WO2020108408A1 - Crystalline form of larotrectinib hydrogen sulfate salt, preparation method therefor and use thereof - Google Patents

Crystalline form of larotrectinib hydrogen sulfate salt, preparation method therefor and use thereof Download PDF

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WO2020108408A1
WO2020108408A1 PCT/CN2019/120340 CN2019120340W WO2020108408A1 WO 2020108408 A1 WO2020108408 A1 WO 2020108408A1 CN 2019120340 W CN2019120340 W CN 2019120340W WO 2020108408 A1 WO2020108408 A1 WO 2020108408A1
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crystalline form
form azt
azt
mixed liquid
compound
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PCT/CN2019/120340
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French (fr)
Chinese (zh)
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彭欢
张良
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安礼特（上海）医药科技有限公司
江苏创诺制药有限公司
上海创诺医药集团有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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

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  • the invention relates to the field of medicine, in particular to the crystalline form of latinotinib bisulfate and its preparation and application.
  • Larotrectinib (Larotrectinib, trade name: LOXO-101) is an inhibitor of tropomyosin receptor developed by the American company ARRAY BIOPHARMA, used to treat adults or children with solid tumors carrying the Trk fusion gene.
  • the medicinal form of lalotinib is bisulfate.
  • the drug has obtained the breakthrough therapy certification and orphan drug qualification issued by the US FDA, and has shown good effects on cancer patients carrying the Trk fusion gene in multiple clinical trials.
  • Lalotinib has the chemical name (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a ] Pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, the molecular structure of which is shown in formula (I):
  • Patent WO2016077841 discloses a crystal-free I-HS of the bisulfate salt of the compound of formula (I), but the solubility of the crystal-free type is low, resulting in low bioavailability and affecting the therapeutic effect.
  • the purpose of the present invention is to provide the crystalline form of Lalotinib bisulfate with excellent dissolution performance, mechanical stability performance and high humidity stability performance and its preparation and application.
  • a crystal form of a hydrogen sulfate salt of a compound of formula (I) is selected from the group consisting of crystal form AZT-I, crystal form AZT-II,
  • the XRPD pattern of the crystalline form AZT-I includes 3 or more 2 ⁇ values selected from the group consisting of 15.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.2° ⁇ 0.2°, 24.9° ⁇ 0.2° ;
  • the XRPD pattern of the crystalline form AZT-II includes 3 or more 2 ⁇ values selected from the group consisting of 5.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 19.5° ⁇ 0.2°, and 24.9° ⁇ 0.2°.
  • the XRPD pattern of the crystalline form AZT-I includes 6 or more 2 ⁇ values selected from the group consisting of 14.3° ⁇ 0.2°, 15.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.2° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.9° ⁇ 0.2°.
  • the XRPD pattern of the crystalline form AZT-I includes 6 or more 2 ⁇ values selected from the group consisting of 7.6° ⁇ 0.2°, 8.6° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.8° ⁇ 0.2°, 17.2° ⁇ 0.2°, 18.2° ⁇ 0.2°, 18.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.2° ⁇ 0.2°, 22.2° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.9° ⁇ 0.2°, 25.7° ⁇ 0.2°, 26.2° ⁇ 0.2°, 27.7° ⁇ 0.2°, 28.4° ⁇ 0.2°, 31.4° ⁇ 0.2°.
  • the crystalline form AZT-I has one or more characteristics selected from the group consisting of:
  • the crystalline form AZT-I has an XRPD pattern substantially as shown in FIG. 1;
  • the crystalline form AZT-I has a TGA diagram substantially as shown in FIG. 2.
  • the XRPD pattern of the crystalline form AZT-II includes 3 or more 2 ⁇ values selected from the group consisting of 5.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 16.5° ⁇ 0.2°, 19.5° ⁇ 0.2°, 24.9° ⁇ 0.2°.
  • the XRPD pattern of the crystalline form AZT-II includes 6 or more 2 ⁇ values selected from the group consisting of 5.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.0° ⁇ 0.2°, 16.5° ⁇ 0.2°, 18.3° ⁇ 0.2°, 19.5° ⁇ 0.2°, 24.9° ⁇ 0.2°, 26.0° ⁇ 0.2°.
  • the XRPD pattern of the crystalline form AZT-II includes 6 or more 2 ⁇ values selected from the group consisting of 5.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 9.1° ⁇ 0.2°, 11.0° ⁇ 0.2°, 14.0° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.5° ⁇ 0.2°, 18.3° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.1° ⁇ 0.2°, 20.7° ⁇ 0.2°, 22.1° ⁇ 0.2°, 23.2° ⁇ 0.2°, 24.3° ⁇ 0.2°, 24.9° ⁇ 0.2°, 26.0° ⁇ 0.2°, 26.6° ⁇ 0.2°, 28.7° ⁇ 0.2°, 29.5° ⁇ 0.2 °, 30.0° ⁇ 0.2°.
  • the crystalline form AZT-II has one or more characteristics selected from the group consisting of:
  • the crystalline form AZT-II has an XRPD pattern substantially as shown in FIG. 3;
  • the crystalline form AZT-II has a TGA diagram substantially as shown in FIG. 4;
  • the DSC chart of the crystalline form AZT-II has a characteristic peak in the range of 108-131°C, and the onset is about 111°C;
  • the DSC chart of the crystalline form AZT-II has a characteristic peak in the range of 158-193°C, and the onset is about 175°C;
  • the DSC chart of the crystalline form AZT-II has a characteristic peak in the range of 204-228°C and the onset is about 211°C;
  • the crystalline form AZT-II has a DSC chart substantially as shown in FIG. 5;
  • the solubility of the crystalline form AZT-II in pure water is ⁇ 90mg/mL, preferably ⁇ 100mg/mL;
  • the solubility of the crystalline form AZT-II in a hydrochloric acid solution of pH 1.2 is ⁇ 110 mg/mL, preferably ⁇ 120 mg/mL;
  • the solubility of the crystalline form AZT-II in an acetate solution of pH 4.5 is ⁇ 100 mg/mL, preferably ⁇ 110 mg/mL;
  • the 2 ⁇ value of the XRPD pattern of the crystalline form AZT-I has a deviation of ⁇ 0.5, preferably a deviation of ⁇ 0.3, and more preferably a deviation of ⁇ 0.1.
  • the 2 ⁇ value of the XRPD pattern of the crystalline form AZT-II has a deviation of ⁇ 0.5, preferably a deviation of ⁇ 0.3, and more preferably a deviation of ⁇ 0.1.
  • a method for preparing crystalline form AZT-I is selected from the group consisting of:
  • the first good solvent is selected from the group consisting of water, alcohols, ketones, amides, or a combination thereof.
  • the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, or a combination thereof.
  • the ketones are selected from the group consisting of N-methylpyrrolidone, acetone, methyl isobutyl ketone, methyl butanone, 2-butanone, or a combination thereof.
  • the amides are selected from the group consisting of N,N dimethylformamide, N,N-dimethylacetamide, or a combination thereof.
  • the first organic solvent is selected from the group consisting of isoamyl alcohol, n-amyl alcohol, anisole, ethyl acetate, n-heptane, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, Chloroform, or a combination thereof.
  • the stirring is performed at 5-40°C, preferably 10-30°C, more preferably 15-28°C.
  • a method for preparing crystalline form AZT-II is selected from the group consisting of:
  • a-1) Provide a first mixed liquid and a third mixed liquid, wherein the first mixed liquid contains a first good solvent and a hydrogen sulfate salt of the compound of formula (I) dissolved therein, and the third mixed liquid contains the first An organic solvent and a crystalline form selected from the group consisting of crystalline form AZT-I, crystalline form AZT-II, amorphous form of the hydrogen sulfate salt of the compound of formula (I), and crystalline form I-HS;
  • c-1) Provide crystal form AZT-I;
  • the fourth mixed solution is volatilized at 10-25° C. and crystallized to obtain the crystal form AZT-II.
  • the heating treatment temperature is 40-200°C.
  • the heating treatment time is 3-30 minutes, preferably 10-15 minutes.
  • the second organic solvent is selected from the group consisting of methanol, acetonitrile, or a combination thereof.
  • a pharmaceutical composition comprising the following components:
  • the cancer is caused by TRK fusion mutation.
  • the cancer is selected from the group consisting of lung cancer, colon cancer, thyroid cancer, breast cancer, and childhood tumors.
  • FIG. 1 is an XRPD pattern of the crystalline form AZT-I obtained in Example 1.
  • FIG. 1 is an XRPD pattern of the crystalline form AZT-I obtained in Example 1.
  • FIG. 2 is a TGA diagram of the crystalline form AZT-I obtained in Example 1.
  • FIG. 2 is a TGA diagram of the crystalline form AZT-I obtained in Example 1.
  • FIG. 3 is an XRPD pattern of the crystalline form AZT-II obtained in Example 4.
  • FIG. 4 is a TGA diagram of the crystalline form AZT-II obtained in Example 4.
  • FIG. 4 is a TGA diagram of the crystalline form AZT-II obtained in Example 4.
  • Example 5 is a DSC chart of the crystalline form AZT-II obtained in Example 4.
  • FIG. 6 is a DVS diagram of the crystalline form AZT-II obtained in Example 4.
  • FIG. 6 is a DVS diagram of the crystalline form AZT-II obtained in Example 4.
  • Example 7 is an XRPD pattern before and after DVS of the crystalline form AZT-II obtained in Example 4 (the upper graph is the XRPD graph before DVS and the lower graph is the XRPD graph after DVS).
  • Example 8 is a comparison diagram of the stability XRPD of the crystalline form AZT-II in Example 10 placed at 25°C/92.5% relative humidity for 10 days (the upper picture is the XRPD picture before being placed, and the lower picture is the XRPD picture after being placed).
  • Example 9 is an XRPD pattern before and after milling of the crystalline form AZT-II in Example 11 (the upper graph is the XRPD graph before milling and the lower graph is the XRPD graph after milling).
  • the inventor unexpectedly prepared two crystalline forms of latinoib bisulfate with excellent solubility, mechanical stability and high humidity stability. On this basis, the inventor completed the present invention.
  • onset generally refers to the extrapolated starting temperature.
  • the crystalline form AZT-I provided by the present invention has X-ray powder diffraction patterns with characteristic peaks at 2 ⁇ values of 15.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 24.9° ⁇ 0.2°.
  • the crystalline form AZT-I provided by the present invention has an X-ray powder diffraction pattern at 2 ⁇ values of 14.3° ⁇ 0.2°, 15.8° ⁇ 0.2°, 18.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.2° There are characteristic peaks at ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.9° ⁇ 0.2°.
  • the crystalline form AZT-I provided by the present invention has an X-ray powder diffraction pattern at 2 ⁇ values of 7.6° ⁇ 0.2°, 8.6° ⁇ 0.2°, 14.3° ⁇ 0.2°, 15.8° ⁇ 0.2°, 17.2° ⁇ 0.2°, 18.2° ⁇ 0.2°, 18.8° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.2° ⁇ 0.2°, 22.2° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.4° ⁇ 0.2°, 24.9° ⁇ 0.2
  • X-ray powder diffraction (XRPD) pattern of the crystalline form AZT-I provided by the present invention is basically shown in FIG. 1.
  • thermogravimetric analysis (TGA) curve of the crystalline form AZT-I provided by the present invention is basically shown in FIG. 2.
  • the present invention provides a method for preparing the above crystalline form AZT-I, which comprises dissolving the bisulfate salt of the compound of formula (I) in an organic solvent to obtain a mixture, and then adding the mixture dropwise to an anti-solvent and stirring Crystallization, the resulting solid is crystalline form AZT-I.
  • the mixture is filtered before being added dropwise to the anti-solvent.
  • the organic solvent includes a single or mixed system of water, alcohols, ketones, and amide solvents, preferably N-methylpyrrolidone.
  • the anti-solvent may be isoamyl alcohol, n-amyl alcohol, anisole, ethyl acetate, n-heptane, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran and chloroform.
  • the present invention provides a method for preparing the above crystalline form AZT-I, which comprises dissolving the hydrogen sulfate salt of the compound of formula (I) in an organic solvent to obtain a mixture, and then placing the mixture in a sealed anti-solvent atmosphere and stirring Crystallization, collecting the solid is the crystalline form AZT-I.
  • the mixture is filtered before being added dropwise to the anti-solvent.
  • the organic solvent includes a single or mixed system of water, alcohols, ketones, and amide solvents, preferably N-methylpyrrolidone.
  • the anti-solvent may be isoamyl alcohol, n-amyl alcohol, anisole, ethyl acetate, n-heptane, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran and chloroform.
  • the present invention provides a method for preparing the above crystalline form AZT-I, which comprises placing the bisulfate amorphous form of the compound of formula (I) (prepared according to Example 3 of WO2016077841) in an anti-solvent and stirring , Collect the solid to get crystalline form AZT-I.
  • the anti-solvent may be isoamyl alcohol, n-amyl alcohol, anisole, ethyl acetate, n-heptane, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran and chloroform.
  • stirring temperature is 5-25°C.
  • stirring time is 2 days.
  • the present invention provides a crystalline form AZT-II whose X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ values of 5.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 19.5° ⁇ 0.2°, and 24.9° ⁇ 0.2°.
  • the crystalline form AZT-II provided by the present invention has an X-ray powder diffraction pattern at 2 ⁇ values of 5.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 16.5° ⁇ 0.2°, 19.5° ⁇ 0.2°, 24.9° There is a characteristic peak at ⁇ 0.2°.
  • the crystalline form AZT-II provided by the present invention has an X-ray powder diffraction pattern at 2 ⁇ values of 5.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.0° ⁇ 0.2°, 16.5° There are characteristic peaks at ⁇ 0.2°, 18.3° ⁇ 0.2°, 19.5° ⁇ 0.2°, 24.9° ⁇ 0.2°, 26.0° ⁇ 0.2°.
  • the crystalline form AZT-II provided by the present invention has an X-ray powder diffraction pattern at 2 ⁇ values of 5.5° ⁇ 0.2°, 7.3° ⁇ 0.2°, 7.8° ⁇ 0.2°, 9.1° ⁇ 0.2°, 11.0° ⁇ 0.2°, 14.0° ⁇ 0.2°, 15.6° ⁇ 0.2°, 16.5° ⁇ 0.2°, 18.3° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.1° ⁇ 0.2°, 20.7° ⁇ 0.2°, 22.1° ⁇ 0.2 °, 23.2° ⁇ 0.2°, 24.3° ⁇ 0.2°, 24.9° ⁇ 0.2°, 26.0° ⁇ 0.2°, 26.6° ⁇ 0.2°, 28.7° ⁇ 0.2°, 29.5° ⁇ 0.2°, 30.0° ⁇ 0.2° With characteristic peaks.
  • X-ray diffraction (XRPD) pattern of the crystalline form AZT-II provided by the present invention is basically shown in FIG. 3.
  • thermogravimetric analysis (TGA) curve of the crystalline form AZT-II provided by the present invention is basically shown in FIG. 4.
  • DSC differential scanning calorimetry
  • the present invention provides a method for preparing the above crystalline form AZT-II, which comprises dissolving the hydrogen sulfate salt of the compound of formula (I) in a suitable organic solvent, and then adding the solution dropwise to methylene chloride, After stirring and crystallization, the solid obtained is the crystalline form AZT-II.
  • dichloromethane contains seed crystals selected from the group consisting of amorphous form of the compound (I) bisulfate, crystalline form I-HS, crystalline form AZT-I, crystalline form AZT-II .
  • the organic solvent includes a single or mixed system of water, alcohols, ketones, and amide solvents.
  • organic solvent is selected from N-methylpyrrolidone, N,N dimethylformamide, N,N dimethylacetamide.
  • the present invention provides a method for preparing the above crystalline form AZT-II, which includes heating AZT-I to 50-190°C under the protection of nitrogen, and the resulting solid is crystalline form AZT-II.
  • the present invention provides a method for preparing the above-mentioned crystalline form AZT-II, which includes leaving the AZT-I open at 5-25°C for a period of time, and the resulting solid is the crystalline form AZT-II.
  • the period of time is 8-10 days.
  • the present invention provides a method for preparing the above-mentioned crystalline form AZT-II, which includes dissolving the hydrogen sulfate salt of the compound of formula (I) in a methanol/acetonitrile (1:4, v/v) system and placing Evaporate at -25°C until a solid precipitates, and the resulting solid is the crystalline form AZT-II.
  • the crystalline form AZT-I can be converted into the crystalline form AZT-II relatively easily and quickly.
  • the present invention can also provide a pharmaceutical composition
  • a pharmaceutical composition comprising the crystalline form of the compound of formula (I) bisulfate and a pharmaceutically acceptable carrier.
  • the crystalline form of the compound of formula (I) is selected Automorphic AZT-I and crystalline form AZT-II.
  • the present invention can also provide the use of the crystalline form of the compound (I) bisulfate in the preparation of a medicament for treating cancer.
  • the crystalline form of the compound (I) bisulfate is selected from the crystalline form AZT-I and Crystal form AZT-II.
  • the present invention can also provide the use of the crystalline form of the compound (I) bisulfate in the preparation of the compound of formula (I) or other salts.
  • the crystalline form of the compound (I) is selected from the crystalline form AZT-I And crystal form AZT-II.
  • the crystalline form AZT-I and the crystalline form AZT-II of the present invention can be used to prepare Lalotinib free base or other salts of Lalotinib.
  • the method of free base or salt formation can be prepared according to conventional methods.
  • the crystalline form of the present invention has excellent solubility, can reduce the amount of solvent used, save resources and reduce costs.
  • the crystalline form AZT-I and the crystalline form AZT-II of the present invention can be used to prepare a medicine for treating cancer, and the medicine can be prepared by a method commonly used in the art.
  • the cancer is caused by TRK (troponin receptor kinase) fusion mutation, such as lung cancer, colon cancer, thyroid cancer, breast cancer, and some children's tumors.
  • TRK troponin receptor kinase
  • the present invention has the following main advantages:
  • the crystalline form has excellent dissolution performance, mechanical stability and high humidity stability
  • the preparation method of the crystal form has the characteristics of simple and easy operation, low cost, and suitable for application in drug research and development and industrial production;
  • the obtained pharmaceutical composition prepared in the crystal form has better dissolution, which has excellent absorption performance and bioavailability after being administered to a patient.
  • the crystal water of the crystal form in the present invention comes from air or a solvent.
  • the solvents used in the present invention are all analytically pure and have a water content of about 0.1%.
  • Larotinib bisulfate or larotinib bisulfate as the raw material in the examples is obtained by purchasing or referring to the patent WO2016077841. All the test methods of the present invention are general methods, and the test parameters are as follows:
  • X-ray powder diffraction instrument Bruker D2 Phaser X-ray powder diffraction instrument; radiation source Cu Generator (Generator) kv: 30kv; Generator (Generator) mA: 10mA; initial 2 ⁇ : 2.000°, scanning range: 2.000 ⁇ 35.000°, scanning step length 0.02°, scanning speed 0.1s/step.
  • Thermogravimetric analysis (TGA) instrument TGA55 type of American TA company; temperature range: 20 ⁇ 300°C; heating rate: 10°C/min; nitrogen flow rate: 40mL/min.
  • DSC Differential scanning calorimetry
  • Dynamic Moisture Absorption Instrument (DVS) instrument TA model Q5000 SA of American TA Company; temperature: 25°C; nitrogen flow rate: 50mL/min; mass change per unit time: 0.002%/min; relative humidity range: 0%RH-90% RH.
  • DVS Dynamic Moisture Absorption Instrument
  • the XRPD test is performed on the obtained solid, and the X-ray powder diffraction pattern is shown in FIG. 1; the TGA test is performed on the obtained solid, and the spectrum is shown in FIG. 2.
  • the obtained solid was subjected to XRPD test, and its X-ray powder diffraction pattern was basically as shown in FIG. 1.
  • the obtained solid was the AZT-I crystal form of the compound of formula (I) bisulfate.
  • the obtained solid was subjected to XRPD test, and its X-ray powder diffraction pattern was basically as shown in FIG. 1.
  • the obtained solid was the AZT-I crystal form of the compound of formula (I).
  • the solid obtained is the crystalline form AZT-II.
  • the XRPD test was performed on the obtained solid, and the X-ray powder diffraction pattern was shown in FIG. 3; the TGA test was performed on the obtained solid, and the spectrum is shown in FIG. 4.
  • the DSC test was performed on the obtained solid, and the spectrum is shown in FIG. 5. As shown.
  • the crystalline form AZT-II has an endothermic peak in the range of 108-131°C and onset of about 111°C; it has an endothermic peak in the range of 158-193°C and onset of about 175°C; There is an endothermic peak, onset about 211 °C.
  • the solid obtained is the crystalline form AZT-II.
  • the XRPD test was performed on the obtained solid, and its X-ray powder diffraction pattern was basically shown in FIG. 3.
  • the crystalline form AZT-I in the above Example 1 is heated to 50-190°C under the protection of nitrogen, and the obtained solid is the crystalline form AZT-II.
  • the XRPD test was performed on the obtained solid, and its X-ray powder diffraction pattern was basically shown in FIG. 3.
  • Example 1 The crystalline form AZT-I in Example 1 above was left open at 5-25°C for 9 days, and the resulting solid was the crystalline form AZT-II.
  • the XRPD test was performed on the obtained solid, and its X-ray powder diffraction pattern was basically shown in FIG. 3.
  • the XRPD test was performed on the obtained solid, and its X-ray powder diffraction pattern was basically shown in FIG. 3.
  • Example 9 Solubility of crystalline form AZT-II and crystal-free I-HS disclosed in WO2016077841
  • Example 10 Study on the hygroscopicity of crystalline form AZT-II
  • Example 4 Approximately 10 mg of the crystalline form AZT-II obtained in Example 4 was used to test its moisture absorption property using a dynamic moisture adsorption (DVS) instrument.
  • DVD dynamic moisture adsorption
  • the DVS pattern of the crystalline form AZT-II is shown in Fig. 6, and the weight gain is 0.3% at 80% relative humidity.
  • the XRPD comparison chart of the crystalline form AZT-II before and after the moisture absorption test is shown in Figure 7 (the upper picture is the XRPD picture before the test and the lower picture is the XRPD picture after the test)
  • the crystal form of AZT-II did not change before and after the hygroscopicity test.
  • Example 11 Crystal form AZT-II crystal form stability under high humidity
  • the crystalline form AZT-II obtained in the above example was placed in an open environment at 25°C/92.5%RH for 10 days, and XPRD was tested on days 0 and 10. The results are shown in FIG. It is still crystalline form AZT-II.
  • Example 12 Mechanical stability of crystalline form AZT-II
  • Example 4 After the AZT-II crystal form in the above Example 4 was rapidly milled at 25°C for 5 min, the XRPD was measured. As shown in FIG. 9, the crystalline forms remained unchanged.

Abstract

The present invention relates to a crystalline form of Larotrectinib hydrogen sulfate salt and a preparation method therefor and a use thereof. In particular, the crystalline form of Larotrectinib hydrogen sulfate salt disclosed in the present invention has excellent solubility, stable mechanical properties and stability under high humidity conditions.

Description

拉洛替尼硫酸氢盐晶型及其制备和应用Lalotinib bisulfate crystal form and its preparation and application 技术领域Technical field
本发明涉及医药领域，具体地涉及拉洛替尼硫酸氢盐晶型及其制备和应用。The invention relates to the field of medicine, in particular to the crystalline form of latinotinib bisulfate and its preparation and application.
背景技术Background technique
拉洛替尼(Larotrectinib，商品名：LOXO-101)是由美国ARRAY BIOPHARMA公司研发的一种原肌球蛋白受体的抑制剂，用于治疗携带Trk融合基因的成人或儿童实体瘤患者。拉洛替尼的药用形式是硫酸氢盐。该药物已经获得美国FDA颁发的突破性疗法认定和孤儿药资格，且在多项临床试验中对携带Trk融合基因的癌症患者表现出良好的疗效。拉洛替尼的化学名称为(S)-N-(5-((R)-2-(2,5-二氟苯基)吡咯烷-1-基)吡唑并[1,5-a]嘧啶-3-基)-3-羟基吡咯烷-1-甲酰胺，其分子结构如式(I)所示：Larotrectinib (Larotrectinib, trade name: LOXO-101) is an inhibitor of tropomyosin receptor developed by the American company ARRAY BIOPHARMA, used to treat adults or children with solid tumors carrying the Trk fusion gene. The medicinal form of lalotinib is bisulfate. The drug has obtained the breakthrough therapy certification and orphan drug qualification issued by the US FDA, and has shown good effects on cancer patients carrying the Trk fusion gene in multiple clinical trials. Lalotinib has the chemical name (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a ] Pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide, the molecular structure of which is shown in formula (I):
Figure PCTCN2019120340-appb-000001
Figure PCTCN2019120340-appb-000001
晶型不同可造成药物的溶解度和稳定性的差异，从而影响药物的吸收和生物利用度，进而导致临床效果的不同。因此，多晶型筛选是药物研发中一个至关重要的研究内容。Different crystal forms can cause differences in the solubility and stability of the drug, which affects the absorption and bioavailability of the drug, which in turn leads to different clinical effects. Therefore, polymorphic screening is a crucial research content in drug development.
专利WO2016077841公开了式(I)化合物硫酸氢盐的一个无水晶型I-HS，但该无水晶型的溶解度较低，从而导致其生物利用度低，影响治疗效果。Patent WO2016077841 discloses a crystal-free I-HS of the bisulfate salt of the compound of formula (I), but the solubility of the crystal-free type is low, resulting in low bioavailability and affecting the therapeutic effect.
因此，需要研究出一种同时具有较好的稳定性和溶解性的式(I)化合物的硫酸氢盐新晶型以及操作简便易行、成本低廉、适宜应用于药物研发和工业化生产中的该新晶型的制备方法。Therefore, there is a need to develop a new crystal form of the bisulfate salt of the compound of formula (I) which has good stability and solubility, and is easy to operate, low in cost, suitable for drug development and industrial production. Preparation method of new crystal form.
发明内容Summary of the invention
本发明的目的在于提供具有优异的溶解性能、机械稳定性能和高湿稳定性能的拉洛替尼硫酸氢盐晶型及其制备和应用。The purpose of the present invention is to provide the crystalline form of Lalotinib bisulfate with excellent dissolution performance, mechanical stability performance and high humidity stability performance and its preparation and application.
本发明的第一方面，提供了一种式(I)化合物的硫酸氢盐的晶型，所述晶型选自下组：晶型AZT-I、晶型AZT-II，According to a first aspect of the present invention, there is provided a crystal form of a hydrogen sulfate salt of a compound of formula (I), the crystal form is selected from the group consisting of crystal form AZT-I, crystal form AZT-II,
Figure PCTCN2019120340-appb-000002
Figure PCTCN2019120340-appb-000002
其中，所述晶型AZT-I的XRPD图谱包括3个或3个以上选自下组的2θ值：15.8°±0.2°、20.4°±0.2°、21.2°±0.2°、24.9°±0.2°；Wherein, the XRPD pattern of the crystalline form AZT-I includes 3 or more 2θ values selected from the group consisting of 15.8°±0.2°, 20.4°±0.2°, 21.2°±0.2°, 24.9°±0.2° ;
所述晶型AZT-II的XRPD图谱包括3个或3个以上选自下组的2θ值：5.5°±0.2°、7.3°±0.2°、19.5°±0.2°、24.9°±0.2°。The XRPD pattern of the crystalline form AZT-II includes 3 or more 2θ values selected from the group consisting of 5.5°±0.2°, 7.3°±0.2°, 19.5°±0.2°, and 24.9°±0.2°.
在另一优选例中，所述晶型AZT-I的XRPD图谱包括6个或6个以上选自下组的2θ值：14.3°±0.2°、15.8°±0.2°、18.8°±0.2°、20.4°±0.2°、21.2°±0.2°、22.7°±0.2°、23.4°±0.2°、24.9°±0.2°。In another preferred example, the XRPD pattern of the crystalline form AZT-I includes 6 or more 2θ values selected from the group consisting of 14.3°±0.2°, 15.8°±0.2°, 18.8°±0.2°, 20.4°±0.2°, 21.2°±0.2°, 22.7°±0.2°, 23.4°±0.2°, 24.9°±0.2°.
在另一优选例中，所述晶型AZT-I的XRPD图谱包括6个或6个以上选自下组的2θ值：7.6°±0.2°、8.6°±0.2°、14.3°±0.2°、15.8°±0.2°、17.2°±0.2°、18.2°±0.2°、18.8°±0.2°、20.4°±0.2°、21.2°±0.2°、22.2°±0.2°、22.7°±0.2°、23.4°±0.2°、24.9°±0.2°、25.7°±0.2°、26.2°±0.2°、27.7°±0.2°、28.4°±0.2°、31.4°±0.2°。In another preferred example, the XRPD pattern of the crystalline form AZT-I includes 6 or more 2θ values selected from the group consisting of 7.6°±0.2°, 8.6°±0.2°, 14.3°±0.2°, 15.8°±0.2°, 17.2°±0.2°, 18.2°±0.2°, 18.8°±0.2°, 20.4°±0.2°, 21.2°±0.2°, 22.2°±0.2°, 22.7°±0.2°, 23.4° ±0.2°, 24.9°±0.2°, 25.7°±0.2°, 26.2°±0.2°, 27.7°±0.2°, 28.4°±0.2°, 31.4°±0.2°.
在另一优选例中，所述晶型AZT-I具有选自下组的一个或多个特征：In another preferred example, the crystalline form AZT-I has one or more characteristics selected from the group consisting of:
1)所述晶型AZT-I具有基本如图1所示的XRPD图谱；1) The crystalline form AZT-I has an XRPD pattern substantially as shown in FIG. 1;
2)所述晶型AZT-I的TGA图在25－190℃失重约15-21％；2) The TGA diagram of the crystalline form AZT-I loses about 15-21% at 25-190°C;
3)所述晶型AZT-I具有基本如图2所示的TGA图。3) The crystalline form AZT-I has a TGA diagram substantially as shown in FIG. 2.
在另一优选例中，所述晶型AZT-II的XRPD图谱包括3个或3个以上选自下组的2θ值：5.5°±0.2°、7.3°±0.2°、16.5°±0.2°、19.5°±0.2°、24.9°±0.2°。In another preferred example, the XRPD pattern of the crystalline form AZT-II includes 3 or more 2θ values selected from the group consisting of 5.5°±0.2°, 7.3°±0.2°, 16.5°±0.2°, 19.5°±0.2°, 24.9°±0.2°.
在另一优选例中，所述晶型AZT-II的XRPD图谱包括6个或6个以上选自下组的2θ值：5.5°±0.2°、7.3°±0.2°、7.8°±0.2°、11.0°±0.2°、16.5°±0.2°、18.3°±0.2°、19.5°±0.2°、24.9°±0.2°、26.0°±0.2°。In another preferred example, the XRPD pattern of the crystalline form AZT-II includes 6 or more 2θ values selected from the group consisting of 5.5°±0.2°, 7.3°±0.2°, 7.8°±0.2°, 11.0°±0.2°, 16.5°±0.2°, 18.3°±0.2°, 19.5°±0.2°, 24.9°±0.2°, 26.0°±0.2°.
在另一优选例中，所述晶型AZT-II的XRPD图谱包括6个或6个以上选自下组的2θ值：5.5°±0.2°、7.3°±0.2°、7.8°±0.2°、9.1°±0.2°、11.0°±0.2°、14.0°±0.2°、15.6°±0.2°、16.5°±0.2°、18.3°±0.2°、19.5°±0.2°、20.1°±0.2°、20.7°±0.2°、22.1°±0.2°、23.2°±0.2°、24.3°±0.2°、 24.9°±0.2°、26.0°±0.2°、26.6°±0.2°、28.7°±0.2°、29.5°±0.2°、30.0°±0.2°。In another preferred example, the XRPD pattern of the crystalline form AZT-II includes 6 or more 2θ values selected from the group consisting of 5.5°±0.2°, 7.3°±0.2°, 7.8°±0.2°, 9.1°±0.2°, 11.0°±0.2°, 14.0°±0.2°, 15.6°±0.2°, 16.5°±0.2°, 18.3°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.7° ±0.2°, 22.1°±0.2°, 23.2°±0.2°, 24.3°±0.2°, 24.9°±0.2°, 26.0°±0.2°, 26.6°±0.2°, 28.7°±0.2°, 29.5°±0.2 °, 30.0°±0.2°.
在另一优选例中，所述晶型AZT-II具有选自下组的一个或多个特征：In another preferred example, the crystalline form AZT-II has one or more characteristics selected from the group consisting of:
1)所述晶型AZT-II具有基本如图3所示的XRPD图谱；1) The crystalline form AZT-II has an XRPD pattern substantially as shown in FIG. 3;
2)所述晶型AZT-II的TGA图在25－190℃失重约1-10％；2) The TGA diagram of the crystalline form AZT-II loses about 1-10% at 25-190°C;
3)所述晶型AZT-II具有基本如图4所示的TGA图；3) The crystalline form AZT-II has a TGA diagram substantially as shown in FIG. 4;
4)所述晶型AZT-II的DSC图在108－131℃范围内有一特征峰，onset约111℃；4) The DSC chart of the crystalline form AZT-II has a characteristic peak in the range of 108-131℃, and the onset is about 111℃;
5)所述晶型AZT-II的DSC图在158－193℃范围内有一特征峰，onset约175℃；5) The DSC chart of the crystalline form AZT-II has a characteristic peak in the range of 158-193℃, and the onset is about 175℃;
6)所述晶型AZT-II的DSC图在204－228℃范围内有一特征峰，onset约211℃；6) The DSC chart of the crystalline form AZT-II has a characteristic peak in the range of 204-228°C and the onset is about 211°C;
7)所述晶型AZT-II具有基本如图5所示的DSC图；7) The crystalline form AZT-II has a DSC chart substantially as shown in FIG. 5;
8)所述晶型AZT-II为水合物；8) The crystalline form AZT-II is a hydrate;
9)在25℃下，所述晶型AZT-II在纯水中的溶解度≥90mg/mL，较佳地≥100mg/mL；9) At 25°C, the solubility of the crystalline form AZT-II in pure water is ≥90mg/mL, preferably ≥100mg/mL;
10)在25℃下，所述晶型AZT-II在pH1.2的盐酸溶液中的溶解度≥110mg/mL，较佳地≥120mg/mL；10) At 25°C, the solubility of the crystalline form AZT-II in a hydrochloric acid solution of pH 1.2 is ≥110 mg/mL, preferably ≥120 mg/mL;
11)在25℃下，所述晶型AZT-II在pH4.5的醋酸盐溶液中的溶解度≥100mg/mL，较佳地≥110mg/mL；11) At 25°C, the solubility of the crystalline form AZT-II in an acetate solution of pH 4.5 is ≥100 mg/mL, preferably ≥110 mg/mL;
12)所述晶型AZT-II在80％相对湿度下的增重≤0.5％。12) The weight gain of the crystalline form AZT-II at 80% relative humidity is ≤0.5%.
在另一优选例中，所述晶型AZT-I的XRPD图谱的2θ值存在±0.5的偏差，较佳地存在±0.3的偏差，更佳地存在±0.1的偏差。In another preferred example, the 2θ value of the XRPD pattern of the crystalline form AZT-I has a deviation of ±0.5, preferably a deviation of ±0.3, and more preferably a deviation of ±0.1.
在另一优选例中，所述晶型AZT-II的XRPD图谱的2θ值存在±0.5的偏差，较佳地存在±0.3的偏差，更佳地存在±0.1的偏差。In another preferred example, the 2θ value of the XRPD pattern of the crystalline form AZT-II has a deviation of ±0.5, preferably a deviation of ±0.3, and more preferably a deviation of ±0.1.
本发明的第二方面，提供了一种晶型AZT-I的制备方法，所述方法选自下组：According to a second aspect of the present invention, there is provided a method for preparing crystalline form AZT-I, the method is selected from the group consisting of:
方案一：Option One:
a1)提供第一混合液和第一有机溶剂，所述第一混合液包含第一良溶剂和溶于其中的式(I)化合物的硫酸氢盐；a1) providing a first mixed solution and a first organic solvent, the first mixed solution comprising a first good solvent and a hydrogen sulfate salt of the compound of formula (I) dissolved therein;
a2)过滤所述第一混合液，得到第一滤液；a2) filtering the first mixed liquid to obtain a first filtrate;
a3)在搅拌条件下，将所述第一滤液滴入所述第一有机溶剂，析晶得到所述晶型AZT-I；a3) Under stirring conditions, drop the first filtrate drop into the first organic solvent, and crystallize to obtain the crystal form AZT-I;
方案二：Option II:
b1)提供第一混合液，所述第一混合液包含第一良溶剂和溶于其中的式(I)化合物的硫酸氢盐；b1) providing a first mixed liquid comprising the first good solvent and the bisulfate salt of the compound of formula (I) dissolved therein;
b2)过滤所述第一混合液，得到第一滤液；b2) filtering the first mixed liquid to obtain a first filtrate;
b3)将所述第一滤液置于封闭的第一有机溶剂氛围中，析晶得到所述晶型AZT-I；b3) Place the first filtrate in a closed atmosphere of the first organic solvent, and crystallize to obtain the crystal form AZT-I;
方案三：third solution:
c1)提供式(I)化合物的硫酸氢盐的无定型和第一有机溶剂；c1) Provide the amorphous and first organic solvent of the hydrogen sulfate salt of the compound of formula (I);
c2)混合所述式(I)化合物的硫酸氢盐的无定型和所述第一有机溶剂，得到第二混合液；c2) mixing the amorphous form of the bisulfate of the compound of formula (I) and the first organic solvent to obtain a second mixed liquid;
c3)搅拌所述第二混合液，析晶得到所述晶型AZT-I。c3) Stir the second mixed liquid and crystallize to obtain the crystal form AZT-I.
在另一优选例中，所述第一良溶剂选自下组：水、醇类、酮类、酰胺类、或其组合。In another preferred example, the first good solvent is selected from the group consisting of water, alcohols, ketones, amides, or a combination thereof.
在另一优选例中，所述醇类选自下组：甲醇、乙醇、异丙醇、正丁醇、或其组合。In another preferred example, the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, or a combination thereof.
在另一优选例中，所述酮类选自下组：N-甲基吡咯烷酮、丙酮、甲基异丁基酮、甲基丁酮、2-丁酮、或其组合。In another preferred example, the ketones are selected from the group consisting of N-methylpyrrolidone, acetone, methyl isobutyl ketone, methyl butanone, 2-butanone, or a combination thereof.
在另一优选例中，所述酰胺类选自下组：N,N二甲基甲酰胺、N,N-二甲基乙酰胺、或其组合。In another preferred example, the amides are selected from the group consisting of N,N dimethylformamide, N,N-dimethylacetamide, or a combination thereof.
在另一优选例中，所述第一有机溶剂选自下组：异戊醇、正戊醇、苯甲醚、乙酸乙酯、正庚烷、二氯甲烷、四氢呋喃、2-甲基四氢呋喃、氯仿、或其组合。In another preferred example, the first organic solvent is selected from the group consisting of isoamyl alcohol, n-amyl alcohol, anisole, ethyl acetate, n-heptane, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran, Chloroform, or a combination thereof.
在另一优选例中，所述搅拌在5-40℃下进行，较佳地10-30℃，更佳地15-28℃。In another preferred example, the stirring is performed at 5-40°C, preferably 10-30°C, more preferably 15-28°C.
本发明的第三方面，提供了一种晶型AZT-II的制备方法，所述方法选自下组：According to a third aspect of the present invention, there is provided a method for preparing crystalline form AZT-II, the method is selected from the group consisting of:
方案四：Option four:
a-1)提供第一混合液和第三混合液，其中所述第一混合液包含第一良溶剂和溶于其中的式(I)化合物的硫酸氢盐，所述第三混合液包含第一有机溶剂和选自下组的晶型：晶型AZT-I、晶型AZT-II、式(I)化合物的硫酸氢盐的无定型、晶型I-HS；a-1) Provide a first mixed liquid and a third mixed liquid, wherein the first mixed liquid contains a first good solvent and a hydrogen sulfate salt of the compound of formula (I) dissolved therein, and the third mixed liquid contains the first An organic solvent and a crystalline form selected from the group consisting of crystalline form AZT-I, crystalline form AZT-II, amorphous form of the hydrogen sulfate salt of the compound of formula (I), and crystalline form I-HS;
a-2)过滤所述第一混合液，得到第一滤液；a-2) Filter the first mixed liquid to obtain a first filtrate;
a-3)在搅拌条件下，将所述第一滤液滴入所述第三混合液中，析晶得到所述晶型AZT-II；a-3) Under stirring conditions, drop the first filtrate drop into the third mixed liquid, and crystallize to obtain the crystal form AZT-II;
方案五：Option five:
b-1)提供晶型AZT-I；b-1) Provide crystal form AZT-I;
b-2)在氮气气氛下，加热所述晶型AZT-I，得到所述晶型AZT-II；b-2) Heating the crystal form AZT-I under a nitrogen atmosphere to obtain the crystal form AZT-II;
方案六：Option 6:
c-1)提供晶型AZT-I；c-1) Provide crystal form AZT-I;
c-2)在空气中，在5-40℃下放置所述晶型AZT-I 5-15天，得到所述晶型AZT-II；c-2) Place the crystalline form AZT-I at 5-40°C in the air for 5-15 days to obtain the crystalline form AZT-II;
方案七：Option 7:
d-1)提供第四混合液，所述第四混合液包含第二有机溶剂和溶于其中的式(I)化合物的硫酸氢盐；d-1) providing a fourth mixed liquid comprising a second organic solvent and a hydrogen sulfate salt of the compound of formula (I) dissolved therein;
d-2)将所述第四混合液在10-25℃下挥发，析晶得到所述晶型AZT-II。d-2) The fourth mixed solution is volatilized at 10-25° C. and crystallized to obtain the crystal form AZT-II.
在另一优选例中，所述加热的处理温度为40-200℃。In another preferred example, the heating treatment temperature is 40-200°C.
在另一优选例中，所述加热的处理时间为3－30min，较佳地10－15min。In another preferred example, the heating treatment time is 3-30 minutes, preferably 10-15 minutes.
在另一优选例中，所述第二有机溶剂选自下组：甲醇、乙腈、或其组合。In another preferred example, the second organic solvent is selected from the group consisting of methanol, acetonitrile, or a combination thereof.
本发明的第四方面，提供了一种药物组合物，包含如下组分：According to a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising the following components:
1)治疗有效量的晶型AZT-I和/或晶型AZT-II；和1) A therapeutically effective amount of crystalline form AZT-I and/or crystalline form AZT-II; and
2)药学上可接受的载体。2) A pharmaceutically acceptable carrier.
本发明的第五方面，提供了一种晶型AZT-I或晶型AZT-II或本发明第四方面所述的药物组合物的用途，用于制备预防和/或治疗癌症的药物。According to a fifth aspect of the present invention, there is provided a use of the pharmaceutical composition according to the crystalline form AZT-I or the crystalline form AZT-II or the fourth aspect of the present invention for preparing a medicine for preventing and/or treating cancer.
在另一优选例中，所述癌症为TRK融合突变引起的癌症。In another preferred example, the cancer is caused by TRK fusion mutation.
在另一优选例中，所述癌症选自下组：肺癌、结肠癌、甲状腺癌、乳腺癌、儿童肿瘤。In another preferred example, the cancer is selected from the group consisting of lung cancer, colon cancer, thyroid cancer, breast cancer, and childhood tumors.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It should be understood that, within the scope of the present invention, the above technical features of the present invention and the technical features specifically described in the following (eg, embodiments) can be combined with each other, thereby forming a new or preferred technical solution. Due to space limitations, I will not repeat them here.
附图说明BRIEF DESCRIPTION
图1是实施例1所得晶型AZT-Ⅰ的XRPD图。FIG. 1 is an XRPD pattern of the crystalline form AZT-I obtained in Example 1. FIG.
图2是实施例1所得晶型AZT-Ⅰ的TGA图。2 is a TGA diagram of the crystalline form AZT-I obtained in Example 1. FIG.
图3是实施例4所得晶型AZT-Ⅱ的XRPD图。3 is an XRPD pattern of the crystalline form AZT-II obtained in Example 4. FIG.
图4是实施例4所得晶型AZT-Ⅱ的TGA图。4 is a TGA diagram of the crystalline form AZT-II obtained in Example 4. FIG.
图5是实施例4所得晶型AZT-Ⅱ的DSC图。5 is a DSC chart of the crystalline form AZT-II obtained in Example 4.
图6是实施例4所得晶型AZT-Ⅱ的DVS图。6 is a DVS diagram of the crystalline form AZT-II obtained in Example 4. FIG.
图7是实施例4所得晶型AZT-Ⅱ的DVS前后的XRPD图(上图为DVS前的XRPD图，下图为DVS后的XRPD图)。7 is an XRPD pattern before and after DVS of the crystalline form AZT-II obtained in Example 4 (the upper graph is the XRPD graph before DVS and the lower graph is the XRPD graph after DVS).
图8是实施例10中晶型AZT-Ⅱ在25℃/92.5％相对湿度下放置10天的稳定性XRPD对比图(上图为放置前的XRPD图，下图为放置后的XRPD图)。8 is a comparison diagram of the stability XRPD of the crystalline form AZT-II in Example 10 placed at 25°C/92.5% relative humidity for 10 days (the upper picture is the XRPD picture before being placed, and the lower picture is the XRPD picture after being placed).
图9是实施例11中晶型AZT-Ⅱ碾磨前后的XRPD图(上图为碾磨前的XRPD图，下图为碾磨后的XRPD图)。9 is an XRPD pattern before and after milling of the crystalline form AZT-II in Example 11 (the upper graph is the XRPD graph before milling and the lower graph is the XRPD graph after milling).
具体实施方式detailed description
本发明人经过长期而深入的研究，意外地制备了两种具有优异的溶解性能、机械稳定性能和高湿稳定性能的拉洛替尼硫酸氢盐晶型。在此基础上，发明人完成了本发明。After long-term and intensive research, the inventor unexpectedly prepared two crystalline forms of latinoib bisulfate with excellent solubility, mechanical stability and high humidity stability. On this basis, the inventor completed the present invention.
术语the term
如本文所用，术语“onset”通常指外推的起始温度。As used herein, the term "onset" generally refers to the extrapolated starting temperature.
晶型AZT-I及其制备方法Crystal form AZT-I and its preparation method
本发明提供的晶型AZT-Ⅰ，其X射线粉末衍射图在2θ值为15.8°±0.2°、20.4°±0.2°、21.2°±0.2°、24.9°±0.2°处具有特征峰。The crystalline form AZT-I provided by the present invention has X-ray powder diffraction patterns with characteristic peaks at 2θ values of 15.8°±0.2°, 20.4°±0.2°, 21.2°±0.2°, and 24.9°±0.2°.
更进一步的，本发明提供的晶型AZT-Ⅰ，其X射线粉末衍射图在2θ值为14.3°±0.2°、15.8°±0.2°、18.8°±0.2°、20.4°±0.2°、21.2°±0.2°、22.7°±0.2°、23.4°±0.2°、24.9°±0.2°处具有特征峰。Furthermore, the crystalline form AZT-Ⅰ provided by the present invention has an X-ray powder diffraction pattern at 2θ values of 14.3°±0.2°, 15.8°±0.2°, 18.8°±0.2°, 20.4°±0.2°, 21.2° There are characteristic peaks at ±0.2°, 22.7°±0.2°, 23.4°±0.2°, 24.9°±0.2°.
更进一步的，本发明提供的晶型AZT-Ⅰ，其X射线粉末衍射图在2θ值为7.6°±0.2°、8.6°±0.2°、14.3°±0.2°、15.8°±0.2°、17.2°±0.2°、18.2°±0.2°、18.8°±0.2°、20.4°±0.2°、21.2°±0.2°、22.2°±0.2°、22.7°±0.2°、23.4°±0.2°、24.9°±0.2°、25.7°±0.2°、26.2°±0.2°、27.7°±0.2°、28.4°±0.2°、31.4°±0.2°处具有特征峰。Furthermore, the crystalline form AZT-Ⅰ provided by the present invention has an X-ray powder diffraction pattern at 2θ values of 7.6°±0.2°, 8.6°±0.2°, 14.3°±0.2°, 15.8°±0.2°, 17.2° ±0.2°, 18.2°±0.2°, 18.8°±0.2°, 20.4°±0.2°, 21.2°±0.2°, 22.2°±0.2°, 22.7°±0.2°, 23.4°±0.2°, 24.9°±0.2 There are characteristic peaks at °, 25.7°±0.2°, 26.2°±0.2°, 27.7°±0.2°, 28.4°±0.2°, 31.4°±0.2°.
更进一步的，本发明提供的晶型AZT-Ⅰ，其X-射线粉末衍射(XRPD)图基本 如图1所示。Furthermore, the X-ray powder diffraction (XRPD) pattern of the crystalline form AZT-I provided by the present invention is basically shown in FIG. 1.
更进一步的，本发明提供的晶型AZT-Ⅰ，其热重分析(TGA)曲线基本如图2所示。Furthermore, the thermogravimetric analysis (TGA) curve of the crystalline form AZT-I provided by the present invention is basically shown in FIG. 2.
更进一步的，本发明提供了一种制备上述晶型AZT-Ⅰ的制备方法，包括将式(I)化合物的硫酸氢盐溶于有机溶剂得混合物，再将混合物滴加至反溶剂中，搅拌析晶，所得固体即为晶型AZT-Ⅰ。Furthermore, the present invention provides a method for preparing the above crystalline form AZT-I, which comprises dissolving the bisulfate salt of the compound of formula (I) in an organic solvent to obtain a mixture, and then adding the mixture dropwise to an anti-solvent and stirring Crystallization, the resulting solid is crystalline form AZT-I.
更进一步的，所述的混合物在滴加至反溶剂中前进行过滤。Furthermore, the mixture is filtered before being added dropwise to the anti-solvent.
更进一步的，所述有机溶剂包括水、醇类、酮类、酰胺类溶剂的单一或混合体系，优选N-甲基吡咯烷酮。Further, the organic solvent includes a single or mixed system of water, alcohols, ketones, and amide solvents, preferably N-methylpyrrolidone.
更进一步的，所述反溶剂可选异戊醇、正戊醇、苯甲醚、乙酸乙酯、正庚烷、二氯甲烷、四氢呋喃、2-甲基四氢呋喃和氯仿。Furthermore, the anti-solvent may be isoamyl alcohol, n-amyl alcohol, anisole, ethyl acetate, n-heptane, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran and chloroform.
更进一步的，本发明提供了一种上述晶型AZT-I的制备方法，包括将式(I)化合物的硫酸氢盐溶于有机溶剂得混合物，再混合物置于密闭的反溶剂氛围中，搅拌析晶，收集固体即为晶型AZT-Ⅰ。Furthermore, the present invention provides a method for preparing the above crystalline form AZT-I, which comprises dissolving the hydrogen sulfate salt of the compound of formula (I) in an organic solvent to obtain a mixture, and then placing the mixture in a sealed anti-solvent atmosphere and stirring Crystallization, collecting the solid is the crystalline form AZT-Ⅰ.
更进一步的，所述的混合物在滴加至反溶剂中前进行过滤。Furthermore, the mixture is filtered before being added dropwise to the anti-solvent.
更进一步的，所述有机溶剂包括水、醇类、酮类、酰胺类溶剂的单一或混合体系，优选N-甲基吡咯烷酮。Further, the organic solvent includes a single or mixed system of water, alcohols, ketones, and amide solvents, preferably N-methylpyrrolidone.
更进一步的，所述反溶剂可选异戊醇、正戊醇、苯甲醚、乙酸乙酯、正庚烷、二氯甲烷、四氢呋喃、2-甲基四氢呋喃和氯仿。Furthermore, the anti-solvent may be isoamyl alcohol, n-amyl alcohol, anisole, ethyl acetate, n-heptane, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran and chloroform.
更进一步的，本发明提供了一种上述晶型AZT-I的制备方法，包括将式(I)化合物的硫酸氢盐无定型(参照WO2016077841的实施例3制备得到)置于反溶剂中，搅拌，收集固体得到晶型AZT-Ⅰ。Furthermore, the present invention provides a method for preparing the above crystalline form AZT-I, which comprises placing the bisulfate amorphous form of the compound of formula (I) (prepared according to Example 3 of WO2016077841) in an anti-solvent and stirring , Collect the solid to get crystalline form AZT-Ⅰ.
更进一步的，所述反溶剂可选异戊醇、正戊醇、苯甲醚、乙酸乙酯、正庚烷、二氯甲烷、四氢呋喃、2-甲基四氢呋喃和氯仿。Furthermore, the anti-solvent may be isoamyl alcohol, n-amyl alcohol, anisole, ethyl acetate, n-heptane, dichloromethane, tetrahydrofuran, 2-methyltetrahydrofuran and chloroform.
更进一步的，所述的搅拌温度为5～25℃。Furthermore, the stirring temperature is 5-25°C.
更进一步的，所述的搅拌时间为2天。Furthermore, the stirring time is 2 days.
晶型AZT-II及其制备方法Crystal form AZT-II and its preparation method
本发明提供晶型AZT-Ⅱ，其X射线粉末衍射图在2θ值为5.5°±0.2°、7.3°±0.2°、 19.5°±0.2°、24.9°±0.2°处具有特征峰。The present invention provides a crystalline form AZT-II whose X-ray powder diffraction pattern has characteristic peaks at 2θ values of 5.5°±0.2°, 7.3°±0.2°, 19.5°±0.2°, and 24.9°±0.2°.
更进一步的，本发明提供的晶型AZT-Ⅱ，其X射线粉末衍射图在2θ值为5.5°±0.2°、7.3°±0.2°、16.5°±0.2°、19.5°±0.2°、24.9°±0.2°处具有特征峰。Furthermore, the crystalline form AZT-II provided by the present invention has an X-ray powder diffraction pattern at 2θ values of 5.5°±0.2°, 7.3°±0.2°, 16.5°±0.2°, 19.5°±0.2°, 24.9° There is a characteristic peak at ±0.2°.
更进一步的，本发明提供的晶型AZT-Ⅱ，其X射线粉末衍射图在2θ值为5.5°±0.2°、7.3°±0.2°、7.8°±0.2°、11.0°±0.2°、16.5°±0.2°、18.3°±0.2°、19.5°±0.2°、24.9°±0.2°、26.0°±0.2°处具有特征峰。Furthermore, the crystalline form AZT-II provided by the present invention has an X-ray powder diffraction pattern at 2θ values of 5.5°±0.2°, 7.3°±0.2°, 7.8°±0.2°, 11.0°±0.2°, 16.5° There are characteristic peaks at ±0.2°, 18.3°±0.2°, 19.5°±0.2°, 24.9°±0.2°, 26.0°±0.2°.
更进一步的，本发明提供的晶型AZT-Ⅱ，其X射线粉末衍射图在2θ值为5.5°±0.2°、7.3°±0.2°、7.8°±0.2°、9.1°±0.2°、11.0°±0.2°、14.0°±0.2°、15.6°±0.2°、16.5°±0.2°、18.3°±0.2°、19.5°±0.2°、20.1°±0.2°、20.7°±0.2°、22.1°±0.2°、23.2°±0.2°、24.3°±0.2°、24.9°±0.2°、26.0°±0.2°、26.6°±0.2°、28.7°±0.2°、29.5°±0.2°、30.0°±0.2°处具有特征峰。Furthermore, the crystalline form AZT-II provided by the present invention has an X-ray powder diffraction pattern at 2θ values of 5.5°±0.2°, 7.3°±0.2°, 7.8°±0.2°, 9.1°±0.2°, 11.0° ±0.2°, 14.0°±0.2°, 15.6°±0.2°, 16.5°±0.2°, 18.3°±0.2°, 19.5°±0.2°, 20.1°±0.2°, 20.7°±0.2°, 22.1°±0.2 °, 23.2°±0.2°, 24.3°±0.2°, 24.9°±0.2°, 26.0°±0.2°, 26.6°±0.2°, 28.7°±0.2°, 29.5°±0.2°, 30.0°±0.2° With characteristic peaks.
更进一步的，本发明提供的晶型AZT-Ⅱ，其X-射线衍射(XRPD)图基本如图3所示。Furthermore, the X-ray diffraction (XRPD) pattern of the crystalline form AZT-II provided by the present invention is basically shown in FIG. 3.
更进一步的，本发明提供的晶型AZT-Ⅱ，其热重分析(TGA)曲线基本如图4所示。Furthermore, the thermogravimetric analysis (TGA) curve of the crystalline form AZT-II provided by the present invention is basically shown in FIG. 4.
更进一步的，本发明提供的晶型AZT-Ⅱ，其差示扫描量热分析(DSC)曲线基本如图5所示。Furthermore, the differential scanning calorimetry (DSC) curve of the crystalline form AZT-II provided by the present invention is basically shown in FIG. 5.
更进一步的，本发明提供了一种制备上述晶型AZT-Ⅱ的方法，包括将式(I)化合物的硫酸氢盐溶于适当的有机溶剂中，再将溶液滴加至二氯甲烷中，搅拌析晶，所得固体即为晶型AZT-Ⅱ。Furthermore, the present invention provides a method for preparing the above crystalline form AZT-II, which comprises dissolving the hydrogen sulfate salt of the compound of formula (I) in a suitable organic solvent, and then adding the solution dropwise to methylene chloride, After stirring and crystallization, the solid obtained is the crystalline form AZT-Ⅱ.
更进一步的，所述的二氯甲烷含有晶种，所述的晶种选自式(I)化合物硫酸氢盐的无定型、晶型I-HS、晶型AZT-Ⅰ、晶型AZT-Ⅱ。Furthermore, the dichloromethane contains seed crystals selected from the group consisting of amorphous form of the compound (I) bisulfate, crystalline form I-HS, crystalline form AZT-Ⅰ, crystalline form AZT-Ⅱ .
更进一步的，所述有机溶剂包括水、醇类、酮类、酰胺类溶剂的单一或混合体系。Furthermore, the organic solvent includes a single or mixed system of water, alcohols, ketones, and amide solvents.
更进一步的，所述的有机溶剂选自N-甲基吡咯烷酮、N,N二甲基甲酰胺、N,N二甲基乙酰胺。Furthermore, the organic solvent is selected from N-methylpyrrolidone, N,N dimethylformamide, N,N dimethylacetamide.
更进一步的，本发明提供了一种制备上述晶型AZT-Ⅱ的方法，包括将AZT-Ⅰ在氮气保护下加热至50～190℃，所得固体即为晶型AZT-Ⅱ。Furthermore, the present invention provides a method for preparing the above crystalline form AZT-II, which includes heating AZT-I to 50-190°C under the protection of nitrogen, and the resulting solid is crystalline form AZT-II.
更进一步的，本发明提供了一种制备上述晶型AZT-Ⅱ的方法，包括将AZT-Ⅰ 敞口在5-25℃下放置一段时间，所得固体即为晶型AZT-Ⅱ。Furthermore, the present invention provides a method for preparing the above-mentioned crystalline form AZT-II, which includes leaving the AZT-I open at 5-25°C for a period of time, and the resulting solid is the crystalline form AZT-II.
更进一步的，所述一段时间为8-10天。Furthermore, the period of time is 8-10 days.
更进一步的，本发明提供了一种制备上述晶型AZT-Ⅱ的方法，包括式(I)化合物的硫酸氢盐溶于甲醇/乙腈(1:4，v/v)体系中，放置于10～25℃下挥发，直至有固体析出，所得固体即为晶型AZT-Ⅱ。Furthermore, the present invention provides a method for preparing the above-mentioned crystalline form AZT-II, which includes dissolving the hydrogen sulfate salt of the compound of formula (I) in a methanol/acetonitrile (1:4, v/v) system and placing Evaporate at -25°C until a solid precipitates, and the resulting solid is the crystalline form AZT-II.
在本发明中，晶型AZT-I可较为简便迅速地转换为晶型AZT-II。In the present invention, the crystalline form AZT-I can be converted into the crystalline form AZT-II relatively easily and quickly.
应用application
本发明还可以提供一种药物组合物，所述组合物包括式(I)化合物硫酸氢盐的晶型以及药学上可接受的载体，所述的式(I)化合物硫酸氢盐的晶型选自晶型AZT-Ⅰ和晶型AZT-Ⅱ。The present invention can also provide a pharmaceutical composition comprising the crystalline form of the compound of formula (I) bisulfate and a pharmaceutically acceptable carrier. The crystalline form of the compound of formula (I) is selected Automorphic AZT-Ⅰ and crystalline form AZT-Ⅱ.
本发明还可以提供式(I)化合物硫酸氢盐的晶型在制备用于治疗癌症的药物中的应用，所述的式(I)化合物硫酸氢盐的晶型选自晶型AZT-Ⅰ和晶型AZT-Ⅱ。The present invention can also provide the use of the crystalline form of the compound (I) bisulfate in the preparation of a medicament for treating cancer. The crystalline form of the compound (I) bisulfate is selected from the crystalline form AZT-I and Crystal form AZT-Ⅱ.
本发明还可以提供式(I)化合物硫酸氢盐的晶型在制备式(I)化合物或其它盐的用途，所述的式(I)化合物硫酸氢盐的晶型选自晶型AZT-Ⅰ和晶型AZT-Ⅱ。The present invention can also provide the use of the crystalline form of the compound (I) bisulfate in the preparation of the compound of formula (I) or other salts. The crystalline form of the compound (I) is selected from the crystalline form AZT-Ⅰ And crystal form AZT-Ⅱ.
本发明的晶型AZT-Ⅰ和晶型AZT-Ⅱ可以用来制备拉洛替尼游离碱或拉洛替尼其他盐，游离碱或成盐的方法可按常规方法制得。本发明的晶型具有优异的溶解度，可以减少溶剂使用量，节约资源、降低成本。The crystalline form AZT-I and the crystalline form AZT-II of the present invention can be used to prepare Lalotinib free base or other salts of Lalotinib. The method of free base or salt formation can be prepared according to conventional methods. The crystalline form of the present invention has excellent solubility, can reduce the amount of solvent used, save resources and reduce costs.
本发明晶型AZT-Ⅰ和晶型AZT-Ⅱ可以用于制备治疗癌症的药物，该药物可以通过本领域常用方法制得。所述的癌症为TRK(肌钙蛋白受体激酶)融合突变引起的癌症，如肺癌、结肠癌、甲状腺癌、乳腺癌、某些儿童肿瘤等。The crystalline form AZT-I and the crystalline form AZT-II of the present invention can be used to prepare a medicine for treating cancer, and the medicine can be prepared by a method commonly used in the art. The cancer is caused by TRK (troponin receptor kinase) fusion mutation, such as lung cancer, colon cancer, thyroid cancer, breast cancer, and some children's tumors.
与现有技术相比，本发明具有以下主要优点：Compared with the prior art, the present invention has the following main advantages:
(1)所述晶型具有优异的溶解性能、机械稳定性能和高湿稳定性能；(1) The crystalline form has excellent dissolution performance, mechanical stability and high humidity stability;
(2)所述晶型具有极低的引湿性；(2) The crystal form has extremely low moisture absorption;
(3)所述晶型的制备方法具有操作简便易行、成本低廉、适宜应用于药物研发和工业化生产中的特点；(3) The preparation method of the crystal form has the characteristics of simple and easy operation, low cost, and suitable for application in drug research and development and industrial production;
(4)以所述晶型制备所得药物组合物具有更好的溶出度，其在施用于患者后具有优异的吸收性能和生物利用度。(4) The obtained pharmaceutical composition prepared in the crystal form has better dissolution, which has excellent absorption performance and bioavailability after being administered to a patient.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。The present invention will be further described below in conjunction with specific embodiments. It should be understood that these examples are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions in the following examples generally follow the conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。Unless otherwise defined, all professional and scientific terms used in the text have the same meaning as familiar to those skilled in the art. In addition, any methods and materials similar to or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.
本发明中晶型的结晶水来自空气或溶剂。本发明中所用的溶剂均为分析纯，含水量约为0.1％。实施例中作为原料的拉洛替尼硫酸氢盐或拉洛替尼硫酸氢盐无定型通过购买或者参照专利WO2016077841制备得到。本发明所有的测试方法均为通用方法，测试参数如下：The crystal water of the crystal form in the present invention comes from air or a solvent. The solvents used in the present invention are all analytically pure and have a water content of about 0.1%. Larotinib bisulfate or larotinib bisulfate as the raw material in the examples is obtained by purchasing or referring to the patent WO2016077841. All the test methods of the present invention are general methods, and the test parameters are as follows:
1.XRPD图测定方法：1. XRPD chart measurement method:
X-射线粉末衍射仪器：Bruker D2 Phaser X-射线粉末衍射仪；辐射源Cu
Figure PCTCN2019120340-appb-000003
发生器(Generator)kv：30kv；发生器(Generator)mA：10mA；起始的2θ：2.000°，扫描范围：2.0000～35.000°，扫描步长0.02°，扫描速度0.1s/step。 X-ray powder diffraction instrument: Bruker D2 Phaser X-ray powder diffraction instrument; radiation source Cu
Figure PCTCN2019120340-appb-000003
Generator (Generator) kv: 30kv; Generator (Generator) mA: 10mA; initial 2θ: 2.000°, scanning range: 2.000～35.000°, scanning step length 0.02°, scanning speed 0.1s/step.
2.TGA图测定方法：2. TGA chart measurement method:
热重分析法(TGA)仪器：美国TA公司的TGA55型；温度范围：20～300℃；加热速率：10℃/min；氮气流速：40mL/min。Thermogravimetric analysis (TGA) instrument: TGA55 type of American TA company; temperature range: 20～300℃; heating rate: 10℃/min; nitrogen flow rate: 40mL/min.
3.DSC图测定方法：3. DSC measurement method:
差示扫描量热法(DSC)仪器：美国TA公司的TA Q2000型；温度范围：25～300℃，加热速率：10℃/min，氮气流速：50mL/min。Differential scanning calorimetry (DSC) instrument: TA model Q2000 of American TA company; temperature range: 25～300℃, heating rate: 10℃/min, nitrogen flow rate: 50mL/min.
4.DVS图测定方法：4. DVS chart measurement method:
动态水分吸附仪(DVS)仪器：美国TA公司的TA Q5000 SA型；温度：25℃；氮气流速：50mL/min；单位时间质量变化：0.002％/min；相对湿度范围：0％RH-90％RH。Dynamic Moisture Absorption Instrument (DVS) instrument: TA model Q5000 SA of American TA Company; temperature: 25°C; nitrogen flow rate: 50mL/min; mass change per unit time: 0.002%/min; relative humidity range: 0%RH-90% RH.
实施例1：晶型AZT-Ⅰ的制备Example 1: Preparation of crystalline form AZT-Ⅰ
称取47.1mg式(I)化合物的硫酸氢盐溶于0.5mL N-甲基吡咯烷酮中，过滤。在25℃下，将0.2mL滤液缓慢滴入2.0mL氯仿，搅拌，直至有固体析出。所得固体为式(I)化合物硫酸氢盐晶型AZT-Ⅰ。Weigh 47.1 mg of the hydrogen sulfate salt of the compound of formula (I) dissolved in 0.5 mL of N-methylpyrrolidone and filter. At 25°C, 0.2 mL of the filtrate was slowly dropped into 2.0 mL of chloroform and stirred until a solid precipitated. The resulting solid is the crystalline form AZT-I of the compound of formula (I) bisulfate.
对得到的固体进行XRPD测试，其X-射线粉末衍射图如图1所示；对所得固体进行TGA测试，其谱图如图2所示。The XRPD test is performed on the obtained solid, and the X-ray powder diffraction pattern is shown in FIG. 1; the TGA test is performed on the obtained solid, and the spectrum is shown in FIG. 2.
从图1可知：晶型AZT-Ⅰ的主要衍射峰以及相对强度如表1所示。It can be seen from FIG. 1 that the main diffraction peaks and relative intensities of crystalline form AZT-I are shown in Table 1.
表1Table 1
2θ(°)2θ(°) CountsCounts
7.67.6 17.4％17.4%
8.68.6 17.9％17.9%
14.3°14.3° 39.4％39.4%
15.8°15.8° 54.6％54.6%
17.2°17.2° 28.9％28.9%
18.2°18.2° 28.5％28.5%
18.8°18.8° 55.3％55.3%
20.4°20.4° 100.0％100.0%
21.2°21.2° 52.1％52.1%
22.2°22.2° 36.3％36.3%
22.7°22.7° 51.3％51.3%
23.4°23.4° 56.6％56.6%
24.9°24.9° 64.7％64.7%
25.7°25.7° 30.0％30.0%
26.2°26.2° 32.6％32.6%
27.7°27.7° 16.4％16.4%
28.4°28.4° 16.4％16.4%
31.4°31.4° 28.9％28.9%
从图2可知：晶型AZT-Ⅰ在25～190℃失重约为18％。It can be seen from Figure 2 that the crystalline form AZT-I loses about 18% at 25-190°C.
实施例2：晶型AZT-Ⅰ的制备Example 2: Preparation of crystalline form AZT-Ⅰ
称取30.0mg式(I)化合物硫酸氢盐溶于0.2mL N,N-二甲基乙酰胺中，过滤。在25℃下，将滤液置于密闭的氯仿氛围中，直至有固体析出。Weigh 30.0 mg of the compound of formula (I) bisulfate in 0.2 mL of N,N-dimethylacetamide and filter. At 25°C, the filtrate was placed in a closed chloroform atmosphere until solids precipitated.
对得到的固体进行XRPD测试，其X-射线粉末衍射图基本如图1所示，所得固体为式(I)化合物硫酸氢盐晶型AZT-Ⅰ。The obtained solid was subjected to XRPD test, and its X-ray powder diffraction pattern was basically as shown in FIG. 1. The obtained solid was the AZT-I crystal form of the compound of formula (I) bisulfate.
实施例3：晶型AZT-Ⅰ的制备Example 3: Preparation of crystalline form AZT-Ⅰ
取适量(如10mg)式(I)化合物硫酸氢盐无定型于0.5mL氯仿中，在5～25℃下，搅拌2天。Take an appropriate amount (eg 10 mg) of the compound of formula (I) bisulfate amorphous in 0.5 mL of chloroform and stir at 5-25°C for 2 days.
对得到的固体进行XRPD测试，其X-射线粉末衍射图基本如图1所示，所得固体为式(I)化合物硫酸氢盐晶型AZT-Ⅰ。The obtained solid was subjected to XRPD test, and its X-ray powder diffraction pattern was basically as shown in FIG. 1. The obtained solid was the AZT-I crystal form of the compound of formula (I).
实施例4：晶型AZT-Ⅱ的制备Example 4: Preparation of crystalline form AZT-Ⅱ
称取68.0mg式(I)化合物硫酸氢盐溶于0.5mL N-甲基吡咯烷酮中，过滤，滤液备用。在4.5mL二氯甲烷中加入5mg实施例1所述晶型AZT-Ⅰ，并在-20～25℃下搅拌。将滤液缓慢滴入上述二氯甲烷悬浊液中，继续搅拌，直至有固体析出。Weigh 68.0 mg of the compound of formula (I) bisulfate in 0.5 mL of N-methylpyrrolidone, filter, and the filtrate is set aside. In 4.5 mL of dichloromethane, 5 mg of the crystalline form AZT-I described in Example 1 was added, and stirred at -20 to 25°C. The filtrate was slowly dropped into the above methylene chloride suspension, and stirring was continued until a solid precipitated.
所得固体即为晶型AZT-Ⅱ。对得到的固体进行XRPD测试，其X-射线粉末衍射图如图3所示；对所得固体进行TGA测试，其谱图如图4所示；对所得固体进行DSC测试，其谱图如图5所示。The solid obtained is the crystalline form AZT-II. The XRPD test was performed on the obtained solid, and the X-ray powder diffraction pattern was shown in FIG. 3; the TGA test was performed on the obtained solid, and the spectrum is shown in FIG. 4. The DSC test was performed on the obtained solid, and the spectrum is shown in FIG. 5. As shown.
从图3可知：晶型AZT-Ⅱ的主要衍射峰以及相对强度如表2所示。It can be seen from FIG. 3 that the main diffraction peak and relative intensity of the crystalline form AZT-Ⅱ are shown in Table 2.
表2Table 2
2θ(°)2θ(°) CountsCounts
5.5°5.5° 39.9％39.9%
7.3°7.3° 26.0％26.0%
7.8°7.8° 12.7％12.7%
9.1°9.1° 13.1％13.1%
11.0°11.0° 23.1％23.1%
14.0°14.0° 9.2％9.2%
15.6°15.6° 20.2％20.2%
16.5°16.5° 64.2％64.2%
18.3°18.3° 90.3％90.3%
19.5°19.5° 54.7％54.7%
20.1°20.1° 68.6％68.6%
20.7°20.7° 100.0％100.0%
22.1°22.1° 26.3％26.3%
23.2°23.2° 30.1％30.1%
24.3°24.3° 70.3％70.3%
24.9°24.9° 62.5％62.5%
26.0°26.0° 30.8％30.8%
26.6°26.6° 28.6％28.6%
28.7°28.7° 24.9％24.9%
29.5°29.5° 19.2％19.2%
30.0°30.0° 14.0％14.0%
从图4可知：晶型AZT-Ⅱ在25～190℃失重约3％-9％。It can be seen from FIG. 4 that the crystalline form AZT-II loses about 3%-9% at 25-190°C.
从图5可知：晶型AZT-Ⅱ在108－131℃范围内有一吸热峰，onset约111℃；在158－193℃范围内有一吸热峰，onset约175℃；在204－228℃范围内有一吸热峰，onset约211℃。It can be seen from Fig. 5 that the crystalline form AZT-Ⅱ has an endothermic peak in the range of 108-131°C and onset of about 111°C; it has an endothermic peak in the range of 158-193°C and onset of about 175°C; There is an endothermic peak, onset about 211 ℃.
实施例5：晶型AZT-Ⅱ的制备Example 5: Preparation of crystalline form AZT-Ⅱ
称取60.0mg式(I)化合物硫酸氢盐溶于0.5Ml N-甲基吡咯烷酮中，过滤，滤液备用。在4.5mL二氯甲烷中加入5mg实施例4所述晶型AZT-Ⅱ，并在-20～25℃下搅拌。将滤液缓慢滴入上述二氯甲烷悬浊液中，继续搅拌，直至有固体析出。Weigh 60.0 mg of the compound of formula (I) bisulfate in 0.5 Ml of N-methylpyrrolidone, filter, and the filtrate is set aside. Add 5 mg of the crystalline form AZT-II described in Example 4 to 4.5 mL of methylene chloride, and stir at -20 to 25°C. The filtrate was slowly dropped into the above methylene chloride suspension, and stirring was continued until a solid precipitated.
所得固体即为晶型AZT-Ⅱ。对得到的固体进行XRPD测试，其X-射线粉末衍射图基本如图3所示。The solid obtained is the crystalline form AZT-II. The XRPD test was performed on the obtained solid, and its X-ray powder diffraction pattern was basically shown in FIG. 3.
实施例6：晶型AZT-Ⅱ的制备Example 6: Preparation of crystalline form AZT-Ⅱ
将上述实施例1中的晶型AZT-Ⅰ在氮气保护下加热至50～190℃，所得固体即为晶型AZT-Ⅱ。The crystalline form AZT-I in the above Example 1 is heated to 50-190°C under the protection of nitrogen, and the obtained solid is the crystalline form AZT-II.
对得到的固体进行XRPD测试，其X-射线粉末衍射图基本如图3所示。The XRPD test was performed on the obtained solid, and its X-ray powder diffraction pattern was basically shown in FIG. 3.
实施例7：晶型AZT-Ⅱ的制备Example 7: Preparation of crystalline form AZT-Ⅱ
将上述实施例1中的晶型AZT-Ⅰ敞口放置在5～25℃下9天，所得固体即为晶型AZT-Ⅱ。The crystalline form AZT-I in Example 1 above was left open at 5-25°C for 9 days, and the resulting solid was the crystalline form AZT-II.
对得到的固体进行XRPD测试，其X-射线粉末衍射图基本如图3所示。The XRPD test was performed on the obtained solid, and its X-ray powder diffraction pattern was basically shown in FIG. 3.
实施例8：晶型AZT-Ⅱ的制备Example 8: Preparation of crystalline form AZT-Ⅱ
称取10.0mg式(I)化合物硫酸氢盐溶于1ml甲醇/乙腈(1:4，v/v)中，将溶液放置于10～25℃下挥发，直至有固体析出。Weigh 10.0 mg of the hydrogen sulfate salt of the compound of formula (I) in 1 ml of methanol/acetonitrile (1:4, v/v), and place the solution at 10-25°C to evaporate until a solid precipitates.
对得到的固体进行XRPD测试，其X-射线粉末衍射图基本如图3所示。The XRPD test was performed on the obtained solid, and its X-ray powder diffraction pattern was basically shown in FIG. 3.
实施例9：晶型AZT-Ⅱ和WO2016077841公开的无水晶型I-HS的溶解度Example 9: Solubility of crystalline form AZT-Ⅱ and crystal-free I-HS disclosed in WO2016077841
测试晶型AZT-Ⅱ和无水晶型I-HS在25℃不同pH环境下的溶解度，结果如表3所示。The solubility of the crystalline form AZT-Ⅱ and the non-crystal form I-HS in different pH environments at 25°C was tested. The results are shown in Table 3.
表3table 3
Figure PCTCN2019120340-appb-000004
Figure PCTCN2019120340-appb-000004
表3的结果表明：晶型AZT-Ⅱ与无水晶型I-HS相比，具有更高的溶解度。The results in Table 3 show that the crystalline form AZT-II has a higher solubility than the non-crystalline form I-HS.
实施例10：晶型AZT-Ⅱ的引湿性研究Example 10: Study on the hygroscopicity of crystalline form AZT-Ⅱ
取本实施例4得到的晶型AZT-Ⅱ约10mg采用动态水分吸附(DVS)仪测试其引湿性。Approximately 10 mg of the crystalline form AZT-II obtained in Example 4 was used to test its moisture absorption property using a dynamic moisture adsorption (DVS) instrument.
晶型AZT-Ⅱ的DVS图如图6所示，在80％相对湿度下增重0.3％。无水晶型I-HS在80％相对湿度下增重约1％(如WO2016077841的表14所示)。可见本发明提供的晶型AZT-Ⅱ具有比无水晶型I-HS更低的吸湿性。The DVS pattern of the crystalline form AZT-Ⅱ is shown in Fig. 6, and the weight gain is 0.3% at 80% relative humidity. The crystal-free I-HS gains about 1% at 80% relative humidity (as shown in Table 14 of WO2016077841). It can be seen that the crystalline form AZT-II provided by the present invention has lower hygroscopicity than the non-crystalline type I-HS.
晶型AZT-Ⅱ测试引湿性前后的XRPD对比图如图7所示(上图为测试前的XRPD图，下图为测试后的XRPD图)，由测试引湿性前后的XRPD图可知，晶型AZT-Ⅱ在引湿性测试前后其晶型未发生变化。The XRPD comparison chart of the crystalline form AZT-Ⅱ before and after the moisture absorption test is shown in Figure 7 (the upper picture is the XRPD picture before the test and the lower picture is the XRPD picture after the test) The crystal form of AZT-Ⅱ did not change before and after the hygroscopicity test.
实施例11：晶型AZT-Ⅱ高湿度下的晶型稳定性Example 11: Crystal form AZT-Ⅱ crystal form stability under high humidity
将上述实施例中得到的晶型AZT-Ⅱ敞口放置于25℃/92.5％RH环境下放置10天，于第0、10天测试XPRD，结果如图8所示，晶型均不变，仍为晶型AZT-Ⅱ。The crystalline form AZT-Ⅱ obtained in the above example was placed in an open environment at 25°C/92.5%RH for 10 days, and XPRD was tested on days 0 and 10. The results are shown in FIG. It is still crystalline form AZT-Ⅱ.
实施例12：晶型AZT-Ⅱ的机械稳定性Example 12: Mechanical stability of crystalline form AZT-Ⅱ
将上述实施例4中的晶型AZT-Ⅱ在25℃下快速碾磨5min后，测XRPD，结果如图9所示，晶型均不变。After the AZT-II crystal form in the above Example 4 was rapidly milled at 25°C for 5 min, the XRPD was measured. As shown in FIG. 9, the crystalline forms remained unchanged.
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。All documents mentioned in the present invention are cited as references in this application, just as each document is individually cited as a reference. In addition, it should be understood that after reading the above teaching content of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims (10)

  1. 一种式(I)化合物的硫酸氢盐的晶型，其特征在于，所述晶型选自下组：晶型AZT-I、晶型AZT-II，A crystal form of the hydrogen sulfate salt of the compound of formula (I), characterized in that the crystal form is selected from the group consisting of crystal form AZT-I and crystal form AZT-II,
    Figure PCTCN2019120340-appb-100001
    Figure PCTCN2019120340-appb-100001
    其中，所述晶型AZT-I的XRPD图谱包括3个或3个以上选自下组的2θ值：15.8°±0.2°、20.4°±0.2°、21.2°±0.2°、24.9°±0.2°；Wherein, the XRPD pattern of the crystalline form AZT-I includes 3 or more 2θ values selected from the group consisting of 15.8°±0.2°, 20.4°±0.2°, 21.2°±0.2°, 24.9°±0.2° ;
    所述晶型AZT-II的XRPD图谱包括3个或3个以上选自下组的2θ值：5.5°±0.2°、7.3°±0.2°、19.5°±0.2°、24.9°±0.2°。The XRPD pattern of the crystalline form AZT-II includes 3 or more 2θ values selected from the group consisting of 5.5°±0.2°, 7.3°±0.2°, 19.5°±0.2°, and 24.9°±0.2°.
  2. 如权利要求1所述的晶型，其特征在于，所述晶型AZT-I的XRPD图谱包括6个或6个以上选自下组的2θ值：14.3°±0.2°、15.8°±0.2°、18.8°±0.2°、20.4°±0.2°、21.2°±0.2°、22.7°±0.2°、23.4°±0.2°、24.9°±0.2°。The crystal form according to claim 1, wherein the XRPD pattern of the crystal form AZT-I includes 6 or more 2θ values selected from the group consisting of 14.3°±0.2°, 15.8°±0.2° , 18.8°±0.2°, 20.4°±0.2°, 21.2°±0.2°, 22.7°±0.2°, 23.4°±0.2°, 24.9°±0.2°.
  3. 如权利要求1所述的晶型，其特征在于，所述晶型AZT-I具有选自下组的一个或多个特征：The crystalline form of claim 1, wherein the crystalline form AZT-I has one or more characteristics selected from the group consisting of:
    1)所述晶型AZT-I具有基本如图1所示的XRPD图谱；1) The crystalline form AZT-I has an XRPD pattern substantially as shown in FIG. 1;
    2)所述晶型AZT-I的TGA图在25－190℃失重约15-21％；2) The TGA diagram of the crystalline form AZT-I loses about 15-21% at 25-190°C;
    3)所述晶型AZT-I具有基本如图2所示的TGA图。3) The crystalline form AZT-I has a TGA diagram substantially as shown in FIG. 2.
  4. 如权利要求1所述的晶型，其特征在于，所述晶型AZT-II的XRPD图谱包括6个或6个以上选自下组的2θ值：5.5°±0.2°、7.3°±0.2°、7.8°±0.2°、11.0°±0.2°、16.5°±0.2°、18.3°±0.2°、19.5°±0.2°、24.9°±0.2°、26.0°±0.2°。The crystalline form of claim 1, wherein the XRPD pattern of the crystalline form AZT-II includes 6 or more 2θ values selected from the group consisting of 5.5°±0.2°, 7.3°±0.2° , 7.8°±0.2°, 11.0°±0.2°, 16.5°±0.2°, 18.3°±0.2°, 19.5°±0.2°, 24.9°±0.2°, 26.0°±0.2°.
  5. 如权利要求1所述的晶型，其特征在于，所述晶型AZT-II具有选自下组的一个或多个特征：The crystalline form of claim 1, wherein the crystalline form AZT-II has one or more characteristics selected from the group consisting of:
    1)所述晶型AZT-II具有基本如图3所示的XRPD图谱；1) The crystalline form AZT-II has an XRPD pattern substantially as shown in FIG. 3;
    2)所述晶型AZT-II的TGA图在25－190℃失重约1-10％；2) The TGA diagram of the crystalline form AZT-II loses about 1-10% at 25-190°C;
    3)所述晶型AZT-II具有基本如图4所示的TGA图；3) The crystalline form AZT-II has a TGA diagram substantially as shown in FIG. 4;
    4)所述晶型AZT-II的DSC图在108－131℃范围内有一特征峰，onset约111℃；4) The DSC chart of the crystalline form AZT-II has a characteristic peak in the range of 108-131℃, and the onset is about 111℃;
    5)所述晶型AZT-II的DSC图在158－193℃范围内有一特征峰，onset约175℃；5) The DSC chart of the crystalline form AZT-II has a characteristic peak in the range of 158-193℃, and the onset is about 175℃;
    6)所述晶型AZT-II的DSC图在204－228℃范围内有一特征峰，onset约211℃；6) The DSC chart of the crystalline form AZT-II has a characteristic peak in the range of 204-228°C and the onset is about 211°C;
    7)所述晶型AZT-II具有基本如图5所示的DSC图；7) The crystalline form AZT-II has a DSC chart substantially as shown in FIG. 5;
    8)所述晶型AZT-II为水合物。8) The crystalline form AZT-II is a hydrate.
  6. 一种晶型AZT-I的制备方法，其特征在于，所述方法选自下组：A preparation method of crystalline form AZT-I, characterized in that the method is selected from the following group:
    方案一：Option One:
    a1)提供第一混合液和第一有机溶剂，所述第一混合液包含第一良溶剂和溶于其中的式(I)化合物的硫酸氢盐；a1) providing a first mixed solution and a first organic solvent, the first mixed solution comprising a first good solvent and a hydrogen sulfate salt of the compound of formula (I) dissolved therein;
    a2)过滤所述第一混合液，得到第一滤液；a2) filtering the first mixed liquid to obtain a first filtrate;
    a3)在搅拌条件下，将所述第一滤液滴入所述第一有机溶剂，析晶得到所述晶型AZT-I；a3) Under stirring conditions, drop the first filtrate drop into the first organic solvent, and crystallize to obtain the crystal form AZT-I;
    方案二：Option II:
    b1)提供第一混合液，所述第一混合液包含第一良溶剂和溶于其中的式(I)化合物的硫酸氢盐；b1) providing a first mixed liquid comprising the first good solvent and the bisulfate salt of the compound of formula (I) dissolved therein;
    b2)过滤所述第一混合液，得到第一滤液；b2) filtering the first mixed liquid to obtain a first filtrate;
    b3)将所述第一滤液置于封闭的第一有机溶剂氛围中，析晶得到所述晶型AZT-I；b3) Place the first filtrate in a closed atmosphere of the first organic solvent, and crystallize to obtain the crystal form AZT-I;
    方案三：third solution:
    c1)提供式(I)化合物的硫酸氢盐的无定型和第一有机溶剂；c1) Provide the amorphous and first organic solvent of the hydrogen sulfate salt of the compound of formula (I);
    c2)混合所述式(I)化合物的硫酸氢盐的无定型和所述第一有机溶剂，得到第二混合液；c2) mixing the amorphous form of the bisulfate of the compound of formula (I) and the first organic solvent to obtain a second mixed liquid;
    c3)搅拌所述第二混合液，析晶得到所述晶型AZT-I。c3) Stir the second mixed liquid and crystallize to obtain the crystal form AZT-I.
  7. 一种晶型AZT-II的制备方法，其特征在于，所述方法选自下组：A method for preparing crystalline form AZT-II, characterized in that the method is selected from the following group:
    方案四：Option four:
    a-1)提供第一混合液和第三混合液，其中所述第一混合液包含第一良溶剂和溶于其中的式(I)化合物的硫酸氢盐，所述第三混合液包含第一有机溶剂和选自下组的晶型：晶型AZT-I、晶型AZT-II、式(I)化合物的硫酸氢盐的无定型、晶型I-HS；a-1) Provide a first mixed liquid and a third mixed liquid, wherein the first mixed liquid contains a first good solvent and a hydrogen sulfate salt of the compound of formula (I) dissolved therein, and the third mixed liquid contains the first An organic solvent and a crystalline form selected from the group consisting of crystalline form AZT-I, crystalline form AZT-II, amorphous form of the hydrogen sulfate salt of the compound of formula (I), and crystalline form I-HS;
    a-2)过滤所述第一混合液，得到第一滤液；a-2) Filter the first mixed liquid to obtain a first filtrate;
    a-3)在搅拌条件下，将所述第一滤液滴入所述第三混合液中，析晶得到所述晶型AZT-II；a-3) Under stirring conditions, drop the first filtrate drop into the third mixed liquid, and crystallize to obtain the crystal form AZT-II;
    方案五：Option five:
    b-1)提供晶型AZT-I；b-1) Provide crystal form AZT-I;
    b-2)在氮气气氛下，加热所述晶型AZT-I，得到所述晶型AZT-II；b-2) Heating the crystal form AZT-I under a nitrogen atmosphere to obtain the crystal form AZT-II;
    方案六：Option 6:
    c-1)提供晶型AZT-I；c-1) Provide crystal form AZT-I;
    c-2)在空气中，在5-40℃下放置所述晶型AZT-I 5-15天，得到所述晶型AZT-II；c-2) Place the crystalline form AZT-I at 5-40°C in the air for 5-15 days to obtain the crystalline form AZT-II;
    方案七：Option 7:
    d-1)提供第四混合液，所述第四混合液包含第二有机溶剂和溶于其中的式(I)化合物的硫酸氢盐；d-1) providing a fourth mixed liquid comprising a second organic solvent and a hydrogen sulfate salt of the compound of formula (I) dissolved therein;
    d-2)将所述第四混合液在10-25℃下挥发，析晶得到所述晶型AZT-II。d-2) The fourth mixed solution is volatilized at 10-25° C. and crystallized to obtain the crystal form AZT-II.
  8. 一种药物组合物，其特征在于，包含如下组分：A pharmaceutical composition characterized by comprising the following components:
    1)治疗有效量的晶型AZT-I和/或晶型AZT-II；和1) A therapeutically effective amount of crystalline form AZT-I and/or crystalline form AZT-II; and
    2)药学上可接受的载体。2) A pharmaceutically acceptable carrier.
  9. 一种晶型AZT-I或晶型AZT-II或权利要求8所述的药物组合物的用途，其特征在于，用于制备预防和/或治疗癌症的药物。The use of the crystalline form AZT-I or the crystalline form AZT-II or the pharmaceutical composition according to claim 8, characterized in that it is used to prepare a medicine for preventing and/or treating cancer.
  10. 如权利要求9所述的用途，其特征在于，所述癌症为TRK融合突变引起的癌症。The use according to claim 9, wherein the cancer is caused by TRK fusion mutation.
PCT/CN2019/120340 2018-11-28 2019-11-22 Crystalline form of larotrectinib hydrogen sulfate salt, preparation method therefor and use thereof WO2020108408A1 (en)

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