硫酸氢氯吡格雷片处方和制备工艺研究

硫酸氢氯吡格雷片剂的制备流程英文回答：The preparation process of clopidogrel hydrogen sulfate tablets can be divided into several steps: raw material selection, formulation design, granulation, tablet compression, coating, and packaging.Firstly, raw materials need to be selected. The main active ingredient is clopidogrel hydrogen sulfate, which is a white to off-white powder. Other excipients, such as fillers, binders, disintegrants, and lubricants, are also necessary for tablet formulation.Next, the formulation design is conducted. The purpose is to determine the optimal composition and dosage of each ingredient in the tablet. This includes the selection of suitable fillers, binders, and disintegrants to achieve the desired tablet characteristics, such as hardness,friability, and disintegration time. The formulation designalso involves determining the appropriate concentration of the active ingredient and the use of any necessary coating materials.After the formulation design, the granulation process begins. Granulation is the process of combining the active ingredient and excipients to form granules. This can be done through wet granulation or dry granulation methods. Wet granulation involves mixing the ingredients with a liquid binder, such as water or alcohol, and then drying the mixture to form granules. Dry granulation, on the other hand, involves compressing the ingredients into compacted masses and then breaking them down into granules.Once the granules are formed, they are compressed into tablets using a tablet compression machine. The compression process involves filling the granules into the die cavity and applying pressure to form the tablets. The tablets are then checked for weight, hardness, and other quality parameters.After compression, the tablets may undergo a coatingprocess. Coating is done to improve the appearance, taste, and stability of the tablets. It can also provide a protective layer to prevent moisture absorption or to mask the taste of the active ingredient. The coating material is usually a polymer solution or suspension, which is applied to the tablets using a coating machine. The coated tablets are then dried and inspected for quality.Finally, the tablets are packaged in suitable containers, such as blister packs or bottles, to protect them from moisture, light, and physical damage. The packaging process may also involve labeling and batch coding for identification and traceability purposes.Overall, the preparation process of clopidogrel hydrogen sulfate tablets involves careful selection of raw materials, formulation design, granulation, tablet compression, coating, and packaging. Each step plays a crucial role in ensuring the quality, efficacy, andstability of the final product.中文回答：克洛匹多氢硫酸盐片剂的制备流程可以分为几个步骤，原材料选择、配方设计、制粒、压片、包衣和包装。

氯吡格雷的合成线路研究李超（上海交通大学药学院，200240）摘要：氯吡格雷是一种新型的具有不可逆抑制血小板聚集的噻吩并吡啶化合物，医治效果明确，国内外用量已增大。

法国赛洛菲公司在我国申请的行政保护已通过时。

由于生产技术有必然难度，目前国内产品大部份为入口。

拉通工艺线路并进行工艺改进，将代替入口，具有较大的现实意义和经济效益。

关键词：氯吡格雷Introduction to synthesis route of clopidogrelLi Chao(College of Pharmacy, Shanghai Jiao Tong University, 200240)AbstractClopidogrel is one of thieno[3,2-c]pyridine derivatives, which can inhibit ADP-induced platelet aggregation. The treat effect is clear and the demand is increasing in domestic and abroad. Sanofi corporation hasapplied administrative protection, which is overdue in china. Because the product technique has some difficulties and most of the domestic products are imports, it will be to have practical importance and economic benefit to replace imports in the condition of getting through and improving the technology route.A new route consisting of sulfonylation, methylesterification, nucleophilic substitution, condensation ring closure and salification is studied in this paper . The single-factor optimization and the orthogonal test are adopted.According to the above results of optimization, the overall yield of clopidogrel hydrogen sulfate is 39%. This new route is practical and economic because of the available raw materials, simple operation, mild reaction conditions, reduced wastes, simple postprocessing and high yield.Keywords: clopidogrel一．前言氯吡格雷（clopidogrel）是噻氯匹定的乙酸衍生物，由法国赛诺菲圣德拉堡制药公司于1986 年研究开发的新一代的血小板聚集抑制剂，化学名称(S)-α-(2-氯苯基)-6,7-二氯噻吩并[3,2-c]吡啶-5(4H)-乙酸甲酯，英文名methyl(+)-(S)-a-(o-chloropheny-l)-6,7-dihydrothieno[3, 2-c]pyridine-5(4H)-acetate，临床用其硫酸盐，商品名为波立维（Plavi x）[1]。

中国药科大学本科毕业论文论文题目复方阿司匹林硫酸氢氯吡格雷片的研制英文题目Preparation of Compound Aspirin-Clopidogrel bisulphate tablets专业药物制剂院部药学院学号 0742020 姓名刘蕾指导教师吴琼珠课题完成场所江宁校区G132室论文工作时间： 2010 年 12 月至 2011 年 6 月复方硫酸氢氯吡格雷缓释片的研制目录摘要： (5)A BSTRACT: (6)前言 (8)第一章复方阿司匹林硫酸氢氯吡格雷缓释片的处方前研究10 1材料和仪器 (10)1.1材料 (10)1.2仪器 (11)2.硫酸氢氯吡格雷单层片的处方前研究 (11)2.1速释层辅料的稳定性 (11)2.2辅料配伍稳定性 (12)3.阿司匹林缓释层的处方前研究 (13)3.1缓释层主辅料 (13)4速释层硫酸氢氯吡格雷的方法学建立 (13)4.1CPB单层片的有关物质测定 (13)4.1.1仪器和材料........................ 错误！未定义书签。

4.1.2色谱条件 (13)4.1.3溶液的配制 (13)4.1.4过程及结果讨论 (14)4.1.5小结 (15)4.2CPB标准曲线的制备 (16)4.3稳定性试验 (16)4.4CPB的体外溶出度测定 (16)4.4.1 P H=2盐酸缓冲液的配制 (16)4.4.2对照液的配制 (17)4.4.3溶出度的测定 (17)5阿司匹林的方法学建立 (18)5.1阿司匹林标准曲线的制备 (18)5.2稳定性试验 (18)5.3阿司匹林的体外释放度测定 (19)6．本章小结 (19)第二章复方阿司匹林硫酸氢氯吡格雷片的处方筛选 (20)1．方法与结果 (21)1.1硫酸氢氯吡格雷的处方筛选 (21)1.1.1处方分析 (21)1.1.2硫酸氢氯吡格雷片的制备工艺 (21)1.1.3主辅料的筛选 (21)1.1.4乳糖和甘露醇的选择 (23)1.2阿司匹林的处方筛选 (24)1.2.1阿司匹林缓释层的处方优化 (24)2.小结： (29)第三章复方阿司匹林硫酸氢氯吡格雷片的研究 (30)1复方双层片的最终处方 (30)2复方双层片的制备...................... 错误！未定义书签。

硫酸氢氯吡格雷片的制剂工艺研究作者：章佳佳来源：《中国实用医药》2014年第08期【摘要】目的本论文通过对硫酸氢氯吡格雷片制剂工艺研究，找到最佳原辅料配比。

方法对硫酸氢氯吡格雷片的脆碎度、溶出度进行检测，评价包衣效果。

结果开发出最优处方：硫酸氢氯吡格雷原料药32.75%、羟丙甲纤维素K4M 1%、微晶纤维素55%、羧甲基淀粉钠7%、十二烷基硫酸钠4%和硬脂酸镁0.25%。

结论硫酸氢氯吡格雷片符合标准。

【关键词】硫酸氢氯吡格雷片；溶出度；薄膜包衣硫酸氢氯吡格雷作为一种新型高效的抗血小板药物，与其他抗血小板药物相比，具有疗效好、费用低、副作用小等优点[1-3]。

特别适合于对阿司匹林不能耐受的患者[4]。

本文对硫酸氢氯吡格雷片进行制剂工艺研究，找到最佳配比。

1 仪器材料与试剂1. 1 主要仪器主要仪器：DP-30单冲压片机（北京国药龙立有限公司）、BG-10高效包衣锅（北京航天工业研究所）、RC-8溶出度检测仪（北京国药龙立有限公司）、CS-1脆碎度检测仪（北京国药龙立有限公司）。

1. 2 材料与试剂主要材料：硫酸氢氯吡格雷原研药（浙江车头制药厂）、硫酸氢氯吡格雷原料药（杭州赛诺菲民生制药有限公司）。

2 实验方法2. 1 处方设计处方设计。

2. 2 脆碎度试验参照脆碎度测定法（《中国药典》2010年版二部附录XG）试验。

2. 3 包衣试验搅拌器内加入230 g卡洛康薄膜包衣粉，加入1150 ml水，搅拌45 min 后，备用。

取卡洛康空白片，投入预热的包衣锅中，待片芯温度达到40～45℃时，加入200余片硫酸氢氯吡格雷素片。

2. 4 溶出度试验参照溶出度测定法（《中国药典》2010年版二部附录XC第二法）试验。

3 实验结果3. 1 脆碎度试验结果不同处方的硫酸氢氯吡格雷片的脆碎度试验结果，各处方均无断裂片无龟裂片无粉碎片，脆碎度分别为0.027、0.030、0.021、0.018、0.015、0.031、0.025、0.020。

墩禽咨丫申粤咨素杯 yf p}30111338582510呀之己Spsu15Xrorr nurnsxzrf-}VIpszrz znpujrusq ToI摘要氯吡格雷是一种新型的拮抗血小板聚集的药物，属于噻吩并吡啶类化合物。

其疗效明显，但是其生产技术有相当的难度。

本文对其合成路线以及合成工艺进行了进一步的研究。

(1)本文综合调研了合成硫酸氢氯吡格雷的文献和专利，选择了三条路线合成氯吡格雷。

路线一以(R)-邻氯扁桃酸为原料合成了 e.e.值符合欧洲药典标准的硫酸氢氯吡格雷盐，首次使用纤维素柱测定硫酸氢氯吡格雷的 e.e.值，收率由 51%提高到了 60%，得到的（S）-硫酸氢氯吡格雷经分析是Ⅰ晶型。

路线二以(S)-邻氯苯甘氨酸甲酯为原料经 Mannich 缩合等四步反应合成了(S)-硫酸氢氯吡格雷，在合成关键中间体(S)-2-(2-噻吩乙胺基)(2-氯苯基)乙酸甲酯的步骤中，经过合成条件的优化，得到的产物比旋度优于文献数据。

路线三以外消旋的(RS)-邻氯苯甘氨酸为原料，重点研究了甲酯化、与对甲苯磺酸噻吩-2-乙酯的亲核取代反应、与多聚甲醛发生 Mannich 缩合、中间体和外消旋(RS)-氯吡格雷进行拆分等反应条件的探索。

首次发现以 325 目的碳酸钾粉末为碱，乙腈为溶剂，过 325 目的 KI 作为催化剂，83℃回流 30h，以 77.34%的收率得到(RS)-(±)-2-(2-噻吩乙胺基)(2-氯苯基)乙酸甲酯盐酸盐。

摸索了产物(RS)-氯吡格雷的拆分条件，得到了 e.e.值 98.9%的单一构型硫酸氢氯吡格雷盐。

路线三的总收率为 25.35%，高于文献报道的收率 19.5%。

（2）本论文最后对得到的(S)-硫酸氢氯吡格雷进行了比旋度、干燥失重、有关物质和含量测定等质量检验，符合新药转正标准-硫酸氢氯吡格雷部分的规定。

关键词：(RS)-氯吡格雷, (S)-硫酸氢氯吡格雷，手性合成,手性拆分,工艺研究IIAbstractClopidogrel is one of the new thieno [3,2-c] pyridine derivatives, which caninhibit ADP-induced platelet aggregation.The effect of Clopidogrel is remarkable,butthe production techniques have considerable difficulty.This thesisis mainly focusedon the further study of the synthetic route and process of the Clopidogrel.(1)Three synthetic routes were selected on the basis of the comprehensiveresearch on the literatures and patents about the synthesis of Clopidogrel hydrogensulfate.The first route , e.e. values of Clopidogrel bisulphate confirmed to the Europeanpharmacopoeia standard was synthesized by (R)- 2-(2-Chlorophenyl)-2-(hydroxyl)acetic acid as raw material.The cellulose column was first applied for thedetermination of Clopidogrel hydrogen sulfate e.e. values. Theyield of (S) -clopidogrel hydrogen sulfate was raised from 51% to 60%. The crystal form of(S)-Clopidogrel hydrogen sulfate which was synthesized by this route was form-Ⅰ.The second route,(S)-Clopidogrel hydrogen sulfate was synthesized by (S)-methyl-α-amino-α-(2-chl-orophenyl)acetate via four steps reactions includingMannich condensation etc. After optimizing the synthetic conditions，the specificoptical rotation of the intermediate (S)-(+)-methyl-α-[[2-(thien-2-yl]amino]-α-(2-chlorophenyl)acetate is superior to the literature data when this key intermediates wassynthesized.The third route,(RS)-α-amino-α-(2-chlorophenyl)acetic acid was usedas rawmaterial. In this route, the reaction conditions of methyl ester reaction,substitutereaction with 2-(2-Thieny)ethyl tosylat，Mannich reaction with paraformaldehydeand the chiral separate reaction of racemic (RS)-Clopidogrel etc were mainlyexplored.The intermediate (RS)-(±)-methyl-α-[[2-(thien-2-yl]amino]-α-(2-chlorophenyl)acetate hydrochloride was got in the yield of77.34%,and theconditions of this reaction were potassium carbonate powder as base who has passedthrough the 325 mesh sieve , acetonitrile as solvent, over a 325 mesh sieve KI ascatalyst, 83℃ refluxed for 30 hours and those conditions werefirst been reported.II IAfter gropping for the resolution conditions of final product (RS)-Clopidogrel,we get(S)-Clopidogrel hydrogen sulfate salt with the e.e. value of98.89%.The total yieldwas 25.35% , higher than the yield of 19.5% reported in the literature. (2)Finally, quality inspection of the (S)-Clopidogrel hydrogen sulfate werecarried out,including the specific optical rotation,loss on drying,determination ofrelated substances and content determination.All of those indicators were conformedto the state pharmacopoeia commission on new drug obtainment of the provisions ofthe standard - Clopidogrel hydrogen sulfate parts.Key words: (RS)-Clopidogrel,(S)-Clopidogrel hydrogen sulfate,chiral synthesis,chiral resolution, process studyIV目录摘要......................................................................... .. (I)ABSTRACT................................................................... (II)1 前言 ........................................................................ . (1)1.1 课题背景......................................................................... (1)1.2 抗血栓药物简介 ........................................................................ .. (1)1.2.1 环氧化酶抑制剂(TXA2) ......................................................................... . (2)1.2.2 二磷酸腺苷(ADP)受体拮抗剂—噻吩吡啶类 (3)1.2.3 血小板膜糖蛋白(GPⅡb/Ⅲa)拮抗剂 (7)1.2.4 磷酸二酯酶(PDE)抑制剂......................................................................... (7)1.2.5 其他药物......................................................................... .. (8)1.3 总结......................................................................... (10)参考文献......................................................................... (10)2 硫酸氢氯吡格雷介绍......................................................................... .. (12)2.1 氯吡格雷开发研究介绍......................................................................... . (12)2.2 硫酸氢氯吡格雷理化性质......................................................................... (12)2.3 硫酸氢氯吡格雷药理药代学介绍 (13)参考文献......................................................................... (14)3 氯吡格雷合成路线及拆分文献综述 (15)3.1 主要合成工艺路线 ........................................................................ . (15)3.1.1 先合成再拆分法 ........................................................................ .. (15)3.1.2 先缩合后环合法 ........................................................................ .. (17)V3.1.3 先拆分后合成法 ........................................................................ .. (21)3.1.4 以手性源原料直接合成......................................................................... (25)3.1.5 合成路线总结......................................................................... .. (27)3.2 手性拆分介绍......................................................................... .. (27)3.2.1 手性介绍......................................................................... (27)3.2.2 手性化合物的得到方法......................................................................... (28)3.2.3 外消旋体的拆分方法 ........................................................................ . (29)3.3 本论文的研究目的与研究内容 ....................................................................31参考文献......................................................................... (33)4 结果与讨论 ........................................................................ (36)4.1 路线一的实验结果与讨论......................................................................... (36)4.1.1 路线一的介绍......................................................................... .. (36)4.1.2 化合物(R)-3-27 的重结晶条件优化 (36)4.1.3 氯吡格雷的成盐条件优化 ........................................................................384.1.4 (S)-硫酸氢氯吡格雷的晶型确认 (38)4.1.5 硫酸氢氯吡格雷 e.e.值测定的色谱条件探索 (40)4.1.6 路线一结果与讨论......................................................................... . (42)4.2 路线二的实验结果与讨论......................................................................... (43)4.2.1 路线二的介绍......................................................................... .. (43)4.2.2 2-（2-噻吩基）对甲苯磺酸酯的制备 (44)4.2.3 化合物(S)-2-(2-噻吩乙胺基)(2-氯苯基)乙酸甲酯的制备 (47)4.3 路线三的试验结果与讨论......................................................................... (51)4.3.1 路线三的介绍......................................................................... (51)4.3.2 化合物(RS)-邻氯苯甘氨酸甲酯盐酸盐的制备 (52)4.3.3 化合物(RS)-2-(2-噻吩乙胺基)(2-氯苯基)乙酸甲酯盐酸盐的制备 (55)4.3.4 化合物(RS)-3-13 成盐酸盐的反应 (60)4.3.5 化合物(RS)-α-2-(氯苯基)-6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-乙酸甲酯的制备........................................................................... .. (61)V I4.4 路线三部分产物的拆分 ........................................................................ .. (65)4.4.1 中间体(RS)-2-(2-噻吩乙胺基)(2-氯苯基)乙酸甲酯的拆分 (66)4.4.2 外消旋氯吡格雷的拆分......................................................................... (70)4.5 质量检验部分 ........................................................................ (73)4.5.1 性状......................................................................... . (73)4.5.2 比旋度 ........................................................................ . (73)4.5.3 干燥失重......................................................................... (74)4.5.4 有关物质......................................................................... (74)4.5.5 含量测定......................................................................... (76)参考文献......................................................................... (78)5 实验部分......................................................................... . (80)5.1 实验仪器和试剂 ........................................................................ .. (80)5.1.1 实验仪器......................................................................... (80)5.1.2 实验试剂......................................................................... (80)5.2 化学实验......................................................................... . (81)5.2.1 化合物 3-19 的制备 ........................................................................ (81)5.2.2 化合物 3-32 的制备 ........................................................................ (81)5.2.3 化合物(RS)-3-13 的制备......................................................................... .. 815.2.4 化合物(RS)-3-31 的制备......................................................................... .. 825.2.5 化合物(RS)-1-4 的制备......................................................................... . (82)5.2.6 化合物(RS)-2-1 的制备......................................................................... . (82)5.2.7 化合物(S)-2-1 的制备......................................................................... (82)结论......................................................................... (84)附图清单和附图......................................................................... . (85)个人简历及攻读硕士期间发表的论文 (94)V II致谢......................................................................... (95)11 前言1.1 课题背景近年来，心脑血管疾病成为了世界上威胁全球人类健康与生命的头号杀手[1]。