CN102690210A - 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 - Google Patents

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 Download PDF

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CN102690210A
CN102690210A CN2011100708280A CN201110070828A CN102690210A CN 102690210 A CN102690210 A CN 102690210A CN 2011100708280 A CN2011100708280 A CN 2011100708280A CN 201110070828 A CN201110070828 A CN 201110070828A CN 102690210 A CN102690210 A CN 102690210A
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agomelatine
preparation
crystallization
crystal formation
acetate
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黄雨
童玲
朱雪焱
单汉滨
袁哲东
俞雄
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Shanghai Institute of Pharmaceutical Industry
Laboratoires Servier SAS
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Laboratoires Servier SAS
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Priority to CN2011100708280A priority Critical patent/CN102690210A/zh
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Priority to GEAP201213263A priority patent/GEP20156386B/en
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Priority to PCT/CN2012/072816 priority patent/WO2012126385A1/zh
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Publication of CN102690210A publication Critical patent/CN102690210A/zh
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Abstract

本发明提供了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。该新的晶型纯度好、晶型稳定且重现性好，其制备方法易于放大，在稳定性和溶解度上，更优于现有报道的多数晶型。因此，本发明的晶型Ⅶ在制剂方面具有优势。

Description

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
技术领域
本发明涉及阿戈美拉汀或N-[2-(7-甲氧基-1-萘基)乙基]乙酰胺的一种新晶型，及其制备方法、应用和包含其的药物组合物。 
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，商品名Valdoxan，化学结构如下式(Ⅰ)： 
Figure BDA0000051669840000011
它具有双重作用，不仅是褪黑激素能***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***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***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、其制备及其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、晶型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。 
对于阿戈美拉汀已有多篇文献报道，例如在专利CN200510071611.6、CN200610108396.7、CN200610108394.8、CN200610108395.2、CN200910047329.2、CN200910245029.5等公开了阿戈美拉汀的多种晶型及其制备方法。 
其中晶型Ⅱ是通过乙醇与水重结晶制得。晶型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。晶型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；晶型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，晶型Ⅵ通过醋酸和水重结晶所得。 
众所周知，由于化合物可以呈现出不同的分子排列，而拥有不同的固体型态，即同质多晶型。在药物中不同的晶型可能会导致药物的在溶出以及生物利用度的不同，因此寻找药物中纯度好，重现性好，易于生产应用，溶出及生物利用度优良的晶型，在药物的开发中显的尤为重要。 
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Ⅶ，并提供制备这一晶型的方法，且该晶型与已上市的药物(Valdoxan)中的Ⅱ晶型比较，在制剂方面显示出有价值的特性，且该制备方法重现性好。 
本发明的阿戈美拉汀的晶型Ⅶ可用于治疗褪黑素能***疾病、睡眠障碍、紧张、焦虑症、季节性情感障碍、严重抑郁症、心血管疾病、消化***疾病、飞行时差引起的失眠或疲劳、精神***症、恐惧症、抑郁症。 
本发明的另一目的是提供阿戈美拉汀的晶型Ⅶ的制备方法，该制备方法操作简单，重现性好。 
本发明的又一目的是提供药物组合物，其包含本发明的阿戈美拉汀的晶型Ⅶ以及可药用辅料或赋形剂。 
可配制所述药物组合物以用于各种施用途径，尤其是用于口服施用或注射。 
可根据待治疗疾病的性质和严重性、施用途径以及患者的年龄及体重调节施用剂量。剂量可在每天0.1mg至1g之间变化，可以一次或分多次施用。 
本发明的阿戈美拉汀的晶型以下列的X射线衍射图表征，并以布拉格2θ角、晶面间距d、相对强度来表示： 
Figure BDA0000051669840000031
用X射线衍射测定本发明的结晶时，有时由于测定的仪器或测定的条件，对于所测得的峰而言稍有测定误差，具体来说，例如，2θ值的测定误差有时为约±0.2，即使使用非常精密的设备时，有时也会产生约±0.1的误差。因此，在确定每种结晶结构时，应该将此误差考虑在内。 
XRD测试条件： 
仪器型号：Bruker D8 ADVANCE X射线衍射仪 
实验参数： 
检测器：LynxEye检测器 
光源：CuKα 40kV 40mA 
单色器：Ni滤片 
发散狭缝：1° 
DivH.L.Slit：1.0mm 
探测器：LynxEye探测器 
扫描方式：θ-θ连续扫描 
扫描范围：3°～45° 
步长：0.02° 
扫描速度：8.0°/min 
扫描温度：室温 
DSC测试条件： 
仪器型号：NETZSCH DSC 204F1 
实验条件： 
坩埚类型：标准铝坩埚(针刺穿孔) 
吹扫气：高纯氮20ml/min；保护气：高纯氮60ml/min。 
温度范围：室温～250℃ 
升温速率：10℃/min 
TGA测试条件 
仪器型号NETZSCH TG 209F1 
实验条件 
坩埚类型：Al2O3
吹扫气：N2 20ml/min；保护气：N2 10ml/min 
温度范围：室温～300℃ 
升温速率：10℃/min 
本发明晶型Ⅶ的制备方法，该方法是将阿戈美拉汀复合物(式Ⅱ或Ⅲ)溶于醋酸，然后向其中加入醋酸盐(优选醋酸钾或醋酸铵)，通过向所得到的反应液中滴加水并在17-23℃进行搅拌，使结晶析出，然后将结晶与液相分离。 
本发明所述的醋酸，其加入量无特殊要求，以能溶解原料为准，并可根据需求适当加热助溶。 
式Ⅱ或Ⅲ阿戈美拉汀复合物与醋酸盐的摩尔比优选为1∶1-1.5，特别优选1∶1-1.1。所述醋酸盐包括醋酸钾、醋酸铵。 
本发明所述制备方法中，醋酸与水的体积份数比为1∶10-30。 
在本发明晶型Ⅶ的制备方法的一个优选的实施方案中，在所得到的反应液为19-25℃、特别是在约22℃或23℃时，通过向其中滴加水使结晶析出。 
在另一个优选的实施方案中，通过向所得到的反应液中滴加水并在约20℃进行搅拌，例如搅拌约2小时，使结晶析出。 
在另一个优选的实施方案中，在加入醋酸盐后将反应液加热至30-50℃，得到澄清的溶液；使该溶液自然冷却，通过向其中滴加水使结晶析出。 
本发明得到了一种新的阿戈美拉汀的晶型Ⅶ，纯度好、晶型稳定且重现性好，易于放大制备，在制剂方面具有优势。与现有晶型相比，表现出良好的稳定性和优良的溶解度。 
根据中国专利申请CN 201010126254.X和CN 201010126263.9，上述式Ⅱ或Ⅲ阿戈美拉汀复合物可通过以下的制备方法来制备，该方法是将阿戈美拉汀与各种形式的HCl或HBr反应形成水合物。具体步骤为两种：先将阿戈美拉汀溶解于含水有机溶剂，然后通入HCl或HBr气体，再将结晶析出的固体洗涤、干燥；或者将阿戈美拉汀加入到含有HCl或HBr的溶剂中，再将结晶析出的固体洗涤、干燥。如果使用第一种方法通入HCl或HBr过多反而会造成收率降低，而第二种方法对于溶剂中HCl或HBr的量则容易控制，所以优选第二种方法。 
其中，也可以将阿戈美拉汀加入到含水有机溶剂中，再滴加含HCl或HBr的溶剂，再将结晶析出的固体洗涤、干燥。 
同样也可以将阿戈美拉汀加入到有机溶剂中，再滴加HCl或HBr水溶液，再将结晶析出的固体洗涤、干燥。 
所引用或提及的参考文献的全部内容引入本申请作为参考。 
附图说明
图1A和图1B是本发明实施例1所得晶型VII的X射线衍射图谱； 
图2是本发明实施例1所得晶型Ⅶ的DSC吸热转变图谱； 
图3为本发明实施例5产物进行热重分析的TGA曲线图； 
图4为本发明实施例6产物进行热重分析的TGA曲线图。 
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。 
实施例1： 
将式Ⅲ阿戈美拉汀复合物(7.6g)溶于AcOH(19ml)溶液中，加入KOAc(3.5g)；加热至40℃，得澄清溶液；自然冷却，溶液逐渐变浑浊，于22℃，滴加水(250ml)，并在～20℃搅拌2小时；过滤，用水洗涤滤饼，50℃下真空干燥至恒重，得到白色固体4.5g，纯度：99.8％ 
熔点：98-100℃ 
实施例2： 
将式Ⅱ阿戈美拉汀复合物(2g)溶于AcOH(5ml)，加入NH4OAc(0.57g)；加热至40℃，得澄清溶液；自然冷却，溶液逐渐变浑浊，于22℃，滴加水(150ml)，并在～20℃搅拌2小时；过滤，用水洗涤滤饼，50℃下真空干燥至恒重，得到白色固体1.4g，纯度：99.7％ 
熔点：98-100℃ 
实施例3： 
将式Ⅲ阿戈美拉汀复合物(40g)溶于AcOH(130ml)溶液中，加入NH4OAc(10g)；加热至40℃，得澄清溶液；自然冷却，溶液逐渐变浑浊，于23℃，滴加水(2.6L)，并在～20℃搅拌2小时；过滤，用水洗涤滤饼，50℃下真空干燥至恒重，得到白色固体25g，纯度：99.8％ 
熔点：98-100℃ 
实施例4： 
将晶型Ⅱ、Ⅲ、Ⅵ、Ⅶ(得自实施例3)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样品的稳定性进行研究。 
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10mmol/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、Ⅵ、Ⅶ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 
Figure BDA0000051669840000071
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   晶型Ⅵ   晶型Ⅶ
  溶解度(mg/ml)   0.301   0.336   0.330
4、晶型稳定性测定 
测定方法采用药典中稳定性考核方法： 
1)影响因素实验(敞口10天)：高温(60℃)，光照(4500lx)，高湿(92.5％RH，25℃) 
2)加速实验(密闭6个月)：温度为40℃，湿度为75％RH 
3)长期实验(密闭6个月)：温度为25℃，湿度为60％RH 
表三 
根据测试结果看到，本发明的阿戈美拉汀的新晶型Ⅶ在制备工艺、稳定性和溶解度均与目前的晶型相比存在明显的优势，更利于成药。 
实施例5：式Ⅱ阿戈美拉汀复合物 
将10g阿戈美拉汀加入到100ml乙酸乙酯溶液中，10℃条件下逐滴加入HCl(36％)水溶液4.6g，搅拌1个小时；过滤，固体用乙酸乙酯10ml洗涤两次，40℃下干燥得到式Ⅱ的白色固体10.2g；纯度：99.8％，收率：88.7％。 
Cl元素分析： 
理论计算值：Cl含量为11.91wt％ 
实测值：Cl含量为11.86wt％ 
式Ⅱ阿戈美拉汀复合物结晶水含量测定： 
根据计算得C15H17NO2·HCl·H2O中结晶水的理论含量为6.06wt％。 
5.1费休氏法(《中国药典》2010版附录VIII M) 
取实施例5产物按照所述费休氏法测试，实测结晶水含量：6.15wt％ 
5.2热重分析(《中国药典》2010版附录VIII Q) 
取实施例5产物按照所述热分析法测试，测得结晶水损失量6.67wt％，即原产物中含有结晶水6.67wt％。TGA曲线请参见图3。 
实施例6：式Ⅲ阿戈美拉汀复合物 
将100g阿戈美拉汀搅拌溶解于800ml乙酸乙酯中，低温下逐滴加入HBr水溶液(8.32g，40％)，搅拌1个小时；过滤，固体用乙酸乙酯100ml洗涤两次，在40℃下干燥得到白色固体120g；纯度：99.9％，收率：85.3％。 
分析结果(C15H17NO2·HBr·H2O) 
计算值：Br％(23.35％) 
实测值：Br％(23.29％) 
式Ⅲ阿戈美拉汀复合物结晶水含量测定： 
根据计算得C15H17NO2·HBr·H2O中结晶水的理论含量为5.26wt％。 
6.1费休氏法(《中国药典》2010版附录VIII M) 
取实施例6产物按照所述费休氏法测试，实测结晶水含量：5.10wt％ 
6.2热重分析(《中国药典》2010版附录VIII Q) 
取实施例6产物按照所述热分析法测试，测得结晶水损失量5.70wt％，即原产物中含有结晶水5.70wt％。TGA曲线请参见图4。 
实施例7：药物组合物的制备 
Figure BDA0000051669840000091

Claims (10)

1.阿戈美拉汀的晶型，其以下列的X射线衍射图表征，并以布拉格2θ角、晶面间距d和相对强度表示：
Figure FDA0000051669830000011
并且其还包括峰衍射角在上述2θ±0.2°的误差内匹配的晶体。
2.如权利要求1所述的阿戈美拉汀的晶型的制备方法，将式Ⅱ或Ⅲ阿戈美拉汀复合物溶于醋酸，然后向其中加入醋酸盐，通过向所得到的反应液中滴加水并在17-23℃进行搅拌，使结晶析出，然后将结晶与液相分离
Figure FDA0000051669830000012
3.如权利要求2所述的制备方法，其中，式Ⅱ或Ⅲ阿戈美拉汀复合物与醋酸盐的摩尔比为1∶1-1.5，优选1∶1-1.1。
4.如权利要求2或3所述的制备方法，其中，醋酸与水的体积份数比为1∶10-30。
5.如权利要求2-4中任意一项所述的制备方法，其中，所述醋酸盐是醋酸钾或者醋酸铵。
6.如权利要求2-5中任意一项所述的制备方法，其中，在所得到的反应液为19-25℃、特别是在22或23℃时，通过向其中滴加水使结晶析出。
7.如权利要求2-6中任意一项所述的制备方法，其中，通过向所得到的反应液中滴加水并在20℃进行搅拌，使结晶析出。
8.如权利要求2-7中任意一项所述的制备方法，其中，在加入醋酸盐后将反应液加热至30-50℃，得到澄清的溶液；使该溶液自然冷却，通过向其中滴加水使结晶析出。
9.药物组合物，其包含如权利要求1所述的阿戈美拉汀的晶型以及可药用辅料或赋形剂。
10.如权利要求1所述的阿戈美拉汀的晶型在制备药物中的应用，所述药物用于治疗褪黑素能***疾病、睡眠障碍、紧张、焦虑症、季节性情感障碍、严重抑郁症、心血管疾病、消化***疾病、飞行时差引起的失眠或疲劳、精神***症、恐惧症或抑郁症。
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HRP20171831T1 (hr) 2017-12-29
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EP2690087B1 (en) 2017-08-30
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