Halothane

C2HBrClF3 197.4

Action and use General anaesthetic.

DEFINITION

Halothane is (RS)-2-bromo-2-chloro-1,1,1-trifluoroethane to which 0.01 per cent m/m of thymol has

been added.

CHARACTERS

A clear, colourless, mobile, heavy, non-flammable liquid, slightly soluble in water, miscible with

ethanol, with ether and with trichloroethylene.

IDENTIFICATION

First identification: B.

Second identification: A, C.

A. It complies with the test for distillation range (see Tests).

B. Examine by infrared absorption spectrophotometry (2.2.24), comparing with the Ph. Eur. Reference spectrum of halothane. Examine the substance in a 0.1 mm cell.

C. Add 0.1 ml of the substance to be examined to 2 ml of 2-methyl-2-propanol R in a test-tube. Add

1 ml of copper edetate solution R, 0.5 ml of concentrated ammonia R and a mixture of 0.4 ml of strong hydrogen peroxide solution R and 1.6 ml of water R (solution a). Prepare a blank at the same time (solution b). Place both tubes in a water-bath at 50°C for 15 min, cool and add 0.3 ml of glacial acetic acid R. To 1 ml of each of solutions (a) and (b) add 0.5 ml of a mixture of equal volumes of freshly prepared alizarin S solution R and zirconyl nitrate solution R. Solution (a) is yellow and solution (b) is red.

To 1 ml of each of solutions (a) and (b) add 1 ml of buffer solution pH 5.2 R, 1 ml of phenol red

solution R diluted 1 in 10 with water R and 0.1 ml of chloramine solution R. Solution (a) is bluish-violet and solution (b) is yellow.

To 2 ml of each of solutions (a) and (b) add 0.5 ml of a mixture of 25 volumes of sulphuric acid R and 75 volumes of water R, 0.5 ml of acetone R and 0.2 ml of a 50 g/l solution of potassium bromate R and shake. Warm the tubes in a water-bath at 50°C for 2 min, cool and add 0.5 ml of a mixture of equal volumes of nitric acid R and water R and 0.5 ml of silver nitrate solution R2. Solution (a) is opalescent and a white precipitate is formed after a few minutes; solution (b) remains clear.

TESTS

Acidity or alkalinity To 20 ml add 20 ml of carbon dioxide-free water R, shake for 3 min and allow to stand. Separate the aqueous layer and add 0.2 ml of bromocresol purple solution R. Not more than 0.1 ml of 0.01M sodium hydroxide or 0.6 ml of 0.01M hydrochloric acid is required to change the colour of the indicator.

Relative density (2.2.5). 1.872 to 1.877.

Distillation range (2.2.11). It distils completely between 49.0°C and 51.0°C, 95 per cent distilling

within a range of 1.0°C.

Volatile related substances Examine by gas chromatography (2.2.28), using trichlorotrifluoroethane

CRS as the internal standard.

Test solution (a). Use the substance to be examined.

Test solution (b). Dilute 5.0 ml of trichlorotrifluoroethane CRS to 100.0 ml with the substance to be

examined. Dilute 1.0 ml of the solution to 100.0 ml with the substance to be examined. Dilute

1.0 ml of this solution to 10.0 ml with the substance to be examined.

The chromatographic procedure may be carried out using:

— a column 2.75 m long and 5 mm in internal diameter packed with silanised diatomaceous earth for gas chromatography R1 (180 μm to 250 μm), the first 1.8 m being impregnated with 30 per cent

m/m of macrogol 400 R and the remainder with 30 per cent m/m of dinonyl phthalate R,

— nitrogen for chromatography R as the carrier gas at a flow rate of 30 ml/min,

— a flame-ionisation detector,

maintaining the temperature of the column at 50°C. Inject 5 μl of test solutions (a) and (b).

In the chromatogram obtained with test solution (b), the sum of the areas of the peaks, apart from the principal peak and the peak due to the internal standard, is not greater than the area of the peak due to the internal standard, corrected if necessary for any impurity with the same retention time as the internal standard (0.005 per cent).

Bromides and chlorides To 10 ml add 20 ml of water R and shake for 3 min. To 5 ml of the

aqueous layer add 5 ml of water R, 0.05 ml of nitric acid R and 0.2 ml of silver nitrate solution R1. The solution is not more opalescent than a mixture of 5 ml of the aqueous layer and 5 ml of water R.

Bromine and chlorine To 10 ml of the aqueous layer obtained in the test for bromides and

chlorides add 1 ml of potassium iodide and starch solution R. No blue colour is produced.

Thymol Examine by gas chromatography (2.2.28), using menthol R as the internal standard.

Internal standard solution. Dissolve 0.10 g of menthol R in methylene chloride R and dilute to 100.0 ml with the same solvent.

Test solution. To 20.0 ml of the substance to be examined add 5.0 ml of the internal standard

solution.

Reference solution. Dissolve 20.0 mg of thymol R in methylene chloride R and dilute to 100.0 ml with the same solvent. To 20.0 ml, add 5.0 ml of the internal standard solution.

The chromatographic procedure may be carried out using:

— a fused-silica capillary column 15 m long and 0.53 mm in internal diameter coated with a 1.5 μm

film of polydimethylsiloxane R,

— nitrogen for chromatography R as the carrier gas at a flow rate of 15 ml/min,

— a flame-ionisation detector,

maintaining the temperature of the column at 150°C and that of the injection port at 170°C and of

the detector at 200°C.

Inject separately 1.0 μl of the internal standard solution and of the test and reference solutions. In

the chromatogram obtained with the test solution, the area of the peak due to thymol is not less than

75 per cent and not more than 115 per cent of the area of the corresponding peak in the chromatogram obtained with the reference solution (0.008 per cent m/m to 0.012 per cent m/m).

Non-volatile matter Evaporate 50 ml to dryness on a water-bath and dry the residue in an oven at

100°C to 105°C for 2 h. The residue weighs not more than 1 mg (20 mg/l).

STORAGE

Store in an airtight container, protected from light, at a temperature not exceeding 25°C. The choice

of material for the container is made taking into account the particular reactivity of halothane with

certain metals

Дата добавления: 2014-12-26