瑞舒伐他汀钙EP分析方法25-03

Reference:PA/PH/Exp.P4/T (11)36ANP XXXX:2631ROSUVASTATIN CALCIUMRosuvastatinum calcicumC 44H 54CaF 2N 6O 12S 2M r 1001[147098-20-2]DEFINITION Calcium bis[(3R ,5S ,6E )-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoate].Content :97.0per cent to 102.0per cent (anhydrous substance).CHARACTERSAppearance :white or almost white,hygroscopic powder.Solubility :slightly soluble in water,freely soluble in methylene chloride,practically insoluble in anhydrous ethanol.IDENTIFICATIONA.Infrared absorption spectrophotometry (2.2.24).Comparison :rosuvastatin calcium CRS .B.Enantiomeric purity (see Tests).Results :the principal peak in the chromatogram obtained with the test solution is similar in retention time to the principal peak in the chromatogram obtained with reference solution (c).C.It gives reaction (b)of calcium (2.3.1).TESTSRelated substances .Liquid chromatography (2.2.29).Carry out the test protected from light.Test solution .Dissolve 35.0mg of the substance to be examined in 12mL of acetonitrile for chromatography R and dilute to 50.0mL with water for chromatography R .Reference solution (a).Dissolve 35.0mg of rosuvastatin calcium CRS in 12mL of acetonitrile for chromatography R and dilute to 50.0mL with water for chromatography R .Reference solution (b).To 1.0mL of the test solution add 24mL of acetonitrile forchromatography R and dilute to 100.0mL with water for chromatography R .To 2.0mL of this solution add 2mL of acetonitrile for chromatography R and dilute to 10.0mL with water for chromatography R .Reference solution (c).In order to prepare impurity B in situ ,dissolve 10mg of the substance to be examined in 10mL of a 1per cent V/V solution of trifluoroacetic acid R in acetonitrile for chromatography R .Stopper and heat at 40°C for 1h.Cool,add 20mL of water forchromatography R and adjust to pH 6-8with a 42g/L solution of sodium hydroxide R .Dilute to 50mL with water for chromatography R .Reference solution (d).Dissolve 5mg of rosuvastatin impurity A CRS in 10mL of acetonitrile forReference solution(e).In order to prepare impurity C in situ,heat0.25g of the substance to be examined at50°C for7days in amber glassware with a porous cover(57).Dissolve50mg in11mL of acetonitrile for chromatography R,add3.0mL of reference solution(c)and1.0mL of reference solution(d).Dilute to50.0mL with water for chromatography R.Column:–size:l=0.15m,Ø=3.0mm;–stationary phase:base-deactivated end-capped octadecylsilyl silica gel for chromatography R (3µm)(58);–temperature:40°C.Mobile phase:–mobile phase A:1per cent V/V solution of trifluoroacetic acid R,acetonitrile for chromatography R,water for chromatography R(1:29:70V/V/V);–mobile phase B:1per cent V/V solution of trifluoroacetic acid R,water for chromatography R, acetonitrile for chromatography R(1:24:75V/V/V);Time (min)Mobile phase A(per cent V/V)Mobile phase B(per cent V/V)0-30100030-50100ĺ600ĺ4050-6060ĺ040ĺ10060-750100Flow rate:0.75mL/min.Detection:spectrophotometer at242nm.Injection:10µL of the test solution and reference solutions(b)and(e).Identification of impurities:use the chromatogram obtained with reference solution(e)to identify the peaks due to impurities A,B and C.Relative retention with reference to rosuvastatin(retention time=about25min):impurity A=about0.9;impurity B=about1.1;impurity C=about1.5.System suitability:reference solution(e):–resolution:minimum2.0between the peaks due to rosuvastatin and impurity B.Calculation of percentage contents:–correction factor:multiply the peak area of impurity C by2.1;–for each impurity,use the concentration of rosuvastatin in reference solution(b).Limits:–impurity C:maximum0.6per cent;–impurity B:maximum0.5per cent;–impurity A:maximum0.2per cent;–unspecified impurities:for each impurity,maximum0.10per cent;–total:maximum1.2per cent;–reporting threshold:0.05per cent.(57)Place a small vial containing the substance inside a small beaker and then cover the beaker withfilter paper secured with an elastic band.The following chromatogram is shown for information but will not be published in the EuropeanPharmacopoeia.1.impurity A 3.impurity B 5.impurity E7.impurity F2.rosuvastatin 4.impurity C 6.impurity JFigure2631.-1.–Chromatogram for the test for related substances of rosuvastatin calcium: reference solution(e)spiked with impurities E,F and JEnantiomeric purity.Liquid chromatography(2.2.29).Prepare the solutions immediately before use and protect them from light throughout the test.Solvent mixture:acetonitrile for chromatography R,water for chromatography R(25:75V/V). Test solution.Dissolve25.0mg of the substance to be examined in6mL of acetonitrile for chromatography R and dilute to25.0mL with water for chromatography R.Reference solution(a).Dilute1.0mL of the test solution to100.0mL with the solvent mixture. Dilute1.0mL of this solution to10.0mL with the solvent mixture.Reference solution(b).Dissolve5mg of rosuvastatin impurity G CRS in a mixture of12mLof acetonitrile for chromatography R and10mL of water for chromatography R with the aid of ultrasound and dilute to50.0mL with water for chromatography R.Reference solution(c).To25mg of the substance to be examined add1.0mL of reference solution(b),6mL of acetonitrile for chromatography R and dissolve with the aid of ultrasound; dilute to25mL with water for chromatography R.Column:–size:l=0.15m,Ø=4.6mm;–stationary phase:silica gel OJ for chiral separations R(5µm)(59);–temperature:35°C.Mobile phase:acetonitrile for chromatography R,0.1per cent V/V solution of trifluoroaceticacid R(25:75V/V).Flow rate:0.5mL/min.Detection:spectrophotometer at254nm.Injection:10µL of the test solution and reference solutions(a)and(c).Run time:3times the retention time of rosuvastatin.Identification of impurities:use the chromatogram supplied with rosuvastatin impurity G CRS and the chromatogram obtained with reference solution(c)to identify the peak due to impurity G. Relative retention with reference to rosuvastatin(retention time=about25min):impurity G=about 0.9.System suitability:reference solution(c):–resolution:minimum1.5between the peaks due to impurity G and rosuvastatin.Calculation of percentage content:–use the concentration of rosuvastatin in reference solution(a).Limit:–impurity G:maximum0.1per cent.The following chromatogram is shown for information but will not be published in the EuropeanPharmacopoeia.1.impurity G2.rosuvastatinFigure2631.-2.–Chromatogram for the test for enantiomeric purity of rosuvastatin calcium:reference solution(c)Chlorides:maximum0.2per cent.Dissolve0.15g in60mL of water R by heating to boiling while stirring.Add4mL of dilute nitric acid R,allow to cool to room temperature and titrate with0.01M silver nitrate,determining the end-point potentiometrically(2.2.20)using a silver indicator electrode and a silver-silver chloride reference electrode.1.0mL of0.01M silver nitrate is equivalent to0.3545mg of Cl.ASSAYLiquid chromatography(2.2.29)as described in the test for related substances with the following modification.Injection:test solution and reference solution(a).Calculate the percentage content of C44H54CaF2N6O12S2taking into account the assigned contentof rosuvastatin calcium CRS.STORAGEIn an airtight container protected from light at a temperature of2°C to8°C.IMPURITIESSpecified impurities:A,B,C,G.Other detectable impurities(the following substances would,if present at a sufficient level,be detected by one or other of the tests in the monograph.They are limited by the general acceptance criterion for other/unspecified impurities and/or by the general monograph Substances for pharmaceutical use(2034).It is therefore not necessary to identify these impurities for demonstration of compliance.See also5.10.Control of impurities in substances for pharmaceutical use):D,E,F,H,I,J.A.(3R,5S,6E)-7-[4-(4-fluorophenyl)-2-[[(2-hydroxy-2-methylpropyl)sulfonyl](methyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid,B.(3RS,5RS,6E)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid,C.(3R,6E)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]-D.N-[4-(4-fluorophenyl)-5-[(E)-2-[(2S,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl]ethenyl]-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide,E.(3R,5S,6E)-7-[4-(4-fluorophenyl)-2-[([2-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]-2-hydroxyethyl]sulfonyl)(methyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid,F.1,1-dimethylethyl[(4R,6S)-6-[(E)-2-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]ethenyl]-2,2-dimethyl-1,3-dioxan-4-yl]acetate,G.(3S,5R,6E)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid,H.(3R,5RS)-5-[8-fluoro-2-[methyl(methylsulfonyl)amino]-4-(propan-2-yl)-5,6-I.(3S,5RS)-5-[8-fluoro-2-[methyl(methylsulfonyl)amino]-4-(propan-2-yl)-5,6-dihydrobenzo[h]quinazolin-6-yl]-3,5-dihydroxypentanoic acid,J.(3R,5S,6E)-7-[4-(4-fluorophenyl)-2-[([(E)-2-[4-(4-fluorophenyl)-2-[methyl(methylsulfon-yl)amino]-6-(propan-2-yl)pyrimidin-5-yl]ethenyl]sulfonyl)(methyl)amino]-6-(propan-2-yl)pyri-midin-5-yl]-3,5-dihydroxyhept-6-enoic acid.。