WO2020135058A1 - Nouvelle forme cristalline de roxadustat et procédé de préparation associé - Google Patents

Nouvelle forme cristalline de roxadustat et procédé de préparation associé Download PDF

Info

Publication number
WO2020135058A1
WO2020135058A1 PCT/CN2019/124634 CN2019124634W WO2020135058A1 WO 2020135058 A1 WO2020135058 A1 WO 2020135058A1 CN 2019124634 W CN2019124634 W CN 2019124634W WO 2020135058 A1 WO2020135058 A1 WO 2020135058A1
Authority
WO
WIPO (PCT)
Prior art keywords
arz
crystalline form
solvent
crystal form
solution
Prior art date
Application number
PCT/CN2019/124634
Other languages
English (en)
Chinese (zh)
Inventor
李庆秋
申淑匣
修平
张良
Original Assignee
安礼特（上海）医药科技有限公司
江苏创诺制药有限公司
上海创诺医药集团有限公司
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 安礼特（上海）医药科技有限公司, 江苏创诺制药有限公司, 上海创诺医药集团有限公司 filed Critical 安礼特（上海）医药科技有限公司
Publication of WO2020135058A1 publication Critical patent/WO2020135058A1/fr

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P7/06—Antianaemics
    • 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 belongs to the technical field of medicinal chemistry, and particularly relates to a new crystalline form of rosastat and its preparation method.
  • Roxastat the English name Roxadustat, its chemical name: [(4-hydroxy-1-methyl-7-phenoxy-isoquinoline-3-carbonyl)-amino]-acetic acid, the trade name is: Bomei, molecular formula: C 19 H 16 N 2 O 5 , molecular weight: 352.11, CAS number: 808118-40-3, chemical structural formula:
  • the drug is a disease developed by FibroGen for the treatment of renal anemia. It was applied for listing in the country in November 2017. The United States and Europe are in phase III clinical trials. In the second half of 2018, they submitted an NDA application in the United States.
  • WO2014014835 discloses the crystalline form A, crystalline form B, crystalline form C and crystalline form D of rosastat and the preparation method thereof, wherein: crystalline form A is anhydrous, crystalline form B is hemihydrate, crystalline form C is a hexafluoropropan-2-ol solvate, and Form D is a co-solvate of DMSO and water.
  • the crystal form A has good chemical stability, and the crystal form B and the crystal form D are easily converted to the crystal form A under the condition of high temperature and high humidity.
  • Form A has good stability, its solubility is poor; Form B has poor stability and can be easily converted to Form A.
  • WO2013013609 discloses crystalline form I, crystalline form II, crystalline form III, crystalline form IV, crystalline form V, crystalline form VI, crystalline form VII of rosastat. Most of the disclosed crystal forms are solvates and are not suitable for industrial production.
  • the object of the present invention is to provide a new crystalline form of rosastat which has both excellent solubility and excellent stability.
  • the crystalline form is selected from the group consisting of crystalline form ARZ-A, crystalline form ARZ-B, crystalline form ARZ-E, crystalline form ARZ-F, crystalline form ARZ-G, crystalline form ARZ-H, crystalline form ARZ- J, or crystal form ARZ-K.
  • the crystal form is the monohydrate crystal form ARZ-A of the compound of formula I, and the X-ray powder diffraction pattern of the crystal form ARZ-A is 6.7 ⁇ 0.2°, 8.0 ⁇ at 2 ⁇ There are characteristic peaks at 0.2°, 9.3 ⁇ 0.2, and 13.2 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form ARZ-A is 16.0 ⁇ 0.2°, 17.7 ⁇ 0.2°, 18.3 ⁇ 0.2°, 20.0 ⁇ 0.2°, 21.0 ⁇ 0.2°, 23.0 at 2 ⁇ There are also characteristic peaks at ⁇ 0.2°, 25.3 ⁇ 0.2°, 25.8 ⁇ 0.2°, and/or 27.7 ⁇ 0.2°.
  • the TGA pattern of the crystalline form ARZ-A has a weight loss of 3-6% at 30-80°C.
  • the DSC pattern of the crystalline form ARZ-A has a characteristic peak in the range of 70-90°C, a characteristic peak in the range of 110-125°C, and melting decomposition in the range of 220-225°C.
  • the TGA diagram of the crystalline form ARZ-A is basically shown in FIG. 2.
  • the X-ray powder diffraction pattern of the crystalline form ARZ-A is basically shown in FIG. 1.
  • the DSC chart of the crystalline form ARZ-A is basically shown in FIG. 3.
  • the 1 H-NMR chart of the crystalline form ARZ-A is basically shown in FIG. 4.
  • the crystal form is a hemihydrate crystal form ARZ-B
  • the X-ray powder diffraction pattern of the crystal form ARZ-B is 3.1 ⁇ 0.2°, 6.2 ⁇ 0.2° at 2 ⁇ , and There is a characteristic peak at 27.0 ⁇ 0.2°.
  • the crystalline form is crystalline form ARZ-E
  • the X-ray powder diffraction pattern of the crystalline form ARZ-E is 5.1 ⁇ 0.2°, 8.2 ⁇ 0.2°, 10.4 ⁇ 0.2° at 2 ⁇ , And 11.4 ⁇ 0.2° have characteristic peaks.
  • the crystalline form is crystalline form ARZ-F
  • the X-ray powder diffraction pattern of the crystalline form ARZ-F is 10.2 ⁇ 0.2°, 11.5 ⁇ 0.2°, 13.5 ⁇ 0.2° at 2 ⁇ , 15.1 ⁇ 0.2 ° has a characteristic peak.
  • the crystalline form is crystalline form ARZ-G
  • the X-ray powder diffraction pattern of the crystalline form ARZ-G has characteristic peaks at 2 ⁇ of 12.5 ⁇ 0.2° and 15.3 ⁇ 0.2°.
  • the crystalline form is crystalline form ARZ-H
  • the X-ray powder diffraction pattern of the crystalline form ARZ-H has characteristic peaks at 2 ⁇ of 9.7 ⁇ 0.2° and 13.6 ⁇ 0.2°.
  • the crystalline form is crystalline form ARZ-J
  • the X-ray powder diffraction pattern of the crystalline form ARZ-J is 8.0 ⁇ 0.2°, 12.1 ⁇ 0.2°, 16.3 ⁇ 0.2° at 2 ⁇ There is a characteristic peak.
  • the crystalline form is crystalline form ARZ-K
  • the X-ray powder diffraction pattern of the crystalline form ARZ-K is at 2 ⁇ of 10.9 ⁇ 0.2, 14.9 ⁇ 0.2°, 21.1 ⁇ 0.2° With characteristic peaks.
  • the TGA pattern of the crystalline form ARZ-B has a 2-5% weight loss at 30-90°C.
  • the X-ray powder diffraction pattern of the crystalline form ARZ-B is basically shown in FIG. 5.
  • the TGA diagram of the crystalline form ARZ-B is basically shown in FIG. 6.
  • the TGA pattern of the crystalline form ARZ-E has a weight loss of 15-19% at 60-130°C.
  • the X-ray powder diffraction pattern of the crystalline form ARZ-E is basically shown in FIG. 13.
  • the TGA diagram of the crystalline form ARZ-E is basically as shown in FIG. 14.
  • the TGA pattern of the crystalline form ARZ-F has a 4-7% weight loss at 50-200°C.
  • the DSC pattern of the crystalline form ARZ-F has a characteristic peak in the range of 143-160°C, and melts and decomposes in the range of 217-225°C.
  • the X-ray powder diffraction pattern of the crystalline form ARZ-F is basically as shown in FIG. 15.
  • the TGA diagram of the crystalline form ARZ-F is basically shown in FIG. 16.
  • the DSC chart of the crystalline form ARZ-F is basically shown in FIG. 17.
  • the 1 H-NMR chart of the crystalline form ARZ-F is basically shown in FIG. 18.
  • the TGA pattern of the crystalline form ARZ-G has a weight loss of 16-19% at 80-120°C.
  • the DSC pattern of the crystalline form ARZ-G has a characteristic peak in the range of 90-120°C, and melts and decomposes in the range of 220-225°C.
  • the X-ray powder diffraction pattern of the crystalline form ARZ-G is basically shown in FIG. 19.
  • the TGA diagram of the crystalline form ARZ-G is basically as shown in FIG. 20.
  • the DSC chart of the crystalline form ARZ-G is basically shown in FIG. 21.
  • the TGA pattern of the crystalline form ARZ-H has a weight loss of 8.5-12% at 80-120°C.
  • the X-ray powder diffraction pattern of the crystalline form ARZ-H is basically shown in FIG. 22.
  • the TGA diagram of the crystalline form ARZ-H is basically shown in FIG. 23.
  • the TGA pattern of the crystalline form ARZ-J has a weight loss of 10-13% at 70-110°C.
  • the DSC pattern of the crystalline form ARZ-J has a characteristic peak in the range of 88-110°C, and melts and decomposes in the range of 222-225°C.
  • the X-ray powder diffraction pattern of the crystalline form ARZ-J is basically as shown in FIG. 27.
  • the TGA diagram of the crystalline form ARZ-J is basically as shown in FIG. 28.
  • the DSC chart of the crystalline form ARZ-J is basically shown in FIG. 29.
  • the TGA pattern of the crystalline form ARZ-K has a weight loss of 10-12% at 80-125°C.
  • the X-ray powder diffraction pattern of the crystalline form ARZ-K is basically as shown in FIG. 30.
  • the TGA diagram of the crystalline form ARZ-K is basically shown in FIG. 31.
  • the method for separating the solid from the solution of the compound of formula I in the first solvent includes: lyophilizing the solution, cooling the solution, and causing the solution to The solvent evaporates, a second solvent is added to the solution, and/or, a solution of hydrogen chloride in the second solvent is added to the solution.
  • the method for separating the solid from the mixture of the compound of formula I in the first solvent includes direct solid-liquid separation.
  • step (i) the solution of the compound of formula I in the first solvent is the solution after filtration treatment.
  • the first solvent is selected from the group consisting of solvent a1, solvent b1, solvent e1, solvent f1, solvent g1, solvent h1, solvent j1, or solvent k1.
  • the second solvent is selected from the group consisting of solvent a2, solvent b2, solvent e2, solvent f2, solvent g2, solvent h2, solvent j2, or solvent k2.
  • the method is a method selected from the group consisting of method A-1, method A-2, or method A-3;
  • Method A-1 includes the steps of: (ia) dissolving the compound of formula I in a solvent a1 to obtain a solution a1 (preferably, the solution a1 is a filtered solution a1); (ii-a) freezing the solution a1 Dry processing to obtain a solid, the solid is crystalline form ARZ-A;
  • Method A-2 includes the steps of: (ia) dissolving the compound of formula I in a solvent a1 to obtain a solution a2 (preferably, the solution a2 is a filtered solution a2); (ii-a) dropping into the solution a2 Adding solvent a2 to obtain mixture a2; treating mixture a2 to obtain solid, the solid is crystalline form ARZ-A;
  • Method A-3 includes the steps of: (ia) dissolving the compound of formula I in a solvent a1 to obtain a solution a3 (preferably, the solution a3 is a filtered solution a3); (ii-a) to the solution a3 Processing to obtain a solid, the solid is crystalline form ARZ-A;
  • the solvent a1 refers to a solvent that can completely dissolve rosarox at 10 to 150°C; preferably, the solvent a1 is selected from the group consisting of pyridine, N,N-dimethylformamide, Dimethyl sulfoxide, formic acid, acetic acid, acetone, N-methylpyrrolidone, tetrahydrofuran, dimethyltetrahydrofuran, 1,4-dioxane, methanol, methylene chloride, methyl isobutyl ketone, water or a combination thereof Thing.
  • the solvent a1 is selected from the group consisting of pyridine, N,N-dimethylformamide, Dimethyl sulfoxide, formic acid, acetic acid, acetone, N-methylpyrrolidone, tetrahydrofuran, dimethyltetrahydrofuran, 1,4-dioxane, methanol, methylene chloride, methyl isobutyl ketone,
  • the solvent a1 is selected from the group consisting of dimethyl sulfoxide, dimethyltetrahydrofuran, formic acid, acetic acid, methyl isobutyl ketone (MIBK), acetone, Water, or a combination thereof.
  • the solvent a1 is selected from the group consisting of N,N-dimethylformamide, methyl isobutyl ketone, dimethyl sulfoxide, formic acid, acetic acid, water, or a combination thereof.
  • the solvent a1 is a combination of formic acid and solvent a3, and the a3 is selected from the group consisting of methanol, ethanol, and/or water; or, the solvent a1 is dimethyltetrahydrofuran.
  • the volume ratio of formic acid and solvent a3 is (0.5-10):1.
  • the solvent a1 is selected from the group consisting of a combination of formic acid and acetone, dimethyl sulfoxide, or a combination of dimethyl sulfoxide and methyl isobutyl ketone
  • the solvent a1 is N,N-dimethylformamide or formic acid.
  • step (i-a) the dissolution temperature of the compound of formula I in the solvent a1 is 10-100°C.
  • the solvent a2 is selected from the group consisting of cyclohexane, isopropyl ether, n-heptane, anisole, diphenyl ether, or a combination thereof; preferably: the solvent a2 is selected from Lower group: cyclohexane, or isopropyl ether, or a combination thereof.
  • the concentration of the compound of formula I is 0.005 to 1.0 g/mL; preferably, 0.01 to 0.5 g/mL.
  • the treatment is selected from: cooling to 5-15°C or volatile solvent.
  • the method when the crystal form is ARZ-B, includes the steps of: (ib) dissolving the compound of formula I in a solvent b1 to obtain a solution b1 (preferably the obtained solution b1 is the filtered solution b1); (ii-b) add the solvent b2 to the solution b1, volatilize the solvent to obtain a solid, the solid is the crystalline form ARZ-B; wherein, the solvent b1 is methanol and methylene chloride Mixed solvent, and the solvent b2 is anisole.
  • the volume ratio of methanol to methylene chloride is (0.3-30):1; preferably, (0.6-15):1.
  • step (i-b) is: the dissolution temperature of the compound of formula I in the solvent b1 is 50-100°C.
  • the concentration of the compound of formula I in the solution b1 is 0.005 to 1.0 g/mL, preferably 0.01 to 0.5 g/mL.
  • the method when the crystal form is ARZ-E, includes the steps of: (ie) dissolving the compound of formula I in a solvent e1 to obtain a solution e1 (preferably the solution e1 It is a solution e1) which has been filtered; (ii-e) Add solvent e2, and volatilize the solvent to obtain a solid, which is crystalline form ARZ-E;
  • the solvent e1 includes: methyl isobutyl ketone and another solvent selected from the group consisting of pyridine, N,N-dimethylformamide, dimethyl sulfoxide, formic acid, acetic acid, N-methyl Pyrrolidone, tetrahydrofuran, 1,4 dioxane, methanol, methylene chloride, water, or a combination thereof;
  • the solvent e2 is selected from cyclohexane, isopropyl ether, anisole, diphenyl ether, or a combination thereof .
  • the volume ratio of methyl isobutyl ketone to the solvent e1 is 1: (1-20).
  • the concentration of the compound of formula I in the solution 1e is 0.005 to 1.0 g/mL; preferably, 0.01 to 0.5 g/mL.
  • the method when the crystal form is ARZ-F, includes the steps of: (if) dissolving the compound of formula I in a solvent f1 to obtain a solution f1 (preferably the solution f1 It is a solution f1) which has been filtered; (ii-f) The solvent is volatilized to obtain crystals, which are the crystal form ARZ-F;
  • the solvent f1 includes isoamyl alcohol and another solvent selected from the group consisting of pyridine, N,N-dimethylformamide, dimethyl sulfoxide, formic acid, acetic acid, N-methylpyrrolidone, methyl alcohol Isobutyl ketone, tetrahydrofuran, 1,4 dioxane, methanol, dichloromethane, water, or a combination thereof.
  • the volume ratio of isoamyl alcohol to the solvent f1 is 1: (1-15).
  • the dissolution temperature of the compound of formula I in the solvent f1 is 10-100°C; preferably, it is 20-35°C.
  • step (i-f) when the solvent is volatilized, the volatilization temperature is greater than 35°C.
  • the concentration of the compound of formula I in the solution f1 is 0.005 to 1.0 g/mL, preferably 0.01 to 0.5 g/mL.
  • the method when the crystalline form is crystalline form ARZ-G, the method includes the steps of: (ig) dissolving the compound of formula I in the solvent g1, and the solvent g1 is pyridine to obtain a solution g1; ( ii-g) The solvent g2 is added to the solvent g1 to crystallize to obtain a solid, which is a crystal form ARZ-G.
  • the dissolution temperature of the compound of formula I in the solvent g1 is 10-100°C; preferably, 20-35°C.
  • the solvent g2 is selected from the group consisting of n-heptane, cyclohexane, isopropyl ether, anisole, diphenyl ether, or a combination thereof.
  • the concentration of the compound of formula I in the solution g1 is 0.005 to 1.0 g/mL, preferably 0.01 to 0.5 g/mL.
  • the method when the crystal form is ARZ-H, includes the steps of: (ih) dissolving the compound of formula I in a solvent h1 to obtain a solution h1 (preferably the solution h1 It is the solution h1) after being filtered; (ii-h) Add the solvent h2 to the solution h1, volatilize the solvent to obtain a solid, and the obtained solid is the crystalline form ARZ-H;
  • the solvent 1h is pyridine
  • the solvent h2 is selected from the group consisting of methyl isobutyl ketone, acetone, or a combination thereof.
  • the dissolution temperature of the compound of formula I in the solvent for 1 h is 10-100°C; preferably, it is 20-35°C.
  • the concentration of the compound of formula I in the solution h1 is 0.005 to 1.0 g/mL, preferably 0.01 to 0.5 g/mL.
  • the method includes the steps of: (ij) dissolving the compound of formula I in a solvent j1 to obtain a solution j1 (preferably the solution j1 is passed through Filtered solution j1); (ii-j) Add solvent j2 to solution j1 to precipitate a solid, the resulting solid is the crystalline form ARZ-J;
  • the solvent j1 is 1.4-dioxane
  • the solvent j2 is selected from the group consisting of n-heptane, cyclohexane, isopropyl ether, anisole, diphenyl ether, or a combination thereof.
  • the dissolution temperature of the compound of formula I in the solvent j1 is 10-100°C; preferably, 50-70°C.
  • step (i-j) the mass-to-volume ratio (g:ml) of the compound of formula I to the solvent j1 is 4:1 to 8:1
  • the concentration of the compound of formula I is 0.005 to 1.0 g/mL; preferably, 0.005 to 0.02 g/mL.
  • step (ii-j) the temperature when the solvent j2 is added to the solution j1 is 20-40°C.
  • the method when the crystalline form is crystalline form ARZ-K, includes the steps of: (ik) providing a mixture of the compound of formula I in a solvent k1, wherein the solvent k1 is 1.4-diox In the six rings; (ii-k) stir the mixture to obtain crystalline form ARZ-K.
  • step (i-k) the mass volume ratio (g:ml) of the compound of formula I to the solvent k1 is 8:1-20:1.
  • composition comprising (i) the crystalline form of claim 1, and (ii) a pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier includes: filler, disintegrant, binder, lubricant, or a combination thereof.
  • the filler includes starch, lactose, microcrystalline cellulose, dextrin, mannitol, magnesium oxide, calcium sulfate, or a combination thereof.
  • the disintegrant includes: carboxymethyl cellulose and its salts, croscarmellose and its salts, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl Cellulose, or a combination thereof.
  • the binder includes povidone, hydroxypropyl methyl cellulose, starch slurry, or a combination thereof.
  • the lubricant includes magnesium stearate, calcium stearate, or a combination thereof.
  • a method for treating and/or preventing renal anemia characterized in that the method comprises: administering a safe and effective amount of the crystalline form according to the first aspect to a subject in need .
  • FIG. 1 is an XRPD spectrum of the crystalline form ARZ-A of rosastatin according to the present invention
  • FIG. 6 is a TGA spectrum diagram of the crystalline form ARZ-B of rosastatin according to the present invention.
  • FIG. 11 is a TGA spectrum diagram of the crystalline form ARZ-D of rosastatin according to the present invention.
  • 16 is a TGA spectrum diagram of the crystalline form ARZ-F of rosastatin according to the present invention.
  • 17 is a DSC spectrum of the crystalline form ARZ-F of rosastatin according to the present invention.
  • 21 is a DSC spectrum of the crystalline form ARZ-G of rosastatin according to the present invention.
  • FIG. 24 is an XRPD spectrum of the crystalline form ARZ-I of rosastatin according to the present invention.
  • FIG. 26 is a DSC spectrum of the crystalline form ARZ-I of rosastatin according to the present invention.
  • FIG. 27 is an XRPD spectrum of the crystalline form ARZ-J of rosastat according to the present invention.
  • FIG. 28 is a TGA spectrum of the crystalline form ARZ-J of rosastatin according to the present invention.
  • FIG. 29 is a DSC spectrum of the crystalline form ARZ-J of rosastatin according to the present invention.
  • FIG. 31 is a TGA spectrum of the crystalline form ARZ-K of rosastatin according to the present invention.
  • FIG. 32 is an XRPD spectrum of the crystalline form ARZ-L of rosastat in the present invention.
  • FIG. 33 is a TGA spectrum of the crystalline form ARZ-L of rosastatin according to the present invention.
  • FIG. 34 is a DSC spectrum of the crystalline form ARZ-L of rosastatin according to the present invention.
  • the inventor has gone through extensive and in-depth research. After a lot of experiments, a series of new crystalline forms of rosastatin were obtained for the first time.
  • the new crystalline forms include crystalline form ARZ-A, crystalline form ARZ-B, crystalline form ARZ-E, crystalline form ARZ-F, crystalline form ARZ-G, crystal form ARZ-H, crystal form ARZ-J, crystal form ARZ-K.
  • These new crystal forms have excellent solubility and stability (including thermal stability, high humidity stability, and pressure stability).
  • the crystalline form solvent of the present invention has little residue, especially the crystalline form ARZ-A which does not have a solvent The problem of toxicity. Based on this, the inventor completed the present invention.
  • rosastat and “rosastat” are used interchangeably and refer to compounds of formula I.
  • binder X-ray diffraction or "X-ray powder diffraction” are used interchangeably;
  • binder X-ray diffraction pattern or "X-ray powder diffraction pattern” are used interchangeably.
  • the present invention provides a new crystalline form of rosastat and has a superior solubility and stability and is very suitable for the production of formulations and a preparation method thereof.
  • a crystalline form of rosastat ie, a compound of formula I
  • the crystalline form is selected from the group consisting of crystalline form ARZ-A, crystalline form ARZ-B, crystalline form ARZ-C , Crystal form ARZ-D, crystal form ARZ-E, crystal form ARZ-F, crystal form ARZ-G, crystal form ARZ-H, crystal form ARZ-I, crystal form ARZ-J, or crystal form ARZ-K.
  • the crystalline form provided by the present invention is crystalline form ARZ-A, and the crystalline form ARZ-A is a monohydrate.
  • the X-ray powder diffraction pattern of the crystalline form ARZ-A has characteristic peaks at 2 ⁇ of 6.7 ⁇ 0.2°, 8.0 ⁇ 0.2°, 9.3 ⁇ 0.2°, and 13.2 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form ARZ-A at 2 ⁇ is 6.7 ⁇ 0.2°, 8.0 ⁇ 0.2°, 9.3 ⁇ 0.2°, 13.2 ⁇ 0.2°, 16.0 ⁇ 0.2°, 17.7 ⁇ 0.2° , 18.3 ⁇ 0.2°, 20.0 ⁇ 0.2°, 21.0 ⁇ 0.2°, 23.0 ⁇ 0.2°, 25.3 ⁇ 0.2°, 25.8 ⁇ 0.2°, 27.7 ⁇ 0.2° have characteristic peaks.
  • the crystalline form ARZ-A of rosastatin according to the present invention has the following characteristic peak and relative intensity under powder X-ray diffraction:
  • the X-ray powder diffraction pattern of the crystalline form ARZ-A is basically shown in FIG. 1.
  • the TGA pattern of the crystalline form ARZ-A has a weight loss of 3-6% at 30-80°C.
  • TGA diagram of the crystalline form ARZ-A is basically shown in FIG. 2.
  • the DSC pattern of the crystalline form ARZ-A has a characteristic peak in the range of 70-90°C, a characteristic peak in the range of 110-125°C, and melting decomposition in the range of 220-225°C.
  • the present invention also provides a method for preparing the crystalline form ARZ-A, including a method selected from the group consisting of:
  • Method A-1 (i) dissolve roxastat (ie, compound of formula I) in solvent a1 (preferably solvent a1-1) to obtain solution a1; (ii) solution a1 is lyophilized to obtain a solid , The solid is crystalline ARZ-A; or
  • Method A-2 (i) dissolve roxastat (that is, the compound of formula I) in solvent a1 (preferably solvent a1-2) to obtain a solution a2; (ii) dropwise add the solvent a2 to the solution a2, Treated solid, the solid is crystalline form ARZ-A; or
  • Method A-3 (i) dissolve roxastat (ie, the compound of formula I) in a solvent a1 (preferably solvent a1-3) to obtain a solution a3; (ii) process the solution a3 to obtain a solid,
  • the solid is crystalline form ARZ-A.
  • the solvent a1 refers to a solvent capable of completely dissolving rosastatin at 10 to 150°C.
  • the solvent a1-1 or a1-2 is selected from the group consisting of pyridine, N,N-dimethylformamide, dimethylsulfoxide, formic acid, acetic acid, acetone, N-methylpyrrolidone, tetrahydrofuran , Dimethyltetrahydrofuran, 1,4-dioxane, methanol, dichloromethane, methyl isobutyl ketone, water or a combination thereof; preferably, selected from the group consisting of dimethyl sulfoxide and dimethyl Tetrahydrofuran, formic acid, acetic acid, methyl isobutyl ketone (MIBK), acetone, water, or a combination thereof; more preferably, selected from the group consisting of dimethyl sulfoxide, formic acid, acetic acid, methyl isobutyl ketone or combination.
  • MIBK isobutyl ketone
  • the solvent a1-3 is selected from the group consisting of pyridine, N,N-dimethylformamide, dimethylsulfoxide, formic acid, acetic acid, N-methylpyrrolidone, tetrahydrofuran, 1,4 di Oxane, methanol, methylene chloride, water, or a combination thereof; preferably, selected from the group consisting of N,N-dimethylformamide, dimethyl sulfoxide, formic acid, acetic acid, water, or a combination thereof; more Preferably, it is selected from the group consisting of dimethyl sulfoxide, formic acid, acetic acid, water, or a combination thereof.
  • dissolution temperature of rosastat in solvent a1 is 10-100°C.
  • the solvent a2 is selected from the group consisting of cyclohexane, n-heptane, anisole, and dianisole.
  • the concentration of rosastatin in the solutions a1, a2 or a3 is 0.005 to 1.0 g/mL, preferably 0.01 to 0.5 g/mL.
  • the treatment in the method A-2 or the method A-3 is selected from the group consisting of cooling to 5-15°C or volatile solvents.
  • a filtering step is further included, that is, the solution a1, a2 or a3 is the filtered solution a1, a2 or a3.
  • the crystalline form provided by the present invention is crystalline form ARZ-B, and the crystalline form ARZ-B is a hemihydrate, the powder X-ray diffraction pattern of the crystalline form ARZ-B, at 2 ⁇ is There are characteristic peaks at 3.1 ⁇ 0.2°, 6.2 ⁇ 0.2°, 27.0 ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the crystalline form ARZ-B is 3.1 ⁇ 0.2°, 6.2 ⁇ 0.2°, 8.1 ⁇ 0.2°, 8.3 ⁇ 0.2°15.9 ⁇ 0.2°, 16.5 ⁇ 0.2°, at 2 ⁇ . There are characteristic peaks at 22.5 ⁇ 0.2° and 27.0 ⁇ 0.2°.
  • the crystal form ARZ-B has the following characteristic peak and relative intensity under powder X-ray diffraction:
  • the powder X-ray diffraction pattern of the crystalline form ARZ-B is basically shown in FIG. 5.
  • the TGA pattern of the crystalline form ARZ-B has a weight loss of 2-5% at 30-90°C.
  • TGA diagram of the crystalline form ARZ-B is basically shown in FIG. 6.
  • the present invention provides a method for preparing the crystalline form ARZ-B, including the steps of: (i) dissolving rosastat in a solvent b1 to obtain a solution b1; (ii) adding anisole to the solution b1 That is, solvent b2, the solvent is volatilized to obtain a solid.
  • dissolution temperature of roxastat in solvent b1 is 50-100°C.
  • the solvent b1 is selected from the group consisting of THF, methanol, DCM, water, or a combination thereof.
  • the solution b1 is further filtered to obtain the filtered solution b1.
  • the concentration of rosastatin in the solution b1 may be 0.005 to 1.0 g/mL, preferably 0.01 to 0.5 g/mL.
  • volatilization temperature of the volatile solvent is greater than 20°C.
  • the crystalline form provided by the present invention is the crystalline form ARZ-C.
  • the crystalline form ARZ-C is 6.5 ⁇ 0.2°, 13.2 ⁇ 0.2°, 19.8 ⁇ at 2 ⁇ , 2 ⁇ There is a characteristic peak at 0.2.
  • the crystal form ARZ-C has the following characteristic peak and relative intensity under powder X-ray diffraction:
  • the X-ray powder diffraction pattern of the crystalline form ARZ-C is basically shown in FIG. 7.
  • the TGA pattern of the crystalline form ARZ-C has a weight loss of 4.5-7% at 90-140°C.
  • TGA diagram of the crystalline form ARZ-C is basically shown in FIG. 8.
  • the DSC pattern of the crystalline form ARZ-C has a characteristic peak in the range of 100-130°C, and melts and decomposes in the range of 223-225°C.
  • the present invention provides a method for preparing the crystalline form ARZ-C, which includes the following steps: (i) dissolving rosastat in a solvent c1 to obtain a solution c1, (ii) and then cooling and crystallizing, Crystal form ARZ-C was obtained.
  • the dissolution temperature of roxastat in solvent c1 is 10-100°C, preferably 50-70°C.
  • the solvent c1 includes: formic acid and another solvent selected from the group consisting of pyridine, N,N-dimethylformamide, dimethyl sulfoxide, acetic acid, N-methylpyrrolidone, tetrahydrofuran, 1,4 dioxane, methanol, dichloromethane, methyl isobutyl ketone, water, or a combination thereof.
  • the concentration of rosastatin in the solution c1 may be 0.005 to 1.0 g/mL, preferably 0.01 to 0.5 g/mL.
  • the crystalline form provided by the present invention is crystalline form ARZ-D.
  • the 2 ⁇ is 4.9 ⁇ 0.2°, 6.3 ⁇ 0.2°, 7.7 ⁇ 0.2°, 8.3 ⁇ 0.2°, 13.0
  • the crystalline form ARZ-D of rosastat has the following characteristic peak and relative intensity under powder X-ray diffraction:
  • the X-ray powder diffraction pattern of the crystalline form ARZ-D is basically shown in FIG. 10.
  • the TGA pattern of the crystalline form ARZ-D has a weight loss of 7.5-9.0% at 40-140°C.
  • TGA diagram of the ARZ-D crystal form is basically shown in FIG. 11.
  • the DSC pattern of the crystalline form ARZ-D has a characteristic peak in the range of 110-140°C, and melts and decomposes in the range of 223-225°C.
  • the present invention provides a method for preparing the crystalline form ARZ-D, including the following steps: (i) dissolve rosastat in a solvent d1 to obtain a solution d1; (ii) add to the solution d1 The anisole crystallizes and the resulting solid is the crystalline form ARZ-D.
  • the concentration of rosastatin in the solution d1 may be 0.005 to 1.0 g/mL, preferably 0.01 to 0.5 g/mL.
  • the dissolution temperature of roxastat in the solvent d1 is 10-100°C.
  • the solvent d1 includes formic acid and another solvent selected from the group consisting of pyridine, N,N-dimethylformamide, dimethyl sulfoxide, acetic acid, N-methylpyrrolidone, tetrahydrofuran, 1,4 dioxane, methanol, dichloromethane, methyl isobutyl ketone, water, or a combination thereof.
  • the solution d1 is a solution d1 that has undergone a filtering process.
  • the crystallization temperature of anisole added for crystallization is 5 to -15°C.
  • the crystalline form is crystalline form ARZ-E, and its X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ of 5.1 ⁇ 0.2°, 8.2 ⁇ 0.2°, 10.4 ⁇ 0.2°, 11.4 ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the crystalline form ARZ-E at 2 ⁇ is 5.1 ⁇ 0.2°, 8.2 ⁇ 0.2°, 10.4 ⁇ 0.2°, 11.4 ⁇ 0.2°15.9 ⁇ 0.2°, 18.0 ⁇ 0.2°, 20.0
  • the powder ARX-E has the following characteristic peaks and relative intensity under powder X-ray diffraction:
  • the X-ray powder diffraction pattern of the crystalline form ARZ-E is basically shown in FIG. 13.
  • the TGA pattern of the crystalline form ARZ-E has a weight loss of 15-19% at 60-130°C.
  • TGA diagram of the crystalline form ARZ-E is basically shown in FIG. 14.
  • the present invention provides a method for preparing the crystalline form ARZ-E, including the following steps: (i) dissolve roxastat in a solvent e1 (for example, N,N-dimethylformamide and formaldehyde In the mixed solvent of isobutyl ketone), the solution e1 is obtained; (ii) The solvent e2 is added to the solution e1, and the solvent is volatilized to obtain a solid.
  • a solvent e1 for example, N,N-dimethylformamide and formaldehyde In the mixed solvent of isobutyl ketone
  • the mixed solvent e1 is a mixed solvent, which includes methyl isobutyl ketone and another solvent selected from the group consisting of pyridine, N,N-dimethylformamide, dimethyl sulfoxide, Formic acid, acetic acid, N-methylpyrrolidone, tetrahydrofuran, 1,4 dioxane, methanol, dichloromethane, water, or a combination thereof.
  • the solvent e2 is selected from the group consisting of cyclohexane, isopropyl ether, anisole, diphenyl ether, tertiary methyl ether, and cyclopentane.
  • the concentration of rosastatin in the solution e1 may be 0.005 to 1.0 g/mL, preferably 0.01 to 0.5 g/mL.
  • the crystalline form provided by the present invention is crystalline form ARZ-F, and its X-ray powder diffraction pattern has characteristics at 2 ⁇ of 10.2 ⁇ 0.2°, 11.5 ⁇ 0.2°, 13.5 ⁇ 0.2°, 15.1 ⁇ 0.2° peak.
  • the crystalline form ARZ-F has the following characteristic peak and relative intensity under powder X-ray diffraction:
  • the powder X-ray diffraction pattern of the crystalline form ARZ-F is basically shown in FIG. 15.
  • the TGA pattern of the crystalline form ARZ-F has a weight loss of 4-7% at 50-200°C.
  • TGA diagram of the ARZ-F crystal form is basically shown in FIG. 16.
  • the DSC pattern of the crystalline form ARZ-F has a characteristic peak in the range of 143-160°C, and melts and decomposes in the range of 217-225°C.
  • the present invention provides a method for preparing the crystalline form ARZ-F, which includes the following steps: rosastat is dissolved in the solvent f1 to obtain a solution f1; and the solvent is evaporated to obtain crystals.
  • the solvent f1 includes isoamyl alcohol and another solvent selected from the group consisting of pyridine, N,N-dimethylformamide, dimethyl sulfoxide, formic acid, acetic acid, and N-methylpyrrolidone , Methyl isobutyl ketone, tetrahydrofuran, 1,4 dioxane, methanol, dichloromethane, water or a combination thereof.
  • the dissolution temperature of rosastat in solvent f1 is 10-100°C, preferably 20-35°C
  • the temperature of the volatile solvent is greater than 35°C.
  • the solution f1 is the solution f1 after being filtered.
  • the concentration of the solution f1 may be 0.005 to 1.0 g/mL, preferably 0.01 to 0.5 g/mL.
  • the crystalline form provided by the present invention is crystalline form ARZ-G, and its powder X-ray diffraction pattern has characteristic peaks at 2 ⁇ of 12.5 ⁇ 0.2° and 15.3 ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the crystalline form ARZ-G at 2 ⁇ is 8.6 ⁇ 0.2°, 12.5 ⁇ 0.2°, 15.3 ⁇ 0.2°, 15.8 ⁇ 0.2°, 18.8 ⁇ 0.2°, 19.8 ⁇ 0.2°, There are characteristic peaks at 20.2 ⁇ 0.2°, 24.7 ⁇ 0.2°, and 28.0 ⁇ 0.2°.
  • the crystal form ARZ-G has the following characteristic peak and relative intensity under powder X-ray diffraction:
  • the X-ray powder diffraction pattern of the crystalline form ARZ-G is basically shown in FIG. 19.
  • the TGA pattern of the crystalline form ARZ-G has a weight loss of 16-19% at 80-120°C.
  • TGA diagram of the ARZ-G crystal form is basically shown in FIG. 20.
  • the DSC pattern of the crystalline form ARZ-G has a characteristic peak in the range of 90-120°C, and melts and decomposes in the range of 220-225°C.
  • the DSC chart of the crystalline form ARZ-G is basically shown in FIG. 21.
  • the present invention provides a method for preparing the crystalline form ARZ-G, including the following steps: (i) dissolve roxastat in pyridine (ie, solvent g1), solution g1; (ii) solution The solvent g2 is added to g1 to crystallize to obtain a solid, and the obtained solid is the crystalline form ARZ-G.
  • the dissolution temperature of rosastat in the solvent g1 is 10-100°C, preferably 20-35°C.
  • the concentration of rosastatin in the solution g1 may be 0.005 to 1.0 g/mL, preferably 0.01 to 0.5 g/mL.
  • the solvent g2 is selected from the group consisting of n-heptane, cyclohexane, isopropyl ether, anisole, and diphenyl ether.
  • the crystallization temperature is 10-30°C.
  • the crystalline form of the present invention is crystalline form ARZ-H
  • the powder X-ray diffraction pattern of the crystalline form ARZ-H has characteristic peaks at 2 ⁇ of 9.7 ⁇ 0.2° and 13.6 ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the crystalline form ARZ-H at 2 ⁇ is 9.7 ⁇ 0.2°, 11.2 ⁇ 0.2°, 13.6 ⁇ 0.2°, 19.3 ⁇ 0.2°, 20.0 ⁇ 0.2°, 21.7 ⁇ 0.2°, There are characteristic peaks at 27.0 ⁇ 0.2°.
  • the crystalline form ARZ-H has the following characteristic peak and relative intensity under powder X-ray diffraction:
  • the X-ray powder diffraction pattern of the crystalline form ARZ-H is basically shown in FIG. 22.
  • the TGA pattern of the crystalline form ARZ-H has a weight loss of 8.5-12% at 80-120°C.
  • TGA diagram of the ARZ-H crystal form is basically shown in FIG. 23.
  • the present invention provides a method for preparing the crystalline form ARZ-H, which includes the following steps: (i) dissolve roxastat in pyridine, a solvent h1, to obtain a solution h1; (ii) to the solution h1 The solvent h2 is added to it, and the solvent is volatilized to obtain a solid, and the obtained solid is the crystalline form ARZ-H.
  • the dissolution temperature of the rosastat in the solvent h1 is 10-100°C, preferably 20-35°C.
  • the concentration of the solution h1 is 0.005 to 1.0 g/mL, preferably 0.01 to 0.5 g/mL.
  • the solution h1 is a solution h1 that has undergone a filtering process.
  • the solvent h2 is selected from the group consisting of methyl isobutyl ketone, acetone, or a combination thereof.
  • the volatilization temperature of the volatile solvent is above 240°C.
  • the crystalline form is crystalline form ARZ-I, and its powder X-ray diffraction pattern at 2 ⁇ is 2 ⁇ is 8.9 ⁇ 0.2°, 15.6 ⁇ 0.2°, 15.8 ⁇ 0.2°, 16.3 ⁇ 0.2°, 18.2 There are characteristic peaks at ⁇ 0.2°18.9 ⁇ 0.2° and 23.4 ⁇ 0.2°.
  • crystal form ARZ-I has the following characteristic peak and relative intensity under powder X-ray diffraction:
  • the powder X-ray diffraction pattern of the crystalline form ARZ-I is basically shown in FIG. 24.
  • the TGA pattern of the crystalline form ARZ-I has a weight loss of 12-15% at 50-170°C.
  • TGA diagram of the crystalline form ARZ-I is basically shown in FIG. 25.
  • the DSC chart of the crystalline form ARZ-I has a characteristic peak in the range of 100-140°C, and melts and decomposes in the range of 220-225°C.
  • the present invention provides a method for preparing crystalline form ARZ-I, including the following steps: (i) dissolve rosastat in solvent i1 to obtain solution i1; (ii) add solvent i2 to solution i1, Volatile solvent gives the crystalline form ARZ-I.
  • the solvent i1 includes pyridine and another solvent selected from the group consisting of pyridine, N,N-dimethylformamide, dimethyl sulfoxide, formic acid, acetic acid, N-methylpyrrolidone, methyl alcohol Isobutyl ketone, tetrahydrofuran, 1,4 dioxane, methanol, dichloromethane, water or a combination thereof.
  • the concentration of rosastatin in the solution i1 is 0.005 to 1.0 g/mL, preferably 0.01 to 0.5 g/mL.
  • the solvent i2 is selected from the group consisting of isopentane, n-heptane, isopropanol, tert-butanol or a combination thereof.
  • volatilization temperature of the volatile solvent is above 20°C.
  • the crystalline form provided by the present invention is crystalline form ARZ-J, and its powder X-ray diffraction pattern has characteristic peaks at 2 ⁇ of 8.0 ⁇ 0.2°, 12.1 ⁇ 0.2°, and 16.3 ⁇ 0.2°.
  • crystal form ARZ-J has the following characteristic peak and relative intensity under powder X-ray diffraction:
  • the X-ray powder diffraction pattern of the crystalline form ARZ-J is basically shown in FIG. 27.
  • the TGA pattern of the crystalline form ARZ-J has a weight loss of 10-13% at 70-110°C.
  • TGA diagram of the ARZ-J crystal form is basically shown in FIG. 28.
  • the DSC pattern of the crystalline form ARZ-J has a characteristic peak in the range of 88-110°C, and melts and decomposes in the range of 222-225°C.
  • the present invention provides a method for preparing crystalline form ARZ-J, which includes the following steps: (i) dissolve roxastat in 1.4-dioxane, that is, solvent j1, to obtain a solution j1; (ii) The solvent j2 is added to the solution j1, and a solid is precipitated. The obtained solid is the crystalline form ARZ-J.
  • the dissolution temperature of the rosastat in the solvent j1 is selected from 10-100°C, preferably 50-70°C.
  • the mass volume ratio (mg:ml) of the rosastat and (solvent j1 such as 1,4-dioxane) is 4:1 ⁇ 8:1
  • the solvent j2 is selected from the group consisting of n-heptane, cyclohexane, isopropyl ether, anisole, diphenyl ether, or a combination thereof.
  • the temperature of the solvent j2 is 20-40°C.
  • the solution j1 is the solution j1 after being filtered.
  • the concentration of rosastatin in the solution j1 may be 0.005 to 1.0 g/mL, preferably 0.005 to 0.02 g/mL.
  • the crystalline form of the present invention is crystalline form ARZ-K, and its X-ray powder diffraction pattern has characteristic peaks at 2 ⁇ of 10.9 ⁇ 0.2, 14.9 ⁇ 0.2°, and 21.1 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form ARZ-K is 10.1 ⁇ 0.2°, 10.7 ⁇ 0.2°, 10.9 ⁇ 0.2, 12.8 ⁇ 0.2°, 14.9 ⁇ 0.2°, 21.1 ⁇ 0.2°, 21.7 ⁇ 0.2 at 2 ⁇ , With characteristic peak at 24.0 ⁇ 0.2°.
  • the crystalline form ARZ-K has the following characteristic peaks and relative intensities under powder X-ray diffraction:
  • the powder X-ray diffraction pattern of the crystalline form ARZ-K is basically shown in FIG. 30.
  • the TGA pattern of the crystalline form ARZ-K has a weight loss of 10-12% at 80-125°C.
  • TGA diagram of the ARZ-K crystal form is basically shown in FIG. 31.
  • the present invention provides a method for preparing crystalline form ARZ-K, including the following steps: (i) providing a mixture of roxastat in 1.4-dioxane, ie, solvent k1, (ii) stirring the mixture, After filtering, the crystal form ARZ-K is obtained.
  • stirring temperature is 10-60°C.
  • the mass volume ratio (g:ml) of the compound of formula I to the solvent k1 is 8:1 to 20:1.
  • the crystalline form provided by the present invention is a rosastat hydrochloride crystal form ARZ-L
  • the crystalline form ARZ-L is rosastat hydrochloride monohydrate
  • the powder X-ray diffraction pattern at 2 ⁇ is 2 ⁇ is 4.0 ⁇ 0.2°, 8.2 ⁇ 0.2°, 11.0 ⁇ 0.2, 12.4 ⁇ 0.2°, 13.9 ⁇ 0.2°, 16.3 ⁇ 0.2°, 16.4 ⁇ 0.2°, 17.2 ⁇ 0.2°, There are characteristic peaks at 21.2 ⁇ 0.2° and 22.8 ⁇ 0.2°.
  • the crystal form ARZ-L has the following characteristic peak and relative intensity under powder X-ray diffraction:
  • the powder X-ray diffraction pattern of the crystalline form ARZ-L is basically shown in FIG. 32.
  • the TGA pattern of the crystalline form ARZ-L has a weight loss of 2-5% at 100-140°C.
  • TGA diagram of the crystalline form ARZ-L is basically shown in FIG. 33.
  • the DSC pattern of the crystalline form ARZ-L has a characteristic peak in the range of 145-170°C, a characteristic peak in the range of 199-205°C, and melting decomposition in the range of 221-225°C.
  • the present invention provides a method for preparing the crystalline form ARZ-L, including the following steps: (i) dissolve rosastatide in a solvent l1 to obtain a solution l1; (ii) into a solution l1 A solution of methyl tert-butyl ether through which hydrogen chloride gas is passed, that is, a solution of hydrogen chloride in methyl tert-butyl ether, is added, and the crystal form is crystallized to obtain the crystal form ARZ-L.
  • the dissolution temperature of rosastatin salt in solvent 11 is 10-100°C.
  • the crystallization temperature is less than 40°C.
  • the rosastatin salt is rosastatin sodium salt.
  • the solvent l1 refers to a solvent capable of completely dissolving rosastatin salt at 10 to 150°C, including: N,N-dimethylformamide, formic acid, acetic acid, N-methyl Pyrrolidone, tetrahydrofuran, methanol, methylene chloride, methyl isobutyl ketone, or a combination thereof.
  • the third aspect of the present invention can provide a method for preparing other crystal forms (ie, a method for crystal transformation) of rosastatin crystal form and rosastat hydrochloride crystal form, and the preparation methods are all completed by conventional experimental means.
  • the fourth aspect of the present invention may provide a pharmaceutical composition comprising a crystalline form of rosastat or crystalline form of rosastat hydrochloride and a pharmaceutically acceptable carrier, the crystalline form of rosastat is selected from Crystal Form ARZ-A, Crystal Form ARZ-B, Crystal Form ARZ-C, Crystal Form ARZ-D, Crystal Form ARZ-E, Crystal Form ARZ-F, Crystal Form ARZ-G, Crystal Form ARZ-H, Crystal Form ARZ-I, crystalline form ARZ-J, crystalline form ARZ-K, the crystalline form of rosastat hydrochloride is crystalline form ARZ-L.
  • the fifth aspect of the present invention may provide the crystal form ARZ-A, crystal form ARZ-B, crystal form ARZ-C, crystal form ARZ-D, crystal form ARZ-E, crystal form ARZ-F, crystal form ARZ- G.
  • the new crystal form of the compound of formula I provided by the present invention has high stability for long-term storage, is not easy to decompose at high temperature, has high solubility, and has high stability in different dissolution media;
  • the crystal form of the present invention also has the advantages of being difficult to raise, not easy to absorb moisture, and high bioavailability; and the method for preparing the crystal form of the present invention is simple and easy to post-process (for example, the speed of filtering and separating the crystal form is fast).
  • the crystal form of the present invention has the following main advantages:
  • crystal form ARZ-A has better thermal stability, high humidity stability and pressure stability than the semimolecular hydrate (crystal form B), which is of great significance for the preparation and storage of subsequent formulations;
  • the crystal form ARZ-A has the advantage of good solubility for the existing anhydrous crystal form A
  • the crystal form ARZ-B has a simple preparation process
  • the crystal forms ARZ-E and ARZ-F are not only easy to prepare, but also have low solvent toxicity;
  • the crystal forms ARZ-G, ARZ-H, ARZ-J, and ARZ-K not only have a simple preparation process and are easy to scale up, but also have good crystal form stability.
  • the crystalline form of the present invention has excellent therapeutic and preventive effects on renal anemia
  • the crystalline form of the present invention and the pharmaceutical composition containing the crystalline form of the present invention as the main active ingredient can be used for the treatment and/or prevention of renal anemia .
  • the pharmaceutical composition of the present invention contains the crystalline form of the present invention and a pharmaceutically acceptable excipient or carrier within a safe and effective amount.
  • safe and effective amount refers to: the amount of the compound (or crystalline form) is sufficient to significantly improve the condition without causing serious side effects.
  • the pharmaceutical composition contains 1-2000 mg of the crystalline form/dose of the present invention, and more preferably, 10-200 mg of the crystalline form/dose of the present invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” refers to one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility” here means that the components of the composition can be blended with the active ingredient of the present invention and between them without significantly reducing the efficacy of the active ingredient.
  • Examples of pharmaceutically acceptable carrier parts are cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid) , Magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), coloring agents, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.
  • cellulose and its derivatives such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.
  • gelatin such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose
  • the mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), And topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) disintegrants, for example, agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) retarding solvents, such as paraffin; (f) Absorption accelerators, such as quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and g
  • Solid dosage forms such as tablets, sugar pills, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain an opaque agent, and the release of the active ingredient in this composition can be released in a certain part of the digestive tract in a delayed manner.
  • coatings and shell materials such as enteric coatings and other materials known in the art. They may contain an opaque agent, and the release of the active ingredient in this composition can be released in a certain part of the digestive tract in a delayed manner.
  • embedding components that can be used are polymeric substances and waxy substances. If necessary, the active ingredient may also be in the form of microcapsules with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures.
  • the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide, and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide
  • composition may also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and flavors.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweeteners, flavoring agents, and flavors.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • composition for parenteral injection may contain a physiologically acceptable sterile aqueous or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.
  • the dosage forms of the polymorph of the present invention for topical administration include ointments, powders, patches, sprays, and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required if necessary.
  • the crystalline form of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the polymorph of the present invention is suitable for mammals (such as humans) in need of treatment, wherein the dose when administered is a pharmacologically considered effective dose for humans with a weight of 60 kg
  • the daily dose is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health status, etc., which are within the skills of skilled physicians.
  • the crystal water of the crystal form in the present invention comes from air or a solvent.
  • the solvents used in the present invention are all analytically pure, and the water content is about 0.1%.
  • the rosastat in the present invention is prepared according to the preparation method described in WO2004108681 or obtained through commercial sources.
  • the raw materials of rosastat in the examples of the present invention refer to the crystalline form A disclosed in WO2014014835 unless otherwise specified.
  • X-ray powder diffraction instrument Bruker D2Phaser X-ray powder diffraction instrument; radiation source Cu ; Generator (Generator) kv: 30kv; Generator (Generator) mA: 10mA; initial 2 ⁇ : 2.000°, scanning range: 2 ⁇ 35°.
  • Thermogravimetric analysis (TGA) instrument TGA55 type of American TA company, within the range of 20 ⁇ 300 °C, heating rate 10 °C/min, nitrogen flow rate 40mL/min.
  • DSC Differential scanning calorimetry
  • rosastat raw material was dissolved in 1.5 mL of N,N-dimethylformamide to obtain a clear solution and filtered; the room temperature was quickly volatilized to obtain crystals.
  • XRPD detection of the obtained solid the XRPD pattern is basically shown in Figure 1; TGA detection of the obtained solid, the TGA pattern is basically shown in Figure 2; DSC detection of the obtained solid, the DSC pattern is basically shown in Figure 3 .
  • the resulting solid is crystalline ARZ-A.
  • rosastat raw material was dissolved in 5 mL of formic acid to obtain a clear solution; cooled to room temperature and filtered, the filtrate was placed at 0°C with magnetic stirring to obtain crystals.
  • XRPD detection of the obtained solid the XRPD pattern is basically shown in Figure 1; TGA detection of the obtained solid, the TGA pattern is basically shown in Figure 2; DSC detection of the obtained solid, the DSC pattern is basically shown in Figure 3 .
  • the resulting solid is crystalline ARZ-A.
  • the crystal form ARZ-A prepared by the present invention has good stability.
  • Form ARZ-A has better solubility, which is convenient for improving the bioavailability of the drug in vivo.
  • rosastat raw material was dissolved in 1.5 mL of formic acid/dimethyl sulfoxide mixed solvent (2:1)), and a clear solution was obtained. After filtration, the solvent was quickly evaporated at room temperature to obtain a solid.
  • XRPD test is performed on the obtained solid, and the X-ray powder diffraction pattern is basically shown in FIG. 7; TGA test is performed on the obtained solid, and the spectrum is basically shown in FIG. 8; DSC test is performed on the obtained solid, and the spectrum is basically As shown in FIG. 9, the obtained solid is crystalline form ARZ-C.
  • rosastat starting material was dissolved in 0.5 mL of pyridine to obtain a clear solution and then filtered; 3 ml of n-heptane was added dropwise and crystallized to obtain a solid.
  • XRPD test is performed on the obtained solid, and the X-ray powder diffraction pattern is shown in FIG. 19; TGA test is performed on the obtained solid, and the spectrum is shown in FIG. 20; DSC test is performed on the obtained solid, and the spectrum is shown in FIG. 21. As shown.
  • rosastatin sodium salt was dissolved in 1.5 mL of methyl tert-butyl ether to obtain a clear solution, and then filtered, and a solution of hydrochloric acid in methyl tert-butyl ether was added dropwise at room temperature to obtain a solid.
  • XRPD test is performed on the obtained solid, and the X-ray powder diffraction pattern is shown in Figure 32; TGA test is performed on the obtained solid, and the spectrum is shown in Figure 33; DSC test is performed on the obtained solid, and the spectrum is shown in Figure 34 As shown.
  • the new crystal form of the present invention can be used to prepare a medicament for treating renal anemia, and the medicament can be prepared by a method commonly used in the art.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Urology & Nephrology (AREA)
  • Diabetes (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne une nouvelle forme cristalline de roxadustat et un procédé de préparation associé. La forme cristalline ARZ-A fournie par la présente invention a une meilleure stabilité et une meilleure solubilité que la forme cristalline d'origine. Le procédé de préparation de la forme cristalline fourni par l'invention est simple et facile, et la toxicité du solvant utilisé est faible, la stabilité de la forme cristalline est bonne, et par conséquent le procédé de préparation est plus approprié pour une mise à l'échelle de production. (I)
PCT/CN2019/124634 2018-12-29 2019-12-11 Nouvelle forme cristalline de roxadustat et procédé de préparation associé WO2020135058A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201811639233.0A CN109369525A (zh) 2018-12-29 2018-12-29 罗沙司它的新晶型及其制备方法
CN201811639233.0 2018-12-29

Publications (1)

Publication Number Publication Date
WO2020135058A1 true WO2020135058A1 (fr) 2020-07-02

Family

ID=65372282

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2019/124634 WO2020135058A1 (fr) 2018-12-29 2019-12-11 Nouvelle forme cristalline de roxadustat et procédé de préparation associé

Country Status (2)

Country Link
CN (1) CN109369525A (fr)
WO (1) WO2020135058A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112679428A (zh) * 2019-10-17 2021-04-20 罗欣药业(上海)有限公司 罗沙司他新晶型及其制备方法
CN114344301B (zh) * 2019-10-22 2023-06-23 苏州科睿思制药有限公司 一种低氧诱导因子脯氨酰羟化酶抑制剂晶型
CN112961107B (zh) * 2019-12-13 2024-06-25 罗欣药业(上海)有限公司 罗沙司他的晶型及其制备方法
CN111205224B (zh) * 2020-04-22 2020-08-25 南京佰麦生物技术有限公司 一种罗沙司他水合物的晶型及其制备方法和应用
CN114057643B (zh) * 2020-08-04 2023-02-28 成都苑东生物制药股份有限公司 一种罗沙司他共晶及其制备方法
CN115724796A (zh) * 2021-08-26 2023-03-03 成都苑东生物制药股份有限公司 一种罗沙司他新晶型及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104024227A (zh) * 2011-07-22 2014-09-03 北京贝美拓新药研发有限公司 抑制脯氨酸羟化酶活性的化合物的晶型及其应用
CN104684897A (zh) * 2012-07-16 2015-06-03 菲布罗根有限公司 脯氨酰羟化酶抑制剂的晶体形态
CN106187888A (zh) * 2016-07-18 2016-12-07 江苏德源药业股份有限公司 Fg‑4592单晶及其制备方法

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104892509B (zh) * 2015-06-04 2018-03-09 苏州明锐医药科技有限公司 诺得司他的制备方法
CN106916105A (zh) * 2015-12-28 2017-07-04 徐州万邦金桥制药有限公司 一种纯化可博美的方法
CN107954931B (zh) * 2016-10-17 2021-06-22 上海医药集团青岛国风药业股份有限公司 一种诺得司他的制备方法
CN108017583B (zh) * 2016-11-01 2021-04-06 徐州万邦金桥制药有限公司 一种可博美的制备方法
CN109956870A (zh) * 2017-12-14 2019-07-02 南京卡文迪许生物工程技术有限公司 一种罗沙司他的合成方法及其中间体化合物
CN108424388B (zh) * 2018-04-19 2020-08-21 杭州科巢生物科技有限公司 一种慢性贫血药物的制备方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104024227A (zh) * 2011-07-22 2014-09-03 北京贝美拓新药研发有限公司 抑制脯氨酸羟化酶活性的化合物的晶型及其应用
CN104684897A (zh) * 2012-07-16 2015-06-03 菲布罗根有限公司 脯氨酰羟化酶抑制剂的晶体形态
CN106187888A (zh) * 2016-07-18 2016-12-07 江苏德源药业股份有限公司 Fg‑4592单晶及其制备方法

Also Published As

Publication number Publication date
CN109369525A (zh) 2019-02-22

Similar Documents

Publication Publication Date Title
WO2020135058A1 (fr) Nouvelle forme cristalline de roxadustat et procédé de préparation associé
WO2020185812A1 (fr) Formes à l'état solide de riprétinib
WO2018000250A1 (fr) Nouvelle forme cristalline ibrutinib et méthode de préparation de celle-ci
WO2018049632A1 (fr) Forme cristalline d'ozanimod, procédé de préparation et composition pharmaceutique associés
WO2015014315A1 (fr) Forme cristalline d'inhibiteur et son procédé de préparation et son utilisation
WO2022017478A1 (fr) Nouvelle forme cristalline de cyclohexane formamide et son procédé de préparation
JP2017081989A (ja) 所定の粒子径を有する純粋な非多形結晶性胆汁酸の最適合成
WO2017050241A1 (fr) Forme cristalline a de nicotinate d'inositol et procédé de préparation de celle-ci
JP5662719B2 (ja) ２−［［［２−［（ヒドロキシアセチル）アミノ］−４−ピリジニル］メチル］チオ］−ｎ−［４−（トリフルオロメトキシ）フェニル］−３−ピリジンカルボキサミドのベンゼンスルホン酸塩、その結晶、その結晶多形およびそれらの製造方法
KR102522895B1 (ko) Jak 키나아제 억제제 바이설페이트의 결정형 및 이의 제조방법
WO2018109786A1 (fr) Nouveaux polymorphes et sels de dérivés de carbamoyle pyridone polycycliques
WO2022258060A1 (fr) Forme cristalline de lanifibranor et son procédé de préparation
WO2021139797A1 (fr) Forme cristalline de l'entrectinib et procédé de préparation pour celle-ci
WO2022052925A1 (fr) Forme cristalline de repotrectinib et son procédé de préparation
MXPA04009009A (es) Pseudopolimorfos isoestructurales de 9-desoxo-9a-aza-9a-metil-9a-homoeritromicina a.
CN114773336B (zh) 一种游离态plx5622晶型及其制备方法
CN118525027A (zh) 还原型β‐烟酰胺单核苷酸二钠盐的多晶型及其制法和用途
WO2018228205A1 (fr) Polymorphe de chlorhydrate de 2-[4-(méthylaminométhyl)phényl]-5-fluoro-benzofuran-7-carboxamide, son procédé de préparation et son application
JP2018199718A (ja) ３−ホルミルリファマイシンｓｖ及び３−ホルミルリファマイシンｓの３−（４−シンナミル−１−ピペラジニル）アミノ誘導体を含有する医薬製剤並びにこれらの製造方法
JP2023543055A (ja) テガビビントの結晶形態、調製方法、及びその使用
WO2020244148A1 (fr) Forme cristalline a de doramectine, forme cristalline b de doramectine et procédé de préparation associé
TW201800393A (zh) ９－胺基甲基取代的四環素類化合物的晶型及其製備方法
WO2016197980A1 (fr) Forme cristalline a de la baicaline, procédé de préparation et application correspondante
CN113045554A (zh) 一种非索替尼晶型及其制备方法
WO2017015784A1 (fr) Azine-fumarate à orbitale, hydrate, forme cristalline et leur procédé de préparation

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: 19902438

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: 19902438

Country of ref document: EP

Kind code of ref document: A1