CN103145731A - 奥氮平晶型及其制备方法和用途 - Google Patents

奥氮平晶型及其制备方法和用途 Download PDF

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CN103145731A
CN103145731A CN2013100605279A CN201310060527A CN103145731A CN 103145731 A CN103145731 A CN 103145731A CN 2013100605279 A CN2013100605279 A CN 2013100605279A CN 201310060527 A CN201310060527 A CN 201310060527A CN 103145731 A CN103145731 A CN 103145731A
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olanzapine
crystal form
preparation
olanzapine crystal
organic solvents
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CN103145731B (zh
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吕爱锋
赵军军
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Jiangsu Best Pharmaceutical Co ltd
China Pharmaceutical University
Jiangsu Hansoh Pharmaceutical Group Co Ltd
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Abstract

本发明涉及奥氮平晶型及其制备方法和用途。具体而言，本发明公开了一种奥氮平晶型、其制备方法、其药物组合物及其制药用途，其XRD特征峰如图所示。本发明的奥氮平晶型性质稳定，可重复性好，适合药物开发。

Description

奥氮平晶型及其制备方法和用途
技术领域
本发明涉及一种奥氮平晶型、其制备方法、其药物组合物及其制药用途。
背景技术
目前有许多抗精神病药，噻吩并苯并二氮杂
Figure BDA00002858813400011
是其中的一类，该类化合物在英国专利1533235中公开，其具有下述通式。
Figure BDA00002858813400012
在该类化合物中，已经发现其中一个化合物：2-甲基-10-(4-甲基-哌嗪基)-4H-噻吩并[2,3-b][1,5]苯并二氮杂
Figure BDA00002858813400013
（式I），或它的酸加成盐具有明显的优点，
Figure BDA00002858813400014
针对该化合物又单独申请了专利（美国专利5,229,382），该化合物的通用名为奥氮平（Olanzapine）。另外，奥氮平有一篇制备方法的中国专利（ZL91103346.7），该方法与美国专利5,229,382方法相同，包括：
（a）使N-甲基哌嗪与式（IV）化合物反应
Figure BDA00002858813400021
或（b）使式（V）化合物发生闭环反应
Figure BDA00002858813400022
药物晶型研究和药物固态研发在制药业具有举足轻重的意义。药物分子通常有不同的固体形态，包括盐类，多晶，共晶，无定形，水合物和溶剂合物；同一药物分子的不同晶型，在晶体结构，稳定性，可生产性和生物利用度等性质方面可能会有显著差异，从而直接影响药物的疗效以及可开发性。因此，任何一个药品研发，都需要进行全面系统的多晶型筛选，找到尽可能多的晶型，然后使用各种固态方法对这些晶型进行深入的研究，从而找到最适合开发的晶型。
发明内容
本发明的目的在于提供一种奥氮平晶型，其使用Cu-Kα辐射、以d值表示的XRD光谱在约5.175、4.300、4.026和3.723有峰。进一步，其使用Cu-Kα辐射所得XRD光谱如附图1所示。
本发明的另一目的在于提供上述奥氮平晶型的制备方法，其包括：
采用混合有机溶剂溶解奥氮平，奥氮平与混合有机溶剂的质量体积比为1:8~1:10，加热回流，回流温度下加入硅胶后搅拌，趁热过滤硅胶，10℃～20℃条件下析晶，然后过滤得目标晶型。其中，混合有机溶剂含有甲醇和乙醚，其中甲醇和乙醚的体积比为4:1；析晶温度优选15℃。
本发明的另一目的在于提供一种治疗精神分裂症的药物组合物，其含有治疗有效量的上述奥氮平晶型作为有效成分以及药学上可接受的载体。
本发明的另一目的在于提供上述奥氮平晶型或者治疗精神分裂症的药物组合物在制备用于治疗精神分裂症的药物中的用途。
本发明提供的奥氮平晶型性质稳定，可重复性好，适合药物开发。
附图说明
图1为奥氮平晶型的XRD图谱。
具体实施方式
实施例1
将奥氮平1.2g与甲醇和乙醚的混合溶剂10.0ml（甲醇和乙醚的体积比为4:1）置于反应瓶中，加热至回流1h，完全溶解后，向热的溶液中加入硅胶，回流温度下搅拌半小时，趁热从溶液中将硅胶滤出，搅拌冷却至10℃，恒温析晶20小时，过滤，真空干燥得到目标晶型I1.1g，经附图1确证其结构。
实施例2
将奥氮平1.2g与甲醇和乙醚的混合溶剂11.5ml（甲醇和乙醚的体积比为4:1）置于反应瓶中，加热至回流1h，完全溶解后，向热的溶液中加入硅胶，回流温度下搅拌半小时，趁热从溶液中将硅胶滤出，搅拌冷却至15℃，恒温析晶20小时，过滤，真空干燥得到目标晶型I1.0g，经附图1确证其结构。
实施例3
将奥氮平2.2g与甲醇和乙醚的混合溶剂20.0ml（甲醇和乙醚的体积比为4:1）置于反应瓶中，加热至回流1h，完全溶解后，向热的溶液中加入硅胶，回流温度下搅拌半小时，趁热从溶液中将硅胶滤出，搅拌冷却至20℃，恒温析晶20小时，过滤，真空干燥得到目标晶型I1.5g，经附图1确证其结构。
实验例1稳定性实验
按照实施例1～3顺序制备三批该晶型样品，在温度40℃、湿度75%条件下进行了6个月稳定性考察。结果表明，该晶型非常稳定，稳定性数据如表1所示：
表1温度40℃、湿度75%条件下的稳定性数据
将样品在温度25℃、湿度60%条件下进行24个月稳定性考察。结果表明，该晶型非常稳定，稳定性数据如表2：
表2温度25℃、湿度60%条件下的稳定性数据
Figure BDA00002858813400042
Figure BDA00002858813400051

Claims (7)

1.一种奥氮平晶型，其使用Cu-Kα辐射、以d值表示的XRD光谱在约5.175、4.300、4.026和3.723有峰。
2.根据权利要求1所述的奥氮平晶型，其使用Cu-Kα辐射所得XRD光谱如附图1所示。
3.一种根据权利要求1或2所述的奥氮平晶型的制备方法，其包括采用混合有机溶剂溶解奥氮平，其中奥氮平与混合有机溶剂的质量体积比为1:8~1:10，加热回流，回流温度下加入硅胶后搅拌，趁热过滤硅胶，在10℃～20℃条件下析晶，然后过滤得目标晶型。
4.根据权利要求3所述的制备方法，其中所述混合有机溶剂含有甲醇和乙醚，其中甲醇和乙醚的体积比为4:1。
5.根据权利要求3所述的制备方法，其中所述析晶温度为15℃。
6.一种治疗精神分裂症的药物组合物，其含有治疗有效量的如权利要求1或2所述的奥氮平晶型作为有效成分以及药学上可接受的载体。
7.根据权利要求1或2所述的奥氮平晶型或者根据权利要求6所述的治疗精神分裂症的药物组合物在制备用于治疗精神分裂症的药物中的用途。
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1179160A (zh) * 1995-03-24 1998-04-15 伊莱利利公司 2－甲基－噻吩并苯并二氮杂䓬的结晶形式及制备方法
US20040198721A1 (en) * 2002-12-24 2004-10-07 Dolitzky Ben Zion Novel crystal forms, methods for their preparation and method for preparation of olanzapine
WO2007105225A1 (en) * 2006-03-14 2007-09-20 Jubilant Organosys Limited PROCESS FOR PRODUCING PURE AND STABLE FORM OF 2-METHYL-4-(4- METHYL- 1 -PIPERAZINYL)-10H-THIENO[2,3-b] [ 1,5]BENZODIAZEPINE
CN101735239A (zh) * 2008-11-06 2010-06-16 齐鲁制药有限公司 一种无水奥氮平晶型ii的制备方法
US20100174066A1 (en) * 2005-03-21 2010-07-08 Venkataraman Sundaram Process for preparing crystalline form i of olanzapine
CN102093386A (zh) * 2011-01-05 2011-06-15 浙江华海药业股份有限公司 一种制备奥兰扎平晶型ⅱ的方法

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1179160A (zh) * 1995-03-24 1998-04-15 伊莱利利公司 2－甲基－噻吩并苯并二氮杂䓬的结晶形式及制备方法
US20040198721A1 (en) * 2002-12-24 2004-10-07 Dolitzky Ben Zion Novel crystal forms, methods for their preparation and method for preparation of olanzapine
US20100174066A1 (en) * 2005-03-21 2010-07-08 Venkataraman Sundaram Process for preparing crystalline form i of olanzapine
WO2007105225A1 (en) * 2006-03-14 2007-09-20 Jubilant Organosys Limited PROCESS FOR PRODUCING PURE AND STABLE FORM OF 2-METHYL-4-(4- METHYL- 1 -PIPERAZINYL)-10H-THIENO[2,3-b] [ 1,5]BENZODIAZEPINE
CN101735239A (zh) * 2008-11-06 2010-06-16 齐鲁制药有限公司 一种无水奥氮平晶型ii的制备方法
CN102093386A (zh) * 2011-01-05 2011-06-15 浙江华海药业股份有限公司 一种制备奥兰扎平晶型ⅱ的方法

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