CN114634474A - 双氢杨梅素的共晶化合物及其制备方法 - Google Patents
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Abstract
本发明的目的在于提供一种新的双氢杨梅素的共晶化合物,与双氢杨梅素相比能够增加其溶解度、提高稳定性以及提高生物利用度,共晶形成物的引入,能够改善药物本身的结晶性能及物化性质。本发明以异烟酰胺或4,4′‑联吡啶为共晶形成物,通过非共价键,在晶胞中相互作用结合生成。
Description
技术领域
本发明属于药物共晶技术领域,具体涉及一种双氢杨梅素的共晶化合物及其制备方法。
背景技术
双氢杨梅素是来源于中药藤茶的主要活性成分,属于黄酮醇类物质,具有多种药理活性如清除自由基、抗氧化、抗血栓、抗肿瘤、消炎等多种功效;现有大量研究表明,双氢杨梅素对肝脏疾病具有显著的治疗作用,具有预防酒精肝、脂肪肝、抑制肝细胞恶化、降低肝癌的发病率等作用,因此具有明确而广阔的应用前景。但双氢杨梅素在水中溶解度低、渗透性差,导致其口服生物利用度较低。因此,改善双氢杨梅素的溶解性等性质进而改善生物利用度成为一个有待解决的问题。
发明内容
本发明的目的在于提供一种新的双氢杨梅素的共晶化合物(药物共晶),与双氢杨梅素相比能够增加其溶解度、提高稳定性以及提高生物利用度。药物共晶在修饰药物活性成分理化性质方面的应用备受关注,药物共晶是活性药物成分(API)与共晶形成物(CCF)通过非共价相互作用形成的新的结晶形式。共晶形成物的引入,能够改善药物本身的结晶性能及物化性质。
本发明以异烟酰胺或4,4′-联吡啶为共晶形成物,详述如下:
技术方案一:
双氢杨梅素-异烟酰胺药物共晶,以双氢杨梅素作为活性药物成分,以异烟酰胺为共晶形成物,由双氢杨梅素和异烟酰胺通过非共价键,在晶胞中以1∶1的方式相互作用结合生成。双氢杨梅素-异烟酰胺药物共晶属于单斜晶系,空间群,轴长 轴角α=100.827(4)°,β=106.501(4)°,γ=103.454(4)°, 两种成分的化学结构示意如下:
该共晶粉末的X射线衍射图谱在2θ为5.54°,6.56°,10.16°,12.16°,12.44°,13.40°,14.14°,15.20°,16.72°,18.25°,18.74°,20.60°,21.60°,23.12°,24.03°,24.68°,25.30°,27.34°等处具有特征峰。
差示扫描量热(DSC)分析表明,该共晶在201℃有一吸热峰,熔点介于双氢杨梅素和异烟酰胺之间。
该共晶红外图谱在3379cm-1、1634cm-1、842cm-1、755cm-1、630cm-1等处具有特征峰。
技术方案二:
双氢杨梅素-4,4′-联吡啶药物共晶,以双氢杨梅素作为活性药物成分,以4,4′-联吡啶为共晶形成物,由双氢杨梅素和4,4′-联吡啶以1∶2.5通过非共价键相互作用结合生成。双氢杨梅素-4,4′-联吡啶药物共晶属于三斜晶系,空间群为轴长为 轴角α=112.648(3)°,β=95.628(2)°,γ=95.179(2)°,两种成分的化学结构示意如下:
该共晶粉末的X射线衍射图谱在2θ为5.54°,6.56°,10.16°,12.16°,12.44°,13.40°,14.14°,15.20°,16.72°,18.25°,18.74°,20.60°,21.60°,23.12°,24.03°,24.68°,25.30°,27.34°等处具有特征峰处。
DSC分析表明,该共晶在231℃有一吸热峰,熔点介于双氢杨梅素和4,4′-联吡啶之间。
该共晶红外图谱在3395cm-1、1642cm-1、1457cm-1、805cm-1、732cm-1、620cm-1等处具有特征峰。
制备方法:
一、双氢杨梅素-异烟酰胺共晶的制备方法有两种,详述如下:
1.一种双氢杨梅素-异烟酰胺共晶的制备方法,包括以下步骤:(1)双氢杨梅素-异烟酰胺按照摩尔比为1∶1的置于5mL的研磨罐中,滴加2~3滴的助研溶剂乙腈研磨。(2)将上述研磨粉末置于玻璃容器中加入加甲醇和其它有机溶剂的混合溶剂中,搅拌至粉末全部溶解后,将溶剂置于常温中缓慢挥发,得到棱柱状结晶。
所述的有机溶剂为乙腈、异丙醇、丙酮、甲醇、乙醇。
所述的有机溶剂为乙腈、异丙醇、丙酮、甲醇、乙醇或者水中的两种以上的混合物。
2.一种双氢杨梅素-异烟酰胺共晶制备方法,包括以下步骤:(1)将双氢杨梅素和异烟酰胺按一定摩尔比置于烧杯中,加入合适溶剂,在20~60℃下进行恒温搅拌3~6小时。(2)过滤,将溶液置于常温中挥发,即得双氢杨梅素-异烟酰胺共晶粉末。
所述的双氢杨梅素和异烟酰胺摩尔比为1∶1~1∶3。
所述的有机溶剂选自乙腈、异丙醇、丙酮、甲醇、乙醇。
二、双氢杨梅素-4,4′-联吡啶共晶的制备方法有两种,详述如下:
1.一种双氢杨梅素-4,4′-联吡啶共晶的制备方法,包括以下步骤:(1)双氢杨梅素-4,4′-联吡啶按照摩尔比为1∶2.5的置于5mL的研磨罐中,滴加2~3滴的助研溶剂乙腈研磨。(2)将上述研磨粉末置于玻璃容器中加入加乙腈和其它有机溶剂的混合溶剂中,搅拌至粉末全部溶解后,将溶剂置于常温中缓慢挥发,得到黄色针状结晶。
所述的有机溶剂为乙腈、异丙醇、丙酮、甲醇或乙醇。
所述的有机溶剂为乙腈、异丙醇、丙酮、甲醇或乙醇或者水中的两种以上的混合物。
2.一种双氢杨梅素-4,4′-联吡啶共晶制备方法,包括以下步骤:(1)将双氢杨梅素和4,4′-联吡啶按一定摩尔比置于烧杯中,加入合适溶剂,在20~60℃下进行恒温搅拌12~24小时。(2)过滤,将过滤粉末真空干燥后,即得双氢杨梅素-4,4′-联吡啶共晶粉末。
所述的双氢杨梅素和4,4′-联吡啶摩尔比为1∶1~1∶3。
所述的有机溶剂选自乙腈、异丙醇、丙酮、甲醇或乙醇。
有益效果
本发明提供的双氢杨梅素共晶相比原料药双氢杨梅素溶解度及溶出速率有明显的提高,并且共晶其生物利用度与原料药双氢杨梅素相比有显著的提升,节约了双氢杨梅素在成药时的用药量,从而到达提高其吸收的目的,对于药物疗效及安全性的提高具有重要意义。本发明提供的双氢杨梅素共晶在水溶液中溶解度较原料药提高了46%,在pH为1.2的盐酸溶液中的溶出速率提高约1.3倍;其相对生物利用度较原料药提高了近2倍。
附图说明:
图1是双氢杨梅素-异烟酰胺共晶单晶结构图;
图2是双氢杨梅素-异烟酰胺共晶粉末X射线衍射(PXRD)图;
图3是双氢杨梅素-异烟酰胺共晶差示扫描量热分析(DSC)图;
图4是双氢杨梅素-异烟酰胺共晶红外(IR)谱图;
图5是双氢杨梅素-异烟酰胺共晶溶出曲线图;
图6是双氢杨梅素-异烟酰胺共晶血药浓度曲线图;
图7是双氢杨梅素-4,4′-联吡啶共晶单晶结构图;
图8是双氢杨梅素-4,4′-联吡啶共晶粉末X射线衍射(PXRD)图;
图9是双氢杨梅素-4,4′-联吡啶共晶差示扫描量热分析(DSC)图;
图10是双氢杨梅素-4,4′-联吡啶共晶红外(IR)谱图;
图11是双氢杨梅素-4,4′-联吡啶共晶溶出曲线图;
图12是双氢杨梅素-4,4′-联吡啶共晶血药浓度曲线图。
具体实施方式
下面将结合本发明的附图,对本发明实施例中的技术方案进行清楚、完整地描述。
实施例1:
双氢杨梅素-异烟酰胺药物共晶,以双氢杨梅素作为活性药物成分,以异烟酰胺为共晶形成物,由双氢杨梅素和异烟酰胺通过非共价键,在晶胞中以1∶1的方式相互作用结合生成。双氢杨梅素-异烟酰胺药物共晶属于单斜晶系,空间群,轴长 轴角α=100.827(4)°,β=106.501(4)°,γ=103.454(4)°,其制备方法如下:
1.一种双氢杨梅素-异烟酰胺共晶的制备方法,包括以下步骤:(1)双氢杨梅素-异烟酰胺按照摩尔比为1∶1的置于5mL的研磨罐中,滴加2~3滴的助研溶剂乙腈研磨。(2)将上述研磨粉末置于玻璃容器中加入加甲醇和其它有机溶剂的混合溶剂中,搅拌至粉末全部溶解后,将溶剂置于常温中缓慢挥发,得到棱柱状结晶。
所述的有机溶剂为乙腈、异丙醇、丙酮、甲醇、乙醇。
所述的有机溶剂为乙腈、异丙醇、丙酮、甲醇、乙醇或者水中的两种以上的混合物。
2.一种双氢杨梅素-异烟酰胺共晶制备方法,包括以下步骤:(1)将双氢杨梅素和异烟酰胺按一定摩尔比置于烧杯中,加入合适溶剂,在20~60℃下进行恒温搅拌3~6小时。(2)过滤,将溶液置于常温中挥发,即得双氢杨梅素-异烟酰胺共晶粉末。
所述的双氢杨梅素和异烟酰胺摩尔比为1∶1~1∶3。
所述的有机溶剂选自乙腈、异丙醇、丙酮、甲醇、乙醇。
实施例2:
双氢杨梅素-4,4′-联吡啶药物共晶,以双氢杨梅素作为活性药物成分,以4,4′-联吡啶为共晶形成物,由双氢杨梅素和4,4′-联吡啶以1∶2.5通过非共价键相互作用结合生成。双氢杨梅素-4,4′-联吡啶药物共晶属于三斜晶系,空间群为轴长 轴角α=112.648(3)°,β=95.628(2)°,γ=95.179(2)°,其制备方法如下:
1.一种双氢杨梅素-4,4′-联吡啶共晶的制备方法,包括以下步骤:(1)双氢杨梅素-4,4′-联吡啶按照摩尔比为1∶2.5的置于5mL的研磨罐中,滴加2~3滴的助研溶剂乙腈研磨。(2)将上述研磨粉末置于玻璃容器中加入加乙腈和其它有机溶剂的混合溶剂中,搅拌至粉末全部溶解后,将溶剂置于常温中缓慢挥发,得到黄色针状结晶。
所述的有机溶剂为乙腈、异丙醇、丙酮、甲醇或乙醇。
所述的有机溶剂为乙腈、异丙醇、丙酮、甲醇或乙醇或者水中的两种以上的混合物。
2.一种双氢杨梅素-4,4′-联吡啶共晶制备方法,包括以下步骤:(1)将双氢杨梅素和4,4′-联吡啶按一定摩尔比置于烧杯中,加入合适溶剂,在20~60℃下进行恒温搅拌12~24小时。(2)过滤,将过滤粉末真空干燥后,即得双氢杨梅素-4,4′-联吡啶共晶粉末。
所述的双氢杨梅素和4,4′-联吡啶摩尔比为1∶1~1∶3。
所述的有机溶剂选自乙腈、异丙醇、丙酮、甲醇或乙醇。
本发明中检测药物共晶结构及性能的仪器如下:
1.共晶单晶结构由Rigaku Oxford X-射线单晶衍射仪测定。
2.X-射线粉末衍射仪由Rigaku/MiniFlex 600 X-射线粉末衍射仪测定,扫速5°/min,2θ范围为5°-45°。
3.差示扫描量热分析由STA449差示扫描量热仪测定,氮气气氛,加热速率为10℃/min,测试温度为室温至450℃。
4.红外光谱由Nicolet Nexus 470红外光谱仪测定,扫描范围400-4000cm-1。
5.溶解度、溶出度及血药浓度由Waters 2695高效液相色谱仪测定。
Claims (7)
1.双氢杨梅素的共晶化合物,以双氢杨梅素与共晶形成物通过非共价相互作用形成结晶。
4.双氢杨梅素-异烟酰胺共晶的制备方法:(1)双氢杨梅素-异烟酰胺按照摩尔比为1∶1的置于5mL的研磨罐中,滴加2~3滴的助研溶剂乙腈研磨;(2)将上述研磨粉末置于玻璃容器中加入甲醇和其它有机溶剂的混合溶剂中,搅拌至粉末全部溶解后,将溶剂置于常温中缓慢挥发,得到棱柱状结晶;所述的有机溶剂为乙腈或异丙醇或丙酮或甲醇或乙醇或两种以上的混合物。
5.双氢杨梅素-异烟酰胺共晶的制备方法:(1)将双氢杨梅素和异烟酰胺按1∶1~1∶3摩尔比置于烧杯中,加入溶剂,在20~60℃下进行恒温搅拌3~6小时;所述溶剂为乙腈或异丙醇或丙酮或甲醇或乙醇;(2)过滤,将溶液置于常温中挥发,即得双氢杨梅素-异烟酰胺共晶粉末。
6.双氢杨梅素-4,4′-联吡啶共晶的制备方法:(1)双氢杨梅素-4,4′-联吡啶按照摩尔比为1∶2.5的置于5mL的研磨罐中,滴加2~3滴的助研溶剂乙腈研磨;(2)将上述研磨粉末置于玻璃容器中加入加乙腈和其它有机溶剂的混合溶剂中,搅拌至粉末全部溶解后,将溶剂置于常温中缓慢挥发,得到黄色针状结晶;所述的有机溶剂为乙腈或异丙醇或丙酮或甲醇或乙醇或两种以上的混合物。
7.双氢杨梅素-4,4′-联吡啶共晶的制备方法:(1)将双氢杨梅素和4,4′-联吡啶按1∶1~1∶3摩尔比置于烧杯中,加入合适溶剂,在20~60℃下进行恒温搅拌12~24小时;所述溶剂为乙腈或异丙醇或丙酮或甲醇或乙醇;(2)过滤,将过滤粉末真空干燥后,即得双氢杨梅素-4,4′-联吡啶共晶粉末。
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