Friday, 17 July 2009

Monographs: Pharmaceutical substances: Carbamazepinum - Carbamazepine

Molecular formula. C15H12N2O

Relative molecular mass. 236.3

Graphic formula.

Chemical name. 5H-Dibenz[b,f]azepine-5-carboxamide; CAS Reg. No. 298-46-4.

Description. A white to yellowish white, crystalline powder; odourless or almost odourless.

Solubility. Practically insoluble in water and ether R; soluble in ethanol (~750 g/l) TS.

Category. Antiepileptic drug.

Storage. Carbamazepine should be kept in a tightly closed container.


Definition. Carbamazepine contains not less than 98.0% and not more than 102.0% of C15H12N2O, calculated with reference to the dried substance.

Identity tests

• Either test A or tests B, C and D may be applied.

A. Carry out the examination as described under 1.7 Spectrophotometry in the infrared region. The infrared absorption spectrum obtained from the test substance without pretreatment is concordant with the spectrum obtained from carbamazepine RS or with the reference spectrum of carbamazepine.

B. See the test described below under "Related substances". The principal spot obtained with solution C corresponds in position, appearance, and intensity with that obtained with solution D.

C. Expose a small amount of the test substance to ultraviolet light (365 nm); an intense blue fluorescence is observed.

D. Heat 0.1 g with 2 ml of nitric acid (~1000 g/l) TS in a water-bath for 3 minutes; an orange-red colour is produced.

Melting range. 189-193 °C.

Heavy metals. Use 1.0 g for the preparation of the test solution as described under 2.2.3 Limit test for heavy metals, Procedure 3; determine the heavy metals content according to Method A; not more than 10 μg/g.

Sulfated ash. Not more than 1.0 mg/g.

Loss on drying. Dry to constant weight at 105°C; it loses not more than 5.0 mg/g.

Acidity or alkalinity. Stir 1.0 g with 20 ml of carbon-dioxide-free water R for 15 minutes and filter. To 10 ml of the filtrate add 0.1 ml of phenolphthalein/ethanol TS and titrate with carbonate-free sodium hydroxide (0.01 mol/l) VS; not more than 0.5 ml is required to obtain a pink colour. Add 0.15 ml of methyl red/ethanol TS and titrate with hydrochloric acid (0.01 mol/l) VS; not more than 1.0 ml is required to obtain a red colour.

Related substances. Carry out the test as described under 1.14.1 Thin-layer chromatography, using silica gel R6 as the coating substance and a mixture of 86 volumes of toluene R and 14 volumes of methanol R as the mobile phase. Apply separately to the plate 2 μl of each of 5 solutions in a mixture of equal volumes of ethanol (~750 g/l) TS and chloroform R containing (A) 0.050 g of the test substance per ml, (B) 0.050 mg of iminodibenzyl R per ml, (C) 5.0 mg of the test substance per ml, (D) 5.0 mg of carbamazepine RS per ml, and (E) 5.0 μg of carbamazepine RS per ml. After removing the plate from the chromatographic chamber, allow it to dry in air, spray it with potassium dichromate TS3, and examine the chromatogram in daylight. Any spot obtained with solution A, other than the principal spot, is not more intense than that obtained with solution B. Then heat the plate at 140 °C for 15 minutes and examine the chromatogram in ultraviolet light (254 nm). Any additional spot obtained with solution A is not more intense than that obtained with solution E.

Assay. Dissolve about 0.1 g, accurately weighed, in sufficient ethanol (~750 g/l) TS to produce 100 ml. Dilute 10 ml of this solution to 100 ml with the same solvent, and again dilute 10 ml of this dilution to 100 ml with ethanol (~750 g/l) TS. Measure the absorbance of a 1-cm layer of the resulting solution at the maximum at about 285 nm. Calculate the amount of C15H12N2O in the substance being tested by comparison with carbamazepine RS, similarly and concurrently examined. In an adequately calibrated spectrophotometer the absorbance of the reference solution should be 0.49 ± 0.02.

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