WO2017202351A1 - 一种钠-葡萄糖协同转运蛋白抑制剂药物的新晶型及其制备方法和用途 - Google Patents

一种钠-葡萄糖协同转运蛋白抑制剂药物的新晶型及其制备方法和用途 Download PDF

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WO2017202351A1
WO2017202351A1 PCT/CN2017/085813 CN2017085813W WO2017202351A1 WO 2017202351 A1 WO2017202351 A1 WO 2017202351A1 CN 2017085813 W CN2017085813 W CN 2017085813W WO 2017202351 A1 WO2017202351 A1 WO 2017202351A1
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sotagliflozin
ray powder
powder diffraction
solid
characteristic peaks
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PCT/CN2017/085813
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English (en)
French (fr)
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陈敏华
张炎锋
邹坡
刘凯
张晓宇
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苏州科睿思制药有限公司
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Application filed by 苏州科睿思制药有限公司 filed Critical 苏州科睿思制药有限公司
Priority to JP2019514170A priority Critical patent/JP6727419B2/ja
Priority to US16/304,280 priority patent/US10626135B2/en
Priority to EP17802197.8A priority patent/EP3466958B1/en
Priority to CN201780029501.4A priority patent/CN109195980B/zh
Publication of WO2017202351A1 publication Critical patent/WO2017202351A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/02—Acyclic radicals, not substituted by cyclic structures
    • C07H15/14—Acyclic radicals, not substituted by cyclic structures attached to a sulfur, selenium or tellurium atom of a saccharide radical
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C07H1/06—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of pharmaceutical crystal technology.
  • it relates to a novel crystalline form of a sodium-glucose cotransporter inhibitor drug, a process for its preparation and use.
  • Sotagliflozin is a dual inhibitor of the experimental new oral sodium-glucose cotransporters 1 and 2 (SGLT-1 and SGLT-2) developed by Lexicon, currently in clinical phase III. May become a treatment option for people with diabetes. Sotagliflozin has previously shown encouraging results in exploratory (phase II) studies, including lowering blood glucose, improving glycemic variability, and reducing the dose of insulin during meals compared to placebo in type 1 diabetes. Exploratory phase II studies in patients with type 2 diabetes, including those with kidney damage, have shown that they can lower blood sugar, lose weight and improve blood pressure.
  • Sotagliflozin (2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro- 2H-pyran-3,4,5-triol, the structural formula of which is as shown in formula (I):
  • Patent CN101343296B discloses the synthesis method of Sotagliflozin, but does not describe the crystal form information related to Sotagliflozin.
  • Two uncrystallized 1-shaped crystals and 2-shaped crystals of Sotagliflozin are disclosed in the patent CN102112483A (which is incorporated herein by reference) (the present invention is hereinafter referred to as the existing 1-shaped crystal and the existing 2-shaped crystal, respectively. ).
  • the inventors of the present invention have found that the existing 1-shaped crystals have poor repeatability, and the conventional 2-shaped crystals are easily prepared in comparison with the 1-shaped crystals, whereas the existing 2-shaped crystals are unstable under high water activity.
  • the existing 2-shaped crystals have poor grinding stability, and crystal change is easy to occur in the process of preparing the preparation; the existing 2-shaped crystals also have defects such as wide particle size distribution and uneven particle size distribution, which are disadvantageous to drugs. Post-processing of the development process.
  • New crystalline forms of pharmaceutically active ingredients broaden the formulation of the raw materials that may be used in the formulation and may result in more processing advantages or substances with better physicochemical properties, among which Processing advantages such as easy processing, easy purification or as an intermediate crystal form to promote conversion to other crystal forms, etc., better physical and chemical properties such as better bioavailability, storage stability and so on.
  • Processing advantages such as easy processing, easy purification or as an intermediate crystal form to promote conversion to other crystal forms, etc., better physical and chemical properties such as better bioavailability, storage stability and so on.
  • the new crystalline form can also help improve the performance of the drug.
  • the main object of the present invention is to provide a novel crystalline form of Sotagliflozin which is stable, and a preparation method and use thereof.
  • the present invention provides various novel crystal forms of Sotagliflozin, which are named as Form I, Form II, Form III, Form V, Form VI, Form VII, and Form VIII, respectively.
  • the first solution adopted by the present invention is to provide crystal form I of Sotagliflozin using Cu-K ⁇ radiation, and the X-ray powder diffraction pattern of the crystal form I is 3.6° ⁇ 0.2°, 12.7 at a diffraction angle 2 ⁇ . There are characteristic peaks at ° ⁇ 0.2° and 14.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form I of the present invention is also preferably at a diffraction angle 2 ⁇ of 15.6° ⁇ 0.2°, 17.1° ⁇ 0.2°, 18.7° ⁇ 0.2°, 9.0° ⁇ 0.2°, 21.0.
  • a diffraction angle 2 ⁇ 15.6° ⁇ 0.2°, 17.1° ⁇ 0.2°, 18.7° ⁇ 0.2°, 9.0° ⁇ 0.2°, 21.0.
  • ° ⁇ 0.2° and 25.7° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction pattern of Form I is also at one or two or three of the diffraction angles 2 ⁇ of 15.6° ⁇ 0.2°, 17.1° ⁇ 0.2° and 18.7° ⁇ 0.2°. There are characteristic peaks. More preferably, the X-ray powder diffraction pattern of Form I of the present invention has characteristic peaks at diffraction angles 2 ⁇ of 15.6° ⁇ 0.2°, 17.1° ⁇ 0.2°, and 18.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form I of the present invention is also one or both of diffraction angle 2 ⁇ of 9.0° ⁇ 0.2°, 21.0° ⁇ 0.2°, and 25.7° ⁇ 0.2°. There are characteristic peaks at or at three locations. More preferably, the X-ray powder diffraction pattern of Form I of the present invention has characteristic peaks at diffraction angles 2 ⁇ of 9.0° ⁇ 0.2°, 21.0° ⁇ 0.2°, and 25.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form I is 3.6° ⁇ 0.2°, 9.0° ⁇ 0.2°, 12.7° ⁇ 0.2°, 14.1° ⁇ 0.2° at diffraction angles 2 ⁇ . Characteristic peaks at 15.6 ° ⁇ 0.2 °, 17.1 ° ⁇ 0.2 °, 18.7 ° ⁇ 0.2 °, 21.0 ° ⁇ 0.2 ° and 25.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I is 3.6 ° ⁇ 0.2 °, 9.0 ° ⁇ 0.2 °, 12.7 ° ⁇ 0.2 °, 14.1 ° ⁇ 0.2 at diffraction angles 2 ⁇ . Characteristic peaks at °, 15.6 ° ⁇ 0.2 °, 17.1 ° ⁇ 0.2 °, 18.7 ° ⁇ 0.2 °, 21.0 ° ⁇ 0.2 °, and 25.7 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I of the present invention is substantially as shown in FIG.
  • Form I of the present invention is a hydrate.
  • the Form I of the present invention begins to dehydrate when heated to around 69 ° C, the DSC of which is shown in FIG.
  • Form I of the present invention when thermogravimetric analysis (TGA) is performed, Form I of the present invention has a mass loss gradient of about 3.3% when heated to 115 ° C, the TGA of which is shown in FIG.
  • the present invention still further provides a process for the preparation of Form I, which is selected from the group consisting of:
  • Method 1 Sotgliflozin solid is dissolved in an alcohol, ketone or cyclic ether solvent to obtain Sotagliflozin solution, water is slowly added dropwise to the solution or the solution is added dropwise to water, and a solid is precipitated, and stirred at room temperature for 1 to 72 hours. Filter drying to obtain a white solid, which is the crystalline form I of the present invention.
  • Method 2 Sotagliflozin solid was added to water, and a suspension was prepared, suspended and stirred at room temperature for 5 to 15 days, and dried by filtration to obtain Form I of the present invention.
  • the alcohol, ketone, and cyclic ether solvents in Process 1 are each preferably methanol, acetone, or tetrahydrofuran.
  • the stirring time in Process 1 is preferably from 6 to 72 hours, more preferably from 12 to 72 hours, and specifically, for example, about 24 hours.
  • the stirring time in the method 2 is preferably from 6 to 15 days, more preferably from 7 to 12 days, still more preferably 8 days.
  • the second solution adopted by the present invention is to provide Form II of Sotagliflozin, using Cu-K ⁇ radiation, the X-ray powder diffraction pattern of the Form II is 3.7° ⁇ 0.2°, 4.5° ⁇ 0.2° at the diffraction angle 2 ⁇ and There are characteristic peaks at 14.6 ° ⁇ 0.2 °.
  • the crystal form II of the present invention is also preferably at a diffraction angle 2 ⁇ of 13.4° ⁇ 0.2°, 18.1° ⁇ 0.2°, 6.2° ⁇ 0.2°, 22.0° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 15.9. There are characteristic peaks at one or more of ° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II is also in one or two or three of the diffraction angles 2 ⁇ of 13.4° ⁇ 0.2°, 18.1° ⁇ 0.2° and 6.2° ⁇ 0.2°. There are characteristic peaks. More preferably, the X-ray powder diffraction pattern of Form II has characteristic peaks at diffraction angles 2 ⁇ of 13.4° ⁇ 0.2°, 18.1° ⁇ 0.2°, and 6.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II is at one or two or three points in the diffraction angle 2 ⁇ of 22.0° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 15.9° ⁇ 0.2°. There are characteristic peaks. More preferably, the X-ray powder diffraction pattern of Form II of the present invention has characteristic peaks at diffraction angles 2 ⁇ of 22.0° ⁇ 0.2°, 10.6° ⁇ 0.2°, and 15.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II is 3.7° ⁇ 0.2°, 4.5° ⁇ 0.2°, 6.2° ⁇ 0.2°, 10.6° ⁇ 0.2° at the diffraction angle 2 ⁇ , There are characteristic peaks at 13.4 ° ⁇ 0.2 °, 14.6 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 ° and 22.0 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form II of the present invention is substantially as shown in FIG.
  • Form II of the invention is a hydrate.
  • the Form II of the present invention begins to dehydrate when heated to around 62 ° C, the DSC of which is shown in FIG.
  • Form II of the present invention when thermogravimetric analysis (TGA) is performed, Form II of the present invention has a mass loss gradient of about 5.7% when heated to 112 ° C, the TGA of which is shown in FIG.
  • the present invention still further provides a process for the preparation of Form II of the present invention, which is selected from the group consisting of:
  • Method 1 Sotgliflozin solid is dissolved in an alkyl nitrile solvent to obtain Sotagliflozin solution, water is slowly added dropwise to the solution or the solution is added dropwise to water, and a solid is precipitated, stirred at room temperature for 1 to 72 hours, and dried by filtration to obtain a white solid.
  • Sotagliflozin solution water is slowly added dropwise to the solution or the solution is added dropwise to water, and a solid is precipitated, stirred at room temperature for 1 to 72 hours, and dried by filtration to obtain a white solid.
  • Method 2 Soapliflozin solid is dissolved in a cyclic ether solvent or an ester solvent to obtain a Sotagliflozin solution, and n-heptane is slowly added dropwise to the solution or the solution is added dropwise to n-heptane, and a solid is precipitated, and stirred at room temperature. ⁇ 72 hours, filtration and drying to obtain a white solid, which is the crystalline form II of the present invention.
  • Method 3 Soapliflozin solid is dissolved in a ketone solvent to obtain a Sotagliflozin solution, toluene is slowly added dropwise to the solution or the solution is added dropwise to toluene, and a solid is precipitated, stirred at room temperature for 1 to 72 hours, and dried by filtration to obtain a white solid.
  • a solid is precipitated, stirred at room temperature for 1 to 72 hours, and dried by filtration to obtain a white solid.
  • Method 4 adding Sotagliflozin solid (preferably existing 2-shaped crystal) to a mixed solvent of a ketone solvent and water or a mixed solvent of an alkyl nitrile solvent and water, and suspending and stirring at a temperature of 50 to 75 ° C for 5 to 20 Days, filtration and drying gave the crystalline form II of the present invention.
  • Sotagliflozin solid preferably existing 2-shaped crystal
  • the alkyl nitrile solvent described in the method 1 is preferably acetonitrile; the stirring time described in the method 1 is preferably 6 to 72 hours, more preferably 6 to 36 hours, further preferably 12 to 36 hours, still more preferably 24 to 30 hours. ;
  • the cyclic ether solvent and the ester solvent described in the method 2 are preferably tetrahydrofuran and ethyl acetate, respectively; and the stirring time described in the method 2 is preferably 6 to 72 hours, more preferably 6 to 36 hours, still more preferably 12 to 36 hours. , further preferably 24 to 30 hours;
  • the ketone solvent described in the method 3 is preferably acetone;
  • the stirring time described in the method 3 is preferably 6 to 72 hours, more preferably 6 to 36 hours, further preferably 12 to 36 hours, still more preferably 24 to 30 hours;
  • the mixed solvent of the ketone solvent and water described in the method 4 is preferably a mixed solvent of acetone and water, and the volume ratio of the two may be 1/2 to 1/10, preferably 1/3 to 1/8, more preferably 1/4 to 1/6;
  • the mixed solvent of the alkyl nitrile solvent and water is a mixed solvent of acetonitrile and water, and the volume of the two may be 1/2 to 1/10, preferably 1/3 to 1/8, more preferably 1/4 to 1/6;
  • the stirring time in Process 4 is preferably from 8 to 18 days, more preferably from 10 to 15 days, specifically, for example, 14 days.
  • a third solution adopted by the present invention is to provide Form III of Sotagliflozin using Cu-K ⁇ radiation, and the X-ray powder diffraction of the Form III is 4.3° ⁇ 0.2°, 14.6° ⁇ 0.2° at a diffraction angle 2 ⁇ and There are characteristic peaks at 19.6 ° ⁇ 0.2 °.
  • the crystal form III of the present invention is also preferably at a diffraction angle 2 ⁇ of 4.9° ⁇ 0.2°, 15.3° ⁇ 0.2°, 17.5° ⁇ 0.2°, 12.8° ⁇ 0.2°, 25.0° ⁇ 0.2°, and 26.4. There are characteristic peaks at one or more of ° ⁇ 0.2°.
  • the X-ray powder diffraction of Form III has one or two or three places in the diffraction angle 2 ⁇ of 4.9° ⁇ 0.2°, 15.3° ⁇ 0.2°, and 17.5° ⁇ 0.2°. Characteristic peaks; more preferably, the X-ray powder diffraction pattern of Form III has characteristic peaks at diffraction angles 2 ⁇ of 4.9° ⁇ 0.2°, 15.3° ⁇ 0.2°, and 17.5° ⁇ 0.2°.
  • the X-ray powder diffraction of Form III is at one or two or three points in the diffraction angle 2 ⁇ of 12.8° ⁇ 0.2°, 25.0° ⁇ 0.2°, and 26.4° ⁇ 0.2°. There are characteristic peaks; more preferably, the X-ray powder diffraction pattern of Form III has characteristic peaks at diffraction angles 2 ⁇ of 12.8° ⁇ 0.2°, 25.0° ⁇ 0.2°, and 26.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form III of the present invention is 4.3° ⁇ 0.2°, 4.9° ⁇ 0.2°, 12.8° ⁇ 0.2°, 14.6° ⁇ 0.2°, 15.3 at diffraction angles 2 ⁇ . Characteristic peaks are found at ° ⁇ 0.2°, 17.5° ⁇ 0.2°, 25.0° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 26.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form III of the present invention is substantially as shown in FIG.
  • Form III of the present invention is an anhydride.
  • Form III begins to melt as it is heated to around 131 °C, and its DSC is as shown in FIG.
  • TGA thermogravimetric analysis
  • the present invention still further provides a method for producing the crystalline form III of the present invention, which is selected from the group consisting of:
  • the halogenated alkane described in Process 1 may and preferably is chloroform; the halogenated alkane and alkane described in Process 2 may and preferably are, respectively, chloroform and n-heptane, halogenated alkanes and alkanes.
  • the volume ratio may be from 1/1 to 10/1, more preferably from 3/1 to 6/1, specifically, for example, 4/1.
  • the fourth scheme adopted by the present invention is to provide a crystalline form V of Sotagliflozin using Cu-K ⁇ radiation, and the X-ray powder diffraction of the crystalline form V is 5.4° ⁇ 0.2°, 9.9° ⁇ 0.2° at a diffraction angle 2 ⁇ and There are characteristic peaks at 19.7 ° ⁇ 0.2 °.
  • the crystal form V of the present invention is also preferably at a diffraction angle 2 ⁇ of 12.8° ⁇ 0.2°, 13.6° ⁇ 0.2°, 15.1° ⁇ 0.2°, 6.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, and 20.4. There are characteristic peaks at one or more of ° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form V is at one or two or three of diffraction angles 2 ⁇ of 12.8° ⁇ 0.2°, 13.6° ⁇ 0.2°, and 15.1° ⁇ 0.2°. Characteristic peaks are present; preferably, the X-ray powder diffraction pattern of the Form V has characteristic peaks at diffraction angles 2 ⁇ of 12.8° ⁇ 0.2°, 13.6° ⁇ 0.2°, and 15.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form V is at one or two of diffraction angles 2 ⁇ of 6.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, and 20.4° ⁇ 0.2° or There are characteristic peaks at three places; preferably, the X-ray powder diffraction pattern of the Form V has characteristic peaks at diffraction angles 2 ⁇ of 6.5° ⁇ 0.2°, 18.2° ⁇ 0.2°, and 20.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form V of the present invention is 5.4° ⁇ 0.2°, 6.5° ⁇ 0.2°, 9.9° ⁇ 0.2°, 12.8° ⁇ 0.2°, 13.6 at the diffraction angle 2 ⁇ . Characteristic peaks are found at ° ⁇ 0.2°, 15.1° ⁇ 0.2°, 18.2° ⁇ 0.2°, 19.7° ⁇ 0.2°, and 20.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form V of the present invention is substantially as shown in FIG.
  • Form V of the present invention is a hydrate.
  • the crystalline form V of the present invention begins to dehydrate when heated to around 30 ° C, and its DSC is as shown in FIG.
  • thermogravimetric analysis TGA
  • the crystalline form V of the present invention has a mass loss gradient of about 12.7% when heated to 115 ° C, the TGA of which is shown in FIG.
  • the present invention still further provides a method for preparing the crystal form V of the present invention, which comprises: at a heating temperature of 40 to 70 ° C, The Sotagliflozin solid is dissolved in a mixed solvent of an alcohol solvent and water to form a clear solution, and the resulting clear solution is transferred to a cooling environment at a temperature of 0 to 10 ° C, stirred for 12 to 96 hours, and dried by filtration to give a white solid.
  • the heating temperature is preferably 50 to 60 ° C; the temperature of the cooling environment is preferably about 5 ° C; the alcohol solvent is preferably methanol, and the volume ratio of the alcohol solvent (methanol) to water may be 2/1 to 2/3, more preferably 1/1; in a cooling environment, the stirring time is preferably 36 to 96 hours, more preferably 48 to 96 hours, and most preferably 72 to 84 hours.
  • the fifth solution adopted by the present invention is to provide a crystalline form VI of Sotagliflozin using Cu-K ⁇ radiation, and the X-ray powder diffraction of the crystalline form VI is 4.8° ⁇ 0.2°, 9.5° ⁇ 0.2° at a diffraction angle 2 ⁇ and There are characteristic peaks at 14.5 ° ⁇ 0.2 °.
  • the crystal form VI of the present invention is also preferably at a diffraction angle 2 ⁇ of 11.1° ⁇ 0.2°, 19.1° ⁇ 0.2°, 21.5° ⁇ 0.2°, 7.7° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 25.4. There are characteristic peaks at one or more of ° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form VI has one or two or three places in the diffraction angle 2 ⁇ of 11.1° ⁇ 0.2°, 19.1° ⁇ 0.2°, and 21.5° ⁇ 0.2°. Characteristic peaks; more preferably, the X-ray powder diffraction pattern of Form VI of the present invention has characteristic peaks at diffraction angles 2 ⁇ of 11.1° ⁇ 0.2°, 19.1° ⁇ 0.2°, and 21.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form VI is at one or two of diffraction angles 2 ⁇ of 7.7° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 25.4° ⁇ 0.2° or There are characteristic peaks at three places; more preferably, the X-ray powder diffraction pattern of Form VI of the present invention has characteristic peaks at diffraction angles 2 ⁇ of 7.7° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 25.4° ⁇ 0.2°.
  • the X-ray powder diffraction of Form VI of the present invention is 4.8 ° ⁇ 0.2 °, 7.7 ° ⁇ 0.2 °, 9.5 ° ⁇ 0.2 °, 11.1 ° ⁇ 0.2 °, 14.5 at diffraction angle 2 ⁇ . Characteristic peaks are found at ° ⁇ 0.2°, 19.1° ⁇ 0.2°, 20.0° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 25.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form VI of the present invention is substantially as shown in FIG.
  • Form VI of the present invention is a hydrate.
  • the Form VI of the present invention begins to dehydrate when heated to around 80 ° C, and its DSC is as shown in FIG.
  • the Form VI of the present invention when thermogravimetric analysis (TGA) is performed, has a mass loss gradient of about 3.6% when heated to 116 ° C, the TGA of which is shown in FIG.
  • the present invention still further provides a method for preparing the crystalline form VI of the present invention, which comprises: placing the Sotagliflozin solid in water, suspending and stirring at a temperature of 35 to 65 ° C for 24 to 96 hours, and filtering and drying to obtain a crystal form VI.
  • the temperature at the time of suspension stirring is preferably 45 to 55 ° C, and more preferably about 50 ° C.
  • the suspension stirring time is preferably from 36 to 84 hours, more preferably from 48 to 84 hours, and most preferably about 72 hours.
  • the sixth scheme adopted by the present invention is to provide Form VII of Sotagliflozin using Cu-K ⁇ radiation, and the X-ray powder diffraction pattern of the Form VII is 10.5° ⁇ 0.2°, 13.8° ⁇ 0.2° at the diffraction angle 2 ⁇ and There are characteristic peaks at 15.8 ° ⁇ 0.2 °.
  • the crystalline form VII of the present invention is also preferably at a diffraction angle 2 ⁇ of 16.7° ⁇ 0.2°, 20.3° ⁇ 0.2°, 22.6° ⁇ 0.2°, 6.7° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 19.1. There are characteristic peaks at one or more of ° ⁇ 0.2°.
  • the X-ray powder diffraction of Form VII is at one or two or three of the diffraction angles 2 ⁇ of 16.7° ⁇ 0.2°, 20.3° ⁇ 0.2°, and 22.6° ⁇ 0.2°. Characteristic peaks; more preferably, the X-ray powder diffraction pattern of Form VII has characteristic peaks at diffraction angles 2 ⁇ of 16.7° ⁇ 0.2°, 20.3° ⁇ 0.2°, and 22.6° ⁇ 0.2°.
  • the X-ray powder diffraction of Form VII is at one or two or three points in the diffraction angle 2 ⁇ of 6.7° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 19.1° ⁇ 0.2°. There are characteristic peaks; more preferably, the X-ray powder diffraction pattern of Form VII has characteristic peaks at diffraction angles 2 ⁇ of 6.7° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 19.1° ⁇ 0.2°.
  • the X-ray powder diffraction of Form VII of the present invention is 6.7 ° ⁇ 0.2 °, 10.5 ° ⁇ 0.2 °, 13.8 ° ⁇ 0.2 °, 15.8 ° ⁇ 0.2 °, 16.7 at diffraction angles 2 ⁇ . Characteristic peaks were found at ° ⁇ 0.2°, 18.5° ⁇ 0.2°, 19.1° ⁇ 0.2°, 20.3° ⁇ 0.2°, and 22.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form VII of the present invention is substantially as shown in FIG.
  • Form VII of the present invention begins to melt as it is heated to around 120 ° C, the DSC of which is shown in FIG.
  • Form VII of the present invention when subjected to thermogravimetric analysis (TGA), Form VII of the present invention has a mass loss gradient of about 1.9% when heated to 114 ° C, the TGA of which is shown in FIG.
  • the present invention still further provides a method for preparing the crystalline form VII of the present invention, which comprises: heating the Sotagliflozin crystal form II of the present invention to a temperature of 5 to 10 ° C / min to a temperature of 90 to 100 ° C, and retaining at 90 ° C to 100 ° C 0.5 to 5 minutes gave a white solid.
  • the Form II of the present invention is heated to 90 ° C at a temperature increase rate of 10 ° C / min, and left at 90 ° C for 0.5 min to give a white solid, which gives the Form VII of the present invention.
  • the seventh solution adopted by the present invention is to provide Form VIII of Sotaglflozin, using Cu-K ⁇ radiation, the crystal form
  • the X-ray powder diffraction of VIII has characteristic peaks at diffraction angles 2 ⁇ of 6.2° ⁇ 0.2°, 10.9° ⁇ 0.2°, and 17.7° ⁇ 0.2°.
  • the crystalline form VIII of the present invention is also preferably at a diffraction angle 2 ⁇ of 6.2° ⁇ 0.2°, 10.4° ⁇ 0.2°, 10.9° ⁇ 0.2°, 14.9° ⁇ 0.2°, 15.7° ⁇ 0.2°, 17.7.
  • the X-ray powder diffraction of Form VIII is also at one or two or three of the diffraction angles 2 ⁇ of 14.9° ⁇ 0.2°, 15.7° ⁇ 0.2° and 20.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form VIII of the present invention has characteristic peaks at diffraction angles 2 ⁇ of 14.9° ⁇ 0.2°, 15.7° ⁇ 0.2°, and 20.9° ⁇ 0.2°.
  • the X-ray powder diffraction of Form VIII of the present invention is at one or two of diffraction angles 2 ⁇ of 10.4° ⁇ 0.2°, 18.8° ⁇ 0.2°, 24.1° ⁇ 0.2°. Or three have characteristic peaks; more preferably, the X-ray powder diffraction pattern of Form VIII of the present invention has characteristic peaks at diffraction angles 2 ⁇ of 10.4° ⁇ 0.2°, 18.8° ⁇ 0.2°, and 24.1° ⁇ 0.2°.
  • the X-ray powder diffraction of Form VIII of the present invention is 6.2 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 10.9 ° ⁇ 0.2 °, 14.9 ° ⁇ 0.2 °, 15.7 at diffraction angles 2 ⁇ . Characteristic peaks are found at ° ⁇ 0.2°, 17.7° ⁇ 0.2°, 18.8° ⁇ 0.2°, 20.9° ⁇ 0.2°, and 24.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form VIII of the present invention is substantially as shown in FIG.
  • Form VIII begins to desolvate upon heating to around 91 ° C, the DSC of which is shown in FIG.
  • the present invention still further provides a method for producing the crystalline form VIII of the present invention, which comprises heating the solid of the crystalline form V of the present invention to a temperature of 60 to 80 ° C for 2 minutes or longer, and the obtained solid is the crystalline form of the present invention.
  • the preferred heating rate is 10 ° C / min; preferably heated to about 65 ° C.
  • the crystalline form I, crystalline form II, crystalline form III, crystalline form V, crystalline form VI, crystalline form VII and crystalline form VIII of Sotagliflozin of the present invention have the following beneficial properties:
  • Form I and Form II Compared with the existing 2-shaped crystals, the advantages of Form I and Form II include that it is more stable in high water activity environments; Form I and Form VI are better than existing 2-shaped crystals.
  • the mechanical stability is more suitable for medicine and storage; the existing 2-shaped crystal has a wide particle size distribution, agglomeration phenomenon, and is fine needle-like, and the crystal size I, crystal form V, crystal form VII, and form VIII have uniform particle size distribution. It helps to simplify the post-treatment process of the preparation process and improve the quality control; Form II, Form III, Form VII, and Form VIII have higher solubility than the existing 2-shaped crystals, which is beneficial to drug absorption.
  • the present invention solves the problems of prior art crystal forms by providing Sotagliflozin new Form I, Form II, Form III, Form V, Form VI, Form VII, Form VIII.
  • These new crystal forms have at least one selected from the following Advantages: high solubility, simple preparation and low toxicity, good crystallinity, good particle morphology, low moisture absorption, better fluidity and better stability.
  • crystal or “crystal form” refers to the characterization by the X-ray diffraction pattern shown.
  • Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized, with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • the X-ray diffraction pattern will generally vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the X-ray diffraction pattern of one crystal form in the present invention need not be identical to the X-ray diffraction pattern in the examples referred to herein. Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • Crystal form and “polymorph” and other related terms are used in the present invention to mean that a solid compound exists in a specific crystalline state in a crystal structure.
  • the difference in physical and chemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate and the like.
  • phrases "effective therapeutic amount” or “therapeutically effective amount” as used in the present invention refers to a biological response or drug that is caused by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. The amount of active compound or agent that is reacted.
  • the novel crystalline form of Sotagliflozin of the present invention including Form I, Form II, Form III, Form V, Form VI, Form VII, Form VIII are pure, single, Basically, no other crystal forms are mixed.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • Form I, Form II, Form III, Form V, Form VI, Form VII or Form VIII of Sotagliflozin provided by the present invention have advantageous properties suitable for the above dosage forms.
  • the present invention provides that one or more of Form I, Form II, Form III, Form V, Form VI, Form VII or Form VIII of Sotagliflozin have a suppression of SGLT, especially inhibition.
  • the drugs that act on SGLT-2 use.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Form I, Form II, Form III, Form V, Form VI, Form VII, Form VIII or the like of Sotagliflozin of the present invention.
  • the pharmaceutical composition is for preventing and/or treating diabetes.
  • the pharmaceutical composition can be prepared by methods well known in the art and will not be described herein.
  • Example 1 is an X-ray powder diffraction pattern of Form I in Example 1;
  • Figure 5 is an X-ray powder diffraction pattern of Form II in Example 7;
  • Example 6 is a differential scanning calorimetry diagram of Form II in Example 7.
  • Figure 7 is a thermogravimetric analysis diagram of Form II in Example 7.
  • Figure 8 is a liquid nuclear magnetic resonance spectrum of Form II in Example 7.
  • Figure 9 is an X-ray powder diffraction pattern of Form III in Example 13;
  • Figure 10 is a differential scanning calorimetry diagram of Form III in Example 13;
  • Figure 11 is a thermogravimetric analysis diagram of Form III in Example 13;
  • Figure 12 is a liquid nuclear magnetic resonance spectrum of Form III in Example 13;
  • Figure 13 is an X-ray powder diffraction pattern of Form V in Example 15;
  • Figure 14 is a differential scanning calorimetry diagram of Form V in Example 15;
  • Figure 15 is a thermogravimetric analysis diagram of Form V in Example 15;
  • Figure 16 is a liquid nuclear magnetic hydrogen spectrum diagram of Form V in Example 15;
  • Figure 17 is an X-ray powder diffraction pattern of Form VI in Example 17;
  • Figure 18 is a differential scanning calorimetry diagram of Form VI in Example 17;
  • Figure 19 is a thermogravimetric analysis diagram of Form VI in Example 17;
  • Figure 20 is a liquid nuclear magnetic resonance spectrum of Form VI in Example 17;
  • Figure 21 is an X-ray powder diffraction pattern of Form VII in Example 19;
  • Figure 22 is a differential scanning calorimetry diagram of Form VII in Example 19;
  • Figure 23 is a thermogravimetric analysis diagram of Form VII in Example 19;
  • Figure 24 is a graph showing the liquid nuclear magnetic hydrogen spectrum of Form VII in Example 19;
  • Figure 25 is an X-ray powder diffraction pattern of Form VIII in Example 20;
  • Figure 26 is a differential scanning calorimetry diagram of Form VIII in Example 20;
  • Figure 27 is an X-ray powder diffraction pattern of Form I in Example 2.
  • Figure 28 is an X-ray powder diffraction pattern of Form I in Example 3.
  • Figure 29 is an X-ray powder diffraction pattern of Form I in Example 4.
  • Figure 30 is an X-ray powder diffraction pattern of Form I in Example 5.
  • Figure 31 is an X-ray powder diffraction pattern of Form I in Example 6;
  • Figure 32 is an X-ray powder diffraction pattern of Form II in Example 8.
  • Figure 33 is an X-ray powder diffraction pattern of Form II in Example 9;
  • Figure 34 is an X-ray powder diffraction pattern of Form II in Example 10.
  • Figure 35 is an X-ray powder diffraction pattern of Form II in Example 11.
  • Figure 36 is an X-ray powder diffraction pattern of Form II in Example 12;
  • Figure 37 is an X-ray powder diffraction pattern of Form III in Example 14.
  • Figure 38 is an X-ray powder diffraction pattern of Form V in Example 16.
  • Figure 39 is an X-ray powder diffraction pattern of Form VI in Example 18.
  • Figure 40 is a DVS diagram of Form I in Example 22;
  • Figure 41 is a DVS diagram of Form II in Example 23;
  • Figure 42 is a DVS diagram of Form III in Example 24;
  • Figure 43 is a DVS diagram of Form VI in Example 25;
  • Figure 44 is a comparison chart of XRPD of the Form I of the present invention placed at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity for 3 months;
  • Figure 45 is a comparison chart of XRPD of the Form II of the present invention placed at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity for 3 months;
  • Figure 46 is a comparison chart of XRPD of the Form III of the present invention placed at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity for 3 months;
  • Figure 47 is a comparison chart of XRPD of the Form VI of the present invention placed at 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity for 3 months;
  • Figure 48 is a polarizing microscope diagram of a conventional 2-shaped crystal
  • Figure 49 is a polarizing microscope diagram of Form I of the present invention.
  • Figure 50 is a PSD diagram of a conventional 2-shaped crystal
  • Figure 51 is a PSD diagram of Form I of the present invention.
  • Figure 52 is a PSD diagram of a crystal form V of the present invention.
  • Figure 53 is a comparison diagram of XRPD before and after grinding of a conventional 2-shaped crystal
  • Figure 54 is a comparison diagram of XRPD before and after grinding of Form I of the present invention.
  • Figure 55 is a comparison diagram of XRPD before and after grinding of the crystal form VI of the present invention.
  • Figure 56 is a polarizing microscope diagram of Form VII of the present invention.
  • Figure 57 is a PSD diagram of Form VIII of the present invention.
  • Figure 58 is a DVS diagram of Form VII in Example 31;
  • Figure 59 is a DVS diagram of Form VIII in Example 32.
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • DVS dynamic moisture adsorption
  • PSD particle size distribution
  • PLM polarized light microscopy
  • 1 H NMR liquid nuclear magnetic hydrogen spectroscopy
  • 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 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
  • DSC Differential thermal analysis
  • Thermogravimetric analysis (TGA) data was taken from the TA Instruments Q5000TGA, the instrument control software was Thermal AdVantage, and the analysis software was Universal Analysis. Usually, 5 to 15 mg of the sample is placed in a platinum crucible, and the sample is raised from room temperature to 300 ° C under the protection of 50 mL/min dry N 2 at a heating rate of 10 ° C/min, while the TA software records the sample during the heating process. The weight changes.
  • the water content of the crystalline form of the present invention is calculated based on the TGA weight loss estimation. As is known to those skilled in the art, TGA weight loss is a reference for the water content of the crystalline form, but does not absolutely represent the number of molecules of the crystalline form.
  • 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:
  • H NMR data (1 HNMR) collected from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide or deuterated chloroform to prepare a solution of 2-10 mg/mL.
  • 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 purity of the present invention is detected by high performance liquid chromatography, and the detection method is as follows:
  • the solubility of the present invention is detected by high performance liquid chromatography, and the detection method is as follows:
  • Sotagliflozin starting material used in the following examples may be obtained by the preparation method of the patent CN101343296B or obtained by a commercially available method, or may be prepared according to the method of the present invention.
  • the solid obtained in this example was tested to be Form I of the present invention.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 1, and the XRPD pattern thereof is shown in Fig. 1.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 2, and the XRPD pattern thereof is shown in Fig. 27.
  • the DSC image is shown in Figure 2
  • the TGA is shown in Figure 3
  • the 1 H NMR is shown in Figure 4.
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 4, and the XRPD pattern thereof is shown in Fig. 29.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 5, and the XRPD pattern thereof is shown in Fig. 30.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 6, and the XRPD pattern thereof is shown in Fig. 31.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 7, and the XRPD pattern thereof is shown in Fig. 5.
  • the DSC image is shown in Fig. 6, the TGA is shown in Fig. 7, and the 1 H NMR is shown in Fig. 8.
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 8, and its XRPD pattern is shown in Fig. 32.
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 9, and its XRPD pattern is shown in Fig. 33.
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 10, and its XRPD pattern is shown in Fig. 34.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 11, and the XRPD pattern thereof is shown in Fig. 35.
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 12, and its XRPD pattern is shown in Fig. 36.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 13, the XRPD pattern thereof is shown in Fig. 9, the DSC image is shown in Fig. 10, the TGA is shown in Fig. 11, and the 1 H NMR is shown in Fig. 12.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 14, and the XRPD pattern thereof is shown in Fig. 37.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 15, the XRPD pattern thereof is shown in Fig. 13, the DSC image is shown in Fig. 14, the TGA is shown in Fig. 15, and the 1 H NMR is shown in Fig. 16.
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 16, and its XRPD pattern is shown in Fig. 38.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 17, the XRPD pattern thereof is shown in Fig. 17, the DSC image is shown in Fig. 18, the TGA is shown in Fig. 19, and the 1 H NMR is shown in Fig. 22.
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 18, and its XRPD pattern is shown in Fig. 39.
  • the X-ray powder diffraction data of the solid obtained in this example are shown in Table 19, the XRPD pattern thereof is shown in Fig. 21, the DSC is shown in Fig. 22, the TGA is shown in Fig. 23, and the 1 H NMR is shown in Fig. 24.
  • the X-ray powder diffraction data of the solid obtained in this example is shown in Table 20, the XRPD pattern thereof is shown in Fig. 25, and the DSC is shown in Fig. 26.
  • the existing 2-shaped crystal disclosed in CN102112483A was mixed with the crystal form I and the crystal form II of the present invention, and added to different water activity systems for stirring. After 70 hours, it was characterized by XRPD, and the results are shown in Table 21. .
  • solvents selected for the different water activities in the present invention include, but are not limited to, H2O and IPA, and the same conclusions as in this experiment can be obtained in other solvents suitable for formulating different water activities.
  • the crystalline form I, the crystalline form II, the crystalline form III, the crystalline form VII of the present invention and the existing 2-shaped crystal are respectively formulated into a saturated solution by using SGF (simulated artificial gastric juice), and the crystalline form II and the crystalline form III of the present invention are obtained.
  • Form VII, Form VIII and existing 2 crystals were prepared into a saturated solution with pH 6.5 FaSSIF (in artificial intestinal juice under fasting conditions), and the saturated solution was determined by high performance liquid chromatography (HPLC) after 1 hour. The content of the sample.
  • the experimental results are shown in Tables 26-27.
  • the test results show that the solubility of Form I, Form III and Form VII of the present invention is significantly higher than that of the existing 2-form crystals in SGF, which is 1.7 times, 2.2 times and 2.5 times higher than the existing 2-shaped crystals, respectively.
  • the solubility of Form III, Form VII and Form VIII of the present invention in FaSSIF is significantly higher than that of the existing 2-shaped crystal, which is 1.4, 1.5 and 1.4 times higher than the existing 2-shaped crystal, respectively.
  • the crystal form I, the crystal form II, the crystal form III, and the form VI of the present invention were each placed under conditions of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 3 months, and XRPD was measured.
  • the XRPD of crystal forms I, II, III, and VI placed under the above two conditions for about 3 months is shown in Fig. 44, Fig. 45, Fig. 46, and Fig. 47, respectively.
  • the experimental results are summarized in Table 28. The results show that the crystal form I, the crystal form II, the crystal form III, and the form VI of the present invention are placed under the conditions of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 3 months. it is good.
  • a polarizing microscope picture was taken from the existing 2-shaped crystal and the crystal form I of the present invention.
  • the polarizing microscope of the conventional 2-shaped crystal is shown in Fig. 48, and the polarizing microscope of the crystal form I of the present invention is shown in Fig. 49.
  • the existing 2-shaped crystal is a fine needle
  • the crystal form I of the present invention is in the form of a rod, 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 polarizing microscope of the crystalline form VII of the present invention is shown in Fig. 56.
  • the crystalline form VII is an irregular massive solid state, and the particle size distribution is uniform, compared with the needle-like morphology of the 2-shaped crystal.
  • the crystal has better fluidity, can significantly improve the filtration efficiency of the drug substance, and contribute to the dispersion of the drug in the preparation process.
  • the crystal form I, the crystal form V, the form VIII of the present invention and the conventional 2-shaped crystal were tested for particle size distribution, and the results are shown in Table 29.
  • the PSD diagram of the existing 2-shaped crystal is shown in FIG. 50
  • the PSD diagram of the crystal form I of the present invention is shown in FIG. 51
  • the PSD diagram of the crystal form V of the present invention is shown in FIG. 52
  • the present invention is shown in FIG.
  • the PSD diagram of Form VIII is shown in Figure 57.
  • the uneven particle size distribution and particle agglomeration have a very adverse effect on the uniformity of the preparation, which in turn affects Dissolution of drugs, absorption of drugs, resulting in uneven absorption or dissolution, different batches have large differences.
  • the crystal form I, the crystal form V and the form VIII of the invention have a narrow particle size distribution and almost single normal distribution, and the uniform particle size distribution helps to ensure the uniformity of the preparation and simplify the pre-treatment process. It has a positive impact on the development of drugs.
  • the crystalline form I, the crystalline form VI, and the existing 2-shaped crystal of the present invention were placed in a mortar and manually ground for 5 minutes to test the solid XRPD.
  • the XRPD comparison chart of the existing 2-shaped crystal, the crystal form I and the crystal form VI of the present invention before and after grinding are respectively shown in FIG. 53 to FIG. 55 (the upper drawing is an XRPD pattern before grinding, and the lower drawing is after grinding for 5 minutes).
  • the XRPD pattern the results are shown in Table 30.

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Abstract

本发明涉及一种钠-葡萄糖协同转运蛋白抑制剂药物（Sotagliflozin）的新晶型及其制备方法和用途，本发明另外涉及包含Sotagliflozin新晶型的药物组合物及使用Sotagliflozin新晶型及医药组合物治疗疾病的方法。本发明提供的晶型具有良好的稳定性、较低的引湿性、工艺可开发和易处理性等有利性能，且制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。

Description

一种钠-葡萄糖协同转运蛋白抑制剂药物的新晶型及其制备方法和用途 技术领域
本发明涉及药物晶体技术领域。具体而言，涉及一种钠-葡萄糖协同转运蛋白抑制剂药物的新晶型及其制备方法和用途。
背景技术
Sotagliflozin是由莱西肯医药公司(Lexicon)研发的一款试验性新型口服钠-葡萄糖协同转运蛋白1和2(SGLT-1和SGLT-2)双重抑制剂，目前处于临床III期，该药物有可能成为糖尿病患者的一种治疗选择。Sotagliflozin先前在探索性(II期)研究中已显示出令人鼓舞的结果，包括降低血糖、改善血糖可变性及用于1型糖尿病时与安慰剂相比可减少餐时胰岛素的剂量。在2型糖尿病患者(包括那些有肾损伤的患者)中进行的探索性II期研究表明其可以降低血糖、减轻体重及改善血压。Sotagliflozin的化学名称为：(2S,3R,4R,5S,6R)-2-(4-氯-3-(4-乙氧基苄基)苯基)-6-(甲基硫)四氢-2H-吡喃-3,4,5-三醇，其结构式如式(I)所示：
Figure PCTCN2017085813-appb-000001
专利CN101343296B公开了Sotagliflozin的合成方法，但并未记载Sotagliflozin相关的晶型信息。专利CN102112483A(其通过引用的方式并入到本申请中)中公开了Sotagliflozin的两个无水晶型1形晶体和2形晶体(本发明以下分别简称为现有1形晶体和现有2形晶体)。本发明的发明人发现，现有1形晶体重复性差，现有2形晶体相比1形晶体易重复制备，然而现有2形晶体在高水活度下并不稳定。同时还发现现有2形晶体的研磨稳定性较差，在制备制剂的过程中容易发生转晶；现有2形晶体还还存在粒径分布宽，粒径分布不均匀等缺陷，不利于药物开发过程的后处理。
药物活性成分新的晶型(包括无水物、水合物、溶剂化物等)扩大了制剂学上可选用的原料形态，并可能会产生更具加工优势或提供具有更好理化特性的物质，其中加工优势比如易加工处理、易提纯或作为中间晶型促进转化为其他晶型等，更好理化特性比如具有更好的生物利用度、储存更稳定等。对某些药学上有用的化合物来说，其新晶型还可以帮助改善药物的性能。
因此，仍有需要开发Sotagliflozin的新的且与现有的晶型例如现有1形晶体和2形晶体相比在某一个或几个方面更优越的晶型，以便于更好的进行工业化药物制剂生产和满足后期药品运用中对于晶体性质或药品性质的严苛要求。
发明内容
本发明的主要目的是提供Sotagliflozin稳定的新晶型及其制备方法和用途。
本发明提供了Sotagliflozin的多种新晶型，分别命名为晶型I、晶型II、晶型III、晶型V、晶型VI、晶型VII、晶型VIII。为实现上述目的，本发明采取的第一种方案是：提供Sotagliflozin的晶型I，使用Cu-Kα辐射，该晶型I的X射线粉末衍射图在衍射角2θ为3.6°±0.2°、12.7°±0.2°及14.1°±0.2°处有特征峰。
除上述特征峰外，本发明的晶型I的X射线粉末衍射图还优选在衍射角2θ为15.6°±0.2°、17.1°±0.2°、18.7°±0.2°、9.0°±0.2°、21.0°±0.2°、25.7°±0.2°中的一处或多处具有特征峰。
根据本发明的一个优选方面，晶型I的X射线粉末衍射图还在衍射角2θ为15.6°±0.2°、17.1°±0.2°及18.7°±0.2°中的一处或两处或三处有特征峰。更优选地，本发明的晶型I的X射线粉末衍射图在衍射角2θ为15.6°±0.2°、17.1°±0.2°及18.7°±0.2°处有特征峰。
根据本发明的又一优选方面，本发明的晶型I的X射线粉末衍射图还在衍射角2θ为9.0°±0.2°、21.0°±0.2°及25.7°±0.2°中的一处或两处或三处有特征峰。更优选地，本发明的晶型I的X射线粉末衍射图在衍射角2θ为9.0°±0.2°、21.0°±0.2°及25.7°±0.2°处有特征峰。
在本发明的一个具体且优选的实施方式中，晶型I的X射线粉末衍射图在衍射角2θ为3.6°±0.2°、9.0°±0.2°、12.7°±0.2°、14.1°±0.2°、15.6°±0.2°、17.1°±0.2°、18.7°±0.2°、21.0°±0.2°及25.7°±0.2°处有特征峰。
在本发明的又一个具体且优选的实施方式中，晶型I的X射线粉末衍射图在衍射角2θ为3.6°±0.2°、9.0°±0.2°、12.7°±0.2°、14.1°±0.2°、15.6°±0.2°、17.1°±0.2°、18.7°±0.2°、21.0°±0.2°及25.7°±0.2°处有特征峰。
在一个优选的实施例中，本发明的晶型I的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，本发明的晶型I是水合物。
在一个优选的实施例中，当进行差示扫描量热分析(DSC)时，本发明的晶型I加热至69℃附近时开始脱水，其DSC如图2所示。
在一个优选的实施例中，当进行热重分析(TGA)时，本发明的晶型I加热至115℃时，具有约3.3％的质量损失梯度，其TGA如图3所示。
在一个具体的实施例中，本发明的晶型I的液态核磁氢谱数据如下所示，1H NMR(400 MHz,CDCl3)δ7.38(d,J＝8.2Hz,1H),7.21(dd,J＝8.2,2.1Hz,1H),7.16(d,J＝2.0Hz,1H),7.09(d,J＝8.7Hz,2H),6.86-6.76(m,2H),4.37(d,J＝9.6Hz,1H),4.18(d,J＝9.4Hz,1H),4.10-3.96(m,4H),3.68(td,J＝8.8,2.3Hz,1H),3.58-3.46(m,2H),2.79(d,J＝2.3Hz,1H),2.51(d,J＝1.9Hz,1H),2.18(s,3H),1.40(t,J＝7.0Hz,3H)，其液态核磁氢谱图如图4所示。
本发明还进一步提供晶型I的制备方法，其选自：
方法1：将Sotagliflozin固体溶于醇类、酮类或环醚类溶剂中得到Sotagliflozin溶液，向溶液中缓慢滴加水或者将溶液滴加到水中，有固体析出，在室温下搅拌1～72小时，过滤干燥得到白色固体，即为本发明的晶型I；或
方法2：将Sotagliflozin固体加入到水中，配成悬浮液，在室温下悬浮搅拌5～15天，过滤干燥，得到本发明的晶型I。
根据本发明的一个具体且优选方面，方法1中所述醇类、酮类、环醚类溶剂分别优选为甲醇、丙酮、四氢呋喃。
根据本发明，方法1中所述搅拌时间优选为6～72小时，更优选为12～72小时，具体可以为例如约24小时。
根据本发明，方法2中所述搅拌时间优选为6～15天，更优选为7～12天，进一步优选为8天。
本发明采取的第二种方案是：提供Sotagliflozin的晶型II，使用Cu-Kα辐射，该晶型II的X射线粉末衍射图在衍射角2θ为3.7°±0.2°、4.5°±0.2°及14.6°±0.2°处有特征峰。
除上述特征峰外，本发明的晶型II还优选在衍射角2θ为13.4°±0.2°、18.1°±0.2°、6.2°±0.2°、22.0°±0.2°、10.6°±0.2°及15.9°±0.2°中的一处或多处有特征峰。
根据本发明的一个优选方面，晶型II的X射线粉末衍射图还在衍射角2θ为13.4°±0.2°、18.1°±0.2°及6.2°±0.2°中的一处或两处或三处有特征峰。更优选地，晶型II的X射线粉末衍射图在衍射角2θ为13.4°±0.2°、18.1°±0.2°及6.2°±0.2°处有特征峰。
根据本发明的又一优选方面，晶型II的X射线粉末衍射图在衍射角2θ为22.0°±0.2°、10.6°±0.2°及15.9°±0.2°中的一处或两处或三处有特征峰。更优选地，本发明的晶型II的X射线粉末衍射图在衍射角2θ为22.0°±0.2°、10.6°±0.2°及15.9°±0.2°处有特征峰。
在根据本发明的一个优选的实施方式中，晶型II的X射线粉末衍射图在衍射角2θ为3.7°±0.2°、4.5°±0.2°、6.2°±0.2°、10.6°±0.2°、13.4°±0.2°、14.6°±0.2°、15.9°±0.2°、18.1°±0.2°及22.0°±0.2°处有特征峰。
在一个优选的实施例中，本发明的晶型II的X射线粉末衍射图基本如图5所示。
在一个具体的实施例中，本发明的晶型II是水合物。
在一个优选的实施例中，当进行差示扫描量热分析(DSC)时，本发明的晶型II加热至62℃附近时开始脱水，其DSC如图6所示。
在一个优选的实施例中，当进行热重分析(TGA)时，本发明的晶型II加热至112℃时，具有约5.7％的质量损失梯度，其TGA如图7所示。
在一个具体的实施例中，本发明的晶型II的液态核磁氢谱数据如下所示，1H NMR(400MHz,CDCl3)δ7.38(d,J＝8.2Hz,1H),7.21(dd,J＝8.2,2.1Hz,1H),7.16(d,J＝2.0Hz,1H),7.09(d,J＝8.6Hz,2H),6.85–6.78(m,2H),4.37(d,J＝9.6Hz,1H),4.18(d,J＝9.4Hz,1H),4.11–3.96(m,4H),3.68(td,J＝8.9,2.3Hz,1H),3.52(tdd,J＝12.1,9.3,2.5Hz,2H),2.79(d,J＝2.3Hz,1H),2.51(d,J＝1.9Hz,1H),2.18(s,3H),1.40(t,J＝7.0Hz,3H)，其液态核磁氢谱图如图8所示。
本发明还进一步提供本发明的晶型II的制备方法，其选自：
方法1：将Sotagliflozin固体溶于烷基腈类溶剂中得到Sotagliflozin溶液，向溶液中缓慢滴加水或者将溶液滴加到水中，有固体析出，在室温下搅拌1～72小时，过滤干燥得到白色固体，即为本发明的晶型II；或
方法2：将Sotagliflozin固体溶于环醚类溶剂或酯类溶剂中得到Sotagliflozin溶液，向溶液中缓慢滴加正庚烷或者将溶液滴加到正庚烷中，有固体析出，在室温下搅拌1～72小时，过滤干燥得到白色固体，即为本发明的晶型II；或
方法3：将Sotagliflozin固体溶于酮类溶剂中得到Sotagliflozin溶液，向溶液中缓慢滴加甲苯或者将溶液滴加到甲苯中，有固体析出，在室温下搅拌1～72小时，过滤干燥得到白色固体，即为本发明的晶型II；或
方法4：将Sotagliflozin固体(优选现有2形晶体)加入到酮类溶剂与水的混合溶剂或烷基腈类溶剂与水的混合溶剂中，在温度50℃～75℃下悬浮搅拌5～20天，过滤干燥，得到本发明的晶型II。
在本发明的晶型II的制备方法中：
方法1中所述的烷基腈类溶剂优选为乙腈；方法1中所述的搅拌时间优选6～72小时，更优选6～36小时，进一步优选12～36小时，更进一步优选24～30小时；
方法2中所述的环醚类溶剂、酯类溶剂分别优选为四氢呋喃和乙酸乙酯；方法2中所述的搅拌时间优选6～72小时，更优选6～36小时，进一步优选12～36小时，更进一步优选24～30小时；
方法3中所述的酮类溶剂优选为丙酮；方法3中所述的搅拌时间优选6～72小时，更优选6～36小时，进一步优选12～36小时，更进一步优选24～30小时；
方法4中所述的酮类溶剂与水的混合溶剂优选为丙酮与水的混合溶剂，二者的体积比可以为1/2～1/10，优选为1/3～1/8，更优选为1/4～1/6；所述的烷基腈类溶剂与水的混合溶剂为乙腈与水的混合溶剂，二者的体积可以为1/2～1/10，优选为1/3～1/8，更优选为1/4～1/6；方法4中的搅拌时间优选为8～18天，更优选为10～15天，具体例如14天。
本发明采取的第三种方案是：提供Sotagliflozin的晶型III，使用Cu-Kα辐射，该晶型III的X-射线粉末衍射在衍射角2θ为4.3°±0.2°、14.6°±0.2°及19.6°±0.2°处有特征峰。
除上述特征峰外，本发明的晶型III还优选在衍射角2θ为4.9°±0.2°、15.3°±0.2°、17.5°±0.2°、12.8°±0.2°、25.0°±0.2°及26.4°±0.2°中的一处或多处有特征峰。
根据本发明的一个优选方面，晶型III的X-射线粉末衍射在衍射角2θ为4.9°±0.2°、15.3°±0.2°及17.5°±0.2°中的一处或两处或三处有特征峰；更优选地，晶型III的X射线粉末衍射图在衍射角2θ为4.9°±0.2°、15.3°±0.2°及17.5°±0.2°处有特征峰。
根据本发明的又一优选方面，晶型III的X-射线粉末衍射在衍射角2θ为12.8°±0.2°、25.0°±0.2°及26.4°±0.2°中的一处或两处或三处有特征峰；更优选地，晶型III的X射线粉末衍射图在衍射角2θ为12.8°±0.2°、25.0°±0.2°及26.4°±0.2°处有特征峰。
在一个优选的实施方式中，本发明的晶型III的X射线粉末衍射图在衍射角2θ为4.3°±0.2°、4.9°±0.2°、12.8°±0.2°、14.6°±0.2°、15.3°±0.2°、17.5°±0.2°、25.0°±0.2°、19.6°±0.2°及26.4°±0.2°处有特征峰。
在一个优选的实施例中，本发明的晶型III的X射线粉末衍射图基本如图9所示。
在一个具体的实施例中，本发明的晶型III是无水物。
在一个优选的实施例中，当进行差示扫描量热分析(DSC)时，晶型III加热至131℃附近时开始熔化，其DSC如图10所示。
在一个优选的实施例中，当进行热重分析(TGA)时，晶型III加热至125℃时，具有约1.3％的质量损失梯度，其TGA如图11所示。
在一个具体的实施例中，本发明的晶型III的液态核磁氢谱数据如下所示，1H NMR(400MHz,DMSO)δ7.38(d,J＝8.2Hz,1H),7.26(d,J＝1.9Hz,1H),7.20(dd,J＝8.3,2.0Hz,1H),7.10(d,J＝8.6Hz,2H),6.83(d,J＝8.6Hz,2H),5.26(d,J＝5.7Hz,1H),5.17(d,J＝4.8Hz,1H),4.98(d,J＝5.7Hz,1H),4.34(d,J＝9.4Hz,1H),4.09(d,J＝9.4Hz,1H),4.03-3.92(m,4H),3.26(td,J＝8.6,4.9Hz,1H),3.22–3.10(m,2H),2.03(s,3H),1.30(t,J＝7.0Hz,3H)，液态核磁氢谱图如图12所示。
本发明还进一步提供本发明的晶型III的制备方法，其选自：
方法1：将Sotagliflozin固体溶于卤代烷烃中，在室温下缓慢挥发得到白色固体。
方法2：将Sotagliflozin固体溶于卤代烷烃与烷烃的混合溶剂中，在室温下缓慢挥发得到白色固体。
在本发明的晶型III的制备方法中，方法1中所述的卤代烷烃可以且优选为氯仿；方法2所述的卤代烷烃和烷烃分别可以且优选为氯仿和正庚烷，卤代烷烃和烷烃的体积比可以为1/1～10/1，更优选为3/1～6/1，具体例如4/1。
本发明采取的第四种方案是：提供Sotagliflozin的晶型V，使用Cu-Kα辐射，该晶型V的X-射线粉末衍射在衍射角2θ为5.4°±0.2°、9.9°±0.2°及19.7°±0.2°处有特征峰。
除上述特征峰外，本发明的晶型V还优选在衍射角2θ为12.8°±0.2°、13.6°±0.2°、15.1°±0.2°，6.5°±0.2°、18.2°±0.2°及20.4°±0.2°中的一处或多处有特征峰。
根据本发明的一个优选方面，所述晶型V的X-射线粉末衍射在衍射角2θ为12.8°±0.2°、13.6°±0.2°及15.1°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型V的X射线粉末衍射图在衍射角2θ为12.8°±0.2°、13.6°±0.2°及15.1°±0.2°处有特征峰。
根据本发明的又一优选方面，所述晶型V的X-射线粉末衍射在衍射角2θ为6.5°±0.2°、18.2°±0.2°及20.4°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型V的X射线粉末衍射图在衍射角2θ为6.5°±0.2°、18.2°±0.2°及20.4°±0.2°处有特征峰。
在一个优选的实施方式中，本发明的晶型V的X-射线粉末衍射在衍射角2θ为5.4°±0.2°、6.5°±0.2°、9.9°±0.2°、12.8°±0.2°、13.6°±0.2°、15.1°±0.2°、18.2°±0.2°、19.7°±0.2°及20.4°±0.2°处有特征峰。
在一个优选的实施例中，本发明的晶型V的X射线粉末衍射图基本如图13所示。
在一个具体的实施例中，本发明的晶型V是水合物。
在一个优选的实施例中，当进行差示扫描量热分析(DSC)时，本发明的晶型V加热至30℃附近时开始脱水，其DSC如图14所示。
在一个优选的实施例中，当进行热重分析(TGA)时，本发明的晶型V加热至115℃时，具有约12.7％的质量损失梯度，其TGA如图15所示。
在一个具体的实施例中，本发明的晶型V的液态核磁氢谱数据如下所示，1H NMR(400MHz,CDCl3)δ7.38(d,J＝8.2Hz,1H),7.21(dd,J＝8.2,2.1Hz,1H),7.16(d,J＝2.0Hz,1H),7.09(d,J＝8.6Hz,2H),6.82(d,J＝8.6Hz,2H),4.37(d,J＝9.6Hz,1H),4.18(d,J＝9.4Hz,1H),4.11–3.95(m,4H),3.72–3.65(m,1H),3.52(ddd,J＝21.5,9.3,2.4Hz,2H),2.81(d,J＝2.3Hz,1H),2.52(d,J＝1.9Hz,1H),2.18(s,3H),1.40(t,J＝7.0Hz,3H)，其液态核磁氢谱图如图16所示。
本发明还进一步提供本发明的晶型V的制备方法，其包括：在加热温度40～70℃下，将 Sotagliflozin固体溶于醇类溶剂与水的混合溶剂中，配成澄清溶液，将所得澄清溶液转移至温度0～10℃的冷却环境，搅拌12～96小时，过滤干燥得到白色固体。
在本发明的晶型V的制备方法中，加热温度优选50～60℃；冷却环境的温度优选为约5℃；醇类溶剂优选为甲醇，醇类溶剂(甲醇)与水的体积比可以为2/1～2/3，更优选地为1/1；冷却环境下，搅拌的时间优选为36～96小时，更优选为48～96小时，最优选72～84小时。
本发明采取的第五种方案是：提供Sotagliflozin的晶型VI，使用Cu-Kα辐射，该晶型VI的X-射线粉末衍射在衍射角2θ为4.8°±0.2°、9.5°±0.2°及14.5°±0.2°处有特征峰。
除上述特征峰外，本发明的晶型VI还优选在衍射角2θ为11.1°±0.2°、19.1°±0.2°、21.5°±0.2°、7.7°±0.2°、20.0°±0.2°及25.4°±0.2°中的一处或多处有特征峰。
根据本发明的一个优选方面，晶型VI的X-射线粉末衍射在衍射角2θ为11.1°±0.2°、19.1°±0.2°及21.5°±0.2°中的一处或两处或三处有特征峰；更优选地，本发明的晶型VI的X射线粉末衍射图在衍射角2θ为11.1°±0.2°、19.1°±0.2°及21.5°±0.2°处有特征峰。
根据本发明的又一优选方面，所述晶型VI的X-射线粉末衍射在衍射角2θ为7.7°±0.2°、20.0°±0.2°及25.4°±0.2°中的一处或两处或三处有特征峰；更优选地，本发明的晶型VI的X射线粉末衍射图在衍射角2θ为7.7°±0.2°、20.0°±0.2°及25.4°±0.2°处有特征峰。
在一个优选的实施方式中，本发明的晶型VI的X-射线粉末衍射在衍射角2θ为4.8°±0.2°、7.7°±0.2°、9.5°±0.2°、11.1°±0.2°、14.5°±0.2°、19.1°±0.2°、20.0°±0.2°、21.5°±0.2°及25.4°±0.2°处有特征峰。
在一个优选的实施例中，本发明的晶型VI的X射线粉末衍射图基本如图17所示。
在一个具体实施例中，本发明的晶型VI是水合物。
在一个优选的实施例中，当进行差示扫描量热分析(DSC)时，本发明的晶型VI加热至80℃附近时开始脱水，其DSC如图18所示。
在一个优选的实施例中，当进行热重分析(TGA)时，本发明的晶型VI加热至116℃时，具有约3.6％的质量损失梯度，其TGA如图19所示。
在一个具体实施例中，本发明的晶型VI的液态核磁氢谱数据如下所示，1H NMR(400MHz,CDCl3)δ7.38(d,J＝8.2Hz,1H),7.21(dd,J＝8.2,2.1Hz,1H),7.17(d,J＝2.0Hz,1H),7.09(d,J＝8.7Hz,2H),6.85–6.79(m,2H),4.37(d,J＝9.6Hz,1H),4.18(d,J＝9.4Hz,1H),4.11–3.96(m,4H),3.68(t,J＝9.0Hz,1H),3.58-3.46(m,2H),2.83(s,1H),2.53(d,J＝1.6Hz,1H),2.18(s,3H),1.40(t,J＝7.0Hz,3H)，其液态核磁氢谱图如图20所示。
本发明还进一步提供本发明的晶型VI的制备方法，其包括：将Sotagliflozin固体放入水中，在温度35～65℃下悬浮搅拌24～96小时，过滤干燥，得到晶型VI。
本发明的晶型VI的制备方法中，悬浮搅拌时的温度优选为45～55℃，更优选为约50℃。；悬浮搅拌时间优选为36～84小时，更优选为48～84小时，最优选为约72小时。
本发明采取的第六种方案是：提供Sotagliflozin的晶型VII，使用Cu-Kα辐射，该晶型VII的X射线粉末衍射图在衍射角2θ为10.5°±0.2°、13.8°±0.2°及15.8°±0.2°处有特征峰。
除上述特征峰外，本发明的晶型VII还优选在衍射角2θ为16.7°±0.2°、20.3°±0.2°、22.6°±0.2°、6.7°±0.2°、18.5°±0.2°及19.1°±0.2°中的一处或多处有特征峰。
根据本发明的一个优选方面，晶型VII的X-射线粉末衍射在衍射角2θ为16.7°±0.2°、20.3°±0.2°及22.6°±0.2°中的一处或两处或三处有特征峰；更优选地，所述晶型VII的X射线粉末衍射图在衍射角2θ为16.7°±0.2°、20.3°±0.2°及22.6°±0.2°处有特征峰。
根据本发明的又一优选方面，晶型VII的X-射线粉末衍射在衍射角2θ为6.7°±0.2°、18.5°±0.2°及19.1°±0.2°中的一处或两处或三处有特征峰；更优选地，所述晶型VII的X射线粉末衍射图在衍射角2θ为6.7°±0.2°、18.5°±0.2°及19.1°±0.2°处有特征峰。
在一个优选的实施方式中，本发明的晶型VII的X-射线粉末衍射在衍射角2θ为6.7°±0.2°、10.5°±0.2°、13.8°±0.2°、15.8°±0.2°、16.7°±0.2°、18.5°±0.2°、19.1°±0.2°、20.3°±0.2°及22.6°±0.2°处有特征峰。
在一个优选的实施例中，本发明的晶型VII的X射线粉末衍射图基本如图21所示。
在一个优选的实施例中，当进行差示扫描量热分析(DSC)时，本发明的晶型VII加热至120℃附近时开始熔化，其DSC如图22所示。
在一个优选的实施例中，当进行热重分析(TGA)时，本发明的晶型VII加热至114℃时，具有约1.9％的质量损失梯度，其TGA如图23所示。
在一个具体实施例中，本发明的晶型VII的液态核磁氢谱数据如下所示，1H NMR(400MHz,CDCl3)δ7.38(d,J＝8.2Hz,1H),7.21(dd,J＝8.2,2.1Hz,1H),7.16(d,J＝2.1Hz,1H),7.09(d,J＝8.7Hz,2H),6.85-6.79(m,2H),4.37(d,J＝9.6Hz,1H),4.18(d,J＝9.4Hz,1H),4.10-3.97(m,4H),3.71-3.64(m,1H),3.58-3.45(m,2H),2.81(d,J＝2.2Hz,1H),2.53(d,J＝1.9Hz,1H),2.18(s,3H),1.40(t,J＝7.0Hz,3H)，其液态核磁氢谱图如图24所示。
本发明还进一步提供本发明的晶型VII的制备方法，其包括：将本发明Sotagliflozin晶型II以5～10℃/min的升温速率加热至90～100℃，并在90℃～100℃保留0.5～5分钟，得到白色固体。
在一个具体的实施例中，将本发明的晶型II以10℃/min的升温速率加热至90℃，并在90℃保留0.5min，得到白色固体，即得本发明的晶型VII。
本发明采取的第七种方案是：提供Sotagliflozin的晶型VIII，使用Cu-Kα辐射，该晶型 VIII的X-射线粉末衍射在衍射角2θ为6.2°±0.2°、10.9°±0.2°及17.7°±0.2°处有特征峰。
除上述特征峰外，本发明的晶型VIII还优选在衍射角2θ为6.2°±0.2°、10.4°±0.2°、10.9°±0.2°、14.9°±0.2°、15.7°±0.2°、17.7°±0.2°、18.8°±0.2°、20.9°±0.2°及24.1°±0.2°中的一处或多处有特征峰。
根据本发明的一个优选方面，晶型VIII的X-射线粉末衍射还在衍射角2θ为14.9°±0.2°、15.7°±0.2°及20.9°±0.2°中的一处或两处或三处有特征峰；更优选地，本发明的晶型VIII的X射线粉末衍射图在衍射角2θ为14.9°±0.2°、15.7°±0.2°及20.9°±0.2°处有特征峰。
根据本发明的又一优选方面，本发明的晶型VIII的X-射线粉末衍射在衍射角2θ为10.4°±0.2°、18.8°±0.2°、24.1°±0.2°中的一处或两处或三处有特征峰；更优选地，本发明的晶型VIII的X射线粉末衍射图在衍射角2θ为10.4°±0.2°、18.8°±0.2°、24.1°±0.2°处有特征峰。
在一个优选的实施方式中，本发明的晶型VIII的X-射线粉末衍射在衍射角2θ为6.2°±0.2°、10.4°±0.2°、10.9°±0.2°、14.9°±0.2°、15.7°±0.2°、17.7°±0.2°、18.8°±0.2°、20.9°±0.2°及24.1°±0.2°处有特征峰。
在一个优选的实施例中，本发明的晶型VIII的X射线粉末衍射图基本如图25所示。
在一个优选的实施例中，当进行差示扫描量热分析(DSC)时，晶型VIII加热至91℃附近时开始脱溶剂，其DSC如图26所示。
本发明还进一步提供本发明的晶型VIII的制备方法，其包括：将本发明的晶型V的固体加热到温度60～80℃，并恒定2分钟以上，所得固体即为本发明的晶型VIII。其中：优选的加热速率为10℃/分钟；优选加热到约65℃。
本发明的Sotagliflozin的晶型I、晶型II、晶型III、晶型V、晶型VI、晶型VII以及晶型VIII具有以下有益性质：
①稳定性好；
②制备工艺简单，可重复放大；
③结晶度好；
此外，与现有2形晶体相比，晶型I、晶型II的优势包括其在高水活度环境中更稳定；相比现有2形晶体，晶型I和晶型VI具有更好的机械稳定性，更适合成药和储存；现有2形晶体粒度分布较宽，有团聚现象，且呈细针状，晶型I、晶型V、晶型VII、晶型VIII粒度分布均匀，有助于简化制剂过程的后处理工艺，提高质量控制；晶型II、晶型III、晶型VII、晶型VIII具有相比现有2形晶体，具有更高的溶解度，有利于药物吸收。
本发明通过提供Sotagliflozin新的晶型I、晶型II、晶型III、晶型V、晶型VI、晶型VII、晶型VIII，解决了现有技术晶型存在的问题。这些新的晶型具有选自以下至少一项的有 利性质：溶解度高，制备简单且所用溶剂毒性低，结晶度好，好的颗粒形态、低吸湿性、更好的流动性、更好的稳定性。
本发明中，“晶体”或“晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。另外，由于样品高度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X-射线衍射图不必和这里所指的例子中的X射线衍射图完全一致。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
“晶型”和“多晶型”以及其他相关词汇在本发明中指的是固体化合物在晶体结构中以特定的晶型状态存在。多晶型理化性质的不同可以体现在储存稳定性、可压缩性、密度、溶出速度等方面。
本发明中所使用的短语“有效治疗量”或“治疗有效量”是指引起由研究人员、兽医、医生或其他临床医师在组织、系统、动物、个体或人中所要寻求的生物反应或药物反应的活性化合物或药剂的量。
在一些实施方案中，本发明的Sotagliflozin的新晶型，包括晶型I、晶型II、晶型III、晶型V、晶型VI、晶型VII、晶型VIII是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
本发明提供的Sotagliflozin的晶型I、晶型II、晶型III、晶型V、晶型VI、晶型VII或晶型VIII具有适用于上述剂型的有利性质。
此外，本发明提供Sotagliflozin的晶型I、晶型II、晶型III、晶型V、晶型VI、晶型VII或晶型VIII中的一种或多种在制备具有抑制SGLT，尤其是抑制SGLT-2作用的药物中的 用途。
本发明还提供一种药物组合物，其包含治疗有效量的本发明的Sotagliflozin的晶型I、晶型II、晶型III、晶型V、晶型VI、晶型VII、晶型VIII或这些晶型的任意组合及药学上可接受的载体、稀释剂或赋形剂。优选地，所述药物组合物用于预防和/或治疗糖尿病。该药物组合物可以采取本领域公知的方法来制备，在此不进行赘述。
附图说明
图1为实施例1中晶型I的X射线粉末衍射图；
图2为实施例2中晶型I的差示扫描量热分析图；
图3为实施例2中晶型I的热重分析图；
图4为实施例2中晶型I的液态核磁氢谱图；
图5为实施例7中晶型II的X射线粉末衍射图；
图6为实施例7中晶型II的差示扫描量热分析图；
图7为实施例7中晶型II的热重分析图；
图8为实施例7中晶型II的液态核磁氢谱图；
图9为实施例13中晶型III的X射线粉末衍射图；
图10为实施例13中晶型III的差示扫描量热分析图；
图11为实施例13中晶型III的热重分析图；
图12为实施例13中晶型III的液态核磁氢谱图；
图13为实施例15中晶型V的X射线粉末衍射图；
图14为实施例15中晶型V的差示扫描量热分析图；
图15为实施例15中晶型V的热重分析图；
图16为实施例15中晶型V的液态核磁氢谱图；
图17为实施例17中晶型VI的X射线粉末衍射图；
图18为实施例17中晶型VI的差示扫描量热分析图；
图19为实施例17中晶型VI的热重分析图；
图20为实施例17中晶型VI的液态核磁氢谱图；
图21为实施例19中晶型VII的X射线粉末衍射图；
图22为实施例19中晶型VII的差示扫描量热分析图；
图23为实施例19中晶型VII的热重分析图；
图24为实施例19中晶型VII的液态核磁氢谱图；
图25为实施例20中晶型VIII的X射线粉末衍射图；
图26为实施例20中晶型VIII的差示扫描量热分析图；
图27为实施例2中晶型I的X射线粉末衍射图；
图28为实施例3中晶型I的X射线粉末衍射图；
图29为实施例4中晶型I的X射线粉末衍射图；
图30为实施例5中晶型I的X射线粉末衍射图；
图31为实施例6中晶型I的X射线粉末衍射图；
图32为实施例8中晶型II的X射线粉末衍射图；
图33为实施例9中晶型II的X射线粉末衍射图；
图34为实施例10中晶型II的X射线粉末衍射图；
图35为实施例11中晶型II的X射线粉末衍射图；
图36为实施例12中晶型II的X射线粉末衍射图；
图37为实施例14中晶型III的X射线粉末衍射图；
图38为实施例16中晶型V的X射线粉末衍射图；
图39为实施例18中晶型VI的X射线粉末衍射图；
图40为实施例22中晶型I的DVS图；
图41为实施例23中晶型II的DVS图；
图42为实施例24中晶型III的DVS图；
图43为实施例25中晶型VI的DVS图；
图44为本发明的晶型I放置在25℃/60％相对湿度、40℃/75％相对湿度的条件下放置3个月前后的XRPD对比图；
图45为本发明的晶型II放置在25℃/60％相对湿度、40℃/75％相对湿度的条件下放置3个月前后的XRPD对比图；
图46为本发明的晶型III放置在25℃/60％相对湿度、40℃/75％相对湿度的条件下放置3个月前后的XRPD对比图；
图47为本发明的晶型VI放置在25℃/60％相对湿度、40℃/75％相对湿度的条件下放置3个月前后的XRPD对比图；
图48为现有2形晶体的偏光显微镜图；
图49为本发明晶型I的偏光显微镜图；
图50为现有2形晶体的PSD图；
图51为本发明晶型I的PSD图；
图52为本发明晶型V的PSD图；
图53为现有2形晶体的研磨前后的XRPD对比图；
图54为本发明的晶型I研磨前后的XRPD对比图；
图55为本发明的晶型VI研磨前后的XRPD对比图；
图56为本发明晶型VII的偏光显微镜图；
图57为本发明晶型VIII的PSD图；
图58为实施例31中晶型VII的DVS图；
图59为实施例32中晶型VIII的DVS图。
具体实施方式
本发明进一步参考以下实施例限定，所述实施例详细描述本发明的晶型的制备和使用方法。对本领域技术人员显而易见的是，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射；DSC：差示扫描量热分析；TGA：热重分析；
DVS：动态水分吸附；PSD：粒径分布；PLM：偏光显微镜；1H NMR：液态核磁氢谱；
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
采集数据所用的仪器及方法：
本发明所述的X射线粉末衍射图在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 PCTCN2017085813-appb-000002
：1.540598；Kα2
Figure PCTCN2017085813-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
差热分析(DSC)数据采自于TA Instruments Q2000MDSC，仪器控制软件是Thermal Advantage，分析软件是Universal Analysis。通常取1～10毫克的样品放置于加盖(除非特别说明)的铝坩埚内，以10℃/min的升温速度在50mL/min干燥N2的保护下将样品从室温升至约300℃，同时TA软件记录样品在升温过程中的热量变化。在本申请中，熔点是按起始温度 来报告的。
热重分析(TGA)数据采自于TA Instruments Q5000TGA，仪器控制软件是Thermal AdVantage，分析软件是Universal Analysis。通常取5～15mg的样品放置于白金坩埚内，以10℃/min的升温速度在50mL/min干燥N2的保护下将样品从室温升至300℃，同时TA软件记录样品在升温过程中的重量变化。本发明晶型的含水量是根据TGA失重推测算出，如本领域技术人员所知，TGA失重是晶型含水量的参考，但并不能绝对代表晶型所含水分子数。
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：20％RH-95％RH-0％RH-95％RH
核磁共振氢谱数据(1HNMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜或氘代氯仿溶解，配成2-10mg/mL的溶液。
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 PCTCN2017085813-appb-000004
*：流速60％为65毫升/秒的60％。
本发明中纯度的检测采用高效液相色谱法检测，其检测方法如下：
Figure PCTCN2017085813-appb-000005
Figure PCTCN2017085813-appb-000006
本发明中溶解度的检测采用高效液相色谱法检测，其检测方法如下：
Figure PCTCN2017085813-appb-000007
除非特殊说明，以下实施例均在室温条件下操作。
以下各实施例中所使用的Sotagliflozin原料或可通过专利CN101343296B中的制备方法得到或通过市售的方式得到，或可根据本发明方法制备。
实施例1Sotagliflozin的晶型I的制备方法
称取456.4mg Sotagliflozin固体置于20mL玻璃瓶中，加入2.0mL丙酮，固体溶解得到澄清溶液。磁力搅拌下，将澄清溶液缓慢加入到18mL水中，立即有白色固体析出。室温下继续搅拌3天，过滤干燥得到白色固体。
经检测，本实施例得到的固体为本发明的晶型I。本实施例所得固体的X射线粉末衍射数据如表1所示，其XRPD图如图1所示。
表1
2theta d间隔 强度％
3.64 24.25 84.09
9.04 9.78 28.39
9.58 9.23 25.55
10.41 8.49 7.12
10.95 8.08 12.55
12.73 6.95 70.82
14.11 6.28 100.00
14.62 6.06 83.36
15.58 5.69 3.73
17.13 5.18 72.62
18.16 4.88 5.03
18.74 4.74 40.78
19.25 4.61 3.29
20.02 4.44 3.16
20.95 4.24 31.08
21.64 4.11 4.12
22.03 4.03 14.09
23.66 3.76 0.56
24.33 3.66 1.27
25.65 3.47 18.25
26.89 3.32 6.76
28.48 3.13 3.18
29.10 3.07 2.16
29.51 3.03 10.36
29.84 2.99 9.77
30.88 2.90 6.85
31.65 2.83 3.84
32.70 2.74 7.68
34.55 2.60 5.43
36.45 2.47 6.05
37.13 2.42 6.77
38.02 2.37 5.82
38.26 2.35 8.16
38.97 2.31 1.82
实施例2Sotagliflozin的晶型I的制备方法
称取41.4mg Sotagliflozin固体置于5mL玻璃小瓶中，加入0.2mL丙酮，固体溶解得到澄清溶液。磁力搅拌下缓慢加入2.0mL水，立即有白色固体析出，搅拌24小时后，干燥过滤得到白色固体。经检测，本实施例得到的固体为本发明的晶型I。
本实施例所得固体的X射线粉末衍射数据如表2所示，其XRPD图如图27所示。DSC图像如图2所示，TGA如图3所示，1H NMR如图4所示。
表2
2theta d间隔 强度％
3.63 24.36 100.00
9.11 9.71 13.21
9.61 9.21 11.92
12.79 6.92 27.92
14.18 6.24 38.88
14.65 6.05 25.53
15.65 5.66 14.91
17.15 5.17 26.56
18.81 4.72 15.44
19.78 4.49 8.52
21.05 4.22 26.59
21.74 4.09 20.20
22.05 4.03 7.39
23.52 3.78 4.64
25.70 3.47 10.65
26.92 3.31 19.09
27.69 3.22 3.52
28.44 3.14 5.24
29.59 3.02 5.66
29.89 2.99 6.85
30.97 2.89 2.83
32.76 2.73 5.37
33.86 2.65 3.17
34.69 2.59 1.96
36.55 2.46 6.01
37.27 2.41 3.91
38.41 2.34 5.52
39.03 2.31 2.15
实施例3Sotagliflozin的晶型I的制备方法
称取8.1mg Sotagliflozin固体置于1.5mL玻璃小瓶中，加入0.2mL甲醇，固体溶解得到澄清溶液。磁力搅拌下缓慢加入1.5mL水，立即有白色固体析出。室温下继续搅拌24小时，过滤干燥得到白色固体。经检测，本实施例得到的固体为本发明的晶型I。
本实施例所得固体的X射线粉末衍射数据如表3所示，其XRPD图如图28所示。
表3
2theta d间隔 强度％
3.67 24.10 100.00
9.02 9.80 26.87
9.57 9.24 23.03
10.92 8.10 6.98
12.72 6.96 43.51
14.09 6.28 57.44
14.61 6.06 58.67
15.58 5.69 21.55
17.12 5.18 38.86
18.73 4.74 23.59
20.95 4.24 24.07
21.70 4.10 12.42
22.04 4.03 9.06
25.70 3.47 14.94
26.92 3.31 10.69
28.38 3.14 3.43
29.52 3.03 5.47
29.87 2.99 6.66
36.43 2.47 5.71
37.27 2.41 4.55
38.34 2.35 5.39
实施例4Sotagliflozin的晶型I的制备方法
称取8.5mg Sotagliflozin固体置于1.5mL玻璃小瓶中，加入0.075mL丙酮，固体溶解得到澄清溶液。磁力搅拌下缓慢加入1.5mL水，立即有白色固体析出。室温下继续搅拌24小时，过滤干燥得到白色固体。经检测，本实施例得到的固体为本发明的晶型I。
本实施例所得固体的X射线粉末衍射数据如表4所示，其XRPD图如图29所示。
表4
2theta d间隔 强度％
3.65 24.23 75.50
9.04 9.78 12.93
9.57 9.24 12.57
10.95 8.08 13.52
12.73 6.95 30.67
14.11 6.28 42.82
14.62 6.06 100.00
15.58 5.69 16.35
17.14 5.17 38.31
18.26 4.86 2.40
18.74 4.74 23.10
20.96 4.24 14.57
21.66 4.10 6.82
22.02 4.04 7.60
25.70 3.46 18.95
26.91 3.31 6.91
29.53 3.03 14.41
30.92 2.89 3.19
32.72 2.74 6.04
34.57 2.59 4.03
36.46 2.46 4.48
37.18 2.42 6.04
38.31 2.35 5.73
实施例5Sotagliflozin的晶型I的制备方法
称取8.0mg Sotagliflozin固体置于1.5mL玻璃小瓶中，加入0.075mL四氢呋喃，固体溶解得到澄清溶液。磁力搅拌下，将澄清溶液缓慢加入到1.5mL水中，立即有白色固体析出。室温下继续搅拌24小时，过滤干燥得到白色固体。经检测，本实施例得到的固体为本发明的晶型I。
本实施例所得固体的X射线粉末衍射数据如表5所示，其XRPD图如图30所示。
表5
2theta d间隔 强度％
3.66 24.16 100.00
9.04 9.78 24.71
9.58 9.24 24.22
10.41 8.50 5.08
10.95 8.08 6.91
12.73 6.96 59.25
14.11 6.28 81.65
14.62 6.06 63.19
15.58 5.69 25.79
17.13 5.18 50.02
18.75 4.73 31.86
19.74 4.50 13.54
20.95 4.24 44.43
21.70 4.10 3.39
22.04 4.03 17.63
23.50 3.79 6.17
25.65 3.47 16.01
26.92 3.31 27.49
27.71 3.22 5.51
28.36 3.15 6.31
29.50 3.03 10.12
29.85 2.99 10.54
32.69 2.74 6.26
33.84 2.65 5.00
36.52 2.46 4.75
37.25 2.41 5.16
38.24 2.35 5.55
实施例6Sotagliflozin的晶型I的制备方法
称取10.4mg Sotagliflozin固体(现有2形晶体)置于1.5mL玻璃小瓶中，加入0.5mL水，在室温下搅拌8天，过滤干燥得到白色固体。经检测，本实施例得到的固体为本发明的晶型I。
本实施例所得固体的X射线粉末衍射数据如表6所示，其XRPD图如图31所示。
表6
2theta d间隔 强度％
3.66 24.16 100.00
9.04 9.78 17.51
9.58 9.23 17.83
10.39 8.51 4.94
10.93 8.10 14.52
12.73 6.95 50.78
14.10 6.28 74.17
14.61 6.06 81.09
15.59 5.69 26.51
17.13 5.18 54.75
18.73 4.74 28.86
19.74 4.50 7.45
20.97 4.24 29.78
21.69 4.10 20.67
22.03 4.04 10.90
23.50 3.79 4.90
25.70 3.47 21.77
26.87 3.32 16.11
28.46 3.14 7.14
29.50 3.03 10.43
30.76 2.91 4.27
32.73 2.74 6.95
34.52 2.60 3.69
36.46 2.46 6.10
37.16 2.42 7.14
38.21 2.36 6.20
实施例7Sotagliflozin的晶型II的制备方法
称取39.5mg Sotagliflozin固体置于20mL玻璃瓶中，加入0.8mL乙酸乙酯，固体溶解得到澄清溶液。磁力搅拌下缓慢加入5.0mL正庚烷，搅拌24小时过滤干燥得到白色固体。经检测，本实施例得到的固体为本发明的晶型II。
本实施例所得固体的X射线粉末衍射数据如表7所示，其XRPD图如图5所示。DSC图像如图6所示，TGA如图7所示，1H NMR如图8所示。
表7
2theta d间隔 强度％
3.63 24.32 53.76
4.44 19.90 37.45
5.26 16.81 16.15
6.22 14.21 13.53
7.26 12.18 14.75
7.90 11.19 20.16
9.14 9.68 20.00
10.57 8.37 31.29
12.42 7.12 15.47
13.40 6.61 46.21
14.16 6.25 30.33
14.61 6.06 100.00
15.89 5.58 38.14
18.15 4.89 52.34
18.69 4.75 15.15
19.04 4.66 15.39
19.42 4.57 21.35
20.92 4.25 17.99
22.02 4.04 40.68
22.41 3.97 16.00
23.30 3.82 11.21
23.88 3.73 11.99
25.01 3.56 17.21
25.42 3.50 12.17
25.84 3.45 18.31
26.62 3.35 10.16
29.12 3.07 7.60
29.44 3.03 8.05
30.16 2.96 6.94
31.39 2.85 5.29
32.08 2.79 5.09
34.42 2.61 3.17
37.03 2.43 1.76
实施例8Sotagliflozin的晶型II的制备方法
称取8.5mg Sotagliflozin固体置于1.5mL玻璃瓶中，加入0.3mL乙腈，固体溶解得到澄清溶液。磁力搅拌下缓慢加入1.5mL水，立即有白色固体析出。室温下继续搅拌24小时，过滤干燥得到白色固体。经检测，本实施例得到的固体为本发明的晶型II。
本实施例所得固体的X射线粉末衍射数据如表8所示，其XRPD图如图32所示。
表8
2theta d间隔 强度％
3.67 24.05 79.75
4.47 19.78 51.83
5.29 16.71 27.66
6.19 14.29 18.29
7.30 12.11 23.28
7.92 11.17 13.55
9.13 9.69 10.12
10.58 8.36 13.10
13.37 6.62 13.13
14.17 6.25 10.22
14.61 6.06 100.00
15.89 5.58 9.98
18.13 4.89 39.54
19.05 4.66 7.84
20.91 4.25 6.52
22.03 4.03 34.58
23.91 3.72 4.26
24.99 3.56 3.97
25.40 3.51 7.21
25.88 3.44 10.78
29.48 3.03 5.47
实施例9Sotagliflozin的晶型II的制备方法
称取8.4mg Sotagliflozin固体置于1.5mL玻璃瓶中，加入0.075mL四氢呋喃，固体溶解得到澄清溶液。磁力搅拌下缓慢加入1.5mL正庚烷，立即有白色固体析出。室温下继续搅拌24小时，过滤干燥得到白色固体。经检测，本实施例得到的固体为本发明的晶型II。
本实施例所得固体的X射线粉末衍射数据如表9所示，其XRPD图如图33所示。
表9
2theta d间隔 强度％
3.65 24.21 100.00
4.44 19.88 91.39
5.28 16.73 36.18
6.20 14.26 24.64
7.27 12.16 13.40
7.91 11.18 15.39
9.11 9.71 13.78
10.56 8.38 17.31
12.42 7.12 6.32
13.38 6.62 25.51
14.60 6.07 78.78
15.87 5.58 16.26
18.15 4.89 32.76
19.39 4.58 6.67
20.89 4.25 5.87
22.03 4.04 20.43
25.84 3.45 5.58
29.16 3.06 1.83
34.17 2.62 1.61
实施例10Sotagliflozin的晶型II的制备方法
称取8.4mg Sotagliflozin固体置于1.5mL玻璃瓶中，加入0.075mL丙酮，固体溶解得到澄清溶液。磁力搅拌下缓慢加入1.5mL甲苯，搅拌24小时过滤干燥得到白色固体。经检测，本实施例得到的固体为本发明的晶型II。
本实施例所得固体的X射线粉末衍射数据如表10所示，其XRPD图如图34所示。
表10
2theta d间隔 强度％
3.65 24.20 47.15
4.43 19.93 71.37
5.28 16.74 26.67
6.18 14.30 20.56
7.28 12.14 12.33
7.91 11.17 14.46
9.13 9.68 17.08
10.58 8.36 20.02
10.93 8.09 8.25
12.40 7.14 8.83
13.39 6.62 40.04
14.19 6.24 15.74
14.60 6.07 100.00
15.90 5.57 22.02
18.15 4.89 38.85
18.64 4.76 7.78
19.46 4.56 9.65
20.95 4.24 8.48
21.38 4.16 6.51
22.03 4.03 29.40
22.45 3.96 8.03
23.31 3.82 4.95
23.95 3.72 4.57
24.48 3.64 4.12
24.99 3.56 8.52
25.44 3.50 7.14
25.90 3.44 10.55
26.67 3.34 3.35
29.51 3.03 4.74
实施例11Sotagliflozin的晶型II的制备方法
称取8.3mg Sotagliflozin固体(专利无水晶型2形晶体)置于1.5mL玻璃小瓶中，加入0.35mL乙腈与水的混合溶剂(乙腈与水的体积比为1/6)，在70℃下搅拌14天，过滤干燥得到白色固体。经检测，本实施例得到的固体为本发明的晶型II。
本实施例所得固体的X射线粉末衍射数据如表11所示，其XRPD图如图35所示。
表11
2theta d间隔 强度％
3.68 24.02 100.00
4.46 19.80 82.61
5.24 16.88 33.85
6.19 14.27 23.59
7.27 12.17 17.29
7.88 11.22 7.76
9.12 9.70 11.04
10.55 8.38 9.69
12.40 7.14 3.47
13.37 6.62 21.63
14.60 6.07 56.69
15.90 5.57 7.91
18.13 4.89 32.85
18.68 4.75 4.53
22.03 4.04 21.64
22.77 3.91 3.56
24.96 3.57 3.79
29.47 3.03 3.47
33.30 2.69 1.56
33.89 2.65 1.99
实施例12Sotagliflozin的晶型II的制备方法
称取8.3mg Sotagliflozin固体(现有2形晶体)置于1.5mL玻璃小瓶中，加入0.35mL丙酮与水的混合溶剂(丙酮与水的体积比为1/6)，并将小瓶加盖密封，在70℃下搅拌14天，过滤干燥得到白色固体。经检测，本实施例得到的固体为本发明的晶型II。
本实施例所得固体的X射线粉末衍射数据如表12所示，其XRPD图如图36所示。
表12
2theta d间隔 强度％
3.67 24.07 100.00
4.45 19.87 33.61
6.16 14.35 11.16
7.27 12.15 10.97
9.12 9.70 9.69
10.57 8.37 4.22
10.96 8.07 5.43
12.44 7.11 3.09
13.38 6.62 8.40
14.61 6.06 59.97
15.19 5.83 2.45
15.89 5.58 3.27
18.13 4.89 16.88
18.67 4.75 2.45
19.46 4.56 1.69
21.68 4.10 4.95
22.02 4.04 30.32
25.00 3.56 3.33
25.42 3.50 3.67
25.86 3.45 2.82
29.50 3.03 5.79
30.95 2.89 1.11
32.22 2.78 1.35
33.31 2.69 2.29
34.55 2.60 1.23
实施例13Sotagliflozin的晶型III的制备方法
称取39.2mg Sotagliflozin固体置于3mL玻璃小瓶中，加入1.0mL氯仿，固体溶解得到澄清溶液。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本发明的晶 型III。
本实施例所得固体的X射线粉末衍射数据如表13所示，其XRPD图如图9所示，DSC图像如图10所示，TGA如图11所示，1H NMR如图12所示。
表13
2theta d间隔 强度％
3.62 24.42 23.29
4.33 20.39 100.00
4.95 17.87 32.99
7.29 12.12 11.62
8.15 10.85 6.78
8.96 9.87 13.75
11.17 7.92 6.23
12.53 7.06 8.09
12.84 6.89 14.94
13.31 6.65 7.65
14.65 6.05 75.97
14.93 5.93 44.75
15.32 5.78 30.60
15.64 5.67 17.28
16.35 5.42 4.06
17.47 5.08 22.73
17.96 4.94 7.73
18.61 4.77 15.04
19.60 4.53 42.47
20.97 4.24 6.70
21.53 4.13 15.24
22.01 4.04 5.30
22.48 3.95 8.56
22.93 3.88 7.08
23.97 3.71 5.64
24.57 3.62 10.61
25.01 3.56 9.38
25.89 3.44 4.87
26.35 3.38 11.83
26.65 3.34 5.17
28.38 3.15 2.37
28.74 3.11 3.28
29.86 2.99 3.45
33.67 2.66 2.12
35.41 2.53 1.46
36.53 2.46 1.94
37.25 2.41 2.75
38.46 2.34 2.17
40.01 2.25 2.38
实施例14Sotagliflozin的晶型III的制备方法
称取5.4mg Sotagliflozin固体置于1.5mL玻璃小瓶中，加入0.5mL氯仿与正庚烷的混合溶剂(氯仿与正庚烷的体积比为4/1)，固体溶解得到澄清溶液。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本发明的晶型III。
本实施例所得固体的X射线粉末衍射数据如表14所示，其XRPD图如图37所示。
表14
2theta d间隔 强度％
4.33 20.40 100.00
4.95 17.86 12.22
12.83 6.90 7.66
14.65 6.05 47.35
14.93 5.94 19.25
15.33 5.78 31.70
16.35 5.42 2.64
17.47 5.08 32.43
18.61 4.77 5.76
19.61 4.53 46.30
20.71 4.29 1.99
21.51 4.13 3.87
22.45 3.96 5.19
24.00 3.71 3.10
25.02 3.56 9.91
26.36 3.38 14.22
28.38 3.14 2.38
33.11 2.71 2.85
33.94 2.64 2.53
35.38 2.54 2.11
37.32 2.41 1.75
实施例15Sotagliflozin的晶型V的制备方法
称取44.3mg Sotagliflozin固体置于5mL玻璃小瓶中，加入4mL甲醇与水的混合溶剂(甲醇与水的体积比为1/1)，在50℃下固体溶解得到澄清溶液。将澄清溶液转移至5℃的环境，搅拌3天，有白色固体析出。经检测，本实施例得到的固体为本发明的晶型V。
本实施例所得固体的X射线粉末衍射数据如表15所示，其XRPD图如图13所示，DSC图像如图14所示，TGA如图15所示，1H NMR如图16所示。
表15
2theta d间隔 强度％
5.42 16.30 100.00
6.54 13.52 28.05
6.83 12.95 11.09
7.60 11.63 4.48
8.12 10.89 3.11
9.19 9.62 7.06
9.90 8.93 76.05
10.48 8.44 17.21
12.24 7.23 7.96
12.80 6.92 35.18
13.11 6.75 6.18
13.63 6.50 17.96
15.12 5.86 27.13
15.47 5.73 7.98
15.64 5.67 6.59
15.93 5.56 14.04
17.60 5.04 8.76
18.18 4.88 13.48
19.74 4.50 38.20
20.42 4.35 11.13
21.88 4.06 9.62
22.30 3.99 3.88
23.65 3.76 9.75
24.19 3.68 7.87
25.07 3.55 4.58
27.47 3.25 6.05
29.45 3.03 5.02
30.78 2.91 0.93
31.69 2.82 1.11
实施例16Sotagliflozin的晶型V的制备方法
称取101.8mg Sotagliflozin固体置于20mL玻璃瓶中，加入10mL甲醇与水的混合溶剂(甲醇与水的体积比为2/3)，在50℃下固体溶解得到澄清溶液。将澄清溶液转移至5℃的环境，搅拌24小时，有白色固体析出。经检测，本实施例得到的固体为本发明的晶型V。
本实施例所得固体的X射线粉末衍射数据如表16所示，其XRPD图如图38所示。
表16
2theta d间隔 强度％
5.42 16.30 93.32
6.53 13.54 41.77
6.83 12.95 23.87
7.61 11.62 10.71
9.18 9.63 12.99
9.90 8.93 100.00
10.48 8.44 35.35
12.25 7.23 16.13
12.80 6.92 57.47
13.12 6.75 9.19
13.62 6.50 39.72
15.13 5.86 31.65
15.45 5.73 12.61
15.64 5.67 12.42
15.94 5.56 17.52
17.59 5.04 13.03
18.18 4.88 27.23
19.74 4.50 51.29
20.43 4.35 19.73
21.90 4.06 12.93
22.29 3.99 6.02
23.67 3.76 14.82
24.21 3.68 13.74
25.08 3.55 5.95
27.48 3.25 8.99
29.52 3.03 5.95
30.88 2.90 3.78
35.25 2.55 1.96
实施例17Sotagliflozin的晶型VI的制备方法
称取115.0mg Sotagliflozin固体(现有2形晶体)置于5mL玻璃小瓶中，加入3mL水，在50℃下搅拌7天，过滤干燥得到白色固体。经检测，本实施例得到的固体为本发明晶型VI。
本实施例所得固体的X射线粉末衍射数据如表17所示，其XRPD图如图17所示，DSC图像如图18所示，TGA如图19所示，1H NMR如图22所示。
表17
2theta d间隔 强度％
4.80 18.40 51.47
7.24 12.21 4.53
7.74 11.42 31.73
9.51 9.30 100.00
10.68 8.28 25.89
11.06 8.00 18.51
12.88 6.87 3.30
13.35 6.63 6.08
14.13 6.27 31.24
14.51 6.10 62.42
14.69 6.03 52.57
15.55 5.70 17.29
16.13 5.49 3.38
17.67 5.02 2.74
18.61 4.77 15.45
19.12 4.64 32.12
19.41 4.57 7.35
20.00 4.44 25.15
20.60 4.31 8.63
21.50 4.13 31.60
21.93 4.05 3.05
22.26 3.99 4.14
23.77 3.74 6.45
24.32 3.66 4.16
25.42 3.50 23.31
26.48 3.37 4.08
28.87 3.09 6.83
29.65 3.01 13.05
30.88 2.90 2.08
33.54 2.67 1.77
34.48 2.60 2.60
38.64 2.33 0.70
实施例18Sotagliflozin的晶型VI的制备方法
称取18.8mg Sotagliflozin固体(现有2形晶体)置于1.5mL玻璃小瓶中，加入0.8mL水，在50℃下搅拌3天，过滤干燥得到白色固体。经检测，本实施例得到的固体为本发明的晶型VI。
本实施例所得固体的X射线粉末衍射数据如表18所示，其XRPD图如图39所示。
表18
2theta d间隔 强度％
3.61 24.50 18.95
4.81 18.39 92.45
5.97 14.80 10.94
7.71 11.47 14.56
9.51 9.30 100.00
10.66 8.30 18.48
11.05 8.00 23.13
14.14 6.27 38.35
14.51 6.11 94.71
14.70 6.03 58.36
15.55 5.70 10.64
19.11 4.64 46.22
19.42 4.57 12.30
20.00 4.44 30.50
20.59 4.31 8.40
21.50 4.13 30.51
23.75 3.75 12.87
24.33 3.66 6.56
25.41 3.51 34.58
28.89 3.09 11.62
29.64 3.01 18.86
38.58 2.33 1.20
实施例19Sotagliflozin的晶型VII的制备方法
称取5.6mg Sotagliflozin固体(本发明的晶型II)，通过程序升温的方式，以10℃/min的加热速率加热至90℃并在90℃保温0.5min，得到白色固体。经检测，本实施例得到的固体为本发明的晶型VII。
本实施例所得固体的X射线粉末衍射数据如表19所示，其XRPD图如图21所示，DSC如图22所示，TGA如图23所示，1H NMR如图24所示。
表19
2theta d间隔 强度％
3.43 25.76 28.08
6.74 13.12 10.21
9.25 9.56 3.52
10.52 8.41 28.05
11.55 7.66 9.82
12.25 7.23 5.05
13.41 6.60 15.73
13.77 6.43 100.00
15.84 5.60 25.97
16.76 5.29 24.87
18.55 4.78 13.04
19.14 4.64 13.51
20.29 4.38 19.00
20.98 4.23 10.62
22.01 4.04 5.70
22.62 3.93 15.97
23.36 3.81 9.77
24.00 3.71 6.79
25.18 3.54 2.98
26.19 3.40 6.94
26.56 3.36 9.66
27.50 3.24 4.22
28.79 3.10 2.89
31.04 2.88 5.03
32.37 2.77 2.28
33.87 2.65 5.02
34.53 2.60 4.13
37.52 2.40 1.20
实施例20Sotagliflozin的晶型VIII的制备方法
称取1.7mg Sotagliflozin固体(本发明的晶型V)，通过程序升温的方式，以10℃/min的加热速率加热至65℃并在65℃保温2min，得到白色固体。经检测，本实施例得到的固体为本发明的晶型VIII。
本实施例所得固体的X射线粉末衍射数据如表20所示，其XRPD图如图25所示，DSC如图26所示。
表20
2theta d间隔 强度％
6.23 14.19 100.00
6.44 13.72 52.98
8.91 9.93 2.27
10.37 8.53 27.84
10.89 8.12 70.03
12.50 7.08 9.74
13.68 6.47 6.05
14.88 5.95 54.69
15.74 5.63 41.14
17.71 5.01 72.38
18.32 4.84 18.25
18.82 4.72 33.91
19.43 4.57 10.41
19.92 4.46 12.53
20.86 4.26 66.09
21.12 4.21 42.29
21.85 4.07 15.63
24.13 3.69 34.81
26.26 3.39 12.55
27.52 3.24 10.01
28.23 3.16 7.13
29.87 2.99 3.93
31.60 2.83 7.07
33.16 2.70 7.22
37.17 2.42 3.12
实施例21稳定性对比研究试验
将CN102112483A公开的现有2形晶体与本发明的晶型I、晶型II混在一起，并加入到不同水活度体系中进行搅拌，70小时后，用XRPD进行表征，结果如表21所示。
表21
溶剂(V/V) 水活度 起始晶型 最终晶型
H2O/IPA＝6:94 0.5 现有2形晶体、晶型I、晶型II 晶型II
H2O/IPA＝11:89 0.7 现有2形晶体、晶型I、晶型II 晶型II
H2O/IPA＝15:85 0.8 现有2形晶体、晶型I、晶型II 晶型II
H2O/IPA＝23:77 0.9 现有2形晶体、晶型I、晶型II 晶型II
H2O/IPA＝35:65 0.95 现有2形晶体、晶型I、晶型II 晶型II
H2O 1.0 现有2形晶体、晶型I、晶型II 晶型I
该试验说明，在高水活度(高湿度)环境中，高于50％相对湿度时，晶型I、晶型II比现有2形晶体稳定。
需要说明的是，本发明中配制不同水活度所选用的溶剂包括但不限于H2O和IPA，在其他适合配制不同水活度的溶剂中，也能得出与本实验相同的结论。
实施例22本发明的晶型I的引湿性试验
称取13.8mg晶型I置于动态水分吸附仪(DVS)仪器中，在25℃条件下，经历一个20％-95％-0-95％相对湿度变化的循环，在80％相对湿度下增重3.55％，引湿性较低，其实验结果如表22所示，DVS图如图40所示。收集固体进行XRPD测试，晶型未发生改变。
表22
Figure PCTCN2017085813-appb-000008
实施例23本发明的晶型II的引湿性试验
称取10.4mg晶型II置于DVS仪器中，在25℃条件下，经历一个20％-95％-0-95％相对湿度变化的循环，在80％相对湿度下增重2.46％，引湿性较低，其实验结果如表23所示，DVS图如图41所示。收集固体进行XRPD测试，晶型未发生改变。
表23
Figure PCTCN2017085813-appb-000009
Figure PCTCN2017085813-appb-000010
实施例24本发明的晶型III的引湿性试验
称取9.1mg晶型III置于DVS仪器中，在25℃条件下，经历一个20％-95％-0-95％相对湿度变化的循环，在80％相对湿度下增重0.13％，引湿性较低，其实验结果如表24所示，DVS图如图42所示。收集固体进行XRPD测试，晶型未发生改变。
表24
Figure PCTCN2017085813-appb-000011
实施例25本发明的晶型VI的引湿性试验
称取4.5mg晶型VI置于DVS仪器中，在25℃条件下，经历一个20％-95％-0-95％相对湿度变化的循环，在80％相对湿度下增重1.80％，引湿性较低，其实验结果如表25所示，DVS图如图43所示。收集固体进行XRPD测试，晶型未发生改变。
表25
Figure PCTCN2017085813-appb-000012
实施例26溶解度试验
将本发明的晶型I、晶型II、晶型III、晶型VII与现有2形晶体，分别用SGF(模拟人工胃液)配制成饱和溶液，将本发明的晶型II、晶型III、晶型VII、晶型VIII与现有2形晶体，分别用pH6.5FaSSIF(空腹状态下人工肠液)中配制成饱和溶液，在1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。实验结果如表26～27所示。试验结果表明，本发明的晶型I、晶型III与晶型VII溶解度较现有2形晶体在SGF中溶解度显著提升，分别提升为现有2形晶体的1.7倍，2.2倍与2.5倍。本发明晶型III、晶型VII、晶型VIII在FaSSIF的溶解度较现有2形晶体显著提升，分别提升为现有2形晶体的1.4倍、1.5倍和1.4倍。
表26
Figure PCTCN2017085813-appb-000013
Figure PCTCN2017085813-appb-000014
表27
Figure PCTCN2017085813-appb-000015
实施例27稳定性试验
将本发明的晶型I、晶型II、晶型III、晶型VI分别在25℃/60％相对湿度、40℃/75％相对湿度的条件下放置3个月，测定其XRPD。晶型I、II、III、VI放置在上述两个条件下3个月前后的XRPD分别如图44、图45、图46、图47所示。实验结果统计于表28中。结果表明，本发明的晶型I、晶型II、晶型III、晶型VI放置在25℃/60％相对湿度、40℃/75％相对湿度的条件下放置3个月的晶型稳定性好。
表28
Figure PCTCN2017085813-appb-000016
实施例28形貌分析试验
取现有2形晶体与本发明的晶型I分别拍摄偏光显微镜图片，现有2形晶体的偏光显微镜图如图48，本发明的晶型I的偏光显微镜图如49所示。可以看出，现有2形晶体呈细针 状，而本发明的晶型I成棒状，颗粒粒径较为均匀。均匀的粒径有助于简化制剂过程的后处理工艺，提高质量控制。本发明晶型VII的偏光显微镜图如图56所示，可以看出，晶型VII为形貌不规则块状固态，粒径分布均匀，与2形晶体的针状形貌相比，块状晶体流动性更好，可以显著提升原料药的过滤效率，有助于药物在制剂过程中的分散。
实施例29粒度对比试验
取本发明的晶型I、晶型V、晶型VIII与现有2形晶体，分别测试粒度分布，其结果如表29所示。
表29
晶型 MV(μm) SD D10(μm) D50(μm) D90(μm)
现有2形晶体 60.43 59.06 2.32 45.00 144.4
本发明的晶型I 14.48 9.76 3.34 8.97 31.63
本发明的晶型V 32.70 24.46 4.38 18.81 72.98
本发明的晶型VIII 51.93 37.50 7.30 36.60 112.4
经检测，现有2形晶体的PSD图如图50所示，本发明的晶型I的PSD图如图51所示，本发明的晶型V的PSD图如图52所示，本发明的晶型VIII的PSD图如图57所示。
结果表明，现有2形晶体的粒径分布比较宽，且成双峰分布，推测为样品团聚导致，不均匀的粒径分布与颗粒团聚对制剂的均一性会产生十分不利的影响，进而影响药品的溶出，药物的吸收，导致吸收或者溶出不均一，不同的批次有较大的差异。而本发明的晶型I、晶型V、晶型VIII的粒径分布较窄，而且几乎呈现单正态分布，均匀的粒径分布有助于保证制剂的均一性，简化制剂前处理工艺，对药品的开发有积极的影响。
实施例30机械稳定性试验
将本发明的晶型I、晶型VI、现有2形晶体，分别置于研钵中，手动研磨5分钟，测试固体XRPD。现有2形晶体、本发明的晶型I及晶型VI三者研磨前后的XRPD对比图分别如图53至图55所示(上图是研磨之前的XRPD图，下图是研磨5分钟之后的XRPD图)，结果如表30所示。
表30
Figure PCTCN2017085813-appb-000017
结果表明，在一定机械应力的作用下，本发明的晶型I、晶型VI未发生改变，结晶度 仅略有降低，包含少量的无定形，仍可保持稳定的物理化学性质。而现有2形晶体结晶度变弱，大部分变为无定形，机械稳定性差。本发明的晶型I、晶型VI的机械稳定性比现有2形晶体好，更适合成药和储存以及工艺过程。
实施例31本发明的晶型VII的引湿性试验
称取11.5mg晶型VII置于DVS仪器中，在25℃条件下，经历一个0％-95％-0％相对湿度变化的循环，在80％相对湿度下增重1.08％，引湿性较低，其实验结果如表31所示，DVS图如图58所示。收集固体进行XRPD测试，晶型未发生改变。
表31
Figure PCTCN2017085813-appb-000018
实施例32本发明的晶型VIII的引湿性试验
称取10.6mg晶型VIII置于DVS仪器中，在25℃条件下，经历一个0％-95％-0％相对湿度变化的循环，在80％相对湿度下增重0.60％，引湿性较低，其实验结果如表32所示，DVS图如图59所示。收集固体进行XRPD测试，晶型未发生改变。
表32
Figure PCTCN2017085813-appb-000019
本领域技术人员可以理解，在本说明书的教导之下，可以对本发明做出一些修改或变化。这些修改和变化也应当在本发明权利要求所限定的范围之内。

Claims (29)

  1. 一种Sotagliflozin的晶型I，其特征在于，其X射线粉末衍射图在2θ值为3.6°±0.2°、12.7°±0.2°及14.1°±0.2°处具有特征峰。
  2. 根据权利要求1所述的晶型I，其特征在于，其X射线粉末衍射图还在2θ值为15.6°±0.2°、17.1°±0.2°及18.7°±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I，其特征在于，其X射线粉末衍射图还在2θ值为9.0°±0.2°、21.0°±0.2°及25.7°±0.2°中的一处或两处或三处具有特征峰。
  4. 一种Sotagliflozin的晶型II，其特征在于，其X射线粉末衍射图在2θ值为3.7°±0.2°、4.5°±0.2°及14.6°±0.2°处具有特征峰。
  5. 根据权利要求4所述的晶型II，其特征在于，其X射线粉末衍射图在2θ值为13.4°±0.2°、18.1°±0.2°及6.2°±0.2°中的一处或两处或三处具有特征峰。
  6. 根据权利要求4所述的晶型II，其特征在于，其X射线粉末衍射图在2θ值为22.0°±0.2°、10.6°±0.2°及15.9°±0.2°中的一处或两处或三处具有特征峰。
  7. 一种Sotagliflozin的晶型III，其特征在于，其X射线粉末衍射图在2θ值为4.3°±0.2°、14.6°±0.2°及19.6°±0.2°处具有特征峰。
  8. 根据权利要求7所述的晶型III，其特征在于，其X射线粉末衍射图还在2θ值为4.9°±0.2°、15.3°±0.2°及17.5°±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III，其特征在于，其X射线粉末衍射图还在2θ值为12.8°±0.2°、25.0°±0.2°及26.4°±0.2°中的一处或两处或三处具有特征峰。
  10. 一种Sotagliflozin的晶型V，其特征在于，其X射线粉末衍射图在2θ值为5.4°±0.2°、9.9°±0.2°及19.7°±0.2°处具有特征峰。
  11. 根据权利要求10所述的晶型V，其特征在于，其X射线粉末衍射图还在2θ值为12.8°±0.2°、13.6°±0.2°及15.1°±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V，其特征在于，其X射线粉末衍射图还在2θ值为6.5°±0.2°、18.2°±0.2°及20.4°±0.2°中的一处或两处或三处具有特征峰。
  13. 一种Sotagliflozin的晶型VI，其特征在于，其X射线粉末衍射图在2θ值为4.8°±0.2°、9.5°±0.2°及14.5°±0.2°处具有特征峰。
  14. 根据权利要求14所述的晶型VI，其特征在于，其X射线粉末衍射图还在2θ值为11.1°±0.2°、19.1°±0.2°及21.5°±0.2°中的一处或两处或三处具有特征峰。
  15. 根据权利要求14所述的晶型VI，其特征在于，其X射线粉末衍射图还在2θ值为7.7°±0.2°、20.0°±0.2°及25.4°±0.2°中的一处或两处或三处具有特征峰。
  16. 一种Sotagliflozin的晶型VII，其特征在于，其X射线粉末衍射图在2θ值为10.5°±0.2°、13.8°±0.2°及15.8°±0.2°处具有特征峰。
  17. 根据权利要求16所述的晶型VII，其特征在于，其X射线粉末衍射图还在2θ值为16.7°±0.2°、20.3°±0.2°及22.6°±0.2°中的一处或两处或三处具有特征峰。
  18. 根据权利要求16所述的晶型VII，其特征在于，其X射线粉末衍射图还在2θ值为6.7°±0.2°、18.5°±0.2°及19.1°±0.2°中的一处或两处或三处具有特征峰。
  19. 一种Sotagliflozin的晶型VIII，其特征在于，其X射线粉末衍射图在2θ值为6.2°±0.2°、10.9°±0.2°及17.7°±0.2°处具有特征峰。
  20. 根据权利要求19所述的晶型VIII，其特征在于，其X射线粉末衍射图还在2θ值为14.9°±0.2°、15.7°±0.2°及20.9°±0.2°中的一处或两处或三处具有特征峰。
  21. 根据权利要求19所述的晶型VIII，其特征在于，其X射线粉末衍射图还在2θ值为10.4°±0.2°、18.8°±0.2°、24.1°±0.2°中的一处或两处或三处具有特征峰。
  22. 一种如权利要求1所述的Sotagliflozin的晶型I的制备方法，其特征在于，包括：
    1)将Sotagliflozin固体溶于醇类、酮类或环醚类溶剂中得到Sotagliflozin溶液，向所述溶液中缓慢滴加水或者将所述溶液滴加到水中，有固体析出，在室温下搅拌1～72小时，过滤干燥得到白色固体；或
    2)将Sotagliflozin固体加入到水中，配成悬浮液，在室温下悬浮搅拌5～15天，过滤干燥，得到白色固体。
  23. 一种如权利要求4所述的Sotagliflozin的晶型II的制备方法，其特征在于，包括：
    1)将Sotagliflozin固体溶于烷基腈类溶剂中得到Sotagliflozin溶液，向该溶液中缓慢滴加水或者将该溶液滴加到水中，有固体析出，在室温下搅拌1～72小时，过滤干燥得到白色固体；或
    2)将Sotagliflozin固体溶于环醚类或酯类溶剂中Sotagliflozin溶液，向该溶液中缓慢滴加正庚烷或者将该溶液滴加到正庚烷中，有固体析出，在室温下搅拌1～72小时，过滤干燥得到白色固体；或
    3)将Sotagliflozin固体溶于酮类溶剂中得到Sotagliflozin溶液，向该溶液中缓慢滴加甲苯或者将该溶液滴加到甲苯中，有固体析出，在室温下搅拌1～72小时，过滤干燥得到白色固体；或
    4)将Sotagliflozin固体加入到酮类溶剂与水的混合溶剂或烷基腈类溶剂与水的混合溶剂中，在50℃～75℃温度下悬浮搅拌5～20天，过滤干燥。
  24. 一种如权利要求7所述的Sotagliflozin的晶型III的制备方法，其特征在于，包括：将Sotagliflozin固体溶于卤代烷烃或卤代烷烃与烷烃的混合溶剂中，在室温下缓慢挥发得到白色固体。
  25. 一种如权利要求10所述的Sotagliflozin的晶型V的制备方法，其特征在于， 包括：在温度40～70℃下，将Sotagliflozin固体溶于醇类溶剂与水的混合溶剂中，配成澄清溶液，将所得澄清溶液转移至0～10℃的冷却环境，搅拌12～96小时，过滤干燥得到白色固体。
  26. 一种如权利要求13所述的Sotagliflozin的晶型VI的制备方法，其特征在于，包括：将Sotagliflozin固体放入水中，在35～65℃温度下悬浮搅拌24～96小时，过滤干燥，得到所述的Sotagliflozin的晶型VI。
  27. 一种如权利要求16所述的Sotagliflozin的晶型VII的制备方法，其特征在于，包括：将如权利要求4所述的Sotagliflozin的晶型II以5～10℃/分钟的升温速率加热至90～100℃，并在90～100℃保留0.5～5分钟，得到白色固体。
  28. 一种如权利要求19所述的Sotagliflozin的晶型VIII的制备方法，其特征在于，包括：将如权利要求10所述的Sotagliflozin的晶型V的固体加热到60～80℃，并恒定2分钟以上，所得固体即为所述的晶型VIII。
  29. 一种药物组合物，所述药物组合物包含治疗有效量的权利要求1所述的晶型I、权利要求4所述的晶型II、权利要求7所述的晶型III、权利要求10所述的晶型V、权利要求13所述的晶型VI、权利要求16所述的晶型VII或权利要求19所述的晶型VIII或这些晶型的任意组合及药学上可接受的载体、稀释剂或赋形剂。
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