CN101585779A - 阿戈美拉汀的新晶型ⅵ及其制备方法和应用 - Google Patents

阿戈美拉汀的新晶型ⅵ及其制备方法和应用 Download PDF

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CN101585779A
CN101585779A CNA2009100473292A CN200910047329A CN101585779A CN 101585779 A CN101585779 A CN 101585779A CN A2009100473292 A CNA2009100473292 A CN A2009100473292A CN 200910047329 A CN200910047329 A CN 200910047329A CN 101585779 A CN101585779 A CN 101585779A
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agomelatine
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单汉滨
张鹏
袁哲东
蒋旭东
黄雨
王胡博
曹旭峰
程兴栋
俞雄
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Abstract

本发明提供了阿戈美拉汀的一种新晶型及其制备方法和应用。阿戈美拉汀的晶型粉末X射线衍射图中，在衍射角度2θ为11.13、11.82、17.49、18.29、19.48、19.72、20.50、21.76、22.54、22.97、24.56、25.36、27.16、31.93度处有主峰。该新的晶型纯度好、晶形稳定且重现性好，在制剂方面具有优势。另外在稳定性和溶解度上更优于现有的几种晶型。

Description

阿戈美拉汀的新晶型Ⅵ及其制备方法和应用
技术领域
本发明涉及式阿戈美拉汀N-[2-(7-甲氧基-1-萘基)]乙酰胺的一种晶型，及其制备方法和应用。
背景技术
阿戈美拉汀(agomelatine)，化学名为N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺，化学结构如下式(I)所示，商品名Valdoxan。
它具有双重作用，不仅是褪黑激素能系统受体的激动剂，还有拮抗5HT2C受体的作用，其性质使其在中枢神经系统具备活性，尤其在严重抑郁症、季节性情感障碍、睡眠障碍、心血管疾病、消化系统疾病、飞行时差引起的失眠和疲劳、食欲紊乱和肥胖症的治疗中具有活性。它是第一个褪黑激素类抗抑郁药，能有效治疗抑郁症，改善睡眠参数和不影响性功能。阿戈美拉汀的制备方法和治疗用途在欧洲专利说明书EP0447285中已有报道。
鉴于该化合物的药学价值，获得纯度好、晶形稳定且重现性好的该化合物是重要的，使其在制剂方面具有优势，并且足够稳定可以长期存储，且对温度、光、湿度或氧气水平没有特定要求。
在中国专利CN200510071611.6、CN200610108396.7、CN200610108394.8、CN200610108395.2说明书中分别公开了三种阿戈美拉汀的II、III、IV、V晶形及其制备方法。
其中晶型II是通过乙醇与水重结晶制得。晶形III的制备方法：在110℃加热阿戈美拉汀直至完全熔化，然后缓慢冷却直至结晶得到。晶形IV的制备方法：在110℃加热阿戈美拉汀直至完全熔化，然后在50和70℃之间迅速冷却，并在70℃维持约5小时直至结晶得到。晶形V的制备方法：对阿戈美拉汀进行所谓的“高能”机械研磨制得。
发明内容
本发明的目的是提供一种新的阿戈美拉汀的晶型，即晶型VI，该晶型在制剂方面显示出有价值的特性。
本发明的另一目的是提供阿戈美拉汀晶型VI的制备方法，该制备方法操作简单，重现性好。
阿戈美拉汀的晶型，其粉末X射线衍射图中，在衍射角度2θ为11.13、11.82、17.49、18.29、19.48、19.72、20.50、21.76、22.54、22.97、24.56、25.36、27.16、31.93度处有主峰。
阿戈美拉汀的晶型，其粉末X射线衍射图中，在有主峰的衍射角度2θ处对应的相对强度(以百分百计)如下表示：
    2θ° 相对强度
    11.13     12.4
    11.82     17.8
    17.49     20.7
    18.29     17.9
  19.48   66.8
  19.72   100
  20.50   14.5
  21.76   19.7
  22.54   22.0
  22.97   26.2
  24.56   13.1
  25.36   16.7
  27.16   12.2
  31.93   10.1
阿戈美拉汀晶型VI的制备方法，该方法是先将阿戈美拉汀溶于醋酸，然后加入0-25℃的水中，结晶析出。
上述阿戈美拉汀晶型VI的制备方法，加入水中时最好缓慢加入，具体操作可以采用滴加的方法，并不停的进行搅拌，以利于结晶析出。
本发明所得到的阿戈美拉汀晶型VI，对其进行药理研究结果显示，可用于治疗褪黑素能系统疾病，睡眠障碍、紧张、焦虑症、季节性情感障碍或严重抑郁症、心血管疾病、消化系统疾病、飞行时差引起的失眠或疲劳、精神分裂症、恐惧症、抑郁症等。
本发明所提供的阿戈美拉汀晶型VI，可与药学上的各种辅料或赋性剂一起制得各种药物剂型，用于口服或注射使用。
本发明得到了一种新的阿戈美拉汀晶型VI，纯度好、晶形稳定且重现性好，在制剂方面具有优势。另外在稳定性和溶解度上更优于现有的几种晶型。
附图说明
图1是本发明实施例1所得晶型VI的X射线衍射图谱。采用Bruker D8 ADVANCE仪测定。测定条件如下：CuKa 40Kv 40mA为光源，步长0.02°，扫描速度：8°/min，扫描范围：3°～80°，室温。
具体实施方式
实施例1
将1g阿戈美拉汀搅拌溶解于4ml醋酸中，缓慢滴加入水80ml中，维持在0℃搅拌3.5小时，过滤，固体用水8ml*2洗涤，55℃下真空干燥至恒重，得到白色固体0.91g。纯度：99.6％，熔点：97-98℃。
实施例2
将1g阿戈美拉汀搅拌溶解于4ml醋酸中，缓慢滴加入水80ml中，维持在5℃搅拌3小时，过滤，固体用水8ml*2洗涤，55℃下真空干燥至恒重，得到白色固体0.90g。纯度：99.6％，熔点：97-98℃。
实施例3
将2g阿戈美拉汀搅拌溶解于8ml醋酸中，缓慢滴加入水160ml中，维持在20℃搅拌3小时，过滤，固体用水16ml*2洗涤，55℃下真空干燥至恒重，得到白色固体1.76g。纯度：99.6％，熔点：97-98℃。
实施例2中所得阿戈美拉汀的晶型，其干燥后的粉末状产品实测X射线衍射图中，晶面间距d、布拉格2θ角和相对强度值为：
  2θ°   d(A)   相对强度
  11.13   7.942   12.4
  11.82   7.481   17.8
  17.49   5.066   20.7
  18.29   4.846   17.9
  19.48   4.553   66.8
  19.72   4.498   100
  20.50   4.328   14.5
  21.76   4.080   19.7
  22.54   3.941   22.0
  22.97   3.868   26.2
  24.56   3.621   13.1
  25.36   3.509   16.7
  27.16   3.280   12.2
  31.93   2.800   10.1
使用的测试仪器？
实验结果测试：
分别将晶型II、III、IV、VI分别放入40℃的恒温箱中，放置20天，通过高效液相色谱法对这些晶型的稳定性进行研究。
1、样品纯度测定
色谱条件：用十八烷基硅烷键合硅胶为填充剂；以10mM/L磷酸缓冲盐(用氢氧化钠调节pH至7.0)和乙腈体积比为2∶7的混合溶液作为流动相；柱温为40℃；检测波长为220nm。通过内标法测定纯度。
用流动相分别将晶型II、III、IV、VI配置成1mg/mL的溶液，各取10μL注入液相色谱仪，记录色谱图。
2、样品含量测定
测定方法参考样品纯度测定的方法，用外标法进行测定，结果见表一：
表一
  样品名称   晶型II纯度  晶型III纯度   晶型IV纯度   晶型VI纯度
  放置前   99.79％   99.77％   99.82％   99.60％
  恒温箱放置20天后   99.24％   99.10％   99.54％   99.55％
3、水溶性测定
测定方法采用HPLC方法，用外标法进行测定。结果如下表二：
表二
  样品名称   晶型II纯度   晶型VI纯度
  纯度   99.79％   99.77％
  溶解度(mg/ml)   1.11   1.24
根据测试结果看到，本发明的阿戈美拉汀新晶型VI在稳定性和溶解度上比现有的几个晶型更有优势。且在制备方法上，也比现有的晶型III、IV、V更有工业应用价值。

Claims (6)

1.阿戈美拉汀的晶型，其粉末X射线衍射图中，在衍射角度2θ为11.13、11.82、17.49、18.29、19.48、19.72、20.50、21.76、22.54、22.97、24.56、25.36、27.16、31.93度处有主峰。
2.如权利要求1所述的阿戈美拉汀的晶型，其粉末X射线衍射图中，在有主峰的衍射角度2θ处对应的相对强度如下：
  2θ°   相对强度   11.13   12.4   11.82   17.8   17.49   20.7   18.29   17.9   19.48   66.8   19.72   100   20.50   14.5   21.76   19.7   22.54   22.0   22.97   26.2   24.56   13.1   25.36   16.7   27.16   12.2   31.93   10.1
3.如权利要求1或2所述的阿戈美拉汀晶型的制备方法，该方法是先将阿戈美拉汀溶于醋酸，然后加入0-25℃的水中，结晶析出。
4.如权利要求3所述的阿戈美拉汀晶型的制备方法，其特征在于：是将阿戈美拉汀的醋酸溶液缓慢加入水中，同时不停搅拌。
5.一种药物组合物，由权利要求1或2所述的阿戈美拉汀晶型和药学上可接受的辅料或赋性剂组成。
6.权利要求1或2所述的阿戈美拉汀晶型在治疗褪黑素能系统疾病，睡眠障碍、紧张、焦虑症、季节性情感障碍或严重抑郁症、心血管疾病、消化系统疾病、飞行时差引起的失眠或疲劳、精神分裂症、恐惧症、抑郁症疾病的药物中的应用。
CN200910047329.2A 2009-03-10 2009-03-10 阿戈美拉汀的晶型vi及其制备方法和应用 Expired - Fee Related CN101585779B (zh)

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US13/138,615 US8614251B2 (en) 2009-03-10 2010-03-09 Crystalline form VI of agomelatine, preparation method and application thereof
UAA201111757A UA100476C2 (en) 2009-03-10 2010-03-09 New crystalline form vi of agomelatine, preparation method and application thereof
GEAP201012406A GEP20146114B (en) 2009-03-10 2010-03-09 New crystalline form vi of agomelatine, preparation method and application thereof
AU2010223720A AU2010223720B2 (en) 2009-03-10 2010-03-09 New crystalline form VI of Agomelatine, preparation method and application thereof
SG2011058559A SG173692A1 (en) 2009-03-10 2010-03-09 New crystalline form vi of agomelatine, preparation method and application thereof
JP2011553265A JP2012519715A (ja) 2009-03-10 2010-03-09 アゴメラチンの新規結晶形態ｖｉ、製造方法及びその応用
EA201101304A EA019127B1 (ru) 2009-03-10 2010-03-09 Новая кристаллическая форма vi агомелатина, ее получение и применение
CA2754276A CA2754276A1 (en) 2009-03-10 2010-03-09 New crystalline form vi of agomelatine, preparation method and application thereof
BRPI1013249A BRPI1013249A2 (pt) 2009-03-10 2010-03-09 "forma cristalina vi da agomelatina, preparação e uso da mesma."
AP2011005914A AP3049A (en) 2009-03-10 2010-03-09 New crystalline form VI of agomelatine, preparation method and application thereof
PE2011001513A PE20120653A1 (es) 2009-03-10 2010-03-09 Forma cristalina iv de la agomelatina y la composicion que la comprende
SG2011088564A SG177886A1 (en) 2009-03-10 2010-03-09 New crystalline form vi of agomelatine, preparation method and application thereof
MX2011009339A MX2011009339A (es) 2009-03-10 2010-03-09 Nueva forma cristalina iv de la agomelatina, preparacion y uso de la misma.
MA34144A MA33100B1 (fr) 2009-03-10 2010-03-09 Nouvelle forme cristalline vi de l'agomelatine son procede de preparation et son application
KR1020117021813A KR20110123266A (ko) 2009-03-10 2010-03-09 신규한 아고멜라틴 결정형 ⅵ, 및 이의 제조 방법 및 용도
PCT/CN2010/070931 WO2010102554A1 (zh) 2009-03-10 2010-03-09 阿戈美拉汀的新晶型ⅵ及其制备方法和应用
EP10750350A EP2431355A4 (en) 2009-03-10 2010-03-09 NOVEL VI-CRYSTALLINE FORM OF AGOMÉLATINE ITS PREPARATION METHOD AND APPLICATION
IL214683A IL214683A0 (en) 2009-03-10 2011-08-16 New crystalline form vi of agomelatine, preparation method and application thereof
ZA2011/06049A ZA201106049B (en) 2009-03-10 2011-08-17 New crystalline form vi of agomelatine, preparation method and application thereof
TN2011000426A TN2011000426A1 (en) 2009-03-10 2011-08-17 New crystalline form vi of agomelatine, preparation method and application thereof
CU20110162A CU20110162A7 (es) 2009-03-10 2011-08-23 Nueva forma cristalina vi de la agomelatina, preparación y uso de la misma
CR20110457A CR20110457A (es) 2009-03-10 2011-08-24 Nueva forma cristalina vi de la agomelatina, preparacion y uso de la misma
CO11109271A CO6410293A2 (es) 2009-03-10 2011-08-26 Nueva formula cristalina vi de la agomelatina preparación y uso de la misma
EC2011011309A ECSP11011309A (es) 2009-03-10 2011-09-07 Nueva forma cristalina vi de la agomelatina, preparación y uso de la misma
NI201100167A NI201100167A (es) 2009-03-10 2011-09-08 Nueva forma cristalina vi de la agomelatina, preparación y uso de la misma
HN2011002408A HN2011002408A (es) 2009-03-10 2011-09-09 Nueva forma cristalina vi de la agomelatina, preparacion y uso de la misma.
CL2011002231A CL2011002231A1 (es) 2009-03-10 2011-09-09 Forma cristalina vi de la agomelatina; proceso de preparacion; composicion farmaceutica; y su uso para tratar estres, ansiedad, trastornos del sueño, enfermedades cardiovasculares, esquizofrenia, fobia, depresion, enfermedades del sistema digestivo.

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WO2011006387A1 (zh) * 2009-07-11 2011-01-20 浙江华海药业股份有限公司 阿戈美拉汀的制备方法、阿戈美拉汀晶形及其制备方法
CN102050756A (zh) * 2009-11-09 2011-05-11 北京利乐生制药科技有限公司 阿戈美拉汀新晶型及其制备方法
WO2011113363A1 (en) * 2010-03-17 2011-09-22 Les Laboratoires Servier Agomelatine hydrobromide hydrate and preparation thereof
CN102557979A (zh) * 2010-12-16 2012-07-11 北大方正集团有限公司 一种阿戈美拉汀的晶型、其制备方法、用途及药物组合物
CN102690210A (zh) * 2011-03-23 2012-09-26 上海医药工业研究院 阿戈美拉汀的新晶型ⅶ、其制备方法、应用和包含其的药物组合物
WO2012126386A1 (zh) * 2011-03-23 2012-09-27 上海医药工业研究院 阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物
WO2013082302A1 (en) 2011-11-30 2013-06-06 Ratiopharm Gmbh Agomelatine-urea complex and crystalline forms thereof
CN101955440B (zh) * 2009-07-17 2014-04-09 江苏万特制药有限公司 一种阿戈美拉汀新晶型及其制备方法

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CN103690499B (zh) * 2013-12-23 2015-05-06 天津泰普药品科技发展有限公司 一种稳定的晶i型阿戈美拉汀片剂及其制备方法
WO2015124496A1 (en) 2014-02-19 2015-08-27 Synthon B.V. Pharmaceutical composition comprising amorphous agomelatine
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US8614251B2 (en) 2009-03-10 2013-12-24 Les Laboratories Servier Crystalline form VI of agomelatine, preparation method and application thereof
WO2010102554A1 (zh) * 2009-03-10 2010-09-16 上海医药工业研究院 阿戈美拉汀的新晶型ⅵ及其制备方法和应用
WO2011006387A1 (zh) * 2009-07-11 2011-01-20 浙江华海药业股份有限公司 阿戈美拉汀的制备方法、阿戈美拉汀晶形及其制备方法
CN101955440B (zh) * 2009-07-17 2014-04-09 江苏万特制药有限公司 一种阿戈美拉汀新晶型及其制备方法
CN102050756A (zh) * 2009-11-09 2011-05-11 北京利乐生制药科技有限公司 阿戈美拉汀新晶型及其制备方法
WO2011113363A1 (en) * 2010-03-17 2011-09-22 Les Laboratoires Servier Agomelatine hydrobromide hydrate and preparation thereof
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US8729132B2 (en) 2010-03-17 2014-05-20 Les Laboratoires Servier Agomelatine hydrobromide hydrate and preparation thereof
CN102557979A (zh) * 2010-12-16 2012-07-11 北大方正集团有限公司 一种阿戈美拉汀的晶型、其制备方法、用途及药物组合物
CN102557979B (zh) * 2010-12-16 2014-11-26 北大方正集团有限公司 一种阿戈美拉汀的晶型、其制备方法、用途及药物组合物
CN103476742A (zh) * 2011-03-23 2013-12-25 上海医药工业研究院 阿戈美拉汀的新晶型ⅶ、其制备方法、应用和包含其的药物组合物
WO2012126386A1 (zh) * 2011-03-23 2012-09-27 上海医药工业研究院 阿戈美拉汀的混晶(形式-ⅷ)、其制备方法、应用和包含其的药物组合物
WO2012126385A1 (zh) * 2011-03-23 2012-09-27 上海医药工业研究院 阿戈美拉汀的新晶型ⅶ、其制备方法、应用和包含其的药物组合物
CN103476742B (zh) * 2011-03-23 2015-04-29 上海医药工业研究院 阿戈美拉汀的新晶型ⅶ、其制备方法、应用和包含其的药物组合物
CN102690210A (zh) * 2011-03-23 2012-09-26 上海医药工业研究院 阿戈美拉汀的新晶型ⅶ、其制备方法、应用和包含其的药物组合物
EA023278B1 (ru) * 2011-03-23 2016-05-31 Шанхай Инститьют Оф Фармасьютикл Индастри Кристаллический агомелатин (форма-viii), способ его получения, применение и содержащая его фармацевтическая композиция
EA023297B1 (ru) * 2011-03-23 2016-05-31 Шанхай Инститьют Оф Фармасьютикл Индастри Кристаллическая форма vii агомелатина, способ ее получения, применение и содержащая ее фармацевтическая композиция
MD4391C1 (ro) * 2011-03-23 2016-08-31 Hanghai Institute Of Pharmaceutical Industry Formă cristalină nouă VII a agomelatinei, procedeu de preparare şi utilizarea acesteia, şi compoziţie farmaceutică care o conţine
US9527803B2 (en) 2011-03-23 2016-12-27 Les Laboratoires Servier Crystal form VII of agomelatine, preparation method and use thereof and pharmaceutical composition containing same
MD4484C1 (ro) * 2011-03-23 2017-12-31 Hanghai Institute Of Pharmaceutical Industry Forma cristalină VIII a agomelatinei, procedeu de preparare, utilizarea acesteia şi compoziţie farmaceutică care o conţine
WO2013082302A1 (en) 2011-11-30 2013-06-06 Ratiopharm Gmbh Agomelatine-urea complex and crystalline forms thereof

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