WO2022170864A1 - Crystal form of beumosul mesylate, preparation method for crystal form, and use thereof - Google Patents

Crystal form of beumosul mesylate, preparation method for crystal form, and use thereof Download PDF

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WO2022170864A1
WO2022170864A1 PCT/CN2021/140731 CN2021140731W WO2022170864A1 WO 2022170864 A1 WO2022170864 A1 WO 2022170864A1 CN 2021140731 W CN2021140731 W CN 2021140731W WO 2022170864 A1 WO2022170864 A1 WO 2022170864A1
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compound
crystal form
mesylate
ray powder
powder diffraction
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PCT/CN2021/140731
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French (fr)
Chinese (zh)
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陈敏华
施文睿
张婧
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苏州科睿思制药有限公司
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to the field of crystal chemistry. Specifically, it relates to the crystalline form of Belumosudil mesylate and its preparation method and use.
  • cGVHD Chronic graft-versus-host disease
  • QOL quality of life
  • alloHCT allogeneic hematopoietic cell transplantation
  • REZUROCK TM (Belumosudil) is approved in the United States for the treatment of adult and pediatric patients 12 years of age and older with cGVHD after failure of at least two prior systemic therapy regimens.
  • Belumosudil is the only approved therapy targeting Rho-related coiled-coil kinase 2 (ROCK2).
  • ROCK2 Rho-related coiled-coil kinase 2
  • a crystal is a solid in which the molecules of a compound are arranged in a three-dimensional order in a microstructure to form a crystal lattice.
  • Polymorphism is the phenomenon in which a compound exists in more than one crystal form. Compounds may exist in one or more crystalline forms, but their existence and identity cannot be specifically expected. APIs with different crystal forms have different physicochemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent. Especially for some insoluble oral solid or semi-solid preparations, the crystal form is very important to the product performance. In addition to this, the physicochemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is an important part of drug research and drug quality control.
  • the prior art does not disclose the solid form of compound I mesylate, only the preparation method of compound I and the brown solid of compound I are disclosed.
  • the preparation method of compound I disclosed in the prior art WO2006105081A2 is as follows: using preparative HPLC to purify the crude product of compound I, and then obtaining compound I, the form of compound I is not disclosed.
  • CN106916145B discloses compound I as a brown solid.
  • the inventors of the present application repeated the preparation methods disclosed in WO2006105081A2 and CN106916145B to obtain solids of compound I, which were named as prior art P1 and prior art P2 respectively.
  • the technology has problems such as high solvent content, low solubility, high hygroscopicity, and poor stability, and is not suitable for medicinal development.
  • the inventors of the present application have carried out in-depth research on the solid form of compound I and its salts, and have unexpectedly found the crystallization of compound I mesylate provided by the invention, which is in solubility, hygroscopicity, Purification, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, bioavailability and other aspects have advantages in at least one aspect, especially no solvent residue, high solubility, good stability, low hygroscopicity, The problems existing in the prior art are solved, and it is of great significance to the development of medicines containing compound I.
  • the main purpose of the present invention is to provide a solid of compound I mesylate, a preparation method thereof, and a pharmaceutical composition comprising the solid.
  • the present invention provides the crystalline form of compound I mesylate.
  • the present invention provides the anhydrate of compound I mesylate.
  • the present invention provides the hydrate of compound I mesylate.
  • the present invention provides the crystalline form CSI of Compound I mesylate (hereinafter referred to as "crystalline form CSI").
  • the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at the diffraction angle 2 ⁇ value of 7.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI has a diffraction angle 2 ⁇ value of 8.4° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.2° ⁇ 0.2° at 1 or 2
  • a diffraction angle 2 ⁇ value of 8.4° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.2° ⁇ 0.2° at 1 or 2
  • characteristic peaks at or at 3 preferably, the X-ray powder diffraction pattern of the crystalline form CSI is at 3 of the diffraction angle 2 ⁇ values of 8.4° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.2° ⁇ 0.2°
  • characteristic peaks are characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSI has a diffraction angle 2 ⁇ value of 16.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 23.5° ⁇ 0.2°, or 2 There are characteristic peaks at or at 3 places; preferably, the X-ray powder diffraction pattern of the crystalline form CSI is at 3 places in the diffraction angle 2 ⁇ value of 16.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 23.5° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSI has diffraction angle 2 ⁇ values of 7.1° ⁇ 0.2°, 8.4° ⁇ 0.2°, 21.5° ⁇ 0.2°, 22.2° ⁇ 0.2° , 16.8° ⁇ 0.2°, 19.5° ⁇ 0.2°, 23.5° ⁇ 0.2°, 17.2° ⁇ 0.2°, 25.5° ⁇ 0.2° any 1, or 2, or 3, or 4, or 5 There are characteristic peaks at, or 6, or 7, or 8, or 9.
  • the X-ray powder diffraction pattern of the crystalline form CSI is substantially as shown in FIG. 3 .
  • thermogravimetric analysis diagram is basically shown in FIG. 4 .
  • the differential scanning calorimetry analysis of the crystalline form CSI is basically as shown in Figure 6, which has an endothermic peak around 267 ° C (the initial temperature is about 264 ° C), and the endothermic peak is the crystalline form.
  • the melting endotherm of CSI is basically as shown in Figure 6, which has an endothermic peak around 267 ° C (the initial temperature is about 264 ° C), and the endothermic peak is the crystalline form.
  • the melting endotherm of CSI is basically as shown in Figure 6, which has an endothermic peak around 267 ° C (the initial temperature is about 264 ° C), and the endothermic peak is the crystalline form.
  • the melting endotherm of CSI is basically as shown in Figure 6, which has an endothermic peak around 267 ° C (the initial temperature is about 264 ° C), and the endothermic peak is the crystalline form.
  • the melting endotherm of CSI is basically as shown in Figure 6, which has an endothermic peak around 267 ° C (the initial
  • the crystalline form CSI is anhydrous.
  • the present invention also provides a preparation method of the crystal form CSI, the preparation method comprising:
  • the alcohol solvent is preferably ethanol; the ketone solvent is preferably acetone; the molar ratio of the solid compound I to methanesulfonic acid is preferably 1:1.
  • the present invention provides the mesylate salt crystal form CSII of Compound I (hereinafter referred to as "crystal form CSII").
  • the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angle 2 ⁇ values of 6.3° ⁇ 0.2°, 12.7° ⁇ 0.2°, 15.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSII has a diffraction angle 2 ⁇ value of 7.9° ⁇ 0.2°, 19.2° ⁇ 0.2°, 19.9° ⁇ 0.2°, or 2
  • a diffraction angle 2 ⁇ value of 7.9° ⁇ 0.2°, 19.2° ⁇ 0.2°, 19.9° ⁇ 0.2°, or 2
  • characteristic peaks at or at 3 places preferably, the X-ray powder diffraction pattern of the crystalline form CSII is at 3 places in the diffraction angle 2 ⁇ value of 7.9° ⁇ 0.2°, 19.2° ⁇ 0.2°, 19.9° ⁇ 0.2°
  • the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at 1 or 2 places in the diffraction angle 2 ⁇ value of 14.5° ⁇ 0.2°, 20.4° ⁇ 0.2°; preferably In particular, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at two positions among the diffraction angle 2 ⁇ values of 14.5° ⁇ 0.2° and 20.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSII has diffraction angle 2 ⁇ values of 6.3° ⁇ 0.2°, 12.7° ⁇ 0.2°, 15.9° ⁇ 0.2°, 7.9° ⁇ 0.2° , 19.2° ⁇ 0.2°, 19.9° ⁇ 0.2°, 14.5° ⁇ 0.2°, 20.4° ⁇ 0.2°, 9.9° ⁇ 0.2°, 25.2° ⁇ 0.2°, 26.5° ⁇ 0.2°, or 2 There are characteristic peaks at, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11.
  • the X-ray powder diffraction pattern of Form CSII is substantially as shown in FIG. 13 .
  • thermogravimetric analysis diagram is basically as shown in FIG. 14 .
  • Non-limitingly, crystalline form CSII has an endothermic peak around 100°C, an exothermic peak around 206°C, and an endothermic peak around 255°C (starting temperature is about 253°C), differential scanning
  • the calorimetric analysis diagram is shown in Figure 15.
  • the crystalline form CSII is a hydrate.
  • the crystalline form CSII contains no more than 10% water by mass.
  • the crystalline form CSII contains no more than 8% water by mass.
  • the crystalline form CSII contains no more than 6% water by mass.
  • the present invention also provides a preparation method of the crystal form CSII, the preparation method comprising:
  • the solid compound I, methanesulfonic acid, a mixed solvent of alcohols and water or a mixed solvent of ethers and water are mixed and stirred to obtain crystal form CSII.
  • the molar ratio of the solid compound I to methanesulfonic acid is preferably 0.9:1-1.1:1, more preferably 1:1;
  • the alcohol solvent is preferably isopropanol;
  • the ether solvent is preferably tetrahydrofuran;
  • the volume ratio of alcohols and water or ethers and water in the mixed solvent is preferably 9:1.
  • the present invention provides the use of crystal form CSI, crystal form CSII or any mixture of the two crystal forms for preparing other crystal forms of compound I methanesulfonic acid.
  • the present invention provides a pharmaceutical composition comprising an effective therapeutic amount of the crystal form of Compound I mesylate and pharmaceutically acceptable excipients.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective therapeutic amount of crystal form CSI, crystal form CSII or any mixture of the two crystal forms and pharmaceutically acceptable excipients.
  • the present invention provides the use of the crystalline form of compound I mesylate in the preparation of ROCK2 inhibitor medicine.
  • the present invention provides the use of crystal form CSI, crystal form CSII or any mixture of the two crystal forms in the preparation of ROCK2 inhibitor drugs.
  • the present invention provides the use of the crystalline form of Compound I mesylate in the preparation of a medicament for the treatment of chronic graft-versus-host disease, systemic sclerosis and idiopathic pulmonary fibrosis.
  • the present invention provides the use of crystal form CSI, crystal form CSII or any mixture of the two crystal forms in the preparation of a drug for the treatment of chronic graft-versus-host disease, systemic sclerosis and idiopathic pulmonary fibrosis.
  • the crystalline form CSI provided by the present invention has higher solubility.
  • the solubility of crystalline form CSI is more than 2 times that of the prior art P1 and 1.5 times that of the prior art P2.
  • Compound I is a poorly water-soluble drug belonging to BCS class IV.
  • the crystal form CSI provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the curative effect of the drug, thereby reducing the amount of the drug side effects and improve the safety of medicines.
  • the crystalline form CSI provided by the present invention has lower hygroscopicity.
  • the test results show that the crystal form of the present invention remains unchanged before and after the CSI moisture absorption test, and the moisture absorption weight gain (0-80% RH) is significantly lower than that of the prior art P1.
  • the hygroscopicity of the crystalline form CSI is better than that of the prior art.
  • high hygroscopicity can easily cause chemical degradation and solid state transformation of the API, which directly affects the physicochemical stability of the API.
  • high hygroscopicity will reduce the fluidity of the API, thereby affecting the processing technology of the API.
  • drugs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, the high hygroscopicity can easily cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
  • the crystal form CSI provided by the invention has low hygroscopicity, is not harsh on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystal form CSI API provided by the present invention has good stability.
  • the crystal form of CSI API is placed under the condition of 25°C/60%RH, the crystal form does not change for at least 6 months, and the chemical purity is above 99.5%, and the purity basically remains unchanged during the storage process. It shows that the crystalline CSI API has good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystalline form of the CSI API has not changed when placed at 40°C/75%RH for at least 6 months, and the crystal form has not changed at 60°C/75%RH for at least 1 month, and the chemical purity is More than 99.5%, the purity remains basically unchanged during storage. It shows that the crystalline CSI API has good stability under accelerated conditions and more severe conditions. High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under accelerated and more severe conditions is critical for the drug.
  • the crystalline form of CSI API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.
  • Crystalline CSI has good physical and chemical stability, ensuring consistent and controllable quality of APIs and preparations, and reducing drug quality changes, bioavailability changes, and toxic and side effects caused by changes in crystal form or impurities.
  • the crystalline form CSI has better grinding stability.
  • the prior art P1 is basically transformed into amorphous after grinding, while the crystal form of the CSI bulk drug of the present invention remains unchanged after grinding, and has good physical stability.
  • it is often necessary to grind and pulverize the API, and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process.
  • the crystalline form CSI provided by the present invention has almost no solvent residue, while the prior art P2 has about 0.34 molar equivalent of ethyl acetate (about 62000 ppm).
  • ethyl acetate is a class 3 solvent with an upper limit of 5000ppm. It can be seen from this that the solvent content of the prior art P2 is far beyond the upper limit and is not suitable for medicinal use.
  • the crystalline form CSII provided by the present invention has higher solubility.
  • the solubility is more than 2 times that of the prior art P1 and 1.3 times that of the prior art P2.
  • Compound I is a poorly water-soluble drug belonging to BCS class IV.
  • the crystal form CSII provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the curative effect of the drug, thereby reducing the amount of the drug side effects and improve the safety of medicines.
  • the crystalline form CSII provided by the present invention has lower hygroscopicity.
  • the test results show that the crystal form of the present invention remains unchanged before and after the moisture absorption test of CSII, and the moisture gain (40-80% RH) is about 1/5 of that of the prior art P1.
  • the hygroscopicity of the crystalline form CSII is obviously better than that of the prior art.
  • high hygroscopicity can easily cause chemical degradation and solid state transformation of the API, which directly affects the physicochemical stability of the API.
  • high hygroscopicity will reduce the fluidity of the API, thereby affecting the processing technology of the API.
  • drugs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, the high hygroscopicity can easily cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
  • the crystal form CSII provided by the invention has low hygroscopicity, is not harsh on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.
  • the crystal form CSII bulk drug provided by the present invention has good stability.
  • the crystal form CSII API is placed under the condition of 25°C/60%RH, the crystal form has not changed for at least 6 months, and the chemical purity is above 99.5%, and the purity basically remains unchanged during the storage process. It shows that the crystalline form CSII API has good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystal form of CSII API has not changed after being placed at 40°C/75%RH for at least 6 months, and the chemical purity is above 99.5%, and the purity remains basically unchanged during storage. It shows that the crystalline form CSII API has good stability under accelerated conditions.
  • Crystal form CSII has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, and reducing drug quality changes, bioavailability changes, and toxic and side effects caused by crystal form changes or impurities.
  • the crystalline form CSII has better grinding stability.
  • the prior art P1 is basically transformed into amorphous after grinding, while the crystal form of the CSI bulk drug of the present invention remains unchanged after grinding, and has good physical stability.
  • it is often necessary to grind and pulverize the API, and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process.
  • the crystalline form CSII provided by the present invention has almost no solvent residue, while the prior art P2 has about 0.34 molar equivalent of ethyl acetate (about 62000 ppm).
  • ethyl acetate is a class 3 solvent with an upper limit of 5000ppm. It can be seen from this that the solvent content of the prior art P2 is far beyond the upper limit and is not suitable for medicinal use.
  • Fig. 1 is the XRPD diagram of the prior art P1
  • FIG. 2 is the XRPD diagram of the prior art P2
  • Figure 3 is the XRPD pattern of the crystalline form CSI
  • Figure 4 is the TGA diagram of the crystal form CSI
  • Figure 5 is the XRPD pattern of the crystalline form CSI
  • Figure 6 is the DSC chart of crystal form CSI
  • FIG. 7 is a XRPD comparison diagram before and after grinding of the prior art P1 (top: after grinding; bottom: before grinding)
  • Fig. 8 is the XRPD comparison diagram of crystal form CSI before and after grinding (top: after grinding; bottom: before grinding)
  • FIG. 9 is a DVS diagram of the prior art P1
  • Figure 10 is the DVS diagram of the crystal form CSI
  • Figure 11 is a comparison chart of XRPD before and after DVS test of crystal form CSI (top: before test; bottom: after test)
  • Figure 12 is the XRPD comparison chart of crystalline form CSI before and after storage under different conditions (from bottom to top: before storage, 25°C/60%RH open packaging for 6 months, 25°C/60%RH sealed packaging for 6 months 6 months at 40°C/75%RH open packaging, 6 months at 40°C/75%RH sealed packaging, 1 month at 60°C/75%RH open packaging, 60°C/75%RH Store in airtight packaging for 1 month)
  • Figure 13 is the XRPD pattern of the crystalline form CSII
  • Figure 14 is a TGA diagram of crystal form CSII
  • Figure 15 is the DSC chart of crystal form CSII
  • Figure 16 is the XRPD comparison diagram of crystal form CSII before and after grinding (top: after grinding; bottom: before grinding)
  • Figure 17 is the XRPD comparison chart before and after the DVS test of the crystal form CSII (top: before test; bottom: after test)
  • Figure 18 is the XRPD comparison chart of crystal form CSII before and after storage under different conditions (from bottom to top: before storage, 25°C/60%RH open packaging for 6 months, 25°C/60%RH sealed packaging for 6 months months, 6 months at 40°C/75%RH open packaging, 6 months at 40°C/75%RH sealed packaging)
  • the X-ray powder diffraction patterns described in the examples of the present invention were collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of the described X-ray powder diffraction are as follows:
  • thermogravimetric analysis (TGA) plots described in the present invention were collected on a TA Q500.
  • the method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:
  • DSC Differential Scanning Calorimetry
  • the dynamic moisture adsorption (DVS) map of the present invention is collected on the Intrinsic dynamic moisture adsorption instrument produced by SMS company (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software.
  • the method parameters of the described dynamic moisture adsorption instrument are as follows:
  • Relative humidity range 0%RH-95%RH
  • the hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) of the present invention was collected from a Bruker Avance II DMX 400 MHz nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL.
  • the dynamic solubility test method of the present invention is shown in Table 1.
  • the related substance detection method of the present invention is shown in Table 2.
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, wherein the magnetic stirring speed is preferably 300-900 rpm, and the mechanical stirring speed is 300-900 rpm. Preferably 100-300 rpm.
  • the “separation” is accomplished by conventional methods in the art, such as centrifugation or filtration.
  • the operation of "centrifugation” is as follows: put the sample to be separated in a centrifuge tube and centrifuge at a speed of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube, and separate the solids.
  • the "drying” is accomplished by conventional methods in the art, such as vacuum drying, blast drying or natural air drying.
  • the drying temperature may be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. Drying time can be 2-48 hours, or overnight. Drying takes place in a fume hood, blast oven or vacuum oven.
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • the “characteristic peak” refers to a representative diffraction peak used to identify crystals.
  • the peak position can usually have an error of ⁇ 0.2°.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction pattern will vary depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of experimental conditions, so the diffraction peak intensity cannot be used as the sole or decisive factor for determining the crystal form.
  • the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the diffraction peak intensities shown in the present invention are illustrative and not for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to here, and any X-ray powder diffraction pattern with the characteristic peaks in these patterns Crystal forms with the same or similar X-ray powder diffraction patterns all fall within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.
  • the crystalline form CSI and crystalline form CSII described herein are pure and substantially not mixed with any other crystalline forms.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.
  • the compound I and/or its salts as raw materials include, but are not limited to, solid form (crystalline or amorphous), oily, liquid form and solution.
  • the compound I and/or its salts as starting materials are in solid form.
  • Compound I used in the following examples can be prepared according to the prior art, for example, according to the method described in the document WO2006105081A2.
  • prior art P1 is obtained, and the XRPD pattern of prior art P1 is shown in FIG. 1 .
  • the resulting solid P2 was calculated to contain about 0.34 molar equivalents of ethyl acetate (about 62,000 ppm).
  • ethyl acetate belongs to class 3 solvents, and the upper limit of its allowable content is 5000ppm.
  • the content of ethyl acetate in the prior art solid P2 is much higher than the upper limit of the ICH guidelines, which is not suitable for medicinal use.
  • Embodiment 2 The preparation method of crystal form CSI
  • samples 1-2 are all crystal forms of CSI according to the present invention.
  • the XRPD pattern of sample 1 obtained in this example is shown in FIG. 3 , and the XRPD data is shown in Table 4.
  • the TGA of sample 1 obtained in this example is shown in FIG. 4 , and when heated to 100° C., there is a mass loss of about 0.2%.
  • Embodiment 3 The preparation method of crystal form CSI
  • the obtained crystalline solid is the crystal form CSI described in the present invention, and its X-ray powder diffraction data is shown in Figure 5, and the XRPD data is shown in Table 5.
  • FeSSIF Simulated Fed State Intestinal Fluid
  • the crystalline form CSI of the present invention and the prior art solid were placed in a mortar and manually ground for 5 minutes, and the XRPD of the samples before and after grinding was tested. The results are shown in Table 7. The results show that the crystalline form CSI has better grinding stability compared with the prior art.
  • Example 7 The hygroscopicity of crystal form CSI and prior art
  • the XRPD of the crystal form CSI before and after the DVS test was tested, and the results are shown in Figure 11.
  • the experimental results show that the crystal form of CSI remains unchanged after undergoing 0%RH-95%RH-0%RH cycles. It shows that the crystalline form CSI has good stability under high humidity.
  • Airtight packaging put the sample in a glass vial, tighten the bottle cap with a cap, and seal it in an aluminum foil bag.
  • Open packaging place the sample in a glass vial, cover the bottle with a layer of aluminum foil and perforate the foil.
  • the experimental results show that the crystalline form CSI can be stable for at least 6 months under the conditions of 25°C/60%RH and 40°C/75%RH. It can be seen that the crystalline form CSI can maintain good stability under long-term and accelerated conditions. Crystalline CSI is stable for at least 1 month under the conditions of 60°C/75%RH, and it can be seen that the stability of crystallized CSI is also very good under more severe conditions.
  • Embodiment 10 The preparation method of crystal form CSII
  • the obtained crystalline solid is the crystal form CSII of the present invention, its X-ray powder diffraction pattern is shown in Figure 13, and the X-ray powder diffraction data is shown in Table 10.
  • the TGA of the crystalline form CSII is shown in Figure 14, and when heated to 100°C, it has a mass loss of about 5.9%.
  • Embodiment 11 The preparation method of crystal form CSII
  • the crystalline form CSII and the prior art solid were placed in a mortar and manually ground for 5 minutes, and the XRPD of the samples before and after grinding was tested. The results are shown in Table 13. The results show that, compared with the prior art, the crystalline form CSII has better grinding stability.
  • the crystal form CSII is a hydrate, and the DVS test takes the ambient humidity (40%RH) as the initial humidity test.
  • the XRPD of the crystal form CSII before and after the DVS test was tested, and the results are shown in Figure 17.
  • the experimental results show that the crystal form of CSII remains unchanged after undergoing a 40-95-0-95% RH cycle. It shows that the crystalline form CSII has good stability under high humidity.
  • Sealed packaging put the sample in a glass vial, tighten the bottle cap with a cap, and seal it in an aluminum foil bag.
  • Open packaging place the sample in a glass vial, cover the bottle with a layer of aluminum foil and perforate the foil.
  • the experimental results show that the crystalline form CSII can be stable for at least 6 months under the conditions of 25°C/60%RH and 40°C/75%RH. It can be seen that the crystalline form CSII has good stability under both long-term and accelerated conditions.

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Abstract

The present invention relates to a crystal form of Belumosudil (hereinafter referred to as compound I) mesylate and a preparation method for the crystal form, a pharmaceutical composition comprising the crystal form, and a use of the crystal form in the preparation of ROCK2 inhibitor drugs and drugs for treating chronic graft versus host disease, systemic sclerosis, and idiopathic pulmonary fibrosis. Compared with the prior art, the crystal form of Belumosudil mesylate provided by the present invention has one or more improved properties, and has important value for the optimization and development of the drugs in the future.

Description

Belumosudil甲磺酸盐的晶型及其制备方法和用途Crystal form of belumosudil mesylate and its preparation method and use 技术领域technical field
本发明涉及晶体化学领域。具体而言，涉及Belumosudil甲磺酸盐的晶型及其制备方法和用途。The present invention relates to the field of crystal chemistry. Specifically, it relates to the crystalline form of Belumosudil mesylate and its preparation method and use.
背景技术Background technique
慢性移植物抗宿主病(cGVHD)是一种免疫介导的炎症和纤维化疾病。它是异基因造血细胞移植(alloHCT)后发病率、死亡率和生活质量(QOL)受损的主要原因。cGVHD影响高达70％的alloHCT接受者。在接受alloHCT后存活超过100天的儿童中，cGVHD的发病率为20％-50％。它是alloHCT术后2年以上非复发性死亡的主要原因。Chronic graft-versus-host disease (cGVHD) is an immune-mediated inflammatory and fibrotic disease. It is a major cause of morbidity, mortality and impaired quality of life (QOL) after allogeneic hematopoietic cell transplantation (alloHCT). cGVHD affects up to 70% of alloHCT recipients. In children surviving more than 100 days after receiving alloHCT, the incidence of cGVHD is 20%-50%. It is the leading cause of non-recurrent death more than 2 years after alloHCT.
REZUROCK TM(Belumosudil)在美国被批准用于治疗至少两个既往系统治疗方案失败后的12岁及以上的成人和儿童cGVHD患者。Belumosudil是唯一一个获批的靶向Rho相关卷曲螺旋蛋白激酶2(ROCK2)的疗法。Belumosudil用于治疗系统性硬化症的研究正在开展中，FDA已授予Belumosudil治疗系统性硬化症的孤儿药资格。 REZUROCK ™ (Belumosudil) is approved in the United States for the treatment of adult and pediatric patients 12 years of age and older with cGVHD after failure of at least two prior systemic therapy regimens. Belumosudil is the only approved therapy targeting Rho-related coiled-coil kinase 2 (ROCK2). Belumosudil is being studied for the treatment of systemic sclerosis, and the FDA has granted orphan drug designation to belumosudil for the treatment of systemic sclerosis.
Belumosudil的化学名称为2-(3-(4-(1H-吲唑-5-基氨基)喹唑啉-2-基)苯氧基)-N-异丙基乙酰胺(以下称为“化合物I”)，其结构式如下：The chemical name for Belumosudil is 2-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenoxy)-N-isopropylacetamide (hereinafter referred to as "the compound I"), its structural formula is as follows:
Figure PCTCN2021140731-appb-000001
Figure PCTCN2021140731-appb-000001
晶体是化合物分子在微观结构中三维有序排列而形成晶格的固体。多晶型是指一种化合物存在多种晶体形式的现象。化合物可能以一种或多种晶型存在，但是无法具体预期其存在与特性。不同晶型的原料药有不同的理化性质，可能导致药物在体内有不同的溶出、吸收，进而在一定程度上影响药物的临床疗效。特别是一些难溶性口服固体或半固体制剂，晶型对产品性能至关重要。除此之外，晶型的理化性质对生产过程至关重要。因此，多晶型是药物研究和药物质量控制的重要内容。A crystal is a solid in which the molecules of a compound are arranged in a three-dimensional order in a microstructure to form a crystal lattice. Polymorphism is the phenomenon in which a compound exists in more than one crystal form. Compounds may exist in one or more crystalline forms, but their existence and identity cannot be specifically expected. APIs with different crystal forms have different physicochemical properties, which may lead to different dissolution and absorption of the drug in the body, thereby affecting the clinical efficacy of the drug to a certain extent. Especially for some insoluble oral solid or semi-solid preparations, the crystal form is very important to the product performance. In addition to this, the physicochemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is an important part of drug research and drug quality control.
现有技术未公开化合物I甲磺酸盐的固体形式，仅公开化合物I的制备方法和化合物I的棕色固体。其中，现有技术WO2006105081A2公开的化合物I的制备方法为：使用制备型HPLC纯化化合物I粗品，继而得到化合物I，未披露化合物I的形态。CN106916145B公开了化合物I的棕色固体。本申请发明人重复了WO2006105081A2及CN106916145B公开的制备方法，得到化合物I的固体，分别 命名为现有技术P1和现有技术P2，并对获得的现有技术固体的性质进行了研究，发现现有技术存在溶剂含量高、溶解度低、引湿性高、稳定性差等问题，不适合药用开发。The prior art does not disclose the solid form of compound I mesylate, only the preparation method of compound I and the brown solid of compound I are disclosed. Among them, the preparation method of compound I disclosed in the prior art WO2006105081A2 is as follows: using preparative HPLC to purify the crude product of compound I, and then obtaining compound I, the form of compound I is not disclosed. CN106916145B discloses compound I as a brown solid. The inventors of the present application repeated the preparation methods disclosed in WO2006105081A2 and CN106916145B to obtain solids of compound I, which were named as prior art P1 and prior art P2 respectively. The technology has problems such as high solvent content, low solubility, high hygroscopicity, and poor stability, and is not suitable for medicinal development.
为克服现有技术的缺点，本申请的发明人针对化合物I及其盐的固体形式进行了深入研究，意外发现了本发明提供的化合物I甲磺酸盐的结晶，其在溶解度，引湿性，提纯作用，稳定性，黏附性，可压性，流动性，体内外溶出，生物有效性等方面中的至少一方面存在优势，特别是无溶剂残留、溶解度高、稳定性好、引湿性低，解决了现有技术存在的问题，对含化合物I药物的开发具有非常重要的意义。In order to overcome the shortcomings of the prior art, the inventors of the present application have carried out in-depth research on the solid form of compound I and its salts, and have unexpectedly found the crystallization of compound I mesylate provided by the invention, which is in solubility, hygroscopicity, Purification, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, bioavailability and other aspects have advantages in at least one aspect, especially no solvent residue, high solubility, good stability, low hygroscopicity, The problems existing in the prior art are solved, and it is of great significance to the development of medicines containing compound I.
发明内容SUMMARY OF THE INVENTION
本发明的主要目的是提供化合物I甲磺酸盐的固体及其制备方法以及包含该固体的药物组合物。The main purpose of the present invention is to provide a solid of compound I mesylate, a preparation method thereof, and a pharmaceutical composition comprising the solid.
根据本发明的目的，本发明提供化合物I甲磺酸盐的晶型。According to the purpose of the present invention, the present invention provides the crystalline form of compound I mesylate.
根据本发明的目的，本发明提供化合物I甲磺酸盐的无水物。According to the purpose of the present invention, the present invention provides the anhydrate of compound I mesylate.
根据本发明的目的，本发明提供化合物I甲磺酸盐的水合物。According to the purpose of the present invention, the present invention provides the hydrate of compound I mesylate.
根据本发明的目的，本发明提供化合物I甲磺酸盐的晶型CSI(以下称作“晶型CSI”)。According to the purpose of the present invention, the present invention provides the crystalline form CSI of Compound I mesylate (hereinafter referred to as "crystalline form CSI").
一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为7.1°±0.2°处有特征峰。In one aspect, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at the diffraction angle 2θ value of 7.1°±0.2°.
进一步地，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为8.4°±0.2°、21.5°±0.2°、22.2°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为8.4°±0.2°、21.5°±0.2°、22.2°±0.2°中的3处有特征峰。Further, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has a diffraction angle 2θ value of 8.4°±0.2°, 21.5°±0.2°, 22.2°±0.2° at 1 or 2 There are characteristic peaks at or at 3; preferably, the X-ray powder diffraction pattern of the crystalline form CSI is at 3 of the diffraction angle 2θ values of 8.4°±0.2°, 21.5°±0.2°, 22.2°±0.2° There are characteristic peaks.
进一步地，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为16.8°±0.2°、19.5°±0.2°、23.5°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为16.8°±0.2°、19.5°±0.2°、23.5°±0.2°中的3处有特征峰。Further, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has a diffraction angle 2θ value of 16.8°±0.2°, 19.5°±0.2°, 23.5°±0.2°, or 2 There are characteristic peaks at or at 3 places; preferably, the X-ray powder diffraction pattern of the crystalline form CSI is at 3 places in the diffraction angle 2θ value of 16.8°±0.2°, 19.5°±0.2°, 23.5°±0.2° There are characteristic peaks.
另一方面，使用Cu-Kα辐射，所述晶型CSI的X射线粉末衍射图在衍射角2θ值为7.1°±0.2°、8.4°±0.2°、21.5°±0.2°、22.2°±0.2°、16.8°±0.2°、19.5°±0.2°、23.5°±0.2°、17.2°±0.2°、25.5°±0.2°中的任意1处、或2处、或3处、或4处、或5处、或6处、或7处、或8处、或9处有特征峰。On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSI has diffraction angle 2θ values of 7.1°±0.2°, 8.4°±0.2°, 21.5°±0.2°, 22.2°±0.2° , 16.8°±0.2°, 19.5°±0.2°, 23.5°±0.2°, 17.2°±0.2°, 25.5°±0.2° any 1, or 2, or 3, or 4, or 5 There are characteristic peaks at, or 6, or 7, or 8, or 9.
非限制性地，晶型CSI的X射线粉末衍射图基本如图3所示。Without limitation, the X-ray powder diffraction pattern of the crystalline form CSI is substantially as shown in FIG. 3 .
非限制性地，晶型CSI加热至100℃时，具有约0.2％的质量损失，热重分析图基本如图4所示。Without limitation, when the crystalline form CSI is heated to 100° C., it has a mass loss of about 0.2%, and the thermogravimetric analysis diagram is basically shown in FIG. 4 .
非限制性地，晶型CSI的差示扫描量热分析图基本如图6所示，其在267℃附近存在一个吸热峰(起始温度约为264℃)，该吸热峰为晶型CSI的熔化吸热峰。Without limitation, the differential scanning calorimetry analysis of the crystalline form CSI is basically as shown in Figure 6, which has an endothermic peak around 267 ° C (the initial temperature is about 264 ° C), and the endothermic peak is the crystalline form. The melting endotherm of CSI.
非限制性地，晶型CSI为无水物。Without limitation, the crystalline form CSI is anhydrous.
根据本发明的目的，本发明还提供所述晶型CSI的制备方法，所述制备方法包括：According to the purpose of the present invention, the present invention also provides a preparation method of the crystal form CSI, the preparation method comprising:
将化合物I固体，甲磺酸与醇类溶剂或酮类溶剂混合，搅拌，得到晶型CSI。Compound I solid, methanesulfonic acid and alcohol solvent or ketone solvent are mixed and stirred to obtain crystal form CSI.
进一步地，所述醇类溶剂优选乙醇；所述酮类溶剂优选丙酮；所述化合物I固体与甲磺酸的摩尔比优选1:1。Further, the alcohol solvent is preferably ethanol; the ketone solvent is preferably acetone; the molar ratio of the solid compound I to methanesulfonic acid is preferably 1:1.
根据本发明的目的，本发明提供化合物I的甲磺酸盐晶型CSII(以下称作“晶型CSII”)。According to the purpose of the present invention, the present invention provides the mesylate salt crystal form CSII of Compound I (hereinafter referred to as "crystal form CSII").
一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为6.3°±0.2°、12.7°±0.2°、15.9°±0.2°处有特征峰。In one aspect, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angle 2θ values of 6.3°±0.2°, 12.7°±0.2°, 15.9°±0.2°.
进一步地，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为7.9°±0.2°、19.2°±0.2°、19.9°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为7.9°±0.2°、19.2°±0.2°、19.9°±0.2°中的3处有特征峰。Further, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has a diffraction angle 2θ value of 7.9°±0.2°, 19.2°±0.2°, 19.9°±0.2°, or 2 There are characteristic peaks at or at 3 places; preferably, the X-ray powder diffraction pattern of the crystalline form CSII is at 3 places in the diffraction angle 2θ value of 7.9°±0.2°, 19.2°±0.2°, 19.9°±0.2° There are characteristic peaks.
进一步地，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为14.5°±0.2°、20.4°±0.2°中的1处、或2处有特征峰；优选地，所述晶型CSII的X射线粉末衍射谱图在衍射角2θ值为14.5°±0.2°、20.4°±0.2°中的2处有特征峰。Further, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at 1 or 2 places in the diffraction angle 2θ value of 14.5°±0.2°, 20.4°±0.2°; preferably In particular, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at two positions among the diffraction angle 2θ values of 14.5°±0.2° and 20.4°±0.2°.
另一方面，使用Cu-Kα辐射，所述晶型CSII的X射线粉末衍射图在衍射角2θ值为6.3°±0.2°、12.7°±0.2°、15.9°±0.2°、7.9°±0.2°、19.2°±0.2°、19.9°±0.2°、14.5°±0.2°、20.4°±0.2°、9.9°±0.2°、25.2°±0.2°、26.5°±0.2°中的任意1处、或2处、或3处、或4处、或5处、或6处、或7处、或8处、或9处、或10处、或11处有特征峰。On the other hand, using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form CSII has diffraction angle 2θ values of 6.3°±0.2°, 12.7°±0.2°, 15.9°±0.2°, 7.9°±0.2° , 19.2°±0.2°, 19.9°±0.2°, 14.5°±0.2°, 20.4°±0.2°, 9.9°±0.2°, 25.2°±0.2°, 26.5°±0.2°, or 2 There are characteristic peaks at, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11.
非限制性地，晶型CSII的X射线粉末衍射图基本如图13所示。Without limitation, the X-ray powder diffraction pattern of Form CSII is substantially as shown in FIG. 13 .
非限制性地，晶型CSII加热至100℃时，具有约5.9％的质量损失，热重分析图基本如图14所示。Without limitation, when the crystalline form CSII is heated to 100° C., it has a mass loss of about 5.9%, and the thermogravimetric analysis diagram is basically as shown in FIG. 14 .
非限制性地，晶型CSII在100℃附近存在一个吸热峰，在206℃附近存在一个放热峰，在255℃附近存在一个吸热峰(起始温度约为253℃)，差示扫描量热分析图如图15所示。Non-limitingly, crystalline form CSII has an endothermic peak around 100°C, an exothermic peak around 206°C, and an endothermic peak around 255°C (starting temperature is about 253°C), differential scanning The calorimetric analysis diagram is shown in Figure 15.
非限制性地，晶型CSII为水合物。Without limitation, the crystalline form CSII is a hydrate.
非限制性地，晶型CSII含有不高于10％质量分数的水。Without limitation, the crystalline form CSII contains no more than 10% water by mass.
进一步地，晶型CSII含有不高于8％质量分数的水。Further, the crystalline form CSII contains no more than 8% water by mass.
进一步地，晶型CSII含有不高于6％质量分数的水。Further, the crystalline form CSII contains no more than 6% water by mass.
根据本发明的目的，本发明还提供所述晶型CSII的制备方法，所述制备方法包括：According to the purpose of the present invention, the present invention also provides a preparation method of the crystal form CSII, the preparation method comprising:
将化合物I固体，甲磺酸，醇类和水的混合溶剂或者醚类和水的混合溶剂混合，搅拌，得到晶型CSII。The solid compound I, methanesulfonic acid, a mixed solvent of alcohols and water or a mixed solvent of ethers and water are mixed and stirred to obtain crystal form CSII.
进一步地，所述化合物I固体与甲磺酸的摩尔比优选0.9:1-1.1:1，更优选1:1；所述醇类溶剂优选异丙醇；所述醚类溶剂优选四氢呋喃；所述混合溶剂中醇类和水或者醚类和水的体积比优选9:1。Further, the molar ratio of the solid compound I to methanesulfonic acid is preferably 0.9:1-1.1:1, more preferably 1:1; the alcohol solvent is preferably isopropanol; the ether solvent is preferably tetrahydrofuran; the The volume ratio of alcohols and water or ethers and water in the mixed solvent is preferably 9:1.
根据本发明的目的，本发明提供晶型CSI、晶型CSII或两种晶型的任意混合用于制备化合物I甲磺酸的其他晶型的用途。According to the purpose of the present invention, the present invention provides the use of crystal form CSI, crystal form CSII or any mixture of the two crystal forms for preparing other crystal forms of compound I methanesulfonic acid.
根据本发明的目的，本发明提供一种药物组合物，所述药物组合物包含有效治疗量的化合物I甲磺酸盐的晶型及药学上可接受的辅料。According to the purpose of the present invention, the present invention provides a pharmaceutical composition comprising an effective therapeutic amount of the crystal form of Compound I mesylate and pharmaceutically acceptable excipients.
进一步地，本发明提供一种药物组合物，所述药物组合物包含有效治疗量的晶型CSI、晶型CSII或两种晶型的任意混合及药学上可接受的辅料。Further, the present invention provides a pharmaceutical composition comprising an effective therapeutic amount of crystal form CSI, crystal form CSII or any mixture of the two crystal forms and pharmaceutically acceptable excipients.
根据本发明的目的，本发明提供化合物I甲磺酸盐的晶型在制备ROCK2抑制剂药物中的用途。According to the purpose of the present invention, the present invention provides the use of the crystalline form of compound I mesylate in the preparation of ROCK2 inhibitor medicine.
进一步地，本发明提供晶型CSI、晶型CSII或两种晶型的任意混合在制备ROCK2抑制剂药物中的用途。Further, the present invention provides the use of crystal form CSI, crystal form CSII or any mixture of the two crystal forms in the preparation of ROCK2 inhibitor drugs.
根据本发明的目的，本发明提供化合物I甲磺酸盐的晶型在制备治疗慢性移植物抗宿主病、系统性硬化症和特发性肺纤维化药物中的用途。According to the purpose of the present invention, the present invention provides the use of the crystalline form of Compound I mesylate in the preparation of a medicament for the treatment of chronic graft-versus-host disease, systemic sclerosis and idiopathic pulmonary fibrosis.
进一步地，本发明提供晶型CSI、晶型CSII或两种晶型的任意混合在制备治疗慢性移植物抗宿主病、系统性硬化症和特发性肺纤维化药物中的用途。Further, the present invention provides the use of crystal form CSI, crystal form CSII or any mixture of the two crystal forms in the preparation of a drug for the treatment of chronic graft-versus-host disease, systemic sclerosis and idiopathic pulmonary fibrosis.
有益效果beneficial effect
本发明提供的晶型CSI具有如下优势：The crystal form CSI provided by the present invention has the following advantages:
(1)与现有技术相比，本发明提供的晶型CSI具有更高的溶解度。在FeSSIF中，晶型CSI的溶解度是现有技术P1的2倍多，是现有技术P2的1.5倍。(1) Compared with the prior art, the crystalline form CSI provided by the present invention has higher solubility. In FeSSIF, the solubility of crystalline form CSI is more than 2 times that of the prior art P1 and 1.5 times that of the prior art P2.
化合物I是水溶性差的药物，属于BCS IV类。本发明提供的晶型CSI有更高的溶解度，有利于提高药物在人体内的吸收，提高生物利用度；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。Compound I is a poorly water-soluble drug belonging to BCS class IV. The crystal form CSI provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the curative effect of the drug, thereby reducing the amount of the drug side effects and improve the safety of medicines.
(2)与现有技术相比，本发明提供的晶型CSI具有更低的引湿性。测试结果表明，本发明晶型CSI引湿性测试前后晶型保持不变，且引湿增重(0-80％RH)明显低于现有技术P1。晶型CSI的引湿性优于现有技术。(2) Compared with the prior art, the crystalline form CSI provided by the present invention has lower hygroscopicity. The test results show that the crystal form of the present invention remains unchanged before and after the CSI moisture absorption test, and the moisture absorption weight gain (0-80% RH) is significantly lower than that of the prior art P1. The hygroscopicity of the crystalline form CSI is better than that of the prior art.
一方面，高引湿性易引起原料药发生化学降解和固体形态转变，从而直接影响原料药的物理化学稳定性。此外，引湿性高会降低原料药的流动性，从而影响原料药的加工工艺。On the one hand, high hygroscopicity can easily cause chemical degradation and solid state transformation of the API, which directly affects the physicochemical stability of the API. In addition, high hygroscopicity will reduce the fluidity of the API, thereby affecting the processing technology of the API.
另一方面，引湿性高的药物在生产和保存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化，影响药物的质量。On the other hand, drugs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, the high hygroscopicity can easily cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
本发明提供的晶型CSI引湿性低，对环境要求不苛刻，降低了物料生产、保存和质量控制成本，具有很强的经济价值。The crystal form CSI provided by the invention has low hygroscopicity, is not harsh on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.
(3)本发明提供的晶型CSI原料药具有良好的稳定性。晶型CSI原料药在25℃/60％RH条件下放置，至少6个月晶型未发生变化，且化学纯度在99.5％以上，储存过程中纯度基本保持不变。说明晶型CSI原料药在长期条件下具有较好的稳定性，有利于药物的储存。(3) The crystal form CSI API provided by the present invention has good stability. The crystal form of CSI API is placed under the condition of 25℃/60%RH, the crystal form does not change for at least 6 months, and the chemical purity is above 99.5%, and the purity basically remains unchanged during the storage process. It shows that the crystalline CSI API has good stability under long-term conditions, which is beneficial to the storage of the drug.
同时，晶型CSI原料药在40℃/75％RH条件下放置至少6个月晶型未发生变化，在60℃/75％RH条件下至少1个月晶型未发生变化，且化学纯度在99.5％以上，储存过程中纯度基本保持不变。说明晶型CSI原料药在加速条件及更严苛的条件下，具有好的稳定性。季节差异、不同地区气候差异和环境因素等带来的高温和高湿条件会影响原料药的储存、运输、生产。因此，原料药在加速条件及更严苛的条件下的稳定性对于药物至关重要。晶型CSI原料药在苛刻的条件下具有更好的稳定性，有利于避免药物储存过程中因转晶或纯度下降对药物质量产生影响。At the same time, the crystalline form of the CSI API has not changed when placed at 40°C/75%RH for at least 6 months, and the crystal form has not changed at 60°C/75%RH for at least 1 month, and the chemical purity is More than 99.5%, the purity remains basically unchanged during storage. It shows that the crystalline CSI API has good stability under accelerated conditions and more severe conditions. High temperature and high humidity conditions caused by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of APIs. Therefore, the stability of the drug substance under accelerated and more severe conditions is critical for the drug. The crystalline form of CSI API has better stability under harsh conditions, which is beneficial to avoid the influence on the quality of the drug due to transcrystallization or decrease in purity during drug storage.
原料药晶型良好的物理和化学稳定性可以确保药物在生产和存储的过程中不会发生转晶且基本没有杂质产生。晶型CSI具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变或杂质产生引起的药物质量变化，生物利用度变化，和毒副作用。The good physical and chemical stability of the crystalline form of the bulk drug can ensure that the drug will not be crystallized during the production and storage process, and basically no impurities will be generated. Crystalline CSI has good physical and chemical stability, ensuring consistent and controllable quality of APIs and preparations, and reducing drug quality changes, bioavailability changes, and toxic and side effects caused by changes in crystal form or impurities.
同时，晶型CSI具有更好的研磨稳定性。现有技术P1研磨后基本转变为无定形，而本发明晶型CSI原料药研磨后晶型保持不变，具有良好的物理稳定性。制剂加工过程中常需要将原料药研磨粉碎，良好的物理稳定性能够降低制剂加工过程中原料药结晶度降低和转晶的风险。Meanwhile, the crystalline form CSI has better grinding stability. The prior art P1 is basically transformed into amorphous after grinding, while the crystal form of the CSI bulk drug of the present invention remains unchanged after grinding, and has good physical stability. In the process of preparation processing, it is often necessary to grind and pulverize the API, and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process.
(4)与现有技术相比，本发明提供的晶型CSI几乎无溶剂残留，而现有技术P2具有约0.34摩尔当量的乙酸乙酯(约62000ppm)。(4) Compared with the prior art, the crystalline form CSI provided by the present invention has almost no solvent residue, while the prior art P2 has about 0.34 molar equivalent of ethyl acetate (about 62000 ppm).
根据ICH指导原则，乙酸乙酯属于3类溶剂，其允许的含量上限为5000ppm。由此可知，现有技术P2的溶剂含量远远超出上限，不适合药用。According to the ICH guidelines, ethyl acetate is a class 3 solvent with an upper limit of 5000ppm. It can be seen from this that the solvent content of the prior art P2 is far beyond the upper limit and is not suitable for medicinal use.
本发明提供的晶型CSII具有如下优势：The crystal form CSII provided by the present invention has the following advantages:
(1)与现有技术相比，本发明提供的晶型CSII具有更高的溶解度。在FeSSIF中，溶解度是现有技术P1的2倍多，是现有技术P2的1.3倍。(1) Compared with the prior art, the crystalline form CSII provided by the present invention has higher solubility. In FeSSIF, the solubility is more than 2 times that of the prior art P1 and 1.3 times that of the prior art P2.
化合物I是水溶性差的药物，属于BCS IV类。本发明提供的晶型CSII有更高的溶解度，有利于提高药物在人体内的吸收，提高生物利用度；另外，更高的溶解度能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。Compound I is a poorly water-soluble drug belonging to BCS class IV. The crystal form CSII provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability; in addition, the higher solubility can reduce the dosage of the drug while ensuring the curative effect of the drug, thereby reducing the amount of the drug side effects and improve the safety of medicines.
(2)与现有技术相比，本发明提供的晶型CSII具有更低的引湿性。测试结果表明，本发明晶型CSII引湿性测试前后晶型保持不变，且引湿增重(40-80％RH)约为现有技术P1的1/5。晶型CSII的引湿性明显优于现有技术。(2) Compared with the prior art, the crystalline form CSII provided by the present invention has lower hygroscopicity. The test results show that the crystal form of the present invention remains unchanged before and after the moisture absorption test of CSII, and the moisture gain (40-80% RH) is about 1/5 of that of the prior art P1. The hygroscopicity of the crystalline form CSII is obviously better than that of the prior art.
一方面，高引湿性易引起原料药发生化学降解和固体形态转变，从而直接影响原料药的物理化学稳定性。此外，引湿性高会降低原料药的流动性，从而影响原料药的加工工艺。On the one hand, high hygroscopicity can easily cause chemical degradation and solid state transformation of the API, which directly affects the physicochemical stability of the API. In addition, high hygroscopicity will reduce the fluidity of the API, thereby affecting the processing technology of the API.
另一方面，引湿性高的药物在生产和保存过程中需要维持低的湿度，对生产提出了更高的要求，需要很高的成本。更重要的是，引湿性高容易造成药物中有效成分含量的变化，影响药物的质量。On the other hand, drugs with high hygroscopicity need to maintain low humidity during production and storage, which puts forward higher requirements for production and requires high costs. More importantly, the high hygroscopicity can easily cause changes in the content of active ingredients in the drug, affecting the quality of the drug.
本发明提供的晶型CSII引湿性低，对环境要求不苛刻，降低了物料生产、保存和质量控制成本，具有很强的经济价值。The crystal form CSII provided by the invention has low hygroscopicity, is not harsh on the environment, reduces the cost of material production, storage and quality control, and has strong economic value.
(3)本发明提供的晶型CSII原料药具有良好的稳定性。晶型CSII原料药在25℃/60％RH条件下放置，至少6个月晶型未发生变化，且化学纯度在99.5％以上，储存过程中纯度基本保持不变。说明晶型CSII原料药在长期条件下具有较好的稳定性，有利于药物的储存。(3) The crystal form CSII bulk drug provided by the present invention has good stability. The crystal form CSII API is placed under the condition of 25℃/60%RH, the crystal form has not changed for at least 6 months, and the chemical purity is above 99.5%, and the purity basically remains unchanged during the storage process. It shows that the crystalline form CSII API has good stability under long-term conditions, which is beneficial to the storage of the drug.
同时，晶型CSII原料药在40℃/75％RH条件下放置至少6个月晶型未发生变化，且化学纯度在99.5％以上，储存过程中纯度基本保持不变。说明晶型CSII原料药在加速条件下，具有好的稳定性。At the same time, the crystal form of CSII API has not changed after being placed at 40°C/75%RH for at least 6 months, and the chemical purity is above 99.5%, and the purity remains basically unchanged during storage. It shows that the crystalline form CSII API has good stability under accelerated conditions.
原料药晶型良好的物理和化学稳定性可以确保药物在生产和存储的过程中不会发生转晶且基本没有杂质产生。晶型CSII具有良好的物理化学稳定性，保证原料药和制剂质量一致可控，减少由于晶型改变或杂质产生引起的药物质量变化，生物利用度变化，和毒副作用。The good physical and chemical stability of the crystalline form of the bulk drug can ensure that the drug will not be crystallized during the production and storage process, and basically no impurities will be generated. Crystal form CSII has good physical and chemical stability, ensuring consistent and controllable quality of raw materials and preparations, and reducing drug quality changes, bioavailability changes, and toxic and side effects caused by crystal form changes or impurities.
同时，晶型CSII具有更好的研磨稳定性。现有技术P1研磨后基本转变为无定形，而本发明晶型CSI原料药研磨后晶型保持不变，具有良好的物理稳定性。制剂加工过程中常需要将原料药研磨粉碎，良好的物理稳定性能够降低制剂加工过程中原料药结晶度降低和转晶的风险。Meanwhile, the crystalline form CSII has better grinding stability. The prior art P1 is basically transformed into amorphous after grinding, while the crystal form of the CSI bulk drug of the present invention remains unchanged after grinding, and has good physical stability. In the process of preparation processing, it is often necessary to grind and pulverize the API, and good physical stability can reduce the risk of lowering the crystallinity of the API and the risk of crystal transformation during the preparation process.
(4)与现有技术相比，本发明提供的晶型CSII几乎无溶剂残留，而现有技术P2具有约0.34摩尔当量的乙酸乙酯(约62000ppm)。(4) Compared with the prior art, the crystalline form CSII provided by the present invention has almost no solvent residue, while the prior art P2 has about 0.34 molar equivalent of ethyl acetate (about 62000 ppm).
根据ICH指导原则，乙酸乙酯属于3类溶剂，其允许的含量上限为5000ppm。由此可知，现有技术P2的溶剂含量远远超出上限，不适合药用。According to the ICH guidelines, ethyl acetate is a class 3 solvent with an upper limit of 5000ppm. It can be seen from this that the solvent content of the prior art P2 is far beyond the upper limit and is not suitable for medicinal use.
附图说明Description of drawings
图1为现有技术P1的XRPD图Fig. 1 is the XRPD diagram of the prior art P1
图2为现有技术P2的XRPD图Figure 2 is the XRPD diagram of the prior art P2
图3为晶型CSI的XRPD图Figure 3 is the XRPD pattern of the crystalline form CSI
图4为晶型CSI的TGA图Figure 4 is the TGA diagram of the crystal form CSI
图5为晶型CSI的XRPD图Figure 5 is the XRPD pattern of the crystalline form CSI
图6为晶型CSI的DSC图Figure 6 is the DSC chart of crystal form CSI
图7为现有技术P1研磨前后的XRPD对比图(上：研磨后；下：研磨前)FIG. 7 is a XRPD comparison diagram before and after grinding of the prior art P1 (top: after grinding; bottom: before grinding)
图8为晶型CSI研磨前后的XRPD对比图(上：研磨后；下：研磨前)Fig. 8 is the XRPD comparison diagram of crystal form CSI before and after grinding (top: after grinding; bottom: before grinding)
图9为现有技术P1的DVS图FIG. 9 is a DVS diagram of the prior art P1
图10为晶型CSI的DVS图Figure 10 is the DVS diagram of the crystal form CSI
图11为晶型CSI的DVS测试前后XRPD对比图(上：测试前；下：测试后)Figure 11 is a comparison chart of XRPD before and after DVS test of crystal form CSI (top: before test; bottom: after test)
图12为晶型CSI在不同条件下放置前后的XRPD对比图(从下至上依次为：放置前，25℃/60％RH敞口包装放置6个月，25℃/60％RH密封包装放置6个月，40℃/75％RH敞口包装放置6个月，40℃/75％RH密封包装放置6个月， 60℃/75％RH敞口包装放置1个月，60℃/75％RH密封包装放置1个月)Figure 12 is the XRPD comparison chart of crystalline form CSI before and after storage under different conditions (from bottom to top: before storage, 25℃/60%RH open packaging for 6 months, 25°C/60%RH sealed packaging for 6 months 6 months at 40°C/75%RH open packaging, 6 months at 40°C/75%RH sealed packaging, 1 month at 60°C/75%RH open packaging, 60°C/75%RH Store in airtight packaging for 1 month)
图13为晶型CSII的XRPD图Figure 13 is the XRPD pattern of the crystalline form CSII
图14为晶型CSII的TGA图Figure 14 is a TGA diagram of crystal form CSII
图15为晶型CSII的DSC图Figure 15 is the DSC chart of crystal form CSII
图16为晶型CSII研磨前后的XRPD对比图(上：研磨后；下：研磨前)Figure 16 is the XRPD comparison diagram of crystal form CSII before and after grinding (top: after grinding; bottom: before grinding)
图17为晶型CSII的DVS测试前后XRPD对比图(上：测试前；下：测试后)Figure 17 is the XRPD comparison chart before and after the DVS test of the crystal form CSII (top: before test; bottom: after test)
图18为晶型CSII在不同条件下放置前后的XRPD对比图(从下至上依次为：放置前，25℃/60％RH敞口包装放置6个月，25℃/60％RH密封包装放置6个月，40℃/75％RH敞口包装放置6个月，40℃/75％RH密封包装放置6个月)Figure 18 is the XRPD comparison chart of crystal form CSII before and after storage under different conditions (from bottom to top: before storage, 25℃/60%RH open packaging for 6 months, 25°C/60%RH sealed packaging for 6 months months, 6 months at 40°C/75%RH open packaging, 6 months at 40°C/75%RH sealed packaging)
具体实施方式Detailed ways
结合以下实施例对本发明做详细说明，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。The present invention will be described in detail with reference to the following examples, which describe in detail the preparation and use methods of the crystal forms of the present invention. It will be apparent to those skilled in the art that many changes in both materials and methods can be practiced without departing from the scope of the present invention.
本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:
XRPD：X射线粉末衍射XRPD: X-ray Powder Diffraction
DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermogravimetric Analysis
DVS：动态水分吸附DVS: Dynamic Moisture Sorption
1H NMR：液态核磁氢谱 1 H NMR: Liquid Hydrogen Nuclear Magnetic Spectroscopy
UPLC：超高效液相色谱UPLC: Ultra High Performance Liquid Chromatography
HPLC：高效液相色谱HPLC: High Performance Liquid Chromatography
RH：相对湿度RH: relative humidity
BCS：生物药剂学分类系统BCS: Biopharmaceutical Classification System
采集数据所用的仪器及方法：Instruments and methods used to collect data:
本发明实施例所述的X射线粉末衍射图在Bruker D2 PHASER X射线粉末衍射仪上采集。所述的X射线粉末衍射的方法参数如下：The X-ray powder diffraction patterns described in the examples of the present invention were collected on a Bruker D2 PHASER X-ray powder diffractometer. The method parameters of the described X-ray powder diffraction are as follows:
X射线光源：Cu,KαX-ray light source: Cu, Kα
Kα1
Figure PCTCN2021140731-appb-000002
1.54060；Kα2
Figure PCTCN2021140731-appb-000003
1.54439 Kα1
Figure PCTCN2021140731-appb-000002
1.54060; Kα2
Figure PCTCN2021140731-appb-000003
1.54439
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：30仟伏特(kV)Voltage: 30 thousand volts (kV)
电流：10毫安培(mA)Current: 10 milliamps (mA)
扫描范围(2θ)：自3.0至40.0度Scanning range (2θ): from 3.0 to 40.0 degrees
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：Thermogravimetric analysis (TGA) plots described in the present invention were collected on a TA Q500. The method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:
扫描速率：10℃/minScan rate: 10°C/min
保护气体：N 2 Shielding gas: N 2
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：Differential Scanning Calorimetry (DSC) graphs according to the present invention were collected on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:
扫描速率：10℃/minScan rate: 10°C/min
保护气体：N 2 Shielding gas: N 2
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic control software。所述的动态水分吸附仪的方法参数如下：The dynamic moisture adsorption (DVS) map of the present invention is collected on the Intrinsic dynamic moisture adsorption instrument produced by SMS company (Surface Measurement Systems Ltd.). The instrument control software is DVS-Intrinsic control software. The method parameters of the described dynamic moisture adsorption instrument are as follows:
温度：25℃Temperature: 25℃
载气，流速：N 2，200毫升/分钟 Carrier gas, flow rate: N 2 , 200 ml/min
相对湿度范围：0％RH-95％RHRelative humidity range: 0%RH-95%RH
本发明所述的核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400MHz核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲基亚砜溶解，配成2-10mg/mL的溶液。 The hydrogen nuclear magnetic resonance spectrum data ( 1 H NMR) of the present invention was collected from a Bruker Avance II DMX 400 MHz nuclear magnetic resonance spectrometer. Weigh 1-5 mg of the sample, dissolve it with 0.5 mL of deuterated dimethyl sulfoxide, and prepare a solution of 2-10 mg/mL.
本发明所述动态溶解度测试方法如表1所示。The dynamic solubility test method of the present invention is shown in Table 1.
表1Table 1
Figure PCTCN2021140731-appb-000004
Figure PCTCN2021140731-appb-000004
本发明所述有关物质检测方法如表2所示。The related substance detection method of the present invention is shown in Table 2.
表2Table 2
Figure PCTCN2021140731-appb-000005
Figure PCTCN2021140731-appb-000005
本发明中，所述“搅拌”采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50-1800转/分钟，其中，磁力搅拌速度优选300-900转/分钟，机械搅拌速度优选100-300转/分钟。In the present invention, the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, wherein the magnetic stirring speed is preferably 300-900 rpm, and the mechanical stirring speed is 300-900 rpm. Preferably 100-300 rpm.
所述“分离”，采用本领域的常规方法完成，例如离心或过滤。“离心”的操作为：将欲分离的样品置于离心管中，以10000转/分的速率进行离心，至固体全部沉至离心管底部，分离固体。The "separation" is accomplished by conventional methods in the art, such as centrifugation or filtration. The operation of "centrifugation" is as follows: put the sample to be separated in a centrifuge tube and centrifuge at a speed of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube, and separate the solids.
所述“干燥”，采用本领域的常规方法完成，例如真空干燥，鼓风干燥或自然晾干。干燥温度可以是室温或更高，优选室温到约60℃，或者到50℃，或者到40℃。干燥时间可以为2-48小时，或者过夜。干燥在通风橱、鼓风烘箱或真空烘箱里进行。The "drying" is accomplished by conventional methods in the art, such as vacuum drying, blast drying or natural air drying. The drying temperature may be room temperature or higher, preferably room temperature to about 60°C, or to 50°C, or to 40°C. Drying time can be 2-48 hours, or overnight. Drying takes place in a fume hood, blast oven or vacuum oven.
所述“室温”不是特定的温度值，是指10-30℃温度范围。The "room temperature" is not a specific temperature value, but refers to a temperature range of 10-30°C.
所述“特征峰”是指用于甄别晶体的有代表性的衍射峰，使用Cu-Kα辐射测试时，峰位置通常可以有±0.2°的误差。The "characteristic peak" refers to a representative diffraction peak used to identify crystals. When using Cu-Kα radiation test, the peak position can usually have an error of ±0.2°.
本发明中，“晶体”或“晶型”可以用X射线粉末衍射表征。本领域技术人员能够理解，X射线粉末衍射图受仪器的条件、样品的准备和样品纯度的影响而有所改变。X射线粉末衍射图中衍射峰的相对强度也可能随着实验条件的 变化而变化，所以衍射峰强度不能作为判定晶型的唯一或决定性因素。事实上，X射线粉末衍射图中衍射峰的相对强度与晶体的择优取向有关，本发明所示的衍射峰强度为说明性而非用于绝对比较。因而，本领域技术人员可以理解的是，本发明所保护晶型的X射线粉末衍射图不必和这里所指的实施例中的X射线粉末衍射图完全一致，任何具有和这些图谱中的特征峰相同或相似的X射线粉末衍射图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的X射线粉末衍射图和一个未知晶型的X射线粉末衍射图相比较，以证实这两组图反映的是相同还是不同的晶型。In the present invention, "crystal" or "crystal form" can be characterized by X-ray powder diffraction. Those skilled in the art will appreciate that the X-ray powder diffraction pattern will vary depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. The relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of experimental conditions, so the diffraction peak intensity cannot be used as the sole or decisive factor for determining the crystal form. In fact, the relative intensities of the diffraction peaks in the X-ray powder diffraction pattern are related to the preferred orientation of the crystals, and the diffraction peak intensities shown in the present invention are illustrative and not for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to here, and any X-ray powder diffraction pattern with the characteristic peaks in these patterns Crystal forms with the same or similar X-ray powder diffraction patterns all fall within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.
在一些实施方案中，本发明所述晶型CSI和晶型CSII是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。In some embodiments, the crystalline form CSI and crystalline form CSII described herein are pure and substantially not mixed with any other crystalline forms. In the present invention, "substantially free" when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.
本发明中术语“约”，当用来指可测量的数值时，例如质量、时间、温度等，意味着可围绕具体数值有一定的浮动的范围，该范围可以为±10％、±5％、±1％、±0.5％、或±0.1％。The term "about" in the present invention, when used to refer to a measurable value, such as mass, time, temperature, etc., means that there can be a certain range around the specific value, and the range can be ±10%, ±5% , ±1%, ±0.5%, or ±0.1%.
除非特殊说明，以下实施例均在室温条件下操作。Unless otherwise specified, the following examples are operated at room temperature.
根据本发明，作为原料的所述化合物I和/或其盐包括但不限于固体形式(结晶或无定形)、油状、液体形式和溶液。优选地，作为原料的化合物I和/或其盐为固体形式。According to the present invention, the compound I and/or its salts as raw materials include, but are not limited to, solid form (crystalline or amorphous), oily, liquid form and solution. Preferably, the compound I and/or its salts as starting materials are in solid form.
以下实施例中所使用的化合物I可根据现有技术制备得到，例如根据WO2006105081A2文献所记载的方法制备获得。Compound I used in the following examples can be prepared according to the prior art, for example, according to the method described in the document WO2006105081A2.
实施例1 现有技术的表征Example 1 Characterization of the prior art
根据WO2006105081A2记载的化合物I的制备方法，获得现有技术P1，现有技术P1的XRPD图如图1所示。According to the preparation method of compound I described in WO2006105081A2, prior art P1 is obtained, and the XRPD pattern of prior art P1 is shown in FIG. 1 .
根据CN106916145B记载的化合物I的制备方法，获得现有技术P2，现有技术P2的XRPD图如图2所示。该固体的 1H NMR数据为： 1H NMR(400MHz,DMSO-d6)δ13.09(s,1H),9.96(s,1H),8.59(d,J＝8.3Hz,1H),8.31(d,J＝1.8Hz,1H),8.15(s,1H),8.09-7.98(m,2H),7.98-7.79(m,4H),7.69-7.56(m,2H),7.41(t,J＝7.9Hz,1H),7.08(ddd,J＝8.2,2.7,1.0Hz,1H),4.51(s,2H),4.03(d,J＝7.1Hz,1.62H),1.99(s,1.02H),1.17(s,1.07H),1.11(d,J＝6.7Hz,6H)，其中1.17ppm和1.99ppm处为乙酸乙酯的核磁共振信号，在4.03ppm处，乙酸乙酯和化合物I的核磁共振信号重叠。经计算，所得固体P2中约含有0.34摩尔当量的乙酸乙酯(约62000ppm)。根据ICH指导原则，乙酸乙酯属于3类溶剂，其允许的含量上限为5000ppm，现有技术固体P2中的乙酸乙酯含量远高于ICH指导原则的上限，不适合药用。 According to the preparation method of compound I described in CN106916145B, prior art P2 is obtained, and the XRPD pattern of prior art P2 is shown in FIG. 2 . The 1 H NMR data for this solid are: 1 H NMR (400 MHz, DMSO-d6) δ 13.09 (s, 1H), 9.96 (s, 1H), 8.59 (d, J=8.3 Hz, 1H), 8.31 (d , J=1.8Hz, 1H), 8.15(s, 1H), 8.09-7.98(m, 2H), 7.98-7.79(m, 4H), 7.69-7.56(m, 2H), 7.41(t, J=7.9 Hz,1H),7.08(ddd,J=8.2,2.7,1.0Hz,1H),4.51(s,2H),4.03(d,J=7.1Hz,1.62H),1.99(s,1.02H),1.17 (s, 1.07H), 1.11 (d, J=6.7Hz, 6H), where the NMR signals of ethyl acetate at 1.17 ppm and 1.99 ppm, and the NMR signals of ethyl acetate and compound I at 4.03 ppm overlapping. The resulting solid P2 was calculated to contain about 0.34 molar equivalents of ethyl acetate (about 62,000 ppm). According to the ICH guidelines, ethyl acetate belongs to class 3 solvents, and the upper limit of its allowable content is 5000ppm. The content of ethyl acetate in the prior art solid P2 is much higher than the upper limit of the ICH guidelines, which is not suitable for medicinal use.
实施例2 晶型CSI的制备方法 Embodiment 2 The preparation method of crystal form CSI
根据表3，称取一定量的化合物I固体于小瓶中，依次加入溶剂和一定体积 的甲磺酸液体，室温搅拌约3天，分离固体，将所得固体50℃真空干燥3小时后得到结晶固体。所得结晶固体分别标记为样品1-2。经XRPD检测，样品1-2均为本发明所述晶型CSI。According to Table 3, a certain amount of solid compound I was weighed into a vial, followed by adding a solvent and a certain volume of methanesulfonic acid liquid, stirring at room temperature for about 3 days, separating the solid, and drying the obtained solid under vacuum at 50 ° C for 3 hours to obtain a crystalline solid . The resulting crystalline solids were designated as samples 1-2, respectively. Through XRPD detection, samples 1-2 are all crystal forms of CSI according to the present invention.
本实施例所得样品1的XRPD图如图3所示，XRPD数据如表4所示。The XRPD pattern of sample 1 obtained in this example is shown in FIG. 3 , and the XRPD data is shown in Table 4.
本实施例所得样品1的TGA如图4所示，加热至100℃时，具有约0.2％质量损失。The TGA of sample 1 obtained in this example is shown in FIG. 4 , and when heated to 100° C., there is a mass loss of about 0.2%.
表3table 3
样品sample 化合物I固体质量(mg)Compound I solid mass (mg) 甲磺酸体积(μL)Methanesulfonic acid volume (μL) 溶剂solvent 溶剂体积(mL)Solvent volume (mL)
11 15.315.3 2.22.2 乙醇Ethanol 0.30.3
22 15.215.2 2.12.1 丙酮acetone 0.30.3
表4Table 4
Figure PCTCN2021140731-appb-000006
Figure PCTCN2021140731-appb-000006
Figure PCTCN2021140731-appb-000007
Figure PCTCN2021140731-appb-000007
实施例3 晶型CSI的制备方法Embodiment 3 The preparation method of crystal form CSI
称取100.7mg的化合物I固体于玻璃小瓶中，依次加入2mL乙醇和14.4μL甲磺酸液体，室温下搅拌约3天，分离固体，将所得固体50℃真空干燥3小时后得到结晶固体。100.7 mg of solid compound I was weighed into a glass vial, 2 mL of ethanol and 14.4 μL of methanesulfonic acid were added in sequence, and the mixture was stirred at room temperature for about 3 days.
经检测，所得结晶固体为本发明所述晶型CSI，其X射线粉末衍射数据如图5，XRPD数据如表5所示。After testing, the obtained crystalline solid is the crystal form CSI described in the present invention, and its X-ray powder diffraction data is shown in Figure 5, and the XRPD data is shown in Table 5.
本发明晶型CSI的 1H NMR数据为： 1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),11.37(s,1H),8.74(d,J＝8.3Hz,1H),8.27–8.15(m,2H),8.08(dt,J＝16.4,8.1Hz,2H),7.93(d,J＝8.0Hz,1H),7.91–7.79(m,3H),7.79–7.68(m,2H),7.55(t,J＝8.0Hz,1H),7.26(dd,J＝8.2,2.5Hz,1H),4.54(s,2H),4.03–3.88(m,1H),2.32(s,3H),1.09(d,J＝6.6Hz,6H)。根据核磁数据可知晶型CSI中化合物I和甲磺酸的摩尔比为1:1。 The 1 H NMR data of the crystal form CSI of the present invention are: 1 H NMR (400MHz, DMSO-d6)δ13.26(s,1H),11.37(s,1H),8.74(d,J=8.3Hz,1H), 8.27–8.15 (m, 2H), 8.08 (dt, J=16.4, 8.1Hz, 2H), 7.93 (d, J=8.0Hz, 1H), 7.91–7.79 (m, 3H), 7.79–7.68 (m, 2H), 7.55(t, J=8.0Hz, 1H), 7.26(dd, J=8.2, 2.5Hz, 1H), 4.54(s, 2H), 4.03–3.88(m, 1H), 2.32(s, 3H) ), 1.09 (d, J=6.6Hz, 6H). According to the NMR data, the molar ratio of compound I and methanesulfonic acid in the crystalline form CSI is 1:1.
表5table 5
Figure PCTCN2021140731-appb-000008
Figure PCTCN2021140731-appb-000008
Figure PCTCN2021140731-appb-000009
Figure PCTCN2021140731-appb-000009
实施例4 晶型CSI的DSC数据检测Example 4 DSC data detection of crystal form CSI
取晶型CSI的样品，进行DSC测试，结果如图6所示，其在267℃附近存在一个吸热峰(起始温度约为264℃)，该吸热峰为熔化吸热峰。A sample of crystal form CSI was taken and tested by DSC. The results are shown in Figure 6. There is an endothermic peak around 267°C (the initial temperature is about 264°C), and the endothermic peak is a melting endothermic peak.
实施例5 晶型CSI和现有技术的动态溶解度Example 5 Dynamic solubility of crystal form CSI and prior art
进行药物溶解度测试以预测药物体内性能的时候，很重要的一点是尽可能的模拟体内条件。FeSSIF(模拟进食状态肠液)可以模拟体内环境，在此介质中测试的溶解度与人体环境中的溶解度更加接近。When conducting drug solubility tests to predict drug performance in vivo, it is important to simulate in vivo conditions as closely as possible. FeSSIF (Simulated Fed State Intestinal Fluid) can simulate the in vivo environment, and the solubility tested in this medium is closer to that in the human environment.
取本发明的晶型CSI及现有技术固体各约10mg分别分散在0.8mL的FeSSIF中配制成饱和溶液，在37℃平衡15分钟后过滤得到澄清饱和溶液，分别用UPLC测试饱和溶液中样品的含量(μg/mL)，结果如表6所示。About 10 mg of each of the crystalline form CSI of the present invention and the solid in the prior art were dispersed in 0.8 mL of FeSSIF to prepare a saturated solution, equilibrated at 37 ° C for 15 minutes, and filtered to obtain a clear saturated solution. UPLC was used to test the samples in the saturated solution. content (μg/mL), the results are shown in Table 6.
表6Table 6
晶型Crystal form FeSSIF中的浓度(μg/mL)Concentration in FeSSIF (μg/mL)
晶型CSIForm CSI 85.4685.46
现有技术P1Prior art P1 35.9335.93
现有技术P2Prior art P2 57.2657.26
结果表明与现有技术相比，晶型CSI具有更高的溶解度。The results show that the crystalline form of CSI has higher solubility compared with the prior art.
实施例6 晶型CSI和现有技术的研磨稳定性Example 6 Grinding stability of crystal form CSI and prior art
将本发明晶型CSI和现有技术固体分别置于研钵中，手动研磨5分钟，测试研磨前后样品的XRPD，结果如表7所示。结果表明，与现有技术相比，晶型CSI 具有更好的研磨稳定性。The crystalline form CSI of the present invention and the prior art solid were placed in a mortar and manually ground for 5 minutes, and the XRPD of the samples before and after grinding was tested. The results are shown in Table 7. The results show that the crystalline form CSI has better grinding stability compared with the prior art.
表7Table 7
研磨前before grinding 研磨后after grinding 研磨前后对比图Comparison before and after grinding
现有技术P1Prior art P1 基本转为无定形basically transformed into amorphous 图7Figure 7
晶型CSIForm CSI 晶型保持不变Crystal form remains unchanged 图8Figure 8
实施例7 晶型CSI和现有技术的引湿性Example 7 The hygroscopicity of crystal form CSI and prior art
称取现有技术固体和本发明晶型CSI各约10mg采用动态水分吸附(DVS)仪测试其引湿性。在相应湿度循环下，记录每个湿度下的质量变化。实验结果如表8所示。About 10 mg of the prior art solid and the crystalline form CSI of the present invention were weighed and tested for their hygroscopicity using a dynamic moisture adsorption (DVS) instrument. Under the corresponding humidity cycle, the mass change at each humidity was recorded. The experimental results are shown in Table 8.
表8Table 8
Figure PCTCN2021140731-appb-000010
Figure PCTCN2021140731-appb-000010
实验结果表明，晶型CSI在0-80％RH条件下引湿性增重为1.15％，现有技术P1在0-80％RH条件下引湿性增重为1.32％，晶型CSI引湿增重明显低于现有技术P1。The experimental results show that the hygroscopic weight gain of crystal form CSI is 1.15% under the condition of 0-80% RH, and the hygroscopic weight gain of the prior art P1 is 1.32% under the condition of 0-80% RH. Significantly lower than the prior art P1.
实施例8 晶型CSI的高湿稳定性Example 8 High humidity stability of crystal form CSI
测试晶型CSI在DVS测试前后的XRPD，结果如图11所示。实验结果表明，晶型CSI在经历了0％RH-95％RH-0％RH循环后，晶型保持不变。表明晶型CSI在高湿下具有良好的稳定性。The XRPD of the crystal form CSI before and after the DVS test was tested, and the results are shown in Figure 11. The experimental results show that the crystal form of CSI remains unchanged after undergoing 0%RH-95%RH-0%RH cycles. It shows that the crystalline form CSI has good stability under high humidity.
实施例9 晶型CSI的物理化学稳定性Example 9 Physical and chemical stability of crystal form CSI
取适量本发明制备得到的晶型CSI，分别在25℃/60％RH、40℃/75％RH和60℃/75％RH条件下放置一段时间，采用UPLC和XRPD测定纯度与晶型。结果如表9所示，XRPD对比图如图12所示。Take an appropriate amount of the crystal form CSI prepared by the present invention, and place it for a period of time under the conditions of 25°C/60%RH, 40°C/75%RH and 60°C/75%RH respectively, and use UPLC and XRPD to determine the purity and crystal form. The results are shown in Table 9, and the XRPD comparison chart is shown in Figure 12.
表9Table 9
Figure PCTCN2021140731-appb-000011
Figure PCTCN2021140731-appb-000011
密封包装：将样品置于玻璃小瓶中，瓶口用瓶盖旋紧，最后密封于铝箔袋中。Airtight packaging: put the sample in a glass vial, tighten the bottle cap with a cap, and seal it in an aluminum foil bag.
敞口包装：将样品置于玻璃小瓶中，瓶口盖上一层铝箔纸并在铝箔纸上开孔。Open packaging: place the sample in a glass vial, cover the bottle with a layer of aluminum foil and perforate the foil.
实验结果表明，晶型CSI在25℃/60％RH和40℃/75％RH条件下至少可稳定6个月，可见晶型CSI在长期和加速条件下均可保持良好的稳定性。晶型CSI在60℃/75％RH条件下至少可稳定1个月，可见在更严苛的条件下晶型CSI稳定性也很好。The experimental results show that the crystalline form CSI can be stable for at least 6 months under the conditions of 25℃/60%RH and 40℃/75%RH. It can be seen that the crystalline form CSI can maintain good stability under long-term and accelerated conditions. Crystalline CSI is stable for at least 1 month under the conditions of 60°C/75%RH, and it can be seen that the stability of crystallized CSI is also very good under more severe conditions.
实施例10 晶型CSII的制备方法 Embodiment 10 The preparation method of crystal form CSII
称取298.2mg的化合物I固体于小瓶中，依次加入6mL四氢呋喃/水(9:1，v/v)的混合溶剂，44μL甲磺酸液体，室温下搅拌约2天，分离固体，所得固体在25℃下真空干燥约2小时后得到结晶固体。Weigh 298.2 mg of solid compound I into a vial, add 6 mL of a mixed solvent of tetrahydrofuran/water (9:1, v/v), and 44 μL of methanesulfonic acid liquid, stir at room temperature for about 2 days, and separate the solid. A crystalline solid was obtained after vacuum drying at 25°C for about 2 hours.
经检测，所得结晶固体为本发明所述晶型CSII，其X射线粉末衍射图如图13，X射线粉末衍射数据如表10所示。After testing, the obtained crystalline solid is the crystal form CSII of the present invention, its X-ray powder diffraction pattern is shown in Figure 13, and the X-ray powder diffraction data is shown in Table 10.
晶型CSII的TGA如图14所示，加热至100℃时，具有约5.9％质量损失。The TGA of the crystalline form CSII is shown in Figure 14, and when heated to 100°C, it has a mass loss of about 5.9%.
DSC如图15所示，在100℃附近存在一个吸热峰；在206℃附近存在一个放热峰；在255℃附近存在一个吸热峰(起始温度约为253℃)。As shown in DSC in Figure 15, there is an endothermic peak around 100°C; an exothermic peak around 206°C; and an endothermic peak around 255°C (the onset temperature is about 253°C).
晶型CSII的核磁数据为： 1H NMR(400MHz,DMSO-d6)δ13.26(s,1H),11.37(s,1H),8.74(d,J＝8.3Hz,1H),8.20(d,J＝12.8Hz,2H),8.08(dt,J＝15.8,8.2Hz,2H),7.93(d,J＝8.0Hz,1H),7.90–7.80(m,3H),7.80–7.66(m,2H),7.55(t,J＝8.0Hz,1H),7.34–7.18(m,1H),4.54(s,2H),3.95(dq,J＝13.6,6.8Hz,1H),2.33(s,3H),1.09(d,J＝6.6Hz,6H)。根据核磁数据可知晶型CSII中化合物I和甲磺酸的摩尔比为1:1。 The nuclear magnetic data of the crystal form CSII are: 1 H NMR (400MHz, DMSO-d6)δ13.26(s,1H),11.37(s,1H),8.74(d,J=8.3Hz,1H),8.20(d, J=12.8Hz, 2H), 8.08 (dt, J=15.8, 8.2Hz, 2H), 7.93 (d, J=8.0Hz, 1H), 7.90–7.80 (m, 3H), 7.80–7.66 (m, 2H) ), 7.55(t, J=8.0Hz, 1H), 7.34–7.18(m, 1H), 4.54(s, 2H), 3.95(dq, J=13.6, 6.8Hz, 1H), 2.33(s, 3H) , 1.09 (d, J=6.6Hz, 6H). According to the NMR data, the molar ratio of compound I and methanesulfonic acid in the crystalline form CSII is 1:1.
表10Table 10
Figure PCTCN2021140731-appb-000012
Figure PCTCN2021140731-appb-000012
Figure PCTCN2021140731-appb-000013
Figure PCTCN2021140731-appb-000013
实施例11 晶型CSII的制备方法Embodiment 11 The preparation method of crystal form CSII
称取29.5mg的化合物I固体于小瓶中，依次加入0.6mL异丙醇/水(9:1，v/v)的混合溶剂，和4.4μL甲磺酸液体，室温下搅拌约3天，分离固体。经检测，所得固体为本发明所述晶型CSII，其X射线粉末衍射数据如表11所示。Weigh 29.5 mg of compound I solid into a vial, add 0.6 mL of isopropanol/water (9:1, v/v) mixed solvent, and 4.4 μL of methanesulfonic acid liquid, stir at room temperature for about 3 days, and separate solid. After testing, the obtained solid is the crystal form CSII of the present invention, and its X-ray powder diffraction data is shown in Table 11.
表11Table 11
Figure PCTCN2021140731-appb-000014
Figure PCTCN2021140731-appb-000014
Figure PCTCN2021140731-appb-000015
Figure PCTCN2021140731-appb-000015
实施例12 晶型CSII和现有技术的动态溶解度Example 12 Dynamic solubility of crystal form CSII and prior art
取本发明的晶型CSII及现有技术固体各约10mg分别分散在0.8mL的FeSSIF中配制成悬浊液，在37℃平衡15分钟后过滤得到澄清饱和溶液，分别用UPLC测试饱和溶液中样品的含量(μg/mL)，结果如表12所示。About 10 mg of each of the present invention's crystalline form CSII and the prior art solid were dispersed in 0.8 mL of FeSSIF to prepare a suspension, equilibrated at 37° C. for 15 minutes, and filtered to obtain a clear saturated solution. UPLC was used to test the samples in the saturated solution. The content (μg/mL), the results are shown in Table 12.
表12Table 12
晶型Crystal form FeSSIF中的浓度(μg/mL)Concentration in FeSSIF (μg/mL)
晶型CSIIForm CSII 75.0775.07
现有技术P1Prior art P1 35.9335.93
现有技术P2Prior art P2 57.2657.26
结果表明晶型CSII与现有技术相比，具有更高的溶解度。The results show that the crystalline form CSII has higher solubility compared with the prior art.
实施例13 晶型CSII和现有技术的研磨稳定性Example 13 Grinding stability of crystal form CSII and prior art
将晶型CSII和现有技术固体分别置于研钵中，手动研磨5分钟，测试研磨前后样品的XRPD，结果如表13所示。结果表明，与现有技术相比，晶型CSII具有更好的研磨稳定性。The crystalline form CSII and the prior art solid were placed in a mortar and manually ground for 5 minutes, and the XRPD of the samples before and after grinding was tested. The results are shown in Table 13. The results show that, compared with the prior art, the crystalline form CSII has better grinding stability.
表13Table 13
研磨前before grinding 研磨后after grinding 研磨前后对比图Comparison before and after grinding
现有技术P1Prior art P1 基本转为无定形basically transformed into amorphous 图7Figure 7
晶型CSIIForm CSII 晶型保持不变Crystal form remains unchanged 图16Figure 16
实施例14 晶型CSII和现有技术的引湿性Example 14 Hygroscopicity of crystal form CSII and prior art
称取现有技术固体和本发明晶型CSII各约10mg，采用动态水分吸附(DVS)仪测试其引湿性。在相应湿度循环下，记录每个湿度下的质量变化。实验结果如表14所示。About 10 mg each of the prior art solid and the crystal form CSII of the present invention were weighed, and the hygroscopicity was tested by a dynamic moisture adsorption (DVS) instrument. Under the corresponding humidity cycle, the mass change at each humidity was recorded. The experimental results are shown in Table 14.
表14Table 14
Figure PCTCN2021140731-appb-000016
Figure PCTCN2021140731-appb-000016
注：晶型CSII为水合物，DVS测试以环境湿度(40％RH)为起始湿度测试。Note: The crystal form CSII is a hydrate, and the DVS test takes the ambient humidity (40%RH) as the initial humidity test.
实验结果表明，晶型CSII在40-80％RH条件下引湿性增重为0.23％，现有技术固体在40-80％RH条件下引湿性增重为1.11％，晶型CSII引湿增重仅为现有技术固体的1/5，明显优于现有技术。The experimental results show that the hygroscopic weight gain of the crystal form CSII is 0.23% under the condition of 40-80% RH, and the hygroscopic weight gain of the prior art solid is 1.11% under the condition of 40-80% RH. It is only 1/5 of the solid state of the prior art, which is obviously better than that of the prior art.
实施例15 晶型CSII的高湿稳定性Example 15 High humidity stability of crystal form CSII
测试晶型CSII在DVS测试前后的XRPD，结果如图17所示。实验结果表 明，晶型CSII在经历了40-95-0-95％RH循环后，晶型保持不变。表明晶型CSII在高湿下具有良好的稳定性。The XRPD of the crystal form CSII before and after the DVS test was tested, and the results are shown in Figure 17. The experimental results show that the crystal form of CSII remains unchanged after undergoing a 40-95-0-95% RH cycle. It shows that the crystalline form CSII has good stability under high humidity.
实施例16 晶型CSII的物理化学稳定性Example 16 Physicochemical stability of crystal form CSII
取适量本发明晶型CSII，分别在25℃/60％RH、40℃/75％RH条件下放置一定时间，采用UPLC和XRPD测定纯度与晶型。结果如表15所示，XRPD对比图如图18所示。Take an appropriate amount of the crystal form CSII of the present invention, and place it for a certain period of time under the conditions of 25°C/60% RH and 40°C/75% RH respectively, and measure the purity and crystal form by UPLC and XRPD. The results are shown in Table 15, and the XRPD comparison chart is shown in Figure 18.
表15Table 15
Figure PCTCN2021140731-appb-000017
Figure PCTCN2021140731-appb-000017
密封包装：将样品置于玻璃小瓶中，瓶口用瓶盖旋紧，最后密封于铝箔袋中。敞口包装：将样品置于玻璃小瓶中，瓶口盖上一层铝箔纸并在铝箔纸上开孔。Sealed packaging: put the sample in a glass vial, tighten the bottle cap with a cap, and seal it in an aluminum foil bag. Open packaging: place the sample in a glass vial, cover the bottle with a layer of aluminum foil and perforate the foil.
实验结果表明，晶型CSII在25℃/60％RH和40℃/75％RH条件下至少可稳定6个月，可见晶型CSII在长期和加速条件下均具有良好的稳定性。The experimental results show that the crystalline form CSII can be stable for at least 6 months under the conditions of 25°C/60%RH and 40°C/75%RH. It can be seen that the crystalline form CSII has good stability under both long-term and accelerated conditions.
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。The above-mentioned embodiments are only intended to illustrate the technical concept and characteristics of the present invention, and the purpose thereof is to enable those who are familiar with the art to understand the content of the present invention and implement them accordingly, and cannot limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention should be included within the protection scope of the present invention.

Claims (23)

  1. 一种化合物I甲磺酸盐的晶型，A crystal form of Compound I mesylate,
    Figure PCTCN2021140731-appb-100001
    Figure PCTCN2021140731-appb-100001
  2. 根据权利要求1所述的化合物I甲磺酸盐的晶型，其特征在于，其为无水物。The crystal form of compound I mesylate according to claim 1, characterized in that it is anhydrous.
  3. 根据权利要求1所述的化合物I甲磺酸盐的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为7.1°±0.2°处具有特征峰。The crystalline form of compound I mesylate according to claim 1, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has characteristic peaks at 2θ values of 7.1°±0.2°.
  4. 根据权利要求3所述的化合物I甲磺酸盐的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为8.4°±0.2°、21.5°±0.2°、22.2°±0.2°中的至少一处具有特征峰。The crystal form of compound I mesylate according to claim 3, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has 2θ values of 8.4°±0.2°, 21.5°±0.2°, 22.2° At least one of °±0.2° has a characteristic peak.
  5. 根据权利要求3所述的化合物I甲磺酸盐的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为16.8°±0.2°、19.5°±0.2°、23.5°±0.2°中的至少一处具有特征峰。The crystal form of compound I mesylate according to claim 3, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has 2θ values of 16.8°±0.2°, 19.5°±0.2°, 23.5° At least one of °±0.2° has a characteristic peak.
  6. 根据权利要求4所述的化合物I甲磺酸盐的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为16.8°±0.2°、19.5°±0.2°、23.5°±0.2°中的至少一处具有特征峰。The crystal form of compound I mesylate according to claim 4, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has 2θ values of 16.8°±0.2°, 19.5°±0.2°, 23.5° At least one of °±0.2° has a characteristic peak.
  7. 根据权利要求3所述的化合物I甲磺酸盐的晶型，其特征在于，X射线粉末衍射图基本如图3所示。The crystal form of compound I mesylate according to claim 3, characterized in that the X-ray powder diffraction pattern is substantially as shown in Figure 3.
  8. 权利要求3所述的化合物I甲磺酸盐的晶型的制备方法，其特征在于，所述方法包括：将化合物I固体，甲磺酸与醇类溶剂或酮类溶剂混合，搅拌，得到化合物I甲磺酸盐的晶型。The preparation method of the crystal form of Compound I mesylate according to claim 3, wherein the method comprises: mixing Compound I solid, methanesulfonic acid and an alcohol solvent or a ketone solvent, stirring, to obtain the compound I crystalline form of mesylate.
  9. 根据权利要求8所述的化合物I甲磺酸盐的晶型的制备方法，其特征在于，所述醇类溶剂为乙醇，所述酮类溶剂为丙酮。The method for preparing the crystal form of compound I mesylate according to claim 8, wherein the alcohol solvent is ethanol, and the ketone solvent is acetone.
  10. 根据权利要求8所述的化合物I甲磺酸盐的晶型的制备方法，其特征在于，所述化合物I固体与甲磺酸的摩尔比为1:1。The preparation method of the crystal form of compound I mesylate according to claim 8, is characterized in that, the mol ratio of described compound I solid and methanesulfonic acid is 1:1.
  11. 根据权利要求1所述的化合物I甲磺酸盐的晶型，其特征在于，其为水合物。The crystal form of compound I mesylate according to claim 1, characterized in that it is a hydrate.
  12. 根据权利要求1所述的化合物I甲磺酸盐的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为6.3°±0.2°、12.7°±0.2°、15.9°±0.2°处具有特征峰。The crystal form of compound I mesylate according to claim 1, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has 2θ values of 6.3°±0.2°, 12.7°±0.2°, 15.9° There are characteristic peaks at °±0.2°.
  13. 根据权利要求12所述的化合物I甲磺酸盐的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为7.9°±0.2°、19.2°±0.2°、19.9°±0.2°中的至少一处具有特征峰。The crystal form of compound I mesylate according to claim 12, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has 2θ values of 7.9°±0.2°, 19.2°±0.2°, 19.9° At least one of °±0.2° has a characteristic peak.
  14. 根据权利要求12所述的化合物I甲磺酸盐的晶型，其特征在于，使用Cu-Kα辐 射，其X射线粉末衍射图在2θ值为14.5°±0.2°、20.4°±0.2°中的至少一处具有特征峰。The crystalline form of Compound I mesylate according to claim 12, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has a 2θ value of 14.5°±0.2° and 20.4°±0.2°. At least one place has a characteristic peak.
  15. 根据权利要求13所述的化合物I甲磺酸盐的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图在2θ值为14.5°±0.2°、20.4°±0.2°中的至少一处具有特征峰。The crystalline form of compound I mesylate according to claim 13, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has a 2θ value of 14.5°±0.2° and 20.4°±0.2°. At least one place has a characteristic peak.
  16. 根据权利要求12所述的化合物I甲磺酸盐的晶型，其特征在于，X射线粉末衍射图基本如图13所示。The crystal form of Compound I mesylate according to claim 12, characterized in that the X-ray powder diffraction pattern is substantially as shown in Figure 13.
  17. 权利要求12所述的化合物I甲磺酸盐的晶型的制备方法，其特征在于，所述方法包括：将化合物I固体，甲磺酸，醇类和水的混合溶剂或者醚类和水的混合溶剂混合，搅拌，得到化合物I甲磺酸盐的晶型。The method for preparing the crystal form of Compound I mesylate according to claim 12, wherein the method comprises: mixing Compound I solid, methanesulfonic acid, a mixed solvent of alcohols and water or a mixture of ethers and water The mixed solvents are mixed and stirred to obtain the crystal form of compound I mesylate.
  18. 根据权利要求17所述的化合物I甲磺酸盐的晶型的制备方法，其特征在于，醇类溶剂为异丙醇；所述醚类溶剂为四氢呋喃。The method for preparing the crystal form of compound I mesylate according to claim 17, wherein the alcohol solvent is isopropanol; the ether solvent is tetrahydrofuran.
  19. 根据权利要求17所述的化合物I甲磺酸盐的晶型的制备方法，其特征在于，所述化合物I固体与甲磺酸的摩尔比为0.9:1-1.1:1。The method for preparing the crystal form of compound I mesylate according to claim 17, wherein the molar ratio of the compound I solid to methanesulfonic acid is 0.9:1-1.1:1.
  20. 根据权利要求17所述的化合物I甲磺酸盐的晶型的制备方法，其特征在于，所述混合溶剂中醇类和水或者醚类和水的体积比为9:1。The method for preparing the crystal form of compound I mesylate according to claim 17, wherein the volume ratio of alcohols and water or ethers and water in the mixed solvent is 9:1.
  21. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1所述的化合物I甲磺酸盐的晶型及药学上可接受的辅料。A pharmaceutical composition comprising an effective therapeutic amount of the crystal form of the compound I mesylate salt of claim 1 and a pharmaceutically acceptable adjuvant.
  22. 权利要求1中所述的化合物I甲磺酸盐的晶型在制备ROCK2抑制剂药物中的用途。Use of the crystal form of compound I mesylate described in claim 1 in the preparation of a ROCK2 inhibitor medicine.
  23. 权利要求1中所述的化合物I甲磺酸盐的晶型在制备治疗慢性移植物抗宿主病、系统性硬化症和特发性肺纤维化药物中的用途。Use of the crystal form of compound I mesylate described in claim 1 in the preparation of a medicament for the treatment of chronic graft-versus-host disease, systemic sclerosis and idiopathic pulmonary fibrosis.
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