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1、欢迎您阅读并下载本文档，本文档来源于互联网整理，如有侵权请联系删除!我们将竭诚为您提供优质的文档！Atorvastatin calcium trihydrateEUROPEAN PHARMACOPOEIA 7.1J. methyl 3-(2RS)-2-bromopropanoylamino-4-methylthiophene-2-carboxylate (bromo compound).04/2011:2191ATORVASTATIN CALCIUM TRIHYDRATEAtorvastatinum calcicum trihydricumC66H68CaF2N4O10,3H2OMr12093
2、44423-98-9DEFINITIONCalcium (3R,5R)-7-2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl-3,5-dihydroxyheptanoatetrihydrate.Content: 97.0 per cent to 102.0 per cent (anhydrous substance).CHARACTERSAppearance: white or almost white powder.Solubility: very slightly soluble
3、 in water, slightly solublein ethanol (96 per cent), practically insoluble in methylenechloride.It shows polymorphism (5.9).IDENTIFICATIONA. Infrared absorption spectrophotometry (2.2.24).Comparison: atorvastatin calcium trihydrate CRS.If the spectra obtained in the solid state show differences,diss
4、olve the substance to be examined and the referencesubstance separately in methanol R, evaporate to drynessand record new spectra using the residues.B. Enantiomeric purity (see Tests).C. Water (see Tests).D. Ignite. The residue gives reaction (b) of calcium (2.3.1).Filtration may be necessary in cas
5、e the residuedoes notcompletely dissolve.TESTSEnantiomeric purity. Liquid chromatography (2.2.29).Solvent mixture: anhydrous ethanol R, methanol R(50:50 V/V).Test solution. Dissolve 10 mg of the substance to be examinedin 4 mL of the solvent mixture and dilute to 10.0 mL withhexane R.Reference solut
6、ion (a). Dissolve 2 mg of atorvastatinimpurity E CRS in methanol R and dilute to 20.0 mL with thesame solvent (solution A). Dissolve 10 mg of the substance to beexamined in 1.25 mL of methanol R, add 0.75 mL of solution Aand 2 mL of anhydrous ethanol R and dilute to 10.0 mL withhexane R.Reference so
7、lution (b). To 2.0 mL of the test solution add40.0 mL of the solvent mixture and dilute to 100.0 mL withhexane R. To 3.0 mL of this solution add 5 mL of the solventmixture and dilute to 20.0 mL with hexane R.Column: size: l = 0.25 m, = 4.6 mm; stationary phase: amylose derivative of silica gel forch
8、romatography R (10 m).Mobile phase: trifluoroacetic acid R, anhydrous ethanol R,hexane R (0.1:6:94 V/V/V).Flow rate: 1.0 mL/min.Detection: spectrophotometer at 244 nm.Injection: 20 L.Run time: 1.2 times the retention time of atorvastatin.Relative retention with reference to atorvastatin (retentionti
9、me = about 44 min): impurity E = about 0.8.System suitability: reference solution (a): resolution : minimum 2.0 between the peaks due toimpurity E and atorvastatin.Limit: impurity E: not more than the area of the principal peakin the chromatogram obtained with reference solution (b)(0.3 per cent).Re
10、lated substances. Liquid chromatography (2.2.29).Test solution (a). Dissolve 40.0 mg of the substance to beexamined in dimethylformamide R and dilute to 100.0 mL withthe same solvent.Test solution (b). Dissolve 50 mg of the substance to beexamined in dimethylformamide R and dilute to 50.0 mL withthe
11、 same solvent.Reference solution (a). Dissolve 40.0 mg of atorvastatincalcium trihydrate CRS in dimethylformamide R and dilute to100.0 mL with the same solvent.Reference solution (b). Dilute 1.0 mL of test solution (b) to100.0 mL with dimethylformamide R. Dilute 1.0 mL of thissolution to 10.0 mL wit
12、h dimethylformamide R.Reference solution (c). Dissolve 2.5 mg of atorvastatinimpurity A CRS, 2.5 mg of atorvastatin impurity B CRS,2.5 mg of atorvastatin impurity C CRS, 2.5 mg of atorvastatinimpurity D CRS and 2.5 mg of the substance to be examinedin dimethylformamide R and dilute to 50.0 mL with t
13、he samesolvent.Column: size: l = 0.25 m, = 4.6 mm; stationary phase: octylsilyl silica gel for chromatography R(5 m); temperature: 35 C.Mobile phase: mobile phase A: tetrahydrofuran R, acetonitrile R, 3.9 g/Lsolution of ammonium acetate R adjusted to pH 5.0 withglacial acetic acid R (12:21:67 V/V/V)
14、; mobile phase B: tetrahydrofuran R, 3.9 g/L solution ofammonium acetate R adjusted to pH 5.0 with glacial aceticacid R, acetonitrile R (12:27:61 V/V/V);Time(min)Mobile phase A(per cent V/V)Mobile phase B(per cent V/V)0 - 40100040 - 701002008070 - 8520080100Flow rate: 1.5 mL/min.Detection: spectroph
15、otometer at 244 nm.Injection: 20 L of test solution (b) and reference solutions (b)and (c).Identification of impurities: use the chromatogram obtainedwith reference solution (c) to identify the peaks due toimpurities A, B, C and D.3380See the information section on general monographs (cover pages)欢迎
16、您阅读并下载本文档，本文档来源于互联网整理，如有侵权请联系删除!我们将竭诚为您提供优质的文档！EUROPEAN PHARMACOPOEIA 7.1Atorvastatin calcium trihydrateRelative retention with reference to atorvastatin(retention time = about 33 min): impurity A = about 0.8;impurity B = about 0.9; impurity C = about 1.2;impurity D = about 2.1.If necessary, adjust
17、the mobile phase by increasing or decreasingthe percentage of acetonitrile or the pH of the ammoniumacetate solution to achieve a retention time of about 33 min foratorvastatin. For example, raising the pH would decrease theretention time of atorvastatin.System suitability: reference solution (c): r
18、esolution : minimum 1.5 between the peaks due toimpurity B and atorvastatin.Limits: impurities A, B: for each impurity, not more than 3 timesthe area of the principal peak in the chromatogram obtainedwith reference solution (b) (0.3 per cent); impurities C, D: for each impurity, not more than 1.5 ti
19、mesthe area of the principal peak in the chromatogram obtainedwith reference solution (b) (0.15 per cent); unspecified impurities: for each impurity, not more than thearea of the principal peak in the chromatogram obtainedwith reference solution (b) (0.10 per cent); total: not more than 15 times the
20、 area of the principal peakin the chromatogram obtained with reference solution (b)(1.5 per cent); disregard limit: 0.5 times the area of the principal peak in thechromatogram obtained with reference solution (b) (0.05 percent); disregard the peak due to dimethylformamide.Sodium: maximum 0.4 per cen
21、t (anhydrous substance).Atomic absorption spectrometry (2.2.23, Method I).Solvent mixture: hydrochloric acid R, water R, methanol R(2:25:75 V/V/V).Test solution. Dissolve 5.0 mg in the solvent mixture and diluteto 100.0 mL with the solvent mixture.Reference solutions. Prepare the reference solutions
22、 usingsodium standard solution (50 ppm Na) R, diluting with thesolvent mixture.Source: sodium hollow-cathode lamp.Wavelength: 589.0 nm.Atomisation device: air-acetylene flame.Heavy metals (2.4.8): maximum 20 ppm.Solvent mixture: water R, methanol R (10:90 V/V).It complies with test H with the follow
23、ing modifications.Test solution. Dissolve 0.250 g of the substance to be examinedin 30 mL of the solvent mixture.Reference solution. Dilute 0.5 mL of lead standard solution(10 ppm Pb) R to 30 mL with the solvent mixture.Blank solution: 30 mL of the solvent mixture.Water (2.5.12): 3.5 per cent to 5.5
24、 per cent, determined on0.130 g.ASSAYLiquid chromatography (2.2.29) as described in the test forrelated substances with the following modification.Injection: test solution (a) and reference solution (a).Calculate the percentage content of C66H68CaF2N4O10from thedeclared content of atorvastatin calci
25、um trihydrate CRS.IMPURITIESSpecified impurities: A, B, C, D, E.Other detectable impurities (the followingsubstances would,if present at a sufficient level, be detected by one or other ofthe tests in the monograph. They are limited by the generalacceptance criterion for other/unspecified impurities
26、and/orby the general monograph Substances for pharmaceutical use(2034). It is therefore not necessary to identify these impuritiesfor demonstration of compliance. See also 5.10. Control ofimpurities in substances for pharmaceutical use): F, G, H.A. (3R,5R)-3,5-dihydroxy-7-5-(1-methylethyl)-2,3-diphe
27、nyl-4-(phenylcarbamoyl)-1H-pyrrol-1-ylheptanoic acid(desfluoroatorvastatin),B. (3RS,5SR)-7-2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl-3,5-dihydroxyheptanoicacid,C. (3R,5R)-7-2,3-bis(4-fluorophenyl)-5-(1-methylethyl)-4-(phenylcarbamoyl)-1H-pyrrol-1-yl-3,5-dihydro
28、xyheptanoicacid (fluoroatorvastatin),D. 3-(4-fluorophenyl)carbonyl-2-(2-methylpropanoyl)-N,3-diphenyloxirane-2-carboxamide,E. (3S,5S)-7-2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl-3,5-dihydroxyheptanoicacid (ent-atorvastatin),General Notices (1) apply to all mono
29、graphs and other texts3381欢迎您阅读并下载本文档，本文档来源于互联网整理，如有侵权请联系删除!我们将竭诚为您提供优质的文档！Atorvastatin calcium trihydrateEUROPEAN PHARMACOPOEIA 7.1F. (3R,5R)-7-(3R,5R)-7-2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl-3,5-dihydroxyheptanoylamino-3,5-dihydroxyheptanoic acid,G. (3R,5
30、R)-7-2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-yl-5-hydroxy-3-methoxyheptanoic acid (3-O-methylatorvastatin),H. (4R,6R)-6-2-2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-(phenylcarbamoyl)-1H-pyrrol-1-ylethyl-4-hydroxytetrahydro-2H-pyran-2-one.3382See the information section on general monographs (cover pages)
