CN106892858A - 一种卡维地洛磷酸二氢盐新晶型 - Google Patents
一种卡维地洛磷酸二氢盐新晶型 Download PDFInfo
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- CN106892858A CN106892858A CN201510967176.9A CN201510967176A CN106892858A CN 106892858 A CN106892858 A CN 106892858A CN 201510967176 A CN201510967176 A CN 201510967176A CN 106892858 A CN106892858 A CN 106892858A
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- dihydric phosphate
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- carvidilol dihydric
- carvidilol
- carvedilol
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- C07—ORGANIC CHEMISTRY
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
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Abstract
本发明涉及一种新的卡维地洛磷酸二氢盐晶型以及其制备方法。所述的卡维地洛磷酸二氢盐新晶型命名为晶型1,使用Cu-Kα辐射检测的X射线粉末衍射图谱中在约4.8,7.3,8.2,11.3,12.7,14.6,15.9,18.4,21.7,24.5(±0.2)处有特征峰。本发明还提供一种制备卡维地洛磷酸二氢盐晶型1的方法,简便、重现性好,所得卡维地洛磷酸二氢盐晶型1纯度高、稳定性好,适于工业化生产。
Description
技术领域
本发明涉及卡维地洛磷酸二氢盐新的可药用晶型(即1-(咔唑-4-基氧基-3-[[2-(邻-甲氧苯氧基)乙基]氨基]-2-丙醇的磷酸二氢盐)。
技术背景
卡维地洛(carvedilol)化学名为1-(咔唑-4-基氧基-3-[[2-(邻-甲氧苯氧基)乙基]氨基]-2-丙醇,其结构式如下式所示:
卡维地洛在美国专利NO.4503067中被公开,公开日期1985年3月5日,该专利涵盖了卡维地洛游离碱及其与无机酸、有机酸反应生成的药物上可接受的卡维地洛盐,其中包含卡维地洛磷酸盐。
卡维地洛是一种α-受体阻断活性的非选择性β-肾上腺素阻滞剂,α-受体阻断活性可影响神经冲动反应,β-肾上腺素阻滞剂对血管有扩张作用,两种药理作用互补,临床上用于高血压、充血性心力衰竭和心绞痛。
卡维地洛含有α-羟基仲胺官能团,pKa值为7.8。卡维地洛溶解度受PH值影响很大,PH>9.0,溶解度相对较低(<1μg/ml),室温下饱和溶解度在PH=7.0时约为23μg/ml,PH=5.0时达到平衡值,溶解度约为100μg/ml。PH<4时卡维地洛溶解度受其质子化形式和在原位形成相应的盐影响,溶解度降低。如在模拟胃酸酸性介质中,因在原位生成卡维地洛盐酸盐,几乎不溶解该介质中。
相对于卡维地洛,卡维地洛盐具有更好的溶解度和化学稳定性,可以最大限度地发挥卡维地洛药理作用,在医学应用中具有更大的优势,其中包括卡维地洛盐在哺乳动物体内通过胃肠道吸收获得预期或者延长全身系统药物水平。
专利文献报道了卡维地洛磷酸二氢盐多种晶型,美国专利US 7268156公开了卡维地洛磷酸二氢盐半水合物(FormⅠ)、卡维地洛磷酸二氢盐二水物(FormⅡ、FormⅣ)、卡维地洛磷酸二氢盐(FormⅤ)以及卡维地洛磷酸二氢盐甲醇溶剂合物Ⅲ。
专利US7763645公开了卡维地洛磷酸二氢盐一水物,专利US8344159开了卡维地洛磷酸二氢盐倍半水合物,专利WO2008002683和WO2009122425f分别公开卡维地洛磷酸二氢盐不同类型的无定型。
发明内容
本发明公开了一种新的纯度高、稳定性好的卡维地洛磷酸二氢盐晶体的晶型。
本发明所述卡维地洛磷酸二氢盐新晶型称为晶型1,使用Cu-Kα辐射检测其X射线粉末衍射图谱中,具有以下特征峰,其2θ角度值及相对强度如下表所示:
2θ | 相对强度 |
±0.2 | 4.8 |
±0.2 | 7.3 |
±0.2 | 8.2 |
±0.2 | 11.3 |
±0.2 | 12.7 |
±0.2 | 14.6 |
±0.2 | 15.9 |
±0.2 | 18.4 |
±0.2 | 21.7 |
±0.2 | 24.5 |
本发明所述的卡维地洛磷酸二氢盐晶型1具有如附图1所示的X粉末衍射图谱。
本发明所述卡维地洛磷酸二氢盐晶型1,其特征在于该晶型有热失重,失重百分比为5%-7%。差示扫描量热法分析图谱显示在78-85℃处有失去结晶水的吸热峰,在约130-135℃处有重结晶的放热峰,在约158-162℃处熔融,出现吸热峰。
本发明所述的卡维地洛磷酸二氢盐晶型1具有如附图2所示的热重分析图谱和差示扫描量热法分析图谱。
本发明同时提供一种制备达卡维地洛磷酸二氢盐晶型1的方法:将卡维地洛二氢盐溶于甲醇中,配置成60-100g/L混悬液,加热到50-70℃使溶液完全溶解,将卡维地洛二氢盐溶于甲醇溶液滴加到预冷至-15-0℃甲醇中,升温至10-20℃搅拌过夜,抽滤、真空干燥卡维地洛二氢盐晶体至恒重。
附图说明
附图1根据本发明实施例1得到的卡维地洛磷酸二氢盐晶型1的X射线粉末衍射(XRPD)图谱。
附图2根据本发明实施例1得到的卡维地洛磷酸二氢盐晶型1的热重分析和差示扫描量热法分析图谱(TGA-DSC)。
具体实施方式
以下的实施例在于详细说明本发明,而非限制本发明
本发明的分析检测条件如下:
1、X-射线粉末衍射数据是使用德国布鲁克公司的BRUKER D8Advance测定的,电压电流:40kV,40mA;测角仪:立式测角仪,半径280mm;狭缝:DS=2°,SS=1/2°,mask=15mm,RS=5.0mm;探测器:LYNXEYE检测器;扫描模式:连续扫描;扫描范围:3°-40°;每步计数时间:0.2s;扫描总时间:390s。
2、DSC-TGA是由瑞士METTLER TOLEDO公司的DSC/TGA 2测定,测试条件为50ml/min N2,升温速度10℃/min。
实施例1
将1g卡维地洛磷酸二氢盐溶于8ml甲醇形成悬浊液,搅拌下加热至70℃使其完全溶解备用。另取2ml甲醇搅拌下冷却至-10℃,将上述卡维地洛磷酸二氢盐甲醇溶液滴加到预冷的甲醇中,滴加过程溶液温度控制在-10至-5℃之间。滴完停止加热,自然升温、搅拌过夜。抽滤、真空50℃干燥10得到卡维地洛磷酸二氢盐晶型1。
实施例2
将1g卡维地洛于10ml甲醇形成悬浊液,搅拌下加热至70℃使其完全溶解备用。向溶液中加入86%(wt)浓磷酸溶液0.35g保温30min溶液保持澄清备用,另取2ml甲醇搅拌下冷却至-10℃,将上述澄清溶液滴加到预冷的甲醇中,滴加过程溶液温度控制在-10至-5℃之间。滴完停止加热,自然升温、搅拌过夜。抽滤、真空50℃干燥10得到卡维地洛磷酸二氢盐晶型1。
实施例3
将10g卡维地洛于100ml甲醇形成悬浊液,搅拌下加热至70℃使其完全溶解备用。向溶液中加入86%(wt)浓磷酸溶液3.5g保温1h溶液保持澄清备用,另取20ml甲醇搅拌下冷却至-5℃,将上述澄清溶液滴加到预冷的甲醇中,滴加过程溶液温度控制在-5至-0℃之间。滴完停止加热,自然升温、搅拌过夜。抽滤、真空50℃干燥10得到卡维地洛磷酸二氢盐晶型1。
实施例4
将10g卡维地洛磷酸二氢盐溶于150ml甲醇形成悬浊液,搅拌下加热至50℃使其完全溶解备用。另取20ml甲醇搅拌下冷却至-5℃,将上述卡维地洛磷酸二氢盐甲醇溶液滴加到预冷的甲醇中,滴加过程溶液温度控制在-5至0℃之间。滴完停止加热,自然升温、搅拌过夜。抽滤、真空50℃干燥10得到卡维地洛磷酸二氢盐晶型1。
实施例5
将100g卡维地洛磷酸二氢盐溶于800ml甲醇形成悬浊液,搅拌下加热至70℃使其完全溶解备用。另取400ml甲醇搅拌下冷却至-10℃,将上述卡维地洛磷酸二氢盐甲醇溶液滴加到预冷的甲醇中,滴加过程溶液温度控制在-10至-5℃之间。滴完停止加热,自然升温、搅拌过夜。抽滤、真空50℃干燥10得到卡维地洛磷酸二氢盐晶型1。
Claims (4)
1.一种卡维地洛磷酸二氢盐(式I)的晶型1,其特征在于所述晶型1的X射线粉末衍射图谱中包括以下2θ角所示的特征峰:4.8,7.3,8.2,11.3,12.7,14.6,15.9,18.4,21.7,24.5(±0.2)。
2.如权利要求1所述的卡维地洛磷酸二氢盐的晶型1,其特征在于其具有如附图1所示的X粉末衍射图谱。
3.如权利要求1所述的卡维地洛磷酸二氢盐的晶型1,其特征在于所述晶型1通过热重分析显示有5%-7%失重,通过差示扫描量热法分析显示在约78-85℃处有失去结晶水的吸热峰,在约130-135℃处有重结晶的放热峰,在158-162℃处有熔融吸热峰。
4.如权利要求1所述的卡维地洛磷酸二氢盐的晶型1,其特征在于其具有如附图2所示的DSC-TGA图谱。
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Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005051322A2 (en) * | 2003-11-25 | 2005-06-09 | Sb Pharmco Puerto Rico Inc. | Controlled release pharmaceutical formulations comprising carvedilol, free based and its salts |
CN1678305A (zh) * | 2002-06-27 | 2005-10-05 | Sb药物波多黎各公司 | 卡维地洛磷酸盐和/或其溶剂合物和/或相应组合物和/或治疗方法 |
WO2008002683A2 (en) * | 2006-06-28 | 2008-01-03 | Teva Pharmaceutical Industries Ltd. | Polymorphous forms of carvedilol phosphate |
WO2008093350A1 (en) * | 2007-01-31 | 2008-08-07 | Lupin Limited | Novel anhydrous crystalline form of carvedilol dihydrogen phosphate |
WO2008142703A1 (en) * | 2007-05-17 | 2008-11-27 | Wanbury Limited | A novel cost effective process for production of carvedilol phosphate |
WO2009008009A1 (en) * | 2007-07-11 | 2009-01-15 | Lupin Limited | Novel crystalline form b of carvedilol dihydrogen phosphate |
WO2009122425A1 (en) * | 2008-04-04 | 2009-10-08 | Shodhana Laboratories Limited | Novel crystalline form of carvedilol dihydrogen phosphate and related processes |
CN101891671A (zh) * | 2010-07-26 | 2010-11-24 | 天津大学 | 一种卡维地洛磷酸二氢盐的晶体及其制备方法 |
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Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1678305A (zh) * | 2002-06-27 | 2005-10-05 | Sb药物波多黎各公司 | 卡维地洛磷酸盐和/或其溶剂合物和/或相应组合物和/或治疗方法 |
WO2005051322A2 (en) * | 2003-11-25 | 2005-06-09 | Sb Pharmco Puerto Rico Inc. | Controlled release pharmaceutical formulations comprising carvedilol, free based and its salts |
WO2008002683A2 (en) * | 2006-06-28 | 2008-01-03 | Teva Pharmaceutical Industries Ltd. | Polymorphous forms of carvedilol phosphate |
WO2008093350A1 (en) * | 2007-01-31 | 2008-08-07 | Lupin Limited | Novel anhydrous crystalline form of carvedilol dihydrogen phosphate |
WO2008142703A1 (en) * | 2007-05-17 | 2008-11-27 | Wanbury Limited | A novel cost effective process for production of carvedilol phosphate |
WO2009008009A1 (en) * | 2007-07-11 | 2009-01-15 | Lupin Limited | Novel crystalline form b of carvedilol dihydrogen phosphate |
WO2009122425A1 (en) * | 2008-04-04 | 2009-10-08 | Shodhana Laboratories Limited | Novel crystalline form of carvedilol dihydrogen phosphate and related processes |
CN101891671A (zh) * | 2010-07-26 | 2010-11-24 | 天津大学 | 一种卡维地洛磷酸二氢盐的晶体及其制备方法 |
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