CN1469863A - 1-[6-氯-5-(三氟甲基)-2-吡啶基]哌嗪盐酸盐的晶形 - Google Patents
1-[6-氯-5-(三氟甲基)-2-吡啶基]哌嗪盐酸盐的晶形 Download PDFInfo
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Abstract
本发明涉及1－[6－氯－5－(三氟甲基)－2－吡啶基]哌嗪盐酸盐(Org12962)的晶形A和B，涉及制备这些晶形的方法，还涉及含有晶形B的药物组合物。
Description
本发明涉及1-[6-氯-5-(三氟甲基)-2-吡啶基]哌嗪盐酸盐的新晶形A和B，涉及制备这些晶形的方法，并且涉及含有晶形B的药物组合物。
从欧洲专利370560(Akzo Nobel N.V.)中已知被称为Org 12962的1-[6-氯-5-(三氟甲基)-2-吡啶基]哌嗪盐酸盐，据描述，它可用于治疗中枢神经***紊乱，特别是抑郁症(Leysen，D.C.M.IDrugs，
2，109-120，1999)和焦虑症(Leysen，D.and Kelder，J.Trends in Drug Research II，49-61，1998 Elsevier Science B.V.，Ed.H.van dergroot)。另外，该化合物可能用于治疗小便失禁(WO9833504：Akzo Nobel N.V.)。EP370560中(表I，3号化合物)描述了Org 12962，其被描述为缺少明确熔点的化合物。对于该化合物的外形没有教导。
现已发现，根据EP370560中所述方法制备的该化合物是多晶形的，是由两种纯晶形的混合物组成。
一般希望制备组成均一且确定的药剂。就多晶形化合物而言，期望它们的生物活性与组成该多晶形化合物的纯晶形晶体的生物活性可比较，或与之相同。然而，如果将该多晶形化合物用作药物，则与它的各纯晶形组分相比较，其具有很大缺陷。晶体结构不同能导致物理化学参数不同，如稳定性、溶解速度、生物有效度、分析数据等不同，所述物理化学参数常常受多晶形化合物中各晶形的强烈影响。这一点格外重要，因为实际上不可能使每批多晶形化合物的组成完全相同。由于这些不同，通常认为在药物中包含多晶形化合物是可理解的，有时要求仅仅使用该多晶形化合物中的一种纯晶形组分。
本发明的目的是，提供基本上纯晶形的化合物Org 12962，其完全或几乎完全不含其它晶形。
术语“完全或几乎完全不含其它晶形的纯晶形”是指含有少于10％、优选少于5％其它晶形的晶形。
本发明的一个方面是，通过使用特定的结晶方法从多晶形化合物Org 12962中获得的三种纯晶形，将它们标志为晶形A、晶形B和晶形C。
进一步发现，Org 12962的晶形B是热力学最稳定的晶形。此外，当与各种药物助剂形成混合物(特别是含有乳糖和/或玉米淀粉的混合物)而保存在黑暗中时，晶形B比晶形A更稳定。因此，本发明的另一个方面涉及提供固体Org 12962的药物制剂，其含有纯晶形B的Org12962。这类药物组合物具有以下优点：可复现性相当可观地增大；在可接受限值内的物理数据总是相同。
通过用盐酸处理1-[6-氯-5-(三氟甲基)-2-吡啶基]哌嗪的游离碱在乙醇中的溶液，随后采用EP370560所述的一般程序来制备Org 12962时，得到非晶形产物或多晶形产物，其中晶形A和晶形B数量的比例在批次与批次间差别很大。
可以通过将1-[6-氯-5-(三氟甲基)-2-吡啶基]哌嗪的盐酸盐在控制条件下从乙醇或乙醇-水混合物中结晶来制备纯晶形A和B。
可以通过将盐酸盐在乙醇/水混合物中的浓溶液快速从回流温度冷却到0℃以下，并且在0℃以下的温度引发成核作用(冷却结晶法)来制备纯晶形A。可以通过例如将结晶烧瓶放入冰-丙酮(约-10℃)中来进行快速冷却。
可以通过以下方法制备纯晶形B：用过量(高达5当量)的盐酸在回流温度下处理游离碱1-[6-氯-5(三氟甲基)-2-吡啶基]哌嗪在乙醇(或乙醇-水)中的溶液，借此在回流温度下引发成核作用，随后将该结晶盐慢慢冷却至环境温度(反应结晶)。
还可以通过搅拌多晶形的Org 12962批料在乙醇/水混合物中的悬浮液，直到完全转化为晶形B，来制备热力学最稳定的晶形B。在室温下进行这种过程时需要好几天[例如：在20℃下将乙醇-水(3∶1)中的20克批料完全转化要用96小时]。在一个优选实施方案中，将悬浮液在回流温度下搅拌，这样在数小时内完全转化为晶形B[例如：在回流温度下将乙醇-水(3∶1)中的1克批料完全转化要用3小时]。
通过将化合物Org 12962从2-甲基丁-2-醇中结晶可以得到Org12962的第三种晶形。晶形C是一种亚稳定晶形，它甚至在-20℃下也会自发地转化为晶形B。
晶形A和B的熔点没有很大不同。这两种纯晶形都在282-284℃间熔融。
本发明的各晶形可用它们的X射线粉末衍射图案以及它们的拉曼光谱来表征，从而彼此相区别。
图1显示了Org 12962的晶形A和B的XRPD光谱。每一个光谱都用衍射角2θ的某些具体值处的强度峰值来表征。晶形A的特征峰值在2θ＝17.50°、17.80°、23.85°、24.50°、25.55°、27.75°和29.40°处。
晶形B的特征峰值在2θ＝20.40°、21.05°、24.80°、25.80°和28.10°处。
对晶形B的单晶进行X射线分析，可确认该结晶的空间群是P21/c，单斜晶，晶胞尺寸为a＝12.848、b＝7.151、c＝14.164、β＝104.85°，以及V＝1257.93。
对晶形A的类似分析显示，该结晶是斜方晶，空间群是Pca21，晶胞尺寸：a＝13.823、b＝7.226、c＝25.256，以及V＝2522.703。
图2显示了晶形A和B的FT拉曼光谱。各个晶形都具有特征吸收峰，如表I所示。这些峰值可用于定量测定纯晶形B中晶形A的量以及纯晶形A中晶形B的量。
表I：Org 12962各晶形的拉曼光谱中的特征吸收峰
| 晶形A(cm-1) | 晶形B(cm-1) | 晶形C(cm-1) |
| 82.2 | 104.6 | 187.1 |
| 106.6 | 147.7 | 209.3 |
| 194.7 | 192.8 | 247.3 |
| 211.2 | 209.5 | 345.4 |
| 356.5 | 360.6 | 459.3 |
| 1037.6 | 1035.9 | 680.1 |
| 1268.2 | 1265.3 | 1058.8 |
| 2997.0 | 2997.1 | 1151.1 |
| 3006.5 | 3001.8 | 2853.4 |
| 3122.4 | 3117.2 | 2998.1 |
| 3105.4 |
本发明的固体Org 12962的药物制剂包含纯晶形B的Org 12962，以及一种或多种药学可接受的添加剂或赋形剂。
这种药物制剂一般采用如片剂、胶囊剂或栓剂的剂量单元形式，不过也包括其它固体或干燥药物制剂形式。优选的药物制剂是片剂形式。除了有效成分—纯晶形B的Org 12962之外，片剂还可以包含某些赋形剂，如稀释剂、粘合剂、助滑剂(glidant)和润滑剂，用它们赋予该片剂令人满意的工艺特性和压缩特性；还可包含崩解剂和增香剂，用它们赋予成品片剂额外的所希望的物理特性。
制造这种剂量单元的方法为大家所熟知，例如标准技术，如标准参考文献中所述的那些方法，Gennaro等人，Remington′s PharmaceuticalSciences(第18版，Mack Publishing Company，特别是第8部分：Pharmaceutical Preparations and TheirmAnufacture)。
适用于治疗抑郁症、焦虑症、肥胖症或小便失禁的Org 12962的剂量单元可以包含约5-500mg的有效成份，更通常为约10-100mg。优选的剂量单元可以包含20-40mg晶形B的Org 12962，每天服用两次。
用以下实施例举例说明本发明。
实施例
一般程序：
用Siemens D5000透射衍射仪获得X射线粉末衍射(XRPD)光谱，所述衍射仪带有初级锗单色仪，Cu-Kα1辐射，设定在35kV和40mA。使用的狭缝：抗分散狭缝2mm，探测器狭缝0.2mm。测量条件：步长0.02°，每步时间10秒。在Scotch带中间测量样品，在测量过程中以15rpm的速度旋转。在图1中描述了纯晶形A和B的XRPD光谱。
使用Bruker RFS 100拉曼光谱仪记录FT-拉曼光谱，所述拉曼光谱仪装有1064nm的Nd-YAG激光(Adlas型DPY 421 N)。使用200mW的激光功率，2cm-1的分辨率测定光谱。一般地，每个光谱收集256个干涉图样。在样品位置，激光光点直径为大约30μ。图2描述了晶形A和B的拉曼光谱。
实施例1
制备Org 12962
A：制备1-[6-氯-5-(三氟甲基)-2-吡啶基]哌嗪
将哌嗪(10337g；120摩尔)溶于95％的含水乙醇(36升)中。将该溶液回流加热，之后在2小时内向其中加入2，6-二氯-3-(三氟甲基)吡啶(8640g；40摩尔)在95％的含水乙醇(9升)中的溶液。再保持回流2小时。将混合物冷却至环境温度，并且通过过滤除去沉淀的哌嗪盐酸盐。在真空下除去乙醇。将残余物溶于乙酸乙酯(30升)。用水(15升)洗涤这一溶液两次，在硫酸镁上干燥，之后在真空下除去溶剂。将残余物倒入水(15升)中，同时搅拌。滤出得到的固体，并用水充分洗涤。
B：1-[6-氯-5-(三氟甲基)-2-吡啶基]哌嗪盐酸盐[Org 12962]
将A中所述润湿的固体溶于96％的含水乙醇(12升)中。过滤溶液一次，以除去一些不溶性物质。用96％的含水乙醇(15升)稀释滤液，之后将氯化氢气体通过该溶液。在成盐过程中将温度上升至回流温度。冷却至0℃后滤出沉淀物，得到粗品(7600g)，将粗品在加热的同时再溶入96％的含水乙醇(11升)和水(2.7升)中。在环境温度下冷却后滤出盐酸盐，用冷乙醇(4升)洗涤，在110℃下真空干燥，得到Org 12962(5500g；45.5％)。
拉曼光谱显示，这一产物由晶形A(77％)和晶形B(23％)的混合物组成。
元素分析：
C10H12N3Cl2F3的计算值(％)：C：39.75；H：4.01；N：13.91
实测值(％)：C：39.81；H：4.07；N：13.85
1H-Nmr(300MHz，在DMSOd6中)：δ(ppm)：3.26(4H；三重峰，J＝5.3Hz)；3.99(4H；三重峰，J＝5.3Hz)；7.08(1H；双峰，J＝9.0Hz)；8.04(1H；双峰，J＝9.0Hz)；9.76(2H；宽单峰：N-H，HCl)。
实施例2
制备纯晶形A的Org 12962
将Org 12962(35克)在96％的含水乙醇(1升)中的溶液在冰/丙酮浴中迅速从回流温度冷却至-10℃，同时用磁性搅拌棒搅拌。在零下的温度自发地发生成核作用。将该混合物在-10℃下搅拌2小时后滤出晶体物质，用少量冷乙醇洗涤并且在室温下真空干燥。
实施例3
制备纯晶形B的Org 12962
将如实施例1中所述而制备的多晶形Org 12962(10kg)溶于乙醇(80升)和水(11升)的混合物中。将该溶液加热到回流温度，在此温度下蒸除溶剂，直到混合物的体积减少到大约15升，开始结晶。将得到的混合物在回流温度下保持5小时，之后将该溶液以17℃/小时的冷却率慢慢冷却至2±2℃。滤出晶体物质，用乙醇(4升)洗涤，然后在60℃下真空干燥24小时。
实施例4
晶形A和B在含赋形剂的混合物中的稳定性
将晶形A的Org 12962(5-10mg)(如实施例2所述制备的批料，其含92％的晶形A和8％的晶形B)的等分样品称重，放入数个圆底试管中。将表II中提到的赋形剂加入每个等分样品，随后加入10μl的水，之后充分混合该悬浮液。
将晶形B的Org 12962(5-10mg)(100％的晶形B)的等分样品称重，放入数个圆底试管中。将表II中提到的赋形剂加入每个等分样品，随后加入100μl的水。将玻璃珠(250-300mg)加入每个试管，之后将样品充分混合1分钟。在室温下真空蒸发剩余的水。
在20℃或60℃下将这些试管保存在黑暗中14天。
将样品溶于20.0ml的70∶30的25mM的pH值2.6的磷酸盐缓冲剂和乙腈混合物中。将这些试管放在超声波仪中20分钟，完成溶解。
使用以下任何一个有效的方法，用高效液相色谱法(hplc)来定量分析每个试管中Org 12962的量：(1)使用Symmetry Shield Reverse PhaseRP 18柱(150×4.6mm)，在40℃下操作，使用1.0毫升/分钟的流速，洗脱剂为25mM的pH值2.6的磷酸盐缓冲剂(也包含15mM的辛烷磺酸)和乙腈的69∶31(v/v)的混合物，或者(2)使用Lichrospher 60 RP Select B柱(125×4.0mm)，在环境温度下操作，使用1.5毫升/分钟的流速，洗脱剂为甲醇和水(也包含5mM的辛烷磺酸)的55∶45(v/v)的混合物。表II中给出了贮存后样品中剩余的Org 12962的量，按初始量的百分比(％)计。
表II在含赋形剂的混合物中Org 12962的稳定性
贮存条件
14天20℃/黑暗 14天60℃/黑暗
| I | II | I | II | |
| 赋形剂 | ％ | ％ | ％ | ％ |
| 乳糖(80mg)* | 94.5 | 99.6 | 91.2 | 97.4 |
| HPC(2mg) | 98.0 | 100.0 | n.d. | 96.5 |
| 玉米淀粉(10mg) | 100.0 | 100.1 | 82.6 | 97.9 |
| 硬脂酸镁(0.5mg) | 97.9 | 99.9 | 93.8 | 97.9 |
| Primojel(4mg) | 95.0 | 100.0 | 94.6 | 96.0 |
| 滑石(0.3mg) | 99.2 | 99.9 | 94.5 | 100.1 |
| 二氧化钛(0.2mg) | 96.0 | 99.8 | 97.5 | 92.9 |
| HPMC(1.3mg) | 95.0 | 100.0 | 91.8 | 97.8 |
| PEG 400(0.3mg) | 96.5 | 99.8 | 92.5 | 96.3 |
I：晶体Org 12962：92％的晶形A和8％的晶形B；
II：晶体Org 12962：100％的晶形B；
*：括号中列出的是加入5.0mg Org 12962的赋形剂的量(单位：mg)
HPC：羟丙基纤维素
HPMC：羟丙基甲基纤维素
PEG：聚乙二醇
表II中的数据显示，含有药物赋形剂的混合物中的Org 12962为纯晶形B时比为纯晶形A时更稳定。贮存在60℃的应激条件下时，在含乳糖、玉米淀粉、Org 12962药物制剂的两种主要组分的混合物中，纯晶形B的改善的稳定性特别显著。
实施例5
含有纯晶形B的Org 12962的药物制剂
制备具有以下组成的Org 12962片剂：
| 成分 | Mg | Mg |
| 晶形B的Org 12962 | 10.0 | 100.0 |
| 羟丙基纤维素(HPC) | 4.0 | 8.0 |
| 玉米淀粉 | 20.0 | 40.0 |
| 胶体二氧化硅 | 3.0 | 6.00 |
| 硬脂酸镁 | 1.0 | 2.0 |
| 乳糖200M，至片剂总重 | 200 | 400 |
将Org 12962与填充剂乳糖和崩解剂玉米淀粉混合均匀，以低剪切操作方式用粘合剂羟丙基纤维素的胶浆将得到的混合物粒化。筛选湿润的物质，在流化床中干燥，再次筛选，最终与胶体二氧化硅和润滑剂硬脂酸镁混合。将得到的颗粒压缩成片剂核芯。
Claims (9)
1.化合物1-[6-氯-5-(三氟甲基)-2-吡啶基]哌嗪盐酸盐(Org 12962)，其特征在于该化合物是纯晶形的，其完全或几乎完全不含其它晶形。
2.权利要求1的化合物，其具有纯晶形A，其特征在于其用CuKα1辐射得到的X射线粉末衍射图案在2θ分别为17.50°、17.80°、23.85°、24.50°、25.55°、27.75°和29.40°的各值处有峰值，而且其拉曼吸收光谱在82.2cm-1、106.6cm-1、194.7cm-1、211.2cm-1、356.5cm-1、1037.6cm-1、1268.2cm-1、2997.0cm-1、3006.5cm-1和3122.4cm-1处有峰值。
3.权利要求1的化合物，其具有纯晶形B，其特征在于其用CuKα1辐射得到的X射线粉末衍射图案在2θ分别为20.40°、21.05°、24.80°、25.80°和28.10°的各值处有峰值，而且其拉曼吸收光谱在104.6cm-1、147.7cm-1、192.8cm-1、209.5cm-1、360.6cm-1、1035.9cm-1、1265.3cm-1、2997.1cm-1、3001.8cm-1和3117.2cm-1处有峰值。
4.权利要求2的化合物的制备方法，其特征在于将1-[6-氯-5-(三氟甲基)-2-吡啶基]哌嗪盐酸盐在乙醇/水混合物中的浓溶液迅速冷却至0℃以下，之后引发自发成核。
5.权利要求3的化合物的制备方法，其特征在于在回流温度下用过量的盐酸对1-[6-氯-5-(三氟甲基)-2-吡啶基]哌嗪在乙醇-水溶液中的浓溶液进行处理，借此在回流温度下引发成核作用，之后将该溶液慢慢冷却至环境温度。
6.权利要求3的化合物的制备方法，其特征在于将多晶形的1-[6-氯-5-(三氟甲基)-2-吡啶基]哌嗪盐酸盐在乙醇/水混合物中的悬浮液静置，直到完全转化为晶形B。
7.权利要求6的方法，其中将所述悬浮液保持在回流温度下。
8.含有药学可接受的赋形剂和Org 12962的药物组合物，其特征在于Org 12962基本上都是纯晶形B，其用CuKα1辐射得到的X射线粉末衍射图案在2θ分别为20.40°、21.05°、24.80°、25.80°和28.10°的各值处有峰值，而且其拉曼吸收光谱在104.6cm-1、147.7cm-1、192.8cm-1、209.5cm-1、360.6cm-1、1035.9cm-1、1265.3cm-1、2997.1cm-1、3001.8cm-1和3117.2cm-1处有峰值。
9.治疗哺乳动物的抑郁症、焦虑症、肥胖症或小便失禁的方法，该方法包括用治疗有效量的权利要求3的纯晶形B的1-[6-氯-5-(三氟甲基)-2-吡啶基]哌嗪盐酸盐进行给药。
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| NO20031698D0 (no) | 2003-04-11 |
| PL366055A1 (en) | 2005-01-24 |
| US20040038985A1 (en) | 2004-02-26 |
| JP2004512282A (ja) | 2004-04-22 |
| CA2425540A1 (en) | 2002-04-18 |
| ZA200302520B (en) | 2004-06-30 |
| HRP20030246A2 (en) | 2003-06-30 |
| WO2002030902A8 (en) | 2004-02-26 |
| IL154982A0 (en) | 2003-10-31 |
| BR0114609A (pt) | 2003-12-23 |
| ECSP034549A (es) | 2003-05-26 |
| RU2003113536A (ru) | 2004-11-10 |
| SK4332003A3 (en) | 2003-10-07 |
| EP1326837A1 (en) | 2003-07-16 |
| AU2002220614A1 (en) | 2002-04-22 |
| MXPA03003233A (es) | 2003-09-10 |
| WO2002030902A1 (en) | 2002-04-18 |
| KR20030060906A (ko) | 2003-07-16 |
| HUP0302842A2 (hu) | 2003-12-29 |
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