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WO2022121670A1 - 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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Publication number
WO2022121670A1
WO2022121670A1 PCT/CN2021/132028 CN2021132028W WO2022121670A1 WO 2022121670 A1 WO2022121670 A1 WO 2022121670A1 CN 2021132028 W CN2021132028 W CN 2021132028W WO 2022121670 A1 WO2022121670 A1 WO 2022121670A1
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Prior art keywords
compound
crystal form
preparation
csi
present
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PCT/CN2021/132028
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English (en)
French (fr)
Inventor
陈敏华
史佳明
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Crystal Pharmaceutical Suzhou Co Ltd
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Crystal Pharmaceutical Suzhou Co Ltd
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Priority to MX2023006854A priority Critical patent/MX2023006854A/es
Priority to CN202180083380.8A priority patent/CN118434732A/zh
Priority to IL303590A priority patent/IL303590A/en
Priority to EP21902377.7A priority patent/EP4261212A4/en
Priority to KR1020237023108A priority patent/KR102872880B1/ko
Priority to CA3201936A priority patent/CA3201936A1/en
Priority to AU2021398051A priority patent/AU2021398051A1/en
Priority to JP2023535327A priority patent/JP2023553930A/ja
Application filed by Crystal Pharmaceutical Suzhou Co Ltd filed Critical Crystal Pharmaceutical Suzhou Co Ltd
Publication of WO2022121670A1 publication Critical patent/WO2022121670A1/zh
Priority to US17/818,846 priority patent/US12049463B2/en
Anticipated expiration legal-status Critical
Priority to CONC2023/0008949A priority patent/CO2023008949A2/es
Priority to US18/676,250 priority patent/US20240391915A1/en
Ceased legal-status Critical Current

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    • 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
    • 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
    • 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
    • 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 crystalline form of Tolebrutinib and 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 both cellular and humoral immunity.
  • BTK signaling inhibitors exhibited dual effects on cellular and humoral immunity.
  • BTK-inhibiting compounds capable of inhibiting antigen-induced B cell activation responsible for neuroinflammation and modulating maladaptive microglia associated with neuroinflammation in the brain and spinal cord may be useful in the treatment of relapsing forms of multiple sclerosis ( relapsing multiple sclerosis, RMS), has better results than currently available treatments.
  • Tolebrutinib an oral selective BTK small molecule inhibitor, has shown safety and efficacy in the treatment of RMS patients.
  • Compound I The chemical name for Tolebrutinib is (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 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 poorly soluble 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.
  • WO2016196840A1 discloses the white solid of compound I, and the inventor of the present application repeats the preparation process of the compound to obtain the amorphous compound of compound I. Further, the inventors of the present application conducted a systematic evaluation of the amorphous properties, and the results showed that the amorphous compound I had problems such as poor stability, high hygroscopicity, and easy degradation, and was not suitable for medicinal use.
  • the inventors of the present application have carried out systematic research on compound I, and found that the compound is easily amorphous and difficult to crystallize.
  • the specific performance is that the inventors of the present application have designed a large number of preparation experiments, including different preparation methods, solvent systems and post-treatment processes, to try to obtain Compound I, which is not easy to crystallize, has good physical and chemical stability, low hygroscopicity, and is not easy to degrade.
  • the results are all amorphous compounds of Compound I, and no crystal form suitable for medicinal use has been obtained.
  • the inventor of the present application further tried more preparation methods, and finally obtained the crystal of compound I provided by the present invention unexpectedly.
  • the crystal has advantages in at least one aspect of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vitro and in vivo dissolution, bioavailability, etc., especially good stability and low hygroscopicity , is not easy to degrade, solves the problems existing in the prior art, and has very important significance for the development of medicines containing compound I.
  • the main purpose of the present invention is to provide a new crystal form of compound I and its preparation method and use.
  • the present invention provides a crystalline form of compound I.
  • crystal form of Compound I provided by the present invention may be crystal form CSI (hereinafter referred to as "crystal form CSI").
  • the X-ray powder diffraction pattern of the crystalline form CSI has a diffraction angle 2 ⁇ value of 1 of 7.7° ⁇ 0.2°, 11.0° ⁇ 0.2°, 22.8° ⁇ 0.2°, or 2 There are characteristic peaks at or at 3 positions; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2 ⁇ of 7.7° ⁇ 0.2°, 11.0° ⁇ 0.2°, and 22.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI has a diffraction angle 2 ⁇ value of 12.0° ⁇ 0.2°, 16.1° ⁇ 0.2°, 18.5° ⁇ 0.2°, or There are characteristic peaks at 2 or 3 places; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2 ⁇ of 12.0° ⁇ 0.2°, 16.1° ⁇ 0.2°, 18.5° ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the crystalline form CSI has a diffraction angle 2 ⁇ value of 13.6° ⁇ 0.2°, 20.1° ⁇ 0.2°, 24.8° ⁇ 0.2°, or There are characteristic peaks at 2 or 3 locations; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2 ⁇ of 13.6° ⁇ 0.2°, 20.1° ⁇ 0.2°, 24.8° ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the crystalline form CSI has diffraction angle 2 ⁇ values of 7.7° ⁇ 0.2°, 11.0° ⁇ 0.2°, 22.8° ⁇ 0.2°, 12.0° ⁇ 0.2° , 16.1° ⁇ 0.2°, 18.5° ⁇ 0.2°, 13.6° ⁇ 0.2°, 20.1° ⁇ 0.2°, 24.8° ⁇ 0.2°, 18.7° ⁇ 0.2° any one, or two, or three, Or 4 places, or 5 places, or 6 places, or 7 places, or 8 places, or 9 places, or 10 places have characteristic peaks.
  • the X-ray powder diffraction pattern of the crystalline form CSI is substantially as shown in FIG. 2 .
  • the differential scanning calorimetry analysis diagram of the crystalline form CSI is basically as shown in FIG. 6 , which begins to appear an endothermic peak near 170° C., and the endothermic peak is a melting endothermic peak.
  • thermogravimetric analysis diagram of the crystalline form CSI is substantially as shown in Figure 5, which has a mass loss of about 0.4% when heated from 31°C to 160°C.
  • the crystalline form CSI is anhydrous.
  • the present invention also provides a preparation method of the crystal form CSI, the preparation method comprising:
  • the compound I solid is placed in a ketone or ether solvent, stirred for a period of time under a certain temperature condition, and the solid is separated to obtain crystal form CSI;
  • ketones are preferably C3-C6 ketones
  • ether solvents are preferably C5 ethers.
  • the ketone is preferably 4-methyl-2-pentanone
  • the ether solvent is preferably methyl tert-butyl ether.
  • the stirring temperature is preferably room temperature-55°C, and the stirring time is preferably more than 25 hours.
  • the present invention provides the use of crystal form CSI for preparing other crystal forms or salts of compound I.
  • the present invention also provides a pharmaceutical composition comprising an effective therapeutic amount of Compound I crystal form and pharmaceutically acceptable excipients.
  • the present invention provides the use of the crystal form of compound I in the preparation of a BTK inhibitor medicine.
  • the present invention provides the use of the crystal form of compound I in the preparation of a medicament for the treatment of multiple sclerosis.
  • crystal form of the compound I is preferably crystal form CSI.
  • the inventors of the present application have studied the prior art and found that the prior art is the amorphous form of Compound I, and through research, it is found that the amorphous form of Compound I has poor chemical stability, is easy to degrade, has high hygroscopicity, is not suitable for medicinal use, and is not suitable for industrial use. production.
  • the present invention provides a crystal form of compound I, the crystal form has excellent physical and chemical stability and low hygroscopicity, and is suitable for the development of medicines containing compound I.
  • Example 1 It can be seen from Example 1 that Compound I is difficult to crystallize, and the preparation methods of various crystal forms can only obtain amorphous. Even in the preparation process, try a variety of crystal preparation methods, control multiple process conditions, such as: solvent types (alcohols, ketones, esters, ethers, acids, water, nitriles, amides, halogenated hydrocarbons, aromatic hydrocarbons, alkanes, sulfone, etc.), temperature, time, volatilization rate, additives and other factors, only amorphous can be obtained.
  • solvent types alcohols, ketones, esters, ethers, acids, water, nitriles, amides, halogenated hydrocarbons, aromatic hydrocarbons, alkanes, sulfone, etc.
  • the crystal form CSI of the present invention is obtained by the inventors of the present application, on the basis of the existing crystal form preparation experiments, by further trying to use a variety of unconventional solvents, and at the same time refining the preparation and post-processing conditions, and finally obtained unexpectedly. It can be seen that the crystal form CSI of the present invention is unpredictable for those skilled in the art.
  • the crystalline CSI API and preparation provided by the present invention have good stability.
  • the crystalline form of CSI API is sealed and placed openly at 25°C/60%RH, the crystal form has not changed for at least 6 months, and the chemical purity is above 99.8%, and the purity remains basically unchanged during storage.
  • the crystal form CSI is mixed with the excipients to make a pharmaceutical preparation, it is placed under the condition of 25°C/60% RH, and the crystal form does not change for 3 months. It shows that the crystalline form CSI API and preparation have good stability under long-term conditions, which is beneficial to the storage of the drug.
  • the crystalline form of CSI API has been sealed and opened for at least 6 months under the condition of 40°C/75%RH, and the crystal form has not changed, and the crystal form has been sealed and opened under the condition of 60°C/75%RH for at least 1 month.
  • the type did not change, and the chemical purity was above 99.8%, the purity remained basically unchanged during storage, and the purity did not change for at least 2 days at 80 °C.
  • the crystal form CSI is mixed with excipients to make a pharmaceutical preparation, and placed under the conditions of 40°C/75% RH, the crystal form has not changed for at least 3 months. It shows that the crystalline form of CSI APIs and preparations have better stability under accelerated conditions and more severe conditions.
  • Crystalline CSI APIs and preparations have better stability under harsh conditions, which is beneficial to avoid the impact on the quality of the drug due to crystallization or the decrease in purity during drug storage.
  • the impurity content of the crystalline CSI API did not exceed the defined limit in all the stability investigation processes, which could meet the requirements of pharmaceutical development.
  • the crystalline form CSI provided by the present invention has lower hygroscopicity.
  • the test results show that the wet weight gain of the crystal form CSI of the present invention is only 1/7 of that of the prior art solid.
  • the crystalline form CSI has a hygroscopic weight gain of 0.53%, which is slightly hygroscopic, and the prior art solid has a hygroscopic weight gain of 3.69% under the condition of 80% RH, which belongs to the hygroscopic property.
  • high hygroscopicity can easily cause chemical degradation and crystal 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, low requirements on storage conditions for industrial production, reduces material production, preservation and quality control costs, and has strong economic value.
  • Fig. 1 is the XRPD pattern of sample 1 of Example 1
  • Fig. 2 is the XRPD pattern of the crystal form CSI obtained in Example 2
  • Fig. 3 is the XRPD pattern of the crystal form CSI obtained in Example 3
  • Fig. 4 is the XRPD pattern of the crystal form CSI obtained in Example 4.
  • Figure 5 is the TGA diagram of the crystal form CSI
  • Figure 6 is the DSC chart of crystal form CSI
  • Figure 7 shows the XRPD stacks before and after the stability of the crystal form CSI (from top to bottom: before placing, placed open at 25°C/60%RH for 6 months, and placed 6 sealed at 25°C/60%RH) month, 6 months exposed at 40°C/75%RH, 6 months sealed at 40°C/75%RH, 1 month exposed at 60°C/75%RH, and 60°C/75%RH Sealed for 1 month)
  • PE polyethylene
  • HDPE High Density Polyethylene
  • the X-ray powder diffraction patterns of the present invention were collected on a Bruker X-ray powder diffractometer.
  • the method parameters of X-ray powder diffraction of the present invention 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
  • Hydrogen nuclear magnetic resonance data ( 1 H NMR) were obtained from a Bruker Avance II DMX 400M HZ 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 related substance detection method of the present invention adopts ultra-high performance liquid chromatography (UPLC), and the instrument parameters are as follows:
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring is preferably 300-900 rev/min, and the mechanical stirring It is 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, 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 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 "opening” refers to placing the sample in a glass bottle, covering the bottle mouth with a layer of aluminum foil and opening 5-10 small holes in the aluminum foil.
  • the “sealing” refers to placing the sample in a sealed glass bottle and sealing the glass bottle in an aluminum foil bag.
  • 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 intensities of the diffraction peaks in the X-ray powder diffraction pattern may also vary with the experimental conditions, so the intensity of the diffraction peaks 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 of the present invention is pure, substantially free from admixture with any other crystalline form.
  • 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 as a starting material includes, but is not limited to, solid form (crystalline or amorphous), oily, liquid form and solution.
  • the compound I as starting material is in solid form.
  • the inventors of the present application have tried various methods for preparing crystal forms and controlled various process conditions, such as: solvent types (alcohols, ketones, esters, ethers, acids, water, nitriles, amides, halogenated hydrocarbons, aromatic hydrocarbons, alkanes, sulfoxides etc.), temperature, time, volatilization rate, additives and other factors, more than one hundred experiments were carried out, all obtained amorphous. Some of the experimental methods and results are shown in Table 2-6.
  • the solid compound I of the mass shown in Table 3 was weighed and placed in a glass bottle, a certain volume of solvent was added to it, and after stirring for a certain period of time under a certain temperature condition, the solid was separated, and the obtained solid was all amorphous through XRPD detection.
  • the X-ray powder diffraction pattern of sample 1 is shown in FIG. 1 .
  • the solid compound I of the mass shown in Table 4 was weighed and placed in a glass bottle. After adding a certain volume of solvent and additives, it was volatilized at room temperature. After XRPD detection, the obtained solids were all amorphous.
  • Rapid volatilization The sample bottle is not covered with a cap, and the opening is open to volatilize.
  • TGA has a mass loss of about 0.4% when it is heated from 31°C to 160°C.
  • the DSC begins to appear an endothermic peak around 170°C, which is the melting endothermic peak of the crystalline form CSI.
  • the crystal form CSI 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 CSI is stable under long-term and accelerated conditions. Can maintain good stability. It can be stable for at least 1 month under the condition of 60°C/75%RH, and the crystal form and purity remain basically unchanged. It can be seen that the stability is also very good under more severe conditions. In the entire stability investigation process of crystal form CSI, the impurity content did not exceed the limit, which can meet the requirements of pharmaceutical development.
  • the prior art solids are placed under the conditions of 25°C/60%RH, 40°C/75%RH, and 60°C/75%RH, and the purity is obviously reduced, especially for 6 months at 40°C/75%RH.
  • Purity decreased by 3.46%, the number of impurities beyond the limit increased to 4; 60°C/75%RH sealed for 1 month, the purity decreased by 2.76%, the number of impurities beyond the limit increased to 2; 60°C/75
  • the purity decreased by more than 6.3%, and the number of impurities exceeding the defined limit increased to 4, which is far lower than the medicinal standard. It can be seen that, compared with the amorphous form of the prior art, the crystalline form CSI of the present invention has very superior chemical stability.
  • the experimental results show that the hygroscopic weight gain of the crystal form CSI is 0.53% under the condition of 80% RH, which is slightly hygroscopic.
  • the hygroscopicity of the crystal form CSI is better than that of the prior art.
  • Moisture gain is less than 15.0% but not less than 2.0%
  • wet weight gain is less than 2.0% but not less than 0.2%
  • wet weight gain is less than 0.2%
  • the CSI formulation packaged in Example 8 was placed under the conditions of 25°C/60%RH and 40°C/75%RH for 3 months, and the formulation stability of the crystal form CSI was investigated.
  • the XRPD comparison charts before and after placement of the formulation are shown in Figure 11.

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Abstract

提供Tolebrutinib(以下称为"化合物I")的晶型及其制备方法，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。Tolebrutinib的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)。在疾病的过程中，硬化，如病变或疤痕，出现在神经细胞的髓鞘中，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，最近的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。
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小分子抑制剂，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 PCTCN2021132028-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化合物的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的性质进行了系统评估，结果表明化合物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，本申请发明人对化合物I进行了系统研究，发现该化合物容易成无定形，不易结晶。具体表现为，本申请发明人设计了大量的制备实验，包括不同的制备方法、溶剂体系和后处理工艺，尝试得到不易转晶、物理化学稳定性好、引湿性低、不易降解的化合物I的固体形态，结果均为化合物I的无定形，未获得符合药用的晶型。本申请发明人进一步尝试更多的制备方法，最终意外得到了本发明提供的化合物I的结晶。该结晶在溶解度，引湿性，提纯效果，稳定性，黏附性，可压性，流动性，体内外溶出，生物有效性等方面中的至少一方面存在优势，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。
根据本发明的目的，本发明提供化合物I的晶型。
进一步地，本发明提供化合物I的晶型可以为晶型CSI(以下称作“晶型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7.7°±0.2°、11.0°±0.2°、22.8°±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为7.7°±0.2°、11.0°±0.2°、22.8°±0.2°处有特征峰。
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12.0°±0.2°、16.1°±0.2°、18.5°±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为12.0°±0.2°、16.1°±0.2°、18.5°±0.2°处有特征峰。
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13.6°±0.2°、20.1°±0.2°、24.8°±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为13.6°±0.2°、20.1°±0.2°、24.8°±0.2°处有特征峰。
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7.7°±0.2°、11.0°±0.2°、22.8°±0.2°、12.0°±0.2°、16.1°±0.2°、18.5°±0.2°、13.6°±0.2°、20.1°±0.2°、24.8°±0.2°、18.7°±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处有特征峰。
非限制性地，使用Cu-Kα辐射，晶型CSI的X射线粉末衍射图基本如图2所示。
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170℃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CSI的热重分析图基本如图5所示，其从31℃加热至160℃时，具有约0.4％的质量损失。
非限制性地，晶型CSI为无水物。
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：
将化合物I固体置于酮类或醚类溶剂中，在一定温度条件下搅拌一段时间，分离固体得 到晶型CSI；
进一步地，所述酮类优选C3-C6的酮，所述醚类溶剂优选C5的醚。
进一步地，所述酮类优选4-甲基-2-戊酮，所述醚类溶剂优选甲基叔丁基醚。
进一步地，所述搅拌温度优选室温-55℃，所述搅拌时间优选25小时以上。
根据本发明的目的，本发明提供晶型CSI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化合物I晶型及药学上可接受的辅料。
进一步地，本发明提供的化合物I的晶型在制备BTK抑制剂药物中的用途。
更进一步地，本发明提供的化合物I的晶型在制备治疗多发性硬化症药物中的用途。
更进一步地，所述化合物I的晶型优选为晶型CSI。
本发明解决的技术问题
本申请发明人研究现有技术，发现现有技术为化合物I的无定形，且通过研究发现化合物I的无定形化学稳定性差，易降解，引湿性高，不适合药用，也不适合产业上的生产。为解决现有技术存在的问题，本发明提供了一种化合物I的晶型，该晶型物理化学稳定性优异，引湿性低，适用于含化合物I药物的开发。
由实施例1可知，化合物I难结晶，多种晶型制备方法仅能获得无定形。即使在制备过程中尝试多种晶型制备方法，控制多个工艺条件，例如：溶剂种类(醇，酮，酯，醚，酸，水，腈，酰胺，卤代烃，芳香烃，烷烃，亚砜等)，温度，时间，挥发速度，添加物等因素，也只能获得无定形。本发明晶型CSI的获得，是本申请发明人在已有的晶型制备实验基础上，进一步尝试使用多种非常规溶剂，同时细化制备和后处理条件，最终意外得到的。由此可见，本发明晶型CSI获得对本领域技术人员而言具有不可预期性。
技术效果
本发明提供的晶型CSI具有以下预料不到的技术效果：
(1)现有技术固体在25℃/60％RH，40℃/75％RH，60℃/75％RH和80℃条件下放置，纯度均有明显降低，尤其是40℃/75％RH敞口放置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密封放置1个月，纯度降低2.76％，超出界定限的杂质个数增加至2个；60℃/75％RH敞口放置仅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。
与现有技术相比，本发明提供的晶型CSI原料药和制剂均具有良好的稳定性。晶型CSI原料药在25℃/60％RH条件下密封和敞口放置，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。晶型CSI与辅料混合做成药物制剂后，在25℃/60％RH条件下放置，至3个月晶型未发生变化。说明晶型CSI原料药和制剂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CSI原料药在40℃/75％RH条件下密封和敞口放置至少6个月晶型未发生变化，在60℃/75％RH条件下密封和敞口放置至少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℃条件下至少2天纯度没有变化。晶型CSI与辅料混合做成药物制剂后，在40℃/75％RH条件下放置，至少3个月晶型未发生变化。说明晶型CSI原料药和制剂在加速条件及更严苛的条件下，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， 原料药和制剂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原料药和制剂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。
此外，晶型CSI原料药在所有稳定性考察过程中，杂质含量均未超出界定限，能够满足药用开发的要求。
(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的引湿增重仅为现有技术固体的1/7。晶型CSI在80％RH条件下引湿性增重为0.53％，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CSI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为实施例1样品1的XRPD图
图2为实施例2所得晶型CSI的XRPD图
图3为实施例3所得晶型CSI的XRPD图
图4为实施例4所得晶型CSI的XRPD图
图5为晶型CSI的TGA图
图6为晶型CSI的DSC图
图7为晶型CSI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25℃/60％RH密封放置6个月，在40℃/75％RH敞口放置6个月，在40℃/75％RH密封放置6个月，在60℃/75％RH敞口放置1个月，在60℃/75％RH密封放置1个月)
图8晶型CSI的DVS图
图9现有技术无定形的DVS图
图10晶型CSI制剂前后的XRPD叠图(从上到下依次为：空白混粉，晶型CSI制剂工艺后，晶型CSI)
图11晶型CSI制剂稳定性放置前后的XRPD叠图(从上到下依次为：放置前，25℃/60％RH放置3个月，40℃/75％RH放置3个月)
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
PE：聚乙烯
LDPE：低密度聚乙烯
HDPE：高密度聚乙烯
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
Kα1
Figure PCTCN2021132028-appb-000002
1.54060；Kα2
Figure PCTCN2021132028-appb-000003
1.54439
Kα2/Kα1强度比例：0.50
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：
扫描速率：10℃/min
保护气体：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：
扫描速率：10℃/min
保护气体：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：
温度：25℃
载气，流速：N 2，200毫升/分钟
相对湿度范围：0％RH-95％RH
核磁共振氢谱数据( 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 PCTCN2021132028-appb-000004
Figure PCTCN2021132028-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“密封”是将样品置于密封的玻璃瓶中，并将玻璃瓶密封于铝箔袋中。
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CSI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：尝试制备化合物I固体形式
本申请发明人尝试多种晶型制备方法，控制多个工艺条件，例如：溶剂种类(醇，酮，酯，醚，酸，水，腈，酰胺，卤代烃，芳香烃，烷烃，亚砜等)，温度，时间，挥发速度，添加物等因素，进行了百个以上实验，均得到无定形。其中部分实验方法及结果见表2-6。
表2
Figure PCTCN2021132028-appb-000006
方法1：搅拌
称量如表3所示质量的化合物I固体置于玻璃瓶中，向其中加入一定体积溶剂，在一定温度条件下搅拌一定时间后，分离固体，经XRPD检测，所得的固体均为无定形。样品1的X射线粉末衍射图如图1所示。
表3
Figure PCTCN2021132028-appb-000007
Figure PCTCN2021132028-appb-000008
方法2：挥发
称量如表4所示质量的化合物I固体置于玻璃瓶中，向其中加入一定体积的溶剂和添加物后，在室温条件下挥发，经XRPD检测，所得的固体均为无定形。
表4
Figure PCTCN2021132028-appb-000009
快速挥发：样品瓶不盖瓶盖，敞口挥发。
慢速挥发：样品瓶盖紧瓶盖，瓶盖上留小孔。
方法3：气固渗透
称量如表5所示质量的化合物I固体置于玻璃瓶中，将玻璃瓶放入装有约5mL对应溶 剂的大玻璃瓶中，加盖密封大玻璃瓶后将其放置于一定温度条件下，以使溶剂气氛与小玻璃瓶中固体充分接触，1天后取瓶中固体，经XRPD检测，所得的固体均为无定形。
表5
样品 质量(mg) 溶剂 温度(℃) 固体形式
1 7.0 正己烷 室温 无定形
2 8.0 水 室温 无定形
3 7.6 二甲基亚砜 室温 无定形
4 9.9 N,N-二甲基乙酰胺 室温 无定形
5 13.0 苯甲醇 5 无定形
6 9.7 L-乳酸乙酯 5 无定形
7 13.1 石油醚 5 无定形
8 11.3 1,3-二氧五环 5 无定形
方法4：气液渗透
称量如表6所示质量的化合物I固体置于玻璃瓶中，向其中加入一定体积的正溶剂溶解样品后，将玻璃瓶敞口放入装有约5mL反溶剂的大玻璃瓶中，加盖密封大玻璃瓶后将其放置于室温条件下，以使反溶剂充分扩散到小玻璃瓶中，扩散进行不同时间后，分离固体，经XRPD检测，所得的固体均为无定形。
表6
Figure PCTCN2021132028-appb-000010
Figure PCTCN2021132028-appb-000011
上述实验结果可知，化合物I易形成无定形，难结晶。本申请发明人进一步尝试使用多种非常规溶剂，同时细化制备和后处理条件，最终意外得到了本发明提供的化合物I的结晶。见实施例2-4。
实施例2：晶型CSI的制备方法
称量300.8mg的化合物I固体加入3mL玻璃瓶中，加入2.0mL 4-甲基-2-戊酮，50℃搅拌约39小时，分离固体。经XRPD检测，所得固体为本发明所述晶型CSI，其X射线粉末衍射图如图2所示，X射线粉末衍射数据如表7所示。
表7
Figure PCTCN2021132028-appb-000012
Figure PCTCN2021132028-appb-000013
实施例3：晶型CSI的制备方法
称量300.1mg的化合物I固体至3mL玻璃瓶中，加入2.0mL的4-甲基-2-戊酮，50℃搅拌约6天，分离固体。经XRPD检测，所得的固体为本发明所述晶型CSI，其X射线粉末衍射图如图3所示，X射线粉末衍射数据如表8所示。
表8
Figure PCTCN2021132028-appb-000014
Figure PCTCN2021132028-appb-000015
实施例4：晶型CSI的制备
称量300.4mg的化合物I固体至玻璃瓶中，加入3.0mL的甲基叔丁基醚，50℃搅拌约68小时，分离固体，75℃真空干燥1h后，经XRPD检测，所得的固体为本发明所述晶型CSI，其X射线粉末衍射数据如表9，图4所示。
TGA如图5所示，将其从31℃加热至160℃时，具有约0.4％的质量损失。
DSC如图6所示，其在170℃附近开始出现一个吸热峰，该吸热峰为晶型CSI的熔化吸热峰。
1HNMR数据为： 1HNMR(400MHz,DMSO)δ(ppm)7.75(d,1H),7.52–7.36(m,4H),7.21(t,1H),7.14(t,J＝7.8Hz,4H),6.98(d,1H),6.91–6.76(m,1H),6.13(dd,J＝16.5,7.0Hz,1H),5.69(dd,J＝16.7,10.8Hz,1H),4.82(s,2H),4.50(t,J＝14.3Hz,1H),4.15(dd,J＝33.9,12.5Hz,2H),3.76(t,J＝13.0Hz,0.5H),3.16(t,J＝12.7Hz,0.5H),2.79–2.61(m,0.5H),2.45–2.29(m,J＝13.0,9.1Hz,1H),2.10–1.74(m,2H),1.66–1.37(m,1H)。(根据化合物I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9
Figure PCTCN2021132028-appb-000016
Figure PCTCN2021132028-appb-000017
实施例5：晶型CSI的物理化学稳定性
称取本发明制备得到的晶型CSI和现有技术无定形，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CSI稳定性放置前后的XRPD叠图如图7所示。
表10
Figure PCTCN2021132028-appb-000018
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CSI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CSI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CSI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敞口放置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密封放置1个月，纯度降低2.76％，超出界定限的杂质个数增加至2个；60℃/75％RH敞口放置仅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CSI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6：晶型CSI的高温稳定性
分别取约10mg本发明制备得到的晶型CSI与现有技术无定形，在80℃条件下放置2天，采用UPLC法测定起始纯度和最终纯度，结果如表11所示。
表11
Figure PCTCN2021132028-appb-000019
结果表明，晶型CSI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CSI在高温稳定性上有明显优势。
实施例7：晶型CSI的引湿性
称取适量本发明晶型CSI与现有技术无定形，采用动态水分吸附(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12所示。晶型CSI的DVS图如图8所示，无定形的DVS图如图9所示
表12
Figure PCTCN2021132028-appb-000020
实验结果表明，晶型CSI在80％RH条件下引湿性增重为0.53％，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CSI引湿性优于现有技术。
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8晶型CSI的制剂制备
称取适量本发明晶型CSI按照表13和表14的处方和工艺进行制片，并在制剂前后进行XRPD测试。制剂前后的XRPD图如图10所示，结果表明本发明晶型CSI在制剂处方工艺前后晶型稳定。
表13
Figure PCTCN2021132028-appb-000021
表14
Figure PCTCN2021132028-appb-000022
实施例9晶型CSI制剂中的稳定性
将实施例8中包装好的CSI制剂在25℃/60％RH以及40℃/75％RH条件下放置3个月，考察晶型CSI的制剂稳定性。制剂放置前后的XRPD对比图如图11所示。
结果表明，晶型CSI制剂在25℃/60％RH和40℃/75％RH条件下可以至少保持3个月稳定。
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 (12)

  1. 一种化合物I的晶型
    Figure PCTCN2021132028-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7.7°±0.2°、11.0°±0.2°、22.8°±0.2°中的至少1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12.0°±0.2°、16.1°±0.2°、18.5°±0.2°中的至少1处具有特征峰。
  4. 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13.6°±0.2°、20.1°±0.2°、24.8°±0.2°中的至少1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2所示。
  6. 一种权利要求2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固体置于酮类或醚类溶剂中，在一定温度条件下搅拌一段时间，分离得到。
  7. 权利要求6所述的制备方法，其特征在于，所述酮类为C3-C6的酮，所述醚类溶剂为C5的醚。
  8. 权利要求6所述的制备方法，其特征在于，所述酮类为4-甲基-2-戊酮，所述醚类溶剂为甲基叔丁基醚。
  9. 权利要求6所述的制备方法，其特征在于，所述搅拌的温度为室温-55℃，所述搅拌的时间为25小时以上。
  10. 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的晶型及药学上可接受的辅料。
  11. 权利要求1中所述的化合物I的晶型在制备BTK抑制剂药物中的用途。
  12. 权利要求1中所述的化合物I的晶型在制备治疗多发性硬化症药物中的用途。
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