Trazodone Hydrochloride

C19H22ClN5O,HCl 408.3 25332-39-2

 

Definition

 

Trazodone Hydrochlorideis 2-3-[4-(3-chloro)phenylpiperazin-1-yl]propyl-1,2,4triazolo[4,3-a]pyridin-3(2H)-one hydrochloride. It contains not less than 99.0% and not more than 101.0% of C19H22ClN5O,HCl, calculated with reference to the dried substance.

 

Characteristics

 

A white or almost white, crystalline powder.

 

Soluble in water ; sparingly soluble in ethanol (96%); practically insoluble in ether .

 

Identification

 

A.    The infrared absorption spectrum, Appendix II A, is concordant with the reference spectrum of trazodone hydrochloride (RS 346). In the preparation of the disc, avoid excessive grinding when triturating the substance being examined with the potassium chloride.

 

B.    Yields the reactions characteristic of chlorides, Appendix VI.

 

Acidity

 

pH of a 1% w/v solution, 3.9 to 4.5, Appendix V L.

 

Heavy metals

 

1.0 g complies with limit test C for heavy metals, Appendix VII. Use 2 ml of lead standard solution (10 ppm Pb) to prepare the standard (20 ppm).

 

3-Chloroaniline

 

To 10 ml of a 1% w/v solution of the substance being examined in a mixture of equal volumes of water  and ethanol  add 2 ml of a freshly prepared 5% w/v solution of 4-dimethylaminobenzaldehyde in ethanol  and 0.1 ml of hydrochloric acid. Shake well and allow to stand for 5 minutes. Any yellow colour produced within 5 minutes of preparation of the solution is not more intense than that produced by treating at the same time and in the same manner 10 ml of a 1 µg per ml solution of 3-chloro-aniline in a mixture of equal volumes of water  and ethanol  beginning at the words 'add 2 ml¼' (100 ppm).

 

Related substances

 

The combined nominal total content of impurities determined in tests A and B below is not more than 1.0% and no single impurity is more than 0.3%.

 

A.    Carry out the method for liquid chromatography, Appendix III D, using three solutions in the mobile phase containing (1) 0.10% w/v of the substance being examined, (2) 0.00050% w/v of the substance being examined and (3) 0.10% w/v of trazodone hydrochloride impurity standard BPCRS.

 

The chromatographic procedure may be carried out using (a) a stainless steel column (25 cm 4.6 mm) packed with stationary phase C (5 µm) (Supelco Suplex pKb 100 is suitable) and a pre-column (1 cm 4.6 mm) packed with the same material placed between the pump and the injector, (b) a mixture of 0.4 volume of diethylamine, 350 volumes of acetonitrile and 650 volumes of water  as the mobile phase with a flow rate of 2.0 ml per minute and (c) a detection wavelength of 254 nm. If necessary adjust the proportions of acetonitrile and water  in the mobile phase to obtain a retention time of about 10 minutes for the principal peak. For solution (1) allow the chromatography to proceed for three times the retention time of the principal peak.

 

The test is not valid unless the chromatogram obtained with solution (3) closely resembles reference chromatogram A supplied with trazodone hydrochloride impurity standard BPCRS.

 

From any secondary peaks in the chromatogram obtained with solution (1) calculate the nominal content of each impurity with a retention time of up to and including that of impurity E, identified from reference chromatogram A. Use, as reference, the principal peak in the chromatogram obtained with solution (2). Disregard any peak with an area less than 0.1 times that of the principal peak in the chromatogram obtained with solution (2) (0.05%).

 

B.    Carry out the method for liquid chromatography, Appendix III D, using three solutions in the mobile phase containing (1) 0.10% w/v of the substance being examined, (2) 0.00050% w/v of the substance being examined and (3) 0.10% w/v of trazodone hydrochloride impurity BPCRS.

 

The chromatographic procedure may be carried out using (a) a stainless steel column (25 cm 4.6 mm) packed with stationary phase C (5 µm) (Supelco Suplex pKb 100 is suitable) and a pre-column (1 cm 4.6 mm) packed with the same material placed between the pump and the injector, (b) a mixture of 0.4 volume of diethylamine, 320 volumes of water  and 680 volumes of acetonitrile as the mobile phase with a flow rate of 1.7 ml per minute and (c) a detection wavelength of 254 nm. If necessary adjust the proportions of acetonitrile and water  in the mobile phase to obtain a retention time of about 2.5 minutes for the principal peak. For solution (1) allow the chromatography to proceed for at least five times the retention time of the principal peak.

 

From any secondary peaks in the chromatogram obtained with solution (1) calculate the nominal content of each impurity with a retention time longer than that of impurity E identified from reference chromatogram B, supplied with trazodone hydrochloride impurity standard BPCRS. Use, as reference, the principal peak in the chromatogram obtained with solution (2). Disregard any peak with an area less than 0.1 times that of the principal peak in the chromatogram obtained with solution (2) (0.05%).

 

Loss on drying

 

When dried to constant weight at 105 at a pressure of 3.5 to 6.5 kPa, loses not more than 0.5% of its weight. Use 1 g.

 

Sulphated ash

 

Not more than 0.2%, Appendix IX A.

 

Assay

 

Dissolve 0.3 g in 60 ml of glacial acetic acid, add 5 ml of mercury(II) acetate solution and carry out Method I for non-aqueous titration, Appendix VIII A, determining the end point potentiometrically. Each ml of 0.1M perchloric acid VS is equivalent to 40.83 mg of C19H22ClN5O,HCl.

 

Storage

 

Trazodone Hydrochloride should be kept in an airtight container  and protected from light.

 

Action and use

 

Antidepressant.

 

IMPURITIES

 

A.    4-(3-chlorophenyl)-1-[3-(3-oxo-2,3-dihydro-1,2,4-triazolo[4,3-a]pyridin-2-yl)propyl]piperazine N1-oxide

 

B.    2-[3-(4-phenylpiperazin-1-yl)propyl]-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one

 

C.    2-3-[4-(4-chlorophenyl)piperazin-1-yl]propyl-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one

 

D.    2-3-[4-(3-bromophenyl)piperazin-1-yl]propyl-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one

 

E.    2-3-[4-(3-chloro-4-ethylphenyl)piperazin-1-yl]propyl-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one

 

F.    1-(3-chloropropyl)-3chlorophenylpiperazine

 

G.    3-[4-(3-chlorophenyl)piperazin-1-yl]propyl isobutyl ether

 

H.    1,3-bis-[4-(3-chlorophenyl)piperazin-1-yl]propane