Edition: BP 2025 (Ph. Eur. 11.6 update)
Galantamine Prolonged-release Capsules from different manufacturers, whilst complying with the requirements of the monograph, are not interchangeable unless otherwise justified and authorised.
Action and use
Cholinesterase inhibitor; treatment of Alzheimer’s disease.
DEFINITION
Galantamine Prolonged-release Capsules contain Galantamine Hydrobromide. They are formulated so that the medicament is released over a period of several hours.
PRODUCTION
A suitable dissolution test is carried out to demonstrate the appropriate release of galantamine. The dissolution profile reflects the in vivo performance which in turn is compatible with the dosage schedule recommended by the manufacturer.
The capsules comply with the requirements stated under Capsules and with the following requirements.
Content of galantamine, C17H21NO3
95.0 to 105.0% of the stated amount.
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(1) To a quantity of the powdered capsule contents containing the equivalent of 4 mg of galantamine, add 10 mL of acetonitrile and mix with the aid of ultrasound for 45 minutes. Centrifuge and use the supernatant liquid.
(2) 0.05% w/v of galantamine hydrobromide BPCRS in acetonitrile.
CHROMATOGRAPHIC CONDITIONS
a) Use as the coating silica gel (Merck silica gel 60 plates are suitable).
(b) Use the mobile phase as described below.
(c) Apply 10 μL of each solution.
(d) Develop the plate to 8 cm.
(e) After removal of the plate, dry in air and spray with potassium iodobismuthate solution, then immediately with hydrogen peroxide solution (3 per cent). Examine the plate in white light.
MOBILE PHASE
1 volume of glacial acetic acid, 4 volumes of butan-1-ol and 5 volumes of water.
CONFIRMATION
The principal spot in the chromatogram obtained with solution (1) is similar in position, colour and size to that in the chromatogram obtained with solution (2).
B. In the Assay, the retention time of the principal peak in the chromatogram obtained with solution (1) is similar to that of the peak in the chromatogram obtained with solution (2).
TESTS
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions prepared in methanol (50%).
For capsules containing less than 24 mg of galantamine
(1) To 5 whole capsules add a quantity of acetonitrile that is equivalent to 20% of the volume of the flask and stir for 30 minutes. Add a quantity of methanol equivalent to 30% of the volume of the flask and stir for a further 30 minutes. Add a quantity of 1M sodium hydroxide equivalent to 5% of the volume of the flask and mix with the aid of ultrasound. Dilute with methanol to produce a solution containing the equivalent of 0.08% w/v of galantamine and filter (a 0.70-μm glass filter is suitable).
For capsules containing 24 mg or more of galantamine
(1) To 7 whole capsules add a quantity of acetonitrile equivalent to 20% of the volume of the flask and stir for 30 minutes. Add a quantity of methanol equivalent to 30% of the volume of the flask and stir for a further 30 minutes. Add a quantity of 1M sodium hydroxide equivalent to 5% of the volume of the flask and mix with the aid of ultrasound. Dilute with methanol to produce a solution containing the equivalent of 0.08% w/v of galantamine and filter (a 0.70-μm glass filter is suitable).
(2) Dilute 1 volume of solution (1) to 200 volumes.
(3) 0.05% w/v of galantamine natural for system suitability EPCRS.
(4) 0.05% w/v of galantamine synthetic for system suitability EPCRS.
(5) 0.1% w/v of galantamine hydrobromide impurity standard BPCRS.
(6) Dilute 1 volume of solution (2) to 5 volumes.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (10 cm × 4.6 mm) packed with end-capped octadecylsilyl amorphous organosilica polymer for chromatography (3.5 μm) (Waters XTerra MS 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 55°.
(e) Use a detection wavelength of 230 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
Mobile phase A 5 volumes of methanol and 95 volumes of a solution containing 0.079% w/v of disodium hydrogen orthophosphate dihydrate and 0.246% w/v of sodium dihydrogen orthophosphate.
Mobile phase B acetonitrile.
| Time (Minutes) | Mobile phase A (% v/v) | Mobile phase B (% v/v) | Comment |
| 0-6 | 100 | 0 | isocratic |
| 6-20 | 100→95 | 0→5 | linear gradient |
| 20-35 | 95→85 | 5→15 | linear gradient |
| 35-50 | 85→80 | 15→20 | linear gradient |
| 50-51 | 80→100 | 20→0 | linear gradient |
| 51-60 | 100 | 0 | re-equilibration |
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to galantamine (retention time about 18 minutes) are: impurity E, about 0.3; impurity 2, about 0.4; impurity 1, about 0.6; impurity C, about 0.8; impurity B, about 1.1; impurity A, about 1.5 and impurity D, 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 C and galantamine is at least 4.5.
LIMITS
Identify any peaks in the chromatogram obtained with solution (1) corresponding to:
impurities A and E using the chromatogram obtained with solution (3) and the chromatogram supplied with galantamine natural for system suitability EPCRS;
impurities C and D using the chromatogram obtained with solution (4) and the chromatogram supplied with galantamine synthetic for system suitability EPCRS;
impurities B, 1, and 2 using the chromatogram obtained with solution (5) and the chromatogram supplied with galantamine hydrobromide impurity standard BPCRS.
Multiply the area of any peak corresponding to impurity A by a correction factor of 0.5.
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity 1 is not greater than 1.5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.75%);
the area of any peak corresponding to impurity E is not greater than 1.2 times the area of the principal peak in the chromatogram obtained with solution (2) (0.6%);
the area of any peak corresponding to impurity B or impurity 2 is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.5% of each);
the area of any peak corresponding to impurity C or impurity D is not greater than 0.8 times the area of the principal peak in the chromatogram obtained with solution (2) (0.4% of each);
the area of any other secondary peak is not greater than 0.4 times the area of the principal peak in the chromatogram obtained with solution (2) (0.2%);
the sum of the areas of all secondary peaks is not greater than 5 times the area of the principal peak in the chromatogram obtained with solution (2) (2.5%).
Disregard any peak with an area less than the area of the principal peak in the chromatogram obtained with solution (6) (0.1%).
ASSAY
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
Solution A 0.4% w/v potassium dihydrogen orthophosphate, adjusted to pH 6.5 with 5M sodium hydroxide.
For capsules containing less than 24 mg of galantamine
(1) To 5 whole capsules add a quantity of acetonitrile that is equivalent to 20% of the volume of the flask and stir for 30 minutes. Add a quantity of methanol equivalent to 30% of the volume of the flask and stir for a further 30 minutes. Add a quantity of 1M sodium hydroxide equivalent to 5% of the volume of the flask and mix with the aid of ultrasound. Dilute with methanol to produce a solution containing the equivalent of 0.08% w/v of galantamine and filter (a 0.70-μm glass filter is suitable). Dilute 1 volume of the filtrate to 10 volumes with methanol (50%).
For capsules containing 24 mg or more of galantamine
(1) To 7 whole capsules add a quantity of acetonitrile equivalent to 20% of the volume of the flask and stir for 30 minutes. Add a quantity of methanol equivalent to 30% of the volume of the flask and stir for a further 30 minutes. Add a quantity of 1M sodium hydroxide equivalent to 5% of the volume of the flask and mix with the aid of ultrasound. Dilute with methanol to produce a solution containing the equivalent of 0.08% w/v of galantamine and filter (a 0.70-μm glass filter is suitable). Dilute 1 volume of the filtrate to 10 volumes with methanol (50%).
(2) 0.1% w/v of galantamine hydrobromide BPCRS in solution A. Dilute 1 volume to 10 volumes with methanol (50%).
(3) 0.05% w/v of galantamine synthetic for system suitability EPCRS in methanol (50%).
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (10 cm × 4.6 mm) packed with end-capped octadecylsilyl amorphous organosilica polymer for chromatography (3.5 μm) (Waters XTerra MS C18 is suitable).
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1.5 mL per minute.
(d) Use a column temperature of 55°.
(e) Use a detection wavelength of 230 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
5 volumes of methanol and 95 volumes of a solution containing 0.079% w/v of disodium hydrogen orthophosphate dihydrate and 0.246% w/v of sodium dihydrogen orthophosphate.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity C and galantamine is at least 4.5.
DETERMINATION OF CONTENT
Calculate the content of C17H21NO3 in the capsules using the declared content of C17H21NO3 in galantamine hydrobromide BPCRS.
LABELLING
The quantity of active ingredient is stated in terms of the equivalent amount of galantamine.
IMPURITIES
The impurities limited by the requirements of this monograph include impurities A to E listed under Galantamine Hydrobromide and:
1. galantamine-N-oxide
2. O-demethylgalantamine
