WO2021078076A1 - Novel crystalline form of acetylated eltrombopag and preparation method thereof - Google Patents

Novel crystalline form of acetylated eltrombopag and preparation method thereof Download PDF

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WO2021078076A1
WO2021078076A1 PCT/CN2020/121710 CN2020121710W WO2021078076A1 WO 2021078076 A1 WO2021078076 A1 WO 2021078076A1 CN 2020121710 W CN2020121710 W CN 2020121710W WO 2021078076 A1 WO2021078076 A1 WO 2021078076A1
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crystal form
eltrombopag
acetylated
ray powder
powder diffraction
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PCT/CN2020/121710
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French (fr)
Chinese (zh)
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张鹏伟
黄河
廖伟龙
李英龙
寇景平
林碧悦
陈勇
王仲清
罗忠华
黄芳芳
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广东东阳光药业有限公司
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Priority to CN202080060751.6A priority Critical patent/CN114341112A/en
Publication of WO2021078076A1 publication Critical patent/WO2021078076A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/06—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D231/08—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with oxygen or sulfur atoms directly attached to ring carbon atoms

Definitions

  • the invention belongs to the field of medicinal chemistry, and relates to a new crystal form of acetylated Eltrombopag and a preparation method thereof.
  • Eltrombopag olamine is a thrombopoietin receptor agonist used to treat certain conditions that cause thrombocytopenia.
  • the structure of Eltrombopag diethanolamine salt is shown in the following formula (1).
  • Eltrombopag has a food effect
  • acetylated Eltrombopag is a prodrug of Eltrombopag and can be used to overcome the food effect of Eltrombopag.
  • Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and there may be great differences, which will affect the storage transfer, application, stability, and efficacy of the drug. In order to obtain an effective crystal form that is conducive to production or pharmaceutical preparations, it is necessary to conduct a comprehensive investigation of the crystallization behavior of the drug to obtain a crystal form that meets the production requirements.
  • the present invention obtains a new crystal form of the compound through a large number of experimental studies on the prodrug of Eltrombopag: acetylated Eltrombopag, which has good stability, good release in the animal body, and simple preparation process Easy to operate and other superior properties.
  • the invention provides a new crystal form of acetylated Eltrombopag and a preparation method thereof.
  • the crystal form has good stability and the preparation method of the crystal form is simple and easy to operate.
  • the present invention provides new crystal forms of acetylated Eltrombopag: crystal form D and crystal form J.
  • the new crystal form was studied, and it was found that the crystal form D and the crystal form J have good performance in terms of stability and the like, and both can be used in the production of pharmaceutical preparations.
  • the crystal form D is characterized in that it has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle by using an X-ray powder diffractometer using Cu-K ⁇ radiation: 6.7, 8.8, 13.4, 14.6, 16.2, 18.9, 21.4, 26.4 and 30.6.
  • the differential scanning calorimetry (DSC) of the crystal form D has endothermic peaks in the range of 167°C-169°C, 211°C-213°C, and 225°C-227°C.
  • the crystal form J is characterized in that it has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle by using an X-ray powder diffractometer using Cu-K ⁇ radiation: 5.8, 8.8, 12, 14.5, 16.5, 22.8 and 25.7.
  • the differential scanning calorimetry (DSC) of the crystal form J has an endothermic peak in the range of 165°C to 167°C.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of acetylated Eltrombopag crystal form D or crystal form J and pharmaceutically acceptable auxiliary materials or excipients.
  • the pharmaceutical composition contains acetylated Eltrombopag, and according to the mass ratio, at least 80% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form D or crystal form J.
  • the pharmaceutical composition can be used to treat thrombocytopenia in patients with chronic idiopathic thrombocytopenic purpura (ITP) after glucocorticoid drugs, immunoglobulin therapy or after splenectomy, and platelets in patients with chronic hepatitis C Reduce symptoms, severe aplastic anemia and other diseases that do not respond to immunosuppressive treatment.
  • ITP chronic idiopathic thrombocytopenic purpura
  • the present invention also provides a method for preparing the acetylated Eltrombopag crystal form D or crystal form J.
  • a method for preparing acetylated Eltrombopag crystal form D includes: mixing the acetylated Eltrombopag with tetrahydrofuran, after the dissolution is complete, adding an anti-solvent to the tetrahydrofuran solution, stirring to precipitate crystals, collecting the crystals, and removing Solvent to obtain crystal form D.
  • a method for preparing acetylated Eltrombopag crystal form J includes: mixing acetylated Eltrombopag with a good solvent, heating to dissolve, and after the dissolution is complete, reducing the temperature to 0°C to 30°C, separating out crystals, and collecting the crystals, The solvent was removed to obtain the crystal form J.
  • the crystal form D and the crystal form J provided by the present invention have good stability, are beneficial to storage, transfer, and operation in the production process, and can be used to prepare a preparation.
  • an object of the present invention is to provide a new crystal form of acetylated Eltrombopag and a preparation method thereof.
  • the crystal form has good stability and the preparation method of the crystal form is simple and easy to operate.
  • the present invention provides new crystal forms of acetylated Eltrombopag: crystal form D and crystal form J.
  • the new crystal form of the present invention was studied, and it was found that the crystal form D and the crystal form J have good performance in terms of stability, release in the body, etc., and can be used in the production of pharmaceutical preparations.
  • the crystal form D is characterized in that it has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle by using an X-ray powder diffractometer using Cu-K ⁇ radiation: 6.7, 8.8, 13.4, 14.6, 16.2, 18.9, 21.4, 26.4 and 30.6.
  • the crystal form D has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 7.1, 14.2, 16.9, 19.9 , 26.0 and 28.6.
  • the crystal form D has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 6.7, 7.1, 8.8, 13.4 , 14.2, 14.6, 16.2, 16.9, 18.9, 19.9, 21.4, 26.0, 26.4, 28.6 and 30.6.
  • the relative intensity of the diffraction peak at 8.8 degrees 2 ⁇ is greater than 70%, or greater than 80%, or greater than 90%, or Greater than 99%.
  • the crystal form D has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 1.
  • the differential scanning calorimetry (DSC) of the crystalline form D has endothermic peaks in the range of 167°C-169°C, 211°C-213°C, and 225°C-227°C.
  • the crystalline form D has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 2.
  • thermogravimetric analysis curve (TGA) of the crystal form D shows that there is a weight loss between 30°C and 120°C, and the weight loss is about 3.66%.
  • the crystal form D has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 3.
  • TGA pattern thermogravimetric analysis curve
  • the purity of the crystal form D is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%. In some embodiments, the purity of the crystal form D is at least 85%, or at least 90%, or at least 95%, or at least 99%.
  • Form J is characterized in that it has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle by using an X-ray powder diffractometer using Cu-K ⁇ radiation: 5.8, 8.8, 12, 14.5, 16.5, 22.8 and 25.7.
  • the crystal form J has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 7.9, 10.5, 12.9, 14.8 , 18.4, 20.8 and 23.8.
  • the crystal form J has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 5.8, 7.9, 8.8, 10.5 , 12, 12.9, 14.5, 14.8, 16.5, 18.4, 20.8, 22.8, 23.8 and 25.7.
  • the crystal form J has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 7.0, 7.9, 10.5, 12.9 , 13.5, 14.0, 14.8, 16.0, 17.2, 17.7, 18.4, 19.3, 20.0, 20.8, 23.8, 24.7 and 27.1.
  • the crystal form J has diffraction peaks at the following 2 ⁇ (unit: degree, error ⁇ 0.2 degree) angle: 5.8, 7.0, 7.9, 8.8 , 10.5, 12, 12.9, 13.5, 14.0, 14.5, 14.8, 16.0, 16.5, 17.2, 17.7, 18.4, 19.3, 20.0, 20.8, 22.8, 23.8, 24.7 and 27.1.
  • the relative intensity of the peak at 2 ⁇ of 14.8 degrees is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.
  • the crystal form J has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 4.
  • XRPD pattern X-ray powder diffraction pattern
  • the differential scanning calorimetry (DSC) of the crystalline form J has an endothermic peak in the range of 165°C to 167°C.
  • the crystalline form J has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 5.
  • thermogravimetric analysis curve (TGA) of the crystal form J shows that there is a weight loss between 30°C and 160°C, and the weight loss is about 4.56%.
  • the crystal form J has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 6.
  • the purity of the crystal form J is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%.
  • the acetylated Eltrombopag crystal form D and crystal form J of the present invention can be used for the treatment of chronic idiopathic thrombocytopenic purpura (ITP) after splenectomy or chronic idiopathic thrombocytopenic purpura (ITP) after glucocorticoid drugs or immunoglobulin treatment is invalid Patients with thrombocytopenia, thrombocytopenia in patients with chronic hepatitis C, and severe aplastic anemia with insufficient response to immunosuppressive therapy.
  • ITP chronic idiopathic thrombocytopenic purpura
  • ITP chronic idiopathic thrombocytopenic purpura
  • immunoglobulin treatment is invalid Patients with thrombocytopenia, thrombocytopenia in patients with chronic hepatitis C, and severe aplastic anemia with insufficient response to immunosuppressive therapy.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of acetylated Eltrombopag crystal form D or crystal form J and pharmaceutically acceptable excipients or excipients.
  • a therapeutically effective amount of acetylated Eltrombopag crystal form D or/and crystal form J is mixed or contacted with one or more pharmaceutical excipients to prepare a pharmaceutical composition or preparation, and the pharmaceutical composition or preparation is It is prepared in a well-known manner in the pharmaceutical field.
  • the pharmaceutical composition or preparation can be used to treat thrombocytopenia in patients with chronic idiopathic thrombocytopenic purpura (ITP) after splenectomy, and patients with chronic hepatitis C that are ineffective in the treatment of glucocorticoid drugs or immunoglobulin.
  • ITP chronic idiopathic thrombocytopenic purpura
  • the present invention provides a pharmaceutical composition, which contains at least 0.1%-10% of the crystal form D or the crystal form J of the total weight of the composition.
  • the present invention provides a pharmaceutical composition, which contains at least 0.1%-5% of the crystal form D or crystal form J of the total weight of the composition.
  • the present invention provides a pharmaceutical composition, which contains at least 0.1%-1% of the crystal form D or the crystal form J of the total weight of the composition.
  • the present invention provides a pharmaceutical composition, which contains at least 0.1%-0.5% of the crystal form D or the crystal form J of the total weight of the composition.
  • a pharmaceutical composition contains acetylated Eltrombopag, and at least 90% of the acetylated Eltrombopag is in the acetylated Eltrombopag crystal form D or crystal.
  • a pharmaceutical composition contains acetylated Eltrombopag, in terms of mass ratio, wherein at least 95% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form D or crystal Type J.
  • a pharmaceutical composition contains acetylated Eltrombopag, and at least 97% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form D or crystal. Type J.
  • a pharmaceutical composition contains acetylated Eltrombopag, in terms of mass ratio, wherein at least 99% of acetylated Eltrombopag is the acetylated Eltrombopag crystal form D or crystal Type J.
  • the purity of crystal form D in the pharmaceutical composition is at least 80%. In some embodiments, the purity of the crystalline form D in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.
  • the purity of the crystal form J in the pharmaceutical composition is at least 80%. In some embodiments, the purity of the crystalline form J in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.
  • the pharmaceutical composition containing acetylated Eltrombopag crystal form D or crystal form J of the present invention can be used to prepare glucocorticoid drugs, immunoglobulin treatment ineffective or chronic idiopathic thrombocytopenia after splenectomy Thrombocytopenia in patients with ITP, as well as thrombocytopenia in patients with chronic hepatitis C, and pharmaceutical preparations for severe aplastic anemia that do not respond to immunosuppressive therapy.
  • the pharmaceutical composition containing acetylated Eltrombopag crystal form D or crystal form J of the present invention can be used to treat chronic idiopathic thrombocytopenia after glucocorticoid drugs, immunoglobulin therapy, or chronic idiopathic thrombocytopenia after splenectomy Thrombocytopenia in patients with chronic hepatitis C (ITP), thrombocytopenia in patients with chronic hepatitis C, and severe aplastic anemia with insufficient response to immunosuppressive therapy.
  • ITP chronic hepatitis C
  • thrombocytopenia in patients with chronic hepatitis C
  • severe aplastic anemia with insufficient response to immunosuppressive therapy.
  • the crystal form D or crystal form J provided by the present invention has better stability, and a more stable crystal form is of great significance for improving the quality of the medicine.
  • the crystal form D and crystal form J provided by the invention have good stability, are not easy to deliquesce under high humidity conditions, and are convenient for long-term storage and placement of the medicine.
  • the crystal form provided by the invention has good stability, can well avoid crystal transformation during drug storage and development, thereby avoiding changes in bioavailability and drug efficacy, and has strong economic value.
  • the present invention proposes a method for preparing the aforementioned acetylated Eltrombopag crystal form D or crystal form J.
  • a method for preparing acetylated Eltrombopag crystal form D includes: mixing the acetylated Eltrombopag with tetrahydrofuran, after the dissolution is complete, adding an anti-solvent to the tetrahydrofuran solution, stirring to precipitate crystals, collecting the crystals, and removing Solvent to obtain crystal form D.
  • a method for preparing acetylated Eltrombopag crystal form D includes: mixing acetylated Eltrombopag with tetrahydrofuran, and after the dissolution is complete, adding an anti-solvent to the tetrahydrofuran solution dropwise to precipitate crystals, The crystals are collected and the solvent is removed to obtain crystal form D.
  • the anti-solvent is water or methanol, or a combination thereof.
  • the mass-volume ratio of the solvent of the acetylated Eltrombopag and tetrahydrofuran is 1:2 to 1:20; more preferably 1:3 ⁇ 1:5.
  • a method for preparing acetylated Eltrombopag crystal form J includes: mixing acetylated Eltrombopag with a good solvent, heating to dissolve, and after the dissolution is complete, reducing the temperature to 0°C to 30°C, separating out crystals, and collecting the crystals, The solvent was removed to obtain the crystal form J.
  • a method for preparing acetylated Eltrombopag crystal form J includes: mixing acetylated Eltrombopag with a good solvent, dissolving by heating, and after the dissolution is complete, reducing the temperature to 0°C to 20°C to precipitate Crystals, crystals are collected, and the solvent is removed to obtain crystal form J.
  • the good solvent is ethylene glycol dimethyl ether, acetone, tetrahydrofuran, a mixed solvent of acetone and ethyl acetate, a mixed solvent of acetone and methyl ethyl ketone, and a mixed solvent of acetone and acetonitrile.
  • the good solvent is a mixed solvent
  • the volume ratio of acetone to ethyl acetate, methyl ethyl ketone or acetonitrile is 1:1.
  • the mass-volume ratio of the acetylated Eltrombopag to the good solvent is 1:20 to 1:50; more preferably 1:25 to 1:40.
  • the “crystal form” of the present invention can be present in the sample at 0.0001%-100%. Therefore, as long as the sample contains trace amounts, for example, greater than 0.0001%, greater than 0.001%, greater than 0.001% or greater than 0.01% of the present invention
  • the “crystal form” of should be understood as falling within the protection scope of the present invention.
  • the present invention tests various parameters on a sample containing a certain "crystal form” that is substantially pure and carries out the determination of the crystal form. Characterization and identification.
  • the differential scanning calorimetry (DSC) of the crystal form has experimental errors and is slightly affected by the dryness of the sample. Between one machine and another machine and between one sample and another sample, the The position and peak value of the thermal peak may be slightly different, and the experimental error or the value of the difference may be less than or equal to 10°C, or less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than It is equal to 1°C, so the peak position or the value of the peak value of the DSC endothermic peak cannot be regarded as absolute.
  • the mass unit is grams and the volume unit is milliliters.
  • RH means relative humidity
  • Figure 1 X-ray powder diffraction (XRPD) pattern of acetylated Eltrombopag Form D.
  • FIG. 1 Differential scanning calorimetry (DSC) graph of acetylated Eltrombopag Form D.
  • Figure 4 X-ray powder diffraction (XRPD) pattern of acetylated Eltrombopag Form J.
  • the reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
  • test instrument In the present invention, the test instrument and method
  • the X-ray powder diffraction (XRPD) pattern was collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero background sample holder with a transflective sample stage.
  • the radiation source used is (Cu, k ⁇ , K ⁇ 1 1.540598; K ⁇ 2 1.544426; K ⁇ 2/K ⁇ 1 intensity ratio: 0.50), where the voltage is set at 45KV, and the current is set at 40mA.
  • the beam divergence of X-rays that is, the effective size of the X-ray confinement on the sample, is 10mm. Using ⁇ - ⁇ Continuous scanning mode, to obtain an effective 2 ⁇ range of 3° ⁇ 40°.
  • the DSC measurement was performed in TA Instruments TM model Q2000 with a sealed disk device. Weigh the sample (approximately 1 to 3 mg) in an aluminum pan, cover it with Tzero, accurately record it to one hundredth of a milligram, and transfer the sample to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data was collected between room temperature and 300°C at a heating rate of 10°C/min. The endothermic peak is drawn downward, and the data is analyzed and displayed by TA Universal Analysis.
  • the TGA measurement was performed in TA Instruments TM model Q500.
  • the operation step is to peel the empty crucible, take about 10 mg of solid sample, place it in the peeled empty crucible, and spread it evenly. After the instrument runs stably, collect data at a heating rate of 10°C/min between room temperature and 300°C under nitrogen purge, and record the spectrum.

Abstract

A novel crystalline form of acetylated eltrombopag and a preparation method thereof belonging to the field of medicinal chemistry. The crystalline form has good stability and facilitates operations in storage, transfer, and production processes, releases well in animals, and can be used to prepare the preparations.

Description

乙酰化艾曲波帕的新晶型及其制备方法New crystal form of acetylated Eltrombopag and preparation method thereof 技术领域Technical field
本发明属于药物化学领域，涉及乙酰化艾曲波帕的新晶型及其制备方法。The invention belongs to the field of medicinal chemistry, and relates to a new crystal form of acetylated Eltrombopag and a preparation method thereof.
背景技术Background technique
艾曲波帕二乙醇胺盐(Eltrombopag olamine)，CAS：496775-62-3，是一种血小板生成素受体激动剂，用于治疗导致血小板减少的某些病症。艾曲波帕二乙醇胺盐结构如下式(1)所示。Eltrombopag olamine, CAS: 496775-62-3, is a thrombopoietin receptor agonist used to treat certain conditions that cause thrombocytopenia. The structure of Eltrombopag diethanolamine salt is shown in the following formula (1).
Figure PCTCN2020121710-appb-000001
Figure PCTCN2020121710-appb-000001
乙酰化艾曲波帕，结构如下式(2)所示。The structure of acetylated Eltrombopag is shown in the following formula (2).
Figure PCTCN2020121710-appb-000002
Figure PCTCN2020121710-appb-000002
艾曲波帕具有食物效应，乙酰化艾曲波帕是艾曲波帕的前药，可用于克服艾曲波帕的食物效应。Eltrombopag has a food effect, and acetylated Eltrombopag is a prodrug of Eltrombopag and can be used to overcome the food effect of Eltrombopag.
药物多晶型是药品研发中的常见现象，是影响药品质量的重要因素。同一药物的不同晶型在外观、流动性、溶解度、储存稳定性、生物利用度等理化性质方面可能会有显著不同，可能存在极大差异，会对药物的储存转移、应用、稳定性、疗效等产生不同的影响；为了得到有效的利于生产或利于药物制剂的晶型，需要对药物的结晶行为进行全面的考察，以得到满足生产要求的晶型。Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and there may be great differences, which will affect the storage transfer, application, stability, and efficacy of the drug. In order to obtain an effective crystal form that is conducive to production or pharmaceutical preparations, it is necessary to conduct a comprehensive investigation of the crystallization behavior of the drug to obtain a crystal form that meets the production requirements.
本发明通过对艾曲波帕的前药：乙酰化艾曲波帕进行大量实验研究，得到了该化合物的新晶型，该新晶型具有稳定性好，在动物体内释放良好，制备工艺简单易操作等优越性质。The present invention obtains a new crystal form of the compound through a large number of experimental studies on the prodrug of Eltrombopag: acetylated Eltrombopag, which has good stability, good release in the animal body, and simple preparation process Easy to operate and other superior properties.
发明内容Summary of the invention
发明概述Summary of the invention
本发明提供了乙酰化艾曲波帕新晶型及其制备方法，该晶型具有良好的稳定性，该晶型的制备方法简单易操作。The invention provides a new crystal form of acetylated Eltrombopag and a preparation method thereof. The crystal form has good stability and the preparation method of the crystal form is simple and easy to operate.
根据本发明的一个方面，本发明提供了乙酰化艾曲波帕的新晶型：晶型D、晶型J。According to one aspect of the present invention, the present invention provides new crystal forms of acetylated Eltrombopag: crystal form D and crystal form J.
对所述新晶型进行研究，发现晶型D和晶型J在稳定性等方面具有良好的性能，均可用于制备药物制剂生产中。The new crystal form was studied, and it was found that the crystal form D and the crystal form J have good performance in terms of stability and the like, and both can be used in the production of pharmaceutical preparations.
所述晶型D的特征在于，通过使用Cu-Kα辐射的X射线粉末衍射仪，其在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：6.7,8.8,13.4,14.6,16.2,18.9,21.4,26.4和30.6。The crystal form D is characterized in that it has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle by using an X-ray powder diffractometer using Cu-Kα radiation: 6.7, 8.8, 13.4, 14.6, 16.2, 18.9, 21.4, 26.4 and 30.6.
所述晶型D的差示扫描量热曲线(DSC)在167℃-169℃，211℃-213℃，225℃-227℃范围内具有吸热峰。The differential scanning calorimetry (DSC) of the crystal form D has endothermic peaks in the range of 167°C-169°C, 211°C-213°C, and 225°C-227°C.
所述晶型J的特征在于，通过使用Cu-Kα辐射的X射线粉末衍射仪，其在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：5.8,8.8,12,14.5,16.5,22.8和25.7。The crystal form J is characterized in that it has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle by using an X-ray powder diffractometer using Cu-Kα radiation: 5.8, 8.8, 12, 14.5, 16.5, 22.8 and 25.7.
所述晶型J的差示扫描量热曲线(DSC)在165℃-167℃范围内具有吸热峰。The differential scanning calorimetry (DSC) of the crystal form J has an endothermic peak in the range of 165°C to 167°C.
本发明还提供了包含治疗有效量的乙酰化艾曲波帕晶型D或晶型J和药学上可接受的辅料或赋形剂的药物组合物。所述的药物组合物，含有乙酰化艾曲波帕，按照质量比计，其中至少80％的乙酰化艾曲波帕为所述乙酰化艾曲波帕晶型D或晶型J。The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of acetylated Eltrombopag crystal form D or crystal form J and pharmaceutically acceptable auxiliary materials or excipients. The pharmaceutical composition contains acetylated Eltrombopag, and according to the mass ratio, at least 80% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form D or crystal form J.
所述药物组合物可以用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少，以及慢性丙型肝炎患者的血小板减少症、对免疫抑制治疗反应不足的重型再生障碍性贫血等疾病。The pharmaceutical composition can be used to treat thrombocytopenia in patients with chronic idiopathic thrombocytopenic purpura (ITP) after glucocorticoid drugs, immunoglobulin therapy or after splenectomy, and platelets in patients with chronic hepatitis C Reduce symptoms, severe aplastic anemia and other diseases that do not respond to immunosuppressive treatment.
本发明还提供了一种制备所述的乙酰化艾曲波帕晶型D或晶型J的方法。The present invention also provides a method for preparing the acetylated Eltrombopag crystal form D or crystal form J.
一种制备乙酰化艾曲波帕晶型D的方法包括：将乙酰化艾曲波帕与四氢呋喃混合，溶解完全后，将反溶剂滴加到该四氢呋喃溶液中，搅拌析出晶体，收集晶体，除去溶剂，得到晶型D。A method for preparing acetylated Eltrombopag crystal form D includes: mixing the acetylated Eltrombopag with tetrahydrofuran, after the dissolution is complete, adding an anti-solvent to the tetrahydrofuran solution, stirring to precipitate crystals, collecting the crystals, and removing Solvent to obtain crystal form D.
一种制备乙酰化艾曲波帕晶型J的方法包括：将乙酰化艾曲波帕与良溶剂混合，加热溶解，溶解完全后，降低温度至0℃～30℃，析出晶体，收集晶体，除去溶剂，得到晶型J。A method for preparing acetylated Eltrombopag crystal form J includes: mixing acetylated Eltrombopag with a good solvent, heating to dissolve, and after the dissolution is complete, reducing the temperature to 0°C to 30°C, separating out crystals, and collecting the crystals, The solvent was removed to obtain the crystal form J.
本发明提供的晶型D，晶型J，均具有较好的稳定性，有利于储存、转移、生产工艺中操作，可以用于制备成制剂。The crystal form D and the crystal form J provided by the present invention have good stability, are beneficial to storage, transfer, and operation in the production process, and can be used to prepare a preparation.
发明详述Detailed description of the invention
本发明旨在至少在一定程度上解决相关技术中的技术问题之一。为此，本发明的一个目的在于提供乙酰化艾曲波帕新晶型及其制备方法，该晶型具有良好的稳定性，该晶型的制备方法简单易操作。The present invention aims to solve one of the technical problems in the related art at least to a certain extent. To this end, an object of the present invention is to provide a new crystal form of acetylated Eltrombopag and a preparation method thereof. The crystal form has good stability and the preparation method of the crystal form is simple and easy to operate.
根据本发明的一个方面，本发明提供了乙酰化艾曲波帕的新晶型：晶型D和晶型J。According to one aspect of the present invention, the present invention provides new crystal forms of acetylated Eltrombopag: crystal form D and crystal form J.
对本发明所述新晶型进行研究，发现晶型D和晶型J在稳定性、体内释放等方面具有良好的性能，可用于制备药物制剂生产中。The new crystal form of the present invention was studied, and it was found that the crystal form D and the crystal form J have good performance in terms of stability, release in the body, etc., and can be used in the production of pharmaceutical preparations.
晶型D的特征在于，通过使用Cu-Kα辐射的X射线粉末衍射仪，其在下列2θ(单位：度，误差±0.2 度)角处具有衍射峰：6.7,8.8,13.4,14.6,16.2,18.9,21.4,26.4和30.6。The crystal form D is characterized in that it has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle by using an X-ray powder diffractometer using Cu-Kα radiation: 6.7, 8.8, 13.4, 14.6, 16.2, 18.9, 21.4, 26.4 and 30.6.
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型D在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：7.1,14.2,16.9,19.9,26.0和28.6。In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the crystal form D has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle: 7.1, 14.2, 16.9, 19.9 , 26.0 and 28.6.
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型D在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：6.7,7.1,8.8,13.4,14.2,14.6,16.2,16.9,18.9,19.9,21.4,26.0,26.4,28.6和30.6。In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the crystal form D has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle: 6.7, 7.1, 8.8, 13.4 , 14.2, 14.6, 16.2, 16.9, 18.9, 19.9, 21.4, 26.0, 26.4, 28.6 and 30.6.
在一些实施例中，乙酰化艾曲波帕晶型D的X-射线粉末衍射图中，在2θ为8.8度的衍射峰的相对强度大于70％，或大于80％，或大于90％，或大于99％。In some embodiments, in the X-ray powder diffraction pattern of acetylated Eltrombopag Form D, the relative intensity of the diffraction peak at 8.8 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%, or Greater than 99%.
在一些实施例中，所述晶型D具有基本上如图1所示的X-射线粉末衍射图谱(XRPD图谱)。In some embodiments, the crystal form D has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 1.
在一些实施例中，所述晶型D的差示扫描量热曲线(DSC)在167℃-169℃，211℃-213℃，225℃-227℃范围内具有吸热峰。In some embodiments, the differential scanning calorimetry (DSC) of the crystalline form D has endothermic peaks in the range of 167°C-169°C, 211°C-213°C, and 225°C-227°C.
在一些实施例中，所述晶型D具有如图2所示的差示扫描量热曲线(DSC图谱)。In some embodiments, the crystalline form D has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 2.
在一些实施例中，所述晶型D的热重分析曲线(TGA)显示在30℃-120℃间有失重，失重量约为3.66％。In some embodiments, the thermogravimetric analysis curve (TGA) of the crystal form D shows that there is a weight loss between 30°C and 120°C, and the weight loss is about 3.66%.
在一些实施例中，所述晶型D具有基本上如图3所示的热重分析曲线(TGA图谱)。In some embodiments, the crystal form D has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 3.
在一些实施例中，所述晶型D的纯度至少为70％，或至少80％，或至少90％，或至少95％，或至少99％。在一些实施例中，所述晶型D的纯度至少为85％，或至少90％，或至少95％，或至少99％。In some embodiments, the purity of the crystal form D is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%. In some embodiments, the purity of the crystal form D is at least 85%, or at least 90%, or at least 95%, or at least 99%.
晶型J的特征在于，通过使用Cu-Kα辐射的X射线粉末衍射仪，其在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：5.8,8.8,12,14.5,16.5,22.8和25.7。Form J is characterized in that it has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle by using an X-ray powder diffractometer using Cu-Kα radiation: 5.8, 8.8, 12, 14.5, 16.5, 22.8 and 25.7.
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型J在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：7.9,10.5,12.9,14.8,18.4,20.8和23.8。In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the crystal form J has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle: 7.9, 10.5, 12.9, 14.8 , 18.4, 20.8 and 23.8.
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型J在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：5.8,7.9,8.8,10.5,12,12.9,14.5,14.8,16.5,18.4,20.8,22.8,23.8和25.7。In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the crystal form J has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle: 5.8, 7.9, 8.8, 10.5 , 12, 12.9, 14.5, 14.8, 16.5, 18.4, 20.8, 22.8, 23.8 and 25.7.
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型J在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：7.0，7.9,10.5,12.9,13.5，14.0，14.8,16.0，17.2，17.7，18.4,19.3,20.0,20.8,23.8，24.7和27.1。In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the crystal form J has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle: 7.0, 7.9, 10.5, 12.9 , 13.5, 14.0, 14.8, 16.0, 17.2, 17.7, 18.4, 19.3, 20.0, 20.8, 23.8, 24.7 and 27.1.
在一些实施例中，通过使用Cu-Kα辐射的X射线粉末衍射仪，所述晶型J在下列2θ(单位：度，误差±0.2度)角处具有衍射峰：5.8,7.0，7.9,8.8,10.5,12,12.9,13.5，14.0，14.5,14.8,16.0，16.5,17.2，17.7，18.4,19.3,20.0,20.8,22.8,23.8，24.7和27.1。In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the crystal form J has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle: 5.8, 7.0, 7.9, 8.8 , 10.5, 12, 12.9, 13.5, 14.0, 14.5, 14.8, 16.0, 16.5, 17.2, 17.7, 18.4, 19.3, 20.0, 20.8, 22.8, 23.8, 24.7 and 27.1.
在一些实施例中，乙酰化艾曲波帕晶型J的X-射线粉末衍射图中，在2θ为14.8度的峰的相对强度大于70％，或大于80％，或大于90％，或大于99％。In some embodiments, in the X-ray powder diffraction pattern of acetylated Eltrombopag Form J, the relative intensity of the peak at 2θ of 14.8 degrees is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.
在一些实施例中，所述晶型J具有基本上如图4所示的X-射线粉末衍射图谱(XRPD图谱)。In some embodiments, the crystal form J has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 4.
在一些实施例中，所述晶型J的差示扫描量热曲线(DSC)在165℃-167℃范围内具有吸热峰。In some embodiments, the differential scanning calorimetry (DSC) of the crystalline form J has an endothermic peak in the range of 165°C to 167°C.
在一些实施例中，所述晶型J具有如图5所示的差示扫描量热曲线(DSC图谱)。In some embodiments, the crystalline form J has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 5.
在一些实施例中，所述晶型J的热重分析曲线(TGA)显示在30℃-160℃间有失重，失重量约为4.56％。In some embodiments, the thermogravimetric analysis curve (TGA) of the crystal form J shows that there is a weight loss between 30°C and 160°C, and the weight loss is about 4.56%.
在一些实施例中，所述晶型J具有基本上如图6所示的热重分析曲线(TGA图谱)。In some embodiments, the crystal form J has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 6.
在一些实施例中，所述晶型J的纯度至少为70％，或至少80％，或至少90％，或至少95％，或至少99％。In some embodiments, the purity of the crystal form J is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%.
本发明所述的乙酰化艾曲波帕晶型D、晶型J，可用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少，以及慢性丙型肝炎患者的血小板减少症、对免疫抑制治疗反应不足的重型再生障碍性贫血等症状。The acetylated Eltrombopag crystal form D and crystal form J of the present invention can be used for the treatment of chronic idiopathic thrombocytopenic purpura (ITP) after splenectomy or chronic idiopathic thrombocytopenic purpura (ITP) after glucocorticoid drugs or immunoglobulin treatment is invalid Patients with thrombocytopenia, thrombocytopenia in patients with chronic hepatitis C, and severe aplastic anemia with insufficient response to immunosuppressive therapy.
本发明的另一个目的在于提供包含治疗有效量的乙酰化艾曲波帕晶型D或晶型J和药学上可接受的辅料或赋形剂的药物组合物。一般是将治疗有效量的乙酰化艾曲波帕晶型D或/和晶型J与一种或多种药用辅料混合或接触制成药物组合物或制剂，该药物组合物或制剂是以制药领域中熟知的方式进行制备的。所述药物组合物或制剂可以用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少，以及慢性丙型肝炎患者的血小板减少症、对免疫抑制治疗反应不足的重型再生障碍性贫血等疾病。Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of acetylated Eltrombopag crystal form D or crystal form J and pharmaceutically acceptable excipients or excipients. Generally, a therapeutically effective amount of acetylated Eltrombopag crystal form D or/and crystal form J is mixed or contacted with one or more pharmaceutical excipients to prepare a pharmaceutical composition or preparation, and the pharmaceutical composition or preparation is It is prepared in a well-known manner in the pharmaceutical field. The pharmaceutical composition or preparation can be used to treat thrombocytopenia in patients with chronic idiopathic thrombocytopenic purpura (ITP) after splenectomy, and patients with chronic hepatitis C that are ineffective in the treatment of glucocorticoid drugs or immunoglobulin. Thrombocytopenia, severe aplastic anemia and other diseases with insufficient response to immunosuppressive therapy.
本发明提供一种药物组合物，其含有至少为组合物的总重量的0.1％-10％的所述晶型D或晶型J。本发明提供一种药物组合物，其含有至少为组合物的总重量的0.1％-5％的所述晶型D或晶型J。本发明提供一种药物组合物，其含有至少为组合物的总重量的0.1％-1％的所述晶型D或晶型J。本发明提供一种药物组合物，其含有至少为组合物的总重量的0.1％-0.5％的所述晶型D或晶型J。The present invention provides a pharmaceutical composition, which contains at least 0.1%-10% of the crystal form D or the crystal form J of the total weight of the composition. The present invention provides a pharmaceutical composition, which contains at least 0.1%-5% of the crystal form D or crystal form J of the total weight of the composition. The present invention provides a pharmaceutical composition, which contains at least 0.1%-1% of the crystal form D or the crystal form J of the total weight of the composition. The present invention provides a pharmaceutical composition, which contains at least 0.1%-0.5% of the crystal form D or the crystal form J of the total weight of the composition.
一种药物组合物，含有乙酰化艾曲波帕，按照质量比计，其中至少80％的乙酰化艾曲波帕为所述乙酰化艾曲波帕晶型D或晶型J。在一些实施方式中，一种药物组合物，含有乙酰化艾曲波帕，按照质量比计，其中至少90％的乙酰化艾曲波帕为所述乙酰化艾曲波帕晶型D或晶型J。在一些实施方式中，一种药物组合物，含有乙酰化艾曲波帕，按照质量比计，其中至少95％的乙酰化艾曲波帕为所述乙酰化艾曲波帕晶型D或晶型J。在一些实施方式中，一种药物组合物，含有乙酰化艾曲波帕，按照质量比计，其中至少97％的乙酰化艾曲波帕为所述乙酰化艾曲波帕晶型D或晶型J。在一些实施方式中，一种药物组合物，含有乙酰化艾曲波帕，按照质量比计，其中至少99％的乙酰化艾曲波帕为所述乙酰化艾曲波帕晶型D或晶型J。A pharmaceutical composition containing acetylated eltrombopag, according to the mass ratio, wherein at least 80% of the acetylated eltrombopag is the acetylated eltrombopag crystal form D or crystal form J. In some embodiments, a pharmaceutical composition contains acetylated Eltrombopag, and at least 90% of the acetylated Eltrombopag is in the acetylated Eltrombopag crystal form D or crystal. Type J. In some embodiments, a pharmaceutical composition contains acetylated Eltrombopag, in terms of mass ratio, wherein at least 95% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form D or crystal Type J. In some embodiments, a pharmaceutical composition contains acetylated Eltrombopag, and at least 97% of the acetylated Eltrombopag is the acetylated Eltrombopag crystal form D or crystal. Type J. In some embodiments, a pharmaceutical composition contains acetylated Eltrombopag, in terms of mass ratio, wherein at least 99% of acetylated Eltrombopag is the acetylated Eltrombopag crystal form D or crystal Type J.
在一些实施方式中，所述药物组合物中，晶型D的纯度至少80％。在一些实施方式中，所述药物组合物中，晶型D的纯度至少85％，或至少90％，或至少95％，或至少99％。In some embodiments, the purity of crystal form D in the pharmaceutical composition is at least 80%. In some embodiments, the purity of the crystalline form D in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.
在一些实施方式中，所述药物组合物中，晶型J的纯度至少80％。在一些实施方式中，所述药物组合物中，晶型J的纯度至少85％，或至少90％，或至少95％，或至少99％。In some embodiments, the purity of the crystal form J in the pharmaceutical composition is at least 80%. In some embodiments, the purity of the crystalline form J in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.
本发明所述的含有乙酰化艾曲波帕晶型D或晶型J的药物组合物，可用于制备经糖皮质激素类药物、 免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少，以及慢性丙型肝炎患者的血小板减少症、对免疫抑制治疗反应不足的重型再生障碍性贫血的药物制剂。本发明所述的含有乙酰化艾曲波帕晶型D或晶型J的药物组合物，可用于治疗经糖皮质激素类药物、免疫球蛋白治疗无效或脾切除术后慢性特发性血小板减少性紫癜(ITP)患者的血小板减少，以及慢性丙型肝炎患者的血小板减少症、对免疫抑制治疗反应不足的重型再生障碍性贫血的方法中。The pharmaceutical composition containing acetylated Eltrombopag crystal form D or crystal form J of the present invention can be used to prepare glucocorticoid drugs, immunoglobulin treatment ineffective or chronic idiopathic thrombocytopenia after splenectomy Thrombocytopenia in patients with ITP, as well as thrombocytopenia in patients with chronic hepatitis C, and pharmaceutical preparations for severe aplastic anemia that do not respond to immunosuppressive therapy. The pharmaceutical composition containing acetylated Eltrombopag crystal form D or crystal form J of the present invention can be used to treat chronic idiopathic thrombocytopenia after glucocorticoid drugs, immunoglobulin therapy, or chronic idiopathic thrombocytopenia after splenectomy Thrombocytopenia in patients with chronic hepatitis C (ITP), thrombocytopenia in patients with chronic hepatitis C, and severe aplastic anemia with insufficient response to immunosuppressive therapy.
本发明提供的晶型D或晶型J，稳定性更好，而更稳定的晶型对于提高药物质量具有重要意义。The crystal form D or crystal form J provided by the present invention has better stability, and a more stable crystal form is of great significance for improving the quality of the medicine.
本发明提供的晶型D、晶型J，均具有良好的稳定性，不易在高湿条件下潮解，方便药物长期贮存放置。本发明提供的晶型稳定性好，能很好的避免药物储存以及开发过程中发生转晶，从而避免生物利用度以及药效的改变，具有很强的经济价值。The crystal form D and crystal form J provided by the invention have good stability, are not easy to deliquesce under high humidity conditions, and are convenient for long-term storage and placement of the medicine. The crystal form provided by the invention has good stability, can well avoid crystal transformation during drug storage and development, thereby avoiding changes in bioavailability and drug efficacy, and has strong economic value.
根据本发明的第二方面，本发明提出了一种制备前面所述的乙酰化艾曲波帕晶型D或晶型J的方法。According to the second aspect of the present invention, the present invention proposes a method for preparing the aforementioned acetylated Eltrombopag crystal form D or crystal form J.
一种制备乙酰化艾曲波帕晶型D的方法包括：将乙酰化艾曲波帕与四氢呋喃混合，溶解完全后，将反溶剂滴加到该四氢呋喃溶液中，搅拌析出晶体，收集晶体，除去溶剂，得到晶型D。在一些实施方式中，一种制备乙酰化艾曲波帕晶型D的方法包括：乙酰化艾曲波帕与四氢呋喃混合，溶解完全后，将反溶剂滴加到该四氢呋喃溶液中，析出晶体，收集晶体，除去溶剂，得到晶型D。所述反溶剂为水或甲醇，或其组合。质量以克(g)计算，溶剂体积以毫升(mL)计算时，所述乙酰化艾曲波帕与四氢呋喃的溶剂的质量体积比为1:2～1:20；更优选地为1:3～1:5。A method for preparing acetylated Eltrombopag crystal form D includes: mixing the acetylated Eltrombopag with tetrahydrofuran, after the dissolution is complete, adding an anti-solvent to the tetrahydrofuran solution, stirring to precipitate crystals, collecting the crystals, and removing Solvent to obtain crystal form D. In some embodiments, a method for preparing acetylated Eltrombopag crystal form D includes: mixing acetylated Eltrombopag with tetrahydrofuran, and after the dissolution is complete, adding an anti-solvent to the tetrahydrofuran solution dropwise to precipitate crystals, The crystals are collected and the solvent is removed to obtain crystal form D. The anti-solvent is water or methanol, or a combination thereof. When the mass is calculated in grams (g) and the solvent volume is calculated in milliliters (mL), the mass-volume ratio of the solvent of the acetylated Eltrombopag and tetrahydrofuran is 1:2 to 1:20; more preferably 1:3 ~ 1:5.
一种制备乙酰化艾曲波帕晶型J的方法包括：将乙酰化艾曲波帕与良溶剂混合，加热溶解，溶解完全后，降低温度至0℃～30℃，析出晶体，收集晶体，除去溶剂，得到晶型J。在一些实施方式中，一种制备乙酰化艾曲波帕晶型J的方法包括：乙酰化艾曲波帕与良溶剂混合，加热溶解，溶解完全后，降低温度至0℃～20℃，析出晶体，收集晶体，除去溶剂，得到晶型J。A method for preparing acetylated Eltrombopag crystal form J includes: mixing acetylated Eltrombopag with a good solvent, heating to dissolve, and after the dissolution is complete, reducing the temperature to 0°C to 30°C, separating out crystals, and collecting the crystals, The solvent was removed to obtain the crystal form J. In some embodiments, a method for preparing acetylated Eltrombopag crystal form J includes: mixing acetylated Eltrombopag with a good solvent, dissolving by heating, and after the dissolution is complete, reducing the temperature to 0°C to 20°C to precipitate Crystals, crystals are collected, and the solvent is removed to obtain crystal form J.
所述良溶剂为乙二醇二甲醚，丙酮，四氢呋喃，丙酮和乙酸乙酯混合溶剂，丙酮和丁酮混合溶剂，丙酮和乙腈混合溶剂。所述良溶剂为混合溶剂时，丙酮和乙酸乙酯、丁酮或乙腈的体积比为1:1。The good solvent is ethylene glycol dimethyl ether, acetone, tetrahydrofuran, a mixed solvent of acetone and ethyl acetate, a mixed solvent of acetone and methyl ethyl ketone, and a mixed solvent of acetone and acetonitrile. When the good solvent is a mixed solvent, the volume ratio of acetone to ethyl acetate, methyl ethyl ketone or acetonitrile is 1:1.
质量以克(g)计算，溶剂体积以毫升(mL)计算时，所述乙酰化艾曲波帕与良溶剂的质量体积比为1:20～1:50；更优选地为1:25～1:40。When the mass is calculated in grams (g) and the solvent volume is calculated in milliliters (mL), the mass-volume ratio of the acetylated Eltrombopag to the good solvent is 1:20 to 1:50; more preferably 1:25 to 1:40.
本发明所述“晶型”可以以0.0001％-100％存在于样品中，因此，只要样品中含有即使痕量例如大于0.0001％，大于0.001％，大于0.001％或者大于0.01％的本发明所述的“晶型”都应当理解为落入本发明的保护范围内。为把本发明所述的“晶型”的各种参数描述得更清楚，本发明通过对含基本上纯净的某种“晶型”时的样品进行测试各种参数并对所述晶型进行表征和鉴别。The "crystal form" of the present invention can be present in the sample at 0.0001%-100%. Therefore, as long as the sample contains trace amounts, for example, greater than 0.0001%, greater than 0.001%, greater than 0.001% or greater than 0.01% of the present invention The "crystal form" of should be understood as falling within the protection scope of the present invention. In order to describe the various parameters of the "crystal form" described in the present invention more clearly, the present invention tests various parameters on a sample containing a certain "crystal form" that is substantially pure and carries out the determination of the crystal form. Characterization and identification.
在本发明上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值。每一个数字的数值有可能会出现1％，2％，或5％等差异。In the context of the present invention, regardless of whether the words "about" or "about" are used, all numbers disclosed herein are approximate values. The value of each number may differ by 1%, 2%, or 5%.
所述晶型的差示扫描量热测定(DSC)有实验误差，并受样品的干燥程度有轻微影响，在一台机器和另 一台机器之间以及一个样品和另一个样品之间，吸热峰的位置和峰值可能会略有差别，实验误差或差别的数值可能小于等于10℃，或小于等于5℃，或小于等于4℃，或小于等于3℃，或小于等于2℃，或小于等于1℃，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。The differential scanning calorimetry (DSC) of the crystal form has experimental errors and is slightly affected by the dryness of the sample. Between one machine and another machine and between one sample and another sample, the The position and peak value of the thermal peak may be slightly different, and the experimental error or the value of the difference may be less than or equal to 10°C, or less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than It is equal to 1°C, so the peak position or the value of the peak value of the DSC endothermic peak cannot be regarded as absolute.
在本发明中，计算质量体积比时，质量单位为克，体积单位为毫升。In the present invention, when calculating the mass-to-volume ratio, the mass unit is grams and the volume unit is milliliters.
在本发明中“RH”为相对湿度。In the present invention, "RH" means relative humidity.
附图说明Description of the drawings
图1：乙酰化艾曲波帕的晶型D的X-射线粉末衍射(XRPD)图。Figure 1: X-ray powder diffraction (XRPD) pattern of acetylated Eltrombopag Form D.
图2：乙酰化艾曲波帕的晶型D的差示扫描量热(DSC)曲线图。Figure 2: Differential scanning calorimetry (DSC) graph of acetylated Eltrombopag Form D.
图3：乙酰化艾曲波帕的晶型D的热重分析(TGA)曲线图。Figure 3: Thermogravimetric analysis (TGA) graph of acetylated Eltrombopag Form D.
图4：乙酰化艾曲波帕的晶型J的X-射线粉末衍射(XRPD)图。Figure 4: X-ray powder diffraction (XRPD) pattern of acetylated Eltrombopag Form J.
图5：乙酰化艾曲波帕的晶型J的差示扫描量热(DSC)曲线图。Figure 5: Differential scanning calorimetry (DSC) graph of acetylated Eltrombopag Form J.
图6：乙酰化艾曲波帕的晶型J的热重分析(TGA)曲线图。Figure 6: Thermogravimetric analysis (TGA) graph of acetylated Eltrombopag Form J.
具体实施方式Detailed ways
下面详细描述本发明的实施例，所述实施例的示例在附图中示出，其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施例是示例性的，旨在用于解释本发明，而不能理解为对本发明的限制。The embodiments of the present invention are described in detail below. Examples of the embodiments are shown in the accompanying drawings, in which the same or similar reference numerals indicate the same or similar elements or elements with the same or similar functions. The embodiments described below with reference to the drawings are exemplary, and are intended to explain the present invention, but should not be construed as limiting the present invention.
为了使本领域的技术人员更好的理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.
本发明所使用的试剂均可以从市场上购得或者可以通过本发明所描述的方法制备而得。The reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.
实施例1乙酰化艾曲波帕晶型D的制备方法Example 1 Preparation method of acetylated Eltrombopag crystal form D
将1g的乙酰化艾曲波帕加入四氢呋喃(2ml)中，加热至55℃搅拌得到澄清溶液后，再将水(20ml)滴加至该乙酰化艾曲波帕的四氢呋喃溶液中。搅拌析出黄色固态产品，搅拌12小时。抽滤并置于干燥箱内50℃真空干燥至恒重，得到黄色粉末0.46g；经XPRD检测，确认为乙酰化艾曲波帕晶型D；其X-射线粉末衍射图谱与图1基本一致，其DSC图谱与图2基本一致，TGA图谱与图3基本一致。1g of acetylated Eltrombopag was added to tetrahydrofuran (2ml), heated to 55°C and stirred to obtain a clear solution, and then water (20ml) was added dropwise to the acetylated Eltrombopag in tetrahydrofuran solution. After stirring, a yellow solid product was precipitated, and the mixture was stirred for 12 hours. Filtration and vacuum drying in a drying box at 50°C to a constant weight to obtain 0.46g of yellow powder; it was confirmed by XPRD that it was acetylated Eltrombopag crystal form D; its X-ray powder diffraction pattern was basically the same as that in Figure 1. , The DSC spectrum is basically the same as Figure 2, and the TGA spectrum is basically the same as Figure 3.
实施例2乙酰化艾曲波帕晶型D的制备方法Example 2 Preparation method of acetylated Eltrombopag crystal form D
将5g的乙酰化艾曲波帕加入四氢呋喃(15ml)中，加热至55℃搅拌得到澄清溶液后，再将水(210ml)滴加至该乙酰化艾曲波帕的四氢呋喃溶液中。搅拌析出黄色固态产品，搅拌12小时。抽滤并置于干燥箱内50℃真空干燥至恒重，得到黄色粉末3.09g。经XPRD检测，确认为乙酰化艾曲波帕晶型D；其X-射线粉末衍射图谱与图1基本一致，其DSC图谱与图2基本一致，TGA图谱与图3基本一致。5g of acetylated Eltrombopag was added to tetrahydrofuran (15ml), heated to 55°C and stirred to obtain a clear solution, and then water (210ml) was added dropwise to the acetylated Eltrombopag in tetrahydrofuran solution. After stirring, a yellow solid product was precipitated, and the mixture was stirred for 12 hours. Filter with suction and place in a drying box at 50°C and vacuum dry to constant weight to obtain 3.09g of yellow powder. XPRD detection confirmed that it is acetylated Eltrombopag crystal form D; its X-ray powder diffraction pattern is basically the same as Figure 1, its DSC pattern is basically the same as Figure 2, and its TGA pattern is basically the same as Figure 3.
实施例3乙酰化艾曲波帕晶型J的制备方法Example 3 Preparation method of acetylated Eltrombopag crystal form J
将500mg的乙酰化艾曲波帕加入丙酮(20ml)中，加热至50℃搅拌得到澄清溶液后，再将该反应体系放置于0℃的低温槽中过夜析晶，搅拌析出黄色固态产品，搅拌12小时。抽滤并置于干燥箱内50℃真空干燥至恒重，得到黄色粉末320mg。经XPRD检测，确认为乙酰化艾曲波帕晶型J；其X-射线粉末衍射图谱与图4基本一致，其DSC图谱与图5基本一致，TGA图谱与图6基本一致。Add 500mg of acetylated Eltrombopag to acetone (20ml), heat to 50°C and stir to obtain a clear solution, then place the reaction system in a low temperature tank at 0°C overnight for crystallization, stirring to precipitate a yellow solid product, stirring 12 hours. Filter with suction and place in a drying box at 50°C and vacuum dry to constant weight to obtain 320 mg of yellow powder. XPRD detection confirmed that it is acetylated Eltrombopag crystal form J; its X-ray powder diffraction pattern is basically consistent with Figure 4, its DSC spectrum is basically consistent with Figure 5, and its TGA spectrum is basically consistent with Figure 6.
实施例4乙酰化艾曲波帕晶型J的制备方法Example 4 Preparation method of acetylated Eltrombopag crystal form J
将1.5g的乙酰化艾曲波帕加入丙酮(55ml)中，加热至50℃搅拌得到澄清溶液后，再将该反应体系放置于0℃的低温槽中，析晶4小时，搅拌析出黄色固态产品。抽滤并置于干燥箱内50℃真空干燥至恒重，得到黄色粉末990mg。经XPRD检测，确认为乙酰化艾曲波帕晶型J；其X-射线粉末衍射图谱与图4基本一致，其DSC图谱与图5基本一致，TGA图谱与图6基本一致。Add 1.5g of acetylated Eltrombopag to acetone (55ml), heat to 50°C and stir to obtain a clear solution, then place the reaction system in a low temperature tank at 0°C, crystallize for 4 hours, and stir to precipitate a yellow solid product. It was filtered with suction and placed in a drying box at 50°C and vacuum dried to constant weight to obtain 990 mg of yellow powder. XPRD detection confirmed that it is acetylated Eltrombopag crystal form J; its X-ray powder diffraction pattern is basically consistent with Figure 4, its DSC spectrum is basically consistent with Figure 5, and its TGA spectrum is basically consistent with Figure 6.
实施例5乙酰化艾曲波帕晶型D的稳定性实验Example 5 Stability experiment of acetylated Eltrombopag crystal form D
取本发明的乙酰化艾曲波帕晶型D样品敞口分别放置于60℃(温度偏差±2℃)/75％相对湿度、25℃/60％相对湿度/4500勒克斯、25℃/92.5％相对湿度条件，10天后取样测XRPD，实验结果如下表1。Take the acetylated Eltrombopag crystal form D sample of the present invention and place it at 60°C (temperature deviation ±2°C)/75% relative humidity, 25°C/60% relative humidity/4500 lux, 25°C/92.5%, respectively. Under relative humidity conditions, samples were taken to measure XRPD after 10 days, and the experimental results are shown in Table 1.
表1晶型D稳定性研究Table 1 Stability study of crystal form D
Figure PCTCN2020121710-appb-000003
Figure PCTCN2020121710-appb-000003
上述结果显示：样品在60℃(温度偏差±2℃)、75％相对湿度，25℃、60％相对湿度、4500勒克斯，25℃、92.5％相对湿度条件分别放置10天后，晶型不变，稳定性良好。The above results show that after the sample is placed at 60°C (temperature deviation ±2°C), 75% relative humidity, 25°C, 60% relative humidity, 4500 Lux, 25°C, and 92.5% relative humidity for 10 days, the crystal form remains unchanged. The stability is good.
实施例6乙酰化艾曲波帕晶型J的稳定性实验Example 6 Stability experiment of acetylated Eltrombopag crystal form J
取本发明的乙酰化艾曲波帕晶型J样品敞口分别放置于60℃(温度偏差±2℃)/75％相对湿度、25℃/60％相对湿度/4500勒克斯、25℃/92.5％相对湿度条件，10天后取样测XRPD，实验结果如下表2。Take the acetylated Eltrombopag crystal form J sample of the present invention and place it at 60°C (temperature deviation ±2°C)/75% relative humidity, 25°C/60% relative humidity/4500 lux, 25°C/92.5%, respectively. Under relative humidity conditions, samples were taken to measure XRPD after 10 days, and the experimental results are shown in Table 2.
表2晶型J稳定性研究Table 2 Stability study of crystal form J
Figure PCTCN2020121710-appb-000004
Figure PCTCN2020121710-appb-000004
上述结果显示：晶型J在光照25℃/60％相对湿度/4500勒克斯、高湿25℃/92.5％相对湿度条件，分别放置10天后，晶型不变，稳定性良好。The above results show that the crystal form J under the conditions of light 25°C/60% relative humidity/4500 lux and high humidity 25°C/92.5% relative humidity, respectively placed for 10 days, the crystal form does not change, and the stability is good.
本发明中，测试仪器及方法In the present invention, the test instrument and method
(1)粉末X-射线衍射(XRPD)研究(1) Powder X-ray diffraction (XRPD) research
在装配有自动化3*15零背景样品架的透射反射样品台的荷兰PANalytical Empyrean X-射线衍射仪上收集X-射线粉末衍射(XRPD)图案。所用辐射源为(Cu，kα，Kα1
Figure PCTCN2020121710-appb-000005
1.540598；Kα2
Figure PCTCN2020121710-appb-000006
1.544426；Kα2/Kα1强度比例：0.50)，其中电压设定在45KV，电流设定在40mA.X-射线的束发散度，即样品上X-射线约束的有效尺寸，为10mm.采用θ-θ连续扫描模式，得到3°～40°的有效2θ范围。取适量样品在环境条件(约18℃～32℃)下于零背景样品架圆形凹槽处，用洁净的载玻片轻压，得到一个平整的平面，并将零背景样品架固定。将样品以0.0168°的扫描步长在3～40°2θ范围内产生传统的XRPD图案。用于数据收集的软件为Data Collector，数据用Data Viewer和HighScore Plus分析和展示。 The X-ray powder diffraction (XRPD) pattern was collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero background sample holder with a transflective sample stage. The radiation source used is (Cu, kα, Kα1
Figure PCTCN2020121710-appb-000005
1.540598; Kα2
Figure PCTCN2020121710-appb-000006
1.544426; Kα2/Kα1 intensity ratio: 0.50), where the voltage is set at 45KV, and the current is set at 40mA. The beam divergence of X-rays, that is, the effective size of the X-ray confinement on the sample, is 10mm. Using θ-θ Continuous scanning mode, to obtain an effective 2θ range of 3°～40°. Take an appropriate amount of sample in the circular groove of the zero background sample holder under ambient conditions (about 18°C ~ 32°C), press lightly with a clean glass slide to obtain a flat surface, and fix the zero background sample holder. The sample is used to generate a traditional XRPD pattern in the range of 3-40°2θ with a scanning step of 0.0168°. The software used for data collection is Data Collector, and the data is analyzed and displayed with Data Viewer and HighScore Plus.
采用上述条件，分别对实施例制备的晶型进行XRPD检测。Using the above conditions, the crystal forms prepared in the examples were tested by XRPD.
(2)差示扫描量热法(DSC)分析(2) Differential scanning calorimetry (DSC) analysis
DSC测量在TA Instruments TM型号Q2000中用密封盘装置进行。将样品(约1～3mg)在铝盘中称量，用Tzero压盖，精密记录到百分之一毫克，并将样品转移至仪器中进行测量。仪器用氮气以50mL/min吹扫。在室温到300℃之间以10℃/min的加热速率收集数据。以吸热峰向下进行绘图,数据用TA Universal Analysis分析和展示。 The DSC measurement was performed in TA Instruments TM model Q2000 with a sealed disk device. Weigh the sample (approximately 1 to 3 mg) in an aluminum pan, cover it with Tzero, accurately record it to one hundredth of a milligram, and transfer the sample to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data was collected between room temperature and 300°C at a heating rate of 10°C/min. The endothermic peak is drawn downward, and the data is analyzed and displayed by TA Universal Analysis.
(3)热重分析(TGA)分析(3) Thermogravimetric analysis (TGA) analysis
TGA测量在TA Instruments TM型号Q500中进行。操作步骤为空坩埚去皮，取固体样品约10mg、于去皮空坩埚内，铺匀即可。待仪器运行稳定后，在氮气吹扫下，室温到300℃之间以10℃/min的加热速率收集数据，记录图谱。 The TGA measurement was performed in TA Instruments TM model Q500. The operation step is to peel the empty crucible, take about 10 mg of solid sample, place it in the peeled empty crucible, and spread it evenly. After the instrument runs stably, collect data at a heating rate of 10°C/min between room temperature and 300°C under nitrogen purge, and record the spectrum.
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外，在不相互矛盾的情况下，本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。In the description of this specification, descriptions with reference to the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" etc. mean specific features described in conjunction with the embodiment or example , Structures, materials or features are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the described specific features, structures, materials or characteristics may be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine the different embodiments or examples and the features of the different embodiments or examples described in this specification without contradicting each other.
尽管上面已经示出和描述了本发明的实施例，可以理解的是，上述实施例是示例性的，不能理解为对本发明的限制，本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。Although the embodiments of the present invention have been shown and described above, it can be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. A person of ordinary skill in the art can comment on the above-mentioned embodiments within the scope of the present invention. The embodiment undergoes changes, modifications, substitutions, and modifications.

Claims (18)

  1. 乙酰化艾曲波帕的晶型，所述晶型为晶型D或晶型J；其特征在于，使用Cu-Kα辐射，以2θ(误差±0.2度)表示的X-射线粉末衍射光谱，其中，晶型D的X-射线粉末衍射图中在2θ为6.7,8.8,13.4,14.6,16.2,18.9,21.4,26.4和30.6度的位置有衍射峰；晶型J的X-射线粉末衍射图中在2θ为5.8,8.8,12,14.5,16.5,22.8和25.7度的位置有衍射峰。The crystal form of acetylated Eltrombopag, the crystal form is crystal form D or crystal form J; it is characterized by using Cu-Kα radiation and X-ray powder diffraction spectrum expressed in 2θ (error ±0.2 degrees), Among them, the X-ray powder diffraction pattern of crystal form D has diffraction peaks at 2θ of 6.7, 8.8, 13.4, 14.6, 16.2, 18.9, 21.4, 26.4 and 30.6 degrees; the X-ray powder diffraction pattern of crystal form J There are diffraction peaks at 2θ of 5.8, 8.8, 12, 14.5, 16.5, 22.8 and 25.7 degrees.
  2. 权利要求1所述的晶型，其中，晶型D的X-射线粉末衍射图中在2θ为7.1,14.2,16.9,19.9,26.0和28.6度的位置有衍射峰；或晶型D的X-射线粉末衍射图中在2θ为6.7,7.1,8.8,13.4,14.2,14.6,16.2,16.9,18.9,19.9,21.4,26.0,26.4,28.6和30.6度的位置有衍射峰；或晶型D的X-射线粉末衍射图如图1所示。The crystal form of claim 1, wherein the X-ray powder diffraction pattern of the crystal form D has diffraction peaks at the positions of 2θ of 7.1, 14.2, 16.9, 19.9, 26.0 and 28.6 degrees; or the X-ray of the crystal form D X-ray powder diffraction pattern has diffraction peaks at the positions of 6.7, 7.1, 8.8, 13.4, 14.2, 14.6, 16.2, 16.9, 18.9, 19.9, 21.4, 26.0, 26.4, 28.6 and 30.6 degrees in 2θ; or X of crystal form D The -ray powder diffraction pattern is shown in Figure 1.
  3. 权利要求1所述的晶型，其中，晶型D的热重分析曲线显示在30℃-120℃间有失重。The crystal form of claim 1, wherein the thermogravimetric analysis curve of the crystal form D shows a weight loss between 30°C and 120°C.
  4. 权利要求1所述的晶型，其中，晶型D的热重分析曲线显示在30℃-120℃间有失重，失重量约为3.66％。The crystal form of claim 1, wherein the thermogravimetric analysis curve of the crystal form D shows a weight loss between 30°C and 120°C, and the weight loss is about 3.66%.
  5. 权利要求1所述的晶型，其中晶型D的纯度至少70％。The crystal form of claim 1, wherein the purity of the crystal form D is at least 70%.
  6. 权利要求1所述的晶型，其中，晶型J的X-射线粉末衍射图中在2θ为7.9,10.5,12.9,14.8,18.4,20.8和23.8度的位置有衍射峰；或晶型J的X-射线粉末衍射图中在2θ为5.8,7.9,8.8,10.5,12,12.9,14.5,14.8,16.5,18.4,20.8,22.8,23.8和25.7度的位置有衍射峰；或晶型J的X-射线粉末衍射图中在2θ为7.0，7.9,10.5,12.9,13.5，14.0，14.8,16.0，17.2，17.7，18.4,19.3,20.0,20.8,23.8，24.7和27.1度的位置有衍射峰；或晶型J的X-射线粉末衍射图中在2θ为5.8,7.0，7.9,8.8,10.5,12,12.9,13.5，14.0，14.5,14.8,16.0，16.5,17.2，17.7，18.4，19.3，20.0，20.8，22.8，23.8，24.7和27.1度的位置有衍射峰；或晶型J的X-射线粉末衍射图如图4所示。The crystal form of claim 1, wherein the X-ray powder diffraction pattern of the crystal form J has diffraction peaks at the positions of 2θ of 7.9, 10.5, 12.9, 14.8, 18.4, 20.8 and 23.8 degrees; or the crystal form J There are diffraction peaks in the X-ray powder diffraction pattern at 2θ of 5.8, 7.9, 8.8, 10.5, 12, 12.9, 14.5, 14.8, 16.5, 18.4, 20.8, 22.8, 23.8 and 25.7 degrees; or X of crystal form J -Ray powder diffraction pattern has diffraction peaks at the positions of 2θ of 7.0, 7.9, 10.5, 12.9, 13.5, 14.0, 14.8, 16.0, 17.2, 17.7, 18.4, 19.3, 20.0, 20.8, 23.8, 24.7 and 27.1 degrees; or The X-ray powder diffraction pattern of crystal form J is 5.8, 7.0, 7.9, 8.8, 10.5, 12, 12.9, 13.5, 14.0, 14.5, 14.8, 16.0, 16.5, 17.2, 17.7, 18.4, 19.3, 20.0 in 2θ. There are diffraction peaks at 20.8, 22.8, 23.8, 24.7 and 27.1 degrees; or the X-ray powder diffraction pattern of crystal form J is shown in Figure 4.
  7. 权利要求1或6所述的晶型，其中，晶型J的热重分析曲线显示在30℃-160℃间有失重。The crystal form of claim 1 or 6, wherein the thermogravimetric analysis curve of the crystal form J shows a weight loss between 30°C and 160°C.
  8. 权利要求1或6所述的晶型，其中，晶型J的热重分析曲线显示在30℃-160℃间有失重，失重量约为4.56％。The crystal form of claim 1 or 6, wherein the thermogravimetric analysis curve of the crystal form J shows a weight loss between 30°C and 160°C, and the weight loss is about 4.56%.
  9. 权利要求1或6所述的晶型，其中，晶型J的纯度至少70％。The crystal form of claim 1 or 6, wherein the purity of the crystal form J is at least 70%.
  10. 一种制备权利要求1-5任一所述的乙酰化艾曲波帕晶型的方法，包括：乙酰化艾曲波帕与四氢呋喃混合，溶解完全后，将反溶剂滴加到乙酰化艾曲波帕的四氢呋喃溶液中，搅拌析出晶体，收集晶体，除去溶剂，得到晶型D；其中，所述的反溶剂为水和甲醇中的至少一种。A method for preparing the acetylated Eltrombopag crystal form of any one of claims 1-5, comprising: mixing the acetylated Eltrombopag with tetrahydrofuran, and after the dissolution is complete, adding an anti-solvent to the acetylated Eltrombopag dropwise In the tetrahydrofuran solution of Popa, the crystals are precipitated by stirring, the crystals are collected, and the solvent is removed to obtain crystal form D; wherein the anti-solvent is at least one of water and methanol.
  11. 根据权利要求10所述的方法，其特征在于所述乙酰化艾曲波帕与四氢呋喃的质量体积比为1g:2ml～1g:20ml。The method according to claim 10, characterized in that the mass-volume ratio of the acetylated Eltrombopag to tetrahydrofuran is 1 g: 2 ml to 1 g: 20 ml.
  12. 一种制备权利要求1或6-9任一所述的乙酰化艾曲波帕晶型的方法，包括：乙酰化艾曲波帕与良溶剂 混合，加热至溶解，溶解完全后，降低温度至0℃～30℃，析出晶体，收集晶体，除去溶剂，得到晶型J；其中，所述的良溶剂选自乙二醇二甲醚，丙酮，四氢呋喃，丙酮和乙酸乙酯混合溶剂，丙酮和丁酮混合溶剂，及丙酮和乙腈混合溶剂中的至少一种。A method for preparing the acetylated Eltrombopag crystal form according to any one of claims 1 or 6-9, comprising: mixing the acetylated Eltrombopag with a good solvent, heating to dissolve, and after the dissolution is complete, reducing the temperature to 0°C to 30°C, crystals are precipitated, the crystals are collected, and the solvent is removed to obtain crystal form J; wherein the good solvent is selected from the group consisting of ethylene glycol dimethyl ether, acetone, tetrahydrofuran, a mixed solvent of acetone and ethyl acetate, acetone and At least one of a mixed solvent of methyl ethyl ketone and a mixed solvent of acetone and acetonitrile.
  13. 根据权利要求12所述的方法，其特征在于所述乙酰化艾曲波帕与良溶剂的质量体积比为1g:20ml～1g:50ml。The method according to claim 12, wherein the mass-volume ratio of the acetylated Eltrombopag to the good solvent is 1 g: 20 ml to 1 g: 50 ml.
  14. 根据权利要求12所述的方法，其中，丙酮和乙酸乙酯的体积比为1:1，丙酮和丁酮的体积比为1:1，或丙酮和乙腈体积比为1:1。The method according to claim 12, wherein the volume ratio of acetone and ethyl acetate is 1:1, the volume ratio of acetone and methyl ethyl ketone is 1:1, or the volume ratio of acetone and acetonitrile is 1:1.
  15. 一种药物组合物，包含治疗有效量的权利要求1-9任一所述的晶型及药学上可接受的辅料。A pharmaceutical composition comprising a therapeutically effective amount of the crystal form according to any one of claims 1-9 and pharmaceutically acceptable excipients.
  16. 根据权利要求15所述的药物组合物，其中，按照质量比计，至少80％的乙酰化艾曲波帕为晶型D或晶型J。The pharmaceutical composition according to claim 15, wherein at least 80% of the acetylated Eltrombopag is crystal form D or crystal form J in terms of mass ratio.
  17. 权利要求15或16所述的药物组合物，其特征在于，所述晶型至少为组合物的总重量的0.1％-10％。The pharmaceutical composition of claim 15 or 16, wherein the crystal form is at least 0.1%-10% of the total weight of the composition.
  18. 权利要求15-17任一所述的药物组合物在制备治疗血小板减少症的药物中的用途。Use of the pharmaceutical composition according to any one of claims 15-17 in the preparation of a medicament for the treatment of thrombocytopenia.
PCT/CN2020/121710 2019-10-21 2020-10-17 Novel crystalline form of acetylated eltrombopag and preparation method thereof WO2021078076A1 (en)

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