CN1827602A - 盐酸伊伐布雷定的γ－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γ－晶形、其制备方法和含有它的药物组合物 Download PDF

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CN1827602A
CN1827602A CNA2006100580784A CN200610058078A CN1827602A CN 1827602 A CN1827602 A CN 1827602A CN A2006100580784 A CNA2006100580784 A CN A2006100580784A CN 200610058078 A CN200610058078 A CN 200610058078A CN 1827602 A CN1827602 A CN 1827602A
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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γ－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γ-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)的新γ-晶形、其制备方法和含有它的药物组合物：
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。
鉴于该化合物的药物价值，所以最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，该晶形必须完全可再现，易于配制且足够稳定以便其长期贮存，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中描述了用于伊伐布雷定及其盐酸盐的合成方法。然而，该对比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γ-晶形，其特征在于如下粉末X射线衍射图，所述衍射图使用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   4.2   1456  144   0.1004   20.762
  2   6.9   125  99   0.8029   12.880
  3   8.4   182  18   0.1004   10.503
  4   10.7   240  32   0.1338   8.249
  5   11.3   74  15   0.2007   7.858
  6   12.0   644  64   0.1004   7.392
  7   12.5   1476  219   0.1506   7.060
  8   13.4   2691  400   0.1506   6.612
  9   14.5   541  80   0.1506   6.119
  10   14.8   104  17   0.1673   5.981
  11   15.9   815  67   0.0836   5.559
  12   16.3   501  74   0.1506   5.419
  13   17.0   1168  154   0.1338   5.210
  14   17.9   430  43   0.1004   4.962
  15   19.0   667  121   0.184   4.672
  16   19.8   527  104   0.2007   4.483
谱线号   2θ角(度)   高(计数)  面积(计数×度)   FWHM(度)   晶面间距(_)
  17   20.2   726  144   0.2007   4.392
  18   20.5   282  28   0.1004   4.323
  19   21.1   2255  260   0.1171   4.208
  20   21.4   694  68   0.1004   4.147
  21   21.6   744  86   0.1171   4.111
  22   22.3   175  35   0.2007   3.987
  23   23.5   310  61   0.2007   3.784
  24   24.2   1635  270   0.1673   3.683
  25   24.5   1335  220   0.1673   3.625
  26   24.9   523  95   0.184   3.568
  27   25.5   657  130   0.2007   3.485
  28   26.0   933  154   0.1673   3.431
  29   26.4   1549  230   0.1506   3.380
  30   26.8   419  83   0.2007   3.323
  31   27.3   350  69   0.2007   3.267
  32   28.0   1108  146   0.1338   3.186
  33   29.1   144  19   0.1338   3.066
本发明涉及制备盐酸伊伐布雷定的γ-晶形的方法，该方法的特征在于将盐酸伊伐布雷定和2-乙氧基乙醇的混合物、盐酸伊伐布雷定、2-乙氧基乙醇和水的混合物或盐酸伊伐布雷定、乙醇和水的混合物加热，直至溶解完全，然后冷却，直至结晶完全，并且通过过滤收集产物。
·在本发明的结晶方法中，能够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。
·可以在冷却步骤中有利地将该溶液种晶。
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γ-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γ-晶形
将40ml 2-乙氧基乙醇预加热至80℃，然后分批加入按照专利说明书EP 0534 859中所述方法获得的8.4g盐酸伊伐布雷定，同时搅拌，并且将该混合物在80℃加热，直至溶解完全。在返回到环境温度后，将该溶液贮存8天，然后通过过滤收集形成的结晶并且用环己烷冲洗。
通过库仑法测定的所获得结晶的含水量为3.5％，与一水合物相当。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γ-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   4.2   1456  144   0.1004   20.762
  2   6.9   125  99   0.8029   12.880
  3   8.4   182  18   0.1004   10.503
  4   10.7   240  32   0.1338   8.249
  5   11.3   74  15   0.2007   7.858
  6   12.0   644  64   0.1004   7.392
  7   12.5   1476  219   0.1506   7.060
  8   13.4   2691  400   0.1506   6.612
  9   14.5   541  80   0.1506   6.119
  10   14.8   104  17   0.1673   5.981
  11   15.9   815  67   0.0836   5.559
  12   16.3   501  74   0.1506   5.419
  13   17.0   1168  154   0.1338   5.210
  14   17.9   430  43   0.1004   4.962
  15   19.0   667  121   0.184   4.672
  16   19.8   527  104   0.2007   4.483
  17   20.2   726  144   0.2007   4.392
  18   20.5   282  28   0.1004   4.323
  19   21.1   2255  260   0.1171   4.208
  20   21.4   694  68   0.1004   4.147
  21   21.6   744  86   0.1171   4.111
  22   22.3   175  35   0.2007   3.987
  23   23.5   310  61   0.2007   3.784
  24   24.2   1635  270   0.1673   3.683
  25   24.5   1335  220   0.1673   3.625
  26   24.9   523  95   0.184   3.568
  27   25.5   657  130   0.2007   3.485
  28   26.0   933  154   0.1673   3.431
  29   26.4   1549  230   0.1506   3.380
  30   26.8   419  83   0.2007   3.323
  31   27.3   350  69   0.2007   3.267
  32   28.0   1108  146   0.1338   3.186
  33   29.1   144  19   0.1338   3.066
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γ-晶形：
其特征在于如下粉末X射线衍射图，所述衍射图使用PANalytical X’PertPro衍射仪与X’Celerator检测器测定，并根据谱线位置(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   4.2   1456  144   0.1004   20.762   2   6.9   125  99   0.8029   12.880   3   8.4   182  18   0.1004   10.503   4   10.7   240  32   0.1338   8.249   5   11.3   74  15   0.2007   7.858   6   12.0   644  64   0.1004   7.392   7   12.5   1476  219   0.1506   7.060   8   13.4   2691  400   0.1506   6.612   9   14.5   541  80   0.1506   6.119   10   14.8   104  17   0.1673   5.981   11   15.9   815  67   0.0836   5.559   12   16.3   501  74   0.1506   5.419
谱线号   2θ角(度)   高(计数)  面积(计数×度)   FWHM(度)   晶面间距(_)   13   17.0   1168  154   0.1338   5.210   14   17.9   430  43   0.1004   4.962   15   19.0   667  121   0.184   4.672   16   19.8   527  104   0.2007   4.483   17   20.2   726  144   0.2007   4.392   18   20.5   282  28   0.1004   4.323   19   21.1   2255  260   0.1171   4.208   20   21.4   694  68   0.1004   4.147   21   21.6   744  86   0.1171   4.111   22   22.3   175  35   0.2007   3.987   23   23.5   310  61   0.2007   3.784   24   24.2   1635  270   0.1673   3.683   25   24.5   1335  220   0.1673   3.625   26   24.9   523  95   0.184   3.568   27   25.5   657  130   0.2007   3.485   28   26.0   933  154   0.1673   3.431   29   26.4   1549  230   0.1506   3.380   30   26.8   419  83   0.2007   3.323   31   27.3   350  69   0.2007   3.267   32   28.0   1108  146   0.1338   3.186   33   29.1   144  19   0.1338   3.066
2.制备根据权利要求1的盐酸伊伐布雷定的γ-晶形的方法，其特征在于将盐酸伊伐布雷定和2-乙氧基乙醇的混合物、盐酸伊伐布雷定、2-乙氧基乙醇和水的混合物或盐酸伊伐布雷定、乙醇和水的混合物加热，直至溶解完全，然后冷却，直至结晶完全，并且通过过滤收集产物。
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γ-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γ-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γ-晶形在制备药物中的用途，所述药物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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