CN1827600A - 盐酸伊伐布雷定的β－晶形、其制备方法和含有它的药物组合物 - Google Patents

盐酸伊伐布雷定的β－晶形、其制备方法和含有它的药物组合物 Download PDF

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CN1827600A
CN1827600A CNA2006100580765A CN200610058076A CN1827600A CN 1827600 A CN1827600 A CN 1827600A CN A2006100580765 A CNA2006100580765 A CN A2006100580765A CN 200610058076 A CN200610058076 A CN 200610058076A CN 1827600 A CN1827600 A CN 1827600A
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S·霍瓦特
M-N·奥古斯特
G·达米安
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Abstract

通式(I)的盐酸伊伐布雷定的β－晶形，其特征在于其粉末X射线衍射图。药物。

Description

盐酸伊伐布雷定的β-晶形、其制备方法和 含有它的药物组合物
本发明涉及通式(I)的盐酸伊伐布雷定(ivabradine hydrochloride)的β-晶形、其制备方法和含有它的药物组合物：
Figure A20061005807600041
伊伐布雷定及其与药学上可接受的酸形成的加成盐、更具体为其盐酸盐具有极为有价值的药理和治疗特性，尤其是减慢心律(bradycardic)特性，从而使得这些化合物可用于治疗或预防心肌缺血的各种临床情况如心绞痛、心肌梗死和相关节律失常，以及涉及节律失常的各种病理情况、尤其是室上性节律失常，和心力衰竭。
欧洲专利说明书EP 0534 859中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、更尤其是其盐酸盐的制备和治疗用途。
鉴于该化合物的药学价值，所以最为重要的是获得具有极佳纯度的该化合物。另外重要的是能够通过一种易于转化成工业化规模的方法合成它，尤其是允许快速过滤和干燥的形式。最终，该形式必须完全可再现、易于配制且足够稳定以允许其长期贮存，而对温度、光或氧的水平没有特定的要求。
专利说明书EP 0534 859中描述了合成伊伐布雷定及其盐酸盐的方法。然而，该文献中未特别详述用于以可再现方式获得表现出那些特征的伊伐布雷定形式的条件。
本申请人目前已经发现，可以获得伊伐布雷定的特定盐、即盐酸盐的一种晶体形式，该晶形得到充分定义并且表现出有价值的稳定性和加工性能的特征。
更具体而言，本发明涉及盐酸伊伐布雷定的β-晶形，其特征在于如下粉末X射线衍射图，该衍射图使用PANalytical X’Pert Pro衍射仪与X’Celerator检测器测定，并根据谱线(ray)位置(布拉格角2θ，以度表示)、谱线高度(以计数表示)、谱线面积(以计数×度表示)、半高处的谱线宽度(“FWHM”，以度表示)和晶面间距d(以_表示)表示：
谱线号   2θ角(度)   高(计数)   面积(计数×度)   FWHM(度)   晶面间距(_)
  1   6.8   130   86   0.6691   13.019
  2   9.2   6141   507   0.0836   9.613
  3   9.7   882   58   0.0669   9.083
  4   10.0   875   72   0.0836   8.837
  5   11.9   190   19   0.1004   7.433
  6   12.2   500   58   0.1171   7.236
  7   13.2   224   30   0.1338   6.694
  8   13.8   633   52   0.0836   6.419
  9   14.3   466   54   0.1171   6.209
  10   14.8   926   76   0.0836   5.977
  11   15.0   716   94   0.1338   5.887
  12   15.7   531   79   0.1506   5.636
  13   16.1   121   16   0.1338   5.502
  14   16.9   1354   223   0.1673   5.254
  15   18.4   5672   562   0.1004   4.824
  16   18.8   1328   131   0.1004   4.716
  17   19.7   1617   347   0.2175   4.508
谱线号   2θ角(度)   高(计数)   面积(计数×度)   FWHM(度)   晶面间距(_)
  18   20.4   296   34   0.1171   4.341
  19   20.7   767   51   0.0669   4.286
  20   21.3   1419   211   0.1506   4.178
  21   21.6   2458   243   0.1004   4.114
  22   22.6   1737   258   0.1506   3.937
  23   23.0   1467   73   0.0502   3.865
  24   23.7   486   128   0.2676   3.751
  25   23.9   504   50   0.1004   3.718
  26   25.3   4606   304   0.0669   3.513
  27   25.7   791   91   0.1171   3.464
  28   26.2   458   91   0.2007   3.406
  29   26.6   221   44   0.2007   3.352
  30   27.4   706   151   0.2175   3.251
  31   27.7   208   27   0.1338   3.215
  32   28.1   483   40   0.0836   3.176
  33   28.8   242   24   0.1004   3.096
  34   29.3   450   74   0.1673   3.049
本发明还涉及制备盐酸伊伐布雷定的β-晶形的方法，该方法的特征在于将盐酸伊伐布雷定和水的混合物或盐酸伊伐布雷定、异丙醇和水的混合物加热，直至溶解完全，然后逐步冷却，直至结晶完全，并且收集形成的晶体。
·在本发明的结晶方法中，可能使用通过任意方法获得的盐酸伊伐布雷定，例如通过专利说明书EP 0534 859中所述的制备方法获得的盐酸伊伐布雷定。
·在冷却步骤中可以有利地将溶液种晶。
本发明还涉及药物组合物，包含作为活性成分的盐酸伊伐布雷定的β-晶形以及一种或多种适宜的惰性无毒性赋形剂。在本发明的药物组合物中，更尤其可以提及的是适合于口服、胃肠外(静脉内或皮下)或鼻部给药的那些，片剂或糖衣丸、舌下片、明胶胶囊、锭剂、栓剂、霜剂、软膏剂、皮肤凝胶、可注射制剂、可饮用的混悬液。
有用的剂量可以根据疾病的性质和严重程度、给药途径和患者的年龄和体重而改变。该剂量在1-500mg/天之间改变，分一次或多次给药。
下列实施例解释本发明。
在下列实验条件下测定X射线粉末衍射光谱：
-PANalytical X’Pert Pro衍射仪、X’Celerator检测器、温控室；
-电压45kV，电流40mA；
-上机(mounting)θ-θ；
-镍(Kβ)滤波器；
-入射线和衍射线索勒缝隙：0.04拉德；
-发散狭缝的固定角：1/8°；
-障板(mask)：10mm；
-防散射狭缝：1/4°；
-测定方式：从3°连续至30°，按0.017°递增；
-测定时间/步骤：19.7s；
-总时间：4min 32s
-测定速度：0.108°/s；
-测定温度：环境。
实施例1：盐酸伊伐布雷定的β-晶形
将720ml纯化水预加热至50℃，然后分批加入按照专利说明书EP0534 859中所述方法获得的250g盐酸伊伐布雷定，同时搅拌，将该混合物在74℃加热，直至溶解完全。将所得澄清溶液在74℃再加热2小时，然后逐步冷却，先冷却至40℃，然后冷却至环境温度。随后将该溶液在环境温度贮存2天，然后使固体混悬液在结晶板上以薄层展开。在适度氮气流中驱散过量的水。
通过库仑法测定的所得产物的含水量为12.4％，与四水合物相当。X射线粉末衍射图：
通过下表中整理的重要谱线，给出了盐酸伊伐布雷定β-晶形的X射线粉末衍射图谱(衍射角)：
谱线号   2θ角(度)   高(计数)  面积(计数×度)   FWHM(度)   晶面间距(_)
  1   6.8   130  86   0.6691   13.019
  2   9.2   6141  507   0.0836   9.613
  3   9.7   882  58   0.0669   9.083
  4   10.0   875  72   0.0836   8.837
  5   11.9   190  19   0.1004   7.433
  6   12.2   500  58   0.1171   7.236
  7   13.2   224  30   0.1338   6.694
  8   13.8   633  52   0.0836   6.419
  9   14.3   466  54   0.1171   6.209
  10   14.8   926  76   0.0836   5.977
  11   15.0   716  94   0.1338   5.887
  12   15.7   531  79   0.1506   5.636
  13   16.1   121  16   0.1338   5.502
  14   16.9   1354  223   0.1673   5.254
  15   18.4   5672  562   0.1004   4.824
  16   18.8   1328  131   0.1004   4.716
  17   19.7   1617  347   0.2175   4.508
  18   20.4   296  34   0.1171   4.341
  19   20.7   767  51   0.0669   4.286
  20   21.3   1419  211   0.1506   4.178
  21   21.6   2458  243   0.1004   4.114
  22   22.6   1737  258   0.1506   3.937
  23   23.0   1467  73   0.0502   3.865
  24   23.7   486  128   0.2676   3.751
  25   23.9   504  50   0.1004   3.718
  26   25.3   4606  304   0.0669   3.513
  27   25.7   791  91   0.1171   3.464
  28   26.2   458  91   0.2007   3.406
  29   26.6   221  44   0.2007   3.352
  30   27.4   706  151   0.2175   3.251
  31   27.7   208  27   0.1338   3.215
  32   28.1   483  40   0.0836   3.176
  33   28.8   242  24   0.1004   3.096
  34   29.3   450  74   0.1673   3.049
实施例2：药物组合物
制备1000片各自含有5mg伊伐布雷定碱的片剂的配方：
实施例1的化合物                          5.39g
玉米淀粉                                 20g
无水胶体二氧化硅                         0.2g
甘露糖醇                                 63.91g
PVP                                      10g
硬脂酸镁                                 0.5g。

Claims (6)

1.通式(I)的盐酸伊伐布雷定的β-晶形：
Figure A2006100580760002C1
其特征在于如下粉末X射线衍射图，该衍射图使用PANalytical X’Pert Pro衍射仪与X’Celerator检测器测定，并用谱线位置(布拉格角2θ，以度表示)、谱线高度(以计数表示)、谱线面积(以计数×度表示)、半高处的谱线宽度(“FWHM”，以度表示)和晶面间距d(以_表示)表示： 谱线号   2θ角(度)   高(计数)   面积(计数×度)   FWHM(度)   晶面间距(_)   1   6.8   130   86   0.6691   13.019   2   9.2   6141   507   0.0836   9.613   3   9.7   882   58   0.0669   9.083   4   10.0   875   72   0.0836   8.837   5   11.9   190   19   0.1004   7.433   6   12.2   500   58   0.1171   7.236   7   13.2   224   30   0.1338   6.694   8   13.8   633   52   0.0836   6.419   9   14.3   466   54   0.1171   6.209   10   14.8   926   76   0.0836   5.977   11   15.0   716   94   0.1338   5.887   12   15.7   531   79   0.1506   5.636   13   16.1   121   16   0.1338   5.502
谱线号   2θ角(度)   高(计数)   面积(计数×度)   FWHM(度)   晶面间距(_)   14   16.9   1354   223   0.1673   5.254   15   18.4   5672   562   0.1004   4.824   16   18.8   1328   131   0.1004   4.716   17   19.7   1617   347   0.2175   4.508   18   20.4   296   34   0.1171   4.341   19   20.7   767   51   0.0669   4.286   20   21.3   1419   211   0.1506   4.178   21   21.6   2458   243   0.1004   4.114   22   22.6   1737   258   0.1506   3.937   23   23.0   1467   73   0.0502   3.865   24   23.7   486   128   0.2676   3.751   25   23.9   504   50   0.1004   3.718   26   25.3   4606   304   0.0669   3.513   27   25.7   791   91   0.1171   3.464   28   26.2   458   91   0.2007   3.406   29   26.6   221   44   0.2007   3.352   30   27.4   706   151   0.2175   3.251   31   27.7   208   27   0.1338   3.215   32   28.1   483   40   0.0836   3.176   33   28.8   242   24   0.1004   3.096   34   29.3   450   74   0.1673   3.049
2.制备根据权利要求1的盐酸伊伐布雷定的β-晶形的方法，其特征在于将盐酸伊伐布雷定和水的混合物或盐酸伊伐布雷定、异丙醇和水的混合物加热直至溶解完全，然后逐步冷却直至结晶完全，并收集形成的晶体。
3.根据权利要求2的方法，其特征在于在冷却步骤中将盐酸伊伐布雷定的溶液种晶。
4.药物组合物，包含作为活性成分的根据权利要求1的盐酸伊伐布雷定的β-晶形以及一种或多种药学上可接受的惰性无毒性载体。
5.根据权利要求1的盐酸伊伐布雷定的β-晶形在制备可用作减慢心率药的药物中的用途。
6.根据权利要求1的盐酸伊伐布雷定的β-晶形在制备药物中的用途，所述药物可用于治疗或预防心肌缺血的各种临床情况如心绞痛、心肌梗死和相关节律失常，以及涉及节律失常的各种病理情况、尤其是室上性节律失常，和心力衰竭。
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TWI499587B (zh) * 2010-06-03 2015-09-11 Jiangsu Hengrui Medicine Co 硫酸伊伐佈雷定及其ｉ型結晶的製備方法
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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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