CN101124231A - 适于药物制剂的氯吡格雷碱及其制备方法 - Google Patents
适于药物制剂的氯吡格雷碱及其制备方法 Download PDFInfo
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- CN101124231A CN101124231A CNA2006800054912A CN200680005491A CN101124231A CN 101124231 A CN101124231 A CN 101124231A CN A2006800054912 A CNA2006800054912 A CN A2006800054912A CN 200680005491 A CN200680005491 A CN 200680005491A CN 101124231 A CN101124231 A CN 101124231A
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- clopidogrel
- organic solvent
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Abstract
本发明提供了适于药物制剂的氯吡格雷碱,及其制备方法。
Description
相关申请
本申请要求于2005年2月24日提出的美国临时申请第60/656,738号、2005年3月7日提出的美国临时申请第60/659,544号、2005年3月14日提出的美国临时申请第60/661,701号和2005年4月26日提出的美国临时申请60/675,371号的利益。通过引证的方式将它们并入到本申请内。
技术领域
本发明涉及适用于制药用途的氯吡格雷碱。
技术背景
动脉粥样硬化指形成导致动脉出现增厚并产生弹性降低的动脉壁斑块。动脉粥样硬化是由动脉的内层受到损害所引起。这种损害是由日常活动及诸如:高胆固醇、高血压、吸烟和感染这类疾病所致。
斑块在受损害的位置处的动脉内壁形成。这些斑块主要由脂肪组织和平滑肌细胞构成。斑块的形成通常导致受损害处出现因血小板聚集而产生的血凝固。此凝固可以导致重要器官的血流量减少或停止,进而引起心脏病发作或其它严重情况。斑块也可以破裂,并沿动脉输送血块,此间称这些血块为栓塞物,如果这些血块沉积在更小的血管内则可以完全阻碍血流。
抗血小板活性方法在对抗由动脉粥样硬化引起的经常性致命后果时是令人满意的。氯吡格雷是诱发性血小板聚集的抑制剂,其通过抑制腺苷二磷酸与其受体相结合而发生作用。氯吡格雷被肝脏新陈代谢为活性态。其抗血小板活性被延长,在用药后甚至长达十天仍可以阻止任何血小板活性。
氯吡格雷化学名称为(+)-(S)-α-(o-氯苯基)-6,7-二氢噻吩并[3,2-c]吡啶-5(4H)-乙酸甲酯,其结构如下:
氯吡格雷公开在美国专利第4,529,596号(EP 99802、JP59027895)、6,258,961号、5,036,156号(EP420706,JP3120286)、6,080,875号(EP971915,JP2001513806)和6,180,793号(EP981529,JP2001525829)中。
氯吡格雷的血小板抑制活性使其成为一种用于减少缺血性中风、心脏病发作或因诸如动脉粥样硬化类血管病引起的跛行发病率的有效药物。通过抑制血小板聚集,氯吡格雷减少动脉阻断的机会,进而防止了中风和心脏病发作。美国专利第5,576,328描述了一种通过使用氟吡格雷来防止二级缺血事件发生的方法,此间通过引证方式将其并入到本申请内。
氯吡格雷当前以其酸式硫酸盐(即硫酸氢盐)形式被使用。氯吡格雷硫酸氢盐的经验式为C16H16Cl N02S·H2S04。它现在以名为PLAVIX片剂形式出售,其内含约98mg的氯吡格雷硫酸氢盐(相当于75mg氯吡格雷碱)。
以PLAVIX为据表明:可将氯吡格雷作为药学上可接受的盐施用给病人。氯吡格雷碱被避免用于制剂,主要是因为它以一种被溶剂和氯吡格雷酸高度污染的油形式存在。早期有关氯吡格雷的专利(美国专利4,847,265)公开:“氯吡格雷碱是一种油,但它的盐酸盐是以一种白色粉末形式存在。油状产品通常难于提纯,对于制备药物组合物而言,优选使用通常可通过重结晶纯化的晶体产物。”最近申请的专利申请W002/059128也声明:“氯吡格雷碱是一种油状液体,为方便制剂配方,可将此碱转化为药学上可接受的盐。”
氯吡格雷碱以油形式存在,使氯吡格雷碱的配方设计不可行,因为此油含有不可接受量的溶剂和氯吡格雷酸。例如,国家食品药品监督管理局要求有效药用成分中存有的乙醇在量上应小于5000ppm。在本领域内,需要具有此纯度的氯吡格雷碱,以满足国家食品药品监督管理局和药品生产质量管理规范(GMP)的要求,以便用于制备药物制剂。
发明概述
在一种实施方案中,本发明提供总残留有机溶剂量小于约2%重量的氯吡格雷碱。在其它实施方案中,提供的氯吡格雷碱中所含总残留有机溶剂量小于约1%重量,小于约0.5%重量,或小于约1000ppm。在一种实施方案中,所述溶剂为甲醇、乙醇或乙酸乙酯中的至少一种。
在另一种实施方案中,根据HPLC(高效液相色谱)测得的面积百分比,本发明提供的氯吡格雷碱含总杂质量小于约0.5%。在其它实施方案中,根据HPLC测得的面积百分比,氯吡格雷酸含量小于约0.3%、或小于约0.1%、或小于约0.02%。
本发明还提供氯吡格雷碱的药用组合物及其用于抑制哺乳动物体内血小板聚集的方法。
在另一种实施方案中,本发明提供制备根据权利要求1至权利要求9中任何一项权利要求所述的氯吡格雷碱的方法,包括如下步骤:
a)提供含有氯吡格雷碱及残留量的至少一种有机溶剂的油;和
b)在减压状态下于转膜(wiped film)蒸发器内将所述油干燥。
发明详述
本发明提供基本上不含有溶剂的氯吡格雷碱的制备方法。本方法允许以工业规模在药物制剂中使用该碱。
术语“工业规模”指至少约0.2kg,更优选地至少约0.5kg,和最优选地至少约1.0kg的批量。
本发明提供的氯吡格雷碱基本不含溶剂,优选地其所含总溶剂少于约2%重量,更优选地所含总溶剂少于约1%重量,甚至更优选地所含总溶剂少于约0.5%重量,和最优选地所含总溶剂少于约1000ppm。在一种实施方案中,溶剂为甲醇、乙醇、乙酸乙酯或二氯甲烷中的至少一种。
本发明提供的氯吡格雷碱可以采用转膜蒸发器(WFE)制备。转膜蒸发器是一种处于减压状态下(即低于一个大气压)在其表面对氯吡格雷碱进行刮擦的设备。典型地,配有刮板、桨片或相类似装置的内旋转转子对氯吡格雷碱膜进行内部分配和快速输送。蒸汽经出口除去并与氯吡格雷碱分离。
根据Gooch热系统(Lebanon,N.J.),擦扫器或转子的设计类型根据诸如:积垢/沉积物形成趋势、粘度、残留水分要求等产品性能和加工要求。典型地使用三种基本类型转子:刚性浆片转子(在其桨尖和加热表面之间留有固定余隙)、配有径向运动式刮板(具有PTFE或石墨元件的转膜(wiped film))的转子,和配有铰接自由摆动式刮板的转子(转膜金属刮板或具有PTFE尖端的金属刮板)。一种可采用的转膜蒸发器从POPE公司(Saukville,Wisconsin)获得。
优选WFE可以在套温约20℃至约250℃下使用,更优选地在约30℃至约200℃下使用,和甚至更优选地在约50℃至约100℃下使用。进料速率优选地是约0.1ml/min至约200ml/min,更优选地是0.1ml/min至约100ml/min,最优选地是约0.1ml/min至约50ml/min。尖端速度优选地是约0.1m/s到约2m/s,更优选地是约1.57m/s。压力通常小于1个大气压,优选地小于约200mmHg,更优选地是小于约100mmHg。其它类型转膜蒸发器可以使用不同的参数。
用于向WFE进料的氯吡格雷碱溶液通过本领域内熟知的常规方法制备。配制溶液用的起始原料可以是氯吡格雷的任何盐,诸如硫酸氢盐或樟脑磺酸盐。或者,可以商业购买油状氯吡格雷碱。使用樟脑磺酸盐的优势是,樟脑磺酸盐用于氯吡格雷的对映体提纯,由此本发明方法可将对映体提纯作为随后步骤予以结合。
在一种实施方案中,氯吡格雷樟脑磺酸盐与有机溶剂混合,所述有机溶剂例如为下列中的至少一种:C1-C5氯代烃类、优选C1-C3氯代烃类、更优选二氯甲烷;环状或非环状C6到C8烷烃,优选地为己烷、环己胺、庚烷或环庚烷;C2-C8醚,优选地为C4-C6醚,更优选地为甲基叔丁基醚(MTBE),二乙醚或四氢呋喃;C4-C7酮,优选地为甲基乙基酮(MEK);C6-C9芳香烃,优选地为苯或甲苯;或C3-C7酯,优选地为乙酸乙酯、乙酸丙酯、乙酸丁酯、乙酸异丁酯或乙酸异丙酯;最优选地,有机溶剂为乙酸乙酯或二氯甲烷。
随后加入碱水,以游离氯吡格雷碱,由此产生水相和有机相。氯吡格雷碱迁移到有机相中,随后将有机相与水相分离。可通过液相分离法或固液相分离法进行分离。优选地,所述碱为无机碱,例如碱金属和碱土金属碱,特别是氢氧化物、碳酸盐和碳酸氢盐,诸如:NaOH、BaOH2、KOH、NaHCO3及其混合物。此碱也可以是诸如:1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)或三丁胺这样的叔胺中的至少一种。由此,此碱可以是无水的或溶解于水溶液中的。最优选地,此碱为NaOH和NaHCO3的混合物。
随后可以蒸发有机相以得到基本不含有溶剂的氯吡格雷碱。例如,可将含氯吡格雷碱的溶剂相置于转膜蒸发器中去除溶剂,使溶剂含量降至可以接受的残留溶剂水平。实施例3举例说明不通过首先蒸发乙酸乙酯,和将残留物溶解于另一溶剂的步骤,而采用WFE将乙酸乙酯由乙酸乙酯相中除去。氯吡格雷碱可类似地由含有另外溶剂的其它有机相制备。
或者,在将有机相放入WFE之前,可将其先蒸发,优选地在减压条件下蒸发,后溶解于挥发性溶剂中。挥发性溶剂优选地为一种与用以制备氯吡格雷碱的第一溶剂(诸如:乙酸乙酯)有共沸点的溶剂。优选地,挥发性溶剂为C1至C4醇中的至少一种,更优选是甲醇或乙醇中的至少一种,和最优选地是甲醇。随后将所得溶液投入到转膜蒸发器中,生产具有可接受量残留溶剂的氯吡格雷碱。实施例1和实施例2举例说明本发明的方法,其中在置入WFE之前,首先蒸发有机相,随后将其溶解于甲醇中。
除转膜蒸发器之外,可以采用的工艺或设备包括,诸如:喷雾干燥(在约30℃以上雾化为热气,例如:氮或氩)和注入压力低于约200mmHg的真空内,更优选地低于约100mmHg;闪蒸器、薄膜蒸发器、降膜蒸馏设备或旋转蒸发器。
本发明提供的氯吡格雷碱也基本上不含有化学杂质。通过HPLC测定表明,本发明提供的氯吡格雷碱含有的总杂质少于约0.5%。具体地,通过HPLC测定的面积百分比表明,本发明提供的氯吡格雷碱含有的氯吡格雷酸少于约0.3%,更优选地少于约0.1%,和最优选地少于约0.05%。在一种实施方案中,通过HPLC测定氯吡格雷酸含量为0.02%。氯吡格雷酸结构如下:
氯吡格雷酸(CLD-酸)
本发明还提供包含氯吡格雷碱和药学上可接受的赋形剂的药用组合物。
除有效成分外,本发明提供的药用制剂可以包含一种或更多种赋形剂。向制剂中加入赋形剂是出于各种目的的。赋形剂的选择和使用的量可以容易地由制剂人员根据经验和对该领域内的标准程序及专业参考书的考虑确定。
稀释剂可以增加固体药物组合物的体积,使含有该组合物的药物制剂对于患者和护理提供者而言更容易使用。用于固体组合物的稀释剂包括,例如微晶纤维素(如Avicel)、微粉纤维素(microfinecellulose)、乳糖、淀粉、预胶化淀粉、碳酸钙、硫酸钙、蔗糖、葡萄糖结合剂、糊精、右旋糖、磷酸二钙二水化物、磷酸三钙、高岭土、碳酸镁、氧化镁、麦芽糖糊精、甘露醇、聚甲基丙烯酸酯(如Eudragit)、氯化钾、粉状纤维素、氯化钠、山梨醇和滑石粉。
压制成如片剂等剂型的固体药物组合物可以包含赋形剂,所述赋形剂的功能包括在压缩后有助于活性成分与其它赋形剂粘合在一起。固体药物组合物的粘合剂包括阿拉伯胶、海藻酸、卡波姆(如carbopol)、羧甲基纤维素钠、糊精、乙基纤维素、明胶、瓜尔胶、氢化植物油、羟乙基纤维素、羟丙基纤维素(如Klucel)、羟丙基甲基纤维素(如Methocel)、液体葡萄糖、硅酸铝镁、麦芽糖糊精、甲基纤维素、聚甲基丙烯酸酯、聚维酮(如Kollidon、Plasdone)、预胶化淀粉、海藻酸钠和淀粉。
压缩的固体药物组合物在患者胃中的溶出速度,可以通过在该组合物中加入崩解剂来提高。崩解剂包括海藻酸、羧甲基纤维素钙、羧甲基纤维素钠(如Ac-Di-Sol、Primellose)、胶体二氧化硅、交联羧甲纤维素钠、交联聚维酮(如Kollidon、Polyplasdone)、瓜尔胶、硅酸铝镁、甲基纤维素、微晶纤维素、波拉克林钾、粉状纤维素、预胶化淀粉、海藻酸钠、羟基乙酸淀粉钠(如Explotab)和淀粉。
可以加入助流剂以改善非压缩固体组合物的流动性,并提高剂量的准确度。可作为助流剂的赋形剂包括胶体二氧化硅、三硅酸镁、粉状纤维素、淀粉、滑石粉和磷酸三钙。
当通过压缩粉状组合物制备如片剂等剂型时,该组合物经受冲头和冲模的压力。一些赋形剂和活性成分容易粘在冲头和冲模的表面上,这会使产品产生麻点和其它表面不规则现象。可以在该组合物中加入润滑剂以减轻粘附,使产品容易脱模。润滑剂包括硬脂酸镁、硬脂酸钙、甘油单硬脂酸酯、棕榈硬脂酸甘油酯、氢化蓖麻油、氢化植物油、矿物油、聚乙二醇、苯甲酸钠、十二烷基硫酸钠、硬脂富马酸钠、硬脂酸、滑石粉和硬脂酸锌。
调味剂和调味增强剂使制剂更合乎患者口味。本发明组合物中可包含的药品所用的一般的调味剂和调味增强剂包括麦芽醇、香草醛、乙基香草醛、薄荷醇、柠檬酸、富马酸、乙基麦芽醇和酒石酸。
还可以用药学上可接受的任何着色剂将固体组合物和液体组合物染色,以改善其外观和/或使患者容易鉴别产品及单位剂量药物。
本发明的液体药物组合物中,将氯吡格雷碱和任何其它固体赋形剂溶解或悬浮于液体载体,如水、植物油、乙醇、聚乙二醇、丙二醇或甘油中。
还可以用药学上可接受的任何着色剂将液体组合物染色,以改善其外观和/或使患者容易鉴别产品及单位剂量药物。
液体药物组合物可以含有乳化剂,使不溶于该液体载体中的活性成分或其它赋形剂均匀地分散于该组合物中。可用于本发明液体组合物的乳化剂包括,如明胶、蛋黄、酪蛋白、胆固醇、阿拉伯胶、西黄蓍胶、角叉菜属、果胶、甲基纤维素、卡波姆、十六醇十八醇混合物和十六醇。
本发明的液体药物组合物还可以含有粘度增强剂,以改善该产品的口感和/或覆盖胃肠道的内层。这样的物质包括阿拉伯胶、海藻酸皂土、卡波姆、羧甲基纤维素钙、羧甲基纤维素钠、十六醇十八醇混合物、甲基纤维素、乙基纤维素、明胶瓜尔胶、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、麦芽糖糊精、聚乙烯醇、聚维酮、碳酸丙二醇酯、丙二醇海藻酸酯、海藻酸钠、羟基乙酸淀粉钠、淀粉西黄蓍胶和黄原胶。
可加入甜味剂,如山梨醇、糖精、糖精钠、蔗糖、阿司帕坦、果糖、甘露醇和转化糖以改善味道。
可加入摄入安全级别的防腐剂和螯合剂,如醇、苯甲酸钠、丁基化羟基甲苯、丁基化羟基茴香醚和乙二胺四乙酸,以提高储藏稳定性。
根据本发明,液体组合物还可以含有缓冲剂,如葡萄糖酸、乳酸、柠檬酸或醋酸、葡萄糖酸钠、乳酸钠、柠檬酸钠或醋酸钠。
本发明的固体组合物包括粉末、颗粒体、聚集体和压缩组合物。所述制剂包括适合口服给药、口腔给药、直肠给药、肠胃外给药(包括皮下给药、肌肉内给药和静脉内给药)、吸入给药和眼内给药的制剂。在任何特定情况下最适合的给药方式将依赖于所治疗病情的性质和严重性。该制剂可以以单位剂型方便地提供,并按制药领域熟知的任何方法制备。
剂型包括固体剂型,如片剂、散剂、胶囊剂、栓剂、小药囊剂、锭剂和糖锭,以及液体糖浆剂、混悬剂和酏剂。
所述剂型可以是在硬囊壳内或软囊壳内含有该组合物,例如粉末状或颗粒状固体组合物的胶囊剂。该囊壳可以由明胶制成,并任选含有如甘油和山梨醇的增塑剂,和遮光剂或着色剂。
可按照本领域所知的方法将所述活性成分和赋形剂制成组合物和制剂。可通过湿法制粒制备供压片或填充胶囊用的组合物。在湿法制粒中,将一些或全部粉末状的活性成分和赋形剂混合,然后在液体(通常为水)存在下进一步混合,使粉末凝结成颗粒。将所述颗粒过筛和/或磨碎成所需大小的颗粒。然后可将该颗粒压片,或者在压片前加入其它赋形剂,如助流剂和/或润滑剂。
可通过常规的干燥混合法制备供压片的组合物。例如,可将活性成分和赋形剂混合而成的组合物压缩成棒状或片状,然后粉碎成压缩的颗粒。接着可将压缩的颗粒压成片剂。
除了干法制粒,还可以用直接压缩技术将经混合的组合物直接压制成压缩的剂型。直接压缩能产生没有细粒的更加均一的片剂。尤其适合直接压片的赋形剂包括微晶纤维素、喷雾干燥乳糖、磷酸二钙二水化物和硅胶。本领域具有直接压片方面的特殊经验和技术的人员知道如何在直接压片中正确使用这些及其它赋形剂。
本发明的胶囊的填充可以包含上述与压片相关的任何混合和制粒过程,但不经历最终的压片步骤。
氯吡格雷碱可以施用于哺乳动物,优选地是对其有需要的人,以抑制血小板聚集并减少诸如:心脏病发作或中风这类的初级或二级缺血事件发生的机会。在一种实施方案中,将氯吡格雷碱作为胶囊使用。
这样参照具体的优选实施方案和例证性实施例描述了本发明,本领域技术人员能够对如上所描述和例证的本发明进行修改,而不偏离说明书中公开的本发明的主旨和范围。提供实施例以帮助理解本发明,但非有意且无论如何也不应该被解释为是为限制其范围。
实施例
除分析结果之外,或除非另有说明,百分比均是指由HPLC(高效液相色谱法)测定所得的面积百分比。
高效液相色谱法(HPLC)
根据美国药典进行分析,采用HPLC在如下参数条件下进行分析:
色谱柱:XTerra苯基5微米4.6×250mm
流动相:500ml水溶液内含5g十二烷基硫酸钠,用H3PO4将pH值调至
3.0,加420ml乙腈和80ml甲醇。
流速: 1.3ml/min
检测器:220nm
样品体 10μL
积:
稀释剂:流动相
HS-GC法测定残留溶剂
1)色谱分析条件
色谱柱: MXT-WAX(Crossbond Carbowax-PEG)、30m×0.53mm
ID、1.0μL膜厚(目录№.70655-Restek-USA),或等同的。
载气: 氦气、常压、约3.6psi(5ml/min,40℃)
进样方式:顶空、分流进样
分流比: 1∶4,使用HP-7694顶空进样器(循环压力技术)
检测器: 火焰离子化检测器
尾吹气: 氦,约25mL/min;
温度:
进样器 180℃
检测器 250℃
升温程序
初始温度: 40℃
初始时间: 1.0min
变化 速率 最终温度 最终时间
(Ramps.)
1 15.0℃/min 150℃7.0min
稀释剂: N,N-二甲基乙酰胺
2)顶空条件:
仪器: HP-7694顶空进样器(循环/压力系统)
瓶压: 12.5psi
温度: 炉: 90℃
环: 100℃
传输线: 110℃
时间:G.C.周期 24min*
样品eq.:35min
增压: 0.20min
环填充: 0.10min
环eq.: 0.05mn
进样时间: 0.50min
振摇: 1(低)
环容量: I mL
顶空瓶: 20mL
3)标准液制备
3.1.甲醇标准液制备
标准溶液约含600μg/mL甲醇
3.2.乙酸乙酯标准液制备
标准溶液约含1000μg/mL乙酸乙酯
3.3.乙醇标准液制备
标准溶液约含1000μg/mL乙醇
3.4.二氯甲烷标准液制备
标准溶液约含120μg/mL二氯甲烷
4)样品分析
约100mg样品溶解于0.5mL N,N-二甲基乙酰胺中
5)步骤
5.1.系统适用性试验
根据顶空G.C.条件,标准溶液进样三次。应满足如下系统适用性要求:对于各三次进样的响应因子和所有六个响应因子,每一种残留溶剂的RSD值均不应该超过10.0%。在任何系统峰或未知峰与最接近的分析物峰之间应获得不小于1.0的分离因子。
5.2.计算
使用如下公式计算测试样中以ppm计的残留溶剂浓度
rspl和rsta:分别指样品溶液色谱图和标准溶液色谱图中的残
留溶剂峰面积(rspl)和(rstd);
Cstd: 注入的标准溶液中残留溶剂浓度,μg/ml
Wspl: 样品重量,g
实施例1、使用转膜蒸发器去除溶剂
于搅拌容器内将氯吡格雷樟脑磺酸盐(120g)溶解于360ml乙酸乙酯中。向其内加入240ml水和47%的氢氧化钠16.3g。再逐渐加入6.8gNaHCO3,各种成分互相混合溶解,静置待相分离。收集上部有机相,在小于10mmHg压力下置于旋转蒸发仪中蒸发。将所得油溶解于甲醇中,得到约24%的溶液。溶于甲醇中的氯吡格雷碱溶液在转膜蒸发器(WFE)(″POPE″的2英寸转膜蒸馏设备)内蒸发。套温设定为60℃。溶液进料速率约为200ml/hr,转子速度约为200RPM。在WFE的底部收集稠浆状产品,进行分析,发现样品为纯氯吡格雷碱。
R-氯吡格雷(CLD):0.06%。未知物:<0.05%。CLD酸:<0.02%。残留溶剂:甲醇:4776ppm;乙酸乙酯:249ppm。
含量:100.2%
实施例2、采用转膜蒸发器去除溶剂
将氯吡格雷樟脑磺酸盐(150g)溶解于450ml二氯甲烷中。向其内加入300ml水和47%的氢氧化钠20.4g。再逐渐加入7.5gNaHCO3,各种成分混合溶解,静置,待相分离。收集下部有机相,置于真空蒸发器内蒸发。将所得油溶解于甲醇中,得到约20%的溶液。溶于甲醇中的氯吡格雷碱溶液在转膜蒸发器(WFE)(″POPE″的2英寸转膜蒸馏设备)内蒸发。套温设定为60℃。溶液进料速率约为200ml/hr,转子速度约为200RPM。在WFE的底部收集产品,进行分析,发现样品为纯氯吡格雷碱。
R-氯吡格雷(CLD):0.04%。未知物:<0.52%。CLD酸:0.3%。
残留溶剂:甲醇:3071ppm;二氯甲烷:38ppm。
含量:99.4%
实施例3、使用转膜蒸发器去除溶剂
将氯吡格雷樟脑磺酸盐(100g)于搅拌容器内溶解于200ml乙酸乙酯中。向其内加入200ml水和47%的氢氧化钠5.6g。再逐渐加入10.35gNaHCO3,各种成分混合溶解,静置,待相分离。收集上部有机相,置于转膜蒸发器(WFE)(″POPE″的2英寸转膜蒸馏设备)内蒸发。套温设定为80℃,压力设定为60-65毫巴。溶液进料速率约为350ml/hr,转子速度约为200RPM。在WFE的底部收集稠浆状产品,进行分析发现样品为纯氯吡格雷碱。
未知物:<0.06%。CLD酸:<0.08%。
RRT,R-氯吡格雷:0.80:0.13。
残留溶剂:乙酸乙酯:2868ppm。
含量:99.7%
实施例4、使用旋转式蒸发器去除溶剂
将氯吡格雷樟脑磺酸盐(20g)于搅拌容器内溶解于60ml甲苯中。向其内加入40ml水和47%的氢氧化钠2.7g。再逐渐加入1.0gNaHCO3,将各种成分混合溶解,静置,待相分离。收集上部有机相,置于旋转式蒸发器内蒸发。套温设定为40℃,压力设定为10毫巴。所得产品溶解于100ml甲醇中,再置于旋转式蒸发器蒸发。所获样品为相对干燥的氯吡格雷碱。
残留溶剂:甲醇:6140ppm.
Claims (19)
1.一种氯吡格雷碱,所述氯吡格雷碱所含的全部残留有机溶剂量少于约2%重量。
2.权利要求1的氯吡格雷碱,其中所述全部残留有机溶剂量少于约1%重量。
3.权利要求1的氯吡格雷碱,其中所述全部残留有机溶剂量少于约0.5%重量。
4.权利要求1的氯吡格雷碱,所述氯吡格雷碱所含的全部残留有机溶剂量少于约1000ppm。
5.权利要求1至权利要求4中任何一项的氯吡格雷碱,其中所述溶剂为甲醇、乙醇或乙酸乙酯中的至少一种。
6.一种氯吡格雷碱,所述氯吡格雷碱根据HPLC测得的面积百分比,其所含总杂质少于约0.5%。
7.一种氯吡格雷碱,所述氯吡格雷碱根据HPLC测得的面积百分比,其所含氯吡格雷酸少于约0.3%。
8.权利要求7的氯吡格雷碱,所述氯吡格雷碱根据HPLC测得的面积百分比,所含氯吡格雷酸少于约0.1%。
9.权利要求8的氯吡格雷碱,所述氯吡格雷碱根据HPLC测得的面积百分比,含约0.02%的氯吡格雷酸。
10.一种药用组合物,所述药用组合物含有权利要求1至权利要求9中任何一项的氯吡格雷碱和至少一种药学上可接受的赋形剂。
11.一种药用组合物,所述药用组合物含有氯吡格雷碱和至少一种药学上可接受的赋形剂。
12.一种抑制哺乳动物血小板聚集的方法,所述方法包括给予哺乳动物权利要求10和权利要求11中任何一项的药用组合物。
13.一种制备权利要求1至权利要求9中任何一项的氯吡格雷碱的方法,所述方法包括如下步骤:
c)提供含有氯吡格雷碱和残留量的至少一种有机溶剂的油;和
d)在减压条件下于转膜蒸发器内干燥所述油。
14.权利要求13的方法,其中所述干燥在如下条件下进行:
a)套温约20℃到约250℃;
b)进料速率约0.1ml/min到约200ml/min;和
c)尖端速度约0.1m/s到约2m/s。
15.权利要求13的方法,其中所述干燥在如下条件下进行:
a)套温约50℃到约100℃;
b)进料速率约0.1ml/min到约50ml/min;
c)尖端速度约0.1m/s到约2m/s;
d)压力小于约100mm Hg。
16.权利要求13的方法,其中所述油通过包括如下步骤的方法制备:
a)提供有机溶剂中的氯吡格雷盐;
b)将此盐与碱反应以得到两相,其中氯吡格雷碱转移到有机相中;
c)分离油状有机相。
17.权利要求16的方法,其中所述有机溶剂为乙酸乙酯。
18.权利要求13的方法,其中所述油通过包括如下步骤的方法制备:
a)提供第一有机溶剂中的氯吡格雷盐;
b)将此盐与碱反应以得到两相,其中氯吡格雷碱转移到有机相中;
c)分离所述有机相;
d)蒸发所述有机相中的第一有机溶剂;
e)添加第二有机溶剂以得到所述油,其中所述第二有机溶剂与第一有机溶剂形成共沸物。
19.权利要求18的方法,其中所述第一有机溶剂为乙酸乙酯或二氯甲烷,且所述第二有机溶剂为甲醇。
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