CN1536999B - 氟伐他汀钠的晶形 - Google Patents
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Abstract
发现了在下文中被称为C、D、E和F型多晶型物的氟伐他汀钠水合物的新晶形。此外，本发明涉及制备这些晶形的方法、制备高结晶的A型氟伐他汀钠的方法、以及包含这些晶形的药物组合物。
Description
本发明涉及氟伐它汀钠的新晶形、其制备方法以及含有这些晶形的药物组合物。
氟伐它汀钠是已知的，其化学名为(±)-7-(3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2-基)-3，5-二羟基-6-庚烯酸单钠盐。氟伐它汀钠是3R，5S-和3S，5R-二羟基对映异构体的外消旋混合物并具有下面的结构式：
氟伐它汀钠是3-羟基-3-甲基戊二酰辅酶A(HMG-CoA)的抑制剂并被用于降低血液胆固醇水平。
在US-A-4,739,073中公开了氟伐它汀以及其钠盐。在该专利中，氟伐它汀钠是通过冷冻干燥而获得的.WO-A-97/49681及其美国的等同专利US-A-6,124,340描述对氟伐它汀钠的冷冻干燥得到了被称为A型的晶形物质和无定形物质的混合物，还公开了一种称作B型的新晶形。如这些专利所述的那样通过冷冻干燥所获得的A型的估算量为约50％。B晶形或是通过包含A型物质的材料在有机溶剂和水的混合浆液中的转化获得的，或是通过从有机溶剂和水混合物中结晶而获得的。该专利还描述了B型的吸湿性低于氟伐他汀钠的A型或无定形形式，其改善了该化合物的处理和储存。但是，仍然需要一种吸湿性低于A型并可由水性溶液来获得的新晶形。
我们现在出人意料地发现，氟伐它汀钠可以被制备成具有改善的稳定性的新型结晶水合物，并且该新型结晶水合物可由水性溶液获得，不存在残留有机溶剂的风险。这些在这里被称为C、D、E和F型的新型结晶水合物更不易受空气湿度的影响并表现出高稳定性并且在正常的环境湿度水平下易于处理。氟伐他汀钠的该新晶形是水含量为3至32％的新型水合物。
因此，本发明提供了如下的氟伐他汀钠的新晶形：
一种表现出具有以d-值
表示的如下特征峰的特征性X-射线粉末衍射图的(±)-7-(3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2-基)-3，5-二羟基-6-庚烯酸单钠盐的结晶多晶型物，在这里被称为C型：
23.8(vs)，11.8(w)，7.8(vs)，7.6(vw)，7.4(vw)，6.4(vw)，6.1(vw)，5.90(w)，5.00(vw)，4.88(w)，4.73(m)，4.56(w)，4.40(vw)，4.12(vw)，4.03(vw)，3.96(vw)，3.50(vw)，3.36(vw)，2.93(vw)，在这里和下文中，括号中的缩写指的是：(vs)＝非常强的强度；(s)＝强的强度；(m)＝中等强度；(w)＝弱的强度；和(vw)＝非常弱的强度。图2描述了C型的特征性X-射线粉末衍射图。
一种表现出具有以d-值
表示的如下特征峰的特征性X-射线粉末衍射图的(±)-7-(3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2.-基)-3，5-二羟基-6-庚烯酸单钠盐的结晶多晶型物，在这里被称为D型：
24.6(vs)，12.5(w)，8.3(vs)，7.4(vw)，6.2(m)，4.97(w)，4.85(vw)，4.52(vw)，4.40(vw)，4.14(vw)，3.96(vw)，3.41(vw)，3.10(vw)，图3描述了D型的特征性X-射线粉末衍射图。
一种表现出具有以d-值
表示的如下特征峰的特征性X-射线粉末衍射图的(±)-7-(3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2-基)-3，5-二羟基-6-庚烯酸单钠盐的结晶多晶型物，在这里被称为E型：
27.6(m)，13.9(vw)，9.2(m)，8.5(vw)，8.1(vw)，7.4(vw)，6.9(s)，6.1(vw)，4.98(m)，4.77(m)，4.63(m)，4.15(w)，4.03(w)，3.97(vw)，3.52(vw)，3.33(vw)，3.08(vw)，2.99(vw)，图4描述了E型的特征性X-射线粉末衍射图。
一种表现出具有以d-值表示的如下特征峰的特征性X-射线粉末衍射图的(±)-7-(3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2-基)-3，5-二羟基-6-庚烯酸单钠盐的结晶多晶型物，在这里被称为F型：
29.6(w)，14.8(vw)，9.9(w)，8.6(vw)，8.3(vw)，7.4(s)，6.6(vw)，6.2(vw)，5.93(w)，5.03(m)，4.94(m)，4.35(vw)，4.23(w)，3.98(vw)，3.54(vw)，2.98(vw)，图5描述了F型的特征性X-射线粉末衍射图。
此外，本发明还涉及制备C、D、E、F型的方法。
C、D、E和F型可以按照将氟伐他汀钠与具有规定相对湿度的大气相接触的方法来进行制备。
氟伐它汀钠的C型一般可用结晶的A、D、E、F型或无定形的氟伐它汀钠、或其混合物来进行制备，例如可通过使其在约15至25％的相对湿度条件下进行平衡(例如6至24小时)来进行制备。估算的水含量通常为3-6％。
氟伐它汀钠的D型一般可以用结晶的A、C、E、F型或无定形的氟伐它汀钠、或其混合物来进行制备，例如可通过将其在约30至50％的相对湿度条件下进行平衡(例如6至24小时)来进行制备。估算的水含量通常为6-12％。
氟伐它汀钠的E型一般可以用结晶的A、C、D、F型或无定形的氟伐它汀钠、或其混合物来进行制备，例如可通过使其在约55至75％的相对湿度条件下进行平衡(例如几天)来进行制备。估算的水含量通常为15-22％。
氟伐它汀钠的F型一般可以用结晶的A、C、D、E型或无定形的氟伐它汀钠、或其混合物来进行制备，例如可通过使其在约80至90％的相对湿度条件下进行平衡(例如几天)来进行制备。估算的水含量通常为24-32％。
相对空气湿度的微小变化可能会造成X-射线粉末衍射图特征峰d-值的微小偏差。例如，在35％的相对湿度下制备的结晶D型氟伐它汀钠在24.6(vs)，12.5(w)，8.3(vs)和6.2(m)表现出以d-值表示的X-射线粉末衍射特征峰，而在50％的相对湿度下制备的样品在26.2(vs)，13.2(w)，8.9(vs)和6.7(m)表现出以d-值表示的X-射线粉末衍射特征峰，见图6。
因此，本发明还涉及(±)-7-(3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2-基)-3，5-二羟基-6-庚烯酸单钠盐的结晶多晶型物，其在X-射线粉末衍射图中以d-值表示的特征峰可具有范围为24.6-26.2(vs)、12.5-13.2(w)、8.3-8.9(vs)和6.2-6.7(m)的微小偏差，该偏差取决于35至50％的相对湿度，其中(vs)＝非常强的强度；(m)＝中等强度；(w)＝弱的强度。
本发明的另一个目的是含有有效量C、D、E或F型结晶多晶型以及可药用载体的药物组合物。
多晶型可以以单一组分或混合物的形式被使用。
对于包含氟伐他汀钠的药物组合物而言，以氟伐他汀钠的总量为基础，其优选地包含25-100％重量，尤其是50-100％重量的至少一种该新晶形。优选地，氟伐他汀钠该新型多晶型的量为75-100％重量，尤其是90-100％重量。十分优选的数量是95-100％重量。
下面的实施例对本发明进行了更详细的说明。所给的温度是摄氏度。
实施例2：C型多晶型的制备
将100mg氟伐它汀钠A样品在X-射线衍射计中在约20％相对湿度的条件下平衡12小时。这种相对湿度足以引起C型的结晶，见图2。
实施例3：D型多晶型的制备
将通过冷冻干燥获得的5克氟伐它汀钠样品在环境温度下在MgCl26H2O饱和溶液之上存放约12小时，即将其在约33％相对湿度条件下存放约12小时。所得的样品是晶状的并相应于D型氟伐他汀钠，见图3。
实施例4：E型多晶型的制备
将100mg氟伐它汀钠A样品在X-射线衍射计中在约65％的相对湿度条件下进行平衡。这种相对湿度足以引起E型的结晶，见图4。
实施例5：F型多晶型的制备
将100mg氟伐它汀钠A样品在X-射线衍射计中在约85％的相对湿度条件下进行平衡。这种相对湿度足以引起F型的结晶，见图5.
实施例6：
在正常的环境湿度条件下将0.5克A型氟伐它汀钠和0.5克D型氟伐它汀钠的混合物在研钵中进行合并，得到一种均匀的米白色粉末。X-射线粉末衍射测量表明该物质是结晶纯的D型氟伐他汀钠。
附图简要说明
图2是C型的特征性X-射线粉末衍射图。
图3是D型的特征性X-射线粉末衍射图。
图4是E型的特征性X-射线粉末衍射图。
图5是F型的特征性X-射线粉末衍射图。
图6表明在35和50％的相对空气湿度下测定的D型特征性X-射线粉末衍射图之间的微小偏差。
Claims (4)
1.一种表现出具有以d-值表示的如下特征峰的特征性X-射线粉末衍射图的(±)-7-(3-(4-氟苯基)-1-(1-甲基乙基)-1H-吲哚-2-基)-3，5-二羟基-6-庚烯酸单钠盐的结晶多晶型物：
24.6(vs)，12.5(w)，8.3(vs)，7.4(vw)，6.2(m)，4.97(w)，4.85(vw)，4.52(vw)，4.40(vw)，4.14(vw)，3.96(vw)，3.41(vw)，3.10(vs)，其中(vs)＝非常强的强度；(m)＝中等强度；(w)＝弱的强度；和(vw)＝非常弱的强度.
2.一种如权利要求1所述的结晶多晶型物的制备方法，其中将氟伐它汀钠与具有规定相对湿度30至50％的大气相接触.
3.如权利要求2所述的方法，用于制备如权利要求1所述的结晶多晶型物，其中所说的相对湿度为35至50％.
4.一种药用组合物，其含有有效量的如权利要求1所述的结晶多晶型物，和可药用载体.
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| Application Number | Priority Date | Filing Date | Title |
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| EP01810756.5 | 2001-08-03 | ||
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| PCT/EP2002/008276 WO2003013512A2 (en) | 2001-08-03 | 2002-07-25 | Crystalline forms of fluvastatin sodium |
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| AT (1) | ATE391502T1 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| ES2247193T3 (es) * | 2000-10-31 | 2006-03-01 | Ciba Specialty Chemicals Holding Inc. | Formas cristalinas del fluvastatin sodico. |
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- 2002-07-25 PL PL02366905A patent/PL366905A1/xx not_active Application Discontinuation
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- 2002-07-25 JP JP2003518521A patent/JP4681808B2/ja not_active Expired - Fee Related
- 2002-07-25 CN CN2011103995817A patent/CN102516150A/zh active Pending
- 2002-07-25 EP EP02794517A patent/EP1429757B8/en not_active Expired - Lifetime
- 2002-07-25 WO PCT/EP2002/008276 patent/WO2003013512A2/en active IP Right Grant
- 2002-07-25 ES ES02794517T patent/ES2304140T3/es not_active Expired - Lifetime
- 2002-07-25 CA CA002454072A patent/CA2454072A1/en not_active Abandoned
- 2002-07-25 AT AT02794517T patent/ATE391502T1/de not_active IP Right Cessation
- 2002-07-25 HU HU0401141A patent/HUP0401141A3/hu unknown
- 2002-07-25 RU RU2004106528/04A patent/RU2334738C2/ru not_active IP Right Cessation
- 2002-07-25 KR KR1020047001615A patent/KR100975782B1/ko not_active IP Right Cessation
- 2002-07-25 AU AU2002333271A patent/AU2002333271B2/en not_active Ceased
- 2002-07-25 IL IL15986102A patent/IL159861A0/xx active IP Right Grant
- 2002-07-30 US US10/208,687 patent/US6696479B2/en not_active Expired - Lifetime
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| US4739073A (en) * | 1983-11-04 | 1988-04-19 | Sandoz Pharmaceuticals Corp. | Intermediates in the synthesis of indole analogs of mevalonolactone and derivatives thereof |
| US6124340A (en) * | 1996-06-24 | 2000-09-26 | Astra Aktiebolag | Polymorphic compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2003013512A2 (en) | 2003-02-20 |
| EP1429757B8 (en) | 2008-07-16 |
| ES2304140T3 (es) | 2008-09-16 |
| HUP0401141A3 (en) | 2011-07-28 |
| KR100975782B1 (ko) | 2010-08-17 |
| US20030032666A1 (en) | 2003-02-13 |
| RU2004106528A (ru) | 2005-07-27 |
| DE60226044D1 (de) | 2008-05-21 |
| JP2010265308A (ja) | 2010-11-25 |
| WO2003013512A3 (en) | 2003-11-20 |
| AU2002333271B2 (en) | 2007-08-09 |
| IL159861A0 (en) | 2004-06-20 |
| JP4681808B2 (ja) | 2011-05-11 |
| CA2454072A1 (en) | 2003-02-20 |
| HUP0401141A2 (hu) | 2004-09-28 |
| RU2334738C2 (ru) | 2008-09-27 |
| EP1429757B1 (en) | 2008-04-09 |
| IL159861A (en) | 2009-02-11 |
| CN1536999A (zh) | 2004-10-13 |
| JP2005501838A (ja) | 2005-01-20 |
| ATE391502T1 (de) | 2008-04-15 |
| CN102516150A (zh) | 2012-06-27 |
| PL366905A1 (en) | 2005-02-07 |
| US6696479B2 (en) | 2004-02-24 |
| EP1429757A2 (en) | 2004-06-23 |
| DE60226044T2 (de) | 2009-05-14 |
| KR20040022226A (ko) | 2004-03-11 |
| AR036205A1 (es) | 2004-08-18 |
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