WO2018196687A1 - New crystal form of lenvatinib methanesulfonate and preparation method thereof - Google Patents

New crystal form of lenvatinib methanesulfonate and preparation method thereof Download PDF

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Publication number
WO2018196687A1
WO2018196687A1 PCT/CN2018/083861 CN2018083861W WO2018196687A1 WO 2018196687 A1 WO2018196687 A1 WO 2018196687A1 CN 2018083861 W CN2018083861 W CN 2018083861W WO 2018196687 A1 WO2018196687 A1 WO 2018196687A1
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crystal form
mesylate
mesylate salt
preparation
ray powder
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PCT/CN2018/083861
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French (fr)
Chinese (zh)
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陈敏华
张炎锋
张龙
邹坡
黄春香
杨朝惠
张晓宇
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苏州科睿思制药有限公司
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Priority to CN201880024174.8A priority Critical patent/CN110494423B/en
Publication of WO2018196687A1 publication Critical patent/WO2018196687A1/en

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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
    • A61K31/435—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
    • 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

Definitions

  • the invention relates to the field of chemical medicine, in particular to a new crystal form of levastatin mesylate and a preparation method thereof.
  • Levartinib is an oral multi-receptor tyrosine kinase (RTK) inhibitor developed by Japan Eisai Co., Ltd. for the treatment of invasive and differentiated thyroid cancer. It was acquired on February 13, 2015. Approved by the FDA, approved by the EMA on May 28, 2015.
  • the chemical name of leventinib is: 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (hereinafter referred to as "compound (I) )"), its structural formula is as follows:
  • CN100569753C discloses crystal forms A, B, C, F, and I of methanesulfonate.
  • the solubility of crystal form A is inferior to that of crystal form C
  • form B is converted to crystal form C under conditions of high humidity or high temperature.
  • WO2016184436A1 discloses mesylate salt form M, which is disclosed in the patent as being more soluble in several biological media than the methanesulfonate salt form C disclosed in patent CN100569753C.
  • the invention provides a new crystal form 1 of methanesulfonate salt, the solubility of which is obviously superior to the prior art crystal form, and the preparation process of the crystal form 1 is simple and the cost is low, which is of great value for the optimization and development of the drug in the future.
  • the present invention provides the crystalline form 1 of the mesylate salt of the compound (I) (hereinafter referred to as "crystal form 1").
  • the X-ray powder diffraction of the Form 1 has characteristic peaks at diffraction angles 2 ⁇ of 7.4° ⁇ 0.2°, 14.8° ⁇ 0.2°, and 24.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form 1 has a characteristic peak at one or more of the diffraction angle 2 ⁇ of 26.6° ⁇ 0.2°, 20.4° ⁇ 0.2°, and 25.8° ⁇ 0.2°. Further, the X-ray powder diffraction of the crystal form 1 has a characteristic peak at a diffraction angle 2 ⁇ of 26.6 ° ⁇ 0.2 °, 20.4 ° ⁇ 0.2 °, 25.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the Form 1 has a characteristic peak at one or more of the diffraction angle 2 ⁇ of 9.7° ⁇ 0.2°, 22.8° ⁇ 0.2°, and 23.3° ⁇ 0.2°. Further, the X-ray powder diffraction of the crystal form 1 has a characteristic peak at a diffraction angle 2 ⁇ of 9.7° ⁇ 0.2°, 22.8° ⁇ 0.2°, and 23.3° ⁇ 0.2°.
  • the X-ray powder diffraction of Form 1 is 7.4 ° ⁇ 0.2 °, 14.8 ° ⁇ 0.2 °, 24.8 ° ⁇ 0.2 °, 26.6 ° ⁇ 0.2 °, 20.4 ° ⁇ at diffraction angle 2 ⁇ 0.2°, 25.8° ⁇ 0.2°, 9.7° ⁇ 0.2°, 22.8° ⁇ 0.2°, 23.3° ⁇ 0.2°, 10.1 ⁇ °°, 11.2° ⁇ 0.2°, 19.3° ⁇ 0.2°, 27.1 ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction pattern of Form 1 is shown in FIG.
  • the present invention also provides a method for preparing the crystal form 1, the preparation method comprising:
  • levastatin mesylate form B or form F in a mixed system of acetonitrile to water volume ratio of 92/8 to 80/20, stirring and decanting at -10 ° C to 25 ° C Obtain; or
  • the crystal form B and the crystal form F are the methanesulfonate crystal form B and the crystal form F disclosed in the patent CN100569753C.
  • the crystal form M is the methanesulfonate crystal form M disclosed in the patent WO2016184436A1.
  • the molar ratio of methanesulfonic acid to lavatinib free base in the method 1) is from 1/1 to 1.5/1, preferably 1/1.0.
  • the temperature described in the method 1) is preferably 5 °C.
  • the volume ratio of acetonitrile to water is preferably 88/12.
  • the temperature described in the method 2) is preferably 5 °C.
  • the present invention provides the crystal form 7 of the mesylate salt of the compound (I) (hereinafter referred to as "crystal form 7").
  • the X-ray powder diffraction of the Form 7 has characteristic peaks at diffraction angles 2 ⁇ of 5.3° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 20.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form 7 has a characteristic peak at one or more of the diffraction angle 2 ⁇ of 16.8° ⁇ 0.2°, 22.4° ⁇ 0.2°, and 24.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form 7 has a characteristic peak at a diffraction angle 2 ⁇ of 16.8° ⁇ 0.2°, 22.4° ⁇ 0.2°, and 24.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form 7 has a characteristic peak at one or more of the diffraction angle 2 ⁇ of 9.6° ⁇ 0.2°, 10.7° ⁇ 0.2°, and 19.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form 7 has a characteristic peak at diffraction angles 2 ⁇ of 9.6° ⁇ 0.2°, 10.7° ⁇ 0.2°, and 19.3° ⁇ 0.2°.
  • the X-ray powder diffraction of Form 7 is 5.3 ° ⁇ 0.2 °, 9.6 ° ⁇ 0.2 °, 10.7 ° ⁇ 0.2 °, 16.8 ° ⁇ 0.2 °, 18.5 ° ⁇ at diffraction angle 2 ⁇
  • the X-ray powder diffraction pattern of Form 7 is as shown in FIG.
  • the present invention also provides a method for preparing the crystal form 7, which comprises adding mesylate to anhydrous acetonitrile using levatinib free base, and stirring at 0 ° C to 35 ° C. The reaction is obtained by crystallization.
  • the molar ratio of the methanesulfonic acid to the lavatinib free base is from 1/1 to 1.5/1, preferably 1/1.0.
  • the temperature is preferably 25 °C.
  • the "room temperature” means 10 ° C to 30 ° C.
  • the “stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the “separation” is accomplished using conventional methods in the art, such as centrifugation or filtration.
  • the “centrifugation” operation was performed by placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until the solids all settled to the bottom of the centrifuge tube.
  • the levavirinib and/or its salt as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the levavirinib and/or a salt thereof as a raw material is in the form of a solid powder.
  • crystal or “polymorph” means confirmed by the X-ray diffraction pattern characterization shown.
  • X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows for some variability.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the mesylate salt form 1, Form 7 of the present invention is pure, unitary, and substantially free of any other crystal form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • Another object of the present invention is to provide a pharmaceutical composition comprising an effective amount of the mesylate salt form 1 and a pharmaceutically acceptable excipient.
  • the present invention provides the use of Form 1 in the manufacture of a tyrosinase inhibitor drug.
  • the present invention provides the use of Form 1 for the preparation of a pharmaceutical preparation for treating thyroid cancer.
  • the lovastatin mesylate salt form 1 of the present invention has the following beneficial properties:
  • the crystal form 1 provided by the invention has good solubility in simulated biological medium and pure water, especially in the artificial intestinal juice (FeSSIF) in the fed state, the solubility is 30 times higher than that in the prior art CN100569753 crystal form C, The solubility in simulated artificial gastric juice (SGF) and water is higher than 10 mg/mL.
  • Levartinib is a poorly soluble drug, and solubility is the rate-limiting factor of drug bioavailability. Therefore, a significant increase in the solubility of Form 1 will help to improve the bioavailability of levavirinib, thereby increasing the drug's drug-forming properties.
  • the efficacy of the drug while ensuring the efficacy of the drug, reducing the dose of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.
  • the crystal form 1 provided by the invention has good physical and chemical stability.
  • the crystal form 1 of the present invention does not change crystal form at 25 ° C / 60% relative humidity for at least 1 week, and the crystal form purity hardly changes; at room temperature / 22.5% relative humidity, room temperature / 43.2% relative humidity, room temperature /
  • the crystal form did not change at 57.6% relative humidity, room temperature/75.3% relative humidity, and room temperature/97.5% relative humidity for at least 5 days.
  • Form 1 has good stability, ensuring that the drug substance is not easily converted into other crystal forms during the storage and formulation process, thereby ensuring consistent and controllable sample quality, which is of great significance for drug development.
  • Example 1 is an XRPD pattern of the mesylate salt form 1 prepared in Example 1.
  • Example 2 is an XRPD pattern of the mesylate salt form 1 prepared in Example 2.
  • Figure 5 is an XRPD pattern of the mesylate salt form 7 prepared in Example 8.
  • Figure 7 is a comparison chart of XRPD of the stability test of the methanesulfonate crystal form 1 in Example 11 (the figure above is before placing, the lower figure is placed after 25°C/60% humidity for one week)
  • Figure 8 is a comparison chart of XRPD of the methanesulfonate crystal form 1 stability test in Example 11 (from top to bottom, starting sample, 22.5% relative humidity, 43.2% relative humidity, 57.6% relative humidity, 75.3% relative) Humidity, sample placed at 97.5% relative humidity for five days)
  • Figure 10 is a TGA diagram of the mesylate salt form 1 prepared in Example 5.
  • Figure 11 is a DSC chart of the methanesulfonate salt form 1 prepared in Example 5.
  • 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 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:
  • levavirinib and/or a salt thereof according to the present invention can be obtained by a method disclosed in the prior art, for example, by the method disclosed in CN100569753C and WO2016184436A1.
  • the white solid obtained in this example was tested to be Form 1 of Levatinib mesylate.
  • the X-ray powder diffraction data is shown in Figure 1, Table 1.
  • the white solid obtained in this example was the crystalline form 1 of Levatinib mesylate, and its X-ray powder diffraction data is shown in Table 2, and its XRPD pattern is shown in FIG.
  • the white solid obtained in this example was tested to be Form 1 of Levatinib mesylate, and its XRPD pattern is shown in FIG.
  • the crystal form 8 has an XRPD pattern as shown in FIG.
  • the TGA of the crystal form is as shown in FIG. 10, and when it is heated to about 150 ° C, it has a mass loss gradient of about 11.2%; the DSC of the crystal form is as shown in FIG. 11 at 87 ° C, 91 ° C, and 117 ° C. An endothermic peak appeared near 162 ° C and 181 ° C; combined with TGA and DSC data, the crystalline form 1 of the present invention was a hydrate.
  • Form B of Leventinibethanesulfonate 5.0 mg was placed in a 1.5 mL glass vial, and 0.6 mL of a mixed solvent of acetonitrile and water (volume ratio of acetonitrile to water of 88/12) was added at 5 Magnetic stirring was carried out for 4 days at ° C to obtain a white solid, and XRPD was immediately detected, and the obtained white solid was methanesulfonate crystal form 1.
  • the white solid obtained in this example was tested to be Form 7 of Levatinib mesylate.
  • the X-ray powder diffraction pattern is shown in Fig. 5, and the data is shown in Table 3.
  • the mesylate salt form 1 of the present invention was placed under the condition of 25 ° C / 60% relative humidity for one week, and the crystal form change was sampled.
  • the XRPD comparison chart of the methanesulfonate crystal form 1 before and after the placement is shown in Fig. 7.
  • the above figure shows the purity of 99.73% after the one placed at 25 ° C / 60% humidity for one week. The purity was 99.74%), and the crystal form showed almost no change, indicating that Form 1 has good physicochemical stability.
  • the solid of the methanesulfonate crystal form 1 was placed at room temperature and humidity for five days, and the solid crystal form was measured.
  • the XRPD comparison chart is shown in Fig. 8 (from top to bottom, the starting sample, 22.5% relative humidity, 43.2% relative humidity, 57.6% relative humidity, 75.3% relative humidity, 97.5% relative humidity for five days).
  • SGF simulated artificial gastric juice
  • pure water pure water
  • the crystal form 1 of the present invention has higher solubility than the prior art crystal form C and crystal form M after being placed in SGF, FeSSIF and water for 24 hours, especially in FeSSIF, the solubility ratio is now There are technical crystal forms that are 30 times higher.
  • the results show that the solubility of the crystalline form 1 of the present invention meets the requirements of medicinal requirements and provides favorable conditions for drug development.

Abstract

The present invention relates to a new crystal form of a Lenvatinib methanesulfonate salt and a preparation method thereof, a pharmaceutical composition containing the crystalline form, and the use of the crystalline form in the preparation of a tyrosinase inhibitor and a pharmaceutical preparation for treating thyroid cancer. The new methanesulfonate crystal form of the present invention has obvious cost advantages, and has one or more improved properties over the prior art, and is of great value for the optimization and development of the drug in the future.

Description

乐伐替尼甲磺酸盐的新晶型及其制备方法New crystal form of levastatin mesylate and preparation method thereof 技术领域Technical field
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。The invention relates to the field of chemical medicine, in particular to a new crystal form of levastatin mesylate and a preparation method thereof.
背景技术Background technique
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(Receptor Tyrosine Kinase，RTK)抑制剂，2015年2月13日获得FDA批准，2015年5月28日获得EMA批准。乐伐替尼的化学名称为：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(以下称“化合物(I)”)，其结构式如下：Levartinib is an oral multi-receptor tyrosine kinase (RTK) inhibitor developed by Japan Eisai Co., Ltd. for the treatment of invasive and differentiated thyroid cancer. It was acquired on February 13, 2015. Approved by the FDA, approved by the EMA on May 28, 2015. The chemical name of leventinib is: 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide (hereinafter referred to as "compound (I) )"), its structural formula is as follows:
Figure PCTCN2018083861-appb-000001
Figure PCTCN2018083861-appb-000001
在药物研究领域，不同的药物晶型具有不同的颜色、熔点、溶解度、溶出性能、化学稳定性、机械稳定性等，这些特性可以影响药物制剂的质量、安全性和有效性，从而导致临床药效差异。因此，晶型研究和控制成为药物研发过程中的重要研究内容。In the field of pharmaceutical research, different drug crystal forms have different colors, melting points, solubility, dissolution properties, chemical stability, mechanical stability, etc. These properties can affect the quality, safety and effectiveness of pharmaceutical preparations, leading to clinical drugs. Difference in effectiveness. Therefore, crystal form research and control has become an important research content in the drug development process.
CN100569753C公开了甲磺酸盐的晶型A、B、C、F、I，专利中披露晶型A的溶解度比晶型C差，晶型B在高湿或高温条件下向晶型C转化，晶型F热力学稳定性较晶型C差，经本申请发明人研究发现，晶型F在水活度a w＝0～0.821的溶液体系中会转变为晶型C，晶型I为醋酸合物结晶，为药用的非理想选择。WO2016184436A1公开了甲磺酸盐晶型M，专利中披露该晶型在几种生物介质中溶解度高于专利CN100569753C中公开的甲磺酸盐晶型C。 CN100569753C discloses crystal forms A, B, C, F, and I of methanesulfonate. The solubility of crystal form A is inferior to that of crystal form C, and form B is converted to crystal form C under conditions of high humidity or high temperature. The thermodynamic stability of the crystalline form F is inferior to that of the crystalline form C. It has been found by the inventors of the present application that the crystalline form F is converted into the crystalline form C in the solution system having the water activity a w =0 to 0.821, and the crystalline form I is the acetic acid. Crystallization is a non-ideal choice for medicinal purposes. WO2016184436A1 discloses mesylate salt form M, which is disclosed in the patent as being more soluble in several biological media than the methanesulfonate salt form C disclosed in patent CN100569753C.
本发明提供了甲磺酸盐的新晶型1，其溶解度明显优于现有技术晶型，且晶型1的制备工艺简单，成本低廉，对未来该药物的优化和开发具有重要价值。The invention provides a new crystal form 1 of methanesulfonate salt, the solubility of which is obviously superior to the prior art crystal form, and the preparation process of the crystal form 1 is simple and the cost is low, which is of great value for the optimization and development of the drug in the future.
发明内容Summary of the invention
根据本发明的目的，本发明提化合物(I)甲磺酸盐的晶型1(以下称作“晶型1”)。According to the object of the present invention, the present invention provides the crystalline form 1 of the mesylate salt of the compound (I) (hereinafter referred to as "crystal form 1").
使用Cu-Kα辐射，所述晶型1的X射线粉末衍射在衍射角2θ为7.4°±0.2°、14.8°±0.2°、24.8°±0.2°处有特征峰。Using Cu-Kα radiation, the X-ray powder diffraction of the Form 1 has characteristic peaks at diffraction angles 2θ of 7.4°±0.2°, 14.8°±0.2°, and 24.8°±0.2°.
进一步地，所述晶型1的X射线粉末衍射在衍射角2θ为26.6°±0.2°、20.4°±0.2°、25.8°±0.2°中的一处或多处有特征峰。更进一步地，所述晶型1的X射线粉末衍射在衍射角 2θ为26.6°±0.2°、20.4°±0.2°、25.8°±0.2°处有特征峰。Further, the X-ray powder diffraction of the Form 1 has a characteristic peak at one or more of the diffraction angle 2θ of 26.6°±0.2°, 20.4°±0.2°, and 25.8°±0.2°. Further, the X-ray powder diffraction of the crystal form 1 has a characteristic peak at a diffraction angle 2θ of 26.6 ° ± 0.2 °, 20.4 ° ± 0.2 °, 25.8 ° ± 0.2 °.
进一步地，所述晶型1的X射线粉末衍射在衍射角2θ为9.7°±0.2°、22.8°±0.2°、23.3°±0.2°中的一处或多处有特征峰。更进一步地，所述晶型1的X射线粉末衍射在衍射角2θ为9.7°±0.2°、22.8°±0.2°、23.3°±0.2°处有特征峰。Further, the X-ray powder diffraction of the Form 1 has a characteristic peak at one or more of the diffraction angle 2θ of 9.7°±0.2°, 22.8°±0.2°, and 23.3°±0.2°. Further, the X-ray powder diffraction of the crystal form 1 has a characteristic peak at a diffraction angle 2θ of 9.7°±0.2°, 22.8°±0.2°, and 23.3°±0.2°.
在一个优选的实施方案中，所述晶型1的X射线粉末衍射在衍射角2θ为7.4°±0.2°、14.8°±0.2°、24.8°±0.2°、26.6°±0.2°、20.4°±0.2°、25.8°±0.2°、9.7°±0.2°、22.8°±0.2°、23.3°±0.2°、10.1°±0.2°、11.2°±0.2°、19.3°±0.2°、27.1±0.2°处有特征峰。In a preferred embodiment, the X-ray powder diffraction of Form 1 is 7.4 ° ± 0.2 °, 14.8 ° ± 0.2 °, 24.8 ° ± 0.2 °, 26.6 ° ± 0.2 °, 20.4 ° ± at diffraction angle 2θ 0.2°, 25.8°±0.2°, 9.7°±0.2°, 22.8°±0.2°, 23.3°±0.2°, 10.1±±°°, 11.2°±0.2°, 19.3°±0.2°, 27.1±0.2° There are characteristic peaks.
非限制性地，在本发明的一个具体实施方案中，晶型1的X射线粉末衍射谱图如图1所示。Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form 1 is shown in FIG.
根据本发明的目的，本发明还提供所述晶型1的制备方法，所述制备方法包括：According to the purpose of the present invention, the present invention also provides a method for preparing the crystal form 1, the preparation method comprising:
1)使用乐伐替尼游离碱在乙腈与水体积比为99/1～80/20的混合体系中加入甲磺酸，于-10℃～25℃条件下搅拌反应析晶而获得；或1) using mevastatin free base in a mixed system of acetonitrile to water volume ratio of 99/1 to 80/20, adding methanesulfonic acid, and stirring and crystallization at -10 ° C to 25 ° C; or
2)使用乐伐替尼甲磺酸盐晶型B或晶型F在乙腈与水体积比为92/8～80/20的混合体系中，于-10℃～25℃条件下搅拌析晶而获得；或2) using levastatin mesylate form B or form F in a mixed system of acetonitrile to water volume ratio of 92/8 to 80/20, stirring and decanting at -10 ° C to 25 ° C Obtain; or
3)使用乐伐替尼甲磺酸盐晶型M置于70％～100％湿度的干燥器内放置2小时～5天获得。3) It is obtained by placing the lovastatin mesylate form M in a drier of 70% to 100% humidity for 2 hours to 5 days.
所述晶型B、晶型F为专利CN100569753C公开的甲磺酸盐晶型B、晶型F。The crystal form B and the crystal form F are the methanesulfonate crystal form B and the crystal form F disclosed in the patent CN100569753C.
所述晶型M为专利WO2016184436A1公开的甲磺酸盐晶型M。The crystal form M is the methanesulfonate crystal form M disclosed in the patent WO2016184436A1.
进一步地，方法1)中所述甲磺酸与乐伐替尼游离碱的投料摩尔比为1/1～1.5/1，优选为1/1.0。Further, the molar ratio of methanesulfonic acid to lavatinib free base in the method 1) is from 1/1 to 1.5/1, preferably 1/1.0.
进一步地，方法1)中所述的温度优选为5℃。Further, the temperature described in the method 1) is preferably 5 °C.
进一步地，方法2)中所述乙腈和水的混合体系中，乙腈与水的体积比优选为88/12。Further, in the mixed system of acetonitrile and water in the method 2), the volume ratio of acetonitrile to water is preferably 88/12.
进一步地，方法2)中所述的温度优选为5℃。Further, the temperature described in the method 2) is preferably 5 °C.
根据本发明的目的，本发明提化合物(I)甲磺酸盐的晶型7(以下称作“晶型7”)。According to the object of the present invention, the present invention provides the crystal form 7 of the mesylate salt of the compound (I) (hereinafter referred to as "crystal form 7").
使用Cu-Kα辐射，所述晶型7的X射线粉末衍射在衍射角2θ为5.3°±0.2°、18.5°±0.2°、20.8°±0.2°处有特征峰。Using Cu-Kα radiation, the X-ray powder diffraction of the Form 7 has characteristic peaks at diffraction angles 2θ of 5.3°±0.2°, 18.5°±0.2°, and 20.8°±0.2°.
进一步地，所述晶型7的X射线粉末衍射在衍射角2θ为16.8°±0.2°、22.4°±0.2°、24.3°±0.2°中的一处或多处有特征峰。Further, the X-ray powder diffraction of the crystal form 7 has a characteristic peak at one or more of the diffraction angle 2θ of 16.8°±0.2°, 22.4°±0.2°, and 24.3°±0.2°.
更进一步地，所述晶型7的X射线粉末衍射在衍射角2θ为16.8°±0.2°、22.4°±0.2°、24.3°±0.2°处有特征峰。Further, the X-ray powder diffraction of the crystal form 7 has a characteristic peak at a diffraction angle 2θ of 16.8°±0.2°, 22.4°±0.2°, and 24.3°±0.2°.
进一步地，所述晶型7的X射线粉末衍射在衍射角2θ为9.6°±0.2°、10.7°±0.2°、19.3°±0.2° 中的一处或多处有特征峰。Further, the X-ray powder diffraction of the crystal form 7 has a characteristic peak at one or more of the diffraction angle 2θ of 9.6°±0.2°, 10.7°±0.2°, and 19.3°±0.2°.
更进一步地，所述晶型7的X射线粉末衍射在衍射角2θ为9.6°±0.2°、10.7°±0.2°、19.3°±0.2°处有特征峰。Further, the X-ray powder diffraction of the crystal form 7 has a characteristic peak at diffraction angles 2θ of 9.6°±0.2°, 10.7°±0.2°, and 19.3°±0.2°.
在一个优选的实施方案中，所述晶型7的X射线粉末衍射在衍射角2θ为5.3°±0.2°、9.6°±0.2°、10.7°±0.2°、16.8°±0.2°、18.5°±0.2°、19.3°±0.2°、20.8°±0.2°、22.4°±0.2°、24.3°±0.2°处有特征峰。In a preferred embodiment, the X-ray powder diffraction of Form 7 is 5.3 ° ± 0.2 °, 9.6 ° ± 0.2 °, 10.7 ° ± 0.2 °, 16.8 ° ± 0.2 °, 18.5 ° ± at diffraction angle 2θ There are characteristic peaks at 0.2°, 19.3°±0.2°, 20.8°±0.2°, 22.4°±0.2°, and 24.3°±0.2°.
非限制性地，在本发明的一个具体实施方案中，晶型7的X射线粉末衍射谱图如图5所示。Without limitation, in one embodiment of the invention, the X-ray powder diffraction pattern of Form 7 is as shown in FIG.
根据本发明的目的，本发明还提供所述晶型7的制备方法，所述制备方法包括使用乐伐替尼游离碱在无水乙腈中加入甲磺酸，于0℃～35℃条件下搅拌反应析晶而获得。According to the object of the present invention, the present invention also provides a method for preparing the crystal form 7, which comprises adding mesylate to anhydrous acetonitrile using levatinib free base, and stirring at 0 ° C to 35 ° C. The reaction is obtained by crystallization.
其中：among them:
进一步地，所述甲磺酸与乐伐替尼游离碱的投料摩尔比为1/1～1.5/1，优选为1/1.0。Further, the molar ratio of the methanesulfonic acid to the lavatinib free base is from 1/1 to 1.5/1, preferably 1/1.0.
进一步地，所述温度优选为25℃。Further, the temperature is preferably 25 °C.
所述“室温”指10℃～30℃。The "room temperature" means 10 ° C to 30 ° C.
所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分钟，优选300～900转/分钟。The "stirring" is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
所述“分离”，采用本领域的常规方法完成，例如离心或过滤。“离心”的操作为：将欲分离的样品置于离心管中，以10000转/分的速率进行离心，至固体全部沉至离心管底部。The "separation" is accomplished using conventional methods in the art, such as centrifugation or filtration. The "centrifugation" operation was performed by placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until the solids all settled to the bottom of the centrifuge tube.
根据本发明，作为原料的所述乐伐替尼和/或其盐指其固体(晶型或无定形)、半固体、蜡或油形式。优选地，作为原料的所述乐伐替尼和/或其盐为固体粉末形式，。According to the present invention, the levavirinib and/or its salt as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form. Preferably, the levavirinib and/or a salt thereof as a raw material is in the form of a solid powder.
本发明中，“晶体”或“多晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱 中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。In the present invention, "crystal" or "polymorph" means confirmed by the X-ray diffraction pattern characterization shown. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor. In fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal. The peak intensities shown here are illustrative and not for absolute comparison. In addition, the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ±0.2° is usually allowed. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, it will be understood by those skilled in the art that the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same. The same peak position can differ by ± 0.2° and the peak intensity allows for some variability. Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention. One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
在一些实施方案中，本发明的甲磺酸盐晶型1、晶型7是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。In some embodiments, the mesylate salt form 1, Form 7 of the present invention is pure, unitary, and substantially free of any other crystal form. In the present invention, "substantially free" when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。It should be noted that the numerical values and numerical ranges recited in the present invention are not to be construed as narrowly construed as a numerical value or a numerical range per se. It will be understood by those skilled in the art that they may vary depending on the specific technical environment without departing from the spirit of the invention. On the basis of the principle, there are fluctuations around specific numerical values. In the present invention, such a floating range which can be foreseen by those skilled in the art is often expressed by the term "about".
本发明的另一个目的是提供一种药用组合物，包含有效量的甲磺酸盐晶型1以及药学上可接受的赋形剂。Another object of the present invention is to provide a pharmaceutical composition comprising an effective amount of the mesylate salt form 1 and a pharmaceutically acceptable excipient.
进一步地，本发明提供晶型1在制备酪氨酸酶抑制剂药物中的用途。Further, the present invention provides the use of Form 1 in the manufacture of a tyrosinase inhibitor drug.
进一步地，本发明提供晶型1在制备治疗甲状腺癌药物制剂中的用途。Further, the present invention provides the use of Form 1 for the preparation of a pharmaceutical preparation for treating thyroid cancer.
本发明的乐伐替尼甲磺酸盐晶型1具有以下有益性质：The lovastatin mesylate salt form 1 of the present invention has the following beneficial properties:
①本发明提供的晶型1在模拟生物介质和纯水中具有良好的溶解度，特别是在进食状态下人工肠液(FeSSIF)中，溶解度比现有技术CN100569753中晶型C高30倍之多，在模拟人工胃液(SGF)和水中溶解度高于10mg/mL。乐伐替尼是难溶性药物，溶解度是药物生物利用度的限速因素，因此，晶型1溶解度的显著提高将有助于提高乐伐替尼药物的生物利用度，从而提高药物的成药性及药效；在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。1 The crystal form 1 provided by the invention has good solubility in simulated biological medium and pure water, especially in the artificial intestinal juice (FeSSIF) in the fed state, the solubility is 30 times higher than that in the prior art CN100569753 crystal form C, The solubility in simulated artificial gastric juice (SGF) and water is higher than 10 mg/mL. Levartinib is a poorly soluble drug, and solubility is the rate-limiting factor of drug bioavailability. Therefore, a significant increase in the solubility of Form 1 will help to improve the bioavailability of levavirinib, thereby increasing the drug's drug-forming properties. And the efficacy of the drug; while ensuring the efficacy of the drug, reducing the dose of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.
②本发明提供的晶型1物理化学稳定性好。本发明的晶型1在25℃/60％相对湿度至少保持1周晶型未发生变化，且晶型纯度几乎未发生变化；在室温/22.5％相对湿度、室温/43.2％相对湿度、室温/57.6％相对湿度、室温/75.3％相对湿度、室温/97.5％相对湿度下至少保持5天晶型未发生变化。作为药物中最关键的活性成分，晶型具有良好的稳定性至关重要。晶型1具有良好的稳定性，保证原料药在存储和制剂工艺过程中，不容易转变成其它晶型，从而保证样品的质量一致可控，对于药物开发具有非常重要的意义。2 The crystal form 1 provided by the invention has good physical and chemical stability. The crystal form 1 of the present invention does not change crystal form at 25 ° C / 60% relative humidity for at least 1 week, and the crystal form purity hardly changes; at room temperature / 22.5% relative humidity, room temperature / 43.2% relative humidity, room temperature / The crystal form did not change at 57.6% relative humidity, room temperature/75.3% relative humidity, and room temperature/97.5% relative humidity for at least 5 days. As the most important active ingredient in the drug, it is important that the crystal form has good stability. Form 1 has good stability, ensuring that the drug substance is not easily converted into other crystal forms during the storage and formulation process, thereby ensuring consistent and controllable sample quality, which is of great significance for drug development.
附图说明DRAWINGS
图1为实施例1制备得到的甲磺酸盐晶型1的XRPD图1 is an XRPD pattern of the mesylate salt form 1 prepared in Example 1.
图2为实施例2制备得到的甲磺酸盐晶型1的XRPD图2 is an XRPD pattern of the mesylate salt form 1 prepared in Example 2.
图3为实施例3制备得到的甲磺酸盐晶型1的XRPD图3 is an XRPD pattern of the mesylate salt form 1 prepared in Example 3.
图4为实施例4制备得到的甲磺酸盐晶型1的XRPD图4 is an XRPD pattern of the mesylate salt form 1 prepared in Example 4.
图5为实施例8制备得到的甲磺酸盐晶型7的XRPD图Figure 5 is an XRPD pattern of the mesylate salt form 7 prepared in Example 8.
图6为实施例9制备得到的甲磺酸盐晶型M的XRPD图6 is an XRPD pattern of the methanesulfonate salt form M prepared in Example 9.
图7为实施例11中甲磺酸盐晶型1稳定性试验的XRPD对比图(上图为放置前，下图为放置在25℃/60％湿度条件下一周后)Figure 7 is a comparison chart of XRPD of the stability test of the methanesulfonate crystal form 1 in Example 11 (the figure above is before placing, the lower figure is placed after 25°C/60% humidity for one week)
图8为实施例11中甲磺酸盐晶型1稳定性试验的XRPD对比图(从上至下依次为起始样品、22.5％相对湿度、43.2％相对湿度、57.6％相对湿度、75.3％相对湿度、97.5％相对湿度下放置五天的样品)Figure 8 is a comparison chart of XRPD of the methanesulfonate crystal form 1 stability test in Example 11 (from top to bottom, starting sample, 22.5% relative humidity, 43.2% relative humidity, 57.6% relative humidity, 75.3% relative) Humidity, sample placed at 97.5% relative humidity for five days)
图9为实施例5制备得到的甲磺酸盐晶型1的XRPD图9 is an XRPD pattern of the mesylate salt form 1 prepared in Example 5.
图10为实施例5制备得到的甲磺酸盐晶型1的TGA图Figure 10 is a TGA diagram of the mesylate salt form 1 prepared in Example 5.
图11为实施例5制备得到的甲磺酸盐晶型1的DSC图Figure 11 is a DSC chart of the methanesulfonate salt form 1 prepared in Example 5.
具体实施方式detailed description
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。The invention is further illustrated by the following examples, but is not intended to limit the scope of the invention. Improvements in the method of preparation and use of the apparatus may be made by those skilled in the art within the scope of the claims, and such modifications are also considered to be within the scope of the invention. Therefore, the scope of the invention should be determined by the appended claims.
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。In the following examples, the test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:
XRPD：X射线粉末衍射XRPD: X-ray powder diffraction
DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermogravimetric Analysis
1H NMR：液态核磁氢谱 1 H NMR: liquid NMR
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：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:
X射线反射参数：Cu,KαX-ray reflection parameters: Cu, Kα
Figure PCTCN2018083861-appb-000002
1.540598；
Figure PCTCN2018083861-appb-000003
1.544426
Figure PCTCN2018083861-appb-000002
1.540598;
Figure PCTCN2018083861-appb-000003
1.544426
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：45千伏特(kV)Voltage: 45 kV (kV)
电流：40毫安培(mA)Current: 40 milliamps (mA)
扫描范围：自3.0至40.0度Scan range: from 3.0 to 40.0 degrees
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：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:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气Protective gas: nitrogen
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：The 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:
扫描速率：10℃/minScan rate: 10 ° C / min
保护气体：氮气Protective gas: nitrogen
本发明使用乐伐替尼和/或其盐可以通过现有技术公开方法制得，例如通过CN100569753C和WO2016184436A1公开的方法制备得到。The use of levavirinib and/or a salt thereof according to the present invention can be obtained by a method disclosed in the prior art, for example, by the method disclosed in CN100569753C and WO2016184436A1.
实施例1乐伐替尼甲磺酸盐晶型1的制备方法Example 1 Preparation method of Levatinib mesylate salt form 1
将200mg的乐伐替尼游离碱固体置于玻璃小瓶中，加入20mL的乙腈。5℃下，缓慢加入30.4μL的甲磺酸(纯度>99％)。磁力搅拌反应18小时，得到白色固体。200 mg of levatinib free base solid was placed in a glass vial and 20 mL of acetonitrile was added. 30.4 μL of methanesulfonic acid (purity >99%) was slowly added at 5 °C. The reaction was stirred magnetically for 18 hours to give a white solid.
经检测，本实施例得到的白色固体为乐伐替尼甲磺酸盐的晶型1。其X射线粉末衍射数据如图1，表1所示。The white solid obtained in this example was tested to be Form 1 of Levatinib mesylate. The X-ray powder diffraction data is shown in Figure 1, Table 1.
表1Table 1
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
5.605.60 15.7915.79 14.2814.28
7.427.42 11.9111.91 48.9648.96
9.719.71 9.119.11 47.0547.05
10.0910.09 8.778.77 51.3951.39
11.2211.22 7.897.89 43.7443.74
12.8912.89 6.876.87 10.4010.40
14.8414.84 5.975.97 42.3842.38
15.6415.64 5.675.67 5.155.15
16.3516.35 5.425.42 7.367.36
16.8716.87 5.265.26 8.838.83
17.6917.69 5.025.02 32.1632.16
18.5918.59 4.774.77 39.5439.54
19.2319.23 4.624.62 62.7562.75
19.6419.64 4.524.52 51.3051.30
20.2320.23 4.394.39 98.2298.22
21.0221.02 4.234.23 27.4827.48
21.9721.97 4.054.05 61.4461.44
22.7522.75 3.913.91 74.3974.39
23.2523.25 3.833.83 74.8074.80
23.7323.73 3.753.75 23.8523.85
24.1724.17 3.683.68 40.1840.18
24.7724.77 3.593.59 100.00100.00
25.1325.13 3.543.54 62.5962.59
25.7125.71 3.463.46 94.1394.13
26.5426.54 3.363.36 70.7970.79
27.1727.17 3.283.28 56.4056.40
27.8327.83 3.213.21 18.5118.51
28.5228.52 3.133.13 25.5325.53
实施例2乐伐替尼甲磺酸盐晶型1的制备方法Example 2 Preparation method of Levatinib mesylate salt form 1
将1.01g的乐伐替尼甲磺酸盐晶型M固体置于97.5％的湿度下，放置两小时后，测试固体XRPD。1.01 g of Levatinib mesylate Form M solid was placed at 97.5% humidity and after standing for two hours, the solid XRPD was tested.
经检测，本实施例得到的白色固体为乐伐替尼甲磺酸盐的晶型1，其X射线粉末衍射数据如表2所示，其XRPD图如图2所示。The white solid obtained in this example was the crystalline form 1 of Levatinib mesylate, and its X-ray powder diffraction data is shown in Table 2, and its XRPD pattern is shown in FIG.
表2Table 2
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
7.367.36 11.811.8 76.276.2
9.639.63 9.19.1 59.359.3
9.829.82 8.98.9 85.585.5
10.2110.21 8.68.6 72.272.2
11.2911.29 7.87.8 47.047.0
12.9012.90 6.86.8 19.819.8
14.7514.75 6.06.0 31.331.3
15.0815.08 5.85.8 33.833.8
17.0817.08 5.25.2 14.514.5
17.4417.44 5.15.1 49.449.4
18.6918.69 4.74.7 14.714.7
19.3119.31 4.64.6 65.365.3
19.4619.46 4.54.5 59.759.7
19.6819.68 4.54.5 53.253.2
20.4020.40 4.34.3 78.878.8
20.6320.63 4.34.3 34.434.4
21.6121.61 4.14.1 12.112.1
22.0822.08 4.04.0 18.918.9
22.7122.71 3.93.9 77.477.4
23.2623.26 3.83.8 74.074.0
23.9623.96 3.73.7 10.810.8
24.3524.35 3.63.6 70.670.6
24.8224.82 3.63.6 94.694.6
25.0925.09 3.53.5 45.245.2
25.8925.89 3.43.4 84.984.9
26.5626.56 3.33.3 100.0100.0
27.0327.03 3.33.3 51.451.4
27.4527.45 3.23.2 14.614.6
28.1328.13 3.23.2 44.444.4
28.5228.52 3.13.1 31.731.7
实施例3乐伐替尼甲磺酸盐晶型1的制备方法Example 3 Preparation method of Levatinib mesylate salt form 1
将104.8mg的乐伐替尼甲磺酸盐的晶型6置于5mL的玻璃小瓶中，加入4mL的乙腈和水的混合溶剂(乙腈和水的体积比为88/12)，在5℃下磁力搅拌6小时，得到白色固体。经检测，本实施例得到的白色固体为乐伐替尼甲磺酸盐的晶型1。其X射线粉末衍射数据如图3所示。104.8 mg of Form 6 of Levatinib mesylate was placed in a 5 mL glass vial, and 4 mL of a mixed solvent of acetonitrile and water (volume ratio of acetonitrile to water of 88/12) was added at 5 ° C. Magnetic stirring for 6 hours gave a white solid. The white solid obtained in this example was tested to be Form 1 of Levatinib mesylate. Its X-ray powder diffraction data is shown in Figure 3.
实施例4乐伐替尼甲磺酸盐晶型1的制备方法Example 4 Preparation method of Levatinib mesylate salt form 1
将1.01g的乐伐替尼甲磺酸盐晶型M固体置于75.3％的湿度下，放置3天后，测试固体XRPD。1.01 g of Levatinib mesylate Form M solid was placed at 75.3% humidity and allowed to stand for 3 days before testing for solid XRPD.
经检测，本实施例得到的白色固体为乐伐替尼甲磺酸盐的晶型1，其XRPD图如图4所示。The white solid obtained in this example was tested to be Form 1 of Levatinib mesylate, and its XRPD pattern is shown in FIG.
实施例5乐伐替尼甲磺酸盐晶型1的制备方法Example 5 Preparation method of Levatinib mesylate salt form 1
将23.5mg的乐伐替尼甲磺酸盐固体Form M置于97.5％的湿度下，放置三天后，测试固体XRPD，经检测，本实施例得到的白色固体为乐伐替尼甲磺酸盐的晶型8，其XRPD图如图9所示。23.5 mg of Levatinib mesylate solid Form M was placed under a humidity of 97.5%, and after standing for three days, the solid XRPD was tested, and the white solid obtained in this example was tested as levabinib mesylate. The crystal form 8 has an XRPD pattern as shown in FIG.
该晶型的TGA如图10所示，将其加热至150℃左右时，具有约11.2％的质量损失梯度；该晶型的DSC如图11所示，在87℃、91℃、117℃、162℃、181℃附近出现吸热峰；结合TGA与DSC数据可知，本发明晶型1为水合物。The TGA of the crystal form is as shown in FIG. 10, and when it is heated to about 150 ° C, it has a mass loss gradient of about 11.2%; the DSC of the crystal form is as shown in FIG. 11 at 87 ° C, 91 ° C, and 117 ° C. An endothermic peak appeared near 162 ° C and 181 ° C; combined with TGA and DSC data, the crystalline form 1 of the present invention was a hydrate.
实施例6通过专利CN100569753C中甲磺酸盐晶型B制备甲磺酸盐晶型1的方法Example 6 Method for preparing methanesulfonate salt form 1 by methanesulfonate salt form B in patent CN100569753C
将5.0mg的乐伐替尼甲磺酸盐的晶型B置于1.5mL的玻璃小瓶中，加入0.6mL的乙腈和水的混合溶剂(乙腈和水的体积比为88/12)，在5℃下磁力搅拌4天，得到白色固体，立即检测XRPD，所得白色固体为甲磺酸盐晶型1。5.0 mg of Form B of Leventinibethanesulfonate was placed in a 1.5 mL glass vial, and 0.6 mL of a mixed solvent of acetonitrile and water (volume ratio of acetonitrile to water of 88/12) was added at 5 Magnetic stirring was carried out for 4 days at ° C to obtain a white solid, and XRPD was immediately detected, and the obtained white solid was methanesulfonate crystal form 1.
实施例7通过专利CN100569753C中甲磺酸盐晶型F制备甲磺酸盐晶型1的方法Example 7 Method for preparing methanesulfonate salt form 1 by methanesulfonate salt form F in patent CN100569753C
将5.0mg的乐伐替尼甲磺酸盐的晶型F置于1.5mL的玻璃小瓶中，加入0.6mL的乙腈和水的混合溶剂(乙腈和水的体积比为88/12)，在5℃下磁力搅拌4天，得到白色固体，立即检测XRPD，所得白色固体为甲磺酸盐晶型1。5.0 mg of Form F of Leventinib mesylate was placed in a 1.5 mL glass vial, and 0.6 mL of a mixed solvent of acetonitrile and water (volume ratio of acetonitrile to water of 88/12) was added at 5 Magnetic stirring was carried out for 4 days at ° C to obtain a white solid, and XRPD was immediately detected, and the obtained white solid was methanesulfonate crystal form 1.
实施例8乐伐替尼甲磺酸盐晶型7的制备方法Example 8 Preparation method of Levatinib mesylate salt form 7
将104.5mg的乐伐替尼游离碱固体置于1.5mL的玻璃小瓶中，加入1.5mL的无水乙腈。室温下，缓慢加入15μL的甲磺酸(纯度>99％)。磁力搅拌反应10分钟，得到白色固体。104.5 mg of levatinib free base solid was placed in a 1.5 mL glass vial and 1.5 mL of anhydrous acetonitrile was added. 15 μL of methanesulfonic acid (purity >99%) was slowly added at room temperature. The reaction was stirred magnetically for 10 minutes to give a white solid.
经检测，本实施例得到的白色固体为乐伐替尼甲磺酸盐的晶型7。其X射线粉末衍射图如图5所示，数据如表3所示。The white solid obtained in this example was tested to be Form 7 of Levatinib mesylate. The X-ray powder diffraction pattern is shown in Fig. 5, and the data is shown in Table 3.
表3table 3
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
5.315.31 16.6616.66 100.00100.00
9.269.26 9.559.55 3.263.26
9.599.59 9.239.23 8.148.14
10.6810.68 8.288.28 4.804.80
11.7011.70 7.577.57 1.191.19
12.2612.26 7.227.22 1.081.08
14.1114.11 6.286.28 4.384.38
16.8216.82 5.275.27 14.1114.11
17.5717.57 5.055.05 4.174.17
18.1118.11 4.904.90 12.4812.48
18.4818.48 4.804.80 25.0525.05
19.2719.27 4.614.61 11.6411.64
20.3620.36 4.364.36 27.2727.27
20.7520.75 4.284.28 43.4943.49
21.0721.07 4.224.22 13.4113.41
21.3821.38 4.164.16 24.3624.36
21.6621.66 4.104.10 12.6712.67
22.4122.41 3.973.97 18.7218.72
23.4223.42 3.803.80 22.0922.09
23.6923.69 3.763.76 21.9921.99
24.2524.25 3.673.67 24.4024.40
25.2025.20 3.533.53 21.2921.29
25.6425.64 3.473.47 16.4516.45
实施例9通过甲磺酸盐晶型1制备专利WO2016184436A1甲磺酸盐晶型M的方法Example 9 Method for preparing patent WO2016184436A1 mesylate salt form M by mesylate salt form 1
取约3.0mg实施例1制备得到的甲磺酸盐晶型1于硅片上，在室温下放置5分钟，所得固体经X射线粉末衍射仪测试即为专利WO2016184436A1甲磺酸盐晶型M，其XRPD图如图6所示。About 3.0 mg of the methanesulfonate salt form 1 prepared in Example 1 was placed on a silicon wafer and allowed to stand at room temperature for 5 minutes. The obtained solid was tested by an X-ray powder diffractometer to be the patent WO2016184436A1 mesylate salt form M. Its XRPD diagram is shown in Figure 6.
实施例10通过甲磺酸盐晶型7制备专利WO2016184436A1甲磺酸盐晶型M的方法Example 10 Method for preparing patent WO2016184436A1 mesylate salt form M by mesylate salt form 7
取约3.0mg实施例6制备得到的甲磺酸盐晶型7于硅片上，在室温下放置5分钟，所得固体经X射线粉末衍射仪测试即为专利WO2016184436A1晶型M。About 3.0 mg of the methanesulfonate salt form 7 prepared in Example 6 was placed on a silicon wafer and allowed to stand at room temperature for 5 minutes. The obtained solid was tested by an X-ray powder diffractometer to be a crystalline form M of the patent WO2016184436A1.
实施例11甲磺酸盐晶型1的稳定性Example 11 Stability of Mesylate Salt Form 1
取本发明甲磺酸盐晶型1放置于25℃/60％相对湿度的条件下一周，取样检测其晶型变化。放置前后甲磺酸盐晶型1的XRPD对比图如图7所示，上图为放置前，下图为放置在25℃/60％湿度条件下一周后，其纯度为99.73％(起始样品的纯度为99.74％)，晶型几乎无变化，表明晶型1具有良好的物理化学稳定性。The mesylate salt form 1 of the present invention was placed under the condition of 25 ° C / 60% relative humidity for one week, and the crystal form change was sampled. The XRPD comparison chart of the methanesulfonate crystal form 1 before and after the placement is shown in Fig. 7. The above figure shows the purity of 99.73% after the one placed at 25 ° C / 60% humidity for one week. The purity was 99.74%), and the crystal form showed almost no change, indicating that Form 1 has good physicochemical stability.
将甲磺酸盐晶型1的固体置于室温、不同湿度下五天，测固体晶型，测试XRPD对比图如图8所示(从上至下依次为起始样品、22.5％相对湿度、43.2％相对湿度、57.6％相对湿度、75.3％相对湿度、97.5％相对湿度下放置五天的样品)。The solid of the methanesulfonate crystal form 1 was placed at room temperature and humidity for five days, and the solid crystal form was measured. The XRPD comparison chart is shown in Fig. 8 (from top to bottom, the starting sample, 22.5% relative humidity, 43.2% relative humidity, 57.6% relative humidity, 75.3% relative humidity, 97.5% relative humidity for five days).
结果表明，乐伐替尼甲磺酸盐晶型1在上述条件下放置，至少保持5天稳定，晶型1具有良好的稳定性。The results showed that the form of levastatin mesylate salt 1 was stable under the above conditions for at least 5 days, and the crystal form 1 had good stability.
实施例12甲磺酸盐晶型1的动态溶解度Example 12 Dynamic Solubility of Mesylate Salt Form 1
将本发明的晶型1、现有技术晶型C以及现有技术晶型M样品分别用SGF(模拟人工胃液)，pH＝5.0 FeSSIF(进食状态下人工肠液)和纯水配制成饱和溶液，在1个小时，4个小时和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。本发明晶型1、现有技术晶型C以及现有技术晶型M的溶解度对比数据如表4所示。The crystal form 1 of the present invention, the prior art crystal form C, and the prior art crystal form M sample are respectively prepared into a saturated solution by using SGF (simulated artificial gastric juice), pH=5.0 FeSSIF (artificial intestinal juice in a fed state) and pure water, respectively. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour, 4 hours, and 24 hours. The solubility comparison data of the crystal form 1, the prior art crystal form C of the present invention and the crystal form M of the prior art are shown in Table 4.
表4Table 4
Figure PCTCN2018083861-appb-000004
Figure PCTCN2018083861-appb-000004
通过上述对比结果可以看出：在SGF、FeSSIF和水中放置24小时后本发明晶型1与现有技术晶型C、晶型M相比，溶解度更高，特别是在FeSSIF中，溶解度比现有技术晶型高30倍之多。结果表明，本发明晶型1的溶解度符合药用要求，为药物开发提供有利条件。It can be seen from the above comparison results that the crystal form 1 of the present invention has higher solubility than the prior art crystal form C and crystal form M after being placed in SGF, FeSSIF and water for 24 hours, especially in FeSSIF, the solubility ratio is now There are technical crystal forms that are 30 times higher. The results show that the solubility of the crystalline form 1 of the present invention meets the requirements of medicinal requirements and provides favorable conditions for drug development.
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。The above embodiments are merely illustrative of the technical concept and the features of the present invention, and the purpose of the present invention is to enable those skilled in the art to understand the present invention and to implement the present invention, and the scope of the present invention is not limited thereto. Equivalent variations or modifications made in accordance with the spirit of the invention are intended to be included within the scope of the invention.

Claims (7)

  1. 一种乐伐替尼甲磺酸盐晶型1，其特征在于，其X射线粉末衍射图在衍射角2θ为7.4°±0.2°、14.8°±0.2°、24.8°±0.2°处具有特征峰。A crystal form of levastatin mesylate salt characterized by having an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2θ of 7.4°±0.2°, 14.8°±0.2°, 24.8°±0.2° .
  2. 根据权利要求1所述的甲磺酸盐晶型1，其特征还在于，其X射线粉末衍射图在衍射角2θ为26.6°±0.2°、20.4°±0.2°、25.8°±0.2°中的一处或多处具有特征峰。The mesylate salt form 1 according to claim 1, which is characterized in that the X-ray powder diffraction pattern thereof is in the diffraction angle 2θ of 26.6°±0.2°, 20.4°±0.2°, 25.8°±0.2°. One or more points have characteristic peaks.
  3. 根据权利要求1所述的甲磺酸盐晶型1，其特征还在于，其X射线粉末衍射图在衍射角2θ为9.7°±0.2°、22.8°±0.2°、23.3°±0.2°中的一处或多处具有特征峰。The mesylate salt form 1 according to claim 1, which is characterized in that the X-ray powder diffraction pattern is in the diffraction angle 2θ of 9.7°±0.2°, 22.8°±0.2°, 23.3°±0.2°. One or more points have characteristic peaks.
  4. 一种乐伐替尼甲磺酸盐晶型1的制备方法，其特征在于，包括：使用乐伐替尼游离碱在乙腈与水体积比为99/1～80/20的混合体系中加入甲磺酸，于-10℃～25℃条件下搅拌反应析晶而获得；其中甲磺酸与乐伐替尼游离碱的投料摩尔比为1/1～1.5/1；或The invention relates to a method for preparing crystal form 1 of levacitrin mesylate, which comprises: adding a group of a mixture of acetonitrile and water in a volume ratio of acetonitrile to water of from 99/1 to 80/20; The sulfonic acid is obtained by stirring and crystallization at -10 ° C to 25 ° C; wherein the molar ratio of methanesulfonic acid to levatinib free base is 1/1 to 1.5/1;
    使用乐伐替尼甲磺酸盐晶型B或晶型F在乙腈与水体积比为92/8～80/20的混合体系中，于-10℃～25℃条件下悬浮搅拌析晶而获得；或Using levotinib mesylate form B or form F in a mixed system of acetonitrile to water volume ratio of 92/8 to 80/20, suspension and crystallization at -10 ° C to 25 ° C to obtain ;or
    使用乐伐替尼甲磺酸盐晶型M置于70％～100％湿度的干燥器内放置2小时～5天获得。It is obtained by placing the lovastatin mesylate form M in a desiccator having a humidity of 70% to 100% for 2 hours to 5 days.
  5. 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所述的甲磺酸盐晶型1以及药学上可接受的赋形剂。A pharmaceutical composition comprising an effective amount of the mesylate salt form 1 of claim 1 and a pharmaceutically acceptable excipient.
  6. 权利要求1中所述的甲磺酸盐晶型1在制备酪氨酸酶抑制剂药物中的用途。Use of the mesylate salt form 1 of claim 1 for the manufacture of a tyrosinase inhibitor drug.
  7. 权利要求1所述的甲磺酸盐晶型1在制备治疗甲状腺癌药物制剂中的用途。Use of the mesylate salt form 1 of claim 1 for the preparation of a pharmaceutical preparation for treating thyroid cancer.
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