CN100374422C - 匹伐他汀钙的晶形 - Google Patents
匹伐他汀钙的晶形 Download PDFInfo
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- CN100374422C CN100374422C CNB2004800039523A CN200480003952A CN100374422C CN 100374422 C CN100374422 C CN 100374422C CN B2004800039523 A CNB2004800039523 A CN B2004800039523A CN 200480003952 A CN200480003952 A CN 200480003952A CN 100374422 C CN100374422 C CN 100374422C
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- dihydroxyl
- fluorophenyl
- quinoline
- cyclopropyl
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
-
- 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
本发明涉及匹伐他汀半钙盐的新晶形,该新晶形以下称为多晶型物形态A,B,C,D,E和F,以及非晶态形态。另外,本发明涉及这些晶形和非晶态形态的制备方法以及包括这些晶形或非晶态形态的药物组合物。
Description
本发明涉及匹伐他汀钙的新晶形和非晶态形态,其制备方法和包括这些形态的药物组合物。
本发明涉及匹伐他汀钙的新晶形和非晶态形态。匹伐他汀也被称为NK-104、伊伐他汀和尼伐他汀(Nisvastatin)。匹伐他汀钙的化学名称为:(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐。匹伐他汀钙具有下式:
匹伐他汀钙近来由日本的Kowa Company Ltd开发为新的化学合成的和高效力的抑制素。在报导的数据基础上,匹伐他汀的效力是剂量依赖性的并显现为等同于阿托伐他汀。此新抑制素在治疗患有血胆固醇过多的患者中是安全的并且具有好的耐受性。可以认为与许多其它通常使用的药物的有效相互作用是极低的。
匹伐他汀的制备方法描述于EP-A-0304063和EP-A-1099694及N.Miyachi等人在Tetrahedron Letters(1993)vol.34,8267-8270页和K.Takahashi等人在Bull.Chem.Soc.Jpn.(1995)vol.6 8,2649-2656中的公开文献中。这些公开文献极详细地描述了匹伐他汀的合成但未描述匹伐他汀的半钙盐。L.A.Sorbera等人在Drugs ofthe Future(1998) vol.23,847-859页和M.Suzuki等人在Bioorganic & Medicinal Chemistry Letters(1999)vol.9,2977-2982页中的公开文献中描述了匹伐他汀钙,然而,未给出它制备的精确过程。匹伐他汀钙制备的完全合成过程描述于EP-A-0520406。在此专利描述的方法中,将匹伐他汀钙从水溶液沉淀,获得熔点为190-192℃的白色结晶材料。已知药物物质可显示多晶现象。多晶现象通常定义为任何物质具有两种或多种不同晶体结构的能力。当结晶时药物物质也可以包裹溶剂分子。这些溶剂化物或水合物称为假多晶型物。也可能遇到非晶态形态。不同的多晶型物、假多晶型物或非晶态形态的不同之处在于它们的物理性能如熔点、溶解度等。这些可明显影响药物性能如溶解速率和生物有效性。在经济上也需要产物对于延长的时间是稳定的而不需要专门的贮存条件。因此重要的是评价药物物质的多晶现象。另外,药物的新结晶多晶型物的发现扩大了材料的所有组成成分,使得制剂科学家必须采用该成分以设计具有目标释放特性或其它所需特征的药物制药剂型。我们现已惊奇地发现了匹伐他汀钙的新颖晶形,该新颖晶形在此记作形态A,B,C,D,E和F,以及匹伐他汀钙的非晶态形态。
因此,本发明涉及匹伐他汀钙盐的多晶型物形态A,B,C,D,E和F以及非晶态形态(2∶1)。
本发明的一个目的是(3R,5S)-7-[2-环丙基-4(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物,该结晶多晶型物在此记作形态A,它显示特征X射线粉末衍射图样,其特征峰以表1中给出的d-值()和2θ表示(vs=非常强烈的强度,s=强烈的强度,m=中等强度,w=弱的强度,vw=非常弱的强度)。
表1:形态A的d-间距和2θ角
d-间距[] | 角度[2θ] | 相对强度 |
17.6 | 5.0 | s |
13.0 | 6.8 | s |
9.7 | 9.1 | s |
8.8 | 10.0 | w |
8.4 | 10.5 | m |
8.1 | 11.0 | m |
6.7 | 13.3 | vw |
6.5 | 13.7 | s |
6.3 | 14.0 | w |
6.0 | 14.7 | w |
5.57 | 15.9 | vw |
5.25 | 16.9 | w |
5.17 | 17.1 | vw |
4.82 | 18.4 | m |
4.64 | 19.1 | w |
4.27 | 20.8 | vs |
4.20 | 21.1 | m |
4.10 | 21.6 | m |
3.87 | 22.9 | m |
3.74 | 23.7 | m |
3.67 | 24.2 | s |
3.53 | 25.2 | w |
3.29 | 27.1 | m |
3.02 | 29.6 | vw |
2.95 | 30.2 | w |
2.63 | 34.0 | w |
本发明的另一个目的是(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物,该结晶多晶型物在此记作形态B,它显示特征X射线粉末衍射图样,其特征峰以表2中给出的d-值()和2θ表示。
表2:形态B的d-间距和2θ角
d-间距[] | 角度[2θ] | 相对强度 |
19.0 | 4.6 | w |
16.6 | 5.3 | vs |
14.2 | 6.2 | s |
11.5 | 7.7 | s |
9.6 | 9.2 | m |
9.2 | 9.6 | m |
8.5 | 10.3 | w |
7.8 | 11.3 | m |
7.6 | 11.7 | w |
7.0 | 12.6 | vw |
6.8 | 13.0 | w |
6.4 | 13.9 | m |
6.0 | 14.7 | vw |
5.94 | 14.9 | w |
5.66 | 15.6 | w |
5.43 | 16.3 | m |
5.22 | 17.0 | vw |
5.10 | 17.4 | vw |
4.92 | 18.0 | w |
4.74 | 18.7 | m |
4.59 | 19.3 | m |
4.43 | 20.0 | s |
4.33 | 20.5 | w |
4.26 | 20.8 | m |
4.19 | 21.2 | w,肩峰 |
4.13 | 21.5 | m |
3.97 | 22.4 | m |
3.83 | 23.2 | s |
3.73 | 23.8 | m |
3.64 | 24.4 | vw |
3.53 | 25.2 | w,宽峰 |
3.42 | 26.0 | w |
3.37 | 26.4 | vw |
3.30 | 27.0 | w |
3.19 | 27.9 | vw |
3.09 | 28.9 | w |
本发明的另一个目的是(3R,5 S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物,该结晶多晶型物在此记作形态C,它显示特征X射线粉末衍射图样,其特征峰以表3中给出的d-值()和2θ表示。
表3:形态C的d-间距和2θ角
d-间距[] | 角度[2θ] | 相对强度 |
21.6 | 4.1 | m |
15.9 | 5.6 | s |
11.4 | 7.8 | m |
10.6 | 8.3 | m |
8.6 | 10.3 | m |
7.7 | 11.6 | w |
5.06 | 17.5 | w |
4.95 | 17.9 | w |
4.74 | 18.7 | m |
4.55 | 19.5 | s |
4.31 | 20.6 | m |
4.13 | 21.5 | vw |
4.06 | 21.9 | m |
3.84 | 23.1 | m |
3.71 | 24.0 | w |
3.58 | 24.8 | w |
本发明的另一个目的是(3R,5 S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物,该结晶多晶型物在此记作形态D,它显示特征X射线粉末衍射图样,其特征峰以表4中给出的d-值()和2θ表示。
表4:形态D的d-间距和2θ角
d-间距[] | 角度[2θ] | 相对强度 |
17.5 | 5.0 | m |
13.5 | 6.5 | m |
13.0 | 6.8 | s |
10.1 | 8.7 | m |
8.8 | 10.0 | m |
8.6 | 10.2 | m |
8.2 | 10.8 | m |
6.8 | 13.1 | w |
6.55 | 13.5 | m |
6.20 | 14.3 | s |
5.78 | 15.3 | vw |
5.52 | 16.1 | m |
5.28 | 16.8 | w |
4.87 | 18.2 | w |
4.80 | 18.5 | m |
4.66 | 19.0 | w |
4.46 | 19.9 | m |
4.34 | 20.5 | m |
4.23 | 21.0 | vs |
4.09 | 21.7 | s |
3.99 | 22.3 | w |
3.80 | 23.4 | m |
3.70 | 24.0 | m |
3.47 | 25.6 | w |
3.40 | 26.2 | m |
本发明的另一个目的是(3R,5 S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物,该结晶多晶型物在此记作形态E,它显示特征X射线粉末衍射图样,其特征峰以表5中给出的d-值()和2θ表示。
表5:形态E的d-间距和2θ角
d-间距[] | 角度[2θ] | 相对强度 |
20.0 | 4.4 | vw |
17.7 | 5.0 | s |
13.4 | 6.6 | s |
13.1 | 6.8 | s |
10.0 | 8.9 | s |
8.8 | 10.0 | m |
8.6 | 10.3 | s |
8.2 | 10.8 | m |
6.6 | 13.3 | s |
6.5 | 13.6 | m |
6.3 | 14.0 | s |
5.84 | 15.2 | vw |
5.56 | 15.9 | w |
5.39 | 16.4 | w |
5.24 | 16.9 | vw |
4.99 | 17.8 | vw |
4.84 | 18.3 | m |
4.69 | 18.9 | w |
4.39 | 20.2 | vs |
4.34 | 20.4 | m |
4.30 | 20.7 | m |
4.24 | 20.9 | m |
4.21 | 21.1 | vs |
4.12 | 21.6 | m |
4.08 | 21.7 | m |
3.99 | 22.3 | m |
3.77 | 23.5 | m |
3.73 | 23.8 | m |
3.69 | 24.1 | w |
3.60 | 24.7 | vw |
3.50 | 25.4 | vw |
3.35 | 26.6 | m |
2.96 | 30.2 | w |
2.64 | 34.0 | vw |
本发明的另一个目的是(3R,5 S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物,该结晶多晶型物在此记作形态F,它显示特征X射线粉末衍射图样,其特征峰以表6中给出的d-值()和2θ表示。
表6:形态F的d-间距和2θ角
d-间距[] | 角度[2θ] | 相对强度 |
17.2 | 5.1 | m |
15.8 | 5.6 | w |
12.6 | 7.0 | s |
10.0 | 8.8 | m |
9.2 | 9.6 | s |
8.7 | 10.2 | w |
8.1 | 10.9 | m |
7.8 | 11.3 | w |
7.4 | 11.9 | m |
7.1 | 12.5 | m |
6.8 | 13.0 | s |
6.5 | 13.7 | m |
6.2 | 14.4 | s |
6.04 | 14.7 | m |
5.79 | 15.3 | vw |
5.70 | 15.5 | w |
5.28 | 16.8 | m |
5.03 | 17.6 | w |
4.85 | 18.3 | m |
4.61 | 19.3 | m |
4.51 | 19.7 | m |
4.30 | 20.6 | m |
4.18 | 21.2 | vs |
4.08 | 21.8 | s |
3.90 | 22.8 | s |
3.84 | 23.1 | w |
3.74 | 23.8 | w,肩峰 |
3.69 | 24.1 | s |
3.59 | 24.8 | s |
3.46 | 25.7 | m |
3.40 | 26.2 | vw |
3.35 | 26.6 | m |
3.31 | 26.9 | w |
3.14 | 28.4 | w |
3.02 | 29.5 | w |
3.00 | 29.8 | vw |
2.89 | 30.9 | m |
试验细节的小变化可引起X射线粉末衍射图样中特征峰的d-值和2θ的小偏差。
本发明的另一个目的是(3R,5 S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的非晶态形态,它显示图7所示的特征X射线粉末衍射图样。
粉末X射线衍射在Philips 1710型粉末X射线衍射仪上使用Cuk(α1)辐射(1.54060)进行;采用±0.1-0.2°的试验误差记录2θ角。X射线粉末衍射图样的理论讨论可见于″X射线衍射过程(X-raydiffraction procedures)″,H.P.Klug和L.E.Alexander,J.Wiley,纽约(1974)。
另外,本发明涉及匹伐他汀钙的形态A,B,C,D,E和F及非晶态形态的制备方法。
形态A通常可以通过匹伐他汀钠与CaCl2在含水反应介质中的反应制备。或者,本发明的形态A也可以从游离酸((3R,5 S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸)或相应内酯与Ca(OH)2,有利地也在含水反应介质中原位获得。含水反应介质通常包含至少80%b.w.水;优选它是水或包含少量来自先前步骤的溶剂和/或反应物的水。形态A可包含至多15%的水,优选约3-12%,更优选9-11%的水。
形态B通常可以通过在包含水作为助溶剂的乙醇中悬浮形态A而制备。水的量优选是约1-50%。
形态C通常可以通过在包含水作为助溶剂的异丙醇中悬浮形态A而制备。水的量优选为约1-50%,特别为1-20%和更优选约5%。形态C也可以从包含水作为助溶剂的异丙醇和酮溶剂的混合物制备。优选,酮溶剂是丙酮,酮溶剂的量是约1-30%,更优选约10%。水的量优选为约1-20%,更优选约5%。
形态D通常可以通过在无水乙醇中悬浮形态A而制备。
形态E通常可以通过在包含水作为助溶剂的1,4-二烷中悬浮形态A而制备。水的量优选为约1-50%。
形态F通常可以通过在包含水作为助溶剂的甲醇中悬浮形态A而制备。水的量优选为约1-50%。
在上述方法中,可以将少量所需晶形的接种晶体加入到反应混合物中。优选少量是约1-20wt%,更优选约5wt%。接种晶体可以在引发结晶的步骤之前或,适当时在该步骤之后加入(例如冷却,加入上述非溶剂等)。在引发结晶之前加入在技术上特别令人感兴趣。
非晶态形态通常可以向匹伐他汀钙在有机溶剂中的浓溶液中加入非溶剂而制备。作为非溶剂可以采用例如庚烷或甲基叔丁基醚,而有机溶剂的例子是1,4-二烷、四氢呋喃和乙基甲基酮。优选非溶剂和溶剂可混溶。非晶态形态也可以由匹伐他汀钙水溶液的冷冻干燥而制备。
多晶型物形态A,B,C,D,E,F以及非晶态形态的制备通常在基本纯的反应体系中进行,该反应体系主要由优选以基本结晶形态的规定离析物,和以上给出的溶剂和/或非溶剂组成。
本发明的另一个目的是基本没有残余有机溶剂的匹伐他汀钙晶形的制备方法。
特别地,本发明涉及.通过将匹伐他汀钙晶形曝露于具有确定相对空气湿度的气氛,而制备基本没有残余有机溶剂的匹伐他汀钙晶形的方法。
更特别地,本发明涉及基本没有残余有机溶剂的任何匹伐他汀钙晶形或非晶态形态的制备方法。这些物质例如可以通过将晶形或非晶态形态曝露于相对空气湿度为5-100%的气氛中而制备。优选地,这些物质由如下方式制备:曝露于具有确定相对空气湿度的惰性气流中以便用水交换残余有机溶剂。通常,采用5-100%,特别地40-80%的相对空气湿度。
本发明的另一个目的是包括有效量的匹伐他汀钙结晶多晶型物形态A,B,C,D,E或F或非晶态形态和药用载体的药物组合物。
这些多晶型物可以作为单一组分或作为与其它晶形或非晶态形态的混合物使用。
关于匹伐他汀钙的新颖多晶型物和非晶态形态,基于匹伐他汀钙的总量计,优选这些形态包含25-100wt%,特别是50-100wt%至少一种新颖形态。优选地,匹伐他汀钙的新颖多晶型物或非晶态形态的这一数量是75-100wt%,特别是90-100wt%。高度优选95-100wt%。
本发明的组合物包括粉末、颗粒、聚集物和其它固体组合物,这些组合物包括至少一种新颖的形态。此外,在本发明考虑之列的组合物进一步包括稀释剂,如纤维素衍生的材料如粉末纤维素、微晶纤维素、微精细纤维素、甲基纤维素、乙基纤维素、羟乙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素盐及其它取代和未取代纤维素;淀粉;预胶凝淀粉;无机稀释剂如碳酸钙和二磷酸钙及制药工业已知的其它稀释剂。还有其它合适的稀释剂包括蜡、糖和糖醇如甘露糖醇和山梨糖醇、丙烯酸酯聚合物和共聚物、以及果胶、糊精和明胶。
在本发明考虑之列的另外赋形剂包括粘合剂,如阿拉伯胶、预胶凝淀粉、藻酸钠、葡萄糖及用于湿法和干法造粒以及直接压片工艺的其它粘合剂。也可以在固体组合物中存在的赋形剂进一步包括崩解剂如淀粉乙醇酸钠、聚乙烯聚吡咯烷酮、低取代羟丙基纤维素等。此外,赋形剂可包括压片润滑剂如硬脂酸镁和钙及硬脂基富马酸钠;香味剂;增甜剂;防腐剂;药用染料和助流剂如二氧化硅。
剂量包括适于口腔、面颊、直肠、胃肠外(包括皮下、肌内和静脉内)、吸入和眼给药的剂量。尽管在任何给定的情况下最合适的途径依赖于治疗的病症的性质和严重性,本发明的最优选途径是口服。剂量可以方便地以单位剂型存在并由制药领域公知的任何方法制备。
剂型包括固体剂型,如片剂、粉剂、胶囊剂、检剂、囊剂、糖锭剂和锭剂以及液体悬浮液和酏剂。尽管说明书不拟是限制性的,但本发明也不拟属于匹伐他汀钙的真溶液,由此损失区别于匹伐他汀钙固体形态的性能。然而,使用新颖形态制备这种溶液在本发明的考虑之列。
胶囊剂量,当然包含在胶囊中的固体组合物,该胶囊可以由明胶或其它常规包裹材料组成。片剂和粉剂可以是包衣的。片剂和粉剂可以由肠溶衣包衣。包肠溶衣的粉剂形态可具有包衣,该包衣包括邻苯二甲酸纤维素乙酸酯、羟丙基甲基-纤维素邻苯二甲酸酯、聚乙烯醇邻苯二甲酸酯、羧甲基乙基纤维素、苯乙烯和马来酸的共聚物、甲基丙烯酸和甲基丙烯酸甲酯的共聚物等材料,并且如果需要,它们可以与合适的增塑剂和/或增量剂一起使用。包衣的片剂可在片剂表面上具有包衣或可以是包括带有肠溶衣的粉末或颗粒的片剂。
本发明药物组合物的优选单位剂量典型地包含0.5-100mg新颖匹伐他汀钙形态或它们彼此或它们与其它形态匹伐他汀钙的混合物。更通常,单位剂量的匹伐他汀钙形态的结合重量是2.5mg-80mg,例如5、10、20或40mg。
如下实施例更详细说明本发明。温度以摄氏度给出。
实施例1:形态A的制备
将4.15gr的(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸叔丁酯(匹伐他汀叔丁酯)在52ml的甲基叔丁基醚和甲醇(10∶3)的混合物中悬浮。向此混合物中加入2.17ml 4M的NaOH水溶液,将获得的黄色溶液在50℃下搅拌2.5小时。将反应混合物冷却到室温,随后加入50ml水并再搅拌一小时。将水相分离,采用20ml甲基叔丁基醚萃取一次。在1小时内向此水溶液中加入0.58gr的CaCl2在80ml水中的溶液。将获得的悬浮液在室温下搅拌约16小时。过滤悬浮液,将获得的固体在40℃和50mbar下干燥约16小时。获得的产物是形态A,它的特征为图1所示的X射线粉末衍射图样。获得的形态A由与FT-IR光谱结合的热重分析的进一步表征揭示约10%的水含量。差示扫描量热法揭示95℃的熔点。
实施例2:形态B的制备
将100mg匹伐他汀钙形态A悬浮在2ml水中并在室温下搅拌30min,随后加入2ml乙醇并另外搅拌18小时。将悬浮液过滤和在空气中干燥,得到36mg形态B。获得的晶形B由图2所示的X射线粉末衍射图样表征。获得的形态B由与FT-IR光谱结合的热重分析的进一步表征揭示约10%的水含量。
实施例3:形态C的制备
将62mg匹伐他汀钙形态A悬浮在2ml包含5%水的异丙醇中。将此悬浮液加热到60℃,它导致形态A的几乎完全溶解,再次冷却到室温。在此温度下将悬浮液搅拌66小时。将获得的悬浮液过滤,采用一些包含5%水的异丙醇洗涤一次,并在空气中干燥。获得的晶形C由图3所示的X射线粉末衍射图样表征。获得的形态C由与FT-IR光谱结合的热重分析的进一步表征揭示样品包含约6.3%异丙醇和少量水。
实施例4:形态C的制备
将65mg匹伐他汀钙形态A悬浮在0.9ml异丙醇、0.1ml丙酮和40μl水的混合物中。搅拌此悬浮液约1小时导致几乎完全的溶解。采用4mg形态C(来自实施例3)接种并搅拌2小时导致浓悬浮液的形成。将此悬浮液采用相同数量的以上溶剂混合物稀释并再搅拌40小时。过滤悬浮液,将获得的固体在40℃下干燥约10min。由X射线粉末衍射的分析指示产物是由图3所示的晶形C。
实施例5:形态D的制备
将60mg匹伐他汀钙形态A悬浮在1ml无水乙醇中并在室温下搅拌20小时。将获得的悬浮液过滤并在空气中干燥。获得的晶形D由图4所示的X射线粉末衍射图样表征。
实施例6:形态E的制备
将60mg匹伐他汀钙形态A悬浮在1,4-二烷和水(1∶1)的混合物中,并在室温下搅拌18小时。将获得的悬浮液过滤和在空气中干燥。获得的晶形E由图5所示的X射线粉末衍射图样表征。
实施例7:形态F的制备
将60mg匹伐他汀钙形态A悬浮在3ml包含20%水的甲醇中,并在40℃下搅拌1小时。将获得的悬浮液缓慢冷却到室温和继续搅拌4小时。将悬浮液再次加热到40℃,搅拌30min,缓慢冷却到室温并另外搅拌15小时。过滤悬浮液和在空气中干燥获得的白色固体。获得的晶形F由图6所示的X射线粉末衍射图样表征。
实施例8:非晶态形态的制备
将62mg匹伐他汀钙形态A溶于0.3ml 1,4-二烷中。向此搅拌的溶液中在室温下缓慢加入2.3ml正庚烷,并再搅拌16小时。将获得的悬浮液过滤并在空气中干燥。获得的固体是非晶态的,如由图7(顶部)中给出的X射线衍射图样所示。
实施例9:非晶态形态的制备
将60mg匹伐他汀钙形态A溶于1.5ml乙基甲基酮中。向此溶液中按每30sec 1ml的步幅加入总计21ml甲基叔丁基醚。将获得的悬浮液在室温下搅拌约16小时。过滤悬浮液和在空气中干燥获得的固体。对产物的X射线衍射研究显示它是非晶态的,参见图7(底部)。获得的产物由与FT-IR光谱结合的热重分析的进一步表征揭示样品包含约5.5%甲基叔丁基醚。差示扫描量热法显示样品的玻璃化转变温度为约68℃。
附图简述
图1是形态A的特征X射线粉末衍射图样。
图2是形态B的特征X射线粉末衍射图样。
图3是形态C的两个特征X射线粉末衍射图样。
图4是形态D的特征X射线粉末衍射图样。
图5是形态E的特征X射线粉末衍射图样。
图6是形态F的特征X射线粉末衍射图样。
图7是非晶态形态的两个特征X射线粉末衍射图样。
Claims (28)
1.(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物A,它显示特征峰以如下2θ表达的特征X射线粉末衍射图样:5.0(s),6.8(s),9.1(s),10.0(w),10.5(m),11.0(m),13.3(vw),13.7(s),14.0(w),14.7(w),15.9(vw),16.9(w),17.1(vw),18.4(m),19.1(w),20.8(vs),21.1(m),21.6(m),22.9(m),23.7(m),24.2(s),25.2(w),27.1(m),29.6(vw),30.2(w),34.0(w);其中(vs)表示非常强烈的强度;(s)表示强烈的强度;(m)表示中等强度;(w)表示弱的强度;(vw)表示非常弱的强度。
2.(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物A,其具有基本如图1所示的X射线粉末衍射图样。
3.(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物B,它显示特征峰以如下2θ表达的特征X射线粉末衍射图样:4.6(w),5.3(vs),6.2(s),7.7(s),9.2(m),9.6(m),10.3(w),11.3(m),11.7(w),12.6(vw),13.0(w),13.9(m),14.7(vw),14.9(w),15.6(w),16.3(m),17.0(vw),17.4(vw),18.0(w),18.7(m),19.3(m),20.0(s),20.5(w),20.8(m),21.2(w,肩峰),21.5(m),22.4(m),23.2(s),23.8(m),24.4(vw),25.2(w,宽峰),26.0(w),26.4(vw),27.0(w),27.9(vw),28.9(w);其中(vs)表示非常强烈的强度;(s)表示强烈的强度;(m)表示中等强度;(w)表示弱的强度;(vw)表示非常弱的强度。
4.(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物B,其具有基本如图2所示的X射线粉末衍射图样。
5.(3R,5S)-7-[2-环丙基-4(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物C,它显示特征峰以如下2θ表达的特征X射线粉末衍射图样:4.1(m),5.6(s),7.8(m),8.3(m),10.3(m),11.6(w),17.5(w),17.9(w),18.7(m),19.5(s),20.6(m),21.5(vw),21.9(m),23.1(m),24.0(w),24.8(w);其中(s)表示强烈的强度;(m)表示中等强度;(w)表示弱的强度;(vw)表示非常弱的强度。
6.(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物C,其具有基本如图3所示的X射线粉末衍射图样。
7.(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物D,它显示特征峰以如下2θ表达的特征X射线粉末衍射图样:5.0(m),6.5(m),6.8(s),8.7(m),10.0(m),10.2(m),10.8(m),13.1(w),13.5(m),14.3(s),15.3(vw),16.1(m),16.8(w),18.2(w),18.5(m),19.0(w),19.9(m),20.5(m),21.0(vs),21.7(s),22.3(w),23.4(m),24.0(m),25.6(w),26.2(m);其中(vs)表示非常强烈的强度;(s)表示强烈的强度;(m)表示中等强度;(w)表示弱的强度;(vw)表示非常弱的强度。
8.(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物D,其具有基本如图4所示的X射线粉末衍射图样。
9.(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物E,它显示特征峰以如下2θ表达的特征X射线粉末衍射图样:4.4(vw),5.0(s),6.6(s),6.8(s),8.9(s),10.0(m),10.3(s),10.8(m),13.3(s),13.6(m),14.0(s),15.2(vw),15.9(w),16.4(w),16.9(vw),17.8(vw),18.3(m),18.9(w),20.2(vs),20.4(m),20.7(m),20.9(m),21.1(vs),21.6(m),21.7(m),22.3(m),23.5(m),23.8(m),24.1(w),24.7(vw),25.4(vw),26.6(m),30.2(w),34.0(vw);其中(vs)表示非常强烈的强度;(s)表示强烈的强度;(m)表示中等强度;(w)表示弱的强度;(vw)表示非常弱的强度。
10.(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物E,其具有基本如图5所示的X射线粉末衍射图样。
11.(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物F,它显示特征峰以如下2θ表达的特征X射线粉末衍射图样:5.1(m),5.6(w),7.0(s),8.8(m),9.6(s),10.2(w),10.9(m),11.3(w),11.9(m),12.5(m),13.0(s),13.7(m),14.4(s),14.7(m),15.3(vw),15.5(w),16.8(m),17.6(w),18.3(m),19.3(m),19.7(m),20.6(m),21.2(vs),21.8(s),22.8(s),23.1(w),23.8(w,肩峰),24.1(s),24.8(s),25.7(m),26.2(vw),26.6(m),26.9(w),28.4(w),29.5(w),29.8(vw),30.9(m);其中(vs)表示非常强烈的强度;(s)表示强烈的强度;(m)表示中等强度;(w)表示弱的强度;(vw)表示非常弱的强度。
12.(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐的结晶多晶型物F,其具有基本如图6所示的X射线粉末衍射图样。
13.制备权利要求3或4的结晶多晶型物的方法,该方法包括在包含水作为助溶剂的乙醇中悬浮权利要求1或2的结晶多晶型物。
14.权利要求13的方法,其中水的量是(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐悬浮液的1-50体积%。
15.制备权利要求5或6的结晶多晶型物的方法,该方法包括在包含水作为助溶剂的异丙醇中悬浮权利要求1或2的结晶多晶型物。
16.权利要求15的方法,其中水的量是(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐悬浮液的1-50体积%。
17.制备权利要求5或6的结晶多晶型物的方法,该方法包括在包含水作为助溶剂的异丙醇和酮溶剂的混合物中悬浮权利要求1或2的结晶多晶型物。
18.权利要求17的方法,其中酮溶剂是丙酮。
19.权利要求17或18的方法,其中酮溶剂的量是(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐悬浮液的1-30体积%。
20.权利要求17或18的方法,其中水的量是(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐悬浮液的1-20体积%。
21.制备权利要求7或8的结晶多晶型物的方法,该方法包括在无水乙醇中悬浮权利要求1或2的结晶多晶型物。
22.制备权利要求9或10的结晶多晶型物的方法,该方法包括在包含水作为助溶剂的1,4-二烷中悬浮权利要求1或2的结晶多晶型物。
23.权利要求22的方法,其中水的量是(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐悬浮液的1-50体积%。
24.制备权利要求9或10的结晶多晶型物的方法,该方法包括在包含水作为助溶剂的甲醇中悬浮权利要求1或2的结晶多晶型物。
25.权利要求24的方法,其中水的量是(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐悬浮液的1-50体积%。
26.权利要求13、15、17、21、22、24中任意-项的方法,其中将(3R,5S)-7-[2-环丙基-4-(4-氟苯基)喹啉-3-基]-3,5-二羟基-6(E)-庚酸半钙盐通过过滤分离并在空气或真空中干燥。
27.根据权利要求13、15、17、21、22、24中任意一项的方法,其中采用所需结晶多晶型物的晶体进行接种。
28.一种药物组合物,它包括有效量的权利要求1-12之一的结晶多晶型物形态,和可药用载体。
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