阿托伐他汀Atorvastatin全套杂质信息列表

阿托伐他汀钙片说明书【药品名称】通用名称：阿托伐他汀钙片商品名称：阿托伐他汀钙片(立普妥)英文名称：Atorvastatin Calcium Tablets拼音全码：ATuoFaTaTingGaiPian(LiPuTuo)【主要成份】本品的主要成分是阿托伐他汀钙，化学名称为：EP,-(R’，R’)]-2-(4-氟苯基)一B·6一二羟基一5一(1-甲基乙基)一3-苯基-4-[(苯胺)基关]－1－氢一吡咯-1-庚酸钙三水台物。

【性状】本品为白色椭圆形薄膜衣片。

【适应症/功能主治】高胆固醇血症原发性高胆固醇血症患者。

包括家族性高胆固醇血症（杂合子型）或混合型高脂血症（相当于Fredrickson分类法的IIa和IIb型）患者，如果饮食治疗和其他非药物治疗疗效不满意，应用本品可治疗其总胆固醇（TC）升高、低密度脂蛋白胆固醇（LDL-C）升高、载脂蛋白B(Apo B)升高和甘油三酯（TG）升高。

在纯合子家族性高胆固醇血症患者，阿托伐他汀可与其他降脂疗法（如LDL血浆透析法）合用或单独使用（当无其他治疗手段时），以降低TC和LDL-C。

冠心病冠心病或冠心病等危症（如：糖尿病、症状性动脉粥样硬化疾病等）合并高胆固醇血症或混合型血脂异常的患者，本品适用于：降低非致死性心肌梗死的风险，降低致死性和非致死性卒中的风险、降低血管重建术的风险，降低因充血性心力衰竭而住院的风险，降低心绞痛的风险。

【规格型号】 20mg*7片【用法用量】病人在开始本品治疗前，应进行标准的低胆固醇饮食控制，在整个治疗期间也应维持合理膳食。

应根据低密度脂蛋白胆固醇基线水平、治疗目标和患者的治疗效果进行剂量的个体化调整。

常用的起始剂量为10mg，每日一次。

剂量调整时间间隔应为4周或更长。

本品最大剂量为每天一次80mg。

可在一天内的任何时间服用，并不受进餐影响。

对于心血管事件的低危患者治疗目标是LDL-C＜4.14mmol/L(或＜160mg/dL)和总胆固醇＜6.62mmol/L(或＜240mg/dL)。

阿托伐他汀钙杂质列表-杂质对照品序号杂质名称或编号英文名CAS结构式及CAS1阿托伐他汀钙杂质A Atorvastatin EPImpurity A(Sodium Salt)433289-83-92阿托伐他汀钙杂质B Atorvastatin EPImpurity B (Calcium Salt)887196-25-03阿托伐他汀钙杂质C Atorvastatin EPImpurity C(Sodium Salt)693793-53-24阿托伐他汀钙杂质D Atorvastatin EPImpurity D148146-51-45阿托伐他汀钙杂质E Atorvastatin EPImpurity E501121-34-2 (FreeAcid)6阿托伐他汀钙杂质F Atorvastatin EPImpurity F(Sodium Salt)1105067-87-57阿托伐他汀钙杂质G Atorvastatin EPImpurity G(Sodium Salt)887196-29-48阿托伐他汀钙杂质H Atorvastatin EPImpurity H125995-03-19阿托伐他汀钙杂质I Atorvastatin EPImpurity I125971-95-1相关杂质1、阿考替胺杂质2、维格列汀杂质3、厄洛替尼杂质4、利伐沙班杂质5、索拉非尼杂质6、阿伐那非杂质7、替卡格雷杂质8、阿哌沙班杂质9、米格列奈杂质10、普拉克索杂质11、氨氯地平杂质12、非不司他杂质13、托法替尼杂质14、达比加群酯杂质15、埃索美拉唑钠杂质16、盐酸氨溴索杂质 17、卡格列净杂质 18 索菲布韦杂质 19、依托考昔杂质及代理其他品牌杂质标准品（EP、USP、LGC、TRC、TLC、MC、SINCO）等。

联系电话：0755 - 89483656深圳菲斯—专注标准品。

in mg, of atenolol (C 14H 22N 2O 3) and chlorthalidone ASSAY(C 14H 11ClN 2O 4S) in each Tablet taken by the formula:•P ROCEDUREBuffer:3.9g/L of ammonium acetate in water. Adjust 2C (V /10)(r U /r S )with glacial acetic acid to a pH of 5.0 ± 0.1.Solution A:Acetonitrile, stabilizer-free tetrahydrofuran,in which C is the concentration, in mg per mL, of the ap-and Buffer (21:12:67)propriate USP Reference Standard in the Standard prepara-Solution B:Acetonitrile, stabilizer-free tetrahydrofuran,tion; V is the volume, in mL, of the volumetric flask used to and Buffer (61:12:27)prepare the stock solution for the Assay preparation; and r U Diluent:N,N-dimethylformamideand r S are the responses for the corresponding analyte ob-Mobile phase:See the gradient table below.tained from the Assay preparation and the Standard prepara-[N OTE —If necessary, adjust the Mobile phase by increas-tion, respectively.ing or decreasing the percentage of acetonitrile or the NOTE —If a trailing peak or shoulder is observed on the pH of the ammonium acetate solution to achieve a chlorthalidone peak with a relative retention time of not retention time of 26–34 min for the atorvastatin peak.]more than 1.1 in the chromatograms of both the Standard preparation and the Assay preparation, sum the areas for the Time Solution ASolution Bchlorthalidone peak with the trailing peak or shoulder to (min)(%)(%)report the peak responses for chlorthalidone.01000401000702080850100Atorvastatin Calcium10001001051000115100System suitability solution:0.05mg/mL of USP Atorva-statin Calcium RS and 0.06mg/mL of USP Atorvastatin Related Compound B RS in DiluentStandard solution:0.4mg/mL of USP Atorvastatin Cal-cium RS in Diluent . [N OTE —Use sonication if necessary.]Sample solution:0.4mg/mL of Atorvastatin Calcium in Diluent . [N OTE —Use sonication if necessary.]Chromatographic system(See Chromatography 〈621〉, System Suitability .)[N OTE —If significant fronting of the peaks for atorvasta-tin related compound B and atorvastatin is observed,C 66H 68CaF 2N 4O 10·3H 2O 1209.42use the following Diluent to prepare the Sample solu-C 66H 68CaF 2N 4O 101155.34tion , Standard solution , and System suitability solution : 1H -Pyrrole-1-heptanoic acid, 2-(4-fluorophenyl)-β,δ-acetonitrile, stabilizer-free tetrahydrofuran, and water dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylami-(1:1:2).]no)carbonyl]-, calcium salt (2:1), trihydrate [R -(R *,R *)]-;Mode:LCCalcium (βR ,δR )-2-(p -fluorophenyl)-β,δ-dihydroxy-5-isopro-Detector:UV 244 nmpyl-3-phenyl-4-(phenylcarbamoyl)pyrrole-1-heptanoate Column:4.6-mm × 25-cm; 5-µm packing L7(1:2), trihydrate [344423-98-9].Column temperature:35° Anhydrous [134523-03-8].Flow rate:1.5mL/min Injection size:20µL DEFINITIONSystem suitabilityAtorvastatin Calcium contains NLT 98.0% and NMTSamples:System suitability solution and Standard 102.0% of C 66H 68 CaF 2N 4O 10, calculated on the anhydrous solutionbasis.Suitability requirementsResolution:NLT 1.5 between the peaks for atorvasta-IDENTIFICATIONtin related compound B and atorvastatin, System suit-•A . I NFRARED A BSORPTION 〈197K 〉 ability solution•B . C ALCIUMTailing factor:NMT 1.6, Standard solutionDiluent:Methanol, water, and hydrochloric acid Relative standard deviation:NMT 0.6%, Standard (75:25:2)solution Blank:DiluentAnalysisSample solution:0.05mg/mL of Atorvastatin Calcium Samples:Standard solution and Sample solutionin Diluent Calculate the percentage of C 66H 68CaF 2N 4O 10 in the por-Analysistion of Atorvastatin Calcium taken:Samples:Sample solution and Blank Spectrometric conditionsResult = (r U /r S ) × (C S /C U ) × 100(See Spectrophotometry and Light-Scattering 〈851〉.)Mode:Atomic absorption spectrophotometry r U = peak response from the Sample solution Analytical wavelength:Calcium emission line at r S = peak response from the Standard solution422.7 nmC S= concentration of USP Atorvastatin Calcium RSFlame:Air–acetylenein the Standard solution (mg/mL)Acceptance criteria:The Sample solution exhibits a sig-C U = concentration of Atorvastatin Calcium in thenificant absorption at the calcium emission line at 422.7Sample solution (mg/mL)nm.Acceptance criteria:98.0%–102.0% on the anhydrous basisIMPURITIESAcceptance criteriaInorganic Impurities Individual impurities:See Impurity Table 1.•H EAVY M ETALSTotal impurities:NMT 1.0%. [N OTE —This total does not Diluent:Methanol and water (9:1)include atorvastatin related compound E, as determined Sample solution:Dissolve 250mg of the sample in in the test for Enantiomeric Purity .]30mL of Diluent .Standard lead solution:Prepared as directed under Impurity Table 1Heavy Metals 〈231〉.Relative Acceptance Reference solution:Dilute 0.5mL of the Standard lead Retention Criteria,solution with Diluent to Time NMT (%)Blank solution:20mL of DiluentAtorvastatin related compound A a 0.80.3Monitor solution: Dissolve 250mg of Atorvastatin Cal-cium in 0.5mL of the Standard lead solution , and dilute Atorvastatin related compound B b 0.90.3with Diluent to 30mL.Atorvastatin1.0n/a AnalysisAtorvastatin related compound C c 1.20.3Samples:Sample solution, Reference solution, Blank so-Atorvastatin related compound D d, e 2.10.1lution, and Monitor solutionAny other individual impurity—0.1To each solution, add 2mL of pH 3.5 Acetate Buffer ,a Desfluoro impurity.prepared as directed under Heavy Metals 〈231〉. Mix,b3S,5R isomer.add to 1.2mL of thioacetamide–glycerin base TS, and c Difluoro impurity.mix immediately. Pass the solutions through a mem-d Epoxide impurity.brane filter of 0.45-µm pore size. Compare the spots e Atorvastatin related compound D may undergo a transformation equi-on the filters obtained with the different solutions:librium with its cyclic hemiketal form. The cyclic hemiketal of atorvastatin the brown color of the spot from the Sample solution related compound D elutes about 1–2 min before atorvastatin related is not more intense than that of the spot from the compound D. Use the sum of the areas of the two peaks as a peakReference solution . The test is invalid if the Reference response for atorvastatin related compound D in the Standard solution and the Sample solution .solution does not show a slight brown color com-pared to the Blank solution , or if the color of the Mon-SPECIFIC TESTSitor solution is not at least as intense as the color of •E NANTIOMERIC P URITYthe Reference solution .Mobile phase:Hexane, dehydrated alcohol, and trifluor-Acceptance criteria:NMT 20ppm oacetic acid (940:60:1)Organic Impurities System suitability stock solution:5mg/mL of USP•P ROCEDUREAtorvastatin Calcium RS and 37.5µg/mL of USP Atorva-Buffer, Solution A, Solution B, Diluent, Mobile phase,statin Related Compound E RS in methanol. [N OTE —System suitability solution, and Chromatographic Atorvastatin related compound E is the 3S,5S enanti-system:Proceed as directed for the Assay .omer of atorvastatin.]Standard solution:1.5µg/mL each of USP Atorvastatin System suitability solution:Transfer 2.0mL of the Sys-Related Compound A RS, USP Atorvastatin Related tem suitability stock solution to a 10-mL volumetric flask,Compound B RS, USP Atorvastatin Related Compound add 2.0mL of dehydrated alcohol, and dilute with hex-C RS, and USP Atorvastatin Related Compound D RS in ane to volume.DiluentSample solution:Transfer 10mg of Atorvastatin Cal-Sample solution:1mg/mL of Atorvastatin Calcium in cium to a 10-mL volumetric flask, dissolve in 2.0mL of Diluent . [N OTE —Use sonication if necessary.]methanol, add 2.0mL of dehydrated alcohol, and dilute Analysiswith hexane to volume.Samples:Standard solution and Sample solutionChromatographic systemChromatograph the Standard solution, and identify the (See Chromatography 〈621〉, System Suitability .)components on the basis of their relative retention Mode:LCtimes, given in Impurity Table 1.Detector:UV 244 nmCalculate the percentage of each of the atorvastatin re-Column:4.6-mm × 25-cm; packing L51lated compounds A, B, C, and D in the portion of Flow rate:1.0mL/min Atorvastatin Calcium taken:Injection size:20µL System suitabilityResult = (r U /r S ) × (C S /C U ) × 100Samples:System suitability solution[N OTE —The elution order of the peaks is atorvastatin r U= peak response of the relevant atorvastatinrelated compound E followed by atorvastatin.]related compound from the Sample solutionResolution:NLT 2.0 between the peaks for atorvastatin r S = peak response of the relevant atorvastatinrelated compound E and atorvastatin related compound from the Standard AnalysissolutionSamples:Sample solutionC S = concentration of the relevant atorvastatinCalculate the percentage of atorvastatin related com-related compound in the Standard solution pound E in the portion of Atorvastatin Calcium taken:(mg/mL)C U = concentration of Atorvastatin Calcium in theResult = (r U /r T ) × 100Sample solution (mg/mL)Calculate the percentage of any other individualr U= peak response for atorvastatin relatedimpurity in the portion of Atorvastatin Calcium taken:compound Er T= sum of the responses of the peaks for Result = (r U /r T ) × 100atorvastatin related compound E and atorvastatinr U= peak response of any other individualAcceptance criteria:NMT 0.3% of atorvastatin related impurity from the Sample solutioncompound Er T= sum of the responses of all the peaks from the Sample solution[N OTE —Disregard any peak observed in the blank; the reporting level for impurities is 0.05%.]•W ATER D ETERMINATION , Method Ia 〈921〉: 3.5%–5.5%Water, Method I 〈921〉: not more than 1.0%.Residue on ignition 〈281〉: not more than 0.1%.ADDITIONAL REQUIREMENTSHeavy metals—•P ACKAGING AND S TORAGE : Preserve in well-closed contain-Test preparation—Thoroughly mix 1.0g of Atovaquone ers, and store at room temperature.with 0.5g of magnesium oxide in a silica crucible. Ignite to •USP R EFERENCE S TANDARDS 〈11〉dull redness until a homogeneous white or grayish-white USP Atorvastatin Calcium RSmass is obtained. If the mixture remains colored after USP Atorvastatin Related Compound A RS30minutes, allow to cool, mix using a fine glass rod, and Desfluoro impurity, or (3R ,5R )-7-[3-(phenylcarbamoyl)-repeat the ignition. If necessary, repeat the operation. Heat 2-isopropyl-4,5-diphenyl-1H -pyrrol-1-yl]-3,5-dihydrox-the residue at 800° for about 1hour. Cool, take up the yheptanoic acid, calcium salt.residue in two 5-mL portions of 6N hydrochloric acid, add C 66H 70CaN 4O 101119.380.1mL of phenolphthalein TS, and then add 13.5 N ammo-USP Atorvastatin Related Compound B RSnium hydroxide until a pink color is obtained. Cool, add 3S ,5R Isomer, or (3S ,5R )-7-[3-(phenylcarbamoyl)-glacial acetic acid until the solution is decolorized, and add 5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H -pyrrol-1-yl]-0.5mL in excess. Filter, if necessary, and wash the filter with 3,5-dihydroxyheptanoic acid, calcium salt.water. Dilute with water to 20mL.C 66H 68CaF 2N 4O 101155.34USP Atorvastatin Related Compound C RSStandard preparation—Add 1.0mL of Standard Lead Solu-Difluoro impurity, or (3R ,5R )-7-[3-(phenylcarbamoyl)-tion (see Special Reagents under Heavy Metals 〈231〉) to 0.5g 4,5-bis(4-fluorophenyl)-2-isopropyl-1H -pyrrol-1-yl]-3,5-of magnesium oxide, and dry between 100° and 105°. Pro-dihydroxyheptanoic acid, calcium salt.ceed as directed for Test preparation, starting with “Ignite to C 66H 66F 4N 4O 101191.34dull redness”.USP Atorvastatin Related Compound D RSBlank preparation—Proceed as directed for Test prepara-Epoxide impurity, or 3-(4-fluorobenzoyl)-2-isobutyryl-tion, omitting the Atovaquone.3-phenyl-oxirane-2-carboxylic acid phenylamide.Procedure—Transfer 12.0mL of the Test preparation to a C 26H 22FNO 4431.4650-mL color-comparison tube, 10.0mL of the StandardUSP Atorvastatin Related Compound E RSpreparation to another, and 10.0mL of the Blank preparation 3S ,5S Enantiomer, or (3S ,5S )-7-[3-(phenylcarbamoyl)-to a third. Then add 2.0mL of the Test preparation to the 5-(4-fluorophenyl)-2-isopropyl-4-phenyl-1H -pyrrol-1-yl]-Standard preparation as well as to the Blank preparation . Add 3,5-dihydroxyheptanoic acid, calcium salt.2mL of pH 3.5 Acetate Buffer (see Heavy Metals 〈231〉) to C 66H 68CaF 2N 4O 101155.34each of the three tubes, mix, add 1.2mL ofthioacetamide–glycerin base TS, and mix. Allow to stand for 2minutes, and view downward over a white surface: the solution from the Standard preparation is slightly brown when compared with the solution from the Blank prepara-tion, and the color of the solution from the Test preparation Atovaquoneis not darker than that of the solution from the Standard preparation (10µg per g).Limit of residual organic solvents—Standard solution—Transfer 1.0mL of methanol and 1.0mL of glacial acetic acid to a 100-mL volumetric flask,dilute with dimethylformamide to volume, and mix. Transfer 5.0mL of this solution to a second 100-mL volumetric flask,dilute with dimethylformamide to volume, and mix.C 22H 19ClO 3366.84Test solution—Transfer about 100mg of Atovaquone, ac-1,4-Naphthalenedione, 2-[4-(4-chlorophenyl)cyclohexyl]-curately weighed, to a 2-mL volumetric flask, dissolve in and 3-hydroxy-, trans -.dilute with dimethylformamide to volume, and mix.2-[trans -4-(p -Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-Chromatographic system (see Chromatography 〈621〉)—The naphthoquinone [95233-18-4].gas chromatograph is equipped with a flame-ionization de-tector and a 4-mm × 2.8-m column that contains 10% liq-» Atovaquone contains not less than 97.5percent uid phase G16 on support S2. The carrier gas is nitrogen,and not more than 101.5percent of C 22H 19ClO 3,flowing at a rate of about 42.5mL per minute. The column calculated on the anhydrous and organic solvent-temperature is maintained at about 180° and the detector free basis.block temperature is maintained at about 250°. Chromato-graph the Standard solution, and record the peak responses Packaging and storage—Preserve in tight, light-resistant as directed for Procedure: the relative retention times are containers.about 0.4 for methanol and 1.0 for acetic acid; the resolu-USP Reference standards 〈11〉—tion, R, between methanol and acetic acid is not less than USP Atovaquone RS14; the column efficiency calculated from the acetic acid USP Atovaquone Related Compound A RSpeak is not less than 700; and the tailing factor for acetic cis -2[4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-acid is not less than 0.8.naphthoquinone.Procedure—Separately inject equal volumes (about 1µL)Identification—of the Standard solution and the Test solution into the chro-matograph, record the chromatograms, and measure the A: Infrared Absorption 〈197M 〉.peak areas for methanol and acetic acid. Calculate the per-B: The retention time of the major peak in the chromato-centage, by weight, of methanol and acetic acid in the por-gram of the Assay preparation corresponds to that in the tion of Atovaquone taken by the formula:chromatogram of the Standard preparation, as obtained in the Assay.0.1(G/W )(r U /r S )in which G is either 0.79, the specific gravity of methanol,or 1.05, the specific gravity of glacial acetic acid, as appro-priate; W is the weight, in mg, of Atovaquone taken to pre-pare the Test solution; and r U and r S are the peak area re-sponses of methanol or acetic acid, as appropriate, obtained Atovaquone Oral Suspensionfrom the Test solution and the Standard solution, respectively:not more than 0.2% of methanol or of acetic acid is found.» Atovaquone Oral Suspension contains not less Related compounds—Using the chromatograms of theAssay preparation and the Resolution solution obtained in the than 90.0percent and not more than 110.0per-Assay, calculate the percentage of atovaquone related com-cent of the labeled amount of atovaquone pounds in the portion of Atovaquone taken by the formula:(C22H19ClO3).100(r i/r s)Packaging and storage—Preserve in tight, light-resistantcontainers.in which r i is the individual peak response of a related com-USP Reference standards 〈11〉—pound, if any, in the chromatogram of the Assay prepara-USP Atovaquone RStion; and r s is the sum of the responses of all the peaks inUSP Atovaquone Related Compound A RSthe chromatogram of the Assay preparation, including thecis-2[4-(4-Chlorophenyl)cyclohexyl]-3-hydroxy-1,4-atovaquone peak. Not more than 1.0% of any related com-naphthoquinone.pound with a retention time corresponding to that of atova-Identification—quone related compound A, as determined from the chro-matogram of the Resolution solution, is found; not more A: Ultraviolet Absorption 〈197U〉—than 0.5% of any related compound with a retention time Medium: a mixture of methanol and water (1:1).of 0.63 or 1.8 relative to that of atovaquone is found; and Solution—Transfer 5.0mL of the Assay preparation and not more than 0.3% of any related compound with a reten- 5.0mL of the Standard preparation, prepared in the Assay, tion time of 0.89 relative to that of atovaquone is found.to separate 50-mL volumetric flasks, dilute with Medium to Not more than 0.2% of any other individual related com-volume, and mix.pound is found; and the sum of all other such related com-B: The retention time of the major peak in the chromato-pounds is not more than 1.0%. The sum of all related com-gram of the Assay preparation corresponds to that in the pounds is not more than 1.5%.chromatogram of the Standard preparation, as obtained in Assay—the Assay.Mobile phase—Prepare a mixture of acetonitrile, water,Uniformity of dosage units 〈905〉—methanol, and phosphoric acid (525:300:175:5). Make ad-FOR ORAL SUSPENSION PACKAGED IN SINGLE-UNIT CONTAINERS: justments if necessary (see System Suitability under Chroma-meets the requirements.tography 〈621〉).Deliverable volume 〈698〉—Diluent—Prepare a mixture of acetonitrile and water(80:20).FOR ORAL SUSPENSION PACKAGED IN MULTIPLE-UNIT CONTAINERS:meets the requirements.Standard preparation—Dissolve an accurately weighedquantity of USP Atovaquone RS in Diluent, and dilute quan-pH 〈791〉: between 3.5 and 7.0.titatively, and stepwise if necessary, with Diluent to obtain a Sedimentation—solution having a known concentration of about 0.25mgFOR ORAL SUSPENSION PACKAGED IN MULTIPLE-UNIT CONTAINERS—per mL.Transfer 50mL of well-mixed Oral Suspension to a glass-Resolution solution—Prepare a solution in Diluent contain-stoppered graduated cylinder, and allow to stand foring about 0.25mg of USP Atovaquone RS and 0.02mg of16hours. Measure the volume, if any, of clear liquid ob-USP Atovaquone Related Compound A RS per mL. Store in served in the cylinder: not more than 1mL of clear liquid is a low-actinic glass container.found.Assay preparation—Transfer about 25mg of Atovaquone,Related compounds—Using the chromatograms of the accurately weighed, to a low-actinic, 100-mL volumetric Resolution solution, the Standard preparation, and the Assay flask, dissolve in and dilute with Diluent to volume, and mix.preparation obtained in the Assay, calculate the percentage Chromatographic system (see Chromatography 〈621〉)—The of atovaquone-related compounds, based on the labeled liquid chromatograph is equipped with a 220-nm detector strength of atovaquone, by the formula:and a 4.6-mm × 25-cm column that contains packing L1.The flow rate is about 3mL per minute. Chromatograph theResolution solution, and record the peak areas as directed forProcedure: the relative retention times are about 0.85 foratovaquone related compound A and 1.0 for atovaquone;and the resolution, R, between atovaquone related com-in which C is the concentration, in mg per mL, of USP pound A and atovaquone is not less than 4. Chromatograph Atovaquone RS in the Standard preparation; D is the density the Standard preparation, and record the peak responses as of Oral Suspension, in g per mL (1.04g per mL at 20° to directed for Procedure: the column efficiency is not less than25°); S is the weight, in g, of Oral Suspension taken to 9000 theoretical plates; the tailing factor is not more than prepare the Assay preparation; L is the labeled amount, in 1.5; and the relative standard deviation for replicate injec-mg per mL, of atovaquone in the Oral Suspension; F i is the tions is not more than 2%.response factor of an individual atovaquone related com-pound relative to the response of atovaquone, specifically, Procedure—Separately inject equal volumes (about 20µL)1.08 for any peak observed at a relative retention time ofof the Standard preparation and the Assay preparation intoabout 0.65, 0.85 for any peak observed at a retention time the chromatograph, record the chromatograms, and meas-corresponding to that of atovaquone related compound A, ure the areas for the major peaks. Calculate the quantity, inas determined from the chromatogram of the Resolution so-mg, of C22H19ClO3 in the portion of Atovaquone taken bylution, and 1.0 for any other related compound peak; r i is the formula:the individual peak response of an atovaquone related com-pound, if any, in the chromatogram of the Assay prepara-100C(r U/r S)tion; and r S is the peak response of atovaquone in the chro-matogram of the Standard preparation. Disregard any peak in which C is the concentration, in mg per mL, of USPhaving a relative retention time of about 0.3, which is due Atovaquone RS in the Standard preparation; and r U and r Sto photodegradation during preparation of the Assay prepa-are the atovaquone peak areas obtained from the Assayration. Not more than 0.5% of an atovaquone related com-preparation and the Standard preparation, respectively.。

阿托伐他汀阿托伐他汀简介一、基本信息中文名称：阿托伐他汀中文别名：阿伐他汀;阿托伐他汀酸;（3s，5s）-7-[2-（4-氟苯基）-3-苯基-4-（苯基氨基甲酰基）-5-异丙基吡咯-1-基]-3，5-二羟基庚酸英文名称：atorvastatin英文别名：（3r，5rr）-7-[2-（4-fluorophenyl）-3-phenyl-4-（phenylcarbamoyl）-5-propan-2-yl-pyrrol-1-yl]-3，5-dihydroxy-heptanoicacid;[1]cas：134523-00-5;110862-48-1分子式：c33h33cafno5分子量：582.6947物化性质熔点176-178°c熔点：176-178℃药理毒理本品为hmg-coa还原酶选择性抑制剂，通过抑制hmg-coa 还原酶和胆固醇在肝脏的生物合成而降低血浆胆固醇和脂蛋白水平，并能通过增加肝细胞表面低密度脂蛋白（ldl）受体数目而增加ldl的摄取和分解代谢。

本品也能减少ldl的生成和其颗粒数。

本品还能降低某些纯合子型家族性高胆固醇血症（fh）的低密度脂蛋白胆固醇（ldl-c）水平，而一类型的人群对其他类型的降脂药物治疗很少有应答。

本品能降低纯合子和杂合子家族性高胆固醇血症、非家族性高胆固醇血症以及混合性脂类代谢障碍患者的血浆总胆固醇（tc）、ldl-c和载脂蛋白b（apob），还能降低极低密度脂蛋白胆固醇（vldl-c）和三酰甘油（tg）的水平，并能不同程度地提高血浆高密度脂蛋白胆固醇（hdl-c）和载脂蛋白a1（apoa1）的水平。

1.9药代特征吸收。

口服后迅速吸收，1-2小时内达到最大血浆浓度，吸收程度随口服剂量的增加而成正比例地增加。

绝对生物利用度约为12%，抑制hmg-coa还原酶的全身利用度约为30%。

无论是否与食物同时服用或在一天中无论何时服用，其降低血浆ldl-c的效果都相似。

类别：技术标准编码：阿托伐他汀钙胶囊生产工艺规程版次：□新订□替代：制定：年月日审核：年月日批准：年月日生效日期：年月日复制：份共页颁发部门：分发部门：目录1．引言2．依据3．适用范围4．责任5．内容5．1．品名5．2．剂型5．3．产品概述5．4．处方5．5．生产工艺流程5．6．生产工艺操作要求及工艺技术参数5．7．批、批量及批号的规定5．8．生产过程的质量控制5．9．原辅料、半成品、成品的质量标准5．10．包装材料的要求5．11．原辅料、半成品、成品的贮存条件及半成品贮存期5．12．标签、说明书的内容5．13．设备一览表5．14．技术安全、劳动保护与工艺卫生5．15．物料消耗定额5．16．物料平衡计算公式5．17．劳动组织及岗位定员5．18．操作工时与生产周期5．19．附录（当工艺发生变更时填写）1．引言：制订本规程的目的是建立阿托伐他汀钙胶囊的生产工艺规程，以提供生产车间组织生产并进行生产操作。

2．依据：国家食品药品监督管理局《药品生产质量管理规范》（1998年修订）。

3．适用范围：阿托伐他汀钙胶囊的生产。

4．责任：生产车间按该工艺规程组织生产和按该规程编制标准操作程序，生产部、质量管理部负责监督该规程的实施。

5．内容5．1．品名通用名称：阿托伐他汀钙胶囊汉语拼音：Atuofatatinggai Jiaonang5．2．剂型硬胶囊剂。

5．3．产品概述本品为胶囊剂，内容物为类白色粉末。

规格为每粒装10mg，功能主治为降血脂药。

5．4．处方5．4．1．主处方：阿托伐他汀钙（三水合物） 216.4g（以阿托伐他汀计：10.0g）碳酸钙 90.0g交联羧甲基纤维素钠 180.0g硬脂酸镁 20.0g制成 20000粒5．4．2．生产工艺5．5．生产工艺流程用示意图描述如下：5．6．生产工艺操作要求及工艺技术参数5．6．1．过筛阿托伐他汀钙过80目筛（注意操作时避光）。

乳糖，微晶纤维素，碳酸钙，交联羧甲基纤维素钠过60目筛，硬脂酸镁过80目筛。

阿托伐他汀钙片药品质量标准正式名：阿托伐他汀钙片汉语拼音：Atuofatatinggai标准号：WS-386（X-338）-99拉丁文或英文：Atorvastatin主要活性成分：本品含阿托伐他汀钙盐（2:1）三水合物((C33H34FN2O5)2Ca·3H2O性状：本品为白色薄膜衣片，除去膜衣后显白色。

鉴别：（1）取本品的细粉适量（约相当于C33H35FN2O5 10mg），加乙醇5ml，振摇使阿托伐他汀钙溶解，滤过，滤液作为供试品的溶液；另取阿托伐他汀钙对照品，用乙醇配制成每1ml含2mg C33H35FN2O5的溶液，作为对照品溶液。

照薄层<aclass="channel_keylink" href="/product/list.asp?sortid=36">色谱</a>法（中国药典1995年版二部附录V B）试验，吸取上述两种溶液各5(l，分别点于同一硅胶GF254薄层板上，以二氯甲烷-甲醇-甲酸（80:5:1）为展开剂，展开后，晾干，置紫外光灯（254nm）下检视，供试品溶液所显主斑点的颜色和位置应与对照品溶液的主斑点相同。

（2）取含量测定项下的溶液，照分光光度法（中国药典1995年版二部附录IV A）测定，在247nm的波长处有最大吸收。

检查：有关物质照阿托伐他汀钙含量测定项下的方法。

称取本品的细粉中华人民共和国国家药品监督管理局发布北京市药品检验所审核国家药品监督管理局药品审评委员会审订北京红惠<a class="channel_keylink" href="/">制药</a>有限公司提出本标准自1999年9月29日起试行，试行期2年。

保护期8年，保护期内，其它单位不得仿制。

适量（约相当于C33H35FN2O512.5mg）于25ml量瓶中，加适量乙腈-0.05mol/L柠檬酸铵溶剂（0.05mol/L柠檬酸用氨水调pH值7.4）（50:50），超声5分钟使阿托伐他汀钙溶解，冷却，用上述溶剂稀释至刻度，摇匀，用0.45(滤膜过滤，取滤液作为供试品溶液；精密量取供试品溶液适量，加上述溶剂稀释成每1ml中含15(g的溶液，作为对照溶液；取对照溶液20(l注入液相<a class="channel_keylink"href="/product/list.asp?sortid=36">色谱</a>仪，调节检测灵敏度，使主成分<a class="channel_keylink"href="/product/list.asp?sortid=36">色谱</a>峰的峰高为记录满标度的25%，再精密量取供试品溶液与对照溶液各20(l，分别注入液相色谱仪，记录色谱图至主成分保留时间的3倍。

阿托伐他汀钙杂质分析本篇通过文献摘录了常用的3条工艺路线，并对可能产生的杂质进行了分析。

一．简要内容路线1：工艺杂质：7-氨基-3,5-二羟基庚酸钙、二酮中间体、缩合物中间体、二胺、二氟阿托伐他汀钙、去氟阿托伐他汀钙、阿托伐他汀叔丁酯、阿托伐他汀甲酯、阿托伐他汀乙酯、阿托伐他汀钙非対映体、阿托阿伐他汀钙对映体降解杂质：阿托伐他汀内酯路线2：工艺杂质：由中间体引入的杂质与“路线1”不同。

即：增加“氧代中间体”，剔除“7-氨基-3,5-二羟基庚酸钙”、“二酮中间体”、“缩合物中间体”、“二胺”。

降解杂质：阿托伐他汀内酯路线3：工艺杂质：由中间体引入的杂质与“路线1”不同。

即增加“阿托伐他汀苯乙酰胺”、“苯乙胺”，剔除“7-氨基-3,5-二羟基庚酸钙”、“二酮中间体”、“缩合物中间体”、“二胺”。

降解杂质：阿托伐他汀内酯二、合成路线概述及相应杂质分析1、合成路线概述若以基本化工原料为起始物，阿托伐他汀钙的合成步骤长，且有许多种不同的合成路线。

原料药中有关物质、特别是定性限以上杂质的引入往往与原料药合成的最后三步反应关系密切，根据最后三步反应可将文献中常见的阿托伐他汀钙合成路线概括为以下三条：路线1：H N OO O+H 23)3OOF3)3二酮中间体合物中间体阿托伐他汀叔丁酯路线2：氧代中间体阿托伐他汀叔丁酯1. NaOH2. CaCl 23)3Atorvastatin calcium路线3：+阿托伐他汀内酯阿托伐他汀内酯2. 工艺引进杂质分析一般而言，上述工艺路线中给出的各中间体、试剂均有可能向原料药中引入有关物质。

因“路线1”极有可能为普遍采用的工艺路线，故以它为主分析原料药中可能杂质。

在“路线1”中，若“缩合物中间体”中含有“胺酯中间体”，在后续酸解、碱解、成盐过程中理论上应转化为7-氨基-3,5-二羟基庚酸钙；若含有“二酮中间体”，理论上也有可能引入原料药中。

据物性推断，实际生产中通过控制缩合物质量等措施，原料药中这两种杂质的含量应易控制在定性限以下。

2. 氟伐他汀中间体>> Fluvastatin intermediates F-1CAS No.:93957-49-4化学名称:3-(4- 氟苯基)-1- 异丙基-1H- 吲哚3-(4'-fluorophenyl)-1-(1'-methylethyl)-1H-indoleCAS No.:154057-56-42-cyclopropyl-4-(4-fluorophenyl)-quinolyl-3-MethylBr2-环丙基-4-(4-氟苯基)-喹啉-3-甲基溴4. 瑞舒伐他汀中间体/罗伐他汀R osuvastatin intermediates C-4、Crestor CAS No.:154026-95-6化学名称:6- 乙酰氧甲基-2,2- 二甲基-1,3- 二氧戊环- 乙酸PRODUCT:(4R-CIS)-6-[ (ACETYLOXY)METHYL ]-2,2-DIMETHYL-1,DescriptionCrestor is used to lower cholesterol and triglycerides (types of fat) in the blood. Rosuvastatin is used along with a proper diet to help lower "bad" cholesterol and fats (such as LDL, triglycerides) and raise "good" cholesterol (HDL) in the blood. It belongs to a group of drugs known as "statins." It works by reducing the amount of cholesterol made by the liver.药品分类管理是根据药品安全有效，使用方便的原则，依其品种、规格、适应症及给药途经不同，对药分别按处方药和“OTC”进行管理。

氨氯地平阿托伐他汀钙片Anlüdiping Atuofatatinggai pianAmlodiping Besylate and Atorvastatin Calcium Tablets 本品含苯磺酸氨氯地平按氨氯地平（C20H25N2O5Cl）计应为标示量的95.0%~105.0%，含阿托伐他汀钙按阿托伐他汀（C33H34FN2O5）计应为标示量的95.0%~105.0%。

【性状】本品为白色薄膜衣片，除去包衣显白色或类白色。

【鉴别】（1）在含量测定项下记录的色谱图中，供试品溶液两主峰的保留时间应与对照品溶液相应的两主峰的保留时间一致。

（2）采用二极管阵列检测器检测，在含量测定项下记录的色谱图中，供试品溶液两主峰的紫外吸收光谱图应与对照品溶液相应的两主峰的紫外吸收光谱图一致。

【检查】有关物质取本品5片，置50ml量瓶（5mg/10mg）或100ml量瓶（5mg/20mg）中，加稀释溶液约量瓶体积的一半，振摇使崩解，加稀释溶液稀释至刻度，摇匀，放入搅拌子搅拌20分钟，放置，使大部分辅料沉淀后，取上清液，用0.45µm的滤膜过滤，取续滤液作为供试品溶液（临用新制）。

取苯磺酸氨氯地平对照品14mg和阿托伐他汀钙对照品27mg，精密称定，同置100ml量瓶中，加稀释液溶解并稀释至刻度，摇匀，再精密量取1ml，置50ml量瓶，用稀释液稀释至刻度，摇匀，作为对照品溶液①，再精密量取对照品溶液①5ml，用稀释溶液稀释至100ml，为对照品溶液②。

照高效液相色谱法（中国药典2010 年版二部附录V A）试验。

用氰基键合硅胶为填充剂（Agilent ZORBAX SB-CN 柱适用），以乙腈-0.05mol/L乙酸铵溶液（用冰醋酸试液调节pH值至5.0）（25∶75）为流动相A，以为乙腈-0.05mol/L乙酸铵溶液（用冰醋酸试液调节pH值至5.0）（50∶50）为流动相B，照下表进行梯度洗脱，流速为每分钟1ml，柱温40℃；检测波长为240nm。