CN105153025A - 肌醇烟酸酯晶型a及其制备方法 - Google Patents
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Abstract
本发明属于化学药物技术领域,尤其涉及肌醇烟酸酯晶型A及其制备方法,所述肌醇烟酸酯晶型A使用Cu-Kα射线测量得到的X-射线粉末衍射分析,2θ值至少在7.05、7.41、9.74、17.80、19.86、23.57、25.48和26.20°处有明显的特征衍射峰,误差范围为±0.2°。所述制备方法为蒸发结晶法、冷却结晶法或反溶剂结晶法中的一种或两种以上的混合结晶方法。本发明,其工艺简单、易于操作、选择性较多,可通过多种方法制得肌醇烟酸酯晶型A,且制得的产品结晶度好、化学稳定性高,通过本发明的方法制备的肌醇烟酸酯晶型A不存在溶剂残留或溶剂超标的问题。
Description
技术领域
本发明属于化学药物技术领域,尤其涉及肌醇烟酸酯晶型A及其制备方法。
背景技术
多晶型现象是指固体物质以两种或两种以上的不同空间排列方式,形成的具有不同物理化学性质的固体状态的现象。在药物研究领域,多晶型还包括了有机溶剂化物、水合物等多组分晶体形式。晶型研究和控制是药物研发过程中的重要研究内容。
肌醇烟酸酯(InositolNicotinate),化学名为顺-1,2,3,5-反-4,6-环己六醇六烟酸酯,是一种温和的周围血管扩张剂,吸收后在体内逐渐水解为烟酸和肌醇,具有烟酸和肌醇二者的药理作用,其血管扩张作用较烟酸缓和而持久,可选择性的使病变部位和受寒冷刺激的敏感部位的血管扩张,而对正常血管的扩张作用则较弱,此外还兼具溶解血栓、抗凝、抗脂肪肝、降低毛细血管脆性等作用,没有服用烟酸后的潮红和胃部不适等副作用。临床上肌醇烟酸酯片主要用于高脂血症、动脉粥样硬化、各种末梢血管障碍性疾病(如闭塞性动脉硬化症、肢端动脉痉挛症、冻伤、血管性偏头痛等)的辅助治疗。
肌醇烟酸酯的结构式如下所示:
肌醇烟酸酯仅溶于热二甲基甲酰胺或二甲基亚砜中,在氯仿中极微溶解,不溶于水、乙醇和其它有机溶剂,该化合物尚未见晶型报道。肌醇烟酸酯的合成一般采用吡啶作溶剂由肌醇与烟酸缩合得到,由于溶解性能差,产品纯化和残留吡啶的除去极其困难,而二甲基甲酰胺或二甲基亚砜为高沸点溶剂,用于结晶纯化又会导致二甲基甲酰胺或二甲基亚砜的超标。
发明内容
本发明的目的之一在于:提供一种结晶度好、化学稳定性高的肌醇烟酸酯晶型A。为解决上述技术问题,本发明的技术方案是:
肌醇烟酸酯晶型A,所述晶型A使用Cu-Kα射线测量得到的X-射线粉末衍射分析,衍射峰具有如下特征:
作为一种改进,使用Cu-Kα射线测量得到的X-射线粉末衍射分析,以度表示的2θ值至少在7.05、7.41、9.74、17.80、19.86、23.57、25.48和26.20处有明显的特征衍射峰,误差范围为±0.2°。
作为一种改进,所述晶型A属于单斜晶系,空间点群为P21/c,晶胞参数:α=γ=90.00°,β=94.5170(10)°;晶胞体积为晶体密度为1.4022g/cm3。
作为一种改进,所述晶型A的差示扫描量热分析在260℃开始熔融,在261.14℃有最大吸热熔融峰。
作为一种改进,所述晶型A的热失重分析的分解温度为300±1℃,在所述分解温度之前未有结晶水或结合溶剂的失重峰。
作为一种改进,所述晶型A的拉曼图谱至少在622cm-1、827cm-1、903cm-1、1033cm-1、1194cm-1、1276cm-1、1302cm-1、1387cm-1、1592cm-1、1720cm-1、1741cm-1、2971cm-1和3067cm-1处具有特征峰,误差范围为±2cm-1。
本发明的目的之二在于:提供一种工艺简单、易于操作、产品结晶度好和稳定性高的肌醇烟酸酯晶型A的制备方法。
为解决上述技术问题,本发明的技术方案是:
所述制备方法为蒸发结晶法、冷却结晶法或反溶剂结晶法中的一种或两种以上的混合结晶方法。
优选的,所述蒸发结晶法包括以下步骤:将肌醇烟酸酯溶解于卤代烷与醇类的混合溶剂或卤代烷与醇水的混合溶剂中,于室温下放置或加热使体系中的卤代烷挥发或蒸发,直至固体结晶物析出,过滤,洗涤,干燥,即得。
优选的,所述冷却结晶法包以下步骤:将肌醇烟酸酯溶解于卤代烷与醇类的混合溶剂或卤代烷与醇水的混合溶剂中,加热溶解,再冷却降温,直至析出固体结晶物,过滤,洗涤,干燥,即得。
优选的,所述反溶剂结晶法包括以下步骤:将肌醇烟酸酯溶解于卤代烷与醇类的混合溶剂或卤代烷与醇水的混合溶剂中,于室温下滴加入醇类溶剂,直至有固体结晶物析出,过滤,洗涤,干燥,即得。
优选的,所述混合结晶方法包括以下步骤:将肌醇烟酸酯溶解于卤代烷与醇类的混合溶剂或卤代烷与醇水的混合溶剂中,加热蒸发卤代烷的同时向反应液中滴加醇类溶剂,直至析出固体结晶物,过滤,洗涤,干燥,即得。
作为一种改进,所述卤代烷为氯仿、二氯甲烷或二氯乙烷中的一种或两种以上。
作为一种改进,所述醇类为甲醇、乙醇或异丙醇中的一种或两种以上。
作为一种改进,所述醇水为甲醇、乙醇或异丙醇中的一种或两种以上与水的混合溶剂。
作为一种改进,所述卤代烷与醇类的混合溶剂中,所述卤代烃与所述醇类的体积比为10:1~1:10,优选为4:1~1:1。
作为一种改进,所述干燥为鼓风干燥或真空干燥,所述干燥温度为室温至110℃,优选为80~100℃。
由于采用了上述技术方案,本发明的有益效果是:
本发明提供的肌醇烟酸酯晶型A的制备方法,其工艺简单、易于操作、选择性较多,可通过多种方法制得肌醇烟酸酯晶型A,且制得的产品结晶度好、化学稳定性高,通过本发明的方法制备的肌醇烟酸酯晶型A不存在溶剂残留或溶剂超标的问题。
附图说明
图1是本发明提供的肌醇烟酸酯晶型A的X-射线粉末衍射(XRPD)图与单晶模拟的粉末衍射;
图2是本发明提供的肌醇烟酸酯晶型A的差示扫描量热分析(DSC)图;
图3是本发明提供的肌醇烟酸酯晶型A的热失重分析(TG)图;
图4是本发明提供的肌醇烟酸酯晶型A的拉曼(Raman)光谱图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
实施例一
将1g肌醇烟酸酯粗品溶解于10mL二氯甲烷/甲醇(10/1,v/v)混合溶剂中,室温下放置2~3d,自然挥发,析出结晶,过滤,室温下真空干燥得高纯度的肌醇烟酸酯晶体。
实施例二
将30g肌醇烟酸酯粗品加入150mL氯仿/乙醇(4/1,v/v)组成的混合溶剂中,室温下搅拌1~2h,使肌醇烟酸酯粗品完全溶解,再向上述反应液中滴加15mL乙醇,加毕,搅拌2~3h,析出白色固体,过滤,洗涤,100℃鼓风干燥1h,得肌醇烟酸酯晶体465g,经粉末X-射线衍射鉴定与实施例一制得的晶型一致。
实施例三
将30g肌醇烟酸酯粗品加入120mL二氯乙烷/异丙醇(1/1,v/v)组成的混合溶剂中,加热至60℃,使肌醇烟酸酯粗品完全溶解,再冷却至0~5℃,析出晶体,过滤,洗涤,110℃鼓风干燥1h,得白色固体25g,经粉末X-射线衍射鉴定与实施例一制得的晶型一致。
实施例四
取100g肌醇烟酸酯粗品溶解于500mL二氯甲烷/95%乙醇(4/1,v/v)混合溶剂中,缓慢滴加入预先加热至70℃的95%乙醇400mL中,控制加热温度与滴加速度,使混合溶剂滴加速率与蒸馏速率基本一致,滴加完毕,再升温蒸馏出部分乙醇,冷却至室温,过滤,用95%乙醇洗涤,80℃鼓风干燥3h,得98g,经粉末X-射线衍射鉴定与实施例一中的晶型一致。
对上述实施例制得的肌醇烟酸酯晶型A进行X-射线粉末衍射分析(XRPD)、差示扫描量热分析(DSC)、热失重分析(TG)、拉曼光谱分析(Raman)等。
XRPD分析:其采用德国布鲁克仪器有限公司BrukerD8advance型的衍射仪于室温进行检测,采用Cu–Kα射线(),2θ角扫描从3度到40度,扫描速度为0.2度/秒。
经粉末X-射线衍射分析,以2θ反射角表示在7.05、7.41、9.74、10.16、11.26、12.75、13.66、17.04、17.80、18.36、19.28、19.86、20.62、20.97、21.58、22.03、23.57、23.93、25.20、25.48、26.20和26.58±0.2°等处具有特征峰。
额外结晶学信息是自单晶X-射线衍射获得,该晶体为斜方晶系,对称空间群为P21/c,晶胞参数:α=γ=90.00°,β=94.5170(10)°;晶胞体积为晶体密度为1.4022g/cm3。晶体结构中没有结合溶剂,单晶衍射模拟的粉末衍射图谱与实验实测的粉末X-射线衍射图谱完全一致,其分析结果见图1。
DSC分析:其采用美国铂金埃尔默公司的DSC8500型差示扫描量热仪进行检测,气氛为氮气,加热速度为10摄氏度/分钟。其分析结果见图2。
TG分析:其采用德国耐驰公司的NetzschTG209F3型热重分析仪检测,温度范围:30-400℃,扫描速率:10K/min,吹扫气:25mL/min。其分析结果见图3。
拉曼(Raman)光谱分析:其采用美国热电公司的DXR显微拉曼光谱仪于室温检测,检测范围为3500-50cm-1拉曼位移。其分析结果见图4。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (10)
1.肌醇烟酸酯晶型A,其特征在于,所述晶型A使用Cu-Kα射线测量得到的X-射线粉末衍射分析,以度表示的2θ值、误差范围为±0.2°,以表示的晶面间距d和以百分数表示的衍射峰的相对强度具有如下特征:
。
2.如权利要求1所述的肌醇烟酸酯晶型A,其特征在于,使用Cu-Kα射线测量得到的X-射线粉末衍射分析,以度表示的2θ值至少在7.05、7.41、9.74、17.80、19.86、23.57、25.48和26.20处有明显的特征衍射峰,误差范围为±0.2°。
3.如权利要求1所述的肌醇烟酸酯晶型A,其特征在于,所述晶型A属于单斜晶系,空间点群为P21/c,晶胞参数: α=γ=90.00°,β=94.5170(10)°;晶胞体积为晶体密度为1.4022g/cm3。
4.如权利要求1所述的肌醇烟酸酯晶型A,其特征在于,所述晶型A的差示扫描量热分析在260℃开始熔融,在261.14℃有最大吸热熔融峰。
5.如权利要求1所述的肌醇烟酸酯晶型A,其特征在于,所述晶型A的热失重分析的分解温度为300±1℃,在所述分解温度之前未有结晶水或结合溶剂的失重峰。
6.如权利要求1所述的肌醇烟酸酯晶型A,其特征在于,所述晶型A的拉曼图谱至少在622cm-1、827cm-1、903cm-1、1033cm-1、1194cm-1、1276cm-1、1302cm-1、1387cm-1、1592cm-1、1720cm-1、1741cm-1、2971cm-1和3067cm-1处具有特征峰,误差范围为±2cm-1。
7.肌醇烟酸酯晶型A的制备方法,其特征在于,所述制备方法为蒸发结晶法、冷却结晶法或反溶剂结晶法中的一种或两种以上的混合结晶方法。
8.如权利要求7所述的肌醇烟酸酯晶型A的制备方法,其特征在于,
所述蒸发结晶法包括以下步骤:将肌醇烟酸酯溶解于卤代烷与醇类的混合溶剂或卤代烷与醇水的混合溶剂中,于室温下放置或加热使体系中的卤代烷挥发或蒸发,直至固体结晶物析出,过滤,洗涤,干燥,即得;
所述冷却结晶法包以下步骤:将肌醇烟酸酯溶解于卤代烷与醇类的混合溶剂或卤代烷与醇水的混合溶剂中,加热溶解,再冷却降温,直至析出固体结晶物,过滤,洗涤,干燥,即得;
所述反溶剂结晶法包括以下步骤:将肌醇烟酸酯溶解于卤代烷与醇类的混合溶剂或卤代烷与醇水的混合溶剂中,于室温下滴加入醇类溶剂,直至有固体结晶物析出,过滤,洗涤,干燥,即得;
所述混合结晶方法包括以下步骤:将肌醇烟酸酯溶解于卤代烷与醇类的混合溶剂或卤代烷与醇水的混合溶剂中,加热蒸发卤代烷的同时向反应液中滴加醇类溶剂,直至析出固体结晶物,过滤,洗涤,干燥,即得。
9.如权利要求8所述的肌醇烟酸酯晶型A的制备方法,其特征在于,所述卤代烷为氯仿、二氯甲烷或二氯乙烷中的一种或两种以上;所述醇类为甲醇、乙醇或异丙醇中的一种或两种以上;所述醇水为甲醇、乙醇或异丙醇中的一种或两种以上与水的混合溶剂;所述卤代烷与醇类的混合溶剂中,所述卤代烃与所述醇类的体积比为10:1~1:10。
10.如权利要求8所述的肌醇烟酸酯晶型A的制备方法,其特征在于,所述干燥为鼓风干燥或真空干燥,所述干燥温度为室温至110℃。
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CN107879973A (zh) * | 2017-11-09 | 2018-04-06 | 华中药业股份有限公司 | 一种甘露六烟酯的精制方法 |
CN109438335A (zh) * | 2018-12-22 | 2019-03-08 | 华中药业股份有限公司 | 一种肌醇烟酸酯的精制方法 |
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