CN116239528A - 一种米力农多元共晶体 - Google Patents
一种米力农多元共晶体 Download PDFInfo
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- CN116239528A CN116239528A CN202111492121.9A CN202111492121A CN116239528A CN 116239528 A CN116239528 A CN 116239528A CN 202111492121 A CN202111492121 A CN 202111492121A CN 116239528 A CN116239528 A CN 116239528A
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- milrinone
- crystal
- baicalein
- methanol
- acetone
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- PZRHRDRVRGEVNW-UHFFFAOYSA-N milrinone Chemical compound N1C(=O)C(C#N)=CC(C=2C=CN=CC=2)=C1C PZRHRDRVRGEVNW-UHFFFAOYSA-N 0.000 title claims abstract description 51
- 229960003574 milrinone Drugs 0.000 title claims abstract description 50
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 19
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- 229940015301 baicalein Drugs 0.000 claims description 18
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 6
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- RNLQIBCLLYYYFJ-UHFFFAOYSA-N amrinone Chemical compound N1C(=O)C(N)=CC(C=2C=CN=CC=2)=C1 RNLQIBCLLYYYFJ-UHFFFAOYSA-N 0.000 description 1
- 239000012752 auxiliary agent Substances 0.000 description 1
- IKIIZLYTISPENI-ZFORQUDYSA-N baicalin Chemical compound O1[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 IKIIZLYTISPENI-ZFORQUDYSA-N 0.000 description 1
- 229960003321 baicalin Drugs 0.000 description 1
- AQHDANHUMGXSJZ-UHFFFAOYSA-N baicalin Natural products OC1C(O)C(C(O)CO)OC1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC=CC=1)O2 AQHDANHUMGXSJZ-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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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
- C07D213/84—Nitriles
- C07D213/85—Nitriles in position 3
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C31/00—Saturated compounds having hydroxy or O-metal groups bound to acyclic carbon atoms
- C07C31/02—Monohydroxylic acyclic alcohols
- C07C31/04—Methanol
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
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- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
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Abstract
本发明提供了一种米力农多元共晶体，所述多元共晶体的晶体单元中含有摩尔比为2：2：2：1的米力农‑黄芩素‑甲醇‑丙酮分子；使用Cu‑Kα辐射，以2θ表示的X射线衍射谱图至少在7.7±0.2°、8.5±0.2°、12.9±0.2°、14.2±0.2°、25.6±0.2°、26.2±0.2°有特征峰。
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，具体为米力农与黄芩素的共晶体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(amirinone)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，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Cl-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。
黄芩素为黄酮类化合物，具有多种药理作用。比如具有降低脑血管阻力，改善脑血循环、增加脑血流量及抗血小板凝集的作用。临床用于脑血管病后瘫痪的治疗。黄芩素是体内的有效成分，黄芩素进入动物体内后，在血液中迅速转化为黄芩苷及其他代谢物。但是由于黄芩素不溶于水，亲水性很差，所以导致难以被吸收，口服吸收差的问题，很大程度上限制了它的临床应用。因而对于黄芩素的制剂开发存在较大的难度。
基于以上问题，仅仅依靠制剂技术解决米力农溶解性和稳定性的问题，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、稳定性高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
针对以上所述的问题，本发明通过研究发现，低水溶性的米力农和黄芩素可以形成稳定存在的多元共晶体，且二者形成的晶体具有米力农或黄芩素所不具备的优异的理化性质，比如显著改善的溶解性、显著改善的稳定性等。此外本发明提供了一种制备米力农多元共晶体的方法，该方法简单、便捷，适合工业化生产。
本发明的具体技术内容如下：
一方面，本发明提供了一种米力农多元共晶体，所述多元共晶体的晶体单元中含有摩尔比为2：2：2：1的米力农-黄芩素-甲醇-丙酮分子。
优选的，所述的米力农多元共晶体，使用Cu-Kα辐射，以2θ表示的X射线衍射谱图至少在7.7±0.2°、8.5±0.2°、12.9±0.2°、14.2±0.2°、25.6±0.2°、26.2±0.2°有特征峰。
优选的，所述的米力农多元共晶体，使用Cu-Kα辐射，以2θ表示的X射线衍射谱图至少在7.0±0.2°、7.7±0.2°、8.5±0.2°、12.1±0.2°、12.9±0.2°、14.2±0.2°、16.9±0.2°、17.1±0.2°、20.8±0.2°、21.1±0.2°、23.0±0.2°、25.6±0.2°、26.2±0.2°有特征峰。
优选的，所述的米力农多元共晶体，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，所述的米力农多元共晶体，其分子式为C59H52N6O15，晶体学参数是：三斜晶系，空间群为P-1，晶胞参数为：
α＝97.1580(10)°、β＝98.9850(10)°、γ＝91.7270(10)°，晶胞体积/>
另一方面，本发明提供了一种制备米力农多元共晶体的方法，包括如下步骤：
将米力农和黄芩素溶于甲醇和丙酮的混合溶剂中，加热搅拌，过滤，降温静置挥发析晶，过滤干燥得到米力农-黄芩素-甲醇-丙酮组成的多元共晶体。
优选地，所述的米力农与混合溶剂的质量体积比为7～20:1，mg/ml；优选10～15:1，mg/ml。
优选地，所述的混合溶剂中甲醇与丙酮的体积比为1：1～2。
优选地，所述的米力农与黄芩素的摩尔比为1：0.8～2.0。
优选地，所述的加热温度为50～70℃；优选为60℃。
优选地，所述的加热搅拌的时间为1～6h。
优选地，所述的降温析晶温度为0～20℃；进一步优选地，降温析晶温度为0～5℃。
优选地，所述的析晶时间为12～72小时。
优选地，所述干燥温度为50～80℃，干燥时间为5～24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，本发明提供一种药物组合物，所述药物组合物含有本发明所述的米力农多元共晶体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-黄芩素-甲醇-丙酮共晶体测试中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-甲醇-丙酮共晶体结晶形式的晶体学数据(如表1)是:三斜晶系，空间群为P-1，晶胞参数为：
α＝97.1580(10)°、β＝98.9850(10)°、γ＝91.7270(10)°，晶胞体积/>
表1米力农多元共晶体的主要晶体学数据
本发明的米力农-黄芩素-甲醇-丙酮共晶体的ORTEP图表明，该结晶形式中含有两分子米力农、两分子黄芩素、一分子丙酮和两分子甲醇，如图2所示。本发明的米力农-黄芩素-甲醇-丙酮共晶的氢键图，如图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)中特征峰详见图1及表2。
表2米力农多元共晶体的PXRD峰
与现有技术相比，本发明取得的技术效果是：
本发明首次提供米力农-黄芩素-甲醇-丙酮共晶体，其制备方法操作简单，结晶过程易于控制，重现性好。二者形成共晶后可显著增强米力农的溶解性，提高口服生物利用度，具有很强的成药价值。
附图说明
图1.米力农多元共晶体的PXRD谱图。
图2.米力农多元共晶体的ORTEP图。
图3.米力农多元共晶体的氢键图。
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300.0mg米力农和422.1mg黄芩素溶于10mL甲醇和10mL丙酮的混合溶剂中，55℃水浴加热搅拌5h，过滤，滤液于0～5℃下静置析晶72h，过滤，65℃干燥12小时得到米力农-黄芩素-甲醇-丙酮共晶体，收率：92％，纯度：99.87％。
实施例2
将250.0mg米力农和352.3mg黄芩素溶于10mL甲醇和15mL丙酮的混合溶剂中，55℃水浴加热搅拌6h，过滤，滤液于0～5℃下静置析晶72h，过滤，65℃干燥12小时得到米力农-黄芩素-甲醇-丙酮共晶体，收率：91％，纯度：99.89％。
实施例3
将150.0mg米力农和211.3mg黄芩素溶于5mL甲醇和10mL丙酮的混合溶剂中，50℃水浴加热搅拌1h，过滤，滤液于0～5℃下静置析晶48h，过滤，65℃干燥12小时得到米力农-黄芩素-甲醇-丙酮共晶体，收率：89％，纯度：99.89％。
实施例4
将300.0mg米力农和422.1mg黄芩素溶于5mL甲醇和10mL丙酮的混合溶剂中，50℃水浴加热搅拌5h，过滤，滤液于10～15℃下静置析晶72h，过滤，60℃干燥16小时得到米力农-黄芩素-甲醇-丙酮共晶体，收率：87％，纯度：99.86％。
实施例5
将100.0mg米力农和128.1mg黄芩素溶于10mL甲醇和5mL丙酮的混合溶剂中，50℃水浴加热搅拌5h，过滤，滤液于20～25℃下静置析晶72h，过滤，65℃干燥24小时得到米力农-黄芩素-甲醇-丙酮共晶体，收率：81％，纯度：99.87％。
稳定性试验
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，具体的检测结果见表3。实验中使用的米力农晶体参照专利CN106361710A制备。
表3米力农多元共晶体的稳定性试验结果
溶解性实验
方法：分别量取10mL的介质(水、0.01mol/LHCl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；HPLC检测，按外标法计算饱和溶液的浓度。
表4米力农多元共晶体的溶解性(mg/mL)
Claims (10)
1.一种米力农多元共晶体，其特征在于，所述多元共晶体的晶体单元中含有摩尔比为2：2：2：1的米力农-黄芩素-甲醇-丙酮分子。
2.如权利要求1所述的共晶体，其特征在于，所述的米力农多元共晶体，使用Cu-Kα辐射，以2θ表示的X射线衍射谱图至少在7.7±0.2°、8.5±0.2°、12.9±0.2°、14.2±0.2°、25.6±0.2°、26.2±0.2°有特征峰。
3.如权利要求1所述的共晶体，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7.0±0.2°、7.7±0.2°、8.5±0.2°、12.1±0.2°、12.9±0.2°、14.2±0.2°、16.9±0.2°、17.1±0.2°、20.8±0.2°、21.1±0.2°、23.0±0.2°、25.6±0.2°、26.2±0.2°有特征峰。
4.如权利要求1所述的共晶体，其特征在于，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。
5.如权利要求1所述的共晶体，其特征在于，其分子式为C59H52N6O15，晶体学参数是：三斜晶系，空间群为P-1，晶胞参数为：
α＝97.1580(10)°、β＝98.9850(10)°、γ＝91.7270(10)°，晶胞体积/>
6.一种制备权利要求1～5任一所述的米力农多元共晶体的方法，包括如下步骤：
将米力农和黄芩素溶于甲醇和丙酮的混合溶剂中，加热搅拌，过滤，降温静置析晶，过滤干燥得到米力农-黄芩素-甲醇-丙酮组成的多元共晶体。
7.如权利要求6所述的制备方法，其特征在于，所述的米力农与混合溶剂的质量体积比为7～20:1，mg/ml。
8.如权利要求6所述的制备方法，其特征在于，所述的混合溶剂中甲醇与丙酮的体积比为1：1～2。
9.如权利要求6所述的制备方法，其特征在于，所述的加热搅拌的时间为1～6h。
10.如权利要求6所述的制备方法，其特征在于，所述的降温析晶温度为0～20℃。
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