WO2016184436A1 - 乐伐替尼甲磺酸盐的新晶型及其制备方法 - Google Patents

乐伐替尼甲磺酸盐的新晶型及其制备方法 Download PDF

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WO2016184436A1
WO2016184436A1 PCT/CN2016/085360 CN2016085360W WO2016184436A1 WO 2016184436 A1 WO2016184436 A1 WO 2016184436A1 CN 2016085360 W CN2016085360 W CN 2016085360W WO 2016184436 A1 WO2016184436 A1 WO 2016184436A1
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formula
compound
salt form
characteristic peaks
mesylate salt
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PCT/CN2016/085360
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English (en)
French (fr)
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陈敏华
张炎锋
刁小娟
张晓宇
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苏州晶云药物科技有限公司
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Priority to US15/575,352 priority Critical patent/US10246418B2/en
Priority to EP16795923.8A priority patent/EP3287444A4/en
Priority to MX2017014799A priority patent/MX2017014799A/es
Priority to JP2018511323A priority patent/JP2018520205A/ja
Priority to CN202110477564.4A priority patent/CN113527203B/zh
Priority to CN201680036277.7A priority patent/CN107848979A/zh
Publication of WO2016184436A1 publication Critical patent/WO2016184436A1/zh
Priority to IL255738A priority patent/IL255738A/en
Priority to US16/364,114 priority patent/US10562855B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/02—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms of an acyclic and saturated carbon skeleton
    • C07C255/03—Mononitriles

Definitions

  • the invention relates to the field of chemical medicine, in particular to a new crystal form of levastatin mesylate and a preparation method and use thereof.
  • Levartinib is an oral multi-receptor tyrosine kinase (RTK) inhibitor developed by Japan Eisai for the treatment of aggressive, differentiated thyroid cancer, which was approved by the FDA on February 13, 2015, and Levatinib mesylate is used in the approved drugs.
  • RTK tyrosine kinase
  • the chemical name of the drug is: 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide, and its structural formula is as shown in formula (I). Show.
  • Patent CN1890220A discloses crystal forms ⁇ , ⁇ of crystal forms A, B, C, F, I and levavirinisulphonate of levabinib mesylate.
  • the inventors of the present invention surprisingly discovered a new crystalline form M of levacitrin mesylate during the course of the study.
  • the crystal form M is different from any one of the crystal forms disclosed in the patent CN1890220A, and the crystal form M of the levacitrin mesylate salt of the invention has good stability, and the process purification effect is remarkable, and the preparation method is prepared.
  • the method is simple and the cost is low, which is of great value to the optimization and development of the drug in the future.
  • Levatinib mesylate is the mesylate salt of the compound of formula (I):
  • the crystal form of Levatinib mesylate provided by the present invention has an X-ray powder diffraction pattern with a value of 11.3° ⁇ 0.2°, 6.1° ⁇ 0.2°, 15.2° ⁇ 0.2°, 17.9° ⁇ 0.2° at 2theta. There are at least three characteristic peaks at 23.5 ° ⁇ 0.2 °, 21.8 ° ⁇ 0.2 °, 7.9 ° ⁇ 0.2 °, 10.1 ° ⁇ 0.2 °, and 22.8 ° ⁇ 0.2 °.
  • the 2theta value of one of the at least three characteristic peaks is 11.3° ⁇ 0.2°.
  • the 2theta values of the other two of the at least three characteristic peaks are 6.1 ° ⁇ 0.2 ° and 15.2 ° ⁇ 0.2 °, respectively.
  • the crystal form of Levatinib mesylate salt provided by the present invention has an X-ray powder diffraction pattern of 21.3.
  • the 2theta values of the three characteristic peaks of the at least six characteristic peaks are 11.3° ⁇ 0.2°, 6.1° ⁇ 0.2°, and 15.2° ⁇ 0.2°, respectively.
  • the 2theta values of the other three of the at least six characteristic peaks are 17.9 ° ⁇ 0.2 °, 23.5 ° ⁇ 0.2 °, 21.8 ° ⁇ 0.2 °, respectively.
  • the X-ray powder diffraction pattern of the form of Levatinib mesylate M is 11.3 ° ⁇ 0.2 °, 6.1 ° ⁇ 0.2 °, 15.2 ° ⁇ 0.2 ° Characteristic peaks are present at 17.9 ° ⁇ 0.2 °, 23.5 ° ⁇ 0.2 °, 21.8 ° ⁇ 0.2 °, 7.9 ° ⁇ 0.2 °, 10.1 ° ⁇ 0.2 °, and 22.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the form of Levatinib mesylate salt provided by the present invention is substantially as shown in FIG.
  • the crystal form of Levatinib mesylate provided by the present invention has a differential scanning calorimetry diagram substantially as shown in FIG. 2 .
  • the crystal form of Levatinib mesylate salt M provided by the present invention is substantially as shown in FIG.
  • Another object of the present invention is to provide a process for the preparation of crystal form M of levotinib mesylate which is obtained by adding a compound of the formula (I) and methanesulfonic acid to a suitable crystallization solvent by stirring.
  • the suitable crystallization solvent comprises a single or mixed system of water, alcohols, ketones, nitriles, cyclic ethers, and aliphatic hydrocarbon solvents.
  • the appropriate crystallization solvent is preferably a nitrile solvent or a nitrile solvent, and particularly preferably acetonitrile.
  • the form of the form of the lovastatin mesylate salt M is as follows: levocinib is suspended in acetonitrile to obtain a suspension, and methanesulfonic acid is added dropwise to the suspension. Stir at room temperature, centrifuge to remove the layer of solid, and dry overnight, that is. Further, the stirring time is preferably 12 hours or longer, more preferably 20 hours or longer. The drying is preferably carried out at room temperature.
  • Another object of the present invention is to provide a pharmaceutical composition comprising an effective amount of crystal form M of Levatinib mesylate, and a pharmaceutically acceptable excipient.
  • the loftinib mesylate salt form M can be used for the preparation of a medicament for treating cancer, particularly a pharmaceutical preparation for thyroid cancer.
  • the present invention also provides the use of the above-mentioned labartinib mesylate salt form M for the preparation of a medicament for treating cancer, in particular a medicament for thyroid cancer.
  • the solubility of the crystal form M of the lovastatin mesylate salt provided by the present invention is significantly improved compared with the crystal form of the existing lovastatin mesylate salt; in addition, the stability of the crystal form M of the present invention is good ( It can well avoid drug storage and crystal transformation during development, so as to avoid bioavailability and drug effect change), crystal shape is good, process purification effect is remarkable, preparation method is simple, cost is low, and the drug is optimized in the future. Development is of great value.
  • Figure 1 is an XRPD pattern of crystal form M of lovastatin mesylate
  • Figure 2 is a DSC chart of crystal form M of lovertinib mesylate
  • Figure 3 is a TGA diagram of crystal form M of lovastatin mesylate
  • Figure 4 is a 1 H NMR chart of crystal form M of lovastatin mesylate
  • Figure 5 is an infrared spectrum of crystal form M of lovertinib mesylate
  • Figure 6 is a polarizing microscope diagram of crystal form M of lovastatin mesylate
  • 7a to 7c are respectively the form of lovastatin mesylate salt M in a) aluminum plastic bag package at 25 ° C / 60% RH; b) in an aluminum plastic bag package at 40 ° C / 75% RH; And c) XRPD comparison chart before and after 7 days of 60 ° C / 75% RH in an aluminum plastic bag package.
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TAQ2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • Polarized Light Microscopy Polarized microscopy data was acquired at room temperature using an Axio Lab. A1 upright microscope.
  • the 1 H NMR data is as follows:
  • the infrared data is as follows:
  • the DSC diagram of Form M is shown in Figure 2, and the TGA diagram is shown in Figure 3.
  • the polarizing microscope of the crystal form M is shown in Fig. 6. It can be seen that the crystal form M has a good crystal form and the particle distribution is uniform.
  • the crystal form M of Levatinib mesylate prepared in Example 1 and the sample No C of the patent CN1890220A without crystal were respectively used with pH 1.8SGF (simulated gastric juice), pH 5.0FeSSIF (simulated artificial intestinal juice in fed state), The pH 6.5 FaSSIF (simulated artificial intestinal juice in the fasting state) and high purity water were made into a saturated solution, and the content of the sample in the saturated solution was determined by high performance liquid chromatography after 24 hours.
  • the experimental results are shown in Table 3.
  • the crystal form M of the present invention did not undergo crystal transformation before and after the placement, and the characteristic peak maintained a high degree of consistency, demonstrating that the crystal form M of the levacitrin mesylate salt of the present invention has excellent stability.

Abstract

本发明涉及乐伐替尼甲磺酸盐的新晶型及其制备方法。本发明提供的甲磺酸盐新晶型可用于治疗侵袭性、分化型甲状腺癌。本发明提供的甲磺酸盐新晶型溶解性和稳定性好，工艺提纯效果显著，制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。

Description

乐伐替尼甲磺酸盐的新晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及乐伐替尼甲磺酸盐的新晶型及其制备方法和用途。
背景技术
乐伐替尼是由日本卫材公司研发的一种用于治疗侵袭性、分化型甲状腺癌的口服多受体酪氨酸激酶(RTK)抑制剂，2015年2月13日获得FDA批准，并且上市获批的药物中使用的是乐伐替尼甲磺酸盐。该药物的化学名称为：4-(3-氯-4-(环丙基氨基羰基)氨基苯氧基)-7-甲氧基-6-喹啉羧酰胺，其结构式如式(I)所示。
Figure PCTCN2016085360-appb-000001
固体化学药物晶型不同，可造成其溶解度和稳定性不同，从而影响药物的吸收和生物利用度，并且会导致临床药效的差异。因此，药物研发中进行全面***的多晶型筛选和盐型筛选，选择最适合开发的晶型或盐型，是不可忽视的重要研究内容之一。
专利CN1890220A公开了乐伐替尼甲磺酸盐的晶型A、B、C、F、I和乐伐替尼乙磺酸盐的晶型α、β。本发明的发明人在研究过程中惊奇地发现了乐伐替尼甲磺酸盐的一种新晶型M。晶型M不同于专利CN1890220A公开的任何一种晶型，并且，本发明的乐伐替尼甲磺酸盐晶型M稳定性好，工艺提纯效果显著，制备方 法简单，成本低廉，对未来该药物的优化和开发具有重要价值。
发明内容
本发明的一个目的是提供一种乐伐替尼甲磺酸盐的新晶型，命名为晶型M，可以提高乐伐替尼甲磺酸盐的溶解性能。
乐伐替尼甲磺酸盐即式(I)化合物的甲磺酸盐：
Figure PCTCN2016085360-appb-000002
本发明提供的乐伐替尼甲磺酸盐晶型M，其X射线粉末衍射图在2theta值为11.3°±0.2°、6.1°±0.2°、15.2°±0.2°、17.9°±0.2°、23.5°±0.2°、21.8°±0.2°、7.9°±0.2°、10.1°±0.2°、22.8°±0.2°处具有至少三个特征峰。
优选地，所述至少三个特征峰中的一个特征峰的2theta值为11.3°±0.2°。
进一步优选地，所述至少三个特征峰中的另二个特征峰的2theta值分别为6.1°±0.2°和15.2°±0.2°。
作为本发明的一个优选方案：本发明提供的乐伐替尼甲磺酸盐晶型M，其X射线粉末衍射图在2theta值为11.3°±0.2°、6.1°±0.2°、15.2°±0.2°、17.9°±0.2°、23.5°±0.2°、21.8°±0.2°、7.9°±0.2°、10.1°±0.2°、22.8°±0.2°处具有至少六个特征峰。进一步优选地，这至少六个特征峰中的三个特征峰的2theta值分别为11.3°±0.2°、6.1°±0.2°、15.2°±0.2°。更进一步优选地，这至少六个特征峰中的另三个特征峰的2theta值分别为17.9°±0.2°、23.5°±0.2°、21.8°±0.2°。
根据本发明的一个具体和特别优选的方面，乐伐替尼甲磺酸盐晶型M的X射线粉末衍射图在2theta值为11.3°±0.2°、6.1°±0.2°、15.2°±0.2°、17.9°±0.2°、23.5°±0.2°、21.8°±0.2°、7.9°±0.2°、10.1°±0.2°、22.8°±0.2°处均具有特征峰。
根据本发明的一个具体实施方式，本发明提供的乐伐替尼甲磺酸盐晶型M其X射线粉末衍射图基本如图1所示。
根据本发明的一个具体实施方式，本发明提供的乐伐替尼甲磺酸盐晶型M，其差示扫描量热分析图基本如图2所示。
根据本发明的一个具体实施方式，本发明提供的乐伐替尼甲磺酸盐晶型M，其热重分析图基本如图3所示。
本发明的另一个目的是提供乐伐替尼甲磺酸盐晶型M的制备方法，其将式(I)化合物与甲磺酸加入到适当的析晶溶剂中，通过搅拌制得。
更进一步的，所述适当的析晶溶剂包括水、醇类，酮类，腈类，环醚类、脂肪烃类溶剂的单一或者混合体系。
更进一步的，所述适当的析晶溶剂优选为腈类溶剂或包括腈类溶剂，具体优选乙腈。
根据本发明的一个具体方面，乐伐替尼甲磺酸盐晶型M的制备方法如下：将乐伐替尼悬浮于乙腈中，得到悬浮液，取甲磺酸滴加到该悬浮液中，室温下搅拌，离心取下层固体，干燥过夜，即得。其中进一步地，搅拌时间优选为12小时以上，更优选20小时以上。所述干燥优选在室温下进行。
本发明的另一个目的是提供一种药用组合物，其包含有效量的乐伐替尼甲磺酸盐晶型M，以及药学上可接受的赋形剂。
更进一步的，本发明所述的药用组合物中，乐伐替尼甲磺酸盐晶型M可用于制备治疗癌症的药物，特别是甲状腺癌药物制剂中的用途。
本发明还提供一种上述的乐伐替尼甲磺酸盐晶型M用于制备治疗癌症的药物，特别是甲状腺癌药物制剂的用途。
本发明的有益效果为：
本发明提供的乐伐替尼甲磺酸盐晶型M与已有的乐伐替尼甲磺酸盐晶型相比，溶解性能显著提升；此外，本发明该晶型M的稳定性好(能很好地避免药物储存以及开发过程中发生转晶，从而避免生物利用度以及药效的改变)，晶体形态好，工艺提纯效果显著，制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。
附图说明
图1为乐伐替尼甲磺酸盐晶型M的XRPD图；
图2为乐伐替尼甲磺酸盐晶型M的DSC图；
图3为乐伐替尼甲磺酸盐晶型M的TGA图；
图4为乐伐替尼甲磺酸盐晶型M的1H NMR图；
图5为乐伐替尼甲磺酸盐晶型M的红外谱图；
图6为乐伐替尼甲磺酸盐晶型M的偏光显微镜图；
图7a～7c分别为乐伐替尼甲磺酸盐晶型M在a)铝塑袋封装中25℃/60％RH条件下；b)铝塑袋封装中40℃/75％RH条件下；以及c)铝塑袋封装中60℃/75％RH条件下放置7天前后的XRPD对比图。
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附 权利要求为准。
下述实施例中，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。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
1H NMR：液态核磁氢谱
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu，Kα
Figure PCTCN2016085360-appb-000003
：1.540598；
Figure PCTCN2016085360-appb-000004
：1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TAQ2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
偏光显微镜测试：偏光显微镜数据通过Axio Lab.A1正置式显微镜在室温下进行采集。
实施例1
乐伐替尼甲磺酸盐晶型M的制备方法：
将50.2mg乐伐替尼悬浮于4.0mL乙腈中，取10μL甲磺酸(质量浓度99.5％)滴加到该悬浮液中，室温下搅拌24小时，离心取下层固体，置于25℃恒温干燥过夜，所得固体经检测为乐伐替尼甲磺酸盐晶型M。
本实施例得到的晶型M的XRPD图如图1，1H NMR如图4，红外谱图如图5。其中：
X射线粉末衍射数据如表1所示。
表1
2theta(°) d间隔 强度％
6.14 14.40 75.59
7.85 11.26 33.94
10.07 8.78 33.61
11.34 7.81 100.00
12.55 7.05 11.76
15.19 5.83 53.50
16.99 5.22 32.29
17.90 4.96 45.13
18.54 4.78 12.19
19.38 4.58 7.49
20.13 4.41 10.55
21.83 4.07 41.20
22.80 3.90 32.45
23.46 3.79 43.92
23.80 3.74 43.36
24.72 3.60 20.03
26.28 3.39 30.01
27.26 3.27 10.06
28.50 3.13 11.88
29.15 3.06 7.19
30.99 2.89 2.58
33.25 2.69 3.62
1H NMR数据如下：
1H-NMR(400MHz，DMSO-d6)δ8.91(d，J＝6.0Hz，1H)，8.73(s，1H)，8.36(d，J＝9.1Hz，1H)，8.04(s，1H)，7.93(s，1H)，7.85(s，1H)，7.56-7.64(m，2H)，7.34(dd，J1＝9.1Hz，J2＝2.7Hz，1H)，7.24(d，J＝2.9Hz，1H)，6.86(d，J＝5.4Hz，1H)，4.09(s，3H)，2.56-2.63(m，1H)，2.31(s，3H)，0.65-0.72(m，2H)，0.41-0.47(m，2H).
红外数据如下：
吸收峰(cm-1)：426.17，535.72，552.31，641.51，674.45，750.73，772.99，842.47，909.84，931.62，983.18，1039.43，1054.78，1091.43，1155.96，1190.77，1238.18，1260.41，1293.34，1325.61，1353.10，1400.53，1457.75，1529.56，1616.33，1669.59，1692.73，3119.43，3249.08，3415.02，3469.14。
晶型M的DSC图如图2，TGA图如图3。晶型M的偏光显微镜图如图6，其中可见晶型M具有较好的结晶形态，颗粒分布均匀。
实施例2
乐伐替尼甲磺酸盐晶型M的制备方法：
将105.3mg乐伐替尼悬浮于12.0mL乙腈中，取30μL甲磺酸(质量浓度99.5％)滴加到该悬浮液中，室温下搅拌24小时，离心取下层固体，置于25℃恒温干燥过夜，所得固体经检测为乐伐替尼甲磺酸盐晶型M。
本实施例得到的晶型M的X射线粉末衍射数据如表2所示。
表2
2theta(°) d间隔 强度％
6.12 14.45 76.19
7.77 11.38 28.62
10.07 8.78 21.83
11.34 7.81 100.00
12.56 7.05 8.67
15.18 5.84 46.69
17.00 5.22 28.50
17.91 4.95 47.27
18.61 4.77 17.60
20.17 4.40 14.60
21.78 4.08 50.93
22.71 3.92 36.31
23.44 3.80 54.89
23.83 3.73 50.46
24.74 3.60 27.04
26.30 3.39 37.22
28.46 3.14 17.39
33.09 2.71 5.53
35.65 2.52 2.98
实施例3
本发明乐伐替尼甲磺酸盐晶型M与专利CN1890220A无水晶型Form C溶解度对比研究：
将实施例1中制备得到的乐伐替尼甲磺酸盐晶型M与专利CN1890220A无水晶型Form C样品分别用pH 1.8SGF(模拟胃液)，pH 5.0FeSSIF(模拟进食状态下人工肠液)，pH 6.5FaSSIF(模拟空腹状态下人工肠液)和高纯水配制成饱和溶液，在24个小时后采用高效液相色谱测定饱和溶液中样品的含量。实验结果如表3所示。
表3
Figure PCTCN2016085360-appb-000005
Figure PCTCN2016085360-appb-000006
结果表明，本发明乐伐替尼甲磺酸盐晶型M比专利CN1890220A无水晶型Form C的溶解度高，特别是其在FaSSIF和高纯水中的溶解性与对比晶型相比具有明显优势。
实施例4
本发明乐伐替尼甲磺酸盐晶型M稳定性研究
取三份乐伐替尼甲磺酸盐晶型M样品，分别置于a)铝塑袋封装中25℃/60％RH条件下；b)铝塑袋封装中40℃/75％RH条件下；以及c)铝塑袋封装中60℃/75％RH条件下，放置7天，对放置前和放置后的样品进行XRPD测试，并将放置前后的图谱进行比对，结果见图7a～7c。从图7a～7c可见，本发明晶型M放置前后没有发生转晶，且特征峰保持了高度的一致性，证明本发明乐伐替尼甲磺酸盐晶型M具有优异的稳定性。

Claims (14)

  1. 一种式(I)化合物的甲磺酸盐晶型M，
    Figure PCTCN2016085360-appb-100001
    其特征在于，其X射线粉末衍射图在2theta值为11.3°±0.2°、6.1°±0.2°、15.2°±0.2°、17.9°±0.2°、23.5°±0.2°、21.8°±0.2°、7.9°±0.2°、10.1°±0.2°、22.8°±0.2°处具有至少三个特征峰。
  2. 根据权利要求1所述的式(I)化合物的甲磺酸盐晶型M，其特征在于：所述至少三个特征峰中的一个特征峰的2theta值为11.3°±0.2°。
  3. 根据权利要求2所述的式(I)化合物的甲磺酸盐晶型M，其特征在于：所述至少三个特征峰中的另二个特征峰的2theta值分别为6.1°±0.2°和15.2°±0.2°。
  4. 根据权利要求1所述的式(I)化合物的甲磺酸盐晶型M，其特征在于：其X射线粉末衍射图在2theta值为11.3°±0.2°、6.1°±0.2°、15.2°±0.2°、17.9°±0.2°、23.5°±0.2°、21.8°±0.2°、7.9°±0.2°、10.1°±0.2°、22.8°±0.2°处具有至少六个特征峰。
  5. 根据权利要求4所述的式(I)化合物的甲磺酸盐晶型M，其特征在于：所述至少六个特征峰中的三个特征峰的2theta值分别为11.3°±0.2°、6.1°±0.2°、15.2°±0.2°。
  6. 根据权利要求5所述的式(I)化合物的甲磺酸盐晶型M，其特征在于：所述至少六个特征峰中的另三个特征峰的2theta值分别为17.9°±0.2°、23.5°±0.2°、 21.8°±0.2°。
  7. 根据权利要求1所述的式(I)化合物的甲磺酸盐晶型M，其特征在于：其X射线粉末衍射图在2theta值为11.3°±0.2°、6.1°±0.2°、15.2°±0.2°、17.9°±0.2°、23.5°±0.2°、21.8°±0.2°、7.9°±0.2°、10.1°±0.2°、22.8°±0.2°处具有特征峰。
  8. 根据权利要求1所述的式(I)化合物的甲磺酸盐晶型M，其特征在于：其X射线粉末衍射图基本上与图1一致。
  9. 一种如权利要求1至8中任一项权利要求所述的式(I)化合物的甲磺酸盐晶型M的制备方法，其特征在于：将式(I)化合物与甲磺酸加入到适当的析晶溶剂中，通过搅拌制得。
  10. 根据权利要求9所述的制备方法，其特征在于：所述析晶溶剂包括水、醇类，酮类，腈类，环醚类、脂肪烃类溶剂的单一或者混合体系。
  11. 根据权利要求10所述的制备方法，其特征在于：所述析晶溶剂是腈类溶剂或包括腈类溶剂。
  12. 根据权利要求11所述的制备方法，其特征在于：所述腈类溶剂是乙腈。
  13. 一种药用组合物，其特征在于：所述药用组合物包含有效量的权利要求1-8中任意一项所述的式(I)化合物的甲磺酸盐晶型M及药学上可接受的赋形剂。
  14. 如权利要求1-8中任意一项所述的式(I)化合物的甲磺酸盐晶型M用于制备治疗癌症的药物，特别是甲状腺癌药物制剂的用途。
PCT/CN2016/085360 2015-05-21 2016-06-08 乐伐替尼甲磺酸盐的新晶型及其制备方法 WO2016184436A1 (zh)

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