Morphine Sulfate

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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(C₁₇H₁₉NO₃)₂ · H₂SO₄ · 5H₂O      758.83

^▲(C₁₇H₁₉NO₃)₂ · H₂SO_{4▲(USP 1-Dec-2023)}          ^▲668.76 _{▲(USP 1-Dec-2023)}

Morphinan-3,6-diol, 7,8-didehydro-4,5-epoxy-17-methyl, (5α,6α), sulfate (2:1) (salt), pentahydrate;

7,8-Didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol sulfate (2:1) (salt), pentahydrate CAS RN^®: 6211-15-0; UNII: X3P646A2J0.

Anhydrous CAS RN^®: 64-31-3; UNII: DY70C97N30.

1 DEFINITION

Morphine Sulfate contains NLT 98.0% and NMT 102.0% of morphine sulfate (C₁₇H₁₉NO₃)₂ · H₂SO₄, calculated on the anhydrous basis.

2 IDENTIFICATION

Change to read:

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K^▲ or 197A

Standard: Dry USP Morphine Sulfate RS at 145° for 1 h.

Sample: Dry Morphine Sulfate at 145° for 1 h.

Acceptance criteria: Meets the requirements _{▲(USP 1-Dec-2023)}

Change to read:

B. ^▲The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay _{▲(USP 1-Dec-2023)}

Delete the following:

^▲C._{▲(USP 1-Dec-2023)}

Change to read:

^▲C_{▲(USP 1-Dec-2023)} IDENTIFICATION TESTS GENERAL (191), Chemical Identification Tests, Sulfate

Sample solution: 20 mg/mL of Morphine Sulfate

Acceptance criteria: Meets the requirements

3 ASSAY

Change to read:

PROCEDURE

Mobile phase: Dissolve 0.73 g of sodium 1-heptanesulfonate in 720 ml of water, and add 280 mL of methanol and 10 ml of glacial acetic acid.

System suitability solution: 0.24 mg/mL of USP Morphine Sulfate RS and 0.15 mg/mL of phenol in Mobile phase

Standard solution: 0.24 mg/mL of USP Morphine Sulfate RS in Mobile phase. Prepare a fresh solution daily.

Sample solution: 0.24 mg/mL of Morphine Sulfate in Mobile phase

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 284 nm

Column: 3.9-mm x 30-cm; ^▲10-µm _{▲(USP 1-Dec-2023)} Packing L1

Flow rate: 1.5 mL/min

Injection volume: 25 µL

System suitability

Samples: System suitability solution and Standard solution

[NOTE-The relative retention times for phenol and morphine ^▲_{▲(USP 1-Dec-2023)} are about 0.7 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 2.0 between phenol and morphine ^▲_{▲(USP 1-Dec-2023)} System suitability solution

Tailing factor: NMT 2.0, ^▲Standard solution_{▲(USP 1-Dec-2023)}

Relative standard deviation: NMT ^▲0.73%_{▲(USP 1-Dec-2023)} Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of morphine sulfate (C₁₇H₁₉NO₃)₂ · H₂SO₄ in the portion of Morphine Sulfate taken:

                         Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of morphine from the Sample solution

r_S = peak response of morphine from the Standard solution

C_S = concentration of anhydrous morphine sulfate in the Standard solution (mg/mL), as determined from the concentration of USP Morphine Sulfate RS corrected for moisture content by a titrimetric water determination

C_U = concentration of Morphine Sulfate in the Sample solution (mg/mL)

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

4 IMPURITIES

4.1 RESIDUE ON IGNITION (281)

Sample: 500 mg of Morphine Sulfate

Acceptance criteria: NMT 0.1%

4.2 CHLORIDE

Sample solution: 10 mg/mL of Morphine Sulfate in water

Analysis: To 10 mL of Sample solution, add 1 mL of 2N nitric acid and 1 mL of silver nitrate TS.

Acceptance criteria: No precipitate or turbidity is produced immediately.

Acceptance criteria: No precipitate or turbidity is produced immediately.

4.3 LIMIT OF FOREIGN ALKALOIDS

Sample solution: Dissolve 1.00 g of Morphine Sulfate in 10 mL of 1 N sodium hydroxide in a separator.

Analysis: Shake the Sample solution, with three successive portions of 15, 10, and 10 mL of chloroform, passing the chloroform solutions through a small filter previously moistened with chloroform. Shake the combined chloroform solutions with 5 mL of water, separate the chloroform layer, and carefully evaporate on a steam bath to dryness. To the residue, add 10.0 mL of 0.020 N sulfuric acid, and heat gently until dissolved. Cool, add 2 drops of methyl red TS, and titrate the excess acid with 0.020 N sodium hydroxide.

Acceptance criteria: NLT 7.5 mL is required (1.5%).

5 SPECIFIC TESTS

Change to read:

5.1 OPTICAL ROTATION (781S), Procedures, Specific Rotation

Sample solution: ^▲_{▲(USP 1-Dec-2023)} 20 mg/mL ^▲of Morphine Sulfate _{▲(USP 1-Dec-2023)} in water

Acceptance criteria: -107° to^▲-110_{▲(USP 1-Dec-2023)}

5.2 ACIDITY

Sample: 500 mg of Morphine Sulfate

Analysis: Dissolve the Sample in 15 mL of water, add 1 drop of methyl red TS, and titrate with 0.020 N sodium hydroxide.

Acceptance criteria: NMT 0.50 mL is required to produce a yellow color.

5.3 WATER DETERMINATION (921), Method 

10.4%-13.4%

Delete the following:

^▲ AMMONIUM SALTS _{▲(USP 1-DE0-2023)}

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight, light-resistant containers. Store up to 40° as permitted by the manufacturer.

USP REFERENCE STANDARDS (11)

USP Morphine Sulfate RS