WO2018103027A1 - 替吡法尼的晶型及其制备方法及药物组合物 - Google Patents

替吡法尼的晶型及其制备方法及药物组合物 Download PDF

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WO2018103027A1
WO2018103027A1 PCT/CN2016/108970 CN2016108970W WO2018103027A1 WO 2018103027 A1 WO2018103027 A1 WO 2018103027A1 CN 2016108970 W CN2016108970 W CN 2016108970W WO 2018103027 A1 WO2018103027 A1 WO 2018103027A1
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solvent
crystal form
solid
stirring
crystal
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PCT/CN2016/108970
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English (en)
French (fr)
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盛晓红
盛晓霞
戴燕丽
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杭州领业医药科技有限公司
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Priority to US16/467,515 priority Critical patent/US10954210B2/en
Priority to PCT/CN2016/108970 priority patent/WO2018103027A1/zh
Priority to CN201680092058.0A priority patent/CN110234639A/zh
Publication of WO2018103027A1 publication Critical patent/WO2018103027A1/zh
Priority to US17/133,508 priority patent/US11639341B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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

  • This application relates to the field of medicinal chemical crystallization technology.
  • the present application relates to crystalline forms of pirifanib, methods for their preparation, pharmaceutical compositions, and uses.
  • Tiprefonib is a farnesyltransferase inhibitor that acts on H-RAS or N-RAS mutant cells and has an anti-proliferative effect. It is capable of blocking the farnesylation of the RAS protein, thereby interfering with its localization on the inner surface of the plasma membrane and subsequent activation of downstream signaling pathways, with potent anti-tumor disease activity.
  • pirifanib is (R)-(+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chloro Phenyl) 1-methyl-2(1H)-quinolinone, English name is Tipifarnib; its chemical structural formula is as follows:
  • Patent Document CN1101392C reports the preparation of tififabine, which is a racemate and does not disclose any characterization data; the patent document CN100567292C reports the preparation of tififafab, which is a mixture of certain enantiomeric excesses and Only the melting point of the mixture is mentioned; the patent document CN1246318C reports the preparation of tifibrin and the method of resolution and purification of tififinib in the enantiomer.
  • the tipirone prepared according to the method provided in CN1246318C is in a crystalline state (indicated herein as "crystal form A"), but has the defects of low crystallinity and poor crystal form stability, and the patent The pirfenibib reported in the literature CN1101392C and CN100567292C are mixtures and lack characteristic data that accurately reflects their physical form and cannot be fully disclosed.
  • the present invention provides crystalline forms of tififafin and methods for their preparation, pharmaceutical compositions and uses comprising the crystalline forms.
  • the crystalline form is a stable crystalline solid and should have one or more improved properties, particularly in terms of crystallinity, hygroscopicity, morphology, formulation processability, crystal form stability, and the like.
  • the present invention also relates to a method for preparing the crystal form, and a package A pharmaceutical composition comprising the crystalline form and uses thereof.
  • one of the contents of the present invention is to provide a solid form of tifibrinide Form I (abbreviated as "Form I" in the present invention) and a process for its preparation.
  • Form I tifibrinide Form I
  • the present invention provides a crystalline form I of the formula (I):
  • the X-ray powder diffraction pattern of the Form I expressed in terms of 2 ⁇ angle has the following characteristic peaks: 8.4° ⁇ 0.2°, 11.9° ⁇ 0.2°, 16.4° ⁇ 0.2°, 17.0° ⁇ 0.2°. , 18.5 ° ⁇ 0.2 ° and 21.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form 1 in terms of 2 ⁇ angle has characteristic peaks at 8.4° ⁇ 0.2°, 11.9° ⁇ 0.2°, 15.3° ⁇ 0.2°. , 16.4 ° ⁇ 0.2 °, 17.0 ° ⁇ 0.2 °, 18.0 ° ⁇ 0.2 °, 18.5 ° ⁇ 0.2 °, 20.4 ° ⁇ 0.2 °, 21.3 ° ⁇ 0.2 °, 21.7 ° ⁇ 0.2 °, 24.8 ° ⁇ 0.2 ° and 26.8 ° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal I expressed in terms of 2 ⁇ angle has the following characteristic peaks and their relative intensities:
  • a typical example of the Form I has an XRPD pattern as shown in FIG.
  • the crystal form I of the present invention has the following beneficial effects:
  • the crystal form I of the present invention has a higher crystallinity.
  • the crystalline form I of the present invention has a relatively high melting point and a melting point of 235 °C.
  • the crystal form I of the present invention has a weight change of less than 0.2% at a relative humidity of 20% to 80%, and is not hygroscopic.
  • Example 48 From Example 48, the crystal form I of the present invention was allowed to stand in an environment of drying at 60 ° C and 40 ° C to 75% RH for 10 days, the crystal form was unchanged, the purity was substantially unchanged, and the stability was better.
  • the crystal form I of the invention has high crystallinity, good stability, low hygroscopicity, better fluidity and better processing characteristics (such as filtration, Drying, weighing, sieving, etc.) is beneficial to improve the uniformity of the preparation, and better to ensure the quality, safety and stability of the active ingredient of the medicinal ingredient and the formulation containing the pirifarn in the process of manufacture and storage. To avoid problems such as uneven content of active ingredients, increased impurities, etc., to avoid special and expensive packaging.
  • the crystalline form I of the present invention has good stability in water, is more suitable for the wet granulation process of the solid preparation or is prepared into an oral suspension dosage form, and can be kept stable during the manufacture and/or storage of the drug.
  • the present invention provides a process for the preparation of Form I, characterized in that the preparation method employs any one of the following methods:
  • the solvent is selected from the group consisting of ethanol, n-propanol, water, nitromethane, acetone, ethyl acetate, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, acetonitrile, dichloromethane, n-heptane or More preferably, the mixture is ethyl acetate, acetonitrile, methyl tert-butyl ether, n-propanol or a mixture thereof;
  • the mass ratio of the volume of the tipironic solid to the solvent is 5 to 100 mg: 1 mL, more preferably 20 to 50 mg: 1 mL;
  • the stirring time is 4 to 5 days;
  • the stirring process is carried out at 10 to 40 ° C;
  • the drying temperature is 40 to 60 ° C, and the drying time is 10 to 48 hours.
  • the solvent is selected from the group consisting of ketones, esters, n-propanol, sec-butanol, n-butanol, water, tetrahydrofuran, 1,4-dioxane, acetonitrile, dichloromethane, toluene or mixtures thereof. More preferably acetone, dichloromethane, water, acetonitrile or a mixture thereof;
  • the mass ratio of the volume of the tipironic solid to the solvent is 5 to 50 mg: 1 mL, more preferably 5 to 25 mg: 1 mL;
  • the volume ratio of the two solvents in the mixture is 1:3 to 3:1;
  • the volatilization process is carried out at 25 to 40 °C.
  • the solvent is selected from the group consisting of alcohols, ketones, esters, acetonitrile or mixtures thereof; more preferably acetone or isopropanol;
  • the mass ratio of the volume of the tipironic solid to the solvent is 40 to 150 mg: 1 mL, more preferably 40 to 100 mg: 1 mL;
  • the temperature at which the solution is formed is 60 to 75 ° C, more preferably 60 to 70 ° C;
  • the temperature of the stirring and crystallization is from -10 to 10 ° C, more preferably from -10 to 0 ° C;
  • the crystallization time is from 1 to 10 hours.
  • the good solvent is selected from the group consisting of alcohols, acetone, ethyl acetate, tetrahydrofuran, nitromethane; more preferably methanol, ethanol, acetone or tetrahydrofuran;
  • the mass to volume ratio of the tififafafa solid to the good solvent is 10 to 50 mg: 1 mL, more preferably 10 to 25 mg: 1 mL;
  • the anti-solvent is selected from the group consisting of water, isopropyl ether, and n-heptane;
  • the stirring time is 3 to 60 minutes;
  • the agitation process is carried out at room temperature.
  • the solvent is selected from the group consisting of alcohols, ketones, esters, ethers, alkanes, tetrahydrofuran, acetonitrile; more preferably ethyl acetate or acetonitrile;
  • the mass ratio of the volume of the tififabine amorphous solid to the solvent is 20 to 100 mg: 1 mL, more preferably 20 to 50 mg: 1 mL;
  • the stirring time is 10 to 20 minutes, more preferably 10 to 15 minutes;
  • the agitation process is carried out at room temperature.
  • a second aspect of the present invention provides a solid form of tifibrinide Form II (abbreviated as "Form II" in the present invention) and a process for its preparation.
  • Form II tifibrinide Form II
  • the present invention provides a crystalline form II of the formula (II):
  • the crystal form II is a monohydrate using Cu-K ⁇ radiation, and the X-ray powder diffraction pattern of the crystal form II represented by 2 ⁇ angle has the following characteristic peaks: 5.3° ⁇ 0.2°, 6.8° ⁇ 0.2°, 8.5. ° ⁇ 0.2°, 16.3° ⁇ 0.2°, 18.0° ⁇ 0.2°, and 20.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form II in terms of 2 ⁇ angle has characteristic peaks at 5.3° ⁇ 0.2°, 6.8° ⁇ 0.2°, 8.5° ⁇ 0.2°. , 12.8 ° ⁇ 0.2 °, 13.8 ° ⁇ 0.2 °, 16.3 ° ⁇ 0.2 °, 16.9 ° ⁇ 0.2 °, 17.1 ° ⁇ 0.2 °, 18.0 ° ⁇ 0.2 °, 18.5 ° ⁇ 0.2 °, 20.9 ° ⁇ 0.2 ° and 27.9 ° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II in terms of 2 theta angle has the following characteristic peaks and their relative intensities:
  • a typical example of the Form II has an XRPD pattern as shown in FIG.
  • the crystal form II of the present invention has the following beneficial effects:
  • the crystal form II of the present invention has a high melting point and a melting point of 235 °C.
  • Example 48 It can be seen from Example 48 that the Form II of the present invention is allowed to stand in an environment of drying at 60 ° C and 40 ° C to 75% RH for 10 days, the crystal form is unchanged, the purity is substantially unchanged, and the stability is better.
  • the crystal form II of the invention has high crystallinity, good stability, better fluidity and better processing characteristics (such as filtration, drying, weighing). , sieving, etc.), which is beneficial to improve the uniformity of the preparation, and can better ensure the quality, safety and stability of the pharmaceutically active ingredient itself and the formulation dosage form containing pirififa in the process of manufacture and storage, and avoid, for example, activity. Problems such as uneven content of ingredients and increased impurities avoid special and expensive packaging.
  • the crystal form II of the invention has good stability in water, is more suitable for the wet granulation process of the solid preparation or is made into the oral suspension dosage form, and can be kept stable during the manufacture and/or storage of the medicine.
  • the present invention provides a process for the preparation of Form II, characterized in that the preparation method employs any one of the following methods:
  • the solvent is selected from the group consisting of methanol, ethanol, trifluoroethanol or a mixture thereof, more preferably methanol;
  • the mass ratio of the volume of the tipironic solid to the solvent is 10 to 50 mg: 1 mL, more preferably 10 to 30 mg: 1 mL;
  • the volatilization process is carried out at 10 to 40 ° C, more preferably 10 to 30 ° C.
  • the solvent is selected from the group consisting of aqueous alcohols, ketones, tetrahydrofuran, 1,4-dioxane, acetonitrile, dimethyl sulfoxide; more preferably aqueous dimethyl sulfoxide;
  • the volume percentage of water in the solvent is 50% to 100%, more preferably 85% to 100%;
  • the mass ratio of the volume of the tipironic solid to the solvent is 25 to 100 mg: 1 mL, more preferably 25 to 35 mg: 1 mL;
  • the stirring time is 10 to 20 minutes, more preferably 10 to 15 minutes;
  • the stirring temperature is 4 to 25 ° C;
  • the drying temperature is 10 to 30 ° C; and the drying time is 10 to 24 hours.
  • the humidifier has a relative humidity of 85% to 100%, more preferably 97%;
  • the standing time is from 1 to 7 days, more preferably 1 day.
  • a third aspect of the present invention provides a solid form of tifibrinide Form III (abbreviated as "Form III" in the present invention) and a process for its preparation.
  • the present invention provides a crystalline form III of the formula (III):
  • the crystal form III is a sesquihydrate, using Cu-K ⁇ radiation, and the X-ray powder diffraction pattern of the crystal form III represented by 2 ⁇ angle has the following characteristic peaks: 6.2° ⁇ 0.2°, 8.8° ⁇ 0.2°, 15.9 ° ⁇ 0.2 ° and 18.2 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the Form III represented by the 2 ⁇ angle has characteristic peaks at the following positions: 6.2° ⁇ 0.2°, 8.8° ⁇ 0.2°, 13.2° ⁇ 0.2°. 15.9° ⁇ 0.2°, 18.2° ⁇ 0.2°, 19.8° ⁇ 0.2°, 22.2° ⁇ 0.2°, and 26.1° ⁇ 0.2°.
  • the crystalline form III has an X-ray powder diffraction pattern having characteristic peaks and relative intensities at the following diffraction angle 2 ⁇ :
  • crystal form III has an XRPD pattern as shown in FIG.
  • the crystal form III of the present invention has the following beneficial effects:
  • Example 48 From Example 48, the crystal form III of the present invention was allowed to stand in an environment of drying at 60 ° C and 40 ° C to 75% RH for 10 days, the crystal form was unchanged, the purity was substantially unchanged, and the stability was better.
  • the crystal form III of the invention has high crystallinity, good stability, low hygroscopicity, better fluidity and better processing characteristics (such as filtration, Drying, weighing, sieving, etc.) is beneficial to improve the uniformity of the preparation, and better to ensure the quality, safety and stability of the active ingredient of the medicinal ingredient and the formulation containing the pirifarn in the process of manufacture and storage.
  • the crystalline form I of the present invention has good stability in water, is more suitable for the wet granulation process of the solid preparation or is prepared into an oral suspension dosage form, and can be kept stable during the manufacture and/or storage of the drug.
  • the present invention provides a process for the preparation of Form III, characterized in that the preparation method employs any one of the following methods:
  • the solvent is selected from the group consisting of water and acetonitrile or a mixed solvent of water and acetone;
  • the volume percentage of water in the solvent is 30% to 50%;
  • the mass to volume ratio of the tipironic solid to the solvent is 14 to 25 mg: 1 mL.
  • the temperature at which the solution is formed is 60 to 70 ° C;
  • the temperature of the stirring and crystallization is more preferably -10 to 0 ° C;
  • the crystallization time is 1 to 24 hours;
  • the drying temperature is 10 to 40 ° C; and the drying time is 10 to 24 hours.
  • the good solvent is selected from the group consisting of acetonitrile, 1,4-dioxane, butanone, isopropyl acetate, more preferably acetonitrile or 1,4-dioxane;
  • the mass to volume ratio of the dipifanib solid to the good solvent is 2 to 25 mg: 1 mL, more preferably 10 to 25 mg: 1 mL;
  • the anti-solvent is water or n-heptane
  • the stirring time is 1 to 24 hours;
  • the stirring process is carried out at room temperature
  • the drying temperature is 10 to 40 ° C; and the drying time is 10 to 24 hours.
  • the solvent is selected from the group consisting of aqueous nitromethane, methyl ethyl ketone, acetonitrile, tetrahydrofuran and water. a mixed solvent, 1,4-dioxane and an aqueous solvent, more preferably an aqueous butanone or an aqueous nitromethane solvent;
  • the mass ratio of the volume of the pirfenidin to the solvent is 5 to 10 mg: 1 mL;
  • the volume percentage of water in the solvent is from 1% to 10%;
  • the volatilization temperature is 10 to 30 ° C, and more preferably 20 to 30 ° C.
  • a fourth aspect of the present invention provides a solid form of tifiprofen form IV (abbreviated as "Form IV" in the present invention) and a process for its preparation.
  • the present invention provides a crystalline form IV of the formula (I):
  • the X-ray powder diffraction pattern of the Form IV expressed in terms of 2 ⁇ angle has the following characteristic peaks: 7.5° ⁇ 0.2°, 13.9° ⁇ 0.2°, 15.8° ⁇ 0.2°, 16.5° ⁇ 0.2°. , 17.4 ° ⁇ 0.2 ° and 18.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the Form IV expressed in terms of 2 ⁇ angle has characteristic peaks at the following positions: 7.5° ⁇ 0.2°, 13.9° ⁇ 0.2°, 15.4° ⁇ 0.2°. 15.8° ⁇ 0.2°, 16.5° ⁇ 0.2°, 17.4° ⁇ 0.2°, 18.1° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.6° ⁇ 0.2°, 24.3° ⁇ 0.2°, 26.5° ⁇ 0.2° and 29.1 ° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form IV expressed in 2 theta angle, has characteristic peaks and their relative intensities at:
  • a typical example of the Form IV has an XRPD pattern as shown in FIG.
  • the Form IV of the present invention has the following beneficial effects:
  • the crystalline form IV of the present invention has a relatively high melting point and a melting point of 235 °C.
  • Example 48 It can be seen from Example 48 that the Form IV of the present invention is allowed to stand in an environment of drying at 60 ° C and 40 ° C to 75% RH for 10 days, the crystal form is unchanged, the purity is substantially unchanged, and the stability is better.
  • the crystal form IV of the invention has high crystallinity, good stability, better fluidity and better processing characteristics (such as filtration, drying, weighing). , sieving, etc.), which is beneficial to improve the uniformity of the preparation, and can better ensure the quality, safety and stability of the pharmaceutically active ingredient itself and the formulation dosage form containing pirififa in the process of manufacture and storage, and avoid, for example, activity. Problems such as uneven content of ingredients and increased impurities avoid special and expensive packaging.
  • the crystalline form IV of the present invention has high solubility, and has better dissolution and bioavailability.
  • the present invention provides a process for the preparation of Form IV, characterized in that the preparation method comprises the following steps:
  • the solvent is selected from the group consisting of ethanol and chloroform;
  • the mass ratio of the volume of the pirfenidin to the solvent is 10 to 25 mg: 1 mL;
  • the volatilization process is carried out at 40 to 50 °C.
  • a fifth aspect of the present invention provides a solid form of pirififa form V (abbreviated as "Form V" in the present invention) and a process for its preparation.
  • the X-ray powder diffraction pattern of the crystal form V expressed in terms of 2 ⁇ angle has the following characteristic peaks: 6.6° ⁇ 0.2°, 7.8° ⁇ 0.2°, 8.5° ⁇ 0.2°, 13.4° ⁇ 0.2°. 15.1° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.2° ⁇ 0.2°, 17.7° ⁇ 0.2°, 17.9° ⁇ 0.2°, 18.5° ⁇ 0.2°, 20.2° ⁇ 0.2° and 20.9° ⁇ 0.2°.
  • a typical example of the crystal form V has an XRPD pattern as shown in FIG.
  • the present invention also provides a process for the preparation of Form V, comprising the steps of: heating Form 2 of the present invention to obtain said Form V.
  • the heating rate is 20 to 30 ° C / minute;
  • the heating end temperature is 80 to 120 °C.
  • a sixth aspect of the present invention provides an amorphous form of pirififa and a process for the preparation thereof.
  • a typical example of the amorphous has an XRPD as shown in FIG.
  • the present invention provides a process for the preparation of a tififaxil amorphous solid, which comprises the steps of: forming a tififafin solid in a solvent to dissolve in a solvent, and concentrating the dry solvent under reduced pressure to obtain the tififene amorphous solid.
  • the solvent is dichloromethane
  • the mass ratio of the volume of the tipironic solid to the solvent is 50 to 100 mg: 1 mL;
  • the concentration under reduced pressure is carried out at 30 to 40 °C.
  • the raw material "tepirfenib” may be a disclosed pirifarnib compound or a crystal form thereof, and includes, for example, but not limited to, reference to patent documents CN1101392C, CN100567292C, Desifenib obtained by any of the methods of CN1246318C. These patent documents are incorporated herein by reference in their entirety.
  • the "room temperature” means 10 to 30 °C.
  • the “overnight” refers to the time across the night, usually 10 to 16 hours.
  • the “stirring” may be carried out by a conventional method in the art, for example, the stirring method includes magnetic stirring, mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the "separation" can be carried out by conventional methods in the art, such as centrifugation or filtration.
  • the filtration under reduced pressure is generally carried out by suction filtration at a pressure of less than atmospheric pressure at room temperature, preferably at a pressure of less than 0.09 MPa.
  • the "drying" can be accomplished using conventional techniques in the art, such as drying at ambient temperature, blast drying or reduced pressure drying.
  • the drying apparatus and method are not limited and may be a fume hood, a blast oven, a spray dryer, a fluidized bed drying or a vacuum oven; the pressure may be reduced or normal pressure, preferably the pressure is less than 0.09 MPa.
  • the drying temperature is 10 to 40 ° C, and the drying time is 10 to 72 hours, preferably 2 to 24 hours, more preferably 2 to 8 hours.
  • the concentration under reduced pressure refers to an operation performed by a rotary evaporator, and the solvent is volatilized under a pressure of less than atmospheric pressure at an experimental temperature of 10 to 50 ° C and a rotation speed of 50 to 200 rpm.
  • crystalline means that the compound is characterized by the X-ray powder diffraction pattern indicated, having a unique ordered molecular arrangement or configuration within the crystal lattice. It is well known to those skilled in the art that the experimental error therein depends on instrument conditions, sample preparation, and sample purity.
  • the 2 ⁇ angle of the peaks in the XRD pattern will typically vary slightly from instrument to sample. The difference of peak angles may vary by 1°, 0.8°, 0.5°, 03°, 0.1°, etc. depending on the instrument. Different values are usually allowed to be ⁇ 0.2°, so the difference in peak angle cannot be used as the sole criterion.
  • the relative intensity of the peaks may vary with sample, sample preparation, and other experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the influence of experimental factors such as sample height causes an overall shift in the peak angle, which usually allows a certain offset.
  • any crystal form having the same or similar characteristic peaks as the X-ray powder diffraction pattern of the present invention is within the scope of the present invention.
  • Single crystal form means a single crystal form as detected by X-ray powder diffraction.
  • the crystal form of the pirifanib of the present invention is substantially pure, single, and substantially free of any mixing. Other crystal forms or amorphous states.
  • substantially pure when used in reference to a new crystalline form means that the new crystalline form comprises at least 80% by weight of the compound present, more preferably at least 90% by weight, especially at least 95% ( Weight), especially at least 99% by weight.
  • Seventh aspect of the present invention is, according to the object of the present invention, a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of a pharmaceutically active ingredient selected from the crystalline form of tifenofibine of the present invention or The crystalline form of tipirofil prepared by the method of the invention, and at least one pharmaceutically acceptable carrier.
  • the crystalline form of tififene comprises cisifarnib Form I, Form II, Form III and Form IV.
  • the pharmaceutical composition may also comprise other pharmaceutically acceptable crystalline forms of tififene (eg Form V) or amorphous.
  • Excipients in the pharmaceutical compositions are well known to those skilled in the art, and the choice of species, usage, and amount is well known to those skilled in the art.
  • examples include sugars, cellulose and its derivatives, starch or modified starch, binders such as microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl fibers , disintegrators such as sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose, dry corn starch, lubricants such as stearic acid, magnesium stearate, stearyl Sodium fumarate, polyethylene glycol, fillers such as kaolin.
  • the administration route of the drug combination includes oral administration, intravenous subcutaneous injection, injection into tissue administration, transdermal administration, rectal administration, and the like.
  • the pharmaceutical combination may be prepared into a certain dosage form depending on the route of administration or need, and may be solid or liquid.
  • Solid oral dosage forms including, for example, tablets, powders, pills, and capsules; liquid oral dosage forms including, for example, solutions, syrups, suspensions, and elixirs; injectable preparations including, for example, solutions and suspensions; spray or Epithelial administration and the like.
  • the formulation may be suitable for immediate, sustained or controlled release of the active ingredient of the drug. It may be a conventional, dispersible, chewable, orally dissolvable or fast dissolving formulation.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art.
  • the crystalline form I, Form II, Form III and Form IV of the present invention are mixed with one or more pharmaceutically acceptable excipients, optionally with Other crystalline forms, amorphous forms of pharmaceutically acceptable tififabine are optionally mixed with one or more other pharmaceutically active ingredients.
  • the solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
  • the present invention provides a crystalline form of tipirofibine of the present invention or a crystalline form of tififene obtained by the process of the present invention in the preparation of a medicament for the treatment and/or prevention of abnormal cell growth diseases use.
  • Such diseases include, but are not limited to, solid tumors and blood cancers associated with RAS mutations or overexpression, such as lung cancer, pancreatic cancer, colon cancer, thyroid follicular carcinoma, myelodysplastic syndrome, mesenchymal origin tumors, melanoma, teratology Fetal cancer, neuroblastoma, glioma, epidermal carcinoma such as head and neck squamous cell carcinoma, salivary gland cancer, benign tumor of the skin, breast cancer, kidney cancer, bone cancer, ovarian cancer, bladder cancer, liver cancer, multiple nerves Hematopoietic tumors of fibroids and lymphoma lineages such as peripheral T lymphoma, myeloid leukemia, myelodysplastic syndrome (MDS), chronic myeloid leukemia, and the like.
  • MDS myeloid leukemia
  • MDS myelodysplastic syndrome
  • the present invention provides a method for treating and/or preventing a cell abnormal growth disease, which comprises administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of the crystal of tifenofibene of the present invention.
  • the aforementioned pharmaceutical composition of Form I, Form II, Form III, and Form IV; the disease is as described above in the specification.
  • the active compounds are usually effective over a wide range of dosages. It is generally considered that the effective amount is 0.0001 mg / From kilograms to 100 mg/kg body weight, especially from 0.001 mg/kg to 10 mg/kg body weight, suitable for administering the desired dose in two, three, four or smaller doses at appropriate intervals throughout the day, Small doses may be formulated in unit dosage form, such as from 0.01 to 500 mg, especially from 0.1 mg to 200 mg, per unit dosage form.
  • Fig. 1 is an X-ray powder diffraction pattern of tipirofil prepared by the method of the patent document CN1246318C.
  • Figure 2 is an X-ray powder diffraction pattern of the crystalline form I of the pirfenibine of the present invention.
  • Figure 3 is a DSC chart of the crystalline form I of the pirfenibine of the present invention.
  • Figure 4 is a TGA map of the crystalline form I of the pirfenibine of the present invention.
  • Figure 5 is an isotherm adsorption curve of the crystalline form I of the pirfenibine of the present invention.
  • Figure 6 is an X-ray powder diffraction pattern of the crystalline form II of pirfenibine of the present invention.
  • Figure 7 is a DSC chart of the crystalline form II of pirfenibine of the present invention.
  • Figure 8 is a TGA pattern of the crystalline form II of pirfenibine of the present invention.
  • Figure 9 is an X-ray powder diffraction pattern of the crystalline form III of pirfenibine of the present invention.
  • Figure 10 is a DSC chart of the crystalline form III of pirifarnib of the present invention.
  • Figure 11 is a TGA pattern of the crystalline form III of pirfenibine of the present invention.
  • Figure 12 is an X-ray powder diffraction pattern of the crystalline form IV of pirifarnib of the present invention.
  • Figure 13 is a DSC chart of the crystalline form IV of pirififa of the present invention.
  • Figure 14 is a TGA map of the crystalline form IV of pirifarnib according to the present invention.
  • Figure 15 is an X-ray powder diffraction pattern of the crystalline form V of pirfenibine of the present invention.
  • Figure 16 is an X-ray powder diffraction pattern of the amorphous form of pirifanib of the present invention.
  • X-ray powder diffraction (XRPD): The instrument was a Bruker D8 Advance diffractometer. The samples were tested at room temperature. The detection conditions are as follows, the angle range is 3 to 40 ° 2 ⁇ , the step size is 0.02 ° 2 ⁇ , and the speed is 0.2 second / step.
  • DSC Differential Thermal Analysis
  • Thermogravimetric analysis (TGA) data was taken from the TA Instruments Q500 TGA.
  • the detection method is as follows: 5 to 15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to 350 by a stepwise high-resolution detection method at a heating rate of 10 ° C/min under the protection of 40 mL/min of dry nitrogen. °C.
  • Infrared spectroscopy (IR) data was taken from Bruker Tensor 27, and instrument control software and data analysis software were OPUS.
  • the ATR device is usually used to collect infrared absorption spectrum in the range of 600-4000 cm-1.
  • the scanning time of the sample and the blank background is 16 seconds, and the instrument resolution is 4 cm-1.
  • Dynamic moisture adsorption analysis (DVS) data and isothermal adsorption analysis data were taken from the TA Instruments Q5000 TGA.
  • the detection method is as follows: 1 to 10 mg of the sample is placed in a platinum crucible, The change in weight during the change of relative humidity from 0% to 80% to 0% is detected.
  • Nuclear magnetic resonance spectroscopy data (1H NMR) were taken from a Bruker Avance II DMX 400 MHz NMR spectrometer. A sample of 1 to 5 mg was weighed and dissolved in a nuclear magnetic sample tube with about 0.5 mL of deuterated reagent for detection.
  • a tepifani solid is prepared according to the method described in the preparation, resolution and purification steps of the compound (I) in the specification of the patent document CN1246318C.
  • tipironib of Preparation Example 1 200 mg was added, and 2.0 mL of dichloromethane was added to dissolve in a solvent, and concentrated under reduced pressure at 40 ° C to obtain 180 mg of tififabine amorphous solid in a yield of 90%.
  • tipirofib Take 40 mg of tipirofib in Preparation Example 1, add 0.5 mL of ethanol to form a suspension, stir and crystallize at 30 ° C, and after 4 days, filter under reduced pressure, and vacuum dry at 50 ° C for 30 hours to obtain 28 mg of tipirofin Form I.
  • the rate is 70%.
  • the cisifarnib Form I can be obtained by replacing the solvent in Example 5 with the following table.
  • the cisifarnib Form I can be obtained by replacing the solvent in Example 10 with the following table.
  • the cisifarnib Form I can be obtained by replacing the solvent in Example 14 with the following table.
  • the cisifarnib Form I can be obtained by replacing the solvent in Example 20 with the following table.
  • Example 1 15 mg of the tipirofil amorphous solid of Example 1 was added, 0.75 mL of acetonitrile was added to form a suspension, and the mixture was stirred and crystallized at room temperature. After 10 minutes, it was filtered under reduced pressure, and dried under vacuum at room temperature for 24 hours to obtain 12.3 mg of tifibrin. Type I, yield 82%.
  • Example 1 15 mg of the tififafene amorphous solid of Example 1 was taken, 0.15 mL of ethanol was added to form a suspension, and the mixture was stirred and crystallized at room temperature. After 20 minutes, it was filtered under reduced pressure, and dried under vacuum at room temperature for 24 hours to obtain 10.5 mg of tipirofamide crystal. Type I, yield 70%.
  • the cisifarnib Form I can be obtained by replacing the solvent in Example 24 with the following table.
  • the samples prepared in Examples 3 to 25 have the same or similar XRPD patterns (not shown), DSC patterns (not shown), TGA patterns (not shown), and Examples 3 to 25.
  • the sample was the same crystalline form as the sample of Example 2.
  • the cisifarnib Form II can be obtained by replacing the solvent in Example 28 with the following table.
  • tipirofil amorphous solid of Example 1 15 mg was taken, 0.6 mL of water was added to form a suspension, and the mixture was stirred and crystallized at 25 ° C. After 15 minutes, it was filtered under reduced pressure, and dried under vacuum at 10 ° C for 24 hours to obtain 14.1 mg of tipyridine. Nitrite II, yield 91%.
  • the cisifarnib Form II can be obtained by replacing the solvent in Example 32 with the following table.
  • Example 1 15 mg of the tipirofil amorphous solid of Example 1 was taken and placed open for one day in a humidifier having a relative humidity of 97% to obtain 14 mg of tipirofil crystal form II in a yield of 90%.
  • the samples prepared in Examples 27 to 34 had the same or similar XRPD patterns (not shown), DSC patterns (not shown), TGA patterns (not shown), and Examples 27 to 34.
  • the sample was the same crystalline form as the sample of Example 26.
  • tipirofib Take 50 mg of tipirofib in Preparation Example 1, and dissolve it in 2.0 mL of acetone solution containing 50% water at 60 ° C, and stir and crystallize at -10 ° C. After 1 hour, filter under reduced pressure, and vacuum dry at 40 ° C for 10 hours. , 43 mg of tipirofibine Form III was obtained in a yield of 82%.
  • tipironib of Preparation Example 1 10 mg was added, 1 mL of acetonitrile was added to form a solution, 15.0 mL of water was added thereto, and the mixture was stirred and crystallized at room temperature. After 24 hours, it was filtered under reduced pressure, and dried under vacuum at 10 ° C for 24 hours to obtain 8 mg of tipirofil crystal form. III, the yield is 76%.
  • the cisifarnib Form III can be obtained by replacing the solvent in Example 39 with the following table.
  • the cisifarnib Form III can be obtained by replacing the solvent in Example 43 with the following table.
  • the samples prepared in Examples 36 to 44 have the same or similar XRPD patterns (not shown), DSC patterns (not shown), TGA patterns (not shown), and Examples 36 to 44.
  • the sample was the same crystalline form as the sample of Example 35.
  • tipirofibrin Form II of Example 26 10 mg was taken and heated to 120 ° C at a temperature increase rate of 30 ° C / min to obtain the cisifarnib Form V.
  • Crystalline and chemical stability placement experiments take 20mg of the present invention, tififene crystal form I, tipirofil crystal form II, tifibrin form III, tipirofib form IV, at 60 ° C The mixture was placed under dry conditions at 40 ° C to 75% RH, and XRD crystal form detection was carried out at the corresponding time.
  • the crystalline form I of the present invention, tifibrin form II, tifibrin form III, tififene form IV are dried at 60 ° C and placed at 40 ° C - 75% RH for 10 days. , each still maintains the original crystal form and the purity is almost no decrease. It is indicated that the crystalline form I of tififene prepared by the present invention, the crystalline form II of pirifarnib, the crystalline form III of pirifarnib, and the crystalline form IV of tipirofib have good crystal form and chemical stability.
  • Crystallization experiment in water 20 mg of tifiprofen crystal form A of Preparation Example 1, respectively, of the present invention, tififene crystal form I, tipirofil crystal form II, tipirofil form III and tipyridine Nitrins IV, each stirred at room temperature for 3 days in water, were subjected to XRD crystal form detection.

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Abstract

一种替吡法尼的晶型，与已知的替吡法尼固体形式相比，该替吡法尼晶型在结晶度、吸湿性、形貌、晶型稳定性和化学稳定性等方面具有优势。还涉及替吡法尼晶型的制备方法，其药物组合物及其在制备用于治疗和／或预防细胞异常生长疾病的用途。

Description

替吡法尼的晶型及其制备方法及药物组合物 技术领域
本申请涉及药物化学结晶技术领域。具体而言，本申请涉及替吡法尼的晶型、其制备方法、药物组合物和用途。
背景技术
替吡法尼是一种法尼基转移酶抑制剂，作用于H-RAS或N-RAS突变细胞，具有抗增殖作用效果。其能够阻断RAS蛋白的法尼基化修饰，从而干扰其在质膜内表面上的定位以及随后下游信号通路的激活，具有有效的抗肿瘤疾病的活性。
替吡法尼化学名称为(R)-(+)-6-[氨基(4-氯苯基)(1-甲基-1H-咪唑-5-基)甲基]-4-(3-氯苯基)1-甲基-2(1H)-喹啉酮，英文名称为Tipifarnib；其化学结构式如下所示：
Figure PCTCN2016108970-appb-000001
专利文献CN1101392C报道了替吡法尼的制备方法，其为外消旋体且未公开任何表征数据；专利文献CN100567292C报道了替吡法尼的制备方法，其为某种对映体过量的混合物且仅提到了该混合物的熔点；专利文献CN1246318C报道了替吡法尼的制备方法及其对映体中替吡法尼的拆分及提纯方法。本发明人研究发现，按照CN1246318C提供的方法制备得到的替吡法尼为结晶态(在本文中以“晶型A”表示)，但其具有结晶度低、晶型稳定性差的缺陷，而专利文献CN1101392C和CN100567292C中报道的替吡法尼均为混合物且缺乏准确体现其物理形式的特征性数据，不能作为充分的公开内容。
鉴于现有技术尚存不足，本领域仍需要开发具有更多改进性能的结晶态的替吡法尼，以满足药物制剂对于活性物质的形态、稳定性等物化性质的严格要求。
发明内容
针对现有技术的不足，本发明的目的是提供替吡法尼的晶型及它们的制备方法、包含所述晶型的药物组合物和用途。所述晶型为稳定的结晶态固体，应具有一种或多种改进的特性，特别在结晶度、吸湿性、形貌、制剂可加工性、晶型稳定性等方面。此外，本发明还涉及所述晶型的制备方法、包 含所述晶型的药物组合物及其用途。
根据本发明的目的，本发明的内容之一是提供固态的替吡法尼晶型I(在本发明中简称为“晶型I”)及其制备方法。
本发明提供结构式如下式(I)所示的晶型I：
Figure PCTCN2016108970-appb-000002
使用Cu-Kα辐射，所述晶型I以2θ角度表示的X-射线粉末衍射图具有以下特征峰：8.4°±0.2°、11.9°±0.2°、16.4°±0.2°、17.0°±0.2°、18.5°±0.2°和21.7°±0.2°。
在本发明优选的一个实施方案中，所述晶型1以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：8.4°±0.2°、11.9°±0.2°、15.3°±0.2°、16.4°±0.2°、17.0°±0.2°、18.0°±0.2°、18.5°±0.2°、20.4°±0.2°、21.3°±0.2°、21.7°±0.2°、24.8°±0.2°和26.8°±0.2°。
在本发明进一步优选的一个实施方案中，所述晶I以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
Figure PCTCN2016108970-appb-000003
Figure PCTCN2016108970-appb-000004
非限制性地，所述晶型I的一个典型实例具有如图2所示的XRPD图谱。
非限制性地，所述晶型I的DSC图谱如图3所示。
非限制性地，所述晶型I的TGA图谱如图4所示。
非限制性地，所述晶型I的等温吸附曲线如图5所示。
与现有技术的晶型A相比，本发明的晶型I具有以下有益效果：
1)由XRPD图谱可知，本发明的晶型I具有更高的结晶度。
2)由DSC图谱可知，本发明的晶型I具有较高的熔点，熔点为235℃。
3)由等温吸附曲线可知，本发明的晶型I在20％～80％的相对湿度下重量变化小于0.2％，不吸湿。
4)由实施例48可知，本发明的晶型I在60℃干燥、40℃-75％RH的环境中放置10天，晶型不变，纯度基本不变，具有更好的稳定性。
5)由对比例1可知，在水中搅拌3天，本发明的晶型I晶型不变，已知的晶型A会转晶为晶型I，本发明的晶型I在水中具有更好的稳定性。
以上增益性质表面：与现有技术的晶型A相比，本发明的晶型I结晶度高、稳定性好、吸湿性低，具有更好的流动性和更优良的加工特性(如过滤、干燥、称量、过筛等操作)，有利于提高制剂均一性，能更好地保证药物活性成分自身和含有替吡法尼的制剂剂型在制造和存储等过程中质量、安全性和稳定性，避免例如活性成分含量不均匀、杂质增加等问题，避免特殊和昂贵的包装。且本发明的晶型I水中稳定性好，更适合固体制剂的湿法制粒工艺或制成口服悬浮液剂型，在药物制造和/或存储等过程中能够保持稳定。
根据本发明的目的，本发明提供晶型I的制备方法，其特征在于，所述制备方法采用下述方法中的任意一种：
1)将替吡法尼固体在溶剂中形成悬浮液，搅拌析晶，进而分离晶体，将析出的晶体分离、干燥，得到所述晶型I；
优选地，所述溶剂选自乙醇、正丙醇、水、硝基甲烷、丙酮、乙酸乙酯、异丙醚、甲基叔丁基醚、四氢呋喃、乙腈、二氯甲烷、正庚烷或其混合物，更优选为乙酸乙酯、乙腈、甲基叔丁基醚、正丙醇或其混合物；
优选地，所述替吡法尼固体与溶剂的质量体积比为5～100mg:1mL，更优选为20～50mg:1mL；
优选地，所述搅拌时间为4～5天；
优选地，所述搅拌过程在10～40℃下进行；
优选地，所述干燥温度为40～60℃，所述干燥时间为10～48小时。
2)将替吡法尼固体在溶剂中形成溶液，挥发至溶剂干，得到所述晶型I；
优选地，所述溶剂选自酮类、酯类、正丙醇、仲丁醇、正丁醇、水、四氢呋喃、1,4-二氧六环、乙腈、二氯甲烷、甲苯或其混合物，更优选为丙酮、二氯甲烷、水、乙腈或其混合物；
优选地，所述替吡法尼固体与溶剂的质量体积比为5～50mg:1mL，更优选为5～25mg:1mL；
优选地，所述混合物中两种溶剂的体积比为1:3～3:1；
优选地，所述挥发过程在25～40℃下进行。
3)将替吡法尼固体在溶剂中形成溶液，搅拌冷却析晶，进而分离晶体，干燥，得到所述晶型I；
优选地，所述溶剂选自醇类、酮类、酯类、乙腈或其混合物；更优选为丙酮或异丙醇；
优选地，所述替吡法尼固体与溶剂的质量体积比为40～150mg:1mL，更优选为40～100mg:1mL；
优选地，所述形成溶液的温度为60～75℃，更优选为60～70℃；
优选地，所述搅拌析晶的温度为为-10～10℃，更优选为-10～0℃；
优选地，所述析晶时间为1～10小时。
4)将替吡法尼固体在良溶剂中形成溶液，加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到所述晶型I；
优选地，所述良溶剂选自醇类、丙酮、乙酸乙酯、四氢呋喃、硝基甲烷；更优选为甲醇、乙醇、丙酮或四氢呋喃；
优选地，所述替吡法尼固体与良溶剂的质量体积比为10～50mg:1mL，更优选为10～25mg:1mL；
优选地，所述抗溶剂选自水、异丙醚、正庚烷；
优选地，所述搅拌时间为3～60分钟；
优选地，所述搅拌过程在室温下进行。
5)将替吡法尼无定型固体在溶剂中形成悬浮液，搅拌析晶，进而分离晶体，将析出的晶体分离、干燥，得到所述晶型I；
优选地，所述溶剂选自醇类、酮类、酯类、醚类、烷烃类、四氢呋喃、乙腈；更优选为乙酸乙酯或乙腈；
优选地，所述替吡法尼无定型固体与溶剂的质量体积比为20～100mg:1mL，更优选为20～50mg:1mL；
优选地，所述搅拌时间为10～20分钟，更优选为10～15分钟；
优选地，所述搅拌过程在室温下进行。
根据本发明的目的，本发明的内容之二是提供固态的替吡法尼晶型II(在本发明中简称为“晶型II”)及其制备方法。
本发明提供结构式如下式(II)所示的晶型II：
Figure PCTCN2016108970-appb-000005
所述晶型II为一水合物，使用Cu-Kα辐射，所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰：5.3°±0.2°、6.8°±0.2°、8.5°±0.2°、16.3°±0.2°、18.0°±0.2°和20.9°±0.2°。
在本发明优选的一个实施方案中，所述晶型II以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：5.3°±0.2°、6.8°±0.2°、8.5°±0.2°、12.8°±0.2°、13.8°±0.2°、16.3°±0.2°、16.9°±0.2°、17.1°±0.2°、18.0°±0.2°、18.5°±0.2°、20.9°±0.2°和27.9°±0.2°。
在本发明进一步优选的一个实施方案中，所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
Figure PCTCN2016108970-appb-000006
Figure PCTCN2016108970-appb-000007
非限制性地，所述晶型II的一个典型实例具有如图6所示的XRPD图谱。
非限制性地，所述晶型II的DSC图谱如图7所示。
非限制性地，所述晶型II的TGA图谱如图8所示。
与现有技术的晶型A相比，本发明的晶型II具有以下有益效果：
1)由XRPD图谱可知，本发明的晶型II具有更高的结晶度。
2)由DSC图谱可知，本发明的晶型II，具有较高的熔点，熔点为235℃。
3)由实施例48可知，本发明的晶型II在60℃干燥、40℃-75％RH的环境中放置10天，晶型不变，纯度基本不变，具有更好的稳定性。
4)由对比例1可知，在水中搅拌3天，本发明的晶型II晶型不变，已知的晶型A会转晶为晶型I，本发明的晶型II在水中具有更好的稳定性。
以上增益性质表面：与现有技术的晶型A相比，本发明的晶型II结晶度高、稳定性好，具有更好的流动性和更优良的加工特性(如过滤、干燥、称量、过筛等操作)，有利于提高制剂均一性，能更好地保证药物活性成分自身和含有替吡法尼的制剂剂型在制造和存储等过程中质量、安全性和稳定性，避免例如活性成分含量不均匀、杂质增加等问题，避免特殊和昂贵的包装。且本发明的晶型II水中稳定性好，更适合固体制剂的湿法制粒工艺或制成口服悬浮液剂型，在药物制造和/或存储等过程中能够保持稳定。
根据本发明的目的，本发明提供晶型II的制备方法，其特征在于，所述制备方法采用下述方法中的任意一种：
1)将替吡法尼固体在溶剂中形成溶液，挥发至溶剂干，得到所述晶型II；
优选地，所述溶剂选自甲醇、乙醇、三氟乙醇或其混合物，更优选为甲醇；
优选地，所述替吡法尼固体与溶剂的质量体积比为10～50mg:1mL，更优选为10～30mg:1mL；
优选地，所述挥发过程在10～40℃下进行，更优选为10～30℃。
2)将替吡法尼无定型固体在溶剂中形成悬浮液，搅拌析晶，进而分离晶体，将析出的晶体分离、干燥，得到所述晶型II；
优选地，所述溶剂选自含水的醇类、酮类、四氢呋喃、1,4-二氧六环、乙腈、二甲亚砜；更优选为含水的二甲亚砜；
优选地，所述溶剂中水的体积百分比为50％～100％，更优选为85％～100％；
优选地，所述替吡法尼固体与溶剂的质量体积比为25～100mg:1mL，更优选为25～35mg:1mL；
优选地，所述搅拌时间为10～20分钟，更优选为10～15分钟；
优选地，所述搅拌温度为4～25℃；
优选地，所述干燥的温度为10～30℃；所述干燥的时间为10～24小时。
3)将替吡法尼无定型固体置于湿度器中，得到所述晶型II；
优选地，所述湿度器相对湿度为85％～100％，更优选为97％；
优选地，所述放置时间为1～7天，更优选为1天。
根据本发明的目的，本发明的内容之三是提供固态的替吡法尼晶型III(在本发明中简称为“晶型III”)及其制备方法。
本发明提供结构式如下式(III)所示的晶型III：
Figure PCTCN2016108970-appb-000008
所述晶型III为倍半水合物，使用Cu-Kα辐射，所述晶型III以2θ角度表示的X-射线粉末衍射图具有以下特征峰：6.2°±0.2°、8.8°±0.2°、15.9°±0.2°和18.2°±0.2°。
在本发明优选的一个实施方案中，所述晶型III以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：6.2°±0.2°、8.8°±0.2°、13.2°±0.2°、15.9°±0.2°、18.2°±0.2°、19.8°±0.2°、22.2°±0.2°和26.1°±0.2°。
在本发明进一步优选的一个实施方案中，所述的晶型III，其X-射线粉末衍射图谱在以下衍射角2θ处具有特征峰及其相对强度：
Figure PCTCN2016108970-appb-000009
非限制性地，所述晶型III的一个典型实例具有如图9所示的XRPD图谱。
非限制性地，所述晶型II的DSC图谱如图10所示。
非限制性地，所述晶型II的TGA图谱如图11所示。
与现有技术的晶型A相比，本发明的晶型III具有以下有益效果：
1)由XRPD图谱可知，本发明的晶型III具有更高的结晶度。
2)由实施例48可知，本发明的晶型III在60℃干燥、40℃-75％RH的环境中放置10天，晶型不变，纯度基本不变，具有更好的稳定性。
3)由对比例1可知，在水中搅拌3天，本发明的晶型III晶型不变，已知的晶型A会转晶为晶型I，本发明的晶型III在水中具有更好的稳定性。
以上增益性质表面：与现有技术的晶型A相比，本发明的晶型III结晶度高、稳定性好、吸湿性低，具有更好的流动性和更优良的加工特性(如过滤、干燥、称量、过筛等操作)，有利于提高制剂均一性，能更好地保证药物活性成分自身和含有替吡法尼的制剂剂型在制造和存储等过程中质量、安全性和稳定性，避免例如活性成分含量不均匀、杂质增加等问题，避免特殊和昂贵的包装。且本发明的晶型I水中稳定性好，更适合固体制剂的湿法制粒工艺或制成口服悬浮液剂型，在药物制造和/或存储等过程中能够保持稳定。
根据本发明的目的，本发明提供晶型III的制备方法，其特征在于，所述制备方法采用下述方法中的任意一种：
1)将替吡法尼固体在溶剂中形成溶液，搅拌冷却析晶，进而分离晶体，干燥，得到所述晶型III；
优选地，所述溶剂选自水与乙腈或水与丙酮的混合溶剂；
优选地，所述溶剂中水的体积百分比为30％～50％；
优选地，所述替吡法尼固体与溶剂的质量体积比为14～25mg:1mL。
优选地，所述形成溶液的温度为60～70℃；
优选地，所述搅拌析晶的温度为更优选为-10～0℃；
优选地，所述析晶时间为1～24小时；
优选地，所述干燥的温度为10～40℃；所述干燥的时间为10～24小时。
2)将替吡法尼固体在良溶剂中形成溶液，加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到所述晶型III；
优选地，所述良溶剂选自乙腈、1,4-二氧六环、丁酮、乙酸异丙酯，更优选为乙腈或1,4-二氧六环；
优选地，所述替吡法尼固体与良溶剂的质量体积比为2～25mg:1mL，更优选为10～25mg:1mL；
优选地，所述抗溶剂为水或正庚烷；
优选地，所述搅拌时间为1～24小时；
优选地，所述搅拌过程在室温下进行；
优选地，所述干燥的温度为10～40℃；所述干燥的时间为10～24小时。
3)将替吡法尼固体在溶剂中形成清液，挥发析晶，得到所述晶型III；
优选地，所述溶剂选自含水的硝基甲烷、丁酮、乙腈、四氢呋喃与水的 混合溶剂、1,4-二氧六环与水溶剂，更优选为含水的丁酮或含水的硝基甲烷溶剂；
优选地，所述替吡法尼固体与溶剂的质量体积比为5～10mg:1mL；
优选地，所述溶剂中水的体积百分比为1％～10％；
优选地，所述挥发温度为10～30℃，更优选为20～30℃。
根据本发明的目的，本发明的内容之四是提供固态的替吡法尼晶型IV(在本发明中简称为“晶型IV”)及其制备方法。
本发明提供结构式如下式(I)所示的晶型IV：
Figure PCTCN2016108970-appb-000010
使用Cu-Kα辐射，所述晶型IV以2θ角度表示的X-射线粉末衍射图具有以下特征峰：7.5°±0.2°、13.9°±0.2°、15.8°±0.2°、16.5°±0.2°、17.4°±0.2°和18.1°±0.2°。
在本发明优选的一个实施方案中，所述晶型IV以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰：7.5°±0.2°、13.9°±0.2°、15.4°±0.2°、15.8°±0.2°、16.5°±0.2°、17.4°±0.2°、18.1°±0.2°、20.7°±0.2°、21.6°±0.2°、24.3°±0.2°、26.5°±0.2°和29.1°±0.2°。
在本发明进一步优选的一个实施方案中，所述晶型IV以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰及其相对强度：
Figure PCTCN2016108970-appb-000011
Figure PCTCN2016108970-appb-000012
非限制性地，所述晶型IV的一个典型实例具有如图12所示的XRPD图谱。
非限制性地，所述晶型IV的DSC图谱如图13所示。
非限制性地，所述晶型IV的TGA图谱如图14所示。
与现有技术的晶型A相比，本发明的晶型IV具有以下有益效果：
1)由XRPD图谱可知，本发明的晶型IV具有更高的结晶度。
2)由DSC图谱可知，本发明的晶型IV具有较高的熔点，熔点为235℃。
3)由对比例1可知，在水中搅拌3天，本发明的晶型III晶型不变，已知的晶型A会转晶为晶型I，本发明的晶型III在水中具有更好的稳定性。
4)由实施例48可知，本发明的晶型IV在60℃干燥、40℃-75％RH的环境中放置10天，晶型不变，纯度基本不变，具有更好的稳定性。
以上增益性质表面：与现有技术的晶型A相比，本发明的晶型IV结晶度高、稳定性好，具有更好的流动性和更优良的加工特性(如过滤、干燥、称量、过筛等操作)，有利于提高制剂均一性，能更好地保证药物活性成分自身和含有替吡法尼的制剂剂型在制造和存储等过程中质量、安全性和稳定性，避免例如活性成分含量不均匀、杂质增加等问题，避免特殊和昂贵的包装。且本发明的晶型IV溶解度高，具有更好的溶出度和生物利用率。
根据本发明的目的，本发明提供晶型IV的制备方法，所其特征在于，所述制备方法包括以下步骤：
将替吡法尼固体在溶剂中形成溶液，挥发至溶剂干，得到所述晶型IV；
优选地，所述溶剂选自乙醇、氯仿；
优选地，所述替吡法尼固体与溶剂的质量体积比为10～25mg:1mL；
优选地，所述挥发过程在40～50℃下进行。
根据本发明的目的，本发明的内容之五是提供固态的替吡法尼晶型V(在本发明中简称为“晶型V”)及其制备方法。
使用Cu-Kα辐射，所述晶型V以2θ角度表示的X-射线粉末衍射图具有以下特征峰：6.6°±0.2°、7.8°±0.2°、8.5°±0.2°、13.4°±0.2°、15.1°±0.2°、15.9°±0.2°、17.2°±0.2°、17.7°±0.2°、17.9°±0.2°、18.5°±0.2°、20.2°±0.2°和20.9°±0.2°。
非限制性地，所述晶型V的一个典型实例具有如图15所示的XRPD图谱。
本发明还提供晶型V的制备方法，包括以下步骤：将本发明的晶型II加热后，得到所述晶型V。
优选地，所述加热速率为20～30℃/分钟；
优选地，所述加热终点温度为80～120℃。
根据本发明的目的，本发明的内容之六是提供替吡法尼无定型及其制备方法。
非限制性地，所述无定型的一个典型实例具有如图16所示的XRPD。
本发明提供替吡法尼无定型固体的制备方法，其包括以下步骤：将替吡法尼固体在溶剂中形成溶夜，减压浓缩干溶剂，得到所述替吡法尼无定型固体。
优选地，所述溶剂为二氯甲烷；
优选地，所述替吡法尼固体与溶剂的质量体积比为50～100mg:1mL；
优选地，所述减压浓缩在30～40℃下进行。
本发明的替吡法尼晶型的各制备方法中：原料“替吡法尼”可以为已公开的替吡法尼化合物或其其晶型，例如包括但不限于参照专利文献CN1101392C、CN100567292C、CN1246318C中任意一种制备方法得到的替吡法尼。这些专利文献通过引用其全文的方式并入到本申请中。
本发明中使用的术语有：
所述“室温”，是指10～30℃。
所述“过夜”，是指跨越晚上的时间，通常指10～16小时。
所述“搅拌”可以采用本领域的常规方法，例如搅拌方式包括磁力搅拌、机械搅拌，搅拌速度为50～1800转/分，优选300～900转/分。
所述“分离”可以采用本领域的常规方法，例如离心或过滤。优选减压过滤，一般是在室温下以小于大气压的压力进行抽滤，优选压力小于0.09MPa。
所述“干燥”，可以采用本领域的常规技术完成，例如常温干燥、鼓风干燥或减压干燥。干燥仪器和方法不受限制，可以是通风橱、鼓风烘箱、喷雾干燥器、流化床干燥或真空烘箱；可以减压或常压，优选压力小于0.09MPa。干燥温度为10～40℃，干燥时间为10～72小时，优选为2～24小时，更优选为2～8小时。
所述减压浓缩是指采用旋转蒸发仪进行的操作，在小于大气压的压力下进行溶剂挥发，实验温度为10～50℃，转速为50～200转/分钟。
本发明中所述的“晶型”是指化合物被所示X-射线粉末衍射图谱表征所证实的，在晶格内具有独特有序的分子排列或构型。本领域技术人员公知，其中的实验误差取决于仪器条件、样品准备和样品纯度。XRD图谱中的峰的2θ角度通常会随着仪器和样品不同而略有不同。峰角度的差值根据不同仪器，不同样品等可能相差1°，0.8°，0.5°,03°,0.1°等，通常允许误差°±0.2°，所以峰角度的差别不能作为唯一标准。峰的相对强度可能随样品、样品制备和其他实验条件而变化，所以峰强度的顺序不能作为唯一或决定性因素。样品高度等实验因素的影响会造成峰角度整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，任何具有与本发明X射线粉末衍射图谱相同或相似特征峰的晶型均属于本发明的范畴。“单一晶型”是指经X-射线粉末衍射检测为单一晶型。
本发明所述替吡法尼的晶型是基本纯的、单一的，基本没有混合任何 其他晶型或非晶态。本发明中“基本纯的”当用来指新晶型时，指这个新晶型占所存在的化合物的至少80％(重量)，更指至少90％(重量)，尤其指至少95％(重量)，特别是指至少99％(重量)。
本发明的内容之七是根据本发明的目的，提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的药物活性成分选自本发明的替吡法尼的晶型或者由本发明方法制备得到的替吡法尼的晶型，以及至少一种药学上可接受的载体。其中，所述替吡法尼晶型包括替吡法尼晶型I、晶型II、晶型III和晶型IV。此外，所述药物组合物还可以包含替吡法尼的其它可药用的晶型(例如晶型V)或无定型。
所述药物组合物中的赋形剂，是本领域技术人员公知的，其种类、用法、用量的选择也是本领域技术人员公知的。例如包括糖类，纤维素及其衍生物，淀粉或改性淀粉，粘合剂如微晶纤维素、乙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、羟乙基纤维素，崩解剂如乙醇酸淀粉钠、交聚维酮、交联羧甲基纤维素、羧甲基纤维素钠、干玉米淀粉，润滑剂如硬脂酸、硬脂酸镁、硬脂酰富马酸钠、聚乙二醇，填充剂如高岭土。
所述药物组合的给药途径包括口服、静脉皮下注射、注射入组织给药、经皮给药、直肠给药等。所述药物组合可以根据给药途径或需要，制备成一定的剂型，可为固态或液态。固体口服剂型，例如包括片剂、粉剂、丸剂和胶囊剂；液体口服剂型，例如包括溶液剂、糖浆剂、混悬剂和酏剂；可注射制剂，例如包括溶液剂和混悬剂；喷雾或上皮给药等。配方可适于药物活性成分的速释、缓释或可控释放。可以是常规的、可分散的、可咀嚼的、口腔溶解的或快速溶化的制剂。
所述药物组合物可以使用本领域技术人员公知的方法来制备。制备药物组合物时，将本发明的替吡法尼晶型I、晶型II、晶型III和晶型IV与一种或多种药学上可接受的赋形剂相混合，任选地与可药用的替吡法尼的其它晶型、无定型物相混合，任选地与一种或多种其他的药物活性成分相混合。固体制剂可以通过直接混合、制粒等工艺来制备。
根据本发明的目的，本发明提供本发明的替吡法尼的晶型或者由本发明制备方法得到的替吡法尼的晶型在制备用于治疗和/或预防细胞异常生长疾病的药物中的用途。所述疾病包括但不限于和RAS突变或过度表达有关的实体肿瘤和血癌，如肺癌、胰腺癌、结肠癌、甲状腺滤泡癌、脊髓发育不良综合症、间质起源的肿瘤、黑色素瘤、畸胎癌、成神经细胞瘤、神经胶质瘤、表皮癌如头颈鳞状细胞癌、唾液腺癌、皮肤的良性肿瘤、乳腺癌、肾癌、骨癌、卵巢癌、膀胱癌、肝癌、多发性神经纤维瘤、淋巴瘤谱系的造血性肿瘤如外周T淋巴细胞瘤、骨髓性白血病、骨髓异常增生综合症(MDS)、慢性粒细胞白血病等。根据本发明的目的，本发明提供一种用于治疗和/或预防细胞异常生长疾病的方法，所述方法包括给予需要的患者治疗和/或预防有效量的本发明的替吡法尼的晶型I、晶型II、晶型III、和晶型IV的前述药物组合物；所述疾病同本说明书的前述内容。
活性化合物通常在很大剂量范围内有效。通常认为有效量为0.0001毫克/ 公斤至100毫克/公斤体重，尤其为0.001毫克/公斤至10毫克/公斤体重，适于在全天内，以适当的间隔分二次、三次、四或更小剂量给与所需剂量，所述小剂量可以以单位计量形式配制，如每单位剂量形式含有活性成分0.01至500mg，尤其0.1毫克至200mg。
附图说明
图1为参考专利文献CN1246318C中方法制备得到的替吡法尼的X-射线粉末衍射图。
图2为本发明替吡法尼晶型I的X-射线粉末衍射图。
图3为本发明替吡法尼晶型I的DSC图谱。
图4为本发明替吡法尼晶型I的TGA图谱。
图5为本发明替吡法尼晶型I的等温吸附曲线。
图6为本发明替吡法尼晶型II的X-射线粉末衍射图。
图7为本发明替吡法尼晶型II的DSC图谱。
图8为本发明替吡法尼晶型II的TGA图谱。
图9为本发明替吡法尼晶型III的X-射线粉末衍射图。
图10为本发明替吡法尼晶型III的DSC图谱。
图11为本发明替吡法尼晶型III的TGA图谱。
图12为本发明替吡法尼晶型IV的X-射线粉末衍射图。
图13为本发明替吡法尼晶型IV的DSC图谱。
图14为本发明替吡法尼晶型IV的TGA图谱。
图15为本发明替吡法尼晶型V的X-射线粉末衍射图。
图16为本发明替吡法尼无定型的X-射线粉末衍射图。
具体实施方案
通过下述实施例将有助于进一步理解本发明，但是不用于限制本发明的内容。
检测仪器及方法：
X-射线粉末衍射(XRPD)：仪器为Bruker D8 Advance diffractometer。样品在室温下测试。检测条件如下，角度范围：3～40°2θ，步长：0.02°2θ，速度：0.2秒/步。
差热分析(DSC)数据采自于TA Instruments Q200MDSC。检测方法为：取1～10毫克的样品放置于密闭铝坩埚内，以10℃/min的升温速度在40mL/min干燥氮气的保护下将样品从室温升至250℃。
热重分析(TGA)数据采自于TA Instruments Q500 TGA。检测方法为：取5～15mg的样品放置于白金坩埚内，采用分段高分辨检测的方式，以10℃/min的升温速度在40mL/min干燥氮气的保护下将样品从室温升至350℃。
红外光谱分析(IR)数据采自于Bruker Tensor 27，仪器控制软件和数据分析软件都是OPUS。通常采用ATR设备，在600-4000cm-1范围内，采集红外吸收光谱，样品和空白背景的扫描时间均为16秒，仪器分辨率4cm-1。
动态水份吸附分析(DVS)数据和等温吸附分析数据采自于TA Instruments Q5000 TGA。检测方法为：取1～10mg的样品放置于白金坩埚内， 检测相对湿度从0％到80％到0％变化过程中的重量变化。核磁氢谱数据(1HNMR)采自于Bruker Avance II DMX 400MHz核磁共振波谱仪。称量1～5mg样品，用约0.5mL氘代试剂溶解到核磁样品管中进行检测。
除非特殊注明，实施例均在室温下操作，溶剂比均为体积比。
实施例中所用的各种试剂如无特别说明均为市售购买。
制备例1
根据专利文献CN1246318C说明书中化合物(I)制备、拆分和纯化步骤所描述的方法制备得到替吡法尼固体。
其XRPD图谱如图1所示。
以上表征结果表明：参考专利文献CN1246318C中化合物(I)所描述的方法制备得到的替吡法尼为晶型A，结晶度较低。
实施例1
取200mg制备例1的替吡法尼，加入2.0mL二氯甲烷溶剂溶清，40℃减压浓缩，得到180mg替吡法尼无定型固体，收率为90％。
其XRPD图谱如图16所示。
实施例2
取20mg制备例1的替吡法尼，加入1.0mL乙酸乙酯形成悬浮液，10℃搅拌析晶，4天后，减压过滤，40℃真空干燥10小时，得到18mg替吡法尼晶型I，，收率为90％。
其XRPD图谱如图2所示。
其DSC图谱如图3所示。
其TGA图谱如图4所示。
其等温吸附曲线如图5所示。
实施例3
取100mg制备例1的替吡法尼，加入0.4mL乙腈和1.6mL甲基叔丁基醚的形成悬浮液，40℃搅拌析晶，5天后，减压过滤，60℃真空干燥48小时，得到88mg替吡法尼晶型I，收率88％。
实施例4
取30mg制备例1的替吡法尼，加入0.3mL正丙醇形成悬浮液，25℃搅拌析晶，4天后，减压过滤，40℃真空干燥24小时，得到25mg替吡法尼晶型I，收率83.3％。
实施例5
取40mg制备例1的替吡法尼，加入0.5mL乙醇形成悬浮液，30℃搅拌析晶，4天后，减压过滤，50℃真空干燥30小时，得到28mg替吡法尼晶型I，收率70％。
实施例6
对实施例5中的溶剂按以下表格进行替换均可获得替吡法尼晶型I。
Figure PCTCN2016108970-appb-000013
Figure PCTCN2016108970-appb-000014
实施例7
取10mg制备例1的替吡法尼，加入2.0mL丙酮溶剂溶清，25℃挥发至干，得到9.5mg替吡法尼晶型I，收率为95％。
实施例8
取10mg制备例1的替吡法尼，加入0.4mL二氯甲烷溶剂溶清，40℃挥发至干，得到9.6mg替吡法尼晶型I，收率为96％。
实施例9
取10mg制备例1的替吡法尼，加入1.0mL乙腈:水＝3:1的混合溶剂溶清，40℃挥发至干，得到8.9mg替吡法尼晶型I，收率为89％。
实施例10
取50mg制备例1的替吡法尼，加入1.0mL甲醇:丙酮＝3:1的混合溶剂溶清，30℃挥发至干，得到40mg替吡法尼晶型I，收率为80％。
实施例11
对实施例10中的溶剂按以下表格进行替换均可获得替吡法尼晶型I。
Figure PCTCN2016108970-appb-000015
实施例12
取20mg制备例1的替吡法尼，60℃条件下，加入0.5mL丙酮形成溶液，-10℃搅拌析晶，10小时后，减压过滤，室温真空干燥过夜，得到17.5mg替吡法尼晶型I，收率88％。
实施例13
取30mg制备例1的替吡法尼，70℃条件下，加入0.3mL异丙醇形成溶液，0℃搅拌析晶，1小时后，减压过滤，室温真空干燥过夜，得到26mg替吡法尼晶型，收率87％。
实施例14
取150mg制备例1的替吡法尼，75℃条件下，加入1.0mL甲醇形成溶液，10℃搅拌析晶，2小时后，减压过滤，室温真空干燥过夜，得到110mg替吡法尼晶型，收率73％。
实施例15
对实施例14中的溶剂按以下表格进行替换均可获得替吡法尼晶型I。
Figure PCTCN2016108970-appb-000016
实施例16
取10mg制备例1的替吡法尼，加入0.4mL甲醇形成溶液，加入5.2mL异丙醚，室温搅拌析晶，3分钟后，减压过滤，室温真空干燥48小时，得到8.4mg替吡法尼晶型I，收率84％。
实施例17
取10mg制备例1的替吡法尼，加入0.4mL四氢呋喃形成溶液，加入4.0mL正庚烷，搅拌析晶，60分钟后，减压过滤，室温真空干燥24小时，得到7.8mg替吡法尼晶型I，收率78％。
实施例18
取10mg制备例1的替吡法尼，加入1.0mL丙酮形成溶液加入5.0mL异丙醚，搅拌析晶，30分钟后，减压过滤，室温真空干燥10小时，得到7.6mg替吡法尼晶型I，收率76％。
实施例19
取10mg制备例1的替吡法尼，加入0.2mL乙醇形成溶液，加入1.8mL水，搅拌析晶，30分钟后，减压过滤，室温真空干燥10小时，得到6.5mg替吡法尼晶型I，收率65％。
实施例20
取40mg制备例1的替吡法尼，加入1.0mL三氟乙醇形成溶液，加入1.8mL水，搅拌析晶，30分钟后，减压过滤，室温真空干燥10小时，得到26mg替吡法尼晶型I，收率65％。
实施例21
对实施例20中的溶剂按以下表格进行替换均可获得替吡法尼晶型I。
Figure PCTCN2016108970-appb-000017
实施例22
取15mg实施例1的替吡法尼无定型固体，加入0.3mL乙酸乙酯形成悬浮液，室温搅拌析晶，15分钟后，减压过滤，室温真空干燥48小时，得到12mg替吡法尼晶型I，收率80％。
实施例23
取15mg实施例1的替吡法尼无定型固体，加入0.75mL乙腈形成混悬液，室温搅拌析晶，10分钟后，减压过滤，室温真空干燥24小时，得到12.3mg替吡法尼晶型I，收率82％。
实施例24
取15mg实施例1的替吡法尼无定型固体，加入0.15mL乙醇形成混悬液，室温搅拌析晶，20分钟后，减压过滤，室温真空干燥24小时，得到10.5mg替吡法尼晶型I，收率70％。
实施例25
对实施例24中的溶剂按以下表格进行替换均可获得替吡法尼晶型I。
Figure PCTCN2016108970-appb-000018
实施例3～25制备得到的样品与实施例2的样品具有相同或相似的XRPD图谱(未示出)、DSC图谱(未示出)、TGA图谱(未示出)，说明实施例3～25样品与实施例2的样品是相同的晶型。
实施例26
取12mg制备例1的替吡法尼，加入0.4mL甲醇溶剂溶清，10℃挥发至干，得到10mg替吡法尼晶型II，收率为80％。
其X-射线粉末衍射图谱如图6所示。
其DSC图谱如图7所示。
其TGA图谱如图8所示。
实施例27
取10mg制备例1所得替吡法尼固体样品10mg，加入1.0mL甲醇溶剂溶清，30℃挥发至干，得到24mg替吡法尼晶型II，收率为77％。
实施例28
取50mg制备例1所得替吡法尼，加入1.0mL三氟乙醇溶清，40℃挥发至干，得到38mg替吡法尼晶型II，收率为73％。
实施例29
对实施例28中的溶剂按以下表格进行替换均可获得替吡法尼晶型II。
Figure PCTCN2016108970-appb-000019
实施例30
取15mg实施例1的替吡法尼无定型固体，加入0.6mL水形成悬浮液，25℃下搅拌析晶，15分钟后，减压过滤，10℃真空干燥24小时，得到14.1mg替吡法尼晶型II，收率91％。
实施例31
取15.75mg实施例1的替吡法尼无定型固体，加入0.45mL含85％水的二甲亚砜溶液形成悬浮液，4℃搅拌析晶，10分钟后，减压过滤，30℃真空干燥10小时，得到13.5mg替吡法尼晶型II，收率83％。
实施例32
取10mg实施例1的替吡法尼无定型固体，加入0.1mL含50％水的乙醇溶液形成悬浮液，10℃搅拌析晶，20分钟后，减压过滤，25℃真空干燥20小时，得到8mg替吡法尼晶型II，收率77％。
实施例33
对实施例32中的溶剂按以下表格进行替换均可获得替吡法尼晶型II。
Figure PCTCN2016108970-appb-000020
实施例34
取15mg实施例1的替吡法尼无定型固体，在相对湿度为97％的湿度器中敞口放置1天，得到14mg替吡法尼晶型II，收率为90％。
实施例27～34制备得到的样品与实施例26的样品具有相同或相似的XRPD图谱(未示出)、DSC图谱(未示出)、TGA图谱(未示出)，说明实施例27～34样品与实施例26的样品是相同的晶型。
实施例35
取50mg制备例1的替吡法尼，60℃条件下，加入2.0mL含50％水的丙酮溶液溶清，-10℃搅拌析晶，1小时后，减压过滤，40℃真空干燥10小时，得到43mg替吡法尼晶型III，收率82％。
其XRPD如图9所示。
其DSC图谱如图10所示。
其TGA图谱如图11所示。
实施例36
取49mg制备例1的替吡法尼，70℃条件下，加入3.5mL含30％水的乙腈溶液溶清，0℃搅拌析晶，24小时后，减压过滤，10℃真空干燥24小时，得到45mg替吡法尼晶型III，收率87％。
实施例37
取10mg制备例1的替吡法尼，加入1mL乙腈形成溶液，加入15.0mL水，室温搅拌析晶，24小时后，减压过滤，10℃真空干燥24小时，得到8mg替吡法尼晶型III，收率76％。
实施例38
取10mg制备例1的替吡法尼，加入0.4mL1,4-二氧六环溶清，加入10.0mL正庚烷，室温搅拌析晶，1小时后，减压过滤，40℃真空干燥10小时，得到8.5mg替吡法尼晶型III，收率81％。
实施例39
取10mg制备例1的替吡法尼，在室温下加入5.0mL乙酸异丙酯溶清，将清液置于室温下搅拌，并滴加入15.0mL正庚烷，室温搅拌析晶，2小时，将析出的固体减压过滤，30℃真空干燥12小时，得到7.3mg替吡法尼晶型III，收率69％。
实施例40
对实施例39中的溶剂按以下表格进行替换均可获得替吡法尼晶型III。
Figure PCTCN2016108970-appb-000021
实施例41
取5mg制备例1的替吡法尼，加入1.0mL含1％水的丁酮溶清，30℃挥发至干，得到4mg替吡法尼晶型III，收率为76％。
实施例42
取10mg制备例1的替吡法尼，加入2.0mL含2％水的硝基甲烷溶清，20℃挥发至干，得到7.6mg替吡法尼晶型III，收率为72％。
实施例43
取8mg制备例1的所得替吡法尼固体样品，加入1.0mL含10％水的乙腈的混合溶液剂溶清，10℃挥发至干，得到5.6mg替吡法尼晶型III，收率为66％。
实施例44
对实施例43中的溶剂按以下表格进行替换均可获得替吡法尼晶型III。
Figure PCTCN2016108970-appb-000022
实施例36～44制备得到的样品与实施例35的样品具有相同或相似的XRPD图谱(未示出)、DSC图谱(未示出)、TGA图谱(未示出)，说明实施例36～44 样品与实施例35的样品是相同的晶型。
实施例45
取10mg制备例1的替吡法尼，加入1.0mL乙醇溶清，40℃挥发至干，得到9mg替吡法尼晶型IV，收率为90％。
其XRPD图谱如图12所示。
其DSC图谱如图13所示。
其TGA图谱如图14所示。
实施例46
取10mg制备例1的替吡法尼，加入0.4mL氯仿溶剂溶清，50℃挥发至干，得到8.5mg替吡法尼晶型IV，收率为85％。
实施例47
取10mg实施例26的替吡法尼晶型II，以30℃/分钟的升温速率加热至120℃，得到所述替吡法尼晶型V。
其XRPD图谱如图15所示。
实施例48
晶型和化学稳定性放置实验：分别取20mg本发明的替吡法尼晶型I、替吡法尼晶型II、替吡法尼晶型III、替吡法尼晶型IV，在60℃干燥条件下和40℃-75％RH进行放置，于对应时间进行XRD晶型检测。
Figure PCTCN2016108970-appb-000023
本发明的替吡法尼晶型I、替吡法尼晶型II、替吡法尼晶型III、替吡法尼晶型IV在60℃干燥条件下和40℃-75％RH放置10天后，仍各自保持原有晶型且纯度均几乎没有下降。说明本发明制备得到的替吡法尼晶型I、替吡法尼晶型II、替吡法尼晶型III、替吡法尼晶型IV具有较好的晶型和化学稳定性。
实施例49
片芯的制备：
将100克本发明的替吡法尼晶型I或晶型II或晶型III或晶型IV(以有效成分计)、570克乳糖和200克淀粉的混合物混匀并随后用5克十二烷基硫酸钠和10克聚乙烯吡咯烷酮的约200毫升水溶液湿润。将湿粉混合物过 筛，干燥并再过筛，然后加入100克微晶纤维素和15克氢化植物油，将整体混匀并压制成片，得到10000片，每片含活性成分10毫克。
包衣：
向10克甲基纤维素的75毫升变性乙醇溶液中加入5克乙基纤维素的150毫升二氯甲烷溶液，然后加入75毫升二氯甲烷和2.5毫升1,2,3-丙三醇。将10克聚乙二醇熔化并溶于75毫升二氯甲烷中，将后一溶液加至前一溶液中并随后加入2.5克十八烷酸镁、5克聚乙烯吡咯酮和30毫升浓缩颜色混悬液并整体均化，在包衣装置中用如此所得混合物对片芯进行包衣。
实施例50
将1.8克4-羟基苯甲酸甲酯和0.2克4-羟基苯甲酸丙酯溶于约0.5毫升沸腾注射用水中，冷却至约50℃后，在搅拌下加入4克乳酸，0.05克丙二醇和4克本发明的替吡法尼晶型I或晶型II或晶型III或晶型IV(以有效成分计)。将上述溶液冷却至室温并用注射用水适量补充至1升体积，得到4毫克/毫升替吡法尼晶型I或晶型II或晶型III或晶型IV(以有效成分计)的溶液，将溶液过滤除菌并装至无菌容器。
对比例1
水中晶浆实验：分别取20mg制备例1的替吡法尼晶型A，本发明的替吡法尼晶型I、替吡法尼晶型II、替吡法尼晶型III和替吡法尼晶型IV，各自在水中室温搅拌3天，进行XRD晶型检测。
Figure PCTCN2016108970-appb-000024
结果显示：替吡法尼晶型A在水中搅拌3天转晶为替吡法尼晶型I，而本发明的替吡法尼晶型I、替吡法尼晶型II、替吡法尼晶型III、替吡法尼晶型IV在水中室温搅拌3天后，仍各自保持原有晶型。说明本发明的替吡法尼晶型I、替吡法尼晶型II、替吡法尼晶型III、替吡法尼晶型IV相比于现有技术在水中具有更好的晶型稳定性
本说明书中所引用的所有专利、专利申请公开、专利申请及非专利出版物，均通过引用以其全文并入本文中。
以上所述，仅为本发明的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本领域的技术人员在本发明所揭露的技术范围内，可不经过创造性劳动想到的变化或替换，都应涵盖在本发明的保护范围之内。因此，本发明的保护范围应该以权利要求书所限定的保护范围为准。

Claims (20)

  1. 结构式如下式(I)所示的替吡法尼晶型I，
    Figure PCTCN2016108970-appb-100001
    其特征在于，使用Cu-Kα辐射，所述晶型I以2θ角度表示的X-射线粉末衍射图具有以下特征峰：8.4°±0.2°、11.9°±0.2°、16.4°±0.2°、17.0°±0.2°、18.5°±0.2°和21.7°±0.2°。
  2. 根据权利要求1所述的替吡法尼晶型I，其特征在于，所述晶型I以2θ角度表示的X-射线粉末衍射图具有以下特征峰：8.4°±0.2°、11.9°±0.2°、15.3°±0.2°、16.4°±0.2°、17.0°±0.2°、18.0°±0.2°、18.5°±0.2°、20.4°±0.2°、21.3°±0.2°、21.7°±0.2°、24.8°±0.2°和26.8°±0.2°。
  3. 根据权利要求2所述的替吡法尼晶型I，其特征在于，所述晶型I以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰及其相对强度：
    Figure PCTCN2016108970-appb-100002
    Figure PCTCN2016108970-appb-100003
  4. 根据权利要求1～3所述的替吡法尼晶型I的制备方法，其特征在于，所述制备方法包括以下方法中的任意一种：
    1)将替吡法尼固体在溶剂中形成悬浮液，搅拌析晶，进而分离晶体，将析出的晶体分离、干燥，得到所述的替吡法尼晶型I；所述溶剂选自乙醇、正丙醇、水、硝基甲烷、丙酮、乙酸乙酯、异丙醚、甲基叔丁基醚、四氢呋喃、乙腈、二氯甲烷、正庚烷或其混合物，优选为乙酸乙酯、乙腈、甲基叔丁基醚、正丙醇或其混合物；
    优选地，所述替吡法尼固体与溶剂的质量体积比为5～100mg:1mL，更优选为20～50mg:1mL；
    优选地，所述搅拌时间为4～5天；
    优选地，所述搅拌过程在10～40℃下进行；
    优选地，所述干燥温度为40～60℃，所述干燥时间为10～48小时；
    2)将替吡法尼固体在溶剂中形成溶液，挥发至溶剂干，得到替吡法尼晶型I；所述溶剂选自酮类、酯类、正丙醇、仲丁醇、正丁醇、水、四氢呋喃、1,4-二氧六环、乙腈、二氯甲烷、甲苯或其混合物，优选为丙酮、二氯甲烷、水、乙腈或其混合物；
    优选地，所述替吡法尼固体与溶剂的质量体积比为5～50mg:1mL，更优选为5～25mg:1mL；
    优选地，所述混合物中两种溶剂的体积比为1:3～3:1；
    优选地，所述挥发过程在25～40℃下进行；
    3)将替吡法尼固体在溶剂中形成溶液，搅拌冷却析晶，进而分离晶体，干燥，得到替吡法尼晶型I；所述溶剂选自醇类、酮类、酯类、乙腈或其混合物；优选为丙酮或异丙醇。
    优选地，所述替吡法尼固体与溶剂的质量体积比为40～150mg:1mL，更优选为40～100mg:1mL。
    优选地，所述形成溶液的温度为60～75℃，更优选为60～70℃；
    优选地，所述搅拌析晶的温度为为-10～10℃，更优选为-10～0℃；
    优选地，所述析晶时间为1～10小时；
    4)将替吡法尼固体在良溶剂中形成溶液，加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到替吡法尼晶型I；所述良溶剂选自醇类、丙酮、乙酸乙酯、四氢呋喃、硝基甲烷；优选为甲醇、乙醇、丙酮或四氢呋喃；
    优选地，所述替吡法尼固体与良溶剂的质量体积比为10～50mg:1mL， 更优选为10～25mg:1mL；
    优选地，所述抗溶剂选自水、异丙醚、正庚烷；
    优选地，所述搅拌时间为3～60分钟；
    优选地，所述搅拌过程在室温下进行；
    5)将替吡法尼无定型固体在溶剂中形成悬浮液，搅拌析晶，进而分离晶体，将析出的晶体分离、干燥，得到所述的替吡法尼晶型I；所述溶剂选自醇类、酮类、酯类、醚类、烷烃类、四氢呋喃、乙腈；优选为乙酸乙酯或乙腈；
    优选地，所述替吡法尼无定型固体与溶剂的质量体积比为20～100mg:1mL，更优选为20～50mg:1mL；
    优选地，所述搅拌时间为10～20分钟，更优选为10～15分钟；
    优选地，所述搅拌过程在室温下进行。
  5. 结构式如下式(II)所示的替吡法尼晶型II，
    Figure PCTCN2016108970-appb-100004
    其特征在于，所述晶型II为一水合物，使用Cu-Kα辐射，所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰:5.3°±0.2°、6.8°±0.2°、8.5°±0.2°、16.3°±0.2°、18.0°±0.2°和20.9°±0.2°。
  6. 根据权利要求5所述的替吡法尼晶型II，其特征在于，所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰：5.3°±0.2°、6.8°±0.2°、8.5°±0.2°、12.8°±0.2°、13.8°±0.2°、16.3°±0.2°、16.9°±0.2°、17.1°±0.2°、18.0°±0.2°、18.5°±0.2°、20.9°±0.2°和27.9°±0.2°。
  7. 根据权利要求6所述的替吡法尼晶型II，其特征在于，所述晶型II以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2016108970-appb-100005
  8. 根据权利要求5～7中任一项所述替吡法尼晶型II的制备方法，其特征在于，所述制备方法包括下述方法中的任意一种：
    1)将替吡法尼固体在溶剂中形成溶液，挥发至溶剂干，得到替吡法尼晶型II；所述溶剂选自甲醇、乙醇、三氟乙醇或其混合物，优选为甲醇；
    优选地，所述替吡法尼固体与溶剂的质量体积比为10～50mg:1mL，更优选为10～30mg:1mL；
    优选地，所述挥发过程在10～40℃下进行，更优选为10～30℃；
    2)将替吡法尼无定型固体在溶剂中形成悬浮液，搅拌析晶，进而分离晶体，将析出的晶体分离、干燥，得到所述的替吡法尼晶型II；所述溶剂选自含水的醇类、酮类、四氢呋喃、1,4-二氧六环、乙腈、二甲亚砜；优选为含水的二甲亚砜；
    优选地，所述溶剂中水的体积百分比为50％～100％，更优选为85％～100％；
    优选地，所述替吡法尼固体与溶剂的质量体积比为25～100mg:1mL，更优选为25～35mg:1mL；
    优选地，所述搅拌时间为10～20分钟，更优选为10～15分钟；
    优选地，所述搅拌温度为4～25℃；
    优选地，所述干燥的温度为10～30℃；所述干燥的时间为10～24小时；
    3)将替吡法尼无定型固体置于湿度器中，得到替吡法尼晶型II；所述湿度器相对湿度为85％～100％，优选为97％；
    优选地，所述放置时间为1～7天，更优选为1天。
  9. 结构式如下式(III)所示的替吡法尼晶型III，
    Figure PCTCN2016108970-appb-100006
    其特征在于，所述晶型III为倍半水合物，使用Cu-Kα辐射，所述晶型III以2θ角度表示的X-射线粉末衍射图具有以下特征峰:6.2°±0.2°、8.8°±0.2°、15.9°±0.2°和18.2°±0.2°。
  10. 根据权利要求9所述的替吡法尼晶型III，其特征在于，所述晶型III以2θ角度表示的X-射线粉末衍射图具有以下特征峰：6.2°±0.2°、8.8°±0.2°、13.2°±0.2°、15.9°±0.2°、18.2°±0.2°、19.8°±0.2°、22.2°±0.2°和26.1°±0.2°。
  11. 根据权利要求10所述的替吡法尼晶型III，其特征在于，所述晶型III以2θ角度表示的X-射线粉末衍射图具有以下特征峰及其相对强度：
    Figure PCTCN2016108970-appb-100007
    Figure PCTCN2016108970-appb-100008
  12. 根据权利要求9～11中任一项所述替吡法尼晶型III的制备方法，其特征在于，所述制备方法包括下述方法中的任意一种：
    1)将替吡法尼固体在溶剂中形成溶液，搅拌冷却析晶，进而分离晶体，干燥，得到替吡法尼晶型III；所述溶剂选自水与乙腈或水与丙酮的混合溶剂；
    优选地，所述溶剂中水的体积百分比为30％～50％；
    优选地，所述替吡法尼固体与溶剂的质量体积比为14～25mg:1mL。
    优选地，所述形成溶液的温度为60～70℃；
    优选地，所述搅拌析晶的温度为-10～0℃；
    优选地，所述析晶时间为1～24小时；
    优选地，所述干燥的温度为10～40℃；所述干燥的时间为10～24小时；
    2)将替吡法尼固体在良溶剂中形成溶液，加入抗溶剂，搅拌析晶，进而分离晶体，干燥，得到替吡法尼晶型III；所述良溶剂选自乙腈、1,4-二氧六环、丁酮、乙酸异丙酯，优选为乙腈或1,4-二氧六环；
    优选地，所述替吡法尼固体与良溶剂的质量体积比为2～25mg:1mL，更优选为10～25mg:1mL。
    优选地，所述抗溶剂为水或正庚烷；
    优选地，所述搅拌时间为1～24小时；
    优选地，所述搅拌过程在室温下进行；
    优选地，所述干燥的温度为10～40℃；所述干燥的时间为10～24小时；
    3)将替吡法尼固体在溶剂中形成清液，挥发析晶，得到所述替吡法尼晶型III；所述溶剂选自含水的硝基甲烷、丁酮、乙腈、四氢呋喃、1,4-二氧六环、乙腈溶剂，优选为含水的丁酮或含水的硝基甲烷溶剂；
    优选地，所述替吡法尼固体与溶剂的质量体积比为5～10mg:1mL；
    优选地，所述溶剂中水的体积百分比为1％～10％；
    优选地，所述挥发温度为10～30℃，更优选为20～30℃。
  13. 结构式如下式(I)所示的替吡法尼晶型IV，
    Figure PCTCN2016108970-appb-100009
    其特征在于，使用Cu-Kα辐射，所述晶型IV以2θ角度表示的X-射线粉末衍射图具有以下特征峰：7.5°±0.2°、13.9°±0.2°、15.8°±0.2°、16.5°±0.2°、17.4°±0.2°和18.1°±0.2°。
  14. 根据权利要求13所述的替吡法尼晶型IV，其特征在于，所述晶型IV以2θ角度表示的X-射线粉末衍射图具有以下特征峰：7.5°±0.2°、13.9°±0.2°、15.4°±0.2°、15.8°±0.2°、16.5°±0.2°、17.4°±0.2°、18.1°±0.2°、20.7°±0.2°、21.6°±0.2°、24.3°±0.2°、26.5°±0.2°和29.1°±0.2°。
  15. 根据权利要求14所述的替吡法尼晶型IV，其特征在于，所述晶型IV以2θ角度表示的X-射线粉末衍射图在以下位置具有特征峰及其相对强度：
    Figure PCTCN2016108970-appb-100010
  16. 根据权利要求12～14所述的替吡法尼晶型IV的制备方法，其特征在于，所述制备方法包括以下步骤：
    将替吡法尼固体在溶剂中形成溶液，挥发至溶剂干，得到替吡法尼晶型IV；
    优选地，所述溶剂选自乙醇、氯仿；
    优选地，所述替吡法尼固体与溶剂的质量体积比为10～25mg:1mL；
    优选地，所述挥发过程在40～50℃下进行。
  17. 一种药物组合物，其包含治疗和/或预防有效量的一种或多种的选 自权利要求1～4中任一项所述的替吡法尼晶型I、权利要求5～8中任一项所述的替吡法尼晶型II、权利要求9～12中任一项所述的替吡法尼晶型III、权利要求13～16中任一项所述的替吡法尼晶型IV，以及至少一种药学上可接受的载体。
  18. 根据权利要求17所述的药物组合物，其特征在于，所述药物组合物选自片剂、胶囊剂、丸剂、粉剂、溶液剂、糖浆剂、混悬剂、酏剂或注射液。
  19. 权利要求1～4中任一项所述的替吡法尼晶型I、权利要求5～8中任一项所述的替吡法尼晶型II、权利要求9～12中任一项所述的替吡法尼晶型III、权利要求13～16中任一项所述的替吡法尼晶型IV，在制备治疗和/或预防细胞异常生长疾病的用途；所述疾病包括但不限于和RAS突变或过度表达有关的实体肿瘤和血癌，如肺癌、胰腺癌、结肠癌、甲状腺滤泡癌、脊髓发育不良综合症、间质起源的肿瘤、黑色素瘤、畸胎癌、成神经细胞瘤、神经胶质瘤、表皮癌如头颈鳞状细胞癌、唾液腺癌、皮肤的良性肿瘤、乳腺癌、肾癌、骨癌、卵巢癌、膀胱癌、肝癌、多发性神经纤维瘤、淋巴瘤谱系的造血性肿瘤如外周T淋巴细胞瘤、骨髓性白血病、骨髓异常增生综合症(MDS)、慢性粒细胞白血病等。
  20. 一种治疗和/或预防细胞异常生长疾病的方法，所述方法包括给予需要的患者治疗和/或预防有效量的一种或多种选自权利要求1～4中任一项所述的替吡法尼晶型I、权利要求5～8中任一项所述的替吡法尼晶型II、权利要求9～12中任一项所述的替吡法尼晶型III、权利要求13～16中任一项所述的替吡法尼晶型IV或权利要求17～19中任一项所述的药物组合物；所述细胞异常生长疾病包括但不限于和RAS突变或过度表达有关的实体肿瘤和血癌，如肺癌、胰腺癌、结肠癌、甲状腺滤泡癌、脊髓发育不良综合症、间质起源的肿瘤、黑色素瘤、畸胎癌、成神经细胞瘤、神经胶质瘤、表皮癌如头颈鳞状细胞癌、唾液腺癌、皮肤的良性肿瘤、乳腺癌、肾癌、骨癌、卵巢癌、膀胱癌、肝癌。多发性神经纤维瘤、淋巴瘤谱系的造血性肿瘤如外周T淋巴细胞瘤、骨髓性白血病、骨髓异常增生综合症(MDS)、慢性粒细胞白血病等。
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