CN116253680A - 一种米力农与酮咯酸共晶及其制备方法 - Google Patents
一种米力农与酮咯酸共晶及其制备方法 Download PDFInfo
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- 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
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- A—HUMAN NECESSITIES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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Abstract
本发明涉及药物共晶技术领域,具体涉及一种米力农‑酮咯酸共晶及其制备方法,所述共晶由米力农与酮咯酸按摩尔比1:1结合形成,使用Cu‑Kα辐射,以2θ表示的X射线衍射谱图在7.9±0.2°、13.3±0.2°、15.7±0.2°、15.8±0.2°、17.8±0.2°处有特征峰;本发明提供的米力农‑酮咯酸共晶具有较好的稳定性,较高的溶解度,制备方法简单易行,成本低廉,便于规模化生产。
Description
技术领域
本发明涉及药物共晶技术领域,具体涉及一种米力农与酮咯酸药物共晶及其制备方法。
背景技术
米力农,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:
米力农是一种强心药,具有增强心肌收缩力和直接扩张血管作用,其作用机理与氨力农相同,耐受性较好。有扩张血管平滑肌作用,能降低心脏负荷,还能极好地改善肾脏和肌肉供血,无严重不良反应。适用于对洋地黄、利尿剂、血管扩张剂治疗无效或效果欠佳的各种原因引起的急、慢性顽固性充血性心力衰竭。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,容易带来毒副作用。如专利CN106361710B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;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,但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。另外,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,影响产品质量。
综上,现有技术仍未能彻底解决米力农自身溶解性差和稳定性差的问题。
发明内容
鉴于现有技术的不足,本申请旨在提供一种具有较高溶解性和良好稳定性的米力农新晶型,具体提供了一种米力农-酮咯酸共晶,并提供了其制备方法。
酮咯酸(Ketorolac)是一种强效镇痛、中度抗炎作用的非甾体抗炎药,该药镇痛作用同吗啡相当,强于阿司匹林、消炎痛及萘普生。化学名称:(+/-)-5-苯甲酰基-2,3-二氢-1H-吡咯并吡咯烷-1-甲酸,分子式:C15H13NO3,结构式为:
本发明的具体a技术内容如下:b
本发明第一方面,提供了米力农-酮咯酸共晶,所述共晶的晶体单元中,米力农与酮咯酸的摩尔比为1:1。
优选的,所述米力农-酮咯酸共晶,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在7.9±0.2°、13.3±0.2°、15.7±0.2°、15.8±0.2°、17.8±0.2°处有特征峰。
优选的,所述米力农-酮咯酸共晶,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在2θ值为7.9±0.2°、8.9±0.2°、10.2±0.2°、13.3±0.2°、15.4±0.2°、15.7±0.2°、15.8±0.2°、17.6±0.2°、17.8±0.2°、30.0±0.2°、31.3±0.2°处具有特征峰。
优选的,所述米力农-酮咯酸共晶,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。
本发明第二方面,提供了一种米力农-酮咯酸共晶的制备方法,其具体步骤包括:将米力农和酮咯酸加入溶剂A中,加热溶解,溶液澄清后,降温析晶,过滤干燥得到米力农-酮咯酸共晶。
优选的,所述溶剂A选自甲醇、丙酮、乙腈和水中的一种或两种。
优选的,所述米力农与酮咯酸的摩尔比为1:0.8~1.2;进一步优选为1:1。
优选的,所述米力农与溶剂A的质量体积比为3~6:1,其中质量以mg计,体积以mL计。
优选的,所述溶解加热的温度为40~60℃,进一步优选为50℃。
优选的,所述降温析晶的温度为10~20℃。
优选的,所述析晶时间为48~72h。
本申请的第三方面,提供一种药物组合物,该组合物包含本发明所述的米力农-酮咯酸共晶和其它药学上可接受的组分。
优选的,所述药物组合物可使用标准和常规的技术,使本发明化合物与制剂学上可接受的固体或液体载体结合,以及使之任意地与制剂学上可接受的辅助剂和赋形剂结合制备而成。
本发明第四方面,还提供了米力农与酮咯酸药物共晶在制备消炎镇痛药物和治疗心力衰竭中的用途。
晶体结构的确认
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CuKa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。
表1 米力农与酮咯酸药物共晶主要晶体学数据
本发明提供的米力农-酮咯酸共晶的ORTEP图表明,该结晶形式中一分子米力农结合一分子酮咯酸,如附图3所示。本发明的米力农-酮咯酸共晶的氢键图,如附图4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 米力农与酮咯酸药物共晶的PXRD峰
本发明中TGA/DSC热分析测试仪及测试条件:TGA/DSC热分析仪:METTLER TOLEDOTGA/DSC3+;动态温度段:30~300℃;加热速率:10℃/min;程序段气体N2;气体流量:50mL/min;坩埚:铝坩埚40μl。
本发明制备的米力农与酮咯酸药物共晶的TGA/DSC测试结果如图2所示,DSC图谱在175.78~210.57℃范围内出现吸热峰,对应吸热峰的峰值为193.22℃;其热重分析(TGA)只存在一个失重台阶,表明该米力农与酮咯酸共晶不存在溶剂,且结构稳定。
本发明所述方法制备的米力农与酮咯酸药物共晶相对于目前报道的米力农晶型具有以下优势:
(1)稳定性高。米力农-酮咯酸药物共晶在固体状态具有较高的稳定性。在高温试验和高湿环境放置后,HPLC纯度仍然高于99.9%,相对于现有米力农晶型,其固体状态稳定性好。
(2)溶解度高。米力农-酮咯酸药物共晶相比其它米力农晶体,溶解度显著提高。
(3)本发明提供的药物共晶的制备方法操作简单,结晶过程易于控制,重现性好,适合工业化生产。
附图说明
图1.米力农与酮咯酸药物共晶的PXRD谱图。
图2.米力农与酮咯酸药物共晶的TGA/DSC图。
图3.米力农与酮咯酸药物共晶的ORTEP图。
图4.米力农与酮咯酸药物共晶的氢键图。
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。
实施例1
将211.2mg米力农和204.2mg酮咯酸加入40mL丙酮中,40℃水浴加热搅拌溶解,溶液澄清后,过滤,滤液10~15℃静置析晶48h,过滤,干燥,得到米农-酮咯酸共晶体,收率:92.6%,HPLC:99.92%。
实施例2
将和211.2mg米力农和255.2mg酮咯酸加入70mL乙腈中,60℃水浴加热搅拌溶解,溶液澄清后,过滤,滤液10~15℃静置析晶72h,过滤,干燥,得到米力农-酮咯酸共晶体,收率:96.1%,HPLC:99.96%。
实施例3
将211.2mg米力农和255.2mg酮咯酸加入35mL丙酮中,50℃水浴加热搅拌溶解,溶液澄清后,过滤,滤液15~20℃静置析晶48h,过滤,干燥,得到米力农-酮咯酸共晶体,收率:93.5%,HPLC:99.90%。
实施例4
将211.2mg米力农和306.2mg酮咯酸加入20mL水和40mL甲醇的混合溶剂中,60℃水浴加热搅拌溶解,溶液澄清后,过滤,滤液10~15℃静置析晶48h,过滤,干燥,得到米力农-酮咯酸共晶体,收率:94.2%,HPLC:99.94%。
实施例5
将211.2mg米力农和255.2mg酮咯酸加入40mL乙醇中,50℃水浴加热搅拌溶解,溶液澄清后,过滤,滤液15~20℃静置析晶48h,过滤,干燥,得到米力农-酮咯酸共晶体,收率:85.5%,HPLC:99.90%。
实施例6
将140.8mg米力农和255.2mg酮咯酸加入60mL四氢呋喃中,50℃水浴加热搅拌溶解,溶液澄清后,过滤,滤液室温静置析晶48h,过滤,干燥,得到米力农-酮咯酸共晶体,收率:80.3%,HPLC:99.90%。
实施例7
将211.2mg米力农和255.2mg酮咯酸加入30mL乙腈中,50℃水浴加热搅拌溶解,溶液澄清后,过滤,滤液0~5℃静置析晶24h,过滤,干燥,得到米力农-酮咯酸共晶体,收率:82.8%,HPLC:99.89%。
对比例1
参照中国专利CN106361710B实施例1制备米力农晶体。
对比例2
参照中国专利CN104387320B实施例1所述的方法,以乙醇-水体系对米力农进行重结晶,得到米力农白色晶体。
对比例3
参照中国专利CN102558044A说明书[0013]的方法,制备米力农晶体。
对比例4
参照中国专利CN1951919A实施例1的方法,制备米力农钠盐。
对比例5
参照中国专利CN1951919A实施例3的方法,制备米力农盐酸盐。
验证实施例
1、稳定性试验
(1)试验材料:实施例2制备的米力农-酮咯酸共晶、对比例1-3制备的米力农晶体,对比例4制备的米力农钠盐、对比例5制备的米力农盐酸盐。
(2)试验方法:参照《中国药典》(2020年版)第四部附录<9001原料药物与制剂稳定性试验指导原则>的方法进行试验,高温试验条件:60℃;强光照射试验条件:4500lx±500lx;高湿试验条件:温度25℃,相对湿度90%±5%。纯度用HPLC法进行检测,分别进行三次平行试验,结果取平均值。
(3)试验结果:试验结果见表3。
表3 稳定性试验测定结果
实验结果表明,本发明实施例制备的米力农-酮咯酸共晶纯度高,且在高温、高湿、强光条件下样品纯度变化较小,稳定性好。
2、溶解度试验
将米力农-酮咯酸共晶、对比例1-3米力农晶体、米力农钠盐、米力农盐酸盐分别置于37℃下的恒温的介质中(0.01mol/L HCl和水)中搅拌,使其过度饱和,取饱和溶液过滤,取续滤液测定,按外标法计算饱和溶液的浓度,结果如表4所示。
表4 溶解度试验结果
试验结果表明,米力农-酮咯酸共晶在0.01mol/L HCl和水中的溶解度相比于米力农的其它晶型,溶解度有了显著提高,有助于提高其生物利用度。
Claims (10)
1.一种米力农-酮咯酸共晶,其特征在于,所述共晶使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在7.9±0.2°、13.3±0.2°、15.7±0.2°、15.8±0.2°、17.8±0.2°处有特征峰。
2.根据权利要求1所述的米力农-酮咯酸共晶,其特征在于,所述共晶使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在2θ值为7.9±0.2°、8.9±0.2°、10.2±0.2°、13.3±0.2°、15.4±0.2°、15.7±0.2°、15.8±0.2°、17.6±0.2°、17.8±0.2°、30.0±0.2°、31.3±0.2°处具有特征峰。
3.根据权利要求1所述的米力农-酮咯酸共晶,其特征在于,所述共晶使用Cu-Kα辐射,其特征峰符合图1所示的X射线粉末衍射图谱。
4.根据权利要求1所述的米力农-酮咯酸共晶,其特征在于,所述共晶的晶体单元中,米力农与酮咯酸的摩尔比为1:1。
5.一种制备权利要求1~4任一项所述米力农-酮咯酸共晶的制备方法,其特征在于,具体步骤包括:将米力农和酮咯酸加入溶剂A中,加热溶解,溶液澄清后,降温析晶,过滤干燥,得到米力农-酮咯酸共晶。
6.根据权利要求5所述的制备方法,其特征在于,所述溶剂A选自甲醇、丙酮、乙腈和水中的一种或两种。
7.根据权利要求5所述的制备方法,其特征在于,所述米力农与酮咯酸的摩尔比为1:0.8~1.2。
8.根据权利要求5所述的制备方法,其特征在于,所述米力农与溶剂A的质量体积比为3~6:1,其中质量以mg计,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10~20℃,析晶时间为48-72h。
10.一种药用组合物,其特征在于:所述药用组合物包含所述的共晶及其它药学上可接受的组分。
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