CN1282320A - (r)-3-[[(4-氟苯基)磺酰基]氨基]-1,2,3,4-四氢-9h-咔唑-9-丙酸(拉马曲班)的热力学稳定形式 - Google Patents
(r)-3-[[(4-氟苯基)磺酰基]氨基]-1,2,3,4-四氢-9h-咔唑-9-丙酸(拉马曲班)的热力学稳定形式 Download PDFInfo
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Abstract
本发明涉及式(Ⅰ)活性化合物拉马曲班的热力学稳定型。所述热力学稳定形式通过熔融亚稳定形式并随后重结晶制备或者通过以热力学稳定形式的晶种对亚稳定活性化合物的溶液种晶来制备。该热力学稳定活性化合物能够用作哮喘药物。
Description
本发明涉及在室温下为热力学稳定的新形式的拉马曲班(ramatroban)、其制备的方法、含有该形式的药物和它们在控制疾病中的用途。
作为血栓烷A2拮抗剂的拉马曲班的制备和用途已在EP 242 518中公开。
在其中描述的方法中,得到结晶形式(modification)的拉马曲班,其在下文中表示为Ⅱ型(modification)。Ⅱ型具有137℃的熔点,并且其熔融焓为80J/g(DSC,加热速率2K min-1)并具有特征X-射线衍射图、IR光谱、13C-固态NMR光谱、FIR光谱、拉曼光谱(图1-6)。目前发现Ⅱ型是亚稳定的,因此不适宜于用在药用制剂例如固体和半固体制剂中。
令人惊奇地是目前发现拉马曲班的第二个晶型为热力学稳定的并且在经过悬浮操作后贮存时也是稳定的,并且由此特别适宜于用在药用制剂例如悬浮剂或霜剂中,而且也适宜于用在通过将活性化合物悬浮例如在水溶液中制粒或湿法研磨制备的其它制剂中。这个新的变型在下文中表示为Ⅰ型。本发明也涉及含有以Ⅰ型形式存在的拉马曲班作为活性成分的药用制剂。所述制剂可以含有一种或多种药学上可接受的辅助剂如粘合剂、溶剂、填充剂等。
J.Halbelian,W.McCrowne,J.Pharm.Sci.58(1969)911和J.-0.Henck等,Pharm.Ind.59(1997)165-169公开了当在固体和半固体制剂例如片剂、悬浮剂和膏剂中使用热力学亚稳定多晶型物时,所述稳定形式能够产生。在此观察到了不合乎需要的结晶生长、生物利用度的变化、结块等伴随的现象。拉马曲班的两种结晶型在室温下的溶解度相差达60%。通过使用本发明稳定Ⅰ型,可以确保作为转化的结果不发生溶解度的变化。这就增加了拉马曲班制剂的安全性并且患者所冒风险由此降低。
与Ⅱ型相比较,Ⅰ型具有清晰可辨别的DSC差示热分析图、X-射线衍射图、13C-固态NMR光谱、FIR光谱和拉曼光谱(图1-6)。Ⅰ型的熔点为151℃和熔融焓为87 J/g。
使用Perkin-Elmer的DSC 7和TGA 7得到DSC和TGA差示热分析图。在Stoe透射衍射计记录X-射线衍射图。使用得自Bruker的傅立叶IR光谱仪IFS 66(IR)、IFS 66v(FIR)和IFS 88(拉曼)记录IR、FIR和拉曼光谱。使用Bruker MSL 300记录13C-固态NMR光谱。
在药用制剂中使用高纯度的拉马曲班的晶型。由于稳定性的原因,Ⅱ型不应含有相对高比例的Ⅱ型。含有低于10%的Ⅱ型的活性化合物的级别是优选的,低于5%是特别优选的。
通过把Ⅱ型拉马曲班悬浮在水或惰性物质如低级醇、酮或烷烃中、用Ⅰ型的结晶种晶并搅拌直到获得所要求程度的转化,特别优选地是直到定量转化为Ⅰ型来制备Ⅰ型。通常,该转化在20-50℃下发生,优选在40℃下发生。分离出所得到Ⅰ型的结晶,室温下真空干燥或在高温下干燥至恒重以除去溶剂。
为制备所需要的晶种,使所述活性化合物彻底熔融并随后迅速冷却至室温。在室温下把由此得到的无定形活性化合物悬浮于惰性溶剂中,并且将其搅拌直到其完全转化为热力学稳定的晶型。过滤残余物并真空干燥至恒重。
实施例
实施例1由熔融物制备晶种
将大约300mg的Ⅱ型拉马曲班彻底熔融并迅速冷却至室温。把无定形物质悬浮于5ml乙醇/水(1∶1)中并在室温下将该悬浮液搅拌24 h。在搅拌时间结束后,过滤该悬浮液,并在室温下真空干燥残余物。
实施例2种晶方法
在大约40℃下将130 g拉马曲班(Ⅱ型)溶于650 g乙酸正丁酯和15 g水中。在40-45℃下真空蒸发掉175 g溶剂。以1 g拉马曲班(Ⅰ型)对该溶液种晶,并在40至45℃下再真空蒸出300g溶剂。把所得到的结晶悬浮液冷却至室温并搅拌几小时。抽气过滤,以乙酸正丁酯和甲基叔丁基醚洗涤并在50℃下真空干燥。得到大约100g的拉马曲班(Ⅰ型)。
实施例3沉淀方法
温热下将75 g的拉马曲班(Ⅱ型)溶解于135 g乙酸乙酯中。在大约40℃下滴加入85 g石油醚(35/60),并且用1 g的拉马曲班(Ⅰ型)对该批种晶。然后在40℃下搅拌该混合物大约2-3小时并然后冷却至室温。再向该悬浮液加入130 g石油醚(35/60),再在室温下搅拌大约5小时。抽气过滤,以100g石油醚(35/60)洗涤并在50℃下真空干燥。得到大约65 g的拉马曲班(Ⅰ型)。
实施例4在悬浮液1中转化
将50 g的拉马曲班(Ⅱ型)悬浮于75g乙酸正丁酯中并与5.0 g的拉马曲班(Ⅰ型)混合。室温下将该混合物搅拌大约100小时。然后,抽气过滤,以甲基叔丁基醚洗涤,并在50℃下真空干燥。得到大约40 g的拉马曲班(Ⅰ型)。
实施例5在悬浮液2中转化
将大约0.5 g的Ⅰ型和Ⅱ型(混合比例为大约1∶1)悬浮于8 ml正庚烷中并在大约80℃下回流。一周后,过滤该悬浮液,并且将该残余物在室温下真空干燥一天。
实施例6片剂的生产
在均化器中用9180 g的HPC-L(367 g)水溶液分散4590 g微粉化的Ⅰ型拉马曲班,然后通过筛目宽为355 im的筛子过滤。在成粒机中使该成粒溶液与13,500 g预先混合并预热的含有3162 g乳糖、4860gHPC-L和540g HPC-M的水溶液反应以形成颗粒。在65℃下干燥生成的颗粒。然后在旋转压片机中进行压制,得到具有9.0 mm直径的片剂。表1差示扫描量热法
表2X-射线衍射法
表2(续)
表2(续)
表2(续)
Ⅰ型 | Ⅱ型 | |
熔点 | 151 | 137 |
熔融焓 | 87 | 80 |
峰最大值[2θ] | |
Ⅰ型 | Ⅱ型 |
7.5 | 7.8 |
9.4 | 8.7 |
10.1 | 10.9 |
10.6 | 12.5 |
12.0 | 13.8 |
12.4 | 14.1 |
13.7 | 15.3 |
14.6 | 15.6 |
15.0 | 16.0 |
16.0 | 16.6 |
峰最大值[2θ] | |
Ⅰ型 | Ⅱ型 |
17.3 | 17.2 |
17.7 | 17.3 |
18.0 | 17.8 |
19.2 | 18.7 |
19.8 | 19.4 |
20.3 | 20.5 |
20.7 | 20.7 |
21.0 | 21.3 |
21.2 | 21.8 |
21.7 | 22.1 |
21.9 | 22.6 |
22.2 | 23.0 |
22.7 | 23.6 |
22.9 | 23.8 |
23.1 | 24.3 |
23.6 | 24.7 |
23.7 | 25.7 |
24.1 | 25.9 |
24.9 | 26.1 |
峰最大值[2θ] | |
Ⅰ型 | Ⅱ型 |
25.6 | 26.5 |
26.2 | 26.8 |
26.6 | 27.1 |
27.5 | 28.0 |
28.0 | 28.4 |
29.5 | 29.0 |
30.0 | 29.6 |
30.1 | 29.9 |
30.5 | 30.4 |
31.0 | 30.7 |
31.7 | 31.2 |
32.2 | 32.2 |
32.6 | 33.0 |
32.8 | 33.4 |
34.4 | 33.6 |
34.6 | 34.3 |
35.1 | 34.7 |
35.5 | 35.5 |
35.8 | 35.7 |
峰最大值[2θ] | |
Ⅰ型 | Ⅱ型 |
36.2 | 35.9 |
36.7 | 36.9 |
36.9 | 37.2 |
37.0 | 37.5 |
37.4 | |
37.7 |
表3IR光谱
表3(续)
表3(续)
表413C-固态NMR光谱
表4(续)
表5FIR光谱
表6拉曼光谱
表6(续)
表6(续)
峰最大值[cm-1] | |
Ⅰ型 | Ⅱ型 |
3338 | 3298 |
3316 | 3244 |
3053 | 2943 |
2944 | 1697 |
1708 | 1615 |
1614 | 1591 |
1592 | 1495 |
1496 | 1466 |
峰最大值[cm-1] | |
Ⅰ型 | Ⅱ型 |
1470 | 1447 |
1431 | 1416 |
1378 | 1379 |
1335 | 1357 |
1318 | 1327 |
1294 | 1305 |
1227 | 1292 |
1179 | 1274 |
1167 | 1240 |
1156 | 1228 |
1097 | 1213 |
1079 | 1186 |
1067 | 1164 |
1055 | 1151 |
1032 | 1103 |
1013 | 1088 |
972 | 1068 |
922 | 1055 |
868 | 1013 |
峰最大值[cm-1] | |
Ⅰ型 | Ⅱ型 |
836 | 980 |
817 | 931 |
782 | 841 |
746 | 817 |
708 | 782 |
671 | 751 |
615 | 710 |
577 | 674 |
550 | 665 |
542 | 626 |
520 | 590 |
575 | |
556 | |
538 | |
520 |
峰最大值[ppm] | |
Ⅰ型 | Ⅱ型 |
181.1 | 179.2 |
164.0 | 163.0 |
139.4 | 141.5 |
138.8 | 137.6 |
136.2 | 136.4 |
135.0 | 132.5 |
127.7 | 129.0 |
120.0 | 128.4 |
118.2 | 127.5 |
117.0 | 122.6 |
109.3 | 121.7 |
107.9 | 117.2 |
106.2 | 115.7 |
54.0 | 109.2 |
53.2 | 106.6 |
52.1 | 51.6 |
50.6 | 40.1 |
峰最大值[ppm] | |
Ⅰ型 | Ⅱ型 |
38.8 | 37.5 |
38.1 | 35.9 |
37.1 | 34.8 |
36.1 | 29.8 |
35.3 | 27.8 |
33.9 | 26.4 |
32.3 | 25.5 |
31.4 | 22.2 |
29.6 | 21.7 |
29.0 | 21.3 |
27.7 | |
24.9 | |
24.1 | |
23.1 | |
20.8 | |
19.8 |
峰最大值[cm-1] | |
Ⅰ型 | Ⅱ型 |
452 | 498 |
429 | 477 |
413 | 449 |
388 | 432 |
368 | 411 |
350 | 395 |
334 | 373 |
324 | 326 |
297 | 291 |
282 | 281 |
264 | 235 |
231 | 201 |
207 | 177 |
176 | 152 |
148 | 116 |
115 | 101 |
101 | 94 |
88 | 88 |
峰最大值[cm-1] | |
Ⅰ型 | Ⅱ型 |
3080 | 3070 |
3069 | 3046 |
3056 | 2960 |
2955 | 2925 |
2925 | 2850 |
2898 | 1615 |
2851 | 1589 |
1613 | 1570 |
1580 | 1467 |
1566 | 1443 |
1471 | 1354 |
1438 | 1315 |
1412 | 1290 |
1369 | 1273 |
1293 | 1228 |
1277 | 1186 |
1236 | 1150 |
峰最大值[cm-1] | |
Ⅰ型 | Ⅱ型 |
1180 | 1100 |
1165 | 1014 |
1155 | 981 |
1123 | 921 |
1091 | 847 |
1059 | 817 |
1012 | 794 |
973 | 693 |
928 | 628 |
833 | 567 |
817 | 520 |
785 | 435 |
743 | 330 |
682 | 287 |
629 | 227 |
574 | 91 |
521 | |
334 | |
283 |
峰最大值[cm-1] | |
Ⅰ型 | Ⅱ型 |
199 | |
122 | |
90 | |
82 |
Claims (11)
1.拉马曲班(ramatroban)的热力学稳定Ⅰ型(modification)。
2.权利要求1的热力学稳定Ⅰ型的拉马曲班,其特征在于所述物质具有151℃的熔点(DSC,2K min-1)。
3.权利要求1的热力学稳定Ⅰ型的拉马曲班,其特征在于其X-衍射图在10.1、12.0和19.8具有反射(2θ)。
4.权利要求1的热力学稳定Ⅰ型的拉马曲班,其特征在于其IR光谱在3338 cm-1、1708 cm-1和1431 cm-1处具有最大峰。
5.权利要求1的热力学稳定Ⅰ型的拉马曲班,其特征在于其13C-固态NMR光谱在107.9 ppm、118.2 ppm和135.0 ppm处具有最大峰。
6.权利要求1的热力学稳定Ⅰ型的拉马曲班,其特征在于其FIR光谱在264 cm-1和207 cm-1处具有最大峰。
7.权利要求1的热力学稳定Ⅰ型的拉马曲班,其特征在于其拉曼光谱在3080 cm-1、1580 cm-1和122 cm-1处具有最大峰。
8.制备权利要求1至7的热力学稳定型Ⅰ的拉马曲班晶种的方法,其特征在于通过熔融和迅速冷却使所述活性化合物转化为无定形、然后通过在惰性溶剂中搅拌将其转化为稳定的Ⅰ型。
9.制备权利要求1至7的热力学稳定形式的拉马曲班的方法,其特征在于将热力学亚稳定型的拉马曲班悬浮于水或惰性有机溶剂中、用稳定的Ⅰ型种晶并进行所述转化直到达到所要求的转化程度。
10.药物,它包括权利要求1至7的热力学稳定形式的拉马曲班。
11.权利要求1至7的热力学稳定型的拉马曲班在控制疾病中的用途。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19757983A DE19757983A1 (de) | 1997-12-24 | 1997-12-24 | Thermodynamisch stabile Form von (r)-3[[(4-Fluorophenyl)sulfonyl]amino]-1,2,3,4-tetrahydro-9H-carbazol-0-propansäure (Ramatroban) |
DE19757983.3 | 1997-12-24 |
Publications (2)
Publication Number | Publication Date |
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CN1282320A true CN1282320A (zh) | 2001-01-31 |
CN1140510C CN1140510C (zh) | 2004-03-03 |
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Application Number | Title | Priority Date | Filing Date |
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CNB98812405XA Expired - Fee Related CN1140510C (zh) | 1997-12-24 | 1998-12-24 | (r)-3-[[(4-氟苯基)磺酰基]氨基]-1,2,3,4-四氢-9h-咔唑-9-丙酸(拉马曲班)的热力学稳定形式 |
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DK (1) | DK1051398T3 (zh) |
ES (1) | ES2218874T3 (zh) |
GT (1) | GT199800198A (zh) |
HK (1) | HK1034517A1 (zh) |
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CN103054857A (zh) * | 2012-12-30 | 2013-04-24 | 北京阜康仁生物制药科技有限公司 | 一种以雷马曲班为活性成分的固体制剂 |
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ES2395120T3 (es) * | 2006-12-20 | 2013-02-08 | Cardoz Ab | Combinación de pemirolast y ramotrobán para su uso en el tratamiento de transtornos inflamatorios |
AU2007344274A1 (en) * | 2007-01-16 | 2008-07-24 | Cardoz Ab | New combination for use in the treatment of inflammatory disorders |
WO2009007674A2 (en) * | 2007-07-11 | 2009-01-15 | Cardoz Ab | Combination for use in the treatment of atherosclerosis comprising a mast cell inhibitor and ramatroban or seratrodast |
CN101434571B (zh) * | 2007-11-13 | 2012-05-30 | 杭州容立医药科技有限公司 | 环烷并[1,2-b]吲哚磺酰胺、其异构体或其盐的合成方法 |
WO2011115069A1 (ja) * | 2010-03-19 | 2011-09-22 | 第一三共株式会社 | 結晶の網羅的探索 |
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DE3631824A1 (de) | 1986-02-21 | 1988-03-31 | Bayer Ag | Cycloalkano(1.2-b)indol-sulfonamide |
CN1015711B (zh) * | 1986-02-21 | 1992-03-04 | 拜尔公司 | 制备环烷并[1,2-b]吲哚-磺酰胺类化合物的方法 |
DE19506739A1 (de) * | 1995-02-27 | 1996-08-29 | Bayer Ag | [3-Amino]-tetrahydrocarbazol-propansäureester |
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CN103054857A (zh) * | 2012-12-30 | 2013-04-24 | 北京阜康仁生物制药科技有限公司 | 一种以雷马曲班为活性成分的固体制剂 |
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