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CN1125049C - 托拉沙得新晶体变型n - Google Patents

托拉沙得新晶体变型n Download PDF

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CN1125049C
CN1125049C CN99811710A CN99811710A CN1125049C CN 1125049 C CN1125049 C CN 1125049C CN 99811710 A CN99811710 A CN 99811710A CN 99811710 A CN99811710 A CN 99811710A CN 1125049 C CN1125049 C CN 1125049C
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D·菲里克
M·杜米克
A·达尼罗夫斯基
B·科莱匹克
I·菲斯特里克
M·欧里希克
J·霍瓦特米库尔希克
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Abstract

本发明涉及托拉沙得新晶体变型N的特征，涉及在添加或不添加晶种的情况下，通过用无机酸或有机酸受控制地酸化碱性托拉沙得溶液来制备托拉沙得新晶体变型N的方法，及其用作制备托拉沙得晶体变型I和药用托拉沙得盐的原料，以及涉及含这种托拉沙得新晶体变型N的药物形态。

Description

托拉沙得新晶体变型N
技术领域
本发明涉及N-(1-甲基乙基氨基羰基)-4-(3-甲基-苯基氨基)-3-吡啶磺酰胺(本文中称为“托拉沙得新晶体变型)，本发明尤其涉及托拉沙得新晶体变型N及其制备方法，及其作为制备托拉沙得晶体变型I和作为制备药用托拉沙得盐的原料，以及包含作为活性成分的所述托拉沙得新晶体变型N的药物形态。
背景技术
拉托沙得是一种具有药理性质的化合物，已公开在德国专利2516025(实施例71)中。作为亨勒襻的利尿剂，它可用作防止心脏或心脏组织受到因与局部供血不足有关的新陈代谢或电解质紊乱而引起的损伤的药剂，可用来治疗血栓形成、心绞痛、气喘、高血压、肾水肿、肺水肿、一级和二级醛甾酮过多症、Bartter氏综合症、肿瘤、青光眼、使眼压下降、急性或慢性支气管炎、还可用来治疗因外伤引起的大脑水肿、局部供血不足、脑震荡、转移或癫痫发作以及治疗因变态反应引起的鼻部感染。
一种物质能以一种以上晶体形态存在的现象称为同质多晶现象，这些不同晶型称为“多晶变型”或“多晶型物”。一般来说，同质多晶现象受物质分子改变构型的可能性或形成不同分子间的作用或分子内相互作用的可能性的影响，尤其是受氢键的影响，同质多晶现象反映出不同多晶型物的晶格中的不同的原子排列。已经发现了几种有机化合物呈同质多晶现象。药物中有约70％巴比妥酸盐、60％磺酰胺和60％甾族化合物已发现有同质多晶现象，而且市场上有约50％所述种类的药物不是以它们最稳定的形态销售的(T.Laird，“精细化学工业中的化学进展及演化、原理和实践教程”(Chemical Development and Scale-up in the Fine ChemicalIndustry，Principles and Practices，Course Manual)”，Scientific Update，Wyvern Cattage，1996)。
物质的不同多晶型物具有不同的晶格能量，因此，在固态时它们显示出不同的物理性质(如形态、密度、熔点、颜色、稳定性、溶解速率、研磨可能性、成粒作用、压紧性等)，在药剂中这些性质会影响各种药物形态的制备、稳定性、溶解性和生物利用度，从而影响药物的作用。
因为一种有关同质多晶现象的完整知识是阐明整个药物研制过程的关键观察结果的先决条件，因此，药物的同质多晶现象是学科专家们研究的课题[J.Haleblian，W.McCrone，“制药科学杂志(J.Pharm.Sci.)”58(1969)911；L.Borka，(Pharm.Acta Helv.)66(1991)16；M.Kuhnert-Brandsttter，“药物学(Pharmazie)”51(1996)443；H.G.Brittain.“制药科学杂志(J.Pharm.Sci)”86(1997)405；W.H.Streng，DDT 2(1997)415；K.Yoshii，“化学制药公报(Chem.Pham.Bull.)”45(1997)338，等]。于是，在决定药物以固体状态及有关剂量大小、稳定性、溶解作用和预期的作用进行生产时，必须确定所有存在的固体形态(在市场上可找到一些计算机程序，例如作为《Cerius 2》程序的模块《Polymorph》，MSI Inc.，USA)，以及确定每种固体形态的稳定性、溶解作用以及热力学性质。只有在确定这些因素的基础上才能为药物配方的研制选出适用的晶型。
现从大量的研究工作中只选出几项研究作介绍。Gordon等人的美国专利4476248保护了一种布洛芬新晶型及其制备方法；Bunnell等人的欧洲专利733635保护了一种奥氮平新晶型及其制备方法以及含这种新晶型药物奥氮平的药物配方；R.B.Gandhi等人的欧洲专利749969保护了从stavudine I、II和III形态的混合物中制备stavudine多晶型I的新方法；A.Caron等人的欧洲专利708103保护了一种依具沙坦新晶型及其制备方法以及含该晶型的药物配方。
众所周知[如从晶体学学报(Acta Cryst.)B34(1978)，2659-2662和“晶体学学报(Acta Cryst.)”B34(1978)，1304-1310可知]托拉沙得可呈两种具有不同单晶胞参数的晶体变型，这已由单晶的X射线衍射实验得到证实。通过缓慢蒸发出托拉沙得在石油醚/乙醇混合物中的溶液的溶剂，在除去溶剂时可同时形成两种晶体变型。晶体变型I的熔点为169℃，呈P 21/c(棱晶)空间群的单斜晶型，而晶体变型II的熔点为162℃，呈P 2/n(薄片)空间群的单斜晶型。此外，Iyakuhin Kenkyu25(1994)，734-750中对晶体变型I熔点为169.22℃作了说明。
根据德国专利2516025中的实施例71，得到的托拉沙得是熔点为163-164℃的晶型。
在美国专利4743693和美国再颁专利34580或美国专利4822807和美国再颁专利34672中，公开了通过向托拉沙得的不稳定变型在水中的悬浮体添加催化量(1％)托拉沙得的稳定变型I，并在室温至90℃搅拌混合物3小时至14天，而由托拉沙得的不稳定变型II制成托拉沙得的稳定变型I的方法。美国专利4743693和美国再颁专利34580公开的托拉沙得的稳定变型I(单斜、P 21/c空间群)的熔点为162℃，托拉沙得的不稳定变型II(单斜，P 2/n空间群)的熔点为169℃，这一结果与“晶体学学报(Acta Cryst.)”B34(1978)，2659-2662，“晶体学学报(ActaCryst.)”B34(1978)1304-1310和Iyakuhin Kenkyu 25(1994)，734-750中所述结果相反。
在美国专利4822807的摘要中，作者们确定托拉沙得的稳定多晶型物I的熔点为162℃，托拉沙得的不稳定多晶型物II的熔点为169℃，而所述专利的权利要求项中说明的每一种多晶型物的熔点与此不同，即多晶型物I的熔点为169℃而多晶型物II的熔点为162℃。
在美国再颁专利34672的摘要中，作者们确定纯的托拉沙得变型I的熔点为162℃，托拉沙得变型II的熔点为169℃，而权利要求项中纯的多晶型物I的熔点为159-161.5℃，不稳定的多晶型物II的熔点为约157.5-约160℃。
发明内容
已经出乎意料地发现，在0-35℃温度下，在添加或不添加晶种的情况下，通过用无机酸或有机酸在15分钟-25小时内受控制地酸化托拉沙得碱性溶液可制得托拉沙得新晶体变型N。
根据本发明方法的托拉沙得碱性溶液是指托拉沙得合成的初始反应混合物的碱性提取液，任何一种托拉沙得晶体变型I、II或N的碱性溶液或任何一种托拉沙得晶体变型I、II或N的相互混合物的碱性溶液。
在本发明方法中，可采用氢氧化锂、氢氧化钠和氢氧化钾的水溶液以及碳酸钠和碳酸钾的水溶液来制备托拉沙得变型的碱性溶液。
可用无机酸如盐酸、硫酸、磷酸和硝酸以及用有机酸如甲酸、乙酸、丙酸、草酸、酒石酸、甲磺酸和对甲苯磺酸来酸化本发明的托拉沙得碱性溶液。
作为本发明方法中的晶种，可采用一种同结构物质的晶体粉末，特别是托拉沙得晶体变型N的晶体粉末。
还业已发现，采用本发明方法托拉沙得不会发生分解，通过本发明方法，可能存在于托拉沙得合成的初始反应混合物的碱性萃取液中或存在于托拉沙得变型I、II或N中的杂质会进入碱中，即可得到化学纯的托拉沙得晶体变型N。
此外，还业已发现，托拉沙得新晶体变型N在通常贮存条件和高湿度条件下是稳定的，这就意味着，它既不会转变成托拉沙得的不稳定变型II，也不会转变成托拉沙得的稳定变型I。
托拉沙得新晶体变型N的特征X射线粉末衍射图是由PHILIPS PW3710衍射仪以Cu X-射线[λ(CuKα1)＝1.54046和λ(Cukα2)＝1.54439]对托拉沙得新晶体变型N的粉末试样作X衍射测定得到的。于是得到的晶格面间的特征间距(以《d》表示；单位为埃)以及与之相对应的特征相对强度(以《I/I0》表示，％)的结果列于表1中。表1
变型N
 d() I/I0(％)
    15.3898     2.8
    12.5973     5.4
    11.4565     5.8
    9.7973     69.8
    9.5493     76.6
    8.6802     28.5
    8.2371     100.0
    7.6351     10.2
    7.3356     13.0
    6.9759     1.2
    6.5351     10.0
    6.3240     7.9
    6.1985     4.5
    5.9521     0.6
    5.6237     24.4
    5.5623     29.7
    5.4040     19.6
    5.1119     10.3
    4.8738     22.7
    4.7865     46.9
    4.6986     45.7
    4.5985     17.9
    4.4602     24.7
    4.3405     90.0
    4.2552     20.7
    4.1829     19.9
    4.0768     19.9
    3.9377     47.1
    3.8659     29.3
    3.8429     35.3
    3.7801     42.8
    3.7248     11.9
    3.6239     31.7
    3.5556     20.5
    3.4825     7.8
    3.4130     8.1
    3.3055     15.5
    3.2298     8.2
    3.1786     10.7
    3.1278     5.6
    3.0699     7.1
    3.0078     17.5
    2.9549     5.1
    2.9056     4.3
    2.8541     1.8
    2.7686     13.9
    2.6988     5.7
    2.6610     6.3
    2.6293     7.3
    2.5549     3.7
    2.5236     2.0
    2.4485     5.3
    2.4161     6.7
    2.3671     2.0
    2.3133     3.6
    2.2788     7.6
    2.2312     3.4
    2.1852     6.2
    2.1468     3.0
    2.0957     4.7
    2.0617     4.1
    2.0273     3.3
    1.9896     3.1
    1.9688     4.1
    1.9274     2.6
    1.8853     2.7
    1.7931     2.1
    1.7449     1.0
    1.7169     1.8
    1.6512     1.0
    1.6122     0.8
    1.5601     0.8
    1.5320     0.3
    1.5057     0.5
    1.4521     0.3
    1.3773     0.6
此外，借助四圆PHILIPS PW 1100/Stoe&Cie衍射仪的Mo X-射线[λ(moKα＝0.71073]记录托拉沙得新晶体变型N单晶衍射，将得到的单晶胞基本结晶学数据与托拉沙得晶型I和II的文献数据[“晶体学学报(Acta Cryst.)”B34(1978)，2659-2662和“晶体学学报(ActaCryst.)”B34(1978)1304-1310]作比较，结果显示，该晶型完全是托拉沙得的一种新晶体变型N。
托拉沙得晶体变型I、II和新晶体变型N的基本结晶学数据(单晶衍射)列于表2中。表2
    参数             托拉沙得的晶体变型
      I        II        N
晶体结构 单斜晶系 单斜晶系 单斜晶系
空间群 P 21/c P 2/n P 21/c
a() 13.308 20.446 11.430
b() 8.223 11.615 19.090
c() 31.970 16.877 16.695
β(°) 107.01 108.90 93.903
V(3) 3345.5 3791.9 3634.7
Z 4×2 4×2 4×2
根据本发明方法制备的托拉沙得新晶体变型N可通过常规方法转变为托拉沙得晶体变型I，即它可用作制备已知的托拉沙得晶体变型I的原料。
根据本发明制备的托拉沙得新晶体变型N可通过常规方法转变成药用托拉沙得盐。
托拉沙得新晶体变型N在水中和人工肠液中的溶解特性(USP23)与托拉沙得的已知晶体变型I和II在相同液体中的溶解特性作比较，结果显示，有明显的差别。
托拉沙得新晶体变型N在人工胃液中的IDR(固有溶解速率)超过1毫克/(平方厘米·分钟)，由此可说明该晶型具有相当好的生物利用度。
根据本发明方法制备的托拉沙得新晶体变型N具有棱晶特性，呈可流动的晶体粉末状，这种晶型具有流动性，即处于“自由流动”形态，其中不会发生静电荷积聚。
根据本发明方法制备的托拉沙得新晶型N可用作利尿剂以及可用作防止心脏或心脏组织受到因与局部供血不足有关的新陈代谢或电解质紊乱而引起的损伤的药剂，可用来治疗血栓形成、心绞痛、气喘、高血压、肾水肿、肺水肿、一级和二级醛甾酮过多症、Bartter氏综合症、肿瘤、青光眼、使眼压下降、急性或慢性支气管炎、还可用来治疗因外伤引起的大脑水肿、局部供血不足、脑震荡、转移或癫痫发作以及治疗因变态反应引起的鼻部感染。
本发明还涉及药物形态，例如包含作为活性成分的、与药用的一种或多种药用添加剂如糖、淀粉、淀粉衍生物、纤维素、纤维素衍生物、脱模剂以及防粘剂和流动性调节剂相混合的托拉沙得新晶型N的片剂。当采用托拉沙得新晶型N来制备各种形态的药物时，也可采用以水处理如用水粒化的步骤。
用于本发明方法的起始物料，即托拉沙得合成的初始反应混合物的碱性提取液可按照德国专利2516025制备，而托拉沙得变型I和II可按照“晶体学学报(Acta Cryst.)”B34(1978)，1304-1310制备。
附图说明
图1显示托拉沙得在水中的溶解试验曲线；
图2显示托拉沙得在人工肠液中的溶解试验曲线。
具体实施方式
下面将通过实施例对本发明作说明。
实施例1
技术上纯净的托拉沙得新晶型N：
按照德国专利2516025制备的托拉沙得合成的反应混合物的初始碱性提取液(1000毫升)，在添加1.4克托拉沙得晶体变型N的情况下以10％乙酸水溶液酸化。在室温下搅拌该悬浮液90分钟。经吸滤分离出晶体，以1升软化水洗涤，然后在50℃的真空干燥箱中干燥3小时。可得到125克熔点为162-165℃的托拉沙得晶体变型N。
所得晶体试样的X-射线粉末衍射图与托拉沙得新晶体变型N相符。按照高压液相色谱法(HPLC)测得的托拉沙得含量＞99％。
实施例2
将按照实施例1制得的托拉沙得晶体变型N(1000克)溶于10倍量的5％氢氧化钾水溶液中，并于20℃，在添加10克托拉沙得晶体变型N的情况下，用5％盐酸水溶液酸化所得溶液。在20℃下搅拌该悬浮液120分钟。经吸滤分离出晶体，以4升软化水洗涤之，然后在50℃的真空干燥箱中干燥3小时。得到961克熔点为165℃的托拉沙得变型N。
所得晶体试样的X-射线粉末衍射图与托拉沙得晶体变型N相符，按照HPLC方法测得的托拉沙得含量＞99.5％，即相当于化学纯托拉沙得。
实施例3
将按照“晶体学学报(Acta Cryst.)”B34(1978)，1304-1310制得的托拉沙得晶体变型I(1.00克)溶于10倍量的10％碳酸钠水溶液中，并于15℃、在添加0.10克托拉沙得变型N的情况下，用5％硫酸水溶液酸化所得溶液。在15℃下搅拌该悬浮液120分钟。经吸滤分离出晶体，以4毫升软化水洗涤之，然后在50℃的真空干燥箱中干燥3小时。得到0.95克熔点为165-166℃的托拉沙得晶体变型N。
所得晶体试样的X-射线粉末衍射图与托拉沙得晶体变型N相符。按照HPLC方法测得的托拉沙得含量＞99.5％，即相当于化学纯托拉沙得。
实施例4
将按照“晶体学学报(Acta Cryst.)”B34(1978)，1304-1310制得的托拉沙得晶体变型II(1.00克)溶于10倍量的10％碳酸钾水溶液中，然后于15℃、在添加0.10克托拉沙得变型N的情况下，用5％硝酸水溶液酸化所得溶液。在15℃下搅拌该悬浮液120分钟。经吸滤分离出晶体，以4毫升软化水洗涤之，然后在50℃的真空干燥箱中干燥3小时。得到0.96克熔点为164-166℃的托拉沙得晶体变型N。
所得晶体试样的X-射线粉末衍射图与托拉沙得晶体变型N相符。按照HPLC方法测得的托拉沙得含量＞99.5％，即相当于化学纯托拉沙得。
实施例5
将按照“晶体学学报(Acta Cryst.)”B34(1978)，1304-1310制备的托拉沙得晶体变型I和II的混合物溶于10倍量的10％氢氧化锂水溶液中，然后于室温、在添加0.10克托拉沙得变型N的情况下，用5％磷酸水溶液酸化所得溶液。在15℃下搅拌该悬浮液240分钟。经吸滤分离出晶体，以4毫升软化水洗涤之，然后在50℃的真空干燥箱中干燥3小时。得到0.97克熔点为165-166℃的托拉沙得晶体变型N。
所得晶体试样的X-射线粉末衍射图与托拉沙得晶体变型N相符。按照HPLC方法测得的托拉沙得含量＞99.5％，即相当于化学纯托拉沙得。
实施例6
将分别按照“晶体学学报(Acta Cryst.)”B34(1978)，1304-1310和实施例1制得的托拉沙得晶体变型I和N的混合物(1.00克)溶于10倍量的5％氢氧化钾水溶液中，然后于30℃、在添加0.10克托拉沙得变型N的情况下，用10％酒石酸水溶液酸化所得溶液。在30℃下搅拌该悬浮液180分钟。经吸滤分离出晶体，以4毫升软化水洗涤之，然后在50℃的真空干燥箱中干燥3小时。得到0.93克熔点为164-166℃的托拉沙得晶体变型N。
所得晶体试样的X-射线粉末衍射图与托拉沙得晶体变型N相符。按照HPLC方法测得的托拉沙得含量＞99.5％，即相当于化学纯托拉沙得。
实施例7
将分别按照“晶体学学报(Acta Cryst.)”B34(1978)，1304-1310和实施例1制得的托拉沙得晶体变型II和N的混合物(1.00克)溶于10倍量的5％氢氧化钠水溶液中，然后于35℃、在添加0.10克托拉沙得变型N的情况下，用5％丙酸水溶液酸化所得溶液。在35℃下搅拌该悬浮液90分钟。经吸滤分离出晶体，用4毫升软化水洗涤之，然后在50℃的真空干燥箱中干燥3小时。得到0.87克熔点为165℃的托拉沙得晶体变型N。
所得晶体试样的X-射线粉末衍射图与托拉沙得晶体变型N相符。按照HPLC方法测得的托拉沙得含量＞99.5％，即相当于化学纯托拉沙得。
实施例8
将按照“晶体学学报(Acta Cryst.)”B34(1978)，1304-1310和实施例1制得的托拉沙得晶体变型I、II和N的混合物(1.00克)溶于10倍量的10％碳酸钠水溶液中，然后于25℃、在添加0.10克托拉沙得变型N的情况下，用5％对甲苯磺酸水溶液酸化所得溶液。在25℃下搅拌该悬浮液60分钟。经吸滤分离出晶体，用4毫升软化水洗涤之，并在50℃的真空干燥箱中干燥3小时。得到0.93克熔点为164-166℃的托拉沙得晶体变型N。
所得晶体试样的X-射线粉末衍射图与托拉沙得晶体变型N相符。按照HPLC方法测得的托拉沙得含量＞99.5％，即相当于化学纯托拉沙得。
实施例9
将按“晶体学学报(Acta Cryst.)”B34(1978)，1304-1310制得的托拉沙得晶体变型I(1.00克)溶于10倍量的10％碳酸钾水溶液中，然后在15℃，用10％乙酸水溶液逐步酸化所得溶液，与此同时逐步使混合物温度降至0℃，在该温度下搅拌该悬浮液25小时。经吸滤分离出晶体，用4毫升软化水洗涤之，然后在50℃真空干燥箱中干燥3小时。得到0.94克熔点为164-166℃的托拉沙得晶体变型N。
所得晶体试样的X-射线粉末衍射图与托拉沙得晶体变型N相符。按照HPLC方法测得的托拉沙得含量＞99.5％，即相当于化学纯托拉沙得。
实施例10
2.5毫克片剂的制备：
以常规方法使托拉沙得晶体变型N与乳糖和玉米淀粉相混合，然后用水粒化，并干燥和过筛(粒料1)。将胶态二氧化硅与硬脂酸镁相混合、过筛并混入粒料1中。然后以常规方法将混合物压成片。对于生产100000片片剂所需的物料如下：
托拉沙得晶体变型N                         0.25千克
乳糖(Lactose Extra Fine Crystal HMS)   6.05千克
玉米淀粉(Starch)                       1.60千克
胶态二氧化硅(Aerosil200)               60.00克
硬脂酸镁                                  40.00克
重蒸馏水                                  1.20千克
实施例11
100毫克片剂的制备：
以常规方法使托拉沙得晶体变型N与乳糖和玉米淀粉及一部分硬脂酸镁相混合。对该混合物进行挤压并过筛以达到所要求的粒度和粒度分布(粒料1)。使胶态二氧化硅与硬脂酸镁相混合、过筛，并混入粒料1中。然后以常规方法将混合物压成片。对于生产100000片片剂所需的物料如下：
托拉沙得晶体变型N                          10.0千克
乳糖(Lactose Extra Fine Crystal HMS)    2.0千克
玉米淀粉(Stareh)                        7.7千克
胶态二氧化硅(Aerosil200)                0.2千克
硬脂酸镁                                   0.1千克
实施例12
将按照“晶体学学报(Acta Cryst.)”B34(1978)，1304-1310和实施例1制得的托拉沙得的微晶变型I、II和N置于37℃的水中和人工肠液中进行溶解试验(USP23)，试验结果列于表3和表4中。表3：托拉沙得在水中的溶解试验(USP23)(37℃，50rpm，1000毫升)
   分钟           ％溶解托拉沙得
变型I 变型II 变型N
0 0 0 0
10 6.7 15.1 15.6
20 13.0 27.8 28.1
30 18.5 39.2 37.7
40 23.5 48.8 43.6
50 28.5 56.3 48.5
60 32.8 65.1 51.1
表4：托拉沙得在人工肠液中的溶解试验(USP23)(37℃，50rpm，pH7.5，
1000毫升)
   分钟           ％溶解托拉沙得
变型I 变型II 变型N
0 0 0 0
10 29.4 73.3 41.0
20 40.5 92.6 59.8
30 48.4 95.5 70.2
40 54.2 96.8 77.6
50 59.2 96.3 82.5
60 65.0 98.2 88.7
表3所列数据已绘成曲线，见图1。表4所列数据已绘成曲线，见图2。

Claims (16)

1.托拉沙得新晶体变型N，其特征在于由PHILIPS PW3710衍射仪以Cu X-射线[λ(CuKα1)＝1.54046埃和λ(CuKα2)＝1.54439埃]测得的其试样的特征X-射线粉末衍射图是以下列晶格面之间的间距表示的：     托拉沙得新晶体变型N     d()     15.3898     12.5973     11.4565     9.7973     9.5493     8.6802     8.2371     7.6351     7.3356     6.9759     6.5351     6.3240     6.1985     5.9521     5.6237     5.5623     5.4040     5.1119     4.8738
    4.7865     4.6986     4.5985     4.4602     4.3405     4.2552     4.1829     4.0768     3.9377     3.8659     3.8429     3.7801     3.7248     3.6239     3.5556     3.4825     3.4130     3.3055     3.2298     3.1786     3.1278     3.0699     3.0078     2.9549     2.9056     2.8541     2.7686     2.6988
    2.6610     2.6293     2.5549     2.5236     2.4485     2.4161     2.3671     2.3133     2.2788     2.2312     2.1852     2.1468     2.0957     2.0617     2.0273     1.9896     1.9688     1.9274     1.8853     1.7931     1.7449     1.7169     1.6512     1.6122     1.5601     1.5320     1.5057     1.4521
    1.3773
并且根据四圆PHILIPS PW1100/Stoe & Cie衍射仪以Mo X-射线[λ(MoKα)＝0.71073埃]测得的其试样单晶体的X-射线衍射，所述托拉沙得新晶体变型N是以下列基本结晶学数据表示的：     参数   托拉沙得的新晶体变型     晶体结构     单斜晶系     空间群     P 21/c     a()     11.430     b()     19.090     c()     16.695     β(°)     93.903     V(3)     3634.7     Z     4×2
2.根据权利要求1的托拉沙得新晶体变型N，其特征在于它是化学纯的。
3.根据权利要求1或2的托拉沙得新晶体变型N，其特征在于它不含水。
4.根据权利要求1或2的托拉沙得新晶体变型N，其特征在于它不含溶剂。
5.制备根据权利要求1的托拉沙得新晶体变型N的方法，其特征在于碱性托拉沙得溶液于0-35℃、在添加或不添加晶种的情况下，以无机酸或有机酸在15分钟-25小时内受控制地酸化。
6.根据权利要求5的托拉沙得新晶体变型N的制备方法，其特征在于采用托拉沙得合成的初始反应混合物的碱性提取液作为碱性托拉沙得溶液。
7.根据权利要求5的托拉沙得新晶体变型N的制备方法，其特征在于采用任何一种托拉沙得晶体变型I、II或N的碱性溶液，或采用任何一种托拉沙得晶体变型I、II或N的相互混合物的碱性溶液作为碱性托拉沙得溶液。
8.根据权利要求5-7任一项的方法，其特征在于采用氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠或碳酸钾的水溶液来制备碱性托拉沙得溶液。
9.根据权利要求5-7任一项的方法，其特征在于采用无机酸或者是有机酸来实施酸化。
10.根据权利要求9的方法，其中所述无机酸是盐酸、硫酸、磷酸或硝酸而所述有机酸是甲酸、乙酸、丙酸、草酸、酒石酸、甲磺酸或对甲苯磺酸。
11.根据权利要求5-7任一项的方法，其特征在于采用托拉沙得晶体变型N的晶体粉末作为晶种。
12.根据权利要求1的托拉沙得新晶体变型N，其特征在于它用作制备托拉沙得晶体变型I的原料。
13.根据权利要求1的托拉沙得新晶体变型N，其特征在于它用作制备药用托拉沙得盐的原料。
14.根据权利要求1的托拉沙得新晶体变型N的用途，用于制备利尿剂；防止心脏或心脏组织受到因与局部供血不足有关的新陈代谢或电解质紊乱而引起的损伤的药剂；用来治疗血栓形成、心绞痛、气喘、高血压、肾水肿、肺水肿、一级和二级醛甾酮过多症、Batter氏综合症、肿瘤、青光眼、使眼压下降、急性或慢性支气管炎的药物；以及用来治疗因外伤引起的大脑水肿、局部供血不足、脑震荡、转移或癫痫发作以及治疗因变态反应引起的鼻部发炎的药物。
15.一种药物组合物，其特征在于该药物包含作为活性成分的、与药用的一种或多种载体、添加剂或稀释剂相混合的根据权利要求1的托拉沙得晶体变型N。
16.根据权利要求15的药物组合物，其特征在于它是片剂。
CN99811710A 1998-10-02 1999-10-01 托拉沙得新晶体变型n Expired - Fee Related CN1125049C (zh)

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CN106038500A (zh) * 2016-05-26 2016-10-26 南京正科医药股份有限公司 一种托拉塞米片
CN115417810B (zh) * 2022-09-22 2023-10-10 南京正科医药股份有限公司 一种托拉塞米晶型ⅰ的精制方法
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