Morphine Sulfate Extended-Release Capsules

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

DOWNLOAD PDF HERE

1 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].

2 IDENTIFICATION

A.

Standard solution and Sample solution: Prepare as directed in the Assay.

Analysis: Inject 10 µl each of the Standard solution and the Sample solution using the Chromatographic system except for the Injection volume in the Assay.

Acceptance criteria: The UV absorption spectrum of the morphine peak of the Sample solution and of the Standard solution exhibits maxima and minima at the same wavelengths, as obtained in the Assay.

B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 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 Table 1.

Table 1

System suitability solution: 400 µg/mL of USP Morphine Sulfate RS and 10 µg/mL each of USP Morphine Related Compound A RS and 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, nominally equivalent to 250 mg of morphine sulfate pentahydrate, to a 100-mL volumetric flask. Add 5 mL of methanol and mix well for NLT 30 min with gentle swirling about every 5. min. Add Diluent up to half of the flask volume and sonicate for NLT 5 min to dissolve. Dilute with Diluent to volume.

Sample solution: Nominally 1.0 mg/mL of morphine sulfate pentahydrate from the Sample stock solution in Diluent. Pass through a suitable filter and use the clear filtrate.

Chromatographic system

(See Chromatography (621), System Suitability)

Mode: LC

Detector: UV 245 nm. For Identification A, use a diode array detector in the range of 200-400 nm.

Columns

Guard: Packing L1

Analytical: 3.9-mm x 30-cm; 10-µm packing L1

Flow rate: 2 mL/min

Injection volume: 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 the labeled amount of morphine sulfate pentahydrate [(C₁₇H₁₉NO₃)₂ · H₂SO₄ · 5H₂O]. in the portion of Capsules taken:

                         Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) ×100

r_U = peak response from the Sample solution

r_S = peak response from the Standard solution

C_S = concentration of USP Morphine Sulfate RS in the Standard solution (mg/mL), calculated on the anhydrous basis

C_U = nominal concentration of morphine sulfate pentahydrate in the Sample solution (mg/mL)

M_r1 = molecular weight of morphine sulfate pentahydrate, 758.83

M_r2 = molecular weight of anhydrous morphine sulfate, 668.77 

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

4.1 DISSOLUTION (711)

4.1.1 Test 1

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: Prepare as directed in Dissolution (711), Procedure, Apparatus 1 and Apparatus 2. Delayed-Release Dosage Forms, Method B Procedure, 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

Mobile phase: Methanol, glacial acetic acid, and water (280:10:720), containing 0.73 g of sodium 1-heptanesulfonate for each 1.01 L of the solvent mixture

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 with a known concentration corresponding to that of the Sample solution

Sample solution: Sample per Dissolution (711).

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 284 nm

Column: 3.9-mm x 30-cm; 10-µm packing L1

Flow rate: 2 mL/min

Injection volume: 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% for the morphine sulfate peak

Analysis

Samples: Standard solution and Sample solution

Tolerances: See Table 2.

Table 2

17 19 2 The percentage of the labeled amount of morphine sulfate pentahydrate [(C₁₇H₁₉NO₃)₂ · H₂SO₄ · 5H₂O] dissolved in 1 h conforms to Dissolution (711), Acceptance Table 3. The percentages of the labeled amount of morphine sulfate pentahydrate [(C₁₇H₁₉NO₃)₂ · H₂SO₄ · 5H₂O] dissolved at the other times specified conform to Dissolution (711), Acceptance Table 2

4.1.2 Test 2: If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 2.

Medium

Acid stage: 0.1 N hydrochloric acid (HCI); 500 mL

Buffer stage: pH 7.5 phosphate buffer (dissolve 40.8 g of monobasic potassium phosphate and 9.6 g of sodium hydroxide in 6 L of water, adjust with phosphoric acid or 2 N sodium hydroxide to a pH of 7.5); 500 mL

Apparatus 1: 100 rpm

Times: 1, 4, 6, and 9 h

Solution A: 0.1% phosphoric acid and 0.1% triethylamine in water

Mobile phase: Solution A and methanol (93:7)

Standard stock solution: 2.0 mg/mL of USP Morphine Sulfate RS in water

Standard solution: 0.16 mg/mL of USP Morphine Sulfate RS in either the Acid stage under Medium or in the Buffer stage under Medium, from Standard stock solution

Sample solution: Pass a portion of the solution under test through a suitable filter of 10-µm pore size. Centrifuge the filtrate if necessary.

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 210 nm

Column: 4.6-mm x 15-cm; 5-µm packing L7

Column temperature: 25°

Flow rate: 1.5 mL/min

Injection volume: 5 µL

Run time: NLT 2 times the retention time of morphine

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

Replace the Acid stage under Medium immediately after 1 h with the Buffer stage under Medium.

19 Calculate the concentration (C) of morphine sulfate pentahydrate [(C₁₇H₁₉NO₃)₂ · H₂SO₄ · 5H₂O] in the sample withdrawn from the vessel at each time point (i):

                         Result_i = (r_U/r_S) x C_S

r_U = peak response of morphine from the Sample solution at each time point (i)

r_S = peak response of morphine from the appropriate Standard solution at each time point (i)

C_S = concentration of USP Morphine Sulfate RS in the appropriate Standard solution (mg/mL)

Calculate the percentage of the labeled amount of morphine sulfate pentahydrate [(C₁₇H₁₉NO₃)₂ · H₂SO₄ · 5H₂O]. dissolved at each time point (1):

                         Result₁ = C₁ x V x (1/L) x 100

                         Result₂ = C₂ x V x (1/L) x 100

                         Result₃ = {[C₃ x (V - V_S)] + (C₂ x V_S)) x (1/L) x 100

                         Result₄ = ({C₄ x [V - (2 x V_S)] + [(C₂ + C₁) x V_S]) x (1/L) x 100

C_i = concentration of morphine sulfate pentahydrate [(C₁₇H₁₉NO₃)₂ · H₂SO₄ · 5H₂O] in the portion of the sample withdrawn at each time point (i) (mg/mL)

V = volume of Medium, 500 mL

L = label claim (mg/Capsule)

V_S = volume of Medium taken (mL)

Tolerances: See Table 3.

Table 3

The percentages of the labeled amount of morphine sulfate pentahydrate released at the times specified conform to Dissolution (711),

Acceptance Table 2.

4.1.3 Test 3: If the product complies with this test, the labeling indicates that the product meets USP Dissolution Test 3. Proceed as directed in Test 1, except for Tolerances.

Tolerances: See Table 4.

Table 4

The percentage of the labeled amount of morphine sulfate pentahydrate [(C₁₇H₁₉NO₃)₂ · H₂SO₄ · 5H₂O] dissolved in 1 h conforms to Dissolution (711), Acceptance Table 3. The percentages of the labeled amount of morphine sulfate pentahydrate [(C₁₇H₁₉NO₃)₂ · H₂SO₄ · 5H₂O] dissolved at the other times specified conform to Dissolution (711), Acceptance Table 2. 

4.2 UNIFORMITY OF DOSAGE UNITS (905)

Meet the requirements

5 IMPURITIES

Change to read:

ORGANIC IMPURITIES

Diluent, ^▲Buffer solution, _{▲(ERR 1-Sep-2019)} Solution A, ^▲Solution B, Mobile phase, _{▲(ERR 1-Sep-2019)} System suitability 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

Standard solution: 0.002 mg/mL of USP Morphine Sulfate RS and 0.005 mg/mL each of USP Morphine Related Compound A RS and USP Morphine Related Compound B RS (pseudomorphine) 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

Signal-to-noise ratio: NLT 10 for morphine sulfate, Sensitivity solution

Relative standard deviation: NMT 5% for morphine related compound A, morphine sulfate, and morphine related compound B, Standard solution

Analysis

Samples: Diluent, Standard solution, and Sample solution

Calculate the percentage of morphine related compound A and morphine related compound B in the portion of Capsules taken:

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

r_U = peak response of morphine related compound A or morphine related compound B from the Sample solution

r_S = peak response of USP Morphine Related Compound A RS or USP Morphine Related Compound B RS from the Standard solution

C_S = concentration of USP Morphine Related Compound A RS or USP Morphine Related Compound B RS in the Standard solution (mg/mL)

C_U = nominal concentration of morphine sulfate pentahydrate in the Sample solution (mg/mL)

Calculate the percentage of any unspecified impurity in the portion of Capsules taken:

                         Result = (r_U/r_S) x 100

r_U = peak response of any individual unspecified impurity from the Sample solution

r_S = peak response of morphine sulfate from the Sample solution

Acceptance criteria: See Table 5. Disregard any peaks below 0.05% and the peaks corresponding to those from the Diluent.

Table 5

^a 7,8-Didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol, N-oxide.

^b 2,2'-Bimorphine.

6 ADDITIONAL REQUIREMENTS

PACKAGING AND STORAGE: Preserve in tight, light-resistant containers, and store at controlled room temperature.

LABELING: When more than one test for Dissolution is given, the Labeling section states the test for Dissolution used only if Test 1 is not used.

USP REFERENCE STANDARDS (11)

USP Morphine Related Compound A RS

7,8-Didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol, N-oxide.

C₁₇H₁₉NO₄             301.34

USP Morphine Related Compound B.RS

2,2'-Bimorphine trihydrate.

C₃₄H₃₆N₂O₆ · 3H₂O        622.72

USP Morphine Sulfate RS