WO2020057622A1 - 卡博替尼苹果酸盐晶型及其制备方法和用途 - Google Patents

卡博替尼苹果酸盐晶型及其制备方法和用途 Download PDF

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WO2020057622A1
WO2020057622A1 PCT/CN2019/106847 CN2019106847W WO2020057622A1 WO 2020057622 A1 WO2020057622 A1 WO 2020057622A1 CN 2019106847 W CN2019106847 W CN 2019106847W WO 2020057622 A1 WO2020057622 A1 WO 2020057622A1
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crystalline form
csiii
solid
solvent
acetic acid
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PCT/CN2019/106847
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English (en)
French (fr)
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陈敏华
张炎锋
翟晓婷
张婧
张群
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苏州科睿思制药有限公司
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Priority to CN201980054691.4A priority Critical patent/CN112638880B/zh
Priority to US17/278,138 priority patent/US20210332014A1/en
Publication of WO2020057622A1 publication Critical patent/WO2020057622A1/zh

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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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/233—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 4
    • 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
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • 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

Definitions

  • the invention relates to the field of medicinal chemistry. Specifically, it relates to the crystal form of cabozantinib malate, the preparation method of the crystal form of cabozantinib malate, and the use of the crystal form of cabozantinib malate.
  • Cabozantinib is an anticancer drug developed by Exelixis. Its indications for the treatment of metastatic medullary thyroid cancer and renal cancer were approved by the FDA in November 2012 and April 2016. In addition, Its indication for treating liver cancer was also approved by the FDA in January 2019. Cabozantinib is marketed as (S) -malate.
  • (S) -malate of cabotinib is N- (4- ⁇ [6,7-bis (methyloxy) quinolin-4-yl] oxy ⁇ phenyl) -N ' -(4-fluorophenyl) cyclopropane-1,1-dicarboxamide (S) -malate (hereinafter referred to as "Compound I” or cabozantinib (S) -malate), its structural formula as follows:
  • the crystalline form is a solid in which the molecules of the compound are arranged in a three-dimensional order in the microstructure to form a lattice.
  • the polymorphism of a drug refers to the existence of two or more different crystalline forms of a drug. Because of the different physical and chemical properties, different crystal forms of the drug may have different dissolution and absorption in the body, which will affect the clinical efficacy and safety of the drug to a certain extent. Especially for poorly soluble solid drugs, the effect of crystalline form will be greater. Therefore, the crystalline form of a drug must be an important part of drug research and an important part of drug quality control.
  • CN102388024A discloses the N-1 crystalline form, N-2 crystalline form, and amorphous form of compound I.
  • Patent data shows that N-2 crystals have better stability than amorphous and N-1 crystals, but their solubility is lower, and their flowability, compressibility, tensile strength, and adhesion are poor.
  • WO2015177758A1 discloses crystalline form M1, crystalline form M2, crystalline form M3 and crystalline form M4 of compound I.
  • crystalline form M4 is a better crystalline form, but this crystalline form also has low solubility, fluidity, compressibility, and The problem of poor tensile strength and adhesion. Therefore, a large number of experimental studies are still needed to provide more crystalline forms with better properties to support the development of Compound I drugs.
  • the inventors of the present application unexpectedly discovered that the compound I crystalline form CSI and crystalline form CSIII provided by the present invention have advantages in physical and chemical properties, formulation processing performance and bioavailability, such as in melting point , Solubility, hygroscopicity, purification, stability, adhesion, compressibility, fluidity, dissolution in vitro and in vivo, bioavailability and other aspects have advantages, especially high solubility, flowability, tensile strength Good adhesion, which provides new and better choices for the development of drugs containing Compound I, which is of great significance.
  • the preparation method of the crystalline form M2 (hereinafter referred to as "the crystalline form M2") disclosed in WO2015177758A1 was poor in reproducibility and the process was difficult to control. Therefore, a stable and controllable preparation method was developed.
  • the process of mass crystal form M2 is also of great value for the development of compound I drugs.
  • the main purpose of the present invention is to provide a new crystalline form of compound I and a method for preparing and using the crystalline form of compound I.
  • the present invention provides a crystalline form CSI of the compound I (hereinafter referred to as "crystalline CSI").
  • the X-ray powder diffraction of the crystal form CSI has characteristic peaks at diffraction angle 2 ⁇ values of 8.5 ° ⁇ 0.2 °, 12.7 ° ⁇ 0.2 °, and 13.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form CSI is characterized by one, or two, or three of the diffraction angle 2 ⁇ values of 12.1 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 19.9 ° ⁇ 0.2 °. Peaks; Preferably, the X-ray powder diffraction of the crystalline form CSI has characteristic peaks at three diffraction angles of 12.1 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, and 19.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form CSI is characterized in that one of the diffraction angle 2 ⁇ values is 14.9 ° ⁇ 0.2 °, 16.7 ° ⁇ 0.2 °, 25.5 ° ⁇ 0.2 °, or 2 or 3 Peaks;
  • the X-ray powder diffraction of the crystal form CSI has characteristic peaks at three of the diffraction angles of 14.9 ° ⁇ 0.2 °, 16.7 ° ⁇ 0.2 °, and 25.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form CSI at the diffraction angle 2 ⁇ values are 8.5 ° ⁇ 0.2 °, 12.7 ° ⁇ 0.2 °, 13.9 ° ⁇ 0.2 °, 12.1 ° ⁇ 0.2 °, 17.9 ° ⁇ 0.2 °, 19.9 ° ⁇ 0.2 °, 14.9 ° ⁇ 0.2 °, 16.7 ° ⁇ 0.2 °, 25.5 ° ⁇ 0.2 ° at any of 3, 4 or 5 or 6 or 7 , Or 8 or 9 have characteristic peaks.
  • the crystalline form CSI is an acetic acid solvate.
  • the present invention further provides a method for preparing the crystalline form CSI.
  • the method includes the following two methods:
  • Method 1 The compound I solid is dissolved in acetic acid or a mixed system of acetic acid and aromatic hydrocarbons, and is rapidly volatilized at 50-80 ° C;
  • Method 2 Dissolve the solid compound I in acetic acid, a mixed solvent of acetic acid and aromatics, a mixed solvent of acetic acid and alkanes, or a mixed solvent of acetic acid and water, and add the aromatics and alkanes to the prepared solution while stirring. , Ester or ketone organic solvents, the precipitated solid is crystal form CSI.
  • the aromatic hydrocarbon is toluene
  • the volume ratio of the acetic acid to the toluene is 2: 1-1: 3, preferably 1: 1.
  • volume ratios of acetic acid and aromatics, acetic acid and alkanes, acetic acid and water in the second method are all 2: 1-1: 3, preferably 1: 1.
  • the aromatic hydrocarbon is toluene
  • the alkane is n-heptane
  • the ester is isopropyl acetate
  • the ketone is methyl isobutyl ketone.
  • stirring in the second method is performed at 0-5 ° C.
  • the present invention provides a crystalline form CSIII of the compound I (hereinafter referred to as "crystalline CSIII").
  • the X-ray powder diffraction of the crystal form CSIII has characteristic peaks at diffraction angle 2 ⁇ values of 8.5 ° ⁇ 0.2 °, 21.3 ° ⁇ 0.2 °, and 23.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form CSIII is characterized by one, or two, or three of a diffraction angle 2 ⁇ value of 14.4 ° ⁇ 0.2 °, 17.8 ° ⁇ 0.2 °, or 12.6 ° ⁇ 0.2 °. Peaks; Preferably, the X-ray powder diffraction of the crystal form CSIII has characteristic peaks at three diffraction angles of 14.4 ° ⁇ 0.2 °, 17.8 ° ⁇ 0.2 °, and 12.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form CSIII is characterized by one, or two, or three of the diffraction angle 2 ⁇ values of 20.5 ° ⁇ 0.2 °, 24.0 ° ⁇ 0.2 °, 16.4 ° ⁇ 0.2 °. Peaks; Preferably, the X-ray powder diffraction of the crystal form CSIII has characteristic peaks at 3 of the diffraction angles of 20.5 ° ⁇ 0.2 °, 24.0 ° ⁇ 0.2 °, and 16.4 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the crystal form CSIII has a diffraction angle 2 ⁇ value of 8.5 ° ⁇ 0.2 °, 21.3 ° ⁇ 0.2 °, 23.0 ° ⁇ 0.2 °, 14.4 ° ⁇ 0.2 °, 17.8 ° ⁇ 0.2 °, 12.6 ° ⁇ 0.2 °, 20.5 ° ⁇ 0.2 °, 24.0 ° ⁇ 0.2 °, 16.4 ° ⁇ 0.2 ° at any 3, or 4 or 5 or 6 or 7 , Or 8 or 9 have characteristic peaks.
  • the present invention also provides a method for preparing the crystalline form CSIII, which includes the following two methods:
  • Method 1 Dissolve Compound I solid in acids or mixed systems of acids and aromatics, acids and alkanes, acids and water, and then add aromatics, alkanes, Ester or ketone organic solvents, solids are precipitated, the solids are separated by filtration, and the obtained solids are slurried in a mixed solvent system of aromatics and water, and the solids are separated again, and the obtained solids are crystalline form CSIII;
  • Step 1 Dissolve the solid of Compound I in an acidic solvent, heat and stir until the solid is completely dissolved, and then naturally cool to room temperature and filter;
  • Step 2 Add aromatic hydrocarbon organic solvent to the clarified solution dropwise, then transfer to 0-10 ° C and continue stirring, filter to separate the solid, and dry;
  • Step 3 The temperature is increased to 50-100 ° C under a nitrogen purge, and then the temperature is lowered to 30 ° C.
  • the obtained solid is a crystalline form CSIII.
  • volume ratio of the acids and aromatics, acids and alkanes, acids and water in the method 1 is 2: 1-1: 3, preferably 1: 1.
  • the acid is acetic acid
  • the aromatic hydrocarbon is preferably toluene
  • the alkane is preferably n-heptane
  • the ester is preferably isopropyl acetate
  • the ketone is preferably methyl Isobutyl ketone.
  • the acid is acetic acid
  • the aromatic hydrocarbon is toluene
  • step 1 of method 2 is performed at 80 ° C
  • the stirring in step 2 is performed at 5 ° C
  • the stirring time in step 2 is 10-20 hours
  • the heating temperature in step 3 To 100 ° C.
  • stirring time in step two of method two is 15 hours.
  • the crystalline form CSI of the present invention has higher solubility.
  • the solubility of the crystalline form CSI of the present invention in water is twice that of the prior art crystalline form N-2, and more than five times that of the prior art crystalline form M4.
  • Cabozantinib is a poorly water-soluble drug and belongs to BCS II. Higher solubility is beneficial to improve the absorption of the drug in the human body, improve bioavailability, and make the drug play a better therapeutic role; In addition, higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug Side effects and improve the safety of medicines.
  • the crystal form CSI of the present invention has a better purification effect.
  • the purity of the crystal form of the invention is greatly improved after being prepared from raw materials.
  • the raw material used in the present invention is prepared by one-time crystallization to obtain the crystal form CSI, the purity is significantly improved, and the content of each impurity is reduced.
  • the chemical purity of drugs is of great significance for ensuring the efficacy and safety of drugs and preventing the occurrence of adverse reactions to drugs. If the drug contains impurities exceeding the limit, it may cause changes in physical and chemical parameters, variations in appearance characteristics, and affect the stability of the drug; the increase in impurities also makes the drug content significantly lower or the activity is reduced, and the toxic and side effects are significantly increased. Therefore, different All drug regulations have strict requirements for impurity content.
  • the crystalline form with good purification effect can show a strong ability to eliminate impurities in the crystallization process, which makes it possible to obtain high-purity APIs through crystallization, which effectively overcomes the low drug stability and poor efficacy caused by low drug purity. , High toxicity and other disadvantages.
  • the crystalline form CSIII of the present invention has higher solubility. Especially in FeSSIF and water, the solubility is both twice and more than the prior art crystalline form N-2 and the prior art crystalline form M4.
  • Cabozantinib is a poorly water-soluble drug and belongs to BCS II. Higher solubility is beneficial to improve the absorption of the drug in the human body, improve bioavailability, and make the drug play a better therapeutic role; In addition, higher solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the drug Side effects and improve the safety of medicines.
  • the crystalline form CSIII provided by the present invention also has the following beneficial effects:
  • the crystalline form CSIII of the present invention has better fluidity.
  • the fluidity evaluation results show that the crystalline form CSIII is significantly better than the prior art crystalline form.
  • Better fluidity can avoid clogging of production equipment and improve production efficiency; better flow performance of crystalline form CSIII ensures the uniformity and content uniformity of preparations, reduces the weight difference of preparations, and improves product quality.
  • the crystalline form CSIII provided by the present invention has better compressibility.
  • the good compressibility of the crystalline form CSIII can effectively improve the hardness / brittleness failure, chipping and other problems in the tableting process, making the preparation process more reliable, improving the appearance of the product and improving the product quality.
  • Better compressibility can also increase tableting speed and thus production efficiency, while reducing the cost of excipients used to improve compressibility.
  • the crystalline form CSIII of the present invention has lower adhesion.
  • the adhesion evaluation results show that the adsorption amount of the crystal form CSIII is much lower than that of the prior art crystal form.
  • the lower adhesion of the crystalline form CSIII can effectively improve or avoid the phenomenon of sticky wheels and sticky punches caused by dry granulation and tablet compression, which is conducive to improving product appearance and weight difference.
  • the lower adhesion of the crystalline form CSIII can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and utensils, facilitate the dispersion of raw materials and mixing with other auxiliary materials, increase the uniformity of mixing when the materials are mixed, and the final product. Content uniformity.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of crystalline form CSI, crystalline form CSIII or any combination of the two crystalline forms, and a pharmaceutically acceptable carrier, dilution Agents or excipients.
  • crystalline form CSI the crystalline form CSIII, or any combination thereof provided in the present invention in the preparation of MET, VEGFR1 / 2/3, ROS1, RET, AXL, NTRK, and KIT inhibitor pharmaceutical preparations.
  • the present invention provides a preparation method of the crystalline form M2 of the compound I.
  • the preparation method includes the steps of dissolving the solid of the compound I or a mixed solid of cabozantinib and (S) -malic acid in a positive solvent. Then, an anti-solvent was added, and the solid was precipitated, and the solid was dried under the condition of relative humidity of more than 30% to obtain a crystalline form M2.
  • the positive solvent is an organic acid or a mixed solvent of an organic acid and an aromatic hydrocarbon
  • the antisolvent is an aromatic hydrocarbon or an ester or an alcohol or a ketone or a mixed solvent of an aromatic hydrocarbon and an ester or an aromatic hydrocarbon and Ketones mixed solvents
  • X-ray powder diffraction of the crystal form M2 at diffraction angles 2 ⁇ values of 8.6 ° ⁇ 0.2 °, 12.6 ° ⁇ 0.2 °, 20.2 ° ⁇ 0.2 °, 23.4 ° ⁇ 0.2 °, 26.1 ° ⁇ 0.2
  • the organic acid is acetic acid
  • the aromatic hydrocarbon is toluene
  • the ester is ethyl acetate or isopropyl acetate
  • the ketone is methyl isobutyl ketone
  • the alcohol is Isopropanol or n-propanol.
  • the temperature of the solvent system when the anti-solvent is added is lower than 15 ° C; preferably, the temperature of the solvent system when the anti-solvent is added is -5 ° C to 10 ° C.
  • M2 seeds may be added before the antisolvent is added; the amount of the seeds is 1 wt% to 10 wt%.
  • volume ratio of the normal solvent and the anti-solvent is 1: 1 to 1:10; preferably, the volume ratio of the normal solvent and the anti-solvent is 2: 5.
  • the process for preparing the crystalline form M2 provided by the present invention has the advantages of good controllability and strong process scalability. It can be seen from the comparative examples that the crystalline form M2 is not prepared but the crystalline form N-1 of CN102388024A is obtained by repeating the preparation method of the prior art.
  • the M2 obtained by the preparation method of the crystalline form M2 provided by the present invention has the advantages of high yield, low solvent residue, and uniform particle distribution. Such a preparation method not only saves costs, but also obtains high-quality raw drug substances. The production of new drugs provides new and better options, and has very important value for the development of this drug.
  • the "stirring" is completed by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm and mechanical stirring It is preferably 100-300 rpm.
  • the "separation” is performed by a conventional method in the art, such as centrifugation or filtration.
  • the operation of “centrifugation” is: placing the sample to be separated in a centrifuge tube, and centrifuging at a speed of 10,000 rpm, until all the solids sink to the bottom of the centrifuge tube.
  • the "drying” may be performed at room temperature or higher.
  • the drying temperature is from room temperature to about 60 ° C, or to 40 ° C, or to 50 ° C.
  • the drying time can be 2-48 hours, or overnight. Drying takes place in a fume hood, blast oven or vacuum oven.
  • volatilization is completed by a conventional method in the art. For example, slow volatilization is to seal the container with a sealing film, puncture the holes, and leave to volatilize; fast volatilization is to volatilize the container by leaving it open.
  • the "cooling down” is performed by conventional methods in the art, such as slow cooling down and rapid cooling down.
  • Slow cooling is usually performed at 0.1 ° C / minute.
  • Rapid temperature reduction is usually to directly transfer samples from an environment that is not lower than room temperature, such as in a refrigerator for cooling.
  • crystalline or “polymorphic form” means confirmed by X-ray powder diffraction pattern characterization.
  • X-ray powder diffraction pattern characterization e.g., crystalline or polymorphic form.
  • the physical and chemical properties discussed herein can be characterized, and the experimental error thereof depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray powder diffraction pattern usually changes with different instrument conditions.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with changes in experimental conditions, so the order of the intensity of the diffraction peaks cannot be the sole or decisive factor.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystals.
  • the diffraction peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the diffraction peak position is usually 5% or less. The errors of these positions should also be taken into account, and usually an error of ⁇ 0.2 ° is allowed.
  • the overall shift of the diffraction peak angle may be caused, and a certain shift is usually allowed.
  • the X-ray powder diffraction pattern of one crystal form in the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiment referred to herein.
  • the crystal forms of the same or similar X-ray powder diffraction patterns belong to the scope of the present invention.
  • Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
  • the crystalline Form CSI, Form CSIII of the present invention is pure, and essentially no other crystalline forms are mixed.
  • substantially absent when used to refer to a new crystalline form means that this crystalline form contains less than 20% by weight of other crystalline forms, especially refers to less than 10% by weight of other crystalline forms, and even less Other crystal forms at less than 5% by weight, and more less than 1% by weight.
  • FIG. 1 is an XRPD pattern of crystal CSI in Example 1.
  • FIG. 1 is an XRPD pattern of crystal CSI in Example 1.
  • FIG. 2 is a TGA diagram of crystalline CSI in Example 1.
  • FIG. 2 is a TGA diagram of crystalline CSI in Example 1.
  • FIG. 3 is a DSC chart of crystal CSI in Example 1.
  • FIG. 4 is a 1 H NMR chart of crystalline form CSI in Example 1.
  • FIG. 4 is a 1 H NMR chart of crystalline form CSI in Example 1.
  • FIG. 5 is an XRPD pattern of crystal CSI in Example 2.
  • FIG. 6 is an XRPD pattern of the crystalline form CSIII in Example 3.
  • FIG. 6 is an XRPD pattern of the crystalline form CSIII in Example 3.
  • FIG. 7 is an XRPD pattern of the crystalline form CSIII in Example 4.
  • FIG. 8 is an XRPD pattern of the crystal form M2 in Example 10.
  • FIG. 9 is a PSD diagram of a crystal form M2 in Example 10.
  • FIG. 10 is a DVS diagram of the crystal form M2 in Example 10.
  • FIG. 11 is an XRPD pattern of the crystal form M2 in Example 11.
  • FIG. 12 is an XRPD pattern of the crystal form M2 in Example 12.
  • Example 13 is an XRPD pattern of the crystal form M2 in Example 14.
  • Figure 14 is an XRPD pattern of the solid obtained after 2 hours of stirring in the comparative example
  • Fig. 15 is an XRPD pattern of the solid obtained after the stirring of the comparative example for 30 hours
  • PSD particle size distribution
  • the X-ray powder diffraction patterns of Examples 1-4, 10-11, 13-14 and Comparative Examples according to the present invention were collected on a Bruker D2 PHASER X-ray powder diffraction apparatus.
  • the X-ray powder diffraction method parameters of the present invention are as follows:
  • the X-ray powder diffraction pattern of Example 12 according to the present invention was collected on a Bruker D8 Discover Ray powder diffractometer.
  • the X-ray powder diffraction method parameters of the present invention are as follows:
  • the differential scanning calorimetry (DSC) map according to the present invention was collected on a TA Q2000.
  • the method parameters of the DSC according to the present invention are as follows:
  • thermogravimetric analysis (TGA) map according to the present invention was collected on a TA Q500.
  • the method parameters of the TGA according to the present invention are as follows:
  • Nuclear magnetic resonance proton data ( 1 H NMR) were collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg / mL.
  • HPLC high-performance liquid chromatography
  • HPLC method parameters for testing the solubility according to the present invention are as follows:
  • Chromatographic column Waters Xbridge C18 150 ⁇ 4.6mm, 5 ⁇ m
  • the elution gradient is as follows:
  • Microtrac S3500 The particle size distribution results described in the present invention are collected on a Microtrac S3500 laser particle size analyzer.
  • Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system. This test uses the wet method, and the test dispersion medium is Isopar.
  • SDC Sample Delivery Controller
  • the method parameters of the laser particle size analyzer are as follows:
  • the flow rate 60% is 60% of 65 ml / sec.
  • the dynamic moisture adsorption (DVS) map of the present invention is collected on an Intrinsic dynamic moisture adsorption instrument produced by SMS (Surface Measurement Systems) Ltd.
  • the instrument control software is DVS-Intrinsic control software.
  • the method parameters of the dynamic moisture adsorption meter are as follows:
  • Relative humidity range 0% RH-95% RH
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30 ° C.
  • the cabozantinib and / or its salt as a raw material includes, but is not limited to, a solid form (crystalline or amorphous), an oily form, a liquid form, and a solution.
  • Compound I and / or a salt thereof as a raw material is in a solid form.
  • Cabozantinib and / or its salts used in the following examples can be prepared according to the prior art, for example, according to the method described in the document CN102388024A.
  • the resulting solid was XRPD / TGA / DSC / 1 H NMR characterization test, which XRPD pattern as shown in Figure 1, the data shown in Table 1. XRPD.
  • the TGA has a mass loss of about 8.5% when heated to 150 ° C., corresponding to the removal of the acetic acid solvent during heating, and the crystalline form CSI is an acetic acid solvate.
  • DSC shows an endothermic peak near 114 ° C, an exothermic peak near 141 ° C, and an endothermic peak near 168 ° C.
  • the obtained solid was tiled on a variable temperature stage, the stage was placed in a closed cavity, and the temperature was raised to 100 ° C under a nitrogen purge, and then cooled to 30 ° C to obtain a white crystalline solid.
  • Simulated gastrointestinal fluids such as FaSSIF (simulated fasting intestinal fluid) and FeSSIF (simulated fasting intestinal fluid) are biologically related media. Such media can better reflect the effect of the gastrointestinal physiological environment on drug release. The solubility tested in the medium is closer to the solubility in the human environment.
  • the crystalline form CSI of the present invention is prepared from the starting material, and the chemical purity of the starting form and the crystalline form CSI of the present invention is measured by HPLC.
  • the test results show that the crystalline form CSI is prepared from the starting material, and the purity of the obtained crystalline form CSI is improved. It is obvious that the contents of various impurities are reduced, which indicates that the crystalline form CSI of the present invention has better purification effect.
  • the Compressibility Index or Carr Index can usually be used to evaluate the fluidity of the powder or intermediate particles.
  • the compressibility coefficient is the standard reference for the definition of powder flowability. United States Pharmacopoeia USP1174, see Table 7 for details.
  • the obtained solid was tested, the chemical purity was 99.77%, the acetic acid residue was less than 1250 ppm, the toluene residue was 325 ppm, the isopropyl acetate residue was 756 ppm, and the n-heptane residue was 2324 ppm, which met the ICH requirements.
  • the obtained solid particle size distribution diagram is shown in FIG. 9, and the crystal particle size D90 is 244.3um, and the distribution is basically normal, indicating that the particle size is more uniform. Larger particle size is beneficial for product filtration and separation.
  • the DVS of the obtained solid is shown in Figure 10. From the DVS chart, it can be seen that when the humidity is lower than 30% RH, the crystal form M2 is rapidly dehydrated, and the crystal water may be removed, so the drying humidity needs to be kept high At 30% RH.
  • Compound I was weighed into a 10 mL glass bottle, and a mixed solvent of acetic acid and toluene was added to dissolve it. The resulting solution was filtered into a 20 mL glass bottle, and the temperature was lowered to 5 ° C. To this solution was slowly added n-propanol or isopropanol or methyl isobutyl ketone (MIBK) or ethyl acetate or isopropyl acetate as an anti-solvent. After the solid was precipitated, the solid was separated by filtration. The solid was dried in a blast oven at 40 ° C (humidity is not less than 40% RH) to obtain the target crystal form M2.
  • MIBK n-propanol or isopropanol or methyl isobutyl ketone
  • Comparative Example WO2015177758A1 discloses a method for preparing crystal form M2

Abstract

本发明涉及卡博替尼苹果酸盐的新晶型、卡博替尼苹果酸盐的制备方法，以及含有卡博替尼苹果酸盐的新晶型的药物组合物，以及卡博替尼苹果酸盐的新晶型在制备制备MET、VEGFR1/2/3、ROS1、RET、AXL、NTRK、KIT抑制剂和治疗甲状腺癌、肺癌、肾癌、肝癌等癌症药物制剂中的用途。本发明提供的卡博替尼苹果酸盐晶型比现有技术具有一种或多种改进的性质，本发明提供的卡博替尼苹果酸盐的制备方法与现有技术相比成本更低、获得的产品质量更好，对未来该药物的优化和开发具有重要价值。

Description

卡博替尼苹果酸盐晶型及其制备方法和用途 技术领域
本发明涉及药物化学领域。具体而言，涉及卡博替尼苹果酸盐的晶型、卡博替尼苹果酸盐的晶型的制备方法以及卡博替尼苹果酸盐晶型的用途。
背景技术
卡博替尼(cabozantinib)是由Exelixis公司研发的抗癌药物，其用于治疗转移性甲状腺髓样癌、肾癌的适应症分别于2012年11月和2016年4月获FDA批准，此外，其用于治疗肝癌的适应症也于2019年1月获得FDA批准。卡博替尼以(S)-苹果酸盐的形式上市。
卡博替尼的(S)-苹果酸盐的化学名称为N-(4-{[6,7-双(甲基氧基)喹啉-4-基]氧基}苯基)-N’-(4-氟苯基)环丙烷-1,1-二甲酰胺(S)-苹果酸盐，(以下称为“化合物I”或卡博替尼(S)-苹果酸盐)，其结构式如下：
Figure PCTCN2019106847-appb-000001
晶型是化合物分子在微观结构中三维有序排列而形成晶格的固体，药物多晶型现象是指药物存在两种或两种以上的不同晶型。因为理化性质不同，药物的不同晶型可能在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效和安全性。特别是对难溶性固体药物，晶型的影响会更大。因此，药物晶型必然是药物研究的重要内容，也是药物质量控制的重要内容。
目前，虽有关于化合物I的晶型的报道，但已经报道的晶型性质尚不够完善，仍存在一些问题，如CN102388024A公开了化合物I的N-1结晶型、N-2结晶型以及非晶型，专利数据显示N-2结晶相比于非晶及N-1结晶具有更好的稳定性，但是其溶解度较低，流动性、可压性、抗张强度、黏附性较差。WO2015177758A1公开了化合物I的晶型M1，晶型M2，晶型M3和晶型 M4，其中晶型M4为较优的晶型，但是该晶型同样存在溶解度低，流动性、可压性、抗张强度、黏附性较差的问题。因此，仍需要进行大量的实验研究来提供更多的性质更好的晶型，以支持化合物I药物的开发。
为克服现有技术的缺点，本申请的发明人意外发现了本发明提供的化合物I晶型CSI和晶型CSIII，其在理化性质，制剂加工性能及生物利用度等方面具有优势，例如在熔点，溶解度，引湿性，提纯作用，稳定性，黏附性，可压性，流动性，体内外溶出，生物有效性等方面中的至少一方面存在优势，特别是溶解度高，流动性、抗张强度、黏附性好，为含化合物I的药物的开发提供了新的更好的选择，具有非常重要的意义。
此外，申请人在研究现有技术晶型时发现，WO2015177758A1公开的晶型M2(以下称为“晶型M2”)的制备方法重复性差，工艺难以控制，因此，开发出稳定可控的制备高质量晶型M2的工艺对化合物I药物的开发同样具有重要价值。
发明内容
本发明的主要目的是提供化合物I的新晶型及化合物I的晶型的制备方法和用途。
根据本发明的目的，本发明提供化合物I的晶型CSI(以下称作“晶型CSI”)。
一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射在衍射角2θ值为8.5°±0.2°、12.7°±0.2°、13.9°±0.2°处有特征峰。
进一步地，所述晶型CSI的X射线粉末衍射在衍射角2θ值为12.1°±0.2°、17.9°±0.2°、19.9°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射在衍射角12.1°±0.2°、17.9°±0.2°、19.9°±0.2°中的3处有特征峰。
进一步地，所述晶型CSI的X射线粉末衍射在衍射角2θ值为14.9°±0.2°、16.7°±0.2°、25.5°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射在衍射角14.9°±0.2°、16.7°±0.2°、25.5°±0.2°中的3处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射在衍射角2θ值为8.5°±0.2°、12.7°±0.2°、13.9°±0.2°、12.1°±0.2°、17.9°±0.2°、19.9°±0.2°、14.9°±0.2°、16.7°±0.2°、25.5°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。
进一步地，所述晶型CSI为乙酸溶剂合物。
非限制性地，晶型CSI的X射线粉末衍射谱图如图1所示。
根据本发明的目的，本发明还提供所述晶型CSI的制备方法，所述制备方法包括如下两种:
方法一：将化合物I固体溶解于乙酸或乙酸和芳香烃类的混合体系中，在50-80℃条件下快速挥发得到；
方法二：将化合物I固体溶解于乙酸、乙酸和芳烃类的混合溶剂、乙酸和烷烃类的混合溶剂或乙酸和水的混合溶剂中，边搅拌边向所配制的溶液中加入芳烃类、烷烃类、酯类或酮类有机溶剂，析出的固体即为晶型CSI。
进一步地，方法一中所述芳香烃类为甲苯，所述乙酸和甲苯的体积比为2:1-1:3，优选为1:1。
进一步地，方法二中所述乙酸和芳烃类、乙酸和烷烃类、乙酸和水的体积比均为2:1-1:3，优选为1:1。
更进一步地，方法二中所述芳香烃类为甲苯，所述烷烃类为正庚烷，所述酯类为乙酸异丙酯，所述酮类为甲基异丁基酮。
更进一步地，方法二中所述搅拌在0-5℃下进行。
根据本发明的目的，本发明提供化合物I的晶型CSIII(以下称作“晶型CSIII”)。
一方面，使用Cu-Kα辐射，所述晶型CSIII的X射线粉末衍射在衍射角2θ值为8.5°±0.2°、21.3°±0.2°、23.0°±0.2°处有特征峰。
进一步地，所述晶型CSIII的X射线粉末衍射在衍射角2θ值为14.4°±0.2°、17.8°±0.2°、12.6°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSIII的X射线粉末衍射在衍射角14.4°±0.2°、17.8°±0.2°、12.6°±0.2°中的3处有特征峰。
进一步地，所述晶型CSIII的X射线粉末衍射在衍射角2θ值为20.5°±0.2°、24.0°±0.2°、16.4°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSIII的X射线粉末衍射在衍射角20.5°±0.2°、24.0°±0.2°、16.4°±0.2°中的3处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSIII的X射线粉末衍射在衍射角2θ值为8.5°±0.2°、21.3°±0.2°、23.0°±0.2°、14.4°±0.2°、17.8°±0.2°、12.6°±0.2°、20.5°±0.2°、24.0°±0.2°、16.4°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。
非限制性地，晶型CSIII的X射线粉末衍射谱图如图6所示。
根据本发明的目的，本发明还提供所述晶型CSIII的制备方法，所述制备方法包括如下两种:
方法一：将化合物I固体溶解于酸类或酸类和芳烃类、酸类和烷烃类、酸类和水的混合体系中，然后边搅拌边向所配制的溶液中加入芳烃类、烷烃类、酯类或酮类有机溶剂，析出 固体，过滤分离固体，并将所得固体在芳烃类和水的混合溶剂体系中打浆，再次分离固体，所得到固体为晶型CSIII；
方法二：
步骤一：取化合物I固体溶于酸类溶剂中，加热搅拌直至固体完全溶解，随后自然冷却至室温，过滤；
步骤二：然后向澄清溶液中滴加芳香烃类有机溶剂，再转移至0-10℃条件下继续搅拌，过滤分离固体，干燥；
步骤三：在氮气吹扫下升温至50-100℃，再降温至30℃，所得到固体为晶型CSIII。
进一步地，方法一中所述酸类和芳烃类、酸类和烷烃类、酸类和水的体积比为2:1-1:3，优选为1:1。
进一步地，方法一中所述酸类为乙酸，所述芳香烃类优选为甲苯，所述烷烃类优选为正庚烷，所述酯类优选为乙酸异丙酯，所述酮类优选为甲基异丁基酮。
更进一步地，方法二中所述酸类为乙酸，所述芳香烃类为甲苯。
进一步地，方法二的步骤一中所述搅拌在80℃下进行，步骤二中所述搅拌在5℃下进行，步骤二中所述搅拌时间为10-20小时，步骤三中所述升温温度至100℃。
进一步地，方法二的步骤二中所述搅拌时间为15小时。
本发明提供的晶型CSI具有以下有益效果：
(1)与现有技术相比，本发明晶型CSI具有更高的溶解度。在具体的实施例中，本发明晶型CSI在水中的溶解度是现有技术晶型N-2的两倍，是现有技术晶型M4的5倍以上。
卡博替尼是水溶性差的药物，属于BCS II。更高的溶解度有利于提高药物在人体内的吸收，提高生物利用度，使药物发挥更好的治疗作用；另外，更高的溶解度能够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。
(2)本发明的晶型CSI具有较好的提纯作用。由原料制备成本发明晶型后纯度具有较大的提高。在具体的实施例中，本发明使用的原料经一次结晶制备得到晶型CSI后，纯度有明显提升，且各个杂质含量均有所降低。
药物的化学纯度对于保证药物的疗效和安全性、防止药物不良反应的发生具有重要意义。如药物中含有超过限量的杂质，就有可能使理化参数变化，外观性状产生变异，并影响药物的稳定性；杂质增多也使药物含量明显偏低或活性降低，毒副作用显著增加,因此，不同的药物法规都对杂质含量有严格的要求。提纯作用好的晶型在结晶工艺中能够体现出极强的杂 质排除能力，使得通过结晶就能得到纯度较高的原料药，有效的克服了药物纯度低带来的药物稳定性低、疗效差、毒性高等缺点。
本发明提供的晶型CSIII具有以下有益效果：
与现有技术相比，本发明晶型CSIII具有更高的溶解度。特别是在FeSSIF和水中，溶解度均是现有技术晶型N-2和现有技术晶型M4的2倍及2倍以上。
卡博替尼是水溶性差的药物，属于BCS II。更高的溶解度有利于提高药物在人体内的吸收，提高生物利用度，使药物发挥更好的治疗作用；另外，更高的溶解度能够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。
进一步地，本发明提供的晶型CSIII还具有以下有益效果：
(1)与现有技术相比，本发明晶型CSIII具有更好的流动性。流动性评价结果表明，晶型CSIII流动性明显优于现有技术晶型。更好的流动性可以避免堵塞生产设备，提升生产效率；晶型CSIII更好的流动性能保证制剂的混合均匀度及含量均匀度、降低制剂的重量差异，提升产品质量。
(2)与现有技术相比，本发明提供的晶型CSIII具有更优的可压性。晶型CSIII好的可压性可以有效改善压片工艺中的硬度/脆碎度不合格、裂片等问题，使制剂工艺更为可靠，改善产品外观，提升产品质量。更优的可压性亦可提升压片速度进而提升生产效率，同时可减少用于改善可压性的辅料的成本支出。
(3)与现有技术相比，本发明晶型CSIII具有更低的黏附性。黏附性评价结果表明，晶型CSIII的吸附量远低于现有技术晶型的吸附量。晶型CSIII更低的黏附性可有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于改善产品外观、重量差异等。此外，晶型CSIII更低的黏附性还能有效减少原料的团聚现象，减少物料和器具之间的吸附，利于原料的分散及与其他辅料的混合，增加物料混合时的混合均匀度及最终产品的含量均匀度。
根据本发明的目的，本发明还提供一种药物组合物，所述药物组合物包含有效治疗量的晶型CSI、晶型CSIII或两种晶型的任意混合及药学上可接受的载体、稀释剂或辅料。
进一步地，本发明提的晶型CSI、晶型CSIII，或它们的任意混合在制备MET、VEGFR1/2/3、ROS1、RET、AXL、NTRK、KIT抑制剂药物制剂中的用途。
更进一步地，本发明提供的晶型CSI、晶型CSIII，或它们的任意混合在制备治疗甲状腺癌、肺癌、胃癌、肝癌药物制剂中的用途。
根据本发明的目的，本发明提供化合物I的晶型M2的制备方法，所述制备方法包括如下步骤：将化合物I固体或卡博替尼与(S)-苹果酸的混合固体溶于正溶剂中，然后加入反溶剂，析出固体后将固体在大于30％相对湿度条件下干燥得到晶型M2。所述正溶剂为有机酸或有机酸和芳香烃类的混合溶剂；所述反溶剂为芳香烃类或酯类或醇类或酮类或芳香烃类和酯类的混合溶剂或芳香烃类和酮类的混合溶剂；所述晶型M2的X射线粉末衍射在衍射角2θ值为8.6°±0.2°,12.6°±0.2°,20.2°±0.2°,23.4°±0.2°,26.1°±0.2°处具有特征峰。
进一步地，所述有机酸类为乙酸；所述芳香烃类为甲苯；所述酯类为乙酸乙酯或乙酸异丙酯；所述酮类为甲基异丁基酮；所述醇类为异丙醇或正丙醇。
进一步地，加入反溶剂时溶剂体系的温度低于15℃；优选的，加入反溶剂时溶剂体系的温度为-5℃-10℃。
进一步地，加入反溶剂前可加入M2晶种；所述晶种量为1wt％至10wt％。
更进一步地，所述正溶剂和反溶剂的体积比为1:1至1:10；优选的，所述正溶剂和反溶剂的体积比为2:5。
本发明提供的晶型M2的制备方法工艺与现有技术制备方法相比，具有可控性好，工艺可放大性强的优势。结合对比例可以看出，重复现有技术制备方法，并未制备得到晶型M2，而是获得了CN102388024A的晶型N-1。此外本发明提供的晶型M2制备方法获得的M2具有收率高、溶剂残留低、颗粒分布均匀的优点，这样的制备方法不仅节约成本，且获得的原料药质量高，对卡博替尼药物的生产制备提供了新的更好的选择，对该药物的开发具有非常重要的价值。
本发明中，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，其中，磁力搅拌优选为300-900转/分钟，机械搅拌优选为100-300转/分钟。
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。
所述“干燥”可以在室温或更高的温度下进行。干燥温度为室温到约60℃，或者到40℃，或者到50℃。干燥时间可以为2-48小时，或者过夜。干燥在通风橱、鼓风烘箱或真空烘箱里进行。
所述“挥发”，采用本领域的常规方法完成，例如缓慢挥发是将容器封上封口膜，扎孔，静置挥发；快速挥发是将容器敞口放置挥发。
所述“降温”，采用本领域的常规方法完成，例如缓慢降温和快速降温。缓慢降温通常以0.1℃/分钟进行。快速降温通常是将样品从不低于室温的环境直接转移如冰箱中进行降温操作。
本发明中，“晶体”或“多晶型”指被X射线粉末衍射图表征证实的。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射线粉末衍射图通常会随着仪器条件的不同而有所改变。特别需要指出的是，X射线粉末衍射图中衍射峰的相对强度也可能随着实验条件的变化而变化，所以衍射峰强度的顺序不能作为唯一或决定性因素。事实上，X射线粉末衍射图中衍射峰的相对强度与晶体的择优取向有关，本文所示的衍射峰强度为说明性而非用于绝对比较。另外，衍射峰位置的实验误差通常在5％或更少，这些位置的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成衍射峰角度的整体偏移，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射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射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X射线粉末衍射图和一个未知晶型的X射线粉末衍射图相比较，以证实这两组图反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型CSI、晶型CSIII是纯的，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。
本发明中术语“约”，当用来指可测量的数值时，例如化合物和制剂的质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。
附图说明
图1为实施例1中晶型CSI的XRPD图
图2为实施例1中晶型CSI的TGA图
图3为实施例1中晶型CSI的DSC图
图4为实施例1中晶型CSI的 1H NMR图
图5为实施例2中晶型CSI的XRPD图
图6为实施例3中晶型CSIII的XRPD图
图7为实施例4中晶型CSIII的XRPD图
图8为实施例10中晶型M2的XRPD图
图9为实施例10中晶型M2的PSD图
图10为实施例10中晶型M2的DVS图
图11为实施例11中晶型M2的XRPD图
图12为实施例12中晶型M2的XRPD图
图13为实施例14中晶型M2的XRPD图
图14为对比例搅拌2小时后得到的固体的XRPD图
图15为对比例继续搅拌30小时后得到的固体的XRPD图
具体实施方式
本发明进一步参考以下实施例限定，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
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
DVS：动态水分吸附
1H NMR：液态核磁氢谱
PSD：粒径分布
HPLC：高效液相色谱
采集数据所用的仪器及方法：
本发明所述的实施例1-4,10-11,13-14以及对比例的X射线粉末衍射图在Bruker D2 PHASER 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射线光源：Cu,Kα
Kα1
Figure PCTCN2019106847-appb-000002
1.54060；Kα2
Figure PCTCN2019106847-appb-000003
1.54439
Kα2/Kα1强度比例：0.50
电压：30千伏特(kV)
电流：10毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的实施例12的X射线粉末衍射图在Bruker D8 Discover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射线光源：Cu,Kα
Kα1
Figure PCTCN2019106847-appb-000004
1.54060；Kα2
Figure PCTCN2019106847-appb-000005
1.54439
Kα2/Kα1强度比例：0.50
电压：40仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自4.0至40.0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 Q500上采集。本发明所述的TGA的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。
本发明中高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为安捷伦紫外检测器(VWD)。
本发明所述的测试溶解度的HPLC方法参数如下：
1、色谱柱：Waters Xbridge C18 150×4.6mm,5μm
2、流动相：A：0.1％TFA水溶液
           B：0.1％TFA乙腈溶液
洗脱梯度如下：
Figure PCTCN2019106847-appb-000006
Figure PCTCN2019106847-appb-000007
3、流速：1mL/min
4、进样量：5μL
5、检测波长：紫外250nm
6、柱温：40℃
7、稀释剂：ACN/H 2O(9:1,v/v)
本发明中所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G。所述的激光粒度分析仪的方法参数如下：
Figure PCTCN2019106847-appb-000008
*：流速60％为65毫升/秒的60％。
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。仪器控制软件是DVS-Intrinsic control software。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N 2,200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
除非特殊说明，以下实施例均在室温条件下操作。所述“室温”不是特定的温度值，是指10-30℃温度范围。
根据本发明，作为原料的所述卡博替尼和/或其盐包括但不限于固体形式(结晶或无定形)、油状、液体形式和溶液。优选地，作为原料的化合物I和/或其盐为固体形式。
以下实施例中所使用的卡博替尼和/或其盐可根据现有技术制备得到，例如根据 CN102388024A文献所记载的方法制备获得。
实施例1 晶型CSI的制备方法：
称取100.5mg化合物I，然后加入10.0mL乙酸和甲苯(1:1,v/v)的混合溶剂，在50℃条件下磁力搅拌至固体完全溶解。将所得的澄清溶液放置于50℃条件下静置挥发，约15天后得到固体样品。
所得固体进行XRPD/TGA/DSC/ 1H NMR测试表征，其XRPD图如附图1所示，XRPD数据如表1所示。
其TGA、DSC和 1H NMR表征结果如下：
TGA如附图2所示，将其加热至150℃时，具有约8.5％的质量损失，对应加热过程中脱去乙酸溶剂，晶型CSI为乙酸溶剂合物。
DSC如附图3所示，在114℃附近出现一个吸热峰，随后在141℃附近出现一个放热峰，然后在168℃附近出现一个的吸热峰。
该晶型的 1H NMR表征结果如附图4所示，出峰结果与该化合物结构吻合(C 28H 24FN 3O 5·C 4H 6O 5),其中苹果酸的3个活泼氢未出峰，化学位移为1.91处的氢对应所含乙酸的非活泼氢。具体出峰为： 1H NMR(400MHz,DMSO-d6)δ10.17(s,1H),10.04(s,1H),8.47(d,J＝5.2Hz,1H),7.76(d,J＝8.9Hz,2H),7.64(dd,J＝9.1,5.1Hz,2H),7.51(s,1H),7.39(s,1H),7.23(d,J＝9.0Hz,2H),7.15(t,J＝8.9Hz,2H),6.43(d,J＝5.2Hz,1H),4.25(dd,J＝7.7,5.0Hz,1H),3.94(d,J＝5.2Hz,6H),2.61(dd,J＝15.7,5.0Hz,1H),2.43(dd,J＝15.7,7.7Hz,1H),1.91(s,2H),1.48(s,4H)。
表1
衍射角2θ 晶面间距(d值) 强度％
8.32 10.63 34.68
8.48 10.43 39.04
11.65 7.60 11.38
12.11 7.31 43.70
12.65 7.00 100.00
13.92 6.36 42.79
14.88 5.95 20.65
16.36 5.42 18.36
16.67 5.32 20.44
17.89 4.96 25.60
19.85 4.47 29.93
21.16 4.20 9.05
23.83 3.73 33.28
25.47 3.50 24.33
26.54 3.36 22.29
27.04 3.30 22.31
28.25 3.16 4.16
29.70 3.01 6.08
32.06 2.79 4.80
实施例2 晶型CSI的制备方法
称取2033.1mg化合物I，然后加入6.0mL乙酸，在50℃条件下磁力搅拌至固体完全溶解。待溶液自然冷却至室温后，过滤得到澄清的乙酸溶液。室温下，边搅拌边向澄清溶液中加入甲苯，每次1.0mL，共加入20.0mL。将所得的悬浊液转移至5℃继续搅拌约24小时。分离析出的固体样品。
经XRPD表征，所得固体的晶型为CSI，相应的XRPD图及XRPD数据见附图5和表2。
表2
衍射角2θ 晶面间距(d值) 强度％
8.31 10.64 38.02
8.47 10.44 39.75
11.63 7.61 18.09
12.08 7.33 100.00
12.65 7.00 79.41
13.92 6.36 73.94
14.88 5.95 14.14
15.61 5.68 3.84
16.36 5.42 15.49
16.67 5.32 22.24
17.00 5.22 9.61
17.47 5.08 19.47
17.79 4.98 25.15
17.88 4.97 24.06
18.17 4.88 11.89
19.85 4.47 41.93
21.32 4.16 4.34
23.47 3.79 9.51
23.83 3.73 9.04
24.31 3.66 3.77
25.08 3.55 3.52
25.48 3.49 13.01
26.99 3.30 6.33
29.63 3.01 4.49
32.09 2.79 4.09
实施例3 晶型CSIII的制备
称取5.1g化合物I固体溶于25.0mL乙酸中，在100℃搅拌至固体完全溶解，待溶液冷却至室温后加入25.0mL甲苯。在室温下过滤得到澄清溶液，转移至反应釜中继续冷却至0℃。然后加入52.1mg的晶种，机械搅拌熟化1.5小时，再继续加入50.0mL的乙酸异丙酯，搅拌20小时后分离固体。将分离出的固体转移至100.5mL的甲苯和水(200:1,v/v)中打浆约2分钟，再分离出固体。
经XRPD表征，所得固体的晶型为CSIII，其XRPD图如附图6所示，XRPD数据如表3所示。
表3
衍射角2θ 晶面间距(d值) 强度％
8.57 10.32 80.15
12.68 6.98 100.00
14.37 6.16 52.82
14.90 5.95 15.34
16.44 5.39 18.43
17.24 5.14 21.60
17.86 4.97 40.50
18.67 4.75 17.60
20.43 4.35 62.33
21.34 4.16 30.84
22.99 3.87 40.83
24.00 3.71 88.06
25.75 3.46 45.21
26.76 3.33 73.15
27.40 3.25 48.68
28.74 3.11 10.75
29.92 2.99 21.38
32.95 2.72 10.42
35.85 2.50 3.74
实施例4 晶型CSIII的制备
称取493.1mg的化合物I固体溶于1.5mL的乙酸中，在80℃下磁力搅拌直至固体完全溶解，随后自然冷却至室温，过滤得到澄清溶液。向澄清溶液中，边搅拌边滴加甲苯，共计加入5.0mL，再转移至5℃条件下继续搅拌。大约搅拌15小时后，过滤分离固体，并转移至60℃/75％RH(相对湿度)条件下放置过夜。
将所得到的固体平铺在变温载物台上，载物台置于密闭的腔体内，在氮气吹扫下升温至100℃，然后冷却至30℃即可得到白色结晶固体。
经XRPD表征，所得固体的晶型为CSIII，其XRPD图如附图7所示，XRPD数据如表4所示。
表4
衍射角2θ 晶面间距(d值) 强度％
4.22 20.93 5.98
6.28 14.08 13.11
8.53 10.37 56.71
12.68 6.98 100.00
14.37 6.16 39.31
16.39 5.41 21.73
17.20 5.15 14.08
17.86 4.97 59.77
17.96 4.94 50.93
18.74 4.74 21.46
19.66 4.52 28.03
20.57 4.32 64.19
21.30 4.17 35.73
23.13 3.84 53.35
24.01 3.71 66.94
24.21 3.68 64.51
25.76 3.46 25.61
27.09 3.29 40.08
29.65 3.01 10.62
30.46 2.93 7.42
32.53 2.75 5.43
33.20 2.70 5.33
实施例5 动态溶解度研究
模拟胃肠道液体例如FaSSIF(模拟禁食状态肠液)、FeSSIF(模拟进食状态肠液)属于生物相关介质，此类介质能更好地反映胃肠道生理环境对药物释放产生的影响，在此类介质中测试的溶解度与人体环境中的溶解度更加接近。
取本发明的晶型CSI及现有技术晶型各20mg分散在1.5mL的水配制成饱和溶液，平衡1小时、4小时后分别用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表5所示。
表5
Figure PCTCN2019106847-appb-000009
取本发明的晶型CSIII及现有技术晶型各20mg分别分散在1.5mL的FaSSIF、1.5mL的FeSSIF及1.5mL的水配制成饱和溶液，平衡1小时、4小时后分别用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表6所示。
表6
Figure PCTCN2019106847-appb-000010
结果表明本发明晶型CSI、晶型CSIII与现有技术相比具有更高的溶解度。
实施例6 提纯效果研究
通过起始物制备本发明晶型CSI，采用HPLC测定起始物、本发明的晶型CSI的化学纯度，测试结果表明，由起始物料制备晶型CSI，制备获得的晶型CSI的纯度提升较为明显，各种杂质含量均有所降低，说明本发明晶型CSI具有较好的提纯效果。
实施例7 流动性研究
制剂工艺过程中，通常可采用可压性系数(Compressibility index)或卡尔系数(Carr Index)来评价粉体或中间体颗粒的流动性，测定方法为将一定量的粉体轻轻装入量筒后测量最初松体积；采用轻敲法使粉体处于最紧状态，测量最终的体积；计算松密度ρ 0与振实密度ρ f；根据公式c＝(ρ f－ρ 0)/ρ f计算可压性系数。
可压性系数对粉体流动性的界定标准参考。美国药典USP1174，详见表7。
表7
可压性系数(％) 流动性
≦10 极好
11-15 好
16-20 一般
21-25 可接受
26-31 差
32-37 很差
>38 极差
晶型CSIII和现有技术晶型的流动性评价结果见表8，结果表明晶型CSI的流动性明显优于现有技术晶型。
表8
  堆密度(g/ml) 振实密度(g/ml) 卡尔系数
晶型CSIII 0.319 0.376 15％
晶型N-2 0.194 0.256 24％
晶型M4 0.251 0.387 35％
实施例8 可压性研究
采用手动压片机进行压片，压片时，选择Φ6mm圆形平冲，分别加入80mg晶型CSIII、现有技术晶型，采用10kN的压力压制成圆形片，室温放置24h，待完全弹性复原后采用片剂硬度测定仪测试其径向破碎力(硬度，H)。采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL计算粉体的抗张强度。在一定的压力下，抗张强度越大的，表示其可压性越好。
每个样品重复三组，计算粉体的抗张强度，求平均值，结果如下表9所示。
表9
晶型 晶型CSIII 晶型N-2 晶型M4
平均抗张强度(MPa) 1.56 1.02 1.23
结果表明，与现有技术晶型相比，晶型CSIII具有更优的可压性。
实施例9 黏附性研究
分别将约30mg晶型CSIII和现有技术晶型的API加入到8mm圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉末量。采用该方法连续压制两次后，记录冲头累计的最终黏附量、压制过程中的最高黏附量和平均黏附量。具体的实验结果见表10。
表10
  最高吸附量(mg) 平均吸附量(mg)
晶型CSIII 0.06 0.045
晶型N-2 0.26 0.20
晶型M4 0.11 0.08
实验结果表明，现有技术晶型的最高吸附量是晶型CSIII的2倍以上，晶型CSIII的黏附 性优于现有技术晶型。
实施例10 晶型M2的制备
称量100.11g的化合物I于1L玻璃瓶中，加入乙酸和甲苯的混合溶剂溶解该固体，得到澄清溶液。将该溶液过滤至5L反应釜中，并降温至5-15℃。加入2.02g晶型M2晶种，熟化0.5h，然后向该悬浊液中缓慢加入乙酸异丙酯和甲苯进行反溶剂添加，析出固体后，抽滤分离固体。并将该固体置于40℃鼓风烘箱干燥(湿度30％RH-40％RH)。经检测所得固体为目标晶型M2，其X射线粉末衍射数据如图8，表11所示。
所得固体经检测，化学纯度为99.77％，乙酸溶残低于1250ppm，甲苯溶残为325ppm，乙酸异丙酯溶残为756ppm，正庚烷溶残为2324ppm，满足ICH要求。所得固体粒径分布图如图9所示，晶体粒径D90为244.3um，且基本呈正态分布，表明颗粒大小较均一。较大的颗粒粒径利于产品的过滤和分离。所得固体的动态水分吸附图(DVS)如图10所示，由DVS图可以看出，当湿度低于30％RH时，晶型M2急剧脱水，可能脱去结晶水，因此干燥湿度需保持高于30％RH。
表11
衍射角2θ d值 强度％
6.26 14.12 4.69
8.60 10.28 57.00
11.64 7.60 8.35
12.27 7.21 51.62
12.56 7.05 100.00
14.35 6.17 31.84
14.78 6.00 17.42
16.46 5.38 12.50
17.29 5.13 14.37
17.77 4.99 19.28
18.49 4.80 10.17
19.00 4.67 11.71
20.29 4.38 25.55
22.26 3.99 14.80
23.20 3.83 32.44
23.45 3.79 37.59
24.20 3.68 12.52
25.31 3.52 15.82
26.12 3.41 31.65
26.68 3.34 20.13
27.16 3.28 30.57
27.64 3.23 17.65
28.82 3.10 4.45
29.47 3.03 8.83
实施例11 晶型M2的制备
称量5.06g的化合物I于100mL玻璃瓶中，加入乙酸和甲苯溶解该固体，得到澄清溶液。将该溶液过滤至250mL反应釜中，降温至0-5℃。加入52.1mg晶型M2晶种，熟化1.5h。向该悬浊液中缓慢加入乙酸异丙酯进行反溶剂添加。待析出固体后，抽滤分离固体，并将该固体置于30℃鼓风烘箱干燥(湿度不低于40％RH)。经检测，所得固体为目标晶型M2，其X射线粉末衍射数据如图11，表12所示。所得固体化学纯度为99.77％，乙酸溶残低于1500ppm。
表12
衍射角2θ d值 强度％
3.99 22.13 23.45
4.33 20.39 22.26
6.21 14.24 13.19
8.65 10.22 81.76
11.62 7.62 10.30
12.25 7.23 46.01
12.56 7.05 100.00
14.36 6.16 41.53
14.43 6.15 36.67
14.79 5.98 22.32
16.51 5.37 21.89
17.26 5.13 20.25
17.77 4.99 25.52
18.53 4.78 11.25
19.00 4.67 21.70
20.25 4.38 34.50
20.39 4.35 36.45
20.79 4.27 28.62
22.31 3.98 26.62
22.79 3.90 27.36
23.24 3.82 50.11
23.45 3.79 53.57
24.22 3.67 17.88
25.24 3.53 19.28
26.15 3.41 51.00
26.68 3.34 26.73
27.10 3.29 36.81
27.64 3.22 25.65
28.86 3.09 7.66
29.37 3.04 13.66
29.56 3.02 15.73
32.52 2.75 5.55
实施例12 晶型M2的制备
称取约8.00g卡博替尼游离碱和2.25g(S)-苹果酸于100mL玻璃瓶中，加入乙酸和甲苯混合溶剂将其溶解，将所得溶液过滤至500mL反应釜中，降温至-5至15℃。加入约200mg晶型M2晶种，并向该悬浊液中缓慢加入乙酸异丙酯和甲苯，待析出固体后，过滤分离固体。将该固体置于40℃鼓风烘箱干燥(湿度不低于40％RH)，得到目标晶型M2。其X射线粉末衍射数据如图12，表13所示。
表13
衍射角2θ d值 强度％
8.59 10.29 87.97
11.63 7.61 9.89
12.25 7.23 52.46
12.56 7.05 100.00
14.33 6.18 46.23
14.74 6.01 24.69
16.53 5.36 27.07
17.25 5.14 23.46
17.80 4.98 27.67
19.04 4.66 30.48
20.11 4.42 38.66
20.70 4.29 37.18
22.21 4.00 34.76
22.76 3.91 43.97
23.40 3.80 94.66
24.14 3.69 19.47
25.26 3.53 31.11
26.15 3.41 70.48
26.63 3.35 43.46
27.03 3.30 61.29
27.58 3.23 34.06
28.80 3.10 10.00
29.41 3.04 26.61
31.28 2.86 4.36
32.47 2.76 11.40
38.07 2.36 7.47
实施例13 晶型M2的制备
称取约50mg化合物I于10mL玻璃瓶中，加入乙酸和甲苯的混合溶剂将其溶解，将所得溶液过滤至20mL玻璃瓶中，降温至5℃。向该溶液中缓慢加入正丙醇或异丙醇或甲基异丁基酮(MIBK)或乙酸乙酯或乙酸异丙酯作为反溶剂，待析出固体后，过滤分离固体。将该固体置于40℃鼓风烘箱干燥(湿度不低于40％RH)，得到目标晶型M2。
实施例14 晶型M2的制备
称取约493.1mg化合物I于5mL玻璃瓶中，加入1.5mL乙酸并加热至80℃使其溶解，将所得溶液冷却至室温并过滤至20mL玻璃瓶中，室温下加入5.0mL甲苯后转移至5℃搅拌过夜。过滤分离固体并在60℃/75％RH条件下干燥22h，得到目标晶型M2。其X射线粉末衍射数据如图13，表14所示。
表14
衍射角2θ d值 强度％
8.61 10.27 80.56
8.72 10.14 47.82
11.64 7.60 9.23
12.28 7.21 53.35
12.56 7.05 100.00
14.37 6.16 48.00
14.81 5.98 17.80
16.55 5.36 22.33
17.30 5.12 19.25
17.61 5.04 20.81
17.83 4.98 20.20
18.55 4.78 11.40
18.95 4.68 15.69
20.19 4.40 24.42
20.42 4.35 35.53
20.72 4.29 22.68
22.29 3.99 22.95
22.76 3.91 23.73
23.39 3.80 47.60
24.25 3.67 13.82
24.77 3.59 7.83
25.24 3.53 18.39
26.08 3.41 31.18
26.19 3.40 38.94
26.67 3.34 26.38
27.11 3.29 25.88
27.64 3.23 18.37
29.42 3.04 12.93
对比例 WO2015177758A1公开晶型M2制备方法
称取335.4mg化合物I于20mL玻璃瓶中，加入1mL丙酸并加热使其溶解，将所得溶液冷却至室温，室温下加入10mL甲基叔丁基醚后继续搅拌，约2小时后分离测试固体，得到无定形，其X射线粉末衍射数据如图14所示。继续搅拌约30小时后，分离测试固体，得到晶型N-1，其X射线粉末衍射数据如图15所示。
实验记过表明，现有技术公开的晶型M2的制备方法重复性差，难以可控的获得晶型M2。
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。

Claims (27)

  1. 一种化合物I的晶型M2的制备方法，所述制备方法包括如下步骤：将化合物I固体或卡博替尼与(S)-苹果酸的混合固体溶于正溶剂中，然后加入反溶剂，析出固体后将固体在大于30％相对湿度条件下干燥或放置得到晶型M2；所述正溶剂为有机酸或有机酸和芳香烃类的混合溶剂；所述反溶剂为芳香烃类或酯类或醇类或酮类或芳香烃类和酯类的混合溶剂或芳香烃类和酮类的混合溶剂；所述晶型M2的X射线粉末衍射在衍射角2θ值为8.6°±0.2°,12.6°±0.2°,20.2°±0.2°,23.4°±0.2°,26.1°±0.2°处具有特征峰。
    Figure PCTCN2019106847-appb-100001
  2. 根据权利要求1所述的晶型M2的制备方法，其特征在于，所述有机酸类为乙酸；所述芳香烃类为甲苯；所述酯类为乙酸乙酯或乙酸异丙酯；所述酮类为甲基异丁基酮；所述醇类为异丙醇或正丙醇。
  3. 根据权利要求1所述的晶型M2的制备方法，其特征在于，加入反溶剂时溶剂体系的温度低于15℃。
  4. 根据权利要求3所述的晶型M2的制备方法，其特征在于，加入反溶剂时溶剂体系的温度为-5℃-10℃。
  5. 根据权利要求1所述的晶型M2的制备方法，其特征在于，加入反溶剂前可加入M2晶种，所述晶种量为1wt％至10wt％。
  6. 根据权利要求1所述的晶型M2的制备方法，其特征在于，所述正溶剂和反溶剂的体积比为1:1至1:10。
  7. 根据权利要求6所述的晶型M2的制备方法，其特征在于，所述正溶剂和反溶剂的体积比为2:5。
  8. 一种化合物I的晶型CSI，其特征在于，其X射线粉末衍射图在2θ值为8.5°±0.2°、12.7°±0.2°、13.9°±0.2°处具有特征峰。
  9. 根据权利要求8所述的晶型CSI，其特征在于，其X射线粉末衍射图在2θ 值为12.1°±0.2°、17.9°±0.2°、19.9°±0.2°中的1处或2处或3处具有特征峰。
  10. 根据权利要求8所述的晶型CSI，其特征在于，其X射线粉末衍射图在2θ值为14.9°±0.2°、16.7°±0.2°、25.5°±0.2°中的1处或2处或3处具有特征峰。
  11. 权利要求8所述的晶型CSI的制备方法，其特征在于可通过如下两个方法制备得到：
    方法一：将化合物I的固体溶解于乙酸或乙酸和芳香烃类的混合体系中，在50-80℃条件下快速挥发得到；
    方法二：将化合物I的固体溶解于乙酸、乙酸和芳烃类的混合溶剂、乙酸和烷烃类的混合溶剂或乙酸和水的混合溶剂中，边搅拌边向所配制的溶液中加入芳烃类、烷烃类、酯类或酮类有机溶剂，析出的固体即为晶型CSI。
  12. 根据权利要求11所述的晶型CSI的制备方法，其特征在于，方法一中所述芳香烃类为甲苯，所述乙酸和甲苯的体积比为2:1-1:3。
  13. 根据权利要求12所述的晶型CSI的制备方法，其特征在于，所述乙酸和甲苯的体积比为1:1。
  14. 根据权利要求11所述的晶型CSI的制备方法，其特征在于，方法二中所述乙酸和芳烃类、乙酸和烷烃类、乙酸和水的体积比均为2:1-1:3。
  15. 根据权利要求11所述的晶型CSI的制备方法，其特征在于，方法二中所述芳香烃类为甲苯，所述烷烃类为正庚烷，所述酯类为乙酸异丙酯，所述酮类为甲基异丁基酮。
  16. 根据权利要求11所述的晶型CSI的制备方法，其特征在于，方法二中所述搅拌温度为0-5℃。
  17. 一种化合物I的晶型CSIII，其特征在于，其X射线粉末衍射图在2θ值为8.5°±0.2°、21.3°±0.2°、23.0°±0.2°处具有特征峰。
  18. 根据权利要求17所述的晶型CSIII，其特征在于，其X射线粉末衍射图在2θ值为14.4°±0.2°、17.8°±0.2°、12.6°±0.2°中的1处或2处或3处具有特征峰。
  19. 根据权利要求17所述的晶型CSIII，其特征在于，其X射线粉末衍射图在2θ值为20.5°±0.2°、24.0°±0.2°、16.4°±0.2°中的1处或2处或3处具有特征峰。
  20. 权利要求17所述的晶型CSIII的制备方法，其特征在于可通过如下两个方法制备得到：
    方法一：将化合物I固体溶解于酸类或酸类和芳烃类、酸类和烷烃类、酸类和水的混合体系中，然后边搅拌边向所配制的溶液中加入芳烃类、烷烃类、酯类或酮类有机溶剂，析出固体，并将所得固体在芳烃类和水的混合溶剂体系中打浆，再次分离固体，所得到固体为晶型CSIII；
    方法二：方法二包括如下三个步骤，
    步骤一：称取化合物I固体溶于酸类溶剂中，加热搅拌直至固体完全溶解，随后自然冷却至室温，过滤；
    步骤二：然后向澄清溶液中滴加芳香烃类有机溶剂，再转移至0-10℃条件下继续搅拌，过滤分离固体，干燥；
    步骤三：在氮气吹扫下升温至50-100℃，再降温至30℃，所得到固体为晶型CSIII。
  21. 根据权利要求20所述的晶型CSIII的制备方法，其特征在于，方法一中所述酸类和芳烃类、酸类和烷烃类、酸类和水的体积比为2:1-1:3。
  22. 根据权利要求20所述的晶型CSIII的制备方法，其特征在于，方法一中所述酸类为乙酸，所述芳香烃类优选为甲苯，所述烷烃类优选为正庚烷，所述酯类优选为乙酸异丙酯，所述酮类优选为甲基异丁基酮。
  23. 根据权利要求20所述的晶型CSIII的制备方法，其特征在于，方法二的步骤一中所述酸类为乙酸，步骤二中所述芳香烃类有机溶剂为甲苯。
  24. 根据权利要求20所述的晶型CSIII的制备方法，其特征在于，方法二的步骤一中所述搅拌在80℃下进行，步骤二中所述搅拌在5℃下进行，搅拌时间为10-20小时，步骤三中所述升温温度至100℃。
  25. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求8中所述的晶型CSI、权利要求17中所述的晶型CSIII或两种晶型的任意混合及药学上可接受的载体、稀释剂或赋形剂。
  26. 权利要求8中所述的晶型CSI、权利要求17中所述的晶型CSIII或两种晶型的任意混合在制备MET、VEGFR1/2/3、ROS1、RET、AXL、NTRK、KIT抑制剂药物中的用途。
  27. 权利要求8中所述的晶型CSI、权利要求17中所述的晶型CSIII或两种晶型的任意混合在制备甲状腺癌、肺癌、胃癌、肝癌药物中的用途。
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