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中文名称英文名称CAS规格图谱用途结构式孟鲁司特Montelukast 151767-02-110mg25mg50mg100mg更大规格请咨询随货COA,HNMR,MS,HPLC等确证谱图新药研发、项目报批纯度高于98%孟鲁司特杂质1(孟鲁司特EP杂质A)Montelukast Impurity 1（Montelukast EPImpurity A）190078-45-610mg25mg50mg100mg更大规格请咨询随货COA,HNMR,MS,HPLC等确证谱图新药研发、项目报批纯度高于98%孟鲁司特杂质2(孟鲁司特EP杂质B)Montelukast Impurity 2（Montelukast EPImpurity B）918972-54-10mg25mg50mg100mg更大规格请咨询随货COA,HNMR,MS,HPLC等确证谱图新药研发、项目报批纯度高于98%孟鲁司特杂质3(孟鲁司特EP杂质C)Montelukast Impurity 3（Montelukast EPImpurity C）909849-96-310mg25mg50mg100mg更大规格请咨询随货COA,HNMR,MS,HPLC等确证谱图新药研发、项目报批纯度高于98%孟鲁司特杂质4(孟鲁司特EP杂质D)Montelukast Impurity 4（Montelukast EPImpurity D）1187586-61-310mg25mg50mg100mg更大规格请咨询随货COA,HNMR,MS,HPLC等确证谱图新药研发、项目报批纯度高于98%扬信医药代理各品种杂质对照品:泊沙康唑杂质、替卡格雷杂质、依折麦布杂质、索拉菲尼相关杂质、索非布韦杂质、氨氯地平杂质、马来酸氯苯那敏杂质、头孢克肟杂质、瑞舒伐他汀杂质、瑞格列奈杂质、恩替卡韦杂质，替诺福韦杂质等；并提供COA、NMR、HPLC、MS等结构确证图谱。
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B RIEFINGMontelukast Sodium Tablets. Because there is no existing USP monograph for this dosage form, a new monograph based on validated methods of analysis is being proposed. The liquid chromatographic procedure in the Assay and the test for Organic Impurities is based on analyses performed with thePhenomenex LUNA Phenyl-hexyl brand of L11 column. The typical retention time for montelukast is about 15 min. The liquid chromatographic procedure in the test for Dissolution is based on analyses performed with the Inertsil Phenyl brand of L11 column. The typical retention time for montelukast is about 1.8 min.(SM4: M. Koleck.)Correspondence Number—C121755Comment deadline: November 30, 2014Add the following:Montelukast Sodium TabletsDEFINITIONMontelukast Sodium Tablets contain Montelukast Sodium equivalent to NLT 94.0% and NMT 105.0% of the labeled amount of montelukast (C 35H 36ClNO 3S).[ NOTE— Avoid exposure of the samples to light. Use low-actinic glassware.]IDENTIFICATION• A. U LTRA VIOLET A BSORPTION 197UDiluent: Methanol and water (3:1)Standard solution: 0.026 mg/mL of USP Montelukast Dicyclohexylamine RS in DiluentSample solution: Nominally 0.02 mg/mL of montelukast prepared as follows. Transfer one Tabletequivalent to 10 mg of montelukast to a suitable volumetric flask, add 25% of the flask volume of water,and let stand for 5–10 min until the Tablet has disintegrated. Add 60% of the flask volume of methanol,shake well, and sonicate for 70 min with occasional shaking. Cool to room temperature, dilute withmethanol to volume, and mix well. Centrifuge a portion of the resulting solution to obtain a clear solution.Wavelength range: 210–400 nmAcceptance criteria: The Sample solution exhibits maxima only at the same wavelengths as the Standard solution .• B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution ,as obtained in the Assay.ASSAY• P ROCEDUREDiluent: Methanol and water (3:1)Solution A: 0.2% (v/v) Trifluoroacetic acid in water Solution B: Methanol and acetonitrile (3:2)Mobile phase: See Table 1.Table 1Time (min)Solution A (%)Solution B (%)0485254555124555222575232575254852304852Standard solution: 0.52 mg/mL of USP Montelukast Dicyclohexylamine RS in DiluentSystem suitability solution: Transfer 10 mL of the Standard solution to a clear 10-mL volumetric flask, add4 µL of hydrogen peroxide, and mix well. Expose the flask for at least 4 h to ambient light or 10 min to a4 kLux cool white light.[ NOTE— Montelukast is partially converted to the cis-isomer under these conditions.]Sensitivity solution: 0.52 µg/mL of USP Montelukast Dicyclohexylamine RS in Diluent from theStandard solutionSample solution: Nominally 0.4 mg/mL of montelukast prepared as follows. Transfer a number of Tablets equivalent to 100 mg of montelukast to a suitable volumetric flask, add 70% of the flask volume ofDiluent, and sonicate for 30 min. Shake for 30 min on a platform shaker. Dilute with Diluent to volume and stir for 30 min. Pass a portion through a suitable filter of 0.45-µm pore size, discarding the first mL of filtrate. Use the filtrate.Chromatographic system(See Chromatography 621, System Suitability.)Mode: LCDetector: UV 255 nmColumnsGuard: 3.0-mm × 4-mm; packing L11Analytical: 4.6-mm × 10-cm; 3-µm packing L11Column temperature: 50Flow rate: 1.5 mL/minInjection volume: 15 µLRun time: 2 times the retention time of montelukastSystem suitabilitySamples: Standard solution, System suitability solution, and Sensitivity solution[ NOTE— The relative retention times of the cis-isomer and montelukast are about 0.92 and 1.0,respectively.]Suitability requirementsResolution: NLT 1.5 between the cis-isomer and montelukast, System suitability solutionRelative standard deviation: NMT 2% for five injections, Standard solutionSignal-to-noise ratio: NLT 10, Sensitivity solutionAnalysisSamples: Standard solution and Sample solutionCalculate the percentage of the labeled amount of montelukast (C35H36ClNO3S) in the portion ofTablets taken:Result = ( r U / r S ) × ( C S / C U ) × ( M r1 / M r2 ) × 100r U= peak response from the Sample solutionr S= peak response from the Standard solutionC S= concentration of USP Montelukast Dicyclohexylamine RS in the Standard solution(mg/mL)C U= nominal concentration of montelukast in the Sample solution (mg/mL)= molecular weight of montelukast, 586.18Mr1= molecular weight of montelukast dicyclohexylamine, 767.50Mr2Acceptance criteria: 94.0%–105.0%PERFORMANCE TESTS• D ISSOLUTION711Medium: 0.5% (w/v) Sodium dodecyl sulfate in water; 900 mL. Do not deaerate.Apparatus 2: 50 rpmTime: 20 minSolution A: 0.2% (v/v) Trifluoroacetic acid in waterSolution B: 0.2% (v/v) Trifluoroacetic acid in acetonitrileMobile phase: Solution A and Solution B (1:1)Standard stock solution: 0.35 mg/mL of USP Montelukast Dicyclohexylamine RS in methanol(equivalent to 0.27 mg/mL of montelukast)Standard solution: (L/900) mg/mL of montelukast in Medium from the Standard stock solution, where L is the label claim in mg/Tablet of montelukast.Sample solution: Pass a portion of the solution under test through a suitable filter or centrifuge to obtain a clear solution.Chromatographic system(See Chromatography 621, System Suitability.)Mode: LCDetector: UV 389 nmColumn: 3.0-mm × 10-cm; 5-µm packing L11Column temperature: 50Flow rate: 0.9 mL/minInjection volume: 20 µLRun time: 1.5 times the retention time of montelukastSystem suitabilitySample: Standard solutionSuitability requirementsTailing factor: NMT 1.5Relative standard deviation: NMT 2%AnalysisSamples: Standard solution and Sample solutionCalculate the percentage of the labeled amount of montelukast (C35H36ClNO3S) dissolved:Result = ( r U / r S ) × C S × V × (1/L) × 100r U= peak response from the Sample solutionr S= peak response from the Standard solutionC S= concentration of montelukast in the Standard solution (mg/mL)V= volume of Medium (900 mL)L= label claim (mg/Tablet)Tolerances: NLT 80% (Q) of the labeled amount of montelukast (C35H36ClNO3S) is dissolved.• U NIFORMITY OF D OSA GE U NITS905Procedure for content uniformitySolution A, Solution B, Mobile phase, and System suitability: Proceed as directed in Dissolution.Diluent: Methanol and water (3:1)Standard solution: 0.052 mg/mL of USP Montelukast Dicyclohexylamine RS in DiluentSample solution: Nominally 0.04 mg/mL of montelukast prepared as follows. Transfer one Tabletequivalent to 10 mg of montelukast to a suitable volumetric flask, add 25% of the flask volume ofwater, and let stand for 5–10 min until the Tablet has disintegrated. Add 60% of the flask volume ofmethanol, shake well, and sonicate for 70 min with occasional shaking. Cool to room temperature,dilute with methanol to volume, and mix well. Pass a portion of the resulting solution through a suitable filter or centrifuge to obtain a clear solution.Chromatographic system: Proceed as directed in Dissolution, except use an Injection volume of 10 µL.AnalysisSamples: Standard solution and Sample solutionCalculate the percentage of the labeled amount of montelukast (C35H36ClNO3S) in the Tablet taken:Result = ( r U / r S ) × ( C S / C U ) × ( M r1 / M r2 ) × 100r U= peak response from the Sample solutionr S= peak response from the Standard solutionC S= concentration of USP Montelukast Dicyclohexylamine RS in the Standardsolution (mg/mL)C U= nominal concentration of montelukast in the Sample solution (mg/mL)Mr1= molecular weight of montelukast, 586.18Mr2= molecular weight of montelukast dicyclohexylamine, 767.50Acceptance criteria: Meet the requirementsIMPURITIES• O RGA NIC I MPURITIESDiluent, Solution A, Solution B, Mobile phase, Standard solution, System suitability solution, Sensitivity solution, Sample solution, Chromatographic system, and System suitability: Proceed as directed in the Assay.AnalysisSamples: Standard solution and Sample solutionCalculate the percentage of any individual degradation product in the portion of Tablets taken:Result = ( r U / r S ) × ( C S / C U ) × ( M r1 / M r2 ) × (1/F) × 100 r U= peak response of any individual degradation product from the Sample solutionr S= peak response of montelukast from the Standard solutionC S= concentration of USP Montelukast Dicyclohexylamine RS in the Standard solution(mg/mL)C U= nominal concentration of montelukast in the Sample solution (mg/mL)Mr1= molecular weight of montelukast, 586.18Mr2= molecular weight of montelukast dicyclohexylamine, 767.50F= relative response factor (see Table 2)Acceptance criteria: See Table 2. Disregard any peak with an area less than that of the Sensitivitysolution.Table 2Name RelativeRetentionTimeRelativeResponseFactorAcceptanceCriteria,NMT (%)Sulfoxide impurity a,b0.45 1.0 2.0 Montelukast ketone impurity c0.71 1.70.2 cis-Isomer d0.92 1.00.2Montelukast 1.0——Methylketone impurity e,f 1.04——Michael Adduct 1g,e 1.16——Michael Adduct 2h,e 1.18——Methylstyrene impurity i,e 1.55——Any other individual degradation product— 1.00.2 Total impurities—— 3.0a These two impurities are not resolved by the method and need to be integratedtogether to determine conformance.b [1-[[[1-[3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfinyl]methyl]cyclopropyl]acetic acid.c (E)-1-{3-[2-(7-Chloroquinolin-2-yl)vinyl]phenyl}-3-[2-(2-hydroxypropan-2-yl)phenyl]propan-1-one.d [1-[[[(1R )-1-[3-[(Z)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropyl]acetic acid.e This is a process impurity and is included in the table for identification only. Thisimpurity is controlled in the drug substance. It is not to be reported for the drug product and should not be included in the total impurities.f [1-[[[(1R )-3-(2-Acetylphenyl)-1-[3-[(E)-2-(7-chloroquinolin-2-yl)ethenyl]phenyl]propyl]sulfanyl]methyl]cyclopropyl]acetic acid.g 1-[[[(1R )-1-[3-[(1R )-1-[[[1-(Carboxymethyl)cyclopropyl]methyl]sulfanyl]-2-(7-chloroquinolin-2-yl)ethyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropyl]acetic acid.h 1-[[[(1R )-1-[3-[(1S )-1-[[[1-(Carboxymethyl)cyclopropyl]methyl]sulfanyl]-2-(7-chloroquinolin-2-yl)ethyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]sulfanyl]methyl]cyclopropyl]acetic acid.i [1-[[[(1R )-1-[3-[(E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl]-3-[2-(1-methylethenyl)phenyl]propyl]sulfanyl]methyl]cyclopropyl]acetic acid.ADDITIONAL REQUIREMENTS• P A CKA GING A ND S TORA GE: Preserve in tight containers, protected from light. Store at controlled room temperature.• USP R EFERENCE S TA NDA RDS11USP Montelukast Dicyclohexylamine RSC35H36ClNO3S · C12H23N 767.502S (USP38)Auxiliary Information - Please check for your question in the FAQs before contacting USP.。
孟鲁司特钠咀嚼片说明书请仔细阅读说明书并在医师指导下使用【药品名称】通用名称：孟鲁司特钠咀嚼片英文名称：Montelukast Sodium Chewable Tablets汉语拼音：Menglusitena Jujuepian【成份】本品主要成份为孟鲁司特钠。
化学名称：[R-(E)]-1-[[[1-[3-[2-(7-氯-2-喹啉)乙烯基]苯基-3-[2-(1-羟基-1-甲基乙基)苯基]丙基]硫]甲基]环丙烷乙酸钠化学结构式：分子式：C35H35ClNNaO3S分子量：608.18【性状】本品4mg为粉红色圆角方形片，一面刻有“4”字样；5mg为粉红色椭圆形片，一面刻有“5”字样。
【适应症】本品适用于2岁至14岁儿童哮喘的预防和长期治疗包括预防白天和夜间的哮喘症状治疗对阿司匹林敏感的哮喘患者以及预防运动诱发的支气管收缩。
本品适用于减轻过敏性鼻炎引起的症状（2岁至14岁儿童的季节性过敏性鼻炎和常年性过敏性鼻炎）。
【规格】4mg（以孟鲁司特计）；5mg（以孟鲁司特计）。
【用法用量】每日一次。
哮喘病人应在睡前服用。
过敏性鼻炎病人可根据自身的情况在需要时间服药。
同时患有哮喘和过敏性鼻炎的病人应每晚用药一次。
6至14岁哮喘和/或过敏性鼻炎儿童患者每日一次，每次一片(5mg)。
2至5岁哮喘和/或过敏性鼻炎儿童患者每日一次，每次一片(4mg)。
一般建议以哮喘控制指标来评价治疗效果，本品的疗效在用药一天内即出现。
本品可与食物同服或另服。
应建议患者无论在哮喘控制还是恶化阶段都坚持服用。
肾功能不全患者、轻至中度肝损害的患者及不同性别的患者无需调整剂量。
孟鲁司特钠咀嚼片与其它哮喘治疗药物的关系本品可加入患者现有的治疗方案中。
减少合并用药的剂量：支气管扩张剂单用支气管扩张剂不能有效控制的哮喘患者，可在治疗方案中加入本品，一旦有临床疗效反应（一般出现在首剂用药后），根据患者的耐受情况，可将支气管扩张剂剂量减少。
吸入糖皮质激素对接受吸入糖皮质激素治疗的哮喘患者加用本品后，可根据患者的耐受情况适当减少糖皮质激素的剂量。
顺尔宁(Singulair)(孟鲁司特钠颗粒)【药品名称】商品名称：顺尔宁(Singulair)通用名称：孟鲁司特钠颗粒英文名称：Montelukast Sodium Oral Granules【成份】本品主要成份为孟鲁司特钠, 其化学名称为：[R-(E)]-1-[[[1-[3-[2-(7-氯-2-喹啉)乙烯基]苯基]-3-[2-(1-羟基-1-甲基乙基)苯基]丙基]硫] 甲基] 环丙烷乙酸钠化学结构式：分子式：C35H35ClNNaO3S分子量: 608.18【适应症】本品适用于1岁以上儿童哮喘的预防和长期治疗，包括预防白天和夜间的哮喘症状，治疗对阿司匹林敏感的哮喘患者以及预防运动诱发的支气管收缩。
本品适用于减...【用法用量】每日一次。
哮喘病人应在睡前服用。
过敏性鼻炎病人可根据自身的情况在需要时间服药。
同时患有哮喘和过敏性鼻炎的病人应每晚用药一次。
1岁至2岁儿童哮喘患者每天一次，每次一袋。
2岁至5岁儿童哮喘患者和/或2岁至5岁过敏性鼻炎患者应每天服用4mg口服颗粒一袋。
口服颗粒的服用本品可直接服用，与一勺室温或冷的软性食物（如苹果酱）混合服用，或溶解于一茶匙室温或冷的婴儿配方奶粉或母乳服用。
在服用时才能打开包装袋。
打开包装袋以后应立即服用全部的剂量（15分钟内）。
与食物、婴儿配方奶粉或母乳混合后的本品不能再贮存至下次继续服用。
本品不应溶解于除婴儿配方奶粉或母乳外的其它液体中服用。
但是服药后可以饮水。
一般建议以哮喘控制指标来评价治疗效果，本品的疗效在用药一天内即出现。
本品可与食物同服或另服。
应建议患者无论在哮喘控制还是恶化阶段都坚持服用。
对肾功能不全患者、轻至中度肝损害的患者及不同性别的患者无需调整剂量。
本品与其它哮喘治疗药物的关系本品可加入患者现有的治疗方案中。
减少合并用药物的剂量:支气管扩张剂单用支气管扩张剂不能有效控制的哮喘患者，可在治疗方案中加入本品，一旦有临床治疗反应（一般出现在首剂用药后），根据患者的耐受情况，可将支气管扩张剂剂量减少。
孟鲁司特钠关键中间体的合成工艺研究作者：齐岩来源：《科学与财富》2016年第31期摘要：本论文对抗哮喘药孟鲁司特钠的重要中间体（E）-2-[3-[3-[2-（7-氯喹啉基）乙烯基]苯基]-3-氧代丙基]苯甲酸甲酯的合成方法进行了研究。
关键词：孟鲁司特钠；中间体；合成孟鲁司特是默克公司研制开发出的一种高选择性半胱氨酰白三烯（Cys-LT）受体拮抗剂，它能竞争性拮抗白三烯D4与Cys-LT1受体的结合。
最早是作为一种新型的非甾体类抗哮喘药而被应用的，并且在临床上取得了肯定的效果。
[1]随着研究的深入，人们发现孟鲁司特不仅可以改善哮喘患者的肺功能，而且在抗炎、免疫等诸多方面也有重要的应用价值。
孟鲁司特钠的化学名为[R-（E）]-1-[[[1-[3-[2-（7-氯-2-喹啉基）乙烯基]苯基]-3-[2-（1-羟基-1-甲基乙基）苯基]丙基]硫代]甲基]环丙基乙酸钠，结构式如图1所示。
由于孟鲁司特钠的合成步骤较多，其价格一直居高不下，对其大量生产和广泛应用造成了严重的阻碍。
（E）-2-[3-[3-[2-（7-氯喹啉基）乙烯基]苯基]-3-氧代丙基]苯甲酸甲酯是孟鲁司特钠合成步骤中的重要中间体，几乎所有合成孟鲁司特的路线都要通过这个中间体[2，3]，所以该中间体合成工艺直接关系到孟鲁司特钠生产的总收率及成本。
因此研究开发该中间体的新合成路线，具有十分重要的经济价值和社会意义。
1.实验材料本实验所用试剂和溶剂均为市售化学纯或者分析纯，文中提及的干燥溶剂的制备方法均为二次蒸馏收集沸点恒定的馏分。
2.合成路线在本研究中，经分析总结每一条孟鲁司特钠合成路线的优缺点和大量试验最终成功摸索出一条新的孟鲁司特关键中间体合成路线。
该路线以廉价的间溴苯甲醛（化合物B）作为起始原料，经过6步反应，得到终产品。
先用乙二醇将其羰基进行保护生成化合物C，然后将化合物C做成格氏试剂在室温下与醋酐反应生成1-[3-（1，3-二氧戊环）-2-苯基]乙酮（化合物D）。
顺尔宁(Singulair)(孟鲁司特钠颗粒)【药品名称】商品名称：顺尔宁(Singulair)通用名称：孟鲁司特钠颗粒英文名称：Montelukast Sodium Oral Granules【成份】本品要紧成份为孟鲁司特钠, 其化学名称为：[R-(E)]-1-[[[1-[3-[2-(7-氯-2-喹啉)乙烯基]苯基]-3-[2-(1-羟基-1-甲基乙基)苯基]丙基]硫] 甲基] 环丙烷乙酸钠化学结构式：分子式：C35H35ClNNaO3S分子量:【适应症】本品适用于1岁以上儿童哮喘的预防和长期医治，包括预防白天和夜间的哮喘病症，医治对阿司匹林灵敏的哮喘患者和预防运动诱发的支气管收缩。
本品适用于减...【用法用量】每日一次。
哮喘病人应在睡前服用。
过敏性鼻炎病人可依照自身的情形在需要时刻服药。
同时患有哮喘和过敏性鼻炎的病人应每晚用药一次。
1岁至2岁儿童哮喘患者天天一次，每次一袋。
2岁至5岁儿童哮喘患者和/或2岁至5岁过敏性鼻炎患者应天天服用4mg口服颗粒一袋。
口服颗粒的服用本品可直接服用，与一勺室温或冷的软性食物（如苹果酱）混合服用，或溶解于一茶匙室温或冷的婴儿配方奶粉或母乳服用。
在服历时才能打开包装袋。
打开包装袋以后应当即服用全数的剂量（15分钟内）。
与食物、婴儿配方奶粉或母乳混合后的本品不能再贮存至下次继续服用。
本品不该溶解于除婴儿配方奶粉或母乳外的其它液体中服用。
可是服药后能够饮水。
一样建议以哮喘操纵指标来评判医治成效，本品的疗效在用药一天内即显现。
本品可与食物同服或另服。
应建议患者不管在哮喘操纵仍是恶化时期都坚持服用。
对肾功能不全患者、轻至中度肝损害的患者及不同性别的患者无需调整剂量。
本品与其它哮喘医治药物的关系本品可加入患者现有的医治方案中。
减少归并用药物的剂量:支气管扩张剂单用支气管扩张剂不能有效操纵的哮喘患者，可在医治方案中加入本品，一旦有临床医治反映（一样出此刻首剂用药后），依照患者的耐受情形，可将支气管扩张剂剂量减少。
核准日期：2006年11月30日修改日期：2008年11月14日修改日期：2009年12月21日修改日期：2010年09月11日修改日期：2011年12月27日修改日期：2012年08月23日修改日期：2012年08月28日修改日期：2013年03月08日修改日期：2013年10月25日修改日期：2014年09月05日修改日期：2016年11月07日孟鲁司特钠片说明书请仔细阅读说明书并在医师指导下使用[药品名称]通用名称：孟鲁司特钠片商品名称：顺尔宁®(Singulair®)英文名称：Montelukast Sodium Tablets汉语拼音：Menglusitena Pian[成份]本品主要成份为孟鲁司特钠，其化学名为[R-(E)]-1-[[[1-[3-[2-(7-氯-2-喹啉)乙烯基]苯基]-3-[2-(1-羟基-1-甲基乙基)苯基]丙基]硫]甲基]环丙烷乙酸钠化学结构式：N Cl S COO-Na+ H3HOH3C分子式：C35H35ClNNaO3S分子量：608.18[性状]本品为浅黄色异形薄膜衣片。
[适应症]本品适用于15岁及15岁以上成人哮喘的预防和长期治疗，包括预防白天和夜间的哮喘症状，治疗对阿司匹林敏感的哮喘患者以及预防运动诱发的支气管收缩。
本品适用于减轻过敏性鼻炎引起的症状（15岁及15岁以上成人的季节性过敏性鼻炎和常年性过敏性鼻炎）。
[规格]10mg（以孟鲁司特计）。
[用法用量]每日一次，每次一片（10mg）。
哮喘病人应在睡前服用。
过敏性鼻炎病人可根据自身的情况在需要时服药。
同时患有哮喘和过敏性鼻炎的病人应每晚用药一次。
15岁及15岁以上患有哮喘和/或过敏性鼻炎的成人患者每日一次，每次10mg。
一般建议以哮喘控制指标来评价治疗效果，本品的疗效在用药一天内即出现。
本品可与食物同服或另服。
应建议患者无论在哮喘控制还是恶化阶段都坚持服用。
老年患者、肾功能不全患者、轻至中度肝损害的患者及不同性别的患者无需调整剂量。
001-1409-2(仮訳).pdfMontelukast SodiumモンテルカストナトリウムC35H35ClNNaO3S: 608.17Sodium (1-{[((1R)-1-{3-[(1E)-2-(7-chloroquinolin-2-yl)ethenyl] phenyl}-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl)sulfanyl] methyl}cyclopropyl)acetate[151767-02-1]Montelukast Sodium contains not less than 98.0% and not more than 102.0% of C35H35ClNNaO3S, calcu-lated on the anhydrous basis and corrected on the amount of the residual solvent.Description Montelukast Sodium occurs as a white to pale yellowish white powder.It is very soluble in methanol and in ethanol (99.5), and freely soluble in water.It is hygroscopic.It turns yellow on exposure to light.Identification(1)Place 0.1 g of Montelukast Sodium in a crucible, and heat until a white residue is formed. To the residue add 2 mL of water, and then filter. To the filtrate add 2 mL of potassium carbonate solution (3 in 20), and heat to boiling: no precipitate is observed. To this solution add 4 mL of potassium hexahydroxoantimonate (V) TS, heat to boiling, and cool immediately in ice water: a white precipitate is formed. Rub the inside wall of the test tube with a glass rod, if necessary.(2)Determine the absorption spectrum of a solution of Montelukast Sodium in a mixture of methanol and water (3:1) (1 in 100,000) as directed under Ultraviolet-visible Spectrophotometry <2.24>, and compare the spectrum with the Reference Spectrum or the spectrum of a solution of Montelukast Sodium RS prepared in the same manner as the sample solution: both spectra exhibit similar intensities of absorption at the same wavelengths.(3)Determine the infrared absorption spectrum of Mon-telukast Sodium as directed in the paste method under Infra-red Spectrophotometry <2.25>, and compare the spectrum with the Reference Spectrum or the spectrum of Montelukast Sodium RS: both spectra exhibit similar intensities of ab-sorption at the same wave numbers. Or, perform the test by the potassium bromide disk method or ATR method, and compare the spectrum with the spectrum of Montelukast So-dium RS: both spectra exhibit similar intensities of absorp-tion at the same wave numbers.Purity (1) Heavy metals－Dissolve 0.5 g of Montelukast Sodium in 20 mL of a mixture of acetone and water (4:1), and use this solution as the sample solution. Separately, take 0.5 mL of Standard Lead Solution, add 20 mL of the mixture of acetone and water (4:1), and use this solution as the stand-ard solution. To the sample solution and the standard solution add 2 mL of acetate buffer solution, pH 3.5, and shake. To these solutions add 1.2 mL of thioacetamide-alkaline glycerin TS, shake immediately, then allow to stand for 2 minutes, and filter through a membrane filter with pore size 0.45 µm (about 13 mm in diameter). Compare the color on the mem-brane filters through which each solution is filtered: the color obtained from the sample solution is not darker than that obtained from the standard solution (not more than 10 ppm).(2)Related substances－Conduct this procedure using light-resistant vessels. Dissolve 50 mg of Montelukast So-dium in 50 mL of a mixture of methanol and water (9:1), and use this solution as the sample solution. Perform the test with 10 µL of the sample solution as directed under Liquid Chromatography <2.01>according to the following condi-tions. Determine each peak area by the automatic integration method, and calculate the amount of them by the area per-centage method: the amount of the peak having the relative retention time of about 1.9 to montelukast (related substance F) is not more than 0.3%, the amount of the peak having the relative retention time of about 0.4 (related substance A) is not more than 0.2%, the amounts of the peaks having the relative retention times of about 0.8 (related substance B) and about 1.2 (related substance E) are not more than 0.15%, respectively, the total amount of the two peaks having the relative retention time about 0.9 (related substances C and D) is not more than 0.15%, and the amounts of the peaks other than montelukast and the peaks mentioned above are not more than 0.10%, respectively. The total amount of the peaks other than montelukast is not more than 0.6%.Operating conditions－Detector, column, column temperature, mobile phase, and flow rate: Proceed as directed in the operating conditions in the Assay.Time span of measurement: For 16 minutes after injection, beginning after the solvent peak.System suitability－System performance: Proceed as directed in the system suitability in the Assay.Test for required detectability: Pipet 1 mL of the sample solution, add the mixture of methanol and water (9:1) to make exactly 100 mL. Pipet 1 mL of this solution, add the mixture of methanol and water (9:1) to make exactly 20 mL, and use this solution as the solution for system suitability test.001-1409-2(仮訳).pdf When the procedure is run with 10 µL of the solution forsystem suitability test under the above operating conditions,the SN ratio of the peak of montelukast is not less than 10.For the calculations mentioned above, the peak areassmaller than that of montelukast, founded in the chromato-gram obtained with 10 µL of the solution for system suitabil-ity test, are excluded.(3)Optical isomer－Conduct this procedure usinglight-resistant vessels. Dissolve 50 mg of Montelukast So-dium in 50 mL of a mixture of water and acetonitrile (1:1),and use this solution as the sample solution. Perform the testwith 10 µL of the sample solution as directed under LiquidChromatography <2.01>according to the following condi-tions. Determine each peak area by the automatic integra-tion method, and calculate the amounts of them by the areapercentage method: the amount of the peak having the rela-tive retention time of about 0.7 to montelukast is not morethan 0.2%.Operating conditions－Detector: An ultraviolet absorption photometer (wave-length: 280 nm).Column: A stainless steel column 4.0 mm in inside diame-ter and 15 cm in length, packed with α1-acid glycoproteinbinding silica gel for liquid chromatography (5 µm in particlediameter).Column temperature: A constant temperature of about30℃.Mobile phase A: Dissolve 2.3 g of ammonium acetate in1000 mL of water, and adjust to pH 5.7 with acetic acid(100).Mobile phase B: A mixture of methanol and acetonitrile(3:2).Flowing of mobile phase: Control the gradient by mixingthe mobile phases A and B as directed in the following table.Time after injection of sample (min) Mobile phase A(vol%)Mobile phase B(vol%)0 －30 70 →60 30 →4030 －35 60 40Flow rate: 0.9 mL per minute (the retention time of mon-telukast is about 25 minutes).System suitability－Test for required detectability: Pipet 1 mL of the sample solution, add the mixture of water and acetonitrile (1:1) to make exactly 100 mL. Pipet 1 mL of this solution, add the mixture of water and acetonitrile (1:1) to make exactly 10 mL. When the procedure is run with 10 µL of this solution under the above operating conditions, the SN ratio of the peak of montelukast is not less than 10.System performance: Dissolve about 5 mg of Montelukast Racemate RS in the mixture of water and acetonitrile (1:1) to make 50 mL. When the procedure is run with 10 µL of this solution under the above operating conditions, the resolution between the peak of montelukast and the peak having the relative retention time of about 0.7 to montelukast is not less than 2.9.(4)Residual solvent－Being specified separately when the drug is granted approval based on the Pharmaceutical Affairs Law.Water <2.48>Not more than 4.0% (0.3 g, volumetric titra-tion, direct titration).Assay Conduct this procedure using light-resistant vessels. Weigh accurately about 50 mg of Montelukast Sodium, and dissolve in a mixture of methanol and water (9:1) to make exactly 50 mL. Pipet 10 mL of this solution, add the mixture of methanol and water (9:1) to make exactly 100 mL, and use this solution as the sample solution. Separately, weigh accurately about 26 mg of Montelukast Dicyclohexylamine RS, dissolve in the mixture of methanol and water (9:1) to make exactly 50 mL. Pipet 5 mL of this solution, add the mixture of methanol and water (9:1) to make exactly 20 mL, and use this solution as the standard solution. Perform the test with exactly 10 µL each of the sample solution and standard solution as directed under Liquid Chromatography <2.01> according to the following conditions. Determine the peak areas, A T and A S, of montelukast in each solution.Amount (mg) of C35H35ClNNaO3S＝M S×A T／A S×5／2 ×0.792M S: Amount (mg) of Montelukast Dicyclohexylamine RSOperating conditions－Detector: An ultraviolet absorption photometer (wave-length: 238 nm).Column: A stainless steel column 4.6 mm in inside diame-ter and 5 cm in length, packed with phenylsilanized silica gel for liquid chromatography (1.8 µm in particle diameter). Column temperature: A constant temperature of about 30℃.Mobile phase A: A mixture of water and trifluoroacetic acid (2000:3).Mobile phase B: A mixture of acetonitrile and trifluoroa-cetic acid (2000:3).Flowing of mobile phase: Control the gradient by mixing the mobile phases A and B as directed in the following table.Time after injectionof sample (min)Mobile phase A(vol%)Mobile phase B(vol%)0 － 3 60 403 －16 60 →49 40 →51 Flow rate: 1.2 mL per minute (the retention time of mon-telukast is about 7 minutes).001-1409-2(仮訳).pdfSystem suitability－System performance: Dissolve 10 mg of Montelukast for Peak Identification RS in the mixture of methanol and water (9:1) to make 10 mL, and use this solution as the solution A for peak identification. Perform the test with 10 µL of the solution A for peak identification under the above operating conditions, and identify the peaks having the relative reten-tion times to montelukast of about 0.4 (related substance A), about 0.9 (related substances C and D), about 1.2 (related substance E), and about 1.9 (related substance F). Place 1 mL of the solution A for peak identification in a clear glass con-tainer, allow to stand for about 20 minutes, and use this solu-tion as the solution B for peak identification. When the pro-cedure is run with 10 µL of the solution B for peak identifi-cation under the above operating conditions, and identify the peak having the relative retention time of about 0.8 to mon-telukast (related substance B), the resolution between the peaks of related substance B and montelukast is not less than 2.5, and between the peaks of montelukast and related sub-stance E is not less than 1.5.System repeatability: When the test is repeated 5 times with 10 µL of the standard solution under the above operat-ing conditions, the relative standard deviation of the peak area of montelukast is not more than 0.73%.Containers and storage Containers－Tight containers Storage－Light-resistant.Related substancesRelated substance A:(1-{[(1-{3-[(1E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl} -3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl)sulfinyl] methyl}cyclopropyl)acetic acid Related substance B:(1-{[((1R)-1-{3-[(1Z)-2-(7-Chloroquinolin-2-yl)ethenyl] phenyl}-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl)sulfanyl]methyl}cyclopropyl)acetic acidRelated substance C:(1-{[((1R)-1-{3-[(1R)-1-({[1-(Carboxymethyl)cyclopropyl] methyl}sulfanyl)-2-(7-chloroquinolin-2-yl)ethyl]phenyl}-3- [2-(1-hydroxy-1-methylethyl)phenyl]propyl)sulfanyl]methyl}cyclopropyl)acetic acidRelated substance D:(1-{[((1R)-1-{3-[(1S)-1-({[1-(Carboxymethyl)cyclopropyl] methyl}sulfanyl)-2-(7-chloroquinolin-2-yl)ethyl]phenyl}-3- [2-(1-hydroxy-1-methylethyl)phenyl]propyl)sulfanyl]methyl}cyclopropyl)acetic acidRelated substance E:(1-{[((1R)-3-(2-Acetylphenyl)-1-{3-[(1E)-2-(7-chloroquinolin -2-yl)ethenyl]phenyl}propyl)sulfanyl]methyl}cyclopropyl)acetic acid001-1409-2(仮訳).pdfRelated substance F:(1-{[((1R)-1-{3-[(1E)-2-(7-Chloroquinolin-2-yl)ethenyl]phenyl}-3-[2-(1-methylethenyl)phenyl]propyl)sulfanyl]methyl}cyclopropyl)acetic acidAdd the following to 9.01 Reference Standards(1):Montelukast Sodium RSMontelukast Dicyclohexylamine RSMontelukast Racemate RSMontelukast for Peak Identification RS。
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impurity2.奥拉西坦杂质oxiracetam3.罗氟司特杂质roflumilast4.阿戈美拉汀杂质Agomelatine5.鲁拉西酮杂质Lurasidone6.莫西沙星杂质moxifloxacin7.阿齐沙坦杂质Azilsartan8.达比加群酯杂质Pradaxa9.利拉利汀杂质Linagliptin10.托法替尼杂质T ofacitinib11.依托考昔杂质12.阿西替尼杂质Axitinib13.维格列汀杂质Vildagliptin14.帕瑞昔布杂质parecoxib15.伊马替尼杂质imatinib16.阿哌沙班杂质Apixaban17.替诺福韦酯杂质T enofovir Disoproxil Fumarate18.普拉格雷杂质Prasugrel19.伊拉地平杂质isradipine20.利托那韦杂质ritonavir21.培美曲塞二钠杂质pemetrexed disodium22.依达拉奉杂质Edaravone23.吉非替尼杂质gefitinib24.替吉奥杂质BCB25.苯达莫司汀杂质Cephalon26.替加环素杂质Tigecycline27.布南色林杂质Blonanserin28.文拉法辛杂质venlafaxine29.替卡格雷杂质30.利伐沙班杂质Rivaroxaban31.伊曲茶碱杂质Istradefylline32.依度沙班杂质Edoxaban33.三氟胸苷杂质Trifluorothymidine34.盐酸阿考替胺杂质acotiamide hydrochloride35.度洛西汀杂质Duloxetine36.泊沙康唑杂质37.泰地唑胺杂质38.沃替西汀杂质39.乐伐替尼杂志40.卡博替尼杂质Cabozantinib41.依鲁替尼杂质42.恩格列净杂质EMpagliflozin43.辛伐他汀杂质simvastatin44.恩杂鲁胺杂质45. 阿苯达唑Albendazole46. 阿达帕林adapalene47. 阿夫唑嗪alfuzosin48. 阿卡地新acadesine49. 阿立哌唑aripiprazole50. 阿莫曲普坦almotriptan51. 阿莫西林amoxicillin52. 阿瑞吡坦Aprepitant53. 阿昔洛韦acyclovir54. 埃罗替尼erlotinib55. 安非他酮bupropion56. 氨苄青霉素ampicillin57. 氨基葡萄糖Glucosamine58. 氨甲环酸tranexamic59. 氨溴索Ambroxol60. 胺碘酮Amiodarone61. 奥氮平olanzapine62. 奥沙利铂Oxaliplatin63. 奥司他韦oseltamivir64. 保胆键素dihydroxydibutylether65. 保特佐米Bortezomib66. 苯达莫司汀Bendamustin67. 比卡鲁胺bicalutamide68. 吡罗昔康piroxicam69. 吡嗪酰胺Pyrazinamide70. 别嘌醇allopurinol71. 波生坦bosentan72. 布洛芬Ibuprofen73. 布美他尼Bumetanide74. 雌甾四烯estratetraenol75. 醋氯芬酸aceclofenac76. 达非那新Darifenacin77. 大黄酸Diacerein78. 地尔硫卓diltiazem79. 地拉罗司deferasirox80. 氨氯地平Amlodipine81. 硝苯地平nifedipine82. 甲氨蝶呤Methotrexate83. 氨基蝶呤Aminopterin84. 丁螺环酮buspirone85. 多奈哌齐Donepezi86. 多立酮Domperidone87. 恩丹西酮ondansetron88. 恩他卡朋entacapone89. 伐昔洛韦valacyclovir90. 泛昔洛韦famciclovir91. 非布索坦Febuxostat92. 非那雄胺inasteride-ep93. 非诺贝特fenofibrate94. 弗斯特罗定fesoterodine95. 伏立康唑Voriconazole96. 氟替卡松丙酸酯fluticasone-propionate97. 氟维司群Fulvestrant98. 格列吡嗪glipizide99. 桂利嗪cinnarizine100. 环苯扎林cyclobenzaprine101. 加巴喷丁gabapentin102. 甲状旁腺激素西那卡塞Cinacalcet 103. 甲状腺素Levothyroxine104. 卡巴拉汀利凡斯的明Rivastigmine RC's 105. 喹硫平Quetiapine106. 奥美拉唑Omeprazole107. 兰索拉唑Lansoprazol108. 雷贝拉唑Rabeprazole109. 泮托拉唑pantoprazol110. 来氟米特leflunomide111. 雷洛昔芬raloxifene112. 雷莫拉宁Ramoplanin113. 雷奈佐利Linezolid114. 利伐沙班Rivaroxaban115. 利培酮Risperidal116. 罗匹尼罗ropinirole117. 阿替洛尔Atenolol118. 比索洛尔Bisoprolol119. 醋丁洛尔Acebutolol120. 美托洛尔metoprolol121. 奈必洛尔nebivolol122. 氯吡格雷Clopidogrel123. 氯雷他定Loratadine124. 霉酚酸mycophenolate125. 美洛昔康meloxicam126. 孟鲁司特montelukast127. 米氮平mirtazapine128. 尼美舒利nimesulide129. 帕罗西汀Paroxetine130. 帕立酮Paliperidone131. 生丁Dipyridamole Dipyridamole 132. 培美曲塞二钠Pemetrexed-disodium 133. 普拉克索Pramipexole134. 喹那普利Quinapril135. 卡托普利captopril136. 赖诺普利Lisinopril137. 雷米普利Ramipril138. 培哚普利Perindopril Imp139. 群多普利Trandolapril140. 伊拉普利Enalapril141. 普瑞巴林pregabalin142. 瑞格列奈Repaglinide143. 塞来西布Celecoxib144. 噻托溴铵Tiotropium bromide 145. 沙丁胺醇salbutamol146. 沙美特罗salmeterol147. 奥美沙坦Olmesartan148. 坎地沙坦Candesartan 149. 罗沙坦Losartan150. 替米沙坦T elmisartan 151. 缬沙坦Valsartan152. 加替沙星gatifloxacin 153. 氟哌酸norfloxacin154. 菲宁达、氧氟沙星Ofloxacin 155. 恩诺沙星enrofloxacin 156. 环丙沙星Ciprofloxacin 157. 莫西沙星moxifloxacin 158. 左氧氟沙星Levofloxacin 159. 舍曲林Sertraline160. 舒马曲坦sumatriptan 161. 双醋瑞因diacerein 162. 双氯芬酸Diclofenac 163. 他达那非T adalafil 164. 阿托伐他汀atorvastatin 165. 洛伐他汀Lovastatin 166. 匹伐他汀pitavastatin 167. 普伐他汀pravastatin 168. 瑞舒伐他汀Rosuvastatin 169. 辛伐他汀Simvastatin170. 坦索罗辛T amsulosin 171. 格列美脲glimepiride172. 吡格列酮pioglitazone 173. 尼扎替丁nizatidine 174. 替卡西林Ticarcillin 175. 酮咯酸氨丁三醇Ketorolac 176. 酮基布洛芬Ketoprofen 177. 头孢氨苄cefalexin178. 头孢克洛cefaclor179. 头孢磺啶cefsulodin 180. 托特罗定tolterodine 181. 拓扑替康topotecan 182. 万古霉素vancomycin 183. 文拉伐辛Venlafaxine 184. 那非Sildenafil185. 西他列汀Sitagliptin 186. 西酞普兰Citalopram 187. 西替利嗪cetirizine 188. 伊立替康Irinotecan 189. 伊马替尼imatinib190. 伊曲康唑Itraconazole 191. 依泽替米贝ezetimibe192. 左乙拉西坦Levetiracetam193. 佐米曲普坦zolmitriptan194. 唑吡坦zolpidem195. 唑尼沙胺Zonisamide依鲁替尼（Ibrutinib）杂质6个，palbociclib杂质6个，泰地唑胺杂质tedizolid phosphate 12个达格列净杂质Dapagliflozin 7个，索非布韦杂质sofosbuvir 20个，替卡格雷杂质Ticagrelor 14个，米拉贝隆杂质Mirabegron 10个，TAK 438杂质10个，沃替西汀杂质Vortioxetine 15个，LCZ696杂质6个非布司他杂质Febuxostat 14个泊沙康唑异构体Posaconazole 14个阿普斯特杂质Apremilast 6个阿奇霉素杂质Azithromycin 14个阿考替胺杂质Acotiamide 14个依托考昔杂质Etoricoxib 14个尼达尼布杂质Nintedanib 8个罗库溴铵杂质Rocuronium Bromide 8个恩杂鲁胺杂质Enzalutamide 4个卢帕他定杂质Rupatadine 6个瑞格非尼杂质Regorafenib 20个色瑞替尼杂质Ceritinib 11个依美斯汀杂质Emedastine8个依匹唑派杂质Brexpiprazole6个依帕司他杂质epalrestat 6个乌苯美司杂质Ubenimex 19个福多司坦杂质Fudosteine 6个马来酸匹杉琼杂质Maleic acid Chinese fir, Joan 6个扎鲁司特杂质Zafirlukast 6个贝利司他杂质belinostat 6个奥扎格雷的杂质ozagrel 6个酒石酸伐尼克兰片杂质Varenicline T artrate T ablets 6个莫扎伐普坦杂质Mozavaptan 5个沙芬酰胺杂质Safinamide 4个沃雷生杂质suvorexant 5个依替巴肽杂质Eptifibatide 5个乐伐替尼杂质lenvatinib 8个。
39 Journal of China Prescription Drug Vol.19 No.4·实验研究·孟鲁司特钠是一种口服的白三烯受体拮抗剂，能特异性抑制气道中的半胱氨酰白三烯（CysLT1）受体，从而改善气道炎症，有效控制哮喘症状[1]。
原研药为默沙东公司研发、生产的咀嚼片，1999年获得中国国家食品药品监督管理局批准正式上市。
在生产孟鲁司特钠咀嚼片时，其生产线通常还用于其他产品，为了防止孟鲁司特钠残留对下一产品的污染，生产结束后需要对生产设备进行有效清洁并进行清洁验证。
而建立可靠的残留物分析方法并对分析方法进行验证是清洁验证的重要保障[2]。
本研究参考GMP验证要求，通过计算确定孟鲁司特钠清洁验证设备残留限度为0.034 μg/cm2。
参照《美国药典》和《日本药典》中孟鲁司特钠的有关物质测定方法[3]，依据清洁验证的特殊要求，对色谱条件进行优化，建立了一种可快速检验生产设备表面孟鲁司特钠残留量的方法。
1 仪器与试药Agilent1260高效液相色谱仪（美国安捷伦）；XPE205DR电子分析天平（美国梅特勒）；水为超纯水；乙腈为Merck色谱纯；甲醇为Merck色谱纯；三氟乙酸为Tedia色谱纯；CIP100为奥星衡迅生命科技（上海）有限公司；其他试剂均为分析纯。
对照品孟鲁司特二环己胺对照品（USP，批号：R035A0，含量为99.3%）。
2 方法与结果2.1 孟鲁司特浓度计算孟鲁司特钠咀嚼片的清洁残留限度为0.034 μg/cm2，擦拭面积为100 cm2，所以擦拭用棉签的理论浓度为3.4 μg/块。
每块棉签的擦拭物溶解于10 ml溶剂中，最后擦拭供试液浓度理论值为0.34 μg/ml，作为分析方法验证中孟鲁司特的100%水平浓度。
2.2 色谱条件参照在USP41和JP17孟鲁司特钠片下有关物质[2]测定方法，经验证后，色谱条件如下：色谱柱为Agilent SB-Phenyl 4.6×75 mm，3.5 μm；以0.2%三氟乙酸水溶液（V/V）-0.2%三氟乙酸乙腈（V/V）（50∶50）为流动相；检测波长为389 nm；进样盘：10℃；流速：0.9 ml/min；柱温：50℃；进样量：50 μl；稀释剂：甲醇-水（3∶1）。
