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Article(id=1222469878645248250, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222469875008790921, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2019-0363, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1560009600000, receivedDateStr=2019-06-09, revisedDate=1563552000000, revisedDateStr=2019-07-20, acceptedDate=null, acceptedDateStr=null, onlineDate=1769389131460, onlineDateStr=2026-01-26, pubDate=1573488000000, pubDateStr=2019-11-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1769389131460, onlineIssueDateStr=2026-01-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1769389131460, creator=13701087609, updateTime=1769389131460, updator=13701087609, issue=Issue{id=1222469875008790921, tenantId=1146029695717560320, journalId=1189982191388893191, year='2019', volume='54', issue='11', pageStart='1881', pageEnd='2140', issueExtLink='null', onlineDate='null', pubDate='1573488000000', pubDateStr='2019-11-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1769389130593, creator='13701087609', updateTime=1769389577080, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1222471747778109959, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222469875008790921, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1222471747778109960, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1222469875008790921, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2069, endPage=2073, ext={EN=ArticleExt(id=1222469880532685179, articleId=1222469878645248250, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Preparation and characterization of rivaroxaban as an anticoagulant, columnId=1218263312677130587, journalTitle=Acta Pharmaceutica Sinica, columnName=Special Reports, runingTitle=null, highlight=null, articleAbstract=

The preparation of polymorphic forms of rivaroxaban was carried out using a recrystallization method based on that for crystal form-Ⅰ. Preparation methods were developed for two crystal forms-Ⅱ (medicinal crystal form) and five crystal forms-Ⅳ and the crystals were then characterized. The crystalline form was identified by applying modern analytical means including X-ray powder diffraction (PXRD), differential scanning calorimetry (DSC), element analysis (EA), mass spectrometry (MS), and infrared spectrum (IR), and the morphology of different crystal forms was observed by scanning electron microscopy (SEM). The results show that the PXRD and DSC characteristics of prepared crystal forms-Ⅱ and Ⅳ are consistent with those described in patents at home and abroad, and the test results with EA, MS and IR are in accordance with the chemical structure of rivaroxaban. The crystal form-Ⅰ is lamellar, the crystal form-Ⅱ is linear and crystalline form-Ⅳ is striped as determined by SEM. In summary, the methods for preparing crystal form-Ⅱ and form-Ⅳ are reliable, the required reagents are easily available, the experimental conditions are easy to implement and the preparation process is simple. Our study provides a new reference for the production and application of rivaroxaban.

, authors=null, authorsList=Yu-xuan MA, Na WANG, Su-yun DAI, Bing WANG, Gang LI, authorCompany=null, correspAuthors=Gang LI, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2019 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1222469882801803849, articleId=1222469878645248250, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=抗凝药利伐沙班的制备与表征, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

以抗凝药利伐沙班晶型Ⅰ为基础，通过重结晶的方法对其进行多晶型的制备，确定了两种晶型Ⅱ（药用晶型）、五种晶型Ⅳ的制备方法。采用X射线粉末衍射（PXRD）、差示扫描量热仪（DSC）、元素分析（EA）、质谱（MS）和红外光谱（IR）等现代分析手段对制备的晶型进行了定性并且通过扫描电子显微镜（SEM）观察了不同晶型的形貌。结果表明，本方法所制备的晶型Ⅱ和Ⅳ的PXRD与DSC分析结果与国内外专利一致，EA、MS和IR的检测结果符合利伐沙班的化学结构，由SEM可知晶型Ⅰ呈片层状，晶型Ⅱ呈线状，晶型Ⅳ呈条状。综上，与国内外专利相比，本研究制备晶型Ⅱ和Ⅳ的方法可靠，所需试剂易得，实验条件易实现，制备过程简捷。本研究为利伐沙班的生产应用提供了新的参考。

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*李钢, Tel: 13701456722, E-mail:
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New crystal form and preparation method and use thereof for rivaroxaban: CN 104211693 A[P]. 2014-12-17., articleTitle=null, refAbstract=null)], funds=[Fund(id=1222469889248449533, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, awardId=BZ201403, language=CN, fundingSource=江苏省大型科学仪器设备共享服务平台资助(BZ201403), fundOrder=null, country=null)], companyList=[AuthorCompany(id=1222469883053462114, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, xref=null, ext=[AuthorCompanyExt(id=1222469883057656420, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, companyId=1222469883053462114, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=School of Life Sciences, Test and Analysis Center, Nanjing Normal University, Nanjing 210023, China), AuthorCompanyExt(id=1222469883070239333, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, companyId=1222469883053462114, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=南京师范大学生命科学学院, 分析测试中心, 江苏 南京 210023)])], figs=[ArticleFig(id=1222469887717528444, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, language=EN, label=null, caption=null, figureFileSmall=ClZPz8XG2dfmASACPQRlyw==, figureFileBig=KBUXGtbtXkRT3Lfz3AcG/Q==, tableContent=null), ArticleFig(id=1222469887784637317, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, language=CN, label=Figure 1, caption= Structure of rivaroxaban (<i>M</i><sub>r</sub> 435.88) , figureFileSmall=ClZPz8XG2dfmASACPQRlyw==, figureFileBig=KBUXGtbtXkRT3Lfz3AcG/Q==, tableContent=null), ArticleFig(id=1222469888006935449, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, language=EN, label=null, caption=null, figureFileSmall=Pn9BSYiSSH9RCZBA1d4APg==, figureFileBig=D+uOlxdTlPhMxcH+XflTow==, tableContent=null), ArticleFig(id=1222469888120181668, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, language=CN, label=Figure 2, caption= X-ray powder diffraction (PXRD) image of rivaroxaban , figureFileSmall=Pn9BSYiSSH9RCZBA1d4APg==, figureFileBig=D+uOlxdTlPhMxcH+XflTow==, tableContent=null), ArticleFig(id=1222469888220844977, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, language=EN, label=null, caption=null, figureFileSmall=7Lssmc62AW3Do/JwxB4/dg==, figureFileBig=CYLr9wO59oIPbDXRPGq3Rw==, tableContent=null), ArticleFig(id=1222469888334091196, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, language=CN, label=Figure 3, caption= Differential scanning calorimetry (DSC) curve of rivaroxaban , figureFileSmall=7Lssmc62AW3Do/JwxB4/dg==, figureFileBig=CYLr9wO59oIPbDXRPGq3Rw==, tableContent=null), ArticleFig(id=1222469888485086147, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, language=EN, label=null, caption=null, figureFileSmall=ibo2CqBDG+OQBmj0/YgU4A==, figureFileBig=xp+1EEPT8yTK+hSw1QEsQg==, tableContent=null), ArticleFig(id=1222469888610915276, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, language=CN, label=Figure 4, caption= Scanning electron microscopy (SEM) image of rivaroxaban form-Ⅰ (A), Ⅱ (B), and Ⅳ (C) , figureFileSmall=ibo2CqBDG+OQBmj0/YgU4A==, figureFileBig=xp+1EEPT8yTK+hSw1QEsQg==, tableContent=null), ArticleFig(id=1222469888736744406, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
No. 2 θ /° 2 θ /° 2 θ /°
Form-Ⅰ CN101282968 Form-Ⅱ CN101282968 Form-Ⅳ CN104211693A
1 8.9 8.9 12.7 12.8 3.5 3.8
2 16.4 16.5 18.0 18.1 7.0 7.4
3 19.4 19.5 19.2 19.0 14.2 14.6
4 19.8 19.9 19.8 19.9 17.7 18.2
5 21.6 21.7 20.7 20.8 19.4 19.9
6 22.4 22.5 22.8 22.9 21.4 21.9
7 25.5 25.6 24.0 24.1 28.6 29.3
8 26.6 26.4 26.6 26.4 31.5 32.0
), ArticleFig(id=1222469888866767839, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1222469878645248250, language=CN, label=Table 1, caption=

The comparison of rivaroxaban and patent. CN101282968 and CN104211693 A are the China patent number of rivaroxaban

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No. 2 θ /° 2 θ /° 2 θ /°
Form-Ⅰ CN101282968 Form-Ⅱ CN101282968 Form-Ⅳ CN104211693A
1 8.9 8.9 12.7 12.8 3.5 3.8
2 16.4 16.5 18.0 18.1 7.0 7.4
3 19.4 19.5 19.2 19.0 14.2 14.6
4 19.8 19.9 19.8 19.9 17.7 18.2
5 21.6 21.7 20.7 20.8 19.4 19.9
6 22.4 22.5 22.8 22.9 21.4 21.9
7 25.5 25.6 24.0 24.1 28.6 29.3
8 26.6 26.4 26.6 26.4 31.5 32.0
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Rivaroxaban C/% H/% S/% N/%
Theoretical value/% 52.31 4.13 7.34 9.64
Actual value/% 53.62 3.68 7.60 9.74
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Elemental analysis data of rivaroxaban

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Rivaroxaban C/% H/% S/% N/%
Theoretical value/% 52.31 4.13 7.34 9.64
Actual value/% 53.62 3.68 7.60 9.74
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抗凝药利伐沙班的制备与表征
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马雨璇 , 王娜 , 戴苏云 , 王冰 , 李钢 *
药学学报 | 研究论文 2019,54(11): 2069-2073
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药学学报 |研究论文 2019 , 54 (11) : 2069 -2073
抗凝药利伐沙班的制备与表征
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马雨璇, 王娜, 戴苏云, 王冰, 李钢*
作者信息
  • 南京师范大学生命科学学院, 分析测试中心, 江苏 南京 210023
通讯作者:
*李钢, Tel: 13701456722, E-mail:
Preparation and characterization of rivaroxaban as an anticoagulant
Yu-xuan MA, Na WANG, Su-yun DAI, Bing WANG, Gang LI*
Affiliations
  • School of Life Sciences, Test and Analysis Center, Nanjing Normal University, Nanjing 210023, China
出版时间: 2019-11-12 doi: 10.16438/j.0513-4870.2019-0363
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以抗凝药利伐沙班晶型Ⅰ为基础，通过重结晶的方法对其进行多晶型的制备，确定了两种晶型Ⅱ（药用晶型）、五种晶型Ⅳ的制备方法。采用X射线粉末衍射（PXRD）、差示扫描量热仪（DSC）、元素分析（EA）、质谱（MS）和红外光谱（IR）等现代分析手段对制备的晶型进行了定性并且通过扫描电子显微镜（SEM）观察了不同晶型的形貌。结果表明，本方法所制备的晶型Ⅱ和Ⅳ的PXRD与DSC分析结果与国内外专利一致，EA、MS和IR的检测结果符合利伐沙班的化学结构，由SEM可知晶型Ⅰ呈片层状，晶型Ⅱ呈线状，晶型Ⅳ呈条状。综上，与国内外专利相比，本研究制备晶型Ⅱ和Ⅳ的方法可靠，所需试剂易得，实验条件易实现，制备过程简捷。本研究为利伐沙班的生产应用提供了新的参考。

利伐沙班  /  多晶型  /  X射线粉末衍射  /  定性分析

The preparation of polymorphic forms of rivaroxaban was carried out using a recrystallization method based on that for crystal form-Ⅰ. Preparation methods were developed for two crystal forms-Ⅱ (medicinal crystal form) and five crystal forms-Ⅳ and the crystals were then characterized. The crystalline form was identified by applying modern analytical means including X-ray powder diffraction (PXRD), differential scanning calorimetry (DSC), element analysis (EA), mass spectrometry (MS), and infrared spectrum (IR), and the morphology of different crystal forms was observed by scanning electron microscopy (SEM). The results show that the PXRD and DSC characteristics of prepared crystal forms-Ⅱ and Ⅳ are consistent with those described in patents at home and abroad, and the test results with EA, MS and IR are in accordance with the chemical structure of rivaroxaban. The crystal form-Ⅰ is lamellar, the crystal form-Ⅱ is linear and crystalline form-Ⅳ is striped as determined by SEM. In summary, the methods for preparing crystal form-Ⅱ and form-Ⅳ are reliable, the required reagents are easily available, the experimental conditions are easy to implement and the preparation process is simple. Our study provides a new reference for the production and application of rivaroxaban.

rivaroxaban  /  polycrystalline form  /  X-ray powder diffraction  /  qualitative analysis
马雨璇, 王娜, 戴苏云, 王冰, 李钢. 抗凝药利伐沙班的制备与表征. 药学学报, 2019 , 54 (11) : 2069 -2073 . DOI: 10.16438/j.0513-4870.2019-0363
Yu-xuan MA, Na WANG, Su-yun DAI, Bing WANG, Gang LI. Preparation and characterization of rivaroxaban as an anticoagulant[J]. Acta Pharmaceutica Sinica, 2019 , 54 (11) : 2069 -2073 . DOI: 10.16438/j.0513-4870.2019-0363
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脑卒中是我国成年人致死和致残的首位原因, 且随着社会老龄化和城市化进程加速, 居民不健康生活方式流行, 心血管病危险因素普遍暴露, 我国脑卒中疾病有爆发式增长的态势。目前, 我国40~74岁居民首次脑卒中标化发病率平均每年增长8.3%。≥40岁居民脑卒中标化患病率由2012年的1.89%上升至2016年的2.19%, 推算≥40岁居民脑卒中现患人数1 242万, 每年196万人因脑卒中死亡[1]。脑卒中已成为影响老年人生活质量的首要因素, 抗血栓药物成了刚性需求[2-4]。利伐沙班(rivaroxaban)的化学名为5-氯-N-({(5S)-2-氧代-3-[4-(3-氧代-4-吗啉基)苯基]-1, 3-噁唑烷-5-基}甲基)-2-噻吩羧酰胺, 如图 1所示, 是由德国拜耳公司和美国强生公司共同研发的一种新型口服抗凝血药物, 属于Xa凝血因子竞争性抑制剂类[5]。在血管损伤的手术中, 由于某些血管病变造成血液异常凝集形成血栓, 栓塞常常发生脱落流入静脉血管, 引起急性静脉栓塞症。血液的异常流动和血管损伤通常是血栓形成的内因, 其中血管受损导致血液中某些凝血因子异常激活和病变是血栓形成的直接原因[6]。利伐沙班通过抑制Xa凝血因子活性来阻碍凝血酶的形成, 阻断了内源性(全部凝血因子都来源于血液内)及外源性(部分凝血因子来源于血液外)凝血途径, 从而起到抗凝作用。目前常用于心房颤动患者和髋关节或膝关节置换术后静脉血栓的预防[7]。该药具有选择性高, 生物利用度好, 不良反应小和患者使用后出血风险低的优点, 一经上市就在临床上广泛应用[8]。
对于同一药物不同晶型的研究通常借助于X-射线粉末衍射法(PXRD)、差示扫描量热分析法(DSC)、扫描电子显微镜法(SEM), 在相关文献[9-11]中已有较多报道。目前对利伐沙班的研究主要在药理和合成工艺方面, 文献[12-15]报道, 利伐沙班存在多晶型, 对药物进行晶型研究在保证药物的稳定性、提高药物的生物利用度、减少毒性和增进治疗效果等方面都具有重要意义。本文主要对利伐沙班多晶型进行了制备, 相比于专利[15, 16]方法而言, 本方法制备的晶型Ⅱ和Ⅳ, 所需溶剂易得, 实验条件简单, 实验过程简捷。同时利用现代分析手段对制备的多晶型结构进行了表征。
材料与方法
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多晶型的制备
仪器与试剂  恒温磁力搅拌器(金坛市医疗仪器厂, 编号614121606);丙酮(上海实验试剂有限公司), 四氢呋喃、乙腈(上海凌峰化学试剂有限公司), 正庚烷、正己烷(国药集团化学试剂有限公司), 异丙醇(上海申博化工有限公司), (上海凌峰化学试剂有限公司), 实验用蒸馏水、冰醋酸(南京化学试剂有限公司)。
材料  利伐沙班晶型Ⅰ样品由南京某公司提供。
方法  A:取利伐沙班晶型Ⅰ放置在烧杯中, 滴加丙酮和四氢呋喃, 加热, 温度控制在30~40 ℃, 直至完全溶解, 缓慢滴加沉淀剂正己烷直至沉淀完全, 过滤, 放在通风橱自然晾干得样品①, 收率约为84.95%。B:取利伐沙班晶型Ⅰ放置在烧杯中, 滴加异丙醇、乙腈和丙酮, 加热方法同A, 然后放在通风橱自然挥发得样品②, 收率约为83.44%。C:参照A, 将沉淀剂换成正庚烷, 得到样品③, 收率约为84.77%。D:取利伐沙班晶型Ⅰ放置在烧杯中, 滴加丙酮和水, 加热溶解, 自然挥发, 得到样品④, 收率约为88.49%。E:取利伐沙班晶型Ⅰ放置在烧杯中, 滴加丙酮和冰醋酸直至完全溶解, 放在通风橱自然挥发得样品⑤, 收率约为93.17%。F:方法与E相同, 将丙酮换成乙腈, 得样品⑥, 收率约为91.87%。G:方法与E相同, 将丙酮换成异丙醇, 得样品⑦, 收率约为92.34%。
利伐沙班样品的定性分析
仪器  天津天马衡基仪器有限公司的FA2004型电子天平; 河南太康科教器材厂的SHB-3型循环水式多用真空泵; 日本理学公司的D/max 2500VL/PC型阳极转靶X射线衍射仪; 日本电子公司的JSM-5610型扫描电子显微镜; 美国Perkin Elmer公司的Analysis Diamond差示扫描量热仪; 上海索谱仪器有限公司的DHG-9070A (101A-1S)鼓风干燥器; 德国元素分析系统公司的Vario EL Ⅲ元素分析仪; 美国瓦里安公司的Varian2200质谱仪; 德国布鲁克公司的VERTEX70型傅里叶变换红外光谱仪。
材料  利伐沙班晶型Ⅰ由南京某公司提供; 利伐沙班晶型Ⅱ、Ⅳ由本实验室转晶制得。
X-射线粉末衍射法分析(PXRD)  测定条件为管压: 45 kV, 管流: 150 mA, Cu-Kα辐射, 石墨弯晶单色器, 发射狭缝(DS)=防散射狭缝(SS)=1°, 接受狭缝(RS)=0.15 mm。扫描速度: 10°·min-1 (粗扫)以及2°·min-1 (精扫), 步宽: 0.02°。
元素分析  样品经干燥后燃烧分解, 定量转换, 检测, 再经数据处理得到C、H、S、N的百分含量。
质谱  以甲醇为溶剂, ESI源为检测条件, 用Varian 2200质谱仪检测样品。
傅里叶变换红外光谱法分析  采用KBr压片法检测样品, 扫描范围4 000~400 cm-1, 分辨率4 cm-1, 扫描次数32次, 用聚苯乙烯膜校正。
差示扫描量热法分析(DSC)  称取样品约2.0 mg放入铝坩埚中密封, 将坩埚放入DSC中进行测试, 以氮气为保护气, 升温速率为10 K·min-1, 升温范围为30~250 ℃, 进行DSC分析。
扫描电子显微镜法分析(SEM)  取样品粘结在样品座上, 镀膜处理后放置于扫描电子显微镜下观察形态结构。测定条件:加速电压10 kV和15 kV, 加大倍率500和3 000, 样品台直径30 mm。
结果
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1 X-射线粉末衍射法分析
对上述得到的7个样品进行PXRD检测(扫描速度: 15°·min-1)可知, 样品①和②为利伐沙班晶型Ⅱ, 样品③~⑦为利伐沙班晶型Ⅳ, 由结果可知样品②和⑦衍射图谱结果最好, 所以从上述样品中选取②和⑦做了进一步检测(扫描速度: 2°·min-1), 衍射数据列于表 1。从表 1和图 2中看出每种晶型都有其各自的特征峰, 晶型Ⅰ在2θ=8.9°、16.4°、19.4°、19.8°、21.6°、22.4°、25.5°和26.6°处有特征峰, 晶型Ⅱ在2θ=12.7°、18.0°、19.2°、19.8°、20.7°、22.8°、24.0°和26.6°处有特征峰, 晶型Ⅳ在2θ=3.5°、7.0°、14.2°、17.7°、19.4°、21.4°、28.6°和31.5°处有特征峰, 与文献[15, 16]报道的一致, 误差在±0.2°以内, 可据此来鉴别利伐沙班不同晶型。晶型Ⅳ整体峰位偏移超过±0.2°, 可能是由于检测前未进行烘干处理, 晶粒间有溶剂存在, 所以晶面间距变大, 衍射角2θ整体偏低。
2 元素分析
对利伐沙班晶型Ⅰ样品进行C、H、S、N的元素分析。数据如表 2, 测定值与理论值的误差在允许的范围之内。元素分析结果基本符合利伐沙班的结构组成C19H18ClN3O5S。
3 质谱分析
对利伐沙班晶型Ⅰ样品进行质谱检测。利伐沙班的相对分子质量为435, 由检测结果可知, 样品的第二高质量峰质荷比为436, 与利伐沙班[M+H]+峰的分子量相符; 样品的最高质量峰质荷比为458.1, 与利伐沙班[M+Na]+峰的分子量相符, 通过质谱分析可证明样品的分子量与文献[15]中利伐沙班的分子量一致。
4 傅里叶变换红外光谱法分析
取利伐沙班晶型Ⅰ、Ⅱ、Ⅳ进行红外光谱检测, 由结果可见3种晶型的红外光谱差异不大。其中1 120和1 210 cm-1是醚键的特征峰; 1 669和1 736 cm-1是羰基的特征峰; 1 646、1 545和3 357 cm-1是酰胺的特征峰, 其中1 646 cm-1是C=O的吸收峰, 3 357 cm-1是-NH的吸收峰, 1 545 cm-1由-NH和C-N偶合产生; 3 024、3 074和3 091 cm-1是苯环上次甲基的特征峰, 828 cm-1表明苯环对位取代; 1 517、1 409和990 cm-1是噻吩环的特征峰。红外检测的结果与利伐沙班结构中所含官能团相符。
5 差示扫描量热仪分析
图 3是利伐沙班晶型Ⅰ、Ⅱ、Ⅳ的DSC对比图。晶型Ⅰ只有一个吸热峰, 测量得到熔点和热焓分别为232.7℃和117.8 J·g-1, 与文献相符; 晶型Ⅱ在197.6℃有一个放热峰, 测量得到热焓为-10.5 J·g-1, 在231.8 ℃有一个吸热峰, 测量得到热焓为101.7 J·g-1, 该吸热峰与晶型Ⅰ的大致相同, 推断197.6 ℃的放热峰为晶型Ⅱ由亚稳晶型转变为稳定的晶型Ⅰ, 因此具有与晶型Ⅰ大致相同的熔点。晶型Ⅳ在63.1 ℃有一个热焓为123.2 J·g-1的小吸热峰, 为溶剂吸附峰, 在233.7 ℃有一个热焓为100.9 J·g-1的大吸热峰, 为熔点峰, 与晶型Ⅳ专利相符。由于3种晶型熔点峰基本一致, 图中只标明了药用晶型Ⅱ的熔点峰。
6 扫描电子显微分析
利伐沙班晶型Ⅰ、Ⅱ、Ⅳ的扫描电镜图片如图 4所示。图 4A为晶型Ⅰ, 加速电压15 kV, 放大倍率500倍, 呈片层状, 厚度约为20 μm; 图 4B为晶型Ⅱ, 加速电压10 kV, 放大倍率3 000倍, 呈线状, 直径约为1~2 μm; 图 4C为晶型Ⅳ, 加速电压10 kV, 放大倍率3 000倍, 呈条状, 宽度约为2~3 μm。由扫描电子显微分析可知, 在这种条件下制备的样品外观形貌上有较大区别。
讨论
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从样品①、②及③~⑦的PXRD检测结果来看, 发现曲线并不完全一致。样品①比样品②在18~23 °的范围少几个峰, 样品③、④比样品⑤~⑦在16~25 °的区间内少个别峰。这是由于样品的择优取向, 样品②⑤⑥⑦的各向同性较好, 各个峰都能显示出来, 样品①、③、④由于择优取向, 前面低角度的峰加强, 导致中部的峰没有显现出来。在热分析中晶型Ⅱ可能出现转晶的情况, 将做进一步考察。
另外, 在制备过程中发现利伐沙班在冰醋酸中(相比于本实验用的其他溶剂)的溶解度相对较大, 是一种毒性较低, 清洁度较好的溶剂。在用丙酮和水制备晶型Ⅳ的过程中要注意控制温度, 温度过高会导致晶型Ⅳ溶解重新析出晶型Ⅰ或两者的混晶。综上, 对各种不同的重结晶方法进行了比较。晶型Ⅱ选择B方法最佳, 操作较A方法简单, 涉及试剂的毒性更小, 得到的样品衍射峰形尖锐、结晶度更好。晶型Ⅳ选择G方法制备最佳, C方法操作复杂、涉及试剂较多, 花费时间较长, D方法受温度影响不易得到纯晶型Ⅳ, G所用的异丙醇与E和F所用的丙酮和乙腈相比挥发性低, 相对操作者毒害小, 从结晶度看G方法制备的样品结晶度高。在制备纯晶型的过程中, 出现了混晶现象, 涉及到药用晶型的定量问题, 将做进一步考察。
基金
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  • 江苏省大型科学仪器设备共享服务平台资助(BZ201403)
文献
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参考文献 引证文献
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2019年第54卷第11期
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文章信息
doi: 10.16438/j.0513-4870.2019-0363
  • 接收时间：2019-06-09
  • 首发时间：2026-01-26
  • 出版时间：2019-11-12
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  • 收稿日期：2019-06-09
  • 修回日期：2019-07-20
基金
江苏省大型科学仪器设备共享服务平台资助(BZ201403)
作者信息
    南京师范大学生命科学学院, 分析测试中心, 江苏 南京 210023

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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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