CN1948292A - δ－结晶形式的盐酸伊伐布雷定,其制备方法以及包含它的药物组合物 - Google Patents

δ－结晶形式的盐酸伊伐布雷定,其制备方法以及包含它的药物组合物 Download PDF

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CN1948292A
CN1948292A CNA2006101322296A CN200610132229A CN1948292A CN 1948292 A CN1948292 A CN 1948292A CN A2006101322296 A CNA2006101322296 A CN A2006101322296A CN 200610132229 A CN200610132229 A CN 200610132229A CN 1948292 A CN1948292 A CN 1948292A
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acid ivabradine
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S·霍瓦特
M-N·奥古斯特
G·达米安
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Abstract

δ－结晶形式的盐酸伊伐布雷定，其制备方法以及包含它的药物组合物δ－结晶形式的式(I)的盐酸伊伐布雷定。其特征在于其粉末X－射线衍射图。药剂。

Description

δ-结晶形式的盐酸伊伐布雷定，其制备方法以及包含它的药物组合物
技术领域
本发明涉及δ-结晶形式的式(I)的盐酸伊伐布雷定(ivabradine)，其制备方法以及包含它的药物组合物。
Figure A20061013222900041
背景技术
伊伐布雷定以及其与药学上可接受的酸形成的加成盐，尤其是其盐酸盐，具有非常有价值的药理学和治疗学特性，尤其减慢心率(bradycardic)的特性，从而使得这些化合物可用于治疗或预防多种心肌缺血性临床状况，如心绞痛、心肌梗塞及有关的心脏节律紊乱，也可用于多种涉及心脏节律紊乱的病理学，特别是室上性心脏节律紊乱，以及心力衰竭。
欧洲专利说明书EP 0 534 859已经描述了伊伐布雷定及其与药学上可接受的酸形成的加成盐，特别是其盐酸盐的制备和治疗学用途。
考虑到该化合物的药学价值，获得高纯度的该化合物非常重要。能够通过非常容易转化为产业规模的方法手段，尤其是允许快速过滤和干燥的形式合成该化合物也是很重要的。最后，该形式也必须能够完美地再生、容易配制，并且足够稳定，以允许长期存储而对温度、光照和氧水平没有特别要求。
专利说明书EP 0 534 859描述了伊伐布雷定及其盐酸盐的合成方法。然而，该文献没有说明获得以可再现的方式显示上述特征的形式的伊伐布雷定的条件。
发明内容
申请人现在已经发现，伊伐布雷定的一种特定的盐，即盐酸盐，可以以完全确定的结晶形式获得，其显示有价值的稳定性和可加工性特征。
更具体地讲，本发明涉及δ-结晶形式的伊伐布雷定的盐酸盐，其特征为以下的粉末X-射线衍射图，该图用PANalytical X′Pert Pro衍射计和X′Celerator探测器测得，以线的位置(布喇格角2θ，以度表示)、线高(以计数表示)、线面积(以计数×度表示)、半高时的线宽(″FWHM″，以度表示)和晶面间距d(以_表示)表示：
线编号   角2θ(度)   高(计数)   面积(计数×度)   FWHM(度)   晶面间距(_)
  1   4.1   1115   110   0.1004   21.753
  2   6.8   183   145   0.8029   12.907
  3   8.4   755   75   0.1004   10.531
  4   10.9   1104   128   0.1171   8.087
  5   12.2   195   19   0.1004   7.268
  6   14.3   569   75   0.1338   6.214
  7   14.7   1847   274   0.1506   6.013
  8   15.3   1734   315   0.184   5.802
  9   16.3   1164   154   0.1338   5.442
  10   16.8   3420   734   0.2175   5.269
  11   17.5   790   78   0.1004   5.069
  12   17.9   3389   503   0.1506   4.960
  13   19.2   2467   407   0.1673   4.635
  14   19.8   145   29   0.2007   4.477
  15   20.4   313   52   0.1673   4.362
  16   21.2   928   169   0.184   4.198
  17   21.7   2093   414   0.2007   4.099
  18   22.2   3850   635   0.1673   4.007
  19   22.5   576   76   0.1338   3.948
  20   23.1   1588   236   0.1506   3.855
  21   24.8   1665   247   0.1506   3.594
  22   25.2   1212   120   0.1004   3.534
  23   25.6   1507   249   0.1673   3.477
  24   26.7   2042   303   0.1506   3.342
  25   27.6   2281   414   0.184   3.229
  26   28.4   485   96   0.2007   3.138
  27   29.6   599   99   0.1673   3.014
本发明还涉及δ-结晶形式的盐酸伊伐布雷定的制备方法，该方法的特征是将乙腈或乙腈与水的混合物预热，加入盐酸伊伐布雷定，将获得的溶液冷却到室温，保持在室温直至结晶完成，收集所形成的晶体。
在依据本发明的结晶方法中，可以使用由任何方法获得的盐酸伊伐布雷定，例如由专利说明书EP 0 534 859中所述的制备方法获得的盐酸伊伐布雷定。
有利地，可以在冷却步骤期间向溶液中加入晶种。
优选将乙腈或乙腈与水的混合物预热至60℃和回流温度之间的温度，更优选预热至65和75℃之间。
优选稀释度大于15ml/g，更优选在50和100ml/g之间。
本发明还涉及药物组合物，所述药物组合物包含作为活性成分的δ-结晶形式的盐酸伊伐布雷定和一种或多种合适的、惰性且无毒的赋形剂。在根据本发明的药物组合物中，可能更特别要提到的是那些适合于口服、肠胃外(静脉内或皮下)或经鼻施用的药片或糖衣丸、舌下用药片、胶囊、锭剂、栓剂、霜、软膏、皮肤凝胶、可注射制剂、可饮用的混悬液。
可用剂量可根据疾病的性质和严重性、施药途径和患者的年龄和体重而有所不同。剂量在每天1至500mg之间变化，可以单次或分多次给药。
下面的实施例阐述了本发明。
在下述实验条件下测量X射线粉末衍射光谱。
-PANalytical X′Pert Pro衍射计，X′Celerator探测器，温控室，
-电压45kV，电流强度40mA，
-设定(mounting)θ-θ，
-镍(Kβ)过滤器，
-入射光和衍射光Soller狭缝：0.04rad，
-自动散射狭缝：10mm辐射长度，
-掩盖：10mm，
-反散射(antiscatter)狭缝：1/2°，
-测量模式：自3°至30°连续测量，增量为0.017°，
-每步的测量时间：19.7秒，
-总时间：4分32秒，
-测量速度：0.108°/s，
-测量温度：周围温度。
实施例1：δ-结晶形式的盐酸伊伐布雷定
将160ml乙腈预热到70℃，然后一部分一部分地加入由专利说明书EP0534859中所述的方法获得的2g盐酸伊伐布雷定，同时搅拌，直至完全溶解。然后将所述溶液于周围温度下保存2天。真空过滤出晶体并在结晶盘上铺展。
通过库仑法测定所得产物的水含量为2.8％。
粉末X-射线衍射图：
在下表中用明显的线给出了δ-形式的盐酸伊伐布雷定的粉末X-射线衍射图型(衍射角)：
线编号   角2θ(度)   高(计数)   面积(计数×度)   FWHM(度)   晶面间距(_)
  1   4.1   1115   110   0.1004   21.753
  2   6.8   183   145   0.8029   12.907
  3   8.4   755   75   0.1004   10.531
  4   10.9   1104   128   0.1171   8.087
  5   12.2   195   19   0.1004   7.268
  6   14.3   569   75   0.1338   6.214
  7   14.7   1847   274   0.1506   6.013
  8   15.3   1734   315   0.184   5.802
  9   16.3   1164   154   0.1338   5.442
  10   16.8   3420   734   0.2175   5.269
  11   17.5   790   78   0.1004   5.069
  12   17.9   3389   503   0.1506   4.960
  13   19.2   2467   407   0.1673   4.635
  14   19.8   145   29   0.2007   4.477
  15   20.4   313   52   0.1673   4.362
  16   21.2   928   169   0.184   4.198
  17   21.7   2093   414   0.2007   4.099
  18   22.2   3850   635   0.1673   4.007
  19   22.5   576   76   0.1338   3.948
  20   23.1   1588   236   0.1506   3.855
  21   24.8   1665   247   0.1506   3.594
  22   25.2   1212   120   0.1004   3.534
  23   25.6   1507   249   0.1673   3.477
  24   26.7   2042   303   0.1506   3.342
  25   27.6   2281   414   0.184   3.229
  26   28.4   485   96   0.2007   3.138
  27   29.6   599   99   0.1673   3.014
实施例2：药物组合物
用于制备1000片药片、其中每片药片含5mg伊伐布雷定碱的配方：
实施例1的化合物........................................5.39g
玉米淀粉.................................................20g
无水胶态二氧化硅........................................0.2g
甘露醇................................................63.91g
PVP......................................................10g
硬脂酸镁................................................0.5g

Claims (6)

1.δ-结晶形式的式(I)的盐酸伊伐布雷定：
其特征在于下述的粉末X-射线衍射图，该图用PANalytical X′Pert Pro衍射计和X′Celerator探测器测得，以线的位置(布喇格角2θ，以度表示)、线高(以计数表示)、线面积(以计数×度表示)、半高时的线宽(″FWHM″，以度表示)和晶面间距d(以_表示)表示： 线编号   角2θ(度)   高(计数)   面积(计数×度)   FWHM(度)   晶面间距(_)   1   4.1   1115   110   0.1004   21.753   2   6.8   183   145   0.8029   12.907   3   8.4   755   75   0.1004   10.531   4   10.9   1104   128   0.1171   8.087   5   12.2   195   19   0.1004   7.268   6   14.3   569   75   0.1338   6.214   7   14.7   1847   274   0.1506   6.013   8   15.3   1734   315   0.184   5.802   9   16.3   1164   154   0.1338   5.442   10   16.8   3420   734   0.2175   5.269   11   17.5   790   78   0.1004   5.069   12   17.9   3389   503   0.1506   4.960
  13   19.2   2467   407   0.1673   4.635   14   19.8   145   29   0.2007   4.477   15   20.4   313   52   0.1673   4.362   16   21.2   928   169   0.184   4.198   17   21.7   2093   414   0.2007   4.099   18   22.2   3850   635   0.1673   4.007   19   22.5   576   76   0.1338   3.948   20   23.1   1588   236   0.1506   3.855   21   24.8   1665   247   0.1506   3.594   22   25.2   1212   120   0.1004   3.534   23   25.6   1507   249   0.1673   3.477   24   26.7   2042   303   0.1506   3.342   25   27.6   2281   414   0.184   3.229   26   28.4   485   96   0.2007   3.138   27   29.6   599   99   0.1673   3.014
。
2.根据权利要求1的δ-结晶形式的盐酸伊伐布雷定的制备方法，其特征在于将乙腈或乙腈与水的混合物预热，加入盐酸伊伐布雷定，将获得的溶液冷却到室温，保持在室温直至结晶完成，收集所形成的晶体。
3.根据权利要求2的方法，其特征在于在冷却步骤期间向所述盐酸伊伐布雷定的溶液中加入晶种。
4.药物组合物，其包含作为活性成分的根据权利要求1的δ-结晶形式的盐酸伊伐布雷定，和一种或多种药学上可接受的、惰性、无毒载体。
5.根据权利要求1的δ-结晶形式的盐酸伊伐布雷定在生产用作减慢心率药的药物中的用途。
6.根据权要求1的δ-结晶形式的盐酸伊伐布雷定在生产用于治疗或预防各种心肌缺血性临床状况，例如心绞痛、心肌梗塞及有关的心脏节律紊乱，以及用于多种涉及心脏节律紊乱的病理学，特别是室上性心脏节律紊乱，以及心力衰竭的药物中的用途。
CNA2006101322296A 2005-10-11 2006-10-11 δ－结晶形式的盐酸伊伐布雷定,其制备方法以及包含它的药物组合物 Pending CN1948292A (zh)

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FR0510352A FR2891826B1 (fr) 2005-10-11 2005-10-11 Forme cristalline 6 du chlorhydrate de l'ivabradine, son procede de preparation et les compositions pharmaceutiques qui la contiennent

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WO2010081342A1 (zh) 2009-01-13 2010-07-22 江苏恒瑞医药股份有限公司 硫酸伊伐布雷定及其i型结晶的制备方法
CN107056706A (zh) * 2015-12-21 2017-08-18 江苏恒瑞医药股份有限公司 一种用于制备盐酸伊伐布雷定α晶型的方法
CN107056706B (zh) * 2015-12-21 2020-05-05 江苏恒瑞医药股份有限公司 一种用于制备盐酸伊伐布雷定α晶型的方法

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