WO2015035531A1 - Forme cristalline du régorafénib, son procédé de préparation et son utilisation - Google Patents

Forme cristalline du régorafénib, son procédé de préparation et son utilisation Download PDF

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WO2015035531A1
WO2015035531A1 PCT/CN2013/001056 CN2013001056W WO2015035531A1 WO 2015035531 A1 WO2015035531 A1 WO 2015035531A1 CN 2013001056 W CN2013001056 W CN 2013001056W WO 2015035531 A1 WO2015035531 A1 WO 2015035531A1
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regorafenib
crystal form
soluble solvent
acid
hours
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PCT/CN2013/001056
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English (en)
Chinese (zh)
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宋小叶
劳海萍
盛晓霞
盛晓红
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杭州普晒医药科技有限公司
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Priority to CN201380052962.5A priority Critical patent/CN104736521B/zh
Priority to PCT/CN2013/001056 priority patent/WO2015035531A1/fr
Publication of WO2015035531A1 publication Critical patent/WO2015035531A1/fr

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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • 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

  • This application relates to the field of medicinal chemical crystallization technology.
  • it relates to a rifafenib salt and a crystalline form thereof, and to a process for the preparation of the regorafenib salt and a crystalline form thereof, a pharmaceutical composition thereof and use thereof.
  • Regfinini is an anti-cancer drug approved by the FDA on September 27, 2012. Regfinib is a multi-targeted tyrosine kinase inhibitor for the treatment of metastatic colorectal cancer.
  • the developer is Bayer Healthcare Pharmaceuticals.
  • the trade name is Stivarga, which is marketed as a monohydrate of regorafenib free base.
  • Patent document WO2008/043446 discloses resveripin monohydrate and its preparation method, and discloses its X-ray diffraction pattern (XRD), thermogravimetric analysis/difference scanning analysis (TGA/DSC), Raman spectroscopy, Characterization data of infrared optical (IR), near-infrared (NIR), far-infrared (FI) and 13C-solid-state nuclear magnetic resonance ( 13 C-NMR), the compound has a water content of 3.6% (weight) ).
  • XRD X-ray diffraction pattern
  • TGA/DSC thermogravimetric analysis/difference scanning analysis
  • Raman spectroscopy Raman spectroscopy
  • IR infrared optical
  • NIR near-infrared
  • FI far-infrared
  • Patent document WO2008/058644 discloses crystal form II of regorafenib and a preparation method thereof, the melting point of which is 181 ° C, TGA shows weight loss ⁇ 0.4%, and the advantage of crystal form II is that it is regia in water and organic solvent.
  • Non-Nickel Form I which has a melting point of 186 to 206 ° C, and TGA shows a weight loss of ⁇ 0.4%.
  • the document is also open Characterization data of XRD, TGA/DSC, Raman spectroscopy, IR, NIR, FIR and 13 C-NMR of Regefenib Form II and Form I.
  • Patent document WO2008/055629 discloses crystal form III of regorafenib and a preparation method thereof, which has a melting point of 141 ° C, TGA shows a weight loss of ⁇ 0.4%, and discloses XRD, TGA/DSC, Raman spectroscopy of Form III. Characterization data of IR, NIR, FIR and 13 C-NMR. The advantage of crystalline germanium is high solubility in water and organic solvents. In addition, this patent document also discloses the manner in which rifafenib monohydrate is converted to Form III.
  • Patent document WO 2013/000917 discloses the use of regorafenib and its hydrates, solvates and pharmaceutically acceptable salts or crystal forms thereof for the preparation of a medicament for the treatment of ophthalmic diseases, but does not disclose its pharmaceutically acceptable Preparation of salts or crystal forms or their characterization data.
  • the present inventors have found that the crystal forms of crystal form I, crystal form II, crystal form III and regorafenil monohydrate of rifafenib free base are both hydrophobic and have very poor solubility in water; Nitrobenzene sulfonate has poor solubilization effect in water; Reigefinoxime sulfonate has a weight change of about 7.2% in the range of 20% ⁇ 80% relative humidity, and is easy to absorb water; Regafinil hydrochloride does not absorb at high temperature Stable, after desolvation at 140 ° C, it will be converted to rifafenib free base.
  • the present application provides a rifafenib salt and a crystal form thereof, including regorafenib p-nonylbenzenesulfonate, regorafenib p-chlorobenzenesulfonate, regorafenib 1,5-naphthalene disulfonate , Regafinibethane disulfonate, regorafenib hydrobromide, regorafenibethane, regorafenil 2-naphthalene sulfonate and crystalline forms of these salts.
  • novel regorafenib salt and its crystalline form provided by the present application have one or more superior properties compared to known rifafenib salts and their crystalline forms.
  • Specific improved properties include, for example, higher crystallinity, solubility, dissolution rate, lower hygroscopicity, and better storage stability; in particular, the crystalline form of the regorafenib salt of the present application has favorable non-hygroscopicity. , solubility, good thermal stability and good storage stability.
  • one of the contents of the present application is to provide rifafenib p-nonylbenzenesulfonate and its crystal form, and a process for the preparation thereof.
  • the rifafenib-p-nonylbenzenesulfonate provided by the present application is a compound formed by a 1:1 molar ratio of regorafenib and p-nonylbenzenesulfonic acid, and has the following structural formula: o
  • the present application provides a method for preparing rifafenib-p-nonylbenzenesulfonate, the method comprising: respectively forming a solution system of regorafenib and p-nonylbenzenesulfonic acid in a soluble solvent, regorafenib and The molar ratio of p-nonylbenzenesulfonic acid is 1:1 ⁇ 1:2, and the two systems are mixed to form a suspension, and the solvent is removed to obtain the reggfenibene p-nonylbenzenesulfonate;
  • the solvent is an alcohol, an ester, a ketone, an ether or an alkane; preferably, the soluble NH solvent is removed by filtration.
  • the present application provides a crystalline form T of rifafenib-p-nonylbenzenesulfonate having an X-ray powder diffraction pattern of 4.5 ⁇ 0.2 at 2 Torr. 13.4 ⁇ 0.2. 18.1 ⁇ 0.2. 20.8 ⁇ 0.2. 21.9 ⁇ 0.2. And 23.0 ⁇ 0.2. There is a characteristic peak; further, its X-ray powder diffraction pattern is 4.5 ⁇ 0.2 at 2 ⁇ . , 11.0 ⁇ 0.2. , 11.5 ⁇ 0.2. 13.4 ⁇ 0.2°, 14.8 ⁇ 0.2°, 16.6 ⁇ 0.2°, 18.1 ⁇ 0.2°, 2N0 '.
  • the present application also provides a method for preparing the crystal form T of rifignin, p-nonylbenzenesulfonate, the method package Included: a solution system of rifignin and p-nonylbenzenesulfonic acid in a soluble solvent, respectively, the molar ratio of regorafenib to p-nonylbenzenesulfonic acid is 1: 1 ⁇ 1:2, mixing two The system forms a suspension which is crystallized at a temperature of from -10 ° C to 50 ° C to obtain the crystal form T.
  • the soluble solvent is preferably CH alcohol, C 4 -C 5 ester, C 3 -C 4 ketone, decyl tert-butyl ether or n-heptane; the concentration of the solution in the soluble solvent of regorafenib is preferably The solubility in the soluble solvent is 0.1 to 1 times, more preferably 0.5 to 1 times at the crystallization temperature; the concentration of the soluble solvent solution of the nonylbenzenesulfonic acid is preferably such that it is soluble at the crystallization temperature.
  • the solubility in the solvent is 0.5 to 1 times; the molar ratio of regorafenib to p-nonylbenzenesulfonic acid is preferably 1:1 to 1:1.5; preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 48 hours. More preferably, it is 1 to 10 hours.
  • one or more improved properties such as: better solubility, dissolution rate, lower Hygroscopicity, higher decomposition temperature and better storage stability.
  • the crystal form T weighs 0.04% in the range of 20% to 80% relative humidity, and the weight change is about 0.11 with respect to the regorafenib monohydrate and its crystal form (in the range of 20% to 80% relative humidity) %) is less hygroscopic;
  • the crystal form T is a flaky particle, which is larger than the regagirine monohydrate and its crystalline particles, and has good fluidity;
  • a second aspect of the present application is to provide rifafenib p-chlorobenzenesulfonate and its crystal form, and a process for the preparation thereof.
  • the rifafenib p-chlorobenzene sulfonate provided by the present application is regumble and p-chlorobenzene sulfonic acid.
  • a compound formed by a molar ratio of 1 : 1 has the following structural formula:
  • the present application provides a method for preparing rifafenib p-chlorobenzenesulfonate, the method comprising: separately forming a solution system of regorafenib and p-chlorobenzenesulfonic acid in a soluble solvent, regorafenib and p-chloro Benzenesulfonic acid
  • the molar ratio is 1:1 ⁇ 1:2, the two systems are mixed to form a suspension, and the solvent is removed to obtain the reggfene-p-chlorobenzenesulfonate;
  • the soluble solvent is an alcohol or an ester. , ketones, ethers and alkanes; preferably, the soluble solvent is removed by filtration.
  • the present application provides a crystalline form C of rifafenib p-chlorobenzenesulfonate having an X-ray powder diffraction pattern of 9.0 ⁇ 0.2 at 2 Torr. 9.9 ⁇ 0.2. 18.2 ⁇ 0.2. , 19.9 ⁇ 0.2. , 23. 1 ⁇ 0.2. And 27.4 ⁇ 0.2. There is a characteristic peak; further, the X-ray powder diffraction pattern is 9.0 ⁇ 0.2° and 9.9 ⁇ 0.2 at 2 ⁇ . 12.4 ⁇ 0.2.
  • the present application also provides a method for preparing the crystal form C of the rifafenib p-chlorobenzenesulfonate, the method comprising: respectively forming a solution system of regorafenib and p-chlorobenzenesulfonic acid in a soluble solvent, The molar ratio of gefenib and p-chlorobenzenesulfonic acid is 1:1 ⁇ 1:2, and the two systems are mixed to form a suspension, which is crystallized at a temperature of from -10 ° C to 50 ° C to obtain the crystal form C. .
  • the soluble solvent is preferably a C ⁇ CA alcohols, C 4 ⁇ C 5 esters, C 3 ⁇ C 4-one, Yue tert-butyl ether or n-heptane; concentration of soluble solvent solution is preferably regorafenib
  • concentration of soluble solvent solution is preferably regorafenib
  • the solubility in the soluble solvent is 0.1 to 1 times, more preferably 0.5 to 1 time at the crystallization temperature; the concentration of the soluble solvent solution of p-chlorobenzenesulfonic acid is preferably the soluble solvent at the crystallization temperature
  • the medium solubility is 0.5 to 1 times; the molar ratio of regorafenib to p-chlorobenzenesulfonic acid is preferably 1: 1 to 1: 1.5; preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 48 hours, It is preferably 1 to 10 hours.
  • the reggfenfenib p-chlorobenzene sulfonate and its crystal form C of the present application have one or more improvements. Characteristics such as higher solubility, dissolution rate, higher decomposition temperature and better storage stability.
  • a third aspect of the present application is to provide rifafenib 1,5-naphthalene disulfonate and a crystalline form thereof, and a process for the preparation thereof.
  • the regorafenib 1,5-naphthalenedisulfonate provided by the present application is a compound formed by a 2:1 molar ratio of regorafenib and 1,5-naphthalenedisulfonate, and has the following structural formula:
  • the present application provides a method for preparing the regorafenib 1,5-naphthalene disulfonate, comprising the steps of: respectively forming a solution system of regorafenib and 1,5-naphthalenedisulfonic acid in a soluble solvent;
  • the molar ratio of reguginib to 1,5-naphthalenedisulfonic acid is 1:1 to 2:1.
  • the two systems are mixed to form a suspension, and the solvent is removed to obtain the regorafenib 1,5-naphthalene disulfide.
  • the soluble solvent is an alcohol, an ester, a ketone, an ether or an alkane; preferably, the soluble solvent is removed by filtration.
  • the present application provides a crystalline form N of rifafenib 1,5-naphthalene disulfonate having an X-ray powder diffraction pattern of 7.3 ⁇ 0.2 °, 10.3 ⁇ 0.2 °, 12.8 ⁇ 0.2 °, 15.1 ⁇ 0.2 °, 18.8 at 2 Torr. Characteristic peaks at 0.2° and 26.1 ⁇ 0.2°; further, the X-ray powder diffraction pattern is 7.3 ⁇ 0.2 at 2 Torr. , 8.3 ⁇ 0.2. , 9.6 ⁇ 0.2.
  • the present application also provides a method for preparing the crystal form N of the rifafenib 1,5-naphthalene disulfonate, the method comprising: respectively forming a regent solvent of regorafenib and 1,5-naphthalenedisulfonic acid
  • the molar ratio of regorafenib to 1,5-naphthalenedisulfonic acid is 1: 1 ⁇ 2: 1, mixing two systems to form a suspension, at a temperature of -10 ° C to 50 ° C Crystallization is carried out to obtain the crystal form N.
  • the soluble solvent is preferably CH ⁇ alcohol, C 4 ⁇ C 5 ester, C K 4 ketone, decyl tert-butyl ether or n-heptane; the concentration of the soluble solvent solution of regorafenib is preferably The concentration of the soluble solvent solution in the soluble solvent at a crystallization temperature of 0.1 to 1 times, more preferably 0.5 to 1 times, of the 1,5-naphthalenedisulfonic acid is preferably at a crystallization temperature in a soluble solvent.
  • the molar ratio of regorafenib to 1,5-naphthalene disulfonic acid is preferably 2: 1.5 to 2: 1; preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 48. Hour, more preferably 1 to 10 hours.
  • the reggfenfenil 1,5-naphthalene disulfonate and its crystal form N of the present application have one or A variety of improved properties such as: higher solubility, dissolution rate, higher decomposition temperature and better storage stability.
  • the crystal form N of the Rifafenib 1,5-naphthalene disulfonate has the following beneficial effects:
  • the fourth content of the present application is to provide rifafenib ethanedisulfonate and its crystal form, and a preparation method thereof.
  • the retic ethanedisulfonate provided by the present application is a compound formed by a 2:1 molar ratio of regorafenib and ethanedisulfonate, and its structural formula
  • the present application provides a method for preparing the regorafenib sulphonate, comprising the steps of: respectively forming a solution system of regorafenib and ethanedisulfonic acid in a soluble solvent, regorafenib and ethanedisulfonate
  • the molar ratio of the acid is 1:1 to 2:1, and the two systems are mixed to form a suspension, and the solvent is removed to obtain the reggfenibene ethanedisulfonate;
  • the soluble solvent is an alcohol or an ester. , ketones, ethers or alkanes; preferably, the soluble solvent is removed by filtration.
  • the present application provides crystal form E of rifafenibethane disulfonate having an X-ray powder diffraction pattern of 10.6 ⁇ 0.2 at 2 Torr. 12.1 ⁇ 0.2. , 17.0 ⁇ 0.2. 18.1 ⁇ 0.2. 22.7 ⁇ 0.2. And 23.6. ⁇ 0.2.
  • X-ray powder diffraction pattern is 10.6 ⁇ 0.2 at 2 ⁇ . 12.1 ⁇ 0.2. 14.1 ⁇ 0.2. 15.8 ⁇ 0.2. 17.0 ⁇ 0.2. 18.1 ⁇ 0.2 °, 20.1 ⁇ 0.2 °, 21.3 ⁇ 0.2 °, 22.7 ⁇ 0.2 °, 23.6 ⁇ 0.2. 24.3 ⁇ 0.2. And 27.8 ⁇ 0.2.
  • the X-ray powder diffraction pattern is basically 2 ⁇ characteristic peaks and their relative intensities are as follows:
  • the present application also provides a method for preparing the crystal form E of regorafenib sulphonate, the method comprising: respectively forming a solution system of regorafenib and ethanedisulfonic acid in a soluble solvent, Regigo The molar ratio of nitrite to ethanedisulfonic acid is 1:1 to 2:1, and the two systems are mixed to form a suspension, which is crystallized at a temperature of -10 ° C to 50 ° C to obtain the crystal form E.
  • the soluble solvent is preferably a C ⁇ CA alcohols, C 4 ⁇ C 5 esters, C 3 ⁇ C 4-one, Yue tert-butyl ether or n-heptane; concentration of soluble solvent solution is preferably regorafenib
  • concentration of soluble solvent solution is preferably regorafenib
  • the solubility in the soluble solvent is 0.1 to 1 times, more preferably 0.5 to 1 time at the crystallization temperature; the concentration of the soluble solvent solution of ethanedisulfonic acid is preferably in the soluble solvent at the crystallization temperature 0.5 to 1 times the solubility, the molar ratio of regorafenib to ethanedisulfonic acid is preferably 2: 1.5 to 2: 1; preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 48 hours, more preferably 1 ⁇ 10 hours.
  • the regefefenil disulfonate and its crystal form E of the present application have one or more improvements. Properties such as: higher solubility, dissolution rate, higher decomposition temperature and better storage stability.
  • a fifth aspect of the present application is to provide a reggfinib hydrobromide salt and a crystal form thereof, and a process for the preparation thereof.
  • the regorafenib hydrobromide provided by the present application is a compound formed by the ratio of regorafenib and hydrobromide in a molar ratio of 1:1, and the structural formula is as follows:
  • the present application provides a preparation method of the reggfenfen hydrobromide, comprising the following steps: respectively forming a solution system of regorafenib and hydrobromic acid in a soluble solvent, and a molar ratio of regorafenib and hydrobromic acid The ratio is 1:1 to 1:2, and the two systems are mixed to form a suspension, and the solvent is removed to obtain the reggfenibine hydrobromide; preferably, the soluble solvent is an alcohol, a ketone or an alkane; The soluble solvent is removed by filtration.
  • the present application provides rifafenib hydrobromide crystal form HI having an X-ray powder diffraction pattern of 5.1 ⁇ 0.2 °, 10.1 ⁇ 0.2 °, 15.1 ⁇ 0.2 °, 18.2 ⁇ 0.2 °, 19.5 ⁇ 0.2 ° and 24.8.
  • the present application also provides a method for preparing the regentifene hydrobromide crystal form HI, the method comprising: respectively forming a solution system of regorafenib and hydrobromic acid in a soluble solvent, regorafenib and The molar ratio of hydrobromic acid is 1:1 to 1:2, and the two systems are mixed to form a suspension, which is crystallized at a temperature of -10 ° C to 50 ° C to obtain the crystal form H1.
  • the soluble solvent is preferably a Cr ⁇ C alcohol, a C 3 -C 4 ketone or n-heptane; a degree of 0.1 to 1 times, more preferably 0.5 to 1 times; a concentration of a soluble solvent solution of hydrobromic acid is preferably It has a solubility of 0.5 to 1 times in a soluble solvent at a crystallization temperature; a molar ratio of regorafenib to hydrobromide is preferred The ratio is 1:1 to 1:1.5; preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 48 hours, more preferably 1 to 10 hours.
  • the reggfenfen hydrobromide and its crystalline form m of the present application have one or more improved properties compared to the known regorafenib monohydrate and its crystalline form. For example: higher solubility, dissolution rate and better storage stability.
  • the present application provides a regent feneride hydrobromide crystal form H2 having an X-ray powder diffraction pattern of 20.6 ⁇ 0.2°, 12.0 ⁇ 0.2°, 16.8 ⁇ 0.2°, 19.2 ⁇ 0.2°, 21.3 ⁇ 0.2° and 24.4.
  • the characteristic peak at 0.2°; further, the X-ray powder diffraction pattern is 10.6 ⁇ 0.2 at 2 ⁇ . , 12.0 ⁇ 0.2. , 16.8 ⁇ 0.2. 17.0 ⁇ 0.2. , 18.9 ⁇ 0.2. 19.2 ⁇ 0.2. 20.2 ⁇ 0.2°, 20.5 ⁇ 0.2. 21.3 ⁇ 0.2°, 24.1 ⁇ 0.2. 24.4 ⁇ 0.2. , 25.7 ⁇ 0.2. And 26.5 ⁇ 0.2.
  • the present application provides a method for preparing the reggaefenic acid hydrobromide crystal form H2, the method comprising: forming a suspension of the ragefibrin hydrobromide crystal form m in a solvent, the suspension Crystallization was carried out at a temperature of -io °c ⁇ 50 °c to obtain the crystal form H2.
  • the solvent is selected from the group consisting of ethyl acetate, mercapto tert-butyl ether or a mixture thereof;
  • the amount of the rigafibrin hydrobromide crystal form HI is preferably 1.1 of its solubility in the solvent system at the crystallization temperature. It is preferably 20 times, more preferably 1.5 to 10 times; preferably, the crystallization temperature is room temperature, and the crystallization time is 1 to 72 hours, more preferably 1 to 10 hours.
  • the reggfenfen hydrobromide and its crystalline form H2 of the present application have one or more improved properties compared to the known regorafenib monohydrate and its crystalline form. For example: higher solubility, dissolution rate and better storage stability.
  • the Reggfenibine ethyl sulfonate form H2 has the following beneficial effects:
  • the sigroginib hydrobromide crystal form H2 is a homomorphic crystal of the sigroginib hydrobromide crystal form HI, the properties of which are substantially the same, have a higher decomposition temperature, in the dodecyl group In the presence of sodium sulphate (SDS), it has a better solubilizing effect relative to rifafinib monohydrate and its crystal form.
  • SDS sodium sulphate
  • a sixth aspect of the present application is to provide rifafenibethane sulfonate and a crystalline form thereof, and a process for the preparation thereof.
  • the rifafenibethane sulfonate provided by the present application is a compound formed by a 1:1 molar ratio of regorafenib and ethanesulfonate.
  • the present application provides a method for preparing the regorafenic acid ethyl sulfonate, comprising the steps of: respectively forming a solution system of regorafenib and ethanesulfonic acid in a soluble solvent, and a molar ratio of regorafenib and ethanesulfonic acid The ratio is 1:1 ⁇ 1:2, the two systems are mixed to form a suspension, and the solvent is removed to obtain the reggfenibine sulfonate; preferably, the soluble solvent is an ester, an alcohol or a ketone; Preferably, the soluble solvent is removed by filtration.
  • the present application provides a crystalline form of rifafenibethane sulfonate Etl having an X-ray powder diffraction pattern of 8.2 ⁇ 0.2 at 2 Torr. , 8.9 ⁇ 0.2. , 13.0 ⁇ 0.2. 18.8 ⁇ 0.2. 23.6 ⁇ 0.2. And 24.6 ⁇ 0.2.
  • the X-ray powder diffraction pattern is 8.2 ⁇ 0.2 °, 8.9 ⁇ 0.2 °, 12.2 ⁇ 0.2 °, 13.0 ⁇ 0.2 °, 14.4 ⁇ 0.2 °, 16.2 ⁇ 0.2 °, 17.9 ⁇ 0.2 °, 18.8 ⁇ 0.2 °, 20.1 ⁇ 0.2 °, 22.0 ⁇ 0.2. 23.6 ⁇ 0.2. And 24.6 ⁇ 0.2.
  • There are characteristic peaks; further, the 2 ⁇ characteristic peaks of the X-ray powder diffraction pattern and their relative intensities are as follows:
  • the present application also provides a method for preparing the regentinilethane sulfonate crystal form Etl, the method comprising: respectively forming a solution system of regorafenib and ethanesulfonic acid in a soluble solvent, regorafenib and The molar ratio of ethanesulfonic acid was 1:1 to 1:2, and the two systems were mixed to form a suspension, which was subjected to crystallization at a temperature of -10 ° C to 50 ° C to obtain the crystal form Etl.
  • the soluble solvent is preferably a Cr ⁇ C alcohol, a C 3 ⁇ C 4 ketone or a C 4 ⁇ C 5 ester; the concentration of the soluble solvent solution of regorafenib is preferably at a crystallization temperature in a soluble solvent.
  • the solubility is 0.1 to 1 times, more preferably 0.5 to 1 time; the concentration of the soluble solvent solution of ethanesulfonic acid is preferably 0.5 to 1 times the solubility in a soluble solvent at the crystallization temperature;
  • the molar ratio of ethanesulfonic acid is preferably 1:1 to 1:1.5; preferably, the crystallization temperature is room temperature, and the crystallization time is from 1 to 48 hours, more preferably from 1 to 10 hours.
  • the reggfenfenate salt of the present application and its crystal form Etl have one or more improved properties. For example, higher solubility, dissolution rate, higher decomposition temperature and better storage stability.
  • the present application provides a method for preparing the Riegfried Ethylsulfonate crystal form Et2, the method comprising: forming a suspension of the Reggfenibine ethyl sulfonate form Etl in a solvent, the suspension Crystallization was carried out at -10 ° C to 50 ° C to obtain the crystal form Et 2 .
  • the solvent is selected from the group consisting of mercapto tert-butyl ether, n-heptane or a mixture thereof; the amount of the reggfenibene ethyl sulfonate crystal form Etl is preferably 1.1 of the solubility in the solvent system at the crystallization temperature.
  • the crystallization temperature is room temperature
  • the crystallization time is 1 to 72 hours, more preferably 1 to 10 hours.
  • the reggfenfen hydrobromide and its crystal Et2 of the present application have one or more improved properties, For example: higher solubility, dissolution rate and better storage stability.
  • the reggfene ethanesulfonate crystal form Et2 has the following beneficial effects:
  • the sigroginib hydrobromide crystal form Et2 is a homomorphic crystal of the Reggfenib hydrobromide crystal form Etl, and the properties of the two are substantially the same, and have a higher decomposition temperature in the dodecyl group. In the presence of sodium sulphate (SDS), it has a better solubilizing effect relative to rifafinib monohydrate and its crystal form.
  • SDS sodium sulphate
  • the present application provides Regafinil 2-naphthalenesulfonate, which is formed by a ratio of 1 : 1 of regorafenib and 2-naphthalenesulfonic acid.
  • the crystal form of the Regfini-N-naphthalene sulfonate salt Na has an X-ray powder diffraction pattern of 4.7 ⁇ 0.2 at 2 Torr. , 13.7 ⁇ 0.2. , 16.4 ⁇ 0.2. , 18.0 ⁇ 0.2. 20.2 ⁇ 0.2. And 21.9 ⁇ 0.2.
  • the characteristic peak is further characterized by an X-ray powder diffraction pattern of 4.7 ⁇ 0.2 at 2 Torr. , 10.5 ⁇ 0.2.
  • the present application provides a method for preparing the Rifafinib 2-naphthalene sulfonate crystalline form Na, the method comprising: respectively forming a solution system of regorafenib and 2-naphthalenesulfonic acid in a soluble solvent, Regal The molar ratio of fenidazole to 2-naphthalenesulfonic acid is 1:1 ⁇ 1:2, the two systems are mixed, and the mixture is stirred at -10 ° C to 50 ° C to remove the soluble solvent, and the positive glucan is added. The alkane forms a suspension, and the suspension is crystallized at -10 ° C to 50 ° C to obtain the crystalline form Na.
  • the soluble solvent is preferably CH ⁇ alcohol, C 4 ⁇ C 5 ester, C 3 ⁇ C 4 ketone or decyl tert-butyl ether; the amount of regorafenib is preferably in a soluble solvent at the crystallization temperature Solubility
  • n-heptane is preferably used in an amount of 0.1 to 0.5 times that of the Regginib soluble solvent
  • 2-naphthalenesulfonic acid is preferably used in the crystallization temperature.
  • the solubility in the solvent is 0.5 to 1 times; the molar ratio of regorafenib to 2-naphthalenesulfonic acid is preferably 1:1 to 1:1.5; and the mixture is preferably stirred at room temperature for 1 minute to 48 hours, more preferably 1 to 10 hours; the suspension is preferably stirred at room temperature for 1 to 48 hours, more preferably 1 to 10 hours.
  • the Riegfried 2-naphthalene sulfonate crystalline form Na of the present application has one or more improved properties compared to the known regorafenib monohydrate and its crystalline form. For example: higher solubility, dissolution rate, higher decomposition temperature and better storage stability.
  • the crystal form Na of the Regfinene 2-naphthalene sulfonate has the following beneficial effects:
  • room temperature means a temperature of about 10 to 30 °C.
  • the stirring can be carried out by a conventional method in the art, such as magnetic stirring, mechanical stirring, etc., and the stirring speed is 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the removal of the solvent can be accomplished by conventional techniques in the art, such as filtration, centrifugation or evaporation.
  • the filtration is generally carried out at room temperature under a pressure of less than atmospheric pressure, preferably at a pressure of less than 0.09 MPa.
  • the specific operation of the centrifugation is as follows: The sample to be separated is placed in a centrifuge tube and centrifuged at a rate of 6000 rpm until the solids all sink to the bottom of the centrifuge tube.
  • the evaporation can be carried out at about 20 to 40 ° C under atmospheric pressure or under vacuum, or by evaporation with an inert gas stream.
  • the solvent removal step is carried out for suspension agitation, the solvent is preferably removed by filtration.
  • the various crystal forms obtained in the above methods can be further dried.
  • the drying can be carried out by conventional techniques in the art, such as drying at room temperature, drying by air or drying under reduced pressure, in a fume hood, a blast oven or a vacuum oven; it can be carried out under reduced pressure or without decompression, Preferably the pressure is less than
  • drying temperature is about 30 to 50 ° C; drying time is 10 to 72 hours, preferably 10 to 48 hours, more preferably 10 to 24 hours.
  • the volatilization is a crystallization mode used in the present application, and a solid is obtained by removing the solvent.
  • the evaporation apparatus used is, for example, a rotary evaporator, an evacuated evaporation system, a nitrogen-blowing type evaporation system, or a vortex vacuum evaporation system.
  • the ultrasound can promote dissolution of the sample by: placing the container containing the sample suspension in an ultrasonic cleaner, sonicating at a power of 20 Khz to 40 Khz for 1 to 30 minutes, preferably at 40 Khz for 5 minutes.
  • the starting material, regorafenide free base in the present application can be prepared by the method described in Example 1 of the patent document WO2005/009961, which is incorporated herein by reference.
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more of the Regafinil salts and crystalline forms thereof, and at least one pharmaceutically acceptable Accepted carrier.
  • the regorafenib salt and its crystal form are selected from the group consisting of rifafenib-p-nonylbenzenesulfonate, rifafenib-p-nonylbenzenesulfonate crystal form T, regorafenib p-chlorobenzenesulfonate Acid salt, rifafenib p-chlorobenzene sulfonate crystal form (, regorafenib 1,5-naphthalene disulfonate, regorafenib 1,5-naphthalene disulfonate crystal form N, Regal Non-niobetic acid disulfonate, rifafenib ethy
  • the carrier in the pharmaceutical composition includes sugars, cellulose and derivatives thereof, starch or modified starch, solid inorganic substances such as calcium phosphate, dicalcium phosphate, hydroxyl tracheite, calcium sulfate, calcium carbonate, semi-solid Such as lipid or paraffin, binders such as microcrystalline cellulose, ethyl cellulose, hydroxymethyl cellulose, hydroxypropyl decyl cellulose, hydroxyethyl cellulose, glidants such as colloidal silica, Light anhydrous silicic acid, crystalline cellulose, talc or magnesium stearate, disintegrating agents such as sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethyl cellulose, dried corn Starch, lubricants such as stearic acid, magnesium stearate, sodium stearyl fumarate, polyethylene glycol.
  • solid inorganic substances such as calcium phosphate, dicalcium phosphate, hydroxyl tracheite, calcium s
  • the pharmaceutically acceptable carrier in the pharmaceutical composition includes, but is not limited to, a diluent such as starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, tricalcium phosphate, Mannitol, sorbitol, sugar, etc.; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, copolyvidone, etc.
  • a diluent such as starch, modified starch, lactose, powdered cellulose, microcrystalline cellulose, anhydrous calcium hydrogen phosphate, tricalcium phosphate, Mannitol, sorbitol, sugar, etc.
  • binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, copo
  • a disintegrating agent such as starch, sodium carboxymethyl starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.
  • lubricant such as hard a fatty acid, magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.
  • a glidant such as colloidal silica
  • a complex forming agent such as various grades of cyclodextrin and a resin
  • a speed controlling agent such as hydroxypropylcellulose, hydroxydecylcellulose, hydroxypropylmethylcellulose, ethylcellulose, decylcellulose, decyl decyl acrylate, wax, and the like.
  • Other pharmaceutically acceptable carriers that may be used include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, viscosity modifiers, preservatives, antioxidants, and the like.
  • the pharmaceutical composition may be in a solid or liquid form, such as a solid oral dosage form, including tablets, granules, powders, pills, and capsules; liquid oral dosage forms, including solutions, syrups, suspensions, dispersions, and emulsions. Injectable preparations, including solutions, dispersions, and lyophilizates.
  • the formulation may be adapted for rapid release, delayed release or modified release of the active ingredient. It may be a conventional, dispersible, chewable, orally dissolved or rapidly melted formulation.
  • the administration route includes oral, intravenous, subcutaneous injection, transdermal administration, rectal administration, intranasal administration, sublingual administration and the like. Ready.
  • one or more of the Regfininines salts or crystalline forms thereof of the present application are mixed with one or more pharmaceutically acceptable carriers, optionally with one or more
  • the other pharmaceutically active ingredients are mixed.
  • the solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
  • the present application provides a reggfenibine salt of the present application or a crystalline form thereof, or a pharmaceutical composition comprising the above-described regorafenib salt or a crystalline form thereof, for the preparation of a medicament for the treatment and/or prevention of a hyperproliferative disorder Use, wherein the hyperproliferative disorder is selected from the group consisting of a solid tumor, a lymphoma, a sarcoma, a leukemia, a breast cancer, a respiratory cancer, a brain cancer, a genital cancer, a digestive tract cancer, a urinary tract cancer, an eye cancer, a liver cancer, a skin cancer, Head and neck cancer, squamous adenocarcinoma and/or parasitic adenocarcinoma, especially metastatic colorectal cancer.
  • the hyperproliferative disorder is selected from the group consisting of a solid tumor, a lymphoma, a sarcoma, a leukemia,
  • regorafenib salt and its crystal form are regorafenib-p-nonylbenzenesulfonate, regorafenib-p-nonylbenzenesulfonate crystal form T, regorafenib p-chlorobenzenesulfonate , regium fentanyl p-chlorobenzene sulfonate crystal form C, regorafenib 1,5-naphthalene disulfonate, regorafenib 1,5-naphthalene disulfonate N, regorafenib Sulfonate, regorafenib ethanesulfonate E, regorafenib hydrobromide, rigaginib hydrobromide Hl, reguginib hydrobromide H2, reguginib hydrobromide Acid salt, reguginibethane sulfonate, rifafeni
  • the present application provides a method of treating a hyperproliferative disorder comprising administering to a patient a therapeutically and/or prophylactically effective amount of one or more of the Regafinil salts of the present application or a crystalline form thereof or the foregoing comprising the present application a pharmaceutical composition of the gefini salt or a crystalline form thereof, wherein the reggfenibine salt and its crystalline form include, but are not limited to, regorafenib p-nonylbenzenesulfonate, regorafenib p-nonylbenzenesulfonate Acid crystal form T, regorafenib p-chlorobenzene sulfonate, regorafenib p-chlorobenzene sulfonate crystal form C, regorafenib 1,5-naphthalene disulfonate, regorafenil 1 , 5-naphthalenedisulfonate N, regor
  • Figure 1 is an XRPD pattern of regorafenib prepared according to Example 1 of WO2005/009961.
  • Figure 2 is an XRPD pattern of the crystalline form of regorafenib monohydrate.
  • Figure 3 is a PLM diagram of the crystalline form of regorafenib monohydrate.
  • Figure 4 is a TGA diagram of the crystalline form of regorafenib monohydrate.
  • Figure 5 is a DSC chart of the crystalline form of regorafenib monohydrate.
  • Figure 6 is an isothermal adsorption curve of the crystalline form of regorafenib monohydrate.
  • Figure 7 is an XRPD pattern of rifafenib versus mercaptobenzenesulfonate Form T.
  • Figure 8 is a PLM diagram of the crystal form T of rifigninib versus mercaptobenzenesulfonate.
  • Figure 9 is a TGA diagram of the crystal form T of rifigninib versus mercaptobenzenesulfonate.
  • Figure 10 is a DSC chart of the crystal form T of rifigninib versus mercaptobenzenesulfonate.
  • Figure 11 is an isotherm adsorption curve of rifafenib for the mercaptobenzene sulfonate form T.
  • Figure 12 is an XRPD pattern of rifafenib p-chlorobenzenesulfonate Form C.
  • Figure 13 is a PLM diagram of the crystal form C of rifafenib p-chlorobenzenesulfonate.
  • Figure 14 is a TGA diagram of the crystal form C of rifafenib p-chlorobenzenesulfonate.
  • Figure 15 is a DSC chart of the crystal form C of rifafenib p-chlorobenzenesulfonate.
  • Figure 16 is an isotherm adsorption curve of rifafenib p-chlorobenzenesulfonate crystal form C.
  • Figure 17 is an XRPD pattern of crystalline form N of 1,5-naphthalene disulfonate of regorafenib.
  • Figure 18 is a PLM diagram of the crystalline form N of 1,5-naphthalene disulfonate of regorafenib.
  • Figure 19 is a TGA diagram of crystal form N of 1,5-naphthalene disulfonate of regorafenib.
  • Figure 20 is a DSC chart of the crystalline form N of 1,5-naphthalene disulfonate of regorafenib.
  • Figure 21 is an isotherm adsorption curve of the crystalline form N of 1,5-naphthalene disulfonate of regorafenib.
  • Figure 22 is an XRPD pattern of the crystal form E of rifafenib ethylene disulfonate.
  • Figure 23 is a PLM diagram of crystal form E of regorafenibethane disulfonate.
  • Figure 24 is a TGA diagram of crystal form E of regorafenibethane disulfonate.
  • Figure 25 is a DSC chart of crystal form E of regorafenibethane disulfonate.
  • Figure 26 is an isotherm adsorption curve of crystal form E of regorafenibethane disulfonate.
  • Figure 27 is an XRPD pattern of the ergfinib hydrobromide crystal form HI.
  • Figure 28 is a PLM diagram of rifafenib hydrobromide crystal form HI.
  • Figure 29 is a TGA diagram of the geigerfinil hydrobromide crystal form HI.
  • Figure 30 is a DSC chart of the ergfinib hydrobromide crystal form HI.
  • Figure 31 is an isotherm adsorption curve for the HI of the rifafenib hydrobromide crystal form.
  • Figure 32 is an XRPD pattern of the Reggfenib Hydrobromide Form H2.
  • Figure 33 is an XRPD pattern of the rifafenibine salt form Etl.
  • Figure 34 is a PLM diagram of the rifafenibine salt form Etl.
  • Figure 35 is a TGA diagram of the rifafenibine salt form Etl.
  • Figure 36 is a DSC chart of the crystal form Erl of the rifafenibine sulfonate.
  • Figure 37 is an isotherm adsorption curve of the crystal form Etl of the rifafenibine sulfonate.
  • Figure 38 is an XRPD pattern of the rifafenibine salt form Et2.
  • Figure 39 is an XRPD pattern of the crystalline form Na of 2-naphthylsulfonate of regorafenib.
  • Figure 40 is a PLM diagram of the crystalline form Na of 2-naphthylsulfonate of regorafenib.
  • Figure 41 is a TGA diagram of the crystalline form Na of 2-naphthylsulfonate of regorafenib.
  • Figure 42 is a DSC chart of the crystalline form Na of 2-naphthylsulfonate of regorafenib.
  • Figure 43 is an isotherm adsorption curve of the crystalline form Na of 2-naphthylsulfonate of regorafenib. detailed description
  • X-ray powder diffraction ( XPRD )
  • the instrument used was a Bruker D8 Advance diffractometer with a Ka X-ray with a copper target wavelength of 1.54 nm, a 40 kV and 40 mA operating condition, a ⁇ -2 ⁇ goniometer, Mo single. Colorimeter, Lynxeye detector.
  • the instrument was tested with diamond sand before use.
  • the collection software is a Diffrac Plus XRD Commanded sample that is tested at room temperature and the sample to be tested is placed on a non-reflective sheet.
  • Detailed test conditions are as follows, angle range: 3-40 ° 2 ⁇ , step size: 0.02 ° 2 ⁇ , speed: 0.2 sec / step. Samples were not ground prior to testing unless otherwise stated.
  • the Polarized Light Microscope (PLM) spectrum is derived from a ⁇ -500 ⁇ polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.). Take a small amount of powder sample on the glass slide, add a small amount of mineral oil to better disperse the powder sample, cover the cover glass, and then place the sample on a ⁇ -500 ⁇ polarized light microscope (Shanghai Changfang Optical Instrument Co., Ltd.) On the stage, select the appropriate magnification to observe the shape of the sample and take a picture.
  • PLM Polarized Light Microscope
  • the differential thermal analysis (DSC) data is from the TA Instruments Q200 MDSC, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually take 1 - 10 mg of the sample and place it in an aluminum crucible with a punched hole (unless otherwise specified). The sample is raised from room temperature to a temperature of 10 ° C / min under the protection of 50 ml / min dry N 2 . At 200 °C or 300 °C, the TA software records the change in heat during the temperature rise of the sample. In the present invention, the melting point is reported as the starting temperature.
  • thermogravimetric analysis (TGA) data is from the TA Instruments Q500 TGA, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis. Usually 5-15 mg of the sample is placed in a platinum crucible, and the sample is lifted from room temperature to a temperature of 10 ° C / min under the protection of 50 ml / min dry N 2 at a temperature increase rate of 10 ° C / min. At 300 °C, the TA software records the change in weight of the sample during the heating process.
  • the dynamic moisture adsorption analysis (DVS) data is from the TA Instruments Q5000 TGA, the instrument control software is Thermal Advantage, and the analysis software is Universal Analysis.
  • the TA software records the sample.
  • the isothermal adsorption curve is plotted for the change in weight during the change in relative humidity from 0% to 80% to 0%. Depending on the sample, different adsorption and desorption steps are applied to the sample.
  • Nuclear magnetic analysis (ifiNMR) data was obtained from Bruker Ascend Tm 500. Usually use full frequency excitation, 30PPM, single pulse, 30. Angle excitation, scanning 16 times, digital orthogonal detection, temperature control 298K:.
  • the HPLC analysis data is from the Agilent 1260, the instrument control software is Agilent ChemStation B.04 online, and the analysis software is Agilent ChemStation B.04 offline. ⁇ C18 column, 150mm*4.6mm, column temperature 25 °C, wavelength 220nm, flow rate 1.3ml/min, injection volume 5ul, running time 15min.
  • Mobile phase A is water with 0.05% TFA and mobile phase B is acetonitrile.
  • the gradient is as follows:
  • the temperature in the examples is room temperature unless otherwise specified.
  • Example 1 The prepared sample was substantially identical to the X-ray powder diffraction pattern of Reggfenib Form I disclosed in WO2008/058644.
  • the X-ray powder diffraction pattern is shown in Figure 2.
  • the X-ray powder diffraction pattern of the regorafenib monohydrate disclosed in WO 2008/043446 is substantially the same.
  • the PLM map is shown in Figure 3. Display: Small rod crystals.
  • the TGA map is shown in Figure 4. Display: 4.3% weight loss before 150 °C, decomposition temperature is 211 °C.
  • the X-ray powder diffraction pattern is shown in Fig. 7.
  • the PLM map is shown in Figure 8.
  • the TGA map is shown in Figure 9. Display: Form T decomposition temperature is 238 °C.
  • the isothermal adsorption curve is shown in Figure 11. Display: 20% RH ⁇ 80% RH weight change is 0.04%.
  • the crystal form T is very stable at high temperature, is not easy to absorb moisture, and has a good morphology.
  • the regorafenide prepared in Example 1 was placed in a 50 ml glass bottle, and 28 ml of hydrazine was added. Ultrasonic dissolution after alcohol; weigh 0.45g p-nonylbenzenesulfonic acid in another 20ml glass bottle, add 6ml sterol and ultrasonically dissolve; add decyl benzenesulfonic acid sterol solution to the mixture under stirring After stirring at room temperature for 1 hour, a white solid was precipitated and filtered, decyl alcohol was washed three times, and vacuum dried at 50 ° C for 10 hours to obtain a crystal form of rifafenib-nonylbenzenesulfonate. T. The yield was 1.24 g and the yield was 90.5%.
  • Example 1 1. OOg of the rifafinib prepared in Example 1 was placed in a 250 ml round bottom flask, and 120 ml of ethyl acetate was added thereto, followed by ultrasonic dissolution; 0.54 g of p-nonylbenzenesulfonic acid was weighed into another 20 ml glass vial, After adding 10 ml of ethyl acetate, the solution was sonicated; under stirring, the ethyl acetate solution of p-nonylbenzenesulfonic acid was added to the solution of rigaginib in ethyl acetate, and after stirring at room temperature for 5 hours, a white solid precipitated.
  • Example 14 1.70 g of the Riegfried prepared in Example 1 was weighed into a 100 ml round bottom flask, and dissolved by adding 60 ml of sec-butanol at 50 ° C; 0.68 g of p-chlorobenzenesulfonic acid was weighed into another 100 ml flask, and added. 2 ml of sec-butanol was sonicated; after stirring, a solution of sigroginib in sec-butanol was added dropwise to a solution of p-chlorobenzenesulfonic acid in sec-butanol, and after stirring at 50 ° C for 1 hour, a white solid precipitated.
  • the X-ray powder diffraction pattern is shown in Fig. 12.
  • the PLM map is shown in Figure 13.
  • the TGA map is shown in Figure 14.
  • the isothermal adsorption curve is shown in Figure 16. Display: 20% RH ⁇ 80% RH weight change is 0.38%. HPLC characterization showed that regorafenib and p-chlorobenzenesulfonic acid were salted at a molar ratio of 1:1.
  • the ethyl acetate was washed three times and dried under vacuum at 40 ° C for 10 hours to obtain the crystal form C of the sigroginib p-chlorobenzenesulfonate.
  • the yield was 1.21 g, and the yield was 85.6%.
  • Example 22 Weighed 1.OOg of the rifafinib prepared in Example 1 in a 150 ml round bottom flask, and dissolved in 75 ml of butanone; weighed 0.40 g of p-chlorobenzenesulfonic acid in another 150 ml flask, and added 6 ml of methyl ethyl ketone. Ultrasonic solution; Under stirring, the solution of rifafenib in methyl ethyl ketone was added dropwise to the solution of p-chlorobenzenesulfonic acid in methyl ethyl ketone. After stirring at -10 ° C for 7 hours, a white solid precipitated and stirring was continued for 41 hours.
  • the X-ray powder diffraction pattern is shown in Fig. 17.
  • Display Regentinol 1,5-naphthalene disulfonate crystal form ⁇ PLM map shown in Figure 18.
  • the TGA map is shown in Figure 19.
  • the isothermal adsorption curve is shown in Figure 21. Display: 20% RH ⁇ 80% RH weight change is 3.77%. HPLC characterization showed that regorafenib and 1,5-naphthalenedisulfonic acid were salted in a 2:1 molar ratio.
  • the decyl alcohol was washed three times and dried under vacuum at 40 ° C for 16 hours to obtain a crystal form N of repaginib 1,5-naphthalene disulfonate.
  • the yield was 1.09 g, and the yield was 83.1%.
  • HPLC characterization showed that regorafenib and ethanedisulfonic acid were salted at a molar ratio of 2:1.
  • the PLM map is shown in Figure 23. Display: Small particle crystals.
  • the TGA map is shown in Figure 24. Display: Form E loses 1.12% before 150 °C and decomposes at 234 °C.
  • the isothermal adsorption curve is shown in Fig. 26. Display: 20% RH ⁇ 80% RH weight change is 0.89%.
  • HPLC characterization showed that regorafenib and ethanedisulfonic acid were salted at a molar ratio of 2:1.
  • the regorafenide prepared in Example 1 was dissolved in a 150 ml round bottom flask and dissolved in 60 ml of acetone; 0.26 g of ethanedisulfonic acid was weighed into another 20 ml glass vial, and 8 ml of acetone was added for ultrasonic dissolution. Under stirring, the acetone solution of ethanedisulfonic acid was added to the acetone solution of rifafenib. After stirring at room temperature for 1 hour, a white solid was precipitated. After stirring for 1 hour, it was filtered, washed three times with acetone, and dried at 40 ° C under vacuum. After 16 hours, the form E of rifafenibethane disulfonate was obtained. The yield was 1.15 g, and the yield was 95.1%.
  • the regorafenide prepared in Example 1 was dissolved in a 1 L round bottom flask, and 450 ml of decyl tert-butyl ether was added to dissolve; 0.20 g of ethanedisulfonic acid was weighed into another 20 ml glass vial, and added. 6ml of decyl-tert-butyl ether was sonicated; after stirring, the solution of decyl-tert-butyl ether of ethanedisulfonic acid was added to the solution of sagel tert-butyl ether of regorafenib, and stirred at -10 °C.
  • Fig. 27 The X-ray powder diffraction pattern is shown in Fig. 27. Display: Regafinib hydrobromide crystal form Hl.
  • the PLM map is shown in Figure 28. Display: Small particle crystals.
  • the TGA graphic is shown in Figure 29. Display: Crystal form HI loses 10.47% before 150 °C, and the decomposition temperature is 216 °C.
  • the DSC spectrum is shown in Figure 30. Display: Form HI begins to melt and decompose at 172 °C.
  • the isothermal adsorption curve is shown in Figure 31. Display: 20% RH ⁇ 80% RH weight change is 1.57%. HPLC characterization showed that regorafenib and hydrobromic acid were salted at a molar ratio of 1:1.
  • Example 50 Weighed 1.OOg Example 1 prepared rifafinib in a 250 ml round bottom flask, added 180 ml of isopropanol and sonicated; weighed 0.42 g of hydrobromic acid (concentration of 40% by weight) to another In a 250 ml flask, 8 ml of isopropanol was added and ultrasonically dissolved; under stirring, a solution of regorafenib in isopropanol was added dropwise to a solution of hydrobromic acid in isopropanol, and stirred at 50 ° C for 1 hour to precipitate white. The solid was filtered, washed with isopropyl alcohol three times, and dried under vacuum at 30 ° C for 72 hours to obtain 1.07 g of sig-fibene hydrogen bromide crystal form HI with a yield of 91.6%.
  • the solid was precipitated, and after stirring for further 38 hours, it was filtered, washed three times with n-heptane, and dried under vacuum at 50 ° C for 10 hours to obtain a sig-fibene hydrogen bromide crystal form H1.
  • the yield was 0.80 g, and the yield was 67.2%.
  • rigaginib hydrobromide crystal form HI prepared in Example 49 was placed in a 50 ml glass vial, and 20 ml of ethyl acetate was added. After stirring at room temperature for 72 hours, filtration and vacuum drying at 40 ° C for 10 hours, 0.30 g of a white solid was obtained with a yield of 96.8%.
  • Fig. 32 The X-ray powder diffraction pattern is shown in Fig. 32. Display: Regafinil hydrobromide crystal form H2.
  • Example 56 The ethyl acetate in Example 56 was replaced with mercapto tert-butyl ether, and the other operation was the same as in Example 56 to obtain the crystals of the sig-fibene hydrogen bromide, H2, yield 0.29 g, yield 93.5%.
  • HPLC characterization showed that regorafenib and ethanesulfonic acid were salted at a molar ratio of 1:1.
  • the mixture was further stirred for 1 hour, filtered, and washed with decyl-tert-butyl ether three times, and vacuum-dried at 40 ° C for 10 hours to obtain a yield of 1.12 g of repellamide, and a yield of 70.2%.
  • the X-ray powder diffraction pattern is shown in Fig. 33.
  • the PLM map is shown in Figure 34.
  • the TGA graphic is shown in Figure 35. Display: Form Etl loses 0.45% before 150 °C and decomposes at 224 °C.
  • the isothermal adsorption curve is shown in Figure 37. Display: 20% RH ⁇ 80% RH weight change is 0.54%. HPLC characterization showed that regorafenib and ethanesulfonic acid were salted at a molar ratio of 1:1.
  • the regorafenide free base prepared in Example 1 was placed in a 250 ml round bottom flask, and dissolved in 120 ml of ethyl acetate, and sonicated; 0.23 g of ethanesulfonic acid was weighed into another 250 ml flask.
  • the regorafenide free base prepared in Example 1 was placed in a 50 ml round bottom flask, and ultrasonically dissolved after adding 25 ml of ethanol; 0.46 g of ethanesulfonic acid was weighed into another 5 ml glass vial, and added. 2ml ethanol was sonicated; under stirring, the ethanol solution of ethanesulfonic acid was added dropwise to the ethanol solution of rifafenib. After stirring at room temperature for 5 hours, a white solid precipitated. After stirring for 1 hour, it was filtered and washed three times with ethanol. Drying at 40 ° C for 72 hours under vacuum gave a regentinil ethyl sulfonate crystal form Etl. The yield was 1.19 g, and the yield was 95.9%.
  • the regorafenide free base prepared in Example 1 was placed in a 500 ml round bottom flask, and ultrasonically dissolved after adding 215 ml of n-butanol; 0.35 g of ethanesulfonic acid was weighed into another 5 ml glass vial. Add 3 ml of n-butanol to dissolve ultrasonically; add n-butanol solution of ethanesulfonic acid to the n-butanol solution of rifafenib under stirring, and stir at 50 ° C for 15 hours to precipitate a white solid.
  • the regorafenide free base prepared in Example 1 was placed in a 250 ml round bottom flask, and dissolved in 120 ml of acetone, and sonicated; 0.24 g of ethanesulfonic acid was weighed into another 5 ml glass vial, and added. 4ml acetone was sonicated; under stirring, the acetone solution of ethanesulfonic acid was added dropwise to the acetone solution of rifafenib, and stirred at -10 °C for 2 hours, and a white solid was precipitated. After stirring for 46 hours, the mixture was filtered. The mixture was washed three times and dried under vacuum at 40 ° C for 10 hours to obtain a crystal form of reggfene ethanesulfonate. The yield was 1.15 g, and the yield was 92.7%.
  • Example 69 The mercapto tert-butyl ether of Example 67 was replaced with n-heptane, and the other operation was the same as that of Example 67 to obtain the crystals of the sig-fibene dimethanesulfonate form Et2, yield 0.31 g, yield 93.9%.
  • Example 69 The mercapto tert-butyl ether of Example 67 was replaced with n-heptane, and the other operation was the same as that of Example 67 to obtain the crystals of the sig-fibene dimethanesulfonate form Et2, yield 0.31 g, yield 93.9%.
  • Example 69 The mercapto tert-butyl ether of Example 67 was replaced with n-heptane, and the other operation was the same as that of Example 67 to obtain the crystals of the sig-fibene dimethanesulfonate form Et2, yield 0.31 g, yield 93.9%.
  • the X-ray powder diffraction pattern is shown in Figure 39.
  • the PLM map is shown in Figure 40.
  • the TGA map is shown in Figure 41. Display: Form Na is at a decomposition temperature of 235 °C.
  • the isothermal adsorption curve is shown in Figure 43. Display: 20% RH ⁇ 80% RH weight change is 0.26%. HPLC characterization showed that regorafenib and 2-naphthalenesulfonic acid were salted at a molar ratio of 1:1.
  • the regorafenide free base prepared in Example 1 was placed in a 250 ml round bottom flask and dissolved in 120 ml of ethyl acetate; 0.44 g of 2-naphthalenesulfonic acid was weighed into another 5 ml glass vial. Add 4ml of ethyl acetate to dissolve in the ultrasonic solution; add 2-ethyl naphthalenesulfonic acid in ethyl acetate solution to the ethyl acetate solution of regorafenib, stir at -10 ° C for 1 hour, and quickly evaporate and remove the solvent.
  • the white solid was immediately precipitated by adding 24 ml of n-heptane, and the mixture was stirred at room temperature for 1 hour, filtered, washed three times with ethyl acetate, and dried under vacuum at 40 ° C for 72 hours to obtain the Na-naphthalenesulfonate salt Na of rifafinib.
  • the yield was 1.28 g, and the yield was 88.5%.
  • the regorafenide free base prepared in Example 1 was placed in a 1 L round bottom flask and dissolved in 450 ml of decyl tert-butyl ether; 0.44 g of 2-naphthalenesulfonic acid was weighed into another 5 ml of glass.
  • 4 ml of decyl tert-butyl ether was added to dissolve ultrasonically; a solution of 2-naphthylsulfonic acid in decyl tert-butyl ether was added dropwise to the solution of sagel tert-butyl ether in rifafenib, and stirred at room temperature.
  • T-form of the invention the T-form of rifafenib-p-toluenesulfonate
  • Pluronic F-68 and adjust the pH as needed (H is adjusted to a small dose between 4-9, the large dose is as close as possible to the pH of normal human blood).
  • Dosage of sterile IV solution Dilute the above sterile IV solution to 2 mg with 5 % sterile dextrose
  • lyophilized powder Preparation of lyophilized powder: (i) 135-1350 mg of the lyophilized powder form of the T crystal form of the regium fentanyl p-nonylbenzene sulfonate, dissolved in an appropriate amount of water for injection, sterile filtration, Packed in amps, sealed after lyophilization, and checked for leaks.
  • Intravenous administration of lyophilized powder The lyophilized powder of the above-mentioned T-formed regorafenib-nonylbenzenesulfonate is reconstituted with sterile water for injection or 5% dextrose to a concentration of 21 mg/ml. Further, it was diluted with physiological saline or 5% dextrose into a 0.5 mg/ml solution, and administered by intravenous bolus or intravenous infusion for 15-60 minutes.
  • Rigginib 1,5-naphthalene disulfonate E crystal form regorafenib disulfonate, HI crystal form regorafenib hydrobromide, H2 crystal form regorafenib hydrobromide Salt, Etl crystal form of regorafenibine, Et2 crystal form of regorafenibine crystal form and Na crystal form of regorafenib 2-naphthalene sulfonate, in various salt forms in the formulation
  • the molar amount of the free base and the free base in the p-nonylbenzenesulfonate was the same, and the total amount of the filler and the salt form in the various salt formulations was the same as in Example 96, and the same operation as in Example 96.
  • the capsule particles were prepared by filling a conventional two-piece hard capsule. 100 mg of the powdered active ingredient regorafenib (ie 135 mg of the T-form of the invention, reguginib-nonylbenzenesulfonate) is mixed with 150 mg of lactose and 50 mg of cellulose, and then 6 mg of hard is added. Magnesium citrate, mixed and filled with capsules, that is. Examples 107-114
  • Rigginib 1,5-naphthalene disulfonate E crystal form regorafenib disulfonate, HI crystal form regorafenib hydrobromide, H2 crystal form regorafenib hydrobromide Salt, Etl crystal form of regorafenibine, Et2 crystal form of regorafenibine crystal form and Na crystal form of regorafenib 2-naphthalene sulfonate, in various salt forms in the formulation
  • the molar amount of the free base and the free base in the p-nonylbenzenesulfonate was the same, and the total amount of the filler and the salt form in the various salt formulations was the same as in Example 106, and the same operation as in Example 106.
  • Preparation of soft gelatin capsule Add gelatin, glycerin, preservative to water, stir and heat to about 80 °C to form a transparent glue. Add a light-proofing agent, coloring agent, etc. to the glue. The glue is kept at 60 ° C, and is ready for use; the T-form of the invention is prepared by adding the T-form of sigroginib to the terpene benzene sulfonate in vegetable oil such as soybean oil, cottonseed oil or olive oil, and uniformly forming the mixture.
  • the content of the suspension active soft gelatin of gramage active ingredient regorafenib (ie 135mgT crystal form reguginib p-nonylbenzene sulfonate); also can be used to convert T crystal form regomafenib to decyl benzene sulfonic acid
  • the salt is dissolved in a water-soluble liquid diluent such as polyethylene glycol to form a transparent water-soluble soft capsule content; the glue and the soft capsule content are input into the soft capsule by a pump to press the soft capsule. After the plastic bottle is dried and cleaned, it can meet the required soft plastic bottle.
  • a water-soluble liquid diluent such as polyethylene glycol
  • Preparation of tablets A large number of tablets were prepared by a conventional process. 100 mg of the active ingredient regorafenib (ie 135 mg of the T-form of the invention, reguginib p-nonylbenzenesulfonate), 98.8 mg of lactose, 11 mg of starch, 2 mg of sodium carboxymethyl starch and 275 mg
  • the microcrystalline cellulose is mixed in a mixer, granulated with water as a wetting agent, the wet granules are dried in an oven to a moisture content below 3%, and 2 mg of sodium carboxymethyl starch and 5 mg of stearin are added to the back dry granules.
  • Magnesium acid evenly mixed, determine the main drug component in the granules, determine the tablet weight, and compress. Examples 125-132
  • the molar amount of the free base in the free base and the p-nonylbenzenesulfonate was the same, and the total amount of the filler and the salt form in the various salt formulations was the same as in Example 133, and the same operation as in Example 133.
  • the weight change in the relative humidity range of 20%-80% RH is obtained by DVS detection.
  • Decomposition temperature comparison Obtained by TGA detection.
  • Morphology comparison Obtained by PLM detection.
  • Solubility comparison ⁇ was solubilized with sodium dodecylbenzene sulfonate in combination with HPLC detection. Take lOmg sample and 50mg sodium dodecylbenzene sulfonate in 20ml glass bottle, add 15ml deionized water, 40K z ultrasonic working power ultrasonic for 60min, sample and filter and dilute to 5ml volumetric flask, remove water, use The volume of acetonitrile was adjusted and the concentration was determined by HPLC. The results are shown in Table 1. Table 1 Comparison of performance of different grades of regorafenib

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Abstract

La présente invention concerne un nouveau sel de régorafénib et sa forme cristalline. Par rapport à un monohydrate de régorafénib existant et une forme cristalline de celui-ci, le sel de régorafénib et sa forme cristalline selon la présente invention présentent une ou plusieurs caractéristiques modifiées. L'invention concerne en outre des procédés de préparation du sel de régorafénib et de sa forme cristalline, une composition pharmaceutique le contenant et son utilisation dans la préparation d'un médicament destiné à traiter le cancer colorectal métastatique.
PCT/CN2013/001056 2013-09-12 2013-09-12 Forme cristalline du régorafénib, son procédé de préparation et son utilisation WO2015035531A1 (fr)

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CN1856469A (zh) * 2003-07-23 2006-11-01 拜尔医药品股份有限公司 用于治疗和预防疾病和疾病症状的氟代ω－羧芳基二苯基脲
EP2548867A1 (fr) * 2010-03-18 2013-01-23 Suzhou Zelgen Biopharmaceutical Co., Ltd. Procédé de préparation de diphénylurée deutérée

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EP2595628A1 (fr) * 2010-07-19 2013-05-29 Bayer HealthCare LLC Associations médicamenteuses contenant une oméga-carboxyaryl diphénylurée fluorosubstituée utilisées pour le traitement et la prévention de maladies et d'affections

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CN1856469A (zh) * 2003-07-23 2006-11-01 拜尔医药品股份有限公司 用于治疗和预防疾病和疾病症状的氟代ω－羧芳基二苯基脲
EP2548867A1 (fr) * 2010-03-18 2013-01-23 Suzhou Zelgen Biopharmaceutical Co., Ltd. Procédé de préparation de diphénylurée deutérée

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