CN116332820A - 左乙拉西坦晶型b及其制备方法和用途 - Google Patents
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- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 37
- 239000013078 crystal Substances 0.000 title claims abstract description 36
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- 238000001816 cooling Methods 0.000 claims description 6
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- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
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Abstract
本发明涉及左乙拉西坦晶型B以及它们的制备方法和用途。所述晶型在物理化学稳定性和加工适应性方面具有优异的性质。
Description
技术领域
本发明涉及化学制药领域。更具体地说，本发明涉及左乙拉西坦的晶型B以及所述晶型B的制备方法、含有它们的药物组合物以及它们的制药用途。
背景技术
左乙拉西坦，为吡拉西坦衍生物，是一种新型抗癫痫药物，其结构式如下：
对于药物而言，不同的晶型具有不同的物理化学性质，包括熔点、化学稳定性、表观溶解度、溶解速率、光学和机械性质等，而这些物化性能直接决定了某特定的晶型是否可以成药，并且直接影响到原料药和制剂的质量。因此，有必要对左乙拉西坦晶型的性质进行研究，以满足左乙拉西坦的实际运用。
附图说明
图1为本发明实施例1左乙拉西坦晶型B的X-射线粉末衍射谱图。
发明内容
本发明的目的之一在于提供了一种化学和物理稳定性很好的左乙拉西坦晶型B。所述晶型在化学稳定性和加工(过滤、干燥)适应性方面具有优异的性质。
本发明所述左乙拉西坦晶型B的X-射线粉末衍射图在以下衍射角2θ处具有特征峰：14.7，14.8，15.0，18.2，18.4，20.2，20.4，29.8，29.9，30.3。
进一步地，所述的左乙拉西坦晶型B的X-射线粉末衍射图在以下衍射角2θ处有特征峰10.0，23.1，23.2，23.6，23.7，26.6，26.7，28.5，28.6，30.5，31.7。
进一步地，所述的左乙拉西坦晶型B的X-射线粉末衍射图在以下衍射角2θ处有特征峰23.5，31.9：
更进一步地，本发明的左乙拉西坦晶型B的X-射线粉末衍射谱图具有如下表1所示的2θ和相对强度数据：
表1
非限制性地，本发明的左乙拉西坦晶型B具有如图1所示的X-射线粉末衍射谱图。
本发明进一步提供了左乙拉西坦晶型B的制备方法，所述制备方法包括如下步骤：
(1)将左乙拉西坦加入有机溶剂中；其中，所述左乙拉西坦与有机溶剂的重量体积比g/ml为1:50；
(2)升温至40-60℃，并持续搅拌30min溶解；
(3)缓慢降温至5℃，析晶；
(4)过滤，得左乙拉西坦晶型B；
所述有机溶剂选自丙酮、乙醇或乙酸乙酯中的一种。
本发明还涉及含有左乙拉西坦晶型B的药物组合物，所述药物组合物包含有效量的左乙拉西坦晶型B，以及一种或多种药学上可接受的载体。
本发明还涉及左乙拉西坦晶型B及其药物组合物在制备抗癫痫药物中的应用。
本发明的发明人经过大量研究发现了左乙拉西坦晶型B，其溶解性良好、结晶工艺简单、便于操作、污染小、可实现工业化生产，而且本发明的晶型药物同时具备产品纯度高、理化性质优异、化学稳定性良好、加工(过滤、干燥、)可再现的优点。
具体实施方式
下列实施例进一步解释说明本发明，但是，它们并不构成对本发明范围的限制或限定。
实施例1
将左乙拉西坦1g加入丙酮中，其中，左乙拉西坦与丙酮的重量体积比为1:50；升温至60℃，并持续搅拌30min溶解；趁热过滤，然后缓慢降温至5℃，缓慢析晶2小时，过滤，45℃下真空干燥，得0.65g晶体，HPLC＝98.7％，经测X-射线粉末衍射图谱(XRD)，该晶型的X-射线粉末衍射谱图详见图1，在本发明中将其命名为左乙拉西坦晶型B。
实施例2
将左乙拉西坦1g加入乙醇中，其中，左乙拉西坦与乙醇的重量体积比为1:50；升温至40℃，并持续搅拌30min溶解；趁热过滤，然后缓慢降温至5℃，缓慢析晶2小时，过滤，45℃下真空干燥，得0.63g晶体，HPLC＝98.8％，经测X-射线粉末衍射图谱(XRD)，确认为晶型B。
实施例3
将左乙拉西坦1g加入乙酸乙酯中，其中，左乙拉西坦与乙酸乙酯的重量体积比为1:50；升温至50℃，并持续搅拌30min溶解；趁热过滤，然后缓慢降温至5℃，缓慢析晶2小时，过滤，45℃下真空干燥，得0.61g晶体，HPLC＝98.9％，经测X-射线粉末衍射图谱(XRD)，确认为晶型B。
实施例4
将左乙拉西坦10g加入乙醇中，其中，左乙拉西坦与乙腈的重量体积比为1:50；升温至40℃，并持续搅拌30min溶解；趁热过滤，然后缓慢降温至5℃，缓慢析晶2小时，过滤，45℃下真空干燥，得6.6g晶体，HPLC＝98.8％，经测X-射线粉末衍射图谱(XRD)，确认为晶型B。
Claims (8)
1.一种左乙拉西坦晶型B，其特征在于，其X-射线粉末衍射图在以下衍射角2θ(°)处具有特征峰：14.7，14.8，15.0，18.2，18.4，20.2，20.4，29.8，29.9，30.3。
2.根据权利要求1所述晶型B,其特征在于，所述的左乙拉西坦晶型B的X-射线粉末衍射图在以下衍射角2θ处有特征峰10.0，23.1，23.2，23.6，23.7，26.6，26.7，28.5，28.6，30.5，31.7。
3.根据权利要求1所述晶型B,其特征在于，所述的左乙拉西坦晶型B的X-射线粉末衍射图在以下衍射角2θ处有特征峰23.5，31.9。
4.根据权利要求1所述晶型B,其特征在于，所述的左乙拉西坦晶型B的X-射线粉末衍射谱图具有如下表1所示的2θ和相对强度数据：
表1
5.根据权利要求1所述晶型B,其特征在于，所述的左乙拉西坦晶型B具有如图1所示的X-射线粉末衍射谱图。
6.一种制备根据权利要求1-5中任一项所述的左乙拉西坦晶型B的制备方法，所述方法包括如下步骤：
(1)将左乙拉西坦加入有机溶剂中；其中，所述左乙拉西坦与有机溶剂的重量体积比为1:50；
(2)升温至80-6℃，并持续搅拌30min溶解；
(3)缓慢降温至5℃，析晶；
(4)过滤，得左乙拉西坦晶型B；
所述有机溶剂选自丙酮、乙醇或乙酸乙酯中的一种。
7.一种药物组合物，所述药物组合物包含有效量的左乙拉西坦晶型B，以及一种或多种药学上可接受的载体。
8.如权利要求1-5任一项所述的左乙拉西坦晶型B或权利要求7所述的药物组合物在制备抗癫痫药物中的应用。
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