Pethidine hydrochloride

EUROPEAN PHARMACOPOEIA 5.0

IDENTIFICATION First identification : B, D. Second identification : A, C, D. A. Melting point (2.2.14) : 187 C to 190 C. B. Infrared absorption spectrophotometry (2.2.24). Comparison : Ph. Eur. reference spectrum of pethidine TESTS hydrochloride. C. Dissolve 0.1 g in 10 ml of ethanol R and add 10 ml Relative density (2.2.5) : 1.14 to 1.17. of picric acid solution R. A crystalline precipitate is Saponification value (2.5.6) : 230 to 255, determined on the formed which, when washed with water R and dried at residue obtained in the assay. 100-105 C, melts (2.2.14) at 186 C to 193 C. Mix equal Artificial balsams. Shake 0.20 g with 6 ml of light quantities of the precipitate and the substance to be petroleum R1. The light petroleum solution is clear and examined and determine the melting point of the mixture. colourless and the whole of the insoluble parts of the balsam The melting point is at least 20 C lower than that of the stick to the wall of the test-tube. precipitate. Fatty oils. Shake 1 g with 3 ml of a 1000 g/l solution of D. To 5 ml of solution S (see Tests) add 5 ml of water R. The chloral hydrate R. The resulting solution is as clear as the solution gives reaction (a) of chlorides (2.3.1). 1000 g/l solution of chloral hydrate R. TESTS Turpentine. Evaporate to dryness 4 ml of the solution Solution S. Dissolve 0.5 g in carbon dioxide-free water R obtained in the test for artificial balsams. The residue has and dilute to 25 ml with the same solvent. no odour of turpentine. Appearance of solution. Solution S is clear (2.2.1) and ASSAY colourless (2.2.2, Method II). To 2.50 g in a separating funnel add 7.5 ml of dilute sodium Acidity or alkalinity. To 10 ml of solution S add 0.2 ml hydroxide solution R and 40 ml of peroxide-free ether R of methyl red solution R and 0.2 ml of 0.01 M sodium and shake vigorously for 10 min. Separate the lower hydroxide. The solution is yellow. Add 0.3 ml of 0.01 M layer and shake it with three quantities, each of 15 ml, of hydrochloric acid. The solution is red. peroxide-free ether R. Combine the ether layers, dry over Impurity B. Liquid chromatography (2.2.29). 10 g of anhydrous sodium sulphate R and filter. Wash the sodium sulphate with two quantities, each of 10 ml, Test solution (a). Dissolve 0.100 g of the substance to be of peroxide-free ether R. Combine the ether layers and examined in a mixture of 20 volumes of acetonitrile R and evaporate to dryness. Dry the residue (esters) at 100 C to 80 volumes of water R and dilute to 25.0 ml with the same 105 C for 30 min and weigh. mixture of solvents. Test solution (b). Dissolve 0.125 g of the substance to be STORAGE examined in a mixture of 20 volumes of acetonitrile R and Store protected from light. 80 volumes of water R and dilute to 10.0 ml with the same mixture of solvents. Reference solution (a). Dilute 0.5 ml of test solution (a) to 01/2005:0420 100.0 ml with a mixture of 20 volumes of acetonitrile R and 80 volumes of water R. Reference solution (b). Dissolve 10.0 mg of pethidine PETHIDINE HYDROCHLORIDE impurity A CRS in a mixture of 20 volumes of acetonitrile R and 80 volumes of water R and dilute to 100.0 ml with the Pethidini hydrochloridum same mixture of solvents. Reference solution (c). Dissolve 12.5 mg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine R in a mixture of 20 volumes of acetonitrile R and 80 volumes of water R and dilute to 10.0 ml with the same mixture of solvents. Dilute 1.0 ml of the solution to 100.0 ml with a mixture of 20 volumes of acetonitrile R and 80 volumes of C15H22ClNO2 Mr 283.8 water R. Reference solution (d). Dilute 5.0 ml of reference solution (b) DEFINITION and 1.0 ml of reference solution (c) to 100.0 ml with a mixture of 20 volumes of acetonitrile R and 80 volumes of water R. Ethyl 1-methyl-4-phenylpiperidine-4-carboxylate hydrochloride. Column : Content : 99.0 per cent to 101.0 per cent (dried substance). size : l = 0.25 m, = 4.0 mm, 2216 See the information section on general monographs (cover pages)

solution of phosphomolybdic acid R in alcohol R, using 10 ml for a plate 200 mm square and examine the plate in daylight while heating at 100 C to 105 C for 5 min to 10 min. The zones due to benzyl benzoate and benzyl cinnamate are coloured blue against a yellow background. The chromatogram obtained with the reference solution shows at about the middle a violet-grey zone (thymol). In the chromatogram obtained with the test solution, a blue zone (nerolidol) is seen just below the level of the zone due to thymol in the chromatogram obtained with the reference solution. Just below the zone due to nerolidol, no blue zone is seen corresponding to a quenching zone seen when examined in ultraviolet light at 254 nm (colophony). In the upper and lower part of the chromatogram obtained with the test solution, other faint blue zones may be seen.

PRODUCTION If intended for use in the manufacture of parenteral dosage forms, the manufacturing process is validated to show that the content of impurity B is not more than 0.1 ppm. CHARACTERS Appearance : white, crystalline powder. Solubility : very soluble in water, freely soluble in alcohol.

EUROPEAN PHARMACOPOEIA 5.0

Phenazone

stationary phase: spherical end-capped octadecylsilyl silica gel for chromatography R (5 m) with a specific surface area of 340 m2/g, a pore size of 10 nm and a carbon loading of 19 per cent. Mobile phase : mobile phase A : mix equal volumes of a 42.0 g/l solution of sodium perchlorate R and of a 11.6 g/l solution of phosphoric acid R, adjust to pH 2.0 with triethylamine R, mobile phase B : acetonitrile R,
Time (min) 0 - 15 15 - 31 31 - 40 40 - 41 41 - 50 Mobile phase A (per cent V/V) 80 75 75 55 55 55 80 80 Mobile phase B (per cent V/V) 20 25 25 45 45 45 20 20

STORAGE In an airtight container, protected from light. LABELLING The label states, where applicable, that the substance is suitable for use in the manufacture of parenteral dosage forms. IMPURITIES

Flow rate : 1.0 ml/min. Detection : spectrophotometer at 210 nm. Injection : 50 l ; inject test solution (b) and reference solution (d). Relative retention with reference to pethidine (retention time = about 24 min) : impurity B = about 0.66 ; impurity A = about 0.68. System suitability : reference solution (d) : signal-to-noise ratio : minimum 10 for the first peak, peak-to-valley ratio : minimum 4, where Hp = height above the baseline of the peak due to impurity B, and Hv = height above the baseline of the lowest point of the curve separating this peak from the peak due to impurity A. Limit : impurity B : not more than the area of the corresponding peak in the chromatogram obtained with reference B. 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), solution (d) (10 ppm) if intended for non-parenteral use. Related substances. Liquid chromatography (2.2.29) as described in the test for impurity B with the following modifications. Injection : 20 l ; inject test solution (a) and reference solution (a). Limits : I. ethyl (4RS)-1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine any impurity : not more than the area of the principal 4-carboxylate. peak in the chromatogram obtained with reference solution (a) (0.5 per cent), 01/2005:0421 total: not more than twice the area of the principal peak in the chromatogram obtained with reference solution (a) PHENAZONE (1.0 per cent), disregard limit : 0.1 times the area of the principal peak Phenazonum in the chromatogram obtained with reference solution (a) (0.05 per cent). Loss on drying (2.2.32) : maximum 0.5 per cent, determined on 1.000 g by drying in an oven at 100-105 C. Sulphated ash (2.4.14) : maximum 0.1 per cent, determined on 1.0 g. ASSAY Dissolve 0.220 g in 50 ml of alcohol R. Add 5.0 ml of 0.01 M hydrochloric acid. Titrate with 0.1 M sodium hydroxide determining the end-point potentiometrically (2.2.20). Read the volume added between the 2 points of inflexion. 1 ml of 0.1 M sodium hydroxide is equivalent to 28.38 mg of C15H22ClNO2. General Notices (1) apply to all monographs and other texts C11H12N2O

A. R1 = CH3, R2 = H : 1-methyl-4-phenylpiperidine (MPP), C. R1 = CH3, R2 = CO2H : 1-methyl-4-phenylpiperidine-4carboxylic acid, D. R1 = CH3, R2 = CO2-CH3 : methyl 1-methyl-4phenylpiperidine-4-carboxylate, E. R1 = H, R2 = CO2-CH2-CH3 : ethyl 4-phenylpiperidine-4carboxylate, F. R1 = CH2-C6H5, R2 = CO2H : 1-benzyl-4-phenylpiperidine-4carboxylic acid, G. R1 = CH3, R2 = CO2-CH(CH3)2 : 1-methylethyl 1-methyl-4-phenylpiperidine-4-carboxylate, H. R1 = CH2-C6H5, R2 = CO2-CH2-CH3 : ethyl 1-benzyl-4-phenylpiperidine-4-carboxylate, J. R1 = CH2-CH3, R2 = CO2-CH2-CH3 : ethyl 1-ethyl-4-phenylpiperidine-4-carboxylate,

Mr 188.2

DEFINITION Phenazone contains not less than 99.0 per cent and not more than the equivalent of 100.5 per cent of 1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one, calculated with reference to the dried substance. 2217