CN101643432A - 获得v晶形阿戈美拉汀的新方法 - Google Patents
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- 238000000034 method Methods 0.000 title claims abstract description 18
- YJYPHIXNFHFHND-UHFFFAOYSA-N agomelatine Chemical compound C1=CC=C(CCNC(C)=O)C2=CC(OC)=CC=C21 YJYPHIXNFHFHND-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960002629 agomelatine Drugs 0.000 title claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 10
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- 238000002360 preparation method Methods 0.000 claims description 5
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- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052802 copper Inorganic materials 0.000 claims description 3
- 239000010949 copper Substances 0.000 claims description 3
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 3
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
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- DRLFMBDRBRZALE-UHFFFAOYSA-N melatonin Chemical compound COC1=CC=C2NC=C(CCNC(C)=O)C2=C1 DRLFMBDRBRZALE-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及获得V晶形阿戈美拉汀的新方法。更具体地讲，本发明涉及获得式(I)化合物的V晶形的方法。
Description
技术领域
本发明涉及获得式(I)的阿戈美拉汀或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的V晶形的新方法：
背景技术：
阿戈美拉汀或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺具有有价值的药理学性质。
实际上，其具有双重特性，其一方面是褪黑激素能系统受体的激动剂，另一方面，其又是5-HT2C受体的拮抗剂。这些性质使其具有中枢神经系统活性，并且更尤其是使其具有治疗重症抑郁、季节性情感障碍、睡眠障碍、心血管病状、消化系统病状、由于时差导致的失眠和疲劳、食欲障碍和肥胖的活性。
已经在欧洲专利EP 0 447 285中对阿戈美拉汀、其制备以及其在治疗中的应用进行了描述。
鉴于这种化合物的药用价值，以极佳的纯度获得这种化合物，并且尤其是以具有使其可在对温度、光照、湿度或氧气水平没有特殊要求的情况下长期储存的有价值特性的可充分再现形式获得这种化合物是很重要的。
专利申请EP 1 752 443描述了一种定义明确的阿戈美拉汀结晶形式-V晶形，其特征在于下面的X-射线粉末衍射图，该衍射图是用SiemensD5005衍射仪(铜对阴极)进行测量的，并且以晶面间距d、Bragg′s角2θ和相对强度(表示为相对于最强线的百分比)进行表达：
这种以可再现方式获得的明确定义的晶形具有很有价值的形态学性质，尤其是具有远远高于所述其它形式的比表面积。然而，其储存稳定期很短，并且在所有的情况中，都低于6个月。
发明内容
申请人现在研制了一种以可充分再现的方式获得V晶形形式的阿戈美拉汀的新方法，籍此增加了其随着时间的流逝的稳定性。因此，这种新方法使得可以获得具有与其药学应用相容的性质的V晶形形式的阿戈美拉汀。过去仅能通过所谓的“高能”研磨或通过用已经用研磨获得的结构纯净的形式进行种晶来获得V晶形。
申请人现在令人吃惊地发现，可以用喷雾干燥来获得这种形式。事实上，喷雾干燥是一种用于获得小粒度固体颗粒的常用技术。所得物质常常是无定形的(药学工业中的无定形状态，多晶型现象(Amorphous state，Polymorphism in pharmaceutical industry)，R.Hilfiker编辑，Wiley-VCHWeinheim 2006，第X章，第259-285页，S.Petit和G.Coquerel)。与其相反，在本发明中，可以用喷雾干燥来获得一种定义明确的晶形-V型，并且该晶形具有更好的随着时间的流逝的稳定性。
更具体地讲，本发明涉及一种获得V晶形形式的式(I)的阿戈美拉汀的新方法，该方法的特征在于在喷雾干燥器中将溶解于一种或两种可以以任意比例混溶并且沸点低于120℃的溶剂中的阿戈美拉汀溶液雾化。
喷雾干燥是一种在农业、食品和药学领域中常用的技术，用其来对被喷洒穿越热气体的溶液进行干燥。在实践中，用于干燥溶液的气体是空气，但一些使用有机溶剂的制药方法需要用惰性气体作为干燥气体以避免某些分解过程。
本发明的结晶操作优选地是用喷雾干燥器来进行的。本发明的雾化更优选地是根据使用具有平行流并且更优选地具有并向流(即，喷雾的溶液和干燥气流处于同一个方向上)的喷嘴的雾化原理来进行的。
所用气体有利地是压缩空气或惰性气体，例如氮气。
用于本发明方法的优选溶剂有乙醇、水、异丙醚、甲醇、乙酸乙酯或丙酮。
所用阿戈美拉汀溶液的最小浓度为5g/l，并且更优选使用10g/l的溶液。
本发明方法的入口温度有利地为70℃至120℃。
在本发明的结晶方法中，可以使用用任何方法获得的式(I)的阿戈美拉汀。
具体实施方式
用下文的实施例对本发明进行非限制性说明。
实施例1：N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的V晶形
将阿戈美拉汀在乙醇/异丙醚混合物(50/50：v/v)中的10g/l的溶液引入到BUCHI 190小型喷雾干燥器的雾化器中。干燥室的入口温度为90℃，出口温度为66℃。在收集碗中回收被雾化了的粉末并用下面的晶体学数据对其进行鉴定：
1)用Siemens D5005衍射仪获得的图谱，使用3°-30 °的2θ角范围，0.04°的跨距且每个跨距4秒：
-晶胞的晶体结构：单斜晶，
-晶胞参数：a＝11.967
b＝17.902
c＝15.423
β＝124.5°
-空间群：P21/n
-晶胞中分子的数目：8(Z’＝2)
-晶胞的体积：V晶胞＝2720.0
2)下面的X-射线粉末衍射图，其是用Siemens D5005衍射仪(铜对阴极)测得的，并且以晶面间距d、Bragg′s角2θ和相对强度(表示为相对于最强线的百分比)进行表达：
实施例2：通过雾化获得的N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的V晶形随着时间的流逝的稳定性
将1g实施例1获得的化合物的样品放置在常规储存条件下：环境压力和温度。在21个月后，所得样品的衍射图没有发生变化，其仍然具有所得V晶形的特性。
Claims (5)
1、获得式(I)的阿戈美拉汀的V晶形的方法：
其特征在于在喷雾干燥器中将溶解于一种或两种可以以任意比例混溶并且沸点低于120℃的溶剂中的阿戈美拉汀溶液雾化。
2.如权利要求1所述的制备式(I)化合物的V晶形的方法，其特征在于所得化合物具有下面的X-射线粉末衍射图，该衍射图是用Siemens D5005衍射仪(铜对阴极)测得的，并且以晶面间距d、Bragg′s角2θ和相对强度(表示为相对于最强线的百分比)进行表达：
3.如权利要求1所述的制备式(I)化合物的V晶形的方法，其特征在于所用溶剂是乙醇和异丙醚。
4.如权利要求1所述的制备式(I)化合物的V晶形的方法，其特征在于所用气体是氮气。
5.如权利要求1所述的制备式(I)化合物的V晶形的方法，其特征在于所用阿戈美拉汀溶液的最小浓度为5g/l。
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| FR0804466A FR2934856B1 (fr) | 2008-08-05 | 2008-08-05 | Nouveau procede d'obtention de la forme cristalline v de l'agomelatine |
| FR08/04466 | 2008-08-05 |
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| CN101781226B (zh) | 2009-12-23 | 2012-03-28 | 天津泰普药品科技发展有限公司 | 阿戈美拉汀及其药物组合物 |
| WO2012093402A1 (en) * | 2011-01-04 | 2012-07-12 | Symed Labs Limited | Processes for the preparation of n-[2-(7-methoxy-1-naphthyl)ethyl]acetamide |
| WO2012130837A1 (en) | 2011-03-28 | 2012-10-04 | Ratiopharm Gmbh | Solid agomelatine in non-crystalline form |
| EP2872129B1 (en) | 2012-07-16 | 2017-03-08 | ratiopharm GmbH | Complex of agomelatine and cyclodextrin |
| WO2015124496A1 (en) | 2014-02-19 | 2015-08-27 | Synthon B.V. | Pharmaceutical composition comprising amorphous agomelatine |
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| FR2658818B1 (fr) * | 1990-02-27 | 1993-12-31 | Adir Cie | Nouveaux derives a structure naphtalenique, leur procede de preparation et les compositions pharmaceutiques qui les contiennent. |
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| FR2866335B1 (fr) * | 2004-02-13 | 2006-05-26 | Servier Lab | Nouveau procede de synthese de l'agomelatine |
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| FR2889521B1 (fr) * | 2005-08-03 | 2007-12-28 | Servier Lab | Nouvelle forme cristalline iii de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
| FR2889523B1 (fr) * | 2005-08-03 | 2007-12-28 | Servier Lab | Nouvelle forme cristalline v de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
| US20080280991A1 (en) * | 2007-05-08 | 2008-11-13 | Auspex Pharmaceuticals, Inc. | Substituted naphthalenes |
| FR2923482B1 (fr) * | 2007-11-09 | 2010-01-29 | Servier Lab | Nouvelle forme cristalline vi de l'agomelatine, son procede de preparation et les compositions pharmaceutiques qui la contiennent |
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