Racecadotril

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

DEFINITION

Benzyl [[(2RS)-2-[(acetylsulfanyl)methyl]-3-phenylpropanoyl]amino]acetate.

Content

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

CHARACTERS

Appearance

White or almost white powder.

Solubility

Practically insoluble in water, freely soluble in methanol and in methylene chloride.

IDENTIFICATION

Infrared absorption spectrophotometry (2.2.24).

Comparison  racecadotril CRS.

TESTS

Appearance of solution

The solution is clear (2.2.1) and not more intensely coloured than reference solution Y6 (2.2.2, Method II). Dissolve 5.0 g in 10 mL of acetone R.

Related substances

Liquid chromatography (2.2.29).

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

Test solution (a) Dissolve 50.0 mg of the substance to be examined in the solvent mixture and dilute to 25.0 mL with the solvent mixture.

Test solution (b)  Dilute 5.0 mL of test solution (a) to 25.0 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) Prepare immediately before use. Dissolve 10 mg of racecadotril impurity A CRS in 5.0 mL of the solvent mixture. Dilute 1.0 mL of the solution to 10.0 mL with the solvent mixture. Dilute 1.0 mL of this solution to 100.0 mL with the solvent mixture.

Reference solution (c) Dissolve 5 mg of racecadotril impurity G CRS in the solvent mixture and dilute to 50 mL with the solvent mixture. To 5 mL of this solution add 1 mL of test solution (b) and dilute to 100 mL with the solvent mixture.

Reference solution (d) Dissolve 50.0 mg of racecadotril CRS in the solvent mixture and dilute to 25.0 mL with the solvent mixture. Dilute 5.0 mL of this solution to 25.0 mL with the solvent mixture.

Reference solution (e)  Dissolve 2 mg of racecadotril for peak identification CRS (containing impurities C, E and F) in 1.0 mL of the solvent mixture.

Column:

— size: l = 0.25 m, Ø = 4.0 mm;

— stationary phase: end-capped octadecylsilyl silica gel for chromatography R (5 µm);

— temperature: 30 °C.

Mobile phase:

— mobile phase A: dissolve 1.0 g of potassium dihydrogen phosphate R in water for chromatography R, adjust to pH 2.5 with phosphoric acid R and dilute to 1000 mL with water for chromatography R;

— mobile phase B: acetonitrile R1;

Flow rate  1.0 mL/min.

Detection  Spectrophotometer at 210 nm.

Injection  10 µL of the solvent mixture, test solution (a) and reference solutions (a), (b), (c) and (e).

Identification of impurities Use the chromatogram supplied with racecadotril for peak identification CRS and the chromatogram obtained with reference solution (e) to identify the peaks due to impurities C, E and F.

Relative retention With reference to racecadotril (retention time = about 16 min): impurity A = about 0.2; impurity C = about 0.3; impurity E = about 0.5; impurity F = about 0.9.

System suitability  Reference solution (c):

— resolution: minimum 1.5 between the peaks due to impurity G and racecadotril.

Limits:

— correction factors: for the calculation of content, multiply the peak areas of the following impurities by the corresponding correction factor: impurity C = 1.4; impurity E = 0.6; impurity F = 0.7;

— impurities C, E, F: for each impurity, not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) (0.2 per cent);

— impurity A: not more than the area of the corresponding 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 (a) (0.10 per cent);

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

— disregard limit: 0.5 times the area of the principal peak in the chromatogram obtained with reference solution (a) (0.05 per cent).

Loss on drying (2.2.32)

Maximum 0.5 per cent, determined on 1.000 g by drying in vacuo at 60 °C for 4 h.

Sulfated ash (2.4.14)

Maximum 0.1 per cent, determined on 1.0 g.

ASSAY

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

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

Calculate the percentage content of C₂₁H₂₃NO₄S taking into account the assigned content of racecadotril CRS.

IMPURITIES

Specified impurities  A, C, E, F.

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) B, D, G, H.

A. ethanethioic acid (thioacetic acid),

B. [[(2RS)-2-benzyl-3-sulfanylpropanoyl]amino]acetic acid,

C. [[(2RS)-2-[(acetylsulfanyl)methyl]-3-phenylpropanoyl]amino]acetic acid,

D. 5,10-dibenzyl-4,11-dioxo-7,8-dithia-3,12-diazatetradecanedioic acid,

E. 2-benzylprop-2-enoic acid (2-benzylacrylic acid),

F. benzyl [(2-benzylprop-2-enoyl)amino]acetate,

G. benzyl [[(2RS)-2-benzyl-3-sulfanylpropanoyl]amino]acetate,

H. dibenzyl 5,10-dibenzyl-4,11-dioxo-7,8-dithia-3,12-diazatetradecanedioate.