WO2018233437A1 - 巴瑞克替尼的晶型及其制备方法 - Google Patents

巴瑞克替尼的晶型及其制备方法 Download PDF

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WO2018233437A1
WO2018233437A1 PCT/CN2018/088068 CN2018088068W WO2018233437A1 WO 2018233437 A1 WO2018233437 A1 WO 2018233437A1 CN 2018088068 W CN2018088068 W CN 2018088068W WO 2018233437 A1 WO2018233437 A1 WO 2018233437A1
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crystal form
ray powder
present
crystal
powder diffraction
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PCT/CN2018/088068
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English (en)
French (fr)
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陈敏华
张炎锋
刘启月
张晓宇
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苏州科睿思制药有限公司
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Priority to CN201880031307.4A priority Critical patent/CN110799512A/zh
Priority to US16/625,758 priority patent/US11124517B2/en
Publication of WO2018233437A1 publication Critical patent/WO2018233437A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • 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 invention relates to the field of chemical medicine, in particular to a crystal form of barretinib and a preparation method thereof.
  • Rheumatoid arthritis is a clinically important chronic systemic autoimmune inflammatory disease. Most patients with rheumatoid arthritis suffer from the chronic process of disease, using currently available therapies, which can also lead to progressive joint destruction, deformity, disability, and even early death.
  • JAK Junus kinase
  • JAK family members JAK kinase 1 (JAK1), JAK kinase 2 (JAK2), JAK kinase 3 (JAK3), and Tyrosine Kinase (TYK2).
  • JAK-dependent cytokines are involved in the pathogenesis of a variety of inflammatory and autoimmune diseases, and JAK inhibitors may be widely used to treat various inflammatory diseases.
  • Baricitinib was developed by Incyte and later licensed to Lilly to develop a selective JAK1 and JAK2 inhibitor for the treatment of rheumatoid arthritis. In the kinase assay, barretinib exhibited 100 times higher inhibition against JAK1 and JAK2 than JAK3. Barrickini has been approved for marketing in the European Union on February 13, 2017. The chemical name of the drug is: ⁇ 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl ⁇ acetonitrile, hereinafter referred to as compound (I).
  • Form P1 A free form crystal form of Barretinib disclosed in WO2015166434A1 (hereinafter referred to as "Form P1"), free form Form A disclosed in CN105693731A, which has been found by the present inventors, and Form A and Form P1 are substantially It is the same crystal form.
  • the novel crystalline form G of Barretinib provided by the present invention has more excellent properties in terms of solubility, stability, moisture permeability, density, adhesion, fluidity, etc., and is a preparation of a pharmaceutical preparation containing barrickinib. Providing new and better choices is of great importance for improving the bioavailability and efficacy of drugs.
  • the main object of the present invention is to provide a novel crystalline form of barretinib and a process for its preparation and use.
  • the present invention provides a crystalline form which is at least one of solubility, melting point, density, stability, dissolution, wettability, adhesion, fluidity, bioavailability, and processability, purification, formulation production, and the like. There are advantages.
  • the X-ray powder diffraction of the Form G has a characteristic peak at a diffraction angle 2 ⁇ of 10.9° ⁇ 0.2°, 16.5° ⁇ 0.2°, and 19.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form G has a characteristic peak at one or two or three places where the diffraction angle 2 ⁇ is 14.4° ⁇ 0.2°, 18.2° ⁇ 0.2°, 21.8° ⁇ 0.2°; preferably The X-ray powder diffraction of the Form G has a characteristic peak at a diffraction angle 2 ⁇ of 14.4° ⁇ 0.2°, 18.2° ⁇ 0.2°, and 21.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form G has a characteristic peak at one or two or three places where the diffraction angle 2 ⁇ is 22.8° ⁇ 0.2°, 23.8° ⁇ 0.2°, 26.9° ⁇ 0.2°; preferably The X-ray powder diffraction of the crystal form G has a characteristic peak at a diffraction angle 2 ⁇ of 22.8° ⁇ 0.2°, 23.8° ⁇ 0.2°, and 26.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form G is 10.9° ⁇ 0.2°, 14.4° ⁇ 0.2°, 16.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, 19.0° ⁇ 0.2°, 21.8° at the diffraction angle 2 ⁇ . 3, or 4, or 5, or 6, or 7, or 8, or 9 features at ⁇ 0.2°, 22.8° ⁇ 0.2°, 23.8° ⁇ 0.2°, 26.9° ⁇ 0.2° peak.
  • the X-ray powder diffraction pattern of Form G is as shown in FIG.
  • Another object of the present invention is to provide a process for the preparation of Form G comprising heating barretinib solid to 212 to 225 ° C and allowing to stand at room temperature to obtain Form G.
  • the solid is a solvate, preferably a chloroform solvate.
  • the method for preparing the Form G comprises heating the Barrickinib chloroform solvate from room temperature to 212 ° C, and after leaving for 10 minutes, the sample is taken out to be Form G.
  • the X-ray powder diffraction of the crystal form D has a characteristic peak at diffraction angles 2 ⁇ of 9.4° ⁇ 0.2°, 16.6° ⁇ 0.2°, and 19.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form D has a characteristic peak at one or more of diffraction angles 2 ⁇ of 17.5° ⁇ 0.2°, 25.5° ⁇ 0.2°, and 26.1° ⁇ 0.2°; preferably, the The X-ray powder diffraction of Form D has a characteristic peak at a diffraction angle 2 ⁇ of 17.5° ⁇ 0.2°, 25.5° ⁇ 0.2°, and 26.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form D has a characteristic peak at one or more of diffraction angles 2 ⁇ of 12.4° ⁇ 0.2°, 19.9° ⁇ 0.2°, and 21.3° ⁇ 0.2°; preferably, the The X-ray powder diffraction of Form D has a characteristic peak at a diffraction angle 2 ⁇ of 12.4° ⁇ 0.2°, 19.9° ⁇ 0.2°, and 21.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form D is 9.4° ⁇ 0.2°, 12.4° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.5° ⁇ 0.2°, 19.0° ⁇ at the diffraction angle 2 ⁇ . There are characteristic peaks at 0.2°, 19.9° ⁇ 0.2°, 21.3° ⁇ 0.2°, 25.5° ⁇ 0.2°, and 26.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form D is as shown in FIG.
  • Form D is a 1,4-dioxane solvate.
  • Another object of the present invention is to provide a method for preparing Form D, comprising:
  • the stirring time is preferably 1 day.
  • the X-ray powder diffraction of the Form E has a characteristic peak at a diffraction angle 2 ⁇ of 9.7° ⁇ 0.2°, 18.1° ⁇ 0.2°, and 19.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form E has a characteristic peak at one or more of the diffraction angle 2 ⁇ of 21.3° ⁇ 0.2°, 24.6° ⁇ 0.2°, and 27.7° ⁇ 0.2°; preferably, the The X-ray powder diffraction of Form E has a characteristic peak at a diffraction angle 2 ⁇ of 21.3 ° ⁇ 0.2 °, 24.6 ° ⁇ 0.2 °, and 27.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the Form E has a characteristic peak at one or more of the diffraction angle 2 ⁇ of 21.5° ⁇ 0.2°, 22.5° ⁇ 0.2°, and 26.6° ⁇ 0.2°; preferably, the The X-ray powder diffraction of Form E has a characteristic peak at a diffraction angle 2 ⁇ of 21.5° ⁇ 0.2°, 22.5° ⁇ 0.2°, and 26.6° ⁇ 0.2°.
  • the X-ray powder diffraction of Form E is 9.7 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 °, 19.1 ° ⁇ 0.2 °, 21.3 ° ⁇ 0.2 °, 21.5 ° ⁇ at diffraction angle 2 ⁇
  • the X-ray powder diffraction pattern of Form E is as shown in FIG.
  • Form E is a chloroform solvate.
  • Another object of the present invention is to provide a process for the preparation of Form E comprising:
  • the solid of barretinib is added to the reactor, and a chloroform solvent is added to form a suspension, which is stirred at room temperature for 0.5 to 7 days, and volatilized, and the obtained solid is a crystal form E; the stirring time is preferably 1 day.
  • the X-ray powder diffraction of the Form F has a characteristic peak at diffraction angles 2 ⁇ of 9.0° ⁇ 0.2°, 16.9° ⁇ 0.2°, and 18.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form F has a characteristic peak at one or more of diffraction angles 2 ⁇ of 17.3° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 26.3° ⁇ 0.2°; preferably, the The X-ray powder diffraction of Form F has a characteristic peak at a diffraction angle 2 ⁇ of 17.3° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 26.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form F has a characteristic peak at one or more of diffraction angles 2 ⁇ of 15.5° ⁇ 0.2°, 22.1 ⁇ °°, 23.6° ⁇ 0.2°; preferably, the The X-ray powder diffraction of Form F has characteristic peaks at diffraction angles 2 ⁇ of 15.5° ⁇ 0.2°, 22.1° ⁇ 0.2°, and 23.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form F is 9.0 ° ⁇ 0.2 °, 15.5 ° ⁇ 0.2 °, 16.9 ° ⁇ 0.2 °, 17.3 ° ⁇ 0.2 °, 18.1 ° ⁇ diffraction angle 2 ⁇
  • the X-ray powder diffraction pattern of Form F is as shown in FIG.
  • Form F is a methyl tert-butyl ether solvate.
  • Another object of the present invention is to provide a process for the preparation of Form F comprising:
  • Form E of Barretinib was placed in a reactor, methyl tert-butyl ether solvent was added, and the suspension was stirred at room temperature for at least 1 hour, and centrifuged to obtain a crystalline form F.
  • room temperature is not an accurate temperature value and refers to a temperature range of 10-30 °C.
  • the “stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the "centrifugation" operation was performed by placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until the solids all settled to the bottom of the centrifuge tube.
  • volatilization is carried out by a conventional method in the art.
  • the slow volatilization is to seal the container with a sealing film, puncture the hole, and let it stand for volatilization; the rapid volatilization is to place the container open and volatilize.
  • the barretinib free base and/or its salt as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the barretinib free base and/or its salt as a raw material is in the form of a solid powder.
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows for some variability.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of Form G of the invention together with at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the crystal form G of the present invention has the following advantageous effects as compared with the prior art crystal form (Form P1 or Form A):
  • the crystalline form G provided by the present invention has better solubility than the prior art.
  • the crystal form G of the present invention has a markedly improved solubility in a biological medium as compared with the prior art.
  • Form G has a 7-fold increase in solubility in FaSSIF, a 6-fold increase in FeSSIF, a 7-fold increase in water, and a 1.5-fold increase in solubility in SGF.
  • the significant increase in the solubility of Form G will help to improve the bioavailability of the drug, thereby improving the drug-forming properties and efficacy of the drug; while ensuring the efficacy of the drug, reducing the dose of the drug, thereby reducing the side effects of the drug and improving the drug safety.
  • the crystalline form G of the present invention has lower wettability than the prior art.
  • the test results show that the wettability of the crystal form G at any relative humidity of 0 to 95% is lower than that of the prior art, and the wettability of the prior art is 2 to 7 times that of the crystal form G.
  • the low wettability crystal form does not require special drying conditions in the preparation process, simplifies the preparation and post-treatment process of the drug, and is easy to industrialize; and the low wettability crystal form is advantageous for long-term storage of the drug. Due to the unsatisfactory storage conditions, the material storage and quality control costs will be greatly reduced, which has great economic value.
  • the crystalline form G of the present invention has a greater density than the prior art crystalline form.
  • the experimental results show that the bulk density and tap density of the crystal form G of the present invention are significantly better than those of the prior art crystal form.
  • the bulk density of the crystal form G is four times higher than that of the prior art crystal form, and the tap density of the crystal form G is three times higher than that of the prior art crystal form.
  • the density of crystal form G is large, which is conducive to large-scale production. The greater density can reduce dust, while at the same time reducing occupational hazards, reducing safety hazards and ensuring production safety.
  • the crystalline form G of the present invention has better fluidity than the prior art crystalline form.
  • the fluidity evaluation results show that the crystal form G has good fluidity, while the prior art crystal form has poor fluidity.
  • the better fluidity of Form G can effectively increase the production speed of tableting and filling, and improve production efficiency; it does not need to use some expensive special excipients to improve liquidity and reduce the cost of excipients;
  • the feasibility of direct compression and direct filling of the powder can be improved, the production process is greatly simplified, and the production cost is reduced.
  • the better flowability of the crystal form G ensures the uniformity of the preparation and the uniformity of the content, reduces the weight difference of the dosage form, and improves the product quality.
  • the crystal form G of the present invention has superior adhesion to the prior art crystal form.
  • the results of adhesion evaluation showed that the adsorption amount of the crystal form G was much lower than that of the prior art crystal form, and the adsorption amount of the prior art crystal form was more than three times that of the crystal form G. From the point of view of product quality, the low adhesion of crystal form G can effectively improve or avoid the phenomenon of sticky wheel and sticking caused by dry granulation and tablet tableting, which is beneficial to improve product appearance and weight difference.
  • the low adhesion of Form G can effectively reduce the agglomeration of raw materials, reduce the adsorption between materials and utensils, facilitate the dispersion of raw materials and mixing with other excipients, increase the mixing uniformity of materials and the final product. Content uniformity.
  • the crystalline form G of the present invention has good physical stability.
  • Form G is stable for at least 6 months under the long-term stability conditions (25 ° C / 60% relative humidity) in the Chinese Pharmacopoeia, and accelerated stability conditions in the Chinese Pharmacopoeia (40 ° C / 75% relative humidity) It can be stable for at least 6 months under the more intense high temperature and high humidity conditions (60 ° C / 75% relative humidity and 80 ° C) for at least one week, which proves that Form G has very good physical stability. .
  • As the most critical active ingredient in the drug it is important that the crystal form has good physical and chemical stability.
  • the crystal form has good physical stability, ensuring that the bulk drug is not easily converted into other crystal forms during storage and formulation processes, thereby ensuring consistent and controllable sample quality.
  • the crystal form has good chemical stability, and the purity is basically unchanged during the storage process, which is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
  • the stable crystal form is more controllable during the crystallization process, and impurities and mixed crystals are less likely to occur, which is advantageous for industrial production.
  • Figure 1 is an XRPD pattern of Form G
  • Figure 2 is an XRPD pattern of Form D
  • Figure 3 is a DSC diagram of Form D
  • Figure 4 is a TGA diagram of Form D
  • Figure 5 is an XRPD pattern of Form E
  • Figure 6 is a DSC diagram of Form E
  • Figure 7 is a TGA diagram of Form E
  • Figure 8 is an XRPD pattern of Form F
  • Figure 9 is a DSC diagram of Form F
  • Figure 10 is a TGA diagram of Form F
  • Figure 11 is a 1 H NMR chart of Form G
  • Figure 12 is a DVS diagram of Form G
  • Figure 13 is a DVS diagram of the crystal form in WO2015166434A1
  • Figure 14 is a comparison of XRPD before and after crystal G DVS
  • Figure 15 is a DSC diagram of Form G
  • Figure 16 is a TGA diagram of Form G
  • Figure 17 is a comparison of XRPD of the crystal form G stability study (from top to bottom: initial crystal form G, placed at 25 ° C / 60% relative humidity for 6 months, placed at 40 ° C / 75% relative humidity 6 Month, placed at 60 ° C / 75% relative humidity for 1 week, placed at 80 ° C for 1 week XRPD)
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • H NMR data (1 HNMR) collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • Barretinib Form E 2 mg was raised from room temperature to 212 ° C on a DSC at a rate of 10 ° C/min. After 10 minutes of equilibration, samples were taken for detection. The sample obtained was examined by XRPD as Form G.
  • the X-ray powder diffraction data is shown in Fig. 1, and the XRPD data thereof is shown in Table 1.
  • the DSC pattern of Form G is shown in Figure 15. An endothermic peak appears near the temperature of 218 ° C; its TGA pattern is shown in Figure 16. When heated to 150 ° C, it has a mass loss of about 1.6%.
  • Diffraction angle 2 ⁇ d value strength% 9.44 9.37 64.72 9.69 9.13 66.67 11.95 7.41 5.01 16.06 5.52 14.69 16.85 5.26 9.58 18.10 4.90 100.00 18.33 4.84 91.75 19.06 4.66 58.91 19.27 4.61 52.75 21.31 4.17 39.65 21.45 4.14 25.91 22.54 3.94 15.53 24.60 3.62 28.66 26.58 3.35 18.93 27.75 3.22 31.84 29.49 3.03 15.41 30.19 2.96 10.78 31.93 2.80 3.64 32.96 2.72 6.37
  • Gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting intestinal fluid), FeSSIF (simulated feeding intestinal fluid) are biologically relevant media, and such media can better reflect the gastrointestinal physiological environment for drug release.
  • SGF simulated gastric fluid
  • FaSSIF simulated fasting intestinal fluid
  • FeSSIF simulated feeding intestinal fluid
  • Form G can be stable for at least 6 months at 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity, and can be stable for at least one week at 60 ° C / 75% relative humidity and 80 ° C. Form G maintains good stability under both long-term and accelerated conditions.
  • the DVS of Form G is shown in Figure 12, and the DVS of the prior art form is shown in Figure 13.
  • the XRPD pattern before and after the crystal form G DVS test is shown in Fig. 14, and it can be seen that there is no change in the crystal form G before and after DVS.
  • the results of the wettability test are shown in Table 7. The results show that the wettability of the prior art is 2 to 7 times that of the crystal form G under different relative humidity conditions, and the crystal form G of the present invention has better wettability.
  • the density of the powder is mainly represented by the bulk density and the tap density, wherein the bulk density is the density obtained by dividing the mass of the powder by the volume of the container occupied by the powder, which is also called the bulk density.
  • Tap density refers to the mass of the powder divided by the density of the powder tapped to the tightest volume.
  • Compressibility is generally used to evaluate the fluidity of the powder or intermediate particles, i.e., the degree of compression (c), during the formulation process.
  • Compression also known as the Compressibility Index or the Carr Index, is an important indicator for evaluating liquidity.
  • the criteria for defining the fluidity of the powder are shown in Table 9.

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Abstract

本发明公开了巴瑞克替尼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JAK激酶抑制剂和治疗类风湿性关节炎药物制剂中的用途。本发明提供的巴瑞克替尼新晶型比现有技术具有一种或多种改进的特性，对未来该药物的优化和开发具有重要价值。

Description

巴瑞克替尼的晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及巴瑞克替尼的晶型及其制备方法。
背景技术
类风湿性关节炎(Rheumatoid Arthritis)是临床上重要的慢性全身性自身免疫性炎性疾病。大多数类风湿性关节炎患者会遭受疾病的慢性过程，即使用目前可用的疗法，所述疾病也可能导致进行性关节破坏、畸形、残疾，甚至早期死亡。
JAK(Janus kinase)激酶是一个细胞内非受体酪氨酸激酶家族。目前有四种已知的JAK家族成员：JAK激酶1(JAK1)、JAK激酶2(JAK2)、JAK激酶3(JAK3)和酪氨酸激酶2(Tyrosine Kinase,TYK2)。JAK-依赖性细胞因子参与多种炎症和自身免疫性疾病的发病过程，JAK抑制剂或可广泛用于治疗各种炎性疾病。
巴瑞克替尼(Baricitinib)是因塞特(Incyte)公司开发，后授权给礼来(Lilly)制药开发的一种选择性的JAK1和JAK2抑制剂，用于类风湿性关节炎的治疗，在激酶检测中，巴瑞克替尼针对JAK1和JAK2表现出的抑制强度要比JAK3高100倍。巴瑞克替尼已于2017年2月13日获得欧盟批准上市，该药物的化学名称为：{1-(乙基磺酰基)-3-[4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈，以下称为化合物(I)。
Figure PCTCN2018088068-appb-000001
在药物研究领域，不同的药物晶型具有不同的颜色、熔点、溶解度、溶出性能、化学稳定性、机械稳定性等，这些特性可以影响药物制剂的质量、安全性和有效性，从而导致临床药效差异。因此，晶型研究和控制成为药物研发过程中的重要研究内容。
WO2015166434A1中公开的巴瑞克替尼的一种游离形式晶型(以下称“晶型P1”)，CN105693731A公开的游离形式晶型A，经本发明人研究发现，晶型A与晶型P1实质为相同晶型。
有必要进行全面的晶型筛选，得到更多性质优异的晶型。本发明提供的巴瑞克替尼的新晶型G在溶解度、稳定性、引湿性、密度、黏附性、流动性等方面具有更优异的性质，为含巴瑞克替尼的药物制剂的制备提供了新的更好的选择，对于提高药物的生物利用度和疗效具有非常重要的意义。
发明内容
本发明的主要目的是提供巴瑞克替尼的新晶型及其制备方法和用途。
本发明提供的晶型，其在溶解度、熔点、密度、稳定性、溶出度、引湿性、黏附性、 流动性、生物有效性以及加工性能、提纯作用、制剂生产等方面中的至少一方面上存在优势。
本发明的一个目的是提供一种巴瑞克替尼的新晶型，命名为晶型G。
使用Cu-Kα辐射，所述晶型G的X射线粉末衍射在衍射角2θ为10.9°±0.2°、16.5°±0.2°、19.0°±0.2°处具有特征峰。
进一步地，所述晶型G的X射线粉末衍射在衍射角2θ为14.4°±0.2°、18.2°±0.2°、21.8°±0.2°的一处或两处或三处有特征峰；优选地，所述晶型G的X射线粉末衍射在衍射角2θ为14.4°±0.2°、18.2°±0.2°、21.8°±0.2°处有特征峰。
进一步地，所述晶型G的X射线粉末衍射在衍射角2θ为22.8°±0.2°、23.8°±0.2°、26.9°±0.2°的一处或两处或三处有特征峰；优选地，所述晶型G的X射线粉末衍射在衍射角2θ为22.8°±0.2°、23.8°±0.2°、26.9°±0.2°处有特征峰。
进一步地，所述晶型G的X射线粉末衍射在衍射角2θ为10.9°±0.2°、14.4°±0.2°、16.5°±0.2°、18.2°±0.2°、19.0°±0.2°、21.8°±0.2°、22.8°±0.2°、23.8°±0.2°、26.9°±0.2°处有3个、或4个、或5个、或6个、或7个、或8个、或9个特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型G的X射线粉末衍射谱图如图1所示。
本发明的另一个目的是提供晶型G的制备方法，包括将巴瑞克替尼固体加热至212～225℃，室温下静置得到晶型G。
进一步地，所述固体为溶剂合物，优选为氯仿溶剂合物。
在一个优选的实施方案中，所述晶型G的制备方法，包括将巴瑞克替尼氯仿溶剂合物从室温加热到212℃，保留10分钟后，取出样品即为晶型G。
本发明的一个目的是提供一种巴瑞克替尼的新晶型，命名为晶型D。
使用Cu-Kα辐射，所述晶型D的X射线粉末衍射在衍射角2θ为9.4°±0.2°、16.6°±0.2°、19.0°±0.2°处具有特征峰。
进一步地，所述晶型D的X射线粉末衍射在衍射角2θ为17.5°±0.2°、25.5°±0.2°、26.1°±0.2°的一处或多处有特征峰；优选地，所述晶型D的X射线粉末衍射在衍射角2θ为17.5°±0.2°、25.5°±0.2°、26.1°±0.2°处有特征峰。
进一步地，所述晶型D的X射线粉末衍射在衍射角2θ为12.4°±0.2°、19.9°±0.2°、21.3°±0.2°的一处或多处有特征峰；优选地，所述晶型D的X射线粉末衍射在衍射角2θ为12.4°±0.2°、19.9°±0.2°、21.3°±0.2°处有特征峰。
在一个优选的实施方案中，所述晶型D的X射线粉末衍射在衍射角2θ为9.4°±0.2°、12.4°±0.2°、16.6°±0.2°、17.5°±0.2°、19.0°±0.2°、19.9°±0.2°、21.3°±0.2°、25.5°±0.2°、26.1°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型D的X射线粉末衍射谱图如图2所示。
非限制地，在本发明的一个具体实施方案中，晶型D是1,4-二氧六环溶剂合物。
本发明的另一个目的是提供晶型D的制备方法，包括：
将巴瑞克替尼的固体放入反应器中，加入1,4-二氧六环溶剂，形成混悬液于室温下搅拌1～7天，离心出固体，所得固体为晶型D；所述搅拌时间优选1天。
本发明的一个目的是提供一种巴瑞克替尼的新晶型，命名为晶型E。
使用Cu-Kα辐射，所述晶型E的X射线粉末衍射在衍射角2θ为9.7°±0.2°、18.1°±0.2°、19.1°±0.2°处具有特征峰。
进一步地，所述晶型E的X射线粉末衍射在衍射角2θ为21.3°±0.2°、24.6°±0.2°、27.7°±0.2°的一处或多处有特征峰；优选地，所述晶型E的X射线粉末衍射在衍射角2θ为21.3°±0.2°、24.6°±0.2°、27.7°±0.2°处有特征峰。
进一步地，所述晶型E的X射线粉末衍射在衍射角2θ为21.5°±0.2°、22.5°±0.2°、26.6°±0.2°的一处或多处有特征峰；优选地，所述晶型E的X射线粉末衍射在衍射角2θ为21.5°±0.2°、22.5°±0.2°、26.6°±0.2°处有特征峰。
在一个优选的实施方案中，所述晶型E的X射线粉末衍射在衍射角2θ为9.7°±0.2°、18.1°±0.2°、19.1°±0.2°、21.3°±0.2°、21.5°±0.2°、22.5°±0.2°、24.6°±0.2°、26.6°±0.2°、27.7°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型E的X射线粉末衍射谱图如图5所示。
非限制地，在本发明的一个具体实施方案中，晶型E是氯仿溶剂合物。
本发明的另一个目的是提供晶型E的制备方法，包括：
将巴瑞克替尼的固体加入到反应器中，加入氯仿溶剂，形成混悬液于室温下搅拌0.5～7天，挥发，所得固体为晶型E；所述搅拌时间优选1天。
本发明的一个目的是提供一种巴瑞克替尼的新晶型，命名为晶型F。
使用Cu-Kα辐射，所述晶型F的X射线粉末衍射在衍射角2θ为9.0°±0.2°、16.9°±0.2°、18.1°±0.2°处具有特征峰。
进一步地，所述晶型F的X射线粉末衍射在衍射角2θ为17.3°±0.2°、20.0°±0.2°、26.3°±0.2°的一处或多处有特征峰；优选地，所述晶型F的X射线粉末衍射在衍射角2θ为17.3°±0.2°、20.0°±0.2°、26.3°±0.2°处有特征峰。
进一步地，所述晶型F的X射线粉末衍射在衍射角2θ为15.5°±0.2°、22.1°±0.2°、23.6°±0.2°的一处或多处有特征峰；优选地，所述晶型F的X射线粉末衍射在衍射角2θ为15.5°±0.2°、22.1°±0.2°、23.6°±0.2°处有特征峰。
在一个优选的实施方案中，所述晶型F的X射线粉末衍射在衍射角2θ为9.0°±0.2°、15.5°±0.2°、16.9°±0.2°、17.3°±0.2°、18.1°±0.2°、20.0°±0.2°、22.1°±0.2°、23.6°±0.2°、26.3°±0.2°处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型F的X射线粉末衍射谱图如图8所示。
非限制地，在本发明的一个具体实施方案中，晶型F是甲基叔丁基醚溶剂合物。
本发明的另一个目的是提供晶型F的制备方法，包括：
将巴瑞克替尼的晶型E放置于反应器中，加入甲基叔丁基醚溶剂，形成混悬液于室温下搅拌至少1小时，离心，所得固体为晶型F。
在本发明的晶型的制备方法中：
所述“室温”不是精确的温度值，是指10-30℃温度范围。
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，优选300～900转/分钟。
“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。
所述“挥发”，采用本领域的常规方法完成，例如缓慢挥发是将容器封上封口膜，扎孔，静置挥发；快速挥发是将容器敞口放置挥发。
根据本发明，作为原料的所述巴瑞克替尼游离碱和/或其盐指其固体(晶型或无定形)、半固体、蜡或油形式。优选地，作为原料的所述巴瑞克替尼游离碱和/或其盐为固体粉末形式。
本发明中，“晶体”或“晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的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图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
此外，本发明提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的本发明的晶型G以及至少一种药学上可接受的载体、稀释剂或赋形剂。
进一步地，本发明提供的晶型G在制备JAK激酶抑制剂药物制剂中的用途。
更进一步地，本发明提供的晶型G在制备治疗自身免疫疾病的药物制剂中的用途。
更进一步地，本发明提供的晶型G在制备治疗类风湿性关节炎药物制剂中的用途。
与现有技术晶型(晶型P1或晶型A)相比，本发明晶型G具有下述有益效果：
1)本发明提供的晶型G比现有技术具有更好的溶解度。本发明晶型G与现有技术相比，在生物介质中的溶解度均有显著的提高。特别地，晶型G在FaSSIF中的溶解度提高了7倍，在FeSSIF中提高了6倍，在水中提高了7倍，在SGF中的溶解度提高了1.5倍。晶 型G的溶解度的显著提高将有助于提高药物的生物利用度，从而提高药物的成药性及药效；在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。
2)本发明晶型G相比现有技术具有更低的引湿性。测试结果表明，晶型G在0～95％任意相对湿度下的引湿性均低于现有技术，现有技术的引湿性是晶型G引湿性的2～7倍。低引湿性的晶型在制备过程中无需特殊的干燥条件，简化了药物的制备与后处理工艺，易于工业化生产；并且，低引湿性晶型有利于药品的长期贮存。由于对储存条件要求不苛刻，将大大降低物料储存以及质量控制成本，具有很强的经济价值。
3)本发明晶型G相比于现有技术晶型具有更大的密度。实验结果表明：本发明晶型G的松密度与振实密度均明显优于现有技术晶型。特别地，晶型G的松密度比现有技术晶型高4倍，晶型G的振实密度比现有技术晶型高3倍。晶型G的密度大，有利于大规模生产，更大的密度可减少粉尘，同时又能降低职业危害，减少安全隐患，保障生产安全。
4)本发明晶型G相比于现有技术晶型具有更好的流动性。流动性评价结果表明，晶型G流动性好，而现有技术晶型流动性很差。从生产效率及成本的角度看，晶型G更好的流动性可以有效提升压片和充填的生产速度，提升生产效率；无需使用一些昂贵的特殊辅料改善流动性，减少了辅料的成本支出；此外，可以提高直接压片和粉末直接充填的可行性，大大简化生产工艺，降低生产成本。从产品质量的角度看，晶型G更好的流动性能保证制剂的混合均匀度及含量均匀度、降低剂型的重量差异，提升产品质量。
5)本发明晶型G相比于现有技术晶型具有更优的黏附性。黏附性评价结果表明，晶型G的吸附量远低于现有技术晶型的吸附量，现有技术晶型的吸附量是晶型G的3倍多。从产品质量的角度看，晶型G的黏附性低可有效改善或者避免干法制粒和片剂压片等环节引起的黏轮、黏冲等现象，有利于改善产品外观、重量差异等。此外，晶型G的黏附性低还能有效减少原料的团聚现象，减少物料和器具之间的吸附，利于原料的分散及与其他辅料的混合，增加物料混合时的混合均匀度及终产品的含量均匀度。
6)本发明晶型G具有较好的物理稳定性。晶型G在《中国药典》中的长期稳定性条件(25℃/60％相对湿度)下至少可稳定6个月，在《中国药典》中的加速稳定性条件(40℃/75％相对湿度)下至少可稳定6个月，在更加激烈的高温和高湿条件(60℃/75％相对湿度和80℃)下放置至少可稳定一周，由此证明晶型G具有非常好的物理稳定性。作为药物中最关键的活性成分，晶型具有良好的物理和化学稳定性至关重要。晶型具有良好的物理稳定性，保证原料药在存储和制剂工艺过程中，不容易转变成其它晶型，从而保证样品的质量一致可控。晶型具有良好的化学稳定性，储存过程中纯度基本不变，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。此外，稳定的晶型在结晶工艺过程中更加可控，不容易出现杂质和混晶，利于工业化生产。
附图说明
图1为晶型G的XRPD图
图2为晶型D的XRPD图
图3为晶型D的DSC图
图4为晶型D的TGA图
图5为晶型E的XRPD图
图6为晶型E的DSC图
图7为晶型E的TGA图
图8为晶型F的XRPD图
图9为晶型F的DSC图
图10为晶型F的TGA图
图11为晶型G的 1HNMR图
图12为晶型G的DVS图
图13为WO2015166434A1中晶型的DVS图
图14为晶型G DVS前后的XRPD对比图
图15为晶型G的DSC图
图16为晶型G的TGA图
图17为晶型G稳定性研究的XRPD对比图(由上至下分别为：起始晶型G，25℃/60％相对湿度下放置6个月，40℃/75％相对湿度下放置6个月，60℃/75％相对湿度下放置1周，80℃下放置1周的XRPD图)
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施。
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
1HNMR：液态核磁氢谱
本发明所述的X射线粉末衍射图在Panalytical Empyrean 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射线反射参数：Cu,Kα
Kα1
Figure PCTCN2018088068-appb-000002
：1.540598；Kα2
Figure PCTCN2018088068-appb-000003
：1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
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：氮气
本发明所述的热重分析(TGA)图在TA Q5000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：氮气
核磁共振氢谱数据( 1HNMR)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。
实施例1
巴瑞克替尼晶型G的制备方法：
将2mg的巴瑞克替尼晶型E在DSC上以10℃/分钟的速率从室温升到212℃，平衡10分钟后取出样品检测。经XRPD检测，所得样品为晶型G。其X射线粉末衍射数据如图1，其XRPD数据如表1所示。晶型G的DSC图如图15所示，加热至218℃附近出现一个吸热峰；其TGA图如图16所示，加热至150℃时，具有约1.6％的质量损失。晶型G的 1HNMR如图11所示，具体数据如下：δH(400MHz,DMSO)12.14(1H,s),8.93(1H,s),8.71(1H,s),8.48(1H,s),7.62(1H,s),7.08(1H,d,J3.4),4.60(2H,d,J9.1),4.24(2H,d,J9.1),3.69(2H,s),3.24(2H,q,J7.4),1.25(3H,t,J7.3).
表1
衍射角2θ d值 强度％
10.89 8.12 13.97
14.41 6.15 20.76
16.53 5.36 26.89
18.23 4.87 22.48
19.03 4.66 100.00
19.65 4.52 6.95
20.52 4.33 6.78
21.29 4.17 9.90
21.78 4.08 20.51
22.82 3.90 14.85
23.30 3.82 5.28
23.77 3.74 8.43
25.16 3.54 7.78
26.94 3.31 13.34
28.56 3.13 6.77
29.62 3.02 6.32
31.66 2.83 3.73
32.96 2.72 2.76
34.47 2.60 2.22
实施例2
巴瑞克替尼晶型D的制备方法：
称取59.1mg的巴瑞克替尼晶型(WO2015166434A1)放入1.5mL的玻璃瓶中，加入1mL的1,4-二氧六环，形成混悬液于室温下搅拌1天，离心出固体经检测，经XRPD检测，所得固体为晶型D。其X射线粉末衍射数据如图2，表2所示。晶型D的DSC图如图3所示，加热至86℃时出现一个吸热峰，为脱溶剂信号；其TGA图如图4所示，加热至110℃时约有14.1％的质量损失。
表2
衍射角2θ d值 强度％
9.39 9.42 100.00
12.42 7.13 11.80
12.66 6.99 8.83
13.90 6.37 7.98
14.53 6.10 3.87
15.33 5.78 7.45
16.22 5.46 23.78
16.60 5.34 33.61
17.52 5.06 23.64
18.00 4.93 2.51
18.97 4.68 30.35
19.24 4.61 27.37
19.88 4.47 11.66
20.30 4.37 4.17
21.28 4.17 9.29
21.96 4.05 6.82
22.29 3.99 8.63
22.82 3.90 4.88
24.07 3.70 1.62
25.12 3.55 14.52
25.50 3.49 17.43
26.05 3.42 18.22
26.50 3.36 10.54
26.78 3.33 6.72
28.23 3.16 1.16
29.89 2.99 2.37
35.54 2.53 1.37
36.62 2.45 1.49
37.58 2.39 1.75
实施例3
巴瑞克替尼晶型E的制备方法：
将106.3mg的巴瑞克替尼化合物溶解于1.0mL冰醋酸中，室温下缓慢挥发，得到固体。称取10.0mg的上述固体于1.5mL的玻璃瓶中，加入0.5mL的氯仿溶剂，形成混悬液于室温下搅拌1天后挥发出氯仿得到固体经检测，经XRPD检测，所得固体为晶型E。其X射线粉末衍射数据如图5，表3所示。晶型E的DSC图如图6所示，加热至93℃时出现一个吸热峰，为脱溶剂信号；其TGA图如图7所示，加热至120℃时约有24.1％的质量损失。
表3
衍射角2θ d值 强度％
9.44 9.37 64.72
9.69 9.13 66.67
11.95 7.41 5.01
16.06 5.52 14.69
16.85 5.26 9.58
18.10 4.90 100.00
18.33 4.84 91.75
19.06 4.66 58.91
19.27 4.61 52.75
21.31 4.17 39.65
21.45 4.14 25.91
22.54 3.94 15.53
24.60 3.62 28.66
26.58 3.35 18.93
27.75 3.22 31.84
29.49 3.03 15.41
30.19 2.96 10.78
31.93 2.80 3.64
32.96 2.72 6.37
实施例4
巴瑞克替尼晶型F的制备方法：
称取10.7mg的巴瑞克替尼晶型E于1.5mL的玻璃瓶中，加入0.5mL的甲基叔丁基醚，形成混悬液于室温下搅拌1小时后，离心出固体经检测。经XRPD检测，所得样品为晶型F。其X射线粉末衍射数据如图8，表4所示。晶型F的DSC图如图9所示，加热至82℃时出现一个吸热峰，为脱溶剂信号；其TGA图如图10所示，加热至120℃时约有18.6％的质量损失。
表4
衍射角2θ d值 强度％
4.18 21.12 1.00
5.15 17.16 2.34
8.98 9.85 100.00
10.36 8.54 1.44
11.53 7.67 3.70
12.41 7.14 1.21
14.33 6.18 0.89
15.52 5.71 13.39
16.87 5.26 19.81
17.25 5.14 15.16
18.10 4.90 34.85
19.42 4.57 5.30
19.74 4.50 10.16
20.04 4.43 18.27
21.34 4.16 1.55
22.07 4.03 10.76
23.45 3.79 10.81
23.61 3.77 12.61
24.37 3.65 8.83
25.10 3.55 1.85
26.15 3.41 14.20
26.25 3.39 15.18
27.16 3.28 5.38
27.83 3.21 2.45
29.10 3.07 4.85
31.90 2.81 3.44
32.60 2.75 2.76
35.30 2.54 0.51
实施例5
晶型G的动态溶解度：
胃肠道液体例如SGF(模拟胃液)、FaSSIF(模拟禁食状态肠液)、FeSSIF(模拟喂食状态肠液)属于生物相关介质，此类介质能更好地反映胃肠道生理环境对药物释放产生的影响，在此类介质中测试的溶解度与人体环境中的溶解度更加接近。取本发明的晶型G及现有技术晶型各20mg分别溶于1.5mL的SGF(模拟胃液)、1.5mL的FaSSIF(模拟禁食状态肠液)、1.5mL的FeSSIF(模拟喂食状态肠液)及1.5mL的水配制成饱和溶液，平衡1小时、4小时和24小时后分别用高效液相色谱法测试饱和溶液中样品的含量(mg/mL)，结果如表5所示。
表5
Figure PCTCN2018088068-appb-000004
由表5动态溶解度结果可知，本发明的晶型G在每个取样点的溶解度均远高于现有技术晶型，表明晶型G在SGF、FaSSIF、FeSSIF和水中比现有技术晶型具有更好的溶解度。特别是在FaSSIF、FeSSIF和水介质中，晶型G的溶解度相比于现有技术晶型提升高达7倍，能有效促进药物生物利用度的提高。
实施例6
晶型G的稳定性：
称取本发明制备得到的巴瑞克替尼晶型G各5mg，分别放置在25℃/60％相对湿度、40℃/75％相对湿度、60℃/75％相对湿度、80℃条件下，采用XRPD测定晶型的变化。结果如表6所示，XRPD对比图如图17所示。
表6
Figure PCTCN2018088068-appb-000005
结果表明，晶型G在25℃/60％相对湿度和40℃/75％相对湿度条件下至少可稳定6个月，60℃/75％相对湿度和80℃条件下放置至少可稳定一周，可见，晶型G在长期和加速条件下均可保持良好的稳定性。
实施例7
晶型G的引湿性：
称取本发明晶型G与现有技术晶型各约10mg采用动态水分吸附(DVS)仪测试其引湿性，在0-95％-0相对湿度下循环一次，记录每个湿度下的质量变化。
表7
Figure PCTCN2018088068-appb-000006
晶型G的DVS如图12所示，现有技术晶型的DVS如图13所示。晶型G DVS测试前后的XRPD图如图14所示，可以看出DVS前后晶型G无变化。引湿性测试结果如表7所示，结果表明，在不同相对湿度条件下，现有技术的引湿性是晶型G引湿性的2～7倍，本发明晶型G具有更优的引湿性。
实施例8
晶型G的密度：
粉体的密度主要由堆密度和振实密度来表示，其中，堆密度指粉体质量除以该粉体所占容器的体积所求得的密度，亦称松密度。振实密度指粉体质量除以粉体轻敲至最紧的体积求得的密度。
称取约500mg的现有技术晶型和本发明晶型G的API样品，分别加入到5mL的量筒中，测定其振实前体积，利用公式“松密度ρ 0＝粉体质量/振实前体积”计算出堆密度ρ 0。振动1250次后，使样品压缩至最紧，记录振实后体积，利用公式“振实密度ρ f＝粉体质量/振实后体积”计算振实密度ρ f。实验结果见表8，实验结果表明：本发明晶型G的松密度是现有技术晶型的4倍多，振实密度是现有技术晶型的3倍多，密度性质明显优于现有技术晶型。
表8
晶型 松密度(ρ 0,g/mL) 振实密度(ρ f,g/mL)
现有技术晶型 0.133 0.204
晶型G 0.538 0.614
实施例9
晶型G的流动性：
制剂工艺过程中，通常可采用压缩性来评价粉体或中间体颗粒的流动性，即压缩度(c)。压缩度是指将一定量的粉体轻轻装入量筒后测量最初松体积；采用轻敲法使粉体处于最紧状态，测量最终的体积；计算松密度ρ 0与振实密度ρ f；根据公式c＝(ρ f－ρ 0)/ρ f计算压缩度。压缩度又称为可压性系数(Compressibility index)或卡尔系数(Carr Index)，是评价流动性的重要指标。
可压性系数的测试方法如下：在测定出晶型G和现有技术晶型的API样品堆密度ρ 0和振实密度ρ f的基础上，通过公式c＝(ρ f－ρ 0)/ρ f*100％计算样品可压性系数。可压性系数对粉体流动性的界定标准详见表9。
表9
可压性指数(％) 流动性
≦10 极好
11-15 好
16-20 一般
21-25 可接受
26-31 差
32-37 很差
>38 极差
晶型G和现有技术晶型的流动性评价结果见表10，结果表明晶型G的流动性明显优于现有技术晶型。
表10
晶型 松密度(ρ 0,g/mL) 振实密度(ρ f,g/mL) 可压性指数(％) 流动性
现有技术晶型 0.133 0.204 35.0 很差
晶型G 0.538 0.614 12.5 好
实施例10
晶型G的黏附性：
将30mg晶型G和现有技术晶型的API加入到8mm圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，称量冲头吸附的粉末量。采用该方法连续压制两次后，记录冲头累计的最终吸附量、压制过程中的最高吸附量和平均吸附量。具体的实验结果见表11，实验结果表明，现有技术晶型的吸附量是晶型G的3倍多，晶型G的黏附性优于现有技术晶型。
表11
晶型 最高吸附量(mg) 平均吸附量(mg) 累计的最终吸附量(mg)
现有技术晶型 0.43 0.21 0.41
晶型G 0.12 0.06 0.12
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 (9)

  1. 一种巴瑞克替尼的晶型G，其特征在于，其X射线粉末衍射图在2θ值为10.9°±0.2°、16.5°±0.2°、19.0°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型G，其特征在于，其X射线粉末衍射图在2θ值为14.4°±0.2°、18.2°±0.2°、21.8°±0.2°中的一处或两处或三处具有特征峰。
  3. 根据权利要求1所述的晶型G，其特征在于，其X射线粉末衍射图在2θ值为22.8°±0.2°、23.8°±0.2°、26.9°±0.2°中的一处或两处或三处具有特征峰。
  4. 一种权利要求1所述的晶型G的制备方法，其特征在于：将巴瑞克替尼固体物加热至212～225℃，室温下静置得到晶型G。
  5. 权利要求4所述的固体为溶剂合物，所述溶剂合物为氯仿溶剂合物。
  6. 一种药用组合物，所述药用组合物包含有效治疗量的权利要求1所述的晶型G及药学上可接受的载体、稀释剂或赋形剂。
  7. 权利要求1所述的晶型G在制备JAK激酶抑制剂药物中的用途。
  8. 权利要求1所述的晶型G在制备治疗自身免疫疾病药物中的用途。
  9. 权利要求1所述的晶型G在制备治疗类风湿性关节炎药物制剂中的用途。
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