WO2013178031A1 - Nouvelles formes du télaprévir et ses méthodes de préparation - Google Patents

Nouvelles formes du télaprévir et ses méthodes de préparation Download PDF

Info

Publication number
WO2013178031A1
WO2013178031A1 PCT/CN2013/076096 CN2013076096W WO2013178031A1 WO 2013178031 A1 WO2013178031 A1 WO 2013178031A1 CN 2013076096 W CN2013076096 W CN 2013076096W WO 2013178031 A1 WO2013178031 A1 WO 2013178031A1
Authority
WO
WIPO (PCT)
Prior art keywords
solvent
telaprevir
group
ray powder
solvents
Prior art date
Application number
PCT/CN2013/076096
Other languages
English (en)
Inventor
Weida Wang
Guodong SUN
Qinping XIONG
Original Assignee
Sunshine Lake Pharma Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sunshine Lake Pharma Co., Ltd. filed Critical Sunshine Lake Pharma Co., Ltd.
Publication of WO2013178031A1 publication Critical patent/WO2013178031A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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

Definitions

  • the present invention relates to the field of pharmaceutical chemistry. More particularly, the invention relates to novel forms of Telaprevir, and preparation methods thereof.
  • Telaprevir represented by formula (I) has been approved by FDA for treating adult patients who are infected with Hepatitis C disease such as cirrhosis and also are treatment-naive patients or have been previously subjected to interferon-based treatment as prior null responders;
  • a drug such as Telaprevir may exist in different crystalline forms, which is important for the quality of a medicine. Those crystalline forms have significant differences from each other in appearances, stability, solubilities, melting points, dissolution rates, bioavailabilities, efficacy and the like. Therefore, there is a need for novel crystalline forms of Telaprevir having better physicochemical properties, especially, relatively higher stability, solubilities, bioavailabilities and/or efficacies.
  • US patent US 7820671 discloses a method for preparing Telaprevir, and the Telaprevir with a melting point of 225 °C to 235 °C is obtained by purifying through chromatography.
  • the crystalline and amorphous of Telaprevir have been introduced in US 20060089385, and in which the amorphous was mainly prepared by a spray-drying method;
  • Chinese patent application CN 200780015244 has disclosed the co-crystals of Telaprevir and oxalic acid, however, none of those references has disclosed the substantially pure crystalline form of Telaprevir, moreover, it needs to use special expensive equipments to prepare the crystalline or amorphous form.
  • crystalline form of a compound refers to a unique ordered arrangement and/or conformations of molecules in the crystal lattice of the compound.
  • a crystalline form that is "substantially pure” refers to a crystalline form that is substantially free of one or more other crystalline forms, i.e., the crystalline form has a purity of at least about 60%, at least about 70%, at least about 80%, at least about 85%, at least about 90%), at least about 93%, at least about 95%, at least about 98%>, at least about 99%, at least about 99.5%), at least about 99.6%>, at least about 99.7%, at least about 99.8%, or at least about 99.9%; or the crystalline form has less than 20%, less than 10%, less than 5%, less than 3%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% of the one or more other crystalline forms, based on the total volume or weight of the crystalline form and the one or more other crystalline forms.
  • a crystalline form that is "substantially free" of one or more other crystalline forms refers to a crystalline form containing less than 20%, less than 10%, less than 5%, less than 4%), less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, or less than 0.01% of the one or more other crystalline form, based on the total volume or weight of the crystalline form and the one or more other crystalline forms.
  • an X-ray powder diffraction pattern that is "substantially as depicted" in a figure refers to an X-ray powder diffraction pattern having at least 50%, at least 60%, at least 70%, at least 80%), at least 90%, at least 95%, or at least 99% of the peaks shown in the figure.
  • relative intensity refers to the intensity of a peak with respect to the intensity of the strongest peak in the X-ray powder diffraction (XRPD) pattern which is regarded as 100%.
  • the term "dissolution-solvent” refers to a solvent in which the solubility of Telaprevir is more than 1 g/L, more than 2 g/L, more than 3 g/L, more than 4 g/L, more than 5 g/L, more than 6 g/L, more than 7 g/L, more than 8 g/L, more than 9 g/L, more than 10 g/L, more than 15 g/L, more than 20 g/L, more than 30 g/L, more than 40 g/L, more than 50 g/L, more than 60 g/L, more than 70 g/L, more than 80 g/L, more than 90 g/L, or more than 100 g/L.
  • the solubility of Taprevir in the dissolution-solvent is better than that in anti-solvent.
  • the difference value about the solubility of Telaprevir in dissolution-solvent or anti- solvent may be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or 90%, based on the solubility in dissolution solvents.
  • the solubility of Telaprevir in a dissolution-solvent is higher than that in an anti-solvent about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.
  • the term "anti-solvent” refers to a solvent which can promote supersaturation and/or crystallization.
  • the solubility of Telaprevir in the anti-solvent is less than 0.001 g/L, less than 0.01 g/L, less than 0.1 g/L, less than 0.2 g/L, less than 0.3 g/L, less than 0.4 g/L, less than 0.5 g/L, less than 0.6 g/L, less than 0.8 g/L, less than 1 g/L, less than 2 g/L, less than 3 g/L, less than 4 g/L, less than 5 g/L, less than 6 g/L, less than 7 g/L, less than 8 g/L, less than 9 g/L, or less than 10 g/L.
  • room temperature refers to a temperature between about 18 °C and about 30 °C, or a temperature between about 20 °C and about 25 °C, or a temperature at about 22 °C.
  • peak refers to a feature that one skilled in the art would recognize as not attributable to background noise.
  • R RL+k*(RU-RL), wherein k is a variable ranging from 1% to 100% with a 1% increment, i.e., k is 1%, 2%, 3%, 4%, 5%,..., 50%, 51%, 52%,..., 95%, 96%, 97%, 98%, 99%, or 100%.
  • k is a variable ranging from 1% to 100% with a 1% increment, i.e., k is 1%, 2%, 3%, 4%, 5%,..., 50%, 51%, 52%,..., 95%, 96%, 97%, 98%, 99%, or 100%.
  • any numerical range defined by two R numbers as defined above is also specifically disclosed.
  • the two theta in X-ray powder diffraction is expressed in degrees (°).
  • the present invention provides new forms of Telaprevir and the preparation method thereof.
  • novel forms of Telaprevir and the novel form is substantially pure crystalline form I or amorphous form II.
  • the substantially pure crystalline form I of Telaprevir has an X-ray powder diffraction pattern (XRPD) comprising a peak at about 9.10 degree in term of two theta.
  • XRPD X-ray powder diffraction pattern
  • crystalline form I has an X-ray powder diffraction pattern comprising one or more peaks at about 8.65, 9.10, 9.49, 19.05 and 19.66 degrees in term of two theta.
  • crystalline form I has an X-ray powder diffraction pattern comprising one or more peaks at about 9.10, 9.49, 19.66, 19.05, 8.65, 14.24, 17.51, 18.01, 18.81 and 20.34 degrees in term of two theta.
  • crystalline form I has an X-ray powder diffraction pattern comprising one or more peaks at about 9.10, 9.49, 19.66, 19.05, 8.65, 14.24, 17.51, 18.01, 18.81, 20.34, 10.59, 18.44, 19.94, 20.14 and 20.65 degrees in term of two theta.
  • crystalline form I has an X-ray powder diffraction pattern comprising one or more peaks at about 9.10, 9.49, 19.66, 19.05, 8.65, 14.24, 17.51, 18.01, 18.81, 20.34, 10.59, 18.44, 19.94, 20.14, 20.65, 10.27, 11.83, 12.57, 14.87, 16.20, 17.03, 19.24, 23.36, 24.72, 25.37, 28.49 and 29.68 degrees in term of two theta.
  • crystalline form I has an X-ray powder diffraction pattern substantially as depicted in Figure 1, wherein the peak at about 9.10 degree in term of two theta has a relative intensity more than 50%, more than 60%, more than 70%, more than 80%, more than 90%, or more than 99% with respect to the strongest peak in the X-ray powder diffraction pattern.
  • the melting point of crystalline form I is between about 222 °C to about 224 °C, detected by a capillary method.
  • the X-ray powder diffraction of amorphous form II of Telaprevir is substantially as depicted in Figure 2.
  • the X-ray powder diffraction is measured using CuK alpha radiation, wavelength 1.54 A, wherein an ordinate or Y-axis is diffraction intensities in counts, and an abscissa or X-axis is the diffraction angle two theta in degrees.
  • the two theta values may change slightly from one machine to another, from one sample to another.
  • the difference in value may be about 1 degree, about 0.8 degrees, about 0.5 degrees, about 0.3 degrees, or about 0.1 degrees. Therefore, the above-mentioned values of two theta cannot be regarded as absolute.
  • the crystalline form I or amorphous II of Telaprevir obtained from the processes disclosed is substantially pure.
  • the crude Telaprevir can be prepared by using the process disclosed in US 7820671 or other known methods.
  • the process for preparing the crystalline form I of Telaprevir herein comprises the steps of dissolving Telaprevir and forming crystals.
  • the process for preparing the crystalline form I of Telaprevir herein comprises the steps of dissolving Telaprevir in a dissolution-solvent, then cooling the solution and forming crystals from the solution.
  • Telaprevir is dissolved in a dissolution-solvent at a suitable temperature, wherein the suitable temperature is between environment temperature and the boiling point of the dissolution-solvent. In some embodiments, Telaprevir is dissolved in a dissolution-solvent at the boiling point of the solvent. In some embodiments, Telaprevir is dissolved in a dissolution-solvent at a suitable temperature wherein the temperature is lower than the boiling point of the dissolution-solvent.
  • the solution is cooled by the continuous cooling or gradient cooling.
  • an anti-solvent is added to the solution or the solution is added to an anti-solvent in order to further improve the crystal quality and/or increase the yield.
  • the term “gradient cooling” means that the temperature of the system is reduced to a certain temperature within a period of time, maintaining this temperature for a period of time, repeating this operation until the system reaches to a target temperature; the “continuous cooling” means that the system of temperature is continuously reduced to a target temperature.
  • the dissolution-solvent in the process disclosed herein for preparing crystalline form I of Telaprevir is selected from the group of: alcohol solvents, ester solvents, ether solvents, hydrocarbon solvents, nitrile solvents, ketone solvents, dimethyl formamide, dimethyl sulfoxide and combinations thereof, wherein the alcohol solvents are selected from the group of: methanol, iso-butanol, n-butanol and tert-butanol; wherein the ester solvents are selected from the group of: ethyl acetate, isopropyl acetate and n-butyl acetate; wherein the ether solvents are selected from the group of: methyl tert-butyl ether, tetrahydrofuran and 2-methyltetrahydrofuran; wherein the hydrocarbon solvents are selected from the group of: dichloromethane, chloroform and toluene; wherein the nitrile solvents are selected from aceton
  • the solvent is one or more selected from the group of: methanol, dimethylformamide, dichloromethane, ethyl acetate and methyl tert-butyl ether. In some embodiments, the solvent is one or more selected from the group of: methanol, dimethylformamide, dimethylsulfoxide and methyl tert-butyl ether. In some embodiments, the solvent is a mixture of dichloromethane and ethyl acetate. In some embodiments, the solvent is dichloromethane.
  • the anti-solvent in the process disclosed herein for preparing crystalline form I of Telaprevir is selected from the group of: water, ethanol, ethyl acetate, methyl ethyl ketone, n-hexane and combinations thereof.
  • the process for preparing the crystalline form I of Telaprevir comprises the steps of dissolving Telaprevir in dichloromethane to form a solution, adding methyl tert-butyl ether dropwise, stirring overnight at room temperature, and precipitating out the crystals.
  • the invention provides a method to prepare the amorphous form II of Telaprevir comprising the steps of dissolving Telaprevir in a dissosultion-solvent, removing the solvent and collecting the solid.
  • Telaprevir is dissolved in a dissosultion-solvent at a suitable temperature, wherein the suitable temperature may be any temperature between room temperature and the boiling point of the dissosultion-solvent. In some embodiments, Telaprevir is dissolved in a dissosultion-solvent at the boiling point of the dissosultion-solvent.
  • the method for removing the solvent is distillation under reduced pressure or dried under vaccum or lyophilization.
  • the temperature for removing the solvent may be different with different process.
  • the solvent is removed at room temperature, or at the boiling point of the solvent.
  • the solvent is removed at a temperature between about -20 °C and about 20 °C. In some embodiments, the solvent is removed at 0 °C.
  • the dissolution-solvent in the process disclosed herein for preparing amorphous form II of Telaprevir is selected from the group of: dichloromethane, chloroform, toluene, t-butanol, acetone, tetrahydrofuran, methyl tert-butyl ether, dimethyl sulfoxide, dimethyl formamide, and combinations thereof.
  • the dissolution-solvent is dichloromethane or chloroform.
  • the dissolution-solvent is tetrahydrofuran.
  • the dissolution-solvent is toluene or acetone.
  • the process for preparing the amorphous form II of Telaprevir comprises the steps of dissolving Telaprevir in dichloromethane to form a solution, removing the solvent at room temperature by distilling under reduced pressure, drying under vaccum and collecting the solid.
  • the substantially pure crystalline form I, amorphous form II of Telaprevir disclosed in the present invention generally have good properties such as better thermal stability, free-flowing; which is convenient for operation or storage, can be used in preparing a medicine for treating Hepatitis C in a patient.
  • the process disclosed herein for preparing Telaprevir can get substantially pure forms of Telaprevir, and have good properties such as continuous operation, a low cost and industrial friendly for preparing.
  • a pharmaceutical composition comprising a therapeutically effective amount of forms of Telaprevir disclosed herein such as crystalline form I or amorphous form II and one or more pharmaceutically acceptable carriers, excipients; wherein the excipients or carriers comprise microcrystalline cellulose, polyethylene glycol, or carboxymethylcellulose sodium.
  • the pharmaceutical composition comprises crystalline form I or amorphous form II of Telaprevir, wherein the pharmaceutical compositions are compacted into a dosage form, such as capsules and tablets.
  • the substantially pure crystalline form I, amorphous form II of Telaprevir disclosed in the present invention also can be used with one or more excipients or carriers to prepare a kind of solid dispersion.
  • Figure 1 depicts the X-ray powder diffractogram (XRPD) of the crystalline form I of Telaprevir.
  • Figure 2 depicts the X-ray powder diffractogram (XRPD) of the amorphous form II of Telaprevir.
  • Figure 3 depicts the X-ray powder diffractogram (XRPD), from top to bottom, of the crystalline form I of Telaprevir and the XRPD of which placed at light, high temperature, or high humidity for ten days.
  • XRPD X-ray powder diffractogram
  • Figure 4 depicts the X-ray powder diffractogram (XRPD), from top to bottom, of the amorphous form II of Telaprevir and the XRPD of which placed at light, high temperature, or high humidity for ten days.
  • XRPD X-ray powder diffractogram
  • Telaprevir (2.5 g) was dissolved in methanol (50 mL), the mixture was heated to 60 °C until the solid was dissolved completely. The solution was cooled to room temperature, followed by adding water into the solution until the solution was slightly turbid, stirring overnight at 0 °C to 5 °C, then the crystal was precipitated out and filtered. The solid was dried under vacuum at 40 °C for 12 hours and white solid (2.0 g) was obtained. With detection the white solid was crystalline form I of Telaprevir having an XRPD as depicted in Figure 1.
  • Telaprevir (4.5 g) was dissolved in dimethylformamide (15 mL) to form a solution, and water was added into the solution until the solution was slightly turbid. The mixture was stirred overnight at 0 °C to 5 °C, then the crystal was precipitated out and filtered. The solid was dried under vacuum at 50 °C for 12 hours and white solid (3.5 g) was obtained. The XRPD indicated that it was crystalline form I of Telaprevir.
  • Telaprevir (4.0 g) was dissolved in dichloromethane (16 mL) with stirring. Ethyl acetate (20 mL) was added into the solution, then the mixture was stirred for 4 hours at 0 °C to 5 °C. The precipitate was filtered, and dried under vacuum at 40 °C for 12 hours, then white solid (2.8g) was obtained. The XRPD indicated that it was crystalline form I of Telaprevir.
  • Telaprevir (2.5 g) was dissolved in ethyl acetate (12 mL) to form a solution, followed by stirring for 2 hours at 0 °C to 5 °C, then the solid was filtered and dried under vacuum at 40 °C for 12 hours. White solid (1.7 g) was obtained. The XRPD indicated that it was crystalline form I of Telaprevir.
  • Telaprevir (2.5 g) was dissolved in methyl tert-butyl ether (40 mL) with heating to form a solution, then the solution was cooled, and stirred at 0 °C to 5 °C for 2 hours. The solid was filtered and dried to obtain 1.6 g of product. The XRPD indicated that it was crystalline form I of Telaprevir.
  • Example 6 Telaprevir (2.5 g) was dissolved in dichloromethane (20 mL) with stirring to form a solution. The solution was concentrated at room temperature under vacuum and some foamy solid was obtained. The solid was dried under vacuum at 40 °C for 12 hours, and 2.4 g of solid was obtained. With detection the solid was amorphous form II of Telaprevir having an XRPD as depicted in Figure 2.
  • Telaprevir (2.5 g) was dissolved in tetrahydrofuran (25 mL) with heating and then the solvent was removed by rotary evaporation at 40 °C under vacuum. The solid was collected and dried under vacuum at 40 °C for 12 hours to obtain 2.4 g of white solid.
  • the XRPD indicated that it was amorphous form II of Telaprevir.
  • the samples still are white powder.
  • the X-ray powder diffraction indicates that the crystal form I didn't change at the condition of high temperature, high humidity, or light for ten days. (See figure 3.)

Abstract

Cette invention concerne de nouvelles formes « sensiblement pures » du télaprévir (forme I ou forme II). Ces nouvelles formes sensiblement pures présentent de bonnes performances en termes de stabilité. Elles répondent aux exigences de stabilité d'un médicament et se conservent facilement, elles conviennent à la production commerciale et peuvent être utilisées pour préparer un médicament destiné au traitement de l'hépatite C.
PCT/CN2013/076096 2012-06-01 2013-05-22 Nouvelles formes du télaprévir et ses méthodes de préparation WO2013178031A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201210178437 2012-06-01
CN201210178437.5 2012-06-01
CN201210474474 2012-11-21
CN201210474474.0 2012-11-21

Publications (1)

Publication Number Publication Date
WO2013178031A1 true WO2013178031A1 (fr) 2013-12-05

Family

ID=49672406

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2013/076096 WO2013178031A1 (fr) 2012-06-01 2013-05-22 Nouvelles formes du télaprévir et ses méthodes de préparation

Country Status (1)

Country Link
WO (1) WO2013178031A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005123076A2 (fr) * 2004-06-08 2005-12-29 Vertex Pharmaceuticals, Inc. Compositions pharmaceutiques
WO2007098270A2 (fr) * 2006-02-27 2007-08-30 Vertex Pharmaceuticals Incorporated Co-cristaux et compositions pharmaceutiques les comprenant

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005123076A2 (fr) * 2004-06-08 2005-12-29 Vertex Pharmaceuticals, Inc. Compositions pharmaceutiques
WO2007098270A2 (fr) * 2006-02-27 2007-08-30 Vertex Pharmaceuticals Incorporated Co-cristaux et compositions pharmaceutiques les comprenant

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE IP.COM 21 December 2011 (2011-12-21), DISCLOSED ANONYMOUSLY: "Amorphous (1 S,3aR,6aS)-N-(l (S)-(2-(Cyclopropylamino)oxalyl) butyl)-2-(N-(pyrazin-2-ylcarbonyl)-L-cyclohexylglycyl-3-methyl-Lvalyl)perhydrocyclopenta [c]pyrrole-1-carboxamide", accession no. PCOM000213558D *
DATABASE IP.COM 26 October 2011 (2011-10-26), DISCLOSED ANONYMOUSLY: "New Form of (1S,3aR,6aS)-N-(1 (S)-(2-(Cyclopropylamino)oxalyl) butyl)-2-(N-(pyrazin-2-ylcarbonyl)-L-cyclohexylglycyl-3-methyl-L-valyl)perhydrocyclopenta [c]pyrrole-1-carboxamide", accession no. PCOM000212032D *
DATABASE IP.COM 26 October 2011 (2011-10-26), DISCLOSED ANONYMOUSLY: "New Form of (1S,3aR,6aS)-N-(1 (S)-(2-(Cyclopropylamino)oxalyl) butyl)-2-(N-(pyrazin-2-ylcarbonyl)-L-cyclohexylglycyl-3-methyl-L-valyl)perhydrocyclopenta [c]pyrrole-l -carboxamide", accession no. PCOM000212033D *
DATABASE IP.COM 26 October 2011 (2011-10-26), DISCLOSED ANONYMOUSLY: "New Form of (1S,3aR,6aS)-N-(1(S)-(2-(Cyclopropylamino)oxalyl) butyl)-2-(N-(pyrazin-2-ylcarbonyl)-L-cyclohexylglycyl-3-methyl-L-valyl)perhydrocyclopenta [c]pyrrole-1-carboxamide", accession no. PCOM000212034D *

Similar Documents

Publication Publication Date Title
US20230242515A1 (en) Crystalline form of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3) pyridazine-3-carboxamide
AU2011213431B2 (en) Polymorphs of dasatinib, preparation methods and pharmaceutical compositions thereof
US10882825B2 (en) Non-solvated crystal, preparation method and application thereof
US8252805B2 (en) Forms of lapatinib ditosylate and processes for preparation thereof
WO2012080195A2 (fr) Formes polymorphes de maléate d'asénapine et procédés pour leur préparation
US10118932B2 (en) Solid state forms of spiro-oxindole compounds
WO2016051380A1 (fr) Forme cristalline de dimaléate d'afatinib
CN102282125A (zh) 新方法和纯的多晶型物
US9884859B2 (en) Solid form of pyrazolopyridine compound
WO2013150544A2 (fr) Dispersion solide de chlorhydrate d'ivabradine
EP3867264A1 (fr) Formes à l'état solide de la voclosporine
WO2013178031A1 (fr) Nouvelles formes du télaprévir et ses méthodes de préparation
CN101437791A (zh) 储存后稳定的阿托伐他汀钙的结晶形式
CN108570045B (zh) 氢溴酸山莨菪碱的晶型、其制备方法、药物组合物
CN112479912A (zh) 2-羟基-5-[2-(4-(三氟甲基苯基)乙基氨基)]苯甲酸晶型及其制备方法
KR20170060035A (ko) 나트륨 글루코스 공동운반체 2 억제제의 ｌ- 프롤린 화합물, 및 ｌ- 프롤린 화합물의 모노하이드레이트 및 결정
EP3004104A1 (fr) Forme cristalline de n,n-dicyclopropyl-4-(1,5-diméthyl-1h-pyrazol-3-ylamino)-6-éthyl-1-méthyl-1,6-dihydro-imidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide pour le traitement de troubles myéloprolifératifs
CN111217807A (zh) 一种达沙替尼无定型及其制备方法
WO2017031994A1 (fr) Synthèse de troxacitabine et forme cristalline de troxacitabine
WO2012003413A1 (fr) Nouvelles formes solides de tacédinaline
AU2018201013B2 (en) Crystalline forms of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide mono hydrochloride
CN116554171A (zh) 一种brd4抑制剂类化合物的新晶型、用途及其制备方法
CN103910710B (zh) 阿格列汀新晶型及其制备方法
CN102219752B (zh) 一种1-(2,6-二氟苄基)-1h-1,2,3-三唑-4-甲酰胺的晶型d
CN117567550A (zh) 依洛昔巴特新晶型及其制备方法和用途

Legal Events

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

Ref document number: 13798127

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 13798127

Country of ref document: EP

Kind code of ref document: A1