WO2017193914A1 - 克立硼罗游离形式的晶型及其制备方法和用途 - Google Patents

克立硼罗游离形式的晶型及其制备方法和用途 Download PDF

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Publication number
WO2017193914A1
WO2017193914A1 PCT/CN2017/083631 CN2017083631W WO2017193914A1 WO 2017193914 A1 WO2017193914 A1 WO 2017193914A1 CN 2017083631 W CN2017083631 W CN 2017083631W WO 2017193914 A1 WO2017193914 A1 WO 2017193914A1
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Prior art keywords
crisaborole
free form
solvent
ray powder
free
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PCT/CN2017/083631
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English (en)
French (fr)
Inventor
陈敏华
张炎锋
陆飞
夏楠
张晓宇
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苏州科睿思制药有限公司
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Priority to JP2018558377A priority Critical patent/JP2019520321A/ja
Priority to AU2017262235A priority patent/AU2017262235C1/en
Application filed by 苏州科睿思制药有限公司 filed Critical 苏州科睿思制药有限公司
Priority to KR1020187035217A priority patent/KR102221472B1/ko
Priority to MX2018013742A priority patent/MX2018013742A/es
Priority to CN201780009362.9A priority patent/CN108884111A/zh
Priority to RU2018142490A priority patent/RU2018142490A/ru
Priority to NZ748385A priority patent/NZ748385B2/en
Priority to EP17795532.5A priority patent/EP3456722A4/en
Priority to BR112018073017-3A priority patent/BR112018073017B1/pt
Priority to SG11201809984PA priority patent/SG11201809984PA/en
Priority to US16/099,839 priority patent/US11773113B2/en
Priority to CA3023851A priority patent/CA3023851C/en
Publication of WO2017193914A1 publication Critical patent/WO2017193914A1/zh
Priority to IL262878A priority patent/IL262878A/en
Priority to ZA2018/07892A priority patent/ZA201807892B/en
Priority to US17/012,795 priority patent/US11447506B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/025—Boronic and borinic acid compounds
    • 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
    • A61K31/69—Boron compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • A61P37/08—Antiallergic agents
    • 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 pharmaceutical crystal technology.
  • it relates to a crystal form of the free form of clopidogrel, a process for its preparation and use.
  • Polymorphism or polymorphism is a peculiar property of certain molecular and molecular compositions.
  • the same molecules may form different crystals due to different arrangements, and these crystals have different crystal structures and physical properties such as solubility and stability. , thermal properties, mechanical properties, purification capabilities, X-ray diffraction patterns, infrared absorption spectra, Raman spectroscopy and solid state nuclear magnetic.
  • One or more analytical assays can be used to distinguish between different crystal forms of the same molecule or combination of molecules.
  • New crystalline forms of pharmaceutically active ingredients have been found to produce more processing advantages or to provide materials with better physicochemical properties, such as better bioavailability, storage stability, and ease of use. Processed, easy to purify or as an intermediate crystal form that facilitates conversion to other crystal forms. New crystalline forms of certain pharmaceutically useful compounds can also help improve the performance of the drug. It expands the formulation of raw materials that can be used in the formulation, such as improved dissolution, improved shelf life, easier processing, and the like.
  • Cribboron also known as Crisaborole, AN-2728
  • Crisaborole is a topical boron-containing anti-inflammatory compound developed by Anacor Pharmaceuticals Inc. that inhibits PDE4 activity, thereby inhibiting TNFalpha, IL-12, IL-23 and Release of other cytokines.
  • Crisaborole has a good therapeutic effect on skin diseases such as psoriasis and allergic dermatitis. It was approved by the US FDA on December 14, 2016.
  • the chemical name of Crisaborole is: 4-[(1,3-dihydro-1-hydroxy-2,1-benzooxaborolan-5-yl)oxy]benzonitrile, the chemical structural formula is as follows Formula (I):
  • the inventors of the present invention surprisingly discovered four crystal forms of Crisaborole during the course of the research.
  • the Crisaborole provided by the invention has good crystal form stability, low wettability, uniform particle size distribution, solubility meets medicinal requirements, stable storage, and avoids crystal transformation during the development process, and has great development value.
  • Form I of the free form of Crisaborole (hereinafter referred to as "Form I").
  • the X-ray powder diffraction of the Form I has characteristic peaks at diffraction angles 2 ⁇ of 15.3° ⁇ 0.2°, 26.1° ⁇ 0.2°, and 14.1° ⁇ 0.2°.
  • the X-ray powder diffraction of Form I has characteristic peaks at diffraction angles 2 ⁇ of 18.1 ° ⁇ 0.2 °, 24.8 ° ⁇ 0.2 °, and 16.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of Form I has characteristic peaks at diffraction angles 2 ⁇ of 28.4 ° ⁇ 0.2 °, 21.4 ° ⁇ 0.2 °, 6.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of Form I is at a diffraction angle 2 ⁇ of 15.3° ⁇ 0.2°, 26.1° ⁇ 0.2°, 14.1° ⁇ 0.2°, 18.1° ⁇ 0.2°, 24.8°. There are characteristic peaks at ⁇ 0.2°, 16.0° ⁇ 0.2, 28.4° ⁇ 0.2°, 21.4° ⁇ 0.2°, and 6.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form I is shown in FIG.
  • the present invention also provides a method for preparing the crystalline form I, the preparation method comprising:
  • the Crisaborole free form solid is dissolved in a single volatile solvent and volatilized to obtain a crystalline Form I solid, wherein the single volatile solvent is an alkyl nitrile, an alkyl ether, a halogenated hydrocarbon, or an ester.
  • the single volatile solvent is an alkyl nitrile, an alkyl ether, a halogenated hydrocarbon, or an ester.
  • the alkyl nitrile solvent is acetonitrile.
  • the alkyl ether solvent is methyl tert-butyl ether.
  • the halogenated hydrocarbon solvent is a chlorinated alkane, preferably, the chlorinated alkane is chloroform, dichloromethane,
  • the ester solvent is ethyl acetate.
  • the volatile crystallization is performed at room temperature; or
  • a single solvent includes, but is not limited to, water, aromatic hydrocarbons, preferably water, toluene,
  • the mixed solvent is a mixed solvent of water and alcohol, alkyl nitrile, ester, ketone, amide, cyclic ether or dimethyl sulfoxide, wherein the volume ratio of water to other solvent is between 4:3 and 5 :1, or
  • the mixed solvent is a mixed solvent of a saturated aliphatic hydrocarbon and a ketone, an ester, a cyclic ether, a halogenated hydrocarbon or an alcohol, wherein the saturated aliphatic hydrocarbon is a ketone, an ester, a cyclic ether, a halogenated hydrocarbon or
  • the volume ratio of the alcohol is preferably 5:4 to 7:1; or,
  • the mixed solvent is a mixed solvent of an aromatic hydrocarbon and a halogenated hydrocarbon, and a volume ratio of the aromatic hydrocarbon to the halogenated hydrocarbon is preferably 5:4.
  • the mixed solvent is a mixed solvent of water and methanol, acetonitrile, isopropyl acetate, 1,4-dioxane, acetone, dimethylformamide or dimethyl sulfoxide.
  • the mixed solvent is a mixed solvent of n-heptane and methyl isobutyl ketone, ethyl acetate, 2-methyltetrahydrofuran, chloroform or ethanol.
  • the mixed solvent is a mixed solvent of toluene and dichloromethane.
  • the certain temperature is preferably room temperature to 50 °C.
  • Form II of the free form of Crisaborole (hereinafter referred to as "Form II").
  • the X-ray powder diffraction of the Form II has characteristic peaks at diffraction angles 2 ⁇ of 20.8° ⁇ 0.2°, 16.6° ⁇ 0.2°, and 22.6° ⁇ 0.2°.
  • the X-ray powder diffraction of Form II has characteristic peaks at diffraction angles 2 ⁇ of 27.9 ° ⁇ 0.2 °, 21.8 ° ⁇ 0.2 °, and 17.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of Form II has characteristic peaks at diffraction angles 2 ⁇ of 18.4° ⁇ 0.2°, 21.4° ⁇ 0.2°, 23.1 ° ⁇ 0.2°.
  • the X-ray powder diffraction angle 2 ⁇ of the Form II is 20.8° ⁇ 0.2°, 16.6° ⁇ 0.2°, 22.6° ⁇ 0.2°, 27.9° ⁇ 0.2°, 21.8° ⁇ There are characteristic peaks at 0.2°, 17.6° ⁇ 0.2°, 18.4° ⁇ 0.2°, 21.4° ⁇ 0.2°, and 23.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II is as shown in FIG. Shown.
  • the present invention also provides a method for preparing the crystal form II, the preparation method comprising:
  • the alcohol is preferably methanol
  • the stirring and separating steps are performed at room temperature; or
  • positive solvents include, but are not limited to, alcohols, ketones, cyclic ethers, amides, dimethyl sulfoxide, and anti-solvents, preferably water, wherein:
  • the alcohol solvent is isopropanol.
  • the ketone solvent is acetone
  • the cyclic ether solvent is tetrahydrofuran, 1,4-dioxane,
  • the amide solvent is dimethylformamide
  • the agitation crystallization and separation steps were all carried out at room temperature.
  • Form III of the free form of Crisaborole (hereinafter referred to as "Form III").
  • the X-ray powder diffraction of the Form III has characteristic peaks at diffraction angles 2 ⁇ of 20.6° ⁇ 0.2°, 27.8° ⁇ 0.2°, and 18.6° ⁇ 0.2°.
  • the X-ray powder diffraction of Form III has characteristic peaks at diffraction angles 2 ⁇ of 13.6 ⁇ 0.2°, 19.5 ° ⁇ 0.2 °, and 21.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of Form III has a characteristic peak at a diffraction angle 2 ⁇ of 21.3 ° ⁇ 0.2 °, 16.3 ° ⁇ 0.2 °, 22.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of Form III is at a diffraction angle 2 ⁇ of 20.6° ⁇ 0.2°, 27.8° ⁇ 0.2°, 18.6° ⁇ 0.2°, 13.6 ⁇ 0.2°. Characteristic peaks at 19.5° ⁇ 0.2°, 21.7° ⁇ 0.2°, 21.3° ⁇ 0.2°, 16.3° ⁇ 0.2°, and 22.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form III is shown in FIG.
  • the present invention also provides a method for preparing the crystal form III, the preparation method comprising: The Crisaborole free form solid is dissolved in a ketone solvent and volatilized to obtain a crystalline form III solid, wherein
  • the ketone solvent is preferably acetone.
  • the temperature of the volatile crystallization is room temperature.
  • Form IV of the Crisaborole free form
  • the X-ray powder diffraction of the Form IV has characteristic peaks at diffraction angles 2 ⁇ of 20.0° ⁇ 0.2°, 18.6° ⁇ 0.2°, and 26.4° ⁇ 0.2°.
  • the X-ray powder diffraction of Form IV has characteristic peaks at diffraction angles 2 ⁇ of 5.3 ° ⁇ 0.2 °, 24.9 ° ⁇ 0.2 °, and 23.2 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of Form IV has characteristic peaks at diffraction angles 2 ⁇ of 17.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, and 13.0 ° ⁇ 0.2°.
  • the X-ray powder diffraction of Form IV is at a diffraction angle 2 ⁇ of 20.0° ⁇ 0.2°, 18.6° ⁇ 0.2°, 26.4° ⁇ 0.2°, 5.3° ⁇ 0.2°, 24.9. Characteristic peaks are found at ° ⁇ 0.2°, 23.2° ⁇ 0.2°, 17.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, and 13.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form IV is shown in FIG.
  • the present invention also provides a method for preparing the crystalline form IV, which comprises heating a free form solid of Crisaborole, Form I, Form II or Form III to 120 ° C to 150 ° C. , Form IV solid was obtained. It is preferably heated to 130 ° C - 145 ° C.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more of Crisaborole free form Form I as described above, or Crisaborole free form Form II, Or Crisaborole free form Form III, or Crisaborole free form Form IV, or any combination of these forms, and at least one pharmaceutically acceptable carrier or excipient.
  • Crisaborole free form Form I or Crisaborole free form Form II, or Crisaborole free form Form III, or Crisaborole free form Form IV, or any combination of these forms in the manufacture for the treatment of psoriasis and allergic dermatitis Use in pharmaceutical preparations.
  • room temperature as used in the present invention means 15 to 25 °C.
  • the "stirring” is accomplished by conventional methods in the art, such as magnetic or mechanical agitation, at a rate of from 50 to 1800 rpm, preferably from 300 to 900 rpm, and most preferably at 500 rpm.
  • the “separation” is accomplished using conventional methods in the art, such as centrifugation or filtration.
  • 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.
  • Drying can be carried out at room temperature or higher unless otherwise specified. Drying temperatures range from room temperature to about 60 ° C, or to 40 ° C, or to 50 ° C. The drying time can be from 2 to 48 hours, or overnight. Drying is carried out in a fume hood, a forced air oven or a vacuum oven.
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • 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 diffraction angle 2 ⁇ generally allows an error of ⁇ 0.2°.
  • the X-ray diffraction pattern of one crystal form in the present invention need not be identical to the X-ray diffraction pattern in the examples referred to herein. 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.
  • Crystal form and “polymorph” and other related terms are used in the present invention to mean that a solid compound exists in a specific crystalline state in a crystal structure.
  • the difference in physical and chemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate and the like. In extreme cases, differences in solubility or dissolution rate can cause drug inefficiencies and even toxicity.
  • Figure 1 is an X-ray powder diffraction pattern of Form I obtained in Example 1 of the present invention.
  • Example 2 is a DSC chart of Form I obtained in Example 1 of the present invention.
  • Figure 3 is a TGA diagram of Form I obtained in Example 1 of the present invention.
  • Figure 4 is an X-ray powder diffraction pattern of Form II obtained in Example 4 of the present invention.
  • Figure 5 is a DSC chart of Form II obtained in Example 4 of the present invention.
  • Figure 6 is a TGA diagram of Form II obtained in Example 4 of the present invention.
  • Figure 7 is an X-ray powder diffraction pattern of Form III obtained in Example 6 of the present invention.
  • Figure 8 is a DSC chart of Form III obtained in Example 6 of the present invention.
  • Figure 9 is a TGA chart of Form III obtained in Example 6 of the present invention.
  • Figure 10 is an X-ray powder diffraction pattern of Form IV obtained in Example 8 of the present invention.
  • Figure 11 is a DSC chart of Form IV obtained in Example 9 of the present invention.
  • Figure 12 is a TGA chart of Form IV obtained in Example 9 of the present invention.
  • Figure 13 is an X-ray powder diffraction pattern of Form I obtained in Example 2 of the present invention.
  • Figure 14 is an X-ray powder diffraction pattern of Form I obtained in Example 3 of the present invention.
  • Figure 15 is an X-ray powder diffraction pattern of Form III obtained in Example 7 of the present invention.
  • Figure 16 is an X-ray powder diffraction pattern of Form IV obtained in Example 9 of the present invention.
  • Figure 17 is a DVS diagram of Form I of the present invention.
  • Figure 18 is a DVS diagram of Form II of the present invention.
  • Figure 19 is a DVS diagram of Form III of the present invention.
  • Figure 20 is a DVS diagram of Form IV of the present invention.
  • Figure 21 is a comparison diagram of XRPD before and after grinding of Form I of the present invention.
  • Figure 22 is a comparison diagram of XRPD before and after the polishing of Form IV of the present invention.
  • Figure 23 is a comparison of long-term and accelerated stability XRPD of Form I of the present invention.
  • Figure 24 is a comparison of long-term and accelerated stability XRPD of Form II of the present invention.
  • Figure 25 is a comparison of long-term and accelerated stability XRPD of Form III of the present invention.
  • Figure 26 is a PSD diagram of Form I of the present invention.
  • Figure 27 is a PSD diagram of Form II of the present invention.
  • Figure 28 is a PSD diagram of Form IV of the present invention.
  • Figure 29 is a PLM diagram of Form I of the present invention.
  • Figure 30 is a PLM diagram of Form II of the present invention.
  • Figure 31 is a PLM diagram of Form IV of the present invention.
  • PSD particle size distribution
  • 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 Q500.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • the particle size distribution (PSD) results described in the present invention were collected on a Microtrac S3500 laser particle size analyzer.
  • the Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system.
  • SDC Sample Delivery Controller
  • This test uses a wet method and the test dispersion medium is Isopar G.
  • the method parameters of the laser particle size analyzer are as follows:
  • the flow rate is 60% of 60% of 65 ml/sec.
  • HPLC high performance liquid chromatography
  • DAD diode array detector
  • the elution gradient is as follows:
  • Time (minutes) % Mobile Phase B 0.0 10 3.0 10 20.0 90 25.0 90 25.1 10 30.0 10
  • room temperature means 15 to 25 ° C unless otherwise specified.
  • the Crisaborole free form solids used in the following examples are commercially available.
  • Crisaborole free form solid 202.5 mg was added to a mixed solvent system of 6 mL (methanol: water, volume ratio 1:5), stirred at 50 ° C for 5 days, centrifuged, and dried under vacuum at room temperature to give a white solid crystal.
  • the obtained solid crystal was the crystalline form I of the present invention, and its X-ray powder diffraction spectrum is shown in Fig. 1.
  • the X-ray powder diffraction data is shown in Table 1.
  • Form I of the present invention is a hydrate.
  • the obtained solid crystal was the crystalline form II of the present invention, and its X-ray powder diffraction spectrum is shown in Fig. 4, and the X-ray powder diffraction data thereof is shown in Table 6.
  • Form II of the present invention is a hydrate.
  • Table 8 uses the same preparation method as the present embodiment, adding a certain amount of Crisaborole free form solid to a certain volume of positive solvent, slowly adding a certain volume of anti-solvent at room temperature and magnetic stirring, stirring and crystallization, centrifugation, room temperature Drying in vacuo gave a white solid crystal.
  • the solid was obtained by XRPD as Form II.
  • the obtained solid crystal was the crystalline form III of the present invention, and its X-ray powder diffraction spectrum is shown in Fig. 7.
  • the X-ray powder diffraction data is shown in Table 9.
  • Form III When performing differential scanning calorimetry, Form III begins to show an endothermic peak when heated to around 136 ° C, and its DSC As shown in Figure 8. When thermogravimetric analysis was carried out, Form III had a mass loss gradient of about 2.5% when heated to 145 ° C, and its TGA is as shown in FIG. Form III of the present invention is a hydrate.
  • the obtained solid crystal was the crystalline form IV of the present invention, and its X-ray powder diffraction data is shown in FIG. 10 and Table 11.
  • Form IV of the present invention is an anhydride.
  • the wetting weight gain is not less than 15.0%
  • Humidity Wet weight 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%
  • wetting gain is less than 0.2%
  • the results show that according to the standard of the 2015 edition of the Chinese Pharmacopoeia, the crystalline form I, the crystalline form II, and the crystalline form III of the present invention have almost no hygroscopicity, and the crystalline form IV is slightly hygroscopic, and are not easily affected by high humidity and deliquescent.
  • the relative humidity is as high as 95%
  • the wet weight gain of the crystalline form I, the crystalline form II, and the crystalline form III of the present invention is still low, and has more excellent deliquescent resistance.
  • the samples of the crystal form I, the crystal form II, the crystal form III and the form IV of the present invention are respectively used in a fasting state artificial intestinal juice (FaSSIF) at a pH of 6.5, a artificial intestinal juice (FeSSIF) at a pH of 5.0, and a pH of 1.8.
  • the simulated artificial gastric juice (SGF) and water were mixed into a saturated solution, and the content of the drug in the solution was determined by high performance liquid chromatography (HPLC) at 1 h, 4 h, and 24 h, respectively.
  • HPLC high performance liquid chromatography
  • Form I, Form II, Form III and Form IV of the present invention all meet the medicinal requirements.
  • D10 indicates the particle size distribution (volume distribution) accounts for 10% of the particle size
  • D50 indicates the particle diameter corresponding to the particle size distribution (volume distribution), which is also called the median diameter.
  • D90 indicates the particle size distribution (volume distribution) accounts for 90% of the particle size
  • PSD diagrams for Form I, Form II, and Form IV are shown in Figures 26, 27, and 28, respectively. As can be seen from the figure, the particle size distributions of Form I, Form II and Form IV are relatively uniform.
  • the uniform particle size helps to simplify the post-treatment process of the formulation process and improve quality control.

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Abstract

本发明涉及克立硼罗游离形式的四种晶型及其制备方法。本发明还涉及包含所述晶型的药物组合物及其用途。

Description

克立硼罗游离形式的晶型及其制备方法和用途 技术领域
本发明涉及药物晶体技术领域。具体而言，涉及克立硼罗游离形式的晶型及其制备方法和用途。
背景技术
多晶型或者多晶现象是某些分子和分子组合物的特有性质，相同的分子可能因不同的排列形式而形成不同晶体，而这些晶体具有不同的晶体结构和物理性质，如溶解度、稳定性、热性质、机械性质、纯化能力、X射线衍射图谱、红外吸收图谱、拉曼光谱和固态核磁等。一种或多种分析检测方式可用于区分同一分子或分子组合物的不同晶型。
发现药物活性成分新的晶型(包括无水物、水合物、溶剂化物等)可能会产生更具加工优势或提供具有更好理化特性的物质，比如更好的生物利用度、储存稳定、易加工处理、易提纯或作为促进转化为其他晶型的中间体晶型。某些药学上有用的化合物的新晶型也可以帮助改善药物的性能。它扩大了制剂学上可选用的原料型态，例如改善溶出度、改善储藏期限、更容易加工等。
牛皮癣和过敏性皮肤炎是具有慢性和复发性病程的非传染性炎症疾病。目前，虽然一些治疗可用于控制这些疾病，但是其他治疗方法仍在研究中。合适的治疗方法能够帮助缓解症状并延长发作间隔。克立硼罗(又称为Crisaborole、AN-2728)是由Anacor Pharmaceuticals Inc开发的一种局部给药的含硼抗炎化合物，其抑制PDE4活性，从而抑制TNFalpha、IL-12、IL-23和其他细胞因子的释放。Crisaborole对牛皮癣、过敏性皮肤炎等皮肤病具有很好的治疗作用，于2016年12月14日获得美国FDA批准。Crisaborole的化学名称为：4-[(1,3-二氢-1-羟基-2,1-苯并氧杂硼杂环戊烷-5-基)氧基]苯甲腈，其化学结构式如下式(I)所示：
Figure PCTCN2017083631-appb-000001
而目前现有技术中尚未公开关于Crisaborole晶型的相关报道。因此，有必要对Crisaborole进行全面系统的多晶型筛选，选择具有有益性质的晶型用于Crisaborole产品开发。
本发明的发明人在研究过程中惊奇的发现了Crisaborole的4种晶型。本发明提供的Crisaborole的晶型稳定性良好，引湿性较低，粒度分布均匀，溶解度符合药用要求，能稳定储存，避免药物在开发过程中发生转晶，具有很大的开发价值。
发明内容
针对现有技术的不足，本发明的目的是提供Crisaborole的晶型及其制备方法和用途。
根据本发明的目的，本发明提供Crisaborole游离形式的晶型I(以下称作“晶型I”)。
使用Cu-Kα辐射，所述晶型I的X-射线粉末衍射在衍射角2θ为15.3°±0.2°、26.1°±0.2°、14.1°±0.2°处有特征峰。
在本发明的一个优选实施方案中，所述晶型I的X-射线粉末衍射在衍射角2θ为18.1°±0.2°、24.8°±0.2°、16.0°±0.2°处有特征峰。
在另一个优选的实施方案中，所述晶型I的X-射线粉末衍射在衍射角2θ为28.4°±0.2°、21.4°±0.2°、6.0°±0.2°处有特征峰。
在进一步的优选实施方案中，所述晶型I的X-射线粉末衍射在衍射角2θ为15.3°±0.2°、26.1°±0.2°、14.1°±0.2°、18.1°±0.2°、24.8°±0.2°、16.0°±0.2、28.4°±0.2°、21.4°±0.2°、6.0°±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I的X-射线粉末衍射谱图如图1所示。
根据本发明的目的，本发明还提供所述晶型I的制备方法，所述制备方法包括：
1)将Crisaborole游离形式的固体溶清于单一挥发性溶剂中，挥发析晶得到晶型I固体，其中，单一挥发性溶剂为烷基腈类、烷基醚类、卤代烃类、酯类，
其中：
所述烷基腈类溶剂为乙腈，
所述烷基醚类溶剂为甲基叔丁基醚，
所述卤代烃类溶剂为氯代烷烃类，优选地，所述氯代烷烃为氯仿，二氯甲烷，
所述酯类溶剂为乙酸乙酯，
所述挥发析晶在室温下进行；或者
2)将Crisaborole游离形式的固体样品悬浮于单一溶剂或者混合溶剂中得到悬浮液，于一定温度下搅拌反应，离心分离，干燥，得到晶型I固体，
其中，
单一溶剂包含但不限于水、芳香烃类，优选水、甲苯，
混合溶剂为水与醇类、烷基腈类、酯类、酮类、酰胺类、环醚类或二甲基亚砜的混合溶剂，其中水与其它溶剂的体积比介于4:3至5:1，或者
混合溶剂为饱和脂肪烃类与酮类、酯类、环醚类、卤代烃类或醇类的混合溶剂，其中饱和脂肪烃类与酮类、酯类、环醚类、卤代烃类或醇类的体积比优选5:4至7:1；或者,
混合溶剂为芳香烃类和卤代烃类的混合溶剂，其中芳香烃类和卤代烃类的体积比优选5:4。
优选地，混合溶剂为水与甲醇、乙腈、乙酸异丙酯、1,4-二氧六环、丙酮、二甲基甲酰胺或二甲亚砜的混合溶剂，
优选地，混合溶剂为正庚烷与甲基异丁基酮、乙酸乙酯、2-甲基四氢呋喃、氯仿或乙醇的混合溶剂，
优选地，混合溶剂为甲苯与二氯甲烷的混合溶剂。
所述一定温度优选室温至50℃。
根据本发明的目的，本发明提供Crisaborole游离形式的晶型II(以下称作“晶型II”)。
使用Cu-Kα辐射，所述晶型II的X-射线粉末衍射在衍射角2θ为20.8°±0.2°、16.6°±0.2°、22.6°±0.2°处有特征峰。
在本发明的一个优选实施方案中，所述晶型II的X-射线粉末衍射在衍射角2θ为27.9°±0.2°、21.8°±0.2°、17.6°±0.2°处有特征峰。
在另一个优选的实施方案中，所述晶型II的X-射线粉末衍射在衍射角2θ为18.4°±0.2°、21.4°±0.2°、23.1°±0.2°处有特征峰。
在进一步的优选的实施方案中，所述晶型II的X-射线粉末衍射角2θ为20.8°±0.2°、16.6°±0.2°、22.6°±0.2°、27.9°±0.2°、21.8°±0.2°、17.6°±0.2°、18.4°±0.2°、21.4°±0.2°、23.1°±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II的X-射线粉末衍射谱图如图4 所示。
根据本发明的目的，本发明还提供所述晶型II的制备方法，所述制备方法包括：
1)将Crisaborole游离形式固体样品悬浮于水与醇类的混合溶剂中得到悬浮液，搅拌，离心分离，干燥，得到晶型II固体，其中水与醇类的体积比为1:1，
所述醇类优选甲醇；
所述搅拌与分离步骤均在室温下进行；或者
2)将Crisaborole游离形式固体样品溶于正溶剂中，然后在其中加入反溶剂，搅拌析晶，分离，干燥，得到晶型II固体，其中，Crisaborole游离形式的固体以溶清或完全溶解的方式存在于所述正溶剂中，加入反溶剂的量以得到固体为止，
正溶剂种类包含但不限于醇类、酮类、环醚类、酰胺类，二甲亚砜，反溶剂优选水，其中：
所述醇类溶剂为异丙醇，
所述酮类溶剂为丙酮，
所述环醚类溶剂为四氢呋喃、1,4-二氧六环，
所述酰胺类溶剂为二甲基甲酰胺，
所述搅拌析晶和分离步骤都在室温下进行。
根据本发明的目的，本发明提供Crisaborole游离形式的晶型III(以下称作“晶型III”)。
使用Cu-Kα辐射，所述晶型III的X-射线粉末衍射在衍射角2θ为20.6°±0.2°、27.8°±0.2°、18.6°±0.2°处有特征峰。
在本发明的一个优选实施方案中，所述晶型III的X-射线粉末衍射在衍射角2θ为13.6±0.2°、19.5°±0.2°、21.7°±0.2°处有特征峰。
在另一个优选的实施方案中，所述晶型III的X-射线粉末衍射在衍射角2θ为21.3°±0.2°、16.3°±0.2°、22.5°±0.2°处有特征峰。
在本发明的进一步的优选的实施方案中，所述晶型III的X-射线粉末衍射在衍射角2θ为20.6°±0.2°、27.8°±0.2°、18.6°±0.2°、13.6±0.2°、19.5°±0.2°、21.7°±0.2°、21.3°±0.2°、16.3°±0.2°、22.5°±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III的X-射线粉末衍射谱图如图7所示。
根据本发明的目的，本发明还提供所述晶型III的制备方法，所述制备方法包括：将 Crisaborole游离形式固体溶清于酮类溶剂中，挥发析晶，得到晶型III固体，其中
所述酮类溶剂优选为丙酮，
所述挥发析晶的温度为室温。
根据本发明的目的，本发明提供Crisaborole游离形式的晶型IV(以下称作“晶型IV”)。
使用Cu-Kα辐射，所述晶型IV的X-射线粉末衍射在衍射角2θ为20.0°±0.2°、18.6°±0.2°、26.4°±0.2°处有特征峰。
在本发明的一个优选实施方案中，所述晶型IV的X-射线粉末衍射在衍射角2θ为5.3°±0.2°、24.9°±0.2°、23.2°±0.2°处有特征峰。
在另一个优选的实施方案中，所述晶型IV的X-射线粉末衍射在衍射角2θ为17.2°±0.2°、21.4°±0.2°、13.0°±0.2°处有特征峰。
在进一步的优选的实施方案中，所述晶型IV的X-射线粉末衍射在衍射角2θ为20.0°±0.2°、18.6°±0.2°、26.4°±0.2°、5.3°±0.2°、24.9°±0.2°、23.2°±0.2°、17.2°±0.2°、21.4°±0.2°、13.0°±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IV的X-射线粉末衍射谱图如图10所示。
根据本发明的目的，本发明还提供所述晶型IV的制备方法，所述制备方法包括：将Crisaborole的游离形式固体、晶型I、晶型II或晶型III加热至120℃-150℃，得到晶型IV固体。优选加热至130℃-145℃。
根据本发明的目的，本发明还提供一种药物组合物，其包含治疗和/或预防有效量的一种或多种如上所述的Crisaborole游离形式晶型I、或Crisaborole游离形式晶型II、或Crisaborole游离形式晶型III、或Crisaborole游离形式晶型IV、或这些晶型的任意组合，以及至少一种药学上可接受的载体或赋形剂。
Crisaborole游离形式晶型I、或Crisaborole游离形式晶型II、或Crisaborole游离形式晶型III、或Crisaborole游离形式晶型IV、或这些晶型的任意组合在生产用于制备治疗牛皮癣和过敏性皮肤炎药物制剂中的用途。
在本发明中所述“室温”指15～25℃。
在本发明中，所述的“2θ”与“2theta”所表达的含义一致。
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，最优选500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。
除非特别说明，所述“干燥”可以在室温或更高的温度下进行。干燥温度室温～约60℃，或者到40℃，或者到50℃。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。
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。另外，衍射角2θ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。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。
“晶型”和“多晶型”以及其他相关词汇在本发明中指的是固体化合物在晶体结构中以特定的晶型状态存在。多晶型理化性质的不同可以体现在储存稳定性、可压缩性、密度、溶出速度等方面。在极端的情况下，溶解度或溶出速度的不同可以造成药物低效，甚至毒性。
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。
附图说明
图1为本发明实施例1所得晶型I的X射线粉末衍射图。
图2为本发明实施例1所得晶型I的DSC图。
图3为本发明实施例1所得晶型I的TGA图。
图4为本发明实施例4所得晶型II的X射线粉末衍射图。
图5为本发明实施例4所得晶型II的DSC图。
图6为本发明实施例4所得晶型II的TGA图。
图7为本发明实施例6所得晶型III的X射线粉末衍射图。
图8为本发明实施例6所得晶型III的DSC图。
图9为本发明实施例6所得晶型III的TGA图。
图10为本发明实施例8所得晶型IV的X射线粉末衍射图。
图11为本发明实施例9所得晶型IV的DSC图。
图12为本发明实施例9所得晶型IV的TGA图。
图13为本发明实施例2所得晶型I的X射线粉末衍射图。
图14为本发明实施例3所得晶型I的X射线粉末衍射图。
图15为本发明实施例7所得晶型III的X射线粉末衍射图。
图16为本发明实施例9所得晶型IV的X射线粉末衍射图。
图17为本发明晶型I的DVS图。
图18为本发明晶型II的DVS图。
图19为本发明晶型III的DVS图。
图20为本发明晶型IV的DVS图。
图21为本发明晶型I研磨前后XRPD对比图。
图22为本发明晶型IV研磨前后XRPD对比图。
图23为本发明晶型I的长期与加速稳定性XRPD对比图。
图24为本发明晶型II的长期与加速稳定性XRPD对比图。
图25为本发明晶型III的长期与加速稳定性XRPD对比图。
图26为本发明晶型I的PSD图。
图27为本发明晶型II的PSD图。
图28为本发明晶型IV的PSD图。
图29为本发明晶型I的PLM图。
图30为本发明晶型II的PLM图。
图31为本发明晶型IV的PLM图。
具体实施方式
本发明进一步参考以下实施例限定，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。
采集数据所用的仪器及方法：
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
PSD：粒径分布
PLM：偏光显微镜
HPLC：高效液相色谱
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
Figure PCTCN2017083631-appb-000002
1.540598；
Figure PCTCN2017083631-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 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：氮气
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。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
本发明中所述的粒径分布(PSD)结果是在Microtrac公司的S3500型激光粒度分析仪上采集。Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G。所述的激光粒度分析仪的方法参数如下：
Figure PCTCN2017083631-appb-000004
*：流速60％为65毫升/秒的60％。
高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为二极管阵列检测器(DAD)。本发明所述的HPLC方法参数如下：
1、色谱柱：Waters Xbridge C18 150×4.6mm,5μm
2、流动相：A：0.1％的三氟乙酸水溶液
           B：0.1％的三氟乙酸乙腈溶液
洗脱梯度如下：
时间(分钟) ％流动相B
0.0 10
3.0 10
20.0 90
25.0 90
25.1 10
30.0 10
3、流速：1.0mL/min
4、进样量：5μL
5、检测波长：254nm
6、柱温：40℃
7、稀释剂：50％乙腈
在以下实施例中，除非特殊说明，“室温”指15～25℃。
以下实施例中所使用的Crisaborole游离形式固体可通过商业购买获得。
实施例1
将202.5mgCrisaborole游离形式固体加到6mL(甲醇：水，体积比为1:5)的混合溶剂体系中，50℃下搅拌5天，离心分离，室温下真空干燥，得到白色固体结晶。
经检测，所得固体结晶为本发明所述的晶型I，其X射线粉末衍射谱图如图1。其X射线粉末衍射数据如表1所示。
当进行差示扫描量热分析时，晶型I加热至123℃附近时开始出现吸热峰，其DSC如附图2所示。当进行热重分析时，晶型I加热至120℃时，具有约4.2％的质量损失梯度，其TGA如附图3所示。本发明的晶型I为水合物。
表1
2theta d间隔 强度％
5.98 14.79 21.09
11.98 7.39 2.61
14.07 6.29 53.95
15.31 5.79 100.00
15.96 5.55 33.66
17.56 5.05 6.53
18.14 4.89 42.95
21.34 4.16 26.11
24.86 3.58 39.83
26.09 3.42 65.72
28.40 3.14 31.42
31.33 2.85 7.91
31.68 2.82 5.53
39.24 2.30 2.84
实施例2
将51.4mgCrisaborole游离形式固体加到1mL乙腈溶剂中，溶解后置于室温下敞口挥发，直到溶剂挥发完全，得到白色固体结晶。
经检测，所得固体结晶为本发明所述的晶型I。其X射线粉末衍射数据如图13、表2所示。
表2
2theta d间隔 强度％
5.99 14.76 5.42
12.02 7.36 1.01
14.06 6.30 14.60
15.33 5.78 100.00
15.99 5.54 4.06
17.56 5.05 3.30
18.12 4.90 6.76
20.73 4.28 2.27
21.40 4.15 38.10
21.85 4.07 1.80
23.00 3.87 1.32
24.85 3.58 24.19
26.09 3.41 33.54
26.35 3.38 7.30
28.39 3.14 9.99
29.05 3.07 3.25
30.94 2.89 6.24
31.35 2.85 3.33
31.68 2.82 2.59
32.66 2.74 4.91
33.69 2.66 2.40
表3采用与实施例2相同的方法，将一定质量的Crisaborole游离形式固体加到一定体积的溶剂中，溶解后置于室温下敞口挥发，直到溶剂挥发完全，得到白色固体结晶。得到固体经XRPD测试为晶型I。
表3
Figure PCTCN2017083631-appb-000005
实施例3
将30.7mgCrisaborole游离形式固体加入到1.5mL溶剂水中。室温下磁力搅拌两天，离心分离，室温下真空干燥，得到白色固体结晶。
经检测，所得固体结晶为本发明所述的晶型I，其X射线粉末衍射数据如图14、表4所示。
表4
2theta d间隔 强度％
5.95 14.86 27.13
14.03 6.31 48.74
15.28 5.80 100.00
15.93 5.56 34.94
18.12 4.90 41.14
21.33 4.16 24.57
24.83 3.59 34.19
26.06 3.42 62.24
28.34 3.15 27.26
31.32 2.86 5.69
33.63 2.67 4.16
表5采用与实施例3相同的方法，将一定质量的Crisaborole游离形式固体加入到一定体积溶剂中。室温下磁力搅拌，离心分离，室温下真空干燥，得到白色固体结晶。得到固体经XRPD测试为晶型I。
表5
Figure PCTCN2017083631-appb-000006
实施例4
将34.5mgCrisaborole游离形式固体加入到1.6mL(甲醇：水，体积比为1:1)的混合 溶剂体系中，室温下磁力搅拌，离心，室温下真空干燥，得到白色固体结晶。
经检测，所得固体结晶为本发明所述的晶型II，其X射线粉末衍射谱图如图4,其X射线粉末衍射数据如表6所示。
当进行差示扫描量热分析时，晶型II加热至134℃附近时开始出现吸热峰，其DSC如附图5所示。当进行热重分析时，晶型II加热至115℃时，具有约4.2％的质量损失梯度，其TGA如附图6所示。本发明的晶型II为水合物。
表6
2theta d间隔 强度％
7.01 12.61 2.38
12.17 7.27 3.50
14.21 6.23 4.68
14.77 6.00 1.50
16.55 5.36 37.69
17.60 5.04 9.92
18.32 4.84 8.97
20.76 4.28 100.00
21.35 4.16 11.45
21.75 4.09 11.77
22.55 3.94 19.21
23.08 3.85 6.09
23.43 3.80 4.61
25.97 3.43 4.66
27.00 3.30 2.75
27.89 3.20 24.06
28.65 3.12 3.74
30.03 2.98 3.15
31.44 2.85 4.29
37.29 2.41 2.50
实施例5
将30.3mgCrisaborole游离形式固体加入到0.4mL异丙醇溶剂中，在室温及磁力搅拌下缓慢滴加0.6mL反溶剂水，搅拌析晶5天，离心分离，室温下真空干燥，得到白色固体结晶。
经检测，所得固体结晶为本发明所述的晶型II，其X射线粉末衍射数据表7所示。
表7
2theta d间隔 强度％
12.24 7.23 7.02
14.30 6.19 7.68
15.55 5.70 4.38
16.62 5.33 65.89
17.64 5.03 11.91
18.39 4.82 12.60
19.96 4.45 2.68
20.80 4.27 100.00
21.42 4.15 11.19
21.76 4.08 12.83
22.58 3.94 39.24
23.08 3.85 10.59
23.51 3.78 7.85
24.13 3.69 3.90
24.86 3.58 9.95
26.03 3.42 6.30
27.03 3.30 4.79
27.90 3.20 26.46
28.69 3.11 4.04
31.46 2.84 6.90
表8采用与本实施例相同的制备方法，将一定质量Crisaborole游离形式固体加入到一定体积正溶剂中，在室温及磁力搅拌下缓慢滴加一定体积反溶剂，搅拌析晶，离心分离，室温下真空干燥，得到白色固体结晶。得到固体经XRPD测试为晶型II。
表8
Figure PCTCN2017083631-appb-000007
实施例6
将200.5mgCrisaborole游离形式固体加到装有5mL丙酮溶剂的20mL玻璃瓶中，溶清，用封口膜封住瓶口，并用针头戳几个小孔，室温条件下放置，缓慢挥发，得到白色固体结晶。
经检测，所得固体结晶为本发明所述的晶型III，其X射线粉末衍射谱图如图7。其X射线粉末衍射数据如表9所示。
当进行差示扫描量热分析时，晶型III加热至136℃附近时开始出现吸热峰，其DSC 如附图8所示。当进行热重分析时，晶型III加热至145℃时，具有约2.5％的质量损失梯度，其TGA如附图9所示。本发明的晶型III为水合物。
表9
2theta d间隔 强度％
10.20 8.67 1.03
13.63 6.49 1.19
16.21 5.47 7.54
17.55 5.05 3.06
18.24 4.86 2.64
18.62 4.77 8.91
19.58 4.53 3.64
20.59 4.31 100.00
20.72 4.29 91.97
21.30 4.17 12.98
21.69 4.10 7.34
22.49 3.95 2.14
23.70 3.75 2.18
23.95 3.72 1.80
26.29 3.39 2.04
26.50 3.36 2.82
26.93 3.31 2.79
27.41 3.25 2.88
27.86 3.20 22.34
31.38 2.85 5.26
37.17 2.42 1.12
实施例7
将11.5mgCrisaborole游离形式固体加到0.2mL丙酮溶剂中，室温下挥发，直到溶剂完全挥发，得到白色固体结晶。
经检测，所得固体结晶为本发明所述的晶型III。其X射线粉末衍射数据如图15、表10所示。
表10
2theta d间隔 强度％
13.66 6.48 16.96
15.63 5.67 3.67
16.43 5.40 13.85
18.22 4.87 8.94
18.62 4.76 27.66
19.54 4.54 14.45
20.58 4.32 100.00
21.26 4.18 5.22
21.70 4.10 10.34
22.54 3.94 6.87
23.74 3.75 19.42
26.01 3.43 2.08
27.67 3.22 67.83
28.51 3.13 3.66
31.19 2.87 3.78
37.12 2.42 3.30
实施例8
室温下加约5mgCrisaborole游离形式固体到DSC(Q2000)小盘里，设置加热程序为：加热到90℃，10℃/min；加热到130℃，5℃/min；平衡5分钟，得到固体结晶。
经检测，所得固体结晶为本发明所述的晶型IV，其X射线粉末衍射数据如图10、表11所示。
表11
2theta d间隔 强度％
5.34 16.54 44.99
12.42 7.13 16.46
13.01 6.80 34.31
15.12 5.86 9.66
15.72 5.64 9.34
16.20 5.47 16.87
17.19 5.16 52.62
17.47 5.08 44.48
18.56 4.78 92.02
19.29 4.60 6.44
19.98 4.44 100.00
20.50 4.33 6.81
20.90 4.25 2.46
21.36 4.16 33.74
21.67 4.10 12.74
22.39 3.97 5.76
23.14 3.84 41.01
23.73 3.75 16.09
24.88 3.58 70.56
25.62 3.48 6.62
26.33 3.39 90.16
27.56 3.24 7.25
29.11 3.07 2.09
30.24 2.96 10.28
31.03 2.88 6.06
33.02 2.71 1.14
36.13 2.49 1.37
实施例9
称取11.5mgCrisaborole游离形式固体，加到装有0.2mL丙酮溶剂的玻璃瓶中，室温下敞口挥发，直到溶剂完全挥发，将析出的固体在室温下放到DSC(Q2000)小盘中加热，加热程序设置为：加热到90℃，10℃/min；加热到145℃，5℃/min；平衡5分钟，得到固体结晶。
经检测，所得固体结晶为本发明所述的晶型IV。其X射线粉末衍射谱图如图16。其X射线粉末衍射数据如表12所示。
当进行差示扫描量热分析时，晶型IV加热至172℃附近时开始出现吸热峰，其DSC如附图11所示。当进行热重分析时，晶型IV加热至150℃时，具有约1.4％的质量损失梯度，其TGA如附图12所示。本发明的晶型IV为无水物。
表12
2theta d间隔 强度％
5.35 16.53 59.32
11.50 7.69 8.63
12.47 7.10 13.07
13.01 6.80 25.27
15.75 5.63 12.05
17.22 5.15 33.73
18.58 4.78 80.18
20.03 4.43 100.00
21.39 4.15 28.17
23.21 3.83 34.72
23.74 3.75 17.17
24.91 3.57 53.77
26.39 3.38 86.10
27.62 3.23 9.18
实验部分
实验例1引湿性研究
取约10mg本发明的晶型I、晶型II、晶型III、晶型IV进行动态水分吸附(DVS)测试。结果如表13所示。
表13
Figure PCTCN2017083631-appb-000008
晶型I，晶型II，晶型III，晶型IV的DVS图分别参见图17、图18，图19和图20。
关于引湿性特征描述与引湿性增重的界定(2015年版《中国药典》附录药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
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％
结果表明，根据2015年版《中国药典》的标准，本发明的晶型I，晶型II，晶型III几乎无引湿性，晶型IV略有引湿性，都不易受高湿度影响而潮解。特别的，即使在相对湿度高至95％的条件下，本发明的晶型I，晶型II，晶型III的引湿增重仍然很低，具有更为优异的耐潮解性。
实验例2机械稳定性研究
将本发明的晶型I、晶型IV分别置于研钵中，手动研磨5分钟，测试固体XRPD。结果如表14所示。
表14
起始晶型 最终晶型
晶型I 晶型I
晶型IV 晶型IV
结果表明，在一定机械应力的作用下，本发明的晶型I、晶型IV未发生改变，仍可保持稳定的物理化学性质。晶型Ⅰ、晶型IV研磨前后XRPD对比图分别参见图21至图22(上图是研磨之前的XRPD图，下图是研磨5分钟之后的XRPD图)。
实验例3动态溶解度研究
将本发明的晶型I、晶型II、晶型III、晶型IV的样品分别用pH 6.5的空腹状态下人工肠液(FaSSIF)、pH 5.0的进食状态下人工肠液(FeSSIF)、pH 1.8的模拟人工胃液(SGF)、水配制成饱和溶液，采用高效液相色谱(HPLC)分别测定1h、4h、和24h时溶液中药物的含量。结果如表15所示。
表15
Figure PCTCN2017083631-appb-000009
Figure PCTCN2017083631-appb-000010
ND：未检测到
本发明的晶型I、晶型II、晶型III和晶型IV的溶解度均符合药用要求。
实验例4长期与加速稳定性研究
将本发明的晶型I、晶型II、晶型III的样品分别放置在25℃，60％相对湿度，40℃，75％相对湿度条件下，其晶型变化结果见表16。
表16
Figure PCTCN2017083631-appb-000011
结果表明，本发明的晶型I，晶型II，晶型III在两种湿度下，3个月仍可保持稳定。晶型Ⅰ、晶型II和晶型III的长期与加速稳定性XRPD对比图分别参见图23、图24和图25(在每幅图中，上图是放置前的XRPD图，中图是在放置条件25℃，60％湿度下放置3个月后的XRPD图，下图是是在放置条件40℃，75％湿度下放置3个月后的XRPD图)。
实验例5粒径分布研究
粒度对比试验：
取本发明的晶型I、晶型II、晶型III和晶型IV的样品进行粒径分布测试。
粒径分布结果见表17。
表17
晶型 MV(μm) D10(μm) D50(μm) D90(μm)
晶型I 9.62 1.69 5.52 20.35
晶型II 23.13 8.24 20.46 40.42
晶型III 289.0 21.68 163.0 903.1
晶型IV 52.95 13.43 33.68 99.36
注：
MV：按照体积计算的平均粒径
D10：表示粒径分布中(体积分布)占10％所对应的粒径
D50：表示粒径分布中(体积分布)占50％所对应的粒径，又称中位径
D90：表示粒径分布中(体积分布)占90％所对应的粒径
晶型I、晶型II和晶型IV的PSD图分别参见图26、图27和图28。由图中可以看出，晶型I、晶型II和晶型IV粒径分布比较均匀。
另外，晶型I、晶型II和晶型IV的PLM图分别参见图29、图30和图31。由图中也可以看出，晶型I、晶型II和晶型IV的颗粒粒径较为均匀。
均匀的粒径有助于简化制剂过程的后处理工艺，提高质量控制。
本领域技术人员可以理解，在本说明书的教导之下，可以对本发明做出一些修改或变化。这些修改和变化也应当在本发明权利要求所限定的范围之内。

Claims (21)

  1. 结构式如下所示的Crisaborole游离形式的晶型I，
    Figure PCTCN2017083631-appb-100001
    其特征在于，使用Cu-Kα辐射，所述晶型I的X-射线粉末衍射图在衍射角2θ为15.3°±0.2°、26.1°±0.2°、14.1°±0.2°处有特征峰。
  2. 根据权利要求1所述的Crisaborole游离形式的晶型I，其特征在于，所述晶型I的X-射线粉末衍射图还在衍射角2θ为18.1°±0.2°、24.8°±0.2°、16.0°±0.2°处有特征峰。
  3. 根据权利要求1所述的Crisaborole游离形式的晶型I，其特征在于，所述晶型I的X-射线粉末衍射图还在衍射角2θ为28.4°±0.2°、21.4°±0.2°、6.0°±0.2°处有特征峰。
  4. 权利要求1-3中任一项所述的Crisaborole游离形式的晶型I的制备方法，其特征在于，所述制备方法包括如下几种：
    1)将Crisaborole游离形式固体溶清于单一挥发性溶剂中，挥发析晶，得到晶型I固体，其中所述单一挥发性溶剂为烷基腈类、烷基醚类、卤代烃类、酯类；或
    2)将Crisaborole游离形式固体悬浮于单一溶剂或者混合溶剂中，得到悬浮液，搅拌，分离，干燥，得到晶型I固体，其中所述单一溶剂为水、芳香烃类；所述混合溶剂为水与醇类、烷基腈类、酯类、酮类、酰胺类、环醚类或二甲基亚砜的混合溶剂，其中水与其它溶剂的体积比介于4:3至5:1，或所述混合溶剂为饱和脂肪烃类与酮类、酯类、环醚类、卤代烃类或醇类的混合溶剂，或所述混合溶剂为芳香烃类和卤代烃类的混合溶剂。
  5. 权利要求4所述的Crisaborole游离形式的晶型I的制备方法，所述单一挥发性溶剂为乙腈、甲基叔丁基醚、氯仿、二氯甲烷、乙酸乙酯；所述混合溶剂为水与甲醇、乙腈、乙酸异丙酯、1,4-二氧六环、丙酮、二甲基甲酰胺或二甲亚砜的混合溶剂，或所述混合溶剂为正庚烷与甲基异丁基酮、乙酸乙酯、2-甲基四氢呋喃、氯仿或乙醇的混合溶剂，或所述混合溶剂为甲苯与二氯甲烷的混合溶剂。
  6. 结构式如下所示的Crisaborole游离形式的晶型II，
    Figure PCTCN2017083631-appb-100002
    其特征在于，使用Cu-Kα辐射，所述晶型II的X-射线粉末衍射图在衍射角2θ为20.8°±0.2°、16.6°±0.2°、22.6°±0.2°处有特征峰。
  7. 根据权利要求6所述的Crisaborole游离形式的晶型II，其特征在于，所述晶型II的X-射线粉末衍射图还在衍射角2θ为27.9°±0.2°、21.8°±0.2°、17.6°±0.2°处有特征峰。
  8. 根据权利要求6所述的Crisaborole游离形式的晶型II，其特征在于，所述晶型II的X-射线粉末衍射图还在衍射角2θ为18.4°±0.2°、21.4°±0.2°、23.1°±0.2°处有特征峰。
  9. 权利要求6-8中任一项所述的Crisaborole游离形式的晶型II的制备方法，其特征在于，所述制备方法包括如下几种：
    1)将Crisaborole游离形式固体样品悬浮于水与醇类的混合溶剂中得到悬浮液，搅拌反应，离心分离，干燥得到，其中所述水与醇类的体积比为1:1；或
    2)将Crisaborole游离形式固体溶于正溶剂中，然后在其中加入反溶剂，搅拌析晶，分离，干燥，得到晶型II固体，其中所述正溶剂为醇类、酮类、环醚类、酰胺类，二甲亚砜，反溶剂为水。
  10. 根据权利要求9所述的制备方法，其特征在于，所述正溶剂选自异丙醇、丙酮、1,4-二氧六环、四氢呋喃、二甲基甲酰胺中的一种。
  11. 结构式如下所示的Crisaborole游离形式的晶型III，
    Figure PCTCN2017083631-appb-100003
    其特征在于，使用Cu-Kα辐射，所述晶型III的X-射线粉末衍射图在衍射角2θ为20.6°±0.2°、27.8°±0.2°、18.6°±0.2°处有特征峰。
  12. 根据权利要求11所述的Crisaborole游离形式的晶型III，其特征在于，所述晶型III的X-射线粉末衍射图还在衍射角2θ为13.6±0.2°、19.5°±0.2°、21.7°±0.2°处有特征峰。
  13. 根据权利要求11所述的Crisaborole游离形式的晶型III，其特征在于，所述晶型III的X-射线粉末衍射图还在衍射角2θ为21.3°±0.2°、16.3°±0.2°、22.5°±0.2°处有特征峰。
  14. 权利要求11-13中任一项所述的Crisaborole游离形式的晶型III的制备方法，其特征在于，所述制备方法包括：将Crisaborole游离形式固体溶清于酮类溶剂中，挥发析晶，得到晶型III固体。
  15. 根据权利要求14所述的制备方法，其特征在于，所述酮类为丙酮。
  16. 结构式如下所示的Crisaborole游离形式的晶型IV，
    Figure PCTCN2017083631-appb-100004
    其特征在于，使用Cu-Kα辐射，所述晶型IV的X-射线粉末衍射图在衍射角2θ为20.0°±0.2°、18.6°±0.2°、26.4°±0.2°处有特征峰。
  17. 根据权利要求16所述的Crisaborole游离形式的晶型IV，其特征在于，所述晶型IV的X-射线粉末衍射图还在衍射角2θ为5.3°±0.2°、24.9°±0.2°、23.2°±0.2°处有特征峰。
  18. 根据权利要求16所述的Crisaborole游离形式的晶型IV，其特征在于，所述晶型IV的X-射线粉末衍射图还在衍射角2θ为17.2°±0.2°、21.4°±0.2°、13.0°±0.2°处有特征峰。
  19. 权利要求16-18中任一项所述的Crisaborole游离形式的晶型IV的制备方法，其特征在于，所述制备方法包括：将Crisaborole的游离形式固体、权利要求1-3中任意一项所述的晶型I、权利要求6-8任一项所述的晶型II或权利要求11-13中任意一项所述晶型III加热至130℃-145℃，即得到晶型IV固体。
  20. 一种药物组合物，其包含治疗和/或预防有效量的一种或多种权利要求1-3中任一项所述的Crisaborole游离形式的晶型I、或权利要求6-8中任一项所述的Crisaborole游离形式的晶型II、或权利要求11-13中任一项所述的Crisaborole游离形式的晶型III、或权利要求16-18中任一项所述的Crisaborole的游离形式的晶型IV、或这些晶型的任意组合，以及至少一种药学上可接受的载体或赋形剂。
  21. 权利要求1-3中任一项所述的Crisaborole游离形式的晶型I、或权利要求6-8中任一项所述的Crisaborole游离形式的晶型II、或权利要求11-13中任一项所述的Crisaborole游离形式的晶型III、或权利要求16-18中任一项所述的Crisaborole的游离形式的晶型IV、或这些晶型的任意组合在生产用于制备治疗牛皮癣和过敏性皮肤炎药物制剂中的用途。
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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110780005A (zh) * 2019-11-14 2020-02-11 江苏海岸药业有限公司 一种克立硼罗原料及其合成中间体的分析方法
US10597410B2 (en) 2018-02-02 2020-03-24 Dipharma Francis S.R.L. Intermediates and process for the preparation of a crystalline form of a topical anti-inflammatory agent
CN112375093A (zh) * 2020-11-13 2021-02-19 江苏知原药业股份有限公司 一种克立硼罗晶型化合物及其制备方法
CN113087733A (zh) * 2021-04-06 2021-07-09 南京科默生物医药有限公司 克立硼罗的晶型a、晶型b、晶型c、晶型d、晶型e及其制备方法
EP3737685A4 (en) * 2018-01-09 2021-07-28 Halcyon Labs Private Limited PROCESS FOR PREPARING CRISABOROLE AND ITS INTERMEDIARIES
US11325922B2 (en) * 2017-12-21 2022-05-10 Olon S.P.A. Process for the preparation of Crisaborole in a stable crystal form
WO2024047571A1 (en) * 2022-09-01 2024-03-07 Savoi Guilherme Crisaborole cocrystal derivatives

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111983123A (zh) * 2020-08-14 2020-11-24 江苏海岸药业有限公司 用于治疗皮肤疾病的克立硼罗制剂的体外评价方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007146965A2 (en) * 2006-06-12 2007-12-21 Anacor Pharmaceuticals, Inc. Compounds for the treatment of periodontal disease
CN101420854A (zh) * 2006-02-16 2009-04-29 安纳考尔医药公司 作为抗炎药的含硼的小分子

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN191496B (zh) * 1999-07-30 2003-12-06 Ranbaxy Lab Ltd
GB2383042A (en) * 2001-10-18 2003-06-18 Cipla Ltd Amorphous alendronate sodium
NZ598441A (en) 2005-02-16 2013-07-26 Anacor Pharmaceuticals Inc Boron-containing small molecules
BRPI0621279B1 (pt) 2005-12-30 2021-07-20 Anacor Pharmaceuticals, Inc Moléculas pequenas contendo boro
CN101505603A (zh) * 2005-12-30 2009-08-12 安纳考尔医药公司 含硼的小分子
US20070286822A1 (en) 2006-06-12 2007-12-13 Anacor Pharmaceuticals Inc. Compounds for the Treatment of Periodontal Disease
EP3246034A1 (en) * 2008-03-06 2017-11-22 Anacor Pharmaceuticals, Inc. Boron-containing small molecules as anti-inflammatory agents
DK3383363T3 (da) * 2015-11-30 2021-01-18 Anacor Pharmaceuticals Inc Topiske farmaceutiske formuleringer til behandling af inflammatorisk-relaterede tilstande
WO2017203514A1 (en) * 2016-05-26 2017-11-30 Perrigo Api Ltd Polymorphs of crisaborole and production processes therefor

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101420854A (zh) * 2006-02-16 2009-04-29 安纳考尔医药公司 作为抗炎药的含硼的小分子
WO2007146965A2 (en) * 2006-06-12 2007-12-21 Anacor Pharmaceuticals, Inc. Compounds for the treatment of periodontal disease

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11325922B2 (en) * 2017-12-21 2022-05-10 Olon S.P.A. Process for the preparation of Crisaborole in a stable crystal form
EP3737685A4 (en) * 2018-01-09 2021-07-28 Halcyon Labs Private Limited PROCESS FOR PREPARING CRISABOROLE AND ITS INTERMEDIARIES
US10597410B2 (en) 2018-02-02 2020-03-24 Dipharma Francis S.R.L. Intermediates and process for the preparation of a crystalline form of a topical anti-inflammatory agent
CN110780005A (zh) * 2019-11-14 2020-02-11 江苏海岸药业有限公司 一种克立硼罗原料及其合成中间体的分析方法
CN112375093A (zh) * 2020-11-13 2021-02-19 江苏知原药业股份有限公司 一种克立硼罗晶型化合物及其制备方法
CN113087733A (zh) * 2021-04-06 2021-07-09 南京科默生物医药有限公司 克立硼罗的晶型a、晶型b、晶型c、晶型d、晶型e及其制备方法
WO2024047571A1 (en) * 2022-09-01 2024-03-07 Savoi Guilherme Crisaborole cocrystal derivatives

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