CN1827599A - 盐酸伊伐布雷定的βd－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βd－晶形、其制备方法和含有它的药物组合物 Download PDF

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CN1827599A
CN1827599A CNA2006100580746A CN200610058074A CN1827599A CN 1827599 A CN1827599 A CN 1827599A CN A2006100580746 A CNA2006100580746 A CN A2006100580746A CN 200610058074 A CN200610058074 A CN 200610058074A CN 1827599 A CN1827599 A CN 1827599A
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hydrochloric acid
crystalline form
acid ivabradine
ivabradine
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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βd－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βd-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βd-晶形、其制备方法和含有它的药物组合物：
Figure A20061005807400041
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中描述了用于合成伊伐布雷定及其盐酸盐的方法。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βd-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(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   4.0   244   80   0.3346   22.139
  2   5.9   377   56   0.1506   14.829
  3   6.9   94   50   0.5353   12.835
  4   9.2   1975   293   0.1506   9.623
  5   11.8   136   27   0.2007   7.473
  6   12.5   1826   241   0.1338   7.083
  7   13.6   1834   303   0.1673   6.491
  8   14.5   51   20   0.4015   6.119
  9   16.0   1441   214   0.1506   5.525
  10   17.3   4472   738   0.1673   5.134
  11   18.4   546   108   0.2007   4.808
  12   19.6   1025   169   0.1673   4.524
  13   20.0   688   91   0.1338   4.448
  14   20.4   1027   186   0.184   4.362
  15   21.4   102   24   0.2342   4.143
  16   22.3   1903   283   0.1506   3.990
  17   22.8   674   89   0.1338   3.897
  18   23.0   623   62   0.1004   3.866
  19   24.4   845   56   0.0669   3.647
  20   25.0   3749   557   0.1506   3.554
  21   25.5   512   84   0.1673   3.497
  22   26.6   289   76   0.2676   3.346
  23   28.3   275   91   0.3346   3.151
  24   29.1   126   21   0.1673   3.066
本发明还涉及制备盐酸伊伐布雷定的βd-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，并且收集由此形成的晶体并脱水。
·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βd-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βd-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EP 0534859中所述方法获得的250g盐酸伊伐布雷定，同时搅拌，并且将该混合物在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，首先冷却至40℃，然后冷却至环境温度。随后将该溶液在环境温度下贮存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。
通过以5℃/分钟的速率逐步加热至达80℃的温度，使由此获得的产物脱水。
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βd-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   4.0   244   80   0.3346   22.139
  2   5.9   377   56   0.1506   14.829
  3   6.9   94   50   0.5353   12.835
  4   9.2   1975   293   0.1506   9.623
  5   11.8   136   27   0.2007   7.473
  6   12.5   1826   241   0.1338   7.083
  7   13.6   1834   303   0.1673   6.491
  8   14.5   51   20   0.4015   6.119
  9   16.0   1441   214   0.1506   5.525
  10   17.3   4472   738   0.1673   5.134
  11   18.4   546   108   0.2007   4.808
  12   19.6   1025   169   0.1673   4.524
  13   20.0   688   91   0.1338   4.448
  14   20.4   1027   186   0.184   4.362
  15   21.4   102   24   0.2342   4.143
  16   22.3   1903   283   0.1506   3.990
  17   22.8   674   89   0.1338   3.897
  18   23.0   623   62   0.1004   3.866
  19   24.4   845   56   0.0669   3.647
  20   25.0   3749   557   0.1506   3.554
  21   25.5   512   84   0.1673   3.497
  22   26.6   289   76   0.2676   3.346
  23   28.3   275   91   0.3346   3.151
  24   29.1   126   21   0.1673   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βd-晶形：
Figure A2006100580740002C1
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   4.0   244   80   0.3346   22.139   2   5.9   377   56   0.1506   14.829   3   6.9   94   50   0.5353   12.835   4   9.2   1975   293   0.1506   9.623   5   11.8   136   27   0.2007   7.473   6   12.5   1826   241   0.1338   7.083   7   13.6   1834   303   0.1673   6.491   8   14.5   51   20   0.4015   6.119   9   16.0   1441   214   0.1506   5.525   10   17.3   4472   738   0.1673   5.134   11   18.4   546   108   0.2007   4.808   12   19.6   1025   169   0.1673   4.524   13   20.0   688   91   0.1338   4.448   14   20.4   1027   186   0.184   4.362   15   21.4   102   24   0.2342   4.143   16   22.3   1903   283   0.1506   3.990   17   22.8   674   89   0.1338   3.897   18   23.0   623   62   0.1004   3.866   19   24.4   845   56   0.0669   3.647   20   25.0   3749   557   0.1506   3.554   21   25.5   512   84   0.1673   3.497   22   26.6   289   76   0.2676   3.346   23   28.3   275   91   0.3346   3.151   24   29.1   126   21   0.1673   3.066
2.制备根据权利要求1的盐酸伊伐布雷定的βd-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，并且收集由此形成的晶体，然后脱水。
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βd-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βd-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βd-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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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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