WO2022257845A1 - Tolebrutinib的晶型及其制备方法和用途 - Google Patents

Tolebrutinib的晶型及其制备方法和用途 Download PDF

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WO2022257845A1
WO2022257845A1 PCT/CN2022/096779 CN2022096779W WO2022257845A1 WO 2022257845 A1 WO2022257845 A1 WO 2022257845A1 CN 2022096779 W CN2022096779 W CN 2022096779W WO 2022257845 A1 WO2022257845 A1 WO 2022257845A1
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crystal form
compound
crystal
ray powder
powder diffraction
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PCT/CN2022/096779
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English (en)
French (fr)
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陈敏华
史佳明
张婧
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苏州科睿思制药有限公司
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Priority to KR1020247000650A priority Critical patent/KR20240021217A/ko
Priority to AU2022290946A priority patent/AU2022290946A1/en
Priority to CA3221129A priority patent/CA3221129A1/en
Priority to BR112023025841A priority patent/BR112023025841A2/pt
Priority to CN202280040545.8A priority patent/CN117897381A/zh
Priority to IL309263A priority patent/IL309263A/en
Priority to EP22819443.7A priority patent/EP4353723A1/en
Publication of WO2022257845A1 publication Critical patent/WO2022257845A1/zh
Priority to CONC2024/0000054A priority patent/CO2024000054A2/es

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • 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
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to the field of crystal chemistry. Specifically, it relates to the crystal form of Tolebrutinib, its preparation method and use.
  • MS Multiple Sclerosis
  • CNS central nervous system
  • BTK Bruton's tyrosine kinase pathway
  • B lymphocytes and myeloid cells including central nervous system microglia.
  • Each of these cell types has been implicated in the pathophysiology of MS.
  • BTK signaling is critical for the maturation of B cells into antibody-secreting plasma cells, inhibition of BTK can modulate cellular and humoral immunity.
  • BTK signaling inhibitors exhibit dual effects on cellular and humoral immunity.
  • BTK inhibitory compounds that inhibit antigen-induced B cell activation responsible for neuroinflammation and regulate maladaptive microglia associated with neuroinflammation in the brain and spinal cord may be useful in the treatment of relapsing multiple sclerosis (relapsing multiple sclerosis (RMS), with better outcomes than currently available treatments.
  • RMS relapsing multiple sclerosis
  • Tolebrutinib an oral, selective BTK inhibitor, has shown safety and efficacy in the treatment of RMS patients.
  • Tolebrutinib (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-3-(4-phenoxyphenyl)-1H-imidazo[4,5-c] Pyridin-2(3H)-one (hereinafter referred to as "compound I”), its structural formula is as follows:
  • a crystal is a solid in which compound molecules are arranged three-dimensionally in a microstructure to form a lattice.
  • Polymorphism refers to the phenomenon that a compound exists in multiple crystal forms. Compounds may exist in one or more crystalline forms, but their existence and properties cannot be specifically predicted. APIs with different crystal forms have different physical and chemical properties, which may lead to different dissolution and absorption of drugs in the body, which in turn affects the clinical efficacy of drugs to a certain extent. Especially for some poorly soluble oral solid or semi-solid preparations, the crystal form is crucial to product performance. In addition, the physical and chemical properties of the crystal form are crucial to the production process. Therefore, polymorphism is an important content in drug research and drug quality control.
  • WO2016196840A1 discloses a white solid of compound I, and the inventors of the present application repeated the preparation process to obtain an amorphous form of compound I. Furthermore, the inventors of the present application have found through research on the amorphous form that the amorphous form of Compound I has problems such as poor stability, high hygroscopicity, and easy degradation, and is not suitable for pharmaceutical use.
  • the crystal form of Compound I provided by the present invention has excellent solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, dissolution in vivo and in vitro, and biological effectiveness.
  • the advantages, especially good stability, low hygroscopicity, and not easy to degrade, solve the problems existing in the prior art, and have very important significance for the development of drugs containing compound I.
  • the main purpose of the present invention is to provide a new crystal form of compound I, its preparation method and use, and a pharmaceutical composition comprising the new crystal form.
  • the present invention provides the crystal form CSII of Compound I (hereinafter referred to as "crystal form CSII").
  • the X-ray powder diffraction pattern of the crystal form CSII has characteristic peaks at diffraction angle 2 ⁇ values of 4.1° ⁇ 0.2°, 10.2° ⁇ 0.2°, and 22.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSII has a diffraction angle 2 ⁇ value of 11.3° ⁇ 0.2°, 16.5° ⁇ 0.2°, 17.8° ⁇ 0.2°, or 2 There are characteristic peaks at or 3; preferably, the X-ray powder diffraction pattern of the crystal form CSII has characteristic peaks at diffraction angles 2 ⁇ of 11.3° ⁇ 0.2°, 16.5° ⁇ 0.2°, and 17.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSII has a diffraction angle 2 ⁇ value of 8.2° ⁇ 0.2°, 10.8° ⁇ 0.2°, 24.7° ⁇ 0.2°, or 2 There are characteristic peaks at or 3; preferably, the X-ray powder diffraction pattern of the crystal form CSII has characteristic peaks at diffraction angles 2 ⁇ of 8.2° ⁇ 0.2°, 10.8° ⁇ 0.2°, and 24.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSII has diffraction angle 2 ⁇ values of 4.1° ⁇ 0.2°, 10.2° ⁇ 0.2°, 22.6° ⁇ 0.2°, 11.3° ⁇ 0.2° , 16.5° ⁇ 0.2°, 17.8° ⁇ 0.2°, 8.2° ⁇ 0.2°, 10.8° ⁇ 0.2°, 24.7° ⁇ 0.2°, 20.5° ⁇ 0.2° any one, or two, or three, Or 4, or 5, or 6, or 7, or 8, or 9, or 10 have characteristic peaks.
  • Form CSII is substantially as shown in FIG. 1 using Cu-K ⁇ radiation.
  • thermogravimetric analysis profile of crystalline form CSII is substantially as shown in Figure 2, which has a mass loss of about 0.1% when heated from 26°C to 100°C.
  • differential scanning calorimetry diagram of crystal form CSII is basically shown in FIG. 3 , and an endothermic peak begins to appear around 131° C., which is a melting endothermic peak.
  • Form CSII is an anhydrate.
  • the present invention also provides a preparation method of the crystalline form CSII, the preparation method comprising:
  • the alcohol solvent is preferably C1-C4 alcohols, more preferably ethanol; the certain temperature is preferably 0-50°C, more preferably 50°C; the stirring period is preferably 1 day or more; the high temperature vacuum The preferred drying temperature is 50-75°C; the drying period is 3 hours or more.
  • the present invention provides the crystal form CSIII of Compound I (hereinafter referred to as "crystal form CSIII").
  • the X-ray powder diffraction pattern of the crystal form CSIII has characteristic peaks at diffraction angle 2 ⁇ values of 4.2° ⁇ 0.2°, 11.1° ⁇ 0.2°, and 21.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSIII has a diffraction angle 2 ⁇ value of 20.6° ⁇ 0.2°, 21.0° ⁇ 0.2°, 22.2° ⁇ 0.2° at 1, or 2 There are characteristic peaks at or 3; preferably, the X-ray powder diffraction pattern of the crystal form CSIII has characteristic peaks at diffraction angles 2 ⁇ of 20.6° ⁇ 0.2°, 21.0° ⁇ 0.2°, and 22.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSIII has a diffraction angle 2 ⁇ value of 10.4° ⁇ 0.2°, 17.7° ⁇ 0.2°, 23.1° ⁇ 0.2°, or 2 There are characteristic peaks at or 3; preferably, the X-ray powder diffraction pattern of the crystal form CSIII has characteristic peaks at diffraction angles 2 ⁇ of 10.4° ⁇ 0.2°, 17.7° ⁇ 0.2°, and 23.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSIII has diffraction angle 2 ⁇ values of 4.2° ⁇ 0.2°, 11.1° ⁇ 0.2°, 21.7° ⁇ 0.2°, 20.6° ⁇ 0.2° , 21.0° ⁇ 0.2°, 22.2° ⁇ 0.2°, 10.4° ⁇ 0.2°, 17.7° ⁇ 0.2°, 23.1° ⁇ 0.2°, 8.4° ⁇ 0.2°, 13.3° ⁇ 0.2°, 16.3° ⁇ 0.2°, 24.2 Any one of ° ⁇ 0.2°, 25.4° ⁇ 0.2°, or 2 places, or 3 places, or 4 places, or 5 places, or 6 places, or 7 places, or 8 places, or 9 places, or 10 places or 11, or 12, or 13, or 14 have characteristic peaks.
  • the X-ray powder diffraction pattern of Form CSIII is substantially as shown in FIG. 6 .
  • thermogravimetric analysis diagram of the crystal form CSIII is basically as shown in Figure 7, and it has a mass loss of about 0.5% when it is heated from 26°C to 100°C.
  • the differential scanning calorimetry diagram of the crystal form CSIII is basically shown in FIG. 8 , and an endothermic peak begins to appear around 133° C., which is the melting endothermic peak of the crystal form CSIII.
  • Form CSIII is an anhydrate.
  • the present invention also provides a preparation method of the crystalline form CSIII, the preparation method comprising:
  • the stirring temperature is preferably 0-50°C, more preferably 5°C.
  • the present invention provides the crystal form CSIV of Compound I (hereinafter referred to as "crystal form CSIV").
  • the X-ray powder diffraction pattern of the crystal form CSIV has characteristic peaks at diffraction angle 2 ⁇ values of 8.5° ⁇ 0.2°, 18.6° ⁇ 0.2°, and 22.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSIV has a diffraction angle 2 ⁇ value of 12.9° ⁇ 0.2°, 19.1° ⁇ 0.2°, 23.3° ⁇ 0.2°, or 2 There are characteristic peaks at or 3; preferably, the X-ray powder diffraction pattern of the crystal form CSIV has characteristic peaks at diffraction angles 2 ⁇ of 12.9° ⁇ 0.2°, 19.1° ⁇ 0.2°, and 23.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSIV has a diffraction angle 2 ⁇ value of 13.2° ⁇ 0.2°, 13.8° ⁇ 0.2°, 21.1° ⁇ 0.2°, or 2 There are characteristic peaks at or 3; preferably, the X-ray powder diffraction pattern of the crystal form CSIV has characteristic peaks at diffraction angles 2 ⁇ of 13.2° ⁇ 0.2°, 13.8° ⁇ 0.2°, and 21.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form CSIV has diffraction angle 2 ⁇ values of 8.5° ⁇ 0.2°, 18.6° ⁇ 0.2°, 22.0° ⁇ 0.2°, 12.9° ⁇ 0.2° , 19.1° ⁇ 0.2°, 23.3° ⁇ 0.2°, 13.2° ⁇ 0.2°, 13.8° ⁇ 0.2°, 21.1° ⁇ 0.2°, 7.7° ⁇ 0.2°, 17.2° ⁇ 0.2°, 26.7° ⁇ 0.2° Any 1, or 2, or 3, or 4, or 5, or 6, or 7, or 8, or 9, or 10, or 11, or 12 have characteristic peaks .
  • the X-ray powder diffraction pattern of Form CSIV is substantially as shown in FIG. 11 .
  • the differential scanning calorimetry diagram of crystal form CSIV is basically shown in FIG. 13 , and an endothermic peak begins to appear around 144° C., which is the melting endothermic peak of crystal form CSIV.
  • thermogravimetric analysis profile of crystalline form CSIV is substantially as shown in Figure 14, which has a mass loss of about 0.2% when heated from 29°C to 120°C.
  • crystalline form CSIV is an anhydrate.
  • the present invention also provides a preparation method of the crystalline form CSIV, the preparation method comprising:
  • the ether solvent is preferably C5 ethers, more preferably methyl tert-butyl ether;
  • the aromatic hydrocarbon solvent is preferably C9 aromatic hydrocarbons, more preferably cumene;
  • the stirring temperature is preferably -20°C .
  • the present invention provides crystal form CSII, or crystal form CSIII, or crystal form CSIV, or any mixture of any two crystal forms, or any mixture of three crystal forms for the preparation of other crystal forms of compound I or Use of salt.
  • the present invention also provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystalline form CSII, or crystalline form CSIII, or crystalline form CSIV or any mixture of the three crystalline forms and pharmaceutically Acceptable excipients.
  • crystalline form CSII or crystalline form CSIII, or crystalline form CSIV, or any mixture of any two crystal forms, or any mixture of any three crystal forms provided by the present invention in the preparation of BTK inhibitor drugs.
  • crystalline form CSII, or crystalline form CSIII, or crystalline form CSIV provided by the present invention, or any mixture of any two crystal forms, or any mixture of any three crystal forms in the preparation of a drug for treating multiple sclerosis use.
  • the crystalline form CSII API provided by the present invention has better stability.
  • the purity of the prior art solids is significantly reduced when placed under 25°C/60%RH, 40°C/75%RH, 60°C/75%RH, 80°C and light conditions, especially at 40°C/75%RH 6 After 1 month, the purity decreased by 3.46%, and the number of impurities exceeding the defined limit increased to 4; the purity decreased by more than 6.3%, and the number of impurities exceeding the defined limit increased to 4 after being stored at 60°C/75%RH for only 1 month. Far below the medicinal standard.
  • the crystal form CSII bulk drug provided by the present invention is placed under the condition of 25°C/60%RH, and the crystal form does not change for at least 6 months, and the chemical purity is above 99.8%, and the purity remains basically unchanged during storage. It shows that the crystal form CSII bulk drug has good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystalline form of the CSII bulk drug has not changed after being placed at 40°C/75%RH for at least 6 months, and the crystal form has not changed at least 1 month at 60°C/75%RH, and the chemical purity Above 99.8%, the purity remains basically unchanged during storage, and the purity does not change when placed at 80°C for at least 2 days.
  • the total illuminance of the light source is not lower than 1.2 ⁇ 10 6 lux ⁇ hr, and the energy of the near-ultraviolet lamp is not lower than 200W.
  • the purity has not changed for at least 1 week under the condition of hr/m 2 energy. It shows that the crystal form CSII API has better stability under accelerated conditions, high temperature conditions and light conditions.
  • the crystal form CSII API has better stability under accelerated conditions, high temperature conditions and light conditions, which is beneficial to avoid the impact on the quality of the drug due to crystal transformation or decrease in purity during drug storage.
  • the impurity content of the crystal form CSII bulk drug did not exceed the defined limit during the stability investigation process, which can meet the requirements of pharmaceutical development.
  • the good physical and chemical stability of the crystal form of the API can ensure that the drug will not undergo crystal transformation and basically no impurities will occur during the production and storage process.
  • the crystal form CSII has good physical and chemical stability, which ensures consistent and controllable quality of raw materials and preparations, and reduces drug quality changes, bioavailability changes, and toxic and side effects caused by crystal form changes or impurities.
  • the crystal form CSII has good physical stability under the action of mechanical force.
  • the crystalline form of the crystalline form CSII API remains unchanged after grinding. It is often necessary to grind or pulverize the API during the processing of the preparation. Good physical stability can reduce the risk of crystallinity reduction and crystal transformation of the API during the processing of the preparation.
  • the crystalline form CSII provided by the present invention has lower hygroscopicity.
  • the test results show that the wet weight gain of the crystal form CSII of the present invention is only 1/6 of that of the solid in the prior art.
  • the hygroscopic weight gain of the crystal form CSII is 0.60% under the condition of 80% RH, which is slightly hygroscopic.
  • the weight gain of the solid under the condition of 80% RH is 3.69%, which belongs to the hygroscopic property.
  • high hygroscopicity can easily cause chemical degradation and crystal transformation of the API, which directly affects the physical and chemical stability of the API.
  • high hygroscopicity will reduce the fluidity of APIs, thereby affecting the processing technology of APIs.
  • 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, high hygroscopicity is likely to cause changes in the content of active ingredients in the drug and affect the quality of the drug.
  • the crystal form CSII provided by the invention has low hygroscopicity, low requirements on storage conditions for industrial production, reduces material production, storage and quality control costs, and has strong economic value.
  • the bulk drug of crystal form CSIII provided by the present invention has better stability.
  • the purity of the prior art solids is significantly reduced when placed under 25°C/60%RH, 40°C/75%RH, 60°C/75%RH, 80°C and light conditions, especially at 40°C/75%RH 6 After 1 month, the purity decreased by 3.46%, and the number of impurities exceeding the defined limit increased to 4; the purity decreased by more than 6.3%, and the number of impurities exceeding the defined limit increased to 4 after being stored at 60°C/75%RH for only 1 month. Far below the medicinal standard.
  • the bulk drug of crystal form CSIII provided by the present invention is placed under the condition of 25°C/60%RH, and the crystal form does not change for at least 6 months, and the chemical purity is above 99.9%, and the purity remains basically unchanged during storage. It shows that the crystal form CSIII bulk drug has good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystalline form of the CSIII bulk drug has not changed after being 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 Above 99.8%, the purity remains basically unchanged during storage, and the purity does not change when placed at 80°C for at least 2 days.
  • the total illuminance of the light source is not lower than 1.2 ⁇ 10 6 lux ⁇ hr, and the energy of the near-ultraviolet lamp is not lower than 200W. ⁇ The purity remains unchanged for at least 1 week under the condition of hr/m 2 energy. It shows that the crystal form CSIII API has better stability under accelerated conditions, high temperature conditions and light conditions.
  • the crystal form CSIII API has better stability under accelerated conditions, high temperature conditions and light conditions, which is beneficial to avoid the influence of drug quality due to crystal transformation or purity drop during drug storage.
  • the impurity content of the crystal form CSIII bulk drug did not exceed the defined limit during the stability investigation process, which can meet the requirements of pharmaceutical development.
  • the good physical and chemical stability of the crystal form of the API can ensure that the drug will not undergo crystal transformation and basically no impurities will occur during the production and storage process.
  • the crystal form CSIII has good physical and chemical stability, which ensures consistent and controllable quality of raw materials and preparations, and reduces drug quality changes, bioavailability changes, and toxic and side effects caused by crystal form changes or impurities.
  • the crystal form CSIII after the crystal form CSIII is mixed with excipients to make pharmaceutical preparations, the crystal form does not change, which indicates that the crystal form CSIII preparations are stable during the preparation process and are beneficial to the production of drugs.
  • the crystal form CSIII has good physical stability under the action of mechanical force.
  • the crystal form of the bulk drug of crystal form CSIII remains unchanged after grinding. It is often necessary to grind or pulverize the API during the processing of the preparation. Good physical stability can reduce the risk of crystallinity reduction and crystal transformation of the API during the processing of the preparation.
  • the crystal form CSIII provided by the present invention has lower hygroscopicity.
  • the test results show that the wet weight gain of the crystal form CSIII of the present invention is only 1/6 of that of the solid in the prior art.
  • the hygroscopic weight gain of the crystal form CSIII is 0.66% under the condition of 80% RH, which is slightly hygroscopic.
  • the weight gain of the solid under the condition of 80% RH is 3.69%, which belongs to the hygroscopic property.
  • high hygroscopicity can easily cause chemical degradation and crystal transformation of the API, which directly affects the physical and chemical stability of the API.
  • high hygroscopicity will reduce the fluidity of APIs, thereby affecting the processing technology of APIs.
  • 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, high hygroscopicity is likely to cause changes in the content of active ingredients in the drug and affect the quality of the drug.
  • the crystal form CSIII provided by the invention has low hygroscopicity, low requirements on storage conditions for industrial production, reduces material production, storage and quality control costs, and has strong economic value.
  • the crystalline CSIV bulk drug provided by the present invention has better stability.
  • the purity of the solid in the prior art is significantly reduced by 2.18% when the solid is placed under the condition of 40° C./75% RH for 2 months.
  • the crystal form CSIV bulk drug provided by the present invention is placed under the condition of 25°C/60%RH, and the crystal form does not change for at least 2 months, and the chemical purity is above 99.7%, and the purity remains basically unchanged during storage. It shows that the crystal form CSIV API has good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystalline form of CSIV APIs has not changed after being placed at 40°C/75%RH for at least 2 months, indicating that the crystalline CSIV APIs have better stability under accelerated conditions.
  • the high temperature and high humidity conditions brought about by seasonal differences, climate differences in different regions and environmental factors will affect the storage, transportation and production of raw materials. Therefore, the stability of raw materials under accelerated conditions is very important for drugs.
  • Crystalline CSIV APIs have better stability under accelerated conditions, which is beneficial to avoid the impact on drug quality due to crystal transformation or purity decline during drug storage.
  • the good physical and chemical stability of the crystal form of the API can ensure that the drug will not undergo crystal transformation and basically no impurities will occur during the production and storage process.
  • the crystal form CSIV has good physical and chemical stability, which ensures consistent and controllable quality of raw materials and preparations, and reduces drug quality changes, bioavailability changes, and toxic and side effects caused by crystal form changes or impurities.
  • the crystal form CSIV after the crystal form CSIV is mixed with excipients to make a pharmaceutical preparation, the crystal form does not change, indicating that the preparation process of the crystal form CSIV preparation is stable, which is beneficial to the production of drugs.
  • the crystalline form CSIV has good physical stability under the action of mechanical force.
  • the crystalline form of CSIV bulk drug remains unchanged after grinding. It is often necessary to grind or pulverize the API during the processing of the preparation. Good physical stability can reduce the risk of crystallinity reduction and crystal transformation of the API during the processing of the preparation.
  • the crystal form CSIV provided by the present invention has lower hygroscopicity.
  • the test results show that the wet weight gain of the crystal form CSIV of the present invention is only 1/15 of that of the solid in the prior art.
  • the hygroscopic weight gain of crystal form CSIV is 0.24% under the condition of 80% RH, which belongs to slight hygroscopicity.
  • the hygroscopic weight gain of the solid in the prior art is 3.69% under the condition of 80% RH, which belongs to hygroscopicity.
  • high hygroscopicity can easily cause chemical degradation and crystal transformation of the API, which directly affects the physical and chemical stability of the API.
  • high hygroscopicity will reduce the fluidity of APIs, thereby affecting the processing technology of APIs.
  • 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, high hygroscopicity is likely to cause changes in the content of active ingredients in the drug and affect the quality of the drug.
  • the crystal form CSIV provided by the invention has low hygroscopicity, has low requirements on storage conditions for industrial production, reduces material production, storage and quality control costs, and has strong economic value.
  • Figure 1 is the XRPD pattern of crystal form CSII
  • Figure 2 is the TGA diagram of crystal form CSII
  • Figure 3 is the DSC diagram of crystal form CSII
  • Figure 4 is the XRPD overlay of crystal form CSII stability before and after placement (from top to bottom: before placement, placed in the open at 25°C/60%RH for 6 months, and placed in the open at 40°C/75%RH for 6 months months, stored at 60°C/75%RH for 1 month)
  • Figure 5 is the XRPD overlay of crystal form CSII before and after DVS testing (from top to bottom: before testing, after testing)
  • Figure 6 is the XRPD pattern of crystal form CSIII
  • Figure 7 is the TGA diagram of crystal form CSIII
  • Figure 8 is the DSC diagram of crystal form CSIII
  • Figure 9 is the XRPD overlay of crystal form CSIII stability before and after placement (from top to bottom: before placement, placed in the open at 25°C/60%RH for 6 months, and placed in the open at 40°C/75%RH for 6 months months, stored at 60°C/75%RH for 1 month)
  • Figure 10 is the XRPD overlay of crystalline form CSIII before and after DVS testing (from top to bottom: before testing, after testing)
  • Figure 11 is the XRPD pattern of crystal form CSIV
  • Figure 12 is the XRPD pattern of crystal form CSIV
  • Figure 13 is the DSC diagram of crystal form CSIV
  • Figure 14 is the TGA diagram of crystal form CSIV
  • Figure 15 is the XRPD overlay of crystal form CSIV stability before and after placement (from top to bottom: before placement, placed in the open at 25°C/60%RH for 2 months, and placed in the open at 40°C/75%RH for 2 months months)
  • Figure 16 is the XRPD overlay of crystal form CSIV before and after DVS testing (from top to bottom: before testing, after testing)
  • the X-ray powder diffraction pattern of the present invention is collected on Bruker X-ray powder diffractometer.
  • the method parameter of X-ray powder diffraction of the present invention is as follows:
  • thermogravimetric analysis (TGA) of the present invention is collected on TA Q500.
  • the method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:
  • the DSC figure of the present invention is collected on TA Q2000.
  • the method parameter of differential scanning calorimetry (DSC) of the present invention is as follows:
  • the DVS figure 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 parameter of described dynamic water adsorption instrument is as follows:
  • Relative humidity range 0%RH-95%RH
  • the "stirring” is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm, and mechanical stirring Preferably 100-300 rpm.
  • the “separation” is accomplished by conventional methods in the art, such as centrifugation or filtration.
  • the operation of "centrifugation” is: put the sample to be separated in a centrifuge tube, and centrifuge at a rate of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube, then discard the supernatant and take the solid.
  • the "drying” is accomplished by conventional methods in the art, such as vacuum drying, blast drying or natural 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 is carried out in a fume hood, forced air oven or vacuum oven.
  • room temperature is not a specific temperature value, but refers to a temperature range of 10-30°C.
  • the "opening" means placing the sample in a glass bottle, covering the mouth of the bottle with a layer of aluminum foil and opening 5-10 small holes in the aluminum foil.
  • 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 patterns are subject to variation by the condition of the instrument, sample preparation, and sample purity.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction diagram may also change with the change of the experimental conditions, so the intensity of the diffraction peaks cannot be used as the only or decisive factor for determining the crystal form.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal, and the intensity of the diffraction peaks shown in the present invention is illustrative rather than for absolute comparison. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of the protected crystal form of the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the examples referred to here, and any characteristic peaks with 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 the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of figures reflect the same or different crystal forms.
  • the crystalline form CSII, crystalline form III, and crystalline form IV of the present invention are pure and substantially free from any other crystalline forms.
  • substantially free when used to refer to a new crystal form means that this crystal form contains less than 20% (weight) of other crystal forms, especially refers to less than 10% (weight) of other crystal forms, and even less More than 5% (weight) of other crystal forms, more refers to less than 1% (weight) of other crystal forms.
  • said compound I as starting material includes but not limited to solid form (crystalline or amorphous), oily form, liquid form and solution.
  • compound I as starting material is in solid form.
  • Embodiment 1 the preparation method of crystal form CSII
  • the TGA graph is shown in Fig. 2, which has a mass loss of about 0.1% when it is heated from 26°C to 100°C.
  • the DSC chart is shown in Figure 3, where an endothermic peak begins to appear around 131 °C, which is the melting endothermic peak of crystal form CSII.
  • Embodiment 2 NMR characterization of crystal form CSII
  • the crystal form CSII can be stable for at least 6 months under the conditions of 25°C/60%RH and 40°C/75%RH, and the crystal form and purity remain basically unchanged. It can be seen that the crystal form CSII is stable under long-term and accelerated conditions. Can maintain good stability. It can be kept stable for at least 1 month under the condition of 60°C/75%RH, and the crystal form and purity remain basically unchanged, which shows that the stability is also very good under more stringent conditions. During the entire stability investigation process of crystal form CSII, the impurity content did not exceed the defined limit, which can meet the requirements of pharmaceutical development.
  • the purity of the prior art amorphous is significantly reduced when placed at 25°C/60%RH, 40°C/75%RH, and 60°C/75%RH, especially at 40°C/75%RH for 6 months. Reduced by 3.46%, the number of impurities exceeding the defined limit increased to 4; the purity was reduced by more than 6.3% after being stored at 60°C/75%RH for only one month, and the number of impurities exceeding the defined limit increased to 4, which is far lower than in pharmaceutical standards. It can be seen that the crystal form CSII of the present invention has very superior chemical stability compared with the amorphous form of the prior art.
  • Embodiment 4 the high temperature stability of crystal form CSII
  • Embodiment 5 the light stability of crystal form CSII
  • Embodiment 6 the hygroscopicity of crystal form CSII
  • the experimental results show that the hygroscopic weight gain of crystal form CSII is 0.60% under the condition of 80% RH, which belongs to slight hygroscopicity, and the hygroscopic weight gain of the solid in the prior art is 3.69% under the condition of 80% RH, which belongs to hygroscopicity.
  • the hygroscopic property of crystal form CSII is better than that of the prior art.
  • the crystalline form of CSII remains unchanged after DVS testing, indicating that the crystalline form II has good stability.
  • the weight gain of moisture is not less than 15.0%
  • Moisture-absorbing the weight gain of moisture-absorbing is less than 15.0% but not less than 2.0%
  • the crystalline form CSII was placed in a mortar, manually ground for 5 minutes, and XRPD was tested before and after grinding. The test results showed that the crystalline form of the crystalline form CSII remained unchanged after grinding, indicating that the crystalline form CSII had good grinding stability.
  • Embodiment 9 the preparation method of crystal form CSIII
  • the TGA graph is shown in Fig. 7, which has about 0.5% mass loss when it is heated from 26°C to 100°C.
  • the DSC chart is shown in Figure 8, where an endothermic peak begins to appear around 133°C, which is the melting endothermic peak of crystal form CSIII.
  • the crystal form CSIII can be stable for at least 6 months under the conditions of 25°C/60%RH and 40°C/75%RH, and the crystal form and purity remain basically unchanged. It can be seen that the crystal form CSIII is stable under long-term and accelerated conditions. Can maintain good stability. It can be kept stable for at least 1 month under the condition of 60°C/75%RH, and the crystal form and purity remain basically unchanged, which shows that the stability is also very good under more stringent conditions. During the entire stability investigation process of crystal form CSIII, the impurity content did not exceed the defined limit, which can meet the requirements of pharmaceutical development.
  • the purity of the prior art solids is significantly reduced when placed at 25°C/60%RH, 40°C/75%RH, and 60°C/75%RH, especially at 40°C/75%RH for 6 months. 3.46%, the number of impurities exceeding the defined limit increased to 4; the purity was reduced by more than 6.3% after being placed at 60°C/75%RH for only 1 month, and the number of impurities exceeding the defined limit increased to 4, which is far lower than Pharmaceutical standards. It can be seen that the crystal form CSIII of the present invention has very superior chemical stability compared with the amorphous form of the prior art.
  • Embodiment 13 Light stability of crystal form CSIII
  • the experimental results show that the hygroscopic weight gain of crystal form CSIII is 0.66% under the condition of 80% RH, which belongs to slight hygroscopicity, and the hygroscopic weight gain of the prior art solid is 3.69% under the condition of 80% RH, which belongs to hygroscopicity.
  • the hygroscopicity of the crystal form CSIII is better than that of the prior art.
  • the crystal form of the crystal form CSIII remained unchanged after the DVS test, indicating that the crystal form III has good stability.
  • the crystalline form CSIII was placed in a mortar, manually ground for 5 minutes, and XRPD was tested before and after grinding. The test results showed that the crystalline form of the crystalline form CSIII remained unchanged after grinding, indicating that the crystalline form CSIII had good grinding stability.
  • the DSC chart is shown in Figure 13, and an endothermic peak begins to appear around 144°C, which is the melting endothermic peak of crystal form CSIV.
  • Embodiment 19 TGA test of crystal form CSIV
  • the crystalline form CSIV prepared by the present invention and the amorphous form of the prior art were weighed, packaged openly, and placed under the conditions of 25°C/60%RH and 40°C/75%RH respectively, and the purity and crystal form were determined by UPLC and XRPD. The results are shown in Table 16, and the XRPD overlays of crystal form CSIV stability before and after placement are shown in Figure 15.
  • the crystal form CSIV can be stable for at least 2 months under the conditions of 25°C/60%RH and 40°C/75%RH, and the crystal form and purity remain basically unchanged. It can be seen that the crystal form CSIV is stable under long-term and accelerated conditions. Can maintain good stability. The purity of the solid in the prior art is significantly reduced by 2.18% when placed under the condition of 40°C/75%RH. It can be seen that the crystal form CSIV of the present invention has very superior chemical stability compared with the amorphous form of the prior art.
  • Example 21 High temperature stability of crystal form CSIV
  • Example 22 Light stability of crystal form CSIV
  • the experimental results show that the hygroscopic weight gain of crystal form CSIV is 0.24% under the condition of 80% RH, which is slightly hygroscopic; the hygroscopic weight gain of the amorphous form in the prior art is 3.69% under the condition of 80% RH, which belongs to hygroscopic .
  • the hygroscopicity of the crystal form CSIV is better than that of the prior art.
  • the crystalline form of CSIV remains unchanged after DVS testing, indicating that the crystalline form IV has good stability.
  • the crystalline form CSIV was placed in a mortar and manually ground for 5 minutes. XRPD was tested before and after grinding. The test results showed that the crystal form of the crystalline form CSIV remained unchanged after grinding, indicating that the crystalline form CSIV had good grinding stability.

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Abstract

涉及Tolebrutinib(以下称为"化合物I")的新晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备BTK抑制剂药物和治疗多发性硬化症药物中的用途。提供的Tolebrutinib晶型比现有技术具有一种或多种改进的性质，对未来该药物的优化和开发具有重要价值。

Description

Tolebrutinib的晶型及其制备方法和用途 技术领域
本发明涉及晶体化学领域。具体而言，涉及Tolebrutinib的晶型及其制备方法和用途。
背景技术
多发性硬化症(Multiple Sclerosis，MS)是一种神经系统疾病，影响全球超过100万人。它是青年和中年人神经功能障碍的最常见原因，给患者及其家人带来重大的身体、心理、社会和经济影响。MS涉及免疫介导的过程，在这个过程中，身体免疫系统的异常反应针对中枢神经系统(CNS)。在患病的过程中，神经细胞的髓鞘中出现硬化，如病变或疤痕，干扰电信号的传输。硬化症随时间累积并导致MS患者出现衰弱症状。
免疫调节药一直是MS治疗的主要手段，2017年的一项临床研究结果已经证明了以B淋巴细胞为靶点的药物的有效性(Hauser et al.,N Engl JMed.2017；376(3):221-34)。
布鲁顿酪氨酸激酶(Bruton’s tyrosine kinase，BTK)通路对于B淋巴细胞和髓细胞(包括中枢神经系统小胶质细胞)中的信号传导至关重要。这些细胞类型中的每一种都与MS的病理生理学有关。此外，由于BTK信号传导对于B细胞成熟为分泌抗体的浆细胞至关重要，因此，抑制BTK可以调节细胞免疫和体液免疫。相应的，BTK信号抑制剂表现出了针对细胞免疫和体液免疫的双重作用。
因此，能够抑制负责神经炎症的抗原诱导的B细胞活化并调节与脑和脊髓中的神经炎症相关的适应不良的小胶质细胞的BTK抑制化合物，可能有助于治疗复发型多发性硬化症(relapsing multiple sclerosis，RMS)，与目前可用的治疗方法相比，具有更好的效果。
Tolebrutinib作为一种口服的选择性BTK抑制剂，其在RMS患者治疗中显示出了安全性和有效性。
Tolebrutinib的化学名称为(R)-1-(1-丙烯酰哌啶-3-基)-4-氨基-3-(4-苯氧苯基)-1H-咪唑并[4,5-c]吡啶-2(3H)-酮(以下称为“化合物I”)，其结构式如下：
Figure PCTCN2022096779-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。
WO2016196840A1公开了化合物I的白色固体，本申请发明人重复该制备过程得到化合物I的无定形。进一步的，本申请发明人对该无定形研究发现，化合物I的无定形存在稳定性差、引湿性高、易降解等问题，不适合药用。
为克服现有技术的缺点，仍然需要一种符合药用标准的新晶型，以用于含化合I药物的开发。本申请的发明人意外发现了本发明提供的化合物I晶型，其在溶解度，引湿性，提纯效果，稳定性，黏附性，可压性，流动性，体内外溶出，生物有效性等方面存在优势，特别是稳定性好，引湿性低，不易降解，解决了现有技术存在的问题，对含化合物I的药物开发具有非常重要的意义。
发明内容
本发明的主要目的是提供化合物I的新晶型及其制备方法和用途以及包含该新晶型的药物组合物。
根据本发明的目的，本发明提供化合物I的晶型CSII(以下称作“晶型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4.1°±0.2°、10.2°±0.2°、22.6°±0.2°处有特征峰。
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11.3°±0.2°、16.5°±0.2°、17.8°±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为11.3°±0.2°、16.5°±0.2°、17.8°±0.2°处有特征峰。
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8.2°±0.2°、10.8°±0.2°、24.7°±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为8.2°±0.2°、10.8°±0.2°、24.7°±0.2°处有特征峰。
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4.1°±0.2°、10.2°±0.2°、22.6°±0.2°、11.3°±0.2°、16.5°±0.2°、17.8°±0.2°、8.2°±0.2°、10.8°±0.2°、24.7°±0.2°、20.5°±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处有特征峰。
非限制性地，使用Cu-Kα辐射，晶型CSII的X射线粉末衍射图基本如图1所示。
非限制性地，晶型CSII的热重分析图基本如图2所示，将其从26℃加热至100℃时具有约0.1％的质量损失。
非限制性地，晶型CSII的差示扫描量热分析图基本如图3所示，其在131℃附近开始出现一个吸热峰，该吸热峰为熔化吸热峰。
非限制性地，晶型CSII为无水物。
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：
将化合物I固体置于醇类溶剂中形成悬浊液，在一定温度条件下搅拌一段时间，分离得到固体，所得固体经高温真空干燥一段时间后即得到本发明所述晶型CSII；
进一步地，所述醇类溶剂优选C1-C4醇类，更优选为乙醇；所述一定温度优选0-50℃，更优选50℃；所述搅拌一段时间优选1天及以上；所述高温真空干燥优选温度为50-75℃；所述干燥一段时间为3h及以上。
根据本发明的目的，本发明提供化合物I的晶型CSIII(以下称作“晶型CSIII”)。
一方面，使用Cu-Kα辐射，所述晶型CSIII的X射线粉末衍射图在衍射角2θ值为4.2°±0.2°、 11.1°±0.2°、21.7°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSIII的X射线粉末衍射图在衍射角2θ值为20.6°±0.2°、21.0°±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CSIII的X射线粉末衍射图在衍射角2θ为20.6°±0.2°、21.0°±0.2°、22.2°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSIII的X射线粉末衍射图在衍射角2θ值为10.4°±0.2°、17.7°±0.2°、23.1°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSIII的X射线粉末衍射图在衍射角2θ为10.4°±0.2°、17.7°±0.2°、23.1°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSIII的X射线粉末衍射图在衍射角2θ值为4.2°±0.2°、11.1°±0.2°、21.7°±0.2°、20.6°±0.2°、21.0°±0.2°、22.2°±0.2°、10.4°±0.2°、17.7°±0.2°、23.1°±0.2°、8.4°±0.2°、13.3°±0.2°、16.3°±0.2°、24.2°±0.2°、25.4°±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，或12处，或13处，或14处有特征峰。
非限制性地，使用Cu-Kα辐射，晶型CSIII的X射线粉末衍射图基本如图6所示。
非限制性地，晶型CSIII的热重分析图基本如图7所示，将其26℃加热至100℃时具有约0.5％的质量损失。
非限制性地，晶型CSIII的差示扫描量热分析图基本如图8所示，其在133℃附近开始出现一个吸热峰，该吸热峰为晶型CSIII的熔化吸热峰。
非限制性地，晶型CSIII为无水物。
根据本发明的目的，本发明还提供所述晶型CSIII的制备方法，所述制备方法包括：
将化合物I的固体置于丙酮溶剂中形成悬浊液，搅拌得到所述晶型CSIII；
进一步地，所述搅拌的温度优选0-50℃，更优选5℃。
根据本发明的目的，本发明提供化合物I的晶型CSIV(以下称作“晶型CSIV”)。
一方面，使用Cu-Kα辐射，所述晶型CSIV的X射线粉末衍射图在衍射角2θ值为8.5°±0.2°、18.6°±0.2°、22.0°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSIV的X射线粉末衍射图在衍射角2θ值为12.9°±0.2°、19.1°±0.2°、23.3°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSIV的X射线粉末衍射图在衍射角2θ为12.9°±0.2°、19.1°±0.2°、23.3°±0.2°处有特征峰。
进一步地，使用Cu-Kα辐射，所述晶型CSIV的X射线粉末衍射图在衍射角2θ值为13.2°±0.2°、13.8°±0.2°、21.1°±0.2°中的1处、或2处、或3处有特征峰；优选地，所述晶型CSIV的X射线粉末衍射图在衍射角2θ为13.2°±0.2°、13.8°±0.2°、21.1°±0.2°处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CSIV的X射线粉末衍射图在衍射角2θ值为8.5°±0.2°、18.6°±0.2°、22.0°±0.2°、12.9°±0.2°、19.1°±0.2°、23.3°±0.2°、13.2°±0.2°、13.8°±0.2°、21.1°±0.2°、7.7°±0.2°、17.2°±0.2°、26.7°±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，或12处有特征峰。
非限制性地，使用Cu-Kα辐射，晶型CSIV的X射线粉末衍射图基本如图11所示。
非限制性地，晶型CSIV的差示扫描量热分析图基本如图13所示，其在144℃附近开始出现一个吸热峰，该吸热峰为晶型CSIV的熔化吸热峰。
非限制性地，晶型CSIV的热重分析图基本如图14所示，将其从29℃加热至120℃时具有约0.2％的质量损失。
非限制性地，晶型CSIV为无水物。
根据本发明的目的，本发明还提供所述晶型CSIV的制备方法，所述制备方法包括：
将化合物I固体置于醚类或芳香烃类溶剂中形成悬浊液，在-20℃-5℃条件下搅拌得到本发明晶型CSIV；
进一步地，所述醚类溶剂优选C5醚类，更优选为甲基叔丁基醚；所述芳香烃类溶剂优选C9芳香烃类，更优选为异丙苯；所述搅拌温度优选-20℃。
根据本发明的目的，本发明提供晶型CSII，或晶型CSIII，或晶型CSIV，或任意两种晶型的任意混合，或三种晶型的任意混合用于制备化合物I其他晶型或盐的用途。
根据本发明的目的，本发明还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CSII，或晶型CSIII，或晶型CSIV或三种晶型的任意混合及药学上可接受的辅料。
进一步地，本发明提供的晶型CSII，或晶型CSIII，或晶型CSIV，或任意两种晶型的任意混合，或三种晶型的任意混合在制备BTK抑制剂药物中的用途。
更进一步地，本发明提供的晶型CSII，或晶型CSIII，或晶型CSIV，或任意两种晶型的任意混合，或三种晶型的任意混合在制备治疗多发性硬化症药物中的用途。
技术效果
本发明提供的晶型CSII具有以下预料不到的技术效果：
(1)与现有技术相比，本发明提供的晶型CSII原料药具有更好的稳定性。
现有技术固体在25℃/60％RH，40℃/75％RH，60℃/75％RH，80℃和光照条件下放置，纯度均有明显降低，尤其是40℃/75％RH放置6个月，纯度降低3.46％，超出界定限的杂质个数增加至4个；60℃/75％RH放置仅1个月，纯度降低超过6.3％，超出界定限的杂质个数增加至4个，远远低于药用标准。
本发明提供的晶型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99.8％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。
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，在60℃/75％RH条件下放置至少1个月晶型未发生变化，且化学纯度在99.8％以上，储存过程中纯度基本保持不变，在80℃条件下放置至少2天纯度没有变化，在光源总照度不低于1.2×10 6lux·hr，近紫外灯能量不低于200W·hr/m 2能量的条件下放置至少1周纯度没有变化。说明晶型CSII原料药在加速条件，高温条件和光照条件下，具有更好的稳定性。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。原料药生产、储存和运输过程中必然会存在光照条件的影响，因此，原料药在加速条件，高温条件以及光照条件下的稳定性对于药物至关重要。晶型CSII原料药在加速条件，高温条件以及光照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。此外，晶型CSII原料药在稳定性考察过程中，杂质含量均未超出界定限，能够满足药用开发的要求。
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。
此外，晶型CSII与辅料混合做成药物制剂后，晶型亦未发生改变，说明晶型CSII制剂制备过程中稳定，有利于药物的生产。
进一步地，晶型CSII在机械力作用下具有良好的物理稳定性。晶型CSII原料药研磨后晶型保持不变。制剂加工过程中常需要将原料药研磨或粉碎，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。
(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的引湿增重仅为现有技术固体的1/6。晶型CSII在80％RH条件下引湿性增重为0.60％，属于略有引湿性，现有技术固体在80％RH条件下引湿增重为3.69％，属于有引湿性。
一方面，高引湿性易引起原料药发生化学降解和晶型转变，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。
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。
本发明提供的晶型CSII引湿性低，对工业生产的储存条件要求低，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。
本发明提供的晶型CSIII具有以下预料不到的技术效果：
(1)与现有技术相比，本发明提供的晶型CSIII原料药具有更好的稳定性。
现有技术固体在25℃/60％RH，40℃/75％RH，60℃/75％RH，80℃和光照条件下放置，纯度均有明显降低，尤其是40℃/75％RH放置6个月，纯度降低3.46％，超出界定限的杂质个数增加至4个；60℃/75％RH放置仅1个月，纯度降低超过6.3％，超出界定限的杂质个数增加至4个，远远低于药用标准。
本发明提供的晶型CSIII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99.9％以上，储存过程中纯度基本保持不变。说明晶型CSIII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。
同时，晶型CSIII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条件下放置至少1个月晶型未发生变化，且化学纯度在99.8％以上，储存过程中纯度基本保持不变，在80℃条件下放置至少2天纯度没有变化，在光源总照度不低于1.2×10 6lux·hr，近紫外灯能量不低于200W·hr/m 2能量的条件下放置至少1周纯度没有变化。说明晶型CSIII原料药在加速条件，高温条件和光照条件下，具有更好的稳定性。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。原料药生产、储存和运输过程中必然会存在光照条件的影响，因此，原料药在加速条件，高温条件以及光照条件下的稳定性对于药物至关重要。晶型CSIII原料药在加速条件，高温条件以及光照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。此外，晶型CSIII原料药在稳定性考察过程中，杂质含量均未超出界定限，能够满足药用开发的要求。
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CSIII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。
此外，晶型CSIII与辅料混合做成药物制剂后，晶型亦未发生改变，说明晶型CSIII制剂制备过程中稳定，有利于药物的生产。
进一步地，晶型CSIII在机械力作用下具有良好的物理稳定性。晶型CSIII原料药研磨后晶型保持不变。制剂加工过程中常需要将原料药研磨或粉碎，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。
(2)与现有技术相比，本发明提供的晶型CSIII具有更低的引湿性。测试结果表明，本发明晶型CSIII的引湿增重仅为现有技术固体的1/6。晶型CSIII在80％RH条件下引湿性增重为0.66％，属于略有引湿性，现有技术固体在80％RH条件下引湿增重为3.69％，属于有引湿性。
一方面，高引湿性易引起原料药发生化学降解和晶型转变，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。
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。
本发明提供的晶型CSIII引湿性低，对工业生产的储存条件要求低，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。
本发明提供的晶型CSIV具有以下预料不到的技术效果：
(1)与现有技术相比，本发明提供的晶型CSIV原料药具有更好的稳定性。
现有技术固体在40℃/75％RH条件下放置2个月，纯度有明显降低，纯度降低2.18％。而本发明提供的晶型CSIV原料药在25℃/60％RH条件下放置，至少2个月晶型未发生变化，且化学纯度在99.7％以上，储存过程中纯度基本保持不变。说明晶型CSIV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。
同时，晶型CSIV原料药在40℃/75％RH条件下放置至少2个月晶型未发生变化，说明晶型CSIV原料药在加速条件下，具有更好的稳定性。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，原料药在加速条件下的稳定性对于药物至关重要。晶型CSIV原料药在加速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。
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CSIV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。
此外，晶型CSIV与辅料混合做成药物制剂后，晶型亦未发生改变，说明晶型CSIV制剂制备过程中稳定，有利于药物的生产。
进一步地，晶型CSIV在机械力作用下具有良好的物理稳定性。晶型CSIV原料药研磨后晶型保持不变。制剂加工过程中常需要将原料药研磨或粉碎，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。
(2)与现有技术相比，本发明提供的晶型CSIV具有更低的引湿性。测试结果表明，本发明晶型CSIV的引湿增重仅为现有技术固体的1/15。晶型CSIV在80％RH条件下引湿性增重为0.24％，属于略有引湿性，现有技术固体在80％RH条件下引湿增重为3.69％，属于有引湿性。
一方面，高引湿性易引起原料药发生化学降解和晶型转变，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。
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。
本发明提供的晶型CSIV引湿性低，对工业生产的储存条件要求低，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。
附图说明
图1为晶型CSII的XRPD图
图2为晶型CSII的TGA图
图3为晶型CSII的DSC图
图4为晶型CSII稳定性放置前后的XRPD叠图(从上至下依次为：放置前，在25℃/60％RH敞口放置6个月，在40℃/75％RH敞口放置6个月，在60℃/75％RH敞口放置1个月)
图5为晶型CSII在DVS测试前后的XRPD叠图(从上至下依次为：测试前，测试后)
图6为晶型CSIII的XRPD图
图7为晶型CSIII的TGA图
图8为晶型CSIII的DSC图
图9为晶型CSIII稳定性放置前后的XRPD叠图(从上至下依次为：放置前，在25℃/60％RH敞口放置6个月，在40℃/75％RH敞口放置6个月，在60℃/75％RH敞口放置1个月)
图10为晶型CSIII在DVS测试前后的XRPD叠图(从上至下依次为：测试前，测试后)
图11为晶型CSIV的XRPD图
图12为晶型CSIV的XRPD图
图13为晶型CSIV的DSC图
图14为晶型CSIV的TGA图
图15为晶型CSIV稳定性放置前后的XRPD叠图(从上至下依次为：放置前，在25℃/60％RH敞口放置2个月，在40℃/75％RH敞口放置2个月)
图16为晶型CSIV在DVS测试前后的XRPD叠图(从上至下依次为：测试前，测试后)
具体实施方式
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。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
1H NMR：液态核磁氢谱
RH：相对湿度
UPLC：超高效液相色谱法
LC：液相色谱
TEA：三乙胺
采集数据所用的仪器及方法：
本发明所述的X射线粉末衍射图在Bruker X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Figure PCTCN2022096779-appb-000002
1.54060；
Figure PCTCN2022096779-appb-000003
1.54439
Kα2/Kα1强度比例：0.50
本发明所述的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：
扫描速率：10℃/min
保护气体：N 2
本发明所述的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：
扫描速率：10℃/min
保护气体：N 2
本发明所述的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：
温度：25℃
载气，流速：N 2，200毫升/分钟
相对湿度范围：0％RH-95％RH
1H NMR采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。
本发明的有关物质检测方法，采用超高效液相色谱法(UPLC)，仪器参数如下：
表1
Figure PCTCN2022096779-appb-000004
Figure PCTCN2022096779-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，磁力搅拌优选为300-900转/分钟，机械搅拌优选为100-300转/分钟。
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后弃去上清液，取固体。
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。
所述“室温”不是特定的温度值，是指10-30℃温度范围。
所述“敞口”是将样品置于玻璃瓶中，瓶口盖上一层铝箔纸并在铝箔纸上开5-10个小孔。
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。
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。
在一些实施方案中，本发明的晶型CSII，晶型III，晶型IV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。
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％。
除非特殊说明，以下实施例均在室温条件下操作。
根据本发明，作为原料的所述化合物I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为固体形式。
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WO2016196840A1文献所记载的方法制备获得。
实施例1：晶型CSII的制备方法
称量1000.0mg的化合物I固体，将其加入到20-mL玻璃小瓶中，向小瓶中加入10.0mL的乙醇后在50℃以500rpm的转速磁力搅拌约7天，所得悬浊液在室温静置10天后，抽滤分离固体。将所得固体在50℃真空干燥约3h，60℃真空干燥约17h，75℃真空干燥约5h后，经XRPD检测，为本发明所述晶型CSII，其X射线粉末衍射数据如表2所示，XRPD图如图1所示。
TGA图如图2所示，将其从26℃加热至100℃时，具有约0.1％的质量损失。
DSC图如图3所示，其在131℃附近开始出现一个吸热峰，该吸热峰为晶型CSII的熔化吸热峰。
表2
Figure PCTCN2022096779-appb-000006
Figure PCTCN2022096779-appb-000007
实施例2：晶型CSII的核磁表征
晶型CSII的 1H NMR数据为： 1H NMR(400MHz,DMSO)δ7.76(d,J＝5.6Hz,1H),7.53–7.37(m,4H),7.22(t,J＝10.6,4.2Hz,1H),7.14(t,4H),6.97(d,J＝5.5Hz,1H),6.91–6.71(m,1H),6.14(dd,J＝16.8Hz,1H),5.69(dd,1H),4.81(s,2H),4.51(t,J＝13.4Hz,1H),4.15(dd,J＝34.1,12.7Hz,2H),3.76(t,J＝12.1Hz,0.5H),3.16(t,J＝12.8Hz,0.5H),2.83–2.61(m,0.5H),2.46–2.30(m,1H),2.03–1.77(m,2H),1.66–1.45(m,1H)。(根据化合物的结构，该化合物哌啶环上的其中一个氢在3.33-3.76ppm出峰，其中，裂分出的0.5H因与水的出峰接近，被水峰覆盖。)
实施例3：晶型CSII的物理化学稳定性
称取本发明制备得到的晶型CSII和现有技术无定形，敞口包装，分别放置在25℃/60％RH、40℃/75％RH、60℃/75％RH条件下，采用UPLC和XRPD测定纯度与晶型。结果如表3所示，晶型CSII稳定性放置前后的XRPD叠图如图4所示。
表3
Figure PCTCN2022096779-appb-000008
注：界定限标准参考INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE，IMPURITIES IN NEW DRUG SUBSTANCES Q3A(R2)。化合物I服用剂量为60mg，每天一次。
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，晶型和纯度基本保持不变，可见，晶型CSII在长期和加速条件下均可保持良好的稳定性。60℃/75％RH条件下放置至少可稳定1个月，晶型和纯度基本保持不变，可见在更严苛的条件下稳定性也很好。晶型CSII在整个稳定性考察过程中，杂质含量均未超出界定限，能够满足药用开发的要求。现有技术无定形在25℃/60％RH，40℃/75％RH，60℃/75％RH条件下放置，纯度均有明显降低，尤其是40℃/75％RH放置6个月，纯度降低3.46％，超出界定限的杂质个数增加至4个；60℃/75％RH放置仅1个月，纯度降低达6.3％以上，超出界定限的杂质个数增加至4个，远远低于药用标准。由此可见，本发明晶型CSII相比于现有技术无定形，具有非常优越的化学稳定性。
实施例4：晶型CSII的高温稳定性
分别取适量本发明制备得到的晶型CSII与现有技术无定形，在80℃条件下放置2天，采用UPLC测定放置前后的固体纯度，结果如表4所示。
表4
起始固体 包装条件 纯度变化
晶型CSII 玻璃小瓶加盖 +0.01％
无定形 玻璃小瓶加盖 -1.16％
结果表明，晶型CSII在80℃条件下放置2天化学纯度基本不变，而无定形在相同条件下观察到明显的降解。由此可见，相比于现有技术无定形，本发明晶型CSII在高温稳定性上有明显优势。
实施例5：晶型CSII的光照稳定性
分别取适量本发明制备得到的晶型CSII与现有技术无定形，按照《中国药典》方法在光源总照度不低于1.2×10 6lux·hr，近紫外灯能量不低于200W·hr/m 2能量的条件下放置约1周后，采用UPLC测定放置前后的固体纯度，结果如表5所示。
表5
起始固体 放置时间 纯度变化
晶型CSII 1周 -0.02％
无定形 1周 -0.11％
结果表明，晶型CSII在上述光照条件下放置至少1周化学纯度基本不变，而无定形在相同条件下观察到明显的降解。由此可见，相比于现有技术无定形，本发明晶型CSII在光照稳定性上有明显优势。
实施例6：晶型CSII的引湿性
称取适量本发明晶型CSII与现有技术无定形，采用DVS仪测试其引湿性，在25℃，0％RH-95％RH-0％RH相对湿度下循环一次，记录每个湿度下的质量变化。实验结果如表6所示。晶型CSII在DVS测试前后的XRPD叠图如图5所示。
表6
固体 80％相对湿度的增重
晶型CSII 0.60％
现有技术无定形 3.69％
实验结果表明，晶型CSII在80％RH条件下引湿性增重为0.60％，属于略有引湿性，现有技术固体在80％RH条件下引湿性增重为3.69％，属于有引湿性。晶型CSII引湿性优于现有技术。此外，晶型CSII经DVS测试后晶型保持不变，说明晶型II具有很好的稳定性。
关于引湿性特征描述与引湿性增重的界定(中国药典2020年版通则9103药物引湿性试验指导原则，实验条件：25℃±1℃，80％±2％相对湿度)：
潮解：吸收足量水分形成溶液
极具引湿性：引湿增重不小于15.0％
有引湿性：引湿增重小于15.0％但不小于2.0％
略有引湿性：引湿增重小于2.0％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
(欧洲药典第十版5.11中对引湿性的界定与中国药典类似)
实施例7晶型CSII的研磨稳定性
将晶型CSII置于研钵中，手动研磨5分钟，研磨前后测试XRPD，测试结果表明，晶型CSII经研磨后晶型不变，说明晶型CSII具有良好的研磨稳定性。
实施例8晶型CSII的制剂制备
称取适量本发明晶型CSII按照表7和表8的处方和工艺进行制片，并在制剂前后进行XRPD测试。结果表明本发明晶型CSII在制剂处方工艺后晶型不变。
表7
Figure PCTCN2022096779-appb-000009
表8
Figure PCTCN2022096779-appb-000010
实施例9：晶型CSIII的制备方法
称量491.9mg的化合物I固体，加入到20-mL玻璃小瓶中，向小瓶中加入5mL丙酮配成悬浊液。所得悬浊液在室温搅拌约15分钟后加入3mL丙酮。将体系置于5℃条件下搅拌约4天，分离固体。将所得固体在50℃真空干燥约20h后，经XRPD检测，为本发明所述 晶型CSIII，其X射线粉末衍射数据如表9所示，XRPD图如图6所示。
TGA图如图7所示，将其从26℃加热至100℃时，具有约0.5％的质量损失。
DSC图如图8所示，其在133℃附近开始出现一个吸热峰，该吸热峰为晶型CSIII的熔化吸热峰。
表9
Figure PCTCN2022096779-appb-000011
Figure PCTCN2022096779-appb-000012
实施例10：晶型CSIII的核磁表征
晶型CSIII的 1H NMR数据为： 1H NMR(400MHz,DMSO)δ7.76(d,J＝5.6Hz,1H),7.52–7.36(m,4H),7.21(t,1H),7.14(t,4H),6.97(d,J＝5.5Hz,1H),6.90–6.72(m,1H),6.14(dd,J＝17.0Hz,1H),5.69(dd,J＝13.6Hz,1H),4.81(s,2H),4.51(t,J＝13.5Hz,1H),4.14(dd,J＝33.1,14.1Hz,2H),3.76(t,J＝12.1Hz,0.5H),3.16(t,J＝12.6Hz,0.5H),2.82–2.59(m,0.5H),2.44–2.28(m,1H),2.11–1.75(m,2H),1.68–1.37(m,1H)。(根据化合物的结构，该化合物哌啶环上的其中一个氢在3.33-3.76ppm出峰，其中，裂分出的0.5H因与水的出峰接近，被水峰覆盖。)
实施例11：晶型CSIII的物理化学稳定性
称取本发明制备得到的晶型CSIII和现有技术无定形，敞口包装，分别放置在25℃/60％RH、40℃/75％RH、60℃/75％RH条件下，采用UPLC和XRPD测定纯度与晶型。结果如表10所示，晶型CSIII稳定性放置前后的XRPD叠图如图9所示。
表10
Figure PCTCN2022096779-appb-000013
注：界定限标准参考INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE，IMPURITIES IN NEW DRUG SUBSTANCES Q3A(R2)。化合物I服用剂量为60mg，每天一次。
结果表明，晶型CSIII在25℃/60％RH和40℃/75％RH条件下至少可稳定6个月，晶型和纯度基本保持不变，可见，晶型CSIII在长期和加速条件下均可保持良好的稳定性。60℃/75％RH条件下放置至少可稳定1个月，晶型和纯度基本保持不变，可见在更严苛的条件下稳定性也很好。晶型CSIII在整个稳定性考察过程中，杂质含量均未超出界定限，能够满足药用开发的要求。现有技术固体在25℃/60％RH，40℃/75％RH，60℃/75％RH条件下放置，纯度均有明显降低，尤其是40℃/75％RH放置6个月，纯度降低3.46％，超出界定限的杂质个数增加至4个；60℃/75％RH放置仅1个月，纯度降低达6.3％以上，超出界定限的杂质个数增加至4个，远远低于药用标准。由此可见，本发明晶型CSIII相比于现有技术无定形，具有非常优越的化学稳定性。
实施例12：晶型CSIII的高温稳定性
分别取适量本发明制备得到的晶型CSIII与现有技术无定形，在80℃条件下放置2天，采用UPLC测定放置前后的固体纯度，结果如表11所示。
表11
起始固体 包装条件 纯度变化
晶型CSIII 玻璃小瓶加盖 +0.04％
无定形 玻璃小瓶加盖 -1.16％
结果表明，晶型CSIII在80℃条件下放置2天化学纯度基本不变，而无定形在相同条件下观察到明显的降解。由此可见，相比于现有技术无定形，本发明晶型CSIII在高温稳定性上有明显优势。
实施例13：晶型CSIII的光照稳定性
分别取适量本发明制备得到的晶型CSIII与现有技术无定形，按照《中国药典》方法在光源总照度不低于1.2×10 6lux·hr，近紫外灯能量不低于200W·hr/m 2能量的条件下放置约1周后，采用UPLC测定放置前后的固体纯度，结果如表12所示。
表12
起始固体 放置时间 纯度变化
晶型CSIII 1周 +0.02％
无定形 1周 -0.11％
结果表明，晶型CSIII在上述光照条件下放置至少1周化学纯度基本不变，而无定形在相同条件下观察到明显的降解。由此可见，相比于现有技术无定形，本发明晶型CSIII在光照稳定性上有明显优势。
实施例14：晶型CSIII的引湿性
称取适量本发明晶型CSIII与现有技术无定形，采用DVS仪测试其引湿性，在25℃，0％RH-95％RH-0％RH相对湿度下循环一次，记录每个湿度下的质量变化。实验结果如表13所示。晶型CSIII在DVS测试前后的XRPD叠图如图10所示。
表13
固体 80％相对湿度的增重
晶型CSIII 0.66％
现有技术无定形 3.69％
实验结果表明，晶型CSIII在80％RH条件下引湿性增重为0.66％，属于略有引湿性，现有技术固体在80％RH条件下引湿性增重为3.69％，属于有引湿性。晶型CSIII引湿性优于现有技术。此外，晶型CSIII经DVS测试后晶型保持不变，说明晶型III具有很好的稳定性。
实施例15：晶型CSIII的研磨稳定性
将晶型CSIII置于研钵中，手动研磨5分钟，研磨前后测试XRPD，测试结果表明，晶型CSIII经研磨后晶型不变，说明晶型CSIII具有良好的研磨稳定性。
实施例16晶型CSIII的制剂制备
称取适量本发明晶型CSIII按照表7和表8的处方和工艺进行制片，并在制剂前后进行XRPD测试。结果表明本发明晶型CSIII在制剂处方工艺后晶型不变。
实施例17：晶型CSIV的制备方法
称量11.0mg的化合物I固体加入到玻璃小瓶中，向小瓶中加入0.08mL甲基叔丁基醚配 成悬浊液后在-20℃条件下搅拌约23小时，分离部分固体，经XRPD检测，为本发明晶型CSIV，然后向小瓶中再补加0.08mL甲基叔丁基醚后置于室温条件下搅拌约2天，分离固体。经XRPD检测，所得固体为本发明晶型CSIV，其X射线粉末衍射数据如表14所示，XRPD图如图11所示。
表14
Figure PCTCN2022096779-appb-000014
Figure PCTCN2022096779-appb-000015
实施例18：晶型CSIV的制备
称量300.0mg的化合物I固体置于玻璃小瓶中，向其中加入4.5mL的异丙苯后在-20℃搅拌约39小时，过滤分离固体，50℃真空干燥22h，经XRPD检测，所得的固体为本发明所述晶型CSIV，其X射线粉末衍射数据如表15所示，XRPD图如图12所示。
DSC图如图13所示，其在144℃附近开始出现一个吸热峰，该吸热峰为晶型CSIV的熔化吸热峰。
晶型CSIV的 1H NMR数据为： 1H NMR(400MHz,DMSO)δ7.76(d,J＝5.6Hz,1H),7.53–7.39(m,4H),7.22(t,J＝7.4Hz,1H),7.14(t,J＝7.7Hz,4H),6.97(d,J＝5.5Hz,1H),6.92–6.74(m,1H),6.14(dd,1H),5.69(dd,1H),4.82(s,2H),4.52(t,J＝11.8Hz,1H),4.15(dd,J＝33.2,12.0Hz,2H),3.78(t,J＝12.8Hz,0.5H),3.16(t,J＝12.6Hz,0.5H),2.79–2.63(m,0.5H),2.40–2.25(m,1H),2.07–1.76(m,2H),1.68–1.40(m,1H)。(根据化合物的结构，该化合物哌啶环上的其中一个氢在3.33-3.76ppm出峰，其中，裂分出的0.5H因与水的出峰接近，被水峰覆盖。)
表15
Figure PCTCN2022096779-appb-000016
Figure PCTCN2022096779-appb-000017
Figure PCTCN2022096779-appb-000018
实施例19：晶型CSIV的TGA测试
取适量晶型CSIV固体测试TGA。TGA结果如图14所示，将其从29℃加热至120℃时，具有约0.2％的质量损失。
实施例20：晶型CSIV的物理化学稳定性
称取本发明制备得到的晶型CSIV和现有技术无定形，敞口包装，分别放置在25℃/60％RH、40℃/75％RH条件下，采用UPLC和XRPD测定纯度与晶型。结果如表16所示，晶型CSIV稳定性放置前后的XRPD叠图如图15所示。
表16
Figure PCTCN2022096779-appb-000019
注：界定限标准参考INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE，IMPURITIES IN NEW DRUG SUBSTANCES Q3A(R2)。化合物I服用剂量为60mg，每天一次。
结果表明，晶型CSIV在25℃/60％RH和40℃/75％RH条件下至少可稳定2个月，晶型和纯度基本保持不变，可见，晶型CSIV在长期和加速条件下均可保持良好的稳定性。现有技术固体在40℃/75％RH条件下放置，纯度有明显降低，纯度降低2.18％。由此可见，本发明晶型CSIV相比于现有技术无定形，具有非常优越的化学稳定性。
实施例21：晶型CSIV的高温稳定性
分别取适量本发明制备得到的晶型CSIV与现有技术无定形，在80℃条件下放置2天，采用UPLC测定放置前后的固体纯度，结果如表17所示。
表17
起始固体 包装条件 纯度变化
晶型CSIV 玻璃小瓶加盖 +0.03％
无定形 玻璃小瓶加盖 -1.16％
结果表明，晶型CSIV在80℃条件下放置2天化学纯度基本不变，而无定形在相同条件下观察到明显的降解。由此可见，相比于现有技术无定形，本发明晶型CSIV在高温稳定性上有明显优势。
实施例22：晶型CSIV的光照稳定性
分别取适量本发明制备得到的晶型CSIV与现有技术无定形，按照《中国药典》方法在光 源总照度不低于1.2×10 6lux·hr，近紫外灯能量不低于200W·hr/m 2能量的条件下放置约1周后，采用UPLC测定放置前后的固体纯度，结果如表18所示。
表18
起始固体 放置时间 纯度变化
晶型CSIV 1周 +0.06％
无定形 1周 -0.11％
结果表明，晶型CSIV在上述光照条件下放置至少1周化学纯度基本不变，而无定形在相同条件下观察到明显的降解。由此可见，相比于现有技术无定形，本发明晶型CSIV在光照稳定性上有明显优势。
实施例23：晶型CSIV的引湿性
称取适量本发明晶型CSIV与现有技术无定形，采用DVS仪测试其引湿性，在25℃，0％RH-95％RH-0％RH相对湿度下循环一次，记录每个湿度下的质量变化。实验结果如表19所示。晶型CSIV在DVS测试前后的XRPD叠图如图16所示。
表19
固体 80％相对湿度的增重
晶型CSIV 0.24％
现有技术无定形 3.69％
实验结果表明，晶型CSIV在80％RH条件下引湿性增重为0.24％，属于略有引湿性，现有技术无定形在80％RH条件下引湿性增重为3.69％，属于有引湿性。晶型CSIV引湿性优于现有技术。此外，晶型CSIV经DVS测试后晶型保持不变，说明晶型IV具有很好的稳定性。
实施例24晶型CSIV的研磨稳定性
将晶型CSIV置于研钵中，手动研磨5分钟，研磨前后测试XRPD，测试结果表明，晶型CSIV经研磨后晶型不变，说明晶型CSIV具有良好的研磨稳定性。
实施例25晶型CSIV的制剂制备
称取适量本发明晶型CSIV按照表7和表8的处方和工艺进行制片，并在制剂前后进行XRPD测试。结果表明本发明晶型CSIV在制剂处方工艺后晶型不变。
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。

Claims (24)

  1. 一种化合物I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4.1°±0.2°、10.2°±0.2°、22.6°±0.2°处具有特征峰
    Figure PCTCN2022096779-appb-100001
  2. 根据权利要求1所述的化合物I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11.3°±0.2°、16.5°±0.2°、17.8°±0.2°中的至少一处具有特征峰。
  3. 根据权利要求1所述的化合物I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8.2°±0.2°、10.8°±0.2°、24.7°±0.2°中的至少一处具有特征峰。
  4. 根据权利要求2所述的化合物I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8.2°±0.2°、10.8°±0.2°、24.7°±0.2°中的至少一处具有特征峰。
  5. 根据权利要求1所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图1所示。
  6. 一种权利要求1所述晶型的制备方法，其特征在于，所述制备方法包括：将化合物I固体置于醇类溶剂中形成悬浊液，搅拌，分离得到固体，所得固体经高温真空干燥后得到。
  7. 权利要求6所述的制备方法，其特征在于，所述醇类溶剂为C1-C4醇类，所述搅拌的温度为0-50℃。
  8. 一种化合物I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4.2°±0.2°、11.1°±0.2°、21.7°±0.2°处具有特征峰。
  9. 根据权利要求8所述的化合物I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20.6°±0.2°、21.0°±0.2°、22.2°±0.2°中的至少一处具有特征峰。
  10. 根据权利要求8所述的化合物I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10.4°±0.2°、17.7°±0.2°、23.1°±0.2°中的至少一处具有特征峰。
  11. 根据权利要求9所述的化合物I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10.4°±0.2°、17.7°±0.2°、23.1°±0.2°中的至少一处具有特征峰。
  12. 根据权利要求8所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图6所示。
  13. 一种权利要求8所述晶型的制备方法，其特征在于，所述制备方法包括：将化合物I的固体置于丙酮溶剂中形成悬浊液，搅拌得到。
  14. 权利要求13所述的制备方法，其特征在于，所述搅拌的温度为0-50℃。
  15. 一种化合物I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 8.5°±0.2°、18.6°±0.2°、22.0°±0.2°处具有特征峰。
  16. 根据权利要求15所述的化合物I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12.9°±0.2°、19.1°±0.2°、23.3°±0.2°中的至少一处具有特征峰。
  17. 根据权利要求15所述的化合物I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13.2°±0.2°、13.8°±0.2°、21.1°±0.2°中的至少一处具有特征峰。
  18. 根据权利要求16所述的化合物I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13.2°±0.2°、13.8°±0.2°、21.1°±0.2°中的至少一处具有特征峰。
  19. 根据权利要求15所述的化合物I的晶型，其特征在于，使用Cu-Kα辐射，其X射线粉末衍射图基本如图11所示。
  20. 一种权利要求15所述晶型的制备方法，其特征在于，所述制备方法包括：将化合物I固体置于醚类或芳香烃类溶剂中形成悬浊液，在-20℃-5℃搅拌得到。
  21. 权利要求20所述的制备方法，其特征在于，所述醚类溶剂为C5醚类，所述芳香烃类溶剂为C9芳香烃类，所述搅拌的温度为-20℃。
  22. 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的晶型，或权利要求8所述的化合物I的晶型，或权利要求15所述的化合物I的晶型，或任意两种晶型的任意混合，或三种晶型的任意混合及药学上可接受的辅料。
  23. 权利要求1中所述的化合物I的晶型，或权利要求8所述的化合物I的晶型，或权利要求15所述的化合物I的晶型，或任意两种晶型的任意混合，或三种晶型的任意混合在制备BTK抑制剂药物中的用途。
  24. 权利要求1中所述的化合物I的晶型，或权利要求8所述的化合物I的晶型，或权利要求15所述的化合物I的晶型，或任意两种晶型的任意混合，或三种晶型的任意混合在制备治疗多发性硬化症药物中的用途。
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