Morphine Tablets

General Notices

Action and use

Opioid receptor agonist; analgesic.

Definition

Morphine Tablets contain Morphine Sulfate.

The tablets comply with the requirements stated under Tablets and with the following requirements.

Content of morphine sulfate, (C17H19NO3)2,H2SO4,5H2O

92.5 to 107.5% of the stated amount.

Identification

A. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(1) Remove any coating from the tablets and shake a quantity of the powdered tablet cores containing 5 mg of Morphine Sulfate with 10 mL of ethanol (48%) and filter.
(2) 0.05% w/v of morphine sulfate BPCRS in ethanol (48%).
(3) 0.05% w/v each of morphine sulfate BPCRS and codeine phosphate BPCRS in ethanol (48%).
chromatographic conditions
(a) Use as the coating silica gel (Merck silica gel plates are suitable).
(b) Use the mobile phase as described below.
(c) Apply 10 µL of each solution.
(d) Develop the plate to 15 cm.
(e) After removal of the plate dry in air, spray with potassium iodobismuthate solution R2 and examine in daylight.
mobile phase

2.5 volumes of 13.5m ammonia, 32.5 volumes of acetone, 35 volumes of ethanol (70%) and 35 volumes of toluene.

system suitability

The test is not valid unless the chromatogram obtained with solution (3) shows two clearly separated spots.

confirmation

The principal spot in the chromatogram obtained with solution (1) corresponds in size, position and colour to that in the chromatogram obtained with solution (2).

B. In the Assay, the chromatogram obtained with solution (1) shows a peak with the same retention time as the principal peak in the chromatogram obtained with solution (2).

Tests

Dissolution

Comply with the requirements for Monographs of the British Pharmacopoeia in the dissolution test for tablets and capsules, Appendix XII B1.

test conditions
(a) Use Apparatus 2 rotating the paddle at 50 revolutions per minute.
(b) Use 900 mL of phosphate buffer solution pH 6.5, at a temperature of 37°, as the medium.
procedure

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) After 45 minutes withdraw a sample of the medium and filter. Use the filtered medium, diluted with phosphate buffer solution pH 6.5 if necessary, expected to contain 0.001% w/v of Morphine Sulfate.
(2) 0.001% w/v of morphine sulfate BPCRS in phosphate buffer solution pH 6.5.
(3) 0.03% w/v morphine sulfate BPCRS and 0.00033% w/v pseudomorphine trihydrate BPCRS in the mobile phase.
chromatographic conditions
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 µm) (Phenomenex HyperClone BDS C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1.0 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 281 nm.
(f) Inject 20 µL of each solution.
mobile phase

0.5 volumes of orthophosphoric acid, 300 volumes of acetonitrile and 700 volumes of 0.01m sodium octanesulfonate.

When the chromatograms are recorded under the prescribed conditions, the retention times of morphine sulfate and pseudomorphine are about 2.5 minutes and 3.5 minutes respectively.

system suitability

The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to morphine and pseudomorphine is at least 4.0.

determination of content

Calculate the total content of morphine sulfate, (C17H19NO3)2,H2SO4,5H2O in the medium, using the chromatograms obtained and the declared content of (C17H19NO3)2,H2SO4,5H2O in morphine sulfate BPCRS.

Related substances

Carry out the method for liquid chromatography, Appendix III D, using the following solutions in solvent A.

Solvent A 1.0% v/v solution of acetic acid.

(1) Shake a quantity of powdered tablets containing 62.5 mg of Morphine Sulfate with 30 mL of solvent A, add sufficient solvent A to produce 50 mL and filter.
(2) Dilute 1 volume of solution (1) to 100 volumes.
(3) 0.00025% w/v morphine sulfate BPCRS.
(4) 0.25% w/v of morphine for system suitability EPCRS and 0.0625% w/v of codeine phosphate BPCRS.
(5) Dilute 1 volume of solution (2) to 20 volumes.
chromatographic conditions
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with end-capped octadecylsilyl silica gel for chromatography (5 µm) (Waters Symmetry C18 is suitable).
(b) Use gradient elution and the mobile phase described below.
(c) Use a flow rate of 1.5 mL per minute.
(d) Use a column temperature of 35°.
(e) Use a detection wavelength of 230 nm.
(f) Inject 20 µL of each solution.
mobile phase

Mobile phase A0.101% w/v of sodium heptanesulfonate, adjusted to pH 2.6 with a 50% v/v solution of orthophosphoric acid.

Mobile phase Bmethanol.

When the chromatograms are recorded under the prescribed conditions the retention times relative to morphine (retention time about 12.5 minutes) are: impurity F, about 0.95; impurity E, about 1.1; impurity C, impurity A, about 1.4; about 1.6 and impurity B, about 1.9.

system suitability

The test is not valid unless, in the chromatogram obtained with solution (4), the resolution between the peaks due to impurity F and morphine is at least 4.

limits

Identify any peaks in the chromatogram obtained with solution (1) corresponding to impurity E, impurity C and impurity B using the chromatogram obtained with solution (4) and the chromatogram supplied with morphine for system suitability EPCRS. Multiply the area of any peak corresponding to impurity E, impurity C and impurity B by the following correction factors respectively: 0.5, 0.4 and 0.25.

In the chromatogram obtained with solution (1):

the area of any peak corresponding to impurity B is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (1.0%);

the area of any peak corresponding to impurity A is not greater than half of the area of the principal peak in the chromatogram obtained with solution (2) (0.5%);

the area of any other secondary peaks is not greater than the area of the principal peak in the chromatogram obtained with solution (3) (0.2%);

the sum of the areas of all secondary peaks is not greater than twice the area of the principal peak in the chromatogram obtained with solution (2) (2.0%).

Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (5) (0.05%).

Assay

Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Shake a quantity of the powdered tablets containing 30 mg of Morphine Sulfate with 50 mL of the mobile phase and dilute to 100 mL with the mobile phase and filter.
(2) 0.03% w/v of morphine sulfate BPCRS in the mobile phase.
(3) 0.03% w/v of morphine sulfate BPCRS and 0.00033% w/v of pseudomorphine trihydrate BPCRS in the mobile phase.
chromatographic conditions
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 µm) (Phenomenex HyperClone BDS C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1.0 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 281 nm.
(f) Inject 20 µL of each solution.
mobile phase

0.05 volumes of orthophosphoric acid, 30 volumes of acetonitrile and 70 volumes of 0.01m sodium octanesulfonate.

When the chromatograms are recorded under the prescribed conditions, the retention times of morphine sulfate and pseudomorphine are about 2.5 minutes and 3.5 minutes respectively.

system suitability

The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to morphine and pseudomorphine is at least 4.0.

determination of content

Calculate the content of (C17H19NO3)2,H2SO4,5H2O in the tablets using the declared content of (C17H19NO3)2,H2SO4,5H2O in morphine sulfate BPCRS.

IMPURITIES

The impurities limited by the requirements of this monograph include those listed under Morphine Sulfate.