Carbocisteine

(Ph. Eur. monograph 0885)

C₅H₉NO₄S    179.2    638-23-3

Mucolytic.

Ph Eur

Carbocisteine contains not less than 98.5 per cent and not more than the equivalent of 101.0 per cent of (2R)-2-amino-3-[(carboxymethyl)sulfanyl]propanoic acid, calculated with reference to the dried substance.

A white or almost white, crystalline powder, practically insoluble in water and in alcohol. It dissolves in dilute mineral acids and in dilute solutions of alkali hydroxides.

First identification  A, B.

Second identification  A, C, D.

A. Specific optical rotation (see Tests).

B. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the spectrum obtained with carbocisteine CRS. Examine the substances prepared as discs.

C. Examine the chromatograms obtained in the test for ninhydrin-positive substances. The principal spot in the chromatogram obtained with test solution (b) is similar in position, colour and size to the principal spot in the chromatogram obtained with reference solution (a).

D. Dissolve 0.1 g in 4.5 mL of dilute sodium hydroxide solution R. Heat on a water-bath for 10 min. Cool and add 1 mL of a 25 g/L solution of sodium nitroprusside R. A dark red colour is produced, which changes to brown and then to yellow within a few minutes.

Disperse 5.00 g in 20 mL of water R and add dropwise with shaking 2.5 mL of strongsodium hydroxide solution R. Adjust to pH 6.3 with 1 M sodium hydroxide and dilute to 50.0 mL with water R.

Solution S is clear (2.2.1) and colourless (2.2.2, Method II).

Shake 0.2 g with 20 mL of carbon dioxide-free water R. The pH of the suspension is 2.8 to 3.0.

- 32.5 to - 35.5, determined on solution S and calculated with reference to the dried substance.

Examine by thin-layer chromatography (2.2.27), using a suitable silica gel as the coating substance.

Test solution (a)  Dissolve 0.10 g of the substance to be examined in dilute ammonia R2 and dilute to 10 mL with the same solvent.

Test solution (b)  Dilute 1 mL of test solution (a) to 50 mL with water R.

Reference solution (a)  Dissolve 10 mg of carbocisteine CRS in dilute ammonia R2 and dilute to 50 mL with the same solvent.

Reference solution (b)  Dilute 5 mL of test solution (b) to 20 mL with water R.

Reference solution (c)  Dissolve 10 mg of carbocisteine CRS and 10 mg of arginine hydrochloride CRS in 5 mL of dilute ammonia R2 and dilute to 25 mL with water R.

Apply separately to the plate 5 µL of each solution. Allow the plate to dry in air. Develop over a path of 15 cm using a mixture of 20 volumes of glacial acetic acid R, 20 volumes of water R and 60 volumes of butanol R. Dry the plate in a current of warm air. Spray with ninhydrin solution R and heat at 100 °C to 105 °C for 15 min. Any spot in the chromatogram obtained with test solution (a), apart from the principal spot, is not more intense than the spot in the chromatogram obtained with reference solution (b) (0.5 per cent). The test is not valid unless the chromatogram obtained with reference solution (c) shows two clearly separated principal spots.

Dissolve 33 mg in 5 mL of dilute nitric acid R and dilute to 15 mL with water R. The solution, without further addition of nitric acid, complies with the limit test for chlorides (0.15 per cent).

Dissolve 0.5 g in 5 mL of dilute hydrochloric acid R and dilute to 15 mL with distilled water R. The solution complies with the limit test for sulfates (300 ppm).

2.0 g complies with limit test D for heavy metals (10 ppm). Prepare the standard using 2 mL of lead standard solution (10 ppm Pb) R.

Not more than 0.5 per cent, determined on 1.000 g by drying in an oven at 105 °C for 2 h.

Not more than 0.3 per cent, determined on 1.0 g.

Dissolve 0.150 g in 10 mL of anhydrous formic acid R with slight heating and shake until dissolution is complete. Add 50 mL of anhydrous 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 17.92 mg of C₅H₉NO₄S.

Store protected from light.

Ph Eur