CN116332892A - 一种蛇床子素晶体及其制备方法和应用 - Google Patents
一种蛇床子素晶体及其制备方法和应用 Download PDFInfo
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- CN116332892A CN116332892A CN202310190182.2A CN202310190182A CN116332892A CN 116332892 A CN116332892 A CN 116332892A CN 202310190182 A CN202310190182 A CN 202310190182A CN 116332892 A CN116332892 A CN 116332892A
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Classifications
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- C07B2200/13—Crystalline forms, e.g. polymorphs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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Abstract
本发明提供了一种蛇床子素晶体及其制备方法和应用,所述蛇床子素晶体为是一种新的II晶型,在制备过程中,可以通过溶剂辅助研磨法、高温挥发法、熔融淬冷法或溶析结晶法中的任意一种进行制备。该蛇床子素晶体相较于市面上的蛇床子素显著提高了溶解速率和溶解度,具有更优的生物利用度,大大改善了粉体的流动性和堆密度,为药物制剂和农药制剂的制备提供了更好更优的选择。此外制备方法工艺简单,成本低廉,可进一步开发适用于大规模生产,对于药物和农药开发具有非常重要的意义。
Description
技术领域
本发明属于晶型制备技术领域,涉及蛇床子素晶体及其制备方法和应用。
背景技术
蛇床子素(7-甲氧基-8-异戊烯基香豆素,Osthole)为植物蛇床子提取物的主要成分,结构如下,核心结构由苯环和吡喃酮环组成,蛇床子素除具有香豆素的核心结构外,还有异戊烯结构,异戊烯结构化合物作为植保素在抗病中具有重要作用;
已有研究表明蛇床子素具有多种药理作用,如抗肿瘤、抗炎、抗菌、抗氧化和神经保护等,其广泛的生物活性吸引了农药化学家和医药化学家的广泛关注。蛇床子素对害虫体内的乙酰胆碱酯酶的活性有抑制作用,杀虫活性高、对环境友好、且对害虫不易产生抗性,因此广泛应用于菜青虫、小菜蛾、蚜虫等害虫的防治,而且对植物病原真菌如黄瓜白粉病菌、葡萄霜霉病菌,辣椒疫霉病菌、小麦赤霉病菌等都具有显著的抑制作用。
然而,蛇床子素几乎不溶于水,不良的溶解度和溶解速率使其在临床中的应用受到严重的限制,此外,水溶性差也造成了难以开发成绿色环保的水剂,因此亟待开发水溶性好的蛇床子素固体形式以满足医药和农药领域的迫切需求。
颗粒形态是固体化工产品的重要特性之一,它显著影响前期生产中的过滤分离,烘干过程等操作,以及后期储存运输和下游应用等。市售蛇床子素晶体多为针状,这种晶体堆密度低(0.304g/cm3),流动性差(休止角55°),给下游的生产和应用造成了极大的挑战。因此,开发一种简单的、低成本的生产技术,进一步提高蛇床子素的流动性、堆密度和物理化学稳定性是十分必要的,直接决定了蛇床子素的临床应用效果。
发明内容
为了解决现有技术的不足,本发明的目的是提供蛇床子素晶体及其制备方法和应用,本发明获得的蛇床子素的晶型Ⅱ,显著提高蛇床子素的溶解速率和溶解度,改善了粉体的流动性和堆密度。
本发明的目的之一在于提供一种蛇床子素晶体,所述蛇床子素晶体使用Cu-Kα辐射测量得到的X射线粉末衍射在以2θ角度表示的衍射角在4.5±0.2°、5.4±0.2°、12.8±0.2°、14.1±0.2°、15.0±0.2°、17.0±0.2°、18.0±0.2°、19.0±0.2°、20.5±0.2°、23.6±0.2°、24.0±0.2°、24.5±0.2°、25.2±0.2°、26.1±0.2°、27.3±0.2°、29.0±0.2°、31.6±0.2°和38.6±0.2°处有特征衍射峰。
优选地,所述蛇床子素晶体的差示扫描量热分析DSC图谱在在42-46℃具有特征放热峰,且在83.27℃处发生熔化。
优选地,所述蛇床子素晶体的热重TG图谱在170.25℃处发生失重。
本发明的目的之二在于提供一种如目的之一所述的蛇床子素晶体的制备方法,所述制备方法包括溶剂辅助研磨法、高温挥发法、熔融淬冷法或溶析结晶法中的任意一种。
作为本发明的优选技术方法,所述溶剂辅助研磨法包括:将蛇床子素辅助溶剂作用下通过研磨法制备得到蛇床子素晶体;
优选地,所述蛇床子素与辅助溶剂的添加量的比为0.05-0.2μL/mg;
优选地,所述辅助溶剂包括水、甲醇、乙醇、丙酮、丁酮、甲酸、乙酸、乙酸乙酯、乙酸正丙酯、乙酸正丁酯、乙腈、1,4二氧六环、正丙醇、异丙醇、正丁醇、氯仿、二氯甲烷、三氯甲烷、四氯化碳、己烷、四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺或N-甲基吡咯烷酮中的任意一种或至少两种的组合;
优选地,所述研磨法用功率为20-35Hz,时间为20-40min。
作为本发明的优选技术方法,所述高温挥发法包括:将蛇床子素在溶剂中溶解后,高温挥发获得蛇床子素晶体;
优选地,所述溶剂包括甲醇、乙醇、丙酮、丁酮、甲酸、乙酸、乙酸乙酯、乙酸正丙酯、乙酸正丁酯、乙腈、1,4二氧六环、正丙醇、异丙醇、正丁醇、氯仿、二氯甲烷、三氯甲烷、四氯化碳、己烷、四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺或N-甲基吡咯烷酮中的任意一种或至少两种的组合;
优选地,所述蛇床子素在溶剂中溶解后得到的澄清溶液中蛇床子素的浓度为1-5g/mL;
优选地,所述高温挥发的温度为42-83.27℃。
作为本发明的优选技术方法,所述熔融淬冷法包括:将蛇床子素高温熔化后骤冷获得蛇床子素晶体;
优选地,所述高温熔化的温度为83.27-170℃;
优选地,所述骤冷的温度为-190~70℃,骤冷的时间为5-120min。
作为本发明的优选技术方法,所述溶析结晶法包括:将蛇床子素加入到良溶剂中溶解过滤,将过滤得到的滤液加入反溶剂养晶,得到蛇床子素晶体;
优选地,所述良溶剂包括甲醇、乙醇、丙酮、丁酮、甲酸、乙酸、乙酸乙酯、乙酸正丙酯、乙酸正丁酯、乙腈、1,4二氧六环、正丙醇、异丙醇、正丁醇、氯仿、二氯甲烷、三氯甲烷、四氯化碳、己烷、四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺或N-甲基吡咯烷酮中的任意一种或至少两种的组合;
优选地,所述蛇床子素在良溶剂中溶解获得溶液的浓度为1-5g/mL;
优选地,所述反溶剂包括水、正己烷或正庚烷中的任意一种或至少两种的组合;
优选地,所述反溶剂与良溶剂的体积比为(1-30):1;
优选地,所述制备方法还包括将养晶后得到的混合物进行固液分离以及干燥;
优选地,所述固液分离的方式为过滤。
本发明的目的之三在于提供一种如目的之一所述的蛇床子素晶体在制备抗菌药物、消炎药物、抗癌药物、抗氧化药物、养殖家禽保健药物、杀虫剂或农用杀菌剂中的应用。
本发明的目的之四在于提供一种药物组合物,所述药物组合物包含治疗有效量的本发明的蛇床子素晶体,以及至少一种药学上可接受的赋形剂。
上述药物组合物可制成一定的剂型,通过适合的途径给药。例如口服、肠胃外(包括皮下、肌肉、静脉或皮内)、直肠、透皮、经鼻、***等途径。适合口服给药的剂型包括片剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、锭剂、溶液、糖浆剂或混悬剂,根据需要,可适于药物活性成分的快速释放、延迟释放或调节释放;适合肠胃外给药的剂型包括水性或非水性的无菌注射溶液、乳液或混悬液;适合直肠给药的剂型包括栓剂或灌肠剂;适合透皮给药的剂型包括软膏、霜剂、贴剂;适合经鼻给药的剂型包括气雾剂、喷剂、滴鼻剂;适合***给药的剂型包括栓剂、塞剂、凝胶、糊剂或喷剂。
上述药物组合物中药学上可接受的赋形剂,在固体口服剂型的情况下,包括但不限于:稀释剂,例如淀粉、预胶化淀粉、乳糖等;粘合剂,例如***胶、瓜尔胶、明胶、聚乙烯吡咯烷酮等;崩解剂,例如淀粉、羟基乙酸淀粉钠、预胶化淀粉、胶体二氧化硅等;润滑剂,例如硬脂酸、硬脂酸镁、乙酸钠等;助流剂,例如胶体二氧化硅等;复合物形成剂,例如各种级别的环糊精和树脂;释放速度控制剂,例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素等。可用的其他药学上可接受的赋形剂包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂、抗氧化剂等。每一种赋形剂必须是可接受的,能与配方中的其他成分兼容并且对于患者无害。
所述药物组合物可以使用现有技术中本领域技术人员公知的方法来制备。制备药物组合物时,将本发明蛇床子素晶型Ⅱ与一种或多种药学上可接受的赋形剂相混合,任选地与一种或多种其他的药物活性成分相混合。例如,片剂、胶囊剂、颗粒剂可以通过混合、制粒、压片或填充胶囊等工艺来制备;粉剂通过将研细到合适大小的药物活性成分及赋形剂混合来制备;溶液和糖浆剂可通过将药物活性成分溶解于适当调味的水或水性溶液中来制备;混悬剂可通过将药物活性成分分散于药学上可接受的载体中来制备。
本发明的目的之六在于提供一种农药组合物,农药组合物在真菌性病害和害虫防治上的用途。所述农用组合物或含所述农用组合物的制剂用于防治真菌性病害和虫害;所述真菌性病害包括黄瓜白粉病、黄瓜炭疽病、小麦黑穗病等;所述虫害包括如菜青虫、茶尺蠖、棉铃虫、甜菜夜蛾以及各种蚜虫、各种螨虫等。
本发明所述农用组合物按照本领域技术人员公知的方法,可制备成便于农业上施用的制剂剂型,包括但不限于比如悬浮剂、可湿性粉剂、水分散粒剂、纳米胶囊、纳米水悬浮剂等剂型中的一种。本领域技术人员易于知晓,除含有有效成分外,制剂体系中还含有配制农药制剂所需的助剂。助剂可以选用包括但不限于溶剂、乳化剂、润湿剂、稳定剂、分散剂、增稠剂、pH调节剂、消泡剂、防冻剂、填料等中的一种或几种的混合。
相对于现有技术,本发明具有以下有益效果:
1、制备得到的蛇床子素晶型Ⅱ晶体的晶体形态完全不用于现有技术得到的蛇床子素晶体,表现在显著提高的粉体性质,如更高的堆密度,更好的流动性。
2、本发明中的蛇床子素晶型Ⅱ晶体具有显著提高的生物利用度,临床应用广阔,表现在更优的溶解度和溶解速率,生物利用度得到明显提高。
3、本发明中的蛇床子素晶型Ⅱ制备方法操作简单,质量容易控制,技术和设备简单,成本低廉,可进一步开发,适用于大规模生产。
附图说明
图1是蛇床子素晶体的粉末X射线衍射图;
图2是蛇床子素晶体的DSC图;
图3是蛇床子素晶体的TG图;
图4是蛇床子素晶体和市售蛇床子素晶体在水中的特性溶出对比图。
具体实施方式
应该指出,以下详细说明都是示例性的,旨在对本发明提供进一步的说明。除非另有指明,本文使用的所有技术和科学术语具有与本发明所属技术领域的普通技术人员通常理解的相同含义。下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅是帮助理解本发明,不应视为对本发明的具体限制。
将下列分析方法和设备用于表征本发明的蛇床子素晶型Ⅱ晶体:
X-射线粉末衍射(PXRD):采用的粉末衍射仪为日本理学株式会社生产的D/MAX2500型,测试条件为:采用Cu Kα靶测试,电压40kV,电流100mA,扫描波长采用连续扫描测试,扫描速度为8°/min。收集完数据后采用Jade 7.0软件进行数据分析。
差式扫描量热仪(DSC):采用梅特勒托利多公司的DSC 1/500型仪器测试,将20mg左右样品加入40μL的标准铝坩埚中,密封坩埚,放入炉体。炉体内用高纯氮气做保护气(气速为50mL/min)和反应气(气速为200mL/min)。测量温度范围25~300℃,升温速率5~10℃·min-1。测定加热过程中样品的温度和热量变化,程序控制、数据记录和分析均由梅特勒公司开发的STARe Software 10.0软件完成。
热重分析(TGA):热重分析数据由梅特勒托利多公司的Mettler TG/DSC 1STARe型热重分析仪完成测定。测试条件:样品量:3-5mg;温度范围:25-400℃;升温速率:10℃/min;气体:氮气;流速:20mL/min。
粉体性能测试仪:应用BT-1001智能粉体特性测试仪进行休止角和振实堆密度的测定,将5~10g粉体过100目筛后,装填入粉体测试仪容器,测定休止角,再设定量筒上下振动,振幅5~10mm,测定粉体振实堆密度,重复三次,取平均值。
实施例1
精确称取蛇床子素244.29mg(1mmol),将样品置于研磨罐,放入Retsch MM400研磨仪,4mm钢球一个,频率为35Hz,添加乙酸9μL,乙腈39μL,研磨30min,25℃恒温干燥12h,得到蛇床子素晶体。
本实施例制备得到的蛇床子素晶体的X射线衍射图谱如图1所示,以衍射角2θ表示在为:4.5°、5.4°、9.3°、12.8°、14.1°、15.0°、17.0°、18.0°、19.0°、20.5°、23.6°、24.0°、24.5°、25.2°、26.1°、27.3°、29.0°、31.6°和38.6°处各有特征衍射峰,如表1所示:
表1
通过图1与市面上常规的蛇床子素的XRD结果相比,可以发现是一种新的晶型,记为晶型II。
图2为本实施例得到产品的DSC图,从图2可知:该晶体在42℃~46℃具有放热峰,在83.27℃发生熔化。
图3为本实施例得到产品的TG图,从图3可知:该晶体在170.25℃发生失重。
对实施例1得到的蛇床子素晶体进行测试,可知:其堆密度为0.626g/cm3,休止角为38°。
对实施例1得到的蛇床子素晶体进行溶出测试,分体溶出曲线见图4,通过图4可知:蛇床子素晶型Ⅱ在25℃纯水中的溶解度为52.76mg/L,是市售蛇床子素晶体(12.14mg/L)的4.34倍,相同条件下:蛇床子素晶型Ⅱ(粉末)的溶出曲线下面积为15378.45mg·min/L为市售蛇床子素晶体(3232.02mg·min/L)的4.91倍。
实施例2
精确称取蛇床子素122.145mg(0.5mmol),将样品置于研磨罐,放入Retsch MM400研磨仪,4mm钢球一个,频率为20Hz,添加甲醇6μL,研磨20min,25℃恒温干燥12h,得到蛇床子素晶体。
对实施例2采用与实施例1相同的测试,可以发现通过实施例制备得到的蛇床子素晶体为II晶型。同样,其DSC显示在在42℃~46℃具有放热峰,在83.27℃发生熔化,TG显示在170.25℃发生失重。
对本实施例得到的蛇床子素晶体进行测试,可知:其堆密度为0.613g/cm3,休止角为37°。
实施例3
精确称取蛇床子素原料244.29mg(1mmol),溶解于100mL乙醇和244mL乙酸乙酯的混合溶剂中,溶清后过滤,将滤液置于42℃恒温挥发,晶体产品室温恒温干燥12h,得到蛇床子素晶体。
对该实施例采用与实施例1相同的测试,可以发现通过实施例制备得到的蛇床子素晶体为II晶型。同样,其DSC显示在在42℃~46℃具有放热峰,在83.27℃发生熔化,TG显示在170.25℃发生失重。
对本实施例得到的蛇床子素晶体进行测试,可知:其堆密度为0.603g/cm3,休止角为38°。
实施例4
精确称取蛇床子素原料1g(4.09mmol),溶解于0.2mL二甲基亚砜中,溶清后过滤,将滤液置于83.27℃恒温挥发,晶体产品室温恒温干燥12h,得到蛇床子素晶体。
对该实施例采用与实施例1相同的测试,可以发现通过实施例制备得到的蛇床子素晶体为II晶型。同样,其DSC显示在在42℃~46℃具有放热峰,在83.27℃发生熔化,TG显示在170.25℃发生失重。
对本实施例得到的蛇床子素晶体进行测试,可知:其堆密度为0.623g/cm3,休止角为36°。
实施例5
精确称取蛇床子素原料100mg(0.41mmol),将样品置于玻璃培养皿中,83.27℃恒温10min直至晶体全部熔化,将熔体骤冷至70℃,恒温120min后蛇床子素晶体。
对该实施例采用与实施例1相同的测试,可以发现通过实施例制备得到的蛇床子素晶体为II晶型。同样,其DSC显示在在42℃~46℃具有放热峰,在83.27℃发生熔化,TG显示在170.25℃发生失重。
对本实施例得到的蛇床子素晶体进行测试,可知:其堆密度为0.626g/cm3,休止角为38°。
实施例6
精确称取蛇床子素原料200mg(0.82mmol),将样品置于玻璃培养皿中,170℃恒温10min直至晶体全部熔化,将熔体骤冷至-190℃,恒温5min后获得蛇床子素晶体。
对该实施例采用与实施例1相同的测试,可以发现通过实施例制备得到的蛇床子素晶体为II晶型。同样,其DSC显示在在42℃~46℃具有放热峰,在83.27℃发生熔化,TG显示在170.25℃发生失重。
对本实施例得到的蛇床子素晶体进行测试,可知:其堆密度为0.606g/cm3,休止角为39°。
实施例7
精确称取蛇床子素原料2442.9mg(10mmol),将样品置于0.5mLN,N-二甲基甲酰胺中搅拌溶清,将溶液过滤,将滤液滴加入15mL水中搅拌养晶20min后过滤,室温干燥24h后获得蛇床子素晶体。
对该实施例采用与实施例1相同的测试,可以发现通过实施例制备得到的蛇床子素晶体为II晶型。同样,其DSC显示在在42℃~46℃具有放热峰,在83.27℃发生熔化,TG显示在170.25℃发生失重。
对本实施例得到的蛇床子素晶体进行测试,可知:其堆密度为0.603g/cm3,休止角为41°。
实施例8
精确称取蛇床子素原料50mg(0.041mmol),将样品置于10mL丙酮和40mL三氯甲烷的混合溶剂中搅拌溶清,将溶液过滤,将滤液滴加入40mL正己烷和10mL正庚烷的混合溶剂中搅拌养晶20min后过滤,室温干燥24h后获得蛇床子素晶型Ⅱ。
对该实施例采用与实施例1相同的测试,可以发现通过实施例制备得到的蛇床子素晶体为II晶型。同样,其DSC显示在在42℃~46℃具有放热峰,在83.27℃发生熔化,TG显示在170.25℃发生失重。
对本实施例得到的蛇床子素晶体进行测试,可知:其堆密度为0.622g/cm3,休止角为40°。
本发明中制备得到的蛇床子素晶型Ⅱ的晶体形态完全不用于现有技术的蛇床子素晶体,堆密度高,流动性好,溶解速率和溶解度显著增大,生物利用度大大增加。制备蛇床子素晶型Ⅱ的制备工艺简单,成本低廉,可进一步开发适用于大规模生产。
申请人声明,以上所述仅为本发明的具体实施方式,但本发明的保护范围并不局限于此,所属技术领域的技术人员应该明了,任何属于本技术领域的技术人员在本发明揭露的技术范围内,可轻易想到的变化或替换,均落在本发明的保护范围和公开范围之内。
Claims (10)
1.一种蛇床子素晶体,其特征在于:所述蛇床子素晶体使用Cu-Kα辐射测量得到的X射线粉末衍射在以2θ角度表示的衍射角在4.5±0.2°、5.4±0.2°、12.8±0.2°、14.1±0.2°、15.0±0.2°、17.0±0.2°、18.0±0.2°、19.0±0.2°、20.5±0.2°、23.6±0.2°、24.0±0.2°、24.5±0.2°、25.2±0.2°、26.1±0.2°、27.3±0.2°、29.0±0.2°、31.6±0.2°和38.6±0.2°处有特征衍射峰。
2.根据权利要求1所述的蛇床子素晶体,其特征在于,所述蛇床子素晶体的差示扫描量热分析DSC图谱在在42-46℃具有特征放热峰,且在83.27℃处发生熔化。
3.根据权利要求1所述的蛇床子素晶体,其特征在于,所述蛇床子素晶体的热重TG图谱在170.25℃处发生失重。
4.根据权利要求1-3任一项所述的蛇床子素晶体的制备方法,其特征在于,所述制备方法包括溶剂辅助研磨法、高温挥发法、熔融淬冷法或溶析结晶法中的任意一种。
5.根据权利要求4所述的制备方法,其特征在于,所述溶剂辅助研磨法包括:将蛇床子素辅助溶剂作用下通过研磨法制备得到蛇床子素晶体;
优选地,所述蛇床子素与辅助溶剂的添加量的比为0.05-0.2μL/mg;
优选地,所述辅助溶剂包括水、甲醇、乙醇、丙酮、丁酮、甲酸、乙酸、乙酸乙酯、乙酸正丙酯、乙酸正丁酯、乙腈、1,4二氧六环、正丙醇、异丙醇、正丁醇、氯仿、二氯甲烷、三氯甲烷、四氯化碳、己烷、四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺或N-甲基吡咯烷酮中的任意一种或至少两种的组合;
优选地,所述研磨法用功率为20-35Hz,时间为20-40min。
6.根据权利要求4所述的制备方法,其特征在于,所述高温挥发法包括:将蛇床子素在溶剂中溶解后,高温挥发获得蛇床子素晶体;
优选地,所述溶剂包括甲醇、乙醇、丙酮、丁酮、甲酸、乙酸、乙酸乙酯、乙酸正丙酯、乙酸正丁酯、乙腈、1,4二氧六环、正丙醇、异丙醇、正丁醇、氯仿、二氯甲烷、三氯甲烷、四氯化碳、己烷、四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺或N-甲基吡咯烷酮中的任意一种或至少两种的组合;
优选地,所述蛇床子素在溶剂中溶解后得到的澄清溶液中蛇床子素的浓度为1-5g/mL;
优选地,所述高温挥发的温度为42-83.27℃。
7.根据权利要求4所述的制备方法,其特征在于,所述熔融淬冷法包括:将蛇床子素高温熔化后骤冷获得蛇床子素晶体;
优选地,所述高温熔化的温度为83.27-170℃;
优选地,所述骤冷的温度为-190~70℃,骤冷的时间为5-120min。
8.根据权利要求4所述的制备方法,其特征在于,所述溶析结晶法包括:将蛇床子素加入到良溶剂中溶解过滤,将过滤得到的滤液加入反溶剂养晶,得到蛇床子素晶体;
优选地,所述良溶剂包括甲醇、乙醇、丙酮、丁酮、甲酸、乙酸、乙酸乙酯、乙酸正丙酯、乙酸正丁酯、乙腈、1,4二氧六环、正丙醇、异丙醇、正丁醇、氯仿、二氯甲烷、三氯甲烷、四氯化碳、己烷、四氢呋喃、二甲基亚砜、N,N-二甲基甲酰胺或N-甲基吡咯烷酮中的任意一种或至少两种的组合;
优选地,所述蛇床子素在良溶剂中溶解获得溶液的浓度为1-5g/mL;
优选地,所述反溶剂包括水、正己烷或正庚烷中的任意一种或至少两种的组合;
优选地,所述反溶剂与良溶剂的体积比为(1-30):1;
优选地,所述制备方法还包括将养晶后得到的混合物进行固液分离以及干燥;
优选地,所述固液分离的方式为过滤。
9.根据权利要求1-3任一项所述的蛇床子素晶体在制备抗菌药物、消炎药物、抗癌药物、抗氧化药物、养殖家禽保健药物、杀虫剂或农用杀菌剂中的应用。
10.一种药物组合物或农药组合物,其特征在于,所述药物组合物或农药组合物包括权利要求1-3任一项所述的蛇床子素晶体;
优选地,所述药物组合物用于制备药物制剂,所述药物制剂包括药物组合物以及药学上可接受的辅料和/或载体;
优选地,所述农药组合物用于制备农药制剂,所述农药制剂包括农药组合物以及农药辅料。
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CN108976193A (zh) * | 2018-09-19 | 2018-12-11 | 南方医科大学 | 一种蛇床子素提取方法 |
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CN108976193A (zh) * | 2018-09-19 | 2018-12-11 | 南方医科大学 | 一种蛇床子素提取方法 |
Non-Patent Citations (1)
Title |
---|
田斌等: "蛇床子素化学成分及药理作用研究进展", 中药与临床, vol. 2020, no. 11, 31 December 2020 (2020-12-31), pages 70 - 73 * |
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