CN116239527A - 一种米力农-柠檬酸一水共晶体 - Google Patents
一种米力农-柠檬酸一水共晶体 Download PDFInfo
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- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
本发明属于药物化学技术领域,具体涉及一种米力农‑柠檬酸一水共晶体。本发明提供了一种新的米力农‑柠檬酸一水共晶体,并提供了其制备方法。本发明所述共晶体性质优良,可显著增强米力农的溶解性及稳定性,有助于提高口服生物利用度,改善临床疗效,具有很强的成药价值,其制备方法操作简单、易于控制,适于工业化放大。
Description
技术领域
本发明属于药物化学技术领域,具体涉及一种米力农-柠檬酸一水共晶体。
背景技术
米力农(milrinone),化学名为1,6-二氢-2-甲基-6-氧-[3,4-双吡啶]-5-甲腈,分子式为C12H9N3O,分子量为211.22,为白色或类白色结晶性粉末,其结构式如下:
米力农最早是由美国Sterling公司研制开发成功的抗心力衰竭药物,1987年首次在美国被FDA批准,1992年在美国正式上市,随后相继在英国、法国、德国、荷兰、比利时等国上市销售。
米力农为磷酸二酯酶抑制剂,为氨力农的衍生物,作用机理与氨力农相同。口服和静注均有效,兼有正性肌力作用和血管扩张作用,适用于常规维持治疗无效的严重充血性心力衰竭患者的短期治疗,疗效比氨力农(amirinone)强10~30倍,耐受性较好,不良反应少。本品的正性肌力作用主要是通过抑制磷酸二酯酶,使心肌细胞内环磷酸腺苷(CAMP)浓度增高,细胞内钙增加,心肌收缩力加强,心排血量增加。一般认为是高效、低毒、非洋地黄、非拟交感能的强心药,对缺血性心脏病、扩张型心肌病等所致的严重心衰、肺水肿有显效,优于多巴胺类,不良反应少,不增加心率。因此该药物在治疗充血性心力衰竭(CHF)和外周扩血管等方面发挥了越来越重要的作用。
但是米力农在水中几乎不溶,因此在制备米力农的制剂产品时,需要加入特殊的辅料来改善其溶解性。现有的制剂方法通常采用加入助溶剂及pH调节剂来改善其水溶性,而且用量较大。因此,助溶剂的安全性和助溶效果尤为重要。比如专利CN9151919A公开了使用盐酸、磷酸、硫酸等无机酸成盐后再制备成冻干制剂的方法;专利CN106361710A公开了一种先在乙醇+丙酮+水的溶剂中析出晶体,再使用乳酸作为pH调节剂制备制剂的方法。但是仍未能彻底解决米力农本身溶解性差和稳定性差的问题,比如采用无机酸作为助溶剂,盐酸带入的氯有可能引发高氯血症,而磷酸、硫酸等助溶效果不佳;有机酸中,乳酸助溶效果较好,但乳酸是消旋体,由L-乳酸和D-乳酸组成,由于人体内只有代谢L-乳酸的酶且代谢能力有限,如果摄入过量D-乳酸,还会引起代谢紊乱甚至酸中毒。
而且,根据专利CN105663034A公开内容可知,由于米力农几乎不溶于水,在大生产过程中,会带来溶解时间长,溶解不完全,不溶性微粒超标的问题。现有米力农注射液的制备技术,除热原采用活性炭吸附的方法,而活性炭对米力农的吸附量较大,在活性炭使用量为0.05%,吸附米力农可达到约14%,需过量投料才能保证米力农注射液含量符合规定。而过量投料引起生产成本大量增加,且活性炭在吸附热原的同时,本身也会引入过多不明物质,影响产品质量。
基于以上问题,仅仅依靠制剂技术解决米力农溶解度差和稳定性差的问题,不可避免的会出现辅料和助剂用量过大所带来的临床用药安全隐患。因此,提供一种溶解性好、稳定性好且安全性高的米力农的新晶型,成为了本领域技术人员亟待解决的问题。
发明内容
针对现有技术需要大量助剂及pH调节剂来改善米力农溶解性所带来的用药安全隐患,本发明旨在提供一种具有较高溶解性和安全性的米力农-柠檬酸一水共晶体,其从根本上解决了米力农的溶解问题,可以减少后期制剂制备辅料的使用,提高用药安全性。
本发明的具体技术内容如下:
本发明第一方面,提供一种米力农-柠檬酸一水共晶体,其特征在于,共晶体单元结构中米力农、柠檬酸、水的摩尔比为1:1:1。
优选的,所述米力农-柠檬酸一水共晶体,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图至少在8.5±0.2°、15.1±0.2°、17.6±0.2°、20.5±0.2°、25.1±0.2°、26.8±0.2°、26.9±0.2°有特征峰。
优选的,所述米力农-柠檬酸一水共晶体,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图至少在6.7±0.2°2°、8.5±0.2°、9.9±0.2°、15.1±0.2°、16.2±0.2°、17.6±0.2°、18.6±0.2°、20.5±0.2°、21.5±0.2°、25.1±0.2°、26.8±0.2°、26.9±0.2°、35.8±0.2°、39.9±0.2°、43.4±0.2°有特征峰。
优选的,所述米力农-柠檬酸一水共晶体使用Cu-Kα辐射,其特征峰具有图1所示的X射线粉末衍射图谱。
本发明第二方面,提供一种制备米力农-柠檬酸一水共晶体的方法,步骤如下:
将米力农和一水柠檬酸溶于混合溶剂中,加热搅拌,过滤,降温静置,挥发析晶,过滤、干燥制得米力农-柠檬酸一水共晶体。
优选地,所述混合溶剂选自甲醇、乙醇、乙腈、丙酮、三氟乙醇、水中的一种或多种,优选三氟乙醇、乙腈、水的混合溶剂。
优选地,所述米力农与混合溶剂质量体积比为21.1:1~3;优选21.1:1.5~2.5。
优选地,所述米力农与一水柠檬酸的摩尔比为1:0.8~2.0,优选1:1。
优选地,所述加热温度为50~70℃,优选60℃。
优选地,所述降温析晶温度为0~30℃,优选10~15℃。
所述的析晶时间为1~3天。
优选地,所述干燥温度为45~65℃,干燥时间为8~12小时。
优选地,所述制备米力农-柠檬酸一水共晶体的方法,具体步骤如下:
将米力农和一水柠檬酸溶于混合溶剂中,加热至50~70℃搅拌,过滤,降温至0~30℃静置1~3天,挥发析晶,过滤、45~65℃下干燥8~12小时制得米力农-柠檬酸一水共晶体。
所述制备方法中所用原料米力农可按照现有技术中的任何方法进行制备或者购买自市售产品。
本发明第三方面,提供一种米力农-柠檬酸一水共晶体在制备抗心力衰竭药物方面的用途。
最后,本发明提供一种药物组合物,所述药物组合物含有本发明所述的米力农-柠檬酸一水共晶体及其它在药学上可行的组分。
优选的,所述其它药学上可行的组分可以是可联用的药物活性成分和/或药剂学上可接受的辅料成分。
与现有技术相比,本发明取得的有益效果是:
本发明首次提供米力农-柠檬酸一水共晶体,米力农与柠檬酸形成共晶后可显著增强米力农的溶解性及稳定性,提高口服生物利用度,具有很强的药用价值;且其制备方法操作简单,结晶过程易于控制,重现性好,适于工业化生产。
附图说明
图1.米力农与柠檬酸一水共晶体的PXRD谱图。
图2.米力农与柠檬酸一水共晶体的ORTEP图。
图3.米力农与柠檬酸一水共晶体的氢键图。
具体实施方式
晶体结构的确认
本发明所述米力农-柠檬酸一水共晶体测试中X射线晶体数据在日本理学XtaLABSynergy型号仪器上收集,测试温度293(2)K,用Cu-Ka辐射,以ω扫描方式收集数据并进、行Lp校正。用直接法解析结构,差值傅里叶法找出全部非氢原子,所有碳及氮上的氢原子采用理论加氢得到,采用最小二乘法对结构进行精修。测试及解析本发明制备的米力农与柠檬酸一水共晶体结晶形式的晶体学数据如表1所示。
表1米力农-柠檬酸一水共晶体主要晶体学数据
本发明的米力农-柠檬酸一水共晶体的ORTEP图表明,该结晶形式中含有一分子米力农、一分子柠檬酸和一分子水,如附图2所示。本发明的米力农-柠檬酸一水共晶体的氢键图,如附图3所示。依据上述晶体学数据,其对应的X射线粉末衍射图(Cu-Kα)中特征峰详见附图1及表2。
表2米力农-柠檬酸一水共晶体的PXRD峰
下面通过实施例来进一步说明本发明,应该正确理解的是:本发明的实施例仅仅是用于说明本发明,而不是对本发明的限制,所以,在本发明的方法前提下对本发明的简单改进均属本发明要求保护的范围。
实施例中所用材料可按照现有技术中的任何方法进行制备或者购买自市售产品,其中米力农晶体参照专利CN106361710A制备,米力农盐酸盐、米力农甲磺酸盐、米力农磷酸盐和米力农硫酸盐参照CN1951919A制备。
实施例1
将211.2mg米力农和210.1mg一水柠檬酸溶于10mL甲醇中,60℃下加热搅拌至完全溶解,过滤,降至5~10℃静置2~3天,挥发析晶,过滤,滤饼在真空干燥箱中50℃干燥8~10小时制得米力农-柠檬酸一水共晶,收率:91.0%,纯度:99.94%。
实施例2
将211.1mg米力农和168.1mg一水柠檬酸溶于5mL甲醇和10mL乙腈的混合溶剂中,50℃下加热搅拌至完全溶解,过滤,降至0~5℃静置1~2天,挥发析晶,过滤,滤饼在真空干燥箱中60℃干燥8~10小时制得米力农-柠檬酸的共晶,收率:93.5%,纯度:99.95%。
实施例3
将211.2mg米力农和210.0mg一水柠檬酸溶于10mL三氟乙醇、5mL乙腈和5mL水的混合溶剂中,60℃下加热搅拌至完全溶解,过滤,降至10~15℃静置2~3天,挥发析晶,过滤,滤饼在真空干燥箱中60℃干燥8~10小时制得米力农-柠檬酸一水共晶,收率:95.3%,纯度:99.97%。
实施例4
将211.0mg米力农和420.3mg一水柠檬酸溶于5mL乙醇、10mL丙酮和15mL乙腈的混合溶剂中,60℃下加热搅拌至完全溶解,过滤,室温静置2~3天,挥发析晶,过滤,滤饼在真空干燥箱中45℃干燥10~12小时制得米力农-柠檬酸一水共晶,收率:89.2%,纯度:99.92%。
实施例5
将211.2mg米力农和210.0mg一水柠檬酸溶于15mL甲醇和10mL水的混合溶剂中,70℃下加热搅拌至完全溶解,过滤,降至15~20℃静置2~3天,挥发析晶,过滤,滤饼在真空干燥箱中65℃干燥8~10小时制得米力农-柠檬酸一水共晶,收率:94.3%,纯度:99.93%。
稳定性实验
具体的稳定性试验方法参照《中国药典》2020版第四部有关稳定性考察的指导方法进行,纯度检测用HPLC法进行检测,进行3次平行实验,结果取平均值,具体的检测结果见表3。
表3米力农-柠檬酸一水共晶体在光照、高温及高湿条件下的稳定性试验结果
溶解性实验
方法:分别量取10ml的介质(水、0.01mol/L HCl溶液)于西林瓶中,加入过量的待测样品,将西林瓶密封置于25℃恒温水浴中搅拌1小时,经滤膜过滤,取滤液;通过测试标准对照品的吸光度来计算其溶解度。
表4米力农-柠檬酸一水共晶体在不同介质中的溶解度(mg/mL)
Claims (10)
1.一种米力农-柠檬酸一水共晶体,其特征在于,共晶体单元结构中米力农、柠檬酸、水的摩尔比为1:1:1。
2.根据权利要求1所述的晶型,其特征在于,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在8.5±0.2°、15.1±0.2°、17.6±0.2°、20.5±0.2°、25.1±0.2°、26.8±0.2°、26.9±0.2°有特征峰。
3.根据权利要求1所述的晶型,其特征在于,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在6.7±0.2°2°、8.5±0.2°、9.9±0.2°、15.1±0.2°、16.2±0.2°、17.6±0.2°、18.6±0.2°、20.5±0.2°、21.5±0.2°、25.1±0.2°、26.8±0.2°、26.9±0.2°、35.8±0.2°、39.9±0.2°、43.4±0.2°有特征峰。
4.根据权利要求1所述的晶型,其特征在于,其特征峰具有图1所示的X射线粉末衍射图谱。
5.一种权利要求1-4任一所述米力农-柠檬酸一水共晶体的制备方法,其特征在于,包括如下步骤:将米力农和一水柠檬酸溶于混合溶剂中,加热搅拌,过滤,降温静置,挥发析晶,过滤、干燥制得米力农-柠檬酸一水共晶体。
6.根据权利要求5所述的制备方法,其特征在于,所述混合溶剂选自甲醇、乙醇、乙腈、丙酮、三氟乙醇、水中的一种或多种。
7.根据权利要求5所述的制备方法,其特征在于,所述米力农与混合溶剂质量体积比为21.1:1~3。
8.根据权利要求5所述的方法,其特征在于,所述米力农与一水柠檬酸的摩尔比为1:0.8~2.0。
9.根据权利要求5所述的制备方法,其特征在于,具体步骤如下:将米力农和一水柠檬酸溶于混合溶剂中,加热至50~70℃搅拌,过滤,降温至0~30℃静置1~3天,挥发析晶,过滤、45~65℃下干燥8~12小时制得米力农-柠檬酸一水共晶体。
10.一种权利要求1-4任一所述的米力农-柠檬酸一水共晶体在制备抗心力衰竭药物方面的用途。
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