CN103193864B - 培哚普利的精氨酸盐的δ晶型、其制备方法和包含它的药物组合物 - Google Patents
培哚普利的精氨酸盐的δ晶型、其制备方法和包含它的药物组合物 Download PDFInfo
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Abstract
培哚普利的精氨酸盐的δ晶型、其制备方法和包含它的药物组合物。本发明涉及式(I)的培哚普利L-精氨酸盐的δ晶型:
Description
技术领域
本发明涉及式(I)的培哚普利L-精氨酸盐的δ晶型:
其制备方法和包含它的药物组合物。
背景技术
培哚普利及其药学可接受的盐,更具体地是其精氨酸盐具有有价值的药理学特性。
其主要特性在于抑制血管紧张素I转化酶(或激肽酶II),这能够在一方面防止十肽血管紧张素I转化成八肽血管紧张素II(血管收缩剂),另一方面,防止缓激肽(血管扩张剂)降解成无活性的肽。
那两个作用促成了培哚普利在心血管疾病中的有益作用,更具体地是在动脉高血压、心力衰竭和稳定型冠心病中的有益作用。
培哚普利、其制备方法及其在治疗剂中的用途描述在欧洲专利说明书EP 0049658中。
培哚普利的精氨酸盐首次描述在欧洲专利说明书EP 1354873中。
培哚普利的精氨酸盐的α和β晶型描述在欧洲专利说明书EP 1989182和EP 2016051中。
培哚普利的精氨酸盐的γ晶型描述在专利申请WO 2009/157018中。
得到精氨酸培哚普利的方法描述在专利说明书SI 23001中。
发明内容
鉴于精氨酸培哚普利的药用价值,得到具有极佳稳定性的该药物具有巨大的重要性。
更具体地,本发明涉及式(I)化合物的δ晶型。
本发明的精氨酸培哚普利的δ晶型可以通过根据图1的其X-射线衍射图和/或通过根据图3的其固体NMR光谱得到表征。
在不存在赋形剂和杂质的条件下,本发明精氨酸培哚普利的δ晶型可以通过如下的X-射线粉末衍射图得到表征,其使用具有铜对阴极的衍射计测定并且表示为晶面间距d、2θ布拉格角和相对强度(以占最强线的百分比表示):
将每条线视为具有2-θ±0.2°的准确度。
为信息目的指定相对强度。
在下列测试条件下测定X-射线粉末衍射光谱:
●Panalytical X′Pert Pro衍射计
●X′Celerator检测器
●铜对阴极,电压40kV,电流30mA;
●传送安装;固定样品;
●温度:环境;
●测定范围:3°-40°;
●每个测量值之间的增量:0.017°;
●测量时间/步:49s;
●无内标;
●使用X′Pert Highscore软件(2.2a版)处理测试数据。
在存在赋形剂和杂质的条件下,尤其是在有乳糖的存在下,本发明精氨酸培哚普利的δ晶型的一些X-射线衍射峰可能被掩盖。
根据赋形剂或杂质性质的不同,本发明的精氨酸培哚普利的δ晶型可以通过如下的X-射线粉末衍射峰得到表征,其使用具有铜对阴极的衍射计测定的并且表示为2θ角(°):4.3、11.0、11.1、13.2、14.6、16.0和21.9;或4.3、11.0、11.1、11.9、13.2、14.6,19.2、21.9和22.6;或4.3、11.0、11.1、11.9、12.5、13.2、14.6、16.0、19.2、19.4、21.9、22.2和22.6。
本发明的精氨酸培哚普利的δ晶型还可以通过固态NMR光谱进行表征。
使用具有4mm CP/MAS SB VTN型探头的Bruker SB Avance光谱仪在环境温度在如下条件下记录固态13C NMR光谱:
-频率:125.76MHz,
-谱宽:40kHz,
-样品的魔角自旋速率:10kHz,
-具有SPINAL64去偶(80kHz去偶功率)的CP(交叉极化)脉冲序列,
-重复延迟:10s,
-采集时间:47ms,
-接触时间:4ms,
-扫描次数:4096。
在傅里叶变换前施加5Hz谱线增宽。
将由此得到的光谱参比金刚烷的样品(金刚烷的高频峰设定在38.48ppm)。
在下表中按次序排列了观察到的峰(以ppm±0.2ppm表示):
本发明还涉及培哚普利的精氨酸盐的δ晶型的制备方法,通过使培哚普利精氨酸盐在高于20℃的温度下从乙腈、乙酸乙酯或甲基叔丁基醚和二甲亚砜的二元混合物或乙腈、二甲亚砜和甲苯的三元混合物中结晶或重结晶来进行。
就结晶法而言,可以以另一种培哚普利盐例如叔丁基胺盐开始得到培哚普利的精氨酸盐,使培哚普利的叔丁基胺盐与酸反应,得到游离酸形式的培哚普利,用精氨酸将其在乙腈、乙酸乙酯或甲基叔丁基醚和二甲亚砜的二元混合物或乙腈、二甲亚砜和甲苯的三元混合物中转化成盐。
就重结晶法而言,用作原料的精氨酸培哚普利可以是无水或水合形式、无定形形式或任意的晶型。
当使用乙腈、乙酸乙酯或甲基叔丁基醚和二甲亚砜的二元混合物时,乙腈/二甲亚砜、乙酸乙酯/二甲亚砜或甲基叔丁基醚/二甲亚砜之比优选在90/10w/w-10/90w/w之间,包括边界值。
结晶或重结晶过程中介质的温度优选在25℃-80℃之间,包括25℃和80℃,更优选60-80℃,包括60和80℃。
可以有利地在冷却步骤过程中在混合物中放入晶种(″放入晶种″模式)。
当混合物中不放入晶种(″不放入晶种″模式)时,接触溶剂混合物的时间优选大于6小时。
本发明还涉及包含作为活性成分的式(I)化合物的δ晶型以及一种或多种适宜的无毒惰性赋形剂的药物组合物。在本发明的药物组合物中,可提及的更特别是适于口服、胃肠道外(静脉内或皮下)或经鼻施用的那些,例如片剂或糖衣丸、舌下片、胶囊剂、锭剂、栓剂、乳膏剂、软膏剂、皮肤凝胶、可注射制剂和可饮用混悬剂。
优选通过直接压制制备片剂形式的药物组合物。
可用的剂量可以根据障碍的性质和严重性、施用途径以及患者的年龄及体重进行调节。可用的剂量在每天1mg-20mg之间变化,一次或多次施用,优选2.5-10mg,每天施用一次。
本发明的药物组合物还可以包含一种或多种其他的活性成分,其选自利尿剂诸如吲达帕胺、钙拮抗剂诸如氨氯地平和If电流抑制剂诸如伊伐布雷定。
当本发明的药物组合物还包含吲达帕胺时,吲达帕胺的量优选在0.625-2.5mg之间,包括边界值。
当本发明的药物组合物还包含氨氯地平时,氨氯地平的量优选在5-10mg之间,包括边界值。
当本发明的药物组合物还包含伊伐布雷定时,伊伐布雷定的量优选在5-30mg之间,包括边界值。
附图说明
图1:精氨酸培哚普利的δ晶型的衍射图。
图2:精氨酸培哚普利δ晶型在乙腈/二甲亚砜的二元混合物中的简化的相图。
图3:精氨酸培哚普利δ晶型在10kHz的13C CPMSA光谱。
具体实施方式
下列实施例示例本发明。
在下文的实施例1-4中,用作原料的培哚普利精氨酸盐具有约3-4%的含水量。
缩写:
实施例1:培哚普利的精氨酸盐的δ晶型(乙腈/二甲亚砜25/75w/w的二元混合物,″不放入晶种″模式)
将55.32g培哚普利精氨酸盐、297.50g二甲亚砜和94.49g乙腈导入反应器中。
在70℃在搅拌的同时将该混合物加热7小时,然后以1℃/min冷却至40℃。在40℃30分钟后,用玻璃釉料过滤该混合物。用乙酸乙酯洗涤滤饼,在50℃在风扇循环的烘箱内干燥过夜,得到精氨酸培哚普利的δ晶型,收率为54%。
实施例2:培哚普利的精氨酸盐的δ晶型(乙腈/二甲亚砜25/75w/w的二元混合物,″放入晶种″模式)
将52.2g的培哚普利精氨酸盐、216g的二甲亚砜和76g乙腈导入反应器中。
在搅拌的同时将该混合物加热至70℃。在70℃,加入0.52g的精氨酸培哚普利δ晶型以启动结晶。
在70℃将该混合物加热5小时(直到浊度曲线稳定为止),然后以0.5℃/min冷却至40℃。在40℃30分钟后,在1L不锈钢池中通过过滤介质(直径=5em,过滤阈值=20微米)过滤该混合物。
用乙酸乙酯洗涤滤饼,在50℃在风扇循环的烘箱内干燥过夜。
得到精氨酸培哚普利的δ晶型,收率为72%(扣除晶种)。
实施例3:培哚普利的精氨酸盐的δ晶型(乙腈/二甲亚砜10/90w/w的二元混合物,″放入晶种″模式)
将280g的培哚普利精氨酸盐、950g二甲亚砜和97g的乙腈导入2L反应器中。
将该混悬液加热至80℃,观察到变成溶液。将该混合物维持在80℃5分钟,然后以0.5℃/min的速率冷却至70℃。一旦混合物的温度在70℃,则加入乙腈(197g,倾倒时间=20分钟)。在添加结束时,该混合物保持澄清。在该溶液中放入6g的精氨酸培哚普利的δ晶型。在70℃的阶段应用45分钟。
以0.5℃/min的速率将该混悬液冷却至25℃。在25℃的接触时间是4小时,然后使用2L池过滤。用乙酸乙酯洗涤滤饼,在50℃在风扇循环的烘箱内干燥过夜。得到精氨酸培哚普利的δ晶型,收率为91%(扣除晶种)。
实施例4:培哚普利精氨酸盐的δ晶型(乙腈/二甲亚砜10/90w/w的二元混合物,″在25℃″模式)
将25g的培哚普利精氨酸盐和90g的乙腈/二甲亚砜10/90(w/w)二元混合物导入具有机械搅拌的反应器。在25℃在搅拌下接触72小时后,转变成δ晶型是完全的。
然后过滤该反应混合物,导致精氨酸培哚普利δ晶型的分离,收率为79%。
实施例5:从培哚普利(游离酸)开始的在乙腈/DMSO 25/75中的二元混合物中的培哚普利的精氨酸盐的δ晶型
将培哚普利(12.5g,1eq.)和L-精氨酸(5.32g-0.9eq)混悬于乙腈(20g,d=0.787)和DMSO(61g,d=1.100)的混合物中。将该反应混合物在50℃加热过夜。然后通过用釉料过滤分离产物。洗涤滤饼并干燥。
得到精氨酸培哚普利的δ晶型,相对于培哚普利的收率为79%。
实施例6:培哚普利的精氨酸盐的δ晶型(乙酸乙酯/二甲亚砜70/30w/w的二元混合物,″放入晶种″模式)
将15g精氨酸培哚普利和43.6g的DMSO导入0.5L反应器中。精氨酸培哚普利在该混合物中的浓度为25.6%(重量百分比)。将该混合物加热至约70℃,然后在20分钟内加入102g的乙酸乙酯(乙酸乙酯/DMSO之比:70/30w/w)。
在70℃在该混合物放入晶种0.3g的δ晶型。放入晶种后,将该混合物在搅拌下维持在70℃2小时。应用以0.2℃/min的速率冷却至20℃,然后接触时间为16小时。
在池中用过滤介质(空隙率0.41μm)分离产物。用乙酸乙酯/DMSO的混合物将固体洗涤1次,用乙酸乙酯洗涤2次,在50℃真空烘箱内干燥。
得到精氨酸培哚普利的δ晶型,收率为93%(扣除晶种)。
实施例7:药物组合物
各自包含5mg活性成分的1000片制剂的处方:
精氨酸培哚普利的δ晶型........................................................5g
羟丙基纤维素........................................................................2g
小麦淀粉.................................................................................10g
乳糖.........................................................................................100g
硬脂酸镁.................................................................................3g
滑石粉.....................................................................................3g
实施例8:药物组合物
包含10mg精氨酸培哚普利的片剂,最终重量100mg:
精氨酸培哚普利的δ晶型...................................................10mg
一水合乳糖....................................................................64.2mg
微晶纤维素.........................................................................25mg
硬脂酸镁...........................................................................0.5mg
无水胶态二氧化硅..........................................................0.3mg
实施例9:热稳定性
将在开放的烧瓶中在110℃的δ晶型的热稳定性与来自现有技术的晶型进行比较。
结果如下:
这些结果显示培哚普利精氨酸盐的δ晶型与其他已知的晶型相比具有改善的热稳定性。
Claims (16)
1.式(I)的培哚普利L-精氨酸盐的δ晶型:
其通过采用具有铜对阴极的衍射计测定的并以布拉格角2θ(°)表示的下述X-射线粉末衍射峰表征:4.3、11.0、11.1、13.2、14.6、16.0和21.9。
2.根据权利要求1的式(I)化合物的δ晶型,其通过采用具有铜对阴极的衍射计测定的并以布拉格角2θ表示的下述X-射线粉末衍射峰表征:4.3、11.0、11.1、11.9、12.5、13.2、14.6、16.0、19.2、19.4、20.0、21.9、22.2和22.6。
3.根据权利要求1的式(I)化合物的δ晶型,其通过采用具有铜对阴极的衍射计测定的并以晶面间距d、布拉格角2θ和以占最强线的百分数表示的相对强度表示的下述X-射线粉末衍射图表征:
4.根据权利要求1的式(I)化合物的δ晶型,其通过具有以ppm表示的下列峰的固态13C CPMAS NMR光谱表征:
5.根据权利要求1-4任意一项的式(I)化合物的δ晶型的制备方法,通过在高于20℃的温度下从乙腈、乙酸乙酯或甲基叔丁基醚和二甲亚砜的二元混合物或乙腈、二甲亚砜和甲苯的三元混合物中结晶或重结晶来进行。
6.根据权利要求5的方法,其中乙腈、乙酸乙酯或甲基叔丁基醚和二甲亚砜的二元混合物具有的乙腈/二甲亚砜、乙酸乙酯/二甲亚砜或甲基叔丁基醚/二甲亚砜之比在90/10w/w-10/90w/w。
7.根据权利要求5的方法,其中介质温度在25-80℃之间,包括25℃和80℃。
8.根据权利要求7的方法,其中将所述混合物加热至60-80℃的温度。
9.根据权利要求5的方法,其中所述混合物放入δ晶型的晶种。
10.药物组合物,其包含作为活性成分的根据权利要求1-4任意一项的化合物与至少一种惰性无毒性药学可接受的载体。
11.根据权利要求10的药物组合物,其特征在于它还包含利尿剂、钙拮抗剂或心脏起搏电流抑制剂。
12.根据权利要求11的药物组合物,其特征在于所述利尿剂是吲达帕胺。
13.根据权利要求11的药物组合物,其特征在于所述钙拮抗剂是氨氯地平。
14.根据权利要求11的药物组合物,其特征在于所述心脏起搏电流抑制剂是伊伐布雷定。
15.根据权利要求1-4任意一项的培哚普利L-精氨酸盐的δ晶型,其用于治疗心血管疾病。
16.根据权利要求1-4任意一项的培哚普利L-精氨酸盐的δ晶型,其用于治疗动脉高血压、心力衰竭或稳定型冠心病。
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EP3842035A1 (en) | 2019-12-23 | 2021-06-30 | KRKA, d.d., Novo mesto | Composition for the preparation of perindopril arginine granules, a method for their preparation and pharmaceutical composition comprising the granules |
SI26268A (sl) | 2021-11-18 | 2023-05-31 | Zupet Rok | Postopek za pripravo hidratirane oblike perindopril l-arginina |
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