CN1827601A - 盐酸伊伐布雷定的γd－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γd－晶形、其制备方法和含有它的药物组合物 Download PDF

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CN1827601A
CN1827601A CNA200610058077XA CN200610058077A CN1827601A CN 1827601 A CN1827601 A CN 1827601A CN A200610058077X A CNA200610058077X A CN A200610058077XA CN 200610058077 A CN200610058077 A CN 200610058077A CN 1827601 A CN1827601 A CN 1827601A
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hydrochloric acid
crystalline form
acid ivabradine
counting
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S·霍瓦特
M-N·奥古斯特
G·达米安
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Laboratoires Servier SAS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Abstract

通式(I)的盐酸伊伐布雷定的γd－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γd-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γd-晶形、其制备方法和含有它的药物组合物：
Figure A20061005807700041
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γd-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   4.3   1077   124   0.1171   20.633
  2   6.9   132   70   0.5353   12.787
  3   8.4   269   35   0.1338   10.482
  4   10.6   322   26   0.0836   8.310
  5   11.9   733   97   0.1338   7.414
  6   12.5   1406   278   0.2007   7.069
  7   13.4   2975   442   0.1506   6.619
  8   14.4   825   122   0.1506   6.134
  9   15.8   1036   205   0.2007   5.598
  10   16.3   540   107   0.2007   5.450
  11   16.9   1007   183   0.184   5.233
  12   17.8   499   58   0.1171   4.978
  13   18.9   1062   140   0.1338   4.686
  14   19.8   570   85   0.1506   4.485
  15   20.2   549   63   0.1171   4.399
  16   20.9   2565   635   0.2509   4.241
谱线号   2θ角(度)   高(计数)   面积(计数×度)   FWHM(度)   晶面间距(_)
  17   21.6   531   105   0.2007   4.104
  18   22.3   213   35   0.1673   3.981
  19   23.4   278   27   0.1004   3.807
  20   24.1   1404   185   0.1338   3.694
  21   24.4   1526   176   0.1171   3.650
  22   24.8   676   100   0.1506   3.591
  23   25.4   702   139   0.2007   3.504
  24   26.2   1737   401   0.2342   3.403
  25   26.8   258   51   0.2007   3.331
  26   27.2   182   24   0.1338   3.282
  27   27.9   838   249   0.3011   3.193
  28   29.1   152   20   0.1338   3.071
本发明还涉及制备盐酸伊伐布雷定的γd-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，并且通过过滤收集获得的晶体并脱水。
·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γd-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γd-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，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γd-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   4.3   1077   124   0.1171   20.633
  2   6.9   132   70   0.5353   12.787
  3   8.4   269   35   0.1338   10.482
  4   10.6   322   26   0.0836   8.310
  5   11.9   733   97   0.1338   7.414
  6   12.5   1406   278   0.2007   7.069
  7   13.4   2975   442   0.1506   6.619
  8   14.4   825   122   0.1506   6.134
  9   15.8   1036   205   0.2007   5.598
  10   16.3   540   107   0.2007   5.450
  11   16.9   1007   183   0.184   5.233
  12   17.8   499   58   0.1171   4.978
  13   18.9   1062   140   0.1338   4.686
  14   19.8   570   85   0.1506   4.485
  15   20.2   549   63   0.1171   4.399
  16   20.9   2565   635   0.2509   4.241
  17   21.6   531   105   0.2007   4.104
  18   22.3   213   35   0.1673   3.981
  19   23.4   278   27   0.1004   3.807
  20   24.1   1404   185   0.1338   3.694
  21   24.4   1526   176   0.1171   3.650
  22   24.8   676   100   0.1506   3.591
  23   25.4   702   139   0.2007   3.504
  24   26.2   1737   401   0.2342   3.403
  25   26.8   258   51   0.2007   3.331
  26   27.2   182   24   0.1338   3.282
  27   27.9   838   249   0.3011   3.193
  28   29.1   152   20   0.1338   3.071
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γd-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   4.3   1077   124   0.1171   20.633   2   6.9   132   70   0.5353   12.787   3   8.4   269   35   0.1338   10.482   4   10.6   322   26   0.0836   8.310   5   11.9   733   97   0.1338   7.414   6   12.5   1406   278   0.2007   7.069   7   13.4   2975   442   0.1506   6.619   8   14.4   825   122   0.1506   6.134   9   15.8   1036   205   0.2007   5.598   10   16.3   540   107   0.2007   5.450   11   16.9   1007   183   0.184   5.233   12   17.8   499   58   0.1171   4.978   13   18.9   1062   140   0.1338   4.686
谱线号   2θ角(度)   高(计数)   面积(计数×度)   FWHM(度)   晶面间距(_)   14   19.8   570   85   0.1506   4.485   15   20.2   549   63   0.1171   4.399   16   20.9   2565   635   0.2509   4.241   17   21.6   531   105   0.2007   4.104   18   22.3   213   35   0.1673   3.981   19   23.4   278   27   0.1004   3.807   20   24.1   1404   185   0.1338   3.694   21   24.4   1526   176   0.1171   3.650   22   24.8   676   100   0.1506   3.591   23   25.4   702   139   0.2007   3.504   24   26.2   1737   401   0.2342   3.403   25   26.8   258   51   0.2007   3.331   26   27.2   182   24   0.1338   3.282   27   27.9   838   249   0.3011   3.193   28   29.1   152   20   0.1338   3.071
2.制备根据权利要求1的盐酸伊伐布雷定的γd-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，并且通过过滤收集获得的晶体并脱水。
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γd-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γd-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γd-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。
CNB200610058077XA 2005-02-28 2006-02-28 盐酸伊伐布雷定的γd-晶形、其制备方法和含有它的药物组合物 Active CN100432057C (zh)

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FR0501990A FR2882556B1 (fr) 2005-02-28 2005-02-28 Forme cristalline gamma d du chlorhydrate de l'ivabradine, son procede de preparation, et les compositions pharmaceutiques qui la contiennent
FR0501990 2005-02-28

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CN101353325B (zh) * 2007-07-27 2011-11-09 上海优拓医药科技有限公司 稳定型盐酸伊伐布雷定结晶及其制备方法
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

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