Venlafaxine Hydrochloride 

C17H28ClNO2                                                                                                           Mol. Wt. 313.9 

Venlafaxine Hydrochloride is 1-[(1RS)-2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexanol hydrochloride.

Venlafaxine Hydrochloride contains not less than 99.0 per cent and not more than 101.0 per cent of C17H28ClNO2, calculated on the dried basis.

Category.  Antidepressant.

Dose. 37.5 mg orally twice a day or 25mg orally 3 times a day.

Description. A white or almost white powder. It shows polymorphism (2.5.11).

Identification

2. Determine by infrared absorption spectrophotometry (2.4.6). Compare the spectrum with that obtained withvenlafaxinehydrochloride RS or with the reference spectrum of venlafaxine hydrochloride.

Note- If the spectra obtained in the solid state show differences, dissolve the substance under examination and reference substance in 2-propanol, evaporate to dryness and record new spectra using the residues. 

2. It gives reaction (A) of chlorides (2.3.1).

Tests

Acidity or alkalinity. Dissolve in 0.2 g in 10 ml of carbon dioxide free water.  Add 0.05 ml of methyl red solution and 0.1 ml of 0.01M hydrochloric acid. The solution is pink.  Not more than 0.2 ml of 0.01 M sodium hydroxide is required to change the colour of the indicator to yellow.

Related substances. Determine by liquid chromatography (2.4.14).

Test solution. Dissolve 25.0 mg of the substance under examination in the mobile phase and dilute to 25.0 ml with the mobile phase. 

Reference solution(a). Dilute 1.0 ml of the test solution to 10.0 ml with the mobile phase. Dilute 1.0 ml of this solution to 100.0 ml with the mobile phase.

Reference solution(b). Dissolve the contents of a vial of venlafaxine for system suitability RS (containing impurities D and F) in 1.0 ml of the mobile phase. 

Chromatographic system

     –   a stainless steel column 25 cm x 4.6 mm, packed with octylsilane bonded to porous silica (5 µm),

     –   mobile phase:  a mixture of  149 volumes of a buffer solution prepared by dissolving 1.7 g of ammonium dihydrogen orthophosphate in 149 ml of water, adjusting the pH to 4.4 with orthophosphoric acid and 51 volumes of acetonitrile,

     –   flow rate: 1.2 ml per minute,

     –   spectrophotometer set at 225 nm,

     –   injection volume: 20 µl.

Run the chromatogram 10 times the retention time of venlafaxine.

Name                                                                  Retention time

                                                                                (in minutes)

Venlafaxine                                                                  9.0

Venlafaxine impurity D¹                                            0.9

Venlafaxine impurity F²                                                                   3.4

¹(1-[(1RS)-1-(4-methoxyphenyl)-2-(methylamino) ethyl] cyclohexanol,

2 ((2RS)-2-(cyclohex-1-enyl)-2-(4-methoxyphenyl)-N,N-dimethylethanamine. 

Inject reference solution (b). The test is not valid unless the resolution between the peaks due to venlafaxine and venlafaxine impurity D is not less than 1.5.

Inject reference solution (a), and the test solution.  In the chromatogram obtained with the test solution, the area of the peak due to venlafaxine impurity F is not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.1 per cent), the area of any secondary peak is not more than the area of the principal  peak in the chromatogram obtained with the reference solution (a)  (0.1 per cent), the sum of areas of all the secondary peaks is not more than twice the area  of the principal peak in the chromatogram obtained with the reference solution (a)  (0.2 per cent). Ignore any peak with an area less than 0.5 times of the area of the principal peak in the chromatogram obtained with the reference solution (a) (0.05 per cent).

Sulphated ash  (2.3.18). Not more than 0.1 per cent, determined on 1.0 g.

Loss on drying (2.4.19).  Not more than 0.5 per cent, determined on 1.0 g by drying in a vacuum at 80° for 3 hours.

Assay. Weight 0.25 g dissolve in a mixture of 5 ml of 0.01 M hydrochloric acid and 50 ml of ethanol ( 95 per cent). Titrate with 0.1 M sodium hydroxide. Determining the end-point potentiometrically (2.4.25). Carry out a blank titration.

1 ml of 0.1 M sodium hydroxide is equivalent to 0.03139 g of C17H28ClNO2.

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Solubility. Freely soluble in water and in methanol, soluble in anhydrous ethanol, slightly soluble or practically insoluble in acetone.