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EP-4273144-B1 - CRYSTAL FORM OF ENTRECTINIB AND PREPARATION METHOD THEREFOR

EP4273144B1EP 4273144 B1EP4273144 B1EP 4273144B1EP-4273144-B1

Inventors

  • LENG, CHUANXIN
  • WANG, Huicheng
  • FANG, Xi
  • FAN, CHUANWEN
  • LIN, DONG
  • LIU, TAO
  • HUANG, Zhaowei
  • CHENG, Fang
  • HUANG, Shuailong

Dates

Publication Date
20260506
Application Date
20220124

Claims (12)

  1. A crystal form A of entrectinib of formula I, comprising characteristic diffraction peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at 2θ angles of 7.1°±0.2°, 7.7°±0.2°, 8.5°±0.2°, 10.5°±0.2°, 13.9°±0.2°, 15.6°±0.2°, and 21.5°±0.2°; preferably, the crystal form A of entrectinib comprises characteristic diffraction peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at 2θ angles of 7.1°±0.2°, 7.7°±0.2°, 8.5°±0.2°, 10.5°±0.2°, 13.2°±0.2°, 13.9°±0.2°, 14.4°±0.2°, 15.6°±0.2°, 21.5°±0.2°, 22.6°±0.2°, 23.5°±0.2°, 24.6°±0.2°, and 25.8°±0.2°; more preferably, the crystal form A of entrectinib comprises characteristic diffraction peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at 2θ angles of 7.1°±0.2°, 7.7°±0.2°, 8.5°±0.2°, 10.5°±0.2°, 13.2°±0.2°, 13.9°±0.2°, 14.4°±0.2°, 15.6°±0.2°, 17.2°±0.2°, 18.9°±0.2°, 19.6°±0.2°, 21.5°±0.2°, 22.6°±0.2°, 23.5°±0.2°, 24.6°±0.2°, and 25.8°±0.2°; more preferably, the crystal form A of entrectinib has an X-ray powder diffraction pattern substantially as shown in FIG. 1.
  2. The crystal form A of entrectinib according to claim 1, wherein a DSC pattern of the crystal form A of entrectinib has endothermic peaks respectively at temperatures in the range of 122.0-159.8°C and in the range of 193.2-206.4°C; preferably, the DSC pattern has endothermic peaks at 147.1±2°C and 198.0±0.1°C; more preferably, the crystal form A of entrectinib has a DSC pattern substantially as shown in FIG. 2.
  3. The crystal form A of entrectinib according to claim 1 or 2, wherein a TGA pattern of the crystal form A of entrectinib does not have a significant weight loss prior to product degradation; preferably, the crystal form A of entrectinib has a TGA pattern substantially as shown in FIG. 2.
  4. A method for preparing the crystal form A of entrectinib according to any one of claims 1-3, wherein the method comprises the following steps: adding a crude amorphous form of entrectinib into a mixed solvent of water and acetone, heating and refluxing for dissolution, gradually cooling to -5 to 20°C for crystallization under an ultrasonic oscillation condition, filtering, and drying in air at room temperature to obtain the crystal form A of entrectinib.
  5. The method according to claim 4, wherein a volume ratio of acetone to water is 1:0.1 to 1:2.0, preferably 1:0.8 to 1:1.5, and more preferably 1:1; a mass-to-volume ratio of the crude amorphous form of entrectinib to acetone is 1:5 to 1:40, preferably 1:7 to 1:20, and more preferably 1:8 to 1:15, in a unit of mg/mL.
  6. A method for preparing the crystal form A of entrectinib according to any one of claims 1-3, wherein the method comprises the following steps: adding a crude amorphous form of entrectinib into an organic solvent, heating for dissolution, adding water and a crystal seed of the crystal form A, cooling for crystallization, filtering, and drying to obtain the crystal form A of entrectinib; wherein the organic solvent is selected from one of isopropanol, acetone and acetonitrile or any mixed solvent thereof.
  7. The method according to claim 6, wherein a volume ratio of the organic solvent to water is 1:0.1 to 1:2.0, preferably 1:0.8 to 1:1.5, and more preferably 1:1; a mass-to-volume ratio of the crude amorphous form of entrectinib to the organic solvent is 1:5 to 1:40, preferably 1:7 to 1:30, and more preferably 1:8 to 1:15, in a unit of mg/mL; an adding amount of the crystal seed is 0.1-1% of a feeding amount of the crude amorphous form of entrectinib; the cooling for crystallization is performed at a temperature of -10 to 20°C, preferably -5 to 5°C.
  8. A crystal form B of entrectinib of formula I, comprising diffraction peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at 2θ angles of 8.5°±0.2°, 9.5°±0.2°, 10.4°±0.2°, 11.3°±0.2°, 14.4°±0.2°, 16.0°±0.2°, 18.5°±0.2°, 19.3°±0.2°, 20.5°±0.2°, and 22.3°±0.2°; preferably, the crystal form B of entrectinib comprises diffraction peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at 2θ angles of 8.5°±0.2°, 9.5°±0.2°, 10.4°±0.2°, 11.3°±0.2°, 12.9°±0.2°, 13.8°±0.2°, 14.4°±0.2°, 16.0°±0.2°, 16.6°±0.2°, 17.4°±0.2°, 18.5°±0.2°, 19.3°±0.2°, 20.5°±0.2°, 22.3°±0.2°, 22.8°±0.2°, 23.9°±0.2°, 24.2°±0.2°, 25.5°±0.2°, and 30.1°±0.2°; more preferably, the crystal form B of entrectinib has an X-ray powder diffraction pattern substantially as shown in FIG. 3.
  9. The crystal form B of entrectinib according to claim 8, wherein a DSC pattern of the crystal form B of entrectinib has a significant endothermic peak in the range of 182.3-207.4°C; more preferably, the DSC pattern has an endothermic peak at 196.5°C; more preferably, the crystal form B of entrectinib has a DSC pattern substantially as shown in FIG. 4.
  10. The crystal form B of entrectinib according to claim 8 or 9, wherein a TGA pattern of the crystal form B of entrectinib does not have a significant weight loss prior to product degradation; preferably, the crystal form B of entrectinib of the present disclosure has a TGA pattern substantially as shown in FIG. 4.
  11. A method for preparing the crystal form B of entrectinib according to any one of claims 8-10, wherein the method comprises the following steps: adding a crude amorphous form of entrectinib into dioxane, heating to 80°C for dissolution, adding purified water, cooling to -5 to 20°C for crystallization at a maintained temperature, filtering under sucking, and drying to obtain the crystal form B of entrectinib.
  12. The method according to claim 11, wherein a volume ratio of dioxane to water is 1:0.2 to 1:2.0, preferably 1:0.6 to 1:1.4, and more preferably 1:0.8; a mass-to-volume ratio of the crude amorphous form of entrectinib to dioxane is 1:5 to 1:30, preferably 1:8 to 1:20, and more preferably 1:10 to 1:15, in a unit of mg/mL.

Description

The present application claims priority to the prior application of Patent Application No. 202110150771.9 filed to the China National Intellectual Property Administration on February 3, 2021 and entitled "CRYSTAL FORM OF ENTRECTINIB AND PREPARATION METHOD THEREFOR". TECHNICAL FIELD The present disclosure belongs to the technical field of pharmaceutical chemistry, and in particular relates to a novel crystal form of entrectinib, and a preparation method therefor, and use thereof. BACKGROUND Entrectinib, chemically known as N-[5-(3,5-difluorobenzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-[(tetrahydro-2H-pyran-4-yl)amino]benzamide, is used for the treatment of adult and pediatric patients with advanced recurrent solid tumors that are positive for neurotrophic tyrosine receptor kinase (NTRK) fusion. Rozlytrek is the first drug approved in Japan for targeting NTRK gene fusion tumors, in a range of solid tumor types which are difficult to treat, including pancreatic cancer, thyroid cancer, salivary gland cancer, breast cancer, colorectal cancer, lung cancer, and the like. Various crystal forms of entrectinib have been disclosed in the prior art documents. For example, the international patent application WO2013174876 of the original research company discloses crystal forms 1, 2 and 3 of entrectinib, wherein the crystal form 3 is a solvate of ethyl acetate and n-hexane; the International Patent Application WO2017202674 discloses a crystal form 4 of entrectinib; the Chinese Patent Application CN111171009A discloses 9 crystal forms from AZT-A to AZT-I, wherein the preferred crystal forms are the crystal form AZT-A, the crystal form AZT-B and the crystal form AZT-E. The crystal forms 1, 2 and 4 are all crystallized using a mixed solvent of ethanol and water. Mixed crystals are easy to appear in the crystallization process, and the mixed crystals are ensured not to appear only by very precise control. Thus, the industrial production difficulty is greater. In addition, researches show that the crystal form 1 contains more amorphous forms, the crystallization system is viscous, the filtration is difficult, the large-scale production is not facilitated, the crystal form is unstable and is easy to be converted into another crystal form, and thus the crystal form is not suitable for medicinal use; the crystal form 3 is a solvate of ethyl acetate and n-hexane, the solvent content exceeds the limit required by ICH guidelines, and thus the crystal form is not suitable for medicinal use; the crystallization solvent of the crystal form 4 is the same as that of the crystal form 2, the crystal form 2 is easily obtained in the preparation process, and there are risks in the production; entrectinib is of BCS class 2, belongs to a low-solubility and high-permeability drug, has poor solubility of crystal form 2 and a large particle size, needs to be micronized, and has the problems of serious static electricity, poor fluidity and the like in the micronized samples, thereby affecting the production of formulations; the crystal forms AZT-A, AZT-B, and AZT-E have a large particle size and need to be micronized, and have the problems of serious static electricity, poor fluidity and the like in the micronized samples, that is, the uniformity of mixed powder of the API is affected, and has an adverse effect on the production of formulations. Therefore, a novel crystal form of entrectinib, which has good stability and better solubility, exhibits no static electricity in the production process of API and formulations, has good fluidity, and is easy to realize large-scale production, is urgently needed to be found at present, and the production process needs to be stable and will not be converted into another crystal form or mixed crystal so as to make up for the defects in the prior art. In order to overcome the defects of existing crystal forms of entrectinib in the art, the inventors carry out more intensive and extensive research on crystal forms of entrectinib. In the process, novel crystal forms of entrectinib are obtained, which have good stability, high purity and good solubility, no need for crushing, and no static electricity generation. The preparation method is suitable for large-scale production and is highly practicable, overcoming the defects in the prior art. SUMMARY An object of the present disclosure is to provide novel crystal forms of entrectinib, which have good stability, high purity, a simple preparation process, and high practicability, and a method for preparing the novel crystal forms. A first aspect of the present disclosure provides a novel crystal form A of entrectinib, comprising characteristic diffraction peaks in an X-ray powder diffraction pattern using Cu-Kα radiation at 2θ angles of 7.1°±0.2°, 7.7°±0.2°, 8.5°±0.2°, 10.5°±0.2°, 13.9°±0.2°, 15.6°±0.2°, and 21.5°±0.2°. Specifically, the crystal form A of entrectinib comprises characteristic diffraction peaks in an X-ray powder diffraction pattern using C