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.。
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