Action and use
Beta-adrenoceptor antagonist.
Definition
Metoprolol Tartrate Tablets contain Metoprolol Tartrate.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of metoprolol tartrate, (C15H25NO3)2,C4H6O6
95.0 to 105.0% of the stated amount.
Identification
A. Mix a quantity of the powdered tablets containing 50 mg of Metoprolol Tartrate with 25 mL of
water, add 2 mL of 5
m ammonia, extract with 20 mL of
dichloromethane, filter the dichloromethane layer through
anhydrous sodium sulfate, wash the filter with 10 mL of
dichloromethane and evaporate the combined filtrate and washings to dryness using a rotary evaporator, using gentle heat if necessary. Cool the residue to –18° for 30 minutes and allow to warm to room temperature. The
infrared absorption spectrum of the residue,
Appendix II A, is concordant with the
reference spectrum of metoprolol
(RS 228).
(1) Shake a quantity of the powdered tablets containing 0.5 g of Metoprolol Tartrate with 15 mL of
methanol for 1 hour, add sufficient
methanol to produce 25 mL and mix. Filter through a glass microfibre filter (Whatman GF/F is suitable) and use the filtrate.
(2) 2.0% w/v of
metoprolol tartrate BPCRS in
methanol.
(4) Mix 1 volume of solution (1) with 1 volume of solution (3).
chromatographic conditions
(a) Use a
silica gel H precoated plate (Analtech Uniplate plates are suitable).
(b) Use the mobile phase as described below.
(c) Apply 10 µL of each solution.
(d) Develop the plate to 5 cm.
(e) After removal of the plate, dry in air for about 10 minutes, dry in an oven at 100° for 20 minutes and spray the plate with a solution prepared in the following manner. Dissolve 75 mg of
bromocresol green and 25 mg of
bromophenol blue in 100 mL of
absolute ethanol (solution A); dissolve 0.25 g of
potassium permanganate and 0.5 g of
sodium carbonate in 100 mL of
water (solution B); mix 9 volumes of solution A and 1 volume of solution B and use immediately.
mobile phase
40 volumes of anhydrous formic acid and 140 volumes of ether.
system suitability
The chromatogram obtained with solution (1) closely resembles the chromatogram obtained with solution (2). The test is not valid unless the chromatogram obtained with solution (4) shows two clearly separated principal spots; the spot of lower Rf value is purple and the spot of higher Rf value, which is a single, compact spot, is yellow.
confirmation
In the chromatogram obtained with solution (1) the spot with the higher Rf value corresponds to the spot in the chromatogram obtained with solution (3).
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Shake a quantity of the powdered tablets containing 0.5 g of Metoprolol Tartrate with 20 mL of
chloroform for 10 minutes, centrifuge, remove and retain the supernatant layer. Extract the residue with a further 20 mL quantity of
chloroform, centrifuge and remove the supernatant layer. Evaporate the combined chloroform extracts to dryness at ambient temperature, add sufficient mobile phase to produce 25 mL and mix. Dilute 5 volumes of this solution to 20 volumes with the mobile phase, mix and filter.
(2) Dilute 1 volume of solution (1) to 20 volumes with the mobile phase and dilute 3 volumes of this solution to 50 volumes with the mobile phase.
(4) Prepare the solution in a fume cupboard in the following manner if necessary (see limits below). Place an evaporating dish 10 cm in diameter containing 10 mL of a 0.1% w/v solution of
metoprolol tartrate BPCRS in
0.1m hydrochloric acid so that the surface of the solution is 5 cm from a lamp emitting
ultraviolet light at (254 nm) for 6 hours. Dilute 1 volume of this solution to 50 volumes with the mobile phase.
chromatographic conditions
(b) Use isocratic elution and the mobile phase described below.
(c) Use a flow rate of 1 mL per minute.
(d) Use an ambient column temperature.
(e) Use a detection wavelength of 280 nm.
(f) Inject 20 µL of each solution.
(g) Allow the chromatography to proceed for three times the retention time of metoprolol.
When the chromatograms are recorded under the prescribed conditions, the retention time of metoprolol is about 7 minutes, the relative retention of metoprolol impurity C is 0.3 and the relative retention of metoprolol impurity A is 0.7.
mobile phase
2 volumes of triethylamine, 3 volumes of orthophosphoric acid, 10 volumes of glacial acetic acid, 146 volumes of acetonitrile and 810 volumes of a 0.39% w/v solution of ammonium acetate.
system suitability
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the peaks due to metoprolol and metoprolol impurity A is at least 6.0.
limits
In the chromatogram obtained with solution (1):
the area of any secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.3%);
the sum of the areas of any secondary peaks is not greater than 1.7 times the area of the principal peak in the chromatogram obtained with solution (2) (0.5%).
If any of the above limits are exceeded, and if a secondary peak occurs with a retention time of about 2 minutes (metoprolol impurity C), then in the chromatogram obtained with solution (1): divide the area of the peak corresponding to the principal peak in the chromatogram obtained with solution (4) (metoprolol impurity C) by 10: this divided area is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.3%); the sum of this divided area and the areas of any other secondary peaks is not greater than 1.7 times the area of the principal peak in the chromatogram obtained with solution (2) (0.5%).
Disregard any peak with an area less than 0.17 times the area of the principal peak in the chromatogram obtained with solution (2) (0.05%).
Assay
Weigh and powder 20 tablets. Add to a quantity of the powdered tablets containing 75 mg of Metoprolol Tartrate 150 mL of absolute ethanol, shake with the aid of ultrasound for 15 minutes, allow to cool, add sufficient absolute ethanol to produce 200 mL and filter (Whatman GF/C paper is suitable). To 20 mL of the filtrate add sufficient absolute ethanol to produce 50 mL and measure the absorbance of the resulting solution at the maximum at 274 nm, Appendix II B. Calculate the content of (C15H25NO3)2,C4H6O6 from the absorbance obtained with a 0.015% w/v solution of metoprolol tartrate BPCRS in absolute ethanol and from the declared content of (C15H25NO3)2,C4H6O6 in metoprolol tartrate BPCRS.
Impurities
The impurities limited by the requirements of this monograph include those listed under Metoprolol Tartrate.