Morphine Sulfate Extended-Release Capsules
DEFINITION
Morphine Sulfate Extended-Release Capsules contain NLT 90.0% and NMT 110.0% of the labeled amount of morphine sulfate pentahydrate [(C17H19NO3)2·H2SO4·5H2O].
IDENTIFICATION
•  B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.
ASSAY
•  Procedure
Diluent:  Water. Adjust with phosphoric acid to a pH of 3.6.
Buffer solution:  13.8 mg/mL of monobasic sodium phosphate
Solution A:  Acetonitrile, triethylamine, Buffer solution, and water (25: 0.5: 100: 874.5). Adjust with phosphoric acid to a pH of 3.6.
Solution B:  Acetonitrile
Mobile phase:  See the gradient table below.
Time
(min)
Solution A
(%)
Solution B
(%)
0 100 0
33 100 0
44 85 15
54 85 15
55 100 0
65 100 0
System suitability solution:  400 µg/mL of USP Morphine Sulfate RS, 10 µg/mL of USP Morphine Related Compound A RS, and 10 µg/mL of USP Morphine Related Compound B RS (pseudomorphine) in Diluent
Standard solution:  1.0 mg/mL of USP Morphine Sulfate RS in Diluent
Sample stock solution:  Transfer a weighed portion of the contents from NLT 20 Capsules, equivalent to 250 mg of morphine sulfate, to a 100-mL volumetric flask. Add 5 mL of methanol, and mix well for 30 min with gentle swirling every 5 min. Add Diluent up to half of the flask volume, and sonicate for 5 min to dissolve. Dilute with Diluent to volume.
Sample solution:  1.0 mg/mL of morphine sulfate from Sample stock solution in Diluent. Pass through a suitable filter, and use the clear filtrate.
Chromatographic system  
Mode:  LC
Detector:  UV 245 nm
Guard column:  Packing L1
Column:  3.9-mm × 30-cm; 10-µm packing L1
Flow rate:  2 mL/min
Injection size:  40 µL
System suitability 
Samples:  System suitability solution and Standard solution
Suitability requirements 
Resolution:  NLT 2.0 between the morphine related compound A and morphine sulfate peaks, System suitability solution
Relative standard deviation:  NMT 2.0%, Standard solution
Analysis 
Samples:  Standard solution and Sample solution
Calculate the percentage of (C17H19NO3)2·H2SO4·5H2O in the portion of Capsules taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== concentration of USP Morphine Sulfate RS in the Standard solution (mg/mL)
CU== nominal concentration of the Sample solution (mg/mL)
Acceptance criteria:  90.0%–110.0%
PERFORMANCE TESTS
Change to read:
•  Dissolution 711
pH 7.5 phosphate buffer:  6.8 mg/mL of monobasic potassium phosphate and 1.6 mg/mL of sodium hydroxide. Adjust with phosphoric acid or 2 N sodium hydroxide to a pH of 7.5.
Medium:  Proceed as directed for Procedure for Method B under Apparatus 1 and Apparatus 2, Delayed-Release Dosage Forms, observing the following exceptions. Perform Acid Stage testing, using 500 mL of 0.1 N hydrochloric acid for 1 h; and perform Buffer Stage testing, using 500 mL of pH 7.5 phosphate buffer for NLT 8 h.
Apparatus 1:  100 rpm
Times:  1, 4, 6, and 9 h
Determine the amount of (C17H19NO3)2·H2SO4·5H2O dissolved by using the following method.
Mobile phase:  Methanol, glacial acetic acid, and water (280:10:720),USP35 containing 0.73 g of sodium 1-heptanesulfonate for each 1.01 L of the solvent mixtureUSP35
System suitability solution:  0.1 mg/mL each of phenol and USP Morphine Sulfate RS in Mobile phase
Standard solution:  USP Morphine Sulfate RS in pH 7.5 phosphate buffer to obtain a solution having a known concentration corresponding to that of the Sample solution
Sample solution:  Sample per Dissolution 711.
Chromatographic system  
Mode:  LC
Detector:  UV 284 nm
Column:  3.9-mm × 30-cm; 10-µm packing L1
Flow rate:  2 mL/min
Injection size:  25 µL
System suitability 
Sample:  System suitability solution
[Note—The relative retention times for phenol and morphine sulfate are about 0.8 and 1.0, respectively. ]
Suitability requirements 
Resolution:  NLT 2.0 between the phenol and morphine sulfate peaks
Tailing factor:  NMT 2.0 for the morphine sulfate peak
Relative standard deviation:  NMT 2.0%
Analysis 
Samples:  Standard solution and Sample solution
Tolerances:  The percentage of the labeled amount of (C17H19NO3)2·H2SO4·5H2O dissolved in 1 h conforms to Dissolution 711, Extended-Release Dosage Forms, Acceptance Table 3. The percentages of the labeled amount of (C17H19NO3)2·H2SO4·5H2O dissolved at the other times specified conform to Dissolution 711, Extended-Release Dosage Forms, Acceptance Table 2.
Time
(h)
Amount Dissolved
1 NMT 10%
4 25%–50%
6 50%–90%
9 NLT 85%
•  Uniformity of Dosage Units 905: Meet the requirements
IMPURITIES
Organic Impurities 
•  Procedure
Diluent, Solution A, System suitability solution, Standard solution, Chromatographic system, and Sample solution:  Proceed as directed in the Assay.
Sensitivity solution:  0.5 µg/mL of USP Morphine Sulfate RS in Diluent
System suitability 
Samples:  System suitability solution, Standard solution, and Sensitivity solution
Suitability requirements 
Resolution:  NLT 2.0 between the morphine related compound A and morphine sulfate peaks, System suitability solution
Sensitivity:  Morphine peak is detectable, Sensitivity solution
Relative standard deviation:  NMT 2.0%, Standard solution
Analysis 
Samples:  Diluent and Sample solution [Note—Disregard the peaks corresponding to those obtained in the chromatogram of the Diluent. ]
Calculate the percentage of each impurity in the portion of Capsules taken:
Result = (rU/rS) × (1/F) × 100
rU== peak response for each impurity from the Sample solution
rS== peak response for morphine sulfate from the Standard solution
F== relative response factor from Impurity Table 1
Acceptance criteria 
Any individual impurity:  See Impurity Table 1.
Total impurities:  NMT 1.5%
Impurity Table 1
Name Relative
Retention
Time
Relative
Response
Factor
Acceptance Criteria,
NMT (%)
Morphine related compound Aa 1.4 1.0 0.5
Morphine sulfate 1.0
Morphine related compound Bb 2.3 2.1 0.5
Any unspecified impurity 0.2
a  7,8-Didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol, N-oxide.
b  2,2'-Bimorphine.
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight, light-resistant containers, and store at controlled room temperature.
•  USP Reference Standards 11
USP Morphine Related Compound A RS
7,8-Didehydro-4,5-epoxy-17-methylmorphinan-3,6-diol, N-oxide.
    C17H19NO4        301.34
USP Morphine Related Compound B RS
2,2¢-Bimorphine.
    C34H36N2O6        568.66
USP Morphine 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
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USP35–NF30 Page 3955
Pharmacopeial Forum: Volume No. 36(2) Page 422