Mirtazapine

Edition: BP 2025 (Ph. Eur. 11.6 update)

(Ph. Eur. monograph 2338)

C₁₇H₁₉N₃             265.4           85650-52-8

Action and use

Inhibitor of 5HT and noradrenaline reuptake; antidepressant.

Preparations

Mirtazapine Tablets

Mirtazapine Oral Solution

Mirtazapine Orodispersible Tablets

Ph Eur

DEFINITION

(14bRS)-2-Methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine.

Content

99.0 per cent to 101.0 per cent (anhydrous substance).

CHARACTERS

Appearance

White or almost white powder, slightly hygroscopic to hygroscopic.

Solubility

Practically insoluble in water, freely soluble in anhydrous ethanol.

It shows polymorphism (5.9).

IDENTIFICATION

Infrared absorption spectrophotometry (2.2.24).

Comparison mirtazapine CRS.

If the spectra obtained in the solid state show differences, dissolve the substance to be examined and the reference substance separately in anhydrous ethanol R, evaporate to dryness and record new spectra using the residues.

TESTS

Optical rotation (2.2.7)

-0.10° to + 0.10° (anhydrous substance).

Dissolve 0.250 g in anhydrous ethanol R and dilute to 25.0 mL with the same solvent.

Related substances

Liquid chromatography (2.2.29).

Solvent mixture acetonitrile R, water R (50:50 V/V).

Buffer solution Dissolve 18.0 g of tetramethylammonium hydroxide R in 950 mL of water R. While stirring, adjust to pH 7.4 with phosphoric acid R, then dilute to 1000 mL with water R and mix.

Test solution Dissolve 30 mg of the substance to be examined in the solvent mixture and dilute to 20 mL with the solvent mixture.

Reference solution (a) Dissolve 3 mg of mirtazapine for system suitability CRS (containing impurities A, B, C, D, E and F) in 2 mL of the solvent mixture.

Reference solution (b) Dilute 1.0 mL of the test solution to 100.0 mL with the solvent mixture. Dilute 1.0 mL of this solution to 10.0 mL with the solvent mixture.

Column:

• size: l = 0.25 m, Ø = 4.6 mm;
• stationary phase: end-capped octadecylsilyl silica gel for chromatography R (5 μm);
• temperature: 40 °C.

Mobile phase tetrahydrofuran for chromatography R, methanol R, acetonitrile R, buffer solution (7.5:12.5:15:65 V/V/V/V).

Flow rate 1.5 mL/min.

Detection Spectrophotometer at 240 nm.

Injection 10 μL.

Run time Twice the retention time of mirtazapine.

Identification of impurities Use the chromatogram supplied with mirtazapine for system suitability CRS and the chromatogram obtained with reference solution (a) to identify the peaks due to impurities A, B, C, D, E and F.

Relative retention With reference to mirtazapine (retention time = about 25 min): impurity A = about 0.2; impurity B = about 0.3; impurity C = about 0.35; impurity D = about 0.4; impurity E = about 1.3; impurity F = about 1.35.

System suitability:

• resolution: minimum 1.5 between the peaks due to impurities E and F in the chromatogram obtained with reference solution (a);
• symmetry factor: 0.8 to 2.0 for the principal peak in the chromatogram obtained with reference solution (b).

Limits:

• correction factors: for the calculation of content, multiply the peak areas of the following impurities by the corresponding correction factor: impurity A = 1.3; impurity B = 1.3; impurity F = 0.2;
• impurities A, B, C, D, E, F: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.1 per cent);
• unspecified impurities: for each impurity, not more than the area of the principal peak in the chromatogram obtained with reference solution (b) (0.10 per cent);
• total: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (b) (0.2 per cent);
• disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.05 per cent).

Water (2.5.12)

Maximum 3.5 per cent, determined on 1.00 g.

Sulfated ash (2.4.14)

Maximum 0.1 per cent, determined on 1.0 g.

ASSAY

Dissolve 0.100 g in 35 mL of glacial acetic acid R. Titrate with 0.1 M perchloric acid, determining the end-point potentiometrically (2.2.20).

1 mL of 0.1 M perchloric acid is equivalent to 13.27 mg of C₁₇H₁₉N₃.

STORAGE

In an airtight container.

IMPURITIES

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

A. (14bRS)-2-methyl-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine 2-oxide,

B. [2-[(2RS)-4-methyl-2-phenylpiperazin-1-yl]pyridin-3-yl]methanol,

C. (14bRS)-2-methyl-3,4,10,14b-tetrahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepin-1(2H)-one,

D. (14bRS)-1,2,3,4,10,14b-hexahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepine,

E. (2RS)-4-methyl-1-(3-methylpyridin-2-yl)-2-phenylpiperazine,

F. (14bRS)-2-methyl-1,3,4,14b-tetrahydropyrazino[2,1-a]pyrido[2,3-c][2]benzazepin-10(2H)-one.

Ph Eur