Sertraline Hydrochloride

(Ph. Eur. monograph 1705)

C₁₇H₁₈Cl₃N    342.7    79559-97-0

Selective serotonin reuptake inhibitor; antidepressant.

Sertraline Tablets

Ph Eur

(1S,4S)-4-(3,4-Dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine hydrochloride.

97.5 per cent to 102.0 per cent (anhydrous substance).

White or almost white, crystalline powder.

Slightly soluble in water, sparingly soluble or slightly soluble in anhydrous ethanol, slightly soluble in acetone and in 2-propanol.

It shows polymorphism (5.9).

Carry out either tests A, B, C or tests B, C, D.

A. Specific optical rotation (2.2.7): + 38.8 to + 43.0 (anhydrous substance), measured at 25 °C.

Solvent mixture  Dilute 1 volume of a 103 g/L solution of hydrochloric acid R to 20 volumes with methanol R.

Dissolve 0.250 g in the solvent mixture and dilute to 25.0 mL with the solvent mixture.

B. Infrared absorption spectrophotometry (2.2.24).

Comparison  sertraline hydrochloride CRS.

If the spectra obtained in the solid state show differences, record new spectra using 10 g/L solutions in methylene chloride R.

C. Dissolve 10 mg in 5 mL of anhydrous ethanol R and add 5 mL of water R. The solution gives reaction (a) of chlorides (2.3.1).

D. Enantiomeric purity (see Tests).

Liquid chromatography (2.2.29).

diethylamine R, hexane R, 2-propanol R (1:40:60 V/V/V).

Dissolve 60.0 mg of the substance to be examined in the solvent mixture and dilute to 10.0 mL with the solvent mixture.

Dissolve the contents of a vial of sertraline for system suitability CRS (containing impurity G) in 1.0 mL of the solvent mixture.

Dilute 0.5 mL of the test solution to 100.0 mL with the solvent mixture.

• — size: l = 0.25 m, Ø = 4.6 mm;

• — stationary phase: silica gel AD for chiral separation R (5 µm).

Mobile phase  Mix 30 volumes of hexane R and 70 volumes of a mixture of 1 volume of diethylamine R, 25 volumes of 2-propanol R and 975 volumes of hexane R.

Flow rate  0.4 mL/min.

Detection  Spectrophotometer at 275 nm.

Injection  20 µL.

Run time  30 min.

Elution order  Sertraline, impurity G.

• — resolution: minimum 1.5 between the peaks due to sertraline and impurity G in the chromatogram obtained with reference solution (a);

• — signal-to-noise ratio: minimum 10 for the peak due to sertraline in the chromatogram obtained with reference solution (b).

• — impurity G: not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (b) (1.5 per cent).

Liquid chromatography (2.2.29).

Solvent mixture  Mobile phase A, mobile phase B (50:50 V/V).

Test solution  Dissolve 50.0 mg of the substance to be examined in the solvent mixture and dilute to 50.0 mL with the solvent mixture.

Reference solution (a)  Dissolve 5.0 mg of sertraline impurity E CRS (mandelic acid) in the solvent mixture and dilute to 25.0 mL with the solvent mixture. Dilute 1.0 mL of this solution to 100.0 mL with the solvent mixture.

Reference solution (b)  Dissolve 10 mg of benzoic acid R and 20 mg of mandelic acid R (impurity E) in the solvent mixture and dilute to 50.0 mL with the solvent mixture. Dilute 1.0 mL of this solution to 50.0 mL with the solvent mixture.

• — size: l = 0.25 m, Ø = 4.6 mm;

• — stationary phase: end-capped octadecylsilyl silica gel for chromatography R (3 µm).

• — mobile phase A: dissolve 1.0 g of sodium laurilsulfate R in 800 mL of water R and add 200 mL of acetonitrile R1; add 1.0 mL of phosphoric acid R and mix;

• — mobile phase B: dissolve 1.0 g of sodium laurilsulfate R in 100 mL of water R and add 900 mL of acetonitrile R1; add 1.0 mL of phosphoric acid R and mix;

Flow rate  1 mL/min.

Detection  Spectrophotometer at 220 nm.

Injection  10 µL.

Relative retention  With reference to sertraline (retention time = about 18 min): impurity E = about 0.2; benzoic acid = about 0.3.

System suitability  Reference solution (b):

• — resolution: minimum 5.0 between the peaks due to impurity E and benzoic acid.

• — impurity E: not more than the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent).

Gas chromatography (2.2.28): use the normalisation procedure.

Test solution  Introduce 0.250 g of the substance to be examined into a 15 mL stoppered centrifuge tube, add 2.0 mL of methanol R and 0.20 mL of a 25 per cent solution of potassium carbonate R and mix in a vortex mixer for 30 s. Add 8.0 mL of methylene chloride R, stopper the tube and mix in a vortex mixer for 60 s. Add 1 g of anhydrous sodium sulfate R, mix well and then centrifuge for about 5 min.

Reference solution (a)  Dissolve the contents of a vial of sertraline for peak identification CRS (containing impurities A, B, C and F) in 0.2 mL of methylene chloride R.

Reference solution (b)  Dilute 1.0 mL of the test solution to 100.0 mL with methylene chloride R. Dilute 1.0 mL of this solution to 20.0 mL with methylene chloride R.

• — material: fused silica;

• — size: l = 30 m, Ø = 0.53 mm;

• — stationary phase: polymethylphenylsiloxane R (film thickness 1.0 µm).

Carrier gas  helium for chromatography R.

Flow rate  9 mL/min.

Split ratio  1:10.

Temperature:

Detection  Flame ionisation.

Injection  1 µL.

Identification of impurities  Use the chromatogram supplied with sertraline for peak identification CRS and the chromatogram obtained with reference solution (a) to identify the peaks due to impurities A, B, C and F.

Relative retention  With reference to sertraline (retention time = about 24 min): impurity B = about 0.5; impurities C and D = about 0.7; impurity A = about 1.05; impurity F = about 1.1.

System suitability  Reference solution (a):

• — peak-to-valley ratio: minimum 15, where H_p = height above the baseline of the peak due to impurity A and H_v = height above the baseline of the lowest point of the curve separating this peak from the peak due to sertraline.

• — sum of impurities C and D: maximum 0.8 per cent;

• — impurities A, B, F: for each impurity, maximum 0.2 per cent;

• — unspecified impurities: for each impurity, maximum 0.10 per cent;

• — total: maximum 1.5 per cent;

• — disregard limit: the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05 per cent).

Maximum 20 ppm.

Dissolve 1.0 g in ethanol (96 per cent) R and dilute to 20.0 mL with the same solvent. 12 mL of the solution complies with test B. Prepare the reference solution using lead standard solution (1 ppm Pb) obtained by diluting lead standard solution (100 ppm Pb) R with ethanol (96 per cent) R.

Maximum 0.5 per cent, determined on 2.00 g.

Maximum 0.2 per cent, determined on 1.0 g.

Liquid chromatography (2.2.29).

Buffer solution  To 28.6 mL of glacial acetic acid R slowly add, while stirring and cooling, 34.8 mL of triethylamine R, and dilute to 100 mL with water R. Dilute 10 mL of this solution to 1000 mL with water R.

Test solution  Dissolve 55.0 mg of the substance to be examined in the mobile phase and dilute to 50.0 mL with the mobile phase. Dilute 5.0 mL of this solution to 100.0 mL with the mobile phase.

Reference solution  Dissolve 55.0 mg of sertraline hydrochloride CRS in the mobile phase and dilute to 50.0 mL with the mobile phase. Dilute 5.0 mL of this solution to 100.0 mL with the mobile phase.

• — size: l = 0.15 m, Ø = 3.9 mm;

• — stationary phase: octadecylsilyl silica gel for chromatography R (4 µm);

• — temperature: 30 °C.

Mobile phase  methanol R, buffer solution, acetonitrile R (15:40:45 V/V/V).

Flow rate  1.8 mL/min.

Detection  Spectrophotometer at 254 nm.

Injection  20 µL.

Run time  Twice the retention time of sertraline.

Retention time  Sertraline = about 1.9 min.

Calculate the percentage content of C₁₇H₁₈Cl₃N from the declared content of sertraline hydrochloride CRS.

Protected from light.

Specified impurities  A, B, C, D, E, F, G.

A. (1RS,4SR)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine,

B. (1RS,4RS)-N-methyl-4-phenyl-1,2,3,4-tetrahydronaphthalen-1-amine,

C. (1RS,4RS)-4-(4-chlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine,

D. (1RS,4RS)-4-(3-chlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine,

E. (2R)-hydroxyphenylacetic acid ((R)-mandelic acid),

F. (4R)-4-(3,4-dichlorophenyl)-3,4-dihydronaphthalen-1(2H)-one,

G. (1R,4R)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydronaphthalen-1-amine (sertraline enantiomer).

Ph Eur