CN103833626A - 西达本胺的晶型及其制备方法与应用 - Google Patents

西达本胺的晶型及其制备方法与应用 Download PDF

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CN103833626A
CN103833626A CN201210489178.8A CN201210489178A CN103833626A CN 103833626 A CN103833626 A CN 103833626A CN 201210489178 A CN201210489178 A CN 201210489178A CN 103833626 A CN103833626 A CN 103833626A
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chidamide
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chidamide crystal
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CN103833626B (zh
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鲁先平
李志斌
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Shenzhen Chipscreen Biosciences Co Ltd
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SHENZHEN WEIXIN BIOLOGICAL SCIENCE AND TECHNOLOGY Co Ltd
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Priority to AU2012395573A priority patent/AU2012395573C1/en
Priority to RS20181175A priority patent/RS57856B1/sr
Priority to SI201231417T priority patent/SI2930169T1/sl
Priority to EP12889061.3A priority patent/EP2930169B1/en
Priority to RU2015123682/04A priority patent/RU2603138C1/ru
Priority to JP2015543237A priority patent/JP6387011B2/ja
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Priority to PCT/CN2012/086841 priority patent/WO2014082354A1/zh
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Priority to US14/646,371 priority patent/US9573901B2/en
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Priority to KR1020157014782A priority patent/KR20150082490A/ko
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Abstract

本发明涉及药物化学领域，公开了西达本胺的二种结晶形式即西达本胺晶型A和西达本胺晶型B，以及西达本胺的新的结晶形式的制备方法。本发明所述西达本胺晶型A和西达本胺晶型B在口服吸收性和抑制细胞的分化和增殖的方面性能优异，并且其毒性弱，具有良好的储存和处理稳定性，可用于制备治疗与细胞分化和增殖相关的疾病的药物。

Description

西达本胺的晶型及其制备方法与应用
技术领域
本发明涉及药物化学领域，具体涉及西达本胺的新晶型A、B及其制备方法与应用。
背景技术
西达本胺，英文名为Chidamide，是由深圳微芯生物科技有限责任公司自主设计和合成的具有全新化学结构和全球知识产权的一种新型抗癌药物,其化学名称为N-(2-氨基-4-氟苯基)-4-(N-(3-吡啶丙烯酰基)氨甲基)苯甲酰胺，其化学结构如结构式I所示：
Figure BDA00002472296200011
如专利ZL03139760.3和US7,244,751所述，西达本胺具有组蛋白去乙酰化酶抑制活性，可以用于治疗与分化和增殖相关的疾病，如癌症和牛皮癣，尤其对血癌和实体瘤具有优异疗效。
专利ZL03139760.3和US7,244,751公开了西达本胺的制备方法，但并未说明所得产品是否为晶体物质，也没有说明该化合物是否存在同质多晶现象。在上述专利中，对该化合物活性的评价不是在固态进行的，因此，也没有公开任何与晶体特性有关的说明。
晶型是影响药物质量、疗效和制剂加工性能的重要因素之一。多晶型现象，是指同一化合物，通过控制其不同的生成条件，可形成两种或两种以上的分子空间排列方式，从而产生不同的固体结晶的现象。药物多晶型是药品研发中的常见现象，是影响药品质量的重要因素。同一化合物的不同晶型，其化学组成相同，但微观晶体结构不同，因而导致它们在外观形态、理化性质和生物活性上存在差异。药物的不同晶型往往具有不同的溶解性、储存稳定性、吸水性、密度和生物利用度。药物的晶型直接影响药物的药用制剂的质量、在人体的吸收行为并最终影响该制剂在人体中产生的治疗效果和副作用的获益比。因此，研究药物的同质多晶现象以及不同晶型的制备方法具有重要的意义。
发明内容
有鉴于此，本发明目的是通过晶体学的方法，研究、发现并提供西达本胺的新的晶型及其制备方法与应用。
按照专利ZL03139760.3所述的实施例2所制得的西达本胺纯度较差（约95%）。LC/MS分析结果如图1所示，表明产品中含有4.7%的式II所示结构的N-(2-氨基-5-氟苯基)-4-(N-(3-吡啶丙烯酰基)氨甲基)苯甲酰胺。1H NMR分析结果如图2所示，表明产品中含有1.80%的四氢呋喃，远远超出了人用药品注册技术要求国际协调会议（ICH，International Conference of Harmonizition）规定的0.072%残留溶剂限度。因此该固体不宜用于药剂制造。
Figure BDA00002472296200021
本发明通过晶体学的方法，研究、发现并提供了西达本胺的二种结晶形式，即西达本胺晶型A和西达本胺晶型B。
本发明采用国际上公认的X-射线粉末衍射法（XRPD）来研究和表征西达本胺的新的结晶形式。仪器设备：D/MAX-1200型X-射线粉末衍射仪。测定条件与方法：Cu/K-alpha1（靶），40KV-40mA（工作电压与电流），I（max）=2244，2θ=5-60度（扫描范围），0.005/0.06sec.(扫描速度)，λ=1.54056。
本发明提供的基本上纯净的西达本胺晶型A，其X-射线粉末衍射图如图3所示，其具有如下特性：其X-射线粉末衍射图在反射角2θ约4.18°、6.61°、8.42°、12.69°、17.85°、18.34°、19.27°、20.10°、20.59°、21.58°、23.70°、23.96°、25.52°、27.00°、27.90°、29.59°和29.94°处有特征峰。
本发明还采用红外光谱法（IR）来研究和表征了西达本胺的新的结晶形式。仪器：FT-IR NICOLET 6700（美国）。测定方法：KBr压片法，光谱范围400cm-1-4000cm-1，分辨率为4cm-1。
本发明提供的基本上纯净的西达本胺晶型A，其红外光谱图如图4所示，其具有如下特性：其红外光谱在约3412、3282、3199、3043、1654、1615、1524、1514、1497、1442、1418、1332、1296、1234、1198、1183、1166和1027cm-1处有特征吸收峰。
晶型也可以用技术上公知的其他分析技术表征。例如差示扫描量热法（DSC）。仪器：DSC 204（德国），升温速率：10°C/min，氮气流速：20mL/min。
本发明提供的基本上纯净的西达本胺晶型A，其差示扫描量热分析曲线如图5所示，其具有如下特性：其差示扫描量热分析曲线在约239.4°C处有吸热峰。
本发明提供的基本上纯净的西达本胺晶型B，其X-射线粉末衍射图如图6所示，其具有如下特性：其X-射线粉末衍射图在反射角2θ约4.18°、8.43°、12.65°、16.90°、17.83°、19.47°、20.13°、20.58°、21.22°、21.54°、21.92°、23.94°、25.55°、26.98°、27.92°、29.58°和29.90°处有特征峰。
本发明提供的基本上纯净的西达本胺晶型B其红外光谱图如图7所示，其具有如下特性：其红外光谱在约3412、3327、3272、3196、3043、1653、1619、1570、1515、1496、1444、1419、1331、1357、1296、1278、1267、1232、1198、1184、1166和1038cm-1处有特征吸收峰。
本发明提供的基本上纯净的西达本胺晶型B其其差示扫描量热分析曲线如图8所示，其具有如下特性：其差示扫描量热分析曲线在约214.1°C和241.2°C处有吸热峰。
值得注意的是，对于以上所述晶型的X-射线粉末衍射峰，在一台机器和另一台机器之间以及一个样品和另一个样品之间，X-射线粉末衍射图谱的2θ可能会略有变化，其数值可能相差大约1个单位，或者相差大约0.8个单位，或者相差大约0.5个单位，或者相差大约0.3个单位，或者相差大约0.1个单位，因此所给出的数值不能视为绝对的。
实验结果表面，本发明所述西达本胺晶型A和西达本胺晶型B在溶解度方面具有良好的性能，从而生物利用度高。
本发明还提供了纯度高（>99%）且不含残留溶剂的西达本胺晶型A和晶型B制备方法。
本发明提供的西达本胺晶型A的制备方法为包括：
步骤1：将西达本胺加入2mol/L的稀盐酸中，室温搅拌溶解后加水稀释，然后所得溶液中滴加2mol/L的氢氧化钠溶液，搅拌30分钟，过滤；其中步骤1所述西达本胺与稀盐酸的重量比1:4.2~1:4.4，所述西达本胺与水的重量比1:25~1:30，所述西达本胺与氢氧化钠溶液的重量比为1:2.5~1:2.7；
步骤2：收集过滤所得固体加入水中，滴加2mol/L的氢氧化钠溶液，搅拌60分钟，过滤；收集过滤所得固体，水洗至洗涤液pH值为5~7后干燥即得；其中步骤2所述西达本胺与水的重量比为1:15~1:25，所述西达本胺与氢氧化钠溶液的重量比为1:1.5~1:2.0。
作为优选，步骤2所述干燥为80℃真空干燥24小时。
本发明提供的西达本胺晶型B的制备方法，将西达本胺晶型A加入二甲基亚砜中，室温搅拌溶解，然后滴加水，搅拌30分钟，过滤，收集所得固体干燥即得；其中，所述西达本胺晶型A与二甲基亚砜的重量比1:10~1:20，所述西达本胺晶型A与水的重量比为1:100~1:200。
作为优选，所述干燥为80℃真空干燥24小时。
本发明所述西达本胺晶型A和晶型B制备方法得到晶型A和晶型B含量均>99.0%。
本发明所述西达本胺晶型A和西达本胺晶型B在高温（60°C）、高湿（90%±5%）和强光照射（4500Lx±500Lx）下进行稳定性试验，试验结果表明：西达本胺晶体A和西达本胺晶型B均保持原有晶型不变，含量和杂质总量亦未发生明显改变。西达本胺晶体A和西达本胺晶型B均适合药剂制造和长期储存。本发明所述西达本胺晶型A和西达本胺晶型B在口服吸收性和抑制细胞的分化和增殖的方面性能优异，并且其毒性弱，具有良好的储存和处理稳定性，可用于制备治疗与细胞分化和增殖相关的疾病的药物。因此本发明提供了所述的西达本胺晶型A和西达本胺晶型B在制备用于治疗与细胞分化和增殖相关的疾病的药物中的应用。
进一步的，所述与细胞分化和增殖相关的疾病为癌症或牛皮癣，所述癌症包括血癌或实体瘤。
本发明所述西达本胺新晶型可以进一步制备成口服药的各种固体剂型，如片剂，胶囊剂或颗粒剂。
本发明所述用于治疗与细胞分化和增殖相关的疾病的药用制剂，包括所述西达本胺晶型A或/和所述西达本胺晶型B以及药用辅料。即在一些实施例中所述药用制剂包括西达本胺晶型A和药用辅料；在一些实施例中所述药用制剂包括西达本胺晶型B和药用辅料;在另一些实施例中所述药用制剂包括西达本胺晶型A和西达本胺晶型B的混合物以及药用辅料。
在一些具体实施例中所述制剂含5~20%的西达本胺晶型A或/和西达本胺晶型B以及80~95%的药用辅料。在这些剂型中，活性化合物与至少一种药学上可接受的惰性赋形剂或载体混合，如柠檬酸钠、磷酸钙、填充剂、粘合剂、保湿剂、崩解剂、阻滞剂、吸收促进剂、湿润剂、吸收剂或润滑剂及它们的混合物。其中，填充剂如淀粉，乳糖，蔗糖，葡萄糖，甘露醇和硅酸；粘合剂如羧甲基纤维素，藻酸盐，明胶，聚乙烯吡咯酮，蔗糖和***胶；保湿剂如甘油；崩解剂如琼脂，碳酸钙，土豆淀粉或木薯淀粉，海藻酸，某些硅酸盐和碳酸钠，低取代羟丙基纤维素；阻滞剂溶液如石蜡；吸收促进剂如季胺类化合物；湿润剂如十六醇和单硬脂酸甘油酯；吸收剂如白陶土和皂土；润滑剂如滑石粉，硬脂酸钙，硬脂酸镁，固体聚乙二醇，月桂硫酸钠。
附图说明
图1示按照专利ZL03139760.3所述的实施例2制得的固体的HPLC图谱；
图2示按照专利ZL03139760.3所述的实施例2制得的固体的1H NMR图谱；
图3示本发明实施例1提供的西达本胺晶型A的X-射线粉末衍射图，其通过用铜Kα射线照射获得。在X-射线粉末衍射图中，纵坐标表示用计数/秒（cps）表示的衍射强度，横坐标表示用度表示的衍射角2θ；
图4示本发明实施例1提供的西达本胺晶型A的红外光谱图，纵坐标为透光率(T)，单位为百分率（%）；横坐标为波数，单位为cm-1；
图5示本发明实施例1提供的西达本胺晶型A的差示扫描量热法（DSC）曲线图，纵坐标为热流率，单位为卡/秒；横坐标为温度，单位为℃；
图6示本发明实施例3提供的西达本胺晶型B的X-射线粉末衍射图，其通过用铜Kα射线照射获得。在X-射线粉末衍射图中，纵坐标表示用计数/秒（cps）表示的衍射强度，横坐标表示用度表示的衍射角2θ；
图7示本发明实施例3提供的西达本胺晶型B的红外光谱图，纵坐标为透光率(T)，单位为百分率（%）；横坐标为波数，单位为cm-1；
图8示本发明实施例3提供的西达本胺晶型B的差示扫描量热法（DSC）曲线图，纵坐标为热流率，单位为卡/秒；横坐标为温度，单位为℃。
具体实施方式
本发明实施例公开了西达本胺的晶型及其制备方法与应用。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法进行改动或适当变更与组合，来实现和应用本发明技术。
为了进一步理解本发明，下面结合实施例对本发明进行详细说明。其中本发明所述的百分比除特别注明外，均为重量百分比。说明书中所描述的数值范围，如计量单位、反应条件、化合物物理状态或百分比，均是为了提供明白无误的书面参考。本领域熟练技术人员在实践本专利时，使用在此范围之外或有别于单个数值的温度、浓度、数量等，仍然可以得到预期的结果。
试验方法：
X-射线粉末衍射测试条件：仪器：D/MAX-1200（日本）；辐射源：Cu-Kα（40kV、40mA）。
红外光谱测试条件：仪器：FT-IR NICOLET 6700（美国）；KBr压片法。
差示扫描量热分析测试条件：仪器：DSC 204（德国）；升温速率：10°C/min；氮气流速：20mL/min。
质子核磁共振测试条件：仪器：AV-400（德国）；溶剂：DMSO-d6。
实施例1：西达本胺晶型A的制备
将4.84kg西达本胺（纯度约95%）加入20.91kg 2mol/L的稀盐酸中，室温搅拌溶解，加入137.8kg水，搅拌5分钟。向所得溶液中滴加21.35kg 2mol/L的氢氧化钠溶液，搅拌30分钟，过滤。将所得固体加入96.70kg水中，滴加8.39kg 2mol/L的氢氧化钠溶液，搅拌60分钟，过滤，水洗至滤液pH值为5~7。将所得固体于80℃真空干燥24小时，得到4.32kg西达本胺晶型A，含量99.2%。该晶型的X-射线粉末衍射图、红外光谱、差示扫描量热分析曲线分别如图3、图4、图5所示。
实施例2：西达本胺晶型B的制备
将1g西达本胺晶型A加入10mL二甲基亚砜中，室温搅拌溶解。向所得溶液中滴加100mL水，搅拌30分钟，过滤。将所得固体于80°C真空干燥24小时，得到西达本胺晶型B，含量99.2%。该晶型的X-射线粉末衍射图、红外光谱、差示扫描量热分析曲线分别如图6、图7、图8所示。
实施例3：西达本胺晶型A片剂的制备
处方（1000片）：
Figure BDA00002472296200071
制备工艺：称取处方量的西达本胺晶型A、乳糖、可溶性淀粉、微晶纤维素和羧甲基淀粉钠，混合均匀，以适量水为润湿剂制软材，用20目筛制湿颗粒，于60℃干燥，用18目筛整粒，加入处方量的滑石粉，混合均匀，压片即得。
实施例4：西达本胺晶型A胶囊剂的制备
处方（1000粒）：
Figure BDA00002472296200072
Figure BDA00002472296200081
制备工艺：将西达本胺晶型A过100目筛，将微晶纤维素、乳糖、羧甲基淀粉钠和硬脂酸镁过80目筛，称取处方量的微晶纤维素、乳糖和羧甲基淀粉钠，混合均匀，然后将西达本胺晶型A与其按等量递加法混匀，加入处方量硬脂酸镁混匀，灌装胶囊即得。
实施例5：西达本胺晶型A颗粒剂的制备
处方（1000包）：
Figure BDA00002472296200082
制备工艺：称取处方量的西达本胺晶型A、乳糖、可溶性淀粉、微晶纤维素和羧甲基淀粉钠，混合均匀，以适量水为润湿剂制软材，用20目筛制湿颗粒，于60℃干燥，用18目筛整粒，分装即得。
实施例6：西达本胺晶型B片剂的制备
处方（1000片）：
Figure BDA00002472296200083
制备工艺：称取处方量的西达本胺晶型B、乳糖、可溶性淀粉、微晶纤维素和羧甲基淀粉钠，混合均匀，以适量水为润湿剂制软材，用20目筛制湿颗粒，于60℃干燥，用18目筛整粒，加入处方量的滑石粉，混合均匀，压片即得。
实施例7：西达本胺晶型B胶囊剂的制备
处方（1000粒）：
制备工艺：将西达本胺晶型B过100目筛，将微晶纤维素、乳糖、羧甲基淀粉钠和硬脂酸镁过80目筛，称取处方量的微晶纤维素、乳糖和羧甲基淀粉钠，混合均匀，然后将西达本胺晶型A与其按等量递加法混匀，加入处方量硬脂酸镁混匀，灌装胶囊即得。
实施例8：西达本胺晶型B颗粒剂的制备
处方（1000包）：
制备工艺：称取处方量的西达本胺晶型B、乳糖、可溶性淀粉、微晶纤维素和羧甲基淀粉钠，混合均匀，以适量水为润湿剂制软材，用20目筛制湿颗粒，于60℃干燥，用18目筛整粒，分装即得。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (7)

1.西达本胺晶型A，其特征在于，其X-射线粉末衍射图在反射角2θ约4.18°、6.61°、8.42°、12.69°、17.85°、18.34°、19.27°、20.10°、20.59°、21.58°、23.70°、23.96°、25.52°、27.00°、27.90°、29.59°和29.94°处有特征峰；其红外光谱在约3412、3282、3199、3043、1654、1615、1524、1514、1497、1442、1418、1332、1296、1234、1198、1183、1166和1027cm-1处有特征吸收峰；其差示扫描量热分析曲线在约239.4°C处有吸热峰。
2.权利要求1所述的西达本胺晶型A的制备方法，其特征在于，包括：
步骤1：将西达本胺加入2mol/L的稀盐酸中，室温搅拌溶解后加水稀释，然后所得溶液中滴加2mol/L的氢氧化钠溶液，搅拌30分钟，过滤；其中步骤1所述西达本胺与稀盐酸的重量比1:4.2~1:4.4，所述西达本胺与水的重量比1:25~1:30，所述西达本胺与氢氧化钠溶液的重量比为1:2.5~1:2.7；
步骤2：收集过滤所得固体加入水中，滴加2mol/L的氢氧化钠溶液，搅拌60分钟，过滤；收集过滤所得固体，水洗至洗涤液pH值为5~7后干燥即得；其中步骤2所述西达本胺与水的重量比为1:15~1:25，所述西达本胺与氢氧化钠溶液的重量比为1:1.5~1:2.0。
3.权利要求1所述的西达本胺晶型A在制备用于治疗与细胞分化和增殖相关的疾病的药物中的应用。
4.西达本胺晶型B，其特征在于，其X-射线粉末衍射图在反射角2θ约4.18°、8.43°、12.65°、16.90°、17.83°、19.47°、20.13°、20.58°、21.22°、21.54°、21.92°、23.94°、25.55°、26.98°、27.92°、29.58°和29.90°处有特征峰；其红外光谱在约3412、3327、3272、3196、3043、1653、1619、1570、1515、1496、1444、1419、1331、1357、1296、1278、1267、1232、1198、1184、1166和1038cm-1处有特征吸收峰；其差示扫描量热分析曲线在约214.1°C和241.2°C处有吸热峰。
5.权利要求4所述的西达本胺晶型B的制备方法，其特征在于，将西达本胺晶型A加入二甲基亚砜中，室温搅拌溶解，然后滴加水，搅拌30分钟，过滤，收集所得固体干燥即得；其中，所述西达本胺晶型A与二甲基亚砜的重量比1:10~1:20，所述西达本胺晶型A与水的重量比为1:100~1:200。
6.权利要求4所述的西达本胺晶型B在制备用于治疗与细胞分化和增殖相关的疾病的药物中的应用。
7.一种用于治疗与细胞分化和增殖相关的疾病的药用制剂，其特征在于，包括权利要求1所述西达本胺晶型A或/和权利要求4所述西达本胺晶型B以及药用辅料。
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TWI702949B (zh) * 2017-12-29 2020-09-01 大陸商深圳微芯生物科技股份有限公司 用於治療白血病的聯合用藥物及其在製備用於治療急性髓性白血病的藥物中的用途
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