CN106687470A - 结晶形式的索非布韦及其制备方法 - Google Patents

结晶形式的索非布韦及其制备方法 Download PDF

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CN106687470A
CN106687470A CN201580049016.4A CN201580049016A CN106687470A CN 106687470 A CN106687470 A CN 106687470A CN 201580049016 A CN201580049016 A CN 201580049016A CN 106687470 A CN106687470 A CN 106687470A
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suo feibuwei
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M·加博阿迪
M·卡斯塔尔蒂
G·卡斯塔尔迪
S·赫尔米
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Abstract

索非布韦的晶型α、其制备方法及其在药物组合物中的应用。

Description

结晶形式的索非布韦及其制备方法
本发明涉及索非布韦(sofosbuvir)的稳定多晶型及其制备方法。
索非布韦是用于治疗丙型肝炎的前药。
丙型肝炎是由丙型肝炎病毒(HCV)引起的感染性疾病，其主要影响肝脏。感染通常无症状，但其慢性感染可导致肝脏瘢痕化，最终导致肝硬化，这在多年后通常是明显的。在一些情况下，肝硬化可以发展为肝衰竭、肝癌、食管和胃静脉曲张。HCV主要通过与感染的血液直接接触传递，通常由静脉内药物使用、不良的消毒设备和输血引起。
丙型肝炎病毒在50-80％的感染人群中引起慢性感染，在感染人群中约40-80％被治疗。一般来说，推荐在由病毒引起的肝脏改变的患者中进行药物治疗；参考治疗是聚乙二醇化的干扰素α和利巴韦林的组合，根据HCV病毒基因型，持续24或48周的时间。观察到该治疗导致50-60％的病例的改善。在更难治疗的表型中，这两种药物与波普瑞韦(boceprevir)和特拉匹韦组合使用，使治愈率从40％提高至70％。治疗的副作用是常见的：半数患者具有流感样症状，三分之一具有情绪问题；此外，在前六个月进行的治疗比一旦丙型肝炎变为慢性更有效。
索非布韦是用于治疗丙型肝炎的药物，在年初由EMA批准，其口服并且对病毒的生命周期具有直接作用的机制，作为前药抑制剂NS5B RNA依赖的HCV的RNA聚合酶的pan-基因型，消除病毒复制，其可以并入HCV RNA NS5B聚合酶中并且充当链终止子。
此外，与接受其他治疗的患者相比，索非布韦显示出减少的肝脏疾病并发症和减少的不良反应。
索非布韦是式(I)化合物
化学名称为(2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-二氧代嘧啶-1-基)-4-氟-3-羟基-4-甲基-四氢呋喃-2-基]甲氧基-苯氧基-磷酰基]-氨基丙酸异丙基酯，市售为并记载于US 8,563,530中。
索非布韦的一些多晶型形式在文献中是已知的。
US 8,618,076描述了索非布韦的结晶、水合和溶剂化形式，称为I型(结晶)、2型(结晶)、3型(氯仿溶剂化物)、4型(水合物)、5型(结晶)和6型(结晶)，并且还描述了两种无定形形式。
多晶型是分子在其固态下呈现多于一种晶体或无定形形式的性质。已知一些物质仅以一种结晶或无定形形式存在；其他实际上可以具有两种或更多种结晶形式。多晶型物是具有相同分子式但具有不同物理性质的不同固体，与同族的其它多晶型物相比，其可能是有利的或不利的。
有机化学活性成分的形态对于其药物化学开发是重要的。与其它结晶形式相比，结晶形式可具有许多优点。用于结晶形式的合适方法可以给予活性成分制造商几个优点，例如使用便宜的步骤或溶剂，或具有低环境影响、更高产率和更高纯度的所需产物。
有机化合物的多晶型、结晶形式的数目、它们的稳定性和它们在活生物体中的性能是不可预测的。化合物的不同多晶型物具有不同的晶格能量，并以这种方式显示固态的不同物理性质(例如形状、密度、熔点、颜色、稳定性、溶解速率、易于研磨、造粒等)。在多晶型中，这些形态差异可以对于以下具有显著的效应：研磨固体的流动性(流动性是指在加工成药物产品期间材料被处理的容易性)，不同给药剂型的运输和储存稳定性，产生不同给药剂型的能力，在极性或非极性、质子或非质子溶剂中的溶解度，在水溶液中的溶解度，在胃液中的溶解度，血液溶解度以及最终的生物利用度。
活性成分在患者的胃液中的溶解速率可以具有治疗效果，因为它决定了活性成分可以通过口服给药在血液中达到的最大浓度。多晶型形式的其它重要性质影响：以药物剂量转化活性成分形式的容易性，粉末或颗粒形式的流动性，和决定晶体形式一旦压缩为片剂后是否将彼此粘附的表面性质。
与无定形形式或任何其它多晶型形式相比，多晶型形式可具有不同的热性能。热性能可以通过诸如毛细管熔点和差示扫描量热法(DSC)的技术在实验室中测量，并且可以用于区分各种多晶型形式。多晶型可以具有不同的光谱性质，其可以通过X射线粉末衍射(XRPD)检测。
药物化合物的新多晶型形式的发现提供了改善所述产品的特性的另一种可能性。制药技术的专家扩展了他/她对于可用于开发具有靶向释放曲线或具有其它特征如在含水液体中的流动性和溶解速率的药物剂型的形式的知识。
本发明的目标是提供一种新的稳定且不吸湿的结晶形式，其可以以容易的、可重复的方法制备，具有优异的产率和容易的工业实用性。
我们已发现了索非布韦的一种稳定的且不吸湿的结晶形式，其适用于制备稳定的药物制剂，可获得具有粒径分布以允许良好的可压缩性和流动性。
因此，本发明的目标是索非布韦的结晶形式，以下也称为α型，其特征在于包含以下峰的XRPD：在图1的约7.96；10.28；12.32；16.64；17.00；18.56；19.28；19.88；20.72；21.88；23.08；24.24；25.16；27.00；27.96±0.2°的2θ处。
附图说明
图1：索非布韦α型的XRPD。
新的多晶型形式还通过以下粒径分布(PSD)表征，其中90％颗粒的尺寸为10-50μm，并且通过以下参数表征：
堆积密度 0.22g/ml
振实密度 0.29g/ml
压缩指数 24.4
Hausner比 1.32
本发明的另一个目标是制备结晶α型的索非布韦的方法，其包括将索非布韦溶解在酮中的步骤和将通过所述溶解获得的溶液结晶的步骤。
用于本发明目标方法的酮选自丙酮、甲基乙基酮、异丁基甲基酮和二乙基酮：酮优选选自甲基乙基酮和异丁基甲基酮。
优选地，所述结晶步骤通过冷却溶液或通过缓慢的溶剂蒸发来获得。
根据一个优选的实施方案，本发明的方法包括以下步骤：
i.在50-60℃的温度下将索非布韦溶解在异丁基甲基酮中；
ii.在搅拌下将从步骤i中得到的溶液冷却至20℃的温度直至产物沉淀；
iii.通过过滤分离从步骤ii获得的产物；
iv.在真空下干燥从步骤iii获得的产物。
本发明的制备索非布韦α型的方法特别简单，并且具有容易的工业实用性。
因此，本发明的进一步的目标是索非布韦α型作为药物和含有其作为活性成分与合适的载体的混合物的药物组合物的用途。
除非另有说明，否则本申请中使用的所有术语应以本领域已知的常规含义来理解。术语“约”包括任何测量的常规实验误差。
尽管已经以其特征描述了本发明，但是对于本领域技术人员显而易见的其等同物和修改包括在本发明中。
本发明将通过下面一些实施例进行说明而不限制它。
实施例
在环境温度下使用管CuKa(40Kv，30Ma)作为X射线源通过衍射仪APD 2000ItalStructures进行衍射光谱XRPD。通过2q连续扫描以0.02°/s的扫描速度在3°-40°的范围内以2q收集数据。
实施例1
将5g索非布韦在搅拌下悬浮在反应烧瓶中的15ml异丁基甲基酮中，将温度保持在约50/60℃，并将混合物保持在这样的条件下直至完全溶解。将温度升至约20℃，将混合物保持搅拌约1小时。将所得固体过滤，并在20℃的温度下用异丁基甲基酮(2×5ml)洗涤，并在45-50℃、真空下在烘箱中干燥，得到4.5g索非布韦α型。
PSD＝d(0.1):1.831μm；
d(0.5):5.263μm；
d(0.9):20.369μm。
实施例2
将5g索非布韦在搅拌下悬浮在反应烧瓶中的15ml甲基乙基酮中，将温度升至约50-60℃，将反应混合物保持在这样的条件下直至完全溶解，并将所得溶液转移至结晶器。在室温下蒸发溶剂，得到5g索非布韦α型。
实施例3
将5g的索非布韦在搅拌下悬浮在反应烧瓶中的15ml丙酮中，将温度升至约50-60℃，将反应混合物保持在这样的条件下直至完全溶解，将所得溶液转移至结晶器。在室温下蒸发溶剂，得到5g索非布韦α型。

Claims (10)

1.晶型α的索非布韦，其特征在于包含以下峰的XRPD：7.96；10.28；12.32；16.64；18.56；19.28；19.88；20.72；21.88；23.08；24.24；25.16；27.00；27.96±0.2°2θ。
2.制备根据权利要求1的索非布韦的方法，其特征在于其包括将索非布韦溶解在酮中的步骤和将通过所述溶解获得的溶液结晶的步骤。
3.根据权利要求2的方法，其中所述酮选自丙酮、甲基乙基酮、异丁基甲基酮和二乙基酮。
4.根据权利要求2-3中一项或多项的方法，其中所述酮选自甲基乙基酮和异丁基甲基酮。
5.根据权利要求2-4中一项或多项的方法，其中所述结晶通过冷却或通过溶剂蒸发获得。
6.根据权利要求2-5中一项或多项的方法，其特征在于其包括以下步骤：
i.在50-60℃的温度下将索非布韦溶解在异丁基甲基酮中；
ii.将从步骤i中得到的溶液冷却至20℃的温度直至产物沉淀；
iii.过滤从步骤ii获得的产物；
iv.在真空下干燥从步骤iii获得的产物。
7.药物组合物，其包含根据权利要求1所述的索非布韦。
8.根据权利要求1的索非布韦，其用作药物和用于药物组合物中。
9.根据权利要求2所述的方法，其中用所述方法获得的所述索非布韦具有PSD，其中90％的颗粒的尺寸为10-50μm。
10.根据权利要求2所述的方法，其中用所述方法获得的所述索非布韦具有以下PSD：d(0.1):1.831μm；d(0.5):5.263μm；d(0.9):20.369μm。
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