CN103819440B - 杨梅素药物共晶及其制备方法 - Google Patents

杨梅素药物共晶及其制备方法 Download PDF

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CN103819440B
CN103819440B CN201410087945.1A CN201410087945A CN103819440B CN 103819440 B CN103819440 B CN 103819440B CN 201410087945 A CN201410087945 A CN 201410087945A CN 103819440 B CN103819440 B CN 103819440B
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cyanopyridine
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谢燕
洪超
李国文
姚雅淑
孟厚君
邓冰
付情雪
王慧珍
沈红艺
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Shanghai University of Traditional Chinese Medicine
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Abstract

本发明公开了杨梅素药物共晶及其制备方法。所述的杨梅素药物共晶是以杨梅素作为活性药物成分,以咖啡因、烟酰胺、异烟酰胺或4-氰基吡啶为前驱体,通过分子间氢键形成的杨梅素-咖啡因共晶、杨梅素-烟酰胺共晶、杨梅素-异烟酰胺共晶或杨梅素-4-氰基吡啶共晶;所述共晶是采用溶液介导转晶法制备得到。本发明所述的杨梅素药物共晶,在继承杨梅素药理活性的同时,其溶解性、溶出率及稳定性均相对于杨梅素有显著性提高,有利于开发成药物制剂,可促使杨梅素在医药领域的广泛应用。

Description

杨梅素药物共晶及其制备方法
技术领域
本发明涉及杨梅素药物共晶及其制备方法,属于药物共晶技术领域。
背景技术
常温下,活性药物成分以多种固体形态存在,如多晶型、溶剂化物、水合物、共晶、无定形以及盐等。一个药物的疗效很大程度上取决于药物自身的理化性质及选择的剂型,而药物不同的固体形态对药物的溶解度、稳定性、溶出速率和生物利用度等均有影响。
超分子化学是研究分子间相互作用缔结而形成的复杂有序并且具有特定结构和功能的分子聚集体的科学,其核心内容是通过分子间弱相互作用进行分子识别和超分子自组装,它是“超越分子范畴的化学”,这种分子聚集体简称超分子。随着超分子化学研究工作的深入以及对超分子概念的进一步理解,超分子化学在药学领域的延伸成为必然。超分子药物可定义为两个或两个以上分子通过非共价键形成的药物。随着超分子化学的发展,探讨超分子体系作为药物在医药领域的应用引起人们极大兴趣。
药物共晶本质上是一种超分子自组装系统,是热力学动力学分子识别的平衡结果,在分子自组装过程中,分子间的相互作用以及空间效应影响超分子网络的形成,从而影响晶体的构成。在共晶体系内,不同分子间的相互作用主要有氢键,∏-∏堆积作用,范德华力和卤键。药物共晶的特点在于,保留药物本身药理活性的同时,达到了修饰药物物理化学性质的目的,这为药物共晶在制药工业方面的应用提供了更为广阔的发展空间。在不改变药物结构及本身药理活性的情况下,形成的新晶体可以提高药物的稳定性、改变其熔点、提高其溶解性,降低其引湿性,减缓其释放和溶出度,改善其机械性质、提高其生物利用度,因此,获得更多具有新颖、实用和创造性的药物共晶具有重要的现实意义,特别是一些水不溶性药物。近几年来,药物共晶的研究越来越受到人们的关注。现阶段,国外对药物共晶的研究开始逐渐增多并深入,而国内对其研究还相对较少。对于仿制药来说,药物共晶的研究也可以打破原研药公司对药物晶型的专利保护,利于将仿制药推向市场。
杨梅素作为一种天然的黄酮醇类化学成分,不仅是醋柳黄酮的组成之一,同时也是杨梅科植物杨梅的树皮及叶、红酒中的主要黄酮醇成分,并广泛存在于洋葱、浆果、茶等其他天然植物中,具有一定资源优势,且杨梅素的提取分离及纯化技术已相当成熟。近年的研究显示杨梅素药理活性强,具有抗菌、抗病毒、抗氧化、保护神经、降血糖、抗肝损伤、降低尿酸、防治骨质疏松等多种功效,而其在防治心血管疾病上的作用尤为引人关注,是一种极具开发应用价值的天然药物。
然而杨梅素与其他的黄酮醇类物质一样,水、脂溶性较差,且在弱酸、中性及碱性条件下不稳定,导致其膜渗透性差、半衰期短、生物利用度低等,大大限制了杨梅素在疾病治疗方面的应用。若采用现代前沿技术对杨梅素的各种性能进行改善,将能使其充分发挥疗效,从而真正应用于临床。
发明内容
本发明的目的旨在提供可改善杨梅素溶解性和溶出速率及稳定性的杨梅素药物共晶及其制备方法,以促使杨梅素在医药领域的广泛应用。
为实现上述发明目的,本发明提供的杨梅素药物共晶,是以杨梅素作为活性药物成分,以咖啡因、烟酰胺、异烟酰胺或4-氰基吡啶为前驱体,通过分子间氢键形成的杨梅素-咖啡因共晶、杨梅素-烟酰胺共晶、杨梅素-异烟酰胺共晶或杨梅素-4-氰基吡啶共晶。
进步一说,所述的杨梅素-咖啡因共晶在粉末X射线衍射下,在衍射角度2θ为12.3°、16.1°、24.8°、25.7°处具有主特征峰;在衍射角度2θ为5.3°、10.7°、12.3°、13.4°、14.3°、16.1°、17.9°、18.3°、21.9°、22.3°、24.8°、25.7°、27.1°、28.1°、29.6°处具有特征峰;测试误差为±0.2°。
进一步说,所述的杨梅素-烟酰胺共晶在粉末X射线衍射下,在衍射角度2θ为15.0°、25.1°、25.7°、26.4°、27.3°处具有主特征峰;在衍射角度2θ为6.5°、13.1°、15.0°、15.5°、16.1°、19.7°、24.2°、25.1°、25.7°、26.4°、27.3°、29.9°、41.2°处具有特征峰;测试误差为±0.2°。
进一步说,所述的杨梅素-异烟酰胺共晶在粉末X射线衍射下,在衍射角度2θ为15.0°、25.0°处具有主特征峰;在衍射角度2θ为5.5°、7.4°、15.0°、15.7°、24.1°、25.0°、25.6°、26.5°处具有特征峰;测试误差为±0.2°。
进一步说,所述的杨梅素-4-氰基吡啶共晶在粉末X射线衍射下,在衍射角度2θ为14.9°、16.2°、24.3°、25.8°、27.3°处具有主特征峰;在衍射角度2θ为5.1°、14.2°、14.9°、16.2°、24.3°、25.8°、27.3°、27.8°、29.6°处具有特征峰;测试误差为±0.2°。
本发明所述的杨梅素药物共晶,是采用溶液介导转晶法制备而得,具体说,包括如下步骤:
a)将杨梅素与前驱体加入醇溶剂中,在20~37℃下进行恒温振荡4~24小时;
b)过滤,收集滤饼进行真空干燥,即得杨梅素药物共晶。
作为优选方案,当前驱体为咖啡因时,杨梅素与咖啡因的质量比为2:1~6:1;杨梅素与咖啡因的总质量与醇溶剂的体积比为(59~87)mg:1mL。
作为优选方案,当前驱体为烟酰胺时,杨梅素与烟酰胺的质量比为1:3~1:1,杨梅素与烟酰胺的总质量与醇溶剂的体积比为(140~165)mg:1mL。
作为优选方案,当前驱体为异烟酰胺时,杨梅素与异烟酰胺的质量比为1:3~2:1,杨梅素与异烟酰胺的总质量与醇溶剂的体积比为(120~180)mg:1mL。
作为优选方案,当前驱体为4-氰基吡啶时,杨梅素与4-氰基吡啶的质量比为1:2~2:1,杨梅素与4-氰基吡啶的总质量与醇溶剂的体积比为(110~150)mg:1mL。
与现有技术相比,本发明具有如下显著性进步:通过选择适宜的前驱体与杨梅素形成杨梅素药物共晶,使其在继承杨梅素药理活性的同时,使其溶解性、溶出率及稳定性得到显著性提高,可促使杨梅素在医药领域的广泛应用。
附图说明
图1为杨梅素-咖啡因共晶的DSC图,其中:a为杨梅素,b为杨梅素-咖啡因共晶,c为咖啡因;
图2为杨梅素-咖啡因共晶的PXRD图,其中:a为杨梅素,b为杨梅素-咖啡因共晶,c为咖啡因;
图3为杨梅素-咖啡因共晶的IR图,其中:a为杨梅素,b为杨梅素-咖啡因共晶,c为咖啡因;
图4为杨梅素-咖啡因共晶的SEM图,其中:a为杨梅素,b为杨梅素-咖啡因共晶;
图5为杨梅素-咖啡因共晶在pH=1.2的盐酸缓冲溶液中的溶解速率曲线,其中:a为杨梅素,b为杨梅素-咖啡因共晶;
图6为杨梅素-咖啡因共晶在pH=4.5的醋酸盐缓冲溶液中的溶解速率曲线,其中:a为杨梅素,b为杨梅素-咖啡因共晶;
图7为杨梅素-咖啡因共晶在pH=6.8的磷酸盐缓冲溶液中的溶解速率曲线,其中:a为杨梅素,b为杨梅素-咖啡因共晶;
图8为杨梅素-烟酰胺共晶的DSC图,其中:a为杨梅素,d为杨梅素-烟酰胺共晶,e为烟酰胺;
图9为杨梅素-烟酰胺共晶的PXRD图,其中:a为杨梅素,d为杨梅素-烟酰胺共晶,e为烟酰胺;
图10为杨梅素-烟酰胺共晶的IR图,其中:a为杨梅素,d为杨梅素-烟酰胺共晶,e为烟酰胺;
图11为杨梅素-烟酰胺共晶的SEM图,其中:a为杨梅素,d为杨梅素-烟酰胺共晶;
图12为杨梅素-烟酰胺共晶在pH=1.2的盐酸缓冲溶液中的溶解速率曲线,其中:a为杨梅素,d为杨梅素-烟酰胺共晶;
图13为杨梅素-烟酰胺共晶在pH=4.5的醋酸盐缓冲溶液中的溶解速率曲线,其中:a为杨梅素,d为杨梅素-烟酰胺共晶;
图14为杨梅素-烟酰胺共晶在pH=6.8的磷酸盐缓冲溶液中的溶解速率曲线,其中:a为杨梅素,d为杨梅素-烟酰胺共晶;
图15为杨梅素-异烟酰胺共晶的DSC图,其中:a为杨梅素,f为杨梅素-异烟酰胺共晶,g为异烟酰胺;
图16为杨梅素-异烟酰胺共晶的PXRD图,其中:a为杨梅素,f为杨梅素-异烟酰胺共晶,g为异烟酰胺;
图17为杨梅素-异烟酰胺共晶的IR图,其中:a为杨梅素,f为杨梅素-异烟酰胺共晶,g为异烟酰胺;
图18为杨梅素-异烟酰胺共晶的SEM图,其中:a为杨梅素,f为杨梅素-异烟酰胺共晶;
图19为杨梅素-异烟酰胺共晶在pH=1.2的盐酸缓冲溶液中的溶解速率曲线,其中:a为杨梅素,f为杨梅素-异烟酰胺共晶;
图20为杨梅素-异烟酰胺共晶在pH=4.5的醋酸盐缓冲溶液中的溶解速率曲线,其中:a为杨梅素,f为杨梅素-异烟酰胺共晶;
图21为杨梅素-异烟酰胺共晶在pH=6.8的磷酸盐缓冲溶液中的溶解速率曲线,其中:a为杨梅素,f为杨梅素-异烟酰胺共晶;
图22为杨梅素-4-氰基吡啶共晶的DSC图,其中:a为杨梅素,h为杨梅素-4-氰基吡啶共晶,i为4-氰基吡啶;
图23为杨梅素-4-氰基吡啶共晶的PXRD图,其中:a为杨梅素,h为杨梅素-4-氰基吡啶共晶,i为4-氰基吡啶;
图24为杨梅素-4-氰基吡啶共晶的IR图,其中:a为杨梅素,h为杨梅素-4-氰基吡啶共晶,i为4-氰基吡啶;
图25为杨梅素-4-氰基吡啶共晶的SEM图,其中:a为杨梅素,h为杨梅素-4-氰基吡啶共晶;
图26为杨梅素-4-氰基吡啶共晶在pH=1.2的盐酸缓冲溶液中的溶解速率曲线,其中:a为杨梅素,h为杨梅素-4-氰基吡啶共晶;
图27为杨梅素-4-氰基吡啶共晶在pH=4.5的醋酸盐缓冲溶液中的溶解速率曲线,其中:a为杨梅素,h为杨梅素-4-氰基吡啶共晶;
图28为杨梅素-4-氰基吡啶共晶在pH=6.8的磷酸盐缓冲溶液中的溶解速率曲线,其中:a为杨梅素,h为杨梅素-4-氰基吡啶共晶。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。
本发明中检测药物共晶结构及性能的仪器如下:
1.X射线粉末衍射仪,日本岛津公司生产,型号为XRD-6000X,Cu-K(α),管电压40kV,管电流40mA,扫描速度2°/min;
2.差式扫描量热仪,瑞士梅特勒-托利多公司,型号822e,本发明采用氮气气氛,升温速率10℃/min;
3.傅里叶变换红外光谱分析仪,美国赛默飞世尔公司生产,型号为Nicolet FT-IR-R330,吸收波长为450~4000cm-1,在1cm-1分辨率下扫描64次。
实施例1
分别准确称取408.12mg杨梅素和68.43mg咖啡因于20mL透明玻璃瓶中,加入8mL甲醇,将玻璃瓶密闭放在恒温水浴振荡器中,在25℃下振荡反应12h;停止反应,过滤,取滤饼于真空环境下干燥,所得产品即为杨梅素-咖啡因共晶。
实施例2
分别准确称取525.13mg杨梅素和129.13mg咖啡因于20mL透明玻璃瓶中,加入10mL甲醇,将玻璃瓶密闭放在恒温水浴振荡器中,在25℃下振荡反应12h;停止反应,过滤,取滤饼于真空环境下干燥,所得产品即为杨梅素-咖啡因共晶。
实施例3
分别准确称取633.57mg杨梅素和228.76mg咖啡因于20mL透明玻璃瓶中,加入10mL甲醇,将玻璃瓶密闭放在恒温水浴振荡器中,在25℃下振荡反应12h;停止反应,过滤,取滤饼于真空环境下干燥,所得产品即为杨梅素-咖啡因共晶。
实施例1~3所得的杨梅素-咖啡因共晶的差热(DSC)谱图如图1所示:共晶的熔点不同于原料药和前驱体的熔点,在275℃有一吸热峰,证明了有新相生成。
实施例1~3所得的杨梅素-咖啡因共晶的X射线粉末衍射(PXRD)谱图如图2所示:在2θ为25.3°,10.7°,12.3°,13.4°,14.3°,16.1°,17.9°,18.3°,21.9°,22.3°,24.8°,25.7°,27.1°,28.1°,29.6°左右出现了一系列特征峰,其中,12.3°,16.1°,24.8°,25.7°为主特征峰,这些特征峰的出峰位置既不同于原料药杨梅素也不同于前驱体咖啡因的PXRD谱图,证明了有新晶相生成。
实施例1~3所得的杨梅素-咖啡因共晶的红外谱图(IR)如图3所示:由于分子间氢键作用,杨梅素中-OH、C=O,前驱体中-NH2、C=O、-OH、C=N、-CN等基团在杨梅素共晶的IR图谱中均发生了红移或蓝移,在3249,1705,1646,1616,1602,1551,1503,1466,1415,1384,1360,1319,1233,1201,1165,1025cm-1处出现特征吸收峰,进一步证明了杨梅素共晶的形成。
实施例1~3所得的杨梅素-咖啡因共晶的SEM图如图4所示:杨梅素晶体呈棱柱状,杨梅素-咖啡因共晶呈细棒状,单纯从晶形也可以判断是否形成了共晶。
图5为实施例1~3所得的杨梅素-咖啡因共晶在pH=1.2的盐酸缓冲溶液中的溶解速率曲线,图6为实施例1~3所得的杨梅素-咖啡因共晶在pH=4.5的醋酸盐缓冲溶液中的溶解速率曲线,图7为实施例1~3所得的杨梅素-咖啡因共晶在pH=6.8的磷酸盐缓冲溶液中的溶解速率曲线;由图5至图7可见:本发明所提供的杨梅素-咖啡因共晶在25℃下,在pH=1.2的盐酸、pH=4.5的醋酸盐缓冲液及pH=6.8的磷酸缓冲盐中的溶解度及溶出速率相对于杨梅素均有显著提升。
实施例4
分别准确称取399.98mg杨梅素和1.024g烟酰胺于20mL透明玻璃瓶中,加入10mL甲醇,将玻璃瓶密闭放在恒温水浴振荡器中,在25℃下振荡反应12h;停止反应,过滤,取滤饼于真空环境下干燥,所得产品即为杨梅素-烟酰胺共晶。
实施例5
分别准确称取646.18mg杨梅素和646.53mg烟酰胺于20mL透明玻璃瓶中,加入8mL甲醇,将玻璃瓶密闭放在恒温水浴振荡器中,在25℃下振荡反应12h;停止反应,过滤,取滤饼于真空环境下干燥,所得产品即为杨梅素-烟酰胺共晶。
实施例6
分别准确称取622.28mg杨梅素和905.14mg烟酰胺于20mL透明玻璃瓶中,加入10mL甲醇,将玻璃瓶密闭放在恒温水浴振荡器中,在25℃下振荡反应12h;停止反应,过滤,取滤饼于真空环境下干燥,所得产品即为杨梅素-烟酰胺共晶。
实施例4~6所得的杨梅素-烟酰胺共晶的差热(DSC)谱图如图8所示:共晶的熔点不同于原料药和前驱体的熔点,在214℃有一吸热峰,证明了有新相生成。
实施例4~6所得的杨梅素-烟酰胺共晶的X射线粉末衍射(PXRD)谱图如图9所示:在2θ为6.5°,13.1°,15.0°,15.5°,16.1°,19.7°,24.2°,25.1°,25.7°,26.4°,27.3°,29.9°,41.2°左右出现了一系列特征峰,其中,15.0°,25.1°,25.7°,26.4°,27.3°为主特征峰,这些特征峰的出峰位置既不同于原料药杨梅素也不同于前驱体烟酰胺的PXRD谱图,证明了有新晶相生成。
实施例4~6所得的杨梅素-烟酰胺共晶的红外谱图(IR)如图10所示:由于分子间氢键作用,杨梅素中-OH、C=O,前驱体中-NH2、C=O、-OH、C=N、-CN等基团在杨梅素共晶的IR图谱中均发生了红移或蓝移,在3470,3413,3296,3122,1685,1661,1619,1606,1577,1544,1517,1502,1459,1420,1382,1355,1322,1244,1210,1163,1041,1026,699cm-1处出现特征吸收峰,进一步证明了杨梅素共晶的形成。
实施例4~6所得的杨梅素-烟酰胺共晶的SEM图如图11所示:杨梅素晶体呈棱柱状,杨梅素-烟酰胺共晶呈细棒状,单纯从晶形也可以判断是否形成了共晶。
图12为实施例4~6所得的杨梅素-烟酰胺共晶在pH=1.2的盐酸缓冲溶液中的溶解速率曲线,图13为实施例4~6所得的杨梅素-烟酰胺共晶在pH=4.5的醋酸盐缓冲溶液中的溶解速率曲线,图14为实施例4~6所得的杨梅素-烟酰胺共晶在pH=6.8的磷酸盐缓冲溶液中的溶解速率曲线;由图12至图14可见:本发明所提供的杨梅素-烟酰胺共晶在25℃下,在pH=1.2的盐酸、pH=4.5的醋酸盐缓冲液及pH=6.8的磷酸缓冲盐中的溶解度及溶出速率相对于杨梅素均有显著提升。
实施例7
分别准确称取358.58mg杨梅素和1.0611g异烟酰胺于20mL透明玻璃瓶中,加入8mL甲醇,将玻璃瓶密闭放在恒温水浴振荡器中,在25℃下振荡反应12h;停止反应,过滤,取滤饼于真空环境下干燥,所得产品即为杨梅素-异烟酰胺共晶。
实施例8
分别准确称取445.76mg杨梅素和403.35mg异烟酰胺于20mL透明玻璃瓶中,加入7mL甲醇,将玻璃瓶密闭放在恒温水浴振荡器中,在25℃下振荡反应12h;停止反应,过滤,取滤饼于真空环境下干燥,所得产品即为杨梅素-异烟酰胺共晶。
实施例9
分别准确称取439.56mg杨梅素和765.56mg异烟酰胺于20mL透明玻璃瓶中,加入10mL甲醇,将玻璃瓶密闭放在恒温水浴振荡器中,在25℃下振荡反应12h;停止反应,过滤,取滤饼于真空环境下干燥,所得产品即为杨梅素-异烟酰胺共晶。
实施例7~9所得的杨梅素-异烟酰胺共晶的差热(DSC)谱图如图15所示:共晶的熔点不同于原料药和前驱体的熔点,在255℃有一吸热峰,证明了有新相生成。
实施例7~9所得的杨梅素-异烟酰胺共晶的X射线粉末衍射(PXRD)谱图如图16所示:在2θ为5.5°,7.4°,15.0°,15.7°,24.1°,25.0°,25.6°,26.5°左右出现了一系列特征峰,其中,15.0°,25.0°为主特征峰,这些特征峰的出峰位置既不同于原料药杨梅素也不同于前驱体异烟酰胺的PXRD谱图,证明了有新晶相生成。
实施例7~9所得的杨梅素-异烟酰胺共晶的红外谱图(IR)如图17所示:由于分子间氢键作用,杨梅素中-OH、C=O,前驱体中-NH2、C=O、-OH、C=N、-CN等基团在杨梅素共晶的IR图谱中均发生了红移或蓝移,在3326,1686,1659,1603,1552,1522,1500,1457,1414,1348,1317,1247,1207,1167,1030,1008cm-1处出现特征吸收峰,进一步证明了杨梅素共晶的形成。
实施例7~9所得的杨梅素-异烟酰胺共晶的SEM图如图18所示:杨梅素晶体呈棱柱状,杨梅素-异烟酰胺共晶呈块状,单纯从晶形也可以判断是否形成了共晶。
图19为实施例7~9所得的杨梅素-异烟酰胺共晶在pH=1.2的盐酸缓冲溶液中的溶解速率曲线,图20为实施例7~9所得的杨梅素-异烟酰胺共晶在pH=4.5的醋酸盐缓冲溶液中的溶解速率曲线,图21为实施例7~9所得的杨梅素-异烟酰胺共晶在pH=6.8的磷酸盐缓冲溶液中的溶解速率曲线;由图19至图21可见:本发明所提供的杨梅素-异烟酰胺共晶在25℃下,在pH=1.2的盐酸、pH=4.5的醋酸盐缓冲液及pH=6.8的磷酸缓冲盐中的溶解度及溶出速率相对于杨梅素均有显著提升。
实施例10
分别准确称取315.6mg杨梅素和620.11mg4-氰基吡啶于20mL透明玻璃瓶中,加入7mL甲醇,将玻璃瓶密闭放在恒温水浴振荡器中,在25℃下振荡反应12h;停止反应,过滤,取滤饼于真空环境下干燥,所得产品即为杨梅素-4-氰基吡啶共晶。
实施例11
分别准确称取450.39mg杨梅素和449.4mg4-氰基吡啶于20mL透明玻璃瓶中,加入8mL甲醇,将玻璃瓶密闭放在恒温水浴振荡器中,在25℃下振荡反应12h;停止反应,过滤,取滤饼于真空环境下干燥,所得产品即为杨梅素-4-氰基吡啶共晶。
实施例12
分别准确称取546.24mg杨梅素和886.4mg4-氰基吡啶于20mL透明玻璃瓶中,加入10mL甲醇,将玻璃瓶密闭放在恒温水浴振荡器中,在25℃下振荡反应12h;停止反应,过滤,取滤饼于真空环境下干燥,所得产品即为杨梅素-4-氰基吡啶共晶。
实施例10~12所得的杨梅素-4-氰基吡啶共晶的差热(DSC)谱图如图22所示:共晶的熔点不同于原料药和前驱体的熔点,在187℃有一吸热峰,证明了有新相生成。
实施例10~12所得的杨梅素-4-氰基吡啶共晶的X射线粉末衍射(PXRD)谱图如图23所示:在2θ为5.1°,14.2°,14.9°,16.2°,24.3°,25.8°,27.3°,27.8°,29.6°左右出现了一系列特征峰,其中,14.9°,16.2°,24.3°,25.8°,27.3°为主特征峰,这些特征峰的出峰位置既不同于原料药杨梅素也不同于前驱体4-氰基吡啶的PXRD谱图,证明了有新晶相生成。
实施例10~12所得的杨梅素-4-氰基吡啶共晶的红外谱图(IR)如图24所示:由于分子间氢键作用,杨梅素中-OH、C=O,前驱体中-NH2、C=O、-OH、C=N、-CN等基团在杨梅素共晶的IR图谱中均发生了红移或蓝移,在3252,3394,3330,3091,2918,2850,2346,2237,1735,1663,1648,1608,1570,1560,1542,1508,1473,1419,1388,1346,1326,1275,1252,1208,1165,1111,1069,1039,1001,818,782,760,705,643,561,524cm-1处出现特征吸收峰,进一步证明了杨梅素共晶的形成。
实施例10~12所得的杨梅素-4-氰基吡啶共晶的SEM图如图25所示:杨梅素晶体呈棱柱状,杨梅素-4-氰基吡啶共晶呈块状,单纯从晶形也可以判断是否形成了共晶。
图26为实施例10~12所得的杨梅素-4-氰基吡啶共晶在pH=1.2的盐酸缓冲溶液中的溶解速率曲线,图27为实施例10~12所得的杨梅素-4-氰基吡啶共晶在pH=4.5的醋酸盐缓冲溶液中的溶解速率曲线,图28为实施例10~12所得的杨梅素-4-氰基吡啶共晶在pH=6.8的磷酸盐缓冲溶液中的溶解速率曲线;由图26至图28可见:本发明所提供的杨梅素-4-氰基吡啶共晶在25℃下,在pH=1.2的盐酸、pH=4.5的醋酸盐缓冲液及pH=6.8的磷酸缓冲盐中的溶解度及溶出速率相对于杨梅素均有显著提升。
综上所述可见:本发明通过选择适宜的前驱体与杨梅素形成的杨梅素药物共晶,在继承杨梅素药理活性的同时,其溶解性、溶出率及稳定性相对于杨梅素均得到了显著性提高,有利于开发成药物制剂,可促使杨梅素在医药领域的广泛应用。
最后有必要在此说明的是:以上实施例只用于对本发明的技术方案作进一步详细地说明,不能理解为对本发明保护范围的限制,本领域的技术人员根据本发明的上述内容作出的一些非本质的改进和调整均属于本发明的保护范围。

Claims (5)

1.一种杨梅素药物共晶,其特征在于:是以杨梅素作为活性药物成分,以烟酰胺、异烟酰胺或4-氰基吡啶为前驱体,通过分子间氢键形成的杨梅素-烟酰胺共晶、杨梅素-异烟酰胺共晶或杨梅素-4-氰基吡啶共晶;所述的杨梅素-烟酰胺共晶在粉末X射线衍射下,在衍射角度2θ为15.0°、25.1°、25.7°、26.4°、27.3°处具有主特征峰;在衍射角度2θ为6.5°、13.1°、15.0°、15.5°、16.1°、19.7°、24.2°、25.1°、25.7°、26.4°、27.3°、29.9°、41.2°处具有特征峰;所述的杨梅素-异烟酰胺共晶在粉末X射线衍射下,在衍射角度2θ为15.0°、25.0°处具有主特征峰;在衍射角度2θ为5.5°、7.4°、15.0°、15.7°、24.1°、25.0°、25.6°、26.5°处具有特征峰;所述的杨梅素-4-氰基吡啶共晶在粉末X射线衍射下,在衍射角度2θ为14.9°、16.2°、24.3°、25.8°、27.3°处具有主特征峰;在衍射角度2θ为5.1°、14.2°、14.9°、16.2°、24.3°、25.8°、27.3°、27.8°、29.6°处具有特征峰;测试误差均为±0.2°。
2.一种制备权利要求1所述的杨梅素药物共晶的方法,其特征在于:为溶液介导转晶法,具体包括如下步骤:
a)将杨梅素与前驱体加入醇溶剂中,在20~37℃下进行恒温振荡4~24小时;
b)过滤,收集滤饼进行真空干燥,即得杨梅素药物共晶。
3.如权利要求2所述的方法,其特征在于:当前驱体为烟酰胺时,杨梅素与烟酰胺的质量比为1:3~1:1,杨梅素与烟酰胺的总质量与醇溶剂的体积比为(140~165)mg:1mL。
4.如权利要求2所述的方法,其特征在于:当前驱体为异烟酰胺时,杨梅素与异烟酰胺的质量比为1:3~2:1,杨梅素与异烟酰胺的总质量与醇溶剂的体积比为(120~180)mg:1mL。
5.如权利要求2所述的方法,其特征在于:当前驱体为4-氰基吡啶时,杨梅素与4-氰基吡啶的质量比为1:2~2:1,杨梅素与4-氰基吡啶的总质量与醇溶剂的体积比为(110~150)mg:1mL。
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