Docetaxel Trihydrate

(Ph. Eur. monograph 2449)

C₄₃H₅₃NO₁₄,3H₂O    862    148408-66-6

Taxane cytotoxic.

Ph Eur

5β,20-epoxy-1,7β,10β-Trihydroxy-9-oxotax-11-ene-2α,4,13α-triyl 4-acetate 2-benzoate 13-[(2R,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-3-phenylpropanoate] trihydrate.

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

White or almost white, crystalline powder.

Practically insoluble in water, freely soluble in anhydrous ethanol, soluble in methylene chloride.

A. Specific optical rotation (see Tests).

B. Infrared absorption spectrophotometry (2.2.24).

Comparison   docetaxel trihydrate CRS.

The solution is not more opalescent than reference suspension II (2.2.1) and not more intensely coloured than reference solution B₅ (2.2.2, Method I).

Dissolve 1.0 g in anhydrous ethanol R and dilute to 20 mL with the same solvent.

-41.5 to -38.5 (anhydrous substance).

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

Liquid chromatography (2.2.29).

Solvent mixture  acetic acid R, acetonitrile R1, water R (0.05:50:50 V/V/V).

Test solution  Dissolve 50.0 mg of the substance to be examined in 2.5 mL of anhydrous ethanol R and dilute to 50.0 mL with the solvent mixture.

Reference solution (a)  Dissolve 50.0 mg of docetaxel trihydrate CRS in 2.5 mL of anhydrous ethanol R and dilute to 50.0 mL with 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.

Reference solution (c)  Dissolve 5 mg of docetaxel for system suitability CRS (containing impurities A, B and C) in 0.25 mL of anhydrous ethanol R and dilute to 5.0 mL with the solvent mixture.

• — size: l = 0.15 m, Ø = 4.6 mm;

• — stationary phase: end-capped octadecylsilyl silica gel for chromatography R (3.5 µm);

• — temperature: 45 °C.

• — mobile phase A: water R;

• — mobile phase B: acetonitrile R1;

Flow rate  1.2 mL/min.

Detection  spectrophotometer at 232 nm.

Injection  10 µL of the test solution and reference solutions (b) and (c).

Identification of impurities  Use the chromatogram supplied with docetaxel for system suitability CRS and the chromatogram obtained with reference solution (c) to identify the peaks due to impurities A, B and C.

Relative retention  With reference to docetaxel (retention time = about 27 min): impurity A = about 0.97; impurity B = about 1.08; impurity C = about 1.13.

System suitability  Reference solution (c):

• — resolution: minimum 3.0 between the peaks due to impurity A and docetaxel.

• — correction factor: for the calculation of content, multiply the peak area of impurity A by 1.6;

• — impurity A: not more than 5 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.5 per cent);

• — impurities B, C: for each impurity, not more than 3 times the area of the principal peak in the chromatogram obtained with reference solution (b) (0.3 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 10 times the area of the principal peak in the chromatogram obtained with reference solution (b) (1.0 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).

Maximum 20 ppm.

Solvent mixture  water R, dimethylformamide R (15:85 V/V).

Dissolve, using sonication, 1.0 g in the solvent mixture and dilute to 20 mL with the solvent mixture. 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 the solvent mixture.

5.0 per cent to 7.0 per cent.

Inject 200 µL of a 100 mg/mL solution of the substance to be examined in dimethylformamide R.

Maximum 0.1 per cent, determined on 1.0 g.

Less than 0.3 IU/mg, if intended for use in the manufacture of parenteral preparations without a further appropriate procedure for the removal of bacterial endotoxins.

Liquid chromatography (2.2.29) as described in the test for related substances with the following modification.

Injection  10 µL of the test solution and reference solution (a).

Calculate the percentage content of C₄₃H₅₃NO₁₄ taking into account the assigned content of docetaxel trihydrate CRS.

Protected from light.

Specified impurities   A, B, C.

Other detectable impurities (the following substances would, if present at a sufficient level, be detected by one or other of the tests in the monograph. They are limited by the general acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use (2034). It is therefore not necessary to identify these impurities for demonstration of compliance. See also 5.10. Control of impurities in substances for pharmaceutical use): D.

A. 5β,20-epoxy-1,7β,10β-trihydroxy-9-oxotax-11-ene-2α,4,13α-triyl 4-acetate 13-[(2R,3S)-3-[[(1,1dimethylethoxy)carbonyl]amino]-2-hydroxy-3-phenylpropanoate] 2-[(2E)-2-methylbut-2-enoate] (2-O-desbenzoyl-2-O-tiglyldocetaxel),

B. 5β,20-epoxy-1,7β-dihydroxy-9,10-dioxotax-11-ene-2α,4,13α-triyl 4-acetate 2-benzoate 13-[(2R,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-3-phenylpropanoate] (10-deoxy-10-oxodocetaxel),

C. 5β,20-epoxy-1,7α,10β-trihydroxy-9-oxotax-11-ene-2α,4,13α-triyl 4-acetate 2-benzoate 13-[(2R,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-3-phenylpropanoate] (7-epi-docetaxel),

D. 5β,20-epoxy-1,7α-dihydroxy-9,10-dioxotax-11-ene-2α,4,13α-triyl 4-acetate 2-benzoate 13-[(2R,3S)-3-[[(1,1-dimethylethoxy)carbonyl]amino]-2-hydroxy-3-phenylpropanoate] (10-deoxy-10-oxo-7-epi-docetaxel).

Ph Eur