Prolonged-release Venlafaxine Tablets
Venlafaxine Prolonged-release Tablets from different manufacturers, whilst complying with the requirements of the monograph, are not interchangeable unless otherwise justified and authorised.
Action and use
Inhibition of 5HT and noradrenaline reuptake; antidepressant.
DEFINITION
Venlafaxine Prolonged-release Tablets contain Venlafaxine Hydrochloride. 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 Venlafaxine Hydrochloride. The dissolution profile reflects the performance which in turn is compatible with the dosage schedule recommended by the manufacturer.
The tablets comply with the requirements stated under Tablets and with the following requirements.
Content of venlafaxine, C17H27NO2
95.0 to 105.0% of the stated amount.
IDENTIFICATION
Shake a quantity of the powdered tablets containing the equivalent of 0.35 g of venlafaxine with 100 mL of a mixture of 30 volumes of cyclohexane and 70 volumes of dichloromethane for 30 minutes, filter the extract through anhydrous sodium sulfate and evaporate the filtrate to dryness. Wash the residue with a mixture of 30 volumes of cyclohexane and 70 volumes of dichloromethane, filter and dry the residue. The infrared absorption spectrum of the residue, Appendix II A, is concordant with the reference spectrum of venlafaxine hydrochloride (RS439).
TESTS
Related substances
Carry out the method for liquid chromatography, Appendix III D, using the following solutions.
(1) Mix, with the aid of ultrasound, a quantity of the powdered tablets containing the equivalent of 200 mg of venlafaxine with 80 mL of a 2.4% v/v solution of orthophosphoric acid, shake for a further 30 minutes, cool, add sufficient water to produce 100 mL, mix and centrifuge; use the supernatant liquid.
(2) Dilute 1 volume of solution (1) to 100 volumes with mobile phase A, further dilute 1 volume of this solution to 5 volumes with mobile phase A.
(3) 0.2% w/v of venlafaxine impurity standard BPCRS in mobile phase A.
(4) Dilute 25 volumes of solution (2) to 100 volumes with mobile phase A.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (25 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 μm) (Partisil ODS 3 is suitable).
(b) Use gradient 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 226 nm.
(f) Inject 20 μL of each solution.
MOBILE PHASE
Mobile phase A: 1 volume of triethylamine, 20 volumes of acetonitrile and 80 volumes of water previously adjusted to pH 3.5 with orthophosphoric acid.
Mobile phase B: 1 volume of triethylamine, 50 volumes of acetonitrile and 50 volumes of water previously adjusted to pH 3.5 with orthophosphoric acid.
When the chromatograms are recorded under the prescribed conditions, the retention time of venlafaxine is about 13 minutes. Retention times relative to venlafaxine are: impurity D, about 0.8; impurity F, about 1.7.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the peaks due to impurity D and venlafaxine is at least 1.5.
LIMITS
In the chromatogram obtained with solution (1):
the area of any peak corresponding to impurity D or impurity F is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.2% of each);
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 that of the principal peak in the chromatogram obtained with solution (4) (0.05%).
ASSAY
Weigh and powder 20 tablets. Carry out the method for liquid chromatography, Appendix III D, using the following solutions in the mobile phase.
(1) Shake a quantity of the powdered tablets containing the equivalent of 175 mg of venlafaxine for 30 minutes with 50 mL of methanol, add sufficient methanol to produce 100 mL, mix and filter. Dilute 1 volume of the filtrate to 20 volumes with mobile phase.
(2) 0.01% w/v of venlafaxine hydrochloride BPCRS.
(3) 0.01% w/v of venlafaxine impurity standard BPCRS.
CHROMATOGRAPHIC CONDITIONS
(a) Use a stainless steel column (15 cm × 4.6 mm) packed with octadecylsilyl silica gel for chromatography (5 μm) (Zorbax Rx C18 is suitable)
(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 226 nm.
(f) Inject 10 μL of each solution.
MOBILE PHASE
20 volumes of acetonitrile and 80 volumes of a 1% v/v solution of triethylamine previously adjusted to pH 3.0 with orthophosphoric acid.
Under the prescribed conditions, the retention time of venlafaxine is about 3.5 minutes. If necessary, adjust the acetonitrile content of the mobile phase.
SYSTEM SUITABILITY
The test is not valid unless, in the chromatogram obtained with solution (3), the resolution factor between the peaks due to impurity D and venlafaxine is at least 1.0.
DETERMINATION OF CONTENT
Calculate the content of C17H27NO2 in the tablets using the declared content of C17H27NO2,HCl in venlafaxine hydrochloride BPCRS. Each mg of C17H27NO2,HCl is equivalent to 0.884 mg of C17H27NO2.
LABELLING
The quantity of active ingredient is stated in terms of the equivalent amount of venlafaxine.
IMPURITIES
The impurities limited by the requirements of this monograph include:
D. 1-[(1RS)-1-(4-methoxyphenyl)-2-(methylamino)ethyl]cyclohexanol (European Pharmacopoeia impurity D);
F. (2RS)-2-(cyclohex-1-enyl)-2-(4-methoxyphenyl)-N,N-dimethylethanamine (European Pharmacopoeia impurity F).
