WO2017215617A1 - 奥扎莫德的晶型、其盐酸盐的晶型及其制备方法 - Google Patents

奥扎莫德的晶型、其盐酸盐的晶型及其制备方法 Download PDF

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WO2017215617A1
WO2017215617A1 PCT/CN2017/088314 CN2017088314W WO2017215617A1 WO 2017215617 A1 WO2017215617 A1 WO 2017215617A1 CN 2017088314 W CN2017088314 W CN 2017088314W WO 2017215617 A1 WO2017215617 A1 WO 2017215617A1
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crystal form
ozamod
ray powder
powder diffraction
diffraction pattern
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PCT/CN2017/088314
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English (en)
French (fr)
Inventor
陈敏华
张炎锋
翟晓婷
鄢楷强
杨朝惠
张晓宇
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苏州科睿思制药有限公司
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Priority to EP17812728.8A priority Critical patent/EP3470400A4/en
Priority to US16/310,328 priority patent/US11111223B2/en
Priority to CN202210226424.4A priority patent/CN114957157A/zh
Priority to CN201780029499.0A priority patent/CN109219597A/zh
Publication of WO2017215617A1 publication Critical patent/WO2017215617A1/zh
Priority to US16/748,303 priority patent/US11680050B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • 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 Ozamod, a crystal form of the hydrochloride thereof and a preparation method thereof.
  • Ozanimod is a novel oral selective sphingosine 1 phosphate receptor (S1P1R) modulator developed by Receptos, developed for the treatment of autoimmune diseases, and multiple sclerosis (MS) And ulcerative colitis (UC) is in stage III clinical practice in the United States.
  • S1P1R selective sphingosine 1 phosphate receptor
  • MS multiple sclerosis
  • UC ulcerative colitis
  • Ozamod has very strong pharmacokinetic, pharmacodynamic and safety data, which can perfectly meet the differential development strategy and is expected to be the best second-generation SIP1R modulator.
  • the chemical structural formula of the drug is as shown in the formula (I).
  • the specific medicinal activity is an essential prerequisite for the pharmaceutically active substance to be approved for marketing.
  • requirements are based on various parameters relating to the nature of the active substance itself. Without limitation, examples of such parameters are chemical and solid state stability and storage stability of the active ingredient under various environmental conditions, stability during manufacture of the pharmaceutical composition, and stability of the active ingredient in the final pharmaceutical composition, and the like. .
  • the pharmaceutically active substance used for the preparation of the pharmaceutical composition should be as pure as possible and must have a long-term preservation stability under various environmental conditions. It is essential to avoid the use of a pharmaceutical composition containing, for example, a decomposition product thereof in addition to the actual active substance, in which case the active substance content of the drug may be less than the indicated content.
  • the pharmaceutically active substance is non-hygroscopic, stable to degradation and subsequent changes in its solid form, if the pharmaceutically active substance is hygroscopic in the sense that it absorbs water (slowly or over time), It is not possible to reliably make a pharmaceutically active substance into a drug because the amount of the substance to be added to provide the same dose varies greatly depending on the degree of hydration, and in addition, changes in hydration or solid form can cause physical and chemical properties (such as solubility or dissolution rate). Changes in physical and chemical properties can in turn lead to inconsistent absorption by patients. Therefore, preferably, the pharmaceutically active substance should have only slight hygroscopicity.
  • the chemical stability, solid state stability, "shelf life” and material handling properties of the pharmaceutically active substance are very important factors.
  • the pharmaceutically active substance and any pharmaceutical composition comprising the same should be capable of being effectively stored for a substantial period of time without exhibiting the physicochemical properties of the active substance (eg, its activity, moisture content, solubility properties, solid form, etc.) Significant changes.
  • the drug will typically require treatment to achieve a particle size suitable for inhalation and any crystalline form must be stabilized during this treatment to make the properties of the final product predictable and reliable.
  • the inventors of the present invention discovered several crystal forms of Ozamod and a crystal form of Ozamod hydrochloride during the research, which provided a new choice for the preparation of pharmaceutical preparations containing Ozamod. .
  • the invention provides a new crystal form of Ozamod, a new crystal form of Ozamod hydrochloride and a preparation method and use thereof.
  • the crystal form CS1 provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 12.1 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, and 4.2 ° ⁇ 0.2 °.
  • the crystal form CS1 provided by the present invention has an X-ray powder diffraction pattern including one or two or three places having a 2theta value of 7.4° ⁇ 0.2°, 24.3° ⁇ 0.2°, and 17.7° ⁇ 0.2°. Characteristic peaks; Preferably, the crystal form CS1 provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 7.4 ° ⁇ 0.2 °, 24.3 ° ⁇ 0.2 °, and 17.7 ° ⁇ 0.2 °.
  • the crystal form CS1 provided by the present invention has an X-ray powder diffraction pattern including one or two or three places having a 2theta value of 12.8° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 18.2° ⁇ 0.2°. Characteristic peaks; Preferably, the crystal form CS1 provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 12.8 ° ⁇ 0.2 °, 21.5 ° ⁇ 0.2 °, and 18.2 ° ⁇ 0.2 °.
  • the crystal form CS1 provided by the present invention has an X-ray powder diffraction pattern including a value of 4.2° ⁇ 0.2°, 7.4° ⁇ 0.2°, 10.4° ⁇ 0.2°, 12.1° ⁇ 0.2°, and 12.8 ⁇ . There are characteristic peaks at 0.2°, 17.7° ⁇ 0.2°, 18.2° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 24.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CS1 provided by the present invention is substantially as shown in FIG.
  • the crystal form CS1 provided by the present invention when subjected to differential scanning calorimetry, is heated to a temperature near 98 ° C to start the first endothermic peak, and heating to near 134 ° C begins to appear second.
  • the endothermic peak, the differential scanning calorimetry chart is basically as shown in Fig. 2.
  • the crystal form CS1 provided by the present invention has a mass loss gradient of about 4.3% when heated to 150 ° C when subjected to thermogravimetric analysis, and the thermogravimetric analysis chart is substantially as shown in FIG.
  • Another object of the present invention is to provide a process for the preparation of a crystalline form CS1 comprising the following 1) or 2):
  • the alcohol solvent in the method 1) is preferably methanol; the ketone solvent is preferably acetone; the ester solvent is preferably isopropyl acetate; and the nitrile solvent is preferably acetonitrile.
  • the alcohol in Process 2) is methanol.
  • Another object of the present invention is to provide a crystalline form of Ozamod, designated as Form CS2.
  • the crystal form CS2 provided by the present invention is characterized in that its X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 23.2° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 13.3° ⁇ 0.2°.
  • the crystal form CS2 provided by the present invention has an X-ray powder diffraction pattern including a 2theta value of 15.9 ° ⁇
  • One or two or three of 0.2°, 30.0° ⁇ 0.2°, and 14.2° ⁇ 0.2° have characteristic peaks; preferably, the crystal form CS2 provided by the present invention has an X-ray powder diffraction pattern with a value of 15.9 in the 2theta. Characteristic peaks are found at ° ⁇ 0.2°, 30.0° ⁇ 0.2°, and 14.2° ⁇ 0.2°.
  • the crystal form CS2 provided by the present invention has an X-ray powder diffraction pattern characterized by one or two or three of 2theta values of 4.0° ⁇ 0.2°, 26.5° ⁇ 0.2°, and 17.7° ⁇ 0.2°.
  • the crystalline form CS2 provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at a 2theta value of 4.0 ° ⁇ 0.2 °, 26.5 ° ⁇ 0.2 °, and 17.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystalline form CS2 provided by the present invention includes the values of 2theta of 4.0° ⁇ 0.2°, 13.3° ⁇ 0.2°, 14.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, and 17.7 ⁇ . There are characteristic peaks at 0.2°, 18.5° ⁇ 0.2°, 23.2° ⁇ 0.2°, 26.5° ⁇ 0.2°, and 30.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CS2 provided by the present invention is substantially as shown in FIG.
  • the crystal form CS2 provided by the present invention when performing differential scanning calorimetry, starts to have an endothermic peak near 134 ° C, and the differential scanning calorimetry diagram is substantially as shown in FIG. 5 . Show.
  • the crystal form CS2 provided by the present invention has a mass loss gradient of about 1.1% when heated to 150 ° C when subjected to thermogravimetric analysis, and the thermogravimetric analysis chart is substantially as shown in FIG.
  • Another object of the present invention is to provide a method of preparing a crystalline form CS2 comprising the following 1) or 2):
  • the heating temperature in the method 1) is preferably 110 °C.
  • the nitrile solvent described in the method 2) is acetonitrile;
  • the ketone solvent is acetone, methyl isobutyl ketone;
  • the ester solvent is ethyl acetate;
  • the aromatic hydrocarbon solvent is toluene; and
  • the cyclic ether solvent is 2 -methyltetrahydrofuran;
  • a mixed solvent of an alcohol and water is a mixed solvent of ethanol and water;
  • a mixed solvent of a ketone and water is a mixed solvent of acetone and water;
  • a mixed solvent of an amide and water is dimethylformamide and water Mixed solvent.
  • Another object of the present invention is to provide a crystalline form of Ozamod, designated as Form CS3.
  • the X-ray powder diffraction pattern of the crystalline form CS3 provided by the present invention is included in the 2theta value of 4.4 ° ⁇ 0.2 °, 5.7 ° ⁇ 0.2 °, 7.8 ° ⁇ 0.2 °, 11.0 ° ⁇ 0.2 °, 13.0 ° ⁇ 0.2 °, At least one of 13.7° ⁇ 0.2°, 17.0° ⁇ 0.2°, 23.2° ⁇ 0.2°, 24.1° ⁇ 0.2°, and 26.0° ⁇ 0.2° has a characteristic peak.
  • the crystal form CS3 provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 4.4° ⁇ 0.2°, 13.0° ⁇ 0.2°, 26.0° ⁇ 0.2°, and 11.0° ⁇ 0.2°.
  • the crystal form CS3 provided by the present invention has an X-ray powder diffraction pattern including one or two or three places of 2theta values of 7.8° ⁇ 0.2°, 23.2° ⁇ 0.2°, and 17.0° ⁇ 0.2°. There is a characteristic peak; preferably, the crystal form CS3 provided by the present invention has an X-ray powder diffraction pattern having a characteristic peak at a 2theta value of 7.8° ⁇ 0.2°, 23.2° ⁇ 0.2°, and 17.0° ⁇ 0.2°.
  • the present invention provides a crystalline form CS3 having an X-ray powder diffraction pattern comprising characteristic peaks at one or two of 2theta values of 13.7° ⁇ 0.2° and 24.1° ⁇ 0.2°; preferably, the present invention
  • the crystal form CS3 provided has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 13.7 ° ⁇ 0.2 ° and 24.1 ° ⁇ 0.2 °.
  • the crystal form CS3 provided by the present invention has an X-ray powder diffraction pattern including a value of 5.7° at 2theta.
  • One or two of ⁇ 0.2°, 24.1° ⁇ 0.2° have characteristic peaks; preferably, the crystal form CS3 provided by the present invention has an X-ray powder diffraction pattern with a value of 5.7° ⁇ 0.2°, 24.1° at 2theta. There is a characteristic peak at ⁇ 0.2°.
  • the present invention provides a crystalline form CS3 having an X-ray powder diffraction pattern comprising a value of 4.4 ° ⁇ 0.2 °, 7.8 ° ⁇ 0.2 °, 11.0 ° ⁇ 0.2 °, and 13.0 ° ⁇ 0.2 °. Characteristic peaks at 13.7° ⁇ 0.2°, 17.0° ⁇ 0.2°, 23.2° ⁇ 0.2°, 24.1° ⁇ 0.2°, and 26.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CS3 provided by the present invention is substantially as shown in FIG.
  • the crystal form CS3 provided by the present invention when subjected to differential scanning calorimetry, is heated to a temperature near 112 ° C to start the first endothermic peak, and an exothermic peak appears near the temperature of 121 ° C.
  • the present invention provides a crystalline form CS3 having a mass loss of about 3.1% when heated to 130 ° C when subjected to thermogravimetric analysis, the TGA of which is shown in FIG.
  • the present invention provides a crystalline form CS3 having an X-ray powder diffraction pattern comprising a value of 4.4 ° ⁇ 0.2 °, 5.7 ° ⁇ 0.2 °, 7.8 ° ⁇ 0.2 °, 11.0 ° ⁇ 0.2 °. Characteristic peaks at 13.0 ° ⁇ 0.2 °, 17.0 ° ⁇ 0.2 °, 23.2 ° ⁇ 0.2 °, 24.1 ° ⁇ 0.2 °, and 26.0 ° ⁇ 0.2 °.
  • the present invention provides a crystalline form CS3 having an X-ray powder diffraction pattern substantially as shown in FIG.
  • Another object of the present invention is to provide a method for preparing a crystalline form CS3, which comprises: adding a solid of Ozamod to an alcohol, a nitrile, a dichloromethane, an ester, a sulfoxide, an ethylene glycol The mixed solvent of methyl ether solvent and water was filtered, and the obtained filtrate was volatilized, and the solid was collected to obtain crystal form CS3 of Ozamod.
  • the alcohol solvent is methanol; the nitrile solvent is acetonitrile; the ester solvent is isopropyl acetate; and the sulfoxide solvent is dimethyl sulfoxide.
  • Another object of the invention is to provide a crystalline form of Ozamod, designated as Form CS5.
  • the crystal form CS5 provided by the present invention is characterized in that its X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 4.3 ° ⁇ 0.2 °, 6.8 ° ⁇ 0.2 °, and 16.4 ° ⁇ 0.2 °.
  • the crystal form CS5 provided by the present invention has an X-ray powder diffraction pattern including one or two or three places having a 2theta value of 21.6° ⁇ 0.2°, 8.5° ⁇ 0.2°, and 13.6° ⁇ 0.2°. Characteristic peaks; Preferably, the crystal form CS5 provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 21.6 ° ⁇ 0.2 °, 8.5 ° ⁇ 0.2 °, and 13.6 ° ⁇ 0.2 °.
  • the crystal form CS5 provided by the present invention has an X-ray powder diffraction pattern characterized by one or two or three of 2theta values of 13.0° ⁇ 0.2°, 25.0° ⁇ 0.2°, and 26.0° ⁇ 0.2°.
  • the crystalline form CS5 provided by the present invention has an X-ray powder diffraction pattern having a characteristic peak at a 2theta value of 13.0 ° ⁇ 0.2 °, 25.0 ° ⁇ 0.2 °, and 26.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of the crystalline form CS5 provided by the present invention includes the values of 2theta of 4.3° ⁇ 0.2°, 6.8° ⁇ 0.2°, 8.5° ⁇ 0.2°, 13.0° ⁇ 0.2°, and 13.6° ⁇ . There are characteristic peaks at 0.2°, 16.4° ⁇ 0.2°, 21.6° ⁇ 0.2°, 25.0° ⁇ 0.2°, and 26.0° ⁇ 0.2°.
  • the present invention provides a crystalline form CS5 having an X-ray powder diffraction pattern substantially as shown in FIG.
  • the crystal form CS5 provided by the present invention when performing differential scanning calorimetry, starts to have an endothermic peak when heated to around 65 ° C, and an exothermic peak begins to appear near the temperature of 91 ° C.
  • a second endothermic peak begins to appear near 133 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG.
  • Another object of the present invention is to provide a process for preparing a crystalline form CS5 comprising adding a solid of ozzamod to a cyclic ether solvent, filtering, volatilizing the obtained filtrate, and collecting the solid to obtain a crystalline form CS5 of Ozamod.
  • cyclic ether solvent is 2-methyltetrahydrofuran.
  • Another object of the present invention is to provide a crystalline form of Ozamod, designated as Form CS6.
  • the crystal form CS6 provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 4.4 ° ⁇ 0.2 °, 24.5 ⁇ 0.2 °, 26.5 ° ⁇ 0.2 °, and 13.8 ° ⁇ 0.2 °.
  • the present invention provides a crystalline form CS6 having an X-ray powder diffraction pattern comprising characteristic peaks at one or two of 2theta values of 13.0° ⁇ 0.2° and 25.4 ⁇ 0.2°; preferably, the present invention provides The crystal form CS6 has an X-ray powder diffraction pattern having a characteristic peak at a 2theta value of 13.0 ° ⁇ 0.2 ° and 25.4 ⁇ 0.2 °.
  • the crystal form CS6 provided by the present invention has an X-ray powder diffraction pattern characterized by one or two or three of 2theta values of 8.9° ⁇ 0.2°, 13.4° ⁇ 0.2°, and 11.0° ⁇ 0.2°.
  • the present invention provides a crystalline form CS6 having an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 8.9 ° ⁇ 0.2 °, 13.4 ° ⁇ 0.2 °, and 11.0 ° ⁇ 0.2 °.
  • the crystal form CS6 provided by the present invention has an X-ray powder diffraction pattern including a value of 4.4° ⁇ 0.2°, 8.9° ⁇ 0.2°, 11.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 13.4 ⁇ at 2theta. There are characteristic peaks at 0.2°, 13.8° ⁇ 0.2°, 24.5 ⁇ 0.2°, 25.4 ⁇ 0.2°, and 26.5° ⁇ 0.2°.
  • the present invention provides a crystalline form CS6 having an X-ray powder diffraction pattern substantially as shown in FIG.
  • the crystal form CS6 provided by the present invention when subjected to differential scanning calorimetry, begins to exhibit an exothermic peak near 110 ° C, and an endothermic peak begins to appear near 135 ° C.
  • the differential scanning calorimetry chart is basically as shown in FIG.
  • the crystal form CS6 provided by the present invention has a mass loss gradient of about 1.2% when heated to 120 ° C when subjected to thermogravimetric analysis, and the thermogravimetric analysis chart is substantially as shown in FIG.
  • Another object of the present invention is to provide a method for preparing a crystalline form CS6, which comprises adding a solid of Ozamod or a solvent such as a ketone or chloroform, filtering, volatilizing the obtained filtrate, and collecting the solid to obtain a crystal form of Ozamod. CS6.
  • the ketone solvent is acetone.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Ozamod's Form CS1 or Form CS2 or a mixture of both and a pharmaceutically acceptable carrier, diluent or excipient .
  • a therapeutically effective amount of Form CS1 or Form CS2 or a mixture of both is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation in the pharmaceutical arts Prepared in a well known manner.
  • the crystalline form CS1 or the crystalline form CS2 of Ozamod or the mixture of the two provided by the present invention can be used for the preparation of a medicament for treating an autoimmune disease, in particular for the treatment of multiple sclerosis and ulcerative colitis pharmaceutical preparations .
  • the invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Ozamod's Form CS3 or Form CS5 or Form CS6 or any combination of the three and a pharmaceutically acceptable carrier, diluent or formulation Shape agent.
  • a therapeutically effective amount of Form CS3 or Form CS5 or Form CS6 or any combination of the three is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation, the pharmaceutical composition Or the formulations are prepared in a manner well known in the pharmaceutical art.
  • the use of the crystalline form CS3 or the crystalline form CS5 or the crystalline form CS6 of the Ozamod or any combination of the three provided by the present invention can be used for the preparation of a pharmaceutical preparation of a selective sphingosine 1 phosphate receptor modulator.
  • the crystal form CS3 or the crystal form CS5 or the crystal form CS6 provided by the present invention or any combination of the three can be used for the preparation of a medicament for treating autoimmune diseases, in particular for treating multiple sclerosis and ulcerative colon Inflammatory pharmaceutical preparation use.
  • the present invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Ozamod's crystalline form CS1 or Ozamod's crystalline form CS2 or Ozamod's crystalline form CS3 or Oza Morden's Form CS5 or Ozamod's Form CS6 or any combination thereof and a pharmaceutically acceptable carrier, diluent or excipient.
  • Another object of the present invention is to provide a crystalline form of the hydrochloride salt of Ozamod, designated as the hydrochloride salt form CS1.
  • the hydrochloride salt form CS1 provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta values of 26.1 ° ⁇ 0.2 °, 24.4 ° ⁇ 0.2 °, and 20.1 ° ⁇ 0.2 °.
  • the hydrochloride salt form CS1 provided by the present invention has an X-ray powder diffraction pattern including one or two of 2theta values of 3.9° ⁇ 0.2°, 21.1° ⁇ 0.2°, and 7.9° ⁇ 0.2° or There are characteristic peaks at three places; preferably, the hydrochloride salt form CS1 provided by the present invention has an X-ray powder diffraction pattern with characteristics of 2theta values of 3.9° ⁇ 0.2°, 21.1° ⁇ 0.2°, and 7.9° ⁇ 0.2°. peak.
  • the hydrochloride salt form CS1 provided by the present invention has an X-ray powder diffraction pattern further included in one or two of 2theta values of 11.9° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 13.8° ⁇ 0.2°. Or having three characteristic peaks; preferably, the hydrochloride salt form CS1 provided by the present invention has an X-ray powder diffraction pattern having a 2theta value of 11.9° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 13.8° ⁇ 0.2°. Characteristic peaks.
  • hydrochloride salt form CS1 of the present invention has an X-ray powder diffraction pattern including a value of 3.9° ⁇ 0.2°, 7.9° ⁇ 0.2°, 11.9° ⁇ 0.2°, and 13.8° ⁇ 0.2° at 2theta. 19.6° ⁇ 0.2°, 20.1° ⁇ 0.2°, 21.1° ⁇ 0.2°, 24.4° ⁇ 0.2°, 26.1° ⁇ 0.2°, with characteristic peaks.
  • the hydrochloride salt form CS1 provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the hydrochloride salt form CS1 provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the hydrochloride salt form CS1 provided by the present invention when subjected to differential scanning calorimetry, is heated to a temperature near 238 ° C to start an endothermic peak, and the differential scanning calorimetry diagram is substantially as Figure 18 shows.
  • the hydrochloride salt form CS1 provided by the present invention has a mass loss gradient of about 1.1% when heated to 150 ° C when subjected to thermogravimetric analysis, and the thermogravimetric analysis chart is basically as shown in FIG. 19 . Shown.
  • Another object of the present invention is to provide a process for the preparation of Ozamod hydrochloride salt form CS1, which process comprises 1) or 2) or 3) or 4),
  • volatilization time is the time from the command to the precipitation of solids or Longer; preferably volatilized from 0.5 days to 14 days (or 2 weeks); more preferably for 7 days or 1 week; or
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of the hydrochloride salt form CS1 and a pharmaceutically acceptable carrier, diluent or excipient.
  • a pharmaceutical composition or formulation is generally prepared by mixing or contacting a therapeutically effective amount of the hydrochloride salt form CS1 with one or more pharmaceutical excipients, which is prepared in a manner well known in the pharmaceutical art. .
  • the hydrochloride crystal form CS1 of Ozamod can be used for preparing a medicament for treating an autoimmune disease, particularly in a pharmaceutical preparation of multiple sclerosis and ulcerative colitis. use.
  • room temperature as used herein is not an accurate temperature value and refers to a temperature range of 10-30 °C.
  • reaction time in the "volatilization method” and the “diffusion method” in the present invention refers to the reaction to the time when solids are precipitated or longer.
  • the “stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, preferably 300-900 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. Drying temperature from room temperature to about 60 ° C, or to 40 ° C, or to 50 ° C. 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.
  • 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.
  • polymer refers to a mixture of equal masses of polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate, and hydroxyethyl cellulose.
  • the crystalline form and the hydrochloride crystalline form provided by the present invention have advantages in solubility, melting point, stability, dissolution, bioavailability, and processability, and the crystalline form CS1, crystalline form CS2, and crystalline form CS3 of the present invention.
  • crystal form CS5 crystal form CS6
  • hydrochloride form CS1 has low moisture permeability, good stability, solubility meets medicinal requirements, uniform particle size distribution, good dispersibility, and helps to simplify the post-treatment process of the preparation process.
  • the preparation of pharmaceutical preparations containing ozzamod provides a new and better choice and is very important for drug development.
  • Example 1 is an XRPD pattern of the crystalline form CS1 prepared in Example 1.
  • Example 2 is a DSC chart of the crystalline form CS1 prepared in Example 1.
  • Example 3 is a TGA diagram of the crystalline form CS1 prepared in Example 1.
  • Figure 5 is a DSC chart of the crystalline form CS2 prepared in Example 3.
  • Example 7 is an XRPD pattern of the crystalline form CS3 prepared in Example 5.
  • Example 8 is a DSC chart of the crystalline form CS3 prepared in Example 5.
  • Figure 10 is an XRPD pattern of the crystalline form CS5 prepared in Example 8.
  • Figure 11 is a DSC chart of the crystalline form CS5 prepared in Example 8.
  • Figure 12 is an XRPD pattern of the crystalline form CS6 prepared in Example 9.
  • Figure 13 is a DSC diagram of the crystalline form CS6 of Example 10.
  • Figure 14 is a TGA diagram of the crystalline form CS6 of Example 10.
  • Figure 15 is an XRPD pattern of the crystalline form CS3 prepared in Example 6.
  • Figure 16 is an XRPD pattern of the crystalline form CS6 prepared in Example 10.
  • Figure 17 is an XRPD pattern of the hydrochloride salt form CS1 of the present invention.
  • Figure 18 is a DSC chart of the hydrochloride salt form CS1 prepared in Example 11.
  • Figure 19 is a TGA diagram of the hydrochloride salt form CS1 prepared in Example 11.
  • Figure 20 is an XRPD pattern of the hydrochloride salt form CS1 prepared in Example 11.
  • Example 21 is an XRPD pattern of the hydrochloride salt form CS1 prepared in Example 12.
  • Figure 22 is an XRPD pattern of the hydrochloride salt form CS1 prepared in Example 13.
  • Figure 23 is an XRPD pattern of the hydrochloride salt form CS1 prepared in Example 14.
  • Figure 24 is an XRPD pattern of the hydrochloride salt form CS1 prepared in Example 15.
  • Figure 25 is a DVS diagram of the crystal form CS1 in the embodiment 16.
  • Figure 26 is a DVS diagram of the crystal form CS2 in Example 17.
  • Figure 27 is a DVS diagram of the crystal form CS3 in Example 18.
  • Figure 29 is a DVS diagram of the crystalline form CS6 in Example 20.
  • Figure 30 is a DVS diagram of the hydrochloride salt form CS1 in Example 21.
  • Figure 31 is a comparison of XRPD before and after the stability test of the crystalline form CS1 of Example 22.
  • Figure 32 is a comparison of XRPD before and after the stability test of the crystalline form CS2 of Example 23.
  • Figure 33 is a comparison of XRPD before and after the stability test of the crystalline form CS3 of Example 24.
  • Figure 34 is a comparison of XRPD before and after the stability test of the crystalline form CS5 of Example 25.
  • Figure 35 is a comparison of XRPD before and after the stability test of the crystalline form CS6 of Example 26.
  • Figure 36 is a comparison of XRPD before and after the stability test of the hydrochloride salt crystal form CS1 of Example 27.
  • Example 37 is a PSD diagram of the crystal form CS1 in Example 28.
  • Figure 38 is a PSD diagram of the crystal form CS2 in Example 28.
  • Figure 39 is a PSD diagram of the crystalline form CS3 in Example 28.
  • 40 is a PSD diagram of a crystalline form CS5 in Example 28.
  • Figure 41 is a PSD diagram of the crystalline form CS6 in Example 28.
  • Figure 42 is a PSD diagram of the hydrochloride salt form CS1 in Example 28.
  • Figure 43 is a PLM diagram of the crystal form CS1 in Example 28.
  • Figure 44 is a PLM diagram of the crystal form CS2 in Example 28.
  • Figure 45 is a PLM diagram of the crystal form CS3 in Example 28.
  • Figure 46 is a PLM diagram of the crystal form CS5 in Example 28.
  • Figure 47 is a PLM diagram of the crystalline form CS6 in Example 28.
  • Figure 48 is a PLM diagram of the hydrochloride salt form CS1 in Example 28.
  • Figure 49 is a comparison of XRPD before and after the grinding test of the crystal form CS3 in Example 31.
  • Figure 50 is a comparison of XRPD before and after the grinding test of the crystal form CS5 in Example 31.
  • Figure 51 is a comparison of XRPD before and after the crystal type CS6 grinding test in Example 31.
  • Figure 52 is a comparison of XRPD before and after the salt test of the hydrochloride salt form CS1 in Example 31.
  • Figure 53 is an XRPD of the crystal form CS3 in Example 7.
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • 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 Q5000.
  • 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 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.
  • the Ozamod free form and/or its salt used in the following examples can be obtained according to the method described in the literature of CN102762100A.
  • the solid obtained in this example was a crystalline form CS1.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 1. Its XRPD diagram is shown in Figure 1, its DSC diagram is shown in Figure 2, and its TGA diagram is shown in Figure 3.
  • Example 1 Using the method of Example 1, about 10 mg of the solid of Ozamod hydrochloride was placed in methanol, acetone, isopropyl acetate, acetonitrile, and 1.0-1.5 times the amount of aqueous sodium hydroxide solution was added, and the suspension was turbid. Turn to clarification. After stirring at room temperature for 12 hours, a white solid precipitated, and after centrifugation, it was vacuum-dried, and the obtained solid was detected to be crystalline form CS1, and its XRPD pattern was substantially identical to that of FIG.
  • the solid obtained in this example was a crystalline form CS2.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 2, the XRPD pattern thereof is shown in Fig. 4, the DSC chart is shown in Fig. 5, and the TGA chart is shown in Fig. 6.
  • the X-ray powder diffraction data of Samples 1-10 were 4.0° ⁇ 0.2°, 13.3° ⁇ 0.2°, 14.2° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.5° ⁇ 0.2° at 2theta, Characteristic peaks are found at 23.2 ° ⁇ 0.2 °, 26.5 ° ⁇ 0.2 °, and 30.0 ° ⁇ 0.2 °.
  • the XRPD pattern of Samples 1-10 is substantially identical to Figure 4.
  • the solid obtained in this example was a crystalline form CS3.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 4. Its XRPD diagram is shown in Fig. 7, its DSC diagram is shown in Fig. 8, and its TGA diagram is shown in Fig. 9.
  • the solid obtained in this example was a crystalline form CS3.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 5. Its XRPD diagram is shown in Figure 15.
  • the solid of Ozamod was placed in a solvent of methanol, isopropyl acetate and dimethyl sulfoxide, and the obtained solids were all detected as Ozamod crystal form CS3.
  • the solid obtained in this example was a crystalline form CS3.
  • the X-ray powder diffraction pattern has characteristic peaks at 2theta values of 4.42, 5.70, 7.85, 11.06, 12.99, 17.04, 23.21, 24.11 and 26.04.
  • the XRPD pattern of the crystal form obtained in this example is shown in Fig. 53.
  • the solid obtained in this example was a crystalline form CS5.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 6. Its XRPD diagram is shown in Figure 10, and its DSC diagram is shown in Figure 11.
  • the solid obtained in this example was a crystalline form CS6.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 7. Its XRPD diagram is shown in Figure 12.
  • the solid of Ozamod was volatilized in acetone, and the obtained solid was detected to be crystalline form CS6.
  • the solid obtained in this example was a crystalline form CS6.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 8. Its XRPD diagram is shown in Figure 16.
  • a solid of 10.1 mg of Ozamod hydrochloride was weighed, placed in a 1.5 mL glass vial, and about 0.5 mL of 2-methyltetrahydrofuran was added thereto, and the mixture was stirred at room temperature for 1 week, and dried by centrifugation to give a white solid.
  • the solid obtained in this example was the hydrochloride salt form CS1.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 9. Its XRPD diagram is shown in Figure 20, its DSC diagram is shown in Figure 18, and its TGA diagram is shown in Figure 19.
  • the solid obtained in this example was the hydrochloride salt form CS1.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 10, and its XRPD pattern is shown in Fig. 21.
  • the solid obtained in this example was the hydrochloride salt form CS1.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 11, and its XRPD pattern is shown in Fig. 22.
  • the solid obtained in this example was the hydrochloride salt form CS1.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 12, and its XRPD pattern is shown in Fig. 23.
  • the solid obtained in this example was the hydrochloride salt form CS1.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 13. Its XRPD diagram is shown in Figure 24.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • Ozamod crystal form CS1 was left at 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH for 4 weeks, the crystal form remained unchanged, and the purity did not change significantly. The results show that the Ozamod crystal form CS1 has good stability.
  • Ozamod crystal CS2 Four samples of Ozamod crystal CS2 were placed in a constant temperature and humidity chamber at 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH and 80 ° C for 4 weeks, then The purity was sampled at 1 week, 2 weeks, and 4 weeks, and XRPD was sampled at 4 weeks, and samples were taken only at 1 week at 80 °C.
  • N/A means that it is not detected.
  • Ozamod crystal form CS2 was placed at 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH for 4 weeks and 80 ° C for 1 week, the crystal form remained unchanged, and the purity was not See a significant reduction.
  • the above test results show that Ozamod crystal form CS2 has good stability.
  • Ozamod crystal form CS3 was left at 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH for 4 weeks, the crystal form remained unchanged, and the purity did not change significantly. The results show that Ozamod crystal form CS3 has good stability.
  • the Ozamod crystal form CS5 was left at 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH for 2 weeks, and the crystal form remained unchanged. The results show that Ozamod crystal form CS5 has good stability.
  • Ozamod crystal form CS6 is placed at 25 ° C / 60% RH and 40 ° C / 75% RH for four weeks, the crystal form remains unchanged, and
  • Ozamod hydrochloride salt form CS1 was placed at 25 ° C / 60% RH, 40 ° C / 75% RH, 60 ° C / 75% RH for 4 weeks and 80 ° C for 1 week, the crystal form remained unchanged, And the purity was not significantly reduced.
  • the above test results show that the Ozamod hydrochloride salt form CS1 has good stability.
  • the particle size distribution of the crystal form CS1 of the present invention, the crystal form CS2 of the second embodiment, the crystal form CS3, the form of the form CS2, the form of the form CS6, and the hydrochloride form of the CS1 was measured. The results are shown in Table 26.
  • 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
  • the PSD diagram of the crystal form CS1 is shown in Fig. 37, and the volume average particle diameter of the crystal form CS1 is 22.40 ⁇ m. And the particle size distribution is narrow, almost showing a normal distribution, and the particle size distribution is uniform.
  • the PSD pattern of the crystalline form CS2 is shown in Fig. 38, and the volume average particle diameter of the crystalline form CS2 is 23.24 ⁇ m. And the particle size distribution is narrow, almost showing a normal distribution, and the particle size distribution is uniform.
  • the PSD pattern of the crystalline form CS3 is shown in Fig. 39, and the volume average particle diameter of the crystalline form CS3 is 66.62 ⁇ m. And the particle size distribution is narrow, almost showing a normal distribution, and the particle size distribution is uniform.
  • the PSD pattern of the crystalline form CS5 is shown in Fig. 40, and the volume average particle diameter of the crystalline form CS5 is 68.84 ⁇ m. And the particle size distribution is narrow, almost showing a normal distribution, and the particle size distribution is uniform.
  • the PSD pattern of the crystalline form CS6 is shown in Fig. 41, and the volume average particle diameter of the crystalline form CS6 is 68.91 ⁇ m. And the particle size distribution is better Narrow, almost a normal distribution, uniform particle size distribution.
  • the PSD diagram of the hydrochloride salt form CS1 is shown in Fig. 42, and the hydrochloride salt form CS1 has a volume average particle diameter of 200.7 ⁇ m. Large particle size, in the production process, is conducive to product separation.
  • the PLM diagrams of the crystal form CS1, the crystal form CS2, the form form CS3, the form form CS5, the form form CS6, and the hydrochloride form form CS1 are respectively shown in Fig. 43, Fig. 44, Fig. 45, Fig. 46, Fig. 47 and Fig. 48, respectively. .
  • the crystalline form CS1, the crystalline form CS2, the crystalline form CS5, the crystalline form CS6 and the hydrochloride form CS1 are short rod-shaped, the crystalline form CS3 is in the form of a sheet, and the dispersion is good, and there is little agglomeration. Phenomenon, and the particle size is relatively uniform.
  • the uniform particle size helps to simplify the post-treatment process of the formulation process and improve quality control.
  • the Ozamod crystal form CS1 and the hydrochloride form CS1 sample were prepared into a saturated solution with SGF (simulated artificial gastric juice) and pH 5.0 FeSSIF (artificial intestinal juice under fed condition), respectively, in 1 hour, 4 hours and 24 hours.
  • the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after an hour.
  • HPLC high performance liquid chromatography
  • the Ozamod crystal form CS3 and the crystal form CS5 samples were respectively prepared into a saturated solution by SGF (simulated artificial gastric juice) and high-purity water, and the crystal form CS2 was formulated into a saturated solution by FeSSIF (artificial intestinal juice in the fed state) for 1 hour.
  • the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 4 hours and 24 hours.
  • HPLC high performance liquid chromatography
  • the crystalline form CS3, the crystalline form CS5, the crystalline form CS6, and the hydrochloride salt form CS1 sample of the present invention were placed in a mortar and manually ground for 5 minutes to test the solid XRPD.
  • the results are shown in Fig. 49, Fig. 50, Fig. 51 and Fig. 52, respectively (the upper figure is before grinding, and the lower figure is after grinding).
  • the crystalline drug with better mechanical stability has low requirements on the crystallization equipment, requires no special post-treatment conditions, is more stable in the preparation process, can significantly reduce the development cost of the drug, enhance the quality of the drug, and has strong economic value.
  • the crystalline form CS1 of Ozamod used in the present invention 16-31 is prepared by the method of Example 1; the crystalline form CS2 is prepared by the method of Example 3; CS3 was prepared by the method of Example 6; the form CS5 was prepared by the method of Example 9; the form CS6 was prepared by the method of Example 10; the hydrochloride form CS1 was by the example Prepared by the method of 11.

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Abstract

公开了奥扎莫德的晶型、其盐酸盐的晶型及其制备方法，所述奥扎莫德的晶型及其盐酸盐的晶型可用于治疗自身免疫疾病，特别是多发性硬化症和溃疡性结肠炎，在溶解度，熔点，稳定性、溶出度、生物有效性以及加工性能等方面中的至少一方面上存在优势，为含奥扎莫德的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的价值。

Description

奥扎莫德的晶型、其盐酸盐的晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及奥扎莫德的晶型、其盐酸盐的晶型及其制备方法。
背景技术
奥扎莫德(Ozanimod)是由Receptos公司研发的一种新型口服选择性鞘氨醇1磷酸受体(S1P1R)调节剂，开发用于自身免疫性疾病的治疗，其多发性硬化症(MS)和溃疡性结肠炎(UC)处于美国III期临床。在临床试验中，奥扎莫德具有非常强大的药代动力学、药效及安全性数据，能够完美满足差异化开发战略，有望成为最好的第二代SIP1R调节剂药物。该药物的化学结构式如式(I)所示。
Figure PCTCN2017088314-appb-000001
具体的药用活性是药物活性物质被批准上市必需满足的基本先决条件。然而，有多种其他的要求也是药物活性物质必须遵循的条件。这些要求以各种与其本身活性物质的性质有关的参数为基础。在没有限制下，这些参数的实例为活性成分在各种环境条件下的化学和固态稳定性及储存稳定、在药物组合物制造期间的稳定性，以及活性成分在最终药物组合物的稳定性等。
用于制备药物组合物的药物活性物质应尽可能纯且必须保证在各种环境情况下具有长期保存的稳定性。避免使用含有除了含有确实活性物质外还含有例如其分解产物的药物组合物是最基本的，在这些情形下，药物中的活性物质含量可能少于标示的含量。此外，药学活性物质为非吸湿性、对降解和随后其固体形式的变化均稳定是重要的，如果药学活性物质在其吸收水(缓慢地或随时间)的意义上为吸湿性的，则几乎不可能可靠地将药学活性物质制成药物，原因是待添加以提供相同剂量的物质的量会根据水合程度大幅变化，另外，水合或固体形式的改变可以引起理化性质(例如溶解度或溶解速率)的变化，理化性质的变化可以进而引起患者的不一致的吸收。因此优选地，药物活性物质应只具有轻微吸湿性。
因此，药学活性物质的化学稳定性、固态稳定性、“保存期”和材料处理性质(例如使化合物溶解的容易度)是非常重要的因素。在理想的情况下，药学活性物质和包含其的任何药物组合物应当能够有效储存相当长的时期，而不表现出活性物质的理化性质(例如其活性、水分含量、溶解度性质、固体形式等)的显著变化。此外，药品将通常需要处理以达到适于吸入的粒径且任何结晶型在此处理期间必须稳定以使最终产品的性质可预测并可靠。简言之，在生产商业上可行并且药学上可接受的药物组合物时，无论哪种可能，以一种充分结晶和稳定的形态提供药物都是理想的。
固体化学药物晶型不同，可造成其溶解度和稳定性不同，从而影响药物的吸收和生物利用度，并且会导致临床药效的差异。专利文献CN102762100A或US2011172202A1中涉及式(I) 化合物，然而现有技术中并无奥扎莫德固体形式或晶型公开，现有技术对发现晶型的技术方案既无指导，也无启示。因此，有必要对奥扎莫德进行全面系统的多晶型筛选，选择最适合开发的晶型。
本发明的发明人在研究过程中发现了奥扎莫德的几种晶型和一种奥扎莫德盐酸盐的晶型，为含奥扎莫德的药物制剂的制备提供了新的选择。
发明内容
本发明提供了奥扎莫德的新晶型，奥扎莫德盐酸盐的新晶型及其制备方法和用途。
本发明的一个目的是提供一种奥扎莫德的晶型，命名为晶型CS1。
本发明提供的晶型CS1，其X射线粉末衍射图在2theta值为12.1°±0.2°、10.4°±0.2°、4.2°±0.2°处具有特征峰。
进一步的，本发明提供的晶型CS1，其X射线粉末衍射图包括在2theta值为7.4°±0.2°、24.3°±0.2°、17.7°±0.2°中的一处或两处或三处具有特征峰；优选的，本发明提供的晶型CS1，其X射线粉末衍射图在2theta值为7.4°±0.2°、24.3°±0.2°、17.7°±0.2°处具有特征峰。
进一步的，本发明提供的晶型CS1，其X射线粉末衍射图包括在2theta值为12.8°±0.2°、21.5°±0.2°、18.2°±0.2°中的一处或两处或三处具有特征峰；优选的，本发明提供的晶型CS1，其X射线粉末衍射图在2theta值为12.8°±0.2°、21.5°±0.2°、18.2°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型CS1，其X射线粉末衍射图包括在2theta值为4.2°±0.2°、7.4°±0.2°、10.4°±0.2°、12.1°±0.2°、12.8°±0.2°、17.7°±0.2°、18.2°±0.2°、21.5°±0.2°、24.3°±0.2°处具有特征峰。
在一个优选的实施例中，本发明提供的晶型CS1，其X射线粉末衍射图基本如图1所示。
在一个优选的实施例中，本发明提供的晶型CS1，当进行差示扫描量热分析时，加热至98℃附近开始出现第一个吸热峰，加热至134℃附近开始出现第二个吸热峰，其差示扫描量热分析图基本如图2所示。
在一个优选的实施例中，本发明提供的晶型CS1，当进行热重分析时，加热至150℃时，具有约4.3％的质量损失梯度，其热重分析图基本如图3所示。
本发明的另一个目的是提供晶型CS1的制备方法，所述方法包括以下1)或2)：
1)将奥扎莫德盐酸盐的固体置于醇类、酮类、酯类、腈类溶剂中搅拌，并加入1.0-1.5倍量(优选1.0倍量)的氢氧化钠水溶液，悬浮液由混浊转为澄清。室温下搅拌一段时间，有白色固体析出，离心后干燥，得到奥扎莫德晶型CS1；所述搅拌时间为至少0.5小时；优选至少1小时；更优选12小时；或
2)将奥扎莫德游离形式的固体置于醇类溶剂中搅拌，离心，干燥固体，得到奥扎莫德晶型CS1；所述搅拌时间为至少0.5小时；优选至少1小时；更优选12小时。
进一步的，方法1)中所述醇类溶剂优选甲醇；所述酮类溶剂优选丙酮；所述酯类溶剂优选乙酸异丙酯；所述腈类溶剂优选乙腈。方法2)中所述醇类为甲醇。
本发明的另一个目的是提供一种奥扎莫德的晶型，命名为晶型CS2。
本发明提供的晶型CS2，其特征在于，其X射线粉末衍射图在2theta值为23.2°±0.2°、18.5°±0.2°、13.3°±0.2°处具有特征峰。
进一步的，本发明提供的晶型CS2，其X射线粉末衍射图包括在2theta值为15.9°± 0.2°、30.0°±0.2°、14.2°±0.2°中的一处或两处或三处具有特征峰；优选的，本发明提供的晶型CS2，其X射线粉末衍射图在2theta值为15.9°±0.2°、30.0°±0.2°、14.2°±0.2°处具有特征峰。
进一步的，本发明提供的晶型CS2，其X射线粉末衍射图在2theta值为4.0°±0.2°、26.5°±0.2°、17.7°±0.2°中的一处或两处或三处具有特征峰；优选的，本发明提供的晶型CS2，其X射线粉末衍射图在2theta值为4.0°±0.2°、26.5°±0.2°、17.7°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型CS2，其X射线粉末衍射图包括在2theta值为4.0°±0.2°、13.3°±0.2°、14.2°±0.2°、15.9°±0.2°、17.7°±0.2°、18.5°±0.2°、23.2°±0.2°、26.5°±0.2°、30.0°±0.2°处具有特征峰。
在一个优选的实施例中，本发明提供的晶型CS2，其X射线粉末衍射图基本如图4所示。
在一个优选的实施例中，本发明提供的晶型CS2，当进行差示扫描量热分析时，加热至134℃附近开始出现吸热峰，其差示扫描量热分析图基本如图5所示。
在一个优选的实施例中，本发明提供的晶型CS2，当进行热重分析时，加热至150℃时，具有约1.1％的质量损失梯度，其热重分析图基本如图6所示。
本发明的另一个目的是提供晶型CS2的制备方法，包括以下1)或2)：
1)将奥扎莫德晶型CS1加热到100-130℃得到；或
2)将奥扎莫德游离形式的固体置于腈类、酮类、酯类、芳香烃类、环醚类、水、醇类与水、酮类与水、酰胺类与水的混合溶剂中搅拌，离心，干燥固体，得到奥扎莫德晶型CS2；所述搅拌时间为至少0.5小时；优选至少1小时；更优选12小时。
进一步地，方法1)中所述加热温度优选110℃。
进一步地，方法2)中所述的腈类溶剂是乙腈；酮类溶剂是丙酮、甲基异丁基酮；酯类溶剂是乙酸乙酯；芳香烃类溶剂是甲苯；环醚类溶剂是2-甲基四氢呋喃；醇类与水的混合溶剂是乙醇与水的混合溶剂；酮类与水的混合溶剂是丙酮与水的混合溶剂；酰胺类与水的混合溶剂是二甲基甲酰胺与水的混合溶剂。
本发明的另一个目的是提供一种奥扎莫德的晶型，命名为晶型CS3。
本发明提供的晶型CS3，其X射线粉末衍射图，包括在2theta值为4.4°±0.2°、5.7°±0.2°、7.8°±0.2°、11.0°±0.2°、13.0°±0.2°、13.7°±0.2°、17.0°±0.2°、23.2°±0.2°、24.1°±0.2°、26.0°±0.2°处的至少一处具有特征峰。
进一步的，本发明提供的晶型CS3，其X射线粉末衍射图在2theta值为4.4°±0.2°、13.0°±0.2°、26.0°±0.2°、11.0°±0.2°处具有特征峰。
进一步的，本发明提供的晶型CS3，其X射线粉末衍射图，包括在2theta值为7.8°±0.2°、23.2°±0.2°、17.0°±0.2°中的一处或两处或三处具有特征峰；优选的，本发明提供的晶型CS3，其X射线粉末衍射图在2theta值为7.8°±0.2°、23.2°±0.2°、17.0°±0.2°处具有特征峰。
进一步的，本发明提供的晶型CS3，其X射线粉末衍射图，包括在2theta值为13.7°±0.2°、24.1°±0.2°中的一处或两处具有特征峰；优选的，本发明提供的晶型CS3，其X射线粉末衍射图在2theta值为13.7°±0.2°、24.1°±0.2°处具有特征峰。
进一步的，本发明提供的晶型CS3，其X射线粉末衍射图，包括在2theta值为5.7° ±0.2°、、24.1°±0.2°中的一处或两处具有特征峰；优选的，本发明提供的晶型CS3，其X射线粉末衍射图在2theta值为5.7°±0.2°、24.1°±0.2°处具有特征峰。
在一个优选的实施例中，本发明提供的晶型CS3，其X射线粉末衍射图包括在2theta值为4.4°±0.2°、7.8°±0.2°、11.0°±0.2°、13.0°±0.2°、13.7°±0.2°、17.0°±0.2°、23.2°±0.2°、24.1°±0.2°、26.0°±0.2°处具有特征峰。
在一个优选的实施例中，本发明提供的晶型CS3，其X射线粉末衍射图基本如图7所示。
在一个优选的实施例中，本发明提供的晶型CS3，当进行差示扫描量热分析时，加热至112℃附近开始出现第一个吸热峰，加热至121℃附近出现一个放热峰，在133℃附近出现第二个吸热峰，其DSC如附图8所示。
在一个优选的实施例中，本发明提供的晶型CS3，当进行热重分析时，加热至130℃时，具有约3.1％的质量损失，其TGA如附图9所示。
在一个优选的实施例中，本发明提供的晶型CS3，其X射线粉末衍射图包括在2theta值为4.4°±0.2°、5.7°±0.2°、7.8°±0.2°、11.0°±0.2°、13.0°±0.2°、17.0°±0.2°、23.2°±0.2°、24.1°±0.2°、26.0°±0.2°处具有特征峰。
在一个优选的实施例中，本发明提供的晶型CS3，其X射线粉末衍射图基本如图53所示。
本发明的另一个目的是提供晶型CS3的制备方法，所述方法包括：将奥扎莫德的固体加入到醇类、腈类、二氯甲烷、酯类、亚砜类、乙二醇二甲醚溶剂与水的混合溶剂中，过滤，将所得滤液挥发，收集固体得到奥扎莫德的晶型CS3。
更进一步的，醇类溶剂是甲醇；腈类溶剂是乙腈；酯类溶剂是乙酸异丙酯；亚砜类溶剂是二甲亚砜。
所述本发明的另一个目的是提供一种奥扎莫德的晶型，命名为晶型CS5。
本发明提供的晶型CS5，其特征在于，其X射线粉末衍射图在2theta值为4.3°±0.2°、6.8°±0.2°、16.4°±0.2°处具有特征峰。
进一步的，本发明提供的晶型CS5，其X射线粉末衍射图包括在2theta值为21.6°±0.2°、8.5°±0.2°、13.6°±0.2°中的一处或两处或三处具有特征峰；优选的，本发明提供的晶型CS5，其X射线粉末衍射图在2theta值为21.6°±0.2°、8.5°±0.2°、13.6°±0.2°处具有特征峰。
进一步的，本发明提供的晶型CS5，其X射线粉末衍射图在2theta值为13.0°±0.2°、25.0°±0.2°、26.0°±0.2°中的一处或两处或三处具有特征峰；优选的，本发明提供的晶型CS5，其X射线粉末衍射图在2theta值为13.0°±0.2°、25.0°±0.2°、26.0°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型CS5，其X射线粉末衍射图包括在2theta值为4.3°±0.2°、6.8°±0.2°、8.5°±0.2°、13.0°±0.2°、13.6°±0.2°、16.4°±0.2°、21.6°±0.2°、25.0°±0.2°、26.0°±0.2°处具有特征峰。
在一个优选的实施例中，本发明提供的晶型CS5，其X射线粉末衍射图基本如图10所示。
在一个优选的实施例中，本发明提供的晶型CS5，当进行差示扫描量热分析时，加热至65℃附近开始出现一个吸热峰，加热至91℃附近开始出现一个放热峰，在133℃附近开始出现第二个吸热峰，其差示扫描量热分析图基本如图11所示。
本发明的另一个目的是提供晶型CS5的制备方法，包括奥扎莫德的固体加入到环醚类溶剂中，过滤，将所得滤液挥发，收集固体得到奥扎莫德的晶型CS5。
进一步的，所述环醚类溶剂是2-甲基四氢呋喃。
本发明的另一个目的是提供一种奥扎莫德的晶型，命名为晶型CS6。
本发明提供的晶型CS6，其X射线粉末衍射图在2theta值为4.4°±0.2°、24.5±0.2°、26.5°±0.2°、13.8°±0.2°处具有特征峰。
进一步的，本发明提供的晶型CS6，其X射线粉末衍射图包括在2theta值为13.0°±0.2°、25.4±0.2°中的一处或两处具有特征峰；优选的，本发明提供的晶型CS6，其X射线粉末衍射图在2theta值为13.0°±0.2°、25.4±0.2°处具有特征峰。
进一步的，本发明提供的晶型CS6，其X射线粉末衍射图在2theta值为8.9°±0.2°、13.4°±0.2°、11.0°±0.2°中的一处或两处或三处具有特征峰；优选的，本发明提供的晶型CS6，其X射线粉末衍射图在2theta值为8.9°±0.2°、13.4°±0.2°、11.0°±0.2°处具有特征峰。
更进一步的，本发明提供的晶型CS6，其X射线粉末衍射图包括在2theta值为4.4°±0.2°、8.9°±0.2°、11.0°±0.2°、13.0°±0.2°、13.4°±0.2°、13.8°±0.2°、24.5±0.2°、25.4±0.2°、26.5°±0.2°处具有特征峰。
在一个优选的实施例中，本发明提供的晶型CS6，其X射线粉末衍射图基本如图16所示。
在一个优选的实施例中，本发明提供的晶型CS6，当进行差示扫描量热分析时，加热至110℃附近开始出现一个放热峰，在135℃附近开始出现一个吸热峰，其差示扫描量热分析图基本如图13所示。
在一个优选的实施例中，本发明提供的晶型CS6，当进行热重分析时，加热至120℃时，具有约1.2％的质量损失梯度，其热重分析图基本如图14所示。
本发明的另一个目的是提供晶型CS6的制备方法，包括将奥扎莫德的固体加入到酮类、氯仿等溶剂中，过滤，将所得滤液挥发，收集固体得到奥扎莫德的晶型CS6。
进一步的，所述酮类溶剂是丙酮。
本发明的另一个目的是提供一种药物组合物，包含有效治疗量的奥扎莫德的晶型CS1或晶型CS2或二者的混合物以及药学上可接受的载体、稀释剂或赋形剂。一般是将治疗有效量的晶型CS1或晶型CS2或二者的混合物与一种或多种药用辅料混合或接触制成药物组合物或制剂，该药物组合物或制剂是以制药领域中熟知的方式进行制备的。
本发明提供的奥扎莫德的晶型CS1或晶型CS2或二者的混合物可用于治疗自身免疫疾病的药物的制备，特别是用于治疗多发性硬化症和溃疡性结肠炎药物制剂的用途。
本发明还提供一种药用组合物，包含有效治疗量的奥扎莫德的晶型CS3或晶型CS5或晶型CS6或三者的任意混合以及药学上可接受的载体、稀释剂或赋形剂。一般是将治疗有效量的晶型CS3或晶型CS5或晶型CS6或三者的任意混合与一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的。
本发明提供的奥扎莫德的晶型CS3或晶型CS5或晶型CS6或三者的任意混合可用于制备选择性鞘氨醇1磷酸受体调节剂的药物制剂的用途。
本发明提供的奥扎莫德的晶型CS3或晶型CS5或晶型CS6或三者的任意混合可用于治疗自身免疫疾病的药物的制备，特别是用于治疗多发性硬化症和溃疡性结肠炎药物制剂的 用途。
本发明进一步提供，一种药物组合物，所述药物组合物包含有效治疗量的奥扎莫德的晶型CS1或奥扎莫德的晶型CS2或奥扎莫德的晶型CS3或奥扎莫德的晶型CS5或奥扎莫德的晶型CS6或它们的任意混合及药学上可接受的载体、稀释剂或赋形剂。
进一步提供，奥扎莫德的晶型CS1或奥扎莫德的晶型CS2或奥扎莫德的晶型CS3或奥扎莫德的晶型CS5或奥扎莫德的晶型CS6或它们的任意混合，在生产用于磷酸鞘氨醇1受体激动剂的药物中的用途。
奥扎莫德的晶型CS1或奥扎莫德的晶型CS2或奥扎莫德的晶型CS3或奥扎莫德的晶型CS5或奥扎莫德的晶型CS6或它们的任意混合，在生产用于治疗溃疡性结肠炎药物中的用途。
奥扎莫德的晶型CS1或奥扎莫德的晶型CS2或奥扎莫德的晶型CS3或奥扎莫德的晶型CS5或奥扎莫德的晶型CS6或它们的任意混合，在生产用于治疗多发性硬化症药物制剂中的用途。
本发明的另一个目的是提供一种奥扎莫德的盐酸盐晶型，命名为盐酸盐晶型CS1。
本发明提供的盐酸盐晶型CS1，其X射线粉末衍射图在2theta值为26.1°±0.2°、24.4°±0.2°、20.1°±0.2°处具有特征峰。
进一步的，本发明提供的盐酸盐晶型CS1，其X射线粉末衍射图包括在2theta值为3.9°±0.2°、21.1°±0.2°、7.9°±0.2°中的一处或两处或三处具有特征峰；优选的，本发明提供的盐酸盐晶型CS1，其X射线粉末衍射图在2theta值为3.9°±0.2°、21.1°±0.2°、7.9°±0.2°处具有特征峰。
进一步的，本发明提供的盐酸盐晶型CS1，其X射线粉末衍射图还包括在2theta值为11.9°±0.2°、19.6°±0.2°、13.8°±0.2°中的一处或两处或三处具有特征峰；优选的，本发明提供的盐酸盐晶型CS1，其X射线粉末衍射图在2theta值为11.9°±0.2°、19.6°±0.2°、13.8°±0.2°处具有特征峰。
更进一步的，本发明供的盐酸盐晶型CS1，其X射线粉末衍射图包括在2theta值为3.9°±0.2°、7.9°±0.2°、11.9°±0.2°、13.8°±0.2°、19.6°±0.2°、20.1°±0.2°、21.1°±0.2°、24.4°±0.2°、26.1°±0.2°、处具有特征峰。
在一个优选的实施例中，本发明提供的盐酸盐晶型CS1，其X射线粉末衍射图基本如图17所示。
在一个优选的实施例中，本发明提供的盐酸盐晶型CS1，其X射线粉末衍射图基本如图20所示。
在一个优选的实施例中，本发明提供的盐酸盐晶型CS1，当进行差示扫描量热分析时，加热至238℃附近开始出现吸热峰，其差示扫描量热分析图基本如图18所示。
在一个优选的实施例中，本发明提供的盐酸盐晶型CS1，当进行热重分析时，加热至150℃时，具有约1.1％的质量损失梯度，其热重分析图基本如图19所示。
本发明的另一个目的是提供奥扎莫德盐酸盐晶型CS1的制备方法，所述方法包含1)或2)或3)或4)，
1)将奥扎莫德盐酸盐加入醚类溶剂中，在一定温度下(4-50℃，优选25℃)搅拌一段时间，过滤干燥得到白色固体；所述搅拌时间为至少1小时；优选搅拌时间为至少24小时；更优选搅拌时间为7天或1周；或
2)将奥扎莫德盐酸盐溶于醇类、酯类、或其混合溶剂中，在常温缓慢挥发一段时间，得到白色固体；通常“挥发时间”是指挥发至有固体析出的时间或者更长；优选挥发0.5天-14天(或2周)；更优选挥发7天或1周；或
3)将奥扎莫德盐酸盐溶于酰胺类有机溶剂或它们的混合体系中并形成饱和溶液，将其置于含有奥扎莫德盐酸盐反溶剂的体系中，在常温下缓慢扩散一段时间，过滤干燥后得到白色固体；通常“缓慢扩散时间”是指放置至有固体析出的时间或者更长；优选1天-14天；更优选7天或1周；或
4)将奥扎莫德盐酸盐溶于醇类与水的混合体系，中并形成过饱和溶液，在25-80℃(优选50℃)下充分溶解后过滤，得到的澄清溶液经冷却后，析出白色固体，过滤干燥得到奥扎莫德盐酸盐白色固体；或
本发明的另一个目的是提供一种药物组合物，包含有效量的盐酸盐晶型CS1以及药学上可接受的载体、稀释剂或赋形剂。一般是将治疗有效量的盐酸盐晶型CS1与一种或多种药用辅料混合或接触制成药物组合物或制剂，该药物组合物或制剂是以制药领域中熟知的方式进行制备的。
更进一步的，本发明所述的药物组合物中，奥扎莫德的盐酸盐晶型CS1可用于制备治疗自身免疫疾病的药物，特别是多发性硬化症和溃疡性结肠炎药物制剂中的用途。
本发明所述“室温”不是精确的温度值，是指10-30℃温度范围。
本发明所述“挥发法”、“扩散法”中的反应时间，均指反应至有固体析出的时间或者更长。
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。
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。
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。
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。
所述“高聚物”，是指等质量的聚己内酯、聚乙二醇、聚甲基丙烯酸甲酯、海藻酸钠以及羟乙基纤维素混合组成。
本发明的有益效果为：
目前尚无专利或文献报导奥扎莫德的晶型，本发明的发明人经过研究，突破了这一难题，找到了适合开发的几种新晶型。
本发明提供的晶型及盐酸盐的晶型在溶解度，熔点，稳定性、溶出度、生物有效性以及加工性能等方面中存在优势，本发明的晶型CS1、晶型CS2、晶型CS3、晶型CS5、晶型CS6、盐酸盐晶型CS1引湿性低、稳定性好，溶解度符合药用要求，且粒度分布均匀，分散性好，有助于简化制剂过程的后处理工艺，为含奥扎莫德的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要。
附图说明
图1为实施例1制备的晶型CS1的XRPD图
图2为实施例1制备的晶型CS1的DSC图
图3为实施例1制备的晶型CS1的TGA图
图4为实施例3制备的晶型CS2的XRPD图
图5为实施例3制备的晶型CS2的DSC图
图6为实施例3制备的晶型CS2的TGA图
图7为实施例5制备的晶型CS3的XRPD图
图8为实施例5制备的晶型CS3的DSC图
图9为实施例5制备的晶型CS3的TGA图
图10为实施例8制备的晶型CS5的XRPD图
图11为实施例8制备的晶型CS5的DSC图
图12为实施例9制备的晶型CS6的XRPD图
图13为实施例10晶型CS6的DSC图
图14为实施例10晶型CS6的TGA图
图15为实施例6制备的晶型CS3的XRPD图
图16为实施例10制备的晶型CS6的XRPD图
图17为本发明中盐酸盐晶型CS1的XRPD图
图18为实施例11制备的盐酸盐晶型CS1的DSC图
图19为实施例11制备的盐酸盐晶型CS1的TGA图
图20为实施例11制备的盐酸盐晶型CS1的XRPD图
图21为实施例12制备的盐酸盐晶型CS1的XRPD图
图22为实施例13制备的盐酸盐晶型CS1的XRPD图
图23为实施例14制备的盐酸盐晶型CS1的XRPD图
图24为实施例15制备的盐酸盐晶型CS1的XRPD图
图25为实施例16中晶型CS1的DVS图
图26为实施例17中晶型CS2的DVS图
图27为实施例18中晶型CS3的DVS图
图28为实施例19中晶型CS5的DVS图
图29为实施例20中晶型CS6的DVS图
图30为实施例21中盐酸盐晶型CS1的DVS图
图31为实施例22的晶型CS1稳定性试验前后XRPD对比图
图32为实施例23的晶型CS2稳定性试验前后XRPD对比图
图33为实施例24的晶型CS3稳定性试验前后XRPD对比图
图34为实施例25的晶型CS5稳定性试验前后XRPD对比图
图35为实施例26的晶型CS6稳定性试验前后XRPD对比图
图36为实施例27的盐酸盐晶型CS1稳定性试验前后XRPD对比图
图37为实施例28中晶型CS1的PSD图
图38为实施例28中晶型CS2的PSD图
图39为实施例28中晶型CS3的PSD图
图40为实施例28中晶型CS5的PSD图
图41为实施例28中晶型CS6的PSD图
图42为实施例28中盐酸盐晶型CS1的PSD图
图43为实施例28中晶型CS1的PLM图
图44为实施例28中晶型CS2的PLM图
图45为实施例28中晶型CS3的PLM图
图46为实施例28中晶型CS5的PLM图
图47为实施例28中晶型CS6的PLM图
图48为实施例28中盐酸盐晶型CS1的PLM图
图49为实施例31中晶型CS3研磨试验前后XRPD对比图
图50为实施例31中晶型CS5研磨试验前后XRPD对比图
图51为实施例31中晶型CS6研磨试验前后XRPD对比图
图52为实施例31中盐酸盐晶型CS1研磨试验前后XRPD对比图
图53为实施例7中晶型CS3的XRPD
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
DVS：动态水分吸附
PSD：粒度分布
PLM：偏光显微镜
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 PCTCN2017088314-appb-000002
：1.540598；Kα2
Figure PCTCN2017088314-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
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 PCTCN2017088314-appb-000004
*：流速60％为65毫升/秒的60％。
以下实施例中所使用的奥扎莫德游离形式和/或其盐可根据CN102762100A文献所记载的方法制备获得。
实施例1
奥扎莫德晶型CS1的制备方法：
称取约2.0g的奥扎莫德盐酸盐固体于150mL的玻璃瓶中，加入100mL的无水甲醇，得到为悬浊液，搅拌悬浊液，逐滴加入7mL的氢氧化钠水溶液(32mg/mL)，悬浮液由混浊转为澄清。在室温下搅拌12小时，有白色固体析出，离心干燥，收集固体。
经检测，本实施例得到的固体为晶型CS1。本实施例得到的晶型的X射线粉末衍射数据如表1所示。其XRPD图如图1，其DSC图如图2，其TGA图如图3。
表1
2theta d间隔 强度％
4.24 20.83 53.60
7.37 12.00 20.87
8.78 10.07 3.91
10.45 8.46 60.36
12.07 7.33 100.00
12.82 6.90 9.66
14.19 6.24 6.17
16.17 5.48 1.63
17.19 5.16 4.96
17.65 5.02 9.86
18.22 4.87 7.35
18.69 4.75 1.61
20.18 4.40 2.40
21.51 4.13 9.64
21.95 4.05 2.44
22.35 3.98 5.65
22.82 3.90 3.25
23.51 3.78 2.32
24.35 3.66 19.15
24.74 3.60 3.72
25.69 3.47 0.86
26.63 3.35 0.75
27.30 3.27 1.49
28.60 3.12 1.52
30.90 2.89 2.80
31.26 2.86 1.01
32.44 2.76 0.57
33.63 2.67 1.87
34.77 2.58 0.91
36.41 2.47 1.13
39.25 2.30 1.49
采用实施例1的方法，将约10mg奥扎莫德盐酸盐的固体置于甲醇、丙酮、乙酸异丙酯、乙腈中，并加入1.0-1.5倍量的氢氧化钠水溶液，悬浮液由混浊转为澄清。室温下搅拌12小时，有白色固体析出，离心后真空干燥，所得固体经检测为晶型CS1，其XRPD图与图1基本一致。
实施例2
奥扎莫德晶型CS1的制备方法：
称取约10mg的奥扎莫德固体于1.5mL玻璃瓶中，加入0.5mL甲醇，于室温下搅拌24小时后，得到白色固体结晶。经检测，该白色固体为奥扎莫德晶型CS1，其XRPD图与图1基本一致。
实施例3
奥扎莫德晶型CS2的制备方法：
称取约20mg的奥扎莫德晶型CS1于3mL的玻璃瓶中，将其放入110℃真空干燥1小时后得到白色固体。
经检测，本实施例得到的固体为晶型CS2。本实施例得到的晶型的X射线粉末衍射数据如表2所示，其XRPD图如图4，DSC图如图5，TGA图如图6。
表2
2theta d间隔 强度％
3.96 22.33 20.48
7.95 11.12 11.39
12.02 7.36 4.10
13.33 6.64 35.96
14.16 6.25 21.29
15.89 5.58 19.75
17.72 5.00 12.52
18.49 4.80 36.64
20.08 4.42 11.25
20.77 4.28 4.59
21.36 4.16 7.46
21.53 4.13 8.77
22.56 3.94 8.50
23.19 3.84 100.00
24.22 3.67 4.08
24.97 3.57 3.68
26.47 3.37 17.30
27.46 3.25 3.66
28.40 3.14 1.16
29.98 2.98 28.43
31.45 2.84 1.01
32.19 2.78 2.21
34.53 2.60 0.69
37.45 2.40 0.61
38.43 2.34 0.73
39.50 2.28 1.41
实施例4a-4j
奥扎莫德晶型CS2的制备方法：
称取10份约10mg的奥扎莫德固体于1.5mL玻璃瓶中，加入表3中一定体积的溶剂，室温下搅拌24小时后得到白色固体结晶。表3中实施例所得的固体分别标记为样品1-10。经检测，样品1-10均为奥扎莫德的晶型CS2。样品1-10的X射线粉末衍射数据在2theta值为4.0°±0.2°、13.3°±0.2°、14.2°±0.2°、15.9°±0.2°、17.7°±0.2°、18.5°±0.2°、23.2°±0.2°、26.5°±0.2°、30.0°±0.2°处均有特征峰。样品1-10的XRPD图基本与图4一致。
表3
Figure PCTCN2017088314-appb-000005
实施例5
奥扎莫德晶型CS3的制备方法：
称取约5.0mg的奥扎莫德的固体于3mL的玻璃瓶中，加入约0.4mL的二氯甲烷，过滤后向滤液中加入约0.2mg的高聚物。在室温下缓慢挥发，得到白色固体。
经检测，本实施例得到的固体为晶型CS3。本实施例得到的晶型的X射线粉末衍射数据如表4所示。其XRPD图如图7，其DSC图如图8，其TGA图如图9。
表4
2theta d间隔 强度％
3.04 29.02 12.88
4.43 19.93 100.00
7.84 11.28 16.58
8.92 9.92 10.16
11.03 8.02 15.96
12.96 6.83 83.06
13.43 6.59 11.89
13.72 6.46 33.05
15.80 5.61 3.44
16.57 5.35 5.55
17.00 5.21 19.94
17.98 4.93 4.44
18.38 4.83 4.34
19.83 4.48 6.93
20.06 4.43 8.40
20.57 4.32 5.85
21.53 4.13 7.15
21.98 4.04 6.11
22.56 3.94 8.12
23.17 3.84 23.33
24.09 3.69 14.77
25.14 3.54 12.77
26.00 3.43 41.57
26.68 3.34 9.46
28.42 3.14 6.82
30.67 2.91 1.27
33.98 2.64 0.53
35.51 2.53 0.79
实施例6
奥扎莫德晶型CS3的制备方法：
称取约5mg的奥扎莫德的固体于3mL的玻璃瓶中，加入约1.0mL的乙腈，过滤后将滤液在室温下敞口快速挥发，得到白色固体。
经检测，本实施例得到的固体为晶型CS3。本实施例得到的晶型的X射线粉末衍射数据如表5所示。其XRPD图如图15所示。
表5
2theta d间隔 强度％
4.44 19.89 94.06
5.20 16.98 3.53
7.86 11.25 22.55
8.93 9.90 15.72
9.38 9.433 4.17
11.05 8.00 18.33
12.97 6.83 100.00
13.73 6.45 41.96
14.44 6.13 7.95
15.78 5.62 8.10
16.14 5.49 4.53
17.01 5.21 19.74
18.22 4.87 2.42
20.07 4.42 8.54
20.26 4.39 3.28
20.50 4.34 6.66
21.53 4.13 7.83
21.99 4.04 4.91
22.60 3.93 11.03
23.18 3.84 24.17
24.08 3.70 14.26
25.15 3.54 11.64
26.03 3.42 39.79
26.63 3.35 5.94
28.42 3.14 12.28
30.39 2.94 4.29
37.15 2.42 5.92
37.37 2.41 4.67
采用本实施例的制备方法，将奥扎莫德的固体放置到甲醇、乙酸异丙酯、二甲亚砜溶剂中挥发，所得固体经检测均为奥扎莫德晶型CS3。
实施例7
奥扎莫德晶型CS3的制备方法：
称取约15mg的奥扎莫德的固体于3mL的玻璃瓶中，加入约1.0mL的乙二醇二甲醚/水(1∶1，v/v)混合溶剂溶解，过滤后将滤液在室温下缓慢挥发，得到白色固体。
经检测，本实施例得到的固体为晶型CS3。其X射线粉末衍射图在2theta值为4.42°、5.70°、7.85°、11.06°、12.99°、17.04°、23.21°、24.11°、26.04°处具有特征峰。本实施例得到的晶型的XRPD图如图53所示。
实施例8
奥扎莫德晶型CS5的制备方法：
称取约10mg的奥扎莫德的固体于3mL的玻璃瓶中，加入约2.4mL的2-甲基四氢呋喃，过滤后将滤液在室温下敞口快速挥发，得到白色固体。
经检测，本实施例得到的固体为晶型CS5。本实施例得到的晶型的X射线粉末衍射数据如表6所示。其XRPD图如图10，其DSC图如图11。
表6
2theta d间隔 强度％
4.25 20.80 100.00
6.76 13.08 3.43
7.71 11.47 1.36
8.55 10.34 13.99
10.79 8.20 1.07
12.96 6.83 34.38
13.61 6.51 9.98
14.42 6.14 1.40
15.13 5.85 1.00
16.39 5.41 3.84
16.86 5.26 4.05
17.29 5.13 2.70
18.37 4.83 0.78
19.57 4.54 2.18
20.48 4.34 5.14
21.60 4.12 8.34
22.52 3.95 1.56
23.20 3.83 1.88
24.04 3.70 4.04
24.98 3.56 4.18
26.03 3.42 5.50
27.06 3.30 3.14
28.35 3.15 0.64
29.00 3.08 0.35
30.27 2.95 0.47
31.14 2.87 0.58
32.77 2.73 0.49
35.24 2.55 0.49
37.31 2.41 0.16
实施例9
奥扎莫德晶型CS6的制备方法：
称取约15mg的奥扎莫德的固体于3mL的玻璃瓶中，加入约0.2mL的氯仿，过滤，将滤液在室温下敞口快速挥发，得到白色固体。
经检测，本实施例得到的固体为晶型CS6。本实施例得到的晶型的X射线粉末衍射数据如表7所示。其XRPD图如图12。
表7
2theta d间隔 强度％
4.45 19.88 100.00
7.86 11.24 6.23
8.89 9.95 10.03
11.03 8.02 7.43
13.01 6.81 26.15
13.37 6.62 8.34
13.75 6.44 11.19
14.89 5.95 0.81
15.49 5.72 1.94
15.79 5.61 1.52
16.94 5.23 3.00
17.12 5.18 4.44
17.87 4.96 2.72
19.06 4.66 1.52
19.22 4.62 1.51
20.13 4.41 3.22
21.55 4.12 2.16
22.40 3.97 3.75
22.82 3.90 2.11
23.58 3.77 2.04
24.51 3.63 5.93
25.42 3.50 4.55
26.22 3.40 2.19
26.52 3.36 5.03
27.06 3.30 0.91
27.86 3.20 1.37
28.32 3.15 0.61
28.86 3.09 0.51
30.04 2.97 0.34
32.15 2.78 0.22
33.55 2.67 0.33
37.44 2.40 0.25
采用本实施例中的方法，将奥扎莫德的固体在丙酮中挥发，所得固体经检测为晶型CS6。
实施例10
奥扎莫德晶型CS6的制备方法：
称取约5mg的奥扎莫德的固体于3mL的玻璃瓶中，加入约0.4mL的氯仿，过滤后将该滤液在室温下缓慢挥发，得到白色固体。
经检测，本实施例得到的固体为晶型CS6。本实施例得到的晶型的X射线粉末衍射数据如表8所示。其XRPD图如图16所示。
采用实施例的方法重复制备了10mg晶型CS6，将所得样品检测DSC以及TGA，分别如图13、14所示。
表8
2theta d间隔 强度％
4.44 19.88 100.00
7.86 11.25 11.49
8.89 9.94 19.71
11.03 8.02 12.60
13.00 6.81 53.68
13.37 6.62 15.73
13.75 6.44 21.24
14.95 5.93 2.05
15.44 5.74 2.80
15.78 5.62 1.84
17.08 5.19 4.53
17.87 4.96 5.38
19.11 4.64 2.07
20.06 4.43 4.31
21.55 4.12 4.26
22.43 3.96 6.47
23.44 3.80 1.73
24.51 3.63 3.95
25.34 3.51 3.19
26.18 3.40 3.93
26.61 3.35 4.89
27.75 3.22 1.62
28.94 3.09 1.01
30.18 2.96 0.66
32.42 2.76 0.81
36.51 2.46 0.47
37.42 2.40 0.33
38.94 2.31 0.76
39.35 2.29 0.61
实施例11
奥扎莫德盐酸盐晶型CS1的制备方法：
称取10.1mg的奥扎莫德盐酸盐的固体，放入1.5mL的玻璃瓶中，加入约0.5mL的2-甲基四氢呋喃，在室温下搅拌1周，离心干燥后得到白色固体。
经检测，本实施例得到的固体为盐酸盐晶型CS1。本实施例得到的晶型的X射线粉末衍射数据如表9所示。其XRPD图如图20，其DSC图如图18，其TGA图如图19。
表9
2theta d间隔 强度％
3.93 22.51 58.37
7.93 11.14 23.15
11.95 7.41 21.69
12.56 7.05 70.18
13.02 6.80 82.51
13.77 6.43 85.16
14.86 5.96 6.06
15.97 5.55 21.05
16.91 5.24 30.15
18.19 4.88 20.42
18.54 4.79 4.12
18.79 4.72 33.76
19.59 4.53 38.99
20.07 4.42 46.27
21.11 4.21 64.20
22.75 3.91 26.66
23.22 3.83 10.34
24.41 3.65 100.00
26.10 3.41 93.31
27.11 3.29 9.18
27.90 3.20 20.23
28.31 3.15 6.44
28.99 3.08 8.18
29.85 2.99 7.60
31.11 2.88 5.90
31.55 2.84 11.45
33.37 2.69 3.80
35.35 2.54 5.57
36.66 2.45 6.89
实施例12
奥扎莫德盐酸盐晶型CS1的制备方法：
称取6.0mg的奥扎莫德盐酸盐固体于1.5mL的玻璃瓶中，加入约0.5mL的甲醇溶解，过滤后在室温下挥发1周，收集固体。
经检测，本实施例得到的固体为盐酸盐晶型CS1。本实施例得到的晶型的X射线粉末衍射数据如表10所示，其XRPD图如图21。
表10
2theta d间隔 强度％
3.95 22.37 65.70
7.94 11.13 39.57
8.57 10.32 2.24
11.97 7.39 42.06
12.55 7.05 9.32
13.02 6.80 10.98
13.78 6.438 12.03
15.33 5.78 1.81
15.99 5.54 3.50
18.78 4.73 7.47
19.61 4.53 3.45
20.10 4.42 100.00
21.12 4.21 13.94
22.73 3.91 2.92
24.42 3.65 17.01
25.02 3.56 12.72
26.14 3.41 19.94
27.30 3.27 2.47
27.94 3.19 3.98
28.34 3.15 2.68
29.03 3.08 2.70
29.82 3.00 1.74
31.03 2.88 2.53
31.63 2.83 5.10
32.52 2.75 2.27
33.49 2.68 1.55
35.28 2.54 1.87
36.69 2.45 18.83
37.44 2.40 0.94
38.94 2.31 1.26
39.35 2.29 1.87
实施例13
奥扎莫德盐酸盐晶型CS1的制备方法：
称取5.5mg的奥扎莫德盐酸盐于1.5mL的玻璃瓶中，加入约0.8mL的甲醇/乙酸乙酯的混合溶液(3∶1，v∶v)，并加入约0.2mg的高聚物，在室温下挥发1周，收集固体。
经检测，本实施例得到的固体为盐酸盐晶型CS1。本实施例得到的晶型的X射线粉末衍射数据如表11所示，其XRPD图如图22。
表11
2theta d间隔 强度％
3.90 22.64 100.00
7.92 11.16 29.74
10.98 8.06 3.07
11.94 7.41 33.69
12.56 7.05 73.32
13.05 6.78 78.29
13.78 6.43 78.88
14.94 5.93 6.31
16.04 5.52 17.30
16.96 5.23 14.47
18.21 4.87 11.10
18.76 4.73 29.38
19.63 4.53 30.08
20.09 4.42 62.83
21.13 4.20 51.45
22.74 3.91 20.95
24.42 3.65 70.20
24.99 3.56 20.32
26.12 3.41 67.91
27.99 3.19 13.24
29.06 3.07 8.71
29.82 3.00 10.52
31.67 2.83 11.02
35.31 2.54 3.40
36.72 2.45 9.56
39.04 2.31 1.86
实施例14
奥扎莫德盐酸盐晶型CS1的制备方法：
称取5.9mg的奥扎莫德盐酸盐放入1.5mL的玻璃瓶中，加入约0.3mL的二甲基乙酰胺溶解，将配好的溶液置于含有5mL四氢呋喃的20mL玻璃瓶中，室温下扩散1周，过滤后干燥得到白色固体。
经检测，本实施例得到的固体为盐酸盐晶型CS1。本实施例得到的晶型的X射线粉末衍射数据如表12所示，其XRPD图如图23。
表12
2theta d间隔 强度％
3.94 22.42 29.02
7.94 11.13 40.24
8.59 10.30 6.70
10.08 8.78 3.14
11.98 7.39 43.32
12.56 7.05 30.75
13.03 6.79 34.04
13.78 6.42 38.84
15.31 5.79 2.91
15.96 5.55 12.46
16.95 5.23 4.31
17.31 5.12 2.90
18.22 4.87 2.15
18.79 4.72 20.42
19.62 4.52 8.57
20.10 4.42 100.00
21.08 4.22 21.17
22.03 4.04 4.56
22.73 3.91 5.82
24.40 3.65 30.21
25.01 3.56 16.38
25.47 3.50 3.80
26.13 3.41 34.94
26.77 3.33 4.27
27.02 3.30 3.66
27.30 3.27 5.18
27.90 3.20 6.81
29.01 3.08 2.92
29.98 2.98 3.94
31.07 2.88 2.48
31.57 2.83 6.30
32.48 2.76 2.04
32.96 2.72 2.06
34.21 2.62 1.44
35.27 2.54 2.38
36.68 2.45 17.57
38.85 2.32 2.01
实施例15
奥扎莫德盐酸盐晶型CS1的制备方法：
称取5.4mg的奥扎莫德盐酸盐放入1.5mL的玻璃瓶中，加入约0.3mL的甲醇/水的混合溶液(甲醇与水的体积比为9∶1)，在50℃下溶解过滤，在-20℃条件下快速冷却，过滤后干燥得到白色固体。
经检测，本实施例得到的固体为盐酸盐晶型CS1。本实施例得到的晶型的X射线粉末衍射数据如表13所示。其XRPD图如图24。
表13
2theta d间隔 强度％
3.92 22.54 56.68
7.94 11.14 51.15
9.36 9.45 1.72
9.89 8.95 3.02
11.96 7.40 51.80
12.57 7.04 11.98
13.04 6.79 15.16
13.79 6.42 12.00
15.96 5.55 3.10
16.95 5.23 3.28
18.21 4.87 4.07
18.78 4.73 9.66
19.69 4.51 12.34
20.08 4.42 100.00
21.11 4.21 27.35
21.87 4.06 5.55
22.77 3.91 7.92
24.40 3.65 44.75
25.00 3.56 10.24
26.13 3.41 43.35
26.80 3.33 6.64
27.91 3.20 6.55
28.96 3.08 3.94
29.86 2.99 2.81
31.57 2.83 7.26
33.39 2.68 2.12
36.71 2.45 15.24
实施例16
奥扎莫德晶型CS1的引湿性实验：
取本发明奥扎莫德的晶型CS1约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表14所示。晶型CS1的引湿性实验的DVS图如图25所示。
表14
Figure PCTCN2017088314-appb-000006
结果表明，本发明的奥扎莫德晶型CS1在80％湿度下平衡后增重0.36％，根据引湿性增重的界定标准，属于略有引湿性。
实施例17
奥扎莫德晶型CS2的引湿性实验：
取本发明奥扎莫德的晶型CS2约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表15所示。晶型CS2的引湿性实验的DVS图如图26所示。
表15
Figure PCTCN2017088314-appb-000007
结果表明，本发明的奥扎莫德晶型CS2在80％湿度下平衡后增重0.25％，根据引湿性增重的界定标准，属于略有引湿性。
实施例18
奥扎莫德晶型CS3的引湿性实验：
取本发明奥扎莫德的晶型CS3约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表16所示。晶型CS3的引湿性实验的DVS图如图27所示。
表16
Figure PCTCN2017088314-appb-000008
结果表明，本发明的奥扎莫德晶型CS3在80％湿度下平衡后增重2.25％。
实施例19
奥扎莫德晶型CS5的引湿性实验：
取本发明奥扎莫德的晶型CS5约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表17所示。晶型CS5的引湿性实验的DVS图如图28所示。
表17
Figure PCTCN2017088314-appb-000009
结果表明，本发明的奥扎莫德晶型CS5在80％湿度下平衡后增重0.23％，根据引湿性增重的界定标准，属于略有引湿性。
实施例20
奥扎莫德晶型CS6的引湿性实验：
取本发明奥扎莫德的晶型CS6约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表18所示。晶型CS6的引湿性实验的DVS图如图29所示。
表18
Figure PCTCN2017088314-appb-000010
结果表明，本发明的奥扎莫德晶型CS6在80％湿度下平衡后增重1.68％。
实施例21
奥扎莫德盐酸盐晶型CS1的引湿性实验：
取本发明扎莫德的盐酸盐晶型CS1约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表19所示。盐酸盐晶型CS1的引湿性实验的DVS图如图30所示。
表19
Figure PCTCN2017088314-appb-000011
结果表明，本发明的奥扎莫德盐酸盐晶型CS1在80％湿度下平衡后增重0.55％，根据引湿性增重的界定标准，属于略有引湿性。
关于引湿性特征描述与引湿性增重的界定(中国药典2015年版通则9103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％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
实施例22
奥扎莫德晶型CS1的稳定性试验：
取三份奥扎莫德晶型CS1样品分别置于25℃/60％RH，40℃/75％RH和60℃/75％RH的恒温恒湿箱中敞口放置4周，然后在1周，2周，4周取样测纯度，在4周取样测XRPD。XRPD对比结果如图31(从上至下依次为奥扎莫德晶型CS1起始样品的XRPD图，放置25℃/60％RH，40℃/75％RH和60℃/75％RH条件下4周的XRPD图)，其结果如表20所示。
表20
起始晶型 放置条件 1周纯度％ 2周纯度％ 4周纯度％ 晶型变化
晶型CS1 25℃/60％RH 99.12 99.18 98.97 不变
晶型CS1 40℃/75％RH 99.16 99.17 98.92 不变
晶型CS1 60℃/75％RH 99.26 99.13 98.71 不变
奥扎莫德晶型CS1在25℃/60％RH，40℃/75％RH，60℃/75％RH下放置4周，晶型保持不变，且纯度未见显著变化。结果表明，奥扎莫德晶型CS1具有良好的稳定性。
实施例23
奥扎莫德晶型CS2的稳定性试验：
取四份奥扎莫德晶型CS2样品分别置于25℃/60％RH，40℃/75％RH，60℃/75％RH和80℃的恒温恒湿箱中敞口放置4周，然后在1周，2周，4周取样测纯度，在4周取样测XRPD，其中80℃条件下只在1周取样检测。XRPD对比结果如图32(从上至下依次为奥扎莫德晶型CS2起始样品的XRPD图，放置于25℃/60％RH，40℃/75％RH，60℃/75％RH条件下4周，放置于80℃条件下1周的XRPD图)和表21所示。
表21
起始晶型 放置条件 1周纯度％ 2周纯度％ 4周纯度％ 晶型变化
晶型CS2 25℃/60％RH 99.85 99.63 99.62 不变
晶型CS2 40℃/75％RH 99.84 99.78 99.55 不变
晶型CS2 60℃/75％RH 99.91 99.60 99.63 不变
晶型CS2 80℃ 99.71 N/A N/A 不变
本实施例中N/A表示未检测。
奥扎莫德晶型CS2在25℃/60％RH，40℃/75％RH，60℃/75％RH下放置4周和80℃条件下放置1周，晶型保持不变，且纯度未见显著降低。上述试验结果表明，奥扎莫德晶型CS2具有良好的稳定性。
实施例24
奥扎莫德晶型CS3的稳定性试验：
取三份奥扎莫德晶型CS3样品分别置于25℃/60％RH，40℃/75％RH和60℃/75％RH的恒温恒湿箱中敞口放置4周，然后在1周，2周，4周取样测纯度，在4周取样测XRPD。XRPD对比结果如图33(从上至下依次为奥扎莫德晶型CS3起始样品的XRPD图，放置25℃/60％RH，40℃/75％RH和60℃/75％RH条件下4周的XRPD图)，其结果如表22所示。
表22
起始晶型 放置条件 1周纯度％ 2周纯度％ 4周纯度％ 晶型变化
晶型CS3 25℃/60％RH 99.53 99.30 99.31 不变
晶型CS3 40℃/75％RH 99.52 99.28 99.17 不变
晶型CS3 60℃/75％RH 99.36 98.84 98.54 不变
奥扎莫德晶型CS3在25℃/60％RH，40℃/75％RH，60℃/75％RH下放置4周，晶型保持不变，且纯度未见显著变化。结果表明，奥扎莫德晶型CS3具有良好的稳定性。
实施例25
奥扎莫德晶型CS5的稳定性试验：
取三份奥扎莫德晶型CS5样品分别置于25℃/60％RH，40℃/75％RH和60℃/75％RH的恒温恒湿箱中敞口放置2周，然后取样测XRPD。XRPD对比结果如图34(从上至下依次为奥扎莫德晶型CS5起始样品的XRPD图，放置25℃/60％RH，40℃/75％RH和60℃/75％RH条件下2周的XRPD图)，其结果如表23所示。
表23
起始晶型 放置条件 放置时间 晶型变化
晶型CS5 25℃/60％RH 2周 不变
晶型CS5 40℃/75％RH 2周 不变
晶型CS5 60℃/75％RH 2周 不变
奥扎莫德晶型CS5在25℃/60％RH，40℃/75％RH，60℃/75％RH下放置2周，晶型保持不变。结果表明，奥扎莫德晶型CS5具有良好的稳定性。
实施例26
奥扎莫德晶型CS6的稳定性试验：
取两份奥扎莫德晶型CS6样品分别置于25℃/60％RH和40℃/75％RH的恒温恒湿箱中敞口放置4周，然后在1周，2周，4周取样测纯度，在4周取样测XRPD。XRPD对比结果如图35(从上至下依次为奥扎莫德晶型CS6起始样品的XRPD图，放置在25℃/60％RH，40℃/75％RH条件下4周的XRPD图)，其结果如表24所示。
表24
起始晶型 放置条件 1周纯度％ 2周纯度％ 4周纯度％ 晶型变化
晶型CS6 25℃/60％RH 98.44 98.21 98.27 不变
晶型CS6 40℃/75％RH 98.47 98.33 97.97 不变
奥扎莫德晶型CS6在25℃/60％RH和40℃/75％RH下放置四周，晶型保持不变，且
纯度未见显著变化。结果表明，奥扎莫德晶型CS6具有良好的稳定性。
实施例27
奥扎莫德盐酸盐晶型CS1的稳定性试验：
取四份奥扎莫德盐酸盐晶型CS1样品分别置于25℃/60％RH，40℃/75％RH，60℃/75％RH和80℃的恒温恒湿箱中敞口放置四周，然后在1周，2周，4周取样测纯度，在4周取样测XRPD，其中80℃条件下只在1周取样检测。XRPD对比结果如图36(从上至下依次为奥扎莫德盐酸盐晶型CS1起始样品的XRPD图，放置于25℃/60％RH，40℃/75％RH，60℃/75％RH条件下4周，放置于80℃条件下1周的XRPD图)和表25所示。
表25
Figure PCTCN2017088314-appb-000012
Figure PCTCN2017088314-appb-000013
奥扎莫德盐酸盐晶型CS1在25℃/60％RH，40℃/75％RH，60℃/75％RH下放置4周和80℃条件下放置1周，晶型保持不变，且纯度未见显著降低。上述试验结果表明，奥扎莫德盐酸盐晶型CS1具有良好的稳定性。
实施例28
粒径分布和形态研究试验：
取本发明的晶型CS1、实施例2的晶型CS2、晶型CS3、晶型CS5、晶型CS6、盐酸盐晶型CS1测试粒径分布，结果如表26所示。
表26
晶型 MV(μm) SD D10(μm) D50(μm) D90(μm)
晶型CS1 22.40 15.08 3.15 11.20 48.90
晶型CS2 23.24 11.21 5.78 14.20 42.35
晶型CS3 66.62 39.31 20.36 51.80 130.8
晶型CS5 68.84 61.69 6.55 41.10 173.3
晶型CS6 68.91 54.79 12.87 46.47 161.7
盐酸盐晶型CS1 200.7 168.4 20.84 180.8 397.7
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CS1的PSD图如图37所示，晶型CS1体积平均粒径为22.40微米。且粒径分布较窄，几乎呈现一个正态分布，粒径分布均匀。
晶型CS2的PSD图如图38所示，晶型CS2体积平均粒径为23.24微米。且粒径分布较窄，几乎呈现一个正态分布，粒径分布均匀。
晶型CS3的PSD图如图39所示，晶型CS3体积平均粒径为66.62微米。且粒径分布较窄，几乎呈现一个正态分布，粒径分布均匀。
晶型CS5的PSD图如图40所示，晶型CS5体积平均粒径为68.84微米。且粒径分布较窄，几乎呈现一个正态分布，粒径分布均匀。
晶型CS6的PSD图如图41所示，晶型CS6体积平均粒径为68.91微米。且粒径分布较 窄，几乎呈现一个正态分布，粒径分布均匀。
盐酸盐晶型CS1的PSD图如图42所示，盐酸盐晶型CS1体积平均粒径为200.7微米。粒径较大，在生产过程中，有利于产品的分离。
另外，晶型CS1、晶型CS2、晶型CS3、晶型CS5、晶型CS6和盐酸盐晶型CS1的PLM图分别参见图43、图44、图45、图46、图47和图48。从偏光显微镜的拍摄结果看，晶型CS1、晶型CS2、晶型CS5、晶型CS6和盐酸盐晶型CS1呈短棒状，晶型CS3成片状，且分散性较好，少有团聚现象，而且颗粒粒径较为均匀。
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。
实施例29
溶解度试验研究：
将奥扎莫德晶型CS1、盐酸盐晶型CS1样品分别用SGF(模拟人工胃液)和pH5.0FeSSIF(进食状态下人工肠液)配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。本发明奥扎莫德晶型CS1、盐酸盐晶型CS1的溶解度数据如表27所示。
表27
Figure PCTCN2017088314-appb-000014
实施例30
溶解度试验研究：
将奥扎莫德晶型CS3、晶型CS5样品分别用SGF(模拟人工胃液)和高纯水配制成饱和溶液，将晶型CS2用FeSSIF(进食状态下人工肠液)配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱(HPLC)法测定饱和溶液中样品的含量。本发明奥扎莫德晶型CS3、晶型CS5的溶解度数据如表28所示。
表28
Figure PCTCN2017088314-appb-000015
实施例31
奥扎莫德晶型CS3、晶型CS5、晶型CS6以及盐酸盐晶型CS1的机械稳定性试验：
将本发明晶型CS3、晶型CS5、晶型CS6以及盐酸盐晶型CS1样品置于研钵中，手动研磨5分钟，测试固体XRPD。结果分别如图49、图50、图51和图52所示(上图为研磨前，下图为研磨后)。
结果表明，在一定机械应力的作用下，本发明的奥扎莫德晶型CS3、晶型CS5、晶型CS6以及盐酸盐晶型CS1未发生改变，结晶度略有降低，仍可保持稳定的物理化学性质，适合成药和储存。
更好的机械稳定性表现在一定机械应力的作用下，仍可保持稳定的物理化学性质。具有较好的机械稳定性的晶型药物对结晶设备要求低，无需特别的后处理条件，在制剂过程中更加稳定，可显著降低药物的开发成本，提升药物质量，具有很强的经济价值。
值得说明的是，本发明实施例16-31中使用的奥扎莫德的晶型CS1是通过实施例1的方法制备得到的；晶型CS2是通过实施例3的方法制备得到的；晶型CS3是通过实施例6的方法制备得到的；晶型CS5是通过实施例9的方法制备得到的；晶型CS6是通过实施例10的方法制备得到的；盐酸盐晶型CS1是通过实施例11的方法制备得到的。
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 (36)

  1. 一种奥扎莫德的晶型CS1，其特征在于，其X射线粉末衍射图在2theta值为12.1°±0.2°、10.4°±0.2°、4.2°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型CS1，其特征在于，其X射线粉末衍射图在2theta值为7.4°±0.2°、24.3°±0.2°、17.7°±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CS1，其特征；在于，其X射线粉末衍射图在2theta值为12.8°±0.2°、21.5°±0.2°、18.2°±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CS1，其特征在于，其制备方法包含1)或2)：
    1)将奥扎莫德盐酸盐的固体置于醇类、酮类、酯类、腈类溶剂中搅拌，并加入1-1.5倍量的氢氧化钠水溶液，悬浮液由混浊转为澄清，室温下搅拌一段时间，有白色固体析出，离心后干燥固体，得到奥扎莫德白色固体，为晶型CS1；所述搅拌时间为至少0.5小时；或
    2)将奥扎莫德游离形式的固体置于醇类溶剂中搅拌，离心，干燥固体，得到奥扎莫德晶型CS1；所述搅拌时间为至少0.5小时。
  5. 根据权利要求4所述的制备方法，所述醇类溶剂是甲醇；酮类溶剂是丙酮；酯类溶剂是乙酸异丙酯；腈类溶剂是乙腈。
  6. 一种奥扎莫德的晶型CS2，其特征在于，其X射线粉末衍射图在2theta值为23.2°±0.2°、18.5°±0.2°、13.3°±0.2°处具有特征峰。
  7. 根据权利要求6所述的晶型CS2，其特征在于，其X射线粉末衍射图在2theta值为15.9°±0.2°、30.0°±0.2°、14.2°±0.2°中的一处或两处或三处具有特征峰。
  8. 根据权利要求6所述的晶型CS2，其特征在于，其X射线粉末衍射图在2theta值为4.0°±0.2°、26.5°±0.2°、17.7°±0.2°中的一处或两处或三处具有特征峰。
  9. 一种权利要求6所述的晶型CS2，其特征在于，其制备方法包括以下1)或2)：
    1)将权利要求1所述的奥扎莫德晶型CS1加热到100-130℃得到；或
    2)将奥扎莫德游离形式的固体置于腈类、酮类、酯类、芳香烃类、环醚类、水、醇类与水、酮类与水、酰胺类与水的混合溶剂中搅拌，离心，干燥固体，得到奥扎莫德晶型CS2；所述搅拌时间为至少0.5小时。
  10. 一种奥扎莫德的晶型CS3，其特征在于，其X射线粉末衍射图在2theta值为4.4°±0.2°、13.0°±0.2°、26.0°±0.2°、11.0°±0.2°处具有特征峰。
  11. 根据权利要求10所述的晶型CS3，其特征在于，其X射线粉末衍射图在2theta值为7.8°±0.2°、23.2°±0.2°、17.0°±0.2°中的一处或两处或三处具有特征峰。
  12. 根据权利要求10所述的晶型CS3，其特征在于，其X射线粉末衍射图在2theta值为13.7°±0.2°、24.1°±0.2°中的一处或两处具有特征峰。
  13. 一种权利要求10所述的晶型CS3，其特征在于，其制备方法包括：将奥扎莫德的固体加入到醇类、腈类、二氯甲烷、酯类、亚砜类、乙二醇二甲醚与水的混合溶剂中，过滤，将所得滤液挥发，收集固体得到奥扎莫德的晶型CS3。
  14. 根据权利要求13所述的制备方法，所述醇类溶剂是甲醇；腈类溶剂是乙腈；酯类溶剂是乙酸异丙酯；亚砜类溶剂是二甲亚砜。
  15. 一种奥扎莫德的晶型CS5，其特征在于，其X射线粉末衍射图在2theta值为4.3°±0.2°、6.8°±0.2°、16.4°±0.2°处具有特征峰。
  16. 根据权利要求15所述的晶型CS5，其特征在于，其X射线粉末衍射图在2theta值为21.6°±0.2°、8.5°±0.2°、13.6°±0.2°中的一处或两处或三处具有特征峰。
  17. 根据权利要求15所述的晶型CS5，其特征在于，其X射线粉末衍射图在2theta值为13.0°±0.2°、25.0°±0.2°、26.0°±0.2°中的一处或两处或三处具有特征峰。
  18. 一种权利要求15所述的晶型CS5，其特征在于，其制备方法包括：
    将奥扎莫德的固体加入到环醚类溶剂中，过滤，将所得滤液挥发，收集固体得到奥扎莫德的晶型CS5。
  19. 根据权利要求18的制备方法，其特征在于，所述环醚类溶剂是2-甲基四氢呋喃。
  20. 一种奥扎莫德的晶型CS6，其特征在于，其X射线粉末衍射图在2theta值为4.4°±0.2°、24.5±0.2°、26.5°±0.2°、13.8°±0.2°处具有特征峰。
  21. 根据权利要求20所述的晶型CS6，其特征在于，其X射线粉末衍射图在2theta值为13.0°±0.2°、25.4±0.2°中的一处或两处具有特征峰。
  22. 根据权利要求20所述的晶型CS6，其特征在于，其X射线粉末衍射图在2theta值为8.9°±0.2°、13.4°±0.2°、11.0°±0.2°中的一处或两处或三处具有特征峰。
  23. 一种权利要求20所述的晶型CS6，其特征在于，其制备方法包括：将奥扎莫德的固体加入到酮类、氯仿溶剂中，过滤，将所得滤液挥发，收集固体得到奥扎莫德的晶型CS6。
  24. 根据权利要求23所述的制备方法，其特征在于，所述酮类溶剂是丙酮。
  25. 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所述的晶型CS1或权利要求6所述的晶型CS2或权利要求10所述的晶型CS3或权利要求15所述的晶型CS5或权利要求20所述的晶型CS6或它们的任意混合，及药学上可接受的载体、稀释剂或赋形剂。
  26. 权利要求1所述的晶型CS1或权利要求6所述的晶型CS2或权利要求10所述的晶型CS3或权利要求15所述的晶型CS5或权利要求20所述的晶型CS6或它们的任意混合，在生产用于磷酸鞘氨醇1受体激动剂的药物中的用途。
  27. 权利要求1所述的晶型CS1或权利要求6所述的晶型CS2或权利要求10所述的晶型CS3或权利要求15所述的晶型CS5或权利要求20所述的晶型CS6或它们的任意混合，在生产用于治疗溃疡性结肠炎药物中的用途。
  28. 权利要求1所述的晶型CS1或权利要求6所述的晶型CS2或权利要求10-所述的晶型CS3或权利要求15所述的晶型CS5或权利要求20所述的晶型CS6或它们的任意混合，在生产用于治疗多发性硬化症药物制剂中的用途。
  29. 一种奥扎莫德的盐酸盐晶型CS1，其特征在于，其X射线粉末衍射图在2theta值为26.1°±0.20°、24.4°±0.20°、20.1°±0.20°处具有特征峰。
  30. 根据权利要求29所述的盐酸盐晶型CS1，其特征在于，其X射线粉末衍射图在2theta值为3.9°±0.20°、21.1°±0.20°、7.9°±0.20°中的一处或两处或三处具有特征峰。
  31. 根据权利要求29所述的盐酸盐晶型CS1，其特征在于，其X射线粉末衍射图在2theta值为11.9°±0.20°、19.6°±0.20°、13.8°±0.20°中的一处或两处或三处具有特征峰。
  32. 一种权利要求29所述的盐酸盐晶型CS1，其特征在于，其制备方法包含1)或2)或3)或4)，
    1)将奥扎莫德盐酸盐加入醚类溶剂中，在4～50℃温度下搅拌一段时间，过滤干燥得到白色固体；所述搅拌时间是至少0.5小时；或
    2)将奥扎莫德盐酸盐溶于醇类、酯类、或其混合溶剂中，常温缓慢挥发一段时间，得到白色固体；所述挥发时间为至少0.5天；或
    3)将奥扎莫德盐酸盐溶于酰胺类有机溶剂或它们的混合体系中并形成饱和溶液，将其置于含有奥扎莫德盐酸盐反溶剂的体系中，在常温下缓慢扩散一段时间，过滤干燥后得到白色固体；所述扩散时间为至少1天；或
    4)将奥扎莫德盐酸盐溶于醇类溶剂中，并形成过饱和溶液，在25-80℃下充分溶解后过滤，得到的澄清溶液经冷却后，析出白色固体，过滤干燥得到奥扎莫德盐酸盐白色固体。
  33. 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29所述的奥扎莫德盐酸盐晶型CS1及药学上可接受的载体、稀释剂或赋形剂。
  34. 权利要求29所述的盐酸盐晶型CS1在生产用于磷酸鞘氨醇1受体激动剂的药物中的用途。
  35. 权利要求29所述的盐酸盐晶型CS1在生产用于治疗溃疡性结肠炎药物中的用途。
  36. 权利要求29所述的盐酸盐晶型CS1在生产用于治疗多发性硬化症药物中的用途。
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CN114957157A (zh) 2022-08-30
US20200157065A1 (en) 2020-05-21
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US11680050B2 (en) 2023-06-20

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