Action and use
Cholinesterase inhibitor; treatment of dementia in Alzheimer’s disease and Parkinson’s disease.
DEFINITION
Rivastigmine Transdermal Patches contain Rivastigmine.
The transdermal patches comply with the requirements stated under Patches and with the following requirements.
PRODUCTION
A suitable dissolution test is carried out to demonstrate the appropriate release of rivastigmine.
Content of rivastigmine, C14H22N2O2
90.0 to 110.0% of the stated amount.
IDENTIFICATION
A. Carry out the method for thin-layer chromatography, Appendix III A, using the following solutions.
(1) Remove the release liner from an amount of patches containing 18 mg of Rivastigmine and dissolve the contents in 50 mL of methanol. Mix with the aid of ultrasound for 60 minutes, allow to cool and centrifuge at 3000 rpm for 10 minutes.
(2) 0.058% w/v of rivastigmine hydrogen tartrate BPCRS in methanol.
CHROMATOGRAPHIC CONDITIONS
(a) Use as the coating silica gel F254 (Merck silica gel 60 F254 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 and examine under ultraviolet light (254 nm).
MOBILE PHASE
2 volumes of formic acid, 5 volumes of water, 30 volumes of methanol and 70 volumes of dichloromethane.
CONFIRMATION
The principal spot in the chromatogram obtained with solution (1) is similar in position 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 the mobile phase and protected from light.
(1) Remove the release liners from the patches. Mix with the aid of ultrasound a quantity of whole patches with sufficient tetrahydrofuran to produce a solution containing 0.1% w/v of Rivastigmine, for about 60 minutes. Allow to cool, dilute 1 volume of the solution to 5 volumes and filter (a 0.45-μm PTFE filter is suitable).
(2) Dilute 1 volume of solution (1) to 100 volumes. Dilute 1 volume of the resulting solution to 5 volumes.
(3) 0.1% w/v of rivastigmine for system suitability EPCRS.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with end-capped polar-embedded octadecylsilyl amorphous organosilica polymer for chromatography (5 μm) (XTerra RP 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 217 nm.
(f) Inject 10 μL of each solution.
(g) Allow the chromatography to proceed for 3.5 times the retention time of rivastigmine.
MOBILE PHASE
28 volumes of acetonitrile R1 and 72 volumes of 0.01M sodium heptanesulfonate, adjusted to pH 3.0 with orthophosphoric acid.
When the chromatograms are recorded under the prescribed conditions, the relative retentions with reference to rivastigmine (retention time about 7 minutes) are: impurity A, about 0.5; impurity B, about 0.7 and impurity C, about 2.5.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity A and impurity B is at least 7.0.
LIMITS
Identify any peak corresponding to impurity C in the chromatogram obtained with solution (1), using the chromatogram obtained with solution (3), and multiply the area of this peak by a correction factor of 0.6.
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity A is not greater than 1.5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.3%);
the area of any other secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.2%);
the sum of the areas of all the secondary peaks is not greater than 2.5 times the area of the principal peak in the chromatogram obtained with solution (2) (0.5%).
Disregard any peak with an area less than half the area of the principal peak in the chromatogram obtained with solution (2) (0.1%).
Uniformity of content
Comply with the requirements stated under uniformity of content, Appendix XII C3, Test C, with respect to the individual content of each dosage unit and using the following method of analysis.
Carry out the method for liquid chromatography, Appendix III D, using the following solutions prepared in the mobile phase and protected from light.
(1) Remove the release liner from one patch and dissolve the contents in sufficient tetrahydrofuran to produce a solution containing 0.1% w/v of Rivastigmine. Mix with the aid of ultrasound for 60 minutes. Allow to cool, dilute 1 volume to 10 volumes and filter (a 0.45-μm PTFE filter is suitable).
(2) 0.016% w/v of rivastigmine hydrogen tartrate BPCRS.
(3) 0.1% w/v of rivastigmine for system suitability EPCRS.
CHROMATOGRAPHIC CONDITIONS
The chromatographic conditions described under Related substances may be used.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution between the peaks due to impurity A and impurity B is at least 7.0.
DETERMINATION OF CONTENT
Calculate the content of rivastigmine, C14H22N2O2, in each patch from the chromatograms obtained and using the declared content of C18H28N2O8 in rivastigmine hydrogen tartrate BPCRS. Each mg of C18H28N2O8 is equivalent to 0.6251 mg of C14H22N2O2.
ASSAY
Use the average of the individual results obtained in the test for Uniformity of content.
IMPURITIES
The impurities limited by the requirements of this monograph include impurities A, B and C listed under Rivastigmine.
