WO2020108408A1 - Forme cristalline du sel de sulfate d'hydrogène de larotrectinib, son procédé de préparation et son utilisation - Google Patents

Forme cristalline du sel de sulfate d'hydrogène de larotrectinib, son procédé de préparation et son utilisation 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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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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Publication of WO2020108408A1 publication Critical patent/WO2020108408A1/fr

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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.

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Abstract

La présente invention concerne une forme cristalline du sel de sulfate d'hydrogène de Larotrectinib, son procédé de préparation et son utilisation. En particulier, la forme cristalline du sel de sulfate d'hydrogène de Larotrectinib fournie par la présente invention a une excellente solubilité, des propriétés mécaniques stables et une stabilité dans des conditions d'humidité élevée.
PCT/CN2019/120340 2018-11-28 2019-11-22 Forme cristalline du sel de sulfate d'hydrogène de larotrectinib, son procédé de préparation et son utilisation WO2020108408A1 (fr)

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WO2024023836A1 (fr) * 2022-07-27 2024-02-01 Mylan Laboratories Limited Forme polymorphe de sulfate de larotrectinib

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CN109232582B (zh) * 2018-11-28 2021-02-05 安礼特（上海）医药科技有限公司 拉洛替尼硫酸氢盐晶型及其制备和应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107428760A (zh) * 2014-11-16 2017-12-01 阵列生物制药公司 (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‑甲酰胺硫酸氢盐的晶型
CN109232582A (zh) * 2018-11-28 2019-01-18 安礼特（上海）医药科技有限公司 拉洛替尼硫酸氢盐晶型及其制备和应用

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101634833B1 (ko) * 2008-10-22 2016-06-29 어레이 바이오파마 인크. ＴＲＫ 키나아제 억제제로서 치환된 피라졸로［１,５­ａ］ 피리미딘 화합물
BR112018008357A2 (pt) * 2015-10-26 2018-11-27 Array Biopharma Inc mutações de ponto em câncer resistente a inibidor de trk e métodos relacionados às mesmas
LT3458456T (lt) * 2016-05-18 2021-02-25 Loxo Oncology, Inc. (s)-n-(5-((r)-2-(2,5-difluorfenil)pirolidin-1-il)pirazolo[1,5-a]pirimidin-3-il)-3-hidroksipirolidin-1-karboksamido gavimas

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107428760A (zh) * 2014-11-16 2017-12-01 阵列生物制药公司 (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‑甲酰胺硫酸氢盐的晶型
CN109232582A (zh) * 2018-11-28 2019-01-18 安礼特（上海）医药科技有限公司 拉洛替尼硫酸氢盐晶型及其制备和应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024023836A1 (fr) * 2022-07-27 2024-02-01 Mylan Laboratories Limited Forme polymorphe de sulfate de larotrectinib

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