CN105585520A - 盐酸左布比卡因a晶型及其制备方法 - Google Patents
盐酸左布比卡因a晶型及其制备方法 Download PDFInfo
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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Abstract
本发明涉及盐酸左布比卡因A晶型及制备方法,其特征在于,X-射线粉末衍射图的反射角2θ为9.6-9.8,10.6-10.8,12.5-12.7,13.3-13.5,18.9-19.1,21.5-21.7,其中反射角2θ为9.6-9.8的峰强度为100%。该晶型纯度高,收率高,晶型稳定,以及制备工艺简单、易于实施。
Description
技术领域
本发明涉及盐酸左布比卡因A晶型及制备方法,属于医药制备技术领域。
背景技术
盐酸左布比卡因其化学名为S-(-)-1-丁基-N-(2,6-二甲基苯基)-2-哌啶甲酰胺盐酸盐,结构式如下所示:
盐酸左布比卡因是一种新型长效酰胺类局部麻醉药,主要用于外科硬膜外腔阻滞麻醉,它最早由美国PurduePharma公司开发,于2002年在美国上市。通过提高神经电刺激阈值,延缓神经冲动的传播,降低动作电位的增设速率,阻滞神经冲动的产生和传导。其麻醉维持时间长,肌肉松弛良好,术中无需多次椎管内用药即能维持相对稳定的麻醉深度;麻醉药用量小,对血流动力的变化影响较小、病人有较高的安全性,同时也方便管理。盐酸左布比卡因在儿科手术、面部手术以及治疗偏头痛都有广泛的用途。
对于盐酸左布比卡因,其不同晶型在外观、溶解度、熔点、溶出度、生物有效性等方面可能会有显著不同,从而影响了药物的稳定性、生物利用度及疗效,该种现象在口服固体制剂方面表现得尤为明显。而目前现有文献中均未对所得到的晶型进行表征,因此本发明人就未报道的盐酸左布比卡因的晶体晶型进行了进一步的研究。
发明内容
本发明旨在提供一种纯度高,收率高,晶型稳定的盐酸左布比卡因晶型,以及一种工艺简单、易于实施的制备该药物晶型的方法。
本发明的技术方案是:一种盐酸左布比卡因A晶型,其特征在于,X-射线粉末衍射图的反射角2θ为9.6-9.8,10.6-10.8,12.5-12.7,13.3-13.5,18.9-19.1,21.5-21.7,其中反射角2θ为9.6-9.8的峰强度为100%。
其中,所述的盐酸左布比卡因A晶型在3101-3102、2876-2878、1674-1676、1537-1539、1473-1475、941-957、786-787处有红外吸收峰。
所述的盐酸左布比卡因A晶型的制备方法,包含用混合溶剂溶解盐酸左布比卡因,趁热过滤,分步降温,析出晶体。
其中,所述的分步降温步骤为:首先降温至20℃,析晶2.5小时,然后再降温至0℃,搅拌析晶6h。
所述的混合溶剂为甲乙酮和乙酸乙酯的混合溶剂,溶剂体积比为1:1。
本发明的有益效果在于:该晶型在稳定性等方面具有良好的性能,有利于生产工艺中转移、储存、操作。
附图说明
图1是本发明实施例1中盐酸左布比卡因X-粉末衍射图谱;
图2是本发明实施例1中盐酸左布比卡因红外吸收图谱;
图3是本发明实施例2中盐酸左布比卡因X-粉末衍射图谱;
图4是本发明实施例2中盐酸左布比卡因红外吸收图谱;
图5是本发明实施例3中盐酸左布比卡因X-粉末衍射图谱;
图6是本发明实施例3中盐酸左布比卡因红外吸收图谱。
具体实施方式
实施例1
在3L反应釜中加入甲乙酮900mL和乙酸乙酯900mL,搅拌下,加入盐酸左布比卡因粗品300g,加热至;回流溶清后,加入15g硅胶,继续搅拌1小时;滤液在60℃~70℃下趁热过滤至另一3L反应釜中,降温至20℃析晶2.5小时,然后再降温至0℃析晶6小时。析晶完毕后,过滤得白色固体,然后在60℃下烘干6小时。经过X-粉末衍射测定,见图1,反射角2θ约在9.6786,10.6164,12.5864,13.3324,18.9888,21.5685处有特征峰;经红外吸收光谱检测,见图2,在3103.46,2875.86,1674.21,1537.27,1473.62,786.96cm-1。
实施例2
在5L反应釜中加入甲乙酮2.1L和乙酸乙酯2.3L,搅拌下,加入盐酸左布比卡因粗品700g,加热至80℃;回流溶清后,加入35g硅胶,继续搅拌1小时;滤液在60℃~70℃下趁热过滤至另一5L反应釜中,降温至20℃析晶2.5小时,然后再降温至0℃析晶6小时。析晶完毕后,过滤得白色固体,然后在55℃下烘干6小时。经过X-粉末衍射测定,见图3,反射角2θ约在9.7177,10.6572,12.6361,13.3865,19.0401,21.6302处有特征峰;经红外光谱检测,见图4,在3101.54,2877,79,1674.21,1539.20,1473.62,786.96cm-1。
实施例3
在10L反应釜中加入甲乙酮2.7L和乙酸乙酯3L,搅拌下,加入盐酸左布比卡因粗品1000g,加热至77℃;回流溶清后,加入50g硅胶,继续搅拌1小时;滤液在60℃~70℃下趁热过滤至另一10L反应釜中,降温至20℃析晶2.5小时,然后再降温至0℃析晶6小时。析晶完毕后,过滤得白色固体,然后在62℃下烘干6小时。经过X-粉末衍射测定,见图5,反射角2θ约在9.7355,10.6925,12.6543,13.4132,19.0551,21.6469处有特征峰;经红外光谱检测,见图6,在3103.46,2875.86,1674.21,1537.27,1473.62,786.96cm-1。
Claims (5)
1.一种盐酸左布比卡因A晶型,其特征在于,X-射线粉末衍射图的反射角2θ为9.6-9.8,10.6-10.8,12.5-12.7,13.3-13.5,18.9-19.1,21.5-21.7,其中反射角2θ为9.6-9.8的峰强度为100%。
2.根据权利要求1所述盐酸左布比卡因A晶型,其特征在于,在3101-3102、2876-2878、1674-1676、1537-1539、1473-1475、941-957、786-787处有红外吸收峰。
3.根据权利要求1所述的盐酸左布比卡因A晶型的制备方法,包含用混合溶剂溶解盐酸左布比卡因,趁热过滤,分步降温,析出晶体。
4.根据权利要求1或3所述盐酸左布比卡因A晶型的制备方法,其特征在于分步降温步骤为:首先降温至20℃,析晶2.5小时,然后再降温至0℃,搅拌析晶6h。
5.根据权利要求1或3所述盐酸左布比卡因A晶型的制备方法,其特征在于所述的混合溶剂为甲乙酮和乙酸乙酯的混合溶剂,溶剂体积比为1:1。
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CN107162958A (zh) * | 2017-06-27 | 2017-09-15 | 江苏恒瑞医药股份有限公司 | 布比卡因晶型及其制备方法 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN107162958A (zh) * | 2017-06-27 | 2017-09-15 | 江苏恒瑞医药股份有限公司 | 布比卡因晶型及其制备方法 |
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