL
Apparatus 2:  25 rpm
Time:  45 min
Detector:  UV, maxima at about 284 nm
Cell:  1 cm
Blank:  Medium
Standard solution:  USP Codeine Sulfate RS in Medium
Sample solution:  Pass a portion of the solution under test through a suitable filter of 0.8-µm pore size.
Tolerances:  NLT 75% (Q) of the labeled amount of (C18H21NO3)2·H2SO4·3H2O is dissolved.
•  Uniformity of Dosage Units 905
Procedure for content uniformity 
Standard solution:  110 µg/mL of USP Codeine Sulfate RS in 0.2 N sulfuric acid
Sample solution:  Transfer 1 Tablet to a 50-mL volumetric flask. Add 20 mL of 0.5 N sulfuric acid and 10 mL of water. Shake until the Tablet is disintegrated, and allow to stand for 16 h. Dilute with water to volume, and filter, discarding the first few mL of the filtrate. Dilute the resulting filtrate with 0.2 N sulfuric acid to obtain a solution containing nominally 120 µg/mL of codeine sulfate (trihydrate).
Spectrometric conditions 
Mode:  UV-Vis
Analytical wavelength:  About 284 nm
Cell:  1 cm
Blank:  0.2 N sulfuric acid
Analysis 
Samples:  Standard solution, Sample solution, and Blank
Calculate the percentage of (C18H21NO3)2·H2SO4·3H2O in the Tablet taken:
Result = (AU/AS) × (CS/CU) × (Mr1/Mr2) × 100
AU== absorbance of the Sample solution
AS== absorbance of the Standard solution
CS== concentration of USP Codeine Sulfate RS in the Standard solution (µg/mL)
CU== nominal concentration of codeine sulfate trihydrate in the Sample solution (µg/mL)
Mr1== molecular weight of codeine sulfate trihydrate, 750.87
Mr2== molecular weight of anhydrous codeine sulfate, 696.82
Acceptance criteria:  Meet the requirements
IMPURITIES
Organic Impurities 
•  Procedure
Diluent, Solution A, Solution B, Mobile phase, Standard solution, Sensitivity solution, Sample solution, Chromatographic system, and System suitability:  Proceed as directed in the Assay.
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of each individual impurity in the portion of Tablets 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 ImpurityTable 1)
Acceptance criteria 
Individual impurities:  See Impurity Table 1.
Total impurities:  NMT 0.5%
Impurity Table 1
Name Relative
Retention
Time
Relative
Response
Factor
Acceptance Criteria,
NMT (%)
Codeine-N-oxidea 0.39 1.25 0.2
Codeine sulfate 1.00
Codeinoneb 1.10 1.0 0.3
Individual
unspecified
degradant
0.2
a   7,8-Didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-ol
N-oxide.
b   7,8-Didehydro-4,5-epoxy-3-methoxy-17-methylmorphinan-6-one.
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in well-closed containers.
•  USP Reference Standards 11
USP Codeine Sulfate RS Click to View Structure
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
711 Margareth R.C. Marques, Ph.D.
Senior Scientific Liaison
1-301-816-8106
(GCDF2010) General Chapters - Dosage Forms
Reference Standards RS Technical Services
1-301-816-8129
rstech@usp.org
USP35–NF30 Page 2761
Pharmacopeial Forum: Volume No. 36(4) Page 911