WO2014127735A1 - Solid forms of trelagliptin, preparation method and applications thereof - Google Patents

Solid forms of trelagliptin, preparation method and applications thereof Download PDF

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Publication number
WO2014127735A1
WO2014127735A1 PCT/CN2014/072370 CN2014072370W WO2014127735A1 WO 2014127735 A1 WO2014127735 A1 WO 2014127735A1 CN 2014072370 W CN2014072370 W CN 2014072370W WO 2014127735 A1 WO2014127735 A1 WO 2014127735A1
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Prior art keywords
crystal form
troglitazone
trotagliptin
powder
ray diffraction
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PCT/CN2014/072370
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French (fr)
Chinese (zh)
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付李
袁道义
罗杰
赵雄
徐同利
向志祥
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四川海思科制药有限公司
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Priority to CN201480002130.7A priority Critical patent/CN104603123B/en
Priority to JP2015558339A priority patent/JP2016509031A/en
Publication of WO2014127735A1 publication Critical patent/WO2014127735A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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 present invention relates to the field of organic chemistry and the field of pharmacy, in particular to a solid form of trozastatin, a preparation method and use thereof, a pharmaceutical composition comprising the novel solid form, and the novel solid form for the preparation of a therapeutic dipeptide-based peptide Application of Enzyme IV (DPP-IV) Mediated Diseases in Drugs Background technique
  • Trelaglittin chemical name: 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4- Dioxy-1(2H)-pyrimidinyl]methyl]-4-fluoro-benzonitrile, structure as
  • Tristatin is a dipeptidyl peptidase IV (DPP-IV) inhibitor
  • DPP-IV is a serine amino dipeptidase that removes Xaa-Pro from the amino terminus (N-terminus) of peptides and proteins.
  • Dipeptide is constitutively expressed on epithelial and endothelial cells of various tissues (intestine, liver, kidney, and placenta), also in body fluids, and is also expressed on circulating T-lymphocytes.
  • DPP-IV has been implicated in many human diseases, including but not limited to diabetes (especially type 2 diabetes), diabetic dyslipidemia, impaired glucose tolerance (IGT), fasting plasma glucose damage (IFG), metabolic Acidosis, ketosis, appetite regulation and obesity; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, AIDS and cancer.
  • DPP-IV inhibitors are useful as drugs for the prevention, delay and/or treatment of DPP-IV mediated conditions.
  • Triglitastatin is a long-acting DPP-IV inhibitor developed by Takeda, Japan, and is currently being used in Phase III clinical studies.
  • the treatment of type 2 diabetes is administered once a week, and the same drugs on the market are administered daily, so this product has excellent clinical value and market value.
  • CN1926128A, CN101360723A and the like disclose a method for preparing troglitazone, but neither of them discloses a solid form.
  • Trastatin is a poorly water-soluble compound, which is generally used in solid form in preparations, and is therefore of great significance for the study of its solid form.
  • One of the objects of the present invention is to provide a novel solid form of troglitazone and a process for its preparation.
  • Another object of the present invention is to provide a pharmaceutical composition comprising a new solid form of trozastatin. It is yet another object of the present invention to provide the use of a novel solid form of trozastatin for the manufacture of a medicament for the treatment of a disease mediated by DPP-IV.
  • the present invention first provides a crystalline form of troglitazone of the formula I.
  • the present invention provides crystalline form of crystalline trougliptin, Form B, Form C, Form D, and Form. Still further, the present invention provides an amorphous form of troglitazone.
  • the present invention provides a process for the preparation of the above crystalline trougliptin and amorphous troglitazone.
  • the present invention provides a mixture comprising the above crystalline troxliptin.
  • the present invention provides a pharmaceutical composition comprising the above novel solid form of troglitazone.
  • the present invention provides the use of the above novel solid form of troglitazone for the preparation of a medicament for the treatment of a disease mediated by DPP-IV.
  • the powder X-ray diffraction pattern of the troglitazone crystal form A provided by the present invention is characterized by: a value of 5.7° ⁇ 0.2°, 11.4° ⁇ 0.2°, 12.5° ⁇ 0.2°, 16.8° ⁇ 0.2° at 2 ⁇ , 17.1. ⁇ 0.2°, 19.4° ⁇ 0.2°, 19.9° ⁇ 0.2°, 20.5° ⁇ 0.2°, 22.5. ⁇ 0.2. 22.9. ⁇ 0.2. , 29.1. ⁇ 0.2. There are characteristic diffraction peaks at the same place.
  • the powder X-ray diffraction pattern of troglitazone Form A is characterized by:
  • the 2 ⁇ value is 5.7. ⁇ 0.2°, 11.4. ⁇ 0.2. , 12.5. ⁇ 0.2. 16.8. ⁇ 0.2. 17.1. ⁇ 0.2. 19.4. ⁇ 0.2. , 19.9. ⁇ 0.2. 20.5° ⁇ 0.2°, 21.2° ⁇ 0.2°, 22.5° ⁇ 0.2°, 22.9° ⁇ 0.2°, 25.2° ⁇ 0.2°, 27.6° ⁇ 0.2°, 29.1° ⁇ 0.2°, 32.0° ⁇ 0.2°, etc. Corresponding to characteristic diffraction peaks.
  • the powder X-ray diffraction pattern of the troagliptin crystal form A of the present invention at a 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the troglitazone Form A provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern as shown in FIG.
  • the treprostatine crystalline form A content of the prepared troglitin mixture provided by the present invention (mass content The amount) is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • troglitazone mixture of the present invention refers to troglitazone containing other impurities prepared by direct synthesis by chemical synthesis.
  • the invention provides a preparation method of troglitazone crystal form A, which comprises:
  • the separated solid is dried.
  • the mass/mass ratio of the solvent to trozastatin is generally 4:1 to 20:1; and the dissolution can be carried out by heating.
  • the crystallization may be carried out under standing or under stirring;
  • the crystallization method is a conventional method in the art, such as cooling, distilling off part of the solvent, adding anti-solvent, and adding crystal Single or combined use of methods.
  • the "anti-solvent” refers to a solvent which is poorly soluble in troglitazone at room temperature but which is miscible with the solvent which dissolves trozastatin in step (1), such as ruthenium, ruthenium and petroleum. Ether, etc.
  • the separation may be carried out by a conventional method in the art such as filtration, and alternatively, the separated solid may be washed by the solvent in the above step (1).
  • the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
  • the present invention provides a method for preparing troglitazone crystal form A, which comprises: dissolving statstatin in 7-15 times by weight of isopropanol, and cooling under stirring Crystallization
  • the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
  • the present invention provides a method for preparing troglitazone crystal form, which comprises: dissolving statastigine in 7-15 times by weight of tetrahydrofuran, and cooling and crystallization under stirring ;
  • it is cooled to 0 to 10 ° C for crystallization and filtration;
  • the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
  • the present invention provides a method for preparing troglitazone crystal form, which comprises: dissolving statstatin in 7-15 times by weight of ethyl acetate, and cooling under stirring Crystallization
  • it is cooled to 0 to 10 ° C for crystallization and filtration;
  • the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
  • the powder X-ray diffraction pattern of the troglitin crystal form of the present invention is characterized by a value of 4.9 ° ⁇ 0.2 ° and 5.7 at 2 ⁇ . ⁇ 0.2. , 9.9. ⁇ 0.2. , 11.4. ⁇ 0.2. , 14.8. ⁇ 0.2. 20.2. ⁇ 0.2. , 22.7 ° ⁇ 0.2 °, 27.0. ⁇ 0.2. There are characteristic diffraction peaks at the same place.
  • the powder X-ray diffraction pattern of troglitazone Form B of the present invention is characterized by a value of 4.9 at 2 ⁇ . ⁇ 0.2. , 5.7. ⁇ 0.2. , 9.9. ⁇ 0.2°, 11.4. ⁇ 0.2.
  • the powder X-ray diffraction pattern of the troagliptin crystal form B of the present invention represented by a 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the troglitazone Form B provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern as shown in FIG.
  • the troxreline form B content (mass content) of the prepared troglitin mixture provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • the invention provides a preparation method of troglitazone crystal form B, the method comprising:
  • the separated solid is dried.
  • the mass/mass ratio of methanol to trozastatin is generally from 4:1 to 20:1; and dissolution can be carried out by heating.
  • the crystallization may be carried out under standing or under stirring;
  • the crystallization method is a conventional method in the art, such as cooling, distilling off a part of a solvent, adding a seed crystal, etc. Used alone or in combination.
  • the separation may be carried out by a conventional method in the art such as filtration, and alternatively, the separated solid may be washed with an appropriate amount of methanol.
  • the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
  • the present invention provides a method for preparing troglitazone crystal form B, which comprises: dissolving statstatin in 7-15 times by weight of methanol, and cooling and crystallization under stirring ;
  • the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
  • the powder X-ray diffraction pattern of troigliptin crystal form C provided by the present invention is characterized by a value of 4.9 ° ⁇ 0.2 ° and 9.7 at 2 ⁇ . ⁇ 0.2. , 12.5. ⁇ 0.2. 12.9. ⁇ 0.2. 14.6. ⁇ 0.2. 16.7. ⁇ 0.2. 20.3. ⁇ 0.2. 22.0. ⁇ 0.2. 26.2. ⁇ 0.2. , 34.1 ° ⁇ 0.2 °, etc. correspond to characteristic diffraction peaks.
  • the powder X-ray diffraction pattern of troigliptin Form C of the present invention is characterized by a value of 4.9 at 2 ⁇ . ⁇ 0.2°, 9.7. ⁇ 0.2°, 12.5. ⁇ 0.2°, 12.9. ⁇ 0.2°, 14.6. ⁇ 0.2°, 16.7. ⁇ 0.2°, 20.3. Characteristic diffraction peaks correspond to ⁇ 0.2°, 22.0° ⁇ 0.2°, 22.5° ⁇ 0.2°, 23.2° ⁇ 0.2°, 24.3° ⁇ 0.2°, 26.2° ⁇ 0.2°, 34.1° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of the troglitazone crystal form C of the present invention at a 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the troglitazone crystal form C provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern shown in FIG.
  • the troigliptin crystalline form C provided by the present invention is an ethanolate of trozastatin; in a preferred embodiment, the troigliptin crystalline form C is an ethanolate of trozastatin
  • the molar composition ratio of trozastatin to ethanol is about 1:1, that is, having the structure shown in Formula II,
  • the troglitazone form c content (mass content) of the prepared troglitin mixture provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • the invention provides a preparation method of troglitazone crystal form C, the method comprising:
  • the separated solid is dried.
  • the mass/mass ratio of ethanol to trozastatin is generally from 4:1 to 20:1; and dissolution can be carried out by heating.
  • the crystallization may be carried out under static conditions or under stirring;
  • the crystallization method is a conventional method in the art, such as cooling, distilling off part of the solvent, adding seed crystals, etc. Used alone or in combination.
  • the separation may be carried out by a conventional method in the art such as filtration, and alternatively, the separated solid may be washed with an appropriate amount of ethanol.
  • the drying temperature is usually 10 to 120 ° C, preferably 10 to 50 ° C, and it may be dried at normal pressure or dried under reduced pressure.
  • the present invention provides a method for preparing troglitazone crystal form c, which comprises: dissolving troglitazone in 7-15 times by weight of ethanol, and cooling and crystallization under stirring ;
  • it is cooled to 0 to 10 ° C for crystallization and filtration;
  • the separated crystals are dried at normal pressure or under reduced pressure at 10 to 50 Torr.
  • the powder X-ray diffraction pattern of the troglitin crystal form D provided by the present invention is characterized by a value of 5.5 ° ⁇ 0.2 ° and 12.2 at 2 ⁇ . ⁇ 0.2. 15.7. ⁇ 0.2. 16.8. ⁇ 0.2. 19.7. ⁇ 0.2. 22.2. ⁇ 0.2. There are characteristic diffraction peaks at 22.5° ⁇ 0.2°.
  • the powder X-ray diffraction pattern of troglitazone Form D of the present invention is characterized by a value of 5.5 at a pH of 5.5. Division 0.2. 12.2. Division 0.2. , 12.5. Division 0.2. 15.7. Division 0.2. 16.8. Division 0.2. 19.7. Division 0.2. 20.4. Division 0.2. 22.2° ⁇ 0.2°, 22.5° ⁇ 0.2°, 25.0° ⁇ 0.2°, 26.4° ⁇ 0.2°, 28.7° ⁇ 0.2° correspond to characteristic diffraction peaks.
  • the powder X-ray diffraction pattern of the troagliptin crystal form D of the present invention represented by a 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the troglitazone crystal form D provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern as shown in FIG.
  • the treprostatine crystal form D content (quality included) of the prepared troglitin mixture provided by the present invention The amount is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • the invention provides a preparation method of troglitazone crystal form D, the method comprising:
  • the separated solid is dried.
  • the mass/mass ratio of acetonitrile to trozastatin is generally from 4:1 to 20:1; and dissolution can be carried out by heating.
  • the crystallization may be carried out under static conditions or under stirring;
  • the crystallization method is a conventional method in the art, such as cooling, distilling off part of the solvent, adding seed crystals, etc. Used alone or in combination.
  • the separation may be carried out by a conventional method in the art such as filtration, and alternatively, the separated solid may be washed with an appropriate amount of acetonitrile.
  • the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
  • the present invention provides a method for preparing troglitazone crystal form D, which comprises: dissolving troglitazone in 7-15 times by weight of acetonitrile, and cooling it under standing.
  • it is cooled to 0 to 20 ° C for crystallization and filtration;
  • the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
  • the powder X-ray diffraction pattern of the troglitazone crystal form provided by the present invention is characterized by: a value of 5.1 ° ⁇ 0.2 ° at 2 ⁇ ,
  • the powder X-ray diffraction pattern of the troglitazone crystalline form of the present invention is characterized by: a value of 5.1 ⁇ ⁇ 0.2 °, 5.4 ° ⁇ 0.2 °, 7.0 ° ⁇ 0.2 at 2 ⁇ . °, 9.0 ° ⁇ 0.2 °, 9.3 ° ⁇ 0.2 °, 11.0 ° ⁇ 0.2 °, 13.1 ° ⁇ 0.2 °, 14.3 ° ⁇ 0.2 °, 16.3 ° ⁇ 0.2 °, 21.8 ° ⁇ 0.2 °, 23.9 ° ⁇ 0.2 °, 25.4° ⁇ 0.2°, 26.5° ⁇ 0.2°, etc. correspond to characteristic diffraction peaks.
  • the powder X-ray diffraction pattern of the troglitazone crystal form of the present invention represented by a 2 ⁇ angle has characteristic diffraction peaks and relative intensities at the following positions:
  • the troglitazone Form E provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern shown in FIG.
  • the troxreline Form E content (mass content) of the prepared troglitin mixture provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • the invention provides a preparation method of troglitazone crystal form E, the method comprising:
  • the separated solid is dried.
  • the mass/mass ratio of acetone to trozastatin is generally from 4:1 to 20:1; and dissolution can be carried out by heating.
  • the crystallization may be carried out under static conditions or under stirring;
  • the crystallization method is a conventional method in the art, such as cooling, distilling off part of the solvent, adding seed crystals, etc. Used alone or in combination.
  • the separation may be carried out by a conventional method in the art such as filtration, and optionally, the separated solid may be washed with acetone.
  • the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
  • the present invention provides a method for preparing troglitazone crystal form E, which comprises: dissolving statastigine in 7-15 times by weight of acetone, and cooling and crystallization. ;
  • it is cooled to 0 to 10 ° C for crystallization and filtration;
  • the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
  • the present invention provides an amorphous troglitin which has the characteristics represented by the powder X-ray diffraction pattern shown in Fig. 6.
  • the amount of statin statin (mass content) in the prepared troglitin mixture provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
  • the invention provides various preparation methods of amorphous troglitazone, including:
  • suitable organic solvents include acetone, chloroform, and the like.
  • the mass/mass ratio of solvent to trozastatin is generally from 4:1 to 20:1; dissolution can be carried out by heating.
  • the concentrated organic solvent may be carried out under normal pressure or under reduced pressure.
  • the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
  • troglitazone is heated and melted
  • the heating and melting temperature is generally 165 ° C or higher, preferably 165 to 175 ° C.
  • the present invention provides a method for preparing an amorphous form of troglitazone, which comprises: dissolving statstatin in 7-15 times by weight of acetone, and distilling off under reduced pressure. Acetone is obtained as a residual solid; optionally, the obtained solid is dried at 40 to 70 Torr under normal pressure or reduced pressure.
  • the present invention provides an alternative method of preparing triclinide amorphous comprising: heating and melting troglitazone at 165-170, followed by cooling and solidification.
  • Representative powder X-ray diffraction patterns of the troagliptin crystal forms A, B, C, D, E and amorphous provided by the present invention are shown in Figures 1 to 6.
  • "Representative powder X-ray diffraction pattern” means that the crystal form or amorphous powder X-ray diffraction characteristics conform to the overall morphology of the map, and it is understood that during the test, due to various factors ( If the particle size of the test sample, the method of processing the sample, the instrument, the test parameters, the test operation, etc., the peak position or peak intensity of the powder X-ray diffraction pattern measured by the same crystal form will be certain. difference. In general, the experimental error of the diffraction peak 2 ⁇ in the X-ray powder diffraction pattern can be ⁇ 0.2°.
  • a further object of the present invention is to provide a troglitazone mixture comprising any of the above-described crystalline forms, said crystalline form having a mass content of greater than 70%, preferably greater than 80%, more preferably greater than 90%.
  • the crystalline form described herein is a single crystal form selected from the group consisting of crystal forms A, B, C, D or E, rather than a mixture of the above crystal forms; that is, the mixture
  • the crystalline form contained in one of the crystalline forms A, B, C, D or E has a mass content of greater than 70%, preferably greater than 80%, more preferably greater than 90%.
  • a further object of the present invention is to provide a pharmaceutical composition comprising the above novel solid form of troglitazone and the use of the above novel solid form of troglitazone for the manufacture of a medicament for human use.
  • the invention provides a medicament comprising a therapeutically effective amount of troglitazone Form A, Form B, Form (Formation Form D, Form E or amorphous and pharmaceutical excipients) A composition or formulation.
  • the present invention provides the use of troglitazone Form A, Form B, Form C, Form D, Form E or amorphous in the manufacture of a medicament for the treatment of a disease mediated by DPP-IV.
  • the above pharmaceutical composition or preparation can be prepared according to a conventional production method in the pharmaceutical field, for example, one or more of troigliptin crystal form A, crystal form B, crystal form (form, form D, form E or amorphous). Mix with one or more carriers and then form the desired dosage form.
  • troglitazone Form A, Form B, Form C, Form D, Form E or none The shaped particle size distribution is controlled to be less than 90% less than ⁇ , preferably less than 50 ⁇ , more preferably less than 10 ⁇ .
  • the above pharmaceutical composition or preparation can be used as a long-acting DPP-IV inhibitor for the treatment of diseases mediated by DPP-IV, including type I diabetes, type II diabetes, diabetic lipodystrophy, and impaired glucose tolerance. , fasting plasma glucose damage, metabolic acidosis, ketosis, appetite regulation and obesity, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, AIDS or cancer, etc., among which I, II are preferred Type 2 diabetes.
  • the dosage form of the above pharmaceutical composition or preparation includes: tablets, pills, granules, powders, aerosols, powders, sprays, suspensions, solutions, emulsions, syrups, elixirs, suppositories, injections, coagulation Glues, implants, films, creams, ointments, pastes, patches, etc. They are administered according to the characteristics of the respective dosage form, including oral, sublingual, injection, luminal, transpulmonary/tracheal or transdermal.
  • the amount of the above composition or preparation to be administered is adjusted depending on the nature and severity of the patient's condition, the route of administration, and the age, body weight, etc. of the patient, and the usual weekly dose is between 1 mg and 2 g, preferably between 1 mg and 1000 mg, more preferably 5 mg to Between 700 mg; it can be administered once a week, or it can be administered multiple times, or it can be administered daily.
  • the pharmaceutical composition provided by the present invention is an oral solid preparation, preferably a tablet.
  • the oral solid preparation contains, in addition to the active ingredient troglitazone, a pharmaceutically acceptable excipient, which is a conventional pharmaceutical excipient in the art, including a filler, a disintegrating agent, a binder or a wetting agent. , lubricants, surfactants, solubilizers or co-solvents.
  • the filler generally comprises lactose, microcrystalline cellulose, mannitol, pregelatinized starch, starch, sucrose, dextrin, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium hydrogencarbonate, sodium hydrogencarbonate, Sodium carbonate, hydroxypropyl methylcellulose, ethyl cellulose, and aluminum hydroxide. They may be used singly or in combination, and among them, lactose, microcrystalline cellulose, mannitol, pregelatinized starch or calcium hydrogen phosphate is preferred.
  • the disintegrant generally comprises starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substituted hydroxypropyl fiber. And hydroxypropyl starch and the like. They may be used singly or in combination, and among them, crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose or sodium carboxymethyl starch is preferred.
  • the binder or wetting agent generally comprises povidone (polyvinylpyrrolidone), hydroxypropyl methylcellulose, microcrystalline cellulose, hydroxypropyl cellulose, ethyl cellulose, polyethylene Alcohol, starch syrup, gum arabic, water and various concentrations of ethanol solution. They may be used singly or in combination, and among them, povidone (polyvinylpyrrolidone), microcrystalline cellulose or hydroxypropylcellulose is preferred.
  • the lubricant generally comprises zinc stearate, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, sucrose fatty acid, silica gel (including light silica, hydrated silica). And colloidal silica;), stearic acid, palmitic acid, aluminum silicate and solid polyethylene glycol. They may be used singly or in combination, and among them, magnesium stearate, micronized silica gel or talc is preferred.
  • the surfactant, solubilizer or co-solvent generally includes sodium decyl sulfate, Tween-80, poloxamer, laurel sulfur Sodium and so on. They may be used singly or in combination, and among them, sodium dodecyl sulfate or Tween-80 is preferred.
  • excipients such as sweeteners (such as aspartame, stevioside, etc.), coloring agents (such as yellow iron oxide, red iron oxide, etc.), stabilizers (or stabilizers) may be added to the above composition or formulation.
  • sweeteners such as aspartame, stevioside, etc.
  • coloring agents such as yellow iron oxide, red iron oxide, etc.
  • stabilizers or stabilizers
  • citric acid lactic acid, malic acid and glycine, etc.
  • pH regulators such as calcium carbonate, sodium carbonate, sodium bicarbonate, tartaric acid, fumaric acid, citric acid, etc.
  • the above oral solid preparation can be prepared according to a conventional method for preparing an oral solid preparation in the art, for example, the tablet can be directly subjected to wet granulation tableting, dry granulation tableting, fluidized bed granulation tableting, powder mixing directly Prepared by tableting or the like.
  • the oral solid preparation is a tablet or pellet, it may be further coated as needed to prepare a film-coated tablet or pellet, a sugar-coated tablet or a pellet. Enteric coated tablets or pellets as well as sustained release tablets or pellets.
  • the coating material includes cellulose, acrylic resin and sugars such as hydroxypropylmethylcellulose and sucrose, and a plasticizer, an anti-adhesive agent and an opacifier may be added thereto.
  • the present invention provides a simple preparation method of troagliptin crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or amorphous; and can have high purity, such as HPLC area normalization.
  • the purity of the method can reach 98%, 99% or more than 99.5%; it has the advantages of good stability and formulation adaptability.
  • These advantages are advantageous on the one hand to make them into corresponding preparations, such as their formulations have good stability and effectiveness in preparation and storage; on the other hand, they are also advantageous for making high-purity acid adducts.
  • they can be used to prepare HPLC area normalized purity of 98%, 99% or more, and individual impurities are less than 0.15%, 0.1% or 0.05% of tric succinic acid, benzoic acid, etc.
  • adults can be used to prepare HPLC area normalized purity of 98%, 99% or more, and individual impurities are less than 0.15%, 0.1% or 0.05% of tric succinic acid, benzoic acid,
  • Figure 1 is an X-ray diffraction pattern of troglitazone crystal form A powder
  • Figure 2 is an X-ray diffraction pattern of troglitazone crystal form B powder
  • Figure 3 is an X-ray diffraction pattern of troglitazone crystal form C powder
  • Figure 4 is an X-ray diffraction pattern of troglitazone crystal form D powder
  • Figure 5 is an X-ray diffraction pattern of troglitazone crystal form E powder
  • Figure 6 is an X-ray diffraction pattern of trozastatin amorphous powder. detailed description
  • the nuclear magnetic test in the examples and preparation examples is Bruke AV-II 300MHz or BRUKER AVANCEIII HD 400.
  • DMSO-i/6 deuterated dimethyl sulfoxide
  • tetramethylsilyl was used as an internal standard at room temperature.
  • Example 1 Preparation of troglitazone Form A 2.5 g of troglitazone was dissolved in 25 ml of isopropanol at 75-78 ° C, cooled to 5-10 ° C with stirring, suction filtered, and the obtained solid was dried under reduced pressure at 45-50 Torr. Gliptin crystal form, white solid.
  • the X-ray diffraction pattern of the measured powder is shown in Fig. 1.
  • the measured values are as follows (measured by the diffraction peak corresponding to a relative intensity greater than 1%):
  • troglitazone 2.5g was dissolved in 48ml of isopropanol at 70 ⁇ 75 °C, cooled to 0 ⁇ 5 °C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 55 ⁇ 60 ⁇ . Gliptin crystal form, white solid.
  • troglitazone 2.5 g was dissolved in 25 ml of tetrahydrofuran at 60 to 63 ° C, cooled to 0 to 5 ° C with stirring, and suction filtered to obtain troglitin crystal form A, a white solid.
  • Example 4 Preparation of troglitazone Form A 25g of troglitazone was dissolved in 200ml of tetrahydrofuran at 58 ⁇ 63 °C, cooled to 5 ⁇ 10 °C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 40 ⁇ 45 , to obtain Qugrid. Ting crystal type, white solid.
  • troglitazone 2.5 g was dissolved in 25 ml of ethyl acetate at 71-74 ° C, cooled to 0-10 ° C with stirring, suction filtered, and the obtained solid was dried under reduced pressure at 60-65 Torr. Quagliptin crystal form, white solid.
  • troglitazone 2.5g was dissolved in 25ml of methanol at 57 ⁇ 60°C, cooled to -5 ⁇ 0°C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 40 ⁇ 45 ,. Gliptin crystal form, white solid.
  • the measured X-ray diffraction pattern of the powder is shown in Fig. 2, and the measured values are as follows (measured by the diffraction peak corresponding to a relative intensity greater than 0.4%):
  • troglitazone 2.5 g was dissolved in 32 ml of methanol at 55 to 58 ° C, cooled to 5 to 10 ° C with stirring, and filtered to obtain troglitazone crystal form B, a white solid.
  • troglitazone 25g was dissolved in 470ml of methanol at 55 ⁇ 60°C, cooled to 0 ⁇ 5 °C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 60 ⁇ 65 , to obtain Qugrid. Ting crystal type, white solid.
  • troglitazone 2.5g was dissolved in 25ml of ethanol at 72 ⁇ 75 °C, cooled to 0 ⁇ 5 °C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 45 ⁇ 50 ⁇ to obtain Qugrid. Ting Form C, white solid.
  • the X-ray diffraction pattern of the measured powder is shown in Fig. 3.
  • the measured values are as follows (measured by the diffraction peaks with relative intensities greater than 1%):
  • troglitazone 2.5g was dissolved in 13ml of ethanol at 70 ⁇ 75°C, cooled to 5 ⁇ 10°C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 10 ⁇ 15 ⁇ to obtain Qugrid. Ting Form C, white solid.
  • troglitazone 2.5 g was dissolved in 47 ml of ethanol at 68 to 72 ° C, cooled to 0 to 5 ° C with stirring, and suction filtered to obtain troglitazone crystal form C, a white solid.
  • Example 12 Preparation of troglitazone Form C 25g of troglitazone was dissolved in 630ml of ethanol at 70 ⁇ 74°C, cooled to 5 ⁇ 10°C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 15 ⁇ 20 ⁇ to obtain troglitazone. Form C, white solid.
  • troglitazone 2.5 g was dissolved in 25 ml of acetonitrile at 75-78 ° C, and allowed to stand at 10 to 15 ° C, filtered, and the resulting solid was dried under reduced pressure at 60-65 Torr to obtain a grid.
  • Retin form D white solid.
  • the X-ray diffraction pattern of the measured powder is shown in Fig. 4, and the measured values are as follows (measured by the diffraction peak corresponding to a relative intensity greater than 1%):
  • troglitazone was dissolved in 32 ml of acetonitrile, allowed to stand for cooling to 0-5 Torr, suction filtered, and the obtained solid was dried under reduced pressure at 40 to 45 ° C to obtain troglitazone crystal form. D, white solid.
  • troglitazone 25 g was dissolved in 470 ml of acetonitrile at 75 to 78 ° C, left to cool to 5 to 10 ° C, and filtered to obtain troglitazone crystal form D, a white solid.
  • troglitazone 2.5 g was dissolved in 25 ml of acetone at 50-53 ° C, left to cool to 0-10 ° C, suction filtered, and the obtained solid was dried under reduced pressure at 40-45 Torr. Levin crystal form, white solid.
  • the measured X-ray diffraction pattern of the powder is shown in Fig. 5, and the measured values are as follows (measured by the diffraction peak corresponding to a relative intensity greater than 1%):
  • troglitazone At a reflux temperature, 2.5 g of troglitazone was dissolved in 31 ml of acetone, allowed to stand to cool to 0 to 5 ° C, and suction filtered to obtain troglitazone crystal form E, a white solid.
  • troglitazone 25g was dissolved in 470ml of acetone at 48 ⁇ 50°C, left to cool to 5 ⁇ 10°C, filtered by suction, and the obtained solid was dried under reduced pressure at 55 ⁇ 60 ⁇ to obtain troglitazone. Crystalline ⁇ , white solid.
  • troglitazone 2.5 g was dissolved in 25 ml of acetone at 50 to 53 ° C, concentrated under reduced pressure to give a white solid, and the obtained solid was dried under reduced pressure at 45 to 50 Torr to obtain amorphous troglitazone.
  • the measured powder X-ray diffraction pattern is shown in Fig. 6.
  • troglitazone was dissolved in 22 ml of acetone, and concentrated under reduced pressure to give a white solid.
  • troglitazone 25 g was dissolved in 480 ml of acetone at 50 to 53 ° C, concentrated under reduced pressure to give a white solid, and the obtained solid was dried under reduced pressure at 65 to 70 Torr to obtain amorphous troglitazone.
  • troglitazone 0.5 g was heated and melted, and then cooled to room temperature to obtain troglitazone amorphous.
  • Example 23 Tablet containing 12.5 mg of troglitazone and preparation thereof
  • Example 24 Tablet containing 12.5 mg of troglitazone and preparation thereof
  • troglitazone Form A prepared as in Example 1
  • microcrystalline cellulose mannitol
  • croscarmellose sodium and colloidal silica in the above components
  • it is wet granulated with water, dried, granulated, mixed with magnesium stearate, and tableted.
  • Example 26 Tablet containing 25 mg of troglitazone and preparation thereof
  • Talc powder is listed as a phenolic acid, a phenolic acid, a vitamin 1.0
  • Example 27 Tablet containing 50 mg of troglitazone and preparation thereof
  • Example 28 Tablet containing 50 mg of troglitazone and preparation thereof
  • Example 29 Tablet containing lOOmg of troglitazone and preparation thereof
  • troglitazone crystal form C prepared according to the method of Example 12
  • microcrystalline cellulose mannitol
  • crospovidone s hard microemulsion f-curvature
  • colloidal dioxide After the silicon is mixed, it is wet granulated with water, dried, granulated, mixed with magnesium stearate, and tableted.
  • Example 31 Powder containing lOOmg of troglitazone and preparation thereof
  • troglitazone crystal form C prepared according to the method of Example 12 in the above table components, lactose pulverized through a 100 mesh sieve, and then troglitazone crystal form (, lactose, talc and stearic acid) Mix the magnesium, sub-package, and get it.
  • Example 32 Tablet containing lOOmg of troglitazone and preparation thereof
  • Example 33 Tablet containing 200 mg of troglitazone and preparation thereof
  • Example 34 Tablet containing 400 mg of troglitazone and preparation thereof
  • the obtained concentrate is dissolved in 7500 ml of dichloromethane, and the pH is adjusted to about 3 by adding 2 mol/L hydrochloric acid aqueous solution at 20 to 30 ° C. After adding hydrochloric acid, stirring is continued for about 1 hour, followed by filtration, and the filter cake is sequentially used. The mixture was washed with 4000 ml of chloroformamidine and 2750 ml of tetrahydrofuran, and dried under reduced pressure at 45 to 50 °C.
  • the dried solid was added to a mixture of 4,500 ml of dichloromethane and 9000 ml of water, and the pH was adjusted to 12 with 50% aqueous sodium hydroxide solution, and the aqueous phase was extracted with 3700 ml of dichloromethane, and the organic phase was combined.
  • the organic phase was washed successively with water 3700 ml*2, dried over anhydrous sodium sulfate, and evaporated to dryness to give a white solid.
  • the obtained solid was dried under reduced pressure at 45 to 50 Torr to obtain 502 g of troglitazone (I).
  • trozastatin 45.5 g was dissolved in a mixed solvent consisting of 530 ml of tetrahydrofuran and 200 ml of isopropanol at 55 to 60 ° C, and then a solution of 15.8 g of succinic acid and 250 ml of tetrahydrofuran was added dropwise, and the addition was completed. After stirring for 15 minutes, it was cooled to room temperature and stirring was continued for 12 hours. After filtration, the cake was washed with an appropriate amount of isopropanol and dried under reduced pressure at 50 to 55 ° C to obtain 49.4 g of troglitazone succinate.
  • troglitazone crystal form C has a dissolution rate of more than 85% in 15 minutes in different dissolution media, and the crystal form has good formulation suitability.
  • the relevant substances are detected by HPLC method, and the detection conditions are as follows:
  • Detection method Take the appropriate amount of sample, accurately weigh, add methanol to dissolve and dilute to make about 0.5mg solution per lml as the test solution, accurately measure ⁇ , inject into the liquid chromatograph, record the chromatogram, according to the area The law calculates the relevant substance content.
  • test results are as follows: Time of investigation Investigation conditions Samples Related substances (%) Whether crystal form changes or not, troglitazone crystal form A 0.14%
  • troglitazone crystal form A crystal form B
  • crystal form C crystal form D
  • form E amorphous have good stability.
  • the product Quagstatin C and troglitazone were first ground into a fine powder and added to a conical flask containing 10 ml of water.
  • the water temperature was controlled between 25 ⁇ ⁇ 2 ,, and the vibration was vigorously every 5 minutes. Shake for 30 seconds; observe the dissolution of the sample within 30 minutes, and judge its solubility according to Chinese Pharmacopoeia standards.
  • the experimental results are as follows:
  • the amorphous form of a substance has a better solubility than the crystal form, but the above studies show that the solubility of troglitazone form c in water is greater than that of amorphous.
  • the trozaleadine crystal form, the crystalline form ⁇ , the crystalline form C and the troglitazone succinate having a comparable crystal size were prepared by sieving through a ⁇ sieve. Twenty-four male Sprague-Dawley rats, 240-270 g, were randomly divided into 4 groups. The trozastatin crystal forms A, B, C and troglitazone succinate were administered by gavage at a dose of 10 mg/kg. Quglitastatin).
  • troglitazone crystal Type A, Form B, and Form C have similar biological properties or effects as salts.

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Abstract

The present invention relates to solid forms of trelagliptin, a preparation method therefor and applications thereof, and relates specifically to six new solid forms of the dipeptidyl peptidase-4 inhibitor trelagliptin and preparation methods therefor, as well as to pharmaceutical compositions comprising said solid forms of trelagliptin, and uses of same in the preparation of medicines for the treatment of diseases mediated by dipeptidyl peptidase-4.

Description

曲格列汀的固态形式及其制备方法和用途
Figure imgf000002_0001
Solid form of troglitazone and preparation method and use thereof
Figure imgf000002_0001
本发明涉及有机化学领域和药学领域， 具体涉及曲格列汀的固态形式及其制备方法和用途， 包含这些新固态形式的药物组合物， 以及这些新固态形式用于制备治疗由二肽基肽酶 IV (DPP- IV) 介导的疾病的药物中的应用。 背景技术  The present invention relates to the field of organic chemistry and the field of pharmacy, in particular to a solid form of trozastatin, a preparation method and use thereof, a pharmaceutical composition comprising the novel solid form, and the novel solid form for the preparation of a therapeutic dipeptide-based peptide Application of Enzyme IV (DPP-IV) Mediated Diseases in Drugs Background technique
曲格列汀 （Trelagliptm) ， 化学名为： 2-[[6-[(3R)-3-氨基 -1-哌啶基 ]-3,4-二氢 -3-甲基 -2,4-二氧- 1(2H)-嘧啶基]甲基] -4-氟-苯甲腈， 结构如  Trelaglittin, chemical name: 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4- Dioxy-1(2H)-pyrimidinyl]methyl]-4-fluoro-benzonitrile, structure as
Figure imgf000002_0002
曲格列汀是一种二肽基肽酶 IV (DPP-IV) 抑制剂， DPP-IV 是一种丝氨酸氨基二肽酶， 它从 多肽和蛋白质的氨基末端 （N-末端） 除去 Xaa-Pro二肽。 DPP-IV在多种不同组织 （肠、 肝、 肾和 胎盘） 的上皮与内皮细胞上被组成型表达， 也见于体液中， 同时也在循环中的 T-淋巴细胞上被表 达。 DPP-IV 已经涉及人类许多疾病状态， 包括但不限于糖尿病 （特别是 II 型糖尿病） 、 糖尿病 性血脂异常、 葡萄糖耐量降低 （IGT) 的病况、 空腹血浆葡萄糖受损 （IFG) 的病况、 代谢性酸中 毒、 酮症、 食欲调节和肥胖症； 自身免疫疾病例如炎性肠炎、 多发性硬化和类风湿性关节炎， AIDS 以及癌症等。 DPP-IV抑制剂可作为药物， 用于由 DPP-IV介导的病况的预防、 延迟和 /或治 疗。
Figure imgf000002_0002
Tristatin is a dipeptidyl peptidase IV (DPP-IV) inhibitor, and DPP-IV is a serine amino dipeptidase that removes Xaa-Pro from the amino terminus (N-terminus) of peptides and proteins. Dipeptide. DPP-IV is constitutively expressed on epithelial and endothelial cells of various tissues (intestine, liver, kidney, and placenta), also in body fluids, and is also expressed on circulating T-lymphocytes. DPP-IV has been implicated in many human diseases, including but not limited to diabetes (especially type 2 diabetes), diabetic dyslipidemia, impaired glucose tolerance (IGT), fasting plasma glucose damage (IFG), metabolic Acidosis, ketosis, appetite regulation and obesity; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis, AIDS and cancer. DPP-IV inhibitors are useful as drugs for the prevention, delay and/or treatment of DPP-IV mediated conditions.
曲格列汀是日本武田公司开发的一种长效 DPP-IV抑制剂， 目前正在 III期临床研究中， 用于 Triglitastatin is a long-acting DPP-IV inhibitor developed by Takeda, Japan, and is currently being used in Phase III clinical studies.
II 型糖尿病的治疗， 每周给药一次， 而目前市场上同类药物均为每天给药， 因此本品具有优异的 临床价值和市场价值。 The treatment of type 2 diabetes is administered once a week, and the same drugs on the market are administered daily, so this product has excellent clinical value and market value.
CN1926128A, CN101360723A等公开了曲格列汀的制备方法， 但均未公开其固态形式。 曲格 列汀属水难溶性化合物， 在制剂中一般以固体形式使用， 因此对其固态形式研究具有十分重要的 意义。  CN1926128A, CN101360723A and the like disclose a method for preparing troglitazone, but neither of them discloses a solid form. Trastatin is a poorly water-soluble compound, which is generally used in solid form in preparations, and is therefore of great significance for the study of its solid form.
经对曲格列汀固态形式的研究， 我们发现了多种具有明显粉末 X-射线衍射图谱特征的固态形 式， 这些固态形式制备方法简单、 贮存方便， 适宜于制备多种制剂。 发明内容  Through the study of the solid form of troglitazone, we have found a variety of solid forms with distinct powder X-ray diffraction patterns. These solid forms are simple to prepare and convenient to store, and are suitable for the preparation of various formulations. Summary of the invention
本发明的目的之一在于提供曲格列汀的新固态形式及其制备方法。  One of the objects of the present invention is to provide a novel solid form of troglitazone and a process for its preparation.
本发明的另一目的在于提供含有曲格列汀新固态形式的药物组合物。 本发明的又一目的在于提供曲格列汀新固态形式在制备治疗由 DPP-IV介导的疾病的药物中 的用途。 Another object of the present invention is to provide a pharmaceutical composition comprising a new solid form of trozastatin. It is yet another object of the present invention to provide the use of a novel solid form of trozastatin for the manufacture of a medicament for the treatment of a disease mediated by DPP-IV.
为了实现上述发明目的， 本发明首先提供了一种结晶态的式 I所示的曲格列汀。  In order to achieve the above object, the present invention first provides a crystalline form of troglitazone of the formula I.
进一步的， 本发明提供了结晶态曲格列汀的晶型 、 晶型 B、 晶型 C、 晶型 D以及晶型£。 再进一步的， 本发明提供了一种无定形态的曲格列汀。  Further, the present invention provides crystalline form of crystalline trougliptin, Form B, Form C, Form D, and Form. Still further, the present invention provides an amorphous form of troglitazone.
再进一步的， 本发明提供了上述结晶态曲格列汀及无定型曲格列汀的制备方法。  Still further, the present invention provides a process for the preparation of the above crystalline trougliptin and amorphous troglitazone.
再进一步的， 本发明提供了含有上述结晶态曲格列汀的混合物。  Still further, the present invention provides a mixture comprising the above crystalline troxliptin.
再进一步的， 本发明提供了含有上述曲格列汀新固态形式的药物组合物。  Still further, the present invention provides a pharmaceutical composition comprising the above novel solid form of troglitazone.
更进一步的， 本发明提供了上述曲格列汀新固态形式在制备治疗由 DPP-IV 介导的疾病的药 物中的用途。  Still further, the present invention provides the use of the above novel solid form of troglitazone for the preparation of a medicament for the treatment of a disease mediated by DPP-IV.
曲格列汀晶型 A  Triglitastat crystal form A
本发明提供的曲格列汀晶型 A 的粉末 X-射线衍射图谱的特征为： 在 2Θ 值为 5.7°±0.2°、 11.4°±0.2°、 12.5°±0.2°、 16.8°±0.2°、 17.1。±0.2°、 19.4°±0.2°、 19.9°±0.2°、 20.5°±0.2°、 22.5。±0.2。、 22.9。±0.2。、 29.1。±0.2。等处对应有特征衍射峰。  The powder X-ray diffraction pattern of the troglitazone crystal form A provided by the present invention is characterized by: a value of 5.7°±0.2°, 11.4°±0.2°, 12.5°±0.2°, 16.8°±0.2° at 2Θ, 17.1. ±0.2°, 19.4°±0.2°, 19.9°±0.2°, 20.5°±0.2°, 22.5. ±0.2. 22.9. ±0.2. , 29.1. ±0.2. There are characteristic diffraction peaks at the same place.
在一具体实施方案中， 本发明提供的曲格列汀晶型 A 的粉末 X-射线衍射图谱的特征为： 在 In a specific embodiment, the powder X-ray diffraction pattern of troglitazone Form A provided by the present invention is characterized by:
2Θ 值为 5.7。±0.2°、 11.4。±0.2。、 12.5。±0.2。、 16.8。±0.2。、 17.1。±0.2。、 19.4。±0.2。、 19.9。±0.2。、 20.5°±0.2°、 21.2°±0.2°、 22.5°±0.2°、 22.9°±0.2°、 25.2°±0.2°、 27.6°±0.2°、 29.1°±0.2°、 32.0°±0.2° 等处对应有特征衍射峰。 The 2Θ value is 5.7. ±0.2°, 11.4. ±0.2. , 12.5. ±0.2. 16.8. ±0.2. 17.1. ±0.2. 19.4. ±0.2. , 19.9. ±0.2. 20.5°±0.2°, 21.2°±0.2°, 22.5°±0.2°, 22.9°±0.2°, 25.2°±0.2°, 27.6°±0.2°, 29.1°±0.2°, 32.0°±0.2°, etc. Corresponding to characteristic diffraction peaks.
进一步地， 本发明所述的曲格列汀晶型 A以 2Θ角度表示的粉末 X-射线衍射图谱在以下位置 具有特征衍射峰及相对强度：  Further, the powder X-ray diffraction pattern of the troagliptin crystal form A of the present invention at a 2 Θ angle has characteristic diffraction peaks and relative intensities at the following positions:
Figure imgf000003_0001
Figure imgf000003_0001
在一具体实施方案中， 本发明提供的曲格列汀晶型 A具有如图 1 所示的粉末 X-射线衍射图 谱所代表的特征。  In a specific embodiment, the troglitazone Form A provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern as shown in FIG.
在一具体实施方案中， 本发明提供的制备的曲格列汀混合物中曲格列汀晶型 A含量 （质量含 量） 一般大于 70%， 优选大于 80%， 最优选大于 90%。 In a specific embodiment, the treprostatine crystalline form A content of the prepared troglitin mixture provided by the present invention (mass content The amount) is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本领域技术人员可以理解的是， 本发明所述的曲格列汀混合物指的是用化学合成方法直接合 成制备的含有其他杂质的曲格列汀。  It will be understood by those skilled in the art that the troglitazone mixture of the present invention refers to troglitazone containing other impurities prepared by direct synthesis by chemical synthesis.
本发明提供了一种曲格列汀晶型 A的制备方法， 该方法包括：  The invention provides a preparation method of troglitazone crystal form A, which comprises:
( 1 ) 、 将曲格列汀溶解于异丙醇、 四氢呋喃或乙酸乙酯中；  (1) dissolving trozastatin in isopropanol, tetrahydrofuran or ethyl acetate;
(2 ) 、 析晶；  (2), crystallization;
( 3 ) 、 分离出固体；  (3) separating solids;
(4 ) 、 可选的， 将所分离的固体进行干燥。  (4) Optionally, the separated solid is dried.
上述方法步骤 （1 ) 中， 溶剂与曲格列汀的质量 /质量比一般为 4: 1 至 20: 1 ; 可采用加热的方 式进行溶解。  In the above method step (1), the mass/mass ratio of the solvent to trozastatin is generally 4:1 to 20:1; and the dissolution can be carried out by heating.
上述方法步骤 （2 ) 中， 析晶可以在静置下进行， 也可以在搅拌下进行； 析晶方法为本技术领 域内常规的方法， 如冷却、 蒸除部分溶剂、 加反溶剂、 加晶种等方法的单用或联用。 其中"反溶 剂"是指在常温下对曲格列汀的溶解性不好但能与步骤 （1 ) 中溶解曲格列汀的溶剂混溶的溶剂， 如正已垸、 正庚垸和石油醚等。  In the above method step (2), the crystallization may be carried out under standing or under stirring; the crystallization method is a conventional method in the art, such as cooling, distilling off part of the solvent, adding anti-solvent, and adding crystal Single or combined use of methods. The "anti-solvent" refers to a solvent which is poorly soluble in troglitazone at room temperature but which is miscible with the solvent which dissolves trozastatin in step (1), such as ruthenium, ruthenium and petroleum. Ether, etc.
上述方法步骤 （3 ) 中， 分离可以采用过滤等本技术领域内的常规方法， 可选的， 可用上述步 骤 （1 ) 中的溶剂对所分离的固体进行洗涤。  In the above method step (3), the separation may be carried out by a conventional method in the art such as filtration, and alternatively, the separated solid may be washed by the solvent in the above step (1).
上述方法步骤 （4 ) 中， 干燥温度一般为 30~120°C， 优选 40~70°C， 可以常压干燥， 也可以 减压干燥。  In the above method step (4), the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
在一具体实施方案中， 本发明提供了一种曲格列汀晶型 A的制备方法， 该方法包括： 将曲格 列汀加热溶解于 7-15倍重量的异丙醇中， 搅拌下冷却析晶；  In a specific embodiment, the present invention provides a method for preparing troglitazone crystal form A, which comprises: dissolving statstatin in 7-15 times by weight of isopropanol, and cooling under stirring Crystallization
其中优选冷却至 0~ 10 °c析晶， 过滤；  Preferably, it is cooled to 0 to 10 °c for crystallization, and filtered;
可选的， 所分离的晶体在 40~70Ό下， 常压或减压干燥。  Optionally, the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
在一具体实施方案中， 本发明提供了一种曲格列汀晶型 Α的制备方法， 该方法包括： 将曲格 列汀加热溶解于 7-15倍重量的四氢呋喃中， 搅拌下冷却析晶；  In a specific embodiment, the present invention provides a method for preparing troglitazone crystal form, which comprises: dissolving statastigine in 7-15 times by weight of tetrahydrofuran, and cooling and crystallization under stirring ;
其中优选冷却至 0~10°C析晶， 过滤；  Preferably, it is cooled to 0 to 10 ° C for crystallization and filtration;
可选的， 所分离的晶体在 40~70Ό下， 常压或减压干燥。  Optionally, the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
在一具体实施方案中， 本发明提供了一种曲格列汀晶型 Α的制备方法， 该方法包括： 将曲格 列汀加热溶解于 7-15倍重量的乙酸乙酯中， 搅拌下冷却析晶；  In a specific embodiment, the present invention provides a method for preparing troglitazone crystal form, which comprises: dissolving statstatin in 7-15 times by weight of ethyl acetate, and cooling under stirring Crystallization
其中优选冷却至 0~10°C析晶， 过滤；  Preferably, it is cooled to 0 to 10 ° C for crystallization and filtration;
可选的， 所分离的晶体在 40~70Ό下， 常压或减压干燥。  Optionally, the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
曲格列汀晶型 Β  Troglitazone crystal form Β
本发明提供的曲格列汀晶型 Β 的粉末 X-射线衍射图谱的特征为： 在 2Θ 值为 4.9°±0.2°、 5.7。±0.2。、 9.9。±0.2。、 11.4。±0.2。、 14.8。±0.2。、 20.2。±0.2。、 22.7°±0.2°、 27.0。±0.2。等处对应有特征 衍射峰。 在一具体实施方案中， 本发明所述的曲格列汀晶型 B 的粉末 X-射线衍射图谱的特征为： 在 2Θ 值为 4.9。±0.2。、 5.7。±0.2。、 9.9。±0.2°、 11.4。±0.2。、 12.6。±0.2。、 14.8。±0.2。、 17.1。±0.2。、 20.1°±0.2°、 20.2°±0.2°、 22.7°±0.2°、 23.1°±0.2°、 27.0°±0.2°、 29.6°±0.2°等处对应有特征衍射峰。 The powder X-ray diffraction pattern of the troglitin crystal form of the present invention is characterized by a value of 4.9 ° ± 0.2 ° and 5.7 at 2 。. ±0.2. , 9.9. ±0.2. , 11.4. ±0.2. , 14.8. ±0.2. 20.2. ±0.2. , 22.7 ° ± 0.2 °, 27.0. ±0.2. There are characteristic diffraction peaks at the same place. In a specific embodiment, the powder X-ray diffraction pattern of troglitazone Form B of the present invention is characterized by a value of 4.9 at 2 。. ±0.2. , 5.7. ±0.2. , 9.9. ±0.2°, 11.4. ±0.2. 12.6. ±0.2. , 14.8. ±0.2. 17.1. ±0.2. 20.1°±0.2°, 20.2°±0.2°, 22.7°±0.2°, 23.1°±0.2°, 27.0°±0.2°, 29.6°±0.2° correspond to characteristic diffraction peaks.
进一步地， 本发明所述的曲格列汀晶型 B以 2Θ角度表示的粉末 X-射线衍射图谱在以下位置 具有特征衍射峰及相对强度：  Further, the powder X-ray diffraction pattern of the troagliptin crystal form B of the present invention represented by a 2 Θ angle has characteristic diffraction peaks and relative intensities at the following positions:
Figure imgf000005_0001
Figure imgf000005_0001
在一具体实施方案中， 本发明提供的曲格列汀晶型 B具有如图 2所示的粉末 X-射线衍射图谱 所代表的特征。  In a specific embodiment, the troglitazone Form B provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern as shown in FIG.
在一具体实施方案中， 本发明提供的制备的曲格列汀混合物中曲格列汀晶型 B含量 （质量含 量） 一般大于 70%， 优选大于 80%， 最优选大于 90%。  In a specific embodiment, the troxreline form B content (mass content) of the prepared troglitin mixture provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本发明提供了一种曲格列汀晶型 B的制备方法， 该方法包括：  The invention provides a preparation method of troglitazone crystal form B, the method comprising:
( 1 ) 、 将曲格列汀溶解于甲醇中；  (1) dissolving trozastatin in methanol;
(2 ) 、 析晶；  (2), crystallization;
( 3 ) 、 分离出固体；  (3) separating solids;
(4 ) 、 可选的， 将所分离的固体进行干燥。  (4) Optionally, the separated solid is dried.
上述方法步骤 （1 ) 中， 甲醇与曲格列汀的质量 /质量比一般为 4: 1 至 20: 1 ; 可采用加热的方 式进行溶解。  In the above method step (1), the mass/mass ratio of methanol to trozastatin is generally from 4:1 to 20:1; and dissolution can be carried out by heating.
上述方法步骤 （2 ) 中， 析晶可以在静置下进行， 也可以在搅拌下进行； 析晶方法为本技术领 域内常规的方法， 如冷却、 蒸除部分溶剂、 加晶种等方法的单用或联用。  In the above method step (2), the crystallization may be carried out under standing or under stirring; the crystallization method is a conventional method in the art, such as cooling, distilling off a part of a solvent, adding a seed crystal, etc. Used alone or in combination.
上述方法步骤 （3 ) 中， 分离可以采用过滤等本技术领域内的常规方法， 可选的， 可用适量的 甲醇对所分离的固体进行洗涤。  In the above method step (3), the separation may be carried out by a conventional method in the art such as filtration, and alternatively, the separated solid may be washed with an appropriate amount of methanol.
上述方法步骤 （4 ) 中， 干燥温度一般为 30~120°C， 优选 40~70°C， 可以常压干燥， 也可以 减压干燥。  In the above method step (4), the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
在一具体实施方案中， 本发明提供了一种曲格列汀晶型 B 的制备方法， 该方法包括： 将曲格 列汀加热溶解于 7-15倍重量的甲醇中， 搅拌下冷却析晶；  In a specific embodiment, the present invention provides a method for preparing troglitazone crystal form B, which comprises: dissolving statstatin in 7-15 times by weight of methanol, and cooling and crystallization under stirring ;
其中优选冷却至 -10~10°C析晶， 过滤； 可选的， 所分离的晶体在 40~70Ό下， 常压或减压干燥。 Preferably, it is cooled to -10 to 10 ° C for crystallization and filtration; Optionally, the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
曲格列汀晶型 c  Tristatin crystal form c
本发明提供的曲格列汀晶型 C 的粉末 X-射线衍射图谱的特征为： 在 2Θ 值为 4.9°±0.2°、 9.7。±0.2。、 12.5。±0.2。、 12.9。±0.2。、 14.6。±0.2。、 16.7。±0.2。、 20.3。±0.2。、 22.0。±0.2。、 26.2。±0.2。、 34.1°±0.2°等处对应有特征衍射峰。  The powder X-ray diffraction pattern of troigliptin crystal form C provided by the present invention is characterized by a value of 4.9 ° ± 0.2 ° and 9.7 at 2 。. ±0.2. , 12.5. ±0.2. 12.9. ±0.2. 14.6. ±0.2. 16.7. ±0.2. 20.3. ±0.2. 22.0. ±0.2. 26.2. ±0.2. , 34.1 ° ± 0.2 °, etc. correspond to characteristic diffraction peaks.
在一具体实施方案中， 本发明所述的曲格列汀晶型 C 的粉末 X-射线衍射图谱的特征为： 在 2Θ 值为 4.9。±0.2°、 9.7。±0.2°、 12.5。±0.2°、 12.9。±0.2°、 14.6。±0.2°、 16.7。±0.2°、 20.3。±0.2°、 22.0°±0.2°、 22.5°±0.2°、 23.2°±0.2°、 24.3°±0.2°、 26.2°±0.2°、 34.1°±0.2°等处对应有特征衍射峰。  In a specific embodiment, the powder X-ray diffraction pattern of troigliptin Form C of the present invention is characterized by a value of 4.9 at 2 。. ±0.2°, 9.7. ±0.2°, 12.5. ±0.2°, 12.9. ±0.2°, 14.6. ±0.2°, 16.7. ±0.2°, 20.3. Characteristic diffraction peaks correspond to ±0.2°, 22.0°±0.2°, 22.5°±0.2°, 23.2°±0.2°, 24.3°±0.2°, 26.2°±0.2°, 34.1°±0.2°.
进一步地， 本发明所述的曲格列汀晶型 C以 2Θ角度表示的粉末 X-射线衍射图谱在以下位置 具有特征衍射峰及相对强度：  Further, the powder X-ray diffraction pattern of the troglitazone crystal form C of the present invention at a 2 Θ angle has characteristic diffraction peaks and relative intensities at the following positions:
Figure imgf000006_0002
Figure imgf000006_0002
在一具体实施方案中， 本发明提供的曲格列汀晶型 C具有如图 3所示的粉末 X-射线衍射图谱 所代表的特征。  In a specific embodiment, the troglitazone crystal form C provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern shown in FIG.
在一具体实施方案中， 本发明提供的曲格列汀晶型 C是曲格列汀的乙醇合物； 在一优选实施 方案中， 曲格列汀晶型 C 是曲格列汀的乙醇合物， 其中曲格列汀与乙醇的摩尔组成比约为 1: 1， 即具有如式 II所示结构，  In a specific embodiment, the troigliptin crystalline form C provided by the present invention is an ethanolate of trozastatin; in a preferred embodiment, the troigliptin crystalline form C is an ethanolate of trozastatin The molar composition ratio of trozastatin to ethanol is about 1:1, that is, having the structure shown in Formula II,
Figure imgf000006_0001
Figure imgf000006_0001
II „  II „
在一具体实施方案中， 本发明提供的制备的曲格列汀混合物中曲格列汀晶型 c含量 （质量含 量） 一般大于 70%， 优选大于 80%， 最优选大于 90%。  In a specific embodiment, the troglitazone form c content (mass content) of the prepared troglitin mixture provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本发明提供了一种曲格列汀晶型 C的制备方法， 该方法包括：  The invention provides a preparation method of troglitazone crystal form C, the method comprising:
( 1 ) 、 将曲格列汀溶解于乙醇中；  (1), dissolving troglitazone in ethanol;
(2) 、 析晶； ( 3 ) 、 分离出固体； (2), crystallization; (3) separating solids;
(4 ) 、 可选的， 将所分离的固体进行干燥。  (4) Optionally, the separated solid is dried.
上述方法步骤 （1 ) 中， 乙醇与曲格列汀的质量 /质量比一般为 4: 1 至 20: 1 ; 可采用加热的方 式进行溶解。  In the above method step (1), the mass/mass ratio of ethanol to trozastatin is generally from 4:1 to 20:1; and dissolution can be carried out by heating.
上述方法步骤 （2) 中， 析晶可以在静置下进行， 也可以在搅拌下进行； 析晶方法为本技术领 域内常规的方法， 如冷却、 蒸除部分溶剂、 加晶种等方法的单用或联用。  In the above method step (2), the crystallization may be carried out under static conditions or under stirring; the crystallization method is a conventional method in the art, such as cooling, distilling off part of the solvent, adding seed crystals, etc. Used alone or in combination.
上述方法步骤 （3 ) 中， 分离可以采用过滤等本技术领域内的常规方法， 可选的， 可用适量乙 醇对所分离的固体进行洗涤。  In the above method step (3), the separation may be carried out by a conventional method in the art such as filtration, and alternatively, the separated solid may be washed with an appropriate amount of ethanol.
上述方法步骤 （4 ) 中， 干燥温度一般为 10~120°C， 优选 10~50°C， 可以常压干燥， 也可以 减压干燥。  In the above step (4), the drying temperature is usually 10 to 120 ° C, preferably 10 to 50 ° C, and it may be dried at normal pressure or dried under reduced pressure.
在一具体实施方案中， 本发明提供了一种曲格列汀晶型 c 的制备方法， 该方法包括： 将曲格 列汀加热溶解于 7-15倍重量的乙醇中， 搅拌下冷却析晶；  In a specific embodiment, the present invention provides a method for preparing troglitazone crystal form c, which comprises: dissolving troglitazone in 7-15 times by weight of ethanol, and cooling and crystallization under stirring ;
其中优选冷却至 0~10°C析晶， 过滤；  Preferably, it is cooled to 0 to 10 ° C for crystallization and filtration;
可选的， 所分离的晶体在 10~50Ό下， 常压或减压干燥。  Optionally, the separated crystals are dried at normal pressure or under reduced pressure at 10 to 50 Torr.
曲格列汀晶型 D  Tristatin crystal form D
本发明提供的曲格列汀晶型 D 的粉末 X-射线衍射图谱的特征为： 在 2Θ 值为 5.5°±0.2°、 12.2。±0.2。、 15.7。±0.2。、 16.8。±0.2。、 19.7。±0.2。、 22.2。±0.2。、 22.5°±0.2°等处对应有特征衍射峰。  The powder X-ray diffraction pattern of the troglitin crystal form D provided by the present invention is characterized by a value of 5.5 ° ± 0.2 ° and 12.2 at 2 。. ±0.2. 15.7. ±0.2. 16.8. ±0.2. 19.7. ±0.2. 22.2. ±0.2. There are characteristic diffraction peaks at 22.5°±0.2°.
在一具体实施方案中， 本发明所述的曲格列汀晶型 D 的粉末 X-射线衍射图谱的特征为： 在 2Θ 值为 5.5。士0.2。、 12.2。士0.2。、 12.5。士0.2。、 15.7。士0.2。、 16.8。士0.2。、 19.7。士0.2。、 20.4。士0.2。、 22.2°±0.2°、 22.5°±0.2°、 25.0°±0.2°、 26.4°±0.2°、 28.7°±0.2°等处对应有特征衍射峰。  In a specific embodiment, the powder X-ray diffraction pattern of troglitazone Form D of the present invention is characterized by a value of 5.5 at a pH of 5.5. Division 0.2. 12.2. Division 0.2. , 12.5. Division 0.2. 15.7. Division 0.2. 16.8. Division 0.2. 19.7. Division 0.2. 20.4. Division 0.2. 22.2°±0.2°, 22.5°±0.2°, 25.0°±0.2°, 26.4°±0.2°, 28.7°±0.2° correspond to characteristic diffraction peaks.
进一步地， 本发明所述的曲格列汀晶型 D以 2Θ角度表示的粉末 X-射线衍射图谱在以下位置 具有特征衍射峰及相对强度：  Further, the powder X-ray diffraction pattern of the troagliptin crystal form D of the present invention represented by a 2 Θ angle has characteristic diffraction peaks and relative intensities at the following positions:
Figure imgf000007_0001
Figure imgf000007_0001
在一具体实施方案中， 本发明提供的曲格列汀晶型 D 具有如图 4所示的粉末 X-射线衍射图 谱所代表的特征。  In a specific embodiment, the troglitazone crystal form D provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern as shown in FIG.
在一具体实施方案中， 本发明提供的制备的曲格列汀混合物中曲格列汀晶型 D含量 （质量含 量） 一般大于 70%， 优选大于 80%， 最优选大于 90%。 In a specific embodiment, the treprostatine crystal form D content (quality included) of the prepared troglitin mixture provided by the present invention The amount) is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本发明提供了一种曲格列汀晶型 D的制备方法， 该方法包括：  The invention provides a preparation method of troglitazone crystal form D, the method comprising:
( 1 ) 、 将曲格列汀溶解于乙腈中；  (1), dissolving troglitazone in acetonitrile;
(2 ) 、 析晶；  (2), crystallization;
( 3 ) 、 分离出固体；  (3) separating solids;
(4 ) 、 可选的， 将所分离的固体进行干燥。  (4) Optionally, the separated solid is dried.
上述方法步骤 （1 ) 中， 乙腈与曲格列汀的质量 /质量比一般为 4: 1 至 20: 1 ; 可采用加热的方 式进行溶解。  In the above method step (1), the mass/mass ratio of acetonitrile to trozastatin is generally from 4:1 to 20:1; and dissolution can be carried out by heating.
上述方法步骤 （2) 中， 析晶可以在静置下进行， 也可以在搅拌下进行； 析晶方法为本技术领 域内常规的方法， 如冷却、 蒸除部分溶剂、 加晶种等方法的单用或联用。  In the above method step (2), the crystallization may be carried out under static conditions or under stirring; the crystallization method is a conventional method in the art, such as cooling, distilling off part of the solvent, adding seed crystals, etc. Used alone or in combination.
上述方法步骤 （3 ) 中， 分离可以采用过滤等本技术领域内的常规方法， 可选的， 可用适量乙 腈对所分离的固体进行洗涤。  In the above method step (3), the separation may be carried out by a conventional method in the art such as filtration, and alternatively, the separated solid may be washed with an appropriate amount of acetonitrile.
上述方法步骤 （4 ) 中， 干燥温度一般为 30~120°C， 优选 40~70°C， 可以常压干燥， 也可以 减压干燥。  In the above method step (4), the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
在一具体实施方案中， 本发明提供了一种曲格列汀晶型 D 的制备方法， 该方法包括： 将曲格 列汀加热溶解于 7-15倍重量的乙腈中， 静置下冷却析晶；  In a specific embodiment, the present invention provides a method for preparing troglitazone crystal form D, which comprises: dissolving troglitazone in 7-15 times by weight of acetonitrile, and cooling it under standing. Crystal
其中优选冷却至 0~20°C析晶， 过滤；  Preferably, it is cooled to 0 to 20 ° C for crystallization and filtration;
可选的， 所分离的晶体在 40~70Ό下， 常压或减压干燥。  Optionally, the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
曲格列汀晶型 Ε  Troglitazone crystal form Ε
本发明提供的曲格列汀晶型 Ε 的粉末 X-射线衍射图谱的特征为： 在 2Θ 值为 5.1°±0.2°、 The powder X-ray diffraction pattern of the troglitazone crystal form provided by the present invention is characterized by: a value of 5.1 ° ± 0.2 ° at 2 、,
5.4°±0.2°、 7.0°±0.2°、 9.3°±0.2°、 11.0°±0.2°、 16.3°±0.2°、 23.9°±0.2°、 25.4°±0.2°、 26.5°±0.2°等处 对应有特征衍射峰。 5.4°±0.2°, 7.0°±0.2°, 9.3°±0.2°, 11.0°±0.2°, 16.3°±0.2°, 23.9°±0.2°, 25.4°±0.2°, 26.5°±0.2°, etc. There are characteristic diffraction peaks.
在一具体实施方案中， 本发明所述的曲格列汀晶型 Ε 的粉末 X-射线衍射图谱的特征为： 在 2Θ 值为 5.1°±0.2°、 5.4°±0.2°、 7.0°±0.2°、 9.0°±0.2°、 9.3°±0.2°、 11.0°±0.2°、 13.1°±0.2°、 14.3°±0.2°、 16.3°±0.2°、 21.8°±0.2°、 23.9°±0.2°、 25.4°±0.2°、 26.5°±0.2°等处对应有特征衍射峰。  In a specific embodiment, the powder X-ray diffraction pattern of the troglitazone crystalline form of the present invention is characterized by: a value of 5.1 ± ± 0.2 °, 5.4 ° ± 0.2 °, 7.0 ° ± 0.2 at 2 Θ. °, 9.0 ° ± 0.2 °, 9.3 ° ± 0.2 °, 11.0 ° ± 0.2 °, 13.1 ° ± 0.2 °, 14.3 ° ± 0.2 °, 16.3 ° ± 0.2 °, 21.8 ° ± 0.2 °, 23.9 ° ± 0.2 °, 25.4°±0.2°, 26.5°±0.2°, etc. correspond to characteristic diffraction peaks.
进一步地， 本发明所述的曲格列汀晶型 Ε以 2Θ角度表示的粉末 X-射线衍射图谱在以下位置 具有特征衍射峰及相对强度：  Further, the powder X-ray diffraction pattern of the troglitazone crystal form of the present invention represented by a 2 Θ angle has characteristic diffraction peaks and relative intensities at the following positions:
2Θ 相对强度 (％)  2Θ Relative strength (%)
5.1。±0.2° 100  5.1. ±0.2° 100
5.4°±0.2° 73  5.4°±0.2° 73
7.0°±0.2° 50  7.0°±0.2° 50
9.0°±0.2° 26  9.0°±0.2° 26
9.3°±0.2° 47  9.3°±0.2° 47
11.0°±0.2° 17  11.0°±0.2° 17
13.1°±0.2° 19  13.1°±0.2° 19
14.3°±0.2° 17  14.3°±0.2° 17
16.3°±0.2° 26 21.8。±0.2° 23 16.3°±0.2° 26 21.8. ±0.2° 23
23.9°±0.2° 13  23.9°±0.2° 13
25.4°±0.2° 18  25.4°±0.2° 18
26.5°±0.2° 16  26.5°±0.2° 16
在一具体实施方案中， 本发明提供的曲格列汀晶型 E具有如图 5所示的粉末 X-射线衍射图谱 所代表的特征。  In a specific embodiment, the troglitazone Form E provided by the present invention has the characteristics represented by the powder X-ray diffraction pattern shown in FIG.
在一具体实施方案中， 本发明提供的制备的曲格列汀混合物中曲格列汀晶型 E含量 （质量含 量） 一般大于 70%， 优选大于 80%， 最优选大于 90%。  In a specific embodiment, the troxreline Form E content (mass content) of the prepared troglitin mixture provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本发明提供了一种曲格列汀晶型 E的制备方法， 该方法包括：  The invention provides a preparation method of troglitazone crystal form E, the method comprising:
( 1 ) 、 将曲格列汀溶解于丙酮中；  (1), dissolving troglitazone in acetone;
(2) 、 析晶；  (2), crystallization;
(3 ) 、 分离出固体；  (3) separating solids;
(4) 、 可选的， 将所分离的固体进行干燥。  (4) Optionally, the separated solid is dried.
上述方法步骤 （1 ) 中， 丙酮与曲格列汀的质量 /质量比一般为 4: 1 至 20: 1 ; 可采用加热的方 式进行溶解。  In the above method step (1), the mass/mass ratio of acetone to trozastatin is generally from 4:1 to 20:1; and dissolution can be carried out by heating.
上述方法步骤 （2) 中， 析晶可以在静置下进行， 也可以在搅拌下进行； 析晶方法为本技术领 域内常规的方法， 如冷却、 蒸除部分溶剂、 加晶种等方法的单用或联用。  In the above method step (2), the crystallization may be carried out under static conditions or under stirring; the crystallization method is a conventional method in the art, such as cooling, distilling off part of the solvent, adding seed crystals, etc. Used alone or in combination.
上述方法步骤 （3 ) 中， 分离可以采用过滤等本技术领域内的常规方法， 可选的， 可用丙酮对 所分离的固体进行洗涤。  In the above method step (3), the separation may be carried out by a conventional method in the art such as filtration, and optionally, the separated solid may be washed with acetone.
上述方法步骤 （4 ) 中， 干燥温度一般为 30~120°C， 优选 40~70°C， 可以常压干燥， 也可以 减压干燥。  In the above method step (4), the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
在一具体实施方案中， 本发明提供了一种曲格列汀晶型 E 的制备方法， 该方法包括： 将曲格 列汀加热溶解于 7-15倍重量的丙酮中， 静置冷却析晶；  In a specific embodiment, the present invention provides a method for preparing troglitazone crystal form E, which comprises: dissolving statastigine in 7-15 times by weight of acetone, and cooling and crystallization. ;
其中优选冷却至 0~10°C析晶， 过滤；  Preferably, it is cooled to 0 to 10 ° C for crystallization and filtration;
可选的， 所分离的晶体在 40~70Ό下， 常压或减压干燥。  Optionally, the separated crystals are dried at 40 to 70 Torr under normal pressure or reduced pressure.
无定形曲格列汀  Amorphous troglitazone
本发明提供了一种无定形曲格列汀， 该无定形具有如图 6所示的粉末 X-射线衍射图谱所代表 的特征。  The present invention provides an amorphous troglitin which has the characteristics represented by the powder X-ray diffraction pattern shown in Fig. 6.
在一具体实施方案中， 本发明提供的制备的曲格列汀混合物中无定型曲格列汀含量 （质量含 量） 一般大于 70%， 优选大于 80%， 最优选大于 90%。  In a specific embodiment, the amount of statin statin (mass content) in the prepared troglitin mixture provided by the present invention is generally greater than 70%, preferably greater than 80%, and most preferably greater than 90%.
本发明提供了无定形曲格列汀的多种制备方法， 包括：  The invention provides various preparation methods of amorphous troglitazone, including:
方法一：  method one:
( 1 ) 、 将曲格列汀溶解于适宜的有机溶剂中；  (1), dissolving trozastatin in a suitable organic solvent;
(2) 、 浓縮蒸除有机溶剂得残余固体；  (2), concentrated distillation of organic solvent to obtain residual solids;
(3 ) 、 可选的， 将所得的残余固体进行干燥。 上述方法步骤 （1 ) 中， 适宜的有机溶剂包括丙酮、 三氯甲垸等。 溶剂与曲格列汀的质量 /质 量比一般为 4: 1至 20: 1 ; 可采用加热的方式进行溶解。 (3) Optionally, the obtained residual solid is dried. In the above step (1), suitable organic solvents include acetone, chloroform, and the like. The mass/mass ratio of solvent to trozastatin is generally from 4:1 to 20:1; dissolution can be carried out by heating.
上述方法步骤 （2) 中， 浓縮蒸除有机溶剂可以在常压下进行， 也可以在减压下进行。  In the above step (2), the concentrated organic solvent may be carried out under normal pressure or under reduced pressure.
上述方法步骤 （3 ) 中， 干燥温度一般为 30~120°C， 优选 40~70°C， 可以常压干燥， 也可以 减压干燥。  In the above method step (3), the drying temperature is usually 30 to 120 ° C, preferably 40 to 70 ° C, and it may be dried at normal pressure or dried under reduced pressure.
方法二：  Method Two:
( 1 ) 曲格列汀加热熔化；  (1) troglitazone is heated and melted;
(2) 冷却凝固。  (2) Cooling and solidifying.
上述方法步骤 （1 ) 中， 加热熔化温度为一般在 165°C以上， 优选 165~175°C。  In the above method step (1), the heating and melting temperature is generally 165 ° C or higher, preferably 165 to 175 ° C.
在一具体实施方案中， 本发明提供了一种曲格列汀无定形的制备方法， 该方法包括： 将曲格 列汀加热溶解于 7-15倍重量的丙酮中， 减压浓縮蒸除丙酮， 得残余固体； 可选的， 将所得固体在 40~70Ό下， 常压或减压干燥。  In a specific embodiment, the present invention provides a method for preparing an amorphous form of troglitazone, which comprises: dissolving statstatin in 7-15 times by weight of acetone, and distilling off under reduced pressure. Acetone is obtained as a residual solid; optionally, the obtained solid is dried at 40 to 70 Torr under normal pressure or reduced pressure.
在一具体实施方案中， 本发明提供了曲格列汀无定形的另一种制备方法， 该方法包括： 将曲 格列汀在 165 ~170 下加热熔化， 然后冷却， 凝固。  In a specific embodiment, the present invention provides an alternative method of preparing triclinide amorphous comprising: heating and melting troglitazone at 165-170, followed by cooling and solidification.
上述粉末 X-射线衍射分析是在环境温度及环境湿度下， 经荷兰帕纳科 X'Pert PRO型粉末 X- 射线衍射仪的 CuKa源 （α = 1.54A) 测定完成的。 "环境温度"一般是 0~40Ό； "环境湿度"一般是 30%~80%的相对湿度。  The above powder X-ray diffraction analysis was carried out at ambient temperature and ambient humidity by a CuKa source (α = 1.54A) of a PA's X'Pert PRO powder X-ray diffractometer in the Netherlands. "Environmental temperature" is generally 0~40Ό; "ambient humidity" is generally 30%~80% relative humidity.
本发明提供的曲格列汀晶型 A、 B、 C, D、 E和无定形的代表性的粉末 X-射线衍射图谱列于 附图 1~6 中。 "代表性的粉末 X-射线衍射图谱"是指本晶型或无定形的粉末 X-射线衍射特征符合 本图谱显示的整体形貌， 可以理解的是在测试过程中， 由于受到多种因素 （如测试样品的粒度、 测试时样品的处理方法、 仪器、 测试参数、 测试操作等） 的影响， 同一种晶型所测得的粉末 X-射 线衍射图谱的出峰位置或峰强度会有一定的差异。 一般情况下， X-射线粉末衍射图谱中衍射峰 2Θ 值的实验误差可为 ±0.2°。  Representative powder X-ray diffraction patterns of the troagliptin crystal forms A, B, C, D, E and amorphous provided by the present invention are shown in Figures 1 to 6. "Representative powder X-ray diffraction pattern" means that the crystal form or amorphous powder X-ray diffraction characteristics conform to the overall morphology of the map, and it is understood that during the test, due to various factors ( If the particle size of the test sample, the method of processing the sample, the instrument, the test parameters, the test operation, etc., the peak position or peak intensity of the powder X-ray diffraction pattern measured by the same crystal form will be certain. difference. In general, the experimental error of the diffraction peak 2Θ in the X-ray powder diffraction pattern can be ±0.2°.
本发明的又一目的在于提供含有上述任意所述的晶型的曲格列汀混合物， 所述的晶型质量含 量大于 70%， 优选大于 80%， 更优选大于 90%。  A further object of the present invention is to provide a troglitazone mixture comprising any of the above-described crystalline forms, said crystalline form having a mass content of greater than 70%, preferably greater than 80%, more preferably greater than 90%.
其中应当理解的是， 这里所述的晶型为单一选自晶型 A、 B、 C、 D或 E其中的一种晶型， 而 非上述晶型的混合； 也就是说， 所述的混合物中含有的选自晶型 A、 B、 C、 D或 E其中的一种晶 型的质量含量大于 70%， 优选大于 80%， 更优选大于 90%。  It should be understood that the crystalline form described herein is a single crystal form selected from the group consisting of crystal forms A, B, C, D or E, rather than a mixture of the above crystal forms; that is, the mixture The crystalline form contained in one of the crystalline forms A, B, C, D or E has a mass content of greater than 70%, preferably greater than 80%, more preferably greater than 90%.
本发明的又一目的在于提供含有曲格列汀上述新固态形式的药物组合物和将曲格列汀上述新 固态形式用于制造人用药物的用途。  A further object of the present invention is to provide a pharmaceutical composition comprising the above novel solid form of troglitazone and the use of the above novel solid form of troglitazone for the manufacture of a medicament for human use.
为了实现该目的， 一方面本发明提供了一种包含有效治疗量的曲格列汀晶型 A、 晶型 B、 晶 型( 、 晶型 D、 晶型 E或无定形和药用辅料的药物组合物或制剂。  To achieve this object, in one aspect the invention provides a medicament comprising a therapeutically effective amount of troglitazone Form A, Form B, Form (Formation Form D, Form E or amorphous and pharmaceutical excipients) A composition or formulation.
另一方面， 本发明提供了曲格列汀晶型 A、 晶型 B、 晶型 C、 晶型 D、 晶型 E或无定形在制 备治疗由 DPP-IV介导的疾病的药物中的用途。 上述药物组合物或制剂可以按照药学领域的常规生产方法制备， 例如将曲格列汀晶型 A、 晶 型 B、 晶型（ 、 晶型 D、 晶型 E或无定形的一种或多种与一种或多种载体混合， 然后将其制成所 需的剂型。 在一实施方案中， 曲格列汀晶型 A、 晶型 B、 晶型 C、 晶型 D、 晶型 E或无定形的粒 径分布控制在 90%小于 ΙΟΟμηι, 优选小于 50μηι， 更优选小于 10μηι。 In another aspect, the present invention provides the use of troglitazone Form A, Form B, Form C, Form D, Form E or amorphous in the manufacture of a medicament for the treatment of a disease mediated by DPP-IV. . The above pharmaceutical composition or preparation can be prepared according to a conventional production method in the pharmaceutical field, for example, one or more of troigliptin crystal form A, crystal form B, crystal form (form, form D, form E or amorphous). Mix with one or more carriers and then form the desired dosage form. In one embodiment, troglitazone Form A, Form B, Form C, Form D, Form E or none The shaped particle size distribution is controlled to be less than 90% less than ΙΟΟμηι, preferably less than 50 μηι, more preferably less than 10 μηι.
上述药物组合物或制剂可作为一种长效 DPP-IV抑制剂， 用于治疗由 DPP-IV介导的疾病， 这 些疾病包括 I 型糖尿病、 II 型糖尿病、 糖尿病性脂学异常、 葡萄糖耐量降低、 空腹血浆葡萄糖受 损、 代谢性酸中毒、 酮症、 食欲调节和肥胖症、 炎性肠炎病、 多发性硬化、 银屑病、 类风湿性关 节炎、 AIDS或癌症等， 其中优选 I、 II型糖尿病。  The above pharmaceutical composition or preparation can be used as a long-acting DPP-IV inhibitor for the treatment of diseases mediated by DPP-IV, including type I diabetes, type II diabetes, diabetic lipodystrophy, and impaired glucose tolerance. , fasting plasma glucose damage, metabolic acidosis, ketosis, appetite regulation and obesity, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, AIDS or cancer, etc., among which I, II are preferred Type 2 diabetes.
上述药物组合物或制剂的剂型包括： 片剂、 丸剂、 颗粒剂、 散剂， 气雾剂、 粉雾剂、 喷雾 剂、 混悬剂、 溶液剂、 乳剂、 糖浆剂、 酊剂、 栓剂、 注射剂、 凝胶剂、 植入制、 膜剂、 乳膏剂、 软膏剂、 糊剂、 贴剂等。 它们根据各自剂型的特点， 给药途径包括口服、 舌下、 注射、 腔道、 经 肺 /气管或经皮等。  The dosage form of the above pharmaceutical composition or preparation includes: tablets, pills, granules, powders, aerosols, powders, sprays, suspensions, solutions, emulsions, syrups, elixirs, suppositories, injections, coagulation Glues, implants, films, creams, ointments, pastes, patches, etc. They are administered according to the characteristics of the respective dosage form, including oral, sublingual, injection, luminal, transpulmonary/tracheal or transdermal.
上述组合物或制剂的给药量根据患者病情性质和严重性、 给药途径和患者年龄、 体重等进行 调整， 一般周剂量在 lmg至 2g之间， 优选 lmg至 lOOOmg之间， 更优选 5mg至 700mg之间； 每 周可以一次给药， 也可以多次给药， 也可每日给药。  The amount of the above composition or preparation to be administered is adjusted depending on the nature and severity of the patient's condition, the route of administration, and the age, body weight, etc. of the patient, and the usual weekly dose is between 1 mg and 2 g, preferably between 1 mg and 1000 mg, more preferably 5 mg to Between 700 mg; it can be administered once a week, or it can be administered multiple times, or it can be administered daily.
在一实施方案中， 本发明提供的药物组合物为口服固体制剂， 优选片剂。 该口服固体制剂除 活性成分曲格列汀外， 还含有药用辅料， 所述的药用辅料均是本领域常规的药用辅料， 包括填充 剂、 崩解剂、 粘合剂或润湿剂、 润滑剂、 表面活性剂、 增溶剂或助溶剂等。  In one embodiment, the pharmaceutical composition provided by the present invention is an oral solid preparation, preferably a tablet. The oral solid preparation contains, in addition to the active ingredient troglitazone, a pharmaceutically acceptable excipient, which is a conventional pharmaceutical excipient in the art, including a filler, a disintegrating agent, a binder or a wetting agent. , lubricants, surfactants, solubilizers or co-solvents.
所述的填充剂一般包括乳糖、 微晶纤维素、 甘露醇、 预胶化淀粉、 淀粉、 蔗糖、 糊精、 山梨 醇、 硫酸钙、 磷酸氢钙、 碳酸钙、 碳酸氢钙、 碳酸氢钠、 碳酸钠、 羟丙基甲基纤维素、 乙基纤维 素和氢氧化铝等。 它们可以单独使用也可以混合使用， 其中优选乳糖、 微晶纤维素、 甘露醇、 预 胶化淀粉或磷酸氢钙。  The filler generally comprises lactose, microcrystalline cellulose, mannitol, pregelatinized starch, starch, sucrose, dextrin, sorbitol, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, calcium hydrogencarbonate, sodium hydrogencarbonate, Sodium carbonate, hydroxypropyl methylcellulose, ethyl cellulose, and aluminum hydroxide. They may be used singly or in combination, and among them, lactose, microcrystalline cellulose, mannitol, pregelatinized starch or calcium hydrogen phosphate is preferred.
所述的崩解剂一般包括淀粉、 羧甲基纤维素钠、 羧甲基纤维素钙、 羧甲基淀粉钠、 交联羧甲 基纤维素钠、 交聚维酮、 低取代羟丙基纤维素和羟丙基淀粉等。 它们可以单独使用也可以混合使 用， 其中优选交聚维酮、 交联羧甲基纤维素钠、 低取代羟丙基纤维素或羧甲基淀粉钠。  The disintegrant generally comprises starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substituted hydroxypropyl fiber. And hydroxypropyl starch and the like. They may be used singly or in combination, and among them, crospovidone, croscarmellose sodium, low-substituted hydroxypropylcellulose or sodium carboxymethyl starch is preferred.
所述的粘合剂或润湿剂一般包括聚维酮 （聚乙烯吡咯垸酮） 、 羟丙基甲基纤维素、 微晶纤维 素、 羟丙基纤维素、 乙基纤维素、 聚乙二醇、 淀粉浆、 阿拉伯胶、 水和各种浓度的乙醇溶液等。 它们可以单独使用也可以混合使用， 其中优选聚维酮 （聚乙烯吡咯垸酮） 、 微晶纤维素或羟丙基 纤维素。  The binder or wetting agent generally comprises povidone (polyvinylpyrrolidone), hydroxypropyl methylcellulose, microcrystalline cellulose, hydroxypropyl cellulose, ethyl cellulose, polyethylene Alcohol, starch syrup, gum arabic, water and various concentrations of ethanol solution. They may be used singly or in combination, and among them, povidone (polyvinylpyrrolidone), microcrystalline cellulose or hydroxypropylcellulose is preferred.
所述的润滑剂一般包括硬脂酸锌、 硬脂酸镁、 硬脂酸钙、 硬脂富马酸钠、 滑石粉、 脂肪酸蔗 糖酯、 微粉硅胶 (包括轻质二氧化硅、 水合二氧化硅和胶态二氧化硅；)、 硬脂酸、 棕榈酸、 硅酸铝 和固体聚乙二醇等。 它们可以单独使用也可以混合使用， 其中优选硬脂酸镁、 微粉硅胶或滑石 粉。  The lubricant generally comprises zinc stearate, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, sucrose fatty acid, silica gel (including light silica, hydrated silica). And colloidal silica;), stearic acid, palmitic acid, aluminum silicate and solid polyethylene glycol. They may be used singly or in combination, and among them, magnesium stearate, micronized silica gel or talc is preferred.
所述的表面活性剂、 增溶剂或助溶剂一般包括十二垸基硫酸钠、 吐温 -80、 波洛沙姆、 月桂硫 酸钠等。 它们可以单独使用也可以混合使用， 其中优选十二垸基硫酸钠或吐温 -80。 The surfactant, solubilizer or co-solvent generally includes sodium decyl sulfate, Tween-80, poloxamer, laurel sulfur Sodium and so on. They may be used singly or in combination, and among them, sodium dodecyl sulfate or Tween-80 is preferred.
如果需要的话， 还可以向上述组合物或制剂中添加其他辅料， 如甜味剂 （如阿司帕坦、 甜菊 素等） 、 着色剂 （如黄色氧化铁、 红色氧化铁等） 、 稳定剂 （如柠檬酸、 乳酸、 苹果酸和甘氨酸 等） 、 pH调节剂 （如碳酸钙、 碳酸钠、 碳酸氢钠、 酒石酸、 富马酸、 柠檬酸等） 。  If necessary, other excipients such as sweeteners (such as aspartame, stevioside, etc.), coloring agents (such as yellow iron oxide, red iron oxide, etc.), stabilizers (or stabilizers) may be added to the above composition or formulation. Such as citric acid, lactic acid, malic acid and glycine, etc., pH regulators (such as calcium carbonate, sodium carbonate, sodium bicarbonate, tartaric acid, fumaric acid, citric acid, etc.).
如果需要的话， 上述组合物或制剂中还可以包含其他适宜的活性成分。  If desired, other suitable active ingredients may be included in the above compositions or formulations.
上述口服固体制剂的制备可以按照本技术领域中制备口服固体制剂的常规方法进行， 如： 片 剂可以采用湿法制粒压片、 干法制粒压片、 流化床制粒压片、 粉末混合直接压片等方式制备。 当 所述口服固体制剂为片剂或微丸时， 可根据需要对其进一步包衣， 制成薄膜衣片或微丸、 包糖衣 片或微丸。 包肠溶衣片或微丸以及包缓释片或微丸。 其中包衣材料包括纤维素类、 丙烯酸树脂类 和糖类， 如羟丙基甲基纤维素和蔗糖等， 其中还可添加增塑剂、 抗粘剂和遮光剂等。  The above oral solid preparation can be prepared according to a conventional method for preparing an oral solid preparation in the art, for example, the tablet can be directly subjected to wet granulation tableting, dry granulation tableting, fluidized bed granulation tableting, powder mixing directly Prepared by tableting or the like. When the oral solid preparation is a tablet or pellet, it may be further coated as needed to prepare a film-coated tablet or pellet, a sugar-coated tablet or a pellet. Enteric coated tablets or pellets as well as sustained release tablets or pellets. The coating material includes cellulose, acrylic resin and sugars such as hydroxypropylmethylcellulose and sucrose, and a plasticizer, an anti-adhesive agent and an opacifier may be added thereto.
经实验证明， 本发明提供的曲格列汀晶型 A、 晶型 B、 晶型 C、 晶型 D、 晶型 E或无定形具 有简便的制备方法； 可具有高纯度， 比如 HPLC 面积归一化法纯度可达 98%、 99%或 99.5%以 上； 具有良好的稳定性和制剂适应性等优点。 这些优势一方面有利于用它们制成相应的制剂， 比 如它们的制剂在制备和贮存中具有良好的稳定性与有效性； 另一方面， 也有利于用它们制成高纯 度的酸加成物， 比如利用它们可制成 HPLC面积归一化法纯度达 98%、 99%或 99.5%以上， 单个 杂质小于 0.15%、 0.1%或 0.05%的曲格列汀的琥珀酸、 苯甲酸等酸加成物。  It has been experimentally proved that the present invention provides a simple preparation method of troagliptin crystal form A, crystal form B, crystal form C, crystal form D, crystal form E or amorphous; and can have high purity, such as HPLC area normalization. The purity of the method can reach 98%, 99% or more than 99.5%; it has the advantages of good stability and formulation adaptability. These advantages are advantageous on the one hand to make them into corresponding preparations, such as their formulations have good stability and effectiveness in preparation and storage; on the other hand, they are also advantageous for making high-purity acid adducts. For example, they can be used to prepare HPLC area normalized purity of 98%, 99% or more, and individual impurities are less than 0.15%, 0.1% or 0.05% of tric succinic acid, benzoic acid, etc. Adult.
以下结合实施例的具体实施方式， 对本发明的上述内容再作进一步的详细说明。 但不应将此 理解为本发明上述主题的范围仅限于以下的实例。 在不脱离本发明上述思想情况下， 根据本领域 普通技术知识和惯用手段做出的各种替换或变更， 均应包括在本发明的范围内。 附图说明  The above content of the present invention will be further described in detail below with reference to specific embodiments of the embodiments. However, the scope of the above-mentioned subject matter of the present invention should not be construed as being limited to the following examples. Various changes or modifications may be made without departing from the spirit and scope of the invention. DRAWINGS
图 1为曲格列汀晶型 A粉末 X-射线衍射图谱；  Figure 1 is an X-ray diffraction pattern of troglitazone crystal form A powder;
图 2为曲格列汀晶型 B粉末 X-射线衍射图谱；  Figure 2 is an X-ray diffraction pattern of troglitazone crystal form B powder;
图 3为曲格列汀晶型 C粉末 X-射线衍射图谱；  Figure 3 is an X-ray diffraction pattern of troglitazone crystal form C powder;
图 4为曲格列汀晶型 D粉末 X-射线衍射图谱；  Figure 4 is an X-ray diffraction pattern of troglitazone crystal form D powder;
图 5为曲格列汀晶型 E粉末 X-射线衍射图谱；  Figure 5 is an X-ray diffraction pattern of troglitazone crystal form E powder;
图 6为曲格列汀无定形粉末 X-射线衍射图谱。 具体实施方式  Figure 6 is an X-ray diffraction pattern of trozastatin amorphous powder. detailed description
以下结合附图及实施例详细说明本发明的技术方案， 但本发明的保护范围包括但是不限于 此。  The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the scope of the present invention includes but is not limited thereto.
实施例以及制备例中核磁测试是用 Bruke AV- II 300MHz或 BRUKER AVANCEIII HD 400 The nuclear magnetic test in the examples and preparation examples is Bruke AV-II 300MHz or BRUKER AVANCEIII HD 400.
MHz 核磁共振仪， 氘代二甲基亚砜 （DMSO-i/6) 作测试溶剂， 四甲基硅垸作内标， 在室温下完 成的。 A MHz NMR spectrometer, deuterated dimethyl sulfoxide (DMSO-i/6) was used as the test solvent, and tetramethylsilyl was used as an internal standard at room temperature.
实施例 1 曲格列汀晶型 A的制备 在 75~78°C下， 将曲格列汀 2.5g溶解于异丙醇 25ml中， 搅拌下冷却至 5~10°C， 抽滤， 将所 得固体在 45~50Ό下减压干燥， 得曲格列汀晶型 Α， 白色固体。 Example 1 Preparation of troglitazone Form A 2.5 g of troglitazone was dissolved in 25 ml of isopropanol at 75-78 ° C, cooled to 5-10 ° C with stirring, suction filtered, and the obtained solid was dried under reduced pressure at 45-50 Torr. Gliptin crystal form, white solid.
所测的粉末 X-射线衍射图谱见图 1， 其测量值如下 （取相对强度大于 1%的衍射峰对应的测 量值） ：  The X-ray diffraction pattern of the measured powder is shown in Fig. 1. The measured values are as follows (measured by the diffraction peak corresponding to a relative intensity greater than 1%):
Figure imgf000013_0001
Figure imgf000013_0001
实施例 2曲格列汀晶型 A的制备  Example 2 Preparation of troglitazone crystal form A
在 70~75 °C下， 将曲格列汀 2.5g溶解于异丙醇 48ml中， 搅拌下冷却至 0~5 °C， 抽滤， 将所得固 体在 55~60Ό下减压干燥， 得曲格列汀晶型 Α， 白色固体。  2.5g of troglitazone was dissolved in 48ml of isopropanol at 70~75 °C, cooled to 0~5 °C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 55~60Ό. Gliptin crystal form, white solid.
实施例 3 曲格列汀晶型 Α的制备  Example 3 Preparation of troglitazone crystal form
在 60~63 °C下， 将曲格列汀 2.5g溶解于四氢呋喃 25ml中， 搅拌下冷却至 0~5 °C， 抽滤， 得曲格 列汀晶型 A， 白色固体。  2.5 g of troglitazone was dissolved in 25 ml of tetrahydrofuran at 60 to 63 ° C, cooled to 0 to 5 ° C with stirring, and suction filtered to obtain troglitin crystal form A, a white solid.
实施例 4 曲格列汀晶型 A的制备 在 58~63 °C下， 将曲格列汀 25g溶解于四氢呋喃 200ml中， 搅拌下冷却至 5~10°C， 抽滤， 将 所得固体在 40~45 Ό下减压干燥， 得曲格列汀晶型 Α， 白色固体。 Example 4 Preparation of troglitazone Form A 25g of troglitazone was dissolved in 200ml of tetrahydrofuran at 58~63 °C, cooled to 5~10 °C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 40~45 , to obtain Qugrid. Ting crystal type, white solid.
实施例 5 曲格列汀晶型 Α的制备  Example 5 Preparation of troglitazone crystal form
在 71~74°C下， 将曲格列汀 2.5g溶解于乙酸乙酯 25ml中， 搅拌下冷却至 0~10°C， 抽滤， 将 所得固体于 60~65 Ό下减压干燥， 得曲格列汀晶型 Α， 白色固体。  2.5 g of troglitazone was dissolved in 25 ml of ethyl acetate at 71-74 ° C, cooled to 0-10 ° C with stirring, suction filtered, and the obtained solid was dried under reduced pressure at 60-65 Torr. Quagliptin crystal form, white solid.
实施例 6 曲格列汀晶型 Β的制备  Example 6 Preparation of troglitazone crystal form
在 57~60°C下， 将曲格列汀 2.5g溶解于甲醇 25ml中， 搅拌下冷却至 -5~0°C， 抽滤， 将所得固 体于 40~45 Ό下减压干燥， 得曲格列汀晶型 Β， 白色固体。  2.5g of troglitazone was dissolved in 25ml of methanol at 57~60°C, cooled to -5~0°C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 40~45 ,. Gliptin crystal form, white solid.
所测的粉末 X-射线衍射图谱见图 2， 其测量值如下表 （取相对强度大于 0.4%的衍射峰对应的 测量值） ：  The measured X-ray diffraction pattern of the powder is shown in Fig. 2, and the measured values are as follows (measured by the diffraction peak corresponding to a relative intensity greater than 0.4%):
Figure imgf000014_0001
Figure imgf000014_0001
实施例 7 曲格列汀晶型 B的制备  Example 7 Preparation of troglitazone Form B
在 55~58°C下， 将曲格列汀 2.5g溶解于甲醇 32ml中， 搅拌下冷却至 5~10°C， 抽滤， 得曲格列 汀晶型 B， 白色固体。  2.5 g of troglitazone was dissolved in 32 ml of methanol at 55 to 58 ° C, cooled to 5 to 10 ° C with stirring, and filtered to obtain troglitazone crystal form B, a white solid.
实施例 8 曲格列汀晶型 B的制备  Example 8 Preparation of troglitazone Form B
在 55~60°C下， 将曲格列汀 25g溶解于甲醇 470ml 中， 搅拌下冷却至 0~5 °C， 抽滤， 将所得固 体于 60~65 Ό下减压干燥， 得曲格列汀晶型 Β， 白色固体。  25g of troglitazone was dissolved in 470ml of methanol at 55~60°C, cooled to 0~5 °C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 60~65 , to obtain Qugrid. Ting crystal type, white solid.
实施例 9 曲格列汀晶型 C的制备  Example 9 Preparation of troglitazone crystal form C
在 72~75 °C下， 将曲格列汀 2.5g溶解于乙醇 25ml中， 搅拌下冷却至 0~5 °C， 抽滤， 将所得固体 在 45~50Ό下减压干燥， 得曲格列汀晶型 C， 白色固体。 Ή NMR (300MHz， DMSO-d6) S:7.85-7.89(q， 1H)， 7.25-7.3 l(t , 1H) , 7.11-7.14(d， 1H)， 5.31(s , 1H)， 5.12(s， 2H)， 3.38-3.45(q , 2H) , 3.06(s , 3H) , 3.00-3.04(d , 1H)， 2.87-2.91(d , 1H)， 2.57-2.63(m, 1H)， 2.50(s, 2H)， 2.29-2.36(t, 1H)， 1.60-1.78(q， 2H) , l. l l-1.40(m， 2H)， 1.01-1.06(t, 3H)。 2.5g of troglitazone was dissolved in 25ml of ethanol at 72~75 °C, cooled to 0~5 °C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 45~50Ό to obtain Qugrid. Ting Form C, white solid. NMR NMR (300MHz, DMSO-d6) S: 7.85-7.89 (q, 1H), 7.25-7.3 l(t, 1H), 7.11-7.14(d, 1H), 5.31(s, 1H), 5.12(s, 2H), 3.38-3.45(q , 2H) , 3.06(s , 3H) , 3.00-3.04(d , 1H), 2.87-2.91(d , 1H), 2.57-2.63(m, 1H), 2.50(s, 2H), 2.29-2.36(t, 1H), 1.60-1.78(q, 2H), l. l l-1.40(m, 2H), 1.01-1.06(t, 3H).
上述1 H NMR结果中， S5.12(s， 2H)归属为曲格列汀的 2个苄位 H， 53.38-3.45(q, 2H)归属为 乙醇的 2个亚甲基 H， 从 H数可判断该样品中曲格列汀与乙醇的摩尔组成比约为 1: 1。 In the above 1 H NMR results, S5.12(s, 2H) is assigned to two benzylic sites H of troglitazone, and 53.38-3.45 (q, 2H) is assigned to two methylene groups H of ethanol, from H number It can be judged that the molar composition ratio of trozastatin to ethanol in the sample is about 1:1.
所测的粉末 X-射线衍射图谱见图 3， 其测量值如下表 （取相对强度大于 1%的衍射峰对应的 测量值） ：  The X-ray diffraction pattern of the measured powder is shown in Fig. 3. The measured values are as follows (measured by the diffraction peaks with relative intensities greater than 1%):
Figure imgf000015_0001
Figure imgf000015_0001
实施例 10 曲格列汀晶型 C的制备  Example 10 Preparation of troglitazone crystal form C
在 70~75°C下， 将曲格列汀 2.5g溶解于乙醇 13ml中， 搅拌下冷却至 5~10°C， 抽滤， 将所得 固体在 10~15Ό下减压干燥， 得曲格列汀晶型 C， 白色固体。  2.5g of troglitazone was dissolved in 13ml of ethanol at 70~75°C, cooled to 5~10°C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 10~15Ό to obtain Qugrid. Ting Form C, white solid.
实施例 11 曲格列汀晶型 C的制备  Example 11 Preparation of troglitazone crystal form C
在 68~72°C下， 将曲格列汀 2.5g溶解于乙醇 47ml中， 搅拌下冷却至 0~5 °C， 抽滤， 得曲格列 汀晶型 C， 白色固体。  2.5 g of troglitazone was dissolved in 47 ml of ethanol at 68 to 72 ° C, cooled to 0 to 5 ° C with stirring, and suction filtered to obtain troglitazone crystal form C, a white solid.
实施例 12 曲格列汀晶型 C的制备 在 70~74°C下， 将曲格列汀 25g溶解于乙醇 630ml中， 搅拌下冷却至 5~10°C， 抽滤， 将所得 固体在 15~20Ό下减压干燥， 得曲格列汀晶型 C， 白色固体。 Example 12 Preparation of troglitazone Form C 25g of troglitazone was dissolved in 630ml of ethanol at 70~74°C, cooled to 5~10°C with stirring, filtered by suction, and the obtained solid was dried under reduced pressure at 15~20Ό to obtain troglitazone. Form C, white solid.
实施例 13 曲格列汀晶型 D的制备  Example 13 Preparation of troagliptin crystal form D
在 75~78°C下， 将曲格列汀 2.5g溶解于乙腈 25ml中， 静置冷却至 10~15 °C， 抽滤， 将所得固 体在 60~65 Ό下减压干燥， 得曲格列汀晶型 D， 白色固体。  2.5 g of troglitazone was dissolved in 25 ml of acetonitrile at 75-78 ° C, and allowed to stand at 10 to 15 ° C, filtered, and the resulting solid was dried under reduced pressure at 60-65 Torr to obtain a grid. Retin form D, white solid.
所测的粉末 X-射线衍射图谱见图 4， 其测量值如下表 （取相对强度大于 1%的衍射峰对应的 测量值） ：  The X-ray diffraction pattern of the measured powder is shown in Fig. 4, and the measured values are as follows (measured by the diffraction peak corresponding to a relative intensity greater than 1%):
Figure imgf000016_0001
Figure imgf000016_0001
实施例 14 曲格列汀晶型 D的制备  Example 14 Preparation of troagliptin crystal form D
回流温度下， 将曲格列汀 2.5g溶解于乙腈 32ml 中， 静置冷却至 0~5 Ό， 抽滤， 将所得固体 在 40~45 °C下减压干燥， 得曲格列汀晶型 D， 白色固体。  At reflux temperature, 2.5 g of troglitazone was dissolved in 32 ml of acetonitrile, allowed to stand for cooling to 0-5 Torr, suction filtered, and the obtained solid was dried under reduced pressure at 40 to 45 ° C to obtain troglitazone crystal form. D, white solid.
实施例 15 曲格列汀晶型 D的制备  Example 15 Preparation of troagliptin crystal form D
在 75~78°C下， 将曲格列汀 25g溶解于乙腈 470ml中， 静置冷却至 5~10°C， 抽滤， 得曲格列 汀晶型 D， 白色固体。  25 g of troglitazone was dissolved in 470 ml of acetonitrile at 75 to 78 ° C, left to cool to 5 to 10 ° C, and filtered to obtain troglitazone crystal form D, a white solid.
实施例 16 曲格列汀晶型 E的制备  Example 16 Preparation of troagliptin crystal form E
在 50~53 °C下， 将曲格列汀 2.5g溶解于丙酮 25ml中， 静置冷却至 0~10°C， 抽滤， 将所得固 体在 40~45 Ό下减压干燥， 得曲格列汀晶型 Ε， 白色固体。  2.5 g of troglitazone was dissolved in 25 ml of acetone at 50-53 ° C, left to cool to 0-10 ° C, suction filtered, and the obtained solid was dried under reduced pressure at 40-45 Torr. Levin crystal form, white solid.
所测的粉末 X-射线衍射图谱见图 5， 其测量值如下表 （取相对强度大于 1%的衍射峰对应的 测量值） ：  The measured X-ray diffraction pattern of the powder is shown in Fig. 5, and the measured values are as follows (measured by the diffraction peak corresponding to a relative intensity greater than 1%):
2Θ(°) d(A) 相对强度 (％)  2Θ(°) d(A) Relative intensity (%)
5.101 17.323 100.0  5.101 17.323 100.0
5.416 16.317 73.0  5.416 16.317 73.0
6.993 12.641 50.0  6.993 12.641 50.0
7.338 12.047 12.9 9.021 9.803 25.7 7.338 12.047 12.9 9.021 9.803 25.7
9.296 9.514 47.0  9.296 9.514 47.0
11.028 8.023 16.9  11.028 8.023 16.9
12.265 7.217 15.1  12.265 7.217 15.1
13.145 6.735 19.0  13.145 6.735 19.0
14.342 6.176 16.9  14.342 6.176 16.9
15.098 5.868 9.4  15.098 5.868 9.4
16.342 5.424 25.9  16.342 5.424 25.9
17.911 4.953 8.3  17.911 4.953 8.3
19.054 4.658 12.0  19.054 4.658 12.0
19.767 4.491 13.8  19.767 4.491 13.8
20.416 4.350 21.1  20.416 4.350 21.1
21.182 4.194 17.1  21.182 4.194 17.1
21.819 4.073 23.1  21.819 4.073 23.1
23.039 3.860 14.9  23.039 3.860 14.9
23.864 3.729 13.2  23.864 3.729 13.2
25.376 3.510 18.0  25.376 3.510 18.0
26.484 3.366 15.5  26.484 3.366 15.5
28.382 3.145 8.3  28.382 3.145 8.3
29.293 3.049 6.3  29.293 3.049 6.3
30.823 2.901 4.7  30.823 2.901 4.7
37.914 2.373 1.7 实施例 17 曲格列汀晶型 E的制备  37.914 2.373 1.7 Example 17 Preparation of troagliptin crystal form E
回流温度下， 将曲格列汀 2.5g溶解于丙酮 31ml 中， 静置冷却至 0~5 °C， 抽滤， 得曲格列汀 晶型 E， 白色固体。  At a reflux temperature, 2.5 g of troglitazone was dissolved in 31 ml of acetone, allowed to stand to cool to 0 to 5 ° C, and suction filtered to obtain troglitazone crystal form E, a white solid.
实施例 18 曲格列汀晶型 E的制备  Example 18 Preparation of troagliptin crystal form E
在 48~50°C下， 将曲格列汀 25g溶解于丙酮 470ml中， 静置冷却至 5~10°C， 抽滤， 将所得固 体在 55~60Ό下减压干燥， 得曲格列汀晶型 Ε， 白色固体。  25g of troglitazone was dissolved in 470ml of acetone at 48~50°C, left to cool to 5~10°C, filtered by suction, and the obtained solid was dried under reduced pressure at 55~60Ό to obtain troglitazone. Crystalline Ε, white solid.
实施例 19 曲格列汀无定形的制备  Example 19 Preparation of amorphous troglitazone
在 50~53 °C下， 将曲格列汀 2.5g溶解于丙酮 25ml 中， 减压浓縮得白色固体， 将所得固体在 45~50Ό下减压干燥， 得曲格列汀无定形。  2.5 g of troglitazone was dissolved in 25 ml of acetone at 50 to 53 ° C, concentrated under reduced pressure to give a white solid, and the obtained solid was dried under reduced pressure at 45 to 50 Torr to obtain amorphous troglitazone.
所测的粉末 X-射线衍射图谱见图 6。  The measured powder X-ray diffraction pattern is shown in Fig. 6.
实施例 20 曲格列汀无定形的制备  Example 20 Preparation of ochletine in amorphous form
回流温度下， 将曲格列汀 2.5g溶解于丙酮 22ml 中， 减压浓缩得白色固体， 得曲格列汀无定 形。  At a reflux temperature, 2.5 g of troglitazone was dissolved in 22 ml of acetone, and concentrated under reduced pressure to give a white solid.
实施例 21 曲格列汀无定形的制备  Example 21 Preparation of ostigliptin amorphous
在 50~53 °C下， 将曲格列汀 25g溶解于丙酮 480ml中， 减压浓縮得白色固体， 将所得固体在 65~70Ό下减压干燥， 得曲格列汀无定形。  25 g of troglitazone was dissolved in 480 ml of acetone at 50 to 53 ° C, concentrated under reduced pressure to give a white solid, and the obtained solid was dried under reduced pressure at 65 to 70 Torr to obtain amorphous troglitazone.
实施例 22 曲格列汀无定形的制备  Example 22 Preparation of an amorphous form of troglitazone
在 165~17(TC下， 将曲格列汀 0.5g加热熔化， 然后冷却至室温， 得曲格列汀无定形。  At 165 to 17 (TC), troglitazone 0.5 g was heated and melted, and then cooled to room temperature to obtain troglitazone amorphous.
实施例 23 含 12.5mg曲格列汀的片剂及其制备  Example 23 Tablet containing 12.5 mg of troglitazone and preparation thereof
处方： 组分 含量 （mg/片） prescription: Component content (mg/tablet)
曲格列汀晶型 A 12.5  Tristatin crystal form A 12.5
微晶纤维素 120.0  Microcrystalline cellulose 120.0
乳糖 81.5  Lactose 81.5
交联羧甲基纤维素钠 30.0  Croscone sodium sodium 30.0
胶态二氧化硅 3.0  Colloidal silica 3.0
硬脂酸镁 3.0  Magnesium stearate 3.0
250mg  250mg
制备： 将上表组分中的曲格列汀晶型 A (按实施例 1 的方法制备） 、 微晶纤维素、 乳糖、 交 联羧甲基纤维素钠和胶态二氧化硅混匀后， 用水湿法制粒， 干燥， 整粒， 与硬脂酸镁混匀， 压 片， 即得。  Preparation: After mixing the troglitazone crystal form A (prepared according to the method of Example 1), microcrystalline cellulose, lactose, croscarmellose sodium and colloidal silica in the components of the above table, , wet granulation with water, dry, whole, mixed with magnesium stearate, tablet, that is.
实施例 24 含 12.5mg曲格列汀的片剂及其制备  Example 24 Tablet containing 12.5 mg of troglitazone and preparation thereof
处方：  Prescription:
组分 含量 （mg/片）  Component content (mg/tablet)
曲格列汀晶型 A 12.5  Tristatin crystal form A 12.5
微晶纤维素 120.0  Microcrystalline cellulose 120.0
甘露醇 51.5  Mannitol 51.5
交联羧甲基纤维素钠 10.0  Cross-linked carboxymethyl cellulose sodium 10.0
胶态二氧化硅 3.0  Colloidal silica 3.0
硬脂酸镁 3.0  Magnesium stearate 3.0
200mg  200mg
制备： 将上表组分中的曲格列汀晶型 A (按实施例 1 的方法制备） 、 微晶纤维素、 甘露醇、 交联羧甲基纤维素钠和胶态二氧化硅混匀后， 用水湿法制粒， 干燥， 整粒， 与硬脂酸镁混匀， 压 片， 即得。  Preparation: Mixing troglitazone Form A (prepared as in Example 1), microcrystalline cellulose, mannitol, croscarmellose sodium and colloidal silica in the above components After that, it is wet granulated with water, dried, granulated, mixed with magnesium stearate, and tableted.
实施例 25 含 25mg曲格列汀的片剂及其制备  Example 25 Tablet containing 25 mg of troglitazone and preparation thereof
处方：  Prescription:
组分 含量 （mg/片）  Component content (mg/tablet)
曲格列汀晶型 B 25.0  Tristatin crystal form B 25.0
微晶纤维素 120.0  Microcrystalline cellulose 120.0
乳糖 119.0  Lactose 119.0
交联羧甲基纤维素钠 30.0  Croscone sodium sodium 30.0
胶态二氧化硅 3.0  Colloidal silica 3.0
硬脂酸镁 3.0  Magnesium stearate 3.0
300mg  300mg
制备： 将上表组分中的曲格列汀晶型 B (按实施例 6 的方法制备） 、 微晶纤维素、 乳糖、 交 联羧甲基纤维素钠和胶态二氧化硅混匀后， 用水湿法制粒， 干燥， 整粒， 与硬脂酸镁混匀， 压 片， 即得。  Preparation: After mixing the troglitazone Form B (prepared according to the method of Example 6), microcrystalline cellulose, lactose, croscarmellose sodium and colloidal silica in the components of the above table, , wet granulation with water, dry, whole, mixed with magnesium stearate, tablet, that is.
实施例 26 含 25mg曲格列汀的片剂及其制备  Example 26 Tablet containing 25 mg of troglitazone and preparation thereof
处方：  Prescription:
含量 （mg/片)  Content (mg/tablet)
曲格列汀晶型 B 25  Triglitastat crystal form B 25
微晶纤维素 120.0 甘露醇 50.0 Microcrystalline cellulose 120.0 Mannitol 50.0
微甘硬微甘胶硬交交交曲曲联羧甲基纤维素钠 20.0  Micro-gans hard micro-glam gum hard cross-crossing carboxymethyl cellulose sodium 20.0
格聚脂格聚态脂露露晶晶  Polyester condensate
滑石粉列列纤醇维酸纤醇维一酸一 3.0  Talc powder is listed as a phenolic acid, a phenolic acid, a vitamin 1.0
硬脂酸镁维氧镁汀酮 2.0  Magnesium stearate retinophenone 2.0
素素化晶晶 220mg  Plain crystals 220mg
硅型型  Silicon type
制备： 将上表组分 C中的曲格列汀晶型 B (按实施例 6 的方法制备） 、 微晶纤维素、 甘露醇和 交联羧甲基纤维素钠混匀后， 用水湿法制粒， 干燥， 整粒， 再与滑石粉和硬脂酸镁混匀， 压片， 即得。  Preparation: Mixing troglitazone Form B (prepared according to the method of Example 6), microcrystalline cellulose, mannitol and croscarmellose sodium in component C of the above table, and granulating with water. , dry, whole, and then mix with talc and magnesium stearate, tablet, that is.
实施例 27 含 50mg曲格列汀的片剂及其制备  Example 27 Tablet containing 50 mg of troglitazone and preparation thereof
处方：  Prescription:
组分 含量 （mg/片）  Component content (mg/tablet)
曲格列汀晶型 c 56.4  Tristatin crystal form c 56.4
微晶纤维素 120.0  Microcrystalline cellulose 120.0
乳糖 87.6  Lactose 87.6
交联羧甲基纤维素钠 30.0  Croscone sodium sodium 30.0
胶态二氧化硅 3.0  Colloidal silica 3.0
硬脂酸镁 3.0  Magnesium stearate 3.0
300mg  300mg
制备： 将上表组分中的曲格列汀晶型 C (按实施例 12的方法制备） 、 微晶纤维素、 乳糖、 交 联羧甲基纤维素钠和胶态二氧化硅混匀后， 用水湿法制粒， 干燥， 整粒， 与硬脂酸镁混匀， 压 片， 即得。  Preparation: After mixing the troglitazone crystal form C (prepared according to the method of Example 12), microcrystalline cellulose, lactose, croscarmellose sodium and colloidal silica in the components of the above table, , wet granulation with water, dry, whole, mixed with magnesium stearate, tablet, that is.
实施例 28 含 50mg曲格列汀的片剂及其制备  Example 28 Tablet containing 50 mg of troglitazone and preparation thereof
处方：  Prescription:
组分 含量 （mg/片）  Component content (mg/tablet)
56.4  56.4
150.0  150.0
120.6  120.6
20.0  20.0
3.0  3.0
350mg  350mg
制备： 将上表组分中的曲格列汀晶型 C (按实施例 9 的方法制备） 、 微晶纤维素、 甘露醇和 交聚维酮混匀后， 用水湿法制粒， 干燥， 整粒， 与硬脂酸镁混匀， 压片， 即得。  Preparation: Mixing troglitazone crystal form C (prepared according to the method of Example 9), microcrystalline cellulose, mannitol and crospovidone in the above components, wet granulation with water, drying, whole granules , mix with magnesium stearate, tablet, that is.
实施例 29 含 lOOmg曲格列汀的片剂及其制备  Example 29 Tablet containing lOOmg of troglitazone and preparation thereof
处方：  Prescription:
组分 含量 （mg/片）  Component content (mg/tablet)
113.0  113.0
45.0  45.0
42.0  42.0
10.0  10.0
5.0  5.0
5.0  5.0
220mg 制备： 将上表组分中的曲格列汀晶型 C (按实施例 12的方法制备） 、 微晶纤维素、 甘露醇、 交聚维酮s硬微乳 f曲曲和胶态二氧化硅混匀后， 用水湿法制粒， 干燥， 整粒， 与硬脂酸镁混匀， 压片， 即得。 220mg Preparation: troglitazone crystal form C (prepared according to the method of Example 12), microcrystalline cellulose, mannitol, crospovidone s hard microemulsion f-curvature and colloidal dioxide After the silicon is mixed, it is wet granulated with water, dried, granulated, mixed with magnesium stearate, and tableted.
格糖石脂格糖 S曰  糖糖脂糖 S曰
实施例列粉列酸纤 30 含 lOOmg曲格列汀的颗粒剂及其制备  Examples of powdered acid fiber 30 granules containing lOOmg of troglitazone and preparation thereof
镁维汀  Magnesium statin
处方： 素晶  Prescription: Su Jing
型型  Type
E C 含量 （mg/粒)  E C content (mg/granule)
曲格列汀晶型 C 113.0  Tristatin crystal form C 113.0
甘露醇 374.0  Mannitol 374.0
低取代羟丙级纤维素 10.0  Low substituted hydroxypropyl cellulose 10.0
硬脂酸镁 3.0  Magnesium stearate 3.0
500mg  500mg
制备： 将上表组分中的曲格列汀晶型 C (按实施例 12的方法制备） 、 甘露醇以及低取代羟丙 级纤维素混匀后， 用水湿法制粒， 干燥， 整粒， 再与硬脂酸镁混匀， 分装于复合膜袋中， 即得。  Preparation: Mixing troglitazone Form C (prepared according to the method of Example 12), mannitol and low-substituted hydroxypropyl cellulose in the components of the above table, granulating with water, drying, and granulating, Mix with magnesium stearate and dispense in a composite film bag.
实施例 31 含 lOOmg曲格列汀的散剂及其制备  Example 31 Powder containing lOOmg of troglitazone and preparation thereof
处方：  Prescription:
含量 （mg/粒)  Content (mg/granule)
113.0  113.0
377.0  377.0
5.0  5.0
5.0  5.0
500mg  500mg
制备： 将上表组分中的曲格列汀晶型 C (按实施例 12方法制备） 、 乳糖粉碎过 100目筛， 再 将曲格列汀晶型( 、 乳糖、 滑石粉和硬脂酸镁混匀， 分装， 即得。  Preparation: troglitazone crystal form C (prepared according to the method of Example 12) in the above table components, lactose pulverized through a 100 mesh sieve, and then troglitazone crystal form (, lactose, talc and stearic acid) Mix the magnesium, sub-package, and get it.
实施例 32 含 lOOmg曲格列汀的片剂及其制备  Example 32 Tablet containing lOOmg of troglitazone and preparation thereof
处方：  Prescription:
组分 含量 （mg/片）  Component content (mg/tablet)
曲格列汀晶型 D 100.0  Tristatin crystal form D 100.0
微晶纤维素 120.0  Microcrystalline cellulose 120.0
乳糖 94.0  Lactose 94.0
交联羧甲基纤维素钠 30.0  Croscone sodium sodium 30.0
胶态二氧化硅 3.0  Colloidal silica 3.0
硬脂酸镁 3.0  Magnesium stearate 3.0
350mg  350mg
制备： 将上表组分中的曲格列汀晶型 D (按实施例 13的方法制备） 、 微晶纤维素、 乳糖、 交 联羧甲基纤维素钠和胶态二氧化硅混匀后， 用水湿法制粒， 干燥， 整粒， 与硬脂酸镁混匀， 压 片， 即得。  Preparation: After mixing the troglitazone Form D (prepared according to the method of Example 13), microcrystalline cellulose, lactose, croscarmellose sodium and colloidal silica in the components of the above table, , wet granulation with water, dry, whole, mixed with magnesium stearate, tablet, that is.
实施例 33 含 200mg曲格列汀的片剂及其制备  Example 33 Tablet containing 200 mg of troglitazone and preparation thereof
处方：  Prescription:
组分 含量 （mg/片）  Component content (mg/tablet)
200.0  200.0
100.0  100.0
64.0 交联羧甲基纤维素钠 30.0 64.0 Cross-linked carboxymethyl cellulose sodium 30.0
胶态二氧化硅 3.0  Colloidal silica 3.0
硬脂酸镁 3.0  Magnesium stearate 3.0
400mg  400mg
制备： 将上表组分中的曲格列汀晶型 E (按实施例 16的方法制备） 、 微晶纤维素、 乳糖、 交 联羧甲基纤维素钠和胶态二氧化硅混匀后， 用水湿法制粒， 干燥， 整粒， 与硬脂酸镁混匀， 压 片， 即得。  Preparation: After mixing the troglitazone crystal form E (prepared according to the method of Example 16), microcrystalline cellulose, lactose, croscarmellose sodium and colloidal silica in the components of the above table, , wet granulation with water, dry, whole, mixed with magnesium stearate, tablet, that is.
实施例 34含 400mg曲格列汀的片剂及其制备  Example 34 Tablet containing 400 mg of troglitazone and preparation thereof
处方：  Prescription:
含量 （mg/片）  Content (mg/tablet)
曲格列汀无定形 400.0  Tragliptin amorphous 400.0
微晶纤维素 100.0  Microcrystalline cellulose 100.0
乳糖 64.0  Lactose 64.0
交联羧甲基纤维素钠 30.0  Croscone sodium sodium 30.0
胶态二氧化硅 3.0  Colloidal silica 3.0
硬脂酸镁 3.0  Magnesium stearate 3.0
600mg  600mg
制备： 将上表组分中的曲格列汀无定形 （按实施例 19的方法制备） 、 微晶纤维素、 乳糖、 交 联羧甲基纤维素钠和胶态二氧化硅混匀后， 用水湿法制粒， 干燥， 整粒， 与硬脂酸镁混匀， 压 片， 即得。  Preparation: After the amorphous form of troglitazone (prepared according to the method of Example 19), microcrystalline cellulose, lactose, croscarmellose sodium and colloidal silica are mixed in the components of the above table, Wet granulation with water, drying, granules, mixing with magnesium stearate, tableting, that is.
制备例 1 曲格列汀的制备  Preparation 1 Preparation of troglitazone
( 1 ) 、 2-[(6-氯 -3,4-二 -3-甲基 -2,4-二氧代 -1 (2H) -嘧啶基） 甲基] -4-氟-苯甲腈 (IV)的制备  (1), 2-[(6-Chloro-3,4-di-3-methyl-2,4-dioxo-1 (2H)-pyrimidinyl)methyl]-4-fluoro-benzonitrile Preparation of (IV)
Figure imgf000021_0001
Figure imgf000021_0001
将 3-甲基 -6-氯尿嘧啶 (V,可商业化购得 )425g、 2-溴甲基 -4-氟苯甲腈 (VI,可商业化购得 )714g、 Ν,Ν-二异丙基乙胺 (DIEA)566ml与 N-甲基吡咯垸酮 (NMP)1530ml混合， 在 15~20°C下搅拌反应约 2小时， 然后升温至 55~60°C反应； TLC监控反应结束后， 加水 2200ml稀释后冷却至约 5。C， 过 滤， 固体 45~50°C减压干燥， 得标题化合物 (IV)697g。  3-methyl-6-chlorouracil (V, commercially available) 425 g, 2-bromomethyl-4-fluorobenzonitrile (VI, commercially available) 714 g, Ν, Ν-二566 ml of isopropylethylamine (DIEA) was mixed with 1530 ml of N-methylpyrrolidone (NMP), and the reaction was stirred at 15 to 20 ° C for about 2 hours, and then the temperature was raised to 55 to 60 ° C; the TLC monitoring reaction was completed. After that, it was diluted with 2200 ml of water and cooled to about 5. After filtration, the solid was dried under reduced pressure at 45 to 50 °C toield of Compound (IV) 697 g.
(2)、 2-[[6-[(3R)-3-氨基 -1-哌啶基 ]-3,4-二氢 -3-甲基 -2,4-二氧 -1(2H)-嘧啶基]甲基] -4-氟-苯甲腈 ( I , 曲格列汀)的制  (2) 2-[[6-[(3R)-3-Amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)- Preparation of pyrimidinyl]methyl]-4-fluoro-benzonitrile (I, troglitazone)
Figure imgf000021_0002
Figure imgf000021_0002
将 2-[(6-氯 -3,4-二氢-3-甲基-2,4-二氧代-1 (2H) -嘧啶基） 甲基] -4-氟-苯甲腈 (IV)684g、 (R)-3- 氨基-哌啶二盐酸盐 (ΙΠ,可商业化购得 )441.8g、 异丙醇 6150ml、 碳酸钾 1420g和水 45ml混合， 在 55~60°C下搅拌反应； TLC监控反应结束后， 加入乙腈 2000ml并冷却至室温， 搅拌约 3小时后过 滤， 用乙腈 2000ml*2洗涤滤饼后并入滤液； 滤液在 45~50°C减压浓縮。 将所得浓縮物溶于二氯甲 垸 7500ml中， 在 20~30°C下滴加 2mol/L盐酸水溶液调 pH约 3， 加毕盐酸后继续搅拌约 1小时后 过滤， 滤饼依次用二氯甲垸 4000ml和四氢呋喃 2750ml洗涤， 在 45~50°C下减压干燥。 将干燥所 得的固体加入到由二氯甲垸 4500ml和水 9000ml组成的混合液中， 用 50%的氢氧化钠水溶液调节 pH>12, 分液； 水相用二氯甲垸 3700ml萃取， 合并有机相； 有机相依次经水 3700ml*2洗涤， 无 水硫酸钠干燥， 减压浓縮得白色固体； 所得固体在 45~50Ό下减压干燥， 得曲格列汀 （I) 502g。 2-[(6-Chloro-3,4-dihydro-3-methyl-2,4-dioxo-1 (2H)-pyrimidinyl)methyl]-4-fluoro-benzonitrile (IV 684g, (R)-3-amino-piperidine dihydrochloride (ΙΠ, commercially available) 441.8g, isopropanol 6150ml, potassium carbonate 1420g and water 45ml mixed, The reaction was stirred at 55-60 ° C; after the TLC monitoring reaction was completed, 2000 ml of acetonitrile was added and cooled to room temperature, stirred for about 3 hours, filtered, and the filter cake was washed with acetonitrile 2000 ml * 2 and then filtrated; the filtrate was at 45-50 ° C Concentrate under reduced pressure. The obtained concentrate is dissolved in 7500 ml of dichloromethane, and the pH is adjusted to about 3 by adding 2 mol/L hydrochloric acid aqueous solution at 20 to 30 ° C. After adding hydrochloric acid, stirring is continued for about 1 hour, followed by filtration, and the filter cake is sequentially used. The mixture was washed with 4000 ml of chloroformamidine and 2750 ml of tetrahydrofuran, and dried under reduced pressure at 45 to 50 °C. The dried solid was added to a mixture of 4,500 ml of dichloromethane and 9000 ml of water, and the pH was adjusted to 12 with 50% aqueous sodium hydroxide solution, and the aqueous phase was extracted with 3700 ml of dichloromethane, and the organic phase was combined. The organic phase was washed successively with water 3700 ml*2, dried over anhydrous sodium sulfate, and evaporated to dryness to give a white solid. The obtained solid was dried under reduced pressure at 45 to 50 Torr to obtain 502 g of troglitazone (I).
¾ NMR (400MHz, DMSO-d6) 5:7.94-7.97(m, 1H)， 7.32-7.37(m, 1H) , 7.16-7.19(m, 1H)， 5.32(s , 1H) , 5.18(s， 2H)， 3.11(s , 3H) , 2.98-3.01(m , 1H) , 2.90-2.93(m , 1H) , 2.64-2.69(m , 1H), 2.55-2.60(m, 1H), 2.30-2.35(m, 1H), 1.74-1.78(m， 1H), 1.63-1.68(m, 1H), 1.37-1.48(m, 3H), 1.05-1.14(m, 1H)。  3⁄4 NMR (400MHz, DMSO-d6) 5:7.94-7.97(m, 1H), 7.32-7.37(m, 1H), 7.16-7.19(m, 1H), 5.32(s, 1H), 5.18(s, 2H ), 3.11(s , 3H) , 2.98-3.01(m , 1H) , 2.90-2.93(m , 1H) , 2.64-2.69(m , 1H), 2.55-2.60(m, 1H), 2.30-2.35(m , 1H), 1.74-1.78 (m, 1H), 1.63-1.68 (m, 1H), 1.37-1.48 (m, 3H), 1.05-1.14 (m, 1H).
制备例 2 曲格列汀琥珀酸盐的制备  Preparation 2 Preparation of troglitazone succinate
在 55~60°C下， 将曲格列汀 45.5g 溶于由四氢呋喃 530ml 和异丙醇 200ml 组成的混合溶剂 中， 然后滴加由琥珀酸 15.8g和四氢呋喃 250ml配成的溶液， 滴加完毕后继续搅拌 15分钟， 然后 冷却至室温继续搅拌 12小时； 过滤， 滤饼经适量异丙醇洗涤， 在 50~55 °C下减压干燥， 得曲格列 汀琥珀酸盐 49.4g。  45.5 g of trozastatin was dissolved in a mixed solvent consisting of 530 ml of tetrahydrofuran and 200 ml of isopropanol at 55 to 60 ° C, and then a solution of 15.8 g of succinic acid and 250 ml of tetrahydrofuran was added dropwise, and the addition was completed. After stirring for 15 minutes, it was cooled to room temperature and stirring was continued for 12 hours. After filtration, the cake was washed with an appropriate amount of isopropanol and dried under reduced pressure at 50 to 55 ° C to obtain 49.4 g of troglitazone succinate.
¾ NMR (400MHz， DMSO-d6) S:8.59(s， 4H)， S:7.94-7.98(q， 1H)， 7.33-7.38(m , 1H)， 7.16- 7.19(q， 1H)， 5.39(s , 1H)， 5.10-5.22(q , 2H) , 3.13-3.16(q , 1H)， 3.09(s , 3H) , 3.05(s , 1H)， 2.89-2.92(t, 1H)， 2.61-2.68(m, 2H), 2.30(s, 4H)， 1.73-1.87(m, 2H), 1.33-1.50(m, 2H)。  3⁄4 NMR (400MHz, DMSO-d6) S: 8.59 (s, 4H), S: 7.94-7.98 (q, 1H), 7.33-7.38 (m, 1H), 7.16- 7.19 (q, 1H), 5.39 (s , 1H), 5.10-5.22(q , 2H) , 3.13-3.16(q , 1H), 3.09(s , 3H) , 3.05(s , 1H), 2.89-2.92(t, 1H), 2.61-2.68(m , 2H), 2.30 (s, 4H), 1.73-1.87 (m, 2H), 1.33-1.50 (m, 2H).
上述1 H NMR结果中， S5.10-5.22(q， 2H)归属为曲格列汀的 2个苄位 H， 52.30(s, 4H)归属为琥 珀酸的 4个亚甲基 H， 从 H数可判断该样品中曲格列汀与琥珀酸的摩尔组成比约为 1 : 1。 In the above 1 H NMR results, S5.10-5.22 (q, 2H) is assigned to two benzylic sites H of trozastatin, and 52.30 (s, 4H) is assigned to four methylene groups H of succinic acid, from H. The number can be judged as a molar composition ratio of trozastatin to succinic acid of about 1:1 in the sample.
体外溶出实验  In vitro dissolution test
将按照实施例 29制备的样品在体外不同 pH溶出介质中进行溶出度测定， 结果如下:  The samples prepared in accordance with Example 29 were tested for dissolution in different pH elution media in vitro, and the results were as follows:
Figure imgf000022_0001
Figure imgf000022_0001
上述研究表明， 曲格列汀晶型 C所制成的制剂在不同的溶出介质中， 15分钟内的溶出度均大 于 85%， 该晶型具有良好的制剂适应性。  The above studies show that the formulation of troglitazone crystal form C has a dissolution rate of more than 85% in 15 minutes in different dissolution media, and the crystal form has good formulation suitability.
稳定性实验  Stability test
以下为曲格列汀晶型 A、 晶型 B、 晶型 C、 晶型 D、 晶型 E和无定形分别在高温、 高湿、 强 光条件下进行试验， 10天后进行有关物质和晶型检测。 The following are troxliptin crystal form A, crystal form B, crystal form C, crystal form D, crystal form E and amorphous respectively at high temperature, high humidity, strong The test was carried out under light conditions, and the relevant substances and crystal forms were examined 10 days later.
有关物质用 HPLC法进行检测， 其检测条件为：  The relevant substances are detected by HPLC method, and the detection conditions are as follows:
色谱柱： 十八垸基硅垸键合硅胶柱 （250mmx4.6mm， 5μηι) ；  Column: 18 垸-based silicon germanium bonded silica column (250mm x 4.6mm, 5μηι);
柱温： 40 °C ;  Column temperature: 40 °C;
检测波长： 225nm;  Detection wavelength: 225nm;
流动相： 按下表进行梯度洗脱  Mobile phase: Gradient elution according to the following table
Figure imgf000023_0001
Figure imgf000023_0001
流速 0.8ml/min;  Flow rate 0.8ml/min;
检测方法： 取样品适量， 精密称定， 加甲醇溶解并稀释制成每 lml约含 0.5mg溶液作为供试 品溶液， 精密量取 ΙΟμΙ, 注入液相色谱仪， 记录色谱图， 按照面积归一法计算有关物质含量。  Detection method: Take the appropriate amount of sample, accurately weigh, add methanol to dissolve and dilute to make about 0.5mg solution per lml as the test solution, accurately measure ΙΟμΙ, inject into the liquid chromatograph, record the chromatogram, according to the area The law calculates the relevant substance content.
检测结果如下： 考察时间 考察条件 样品 有关物质 （％) 晶型是否发生变化 曲格列汀晶型 A 0.14%  The test results are as follows: Time of investigation Investigation conditions Samples Related substances (%) Whether crystal form changes or not, troglitazone crystal form A 0.14%
曲格列汀晶型 B 0.16%  Triglitin crystal form B 0.16%
曲格列汀晶型 C 0.13%  Tristatin crystal form C 0.13%
0天 1  0 days 1
曲格列汀晶型 D 0.18%  Tristatin crystal form D 0.18%
曲格列汀晶型 E 0.15%  Tristatin crystal form E 0.15%
曲格列汀晶型无定形 0.28%  Tristatin crystal form amorphous 0.28%
10天 曲格列汀晶型 A 0.16% 否  10 days Triglitin crystal form A 0.16% No
曲格列汀晶型 B 0.19% 否  Tristatin crystal form B 0.19% No
高温 (40°C 曲格列汀晶型 C 0.14% 否  High temperature (40 °C troglitazone crystal form C 0.14% no
±2。C)  ±2. C)
曲格列汀晶型 D 0.23% 否  Tristatin crystal form D 0.23% No
曲格列汀晶型 E 0.18% 否  Tristatin crystal form E 0.18% No
曲格列汀晶型无定形 0.33% 否  Tristatin crystal form amorphous 0.33% No
高湿 曲格列汀晶型 A 0.15% 否 (RH75 % 曲格列汀晶型 B 0.17% 否 ±5%) High-humidity troglitazone crystal form A 0.15% No (RH75 % troagliptin crystal form B 0.17% no ± 5%)
曲格列汀晶型 c 0.13% 否  Tristatin crystal form c 0.13% No
曲格列汀晶型 D 0.20% 否  Tristatin crystal form D 0.20% No
曲格列汀晶型 E 0.17% 否  Tristatin crystal form E 0.17% No
曲格列汀晶型无定形 0.30% 否  Triglitastat crystal form amorphous 0.30% No
上述研究表明： 曲格列汀晶型 A、 晶型 B、 晶型 C、 晶型 D、 晶型 E和无定形具有良好的稳 定性。  The above studies show that: troglitazone crystal form A, crystal form B, crystal form C, form D, form E and amorphous have good stability.
溶解度实验  Solubility test
将产品曲格列汀晶型 C和曲格列汀无定形先研磨成细粉并加入到装有水 10ml 的锥形瓶中， 水温控制在 25 Ό±2Ό之间， 每隔 5分钟强力振摇 30秒； 观察 30分钟内样品的溶解情况， 按中国 药典标准判断其溶解性。 实验结果如下：
Figure imgf000024_0001
The product Quagstatin C and troglitazone were first ground into a fine powder and added to a conical flask containing 10 ml of water. The water temperature was controlled between 25 Ό ± 2 ,, and the vibration was vigorously every 5 minutes. Shake for 30 seconds; observe the dissolution of the sample within 30 minutes, and judge its solubility according to Chinese Pharmacopoeia standards. The experimental results are as follows:
Figure imgf000024_0001
一般情况下， 一个物质的无定形态具有比晶体形态更好的溶解性， 但上述研究表明， 曲格列 汀晶型 c在水中的溶解度大于无定形。  In general, the amorphous form of a substance has a better solubility than the crystal form, but the above studies show that the solubility of troglitazone form c in water is greater than that of amorphous.
动物药代动力学实验  Animal pharmacokinetics experiment
通过使用 μηι筛过筛， 制备具备相当晶体尺寸的曲格列汀晶型 Α、 晶型 Β、 晶型 C和曲格列 汀琥珀酸盐。 选用雄性 SD 大鼠 24 只， 240-270g， 随机分为 4 组， 分别灌胃给予曲格列汀晶型 A、 B、 C 以及曲格列汀琥珀酸盐， 剂量均为 10mg/kg (按曲格列汀计)。 于给药前和给药后 15 分 钟、 30分钟、 1小时、 2小时、 3小时、 4小时、 8小时、 12小时和 24小时通过尾静脉采血， 每 次约 200μί， 3500转 /分钟， 离心 10分钟， 取上层血浆， 通过 LC-MS MS定量分析。 根据血浆药 物浓度 -时间数据， 采用 WmNonlm 6.2 软件按非房室模型计算曲格列汀的药动学参数。 对主要药 动学参数进行 T检验， 结果如下表。  The trozaleadine crystal form, the crystalline form Β, the crystalline form C and the troglitazone succinate having a comparable crystal size were prepared by sieving through a μηι sieve. Twenty-four male Sprague-Dawley rats, 240-270 g, were randomly divided into 4 groups. The trozastatin crystal forms A, B, C and troglitazone succinate were administered by gavage at a dose of 10 mg/kg. Quglitastatin). Blood was collected from the tail vein before administration and at 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration, each time about 200 μί, 3500 rpm, centrifuged After 10 minutes, the upper plasma was taken and quantitatively analyzed by LC-MS MS. Based on plasma drug concentration-time data, the pharmacokinetic parameters of trozastatin were calculated by non-compartmental model using WmNonlm 6.2 software. A T test was performed on the main pharmacokinetic parameters, and the results are shown in the following table.
Figure imgf000024_0002
Figure imgf000024_0002
上述研究表明， 曲格列汀晶型 A、 晶型 B、 晶型 C与曲格列汀琥珀酸盐的主要药动学参数均 没有显著性差异 (P>0.05)， 因此曲格列汀晶型 A、 晶型 B、 晶型 C 具有和盐类似的生物特性或药 效。  The above studies showed that there were no significant differences in the main pharmacokinetic parameters of troagliptin crystal form A, crystal form B, crystal form C and trozastatin succinate (P>0.05), so troglitazone crystal Type A, Form B, and Form C have similar biological properties or effects as salts.

Claims

权利要求书 claims
1、 曲格列汀晶型 A， 其特征在于： 其粉末 X-射线衍射图谱在 2Θ 值为 5.7°±0.2°、 11.4。±0.2°、 12.5。±0.2°、 16.8。±0.2°、 17.1。±0.2°、 19.4。±0.2°、 19.9。±0.2°、 20.5。±0.2°、 22.5°±0.2°、 22.9°±0.2°、 29.1°±0.2°处对应有特征衍射峰或具有如图 1 所示的粉末 X-射线衍射 图谱所代表的特征。 1. Tregliptin crystal form A is characterized by: Its powder X-ray diffraction pattern has a 2Θ value of 5.7°±0.2° and 11.4. ±0.2°, 12.5. ±0.2°, 16.8. ±0.2°, 17.1. ±0.2°, 19.4. ±0.2°, 19.9. ±0.2°, 20.5. ±0.2°, 22.5°±0.2°, 22.9°±0.2°, and 29.1°±0.2° correspond to characteristic diffraction peaks or have characteristics represented by the powder X-ray diffraction pattern as shown in Figure 1.
2、 一种曲格列汀晶型 A的制备方法， 该方法包括： 2. A method for preparing trotagliptin crystal form A, which method includes:
( 1 ) 、 将曲格列汀溶解于异丙醇、 四氢呋喃或乙酸乙酯中； (1) Dissolve trodagliptin in isopropyl alcohol, tetrahydrofuran or ethyl acetate;
(2 ) 、 析晶； (2), crystallization;
( 3 ) 、 分离出固体； (3), separate the solid;
(4 ) 、 可选的， 将所分离的固体进行干燥。 (4) Optionally, dry the separated solid.
3、 曲格列汀晶型 B， 其特征在于： 其粉末 X-射线衍射图谱在 2Θ 值为 4.9°±0.2°、 5.7°±0.2°、 9.9°±0.2°、 11.4°±0.2°、 14.8°±0.2°、 20.2°±0.2°、 22.7°±0.2°、 27.0°±0.2°处对应有特 征衍射峰或具有如图 2所示的粉末 X-射线衍射图谱所代表的特征。 3. Tregliptin crystal form B is characterized by: Its powder X-ray diffraction pattern has 2Θ values of 4.9°±0.2°, 5.7°±0.2°, 9.9°±0.2°, 11.4°±0.2°, 14.8 °±0.2°, 20.2°±0.2°, 22.7°±0.2°, and 27.0°±0.2° correspond to characteristic diffraction peaks or have characteristics represented by the powder X-ray diffraction pattern as shown in Figure 2.
4、 一种曲格列汀晶型 B的制备方法， 该方法包括： 4. A method for preparing trotagliptin crystal form B, which method includes:
( 1 ) 、 将曲格列汀溶解于甲醇中； (1) Dissolve trotagliptin in methanol;
(2 ) 、 析晶； (2), crystallization;
( 3 ) 、 分离出固体； (3), separate the solid;
(4 ) 、 可选的， 将所分离的固体进行干燥。 (4) Optionally, dry the separated solid.
5、 曲格列汀的乙醇合物。 5. The ethanolic compound of trotagliptin.
6、 如权利要求 5所述的乙醇合物， 其晶型为曲格列汀晶型 C， 其特征在于： 其粉末 X-射 线衍射图谱在 2Θ值为 4.9°±0.2°、 9.7°±0.2°、 12.5°±0.2°、 12.9°±0.2°、 14.6°±0.2°、 16.7°±0.2°、 20.3°±0.2°、 22.0°±0.2°、 26.2°±0.2°、 34.1°±0.2°处对应有特征衍射峰或具有如图 3 所示的粉末 X-射线衍射图谱所代表的特征。 6. The ethanol compound according to claim 5, whose crystal form is trotagliptin crystal form C, characterized in that: its powder X-ray diffraction pattern has a 2Θ value of 4.9°±0.2° and 9.7°±0.2 °, 12.5°±0.2°, 12.9°±0.2°, 14.6°±0.2°, 16.7°±0.2°, 20.3°±0.2°, 22.0°±0.2°, 26.2°±0.2°, 34.1°±0.2° Corresponding to characteristic diffraction peaks or having characteristics represented by the powder X-ray diffraction pattern as shown in Figure 3.
7、 一种曲格列汀乙醇合物晶型 C的制备方法， 该方法包括： 7. A method for preparing trotagliptin ethanolate crystal form C. The method includes:
( 1 ) 、 将曲格列汀溶解于乙醇中； (1) Dissolve trotagliptin in ethanol;
(2 ) 、 析晶； (2), crystallization;
( 3 ) 、 分离出固体； (3), separate the solid;
(4 ) 、 可选的， 将所分离的固体进行干燥。 (4) Optionally, dry the separated solid.
8、 曲格列汀晶型 D， 其特征在于： 其粉末 X-射线衍射图谱在 2Θ 值为 5.5°±0.2°、 12.2°±0.2°、 15.7°±0.2°、 16.8°±0.2°、 19.7°±0.2°、 22.2°±0.2°、 22.5°±0.2°处对应有特征衍射峰或 具有如图 4所示的粉末 X-射线衍射图谱所代表的特征。 8. Tregliptin crystal form D is characterized by: Its powder X-ray diffraction pattern has 2Θ values of 5.5°±0.2°, 12.2°±0.2°, 15.7°±0.2°, 16.8°±0.2°, 19.7 °±0.2°, 22.2°±0.2°, and 22.5°±0.2° correspond to characteristic diffraction peaks or have characteristics represented by the powder X-ray diffraction pattern as shown in Figure 4.
9、 一种曲格列汀晶型 D的制备方法， 该方法包括： ( 1 ) 、 将曲格列汀溶解于乙腈中； 9. A method for preparing trotagliptin crystal form D, which method includes: (1) Dissolve trotagliptin in acetonitrile;
(2) 、 析晶； (2), crystallization;
(3 ) 、 分离出固体； (3), separate the solid;
(4) 、 可选的， 将所分离的固体进行干燥。 (4) Optionally, dry the separated solid.
10、 曲格列汀晶型 E， 其特征在于： 其粉末 X-射线衍射图谱在 2Θ 值为 5.1°±0.2°、 5.4°±0.2°、 7.0°±0.2°、 9.3°±0.2°、 11.0°±0.2°、 16.3°±0.2°、 23.9°±0.2°、 25.4°±0.2°、 26.5°±0.2° 处对应有特征衍射峰或具有如图 5所示的粉末 X-射线衍射图谱所代表的特征。 10. Tregliptin crystal form E is characterized by: Its powder X-ray diffraction pattern has 2Θ values of 5.1°±0.2°, 5.4°±0.2°, 7.0°±0.2°, 9.3°±0.2°, 11.0 °±0.2°, 16.3°±0.2°, 23.9°±0.2°, 25.4°±0.2°, 26.5°±0.2° correspond to characteristic diffraction peaks or are represented by powder X-ray diffraction patterns as shown in Figure 5 Characteristics.
11、 一种曲格列汀晶型 E的制备方法， 该方法包括： 11. A method for preparing trotagliptin crystal form E, which method includes:
( 1 ) 、 将曲格列汀溶解于丙酮中； (1) Dissolve trotagliptin in acetone;
(2) 、 析晶； (2), crystallization;
(3 ) 、 分离出固体； (3), separate the solid;
(4) 、 可选的， 将所分离的固体进行干燥。 (4) Optionally, dry the separated solid.
12、 一种无定形曲格列汀， 其特征在于： 具有如图 6 所示的粉末 X-射线衍射图谱所代表 的特征。 12. An amorphous trotagliptin, characterized by: having the characteristics represented by the powder X-ray diffraction pattern shown in Figure 6.
13、 一种无定形曲格列汀的制备方法， 该方法包括： 13. A method for preparing amorphous trotagliptin, which method includes:
( 1 ) 、 将曲格列汀溶解于适宜的有机溶剂中， 其中适宜的有机溶剂包括丙酮、 三氯甲 烧； (1) Dissolve trotagliptin in a suitable organic solvent, where suitable organic solvents include acetone and chloroform;
(2) 、 浓縮蒸除有机溶剂得残余固体； (2) Concentrate and evaporate the organic solvent to obtain residual solid;
(3 ) 、 可选的， 将所得的残余固体进行干燥。 (3) Optionally, dry the residual solid obtained.
14、 含有权利要求 1、 3、 6、 8、 10 任意一项所述的晶型的曲格列汀混合物， 其特征在 于： 所述的晶型质量含量大于 70%， 优选大于 80%， 更优选大于 90%。 14. A trotagliptin mixture containing the crystal form of any one of claims 1, 3, 6, 8, and 10, characterized in that: the mass content of the crystal form is greater than 70%, preferably greater than 80%, and more Preferably greater than 90%.
15、 一种曲格列汀的药物组合物， 其特征在于含有治疗有效量的权利要求 1、 3、 5、 6、 8、 10、 12任意一项所述曲格列汀和药用辅料。 15. A pharmaceutical composition of trotagliptin, characterized by containing a therapeutically effective amount of the trotagliptin described in any one of claims 1, 3, 5, 6, 8, 10, and 12 and pharmaceutical excipients.
16、 根据权利要求 1、 3、 5、 6、 8、 10、 12任一项所述的曲格列汀在制造治疗由二肽基肽 酶 IV介导的疾病的药物中的用途。 16. Use of trolagliptin according to any one of claims 1, 3, 5, 6, 8, 10, and 12 in the manufacture of drugs for treating diseases mediated by dipeptidyl peptidase IV.
PCT/CN2014/072370 2013-02-22 2014-02-21 Solid forms of trelagliptin, preparation method and applications thereof WO2014127735A1 (en)

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