WO2022048613A1 - 一种低氧诱导因子脯氨酰羟化酶抑制剂的晶型及其制备方法 - Google Patents

一种低氧诱导因子脯氨酰羟化酶抑制剂的晶型及其制备方法 Download PDF

Info

Publication number
WO2022048613A1
WO2022048613A1 PCT/CN2021/116336 CN2021116336W WO2022048613A1 WO 2022048613 A1 WO2022048613 A1 WO 2022048613A1 CN 2021116336 W CN2021116336 W CN 2021116336W WO 2022048613 A1 WO2022048613 A1 WO 2022048613A1
Authority
WO
WIPO (PCT)
Prior art keywords
valdurestat
crystal form
solvent
cinnamamide
ray powder
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2021/116336
Other languages
English (en)
French (fr)
Inventor
张娅璇
叶辉青
林碧悦
陈勇
黄芳芳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sunshine Lake Pharma Co Ltd
Original Assignee
Sunshine Lake Pharma Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sunshine Lake Pharma Co Ltd filed Critical Sunshine Lake Pharma Co Ltd
Priority to CN202180052769.6A priority Critical patent/CN115996720A/zh
Publication of WO2022048613A1 publication Critical patent/WO2022048613A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/65—One oxygen atom attached in position 3 or 5

Definitions

  • the invention relates to the field of medicinal chemistry, in particular to a crystal form of a hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor and a preparation method thereof.
  • HIF hypoxia-inducible factor
  • Vadadustat (English name: Vadadustat, CAS number: 1000025-07-9) chemical name is ⁇ [5-(3-chlorophenyl)-3-hydroxypyridine-2-carbonyl]amino ⁇ acetic acid, by Akebia Company Research and development, with the function of treating or preventing anemia, the mechanism of action is hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, which is in clinical phase III as the treatment of anemia caused by secondary chronic kidney disease; its structural formula is shown in the figure shown:
  • HIF hypoxia-inducible factor
  • valdurestat crystal forms A, B and C crystal form B may be converted into crystal form A in the slurry at high temperature, wherein crystal form A is a stable crystal form, but its solubility in water is very poor, Crystalline form B has poor crystallinity and poor stability, and crystal form C has harsh preparation conditions, is difficult to prepare by conventional methods, and has poor reproducibility.
  • Patent WO2015073779A1 does not do more screening research work on the crystal form of valdurestat.
  • the present invention provides a new crystal form of valdurestat and a preparation method and composition thereof.
  • the present invention provides a crystalline form of valdurostat, referred to as a valdurostat-isonicotinoid co-crystal form.
  • a valdurostat-isonicotinoid co-crystal form contains diffraction peaks at 2 theta angles of 14.24, 18.16 and 20.12 degrees.
  • thermogravimetric analysis curve shows that the crystal form has weight loss at 100°C-200°C, and the weight loss is 0.5%-10.0%.
  • the differential scanning calorimetry curve of the crystal form has an endothermic peak at 150°C-210°C.
  • the present invention also provides a method for preparing the valdurestat-isonicotinoid co-crystal form, comprising: dissolving valdurestat in a solvent, then adding isonicotine to the solution, stirring, and filtering , and dried to constant weight to obtain valdurestat-isonicotinoid co-crystal form.
  • the present invention provides a crystalline form of valdurestat, referred to as a valdurestat-cinnamamide co-crystal form.
  • a valdurestat-cinnamamide co-crystal form contains diffraction peaks at 2 ⁇ angles of 4.24, 16.80 and 33.99 degrees.
  • thermogravimetric analysis curve shows that the crystal form has weight loss at 120°C-200°C, and the weight loss is 0.01%-1.5%.
  • the differential scanning calorimetry curve of the crystal form has an endothermic peak at 120°C-180°C.
  • the present invention also provides a method for preparing the valdurestat-cinnamamide co-crystal form, which comprises: dissolving valdurestat in a solvent, then adding cinnamamide to the solution, stirring, filtering, drying to a constant weight to obtain a co-crystal form of valdurestat-cinnamamide.
  • the present invention provides a crystalline form of valdurestat, referred to as a valdurestat-benzamide co-crystal form.
  • a crystalline form of valdurestat referred to as a valdurestat-benzamide co-crystal form.
  • the X-ray powder diffraction pattern of the valdurestat-benzamide co-crystal contains diffraction peaks at 2 ⁇ angles of 6.31, 21.12 and 24.18 degrees.
  • thermogravimetric analysis curve shows that the crystal form has weight loss at 50°C-250°C, and the weight loss is 10.0%-70.0%.
  • the differential scanning calorimetry curve of the crystal form has an endothermic peak at 90°C-150°C.
  • the present invention also provides a method for preparing the valdurestat-benzamide co-crystal form, comprising: dissolving valdurestat in a good solvent, then adding benzamide to the solution, and then adding poor solvent, stirring, a solid was precipitated, filtered, and dried to constant weight to obtain the co-crystal form of valdurestat-benzamide.
  • the present invention provides a crystalline form of valdurostat, referred to as a valdurestat-propionamide co-crystal form.
  • the X-ray powder diffraction pattern of the valdurestat-propionamide co-crystal form contains diffraction peaks at 2 ⁇ angles of 7.37, 15.58 and 20.92 degrees.
  • thermogravimetric analysis curve shows that the crystal form has weight loss at 100°C-180°C, and the weight loss is 1.0%-20.0%.
  • the differential scanning calorimetry curve of the crystal form has an endothermic peak at 80°C-150°C.
  • the present invention also provides a method for preparing the valdurestat-propionamide co-crystal form, which comprises: dissolving valdurestat in a good solvent, then adding propionamide to the solution, and then adding a poor solvent , stirred, a solid was precipitated, filtered, and dried to constant weight to obtain the co-crystal form of valdulostat-propionamide.
  • the present invention also provides a composition comprising any one or more of the aforementioned valdurestat crystal forms.
  • the crystalline form included in the composition is at least 90% of valdurestat in terms of mass ratio. In some embodiments, in terms of mass ratio, in the composition, the crystalline form does not exceed 0.5%-5% of valdurostat.
  • crystal form is used to describe the existing state of a solid compound, and to describe the ionic, atomic or molecular composition, symmetry properties and periodic arrangement of various parameter aggregates within the crystal.
  • relative intensity refers to the ratio of the intensity of the other peaks to the intensity of the first strong peak when the intensity of the first strong peak in a group of diffraction peaks belonging to a certain crystal form is defined as 100%.
  • substantially as shown means that at least 70%, at least 90%, or at least 95%, or at least 99% of the peaks in an X-ray powder diffraction pattern are shown in its pattern.
  • the 2 ⁇ (also known as 2theta or diffraction peak) values in an X-ray powder diffraction pattern are all in degrees (°).
  • the X-ray powder diffraction peaks of the crystalline form, the measurement of the 2 theta or diffraction peaks of its X-ray powder diffraction pattern are subject to experimental error, from one machine to another and from one sample to another , the measurement of the 2 ⁇ or diffraction peaks of the X-ray powder diffraction pattern may vary slightly, and the experimental error or difference may be +/- 0.2 units or +/- 0.1 units or +/- 0.05 units , so the numerical values of the 2 ⁇ or diffraction peaks cannot be regarded as absolute.
  • the differential scanning calorimetry (DSC) curves of the crystal forms are subject to experimental error, and the position and peak of the endothermic peaks may vary slightly from one machine to another and from one sample to another. Differences, experimental errors or differences in numerical values may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C, so the peak position or peak value of the DSC endothermic peak values cannot be considered absolute.
  • thermogravimetric analysis (TGA) of the crystal form has experimental error, the weight loss temperature and amount of weight loss may vary slightly from one machine to another and from one sample to another, experimental error Or the value of the difference may be about +/- 0.1 units, about +/- 0.05 units, or about +/- 0.01 units, so the stated values for temperature of weight loss and amount of weight loss should not be considered absolute.
  • Root temperature means a temperature between about 15°C-32°C or about 20°C-30°C or about 23°C-28°C or about 28°C.
  • the solid when it comes to solid drying, the solid is dried to constant weight.
  • the inventors have developed a crystal form of the compound valdurestat and a preparation method thereof through research.
  • valdurestat-isonicotinoid co-crystal form valdurestat-cinnamamide co-crystal form
  • valdurestat-benzamide co-crystal form valdurestat-propionamide co-crystal form
  • these crystal forms have good properties, high solubility, high bioavailability; or/and good stability, which is conducive to storage, thus meeting the requirements of drug stability ; Low hygroscopicity, or/and good performance in electrostatic, low electrostatic, which is beneficial to operation in the production process.
  • the present invention provides a new crystalline form of valdurostat, which is called a valdurestat-isonicotinoid co-crystal form.
  • the valdurestat-isonicotinoid co-crystal form has the following characteristics: its X-ray powder diffraction pattern comprises diffraction peaks at 2 ⁇ angles of 14.24, 18.16 and 20.12 degrees.
  • the valdurestat-isonicotinoid co-crystalline form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 7.68, 14.24, 15.27, 18.16, 20.12 and 30.43 degree of diffraction peaks.
  • the valdurestat-isonicotinoid co-crystalline form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 7.68, 10.86, 14.24, 15.27, 18.16, 20.12 , 25.84, 29.18, 29.52, 30.43, 31.23, 36.85 and 39.32 degrees of diffraction peaks.
  • the valdurestat-isonicotinoid co-crystalline form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 theta angles of 7.68, 10.86, 25.84, 29.18 and 30.43 degrees Diffraction peaks.
  • the valdurestat-isonicotinoid co-crystalline form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 theta angles of 14.24, 15.27, 29.52, 31.23 and 36.85 degrees Diffraction peaks.
  • the valdurestat-isonicotinoid co-crystalline form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 theta angles of 18.16, 20.12, 25.84, 36.85 and 39.32 degrees Diffraction peaks.
  • the valdurestat-isonicotinoid co-crystal form has an X-ray powder diffraction pattern comprising at least one peak or at least two peaks of diffraction peaks at 2 theta angles of 14.24, 18.16 and 20.12 degrees or three peaks.
  • the X-ray powder diffraction pattern of the valdurostat-isonicotinoid co-crystal form is substantially as shown in FIG. 1 .
  • the valdurestat-isonicotinoid co-crystal form is a co-crystal of valdurestat and isonicotine.
  • the molar ratio of valdurestat to isonicotinoid is 1:1.
  • thermogravimetric analysis curve shows that the crystal form has weight loss at 100°C-200°C, and the weight loss is 0.5%-10.0%.
  • thermogravimetric analysis curve shows that the crystal form has weight loss at 100°C-200°C, and the weight loss is about 2.1%.
  • thermogravimetric analysis plot is substantially as shown in FIG. 2 .
  • the valdurestat-isonicotinoid co-crystal form further has the following characteristics: the differential scanning calorimetry (DSC) curve of the crystal form has an endothermic peak at 150°C-210°C. In some embodiments, the differential scanning calorimetry curve (DSC) of the crystalline form has an endothermic peak at 160°C-200°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the crystalline form has an endothermic peak at 170°C-190°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the crystal form has an endothermic peak at 176°C-180°C, and the endothermic peak peak value is 178°C. In a specific embodiment, the differential scanning calorimetry curve (DSC) of the valdurestat-isonicotinoid co-crystal form is substantially as shown in FIG. 2 .
  • the present invention provides two preparation methods for the co-crystal form of valdurestat-isonicotinoid.
  • the preparation method of the valdurestat-isonicotinoid co-crystal form described in the present invention is simple, easy to operate, mild in conditions, high in yield and high in purity, and is suitable for industrial production.
  • a method for preparing the valdurestat-isonicotinoid co-crystal form comprising: dissolving valdurestat in a solvent, then adding isonicotine to the solution, stirring, filtering, and drying to constant weight, A co-crystal form of valdurestat-isonicotinoid was obtained.
  • the solvent comprises selected from the group consisting of acetone, butanone, N-methylpyrrolidone, ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, n-butyl acetate, isopropyl acetate, At least one of 1,4-dioxane, tetrahydrofuran and acetonitrile.
  • the solvent includes acetone.
  • the solvent is acetone.
  • the concentration is 5 mg/ml-300 mg/ml. In some embodiments, when valdurestat is completely dissolved in the solvent, the concentration is 5mg/ml-200mg/ml; in some embodiments, when valdurestat is completely dissolved in the solvent, the concentration is 5mg/ml- 100mg/ml; in some embodiments, when valdurestat is completely dissolved in the solvent, the concentration is 5mg/ml-50mg/ml; in some embodiments, when valdurestat is completely dissolved in the solvent, the concentration is 10mg/ml-200mg/ml; in some embodiments, when valdurestat is completely dissolved in the solvent, the concentration is 10mg/ml-100mg/ml; in some embodiments, when valdurestat is completely dissolved in the solvent.
  • Another method for preparing the valdurestat-isonicotinoid co-crystal form comprises: dissolving valdurestat in a good solvent, then adding isonicotine to the solution, adding a poor solvent, stirring, The solid was precipitated, filtered, and dried to constant weight to obtain the co-crystal form of valdurostat-isonicotinoid.
  • the good solvent includes at least one selected from acetone, butanone, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, DMF, and DMSO; the poor solvent includes water, n-hexane, cyclohexane At least one of hexane, n-heptane, ether, petroleum ether.
  • the good solvent includes DMF and the poor solvent includes water.
  • the good solvent is DMF and the poor solvent is water.
  • the volume ratio of the good solvent and the poor solvent is 1:1-1:3. In some embodiments, the volume ratio of the good solvent and the poor solvent is 1:1-1:2.5; in some embodiments, the volume ratio of the good solvent and the poor solvent is 1:1- 1:2; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:1-1:1.5. In some embodiments, the volume ratio of the good solvent to the poor solvent is 1:1; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:2; in some embodiments , the volume ratio of the good solvent and the poor solvent is 1:3.
  • the concentration when valdurestat is completely dissolved in a good solvent, the concentration is 5 mg/ml-300 mg/ml. In some embodiments, when valdurestat is completely dissolved in a good solvent, the concentration is 5 mg/ml-200 mg/ml; in some embodiments, when valdurestat is completely dissolved in a good solvent, the concentration is 5 mg/ml ml-100mg/ml; in some embodiments, when valdurestat is completely dissolved in a good solvent, the concentration is 5mg/ml-50mg/ml; in some embodiments, when valdurestat is completely dissolved in a good solvent Then, the concentration is 10mg/ml-200mg/ml; in some embodiments, when valdurostat is completely dissolved in a good solvent, the concentration is 10mg/ml-100mg/ml; After it is
  • the present invention provides a new crystalline form of valdurestat, which is called valdurestat-cinnamamide co-crystal form.
  • the valdurestat-cinnamamide co-crystal form has the following characteristics: its X-ray powder diffraction pattern comprises diffraction peaks at 2 ⁇ angles of 4.24, 16.80 and 33.99 degrees.
  • the valdurestat-cinnamamide co-crystalline form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 theta angles of 4.24, 12.58, 16.80, 21.04, 29.62 and 33.99 degrees diffraction peaks.
  • the valdurestat-cinnamamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 4.24, 8.38, 12.58, 14.14, 16.80, 20.18, Diffraction peaks at 21.04, 25.32, 29.62, 33.99, 38.39 and 39.13 degrees.
  • the valdurestat-cinnamamide co-crystalline form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 4.24, 8.38, 20.18, 25.32, 33.99 and 38.39 degrees diffraction peaks.
  • the valdurestat-cinnamamide co-crystalline form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 theta angles of 12.58, 14.14, 16.80, 20.18, 25.32 and 39.13 degrees diffraction peaks.
  • the valdurestat-cinnamamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 8.38, 14.14, 21.04, 25.32, 29.62 and 38.39 degrees diffraction peaks.
  • the valdurestat-cinnamamide co-crystal form has an X-ray powder diffraction pattern comprising at least one peak or at least two peaks among diffraction peaks at 2 ⁇ angles of 4.24, 16.80 and 33.99 degrees or three peaks.
  • the X-ray powder diffraction pattern of the valdurestat-cinnamamide co-crystal form is substantially as shown in FIG. 3 .
  • the valdurestat-cinnamamide co-crystal form is a co-crystal of valdurestat and cinnamamide.
  • the molar ratio of valdurestat to cinnamamide is 1:1.
  • thermogravimetric analysis curve shows that the crystal form has weight loss at 120°C-200°C, and the weight loss is 0.01%-1.5%.
  • thermogravimetric analysis curve shows that the crystal form has weight loss at 120°C-200°C, and the weight loss is about 0.18%.
  • thermogravimetric analysis plot is substantially as shown in FIG. 4 .
  • the valdurestat-cinnamamide co-crystal form further has the following characteristics: the differential scanning calorimetry (DSC) curve of the crystal form has an endothermic peak at 120°C-180°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the crystalline form has an endothermic peak at 140°C-160°C. In some embodiments, the differential scan of the crystal form has an endothermic peak at 150°C-154°C, and the peak value of the endothermic peak is 152°C. In a specific embodiment, the differential scanning calorimetry curve (DSC) of the valdurestat-cinnamamide co-crystal form is substantially as shown in FIG. 4 .
  • the present invention provides two methods for preparing the valdurestat-cinnamamide co-crystal form.
  • the preparation method of the valdurestat-cinnamamide co-crystal form described in the present invention is simple, easy to operate, mild in conditions, high in yield and high in purity, and is suitable for industrial production.
  • a method for preparing the valdurestat-cinnamamide co-crystal form comprising: dissolving valdurestat in a solvent, then adding cinnamamide to the solution, stirring, filtering, and drying to constant weight to obtain valdurostat Dulastat-cinnamamide co-crystal form.
  • the solvent comprises selected from the group consisting of acetone, butanone, N-methylpyrrolidone, ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, n-butyl acetate, isopropyl acetate, At least one of 1,4-dioxane, tetrahydrofuran and acetonitrile.
  • the solvent includes ethyl acetate. In some embodiments, the solvent is ethyl acetate.
  • the concentration is 5 mg/ml-300 mg/ml. In some embodiments, when valdurestat is completely dissolved in the solvent, the concentration is 5mg/ml-200mg/ml; in some embodiments, when valdurestat is completely dissolved in the solvent, the concentration is 5mg/ml- 100mg/ml; in some embodiments, when valdurestat is completely dissolved in the solvent, the concentration is 5mg/ml-50mg/ml; in some embodiments, when valdurestat is completely dissolved in the solvent, the concentration is 10mg/ml-200mg/ml; in some embodiments, when valdurestat is completely dissolved in the solvent, the concentration is 10mg/ml-100mg/ml; in some embodiments, when valdurestat is completely dissolved in the solvent.
  • Another method for preparing the valdurestat-cinnamamide co-crystal form includes: dissolving valdurestat in a good solvent, then adding cinnamamide to the solution, adding a poor solvent, stirring, and precipitating a solid , filtered, and dried to constant weight to obtain the co-crystal form of valdulostat-cinnamamide.
  • the good solvent includes at least one selected from acetone, butanone, N-methylpyrrolidone, tetrahydrofuran, acetonitrile, DMF, and DMSO; the poor solvent includes water, n-hexane, cyclohexane At least one of hexane, n-heptane, ether, petroleum ether.
  • the good solvent includes DMF and the poor solvent includes water.
  • the good solvent is DMF and the poor solvent is water.
  • the volume ratio of the good solvent and the poor solvent is 1:1-1:3. In some embodiments, the volume ratio of the good solvent and the poor solvent is 1:1-1:2.5; in some embodiments, the volume ratio of the good solvent and the poor solvent is 1:1- 1:2; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:1-1:1.5. In some embodiments, the volume ratio of the good solvent to the poor solvent is 1:1; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:2; in some embodiments , the volume ratio of the good solvent and the poor solvent is 1:3.
  • the concentration when valdurestat is completely dissolved in a good solvent, the concentration is 5 mg/ml-300 mg/ml. In some embodiments, when valdurestat is completely dissolved in a good solvent, the concentration is 5 mg/ml-200 mg/ml; in some embodiments, when valdurestat is completely dissolved in a good solvent, the concentration is 5 mg/ml ml-100mg/ml; in some embodiments, when valdurestat is completely dissolved in a good solvent, the concentration is 5mg/ml-50mg/ml; in some embodiments, when valdurestat is completely dissolved in a good solvent Then, the concentration is 10mg/ml-200mg/ml; in some embodiments, when valdurostat is completely dissolved in a good solvent, the concentration is 10mg/ml-100mg/ml; After it is completely completely
  • the present invention provides a new crystalline form of valdurestat, called valdurestat-benzamide co-crystal form.
  • the valdurestat-benzamide co-crystal form has the following characteristics: its X-ray powder diffraction pattern comprises diffraction peaks at 2 ⁇ angles of 6.31, 21.12 and 24.18 degrees.
  • the valdurestat-benzamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 6.31, 15.58, 17.59, 21.12, 24.18 and 25.05 degree of diffraction peaks.
  • the valdurestat-benzamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 6.31, 9.22, 10.41, 13.50, 14.98, 15.58 , 17.59, 18.24, 18.99, 20.93, 21.12, 24.18, 25.05, 27.42, 27.91, 28.06, 33.63 and 36.51 degrees of diffraction peaks.
  • the valdurestat-benzamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 6.31, 9.22, 10.41, 25.05, 27.42 and 33.63 degree of diffraction peaks.
  • the valdurestat-benzamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 13.50, 15.58, 18.24, 20.93, 24.18 and 36.51 degree of diffraction peaks.
  • the valdurestat-benzamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 14.98, 17.59, 18.99, 21.12, 27.91 and 28.06 degree of diffraction peaks.
  • the valdurestat-benzamide co-crystal form has an X-ray powder diffraction pattern comprising at least one peak or at least two peaks among diffraction peaks at 2 ⁇ angles of 6.31, 21.12 and 24.18 degrees or three peaks.
  • the X-ray powder diffraction pattern of the valdurestat-benzamide co-crystal form is substantially as shown in FIG. 5 .
  • the valdurestat-benzamide co-crystal form is a co-crystal of valdurestat and benzamide.
  • the molar ratio of valdurestat to benzamide is 1:2.
  • thermogravimetric analysis curve shows that the crystal form has weight loss at 50°C-250°C, and the weight loss is 10.0%-70.0%.
  • thermogravimetric analysis curve shows that the crystal form has weight loss at 50°C-250°C, and the weight loss is about 45.3%.
  • thermogravimetric analysis plot is substantially as shown in FIG. 6 .
  • the valdurestat-benzamide co-crystal form further has the following characteristics: the differential scanning calorimetry (DSC) curve of the crystal form has an endothermic peak at 90°C-150°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the crystalline form has an endothermic peak at 100°C-140°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the crystalline form has an endothermic peak at 110°C-130°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the crystalline form has an endothermic peak at 117°C-121°C, and the endothermic peak peak value is 119°C. In a specific embodiment, the differential scanning calorimetry (DSC) curve of the valdurestat-benzamide co-crystal form is substantially as shown in FIG. 6 .
  • the present invention provides a method for preparing the valdurestat-benzamide co-crystal form.
  • the preparation method of the valdurestat-benzamide co-crystal form described in the present invention is simple, easy to operate, mild in conditions, high in yield and high in purity, and is suitable for industrial production.
  • a method for preparing the valdurestat-benzamide co-crystal form comprising: dissolving valdurestat in a good solvent, then adding benzamide to the solution, adding a poor solvent, stirring, and separating out The solid was filtered and dried to constant weight to obtain the co-crystal form of valdulostat-benzamide.
  • the good solvent includes at least one selected from acetone, butanone, N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, acetonitrile, DMF, and DMSO; the poor solvent It includes at least one selected from water, n-hexane, cyclohexane, n-heptane, diethyl ether, and petroleum ether.
  • the good solvent includes acetone, and the poor solvent includes n-heptane.
  • the good solvent is acetone, and the poor solvent is n-heptane.
  • the volume ratio of the good solvent to the poor solvent is 1:1-1:4. In some embodiments, the volume ratio of the good solvent to the poor solvent is 1:1-1:3.5; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:1- 1:3; in some embodiments, the volume ratio of the good solvent and the poor solvent is 1:1-1:2.5; in some embodiments, the volume ratio of the good solvent and the poor solvent is 1:1-1:2; in some embodiments, the volume ratio of the good solvent and the poor solvent is 1:1-1:1.5.
  • the volume ratio of the good solvent to the poor solvent is 1:1; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:2; in some embodiments , the volume ratio of the good solvent and the poor solvent is 1:3; in some embodiments, the volume ratio of the good solvent and the poor solvent is 1:4.
  • the concentration is 5 mg/ml-300 mg/ml. In some embodiments, when valdurestat is completely dissolved in a good solvent, the concentration is 5 mg/ml-200 mg/ml; in some embodiments, when valdurestat is completely dissolved in a good solvent, the concentration is 5 mg/ml ml-100mg/ml; in some embodiments, when valdurestat is completely dissolved in a good solvent, the concentration is 5mg/ml-50mg/ml; in some embodiments, when valdurestat is completely dissolved in a good solvent Then, the concentration is 10mg/ml-200mg/ml; in some embodiments, when valdurostat is completely dissolved in a good solvent, the concentration is 10mg/ml-100mg/ml; After it is completely dissolved in dissolved in
  • the present invention provides a new crystalline form of valdurestat, called valdurestat-propionamide co-crystal form.
  • the valdurestat-propionamide co-crystal form has the following characteristics: its X-ray powder diffraction pattern comprises diffraction peaks with 2 ⁇ angles of 7.37, 15.58 and 20.92 degrees.
  • the valdurestat-propionamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 7.37, 9.11, 15.58, 17.18, 20.92 and 31.08 degrees diffraction peaks.
  • the valdurestat-propionamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystal form comprises 2 ⁇ angles of 7.37, 9.11, 11.09, 13.66, 13.93, 14.82, Diffraction peaks at 15.58, 17.18, 18.11, 20.42, 20.92, 21.69, 22.37, 23.99, 24.78, 28.12, 28.34 and 31.08 degrees.
  • the valdurestat-propionamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 7.37, 13.93, 14.82, 21.69, 28.34 and 31.08 degrees diffraction peaks.
  • the valdurestat-propionamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 9.11, 11.09, 13.66, 20.92, 22.37 and 24.78 degrees diffraction peaks.
  • the valdurestat-propionamide co-crystal form has the following characteristics: the X-ray powder diffraction pattern of the crystalline form comprises 2 ⁇ angles of 15.58, 17.18, 18.11, 20.42, 23.99 and 28.12 degrees diffraction peaks.
  • the valdurestat-propionamide co-crystal form has an X-ray powder diffraction pattern comprising at least one peak or at least two peaks among diffraction peaks at 2 ⁇ angles of 7.37, 15.58 and 20.92 degrees or three peaks.
  • the X-ray powder diffraction pattern of the valdurestat-propionamide co-crystal form is substantially as shown in FIG. 7 .
  • the valdurestat-propionamide co-crystal form is a co-crystal of valdurestat and propionamide.
  • the molar ratio of valdurostat to propionamide is 1:2.
  • the valdurestat-propionamide co-crystal form also has the following characteristics: the thermogravimetric analysis curve (TGA) shows that the crystal form has weight loss at 100°C-180°C, and the weight loss is 1.0%-20.0%. In some embodiments, the thermogravimetric analysis curve (TGA) shows that the crystal form has weight loss at 100°C-180°C, and the weight loss is about 12.1%. In a specific embodiment, the thermogravimetric analysis plot (TGA) is substantially as shown in FIG. 8 .
  • the valdurestat-propionamide co-crystal form also has the following characteristics: the differential scanning calorimetry (DSC) curve of the crystal form has an endothermic peak at 80°C-150°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the crystalline form has an endothermic peak at 100°C-130°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the crystalline form has an endothermic peak at 110°C-120°C. In some embodiments, the differential scanning calorimetry (DSC) curve of the crystalline form has an endothermic peak at 112°C-116°C, and the endothermic peak peak value is 114°C. In a specific embodiment, the differential scanning calorimetry curve (DSC) of the valdurestat-propionamide co-crystal form is substantially as shown in FIG. 8 .
  • the present invention provides a method for preparing the co-crystal form of valdurestat-propionamide.
  • the preparation method of the valdurestat-propionamide co-crystal form described in the present invention is simple, the operation is convenient, the conditions are mild, the yield is high, the purity is high, and is suitable for industrial production.
  • a method for preparing the valdurestat-propionamide co-crystal form comprising: dissolving valdurestat in a good solvent, then adding propionamide to the solution, then adding a poor solvent, stirring, and precipitating a solid, Filtration and drying to constant weight to obtain valdurestat-propionamide co-crystal form.
  • the good solvent includes at least one selected from ethyl acetate, ethyl formate, dimethyl carbonate, methyl acetate, n-butyl acetate, isopropyl acetate, tetrahydrofuran, acetonitrile, DMF, DMSO One; the poor solvent includes at least one selected from n-hexane, cyclohexane, n-heptane, diethyl ether and petroleum ether.
  • the good solvent includes ethyl acetate, and the poor solvent includes n-heptane.
  • the good solvent is ethyl acetate, and the poor solvent is n-heptane.
  • the volume ratio of the good solvent and the poor solvent is 1:1-1:3. In some embodiments, the volume ratio of the good solvent and the poor solvent is 1:1-1:2.5; in some embodiments, the volume ratio of the good solvent and the poor solvent is 1:1- 1:2; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:1-1:1.5. In some embodiments, the volume ratio of the good solvent to the poor solvent is 1:1; in some embodiments, the volume ratio of the good solvent to the poor solvent is 1:2; in some embodiments , the volume ratio of the good solvent and the poor solvent is 1:3.
  • the concentration is 5 mg/ml-300 mg/ml. In some embodiments, when valdurestat is completely dissolved in a good solvent, the concentration is 5 mg/ml-200 mg/ml; in some embodiments, when valdurestat is completely dissolved in a good solvent, the concentration is 5 mg/ml ml-100mg/ml; in some embodiments, when valdurestat is completely dissolved in a good solvent, the concentration is 5mg/ml-50mg/ml; in some embodiments, when valdurestat is completely dissolved in a good solvent Then, the concentration is 10mg/ml-200mg/ml; in some embodiments, when valdurostat is completely dissolved in a good solvent, the concentration is 10mg/ml-100mg/ml; After it is completely dissolved in dissolved in
  • the present invention also provides a composition comprising any one of the aforementioned crystalline forms of valdurestat.
  • the crystalline form or salt is at least 90% of valdurostat, or the crystalline form does not exceed 0.5%-5% of valdurestat.
  • the composition comprises: at least one of the aforementioned crystal forms, and a pharmaceutically acceptable adjuvant or carrier; wherein, in a weight ratio, in terms of valdurestat, the crystal form Either the salt is at least 90% of valdurostat, or the crystalline form is no more than 0.5%-5% of valdurostat.
  • a composition comprises the aforementioned crystalline form of valdurestat, wherein the crystalline form is at least 90% of valdurestat.
  • a composition comprises the aforementioned crystalline form of valdurestat, wherein the crystalline form is at least 95%, or at least 99% of valdurestat.
  • a composition comprises the aforementioned crystalline form of valdurestat, wherein the crystalline form is at least 0.5%-5% of valdurestat in terms of weight ratio.
  • a composition comprises the aforementioned crystalline form of valdurestat, wherein the crystalline form is at least 5% of valdurostat.
  • a composition comprises the aforementioned crystalline form of valdurestat, wherein the crystalline form does not exceed 0.5%-5% of valdurestat in terms of weight ratio. In some embodiments, a composition comprises the aforementioned crystalline form of valdurestat, wherein the crystalline form does not exceed 5% of valdurostat in terms of weight ratio.
  • a composition comprising the aforementioned crystalline form of valdurestat, the crystalline form is valdurestat-isonicotinoid co-crystal form, valdurestat-cinnamamide co-crystal form At least one of valdurestat-benzamide co-crystal form, valdurestat-propionamide co-crystal form.
  • a composition comprising the aforementioned valdurestat-isonicotinoid co-crystal form, valdurestat-cinnamamide co-crystal form, valdurestat-benzamide co-crystal form Form, valdulostat-propionamide co-crystal form.
  • a composition comprising the aforementioned valdurestat-isonicotinoid co-crystal form, valdurestat-cinnamamide co-crystal form, valdurestat-benzyl At least one of the amide co-crystal form and the valdurestat-propionamide co-crystal form; wherein, in terms of valdurestat, the crystalline form is at least 90% of that of valdurestat.
  • a composition comprising the aforementioned valdurestat-isonicotinoid co-crystal form, valdurestat-cinnamamide co-crystal form, valdurestat-benzyl Amide co-crystal form, valdurestat-propionamide co-crystal form, wherein the crystal form is at least 90% of valdurestat.
  • a composition comprising the aforementioned valdurestat-isonicotinoid co-crystal form, valdurestat-cinnamamide co-crystal form, valdurestat-benzyl Amide co-crystal form, valdurestat-propionamide co-crystal form, wherein the crystal form is at least 95%, or at least 99% of valdurestat.
  • a composition comprising the aforementioned valdurestat-isonicotinoid co-crystal form, valdurestat-cinnamamide co-crystal form, valdurestat-benzyl At least one of the amide co-crystal form and the valdurestat-propionamide co-crystal form; wherein, in terms of valdurestat, the crystalline form is at least 0.5%-5% of the valdurestat.
  • a composition comprising the aforementioned valdurestat-isonicotinoid co-crystal form, valdurestat-cinnamamide co-crystal form, valdurestat-benzyl Amide co-crystal form, valdurestat-propionamide co-crystal form, wherein the crystal form is at least 0.5%-5% of valdurestat.
  • a composition comprising the aforementioned valdurestat-isonicotinoid co-crystal form, valdurestat-cinnamamide co-crystal form, valdurestat-benzyl Amide co-crystal form, valdurestat-propionamide co-crystal form, wherein the crystal form is at least 5% of valdurestat.
  • a composition comprising the aforementioned valdurestat-isonicotinoid co-crystal form, valdurestat-cinnamamide co-crystal form, valdurestat-benzyl Amide co-crystal form and valdurestat-propionamide co-crystal form, wherein the crystal form does not exceed 0.5%-5% of valdurestat.
  • a composition comprising the aforementioned valdurestat-isonicotinoid co-crystal form, valdurestat-cinnamamide co-crystal form, valdurestat-benzyl Amide co-crystal form and/or valdurestat-propionamide co-crystal form, wherein the crystal form does not exceed 5% of valdurestat.
  • the composition may also include pharmaceutically acceptable adjuvants or carriers.
  • the pharmaceutically acceptable adjuvants or carriers may include fillers, diluents, lubricants and the like.
  • the composition further comprises a pharmaceutically acceptable adjuvant or carrier including a lubricant.
  • the lubricant is magnesium stearate.
  • composition can be prepared into any suitable pharmaceutical preparations, such as tablets, capsules, granules, suspensions, or injections.
  • Figure 1 shows the X-ray powder diffraction pattern (XRPD) of valdurestat-isonicotinoid co-crystal form
  • Figure 2 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of valdurestat-isonicotinoid co-crystal form
  • Figure 3 shows the X-ray powder diffraction pattern (XRPD) of the valdurestat-cinnamamide co-crystal form
  • Figure 4 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of valdurestat-cinnamamide co-crystal form
  • Figure 5 shows the X-ray powder diffraction pattern (XRPD) of the valdurestat-benzamide co-crystal form
  • Figure 6 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of valdurestat-benzamide co-crystal form
  • Figure 7 shows the X-ray powder diffraction pattern (XRPD) of the co-crystal form of valdurestat-propionamide
  • Figure 8 shows differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) of valdurestat-propionamide co-crystal form
  • Figure 9 shows the X-ray powder diffraction pattern (XRPD) of the valdurestat-isonicotinoid co-crystal form before and after being placed under the conditions of high temperature, high humidity and light for 15 days (from bottom to top: 0 day, high humidity 15 days, high temperature 15 days, light 15 days);
  • XRPD X-ray powder diffraction pattern
  • Figure 10 shows the X-ray powder diffraction pattern (XRPD) of the valdurestat-cinnamamide co-crystal form before and after being placed under the conditions of high temperature, high humidity and light for 15 days (from bottom to top: 0 days, high humidity 15 days) day, high temperature for 15 days, light for 15 days);
  • XRPD X-ray powder diffraction pattern
  • Figure 11 shows the X-ray powder diffraction pattern (XRPD) of the valdurestat-benzamide co-crystal form before and after being placed under the conditions of high temperature, high humidity and light for 15 days (from bottom to top: 0 day, high humidity 15 days, high temperature 15 days, light 15 days);
  • XRPD X-ray powder diffraction pattern
  • Figure 12 shows the X-ray powder diffraction pattern (XRPD) of the valdurestat-propionamide co-crystal form before and after being placed under the conditions of high temperature, high humidity and light for 15 days (from bottom to top: 0 days, high humidity 15 days) day, high temperature for 15 days, light for 15 days);
  • XRPD X-ray powder diffraction pattern
  • Figure 13 shows the X-ray powder diffraction pattern (XRPD) of the valdurestat-isonicotinoid co-crystal form before and after being placed under long-term stability conditions for 12 months (from bottom to top: 0 days, long-term 12 months) ;
  • XRPD X-ray powder diffraction pattern
  • Figure 14 shows the X-ray powder diffraction pattern (XRPD) of the valdulostat-benzamide co-crystal form before and after being placed under long-term stability conditions for 12 months (from bottom to top: 0 days, long-term 12 months) .
  • XRPD X-ray powder diffraction pattern
  • the reagents used in the present invention can be purchased from the market or can be prepared by the methods of the prior art or by the methods described in the present invention.
  • °C degrees Celsius
  • mg represents milligrams
  • mL represents milliliters
  • h hours
  • min represents minutes
  • DMF is N,N-dimethylformamide
  • DMSO dimethyl sulfoxide.
  • X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with a transflective sample stage equipped with an automated 3*15 zero background sample holder.
  • the radiation source used is (Cu, k ⁇ , K ⁇ 1 1.540598; K ⁇ 2 1.544426; K ⁇ 2/K ⁇ 1 intensity ratio: 0.50), where the voltage is set at 45KV and the current is set at 40mA.
  • the beam divergence of X-rays that is, the effective size of the X-ray confinement on the sample, is 10mm. Using ⁇ - ⁇ Continuous scan mode to obtain an effective 2 ⁇ range of 3° to 60°.
  • TGA measurements were performed in a TA Instruments TM Model Q500.
  • the operation step is to peel the empty crucible, take about 10 mg of solid sample, put it in the peeled empty crucible, and spread it evenly.
  • data were collected at a heating rate of 10°C/min between room temperature and 300°C under nitrogen purging, and the spectrum was recorded.
  • the abscissa represents the temperature (Temperature, °C)
  • the ordinate represents the mass percentage (Weight, %).
  • valdurestat crude product (not limited to solid form) was added to 5ml of acetone solvent, stirred at room temperature to obtain a clear solution, then slowly added isonicotine 61.06mg, stirred for one day, and precipitated a white solid, suction filtered and placed in Vacuum drying at 50°C for 24 hours in a drying oven to obtain about 140 mg of white solid.
  • X-ray powder diffraction pattern, its DSC and TGA patterns are shown in Figure 1 and Figure 2.
  • valdurestat crude product (not limited to solid form) was added to 5ml of ethyl acetate solvent, heated to 50°C and stirred to obtain a clear solution, then slowly added 73.58mg of cinnamamide, cooled to room temperature and stirred for one day, and a white solid was precipitated. , filtered with suction and vacuum-dried at 50°C for 24h in a drying oven to obtain about 130 mg of a white solid. After determination, its X-ray powder diffraction pattern, its DSC and TGA patterns are shown in Figure 3 and Figure 4 .
  • valdurostat crude product (not limited to solid form) was added to 1ml of DMF solvent, stirred at room temperature to obtain a clear solution, then slowly added cinnamamide 73.58mg, stirred at room temperature without precipitation of solid, then added 2ml of water, stirred A white solid was precipitated overnight, filtered with suction and dried in a drying oven at 50° C. under vacuum for 24 h to obtain about 130 mg of a white solid. After determination, its X-ray powder diffraction pattern, its DSC and TGA patterns are shown in Figure 3 and Figure 4 .
  • valdurestat crude product (not limited to solid form) was added to 2ml of acetone solvent, stirred at room temperature to obtain a clear solution, then slowly added benzamide 121mg, stirred at room temperature without precipitation of solid, then added 6ml of n-heptane , stirred overnight to separate out a white solid, suction filtered and vacuum-dried at 50°C in a drying oven for 24 h to obtain about 150 mg of a white solid.
  • its X-ray powder diffraction pattern, its DSC and TGA patterns are shown in Figure 5 and Figure 6 .
  • valdurostat crude product (not limited to solid form) was added to 2ml of ethyl acetate solvent, heated to 50°C and stirred to dissolve, slowly added propionamide 73.09mg, stirred at room temperature without precipitation of solid, then added 4ml of n-heptane alkane, stirred overnight to precipitate a white solid, filtered with suction and vacuum-dried at 50°C for 24 h in a drying oven to obtain about 100 mg of a white solid. After measurement, its X-ray powder diffraction pattern, its DSC and TGA patterns are shown in Figure 7 and Figure 8 .
  • the solubility of durestat-isonicotinoid co-crystal in water is 1.6 times that of valdurestat form A, and the solubility of valdurestat-benzamide co-crystal in water is 1.18 times that of valdurestat form A ;
  • the solubility of valdurestat-isonicotinoid co-crystal in pH 6.8 buffer is 1.2 times that of valdurestat crystal form A, and the solubility of valdurestat-benzamide co-crystal in pH 6.8 buffer
  • the solubility of valdurestat in crystalline form A is 1.8 times that of valdurestat; the solubility of valdurestat-cinnamamide co-crystal in pH 6.8 buffer is also higher, which is 1.8 times that of valdurestat crystalline form A.
  • Valdurestat Form A 1.0457 Valdurestat-isonicotinoid co-crystal 1.252 Valdurestat-cinnamamide co-crystal 1.9224 Valdurestat-benzamide co-crystal 1.9172 Valdurestat-Propionamide Co-crystal 1.0296
  • High temperature test Take appropriate amount of crystal samples respectively, lay them flat in weighing bottles, and place them in a constant temperature and humidity box at 60°C ⁇ 5°C and RH 75 ⁇ 5%, and then take the above samples at 0, 5 and 15 days respectively. 100 mg, and its crystal form was tested by powder X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).
  • XRPD powder X-ray powder diffraction
  • DSC differential scanning calorimetry
  • High humidity test Take appropriate amount of crystal samples respectively, lay them flat in weighing bottles, and place them in a constant temperature and humidity box at 25°C and RH 92.5 ⁇ 5%, and then take about 100mg of the above samples at 0, 5 and 15 days, respectively.
  • the crystal form was tested by powder X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

涉及药物化学领域，具体涉及一种低氧诱导因子脯氨酰羟化酶抑制剂的晶型及其制备方法。所述晶型的X射线粉末衍射图包含2θ角为14.24，18.16和20.12度的衍射峰，或者包含2θ角为4.24，16.80和33.99度的衍射峰，或者包含2θ角为6.31，21.12和24.18度的衍射峰，或者包含2θ角为7.37，15.58和20.92度的衍射峰。其中，所述晶型具有较好的性能，可用于治疗或预防贫血；所述晶型的制备方法简单、操作方便，条件温和。

Description

一种低氧诱导因子脯氨酰羟化酶抑制剂的晶型及其制备方法 技术领域
本发明涉及药物化学领域，具体地，本发明涉及一种低氧诱导因子(HIF)脯氨酰羟化酶抑制剂的晶型及其制备方法。
背景技术
伐度司他(英文名：Vadadustat，CAS号：1000025-07-9)化学名称为{[5-(3-氯苯基)-3-羟基吡啶-2-羰基]氨基}乙酸，由Akebia公司研发，具有治疗或预防贫血的功能，作用机制为低氧诱导因子(HIF)脯氨酰羟化酶抑制剂，其作为治疗继发性慢性肾病引发的贫血症处于临床三期；其结构式如图所示：
Figure PCTCN2021116336-appb-000001
原研Akebia公司在WO2015073779A1公开了伐度司他晶型A、B、C，晶型B高温下在浆液中可能转换为晶型A，其中晶型A是稳定晶型，但其水中溶解度非常差，晶型B结晶度差，稳定性较差，晶型C其制备条件苛刻，难以通过常规方法制备，可重现性差。专利WO2015073779A1未对伐度司他的晶型做更多的筛选研究工作。
因此，本领域仍需要系统全面的开发伐度司他不同晶型，以找到更适合药物开发的新晶型和/或共晶。
发明内容
发明概述
本发明提供了伐度司他的新晶型及其制备方法和组合物。
一方面，本发明提供了伐度司他的晶型，称为伐度司他-异烟碱共晶晶型。伐度司他-异烟碱共晶晶型的X射线粉末衍射图包含2θ角为14.24，18.16和20.12度的衍射峰。
热重分析曲线显示所述晶型在100℃-200℃有失重，失重量为0.5％-10.0％。
所述晶型的差示扫描量热曲线在150℃-210℃处具有吸热峰。
本发明还提供了一种制备所述伐度司他-异烟碱共晶晶型的方法，其包括：将伐度司他溶解于溶剂中， 然后在溶液中加入异烟碱，搅拌，过滤，干燥至恒重，得到伐度司他-异烟碱共晶晶型。
一方面，本发明提供了伐度司他的晶型，称为伐度司他-肉桂酰胺共晶晶型。伐度司他-肉桂酰胺共晶晶型的X射线粉末衍射图包含2θ角为4.24，16.80和33.99度的衍射峰。
热重分析曲线显示所述晶型在120℃-200℃有失重，失重量为0.01％-1.5％。
所述晶型的差示扫描量热曲线在120℃-180℃处具有吸热峰。
本发明还提供了一种制备所述伐度司他-肉桂酰胺共晶晶型的方法，其包括：将伐度司他溶解于溶剂中，然后在溶液中加入肉桂酰胺，搅拌，过滤，干燥至恒重，得到伐度司他-肉桂酰胺共晶晶型。
一方面，本发明提供了伐度司他的晶型，称为伐度司他-苯甲酰胺共晶晶型。伐度司他-苯甲酰胺共晶晶型的X射线粉末衍射图包含2θ角为6.31，21.12和24.18度的衍射峰。
热重分析曲线显示所述晶型在50℃-250℃有失重，失重量为10.0％-70.0％。
所述晶型的差示扫描量热曲线在90℃-150℃处具有吸热峰。
本发明还提供了一种制备所述伐度司他-苯甲酰胺共晶晶型的方法，其包括：将伐度司他溶解于良溶剂中，然后在溶液中加入苯甲酰胺，再加入不良溶剂，搅拌，析出固体，过滤，干燥至恒重，得到伐度司他-苯甲酰胺共晶晶型。
一方面，本发明提供了伐度司他的晶型，称为伐度司他-丙酰胺共晶晶型。伐度司他-丙酰胺共晶晶型晶型的X射线粉末衍射图包含2θ角为7.37，15.58和20.92度的衍射峰。
热重分析曲线显示所述晶型在100℃-180℃有失重，失重量为1.0％-20.0％。
所述晶型的差示扫描量热曲线在80℃-150℃处具有吸热峰。
本发明还提供了一种制备所述伐度司他-丙酰胺共晶晶型的方法，其包括：将伐度司他溶解于良溶剂中，然后在溶液中加入丙酰胺，再加入不良溶剂，搅拌，析出固体，过滤，干燥至恒重，得到伐度司他-丙酰胺共晶晶型。
另一方面，本发明还提供一种组合物，所述组合物包含任意一种或多种前述的伐度司他晶型。在一些实施方式中，按照质量比计，所述组合物包括的所述晶型为伐度司他的至少90％。在一些实施方式中，按照质量比计，所述组合物中，所述晶型不超过伐度司他的0.5％-5％。
术语定义
术语“包含”或“包括”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
术语“晶型”用来描述固体化合物的存在状态，描述晶体内部的离子、原子或分子组成、对称性质与周期排列规律的多种参量集合体。
术语“相对强度”是指将归属于某一晶型的一组衍射峰中的第一强峰的强度定义为100％时，其它峰的强度与第一强峰的强度的比值。
术语“基本上如图所示”是指X-射线粉末衍射图中至少70％，至少90％，或至少95％，或至少99％的峰显示在其图中。
在本发明的上下文中，X-射线粉末衍射图中的2θ(又称2theta或衍射峰)值均以度(°)为单位。
当提及图谱和/或图中数据，术语“衍射峰”是指本领域的技术人员不会归属于背景噪音的一个特征。
所述晶型的X-射线粉末衍射峰，其X-射线粉末衍射图谱的2θ或衍射峰的量度有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，X-射线粉末衍射图谱的2θ或衍射峰的量度可能会略有差别，所述实验误差或差别的数值可能是+/-0.2个单位或+/-0.1个单位或+/-0.05个单位，因此所述2θ或衍射峰的数值不能视为绝对的。
所述晶型的差示扫描量热曲线(DSC)有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，吸热峰的位置和峰值可能会略有差别，实验误差或差别的数值可能小于等于5℃，或小于等于4℃，或小于等于3℃，或小于等于2℃，或小于等于1℃，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。
所述晶型的热重分析(TGA)有实验误差，在一台机器和另一台机器之间以及一个样品和另一个样品之间，失重温度和失重的量可能会略有差别，实验误差或差别的数值可能是大约+/-0.1个单位，大约+/-0.05个单位，或者大约+/-0.01个单位，因此所述失重温度和失重的量的数值不能视为绝对的。
在本发明上下文中，无论是否使用“大约”或“约”等字眼，所有在此公开了的数字均为近似值，每一个数字的数值有可能会出现±1％，±2％，或±5％等差异。
“室温”是指温度在大约15℃-32℃或大约20℃-30℃或大约23℃-28℃或大约28℃。
本发明中，涉及到固体干燥时，固体干燥至恒重。
发明详述
发明人通过研究开发了化合物伐度司他的晶型及其制备方法。
本发明提供的伐度司他的晶型，称为伐度司他-异烟碱共晶晶型，伐度司他-肉桂酰胺共晶晶型，伐度司他-苯甲酰胺共晶晶型，伐度司他-丙酰胺共晶晶型，这些晶型具有良好的性能，溶解度高，生物利用度高；或/和在稳定性方面良好，有利于储存，从而符合药物稳定性的要求；吸湿性低，或/和在静电性方面具有良好的性能，静电性低，有利于生产工艺中操作。
第一方面，本发明提供了伐度司他的新晶型，称为伐度司他-异烟碱共晶晶型。
所述伐度司他-异烟碱共晶晶型，具有如下特性：其X射线粉末衍射图包含2θ角为14.24，18.16和 20.12度的衍射峰。
在一些实施方式中，所述伐度司他-异烟碱共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为7.68，14.24，15.27，18.16，20.12和30.43度的衍射峰。
在一些实施方式中，所述伐度司他-异烟碱共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为7.68，10.86，14.24，15.27，18.16，20.12，25.84，29.18，29.52，30.43，31.23，36.85和39.32度的衍射峰。
在一些实施方式中，所述伐度司他-异烟碱共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为7.68，10.86，25.84，29.18和30.43度的衍射峰。
在一些实施方式中，所述伐度司他-异烟碱共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为14.24，15.27，29.52，31.23和36.85度的衍射峰。
在一些实施方式中，所述伐度司他-异烟碱共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为18.16，20.12，25.84，36.85和39.32度的衍射峰。
在一些实施方式中，所述伐度司他-异烟碱共晶晶型，其X射线粉末衍射图包含2θ角为14.24，18.16和20.12度的衍射峰中的至少一个峰或至少两个峰或三个峰。
在一些具体实施方案中，伐度司他-异烟碱共晶晶型的X射线粉末衍射图基本上如图1所示。
所述伐度司他-异烟碱共晶晶型，为伐度司他与异烟碱的共晶。在一些实施方式中，所述伐度司他与异烟碱的摩尔比为1:1。
所述伐度司他-异烟碱共晶晶型，还具有如下特性：热重分析曲线(TGA)显示晶型在100℃-200℃有失重，失重量为0.5％-10.0％。在一些具体实施方案中，热重分析曲线(TGA)显示晶型在100℃-200℃有失重，失重量约为2.1％。在一具体实施方案中，热重分析曲线图(TGA)基本上如图2所示。
所述伐度司他-异烟碱共晶晶型，还具有如下特性：晶型的差示扫描量热曲线(DSC)在150℃-210℃处具有吸热峰。在一些实施方式中，晶型的差示扫描量热曲线(DSC)在160℃-200℃处具有吸热峰。在一些实施例中，晶型的差示扫描量热曲线(DSC)在170℃-190℃处具有吸热峰。在一些实施例中，晶型的差示扫描量热曲线(DSC)在176℃-180℃处具有吸热峰，吸热峰峰顶值为178℃。在一具体实施方案中，所述伐度司他-异烟碱共晶晶型的差示扫描量热曲线(DSC)基本上如图2所示。
第二方面，本发明提供了所述伐度司他-异烟碱共晶晶型的两种制备方法。
本发明中所述伐度司他-异烟碱共晶晶型的制备方法简单、操作方便，条件温和，收率高，纯度高，适用于工业化生产。
一种制备所述伐度司他-异烟碱共晶晶型的方法，包括：将伐度司他溶解于溶剂中，然后在溶液中加入异烟碱，搅拌，过滤，干燥至恒重，得到伐度司他-异烟碱共晶晶型。
在一些实施方式中，所述溶剂包括选自丙酮，丁酮，N-甲基吡咯烷酮，乙酸乙酯，甲酸乙酯，碳酸二甲酯，乙酸甲酯，乙酸正丁酯，乙酸异丙酯，1,4-二氧六环，四氢呋喃，乙腈中的至少一种。在一些实施例中，所述溶剂包括丙酮。在一些实施例中，所述溶剂为丙酮。
在一些实施方式中，所述伐度司他-异烟碱共晶晶型的制备过程中，当伐度司他完全溶解于溶剂后，浓度为5mg/ml-300mg/ml。在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为5mg/ml-200mg/ml；在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为5mg/ml-100mg/ml；在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为5mg/ml-50mg/ml；在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为10mg/ml-200mg/ml；在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为10mg/ml-100mg/ml；在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为10mg/ml-50mg/ml；在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为20mg/ml-100mg/ml。
另一种制备所述伐度司他-异烟碱共晶晶型的方法，包括：将伐度司他溶解于良溶剂中，然后在溶液中加入异烟碱，再加入不良溶剂，搅拌，析出固体，过滤，干燥至恒重，得到伐度司他-异烟碱共晶晶型。
在一些实施方式中，所述良溶剂包括选自丙酮，丁酮，N-甲基吡咯烷酮，四氢呋喃，乙腈，DMF，DMSO中的至少一种；所述不良溶剂包括选自水，正己烷，环己烷，正庚烷，乙醚，石油醚中的至少一种。在一些实施例中，所述良溶剂包括DMF，所述不良溶剂包括水。在一些实施例中，所述良溶剂为DMF，所述不良溶剂为水。
在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:3。在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:2.5；在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:2；在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:1.5。在一些实施例中，所述良溶剂和所述不良溶剂的体积比为1:1；在一些实施例中，所述良溶剂和所述不良溶剂的体积比为1:2；在一些实施例中，所述良溶剂和所述不良溶剂的体积比为1:3。
在一些实施方式中，所述伐度司他-异烟碱共晶晶型的制备过程中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-300mg/ml。在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-200mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-100mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-50mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为10mg/ml-200mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为10mg/ml-100mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为10mg/ml-50mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为20mg/ml-100mg/ml。
第三方面，本发明提供了伐度司他的新晶型，称为伐度司他-肉桂酰胺共晶晶型。
所述伐度司他-肉桂酰胺共晶晶型，具有如下特性：其X射线粉末衍射图包含2θ角为4.24，16.80和 33.99度的衍射峰。
在一些实施方式中，所述伐度司他-肉桂酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为4.24，12.58，16.80，21.04，29.62和33.99度的衍射峰。
在一些实施方式中，所述伐度司他-肉桂酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为4.24，8.38，12.58，14.14，16.80，20.18，21.04，25.32，29.62，33.99，38.39和39.13度的衍射峰。
在一些实施方式中，所述伐度司他-肉桂酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为4.24，8.38，20.18，25.32，33.99和38.39度的衍射峰。
在一些实施方式中，所述伐度司他-肉桂酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为12.58，14.14，16.80，20.18，25.32和39.13度的衍射峰。
在一些实施方式中，所述伐度司他-肉桂酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为8.38，14.14，21.04，25.32，29.62和38.39度的衍射峰。
在一些实施方式中，所述伐度司他-肉桂酰胺共晶晶型，其X射线粉末衍射图包含2θ角为4.24，16.80和33.99度的衍射峰中的至少一个峰或至少两个峰或三个峰。
在一些具体实施方案中，所述伐度司他-肉桂酰胺共晶晶型的X射线粉末衍射图基本上如图3所示。
所述伐度司他-肉桂酰胺共晶晶型，为伐度司他与肉桂酰胺的共晶。在一些实施方式中，所述伐度司他与肉桂酰胺的摩尔比为1:1。
所述伐度司他-肉桂酰胺共晶晶型，还具有如下特性：热重分析曲线(TGA)显示晶型在120℃-200℃有失重，失重量为0.01％-1.5％。在一些具体实施方案中，热重分析曲线(TGA)显示晶型在120℃-200℃有失重，失重量约为0.18％。在一具体实施方案中，热重分析曲线图(TGA)基本上如图4所示。
所述伐度司他-肉桂酰胺共晶晶型，还具有如下特性：晶型的差示扫描量热曲线(DSC)在120℃-180℃处具有吸热峰。在一些实施方式中，晶型的差示扫描量热曲线(DSC)在140℃-160℃处具有吸热峰。在一些实施例中，晶型的差示扫描150℃-154℃处具有吸热峰，吸热峰峰顶值为152℃。在一具体实施方案中，所述伐度司他-肉桂酰胺共晶晶型的差示扫描量热曲线(DSC)基本上如图4所示。
第四方面，本发明提供了所述伐度司他-肉桂酰胺共晶晶型的两种制备方法。
本发明中所述伐度司他-肉桂酰胺共晶晶型的制备方法简单、操作方便，条件温和，收率高，纯度高，适用于工业化生产。
一种制备所述伐度司他-肉桂酰胺共晶晶型的方法，包括：将伐度司他溶解于溶剂中，然后在溶液中加入肉桂酰胺，搅拌，过滤，干燥至恒重，得到伐度司他-肉桂酰胺共晶晶型。
在一些实施方式中，所述溶剂包括选自丙酮，丁酮，N-甲基吡咯烷酮，乙酸乙酯，甲酸乙酯，碳酸二 甲酯，乙酸甲酯，乙酸正丁酯，乙酸异丙酯，1,4-二氧六环，四氢呋喃，乙腈中的至少一种。在一些实施例中，所述溶剂包括乙酸乙酯。在一些实施例中，所述溶剂为乙酸乙酯。
在一些实施方式中，所述伐度司他-肉桂酰胺共晶晶型的制备过程中，当伐度司他完全溶解于溶剂后，浓度为5mg/ml-300mg/ml。在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为5mg/ml-200mg/ml；在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为5mg/ml-100mg/ml；在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为5mg/ml-50mg/ml；在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为10mg/ml-200mg/ml；在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为10mg/ml-100mg/ml；在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为10mg/ml-50mg/ml；在一些实施例中，当伐度司他完全溶解于溶剂后，浓度为20mg/ml-100mg/ml。
另一种制备所述伐度司他-肉桂酰胺共晶晶型的方法，包括：将伐度司他溶解于良溶剂中，然后在溶液中加入肉桂酰胺，再加入不良溶剂，搅拌，析出固体，过滤，干燥至恒重，得到伐度司他-肉桂酰胺共晶晶型。
在一些实施方式中，所述良溶剂包括选自丙酮，丁酮，N-甲基吡咯烷酮，四氢呋喃，乙腈，DMF，DMSO中的至少一种；所述不良溶剂包括选自水，正己烷，环己烷，正庚烷，乙醚，石油醚中的至少一种。在一些实施例中，所述良溶剂包括DMF，所述不良溶剂包括水。在一些实施例中，所述良溶剂为DMF，所述不良溶剂为水。
在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:3。在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:2.5；在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:2；在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:1.5。在一些实施例中，所述良溶剂和所述不良溶剂的体积比为1:1；在一些实施例中，所述良溶剂和所述不良溶剂的体积比为1:2；在一些实施例中，所述良溶剂和所述不良溶剂的体积比为1:3。
在一些实施方式中，所述伐度司他-肉桂酰胺共晶晶型的制备过程中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-300mg/ml。在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-200mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-100mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-50mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为10mg/ml-200mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为10mg/ml-100mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为10mg/ml-50mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为20mg/ml-100mg/ml。
第五方面，本发明提供了伐度司他的新晶型，称为伐度司他-苯甲酰胺共晶晶型。
所述伐度司他-苯甲酰胺共晶晶型，具有如下特性：其X射线粉末衍射图包含2θ角为6.31，21.12和 24.18度的衍射峰。
在一些实施方式中，所述伐度司他-苯甲酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为6.31，15.58，17.59，21.12，24.18和25.05度的衍射峰。
在一些实施方式中，所述伐度司他-苯甲酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为6.31，9.22，10.41，13.50，14.98，15.58，17.59，18.24，18.99，20.93，21.12，24.18，25.05，27.42，27.91，28.06，33.63和36.51度的衍射峰。
在一些实施方式中，所述伐度司他-苯甲酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为6.31，9.22，10.41，25.05，27.42和33.63度的衍射峰。
在一些实施方式中，所述伐度司他-苯甲酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为13.50，15.58，18.24，20.93，24.18和36.51度的衍射峰。
在一些实施方式中，所述伐度司他-苯甲酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为14.98，17.59，18.99，21.12，27.91和28.06度的衍射峰。
在一些实施方式中，所述伐度司他-苯甲酰胺共晶晶型，其X射线粉末衍射图包含2θ角为6.31，21.12和24.18度的衍射峰中的至少一个峰或至少两个峰或三个峰。
在一些具体实施方案中，伐度司他-苯甲酰胺共晶晶型的X射线粉末衍射图基本上如图5所示。
所述伐度司他-苯甲酰胺共晶晶型，为伐度司他与苯甲酰胺的共晶。在一些实施方式中，所述伐度司他与苯甲酰胺的摩尔比为1:2。
所述伐度司他-苯甲酰胺共晶晶型，还具有如下特性：热重分析曲线(TGA)显示晶型在50℃-250℃有失重，失重量为10.0％-70.0％。在一些具体实施方案中，热重分析曲线(TGA)显示晶型在50℃-250℃有失重，失重量约为45.3％。在一具体实施方案中，热重分析曲线图(TGA)基本上如图6所示。
所述伐度司他-苯甲酰胺共晶晶型，还具有如下特性：晶型的差示扫描量热曲线(DSC)在90℃-150℃处具有吸热峰。在一些实施方式中，晶型的差示扫描量热曲线(DSC)在100℃-140℃处具有吸热峰。在一些实施例中，晶型的差示扫描量热曲线(DSC)在110℃-130℃处具有吸热峰。在一些实施例中，晶型的差示扫描量热曲线(DSC)在117℃-121℃处具有吸热峰，吸热峰峰顶值为119℃。在一具体实施方案中，所述伐度司他-苯甲酰胺共晶晶型的差示扫描量热曲线(DSC)基本上如图6所示。
第六方面，本发明提供了所述伐度司他-苯甲酰胺共晶晶型的制备方法。
本发明中所述伐度司他-苯甲酰胺共晶晶型的制备方法简单、操作方便，条件温和，收率高，纯度高，适用于工业化生产。
一种制备所述伐度司他-苯甲酰胺共晶晶型的方法，包括：将伐度司他溶解于良溶剂中，然后在溶液中加入苯甲酰胺，再加入不良溶剂，搅拌，析出固体，过滤，干燥至恒重，得到伐度司他-苯甲酰胺共晶晶型。
在一些实施方式中，所述良溶剂包括选自丙酮，丁酮，N-甲基吡咯烷酮，1,4-二氧六环，四氢呋喃，乙腈，DMF，DMSO中的至少一种；所述不良溶剂包括选自水，正己烷，环己烷，正庚烷，乙醚，石油醚中的至少一种。在一些实施例中，所述良溶剂包括丙酮，所述不良溶剂包括正庚烷。在一些实施例中，所述良溶剂为丙酮，所述不良溶剂为正庚烷。
在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:4。在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:3.5；在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:3；在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:2.5；在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:2；在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:1.5。在一些实施例中，所述良溶剂和所述不良溶剂的体积比为1:1；在一些实施例中，所述良溶剂和所述不良溶剂的体积比为1:2；在一些实施例中，所述良溶剂和所述不良溶剂的体积比为1:3；在一些实施例中，所述良溶剂和所述不良溶剂的体积比为1:4。
在一些实施方式中，所述伐度司他-苯甲酰胺共晶晶型的制备过程中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-300mg/ml。在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-200mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-100mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-50mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为10mg/ml-200mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为10mg/ml-100mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为10mg/ml-50mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为20mg/ml-100mg/ml。
第七方面，本发明提供了伐度司他的新晶型，称为伐度司他-丙酰胺共晶晶型。
所述伐度司他-丙酰胺共晶晶型，具有如下特性：其X射线粉末衍射图包含2θ角为7.37，15.58和20.92度的衍射峰。
在一些实施方式中，所述伐度司他-丙酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为7.37，9.11，15.58，17.18，20.92和31.08度的衍射峰。
在一些实施方式中，所述伐度司他-丙酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为7.37，9.11，11.09，13.66，13.93，14.82，15.58，17.18，18.11，20.42，20.92，21.69，22.37，23.99，24.78，28.12，28.34和31.08度的衍射峰。
在一些实施方式中，所述伐度司他-丙酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为7.37，13.93，14.82，21.69，28.34和31.08度的衍射峰。
在一些实施方式中，所述伐度司他-丙酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为9.11，11.09，13.66，20.92，22.37和24.78度的衍射峰。
在一些实施方式中，所述伐度司他-丙酰胺共晶晶型，具有如下特性：所述晶型的X射线粉末衍射图包含2θ角为15.58，17.18，18.11，20.42，23.99和28.12度的衍射峰。
在一些实施方式中，所述伐度司他-丙酰胺共晶晶型，其X射线粉末衍射图包含2θ角为7.37，15.58和20.92度的衍射峰中的至少一个峰或至少两个峰或三个峰。
在一些具体实施方案中，伐度司他-丙酰胺共晶晶型的X射线粉末衍射图基本上如图7所示。
所述伐度司他-丙酰胺共晶晶型，为伐度司他与丙酰胺的共晶。在一些实施方式中，所述伐度司他与丙酰胺的摩尔比为1:2。
所述伐度司他-丙酰胺共晶晶型，还具有如下特性：热重分析曲线(TGA)显示晶型在100℃-180℃有失重，失重量为1.0％-20.0％。在一些具体实施方案中，热重分析曲线(TGA)显示晶型在100℃-180℃有失重，失重量约为12.1％。在一具体实施方案中，热重分析曲线图(TGA)基本上如图8所示。
所述伐度司他-丙酰胺共晶晶型，还具有如下特性：晶型的差示扫描量热曲线(DSC)在80℃-150℃处具有吸热峰。在一些实施方式中，晶型的差示扫描量热曲线(DSC)在100℃-130℃处具有吸热峰。在一些实施例中，晶型的差示扫描量热曲线(DSC)在110℃-120℃处具有吸热峰。在一些实施例中，晶型的差示扫描量热曲线(DSC)在112℃-116℃处具有吸热峰，吸热峰峰顶值为114℃。在一具体实施方案中，所述伐度司他-丙酰胺共晶晶型的差示扫描量热曲线(DSC)基本上如图8所示。
第八方面，本发明提供了所述伐度司他-丙酰胺共晶晶型的制备方法。
本发明中所述伐度司他-丙酰胺共晶晶型的制备方法简单、操作方便，条件温和，收率高，纯度高，适用于工业化生产。
一种制备所述伐度司他-丙酰胺共晶晶型的方法，包括：将伐度司他溶解于良溶剂中，然后在溶液中加入丙酰胺，再加入不良溶剂，搅拌，析出固体，过滤，干燥至恒重，得到伐度司他-丙酰胺共晶晶型。
在一些实施方式中，所述良溶剂包括选自乙酸乙酯，甲酸乙酯，碳酸二甲酯，乙酸甲酯，乙酸正丁酯，乙酸异丙酯，四氢呋喃，乙腈，DMF，DMSO中的至少一种；所述不良溶剂包括选自正己烷，环己烷，正庚烷，乙醚，石油醚中的至少一种。在一些实施例中，所述良溶剂包括乙酸乙酯，所述不良溶剂包括正庚烷。在一些实施例中，所述良溶剂为乙酸乙酯，所述不良溶剂为正庚烷。
在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:3。在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:2.5；在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:2；在一些实施方式中，所述良溶剂和所述不良溶剂的体积比为1:1-1:1.5。在一些实施例中，所述良溶剂和所述不良溶剂的体积比为1:1；在一些实施例中，所述良溶剂和所述不良溶剂的体积比为1:2；在一些实施例中，所述良溶剂和所述不良溶剂的体积比为1:3。
在一些实施方式中，所述伐度司他-丙酰胺共晶晶型的制备过程中，当伐度司他完全溶解于良溶剂后， 浓度为5mg/ml-300mg/ml。在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-200mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-100mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为5mg/ml-50mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为10mg/ml-200mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为10mg/ml-100mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为10mg/ml-50mg/ml；在一些实施例中，当伐度司他完全溶解于良溶剂后，浓度为20mg/ml-100mg/ml。
第九方面，本发明还提供一种组合物，所述组合物包含任意一种前述的伐度司他的晶型。
所述组合物中，按照重量比计，所述晶型或盐为伐度司他的至少90％，或者所述晶型不超过伐度司他的0.5％-5％。
在一些实施方式中，所述组合物，其包括：至少一种前述的晶型，和药学上可接受的辅料或载体；其中，按照重量比计，以伐度司他计，所述晶型或盐为伐度司他的至少90％，或者所述晶型不超过伐度司他的0.5％-5％。
按照重量比计，在一些实施方式中，一种组合物，包含前述伐度司他的晶型，其中，所述晶型为伐度司他的至少90％。按照重量比计，在一些实施方式中，一种组合物，包含前述伐度司他的晶型，其中，所述晶型为伐度司他的至少95％，或者至少99％。按照重量比计，在一些实施方式中，一种组合物，包含前述伐度司他的晶型，其中，所述晶型为伐度司他的至少0.5％-5％。按照重量比计，在一些实施方式中，一种组合物，包含前述伐度司他的晶型，其中，所述晶型为伐度司他的至少5％。按照重量比计，在一些实施方式中，一种组合物，包含前述伐度司他的晶型，其中，所述晶型不超过伐度司他的0.5％-5％。按照重量比计，在一些实施方式中，一种组合物，包含前述伐度司他的晶型，其中，所述晶型不超过伐度司他的5％。
在一些实施方式中，一种组合物，包含前述的伐度司他的晶型，所述晶型为伐度司他-异烟碱共晶晶型、伐度司他-肉桂酰胺共晶晶型、伐度司他-苯甲酰胺共晶晶型、伐度司他-丙酰胺共晶晶型中的至少一种。在一些实施方式中，一种组合物，包含前述的伐度司他-异烟碱共晶晶型、伐度司他-肉桂酰胺共晶晶型、伐度司他-苯甲酰胺共晶晶型、伐度司他-丙酰胺共晶晶型。
按照重量比计，在一些实施方式中，一种组合物，包含前述伐度司他-异烟碱共晶晶型、伐度司他-肉桂酰胺共晶晶型、伐度司他-苯甲酰胺共晶晶型、伐度司他-丙酰胺共晶晶型中的至少一种；其中，以伐度司他计，所述晶型为伐度司他的至少90％。按照重量比计，在一些实施方式中，一种组合物，包含前述伐度司他-异烟碱共晶晶型、伐度司他-肉桂酰胺共晶晶型、伐度司他-苯甲酰胺共晶晶型、伐度司他-丙酰胺共晶晶型，其中，所述晶型为伐度司他的至少90％。按照重量比计，在一些实施方式中，一种组合物，包含 前述伐度司他-异烟碱共晶晶型、伐度司他-肉桂酰胺共晶晶型、伐度司他-苯甲酰胺共晶晶型、伐度司他-丙酰胺共晶晶型，其中，所述晶型为伐度司他的至少95％，或者至少99％。
按照重量比计，在一些实施方式中，一种组合物，包含前述伐度司他-异烟碱共晶晶型、伐度司他-肉桂酰胺共晶晶型、伐度司他-苯甲酰胺共晶晶型、伐度司他-丙酰胺共晶晶型中的至少一种；其中，以伐度司他计，所述晶型为伐度司他的至少0.5％-5％。按照重量比计，在一些实施方式中，一种组合物，包含前述伐度司他-异烟碱共晶晶型、伐度司他-肉桂酰胺共晶晶型、伐度司他-苯甲酰胺共晶晶型、伐度司他-丙酰胺共晶晶型，其中，所述晶型为伐度司他的至少0.5％-5％。按照重量比计，在一些实施方式中，一种组合物，包含前述伐度司他-异烟碱共晶晶型、伐度司他-肉桂酰胺共晶晶型、伐度司他-苯甲酰胺共晶晶型、伐度司他-丙酰胺共晶晶型，其中，所述晶型为伐度司他的至少5％。按照重量比计，在一些实施方式中，一种组合物，包含前述伐度司他-异烟碱共晶晶型、伐度司他-肉桂酰胺共晶晶型、伐度司他-苯甲酰胺共晶晶型、伐度司他-丙酰胺共晶晶型，其中，所述晶型不超过伐度司他的0.5％-5％。按照重量比计，在一些实施方式中，一种组合物，包含前述伐度司他-异烟碱共晶晶型、伐度司他-肉桂酰胺共晶晶型、伐度司他-苯甲酰胺共晶晶型和/或伐度司他-丙酰胺共晶晶型，其中，所述晶型不超过伐度司他的5％。
所述的组合物，还可以包括药学上可接受的辅料或载体。所述的药学上可接受的辅料或载体，可包括填充剂，稀释剂，润滑剂等。在一些实施方式中，所述组合物还包含药学上可接受的辅料或载体，所述药学上可接受的辅料或载体包括润滑剂。在一些实施方式中，所述润滑剂为硬脂酸镁。
所述的组合物可制备成任何适宜的药物制剂，如片剂，胶囊剂，颗粒剂，混悬剂，或注射剂等。
附图说明
图1示伐度司他-异烟碱共晶晶型的X-射线粉末衍射图(XRPD)；
图2示伐度司他-异烟碱共晶晶型的差示扫描量热曲线图(DSC)和热重分析曲线图(TGA)；
图3示伐度司他-肉桂酰胺共晶晶型的X-射线粉末衍射图(XRPD)；
图4示伐度司他-肉桂酰胺共晶晶型的差示扫描量热曲线图(DSC)和热重分析曲线图(TGA)；
图5示伐度司他-苯甲酰胺共晶晶型的X-射线粉末衍射图(XRPD)；
图6示伐度司他-苯甲酰胺共晶晶型的差示扫描量热曲线图(DSC)和热重分析曲线图(TGA)；
图7示伐度司他-丙酰胺共晶晶型的X-射线粉末衍射图(XRPD)；
图8示伐度司他-丙酰胺共晶晶型的差示扫描量热曲线图(DSC)和热重分析曲线图(TGA)；
图9示伐度司他-异烟碱共晶晶型在高温、高湿、光照的条件下放置15天前后的X-射线粉末衍射图(XRPD)(从下至上依次为0天、高湿15天、高温15天、光照15天)；
图10示伐度司他-肉桂酰胺共晶晶型在高温、高湿、光照的条件下放置15天前后的X-射线粉末衍射图(XRPD)(从下至上依次为0天、高湿15天、高温15天、光照15天)；
图11示伐度司他-苯甲酰胺共晶晶型在高温、高湿、光照的条件下放置15天前后的X-射线粉末衍射图(XRPD)(从下至上依次为0天、高湿15天、高温15天、光照15天)；
图12示伐度司他-丙酰胺共晶晶型在高温、高湿、光照的条件下放置15天前后的X-射线粉末衍射图(XRPD)(从下至上依次为0天、高湿15天、高温15天、光照15天)；
图13示伐度司他-异烟碱共晶晶型在长期稳定性条件下放置12个月前后的X-射线粉末衍射图(XRPD)(从下至上依次为0天、长期12个月)；
图14示伐度司他-苯甲酰胺共晶晶型在长期稳定性条件下放置12个月前后的X-射线粉末衍射图(XRPD)(从下至上依次为0天、长期12个月)。
具体实施方式
为了使本领域的技术人员更好地理解本发明的技术方案，下面进一步披露一些非限制实施例对本发明作进一步的详细说明。
本发明所使用的试剂均可以从市场上购得或者可以通过现有技术的方法制备或者通过本发明所描述的方法制备而得。
本发明中，℃表示摄氏度，mg表示毫克，mL表示毫升，h表示小时，min表示分钟，DMF为N,N-二甲基甲酰胺，DMSO为二甲基亚砜。
仪器参数
除非参数中另行规定，以下所有分析都在室温下进行。
X-射线粉末衍射(XRPD)
在装配有自动化3*15零背景样品架的透射反射样品台的荷兰PANalytical Empyrean X-射线衍射仪上收集X-射线粉末衍射(XRPD)图案。所用辐射源为(Cu，kα，Kα1
Figure PCTCN2021116336-appb-000002
1.540598；Kα2
Figure PCTCN2021116336-appb-000003
1.544426；Kα2/Kα1强度比例：0.50)，其中电压设定在45KV，电流设定在40mA.X-射线的束发散度，即样品上X-射线约束的有效尺寸，为10mm.采用θ-θ连续扫描模式，得到3°～60°的有效2θ范围。取适量样品在环境条件(约18℃～32℃)下于零背景样品架圆形凹槽处，用洁净的载玻片轻压，得到一个平整的平面，并将零背景样品架固定。将样品以0.0167°的扫描步长在3～60°2θ±0.2°范围内产生传统的XRPD图案。用于数据收集的软件为Data Colector，数据用Data Viewer和HighScore Plus分析和展示。在X-射线粉末衍射图中，纵坐标为用计数(counts)表示的衍射强度，横坐标为用度(°)表示的衍射角2θ。
差示扫描量热法(DSC)
使用TA Instruments TM型号Q2000中用密封盘装置进行。将样品(约1～3mg)在铝盘中称量，用Tzero压盖，精密记录到百分之一毫克，并将样品转移至仪器中进行测量。仪器用氮气以50mL/min吹扫。在室温到300℃之间以10℃/min的加热速率收集数据。以吸热峰向下进行绘图,数据用TA Universal Analysis分析和展示。在DSC图中，横坐标表示温度(Temperature,℃)，纵坐标表示单位质量的物质放出的热流量(Heat Flow,W/g)。
热重分析法(TGA)
TGA测量在TA Instruments TM型号Q500中进行。操作步骤为空坩埚去皮，取固体样品约10mg、于去皮空坩埚内，铺匀即可。待仪器运行稳定后，在氮气吹扫下，室温到300℃之间以10℃/min的加热速率收集数据，记录图谱。在TGA图中，横坐标表示温度(Temperature,℃)，纵坐标表示质量百分数(Weight,％)。
伐度司他-异烟碱共晶晶型的制备
实施例1
将150mg的伐度司他粗品(不限定固体形式)加入5ml的丙酮溶剂中，室温下搅拌得到澄清溶液后，再缓慢加入异烟碱61.06mg，搅拌一天，析出白色固体，抽滤并置于干燥箱内50℃真空干燥24h，得到白色固体约140mg。经测定，其X射线粉末衍射图谱、其DSC和TGA图谱参见图1和图2。
实施例2
将150mg的伐度司他粗品(不限定固体形式)加入1ml的DMF溶剂中，室温下搅拌得到澄清溶液后，再缓慢加入异烟碱121mg，室温下搅拌未析出固体，随后加入2ml水，搅拌过夜析出白色固体，抽滤并置于干燥箱内50℃真空干燥24h，得到白色固体约130mg。经测定，其X射线粉末衍射图谱、其DSC和TGA图谱参见图1和图2。
伐度司他-肉桂酰胺共晶晶型的制备
实施例3
将150mg的伐度司他粗品(不限定固体形式)加入5ml的乙酸乙酯溶剂中，加热至50℃搅拌得到澄清溶液后，再缓慢加入肉桂酰胺73.58mg，降至室温搅拌一天，析出白色固体，抽滤并置于干燥箱内50℃真空干燥24h，得到白色固体约130mg。经测定，其X射线粉末衍射图谱、其DSC和TGA图谱参见图3和图4。
实施例4
将150mg的伐度司他粗品(不限定固体形式)加入1ml的DMF溶剂中，室温下搅拌得到澄清溶液后，再缓慢加入肉桂酰胺73.58mg，室温下搅拌未析出固体，随后加入2ml水，搅拌过夜析出白色固体，抽滤并置于干燥箱内50℃真空干燥24h，得到白色固体约130mg。经测定，其X射线粉末衍射图谱、其DSC和TGA图谱参见图3和图4。
伐度司他-苯甲酰胺共晶晶型的制备
实施例5
将150mg的伐度司他粗品(不限定固体形式)加入2ml的丙酮溶剂中，室温下搅拌得到澄清溶液后，再缓慢加入苯甲酰胺121mg，室温下搅拌未析出固体，随后加入6ml正庚烷，搅拌过夜析出白色固体，抽滤并置于干燥箱内50℃真空干燥24h，得到白色固体约150mg。经测定，其X射线粉末衍射图谱、其DSC和TGA图谱参见图5和图6。
伐度司他-丙酰胺共晶晶型的制备
实施例6
将150mg的伐度司他粗品(不限定固体形式)加入2ml的乙酸乙酯溶剂中，加热至50℃搅拌溶清，缓慢加入丙酰胺73.09mg，室温下搅拌未析出固体，随后加入4ml正庚烷，搅拌过夜析出白色固体，抽滤并置于干燥箱内50℃真空干燥24h，得到白色固体约100mg。经测定，其X射线粉末衍射图谱、其DSC和TGA图谱参见图7与图8。
实施例7溶解度测试
按照现行中国药典的溶解度试验指导原则，设计实验，分别测量了伐度司他晶型在水和pH为6.8的缓冲液中的溶解度，溶解度数值以伐度司他计，结果如表1和2所示。结果表明，伐度司他-异烟碱共晶、伐度司他-苯甲酰胺共晶在水中和pH6.8的缓冲液中的溶解度比伐度司他晶型A显著增高，其中，伐度司他-异烟碱共晶在水中的溶解度是伐度司他晶型A的1.6倍，伐度司他-苯甲酰胺共晶在水中的溶解度是伐度司他晶型A的1.18倍；伐度司他-异烟碱共晶在pH6.8的缓冲液中的溶解度是伐度司他晶型A的1.2倍，伐度司他-苯甲酰胺共晶在pH6.8的缓冲液中的溶解度是伐度司他晶型A的1.8倍；伐度司他-肉桂酰胺共晶在pH6.8的缓冲液中的溶解度也较高，是伐度司他晶型A的1.8倍。
表1：水中溶解度数据(37℃，水)
样品 溶解度(以伐度司他计，mg/ml)
伐度司他晶型A 0.0271
伐度司他-异烟碱共晶 0.0439
伐度司他-苯甲酰胺共晶 0.032
表2：缓冲液中溶解度数据(37℃，PH＝6.8磷酸缓冲液)
样品 溶解度(以伐度司他计，mg/ml)
伐度司他晶型A 1.0457
伐度司他-异烟碱共晶 1.252
伐度司他-肉桂酰胺共晶 1.9224
伐度司他-苯甲酰胺共晶 1.9172
伐度司他-丙酰胺共晶 1.0296
实施例8稳定性考察
根据药物制剂稳定性试验指导原则，对伐度司他的晶型进行影响因素实验，包括高温试验、高湿试验和强光照射试验，考察影响其晶型的稳定性条件，结果如表3所示。
高温试验：分别取晶型样品适量，平铺置称量瓶中，在60℃±5℃、RH 75±5％恒温恒湿箱中放置，然后分别于0、5和15天取上述样品约100mg，采用粉末X-射线粉末衍射(XRPD)、差示扫描量热法(DSC)测试其晶型情况。
高湿试验：分别取晶型样品适量，平铺置称量瓶中，在25℃、RH 92.5±5％恒温恒湿箱中放置，然后分别于0、5和15天取上述样品约100mg，采用粉末X-射线粉末衍射(XRPD)、差示扫描量热法(DSC)测试其晶型情况。
光照试验：分别取晶型样品适量，平铺至称量瓶中，在可见光4500Lux±500Lux(VIS)、紫外光1.7W*h/m2(UV)的恒温恒湿箱(25℃、RH 60％±5％)条件下放置，然后分别于0、5和15天取上述样品约100mg，采用粉末X-射线粉末衍射(XRPD)、差示扫描量热法(DSC)测试其晶型情况。
表3：伐度司他的4种共晶晶型在影响因素条件下的稳定性数据
Figure PCTCN2021116336-appb-000004
结果显示，伐度司他-异烟碱共晶晶型、伐度司他-肉桂酰胺共晶晶型、伐度司他-苯甲酰胺共晶晶型在高温、高湿和光照三个影响因素试验条件下放置15天后，粉末X-射线衍射(XRPD)结果表明其在各影响因素下未发生转晶，具有良好的稳定性。伐度司他-丙酰胺共晶晶型在高温条件下放置15天后发生变化，转为伐度司他晶型A。
另一方面，根据药物制剂稳定性试验指导原则，对伐度司他-异烟碱共晶和伐度司他-苯甲酰胺共晶进行长期稳定性实验，结果如表4所示。
长期稳定性实验：分别取晶型样品适量，采用PE和铝箔包装，在25℃±2℃、RH 60±5％恒温恒湿箱中放置，然后分别于0、3、6、9和12月取上述样品约100mg，采用粉末X-射线粉末衍射(XRPD)、差示扫描量热法(DSC)测试其晶型情况。
表4：伐度司他的2种共晶晶型在影响因素条件下的稳定性数据
Figure PCTCN2021116336-appb-000005
结果显示，伐度司他-异烟碱共晶晶型、伐度司他-苯甲酰胺共晶晶型在长期稳定性试验条件下放置12个月后，粉末X-射线衍射(XRPD)结果表明其在各影响因素下未发生转晶，具有良好的稳定性。
本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明内。

Claims (34)

  1. 一种伐度司他-异烟碱共晶晶型，所述晶型的X射线粉末衍射图包含2θ角为14.24，18.16和20.12度的衍射峰。
  2. 根据权利要求1所述的伐度司他-异烟碱共晶晶型，其中，所述晶型的X射线粉末衍射图包含2θ角为7.68，14.24，15.27，18.16，20.12和30.43度的衍射峰；或者所述晶型的X射线粉末衍射图包含2θ角为7.68，10.86，14.24，15.27，18.16，20.12，25.84，29.18，29.52，30.43，31.23，36.85和39.32度的衍射峰；或者所述晶型的X-射线粉末衍射图基本上如图1所示。
  3. 根据权利要求1或2所述的伐度司他-异烟碱共晶晶型，热重分析曲线显示所述晶型在100℃-200℃有失重，失重量为0.5％-10.0％。
  4. 根据权利要求1-3任一项所述的伐度司他-异烟碱共晶晶型，所述晶型的差示扫描量热曲线在150℃-210℃处具有吸热峰。
  5. 根据权利要求1-4任一项所述的伐度司他-异烟碱共晶晶型，其中，所述伐度司他与异烟碱的摩尔比为1:1。
  6. 一种制备权利要求1-5任一项所述的伐度司他-异烟碱共晶晶型的方法，包括：将伐度司他溶解于溶剂中，然后在溶液中加入异烟碱，搅拌，过滤，干燥至恒重，得到伐度司他-异烟碱共晶晶型。
  7. 根据权利要求6所述的方法，所述溶剂包括选自丙酮，丁酮，N-甲基吡咯烷酮，乙酸乙酯，甲酸乙酯，碳酸二甲酯，乙酸甲酯，乙酸正丁酯，乙酸异丙酯，1,4-二氧六环，四氢呋喃，乙腈中的至少一种。
  8. 根据权利要求6或7所述的方法，所述伐度司他完全溶解于溶剂后，浓度为5mg/ml-300mg/ml。
  9. 一种制备权利要求1-5任一项所述的伐度司他-异烟碱共晶晶型的方法，包括：将伐度司他溶解于良溶剂中，然后在溶液中加入异烟碱，再加入不良溶剂，搅拌，析出固体，过滤，干燥至恒重，得到伐度司他-异烟碱共晶晶型。
  10. 根据权利要求9所述的方法，所述良溶剂包括选自丙酮，丁酮，N-甲基吡咯烷酮，四氢呋喃，乙腈，DMF，DMSO中的至少一种；所述不良溶剂包括选自水，正己烷，环己烷，正庚烷，乙醚，石油醚中的至少一种。
  11. 根据权利要求9或10所述的方法，所述良溶剂和所述不良溶剂的体积比为1:1-1:3。
  12. 根据权利要求9-11任一项所述的方法，所述伐度司他完全溶解于良溶剂后，浓度为5mg/ml-300mg/ml。
  13. 一种伐度司他-苯甲酰胺共晶晶型，所述晶型的X射线粉末衍射图包含2θ角为6.31，21.12和24.18度的衍射峰。
  14. 根据权利要求13所述的伐度司他-苯甲酰胺共晶晶型，其中，所述晶型的X射线粉末衍射图包含2θ角为6.31，15.58，17.59，21.12，24.18和25.05度的衍射峰；或者所述晶型的X射线粉末衍射图包含2θ角为6.31，9.22，10.41，13.50，14.98，15.58，17.59，18.24，18.99，20.93，21.12，24.18，25.05，27.42，27.91，28.06，33.63和36.51度的衍射峰；或者所述晶型的X-射线粉末衍射图基本上如图5所 示。
  15. 根据权利要求13或14所述的伐度司他-苯甲酰胺共晶晶型，热重分析曲线显示所述晶型在50℃-250℃有失重，失重量为10.0％-70.0％。
  16. 根据权利要求13-15任一项所述的伐度司他-苯甲酰胺共晶晶型，所述晶型的差示扫描量热曲线在90℃-150℃处具有吸热峰。
  17. 根据权利要求13-16任一项所述的伐度司他-苯甲酰胺共晶晶型，其中，所述伐度司他与苯甲酰胺的摩尔比为1:2。
  18. 一种制备权利要求13-17任一项所述的伐度司他-苯甲酰胺共晶晶型的方法，包括：将伐度司他溶解于良溶剂中，然后在溶液中加入苯甲酰胺，再加入不良溶剂，搅拌，析出固体，过滤，干燥至恒重，得到伐度司他-苯甲酰胺共晶晶型。
  19. 根据权利要求18所述的方法，所述良溶剂包括选自丙酮，丁酮，N-甲基吡咯烷酮，1,4-二氧六环，四氢呋喃，乙腈，DMF，DMSO中的至少一种；所述不良溶剂包括选自水，正己烷，环己烷，正庚烷，乙醚，石油醚中的至少一种。
  20. 根据权利要求18或19所述的方法，所述良溶剂和所述不良溶剂的体积比为1:1-1:4。
  21. 根据权利要求18-20任一项所述的方法，所述伐度司他完全溶解于良溶剂后，浓度为5mg/ml-300mg/ml。
  22. 一种伐度司他-肉桂酰胺共晶晶型，所述晶型的X射线粉末衍射图包含2θ角为4.24，16.80和33.99度的衍射峰。
  23. 根据权利要求22所述的伐度司他-肉桂酰胺共晶晶型，其中，所述晶型的X射线粉末衍射图包含2θ角为4.24，12.58，16.80，21.04，29.62和33.99度的衍射峰；或者所述晶型的X射线粉末衍射图包含2θ角为4.24，8.38，12.58，14.14，16.80，20.18，21.04，25.32，29.62，33.99，38.39和39.13度的衍射峰；或者所述晶型的X-射线粉末衍射图基本上如图3所示。
  24. 根据权利要求22或23所述的伐度司他-肉桂酰胺共晶晶型，热重分析曲线显示所述晶型在120℃-200℃有失重，失重量为0.01％-1.5％。
  25. 根据权利要求22-24任一项所述的伐度司他-肉桂酰胺共晶晶型，所述晶型的差示扫描量热曲线在120℃-180℃处具有吸热峰。
  26. 根据权利要求22-25任一项所述的伐度司他-肉桂酰胺共晶晶型，其中，所述伐度司他与肉桂酰胺的摩尔比为1:1。
  27. 一种制备权利要求22-26任一项所述的伐度司他-肉桂酰胺共晶晶型的方法，包括：将伐度司他溶解于溶剂中，然后在溶液中加入肉桂酰胺，搅拌，过滤，干燥至恒重，得到伐度司他-肉桂酰胺共晶晶型。
  28. 根据权利要求27所述的方法，所述溶剂包括选自丙酮，丁酮，N-甲基吡咯烷酮，乙酸乙酯，甲酸乙 酯，碳酸二甲酯，乙酸甲酯，乙酸正丁酯，乙酸异丙酯，1,4-二氧六环，四氢呋喃，乙腈中的至少一种。
  29. 根据权利要求27或28所述的方法，所述伐度司他完全溶解于溶剂后，浓度为5mg/ml-300mg/ml。
  30. 一种制备权利要求22-26任一项所述的伐度司他-肉桂酰胺共晶晶型的方法，包括：将伐度司他溶解于良溶剂中，然后在溶液中加入肉桂酰胺，再加入不良溶剂，搅拌，析出固体，过滤，干燥至恒重，得到伐度司他-肉桂酰胺共晶晶型。
  31. 根据权利要求30所述的方法，所述良溶剂包括选自丙酮，丁酮，N-甲基吡咯烷酮，四氢呋喃，乙腈，DMF，DMSO中的至少一种；所述不良溶剂包括选自水，正己烷，环己烷，正庚烷，乙醚，石油醚中的至少一种。
  32. 根据权利要求30或31所述的方法，所述良溶剂和所述不良溶剂的体积比为1:1-1:3。
  33. 根据权利要求30-32任一项所述的方法，所述伐度司他完全溶解于良溶剂后，浓度为5mg/ml-300mg/ml。
  34. 一种组合物，其包括：权利要求1-5、权利要求13-17和权利要求22-26任一项中所述的晶型和药学上可接受的辅料或载体；其中，按照重量比计，以伐度司他计，所述晶型为伐度司他的至少90％，或者所述晶型不超过伐度司他的0.5％-5％。
PCT/CN2021/116336 2020-09-04 2021-09-03 一种低氧诱导因子脯氨酰羟化酶抑制剂的晶型及其制备方法 Ceased WO2022048613A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202180052769.6A CN115996720A (zh) 2020-09-04 2021-09-03 一种低氧诱导因子脯氨酰羟化酶抑制剂的晶型及其制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010921370.4 2020-09-04
CN202010921370 2020-09-04

Publications (1)

Publication Number Publication Date
WO2022048613A1 true WO2022048613A1 (zh) 2022-03-10

Family

ID=80492175

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/116336 Ceased WO2022048613A1 (zh) 2020-09-04 2021-09-03 一种低氧诱导因子脯氨酰羟化酶抑制剂的晶型及其制备方法

Country Status (2)

Country Link
CN (1) CN115996720A (zh)
WO (1) WO2022048613A1 (zh)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105916502A (zh) * 2013-11-15 2016-08-31 阿克比治疗有限公司 {[5-(3-氯苯基)-3-羟基吡啶-2-羰基]氨基}乙酸的固体形式，其组合物和用途
WO2018108101A1 (zh) * 2016-12-13 2018-06-21 苏州科睿思制药有限公司 {[5-(3-氯苯基)-3-羟基吡啶-2-羰基]氨基}乙酸的新晶型及其制备方法
CN110218184A (zh) * 2018-03-01 2019-09-10 广东东阳光药业有限公司 诺德司他共晶及其制备方法
WO2020075199A1 (en) * 2018-10-12 2020-04-16 Mylan Laboratories Limited Polymorphic forms of vadadustat
WO2020108941A1 (en) * 2018-11-28 2020-06-04 Sandoz Ag Multi-component crystals of an orally available hif prolyl hydroxylase inhibitor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105916502A (zh) * 2013-11-15 2016-08-31 阿克比治疗有限公司 {[5-(3-氯苯基)-3-羟基吡啶-2-羰基]氨基}乙酸的固体形式，其组合物和用途
WO2018108101A1 (zh) * 2016-12-13 2018-06-21 苏州科睿思制药有限公司 {[5-(3-氯苯基)-3-羟基吡啶-2-羰基]氨基}乙酸的新晶型及其制备方法
CN110218184A (zh) * 2018-03-01 2019-09-10 广东东阳光药业有限公司 诺德司他共晶及其制备方法
WO2020075199A1 (en) * 2018-10-12 2020-04-16 Mylan Laboratories Limited Polymorphic forms of vadadustat
WO2020108941A1 (en) * 2018-11-28 2020-06-04 Sandoz Ag Multi-component crystals of an orally available hif prolyl hydroxylase inhibitor

Also Published As

Publication number Publication date
CN115996720A (zh) 2023-04-21

Similar Documents

Publication Publication Date Title
CN116829144B (zh) 一种化合物的固体形式及其制备方法和用途
CN111377944A (zh) Baloxavir marboxil晶型及其制备方法
CN114746412A (zh) Kd-025的新晶型及其制备方法
WO2019228485A1 (zh) 一种甲磺酸乐伐替尼新晶型及其制备方法
CN101522671A (zh) 5-(1(s)-氨基-2-羟基乙基)-n-[(2,4-二氟苯基)-甲基]-2-[8-甲氧基-2-(三氟甲基)-5-喹啉]-4-唑甲酰胺的顺丁烯二酸盐、甲苯磺酸盐、反丁烯二酸盐和草酸盐盐类，及其制备方法
CN115260108B (zh) 一种酸的共晶及其制备方法
CN114728954A (zh) Tropifexor的新晶型及其制备方法
CN112638865A (zh) 药物共晶体及其制备方法
CN114478512A (zh) 一种酸的晶型及其制备方法
WO2022048613A1 (zh) 一种低氧诱导因子脯氨酰羟化酶抑制剂的晶型及其制备方法
TWI724651B (zh) 貝前列素-314d單水合物晶體及其製備方法
CN113801189B (zh) 一种d因子阻滞剂的晶型及其制备方法
WO2023143090A1 (zh) 一种阿帕他胺溶剂化物新晶型及其制备方法
CN114057643B (zh) 一种罗沙司他共晶及其制备方法
US10301344B2 (en) L-proline complex of sodium-glucose cotransporter 2 inhibitor, monohydrate and crystal form thereof
WO2021057834A1 (zh) 一种酯化合物的晶型及其制备方法
CN106349090B (zh) 一种富马酸比索洛尔ⅰ晶型及其制备方法
WO2019080865A1 (zh) 一种炔基吡啶类脯氨酰羟化酶抑制剂的晶型及其制备方法
CN114105867B (zh) 一种低氧诱导因子脯氨酰羟化酶抑制剂的晶型及其制备方法
CN110776450B (zh) 一种辛波莫德晶型及其制备方法
WO2017028762A1 (zh) 一种萘环化合物的晶型
CN110577522B (zh) 马罗匹坦柠檬酸盐新晶型及其制备方法
WO2019169988A1 (zh) 埃格列净的晶型及其制备方法
CN114728955A (zh) Tropifexor的新晶型及其制备方法
CN110903219A (zh) 酰胺衍生物的盐及其制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21863677

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21863677

Country of ref document: EP

Kind code of ref document: A1