WO2018033149A1 - 奥扎莫德的晶型及其制备方法 - Google Patents

奥扎莫德的晶型及其制备方法 Download PDF

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WO2018033149A1
WO2018033149A1 PCT/CN2017/098125 CN2017098125W WO2018033149A1 WO 2018033149 A1 WO2018033149 A1 WO 2018033149A1 CN 2017098125 W CN2017098125 W CN 2017098125W WO 2018033149 A1 WO2018033149 A1 WO 2018033149A1
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Prior art keywords
ozamod
crystalline form
crystal form
ray powder
powder diffraction
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PCT/CN2017/098125
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English (en)
French (fr)
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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 CN201780045272.5A priority Critical patent/CN109563059A/zh
Priority to EP17841121.1A priority patent/EP3502100A4/en
Priority to US16/326,353 priority patent/US11028060B2/en
Publication of WO2018033149A1 publication Critical patent/WO2018033149A1/zh
Priority to US17/339,080 priority patent/US11897848B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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 and a preparation method thereof.
  • Multiple sclerosis is the most common central demyelinating disease that can cause a variety of symptoms including sensory changes, visual disturbances, muscle weakness, depression, coordination and speech difficulties, severe fatigue, cognitive impairment, and balance disorders. Physical heat and pain, etc., can lead to active disorders and disability.
  • Multiple sclerosis lesions are located in the brain or spinal cord. Multiple sclerosis gradually causes plaque-induced destruction of the myelin sheath of the brain and spinal cord (demyelination). The scar formation of myelin sheath affects the signal transmission of axons. Loss of control of the brain and spinal cord to the periphery, at most parts of the stiffness or loss of function.
  • multiple sclerosis affects the lives of approximately 2.3 million people, with an average age of onset of 20 to 40 years. The cause of multiple sclerosis is unclear and is considered to be an autoimmune disease. There is currently no effective cure.
  • the sphingosine 1 phosphate receptor belongs to the G protein-coupled receptor, which regulates a variety of downstream signaling molecules and cellular functions and has become associated with a variety of diseases (eg, multiple sclerosis, lung cancer, psoriasis, kidney) A novel target molecule associated with injury, uremia, and pain.
  • Fingolimod is the first S1PR protein modulator and the first oral modulator of multiple sclerosis, and was approved by the FDA in the US in 2010.
  • Ozanimod is a new oral selective S1PR modulator developed by Receptos, which is developed for the treatment of autoimmune diseases, especially for the treatment of multiple sclerosis and ulcerative colitis. .
  • Ozamod's clinical results showed better safety than Fingolimod, especially in terms of cardiac safety.
  • the chemical structural formula of the drug is an S-type chiral substance as shown in the formula (I).
  • Solid chemical drugs have different crystal forms that can cause differences in solubility, stability, fluidity, and compressibility, thereby affecting the safety and efficacy of pharmaceutical products containing the compound (see K. Knapman, Modern Drug Discovery, 3, 53). -54,57,2000.), resulting in differences in clinical efficacy.
  • the patent document CN102762100A relates to the compound of the formula (I), and the method for preparing the R-enantiomer of Ozamod is disclosed in the text.
  • the solid form or crystal form of the Ozamod is not disclosed. There are techniques for the discovery of crystal forms without guidance or guidance. Therefore, it is necessary to conduct a comprehensive systematic polymorph screening of Ozamod, and select the crystal form that is most suitable for development.
  • the inventors of the present invention discovered three crystal forms of Ozamod in the course of research, and provided a new choice for the preparation of pharmaceutical preparations containing Ozamod.
  • the present invention provides several crystal forms of Ozamod and methods for their preparation and use.
  • the present invention provides a crystalline form CS9 of Ozamod (hereinafter referred to as "crystalline form CS9") which is a hydrate.
  • the X-ray powder diffraction of the crystalline form CS9 has characteristic peaks at diffraction angle 2 ⁇ values of 11.5° ⁇ 0.2°, 4.3° ⁇ 0.2°, and 24.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS9 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ values of 10.5° ⁇ 0.2°, 25.9° ⁇ 0.2°, and 16.6° ⁇ 0.2°;
  • the X-ray powder diffraction of the crystalline form CS9 has characteristic peaks at diffraction angle 2 ⁇ values of 10.5° ⁇ 0.2°, 25.9° ⁇ 0.2°, and 16.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS9 has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 11.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 23.2° ⁇ 0.2°;
  • the X-ray powder diffraction of the crystalline form CS9 has characteristic peaks at diffraction angle 2 ⁇ values of 11.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 23.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS9 has a diffraction angle 2 ⁇ of 11.5° ⁇ 0.2°, 4.3° ⁇ 0.2°, 24.4° ⁇ 0.2°, 10.5° ⁇ 0.2°, 25.9°. Characteristic peaks are present at ⁇ 0.2°, 16.6° ⁇ 0.2°, 11.0° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 23.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS9 is substantially as shown in FIG.
  • the present invention also provides a method for preparing a crystalline form CS9, characterized in that the method comprises:
  • the solid in the free form of Ozamod is placed in a mixed solvent of a cyclic ether solvent and an aromatic hydrocarbon solvent, and after heating to dissolve the solid, a high polymer is added, and then rapidly transferred to a low temperature to be cooled to obtain a white solid.
  • a mixed solvent of a cyclic ether solvent and an aromatic hydrocarbon solvent for the Ozamod crystal form CS9.
  • the mixed solvent of the cyclic ether solvent and the aromatic hydrocarbon solvent is preferably 1,4-dioxane and toluene, preferably 1,4-dioxane and toluene in a volume ratio of 1:1;
  • the heating temperature is 40 ° C - 80 ° C, preferably 50 ° C;
  • the cooling temperature is -20 ° C to 4 ° C, preferably -20 ° C.
  • the present invention provides a crystal form CS10 of Ozamod (hereinafter referred to as "crystal form CS10”), which is an anhydride.
  • the X-ray powder diffraction of the crystalline form CS10 has characteristic peaks at diffraction angle 2 ⁇ values of 5.7° ⁇ 0.2°, 25.0° ⁇ 0.2°, and 26.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS10 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ values of 13.4° ⁇ 0.2°, 28.3° ⁇ 0.2°, and 16.2° ⁇ 0.2°;
  • the X-ray powder diffraction of the crystalline form CS10 has characteristic peaks at diffraction angle 2 ⁇ values of 13.4° ⁇ 0.2°, 28.3° ⁇ 0.2°, and 16.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS10 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ values of 8.6° ⁇ 0.2°, 19.3° ⁇ 0.2°, and 14.6° ⁇ 0.2°;
  • the X-ray powder diffraction of the crystalline form CS10 has characteristic peaks at diffraction angle 2 ⁇ values of 8.6° ⁇ 0.2°, 19.3° ⁇ 0.2°, and 14.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS10 has a diffraction angle 2 ⁇ of 5.7° ⁇ 0.2°, 25.0° ⁇ 0.2°, 26.6° ⁇ 0.2°, 13.4° ⁇ 0.2°, 28.3°. There are characteristic peaks at ⁇ 0.2°, 16.2° ⁇ 0.2°, 8.6° ⁇ 0.2°, 19.3° ⁇ 0.2°, and 14.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CS10 is substantially as shown in FIG.
  • the present invention also provides a method for preparing a crystalline form CS10, characterized in that the method comprises:
  • the amorphous form of Ozamod was added to a mixed solvent of acetone and water and stirred at room temperature to obtain a solid which was Ozamod crystal form CS10.
  • the volume ratio of the mixed solvent of acetone and water is from 1:10 to 5:1, preferably 1:1.
  • the amorphous preparation method of Ozamod is characterized in that the solid of Ozamod is heated at 150 ° C to melt the solid, and it is rapidly cooled at -20 ° C to obtain Oza Mold's amorphous, its X-ray powder diffraction pattern is basically as shown in Figure 4.
  • the present invention provides a crystal form CS11 of Ozamod (hereinafter referred to as "crystal form CS11”), which is an anhydride.
  • the X-ray powder diffraction of the crystal form CS11 has a characteristic peak at a diffraction angle 2 ⁇ value of 5.7° ⁇ 0.2°, 24.6° ⁇ 0.2°, and 25.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS11 has a characteristic peak at one or two or three of the diffraction angle 2 ⁇ values of 13.4 ⁇ 0.2°, 13.9 ⁇ 0.2°, and 27.0° ⁇ 0.2°;
  • the X-ray powder diffraction of the crystal form CS11 has characteristic peaks at diffraction angle 2 ⁇ values of 13.4 ⁇ 0.2°, 13.9 ⁇ 0.2°, and 27.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS11 has one or more of diffraction angle 2 ⁇ values of 16.2° ⁇ 0.2°, 23.3° ⁇ 0.2°, 26.1° ⁇ 0.2°, and 8.6° ⁇ 0.2°. Characteristic peak; preferably, the X-ray powder diffraction of the crystal form CS11 has characteristic peaks at diffraction angle 2 ⁇ values of 16.2° ⁇ 0.2°, 23.3° ⁇ 0.2°, 26.1° ⁇ 0.2°, and 8.6° ⁇ 0.2°. .
  • the X-ray powder diffraction of the crystalline form CS11 has a diffraction angle 2 ⁇ of 5.7° ⁇ 0.2°, 24.6° ⁇ 0.2°, 25.3° ⁇ 0.2°, 13.4 ⁇ 0.2°, and 13.9 ⁇ 0.2. Characteristic peaks at °, 27.0 ° ⁇ 0.2 °, 16.2 ° ⁇ 0.2 °, 23.3 ° ⁇ 0.2 °, 26.1 ° ⁇ 0.2 °, and 8.6 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form CS11 is substantially as shown in FIG.
  • the present invention also provides a method for preparing a crystalline form CS11, characterized in that the method comprises:
  • the amorphous form of Ozamod is added to a mixed solvent of two alcohols or ketones and alkanes or halogenated hydrocarbons and esters, stirred and separated at room temperature to obtain a solid which is Ozamod crystal form CS11 .
  • the mixed solvent includes methanol and isopropanol, acetone and heptane, chloroform and isopropyl acetate;
  • the mixed solvent has a volume ratio of methanol to isopropanol of 1:3, a volume ratio of acetone to heptane of 1:1, and a volume ratio of chloroform to isopropyl acetate of 1:2.
  • the method for preparing amorphous Ozamod characterized in that the solid of Ozamod is heated at about 150 ° C to melt the solid, and it is rapidly cooled at -20 ° C to obtain Zamod's amorphous shape, its X-ray powder diffraction pattern is basically as shown in Figure 4.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Ozamod's crystalline form CS9 or Form CS10 or Form CS11 or a mixture thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
  • the present invention provides the use of the crystalline form CS9 or the crystalline form CS10 or the crystalline form CS11 of Ozamod or any combination thereof in the manufacture of a medicament for the preparation of a medicament for the treatment of ulcerative colitis.
  • the crystalline form CS9 or the crystalline form CS10 or the crystalline form CS11 of Ozamod, or any mixture thereof, provided by the present invention is used for the production of a pharmaceutical preparation for treating multiple sclerosis.
  • room temperature as used herein is not an accurate temperature value and refers to a temperature range of 10-30 °C.
  • the “stirring” is carried out by a conventional method in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 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.
  • the time of volatilization is the reaction to the time when solids are precipitated or longer.
  • polymer refers to a mixture of equal masses of polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate, and hydroxyethyl cellulose.
  • the low wettability crystal form does not require special drying conditions in the preparation process, simplifies the preparation and post-treatment of the drug, and is easy to industrialize.
  • the crystal form CS10 and the crystal form CS11 of the invention have only a small increase in moisture content under the condition of 80% high humidity, which is slightly hygroscopic and is beneficial to long-term storage of the medicine. Because the storage conditions are not demanding, it is beneficial to reduce material storage and quality control costs, and has strong economic value.
  • Solubility is one of the key properties of drugs, which directly affects the absorption of drugs in the human body.
  • the solubility of different crystalline drugs may be significantly different, and the absorption dynamics in the body may also change, resulting in differences in bioavailability, ultimately affecting The clinical safety and efficacy of the drug.
  • the crystalline form CS9 also has good solubility in water, which is beneficial to improve the bioavailability of the drug.
  • the stability of the crystal form plays a crucial role in judging whether a crystal form has development value, especially maintaining good stability during the commercial period, reducing the drug dissolution rate and bioavailability due to crystal form changes. Changes are important to ensure the efficacy and safety of drugs and prevent the occurrence of adverse drug reactions.
  • the crystal form CS10 and the crystal form CS11 sample of the invention are placed in a constant temperature and humidity chamber of 25 ° C / 60% RH and / or 40 ° C / 75% RH for a period of time without change, and have good stability. .
  • the Ozamod crystal form provided by the invention has obvious advantages in solubility, moisture permeability, stability and the like, and the crystal form CS9, the crystal form CS10 and the crystal form CS11 of the invention have uniform particle size distribution and good dispersibility, which contributes to The post-treatment process that simplifies the formulation process provides a new and better choice for the preparation of pharmaceutical preparations containing Ozamod, which is of great significance for drug development.
  • Embodiment 1 is an XRPD pattern of a crystalline form CS9 in Embodiment 1.
  • FIG. 3 is a TGA diagram of the crystalline form CS9 in the first embodiment.
  • Embodiment 4 is an amorphous XRPD pattern in Embodiment 2.
  • FIG. 5 is an XRPD diagram of the crystal form CS10 in the third embodiment.
  • FIG. 6 is a DSC diagram of the crystalline form CS10 in the third embodiment.
  • Figure 10 is a DSC diagram of the crystalline form CS11 in the fifth embodiment.
  • Figure 11 is a TGA diagram of the crystalline form CS11 in the fifth embodiment.
  • Figure 12 is an XRPD diagram of the crystalline form CS11 in the sixth embodiment.
  • Figure 13 is an XRPD pattern of the crystal form CS11 in the seventh embodiment.
  • Figure 14 is a DVS diagram of the crystal form CS9 in the eighth embodiment.
  • Figure 16 is a DVS diagram of the crystalline form CS11 in the tenth embodiment.
  • 17 is a PSD diagram of a crystalline form CS9 in Example 12.
  • Figure 18 is a PLM diagram of the crystal form CS9 in the embodiment 12.
  • FIG. 21 is a PSD diagram of a crystalline form CS11 in Embodiment 12.
  • Figure 22 is a PLM diagram of the crystalline form CS11 in the embodiment 12.
  • Figure 23 is an XRPD overlay before and after the stability test of the crystalline form CS10 in Example 13.
  • Figure 24 is an XRPD overlay before and after the stability test of the crystalline form CS11 in Example 14.
  • 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 DSC map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry described in the present invention are as follows:
  • thermogravimetric analysis The TGA map of the present invention was acquired on a TA Q5000.
  • the method parameters of the thermogravimetric analysis according to the present invention are as follows:
  • the DVS map 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 as described in CN102762100A.
  • the method of preparation is obtained.
  • the solid obtained in this example was a crystalline form CS9.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 1, and its XRPD pattern is shown in Fig. 1.
  • the first endothermic peak begins to appear near the temperature of 67 ° C, and an exothermic peak begins to appear near the temperature of 81 ° C.
  • the second endothermic peak begins to appear near the temperature of 121 ° C.
  • Its DSC chart is shown in Figure 2.
  • thermogravimetric analysis it was heated to 143 ° C with a mass loss gradient of about 5.5%, and its TGA pattern is shown in FIG.
  • the solid obtained in this example was a crystalline form CS10.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 2. Its XRPD diagram is shown in Figure 5.
  • the first endothermic peak begins to appear near the temperature of 102 ° C, and the first exothermic peak begins to appear when heated to 111 ° C.
  • the second endothermic peak begins to appear when heated to 131 ° C.
  • Its DSC chart is shown in Figure 6.
  • thermogravimetric analysis when heated to 119 ° C, it had a mass loss of about 2.1%, and its TGA chart is shown in FIG.
  • the solid obtained in this example was a crystalline form CS10.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 3, and the XRPD pattern thereof is shown in Fig. 8.
  • the solid obtained in this example was a crystalline form CS11.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 4, and its XRPD pattern is shown in Fig. 9.
  • the first endothermic peak begins to appear near 114 ° C, and the first exothermic peak begins to appear when heated to 120 ° C.
  • a second endothermic peak begins to appear. Its DSC chart is shown in Figure 10.
  • thermogravimetric analysis when heated to 125 ° C, it had a mass loss of about 1.6%, and its TGA pattern is shown in FIG.
  • the solid obtained in this example was a crystalline form CS11.
  • 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 12.
  • the solid obtained in this example was a crystalline form CS11.
  • 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 13.
  • the prepared Ozamod crystal form CS9 sample was made into a saturated solution with pure water, and the content of the sample in the saturated solution was determined by high performance liquid chromatography after 1 hour, 4 hours, and 24 hours.
  • the solubility data of the Ozamod crystal form CS9 of the present invention is shown in Table 10.
  • 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 and PLM diagrams of the crystal form CS9 are shown in Figures 17 and 18, respectively.
  • the PSD diagram shows that the volume average particle size of the crystal form CS9 is 339.9 ⁇ m, and the particle size distribution is narrow, almost showing a normal distribution, and the particle size distribution is uniform. It can be seen from the PLM diagram that the crystalline form CS9 is granular and has good dispersibility.
  • the PSD and PLM diagrams of the crystal form CS10 are shown in Figs. 19 and 20, respectively.
  • the volume average particle size of the crystal form CS10 is 317.2 ⁇ m, and the particle size distribution is narrow, almost showing a normal distribution, and the particle size distribution is uniform from the PLM. It can be seen that the crystalline form CS10 is granular and has good dispersibility.
  • the PSD and PLM diagrams of the crystal form CS11 are shown in Figs. 21 and 22, respectively.
  • the volume average particle diameter of the crystal form CS11 is 137.7 ⁇ m, and the particle size distribution is narrow, almost showing a normal distribution, and the particle size distribution is uniform from the PLM. It can be seen that the crystalline form CS11 is in the form of particles and has good dispersibility.
  • the Ozamod crystal form CS10 sample was placed in a constant temperature and humidity chamber at 40 ° C / 75% RH for two weeks, and then XRPD was sampled.
  • the results are shown in Fig. 23 (from the top to the bottom, the crystalline CS10 reference XRPD pattern, placed in an XRPD pattern of two weeks at 40 ° C / 75% RH). It can be seen that the crystalline form CS10 was left at 40 ° C / 75% RH for two weeks and the crystal form remained unchanged.
  • the above test results show that Ozamod crystal form CS10 has good stability.
  • the Ozamod crystal form CS11 remained unchanged at 25 ° C / 60% RH and 40 ° C / 75% RH for two weeks. The above results indicate that the Ozamod crystal form CS11 has good stability.

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Abstract

提供了奥扎莫德的晶型及其制备方法。所提供的奥扎莫德的晶型，其中包含奥扎莫德的晶型CS9、晶型CS10及晶型CS11，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。所提供的奥扎莫德晶型在溶解度、稳定性、引湿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，对于药物开发具有重要价值。

Description

奥扎莫德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及其制备方法。
背景技术
多发性硬化症是最常见的一种中枢神经脱髓鞘疾病，可引起各种症状，包括感觉改变、视觉障碍、肌肉无力、忧郁、协调与讲话困难、严重的疲劳、认知障碍、平衡障碍、体热和疼痛等，严重的可以导致活动性障碍和残疾。多发性硬化症病变位于脑部或脊髓，多发性硬化症逐渐造成大脑和脊髓的斑块性的神经髓鞘的破坏(脱髓鞘)，髓鞘的瘢痕形成影响神经轴突的信号传递，以失去大脑和脊髓对外周的控制，以至多部位的僵硬或丧失功能。全球范围内，多发性硬化症影响着大约230万人的生活，平均发病年龄一般在20至40岁。多发性硬化症的病因不清，多被认为是自身免疫性疾病，目前尚无有效的根治办法。
鞘氨醇1磷酸蛋白家族成员参与了众多重要的细胞生理过程，包括细胞增殖、新生血管生成及免疫细胞输送等。鞘氨醇1磷酸受体(S1PR)属于G蛋白偶联受体，其能调节多种下游信号分子和细胞功能，已成为与多种疾病(如多发性硬化症、肺癌、银屑病、肾损伤、尿毒症以及疼痛)相关的一种新型靶标分子。Fingolimod是第一款S1PR蛋白调节剂，也是第一款针对多发性硬化症的口服性调节药物，于2010年获得FDA批准在美国上市。
奥扎莫德(Ozanimod)是由Receptos公司研发的一种新型口服选择性S1PR调节剂，开发用于自身免疫性疾病的治疗，特别是对治疗多发性硬化症和溃疡性结肠炎具有明显的效果。在临床试验中，相比于Fingolimod，奥扎莫德临床结果显示具有更好的安全性，特别是在心脏安全方面。基于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S1PR调节剂药物。该药物的化学结构式如式(I)所示，是一种S型手性物质。
Figure PCTCN2017098125-appb-000001
固体化学药物晶型不同，可造成其溶解度、稳定性、流动性和压缩性等不同，从而影响含有该化合物的药物产品的安全性和有效性(参见K.Knapman,Modern Drug Discovery,3,53-54,57,2000.)，从而导致临床药效的差异。专利文献CN102762100A中涉及式(I)化合物，文本中公开了奥扎莫德的R型对映异构体的制备方法，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三种晶型，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几种晶型及其制备方法和用途。
根据本发明的目的，本发明提供奥扎莫德的晶型CS9(以下称作“晶型CS9”)，所述晶型CS9为水合物。
使用Cu-Kα辐射，所述晶型CS9的X射线粉末衍射在衍射角2θ值为11.5°±0.2°、4.3°±0.2°、24.4°±0.2°处具有特征峰。
进一步的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为10.5°±0.2°、25.9°±0.2°、16.6°±0.2°中的一处或两处或三处具有特征峰；优选的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为10.5°±0.2°、25.9°±0.2°、16.6°±0.2°处均有特征峰。
进一步的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为11.0°±0.2°、18.8°±0.2°、23.2°±0.2°中的一处或两处或三处具有特征峰；优选的，所述晶型CS9的X射线粉末衍射在衍射角2θ值为11.0°±0.2°、18.8°±0.2°、23.2°±0.2°处均有特征峰。
在一个优选的实施例中，所述晶型CS9的X射线粉末衍射在衍射角2θ值为11.5°±0.2°、4.3°±0.2°、24.4°±0.2°、10.5°±0.2°、25.9°±0.2°、16.6°±0.2°、11.0°±0.2°、18.8°±0.2°、23.2°±0.2°处具有特征峰。
非限制地，在本发明的一个优选的实施例中，晶型CS9的X射线粉末衍射图基本如图1所示。
根据本发明的目的，本发明还提供了晶型CS9的制备方法，其特征在于，所述方法包含：
将奥扎莫德游离形式的固体置于环醚类溶剂和芳香烃类溶剂的混合溶剂中，加热使固体溶解后，加入高聚物，然后迅速转移至低温下冷却，得到白色固体，所得固体为奥扎莫德晶型CS9。
所述环醚类溶剂和芳香烃类溶剂的混合溶剂优选1,4-二氧六环和甲苯，优选1,4-二氧六环和甲苯的体积比为1:1；
所述加热温度为40℃-80℃，优选50℃；
所述冷却的温度为-20℃-4℃，优选-20℃。
根据本发明的目的，本发明提供奥扎莫德的晶型CS10(以下称作“晶型CS10”)，所述晶型CS10为无水物。
使用Cu-Kα辐射，所述晶型CS10的X射线粉末衍射在衍射角2θ值为5.7°±0.2°、25.0°±0.2°、26.6°±0.2°处具有特征峰。
进一步的，所述晶型CS10的X射线粉末衍射在衍射角2θ值为13.4°±0.2°、28.3°±0.2°、16.2°±0.2°中的一处或两处或三处具有特征峰；优选的，所述晶型CS10的X射线粉末衍射在衍射角2θ值为13.4°±0.2°、28.3°±0.2°、16.2°±0.2°处均有特征峰。
进一步的，所述晶型CS10的X射线粉末衍射在衍射角2θ值为8.6°±0.2°、19.3°±0.2°、14.6°±0.2°中的一处或两处或三处具有特征峰；优选的，所述晶型CS10的X射线粉末衍射在衍射角2θ值为8.6°±0.2°、19.3°±0.2°、14.6°±0.2°处均有特征峰。
在一个优选的实施例中，所述晶型CS10的X射线粉末衍射在衍射角2θ值为5.7°±0.2°、25.0°±0.2°、26.6°±0.2°、13.4°±0.2°、28.3°±0.2°、16.2°±0.2°、8.6°±0.2°、19.3°±0.2°、14.6°±0.2°处具有特征峰。
非限制地，在本发明的一个优选的实施例中，晶型CS10的X射线粉末衍射图基本如图5所示。
根据本发明的目的，本发明还提供了晶型CS10的制备方法，其特征在于，所述方法包含：
将奥扎莫德的无定形形式加入到丙酮和水的混合溶剂中室温下搅拌，得到固体即为奥扎莫德晶型CS10。
所述丙酮和水的混合溶剂的体积比介于1：10-5：1，优选1：1。
所述奥扎莫德无定形的制备方法，其特征在于，将奥扎莫德的固体置于150℃条件下加热，使固体熔融，迅速将其置于-20℃条件下冷却，得到奥扎莫德的无定形，其X射线粉末衍射图基本如图4所示。
根据本发明的目的，本发明提供奥扎莫德的晶型CS11(以下称作“晶型CS11”)，所述晶型CS11为无水物。
使用Cu-Kα辐射，所述晶型CS11的X射线粉末衍射在衍射角2θ值为5.7°±0.2°、24.6°±0.2°、25.3°±0.2°处具有特征峰。
进一步的，所述晶型CS11的X射线粉末衍射在衍射角2θ值为13.4±0.2°、13.9±0.2°、27.0°±0.2°中的一处或两处或三处具有特征峰；优选的，所述晶型CS11的X射线粉末衍射在衍射角2θ值为13.4±0.2°、13.9±0.2°、27.0°±0.2°处均有特征峰。
进一步的，所述晶型CS11的X射线粉末衍射在衍射角2θ值为16.2°±0.2°、23.3°±0.2°、26.1°±0.2°、8.6°±0.2°中的一处或多处具有特征峰；优选的，所述晶型CS11的X射线粉末衍射在衍射角2θ值为16.2°±0.2°、23.3°±0.2°、26.1°±0.2°、8.6°±0.2°处均有特征峰。
在一个优选的实施例中，所述晶型CS11的X射线粉末衍射在衍射角2θ值为5.7°±0.2°、24.6°±0.2°、25.3°±0.2°、13.4±0.2°、13.9±0.2°、27.0°±0.2°、16.2°±0.2°、23.3°±0.2°、26.1°±0.2°、8.6°±0.2°处具有特征峰。
非限制地，在本发明的一个优选的实施例中，晶型CS11的X射线粉末衍射图基本如图8所示。
根据本发明的目的，本发明还提供了晶型CS11的制备方法，其特征在于，所述方法包含：
将奥扎莫德的无定形形式加入两种醇类或酮类和烷烃类或卤代烃和酯类的混合溶剂中，在室温下搅拌、分离，得到固体即为奥扎莫德晶型CS11。
所述混合溶剂包括甲醇和异丙醇，丙酮和庚烷，氯仿和醋酸异丙酯；
优选的，所述混合溶剂中甲醇和异丙醇的体积比为1：3，丙酮和庚烷的体积比为1：1，氯仿和醋酸异丙酯的体积比为1：2。
所述奥扎莫德无定形的制备方法，其特征在于，将奥扎莫德的固体置于约150℃条件下加热，使固体熔融，迅速将其置于-20℃条件下冷却，得到奥扎莫德的无定形，其X射线粉末衍射图基本如图4所示。
本发明的另一个目的是提供一种药物组合物，包含有效治疗量奥扎莫德的晶型CS9或 晶型CS10或晶型CS11或它们混合，及药学上可接受的载体、稀释剂或赋形剂。
本发明提供的奥扎莫德的晶型CS9或晶型CS10或晶型CS11或它们的任意混合，在生产用于选择性鞘氨醇1磷酸受体调节剂的药物中的用途。
本发明提供的奥扎莫德的晶型CS9或晶型CS10或晶型CS11或它们的任意混合，在生产用于制备治疗溃疡性结肠炎药物中的用途。
本发明提供的奥扎莫德的晶型CS9或晶型CS10或晶型CS11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。
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。挥发的时间是反应至有固体析出的时间或者更长时间。
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。
低引湿性的晶型在制备过程中无需特殊的干燥条件，简化了药物的制备与后处理工艺，易于工业化生产。本发明的晶型CS10和晶型CS11在80％高湿度条件下水分含量也只有少量的增加，属于略有引湿性，有利于药品的长期贮存。由于对储存条件要求不苛刻，有利于降低物料储存以及质量控制成本，具有很强的经济价值。
溶解度是药物的关键性质之一，其直接影响药物在人体内的吸收，而不同晶型药物的溶解度可能会存在明显差异，体内吸收动态也会发生变化，造成生物利用度的差异，最终影响到药物的临床安全性和疗效。晶型CS9在水中也具有良好的溶解性，有利于提高药物的生物利用度。
晶型的稳定性对评判一个晶型是否具有开发价值起到至关重要的作用，尤其在市售有效期内保持较好的稳定性，减少药物由于晶型变化而导致药物溶出速率及生物利用度改变，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。本发明的晶型CS10、晶型CS11样品置于25℃/60％RH和/或40℃/75％RH的恒温恒湿箱中敞口放置一段时间均未发生改变，具有较好的稳定性。
本发明提供的奥扎莫德晶型在溶解度、引湿性、稳定性等方面中存在明显优势，本发明的晶型CS9、晶型CS10、晶型CS11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的意义。
附图说明
图1为实施例1中晶型CS9的XRPD图
图2为实施例1中晶型CS9的DSC图
图3为实施例1中晶型CS9的TGA图
图4为实施例2中无定型的XRPD图
图5为实施例3中晶型CS10的XRPD图
图6为实施例3中晶型CS10的DSC图
图7为实施例3中晶型CS10的TGA图
图8为实施例4中晶型CS10的XRPD图
图9为实施例5中晶型CS11的XRPD图
图10为实施例5中晶型CS11的DSC图
图11为实施例5中晶型CS11的TGA图
图12为实施例6中晶型CS11的XRPD图
图13为实施例7中晶型CS11的XRPD图
图14为实施例8中晶型CS9的DVS图
图15为实施例9中晶型CS10的DVS图
图16为实施例10中晶型CS11的DVS图
图17为实施例12中晶型CS9的PSD图
图18为实施例12中晶型CS9的PLM图
图19为实施例12中晶型CS10的PSD图
图20为实施例12中晶型CS10的PLM图
图21为实施例12中晶型CS11的PSD图
图22为实施例12中晶型CS11的PLM图
图23为实施例13中晶型CS10稳定性试验前后XRPD叠图
图24为实施例14中晶型CS11稳定性试验前后XRPD叠图
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
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 PCTCN2017098125-appb-000002
1.540598；Kα2
Figure PCTCN2017098125-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DSC图在TA Q2000上采集。本发明所述的差示扫描量热分析的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的TGA图在TA Q5000上采集。本发明所述的热重分析的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述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 PCTCN2017098125-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CS9的制备方法：
称取约90mg的奥扎莫德游离碱于20mL的玻璃瓶中，加入约2mL的1,4-二氧六环和甲苯的混合溶液(1,4-二氧六环和甲苯的体积比为1：1)于50℃条件下溶解过滤，加入约0.2mg的高聚物。迅速将溶液置于-20℃冷却，得到白色固体。
经检测，本实施例得到的固体为晶型CS9。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。当进行差示扫描量热分析时，加热至67℃附近开始出现第一个吸热峰，加热至81℃附近开始出现一个放热峰，加热至121℃附近开始出现第二个吸热峰，其DSC图如图2。当进行热重分析时，加热至143℃，具有约5.5％的质量损失梯度，其TGA图如图3所示。
表1
2θ d间隔 强度％
4.32 20.46 68.98
5.56 15.91 7.57
6.09 14.51 9.38
6.59 13.41 9.86
10.51 8.42 30.46
10.97 8.08 14.58
11.54 7.67 100.00
12.13 7.30 6.16
13.05 6.79 13.08
13.72 6.45 6.64
14.51 6.10 5.44
15.35 5.77 3.22
15.95 5.56 7.98
16.60 5.34 17.36
18.80 4.72 13.56
21.00 4.23 7.63
22.09 4.02 10.14
23.22 3.83 13.24
23.93 3.72 15.49
24.42 3.65 67.48
25.13 3.54 11.80
25.93 3.44 22.52
26.97 3.31 8.33
29.76 3.00 0.90
33.34 2.69 0.35
36.20 2.48 1.07
37.83 2.38 0.88
实施例2
奥扎莫德无定形的制备方法：
称取约100mg的奥扎莫德的固体于20mL玻璃瓶中，置于150℃热台使之充分熔融，迅速将其放入-20℃环境中冷却，得到奥扎莫德游离形式的无定形。本实施例制备得到的无定形如图4所示。
实施例3
奥扎莫德晶型CS10的制备方法：
称取约10mg的奥扎莫德无定形于1.5mL的玻璃瓶中，加入约0.3mL的甲苯，在室温下搅拌，得到固体。
经检测，本实施例得到的固体为晶型CS10。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5。当进行差示扫描量热分析时，加热至102℃附近开始出现第一个吸热峰，加热至111℃开始出现第一个放热峰，加热至131℃开始出现第二个吸热峰，其DSC图如图6所示。当进行热重分析时，加热至119℃时，具有约2.1％的质量损失，其TGA图如图7所示。
表2
2θ d间隔 强度％
5.69 15.52 100.00
8.58 10.31 17.17
10.80 8.19 7.94
11.44 7.73 14.73
13.38 6.62 41.67
14.59 6.07 11.42
16.19 5.47 17.24
17.20 5.16 5.89
18.55 4.78 3.08
19.27 4.61 11.66
20.37 4.36 3.90
21.69 4.10 7.91
22.64 3.93 9.10
23.04 3.86 9.88
24.16 3.68 9.57
25.04 3.56 20.40
26.62 3.35 13.35
28.34 3.15 8.17
29.96 2.98 1.36
30.35 2.95 1.24
33.24 2.70 0.60
35.52 2.53 0.86
37.88 2.37 0.73
实施例4
奥扎莫德晶型CS10的制备方法：
称取约10mg的奥扎莫德无定形于1.5mL的玻璃瓶中，加入约0.3mL的丙酮和水的混合溶剂(丙酮：水的体积比为1：1)，在室温下搅拌，得到固体。
经检测，本实施例得到的固体为晶型CS10。本实施例得到的晶型的X射线粉末衍射数据如表3，其XRPD图如图8所示。
表3
2θ d间隔 强度％
4.19 21.11 7.45
5.68 15.55 100.00
8.58 10.31 29.07
10.91 8.11 19.01
11.43 7.74 19.44
13.36 6.63 56.86
14.62 6.06 16.70
16.22 5.47 25.10
19.26 4.61 13.82
20.24 4.39 4.54
21.11 4.21 3.92
21.88 4.06 7.23
22.67 3.92 8.87
25.07 3.55 28.56
26.61 3.35 14.49
28.44 3.14 11.91
28.92 3.09 5.09
30.47 2.93 2.98
31.84 2.81 4.57
32.35 2.77 3.17
33.26 2.69 4.12
35.28 2.54 2.46
35.62 2.52 6.17
36.96 2.43 2.34
37.87 2.38 2.93
38.35 2.35 3.15
实施例5
奥扎莫德晶型CS11的制备方法：
称取约10mg的奥扎莫德无定形于1.5mL的玻璃瓶中，加入约0.3mL的甲醇和异丙醇的混合溶剂(甲醇：异丙醇的体积比为1：3)，在室温下搅拌，得到固体。
经检测，本实施例得到的固体为晶型CS11。本实施例得到的晶型的X射线粉末衍射数据如表4，其XRPD图如图9。当进行差示扫描量热分析时，加热至114℃附近开始出现第一个吸热峰，加热至120℃开始出现第一个放热峰，加热至131℃开始出现第二个吸热峰，其DSC图如图10所示。当进行热重分析时，加热至125℃时，具有约1.6％的质量损失，其TGA图如图11所示。
表4
2θ d间隔 强度％
5.73 15.42 100.00
8.63 10.25 21.96
10.77 8.22 8.71
11.53 7.68 18.55
12.97 6.83 18.49
13.36 6.63 52.38
13.90 6.37 17.48
14.57 6.08 13.78
15.35 5.77 9.55
16.21 5.47 24.67
17.36 5.11 8.45
17.71 5.01 3.98
18.40 4.82 4.56
18.89 4.70 8.43
19.51 4.55 19.05
20.24 4.39 7.02
21.63 4.11 9.17
22.42 3.97 7.39
23.33 3.81 13.96
23.71 3.75 9.97
23.95 3.72 9.18
24.58 3.62 23.17
25.32 3.52 20.14
26.13 3.41 13.52
26.96 3.31 17.28
27.89 3.20 10.30
28.82 3.10 5.82
32.86 2.73 0.91
35.58 2.52 0.80
39.10 2.30 1.02
实施例6
奥扎莫德晶型CS11的制备方法：
称取约10mg的奥扎莫德无定形于1.5mL的玻璃瓶中，加入约0.3mL的丙酮和庚烷的混合溶剂(丙酮：庚烷的体积比为1：1)，在室温下搅拌，得到固体。
经检测，本实施例得到的固体为晶型CS11。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12。
表5
2θ d间隔 强度％
5.73 15.41 100.00
6.27 14.10 5.92
8.62 10.25 30.22
11.52 7.68 21.04
13.38 6.62 32.38
13.90 6.37 12.68
14.62 6.06 9.58
15.38 5.76 8.32
16.22 5.46 20.01
17.35 5.11 14.39
18.16 4.88 6.99
18.96 4.68 6.40
19.56 4.54 12.7
20.29 4.38 9.50
21.65 4.11 8.80
22.42 3.97 6.96
23.28 3.82 7.57
23.91 3.72 6.54
24.27 3.67 5.72
24.62 3.62 14.80
25.35 3.51 12.85
26.15 3.41 11.22
26.93 3.31 11.32
27.04 3.30 11.40
27.90 3.20 8.34
28.79 3.10 4.18
31.56 2.84 1.50
33.45 2.68 0.67
35.54 2.53 1.11
实施例7
奥扎莫德晶型CS11的制备方法：
称取约10mg的奥扎莫德无定形于1.5mL的玻璃瓶中，加入约0.3mL的氯仿和醋酸异丙酯的混合溶剂(氯仿：醋酸异丙酯的体积比为1：2)，在室温下搅拌，得到固体。
经检测，本实施例得到的固体为晶型CS11。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13。
表6
2θ d间隔 强度％
5.72 15.45 100.00
7.07 12.51 4.25
8.64 10.24 29.86
9.63 9.19 3.30
10.32 8.57 4.49
10.85 8.15 5.86
11.51 7.69 21.62
11.95 7.41 5.90
12.94 6.84 7.29
13.49 6.57 15.05
13.83 6.40 8.21
14.66 6.04 7.67
15.32 5.78 8.30
16.22 5.46 12.81
17.37 5.11 11.05
17.98 4.93 4.40
18.42 4.82 6.11
19.05 4.66 5.57
19.63 4.52 6.69
20.26 4.38 7.50
21.14 4.20 4.90
21.59 4.12 6.04
22.39 3.97 6.30
23.14 3.84 10.97
23.80 3.74 9.88
24.55 3.63 10.24
25.34 3.51 12.79
26.11 3.41 8.84
26.87 3.32 6.97
27.84 3.20 5.46
28.82 3.10 3.79
29.86 2.99 4.30
33.29 2.69 3.75
34.14 2.63 4.44
实施例8
奥扎莫德晶型CS9的引湿性实验：
取本发明的奥扎莫德的晶型CS9约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表7所示。晶型CS9的引湿性实验的DVS图如图14所示。
表7
Figure PCTCN2017098125-appb-000005
结果表明，本发明的奥扎莫德晶型CS9在80％湿度下平衡后增重2.88％，根据引湿性增重的界定标准，属于有引湿性。
实施例9
奥扎莫德晶型CS10的引湿性实验：
取本发明的奥扎莫德的晶型CS10约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表8所示。晶型CS10的引湿性实验的DVS图如图15所示。
表8
Figure PCTCN2017098125-appb-000006
结果表明，本发明的奥扎莫德晶型CS10在80％湿度下平衡后增重1.02％，属于略有引湿性。
实施例10
奥扎莫德晶型CS11的引湿性实验：
取本发明的奥扎莫德的晶型CS11约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表9所示。晶型CS11的引湿性实验的DVS图如图16所示。
表9
Figure PCTCN2017098125-appb-000007
结果表明，本发明的奥扎莫德晶型CS11在80％湿度下平衡后增重0.57％，属于略有引湿性。
实施例11
奥扎莫德晶型CS9的溶解性研究：
将制备得到的奥扎莫德晶型CS9样品用纯水配制成饱和溶液，在1个小时，4个小时和24个小时后通过高效液相色谱法测定饱和溶液中样品的含量。本发明奥扎莫德晶型CS9的溶解度数据如表10所示。
表10
Figure PCTCN2017098125-appb-000008
结果表明，本发明提供的奥扎莫德晶型CS9在H2O中有良好的溶解度。
实施例12
粒径分布和形态研究实验：
取本发明的奥扎莫德晶型CS9、CS10和CS11测试粒径分布，结果如表11所示。
表11
晶型 MV(μm) SD D10(μm) D50(μm) D90(μm)
晶型CS9 339.9 267.1 50.97 284.3 728.7
晶型CS10 317.2 228.7 65.87 254.8 669.0
晶型CS11 137.7 104.4 27.13 110.4 286.6
本发明中所用到的缩写的解释如下：
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CS9的PSD图和PLM图分别如图17和18所示，PSD图表明晶型CS9体积平均粒径为339.9μm，且粒径分布较窄，几乎呈现一个正态分布，粒径分布均匀，从PLM图中可以看出晶型CS9呈颗粒状，且分散性较好。
晶型CS10的PSD图和PLM图分别如图19和20所示，晶型CS10体积平均粒径为317.2μm，且粒径分布较窄，几乎呈现一个正态分布，粒径分布均匀，从PLM图中可以看出晶型CS10呈颗粒状，且分散性较好。
晶型CS11的PSD图和PLM图分别如图21和22所示，晶型CS11体积平均粒径为137.7μm，且粒径分布较窄，几乎呈现一个正态分布，粒径分布均匀，从PLM图中可以看出晶型CS11呈颗粒状，且分散性较好。
实施例13
奥扎莫德晶型CS10的稳定性试验研究：
取奥扎莫德晶型CS10样品置于40℃/75％RH的恒温恒湿箱中敞口放置两周，然后取样测XRPD。结果如图23(从上至下依次为晶型CS10参比XRPD图，放置于40℃/75％RH条件下两周的XRPD图)。可以看出，晶型CS10在40℃/75％RH下放置两周，晶型保持不变。上述试验结果表明，奥扎莫德晶型CS10具有良好的稳定性。
实施例14
奥扎莫德晶型CS11的稳定性试验研究：
取两份奥扎莫德晶型CS11样品分别置于25℃/60％RH和40℃/75％RH的恒温恒湿箱中敞口放置两周，然后取样测XRPD和纯度。结果如图24(从上至下依次为晶型CS11参比XRPD图，放置于25℃/60％RH和40℃/75％RH条件下两周的XRPD图)所示。
奥扎莫德晶型CS11在25℃/60％RH和40℃/75％RH条件下，两周晶型保持不变。上述结果表明，奥扎莫德晶型CS11具有良好的稳定性。
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 (23)

  1. 一种奥扎莫德的晶型CS10，其特征在于，其X射线粉末衍射图在2θ值为5.7°±0.2°、25.0°±0.2°、26.6°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型CS10，其特征在于，其X射线粉末衍射图2θ值为13.4°±0.2°、28.3°±0.2°、16.2°±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CS10，其特征在于，其X射线粉末衍射图在2θ值为8.6°±0.2°、19.3°±0.2°、14.6°±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CS10的制备方法，其特征在于，所述方法包括：将奥扎莫德的无定形形式加入到芳香烃类溶剂或丙酮和水的混合溶剂中室温下搅拌，得到固体即为奥扎莫德晶型CS10。
  5. 根据权利要求4所述的制备方法，其特征在于，所述芳香烃类溶剂包括甲苯；所述丙酮和水的混合体积比介于1:10-10:1。
  6. 根据权利要求5所述的制备方法，其特征在于，所述丙酮和水的混合体积比为1:1。
  7. 一种奥扎莫德的晶型CS11，其特征在于，其X射线粉末衍射图在2θ值为5.7°±0.2°、24.6°±0.2°、25.3°±0.2°处具有特征峰。
  8. 根据权利要求7所述的晶型CS11，其特征在于，其X射线粉末衍射图2θ值为13.4±0.2°、13.9±0.2°、27.0°±0.2°中的一处或两处或三处具有特征峰。
  9. 根据权利要求7所述的晶型CS11，其特征在于，其X射线粉末衍射图在2θ值为16.2°±0.2°、23.3°±0.2°、26.1°±0.2°、8.6°±0.2°中的一处或多处具有特征峰。
  10. 一种权利要求7所述的晶型CS11的制备方法，其特征在于，所述方法包括：将奥扎莫德的无定形形式加入到醇类、腈类、酮类、烷烃类单一溶剂中，或醇类或酮类和烷烃类或卤代烃和酯类的混合溶剂中，在室温下搅拌、分离，得到固体即为奥扎莫德晶型CS11。
  11. 根据权利要求10所述的制备方法，其特征在于，所述醇类包括甲醇、异丙醇；所述腈类包括乙腈；所述酮类包括丙酮；所述烷烃类包括庚烷；所述卤代烃类包括氯仿；所述酯类包括醋酸异丙酯；所述混合溶剂包括甲醇和异丙醇，丙酮和庚烷，氯仿和醋酸异丙酯的混合溶剂。
  12. 根据权利要求11所述的制备方法，其特征在于，所述混合溶剂中甲醇和异丙醇的体积比为1:3，丙酮和庚烷的体积比为1:1，氯仿和醋酸异丙酯的体积比为1:2。
  13. 根据权利要求4或10所述的无定形，其特征在于，所述无定形的制备方法包括：将奥扎莫德的固体置于150℃条件下加热，使固体熔融，迅速将其置于-20℃条件下冷却，得到奥扎莫德的无定形。
  14. 一种奥扎莫德的晶型CS9，其特征在于，其X射线粉末衍射图在2θ值为11.5°±0.2°、4.3°±0.2°、24.4°±0.2°处具有特征峰。
  15. 根据权利要求14所述的晶型CS9，其特征在于，其X射线粉末衍射图在2θ值为10.5°±0.2°、25.9°±0.2°、16.6°±0.2°中的一处或两处或三处具有特征峰。
  16. 根据权利要求14所述的晶型CS9，其特征在于，其X射线粉末衍射图在2θ值为11.0°±0.2°、18.8°±0.2°、23.2°±0.2°中的一处或两处或三处具有特征峰。
  17. 一种权利要求14中所述的晶型CS9的制备方法，其特征在于，所述方法包含：将奥扎莫德游离形式的固体置于环醚类溶剂和芳香烃类溶剂的混合溶剂中，加热使固体溶解后，加入高聚物，迅速转移至低温下冷却，得到白色固体，所得固体为奥扎莫德晶型CS9。
  18. 根据权利要求17所述的制备方法，其特征在于，所述环醚类溶剂和芳香烃类溶剂的混合溶剂为1,4-二氧六环和甲苯的混合溶剂，体积比介于1:10-10:1；所述加热温度是40℃-80℃；所述冷却的温度是-20℃-4℃。
  19. 根据权利要求18所述的制备方法，其特征在于，所述1,4-二氧六环和甲苯的体积比为1:1；所述加热温度是50℃；所述冷却的温度是-20℃。
  20. 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CS10或权利要求7所述的晶型CS11或权利要求14所述的晶型CS9或它们混合，及药学上可接受的载体、稀释剂或赋形剂。
  21. 权利要求1所述的晶型CS10或权利要求7所述的晶型CS11或权利要求14所述的晶型CS9或它们的任意混合，在生产用于选择性鞘氨醇1磷酸受体调节剂的药物中的用途。
  22. 权利要求1所述的晶型CS10或权利要求7所述的晶型CS11或权利要求14所述的晶型CS9或它们的任意混合，在生产用于制备治疗溃疡性结肠炎药物中的用途。
  23. 权利要求1所述的晶型CS10或权利要求7所述的晶型CS11或权利要求14所述的晶型CS9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的用途。
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