Clomethiazole Capsules

General Notices

Action and use

Hypnotic.

Definition

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.

Content of clomethiazole, C6H8ClNS

92.5 to 107.5% of the stated amount.

Identification

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).

TEST

Related substances

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

(1) Add 100 mL of 1m sulfuric acid to whole capsules containing a total of 0.96 g of Clomethiazole. Immerse in a boiling 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.
(3) Dilute 1 volume of a 0.030% w/v solution of clomethiazole impurity A BPCRS (equivalent to 0.02% w/v impurity A as base) in methanol (solution A) to 50 volumes.
(4) Dilute 1 volume of a 0.020% w/v solution of clomethiazole impurity B BPCRS (quaternary dimer) in methanol (solution B) to 50 volumes.
(5) Dilute 1 volume of a 0.020% w/v solution of clomethiazole impurity C BPCRS in methanol (solution C) to 50 volumes.
(6) Add 1 mL each of solutions A, B and C to 5 mL of solution (2) and dilute to 50 mL.
chromatographic conditions
(a) Use a stainless steel column (25 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.
mobile phase

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.

system suitability

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.

limits

In the chromatogram obtained with solution (1):

the area of any peak corresponding to impurity A is not greater than 3 times the area of the principal peak in the chromatogram obtained with solution (2) (1.5%);

the area of any peak corresponding to impurity B is not greater than 3 times the area of the principal peak in the chromatogram obtained with solution (2) (1.5%);

the area of any peak corresponding impurity C is not greater than 3 times the area of the principal peak in the chromatogram obtained with solution (2) (1.5%);

the area of any other secondary peak is not greater than the area of the principal peak in the chromatogram obtained with solution (2) (0.5%);

the sum of all of the secondary peaks is not greater than 6 times the area of the principal peak in the chromatogram obtained with solution (2) (3.0%).

Disregard any peak with an area less than 0.2 times the principal peak in the chromatogram obtained with solution (2) (0.1%).

Assay

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.

IMPURITIES

The impurities limited by this monograph include those listed under Clomethiazole.