EUROPEAN PHARMACOPOEIA 5.0 Nomegestrol acetate

D. R = S-CH2-CH2-NH2 : 2-[[[2-[(dimethylamino)methyl]thiaz-ol-4-yl]methyl]sulphanyl]ethanamine,

E. R = S-CH2-CH2-NH-CO-CH2-NO2 :N-[2-[[[2-[(dimethyl-amino)methyl]thiazol-4-yl]methyl]sulphanyl]ethyl]-2-ni-troacetamide,

I. R = S-CH2-CH2-NH-CO-NH-CH3 :N-[2-[[[2-[(dimethyl-amino)methyl]thiazol-4-yl]methyl]sulphanyl]ethyl]-N′-me-thylurea,

J. R = OH: [2-[(dimethylamino)methyl]thiazol-4-yl]methanol,

F. (EZ)-N1,N1′-[thiazole-2,4-diylbis(methylenesulphanediyl-ethylene)]bis(N′-methyl-2-nitroethene-1,1-diamine),

G. N,N′-bis[2-[[[2-[(dimethylamino)methyl]thiazol-4-yl]methyl]sulphanyl]ethyl]-2-nitroethene-1,1-diamine,

H. 2-(dimethylamino)thioacetamide,

K. 3-(methylamino)-5,6-dihydro-2H-1,4-thiazin-2-one oxime.

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NOMEGESTROL ACETATE

Nomegestroli acetas

C23H30O4 Mr 370.5

DEFINITIONNomegestrol acetate contains not less than 97.0 per centand not more than the equivalent of 103.0 per cent of6-methyl-3,20-dioxo-19-norpregna-4,6-dien-17-yl acetate,calculated with reference to the dried substance.

CHARACTERSA white or almost white, crystalline powder, practicallyinsoluble in water, freely soluble in acetone, soluble inalcohol.

IDENTIFICATIONExamine by infrared absorption spectrophotometry (2.2.24),comparing with the spectrum obtained with nomegestrolacetate CRS.

TESTS

Appearance of solution. Dissolve 1.0 g in methylenechloride R and dilute to 10 ml with the same solvent. Thesolution is clear (2.2.1) and not more intensely colouredthan reference solution Y5 (2.2.2, Method II).

Specific optical rotation (2.2.7). Dissolve 0.500 g inethanol R and dilute to 25.0 ml with the same solvent. Thespecific optical rotation is −60.0 to −64.0, calculated withreference to the dried substance.

Related substances. Examine by liquid chromatography(2.2.29).Test solution. Dissolve 25.0 mg of the substance to beexamined in methanol R and dilute to 50.0 ml with the samesolvent.Reference solution (a). Dilute 1.0 ml of the test solution to200.0 ml with the mobile phase.Reference solution (b). Dissolve 25.0 mg of nomegestrolacetate impurity A CRS in methanol R and dilute to 50.0 mlwith the same solvent.Reference solution (c). Dissolve 25.0 mg of nomegestrolacetate CRS in 20 ml ofmethanol R, add 0.25 ml of referencesolution (b) and dilute to 50.0 ml with the mobile phase.The chromatographic procedure may be carried out using :— a stainless steel column 0.25 m long and 4.6 mm in

internal diameter packed with octadecylsilyl silica gel forchromatography R (5 µm),

— as mobile phase at a flow rate of 1.3 ml/min a mixture of24 volumes of acetonitrile R, 38 volumes of methanol Rand 38 volumes of water R,

— as detector, a variable wavelength spectrophotometercapable of operating at 245 nm and at 290 nm.

Inject 10 µl of reference solution (c) and record thechromatogram with the detector set at 245 nm.When the chromatogram is recorded in the prescribedconditions, the retention times are : nomegestrol acetateabout 17 min and impurity A about 18.5 min. Adjust thesensitivity of the system at 245 nm so that the height of thepeak due to impurity A in the chromatogram obtained withreference solution (c) is at least 50 per cent of the full scaleof the recorder.Measure the height Hp above the baseline of the peak dueto impurity A and the height Hv above the baseline of thelowest point of the curve separating this peak from the peakdue to nomegestrol acetate. The test is not valid unless Hp isgreater than 5 times Hv.Inject 10 µl of reference solution (a) and record thechromatogram with the detector set at 290 nm. Adjust thesensitivity of the system at 290 nm so that the height of the

General Notices (1) apply to all monographs and other texts 2113

Nonoxinol 9 EUROPEAN PHARMACOPOEIA 5.0

principal peak in the chromatogram obtained with referencesolution (a) is at least 50 per cent of the full scale of therecorder.Inject 10 µl of the test solution and record the chromatogramsat 245 nm and 290 nm for 1.5 times the retention time ofthe principal peak.In the chromatogram obtained with the test solution at290 nm: the area of any peak, apart from the principal peak,is not greater than 0.2 times the area of the principal peakin the chromatogram obtained with reference solution (a)(0.1 per cent). Disregard any peak with an area less than0.04 times that of the principal peak in the chromatogramobtained with reference solution (a) (0.02 per cent). In thechromatogram obtained with the test solution at 245 nm: thearea of any peak corresponding to impurity A is not greaterthan 0.4 times the area of the peak due to impurity A in thechromatogram obtained with reference solution (c) (0.2 percent) ; the area of any peak, apart from the principal peakand any peak corresponding to impurity A, is not greaterthan 0.2 times the area of the peak due to impurity A in thechromatogram obtained with reference solution (c) (0.1 percent). Disregard any peak with an area less than 0.1 timesthat of the peak due to impurity A in the chromatogramobtained with reference solution (c) (0.05 per cent).In the chromatograms obtained at 290 nm and 245 nm, thesum of the related substances apart from impurity A is notgreater than 0.3 per cent.

Loss on drying (2.2.32). Not more than 0.5 per cent,determined on 1.000 g by drying in an oven at 100-105 °C.

ASSAYDissolve 50.0 mg in ethanol R and dilute to 100.0 ml withthe same solvent. Dilute 2.0 ml of the solution to 100.0 mlwith ethanol R. Measure the absorbance (2.2.25) at themaximum at 287 nm.Calculate the content of C23H30O4 taking the specificabsorbance to be 685.

STORAGEStore protected from light.

IMPURITIES

A. 6α-methyl-3,20-dioxo-19-norpregn-4-en-17-yl acetate.

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NONOXINOL 9

Nonoxinolum 9DEFINITIONα-(4-Nonylphenyl)-ω-hydroxynona(oxyethylene).Mixture consisting mainly of monononylphenylethers of macrogols corresponding to the formula :C9H19C6H4-[OCH2-CH2]n-OH where the average value of n is 9.It may contain free macrogols.

CHARACTERSAppearance : clear, colourless or light yellow, viscous liquid.Solubility : miscible with water, with alcohol and withvegetable oils.

IDENTIFICATIONA. Infrared absorption spectrophotometry (2.2.24).

Comparison : Ph. Eur. reference spectrum ofnonoxinol 9.Preparation : film between sodium chloride R plates.

B. It complies with the test for cloud point (see Tests).

TESTS

Acidity or alkalinity. Boil 1.0 g with 20 ml of carbondioxide-free water R for 1 min, with constant stirring.Cool and filter. To 10 ml of the filtrate, add 0.05 ml ofbromothymol blue solution R1. Not more than 0.5 ml of0.01 M hydrochloric acid or 0.01 M sodium hydroxide isrequired to change the colour of the indicator.Hydroxyl value (2.5.3, Method A) : 84 to 94.

Cloud point : 52 °C to 58 °C.Dissolve 1.0 g in 99 g of water R. Transfer about 30 ml ofthis solution into a test-tube, heat on a water-bath and stircontinuously until the solution becomes cloudy. Remove thetest-tube from the water-bath (ensuring that the temperaturedoes not increase more than 2 °C) and continue to stir.The cloud point is the temperature at which the solutionbecomes sufficiently clear that the entire thermometer bulbis plainly seen.

Ethylene oxide and dioxan (2.4.25) : maximum 1 ppm ofethylene oxide and maximum 10 ppm of dioxan.Heavy metals (2.4.8) : maximum 10 ppm.Dissolve 2.0 g in distilled water R and dilute to 20.0 ml withthe same solvent. 12 ml of this solution complies with limittest A. Prepare the standard using lead standard solution(1 ppm Pb) R.

Water (2.5.12) : maximum 0.5 per cent, determined on 2.00 g.

Total ash (2.4.16) : maximum 0.4 per cent, determined on1.0 g.

STORAGEIn an airtight container.

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NORADRENALINE HYDROCHLORIDE

Noradrenalini hydrochloridum

C8H12ClNO3 Mr 205.6

DEFINITION

(R)-2-Amino-1-(3,4-dihydroxyphenyl)ethanol hydrochloride.Content : 98.5 per cent to 101.0 per cent (anhydroussubstance).

CHARACTERSAppearance : white or brownish-white, crystalline powder.Solubility : very soluble in water, slightly soluble in alcohol.It becomes coloured on exposure to air and light.

2114 See the information section on general monographs (cover pages)