CN102958911A - 阿戈美拉汀氯化氢水合物及其制备方法 - Google Patents
阿戈美拉汀氯化氢水合物及其制备方法 Download PDFInfo
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Abstract
本发明涉及式(I)的阿戈美拉汀氯化氢水合物、其制备方法和应用，以及包含其的药物组合物。本发明方法得到的阿戈美拉汀卤化氢水合物溶解性比阿戈美拉汀有显著提高，因而更加适合于制备药物制剂。使用本发明的方法，通过简便的制备工艺，无需特殊的操作，即可得到高纯度的产品。其中X是Cl。
Description
技术领域
本发明涉及阿戈美拉汀氯化氢水合物、其制备方法和应用，以及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，其结构式如下式Ⅱ所示。其商品名为Valdoxan，是法国Servier公司研发的褪黑激素激动剂，兼有拮抗5HT2C受体作用。它是第一个褪黑激素类抗抑郁药，能有效治疗抑郁症，改善睡眠参数和保持性功能。
鉴于该化合物的药学价值，获得纯度优良、溶解度更好、具有很确定且重现性极好的化合物或复合物是相当重要的。
发明内容
本发明的目的就是提供一种阿戈美拉汀氯化氢水合物，该新的化合物溶解度高、稳定性好、纯度高，利于阿戈美拉汀做成药物制剂的实际应用。
本发明的发明人在进行阿戈美拉汀产品纯化时，惊喜的发现阿戈美拉汀能与盐酸混合形成物理化学性质稳定的阿戈美拉汀氯化氢水合物，所述阿戈美拉汀氯化氢水合物适用于药物制剂的制备。而使用其它常用的多种无机酸（如：硫酸、磷酸、过氯酸等）和有机酸（如：乙酸、草酸、酒石酸、富马酸等），均不易得到水合物或者得到的水合物物理化学性质不稳定。
本发明提供的阿戈美拉汀氯化氢水合物，如下式（I）所示：
其中X为Cl。
本发明的另一目的是提供上述阿戈美拉汀氯化氢水合物的制备方法，该方法是将阿戈美拉汀与各种形式的HCl反应形成阿戈美拉汀氯化氢水合物。具体步骤可为两种：先将阿戈美拉汀溶解于含水有机溶剂，然后通入HCl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的溶剂中，再将结晶析出的固体洗涤、干燥。经过多次的实验，本发明的发明人发现，如果使用第一种方法通入HCl过多反而会造成收率降低，而第二种方法对于溶剂中HCl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的溶剂，再将结晶析出的固体洗涤、干燥。
或者，也可以将阿戈美拉汀加入到有机溶剂中，再滴加HCl水溶液，再将结晶析出的固体洗涤、干燥。
本制备方法的反应温度可以是本领域反应时的常见温度，只要低于溶剂的沸点即可，但为了提高反应收率，反应温度为室温或室温以下，较佳的为室温以下，更佳的为0-20℃。
上述阿戈美拉汀氯化氢水合物的制备方法，其有机溶剂的选择没有特别限制，只要能够溶解反应原料阿戈美拉汀及HCl，同时又能使阿戈美拉汀氯化氢水合物析出即可。可使用的有机溶剂包括：乙酸乙酯、乙酸甲酯、乙酸正丁酯、丙酮、乙腈等，优选乙酸乙酯。而如极性较高的有机溶剂，如醇类（乙醇、甲醇等）、DMF、DMSO等都不太合适。
本发明的有益效果：本发明人在众多常用酸中发现阿戈美拉汀能与氯化氢反应生产稳定的阿戈美拉汀氯化氢水合物，且无论是在稳定性、溶解度、吸湿性等物理性质，还是制备难度上均显著优于其它的常用酸与阿戈美拉汀的反应产物。
本发明制备的阿戈美拉汀氯化氢水合物，溶解性比阿戈美拉汀有显著提高，因而更加适合于制备药物制剂；且产品稳定性好、纯度高、溶解度好。在制备工艺上也非常简便，无需特殊的操作，即可得到高纯度的产品。
所述阿戈美拉汀氯化氢水合物的药理研究结果显示，其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、恐惧症或抑郁症。
本发明还提供了药物组合物，其包含本发明的阿戈美拉汀氯化氢水合物以及可药用辅料或赋形剂。
所述药物组合物可被配制以用于各种施用途径，尤其是用于口服或注射施用。
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有用剂量。日剂量为0.1mg至1g，且可分一次或多次施用。
附图简述
为能更清楚理解本发明的目的、特点和优点，以下将结合附图对本发明的代表性实施例进行详细描述。
图1为本发明实施例1产物进行热重分析的TGA曲线图。
图2为本发明实施例7物的X-射线粉末衍射图谱。
实施例
实施例1
将1g阿戈美拉汀加入到20ml乙酸乙酯溶液中，10℃条件下逐滴加入HCl（36%）水溶液0.5g，搅拌1个小时；过滤，固体用乙酸乙酯2ml洗涤两次，40℃下干燥得到白色固体1g；纯度：99.9%，收率：81.7%。
Cl元素分析：
理论计算值：Cl含量为11.91wt%
实测值：Cl含量为11.88wt%
熔点：88-90℃
实施例2
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%
熔点：88-90℃
实施例3
将1g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，室温下逐滴滴入浓硫酸，始终无沉淀析出。
实施例4
将1g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，在-10℃逐滴滴入浓硫酸，始终无沉淀析出。
实施例5
将1g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，在-10℃逐滴滴入冰醋酸，始终无沉淀析出。
实施例6
将1g阿戈美拉汀搅拌溶解于10ml乙酸乙酯中，在-10℃逐滴滴入富马酸，始终无沉淀析出。
实施例7
将100g阿戈美拉汀加入到1L乙酸乙酯溶液中，10℃条件下逐滴加入HCl（36%）水溶液50g，搅拌1个小时；过滤，固体用乙酸乙酯100ml洗涤两次，40℃下干燥得到白色固体101g（纯度：99.7%，收率：82.5%）。
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%
熔点：87-89℃
上述实施例中所用的阿戈美拉汀为市售可得，或者也可以按照现有的制备方法制得。
实施例8：药物组合物
检测方法及其结果
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。分别取实施例1和实施例2产物，通过内标法测定纯度。
用流动相分别配置成1mg/mL的溶液，各取10μL注入液相色谱仪，记录色谱图，所得纯度结果如上述实施例1和实施例2所示。
2、样品稳定性测定
取实施例1产物若干放入40℃的恒温箱中，放置30天，通过高效液相色谱法对这些样品的稳定性进行研究，结果如下表1：
表1
| 实施例1产物 | 0天 | 5天 | 10天 | 30天 |
| AG·HCl·H2O | 99.6% | 99.5% | 99.5% | 99.5% |
其中，AG代表阿戈美拉汀C15H17NO2。
3、水溶性测定
测定方法采用HPLC方法，取实施例1产物用外标法进行测定，并与阿戈美拉汀晶型II进行比较，结果如下表2：
表2
可见，本发明的阿戈美拉汀氯化氢水合物不论在水中，还是在与人体胃液环境接近的0.1N HCl，或者pH为7.0的缓冲盐溶液中，其溶解度都要比阿戈美拉汀好，也就是说其生物利用度较好。
4、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%。
4.1费休氏法（《中国药典》2010版附录VIII M）
取实施例1产物按照所述费休氏法测试，实测结晶水含量：6.15wt%
取实施例7产物按照所述费休氏法测试，实测结晶水含量：6.10wt%
4.2热重分析（《中国药典》2010版附录VIII Q）
取实施例1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1。
TGA方法的测试条件如下：
仪器型号NETZSCH TG 209F1
坩埚类型：Al2O3
吹扫气：N220ml/分钟；
保护气：N210ml/分钟。
温度范围：室温~300℃
升温速率：10℃/分钟
5、晶体结构分析
本发明实施例7的产物的X-射线粉末衍射图谱的测试条件如下：
XRD参数
仪器 Bruker D8ADVANCE X-射线衍射仪
检测器 LynxEye检测器
X-射线 CuKα40kV/40mA
扫描方式 θ/θ
单色器 Ni滤片
发散狭缝(DivSlit) 1°
DivH.L.Slit 1.0mm
扫描 从3°至45°连续扫描，其中0.02°/步
扫描时间 5分钟
扫描速度 8.0°/分钟
扫描温度 室温
阿戈美拉汀氯化氢水合物的X-射线粉末衍射图谱的特征在于如下布拉格2θ角、晶面间距d和相对强度(I%)：
表3
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。具体而言，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。
6、阿戈美拉汀氯化氢水合物稳定性测定
测定方法采用中国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在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9个月）：温度为25℃，湿度为60%RH
结果如下表4
表4
可见，阿戈美拉汀氯化氢水合物除在极端恶劣条件放置下，水分和氯的含量下降外，其它条件下，特别是加速试验和长期试验是稳定的，利于制剂方面的应用。
Claims (13)
1.式I所示的阿戈美拉汀氯化氢水合物：
其中X为Cl。
2.结晶形式的权利要求1所述的阿戈美拉汀氯化氢水合物，其特征在于如下布拉格2θ角、晶面间距d和相对强度：
其还包括其峰衍射角在约±0.2°的误差内匹配的晶体。
3.权利要求1或2所述的阿戈美拉汀氯化氢水合物的制备方法，其中，将阿戈美拉汀与HCl反应形成所述阿戈美拉汀氯化氢水合物。
4.根据权利要求3所述的阿戈美拉汀氯化氢水合物的制备方法，其中，将阿戈美拉汀与HCl在含水的有机溶剂中反应形成所述阿戈美拉汀氯化氢水合物。
5.根据权利要求4所述的阿戈美拉汀氯化氢水合物的制备方法，其中，将阿戈美拉汀溶解于有机溶剂，然后加入HCl水溶液，从而析出产物的结晶。
6.根据权利要求5所述的阿戈美拉汀氯化氢水合物的制备方法，其中，采用滴加的方式加入HCl水溶液。
7.根据权利要求4所述的阿戈美拉汀氯化氢水合物的制备方法，其中，将阿戈美拉汀加入到含有HCl的含水有机溶剂中，从而析出产物的结晶。
8.根据权利要求5或7所述的阿戈美拉汀氯化氢水合物的制备方法，其还包括：结晶析出后将固体洗涤、干燥。
9.根据权利要求5或7所述的阿戈美拉汀氯化氢水合物的制备方法，其中，所述反应的反应温度为0-20℃。
10.根据权利要求5或7所述的阿戈美拉汀氯化氢水合物的制备方法，其中，所述有机溶剂为乙酸乙酯、乙酸甲酯、乙酸正丁酯、丙酮或乙腈。
11.根据权利要求10所述的阿戈美拉汀氯化氢水合物的制备方法，其中，所述有机溶剂为乙酸乙酯。
12.药物组合物，其包含根据权利要求1或2所述的阿戈美拉汀氯化氢水合物和可药用的辅料或赋形剂。
13.权利要求1或2所述的阿戈美拉汀氯化氢水合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、恐惧症或抑郁症的应用。
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| EP2934502A1 (en) | 2012-12-21 | 2015-10-28 | Laboratorios Lesvi S.L. | Process for prepararing n-(2-(7-methoxy-1-naphthalenyl)ethyl) acetamide and solid forms thereof |
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