WO2020186962A1 - 一种草乌甲素e晶型及其制备方法与应用 - Google Patents

一种草乌甲素e晶型及其制备方法与应用 Download PDF

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WO2020186962A1
WO2020186962A1 PCT/CN2020/076156 CN2020076156W WO2020186962A1 WO 2020186962 A1 WO2020186962 A1 WO 2020186962A1 CN 2020076156 W CN2020076156 W CN 2020076156W WO 2020186962 A1 WO2020186962 A1 WO 2020186962A1
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aconitine
crystal form
preparation
crystalline form
water
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PCT/CN2020/076156
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English (en)
French (fr)
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吴琼粉
李彪
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云南昊邦制药有限公司
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Priority to DE112020001265.4T priority Critical patent/DE112020001265T5/de
Priority to JP2021555041A priority patent/JP2022525125A/ja
Priority to KR1020217032662A priority patent/KR20210138669A/ko
Priority to US17/438,753 priority patent/US20220153704A1/en
Publication of WO2020186962A1 publication Critical patent/WO2020186962A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/22—Bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to a crystal form of aconitine A and its preparation method and application.
  • oxaconitine is (1 ⁇ , 6 ⁇ , 14 ⁇ , 16 ⁇ ) tetrahydro-8,13,14-triol-20-ethyl-1,6,16-trimethoxy-4-methoxymethyl- 8-Acetoxy-14-(4'-p-methoxybenzyl)-aconitine. It is a diterpene diester alkaloid extracted and isolated from the root tuber of Aconitum georgei Comber, a plant of the genus Aconitum in the Ranunculaceae family, named Crassicauline A. It was later renamed Bulleyaconitine A (T2), which is a known natural compound in plant species, and its structural formula is as follows:
  • aconitine preparations are widely used clinically to treat rheumatoid arthritis (RA), osteoarthritis, myofibritis, neck and shoulder pain, low back pain, cancer pain and chronic pain caused by various reasons.
  • RA rheumatoid arthritis
  • osteoarthritis myofibritis
  • neck and shoulder pain low back pain
  • cancer pain chronic pain caused by various reasons.
  • Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality.
  • the same drug with different crystal forms has differences in appearance, solubility, melting point, dissolution, and bioavailability, and may even have significant differences, which will affect the stability, bioavailability and efficacy of the drug.
  • the crystal form of the drug will also affect the quality of the pharmaceutical preparation of the drug, the absorption behavior in the human body, and ultimately affect the therapeutic effect of the preparation in the human body and the benefit ratio of side effects.
  • the in-depth research of aconitine A the research on the crystal form and physicochemical properties of aconitine A is of great significance to the evaluation of the efficacy, quality and safety of aconitine A.
  • the Chinese patent with the application number 201710423005.9 discloses dissolving aconitine A with a C1-4 organic solvent, and the obtained aconidin solution is added dropwise to water, stirring while adding, after the addition, suction filtration, and the filter cake is dried. Obtained the amorphous grass Aconitum. At present, there is no relevant report on the crystalline aconitine.
  • the purpose of the present invention is to provide a new crystal form of aconitine and its preparation method.
  • An object of the present invention is to research, discover and provide the crystal form E crystal form of aconitine by crystallographic methods.
  • the substantially pure crystal form E provided by the present invention has an X-ray powder diffraction pattern as shown in Figure 1, and its X-ray powder diffraction pattern has a 2 ⁇ value of 7.8 ⁇ 0.2, 9.4 ⁇ 0.2, 11.5 ⁇ 0.2, 12.4 ⁇ 0.2 , 13.2 ⁇ 0.2, 13.8 ⁇ 0.2, 14.8 ⁇ 0.2, 16.6 ⁇ 0.2, 18.8 ⁇ 0.2, 19.3 ⁇ 0.2, 22.1 ⁇ 0.2, 33.6 ⁇ 0.2 have obvious characteristic absorption peaks.
  • the present invention also adopts thermogravimetric analysis method to study and characterize the crystalline form of aconitine A.
  • the detection conditions are: starting from room temperature, heating gradient: heating up to 400°C at a rate of 10°C/min, and the protective gas is nitrogen.
  • thermogravimetric analysis curve of the substantially pure crystalline form of aconitine A provided by the present invention is shown in Figure 2, and it has the following characteristics: when the temperature rises to 150°C, the sample loses 0.3%.
  • the present invention also adopts the differential scanning calorimetry method to study and characterize the crystal form of aconitine A.
  • the detection method is starting from 25°C, with a heating gradient: heating up to 280°C at a rate of 10°C/min, and the protective gas is nitrogen.
  • the differential scanning calorimetry curve of the substantially pure crystalline form of aconitine E provided by the present invention is shown in Figure 2, and it has the following characteristics: the heat absorption peak is 160-164°C.
  • the characteristic peaks of the X-ray powder diffraction pattern may be between one machine and another machine and between one sample and another sample. There will be slight changes.
  • the value may differ by about 1 unit, or by about 0.8 unit, or by about 0.5 unit, or by about 0.3 unit, or by about 0.1 unit, so the value given cannot be considered For absolute.
  • the values given in the differential scanning calorimetry graph of the above-mentioned crystal forms cannot be regarded as absolute.
  • the crystal form can also be characterized by other analytical techniques known in the art. For example, proton nuclear magnetic resonance spectroscopy ( 1 HNMR), polarized light microscopy (PLM), dynamic moisture adsorption (DVS).
  • 1 HNMR proton nuclear magnetic resonance spectroscopy
  • PLM polarized light microscopy
  • DVS dynamic moisture adsorption
  • the substantially pure crystalline form of aconitine A provided by the present invention has a hydrogen nuclear magnetic resonance spectrum as shown in Fig. 3, a polarized light microscopy analysis chart as shown in Fig. 4, and a dynamic moisture adsorption chart as shown in Fig. 5 .
  • the invention also provides a method for preparing the crystal form of aconitine A with high purity and no residual solvent.
  • the method for preparing the crystalline form of aconitine A provided by the present invention is to add a mixed solution of alcohol and water to aconitine A, stir to obtain suspended solids, and collect the solids by centrifugation; the alcohol is methanol, ethanol or normal Butanol.
  • the volume ratio of alcohol to water in the mixed solution of alcohol and water in the preparation method of the crystalline form of aconitine E of the present invention is 10:1 to 1:10.
  • the ratio of the mixed solution of aconitine A, alcohol and water of the present invention is 3:1-1000:1.
  • the stirring time in the preparation method of the crystalline form of Aconitine A of the present invention is at least 0.5 hours.
  • the stirring temperature in the method for preparing the crystalline form of aconitine E of the present invention is 0°C-50°C.
  • the preparation method of the crystalline form of aconitine E of the present invention has a crystal form content of more than 99%, high purity, consistent X-ray powder diffraction spectrum characteristics and DSC characteristics, stable properties, and good stability to light, humidity and heat .
  • the present invention also provides the application of the crystal form of aconitine A in the preparation of drugs for the prevention and/or treatment of rheumatoid arthritis RA, osteoarthritis, myofibritis, neck and shoulder pain, low back pain or cancer pain.
  • the present invention discloses the preparation method of the aconitine A crystal form and the crystalline form of aconitine A.
  • the X-ray powder diffraction spectrum of the crystal form of the present invention measured by using Cu-K ⁇ rays is shown in Figure 1.
  • the preparation of the crystalline form of Aconitine A is adding a mixed solution of alcohol and water to Aconidin A, stirring to obtain suspended solids, and centrifugation to collect the solids; the alcohol is methanol, ethanol or n-butanol.
  • the preparation process is simple, and the obtained crystal form has high purity, and it is determined to be the E crystal form by XRD, DSC, TGA, 1 HNMR characterization.
  • the obtained crystalline form of Aconitine A is crystal-free, and the stability test results show that the crystal has good stability to light, humidity and heat.
  • test method is usually implemented under conventional conditions or conditions recommended by the manufacturer.
  • the XRPD images were collected on PANalytacal Empyrean and X’Pert3 X-ray powder diffraction analyzers. The scanning parameters are shown in Table 1.
  • TGA Thermogravimetric Analysis
  • DSC Differential Scanning Calorimetry
  • TGA and DSC graphs were collected on TA Q5000 TGA/TA Discovery TGA5500 thermogravimetric analyzer and TA Q2000 DSC/TA Discovery DSC2500 differential scanning calorimeter respectively. Table 2 lists the test parameters.
  • the dynamic moisture adsorption (DVS) curve is collected on the DVS Intrinsic of SMS (Surface Measurement Systems).
  • the relative humidity at 25°C is corrected by the deliquescent point of LiCl, Mg(NO 3 ) 2 and KCl.
  • the DVS test parameters are listed in Table 3.
  • the XRPD chart of the sample is shown in 1
  • the TGA/DSC characterization result chart is shown in Fig. 2
  • the 1 HNMR chart is shown in Fig. 3.
  • the PLM result graph is shown in Figure 4.
  • Example 20 Stability test of aconitine E crystal form
  • Form E continues to slowly adsorb water as the humidity increases. When the humidity reaches 80% RH, 0.12% of water is adsorbed, indicating that the sample has no hygroscopicity.
  • the crystal form of the XRPD characterization result of the crystal form E sample before and after the DVS test did not change. According to the XRPD comparison result, the crystal form of the sample did not change after the DVS test.
  • HPLC results are shown in Table 6. The results indicate that the chemical purity of the samples did not change in the selected test conditions; the XRPD results indicate that the crystal form of the samples did not change in the selected test conditions.
  • the crystal form E has good physical and chemical stability.

Abstract

提供了一种草乌甲素E晶型以及草乌甲素E晶型的制备方法。所述晶型使用Cu-Kα射线测量得到的X-射线粉末衍射谱图如图1所示。所述草乌甲素E晶型的制备为向草乌甲素中加入醇与水的混合溶液中，搅拌得到悬浮固体，离心收集固体；所述醇为甲醇、乙醇或正丁醇。制备工艺过程简单，且获得的晶型纯度高，经XRD、DSC、TGA、1HNMR的表征，确定为E晶型。所得草乌甲素晶体，为无水晶型，经稳定性试验结果表明该晶体对光、湿、热稳定性良好。

Description

一种草乌甲素E晶型及其制备方法与应用
本申请要求于2019年03月15日提交中国专利局、申请号为201910197746.9、发明名称为“一种草乌甲素E晶型及其制备方法与应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及药物化学领域，具体涉及一种草乌甲素E晶型及其制备方法与应用。
背景技术
草乌甲素化学名称为(1α，6α，14α，16β)四氢-8，13，14-三醇-20-乙基-1，6，16-三甲氧基-4-甲氧甲基-8-乙酰氧基-14-(4＇-对甲氧基苯甲酯)-乌头烷。它是从毛莨科乌头属植物——长喙乌头(Aconitum georgei Comber)块根中提取、分离出的一种二萜双酯类生物碱，定名为粗茎乌头碱(Crassicauline A)，后来更名为草乌甲素(Bulleyaconitine A，T2)，属于植物物种中的已知天然化合物，结构式如下：
Figure PCTCN2020076156-appb-000001
目前草乌甲素制剂临床上广泛用于治疗类风湿关节炎(RA)、骨关节炎、肌纤维炎、颈肩痛、腰腿痛、癌性疼痛以及各种原因导致的慢性疼痛。
药物多晶型是药品研发中的常见现象，是影响药品质量的重要因 素。晶型不同的同一药物在外观、溶解度、熔点、溶出度和生物有效性等方面有差别，甚至可能会有显著的不同，因而，会影响药物的稳定性、生物利用度及疗效等。而且药物的晶型还会影响药物的药用制剂的质量、在人体的吸收行为，并最终影响该制剂在人体中产生的治疗效果和副作用的获益比。随着草乌甲素的研究深入，开展草乌甲素晶型、理化性质等研究对于草乌甲素药效、质量、用药安全的评价意义重大。申请号为201710423005.9的中国专利公开了将草乌甲素用C1-4的有机溶剂溶解，得到的草乌甲素溶液滴加至水中，边加边搅拌，加毕，抽滤，滤饼干燥制得无定形草乌甲素。目前还没关于结晶态草乌甲素的相关报道。
发明内容
有鉴于此，本发明目的是提供草乌甲素的新晶型及其制备方法。
本发明的一个目的是通过晶体学的方法，研究、发现并提供了草乌甲素的结晶形式E晶型。
本发明采用国际上公认的X-射线粉末衍射法(XRPD)来研究和表征草乌甲素的结晶形式。测定条件与方法：Cu/K-alpha1(靶)，45KV-40mA(工作电压与电流)，2θ＝3-40(扫描范围)，每步扫描时间(s)为17.8-46.7，扫描步长(2θ)为0.0167-0.0263，
Figure PCTCN2020076156-appb-000002
本发明提供的基本上纯净的E晶型，其X-射线粉末衍射图如图1所示，其X射线粉末衍射图在2θ值为7.8±0.2，9.4±0.2，11.5±0.2，12.4±0.2，13.2±0.2，13.8±0.2，14.8±0.2，16.6±0.2，18.8±0.2，19.3±0.2，22.1±0.2，33.6±0.2处有明显的特征吸收峰。
本发明还采用热重分析法来研究和表征草乌甲素E晶型。检测条件为：从室温开始，升温梯度：以10℃/min的速度升温至400℃，保护气体为氮气。
本发明提供的基本上纯净的草乌甲素E晶型，其热重分析曲线如图2所示，其具有如下特性：当温度升至150℃时，样品失重为0.3％，。
本发明还采用差示扫描量热分析法来研究和表征草乌甲素E晶型。检测方法为从25℃开始，升温梯度：以10℃/min的速度升温至280℃，保护气体为氮气。
本发明提供的基本上纯净的草乌甲素E晶型，其差示扫描量热分析曲线如图2所示，其具有如下特性：热吸峰为160-164℃。
值得注意的是，对于以上所述晶型的X-射线粉末衍射图，在一台机器和另一台机器之间以及一个样品和另一个样品之间，X-射线粉末衍射图的特征峰可能会略有变化，其数值可能相差大约1个单位，或者相差大约0.8个单位，或者相差大约0.5个单位，或者相差大约0.3个单位，或者相差大约0.1个单位，因此所给出的数值不能视为绝对的。同样以上所述晶型的差示扫描量热分析曲线图所给出的数值也不能视为绝对的。
晶型也可以用技术上公知的其他分析技术表征。例如核磁共振氢谱( 1HNMR)、偏光显微分析(PLM)、动态水分吸附(DVS)。
本发明提供的基本上纯净的草乌甲素E晶型，其核磁共振氢谱图如图3所示，其偏光显微分析图如图4所示，其动态水分吸附图如图5所示。
本发明还提供了纯度高且不含残留溶剂的草乌甲素E晶型的制备方法。
本发明提供的所述草乌甲素E晶型的制备方法为向草乌甲素中加入醇与水的混合溶液中，搅拌得到悬浮固体，离心收集固体；所述醇为甲醇、乙醇或正丁醇。
优选的，本发明所述草乌甲素E晶型的制备方法中所述醇与水的混合溶液中醇与水的体积比为10:1-1:10。
优选的，按mg/ml计，本发明草乌甲素与醇和水的混合溶液比为3:1-1000:1。
优选的，本发明所述草乌甲素E晶型的制备方法中所述搅拌时间至少为0.5小时。
优选的，本发明所述草乌甲素E晶型的制备方法中所述搅拌温度为0℃-50℃。
本发明所述草乌甲素E晶型制备方法得到晶型含量大于99％，纯度高，X-射线粉末衍射光谱特征及DSC特征图谱均一致，性质稳定，对光、湿、热稳定性良好。
本发明还提供了所述草乌甲素E晶型在制备预防和/或治疗类风湿关节炎RA、骨关节炎、肌纤维炎、颈肩痛、腰腿痛或癌性疼痛药物中的应用。
由上述技术方案可知，本发明公开了草乌甲素E晶型以及草乌甲素E晶型的制备方法。本发明所述晶型使用Cu-Kα射线测量得到的X-射线粉末衍射谱图如图1所示。所述草乌甲素E晶型的制备为向草乌甲素中加入醇与水的混合溶液中，搅拌得到悬浮固体，离心收集固体；所述醇为甲醇、乙醇或正丁醇。制备工艺过程简单，且获得的晶型纯度高，经XRD、DSC、TGA、 1HNMR的表征，确定为E晶型。所得草乌甲素E晶型，为无水晶型，经稳定性试验结果表明该晶体对光、湿、热稳定性良好。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1晶型E的XRPD图；
图2晶型E的TGA/DSC图；
图3晶型E的 1H NMR图谱；
图4晶型E的PLM图；
图5晶型E的DVS图；
图6晶型EDVS测试前后的XRPD对比图；
图7晶型E稳定性评估前后的XRPD对比图。
具体实施方式
下面将结合本发明实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
为了进一步理解本发明，下面结合具体实施例对本发明进行详细阐述。下述实施例中，除非另有说明，所述的试验方法通常按照常规条件或制造厂商建议的条件实施。
测试参数
XRPD图在PANalytacal Empyrean和X’Pert3 X射线粉末衍射分析仪上采集，扫描参数如表1所示。
表1 XRPD测试参数
Figure PCTCN2020076156-appb-000003
热重分析(TGA)和差示扫描量热(DSC)
TGA和DSC图分别在TA Q5000 TGA/TA Discovery TGA5500热重分析仪和TA Q2000 DSC/TA Discovery DSC2500差示扫描量热仪上 采集，表2列出了测试参数。
表2 TGA和DSC测试参数
参数 TGA DSC
方法 线性升温 线性升温
样品盘 铝盘，敞开 铝盘，压盖
温度范围 室温-设置终点温度 25℃-设置终点温度
扫描速率(℃/分钟) 10 10
保护气体 氮气 氮气
动态水分吸附(DVS)
动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃时的相对湿度用LiCl，Mg(NO 3) 2和KCl的潮解点校正。DVS测试参数列于表3。
表3 DVS测试参数
Figure PCTCN2020076156-appb-000004
液态核磁
液态核磁谱图在Bruker 400M核磁共振仪上采集，DMSO-d6作为溶剂。
实施例1、草乌甲素E晶型的制备和鉴定
称量15mg草乌甲素置于3ml小瓶中，加正丁醇-水(1：1)0.5ml，在5℃下搅拌2小时，离心分离得固体物，固体进行XRPD、TGA/DSC和 1HNMR测试。
XRPD结果表明，在衍射角(2θ角)为7.6±0.2，9.4±0.2，11.3±0.2，12.4±0.2，13.4±0.2，13.9±0.2，14.8±0.2，16.8±0.2，18.8±0.2，19.4±0.2，22.2±0.2，33.1±0.2处有明显的特征吸收峰。TGA/DSC结果表明，当温度升至150℃时，失重为0.3％，DSC曲线显示在160.9℃(起始温度)处出现尖锐的吸热峰，推测可能由熔融引起。结合TGA失重，推测DSC上200℃以上的热信号由样品分解引起。 1HNMR结果表明，样品中无明显溶剂残留。PLM结果显示为无规则的小颗粒组成。
鉴定为晶型E，无水型结晶。
该样品的XRPD图见1，TGA/DSC表征结果图见图2， 1HNMR图见图3。PLM结果图见图4。
实施例2、草乌甲素E晶型的制备
称量15mg草乌甲素置于3ml小瓶中，加正丁醇-水(1：10)0.5ml，在25℃下搅拌0.5小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为163.9℃。
实施例3、草乌甲素E晶型的制备
称量15mg草乌甲素置于3ml小瓶中，加正丁醇-水(1：1)0.3ml，在50℃下搅拌3小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为160℃。
实施例4、草乌甲素E晶型的制备
称量15mg草乌甲素置于3ml小瓶中，加正丁醇-水(1：10)0.3ml，在25℃下搅拌1小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为164℃。
实施例5、草乌甲素E晶型的制备
称量1500mg草乌甲素置于烧杯中，加正丁醇-水(5：1)15ml，在15℃下搅拌5小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为162.9℃。
实施例6、草乌甲素E晶型的制备
称量100mg草乌甲素置于烧杯中，加正丁醇-水(1：8)1ml，在5℃下搅拌10小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为161.5℃。
实施例7、草乌甲素E晶型的制备
称量1000mg草乌甲素置于烧杯中，加正丁醇-水(10：1)1ml，在0℃下搅拌24小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为163.1℃。
实施例8、草乌甲素E晶型的制备
称量15mg草乌甲素置于3ml小瓶中，加甲醇-水(1：10)0.5ml，在25℃下搅拌0.5小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为161.7℃。
实施例9、草乌甲素E晶型的制备
称量15mg草乌甲素置于3ml小瓶中，加甲醇-水(1：1)0.3ml，在50℃下搅拌3小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为162.6℃。
实施例10、草乌甲素E晶型的制备
称量15mg草乌甲素置于3ml小瓶中，加甲醇-水(1：10)0.3ml，在25℃下搅拌1小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为161.8℃。
实施例11、草乌甲素E晶型的制备
称量1500mg草乌甲素置于烧杯中，加甲醇-水(5：1)15ml，在15℃下搅拌5小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为163.98℃。
实施例12、草乌甲素E晶型的制备
称量100mg草乌甲素置于烧杯中，加甲醇-水(1：8)1ml，在5℃下搅拌10小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；；DSC曲线显示吸热峰为161.9℃。
实施例13、草乌甲素E晶型的制备
称量1000mg草乌甲素置于烧杯中，加甲醇-水(10：1)1ml，在0℃下搅拌24小时，离心分离得固体物。固体物进行XRPD测试， 结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为160.2℃。
实施例14、草乌甲素E晶型的制备
称量15mg草乌甲素置于3ml小瓶中，加乙醇-水(1：10)0.5ml，在25℃下搅拌0.5小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为160.8℃。
实施例15、草乌甲素E晶型的制备
称量15mg草乌甲素置于3ml小瓶中，加乙醇-水(1：1)0.3ml，在50℃下搅拌3小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为163℃。
实施例16、草乌甲素E晶型的制备
称量15mg草乌甲素置于3ml小瓶中，加乙醇-水(1：10)0.3ml，在25℃下搅拌1小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为162℃。
实施例17、草乌甲素E晶型的制备
称量1500mg草乌甲素置于烧杯中，加乙醇-水(5：1)15ml，在15℃下搅拌5小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为163.5℃。
实施例18、草乌甲素E晶型的制备
称量100mg草乌甲素置于烧杯中，加乙醇-水(1：8)1ml，在5℃下搅拌10小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为162.4℃。
实施例19、草乌甲素E晶型的制备
称量1000mg草乌甲素置于烧杯中，加乙醇-水(10：1)1ml，在0℃下搅拌24小时，离心分离得固体物。固体物进行XRPD测试，结果与图1一致，确定为草乌甲素E晶型；DSC曲线显示吸热峰为161.6℃。
实施例20、草乌甲素E晶型的稳定性试验
1)晶型E的DVS表征
为了评估无水晶型E的引湿性和在不同湿度条件下的稳定性，在25℃恒温条件下对晶型E样品进行了DVS和XRPD测试。
晶型E随着湿度的增大而持续缓慢吸附水分。当湿度达到80％RH时，共吸附0.12％的水，表明该样品无引湿性。晶型E样品在DVS测试前后XRPD的表征结果晶型没有发生变化，根据XRPD对比结果可知DVS测试后样品的晶型未发生变化。
晶型E的DVS图见图5，晶型E DVS测试前后的XRPD对比图见图6。
2)晶型E固态稳定性评估
为了评估晶型E的固态稳定性，分别称取适量样品在25℃/60％RH和40℃/75％RH条件下敞口放置1周和1个月，在80℃条件下密封放置24小时。对放置后的样品进行XRPD和HPLC表征，以检测晶型变化和化学纯度。
HPLC结果见表6，结果表明在所选测试条件中样品的化学纯度均未发生变化；XRPD结果表明在所选测试条件中样品的晶型未发生 变化。
表4晶型E的稳定性数据汇总
Figure PCTCN2020076156-appb-000005
结论，晶型E具有良好的物理和化学稳定性。
晶型E稳定性评估前后的XRPD对比图见图7。

Claims (10)

  1. 草乌甲素E晶型，其特征在于，其X射线粉末衍射图在2θ值为7.8±0.2，9.4±0.2，11.5±0.2，12.4±0.2，13.2±0.2，13.8±0.2，14.8±0.2，16.6±0.2，18.8±0.2，19.3±0.2，22.1±0.2，33.6±0.2处有明显的特征吸收峰。
  2. 根据权利要求1所述晶型，其特征在于，其热重分析曲线在加热到150℃时，失重0.3％。
  3. 根据权利要求1所述晶型，其特征在于，其差示扫描量热分析曲线的热吸峰为160-164℃。
  4. 根据权利要求1所述晶型，其特征在于，其核磁共振氢谱图如图3所示。
  5. 权利要求1所述的草乌甲素E晶型的制备方法，其特征在于，向草乌甲素中加入醇与水的混合溶液中，搅拌得到悬浮固体，离心收集固体；所述醇为甲醇、乙醇或正丁醇。
  6. 权利要求5所述的草乌甲素E晶型的制备方法，其特征在于，所述醇与水的混合溶液中醇与水的体积比为10:1-1:10。
  7. 权利要求5所述的草乌甲素E晶型的制备方法，其特征在于，按mg/ml计，所述草乌甲素与醇和水的混合溶液的质量体积比为3:1-1000:1。
  8. 权利要求5所述的草乌甲素E晶型的制备方法，其特征在于，所述搅拌时间至少为0.5小时。
  9. 权利要求5所述的草乌甲素E晶型的制备方法，其特征在于，所述搅拌温度为0℃-50℃。
  10. 权利要求1所述草乌甲素E晶型在制备预防和/或治疗类风湿关节炎RA、骨关节炎、肌纤维炎、颈肩痛、腰腿痛或癌性疼痛药物中的应用。
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