CN117105858A - 一种米力农-3,5-吡啶二甲酸水合物晶型 - Google Patents
一种米力农-3,5-吡啶二甲酸水合物晶型 Download PDFInfo
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- CN117105858A CN117105858A CN202211064068.7A CN202211064068A CN117105858A CN 117105858 A CN117105858 A CN 117105858A CN 202211064068 A CN202211064068 A CN 202211064068A CN 117105858 A CN117105858 A CN 117105858A
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- milrinone
- acid hydrate
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- pyridine dicarboxylic
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/79—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了一种米力农‑3,5‑吡啶二甲酸水合物晶型，所述晶型，使用Cu‑Kα辐射，以2θ表示的X射线衍射谱图至少在9.3±0.2°、12.3±0.2°、15.4±0.2°、24.3±0.2°、25.7±0.2°处有特征峰，属于monoclinic晶系，空间群为P21/n，晶胞参数为： α＝90°、β＝95.6650(10)°、γ＝90°，晶胞体积
Description
技术领域
本发明属于药物化学的技术领域，具体涉及米力农新晶型，具体为米力农-3,5-吡啶二甲酸水合物晶型及其制备方法与应用。
背景技术
米力农(milrinone，式I)，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，其结构式为：
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，水溶性差，体内吸收效果差，口服时不良反应较重；现有的米力农注射液存在稳定性差且容易发生降解的问题，需要添加各种辅料。如专利CN106361710A公开了一种先在乙醇+丙酮+水的溶剂中析出晶体，再使用乳酸作为助溶剂，同时添加一定量的维生素E和谷胱甘肽作为抗氧化剂以提高注射液的稳定性，但使用的新晶型本身并没有克服米力农溶解性差的问题，且乳酸是消旋体，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。再如，专利CN19151919A公开了使用盐酸、磷酸、硫酸、甲磺酸、氢氧化钠、氢氧化钾与米力农成盐后再制备成冻干制剂的方法，但米力农盐自身的溶解度和稳定性仍较差。
而且，除溶解度低外，现有技术中米力农晶体的纯化/结晶方法，收率较低。例如，专利CN104387320A以乙醇-水体系对米力农粗品进行结晶，所得白色米力农晶体的纯度为99.7％、收率83.8％；专利CN102558044A采用采用混合溶剂(DMF加一定温度的水)结晶，先用二甲基甲酰胺(DMF)加热溶解，然后在搅拌情况下加入热水，缓慢析晶，能析出均一大小的白色结晶，纯度99.98％，收率82.6％；专利CN104744357A采用水、乙醇、DMF组成的混合溶剂进行提纯，纯度可达99.90％，但同样收率较低；专利CN103965101B用50vt％乙醇回流溶解，过滤，滤液于-5～10℃搅拌析晶即得白色固体米力农，纯度99.97％，收率82.8％。
综上，提供一种溶解性好、稳定性好，且具有良好成药前景的米力农晶型，成为了本领域技术人员亟待解决的问题。
发明内容
针对现有技术存在的问题，本发明旨在提供一种具有较高溶解性和稳定性好的米力农新晶体形式，即米力农-3,5-吡啶二甲酸水合物晶型。此外本发明提供了一种制备米力农-3,5-吡啶二甲酸水合物的方法，该方法简单便捷、收率高，适合工业化生产。
本发明的具体技术内容如下：
一方面，本发明提供一种米力农-3,5-吡啶二甲酸水合物晶型，使用Cu-Kα辐射，以2θ表示的X射线衍射谱图至少在9.3±0.2°、12.3±0.2°、15.4±0.2°、24.3±0.2°、25.7±0.2°处有特征峰。
优选的，所述的米力农-3,5-吡啶二甲酸水合物晶型，使用Cu-Kα辐射，以2θ表示的X射线衍射谱图至少在6.0±0.2°、9.3±0.2°、11.1±0.2°、12.3±0.2°、13.1±0.2°、15.4±0.2°、20.8±0.2°、21.1±0.2°、24.1±0.2°、24.3±0.2°、25.7±0.2°、26.5±0.2°、35.9±0.2°处有特征峰。
优选的，所述的米力农-3,5-吡啶二甲酸水合物晶型，使用Cu-Kα辐射，其特征峰符合图1所示的X射线粉末衍射图谱。
优选的，所述的米力农-3,5-吡啶二甲酸水合物晶型，其分子式为C38H32N8O12，晶体学参数是：monoclinic晶系，空间群为P21/n，晶胞参数为： α＝90°、β＝95.6650(10)°、γ＝90°，晶胞体积/>
另一方面，本发明提供了一种制备米力农-3,5-吡啶二甲酸水合物的方法，包括如下步骤：
将米力农和3,5-吡啶二甲酸溶于混合溶剂中，加热搅拌，过滤，降温析晶，过滤干燥得到米力农-3,5-吡啶二甲酸水合物晶型。
优选地，所述的混合溶剂为甲醇、水、三氟乙醇的混合溶剂或甲醇、水、丙酮的混合溶剂。
优选地，所述混合溶剂的中甲醇、水、和三氟乙醇或丙酮的体积比为1：0.01～0.125：1～2；进一步优选为1：0.01～0.125：1.25～1.5；进一步优选为1：0.05～0.0625：1.25～1.5。
优选地，所述的米力农与混合溶剂的质量体积比为5～12：1；其中米力农的质量以mg计，混合溶剂的体积以ml计。
优选地，所述的米力农与3，5-吡啶二甲酸的摩尔比为1：0.8～1.2，优选1:1。
优选地，所述的加热温度为50～70℃，优选60℃。
所述的降温析晶温度为0～30℃，优选地，降温析晶温度为10～15℃。
所述的析晶时间为10～62小时。
所述干燥温度为50～65℃，干燥时间为8～15小时。
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。
最后，本发明提供一种口服药物组合物，所述药物组合物含有本发明所述的米力农-3,5-吡啶二甲酸水合物晶型及其它在药学上可行的组分。
优选的，所述的其它药学上可行的组分可以是可联用的药物活性成分和/或药剂学上接受的辅料成分。
晶体结构的确认
本发明所述米力农-3,5-吡啶二甲酸水合物晶型测试中，X射线晶体数据在日本理学XtaLAB Synergy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-3,5-吡啶二甲酸水合物晶型的晶体学数据(如表1)是:monoclinic晶系，空间群为P21/n，晶胞参数为： α＝90°、β＝95.6650(10)°、γ＝90°，晶胞体积/>
表1米力农-3,5-吡啶二甲酸水合物晶型主要晶体学数据
本发明的米力农-3,5-吡啶二甲酸水合物晶型的ORTEP图表明，该结晶形式中含有两分子米力农、两分子3,5-吡啶二甲酸和两分子水，如附图2所示。本发明的米力农-3,5-吡啶二甲酸水合物的堆积图，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-3,5-吡啶二甲酸水合物晶型的PXRD峰
与现有技术相比，本发明取得的技术效果是：
本发明提供了一种新的米力农-3,5-吡啶二甲酸水合物晶型，其制备方法操作简单，结晶过程易于控制，重现性好。米力农-3,5-吡啶二甲酸水合物晶型具有较好的稳定性和溶解度，能显著提高米力农的提高口服生物利用度，具有很强的成药价值。
附图说明
图1.米力农-3,5-吡啶二甲酸水合物晶型的PXRD谱图。
图2.米力农-3,5-吡啶二甲酸水合物晶型的ORTEP图。
图3.米力农-3,5-吡啶二甲酸水合物晶型的堆积图。
具体实施方式
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1
将211.2mg米力农和167.1mg 3,5-吡啶二甲酸溶于8mL甲醇和10mL三氟乙醇的混合溶剂中，加入0.5ml水，60℃水浴加热搅拌至完全溶解，过滤，10～15℃降温静置挥发析晶48h，然后过滤，50℃干燥12h，得到米力农-3,5-吡啶二甲酸水合物，收率：96.5％，纯度：99.92％。
实施例2
将211.2mg米力农和200.5mg 3,5-吡啶二甲酸溶于16mL甲醇和22ml丙酮的混合溶剂中，加入1ml水，60℃水浴加热搅拌至完全溶解，过滤，10～15℃降温静置挥发析晶60h，过滤，60℃干燥8h，得到米力农-3,5-吡啶二甲酸水合物，收率：93.8％，纯度：99.95％。
实施例3
将211.2mg米力农和133.7mg 3,5-吡啶二甲酸溶于10mL甲醇和15ml丙酮的混合溶剂中，加入0.5ml水，60℃水浴加热搅拌至完全溶解，过滤，10～15℃降温静置挥发析晶36h，过滤，55℃干燥10h，得到米力农-3,5-吡啶二甲酸水合物，收率：92.5％，纯度：99.91％。
实施例4
将211.2mg米力农和167.1mg 3,5-吡啶二甲酸溶于8mL甲醇和8ml三氟乙醇的混合溶剂中，加入0.5ml水，60℃水浴加热搅拌至完全溶解，过滤，10～15℃降温静置挥发析晶48h，过滤，60℃干燥8h，得到米力农-3,5-吡啶二甲酸水合物，收率：88.3％，纯度：99.92％。
实施例5
将211.2mg米力农和200.5mg 3,5-吡啶二甲酸溶于16mL甲醇和32ml丙酮的混合溶剂中，加入1ml水，60℃水浴加热搅拌至完全溶解，过滤，10～15℃降温静置挥发析晶60h，过滤，60℃干燥8h，得到米力农-3,5-吡啶二甲酸水合物，收率：87.5％，纯度：99.93％。
实施例6
将211.2mg米力农和133.7mg 3,5-吡啶二甲酸溶于10mL甲醇和15ml丙酮的混合溶剂中，60℃水浴加热搅拌至完全溶解，过滤，25℃静置挥发析晶36h，过滤，55℃干燥10h，得到米力农-3,5-吡啶二甲酸水合物，收率：83.7％，纯度：99.91％。
实施例7
将211.2mg米力农和250.6mg 3,5-吡啶二甲酸溶于8mL甲醇和10mL乙腈的混合溶剂中，加入2ml水，60℃水浴加热搅拌至完全溶解，过滤，10～15℃降温静置挥发析晶48h，然后过滤，50℃干燥12h，得到米力农-3,5-吡啶二甲酸水合物，收率：80.1％，纯度：99.92％。
对比例1米力农重结晶
在米力农粗品中加入粗品质量20倍的混合溶剂(体积比，乙醇:水:二甲基甲酰胺＝4:4:1)，缓慢加热至60℃，待粗品全部溶解，加入粗品质量15％的活性炭脱色1小时，趁热抽滤，过滤掉活性炭；将抽滤所得滤液在缓慢搅拌下冷却至室温，析晶，再次抽滤，用乙醇洗涤再次抽滤所得滤饼，然后在60℃下烘干，得类白色晶体；在此类白色晶体中加入该类白色晶体质量20倍的上述混合溶剂，缓慢加热至60℃，待类白色晶体全部溶解，在缓慢搅拌下冷却至室温，析晶，得到白色米力农晶体，纯度：99.90％，收率80.5％。
对比例2
将10g米力农置于500ml烧杯中，滴加0.1N氢氧化钠水溶液并搅拌使之溶解，至pH值7～8，加入溶液体积5倍量的丙酮，冷却，析出白色沉淀，过滤，滤饼用丙酮洗2次，晾干，然后105℃干燥2小时，得米力农钠盐。收率90.2％，纯度99.89％。
对比例3
将10g米力农置于500mL烧杯中，滴加0.1N盐酸溶液并搅拌使之溶解，使溶液pH值4～4.5，加入溶液体积5倍量的丙酮，冷却，析出白色沉淀，过滤，滤饼用丙酮洗2次，凉干，然后105℃干燥2小时，得米力农盐酸盐。收率91.0％，纯度99.91％。
对比例4
将米力农(169.0mg)和没食子酸(136.1mg)等摩尔比混合均匀，逐步添加50μl水并在砂浆中充分研磨45分钟。将研磨后的粉末样品溶解在最小量的甲醇/乙腈/H2O混合溶剂中，甲醇、乙腈、水的体积比为2:1:1，在60℃下快速剧烈搅拌约3h。冷却至室温后过滤所得反应混合物。向过滤液中添加上述粉末样品作为晶种，并使溶液静置以缓慢蒸发1天，获得无色结晶。收率83.5％，纯度99.90％。
验证实施例
1、稳定性实验
具体的稳定性试验方法参照《中国药典》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，结果如表3所示。
表3.不同米力农晶体在光照、高温及高湿条件下的稳定性考察结果
注：本发明实施例1-7制备的米力农-3,5-吡啶二甲酸水合物均具有相近的稳定性效果，表3中米力农-3,5-吡啶二甲酸水合物的稳定性结果以实施例1制备的晶型为例进行测试。
2、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；在270nm的波长处分别测定吸光度，通过测试标准对照品的吸光度来计算其溶解度，结果如表4所示。
表4.不同米力农晶体在不同介质中的溶解度(mg/mL)
注：本发明实施例1-7制备的米力农-3,5-吡啶二甲酸水合物均具有相近的溶解度，表4中米力农-3,5-吡啶二甲酸水合物的溶解度以实施例1制备的晶型为例进行测试。
3、药代动力学试验
方法：体内PK试验采用单剂量口服给药的方法进行，雄性SD大鼠(220-260g)在0％-60％的恒定湿度的安静环境中喂养，温度为25±1℃，从早上7点到晚上7点有节奏的光照。PK实验严格按照中国科技部发布的《实验室管理指南》进行。实验前，将受试大鼠随机分成三组(每组n＝5)，让其自由饮水，禁食过夜。所有测试的样品都悬浮在植物油中，然后以10mg/kg米力农或其等效物的单剂量口服给药。给药后，根据给药情况在设计时间点采集0.5mL血样，检测米力农的血药浓度，结果如表5所示。
表5不同米力农晶体的药代动力学研究结果
注：与对比例1晶体比较，*P<0.05，差异有统计学意义。
试验结果表明，本发明提供的米力农-3,5-吡啶二甲酸水合物相比于米力农的其它晶型起效更快，口服生物利用度更高。
Claims (10)
1.一种米力农-3,5-吡啶二甲酸水合物晶型，其特征在于，使用Cu-Kα辐射，以2θ表示的X射线衍射谱图至少在9.3±0.2°、12.3±0.2°、15.4±0.2°、24.3±0.2°、25.7±0.2°处有特征峰。
2.根据权利要求1所述的米力农-3,5-吡啶二甲酸水合物晶型，其特征在于，使用Cu-Kα辐射，以2θ表示的X射线衍射谱图至少在6.0±0.2°、9.3±0.2°、11.1±0.2°、12.3±0.2°、13.1±0.2°、15.4±0.2°、20.8±0.2°、21.1±0.2°、24.1±0.2°、24.3±0.2°、25.7±0.2°、26.5±0.2°、35.9±0.2°处有特征峰。
3.根据权利要求1所述的米力农-3,5-吡啶二甲酸水合物晶型，其特征在于，使用Cu-Kα辐射，其特征峰符合图1所示的X线粉末衍射图谱。
4.根据权利要求1所述的米力农-3,5-吡啶二甲酸水合物晶型，其特征在于，所述晶型的晶体学参数是：monoclinic晶系，空间群为P21/n，晶胞参数为： α＝90°、β＝95.6650(10)°、γ＝90°，晶胞体积/>
5.一种权利要求1～4任一项所述米力农-3,5-吡啶二甲酸水合物晶型的制备方法，其特征在于，包括如下步骤：将米力农和3,5-吡啶二甲酸溶于混合溶剂中，加热搅拌，过滤，降温析晶，过滤，干燥得到米力农-3,5-吡啶二甲酸水合物晶型。
6.根据权利要求5所述的制备方法，其特征在于，所述混合溶剂为甲醇、水、三氟乙醇的混合溶剂，或甲醇、水、丙酮的混合溶剂。
7.根据权利要求6所述的制备方法，其特征在于，所述混合溶剂中甲醇、水、和三氟乙醇或丙酮的体积比为1：0.01～0.125：1～2。
8.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的质量体积比为5～12：1；其中米力农的质量以mg计，混合溶剂的体积以ml计。
9.根据权利要求5所述的制备方法，其特征在于，所述降温析晶的温度为0～30℃，优选为10～15℃。
10.一种口服药物组合物，其特征在于，所述组合物包含米力农-3,5-吡啶二甲酸水合物及其它药学上可接受的组分。
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