WO2016082795A1 - 色瑞替尼的晶型i及其制备方法 - Google Patents

色瑞替尼的晶型i及其制备方法 Download PDF

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WO2016082795A1
WO2016082795A1 PCT/CN2015/095827 CN2015095827W WO2016082795A1 WO 2016082795 A1 WO2016082795 A1 WO 2016082795A1 CN 2015095827 W CN2015095827 W CN 2015095827W WO 2016082795 A1 WO2016082795 A1 WO 2016082795A1
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crystal form
preparation
ray powder
powder diffraction
diffraction pattern
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PCT/CN2015/095827
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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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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • the invention relates to the field of chemical medicine, in particular to the crystal form I of chromatinib and a preparation method thereof.
  • Ceritinib is a new anticancer drug developed by Novartis. The drug was approved by the US Food and Drug Administration (FDA) on April 29, 2014. Coloritinib is an anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor that blocks the promotion of cancer cell protein for the treatment of crizotinib, but has a metastatic ALK positive non-small Patients with cell lung cancer (NSCLC).
  • ALK anaplastic lymphoma kinase
  • NSCLC metastatic ALK positive non-small Patients with cell lung cancer
  • ceritinib is 5-chloro-N 2 -(2-isopropoxy-5-methyl-4-piperidin-4-yl-phenyl)-N 4 -[2-(propane-2 -sulfonyl)-phenyl]-pyrimidine-2,4-diamine, the structural formula of which is as follows:
  • Drug polymorphism refers to the presence of two or more different crystalline forms of a drug. Polymorphism is widespread in medicine. Different crystal forms of the same drug have significant differences in solubility, melting point, density, stability, etc., which affect the stability, homogeneity, bioavailability, efficacy and safety of the drug to varying degrees. Therefore, the comprehensive systematic polymorph screening in drug development and the selection of the most suitable crystal form are one of the important research contents that cannot be ignored.
  • the invention provides a new crystal form of chromatinib, and the crystal form provided by the invention has favorable properties such as good stability, low moisture absorbing property, process developability and easy handling, and has simple preparation method and low cost. It is of great value to the optimization and development of this drug in the future.
  • the crystal form I provided by the present invention is characterized in that its X-ray powder diffraction pattern has characteristic peaks at 2theta values of 18.5 ° ⁇ 0.2 °, 19.1 ° ⁇ 0.2 ° and 9.3 ⁇ 0.2 °.
  • the crystal form I provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 10.6 ° ⁇ 0.2 ° 1 and 15.8 ° ⁇ 0.2 °.
  • the crystal form I provided by the present invention is further characterized by an X-ray powder diffraction pattern of one or two of 2theta values of 21.3° ⁇ 0.2°, 17.1° ⁇ 0.2°, and 13.2° ⁇ 0.2°. There are characteristic peaks at or at three locations; preferably, the crystalline form I provided by the present invention is further characterized by an X-ray powder diffraction pattern having a 2theta value of 21.3° ⁇ 0.2°, 17.1 ° ⁇ 0.2 °, and 13.2 ° ⁇ 0.2. There is a characteristic peak at °.
  • crystal form I provided by the present invention is further characterized in that its X-ray powder diffraction pattern is substantially as shown in FIG.
  • the crystal form I provided by the present invention is characterized in that an endothermic peak begins to appear near heating to 193.5 ° C, and the differential scanning calorimetry diagram is substantially as shown in FIG. 2 .
  • the crystal form I provided by the present invention is characterized in that it has a weight loss gradient of about 2.34% when heated to 200.0 ° C, and its thermogravimetric analysis chart is basically as shown in FIG. 3 .
  • Another object of the present invention is to provide a process for the preparation of Form I, characterized in that the powder of chromatinib is added to a mixed system of one or more solvents and stirred and obtained.
  • the solvent includes, but is not limited to, a solvent such as an alcohol, a hydrocarbyl nitrile, a cyclic ether, a linear ether, a saturated ketone or the like, preferably ethanol or isopropanol.
  • a solvent such as an alcohol, a hydrocarbyl nitrile, a cyclic ether, a linear ether, a saturated ketone or the like, preferably ethanol or isopropanol.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form I of a therapeutically effective amount of ceratinib and a pharmaceutically acceptable adjuvant.
  • a therapeutically effective amount of Form I of ceritinib is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation which is well known in the pharmaceutical arts. The method is prepared.
  • the crystalline form I of ceritinib can be used for the preparation of a pharmaceutical preparation for treating non-small cell lung cancer.
  • the crystal form provided by the present invention has good stability. It can well avoid drug storage and crystal transformation during development, thus avoiding changes in bioavailability and efficacy.
  • the crystal form provided by the invention has low wettability, is not easily affected by high humidity and deliquesces, and is convenient for long-term storage and placement of the medicine.
  • novel crystal form preparation method provided by the invention is simple and reproducible, the process is controllable, the solvent is not easy to remain and is conventionally available, and is suitable for direct use in industrial production.
  • Figure 1 is an XRPD pattern of Form I
  • Figure 2 is a DSC diagram of Form I
  • Figure 3 is a TGA diagram of Form I
  • Figure 4 is a DVS diagram of Form I
  • Figure 5 is a comparison of XRPD before and after 90 days of Form I placed at 5 °C (above is placed before placement) XRPD diagram, the following figure shows the placed XRPD diagram)
  • Figure 6 is a comparison of XRPD of Form I placed at 25 °C / 60% relative humidity for 90 days (the above figure shows the XRPD pattern before placement, and the figure below shows the XRPD pattern after placement)
  • Figure 7 is a comparison of XRPD of Form I placed at 40 °C / 75% relative humidity for 90 days (the above figure shows the XRPD pattern before placement, and the figure below shows the XRPD pattern after placement)
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer; the powder of the colorizone is obtained by a commercially available method.
  • 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 TA Q2000.
  • 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:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • a powder of 104.3 mg of colorizone was dissolved in 1 mL of dichloromethane, and volatilized at 50 ° C to obtain an amorphous powder.
  • the amorphous powder was added to 2 mL of absolute ethanol and stirred to prepare a suspension.
  • the amorphous powder was added to 0.3 ml of isopropyl alcohol and stirred to prepare a suspension.
  • step 2 The system opening obtained in the step 1 is volatilized to dryness at 65 ° C, then 3 mL of absolute ethanol is added, and the solution is dissolved at 60 ° C;
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the crystal form I prepared by the present invention was allowed to stand under conditions of 5 ° C, 25 ° C / 60% relative humidity, and 40 ° C / 75% relative humidity for 90 days, and its XRPD was measured.
  • the experimental results are shown in Table 5.
  • the XRPD of Form I before and after 90 days placed under the above three conditions are shown in Figures 5, 6, and 7, respectively.
  • the crystal form I prepared in Example 1 and the crystal form A sample disclosed in Patent CN103282359A were separately prepared into a suspension solution with isopropanol, and equilibrated at 5 ° C, 25 ° C and 50 ° C for 24 hours and then passed through high performance liquid chromatography.
  • the content of the sample in the saturated solution was determined by (HPLC) method.
  • Experimental results such as Table 6 shows.
  • the new crystalline form I of the present invention has a lower equilibrium solubility than the crystalline form A disclosed in CN103282359A after equilibration for 24 hours at 5 ° C, 25 ° C and 50 ° C.
  • the thermodynamic stability and solubility of the two crystal forms satisfy the following relationship under the same solvent conditions at a specific temperature: the lower the solubility of the crystal form, the lower the Gibbs free energy of the crystal form, ie The higher the thermodynamic stability of the crystal form.
  • the Gibbs free energy of the crystal form is proportional to the natural logarithm of the solubility of the crystal form, that is, the lower the solubility of the crystal form, the lower the Gibbs free energy, the crystal form is The higher the thermodynamic stability under this condition.
  • the conversion relationship between the phenotypes is only temperature dependent, independent of the solvent conditions in which the crystal form is located, as is well known to those skilled in the art. From this, it can be predicted that the crystal form I of the present invention is more stable in the temperature range of 5 ° C to 50 ° C than the crystal form A disclosed in CN103282359A.
  • Form A disclosed in CN103282359A, has the potential to be converted to Form I during the process or under storage conditions.

Abstract

本发明涉及色瑞替尼的晶型I及其制备方法。本发明提供的晶型具有良好的稳定性、较低的引湿性、工艺可开发和易处理性等有利性能，且制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。

Description

色瑞替尼的晶型I及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及色瑞替尼的晶型I及其制备方法。
背景技术
色瑞替尼(Ceritinib)，是由诺华(Novartis)公司研发的抗癌新药。该药于2014年4月29日获美国食品药物管理局(FDA)批准。色瑞替尼是一种间变性淋巴瘤激酶(ALK)酪氨酸激酶抑制剂，可阻断促进癌细胞发生蛋白，用于既往使用过克唑替尼治疗，但有转移的ALK阳性非小细胞肺癌(NSCLC)患者。色瑞替尼化学名称为5-氯-N2-(2-异丙氧基-5-甲基-4-哌啶-4-基-苯基)-N4-[2-(丙烷-2-磺酰基)-苯基]-嘧啶-2,4-二胺，其结构式如下所示：
Figure PCTCN2015095827-appb-000001
药物多晶型(drug polymorphism)是指药物存在有两种或两种以上的不同晶型物质状态。多晶型现象在药物中广泛存在。同一药物的不同晶型在溶解度、熔点、密度、稳定性等方面有显著的差异，从而不同程度地影响药物的稳定性、均一性、生物利用度、疗效和安全性。因此，药物研发中进行全面系统的多晶型筛选，选择最适合开发的晶型，是不可忽视的重要研究内容之一。
目前，仅诺华公司在专利CN103282359A公开了色瑞替尼的两种晶型形式A、形式B。专利中公开了形式A的熔点为174℃，焓值为132.6J/g，形式B 的熔点为162℃，焓值为76.9J/g，形式A的熔点和焓值均比形式B高，在热力学上，形式A比形式B更稳定。因此仅有形式A是稳定可用于制剂的晶型。
基于此，有必要进一步进行色瑞替尼的多晶型筛选，开发出稳定性好、引湿性低、适合工业化生产的无水晶型，为药物的后续开发提供更多更好的选择。
发明内容
本发明提供一种色瑞替尼的新晶型，本发明提供的晶型具有良好的稳定性、较低的引湿性、工艺可开发和易处理性等有利性能，且制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。
具体的，本发明的一个目的是提供色瑞替尼的无水晶型，命名为晶型I。
本发明提供的晶型I，其特征在于，其X射线粉末衍射图在2theta值为18.5°±0.2°、19.1°±0.2°和9.3±0.2°处具有特征峰。
更进一步的，本发明提供的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为10.6°±0.2°1和15.8°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为21.3°±0.2°、17.1°±0.2°和13.2°±0.2°中的一处或两处或三处具有特征峰；优选的，本发明提供的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为21.3°±0.2°、17.1°±0.2°和13.2°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型I，其特征还在于，其X射线粉末衍射图基本如图1所示。
本发明提供的晶型I，其特征在于，在加热至193.5℃附近开始出现吸热峰，其差示扫描量热分析图基本如图2所示。
本发明提供的晶型I，其特征在于，在加热至200.0℃时，具有约2.34％的重量损失梯度，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晶型I的制备方法，其特征在于，将色瑞替尼的粉末加入到一种或多种溶剂的混合体系内，混悬搅拌得到。
更进一步的，所述溶剂包括但不局限于醇类，烃基腈，环醚，直链醚，饱和酮等溶剂，优选乙醇或异丙醇。
本发明的另一个目的是提供一种包含有效治疗量的色瑞替尼的晶型I和药用辅料的药用组合物。一般是将治疗有效量的色瑞替尼的晶型I与一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的。
更进一步的，本发明所述的药用组合物中，色瑞替尼的晶型I可用于制备治疗非小细胞肺癌药物制剂中的用途。
本发明的有益效果为：
本发明提供的晶型具有良好的稳定性。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。
本发明提供的晶型引湿性较低，不易受高湿度影响而潮解，方便药物的长期贮存放置。
本发明提供的新晶型制备方法简单且重复性好，过程可控，溶剂不易残留且常规易得，适合直接用于工业化生产。
附图说明
图1为晶型I的XRPD图
图2为晶型I的DSC图
图3为晶型I的TGA图
图4为晶型I的DVS图
图5为晶型I放置在5℃条件下90天前后的XRPD对比图(上图为放置前的 XRPD图，下图为放置后的XRPD图)
图6为晶型I放置在25℃/60％相对湿度条件下90天前后的XRPD对比图(上图为放置前的XRPD图，下图为放置后的XRPD图)
图7为晶型I放置在40℃/75％相对湿度条件下90天前后的XRPD对比图(上图为放置前的XRPD图，下图为放置后的XRPD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；所述的色瑞替尼的粉末通过市售的方法获得。
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
DVS：动态水分吸附
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 PCTCN2015095827-appb-000002
：1.540598；
Figure PCTCN2015095827-appb-000003
：1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
发散狭缝：自动
扫描模式：连续
扫描范围：自3.0至40.0度
取样步长：0.013度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000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
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
实施例1
晶型I的制备方法：
1.将104.3mg色瑞替尼的粉末溶解于1mL二氯甲烷中，50℃下挥发得到无定形粉末。
2.将该无定形粉末加入2mL无水乙醇中搅拌，制成悬浊液。
3.将该悬浊液放置于室温下搅拌48小时，过滤，所得滤饼置于50℃恒温干燥箱内干燥过夜，所得固体为晶型I。
本实施例得到的晶型I的X射线粉末衍射数据如表1所示。其XRPD图如图1，其DSC图如图2，其TGA图如图3。
表1
2theta d间隔 强度％
6.99 12.65 11.84
9.33 9.48 22.29
10.57 8.37 58.78
13.19 6.71 36.72
14.57 6.08 33.95
15.80 5.61 50.45
17.02 5.21 41.58
18.46 4.81 100.00
19.05 4.66 57.77
19.37 4.58 72.41
21.25 4.18 50.28
21.56 4.12 66.43
22.71 3.92 19.85
24.39 3.65 13.30
26.86 3.32 11.62
27.85 3.20 6.14
29.47 3.03 7.96
31.73 2.82 4.83
实施例2
晶型I的制备方法：
1.将6.7mg色瑞替尼的粉末溶解于0.1mL二氯甲烷中，50℃下挥发，得到无定形粉末。
2.将该无定形粉末加入0.3ml异丙醇中搅拌，制成悬浊液。
3.将该悬浊液放置于室温下搅拌48小时，过滤，所得滤饼置于50℃恒温干燥箱内干燥过夜，所得固体为晶型I。
本实施例得到的晶型I的X射线粉末衍射数据如表2所示。
表2
2theta d间隔 强度％
6.95 12.73 46.71
9.27 9.54 12.44
10.59 8.35 32.44
13.12 6.75 58.95
14.50 6.11 15.29
15.79 5.61 44.14
17.24 5.14 10.40
18.46 4.81 36.11
19.27 4.61 100.00
21.16 4.20 28.89
21.91 4.06 24.08
22.60 3.93 17.36
24.40 3.65 4.37
27.77 3.21 4.79
29.60 3.02 4.21
实施例3
晶型I的制备方法：
1.将511.2mg色瑞替尼的粉末溶解于4.0mL二氯甲烷，于60℃恒温密闭搅拌24小时；
2.将步骤1所得的体系敞口在65℃条件下挥发至干，然后加入3mL无水乙醇，在60℃条件下溶清；
3.将步骤2中所得溶液转移到室温搅拌，加入色瑞替尼晶型I的晶种，继续搅拌，有大量白色固体析出；
4.离心除去母液，将固体溶解于2mL二氯甲烷中，并在50℃条件下敞口挥干；
5.将挥干的物料中加入3mL乙醇，室温下搅拌20小时，得到白色固体；
6.离心除去母液，再次将固体溶解于2mL二氯甲烷，并在50℃条件下敞口挥干；
7.将挥干的物料中加入3mL乙醇，室温搅拌17小时；
8.离心除去母液，将固体在30℃条件下真空干燥，所得固体经检测为晶型I。
本实施例得到的晶型I的X射线粉末衍射数据如表3所示。
表3
2theta d间隔 强度％
7.22 12.25 28.38
9.43 9.38 11.89
10.71 8.26 70.90
13.37 6.62 35.71
14.57 6.08 15.65
15.67 5.66 47.26
17.11 5.18 24.18
18.52 4.79 43.02
19.11 4.64 25.39
19.69 4.51 100.00
21.01 4.23 15.40
21.48 4.14 43.22
21.79 4.08 49.41
23.12 3.85 21.91
23.54 3.78 13.55
25.31 3.52 10.90
26.93 3.31 11.66
30.07 2.97 5.18
31.99 2.80 3.03
实施例4
晶型I的引湿性实验：
在25℃条件下，取本发明晶型I约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表4所示。引湿性实验的DVS图如图4所示。
表4
Figure PCTCN2015095827-appb-000004
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
结果表明，本发明的晶型I在25℃，80％湿度下平衡后增重1.95％，引湿性较低。
实施例5
晶型I的稳定性实验：
将本发明制备得到的晶型I放置在5℃、25℃/60％相对湿度、40℃/75％相对湿度的条件下放置90天，测定其XRPD。实验结果见表5所示。晶型I在放置在上述三个条件下90天前后的XRPD分别如图5、图6、图7所示。
表5
Figure PCTCN2015095827-appb-000005
实施例6
晶型I与专利CN103282359A的晶型A的稳定性对比实验：
将实施例1制备得到的晶型I与专利CN103282359A公开的晶型A样品分别用异丙醇配制成悬浮溶液，在5℃、25℃和50℃条件下平衡24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。实验结果如 表6所示。
表6
Figure PCTCN2015095827-appb-000006
通过上述对比结果可以看出，在5℃、25℃和50℃条件下平衡24个小时后，本发明的新晶型I与CN103282359A公开的晶型A相比，平衡溶解度更低。根据范德霍夫方程，在特定温度相同溶剂条件下，两个晶型的热力学稳定性与溶解度满足如下关系：晶型的溶解度越低，说明该晶型的吉布斯自由能越低，即该晶型的热力学稳定性越高。在相同溶剂条件下，晶型的吉布斯自由能与该晶型溶解度的自然对数成正比例关系，即晶型的溶解度越低，它的吉布斯自由能就越低，该晶型在该条件下的热力学稳定性越高。无水晶型之间的转化关系只与温度有关，与晶型所处的溶剂条件无关，这是本领域技术人员所公知的。由此可以预测：与CN103282359A公开的晶型A相比，本发明的晶型I在5℃到50℃的温度范围内更稳定。CN103282359A公开的晶型A，存在工艺过程中或储存条件下向晶型I转化的可能。

Claims (12)

  1. 一种色瑞替尼的晶型I，其特征在于，其X射线粉末衍射图在2theta值为18.5°±0.2°、19.1°±0.2°和9.3±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为10.6°±0.2°和15.8°±0.2°处具有特征峰。
  3. 根据权利要求1或2所述的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为21.3°±0.2°、17.1°±0.2°和13.2°±0.2°中的一处或两处或三处具有特征峰。
  4. 根据权利要求3所述的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为21.3°±0.2°、17.1°±0.2°和13.2°±0.2°处具有特征峰。
  5. 根据权利要求1所述的晶型I，其特征在于，其X射线粉末衍射图基本上与图1一致。
  6. 一种色瑞替尼晶型I的制备方法，其特征在于，晶型I是通过色瑞替尼的无定形粉末加入到一种或多种溶剂的混合体系中结晶得到。
  7. 根据权利要求6所述的制备方法，所述结晶方法为混悬搅拌。
  8. 根据权利要求6所述的制备方法，所述溶剂包括醇类，烃基腈，环醚，直链醚，饱和酮溶剂。
  9. 根据权利要求6所述的制备方法，所述溶剂包括低级烷基醇。
  10. 根据权利要求6所述的制备方法，所述溶剂是乙醇或异丙醇。
  11. 一种药用组合物，所述药用组合物包含有效量的权利要求1-5中的任一条所述的晶型I及药学上可接受的赋形剂。
  12. 根据权利要求11所述的药用组合物，其特征在于，所述的晶型I用于制备治疗非小细胞肺癌药物制剂中的用途。
PCT/CN2015/095827 2014-11-28 2015-11-27 色瑞替尼的晶型i及其制备方法 WO2016082795A1 (zh)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101616895A (zh) * 2006-12-08 2009-12-30 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
CN103282359A (zh) * 2010-12-17 2013-09-04 诺华股份有限公司 5-氯-n2-(2-异丙氧基-5-甲基-4-哌啶-4-基-苯基)-n4-[2-(丙烷-2-磺酰基)-苯基]-嘧啶-2,4-二胺的结晶形式

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101616895A (zh) * 2006-12-08 2009-12-30 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
CN103282359A (zh) * 2010-12-17 2013-09-04 诺华股份有限公司 5-氯-n2-(2-异丙氧基-5-甲基-4-哌啶-4-基-苯基)-n4-[2-(丙烷-2-磺酰基)-苯基]-嘧啶-2,4-二胺的结晶形式

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