Anastrozole

(Ph Eur monograph 2406)

C₁₇H₁₉N₅    293.4     120511-73-1

Aromotase inhibitor; treatmentof breast carcinoma.

Ph Eur

2,2′-[5-(1H-1,2,4-Triazol-1-ylmethyl)benzene-1,3-diyl]bis(2-methylpropanenitrile).

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

White or almost white powder.

Very slightly soluble in water, freely soluble in anhydrous ethanol, practically insoluble in cyclohexane.

It shows polymorphism (5.9).

Infrared absorption spectrophotometry (2.2.24).

Comparison    anastrozole CRS.

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

Liquid chromatography (2.2.29).

Solvent mixture    acetonitrile R1, water for chromatography R (50:50 V/V).

Test solution (a)    Dissolve 25 mg of the substance to be examined in the solvent mixture and dilute to 100.0 mL with the solvent mixture.

Test solution (b)    Dissolve 25.0 mg of the substance to be examined in the solvent mixture and dilute to 200.0 mL with the solvent mixture.

Reference solution (a)    Dilute 1.0 mL of test solution (a) 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 (b)    Dissolve 2.5 mg of anastrozole impurity E CRS in 20.0 mL of the solvent mixture. Dilute 1.0 mL of the solution to 50.0 mL with test solution (a).

Reference solution (c)    Dissolve 25.0 mg of anastrozole CRS in the solvent mixture and dilute to 200.0 mL with the solvent mixture.

• — size: l = 0.15 m, Ø = 4.6 mm;

• — stationary phase: end-capped polar-embedded octadecylsilyl amorphous organosilica polymer R (3.5 µm).

• — mobile phase A: phosphoric acid R, water for chromatography R (0.1:100 V/V);

• — mobile phase B: phosphoric acid R, acetonitrile R1 (0.1:100 V/V);

Flow rate    1.0 mL/min.

Detection    Spectrophotometer at 215 nm.

Injection    20 µL of test solution (a) and reference solutions (a) and (b).

Identification of impurities    Use the chromatogram obtained with reference solution (b) to identify the peak due to impurity E.

Relative retention    With reference to anastrozole (retention time = about 29 min): impurity E = about 1.05.

System suitability    Reference solution (b):

• — resolution: minimum 3.5 between the peaks due to anastrozole and impurity E.

• — for each impurity, use the concentration of anastrozole in reference solution (a).

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

• — total: maximum 0.2 per cent;

• — reporting threshold: 0.05 per cent.

Maximum 0.3 per cent, determined on 50.0 mg.

Maximum 0.1 per cent, determined on 1.0 g.

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

Injection    Test solution (b) and reference solution (c).

Calculate the percentage content of C₁₇H₁₉N₅ taking into account the assigned content of anastrozole CRS.

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): A, B, C, D, E, F, G, H, I.

A. 2-[3-[(1RS)-1-cyanoethyl]-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropanenitrile,

B. (2RS)-2,3-bis[3-(1-cyano-1-methylethyl)-5-(1H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropanenitrile,

C. 2,2′-[5-(bromomethyl)benzene-1,3-diyl]bis(2-methylpropanenitrile),

D. 2,2′-[5-(dibromomethyl)benzene-1,3-diyl]bis(2-methylpropanenitrile),

E. 2,2′-[5-(hydroxymethyl)benzene-1,3-diyl]bis(2-methylpropanenitrile),

F. 4-methylbenzenesulfonic acid,

G. 2,2′-[5-(4H-1,2,4-triazol-4-ylmethyl)benzene-1,3-diyl]bis(2-methylpropanenitrile),

H. 2,2′-(5-methylbenzene-1,3-diyl)bis(2-methylpropanenitrile),

I. 2,2′-[5-(chloromethyl)benzene-1,3-diyl]bis(2-methylpropanenitrile).

Ph Eur