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WO2016101912A1 - Forme cristalline d'un sel d'un inhibiteur de kinase du récepteur du facteur de croissance épidermique et son procédé de préparation - Google Patents

Forme cristalline d'un sel d'un inhibiteur de kinase du récepteur du facteur de croissance épidermique et son procédé de préparation Download PDF

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WO2016101912A1
WO2016101912A1 PCT/CN2015/098901 CN2015098901W WO2016101912A1 WO 2016101912 A1 WO2016101912 A1 WO 2016101912A1 CN 2015098901 W CN2015098901 W CN 2015098901W WO 2016101912 A1 WO2016101912 A1 WO 2016101912A1
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Prior art keywords
formula
compound
salt
crystalline form
hydrobromide salt
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PCT/CN2015/098901
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English (en)
Chinese (zh)
Inventor
陈敏华
张炎锋
刘凯
张晓宇
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Crystal Pharmatech Co Ltd
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Crystal Pharmatech Co Ltd
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Priority claimed from CN201410821405.1A external-priority patent/CN104961688A/zh
Priority claimed from CN201510019173.2A external-priority patent/CN105837518A/zh
Application filed by Crystal Pharmatech Co Ltd filed Critical Crystal Pharmatech Co Ltd
Publication of WO2016101912A1 publication Critical patent/WO2016101912A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids

Definitions

  • the present invention relates to the field of chemical and pharmaceutical crystal forms, in particular to N-(3-(2-(4-(4-acetylpiperazin-1-yl)-2-methoxyphenylamino)-5-(three)
  • the crystalline form of the salt of fluoromethyl)pyrimidin-4-ylamino)phenyl)acrylamide more particularly the crystalline form of the hydrobromide and phosphate, and the process for their preparation.
  • N-(3-(2-(4-(4-Acetylpiperazin-1-yl)-2-methoxyphenylamino)-5-(trifluoromethyl)pyrimidin-4-ylamino)benzene Base acrylamide) (aka CO1686), first developed by Clovis Oncology, is a novel oral, targeted covalent (irreversible) mutant third representative dermal growth factor receptor An inhibitor of (EGFR), capable of inhibiting key activating mutations and T790-resistant mutations, leaving the wild-type EGFR signal idle. This drug was developed for the treatment of patients with NSCLC who initially activated the EGFR mutation and the major resistance mutation T790M.
  • CO1686 is currently in clinical phase III and its structure is shown in formula (I):
  • patent WO2013138495 discloses crystal forms of various free bases of CO1686;
  • patent WO2013138502 discloses various crystalline forms of hydrobromide, wherein the form IV/V/VI/VII is a solvate, which is not suitable for medicinal use;
  • Form II is easily converted to Form I and has poor crystallinity;
  • Form VIII produces a gum after heating,
  • Form III is an unstable, amorphous form, which is readily converted to Form I.
  • Form I of the hydrobromide salt is a crystalline form that can be used for medicinal purposes, but the dose of the hydrobromide crystal form that is used clinically continues to climb, so further research and development is necessary to find a specific hydrobromic acid.
  • Salt form I Better performance, such as higher solubility, better stability, lower moisture leaching, new crystal forms of hydrobromide for storage and industrial production, and new salts and crystal forms to meet the subsequent development needs of the drug .
  • the inventors of the present invention conducted intensive studies and extensive screening of hydrobromide salts and other salts of the compounds of formula (I), and surprisingly, the inventors of the present invention have found compounds of formula (I) which are more suitable for drug development.
  • the novel crystal form of the invention has good stability, simple process, easy operation, suitable for storage and industrial production, and provides a new choice for the subsequent development of the drug.
  • a first object of the present invention is to provide five novel crystal forms of the hydrobromide salt of the compound of formula (I) and a process for the preparation thereof.
  • the present invention provides a novel crystalline form of a hydrobromide salt of a compound of formula (I), designated as hydrobromide crystal form A in the present invention.
  • the hydrobromide salt form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2theta (2 ⁇ ) values of 8.9 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 °, and 20.7 ° ⁇ 0.2 °.
  • hydrobromide crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 11.4° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 25.2° ⁇ 0.2°.
  • hydrobromide salt form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 24.5° ⁇ 0.2°, 26.1° ⁇ 0.2°, and 31.1° ⁇ 0.2°.
  • the hydrobromide salt form A provided by the present invention has an X-ray powder diffraction pattern with a 2 ⁇ value of 8.9 ° ⁇ 0.2 °, 11.4 ° ⁇ 0.2 °, 18.1 ° ⁇ 0.2 °, 18.5 ° ⁇ Characteristic peaks are present at 0.2°, 20.7° ⁇ 0.2°, 24.5° ⁇ 0.2°, 25.2° ⁇ 0.2°, 26.1° ⁇ 0.2°, and 31.1° ⁇ 0.2°.
  • the present invention provides Form A with an X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method of the hydrobromide salt crystal form A of the compound of the above formula (I), which comprises: hydrobromide salt of the compound of the formula (I) in a mixed solvent of an alcohol and a halogenated hydrocarbon, not higher than The mixture was stirred at 50 ° C and a solid was collected.
  • the alcohol solvent is preferably an alcohol
  • the halogenated hydrocarbon is preferably chloroform
  • the present invention provides another novel crystalline form of the hydrobromide salt of the compound of formula (I), designated as hydrobromide salt form B in the present invention.
  • the hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 8.2 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, and 22.2 ° ⁇ 0.2 °.
  • hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 10.1 ⁇ 0.2°, 18.2° ⁇ 0.2°, and 23.1° ⁇ 0.2°.
  • hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 21.2° ⁇ 0.2°, 24.7° ⁇ 0.2°, and 27.3° ⁇ 0.2°.
  • the hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern with a 2 ⁇ value of 8.2 ° ⁇ 0.2 °, 10.1 ° ⁇ 0.2 °, 15.9 ° ⁇ 0.2 °, 18.2 ° ⁇ There are characteristic peaks at 0.2°, 21.2° ⁇ 0.2°, 22.2° ⁇ 0.2°, 23.1° ⁇ 0.2°, 24.7° ⁇ 0.2°, and 27.3° ⁇ 0.2°.
  • the hydrobromide salt form B provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the hydrobromide salt form B provided by the present invention begins to have an endothermic peak near heating at 65 ° C, 108 ° C, and 228 ° C, respectively, and the differential scanning calorimetry diagram is substantially as Figure 3 shows.
  • the present invention also provides a process for preparing the hydrobromide salt form B of the compound of the above formula (I), which comprises stirring a hydrobromide salt of the compound of the formula (I) in a mixed solvent of an alcohol and an ether at room temperature. A solid can be obtained.
  • the alcohol solvent is preferably methanol
  • the ether solvent is preferably methyl tert-butyl ether.
  • the present invention provides another novel crystalline form of the hydrobromide salt of the compound of formula (I), which is designated herein as the hydrobromide salt form C.
  • the hydrobromide salt form C provided by the invention has an X-ray powder diffraction pattern with a 2 ⁇ value of 8.1° ⁇ 0.2°, There are characteristic peaks at 16.1 ° ⁇ 0.2 °, 24.8 ° ⁇ 0.2 °.
  • hydrobromide salt form C provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 10.4° ⁇ 0.2°, 20.3° ⁇ 0.2°, and 23.3° ⁇ 0.2°.
  • hydrobromide salt form C provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 13.3° ⁇ 0.2°, 14.7° ⁇ 0.2°, and 16.2° ⁇ 0.2°.
  • the hydrobromide salt form C provided by the present invention has an X-ray powder diffraction pattern with a 2 ⁇ value of 8.1 ° ⁇ 0.2 °, 10.4 ° ⁇ 0.2 °, 13.3 ° ⁇ 0.2 °, and 14.7 ° ⁇ There are characteristic peaks at 0.2°, 16.1° ⁇ 0.2°, 16.2° ⁇ 0.2°, 20.3° ⁇ 0.2°, 23.3° ⁇ 0.2°, and 24.8° ⁇ 0.2°.
  • the hydrobromide salt form C provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method of the hydrobromide salt form C of the compound of the formula (I), which comprises stirring the hydrobromide salt of the compound of the formula (I) in a mixed solvent of an alcohol and an ester at room temperature to collect a solid. , can be obtained by drying.
  • the alcohol solvent is preferably methanol
  • the ester solvent is preferably ethyl acetate
  • the present invention provides another novel crystalline form of the hydrobromide salt of the compound of formula (I), which is designated herein as the hydrobromide salt form D.
  • the hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 20.0° ⁇ 0.2°, 22.8° ⁇ 0.2°, and 24.5° ⁇ 0.2°.
  • hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 21.8° ⁇ 0.2°, 26.7° ⁇ 0.2°, and 7.8° ⁇ 0.2°.
  • hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern having a characteristic peak at a 2 ⁇ value of 11.7° ⁇ 0.2° and 12.6° ⁇ 0.2°.
  • the hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern with 2 ⁇ values of 20.0° ⁇ 0.2°, 22.8° ⁇ 0.2°, 24.5° ⁇ 0.2°, 21.8° ⁇ There are characteristic peaks at 0.2°, 26.7° ⁇ 0.2°, 7.8° ⁇ 0.2°, 11.7° ⁇ 0.2°, and 12.6° ⁇ 0.2°.
  • the hydrobromide salt form D provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method of the hydrobromide salt form D of the compound of the formula (I), which comprises the formula (I)
  • the compound and the hydrobromic acid solution are stirred and crystallized in a ratio of a certain molar ratio in a pure water at a low temperature of 0 to 10 ° C, and the solid is collected and dried.
  • reaction molar ratio of the compound of the formula (I) to hydrobromic acid is 1:1 to 1:2.
  • the present invention provides another novel crystalline form of the hydrobromide salt of the compound of formula (I), which is designated herein as the hydrobromide salt form E.
  • the hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 7.2 ° ⁇ 0.2 °, 12.2 ° ⁇ 0.2 °, and 21.7 ° ⁇ 0.2 °.
  • hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 14.5° ⁇ 0.2°, 23.1° ⁇ 0.2°, and 27.5° ⁇ 0.2°.
  • hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 13.9° ⁇ 0.2°, 19.3° ⁇ 0.2°, and 25.6° ⁇ 0.2°.
  • the hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern with a 2 ⁇ value of 7.2° ⁇ 0.2°, 12.2° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.5° ⁇ There are characteristic peaks at 0.2°, 19.3° ⁇ 0.2°, 21.7° ⁇ 0.2°, 23.1° ⁇ 0.2°, 25.6° ⁇ 0.2°, and 27.5° ⁇ 0.2°.
  • the hydrobromide salt form E provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the invention also provides a preparation method of the hydrobromide salt form E of the compound of the formula (I), which comprises the following steps: arranging and dephosphorizing the compound of the formula (I) and the hydrobromic acid solution in a molar ratio at a certain molar ratio; The solid is not dried.
  • reaction molar ratio of the compound of the formula (I) to hydrobromic acid is 1:1 to 1:2.
  • a second object of the present invention is to provide a phosphate, a new crystalline form of a phosphate of the compound of formula (I) and a process for the preparation thereof.
  • the invention provides a phosphate of a compound of formula (I).
  • the phosphate of the compound of the formula (I) provided by the present invention is in a crystalline form, and is referred to as a phosphate crystal form A in the present invention.
  • the phosphate crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 7.9 ° ⁇ 0.2 °, 22.4 ° ⁇ 0.2 °, and 25.6 ° ⁇ 0.2 °.
  • the phosphate crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 12.7° ⁇ 0.2°, 15.4° ⁇ 0.2°, and 21.3° ⁇ 0.2°.
  • the phosphate crystal form A provided by the present invention has an X-ray powder diffraction pattern having characteristic peaks at 2 ⁇ values of 18.3° ⁇ 0.2°, 20.8° ⁇ 0.2°, and 21.7° ⁇ 0.2°.
  • the present invention provides a phosphate crystal form A having an X-ray powder diffraction pattern having a 2 ⁇ value of 7.9° ⁇ 0.2°, 12.7° ⁇ 0.2°, 15.4° ⁇ 0.2°, and 18.3° ⁇ 0.2°. Characteristic peaks at 20.8° ⁇ 0.2°, 21.3° ⁇ 0.2°, 21.7° ⁇ 0.2°, 22.4° ⁇ 0.2°, and 25.6° ⁇ 0.2°.
  • the phosphate crystal form A provided by the present invention has an X-ray powder diffraction pattern substantially as shown in FIG.
  • the phosphate crystal form A provided by the present invention begins to exhibit an endothermic peak near heating to 192 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG.
  • the present invention provides a crystalline form A of phosphate having a weight loss gradient of about 0.9% when heated to 175 ° C, the thermogravimetric analysis of which is substantially as shown in FIG.
  • the present invention also provides a process for preparing a phosphate of the compound of the above formula (I), which comprises reacting a compound of the formula (I) with phosphoric acid in a ketone or ether solvent, and stirring and crystallization.
  • the ketone solvent is preferably acetone
  • the ether solvent is preferably tetrahydrofuran
  • reaction molar ratio of the compound of the formula (I) to phosphoric acid is 1:0.8 to 1:2.
  • a third object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the phosphate crystal form A of the compound of the formula (I) as an active ingredient or the hydrobromide crystal form A, B, C, D Or one or more of E is an active ingredient, and a pharmaceutically acceptable carrier/excipient.
  • a fourth object of the present invention is to provide a hydrobromide crystal form of the compound of the above formula (I), a phosphate and a crystal form thereof, and a pharmaceutical composition containing the above compound for the preparation of a medicament for treating cancer, particularly non-small cell lung cancer Use in.
  • hydrobromide crystal forms A, B, C, D, E have the following advantages:
  • the phosphate crystal form A of the compound of formula (I) provided by the present invention has the following advantages:
  • the phosphate crystal form A of the present invention has good stability
  • the phosphate form A of the present invention has a higher solubility, which greatly improves the bioavailability and drug efficacy of the drug, and is more suitable for clinical use. It is used in medicine and has a strong economic value.
  • Figure 1 is an XRPD pattern of the hydrobromide salt form A of the compound of formula (I).
  • Figure 2 is an XRPD pattern of the hydrobromide salt form B of the compound of formula (I).
  • Figure 3 is a DSC chart of the hydrobromide salt form B of the compound of formula (I).
  • Figure 4 is an XRPD pattern of the hydrobromide salt form C of the compound of formula (I).
  • Figure 5 is an XRPD pattern of the hydrobromide salt form D of the compound of formula (I).
  • Figure 6 is an XRPD overlay of the hydrobromide salt form D of the compound of formula (I) placed for 2 weeks; a reference chart of Form D from top to bottom, 5 ° C, 25 ° C / 60% RH and 40 ° C / XRPD pattern at 75% RH.
  • Figure 7 is an XRPD pattern of the hydrobromide salt form E of the compound of formula (I).
  • Figure 8 is an XRPD pattern of the crystalline form A of the compound of formula (I).
  • Figure 9 is a DSC chart of the crystalline form A of the compound of formula (I).
  • Figure 10 is a TGA diagram of the crystalline form A of the compound of formula (I).
  • Figure 11 is a 1 H NMR chart of the crystalline form A of the compound of the formula (I).
  • Figure 12 is a DVS diagram of the crystalline form A of the compound of formula (I).
  • Figure 13 is a DVS diagram of WO2013138502 hydrobromide salt form I.
  • Figure 14 is a 3-month stable XRPD stack of the crystalline form A of the compound of formula (I); XRPD reference chart of phosphate form A from top to bottom, phosphate form A at 5 ° C, 25 XRPD pattern at °C/60% RH and 40 °C / 75% RH.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the invention The method parameters of Differential Scanning Calorimetry (DSC) are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • the hydrobromic acid solution refers to a hydrobromic acid aqueous solution having a mass concentration of 40% obtained by a commercially available method.
  • hydrobromide salt of the compound of the formula (I) is prepared by the method of Example 7 of the patent WO2013138502.
  • the hydrobromide salt form D prepared in this example was placed at 5 ° C, 25 ° C / 60% RH, 40 ° C / 75% RH for 2 weeks, focusing on the stability of the crystal form, the test results are shown in Figure 6. (From top to bottom, the crystal form D reference, 5 ° C, 25 ° C / 60% RH, XRPD chart at 40 ° C / 75% RH). The results show that Form D has good stability.
  • the hydrobromide salt form D of the present invention and the sample of the known form VIII are respectively prepared into a saturated solution by using SGF (simulated artificial gastric juice), pH 6.5 FaSSIF (artificial intestinal juice under fasting state) and pure water, and known form I.
  • SGF simulated artificial gastric juice
  • pH 6.5 FaSSIF artificial intestinal juice under fasting state
  • pure water pure water
  • known form I pure water
  • the samples were prepared into a saturated solution by SGF (simulated artificial gastric juice), pH 6.5 FaSSIF (artificial intestinal juice under fasting conditions), and the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC) after 24 hours.
  • HPLC high performance liquid chromatography
  • the hydrobromide salt form D of the present invention has a higher solubility in SGF, FaSSIF, and pure water for 24 hours than that of the known form VIII.
  • the hydrobromide salt form D of the present invention has a higher 24-hour solubility in SGF and FaSSIF than the known form I.
  • the phosphate product prepared by the above method has the following 1 H NMR identification data as follows:
  • the solid obtained in this example was in the form of a crystal, designated as phosphate crystal form A, and its X-ray powder diffraction data is shown in Table 10. Its XRPD pattern in FIG. 8, DSC thereof is shown in Figure 9, which is a TGA graph in FIG. 10, FIG. 1 H NMR shown in Figure 11.
  • the phosphate crystal form A prepared in this example was placed at 5 ° C, 25 ° C / 60% RH, 40 ° C / 75% RH for 3 months, and the XRPD pattern was measured to investigate the stability of the crystal form. As shown in Figure 14.
  • the XRPD reference chart of the phosphate crystal form A is in order from the top to the bottom, and the phosphate crystal form A XRPD pattern at 5 ° C, 25 ° C / 60% RH, 40 ° C / 75% RH.
  • the solid obtained in this example was a phosphate crystal form A, and its X-ray powder diffraction data is shown in Table 11.
  • the phosphate of the compound of the formula (I) of the present invention (abbreviated as phosphate of the present invention) and the hydrobromide salt (abbreviated as known hydrobromide) disclosed in the patent WO2013138502, respectively, are FeSSIF (artificial intestinal juice under satiety state), water
  • the mixture was formulated into a saturated solution, and the content of the sample in the saturated solution was determined by high performance liquid chromatography after 1 hour and 4 hours.
  • the experimental results are shown in Table 12.
  • solubility of the phosphate of the present invention is significantly higher than that of the known hydrobromide salt after being placed in FeSSIF and water for 1 hour and 4 hours, respectively.
  • a dynamic moisture adsorption (DVS) test was carried out by taking 10 mg of the phosphate crystal form A of the present invention and the hydrobromide salt form I (abbreviated as known form I) disclosed in the patent WO2013138502, respectively.
  • the DVS of the phosphate form A of the present invention is shown in Figure 12, and the DVS of the patented hydrobromide form I is shown in Figure 13.

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Abstract

L'invention concerne une forme cristalline d'un sel d'un inhibiteur de kinase du récepteur du facteur de croissance épidermique et un procédé de préparation de celle-ci, et, en particulier, les formes cristallines d'un bromhydrate et d'un phosphate d'un composé de formule (I).
PCT/CN2015/098901 2014-12-25 2015-12-25 Forme cristalline d'un sel d'un inhibiteur de kinase du récepteur du facteur de croissance épidermique et son procédé de préparation Ceased WO2016101912A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN201410821405.1 2014-12-25
CN201410821405.1A CN104961688A (zh) 2014-12-25 2014-12-25 一种表皮生长因子受体激酶抑制剂的磷酸盐及其制备方法
CN201510019173.2A CN105837518A (zh) 2015-01-14 2015-01-14 一种表皮生长因子受体抑制剂的氢溴酸盐新晶型及其制备方法
CN201510019173.2 2015-01-14

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013138502A1 (fr) * 2012-03-15 2013-09-19 Celgene Avilomics Research, Inc. Sels d'inhibiteur de kinases du récepteur de facteur de croissance épidermique
WO2013138495A1 (fr) * 2012-03-15 2013-09-19 Celgene Avilomics Research, Inc. Formes solides d'un inhibiteur de kinases du récepteur du facteur de croissance épidermique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013138502A1 (fr) * 2012-03-15 2013-09-19 Celgene Avilomics Research, Inc. Sels d'inhibiteur de kinases du récepteur de facteur de croissance épidermique
WO2013138495A1 (fr) * 2012-03-15 2013-09-19 Celgene Avilomics Research, Inc. Formes solides d'un inhibiteur de kinases du récepteur du facteur de croissance épidermique

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