CN114437076B - 一种酮咯酸与异烟肼共晶及其制备方法 - Google Patents
一种酮咯酸与异烟肼共晶及其制备方法 Download PDFInfo
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
本发明属于药物共晶技术领域,具体提供了一种酮咯酸与异烟肼共晶,本发明制备的酮咯酸与异烟肼共晶使用Cu‑Kα辐射,以2θ表示的X射线衍射谱图在4.7±0.2°、9.4±0.2°、9.9±0.2°、11.3±0.2°、14.0±0.2°、15.8±0.2°、18.4±0.2°、18.8±0.2°处有特征峰;本发明制备的酮咯酸与异烟肼共晶,收率、纯度高,制备工艺简单,在pH6.8磷酸缓冲溶液中具有较高的溶解度,为制备消炎镇痛药物提供了一种可靠的活性成分。
Description
技术领域
本发明涉及药物共晶技术领域,具体涉及一种酮咯酸与异烟肼共晶及其制备方法与应用。
背景技术
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,CAS号:74103-06-3,分子式:C15H8D5NO3,结构式如下:
目前关于酮咯酸的相关报道较多,主要关于其制备、制剂、理化性质及药理等性质的报道,关于其晶体结构的报道较少。酮咯酸存在多晶型现象,文章Crystal Forms ofKetorolac(Arch Pharm Res,2004,27,357-360)公开了酮咯酸晶型I,晶型II,晶型III,晶型IV的晶型表征数据和制备方法,并对晶型Ⅰ~Ⅳ的溶解度和稳定性进行了研究。结果表明,晶型I的溶解度最高,但10mg晶型Ⅰ在1L蒸馏水完全溶解需要3小时左右,晶型Ⅱ~Ⅳ不能完全溶解,尤其是晶型Ⅳ,5小时后仅能溶解64%;晶型I和晶型Ⅲ稳定性好,但晶型Ⅱ和晶型Ⅳ会出现转晶现象。可见,不同的酮咯酸晶型具有不同的稳定性、物理性质、溶解度等,而这些性质可以直接影响原料药和制剂的稳定性和生物利用度。但现有晶型的溶解性和稳定性还有待进一步提高。
异烟肼对结核杆菌有抑制和杀灭作用,其生物膜穿透性好,由于疗效佳、毒性小、价廉、口服方便,被列为首选抗结核药。本发明通过共晶方法制备得到一种酮咯酸与异烟肼共晶,该共晶能够显著改善酮咯酸的溶解度和稳定性等特性,从而达到提高其口服吸收效果的目的。
发明内容
鉴于现有技术的不足,本申请的目的是提供一种酮咯酸与异烟肼共晶及其制备方法与应用。本发明提供的酮咯酸与异烟肼共晶,结晶形式中含有一分子酮咯酸和一分子异烟肼,具有确切的晶体学主要参数及原子空间位置,溶解度高、结构稳定,且制备方法简单,适于药物研究和工业化生产。
本发明的具体技术方案如下:
本发明一方面提供了一种酮咯酸与异烟肼共晶,所述共晶,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在4.7±0.2°、9.4±0.2°、9.9±0.2°、11.3±0.2°、14.0±0.2°、15.8±0.2°、18.4±0.2°、18.8±0.2°、处有特征峰。
优选地,所述酮咯酸与异烟肼共晶,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图在4.7±0.2°、9.4±0.2°、9.9±0.2°、11.3±0.2°、14.0±0.2°、15.8±0.2°、18.4±0.2°、18.8±0.2°、18.9±0.2°、21.6±0.2°、26.6±0.2°、27.8±0.2°、27.9±0.2°、28.4±0.2°、37.6±0.2°处有特征峰。
优选地,所述酮咯酸与异烟肼共晶使用Cu-Kα辐射,其特征峰符合如图3所示的X射线粉末衍射图谱。
优选地,所述酮咯酸与异烟肼共晶,其分子式为C21H20N4O4,晶体学参数是:单斜晶系,空间群为P21/c,晶胞参数为:α=90°、β=99.0770(10)°、γ=90°,晶胞体积/>
本发明第二方面,提供一种酮咯酸与异烟肼共晶的制备方法,该方法包括以下步骤:将酮咯酸和异烟肼加入有机溶剂A中,加热溶解,溶液澄清后,降温析晶,过滤干燥得酮咯酸与异烟肼共晶。
优选地,所述酮咯酸与异烟肼的摩尔投料比为1:1~2,进一步优选为1:1.0~1.5。
优选地,所述酮咯酸和有机溶剂A的质量体积比为3.2~10.2:1,其中质量以mg计,体积以mL计。
优选地,所述的有机溶剂A选自甲醇、乙醇、丙酮、乙酸乙酯、乙腈和水的一种或两种,进一步优选为甲醇、丙酮、乙腈和水中的一种或两种。
优选地,所述溶解加热的温度为40~60℃。
优选地,降温析晶温度为10~30℃,析晶时间为24~72小时。
进一步优选地,所述制备方法包括以下步骤:将酮咯酸和异烟肼加入有机溶剂A中,40~60℃加热溶解,溶液澄清后,降温至10~30℃析晶24~72小时,过滤,洗涤滤饼,干燥得酮咯酸和异烟肼共晶。
本申请的第三方面提供一种药物组合物,其包括上述制备的酮咯酸与异烟肼共晶,并含有可联合使用的其他活性成分和/或其制剂学上可接受的辅料组分。
优选地,本发明的药物组合物可使用标准和常规的技术,制成片剂、胶囊剂、颗粒剂和丸剂等。
本发明第四方面,还提供了酮咯酸与异烟肼共晶在制备治疗消炎镇痛药物中的用途。
晶体结构的确认
从制备的样品中挑选符合规格尺寸的晶体,对其进行X-射线单晶衍射测试分析。所涉及的X-射线单晶衍射仪器及测试条件为:日本理学XtaLAB Synergy型号仪器上收集,测试温度293(2)K,电压50kv,电流1mA,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。
测试及解析本发明制备的酮咯酸与异烟肼共晶结晶形式的晶体学数据如表1所示:其晶体学参数是:单斜晶系,手性空间群:P21/c;晶胞参数为: α=90°、β=99.0770(10)°、γ=90°,晶胞体积/>本发明的酮咯酸与异烟肼共晶的ORTEP图(图1)表明,该结晶形式中含有一分子酮咯酸和一分子异烟肼。本发明的酮咯酸与异烟肼共晶的氢键图,如图2所示。
表1 酮咯酸与异烟肼共晶主要晶体学数据
本发明中所涉及的X-射线粉末衍射测试仪器及测试条件:X-射线粉末衍射仪:PANalytical EMPYREAN;Cu-Kα;样品台:平板;入射光路:BBHD;衍射光路:PLXCEL;电压45kv,电流40mA;发散狭缝:1/4;防散射狭缝:1;索拉狭缝:0.04rad;步长:0.5s;扫描范围:3~50°。
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3及表2。
表2 酮咯酸与异烟肼共晶的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。
本发明制备的酮咯酸与异烟肼共晶的TGA/DSC测试结果如图4所示,DSC图谱在147.37~165.45℃范围内出现吸热峰,对应吸热峰的峰值为156.20℃;其热重分析(TGA)无失重台阶,表明该酮咯酸与异烟肼共晶不存在溶剂,且结构稳定。
实施例中所制备的所有样品都具有相同的晶体学参数、X-射线粉末衍射图谱及差示扫描量热曲线(DSC/TGA)图。
本发明所述方法制备的酮咯酸与异烟肼共晶相对于目前报道的酮咯酸晶型具有以下优势:
(1)本发明提供的酮咯酸和异烟肼共晶在pH6.8的磷酸缓冲溶液具有较好的溶解度,为制备治疗消炎镇痛药物提供了一种可靠的药物活性成分。
(2)本发明提供的酮咯酸和异烟肼共晶的制备方法操作简单,结晶过程易控制,重现性好,晶体结构稳定,收率和纯度高,适合工业化生产。
附图说明
图1.酮咯酸与异烟肼共晶的ORTEP图。
图2.酮咯酸与异烟肼共晶的氢键图。
图3.酮咯酸与异烟肼共晶的PXRD谱图。
图4.酮咯酸与异烟肼共晶的TGA/DSC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。
原料来源:实验所用酮咯酸可购买也可参照现有技术制备,纯度>99%;其余物料的来源和规格均为市售分析纯或化学纯。
实施例1:
将255mg酮咯酸(1mmoL)和137mg异烟肼(1mmoL)溶于40mL乙腈,60℃加热溶解,溶液溶清后,降温至30℃,静置析晶24小时,过滤干燥得酮咯酸和异烟肼共晶,收率94.6%,HPLC:99.92%。
实施例2:
将255mg酮咯酸(1mmoL)和164mg异烟肼(1.2mmoL)溶于40mL乙腈和10mL水,60℃加热溶解,溶液澄清后,降温至20℃,静置析晶48小时,过滤干燥得酮咯酸和异烟肼共晶,收率98.2%,HPLC:99.95%。
实施例3:
将255mg酮咯酸(1mmoL)和205mg异烟肼(1.5mmoL)溶于15mL乙腈和10mL甲醇,60℃加热溶解,溶液澄清后,降温至20℃,静置析晶36小时,过滤干燥得酮咯酸和异烟肼共晶,收率93.8%,HPLC:99.91%。
实施例4:
将255mg酮咯酸(1mmoL)和137mg异烟肼(1.0mmoL)溶于40mL丙酮,50℃加热溶解,溶液溶清后,降温至25℃,静置析晶72小时,过滤干燥得酮咯酸和异烟肼共晶,收率92.5%,HPLC:99.89%。
实施例5:
将128mg酮咯酸(0.5mmoL)和137mg异烟肼(1mmoL)溶于20mL水和20mL乙醇,40℃加热溶解,溶液澄清后,降温至10℃,静置析晶24小时,过滤干燥得酮咯酸和异烟肼共晶,收率90.2%,HPLC:99.84%。
实施例6:
将255mg酮咯酸(1mmoL)和137mg异烟肼(1mmoL)溶于20mL乙酸乙酯,65℃加热溶解,溶液澄清后,降温至25℃,静置析晶36小时,过滤干燥得酮咯酸和异烟肼共晶,收率88.2%,HPLC:99.82%。
溶解度试验
1.试验材料:实施例1-6制得的酮咯酸与异烟肼共晶和酮咯酸标准品。
2.试验方法:溶解度试验参考《中国药典》(2015年版)有关内容。按照实施例1-6的方法分别放大生产相应的晶体,分别量取10ml的介质(pH7.0水、pH1.0盐酸溶液、pH6.8的磷酸盐缓冲液)于西林瓶中,加入过量的药物,将西林瓶密封置37℃水浴恒温搅拌1小时,经0.2μm滤膜过滤,取续滤液在313nm的波长处分别测定峰面积,通过测试标准对照品的峰面积来计算其溶解度。
液相检测方法:取滤液1mL,加溶剂(0.1%磷酸水:乙腈=7:3)稀释至刻度,摇匀,过滤,精密量取供试品溶液10μL,注入液相色谱仪,按面积归一化法计算。
3.试验结果:溶解度试验结果见表3。
表3 酮咯酸与异烟肼共晶在不同介质中的溶解度
经试验,本发明实施例1-6制备的酮咯酸和异烟肼共晶均具有相近的溶解度效果,相对于酮咯酸标准品(酮咯酸晶型Ⅰ)及其他晶型,酮咯酸与异烟肼共晶在pH6.8的磷酸盐冲液中的溶解度显著提高,对于提高酮咯酸的生物利用度和药效具有重要意义。
Claims (9)
1.一种酮咯酸与异烟肼共晶,其特征在于,使用Cu-Kα辐射,以2θ表示的X射线衍射谱图4.7±0.2°、9.4±0.2°、9.9±0.2°、11.3±0.2°、14.0±0.2°、15.8±0.2°、18.4±0.2°、18.8±0.2°处有特征峰。
2.如权利要求1所述的酮咯酸与异烟肼共晶,其特征在于,使用Cu-Kα辐射,以2θ表示的X射线衍射谱在4.7±0.2°、9.4±0.2°、9.9±0.2°、11.3±0.2°、14.0±0.2°、15.8±0.2°、18.4±0.2°、18.8±0.2°、18.9±0.2°、21.6±0.2°、26.6±0.2°、27.8±0.2°、27.9±0.2°、28.4±0.2°、37.6±0.2°处有特征峰。
3.如权利要求1所述的酮咯酸与异烟肼共晶,其特征在于,使用Cu-Kα辐射,其特征峰符合如图3所示的X射线粉末衍射图谱。
4.如权利要求1所述的酮咯酸与异烟肼共晶,其特征在于,其晶体学参数是:单斜晶系,手性空间群:P21/c;晶胞参数为:a=19.0339(2)Å、b=4.535Å、c=22.4144(3)Å,α=90°、β=99.0770(10)°、γ=90°,晶胞体积V=1910.55(3)Å3。
5.一种权利要求1~4 任一项所述酮咯酸与异烟肼共晶的制备方法,其特征在于,具体制备步骤包括:将酮咯酸和异烟肼加入有机溶剂A中,加热溶解,溶液澄清后,降温析晶,过滤干燥得酮咯酸与异烟肼共晶;所述的有机溶剂A选自甲醇、乙醇、丙酮、乙酸乙酯、乙腈和水中的一种或几种。
6.如权利要求5所述的酮咯酸与异烟肼共晶的制备方法,其特征在于,酮咯酸与异烟肼的摩尔比为1:1~2。
7.如权利要求5所述的酮咯酸与异烟肼共晶的制备方法,其特征在于,酮咯酸和有机溶剂A的质量体积比为3.2~10.2:1,其中质量以mg计,体积以mL计。
8.如权利要求5所述的酮咯酸与异烟肼共晶的制备方法,其特征在于,所述加热溶解的温度为40~60℃;析晶温度为10~30℃;析晶时间为24~72小时。
9.一种药物组合物,其特征在于,包含酮咯酸与异烟肼共晶和其他药学上可接受的辅料。
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