Clomethiazole Capsules

Hypnotic.

Clomethiazole Capsules contain a solution of Clomethiazole in a suitable fixed oil.

The capsules comply with the requirements stated under Capsules and with the following requirements.

92.5 to 107.5% of the stated amount.

A. Shake a quantity of the contents of the capsules containing 20 mg of Clomethiazole with 70 mL of 0.1m hydrochloric acid for 15 minutes and dilute to 100 mL with the same solvent. Filter and dilute 10 mL of the filtrate to 50 mL with 0.1m hydrochloric acid. The light absorption of the resulting solution, Appendix II B, in the range 230 to 350 nm exhibits a maximum only at 257 nm.

B. To a quantity of the contents of the capsules containing 0.3 g of Clomethiazole add 10 mL of 0.1m hydrochloric acid and shake. To the aqueous layer add 5 mL of 1m sodium hydroxide, mix and extract with 15 mL of chloroform. Dry the chloroform layer with anhydrous sodium sulfate, filter and evaporate to remove the solvent. The infrared absorption spectrum of a thin film of the residue, Appendix II A, is concordant with the reference spectrum of clomethiazole (RS 051).

C. Mix a quantity of the contents of the capsules containing 0.1 g of Clomethiazole with 0.2 g of powdered sodium hydroxide, heat to fusion and continue heating for a further few seconds. Cool, add 0.5 mL of water and a slight excess of 2m hydrochloric acid and warm. Any fumes evolved do not turn moistened starch iodate paper blue (distinction from clomethiazole edisilate).

Carry out the method for liquid chromatography, Appendix III D, using the following solutions.

(1) Add 100 mL of 1m sulfuric acid to whole capsules containing a total of 0.96 g of Clomethiazole, immerse in a water bath for 20 seconds, remove from the bath and shake vigorously. Repeat this treatment until the capsule shells have dissolved without exceeding a total heating time of 1 minute. Cool, centrifuge, filter the aqueous layer (Whatman GF/C paper is suitable) and dilute 5 mL of the filtrate to 50 mL with the mobile phase.

(2) Dilute 1 volume of solution (1) to 200 volumes with the mobile phase.

(3) Dilute 1 volume of a 0.030% w/v solution of 4-methyl-5-vinylthiazole edisilate BPCRS in methanol (solution A) to 50 volumes with the mobile phase.

(4) Dilute 1 volume of a 0.020% w/v solution of 5-(2-chloroethyl)-4-methyl-3-[2-(4-methylthiazol-5-yl)ethyl]thiazolium chloride BPCRS (quaternary dimer) in methanol (solution B) to 50 volumes with the mobile phase.

(5) Dilute 1 volume of a 0.020% w/v solution of 4-methyl-5-(2-hydroxyethyl)thiazole BPCRS in methanol (solution C) to 50 volumes with the mobile phase.

(6) Add 1 mL each of solutions A, B and C to 5 mL of the filtrate obtained in the preparation of solution (2) and dilute to 50 mL with the mobile phase.

(a) Use a stainless steel column (20 cm × 4 mm) packed with octadecylsilyl silica gel for chromatography (10 µm) (Lichrosorb RP18 is suitable).

(b) Use isocratic elution and the mobile phase described below.

(c) Use a flow rate of 1 mL per minute.

(d) Use an ambient column temperature.

(e) Use a detection wavelength of 257 nm.

(f) Inject 20 µL of each solution.

30 volumes of methanol and 70 volumes of a solution containing 0.13% w/v of sodium hexanesulfonate and 2.7% w/v of tetramethylammonium hydrogen sulfate, adjusted to pH 2.0 with 5m sodium hydroxide.

The test is not valid unless in the chromatogram obtained with solution (6) baseline separation is achieved between the peaks due to the three specified impurities and also between each of these peaks and the principal peak.

Calculate the content of each of the specified impurities with reference to the stated content of Clomethiazole in the capsules expressing the content of 4-methyl-5-vinyl-thiazole as the base (1 mg of 4-methyl-5-vinylthiazole edisilate is equivalent to 0.568 mg of its base). Calculate the content of each of any other impurities from the areas of their peaks in the chromatogram obtained with solution (1) using the principal peak in the chromatogram obtained with solution (2) as reference and assuming the same response as clomethiazole.

The content of each of the three specified impurities is not greater than 1.5% and the content of any other impurity is not greater than 0.5%. The total content of all the impurities is not greater than 3.0%.

Carry out Method I for non-aqueous titration, Appendix VIII A, using a quantity of the mixed contents of 20 capsules containing 0.4 g of Clomethiazole and crystal violet solution as indicator. Each mL of 0.1m perchloric acid VS is equivalent to 16.16 mg of C₆H₈ClNS.