WO2015054804A1 - Forme solide d'enzalutamide, procédé de préparation et utilisation associée - Google Patents

Forme solide d'enzalutamide, procédé de préparation et utilisation associée Download PDF

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Publication number
WO2015054804A1
WO2015054804A1 PCT/CN2013/001235 CN2013001235W WO2015054804A1 WO 2015054804 A1 WO2015054804 A1 WO 2015054804A1 CN 2013001235 W CN2013001235 W CN 2013001235W WO 2015054804 A1 WO2015054804 A1 WO 2015054804A1
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Prior art keywords
enzalutamide
amorphous
solvent
solution
group
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PCT/CN2013/001235
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English (en)
Chinese (zh)
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沈涛
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 CN201380075784.8A priority Critical patent/CN105188699B/zh
Priority to CN201610953259.7A priority patent/CN106543085A/zh
Priority to PCT/CN2013/001235 priority patent/WO2015054804A1/fr
Publication of WO2015054804A1 publication Critical patent/WO2015054804A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to the field of medicinal chemical crystallization technology.
  • it relates to a novel solid form of enzalutamide, as well as a process for the preparation of the novel solid form, pharmaceutical compositions thereof and uses thereof.
  • Background technique
  • enzalutamide is 4- ⁇ 3-[4-cyano-3-(trifluoromethyl)phenyl] 5,5-dimercapto- 4 -oxo-2-thioimidazolidine- 1-yl ⁇ -2 fluoro-N-mercaptobenzamide, English name Enzalutamide, also known as MDV-3100, molecular formula C l H l6 F 4 N 4 0 2 S, the chemical structural formula is as follows:
  • Enzauramide is an androgen receptor antagonist developed by Medivation and Astdlas Pharma. August 31, 2012, approved by the US Food and Drug Administration (FDA) for the treatment of advanced (metastatic) castration-resistant prostate cancer that has spread or relapsed, even if the patient has previously received too much paclitaxel chemotherapy or reduced testosterone Drug or surgical treatment.
  • FDA US Food and Drug Administration
  • the trade name of enzalutamide is Xtandi
  • the dosage form is oral gelatin soft gelatin.
  • the specification is 40 mg.
  • the recommended dose is 160 mg once a day.
  • the study showed that the median overall survival of patients receiving Xtandi was 18.4 months, which was about 6 months longer than patients receiving placebo.
  • Patent document US7709517 discloses an enzalutamide compound and a preparation method thereof, specifically,
  • US Pat. No. 7,075,517 discloses that the ethyl acetate extract containing enzalutamide is purified by silica column chromatography to obtain the compound, and its nuclear magnetic resonance (1H NMR ) data is disclosed, but the crystal of the compound is not disclosed.
  • Type characterization data As a result of repeated experiments and studies by the present inventors, it has been found that the enzalutamide compound obtained by the method of the above patent document is in a crystalline state.
  • the crystalline material of enzalutamide prepared by the above patented method is referred to as "crystalline ⁇ .
  • the solubility of enzalutamide Form I is low, for example The solubility of Form I in water at room temperature is 2.16 ⁇ g/g, which is not conducive to the dissolution of the drug, which in turn affects its bioavailability.
  • the solid state form of enzalutamide is disclosed in the patent document WO 201 1106570 A1.
  • a solution of enzalutamide in a mixed solvent of isopropyl alcohol and isopropyl acetate (containing 7.3% by mole of isopropyl acetate in a mixed solvent) is cooled and crystallized to obtain White powdery product.
  • WO2011 106570A1 In Example 8, a solution of enzalutamide in dichlorosilane was evaporated, and the crude product was purified by column chromatography to give a product.
  • the crystal form data of the above-described enzalutamide solids are not disclosed in WO 201 1 106570 A1. It has been found by repeated experiments and studies by the present inventors that the enzalutamide solid obtained in WO201 1 106570 A1 is also the above crystal form I.
  • One of the contents of the present invention is to provide an amorphous enzalutamide having the following structural formula and a process for the preparation thereof.
  • the X-ray powder diffraction pattern of the amorphous enzalutamide is substantially as shown in Fig. 6, without any sharp diffraction peaks.
  • the Raman spectrum of the amorphous enzalutamide is at a wave number of 3081, 2994, 2950, 2240, 1760,
  • the differential scanning calorimetry (DSC) of the amorphous enzalutamide showed a glass transition temperature of 46 ° C and a crystal transition temperature of 137 ° C, and a known crystal form I was formed after the crystal transformation.
  • the solubility of the amorphous enzalutamide in water at room temperature is 7.85 ⁇ g / gram, which is higher than the known Form I ( 2.16 ⁇ g / gram).
  • the amorphous enzalutamide was placed at room temperature and in various relative humidity environments for more than one month. The crystal form did not change, and it was still amorphous, and no crystalline matter was formed.
  • the preparation method of the amorphous enzalutamide comprises the steps of: forming a solution of enzalutamide in a soluble solvent, removing the solvent at a rate of at least 5 ml/min, to obtain the amorphous state Lumine.
  • the soluble solvent is selected from the group consisting of CC 3 alcohol, ( ⁇ -(alkane, C 3 -C 4 ketone, C r C 5 ether, C 3 -C 5 ester, C 2 -C 3 nitrile or More preferably, the soluble solvent is selected from the group consisting of decyl alcohol, ethanol, n-propanol, isopropanol, dichlorodecane, chloroform, acetone, ethyl ketone, diethyl ether, decyl tert-butyl ether, tetrahydrofuran, Ethyl acetate, acetonitrile or a mixture thereof.
  • the solvent is removed in a manner selected from the group consisting of rotary evaporation, vacuum evaporation, nitrogen vapor evaporation, lyophilization or spray drying; preferably, the solvent removal rate is 5 to 15 ml. /minute.
  • the solution concentration of the enzalutamide in a soluble solvent is 0.1 to 1.0 times, more preferably 0.8 to 1.0 times, the solubility of enzalutamide in the soluble solvent at the solution temperature, for example,
  • the solution concentration of enzalutamide in a soluble solvent at room temperature is 200 to 300 mg/ml.
  • the amorphous enzalutamide of the present invention has one or more advantageous properties compared to known enzalutamide Form I, such as: solubility, dissolution rate, good storage stability, low hygroscopicity , advantageous processing and processing characteristics, suitable for solid preparation applications, and the like.
  • the amorphous enzalutamide of the present invention has a higher solubility than the crystal form of enzalutamide.
  • a second aspect of the present invention provides an enzalutamide form II having the following structural formula (hereinafter referred to as
  • Crystal form and its preparation method.
  • the X-ray powder diffraction pattern of the crystalline form has a characteristic peak at the following diffraction angle 2: 4.9 soil 0.2°, 9.8 ⁇ 0.2. 11.4 soil 0.2°, 13.6 ⁇ 0.2°, 15.7 ⁇ 0.2° and 17.1 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the Form II has characteristic peaks at the following diffraction angle 2 ⁇ : 4.9 ⁇ 0.2°, 7.9 ⁇ 0.2°, 9.8 ⁇ 0.2°, 11.4 ⁇ 0.2 1 12.7 ⁇ 0.2°, 13.6 Division 0.2. 14.5 ⁇ 0.2 °, 15.4 ⁇ 0.2 °, 15.7 ⁇ 0.2 °, 17.1 ⁇ 0.2 °, 18.6 ⁇ 0.2 ° 25.7 ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form II has characteristic peaks and relative intensities at the following diffraction angles 2 ⁇ :
  • a typical example of the crystal form II has an X-ray powder diffraction pattern as shown in Fig. 11.
  • the Fourier transform infrared spectrum of the crystal form II is 1768, 1644, 1619, 1553, 1444,
  • thermogravimetric analysis (TGA) pattern of Form II shows: an anhydrate.
  • the differential scanning calorimetry (DSC) of the crystalline germanium shows a melting point of 1 13 ⁇ 130 ° C, and crystal transformation occurs after melting, the crystal transformation temperature is 131-148 C, and the melting point of the sample after the crystal transformation is 196 ° C. It was detected as known Form I.
  • the solubility of Form II in water was 4.57 ⁇ g/g at room temperature. Higher than known Form 1 (2.66 ⁇ g/g). It was found by the solubilization experiment that the solubility of Form II in the presence of the solubilizing sodium lauryl sulfate (SDS) was 420.1 ⁇ g/g, which was still higher than the solubility of the known Form I under the same conditions (179.9 ⁇ g/g).
  • SDS sodium lauryl sulfate
  • the Form II was allowed to stand at room temperature and 60% relative humidity for one month, and the crystal form and the melting point were unchanged.
  • the preparation method of the enzalutamide crystal form II of the present invention comprises the following steps: adding a solution of enzalutamide to water, stirring and crystallization at a crystallization temperature, separating and drying the precipitated solid to obtain a solution.
  • the enzalutamide Form II wherein the solvent of the solution is selected from the group consisting of dC 3 alcohol, c 2 -c 3 nitrile, c 2 -c 6 ether or mixtures thereof.
  • the crystallization temperature is 10 ° C ⁇ 40 ° C, preferably room temperature; the crystallization time is 2 minutes ⁇ 10 minutes, preferably 2 minutes ⁇ 5 minutes;
  • the solvent is selected from the group consisting of decyl alcohol, ethanol, acetonitrile, tetrahydrofuran or a mixture thereof; the concentration of the enzalutamide solution is the solubility of enzalutamide in the solvent at the temperature of the solution.
  • the volume of the water is 3 to 10 times the volume of the solvent, preferably 3 to 5 times.
  • the drying may be carried out by a conventional method in the art, such as blast drying, reduced pressure drying or the like.
  • the drying temperature is 20-60 ° C, preferably 30-50 ° C; the drying time is 1-10 hours, preferably 1-5 hours, more preferably 1-2 hours.
  • the pressure is preferably less than 0.09 MPa. Drying can be carried out in a fume hood, a forced air oven or a vacuum oven.
  • the enzalutamide Form II of the present invention has one or more advantageous properties compared to known solid forms of enzalutamide, such as: higher crystallinity, solubility, dissolution rate, good particle morphology Good storage stability, low moisture absorption, favorable processing and handling characteristics, suitable for solid preparation applications, etc.
  • enzalutamide Form II has a higher solubility in Form I than enzalutamide.
  • a third aspect of the present invention provides an enzalutamide crystal form m (hereinafter referred to as "crystalline form”) having the following structural formula and a process for producing the same.
  • the crystalline form III is an isopropyl acetate solvate of enzalutamide, and each molecule of enzalutamide is combined with 0.5. Molecular isopropyl acetate.
  • the X-ray powder diffraction pattern of Form III has characteristic peaks at the following diffraction angle 2 ⁇ :
  • the X-ray powder diffraction pattern of Form III has a characteristic peak at the following diffraction angle 2 ⁇ : 5.2 ⁇ 0, 2°, 10.0 ⁇ 0.2. , 10.2 ⁇ 0.2. 13.3 ⁇ 0.2. , 13.9 ⁇ 0.2 ⁇ , 15.3 ⁇ 0.2 ⁇ , 16.8 ⁇ 0.2 ⁇ , 17.5 ⁇ 0.2 . 20.2 ⁇ 0.2. 22.0 ⁇ 0.2. 23.4 ⁇ 0.2. And 25.6 ⁇ 0.2. .
  • the X-ray powder diffraction pattern of the crystalline form has characteristic peaks and relative intensities at the following diffraction angles 2 ⁇ :
  • a typical example of the crystal form III has an X-ray powder diffraction pattern as shown in Fig. 15.
  • the Fourier infrared light of Form III is at wavenumbers of 1762, 1665, 1621, 1531, 1498, 1445, 141 1, 1384, 1372, 131 1 , 1284, 1217, 1 176, 1142, 1 118, 1055, 1007, 920, 893, 875, 848, 826, 807, 774, 747 cm- 1 have characteristic peaks.
  • the Raman spectrum of Form III has characteristic peaks at wave numbers of 2239, 1781, 1625, 1531, 1378, 1284, 1 183, 1031, 705, 507, 158 cm.
  • thermogravimetric analysis chart of the crystalline form shows that the weight loss at 8.50 to 57 ° C is 8.5%, and the theoretical weight loss of about 0.5 isopropyl acetate molecules is determined to be 0.5 isopropyl acetate. Solvate of the ester molecule.
  • the preparation method of the crystal form III comprises the following steps: removing the solvent of enzalutamide in isopropyl acetate to dryness to obtain the crystal form III of enzalutamide.
  • the temperature at which the solvent is removed is 5 to 35 ° C, preferably 15 to 20 ° C.
  • the method for removing the solvent is preferably a method of naturally volatilizing an isopropyl acetate solution of enzalutamide to a thousand and the container used is not capped or capped and perforated, or a solution of isopropyl acetate in isopropyl acetate is used. Blow dry.
  • the specific operation is as follows: The sample clear solution is placed in an open or capped 5 ml glass vial, naturally volatilized or volatilized or opened with a nitrogen purge to remove the solvent to dryness.
  • the concentration of the isopropyl solution of enzalutamide is 0.1 to 1.0 times, preferably 0.8 to 1.0 times, of the solubility of enzalutamide in isopropyl acetate at the temperature of the solution, for example, at room temperature.
  • the concentration is 25 ⁇ 50 mg/ml.
  • the enzalutamide form m of the present invention has one or more advantageous properties compared to known solid forms of enzalutamide, such as: higher crystallinity, solubility, dissolution rate, good particle morphology Good storage stability, low moisture absorption, favorable processing and handling characteristics, suitable for solid preparation applications, etc.
  • solubility of the enzaluene form in intrinsic crystal form I is higher than that of enzalutamide.
  • novel solid form of the above-described enzalutamide of the present invention is pure, single, and substantially free of any other crystalline form or other amorphous form.
  • substantially free when used to refer to a new solid form means that the other crystalline form or other amorphous form contained in the new solid form is less than 20% by weight, more preferably less than 10% by weight. ), especially less than 5% by weight, especially less than 1% by weight.
  • crystal means that it is confirmed by the X-ray diffraction pattern characterization shown.
  • experimental error therein depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample.
  • X-ray diffraction patterns typically vary with the conditions of the instrument. It is particularly important to note that the relative intensities of the X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be the sole or decisive factor.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, usually allowing an error of 0.2.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • the "room temperature” means 10-30 ° (:.
  • the stirring may be carried out by a conventional method in the art, for example, a stirring method including magnetic stirring, mechanical stirring, and a stirring speed of 50 to 1800 rpm, preferably 300 to 900 rpm.
  • the separation may be carried out by a conventional method in the art, such as filtration, centrifugation or the like.
  • Filtered Gymnastics Place the sample to be separated on the filter paper and filter it under reduced pressure.
  • the specific operation of centrifugation is as follows: The sample to be separated is placed in a centrifuge tube, and then rotated at a high speed until the solid is completely sunk to the bottom of the centrifuge tube, and the centrifugation rate is, for example, 6000 rpm.
  • the "ultrasound" can promote the dissolution of the sample by: placing the container containing the sample solution or suspension in an ultrasonic cleaner, typically sonicating at a frequency of 40 Khz for 20 to 60 seconds.
  • anhydrous means that the product contains not more than 1.5% by weight, or not more than 1% by weight, of water by thermogravimetric analysis (TGA).
  • the starting material enzalutamide of the present invention can be produced according to the method disclosed in Example 56 of Patent Document US7779517.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of one or more new solid forms of enzalutamide selected from the present invention or by the method of the present invention a new solid form of enzalutamide obtained, and at least one pharmaceutically acceptable excipient; the novel solid form of enzalutamide comprising the amorphous enzalutamide, enzalutamide of the invention Form II or enzalutamide Form III.
  • the pharmaceutical composition may also comprise other crystalline, amorphous or salt forms of the pharmaceutically acceptable enzalutamide, including but not limited to Form I as described in U.S. Patent 7,705,517.
  • the pharmaceutical composition may also comprise one or more additional pharmaceutically active ingredients.
  • the above pharmaceutical composition may be in a solid or liquid form, such as a solid oral dosage form, including tablets, granules, powders, pills, powders, and capsules; liquid oral dosage forms, including solutions, syrups, suspensions, dispersions, and Emulsion; Injectable preparations, including solutions, dispersions, and lyophilizates.
  • the formulation may be suitable 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.
  • Routes of administration include oral, intravenous subcutaneous injection, injection into tissue, transdermal administration, rectal administration, intranasal administration, and the like.
  • the pharmaceutically acceptable excipients of the present invention include, but are not limited to, diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dibasic calcium phosphate, tricalcium phosphate, mannose Alcohol, sorbitol, sugar, etc.; binders such as acacia, guar, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, etc.; disintegrant, For example, starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; lubricants such as stearic acid, magnesium stearate, stearic acid Zinc, sodium benzoate, sodium acetate, caprylyl hexanoyl polyoxyglyceride, etc.; glidant, such as colloidal silica; complex forming agents
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art.
  • the novel solid form of enzalutamide of the invention, or a combination thereof is admixed with one or more pharmaceutically acceptable excipients, optionally with a pharmaceutically acceptable enzalutamide
  • Other crystalline, amorphous or salt forms are mixed, optionally with one or more other pharmaceutically active ingredients.
  • the solid preparation can be prepared by a process such as direct mixing, granulation, or the like.
  • the present invention provides the use of the amorphous enzalutamide, enzalutamide Form II or enzalutamide form of the present invention for the preparation of a medicament for the treatment and/or prevention of a hyperproliferative disease.
  • the present invention provides a method of treating and/or preventing a hyperproliferative disease, comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of one or more amorphous forms selected from the present invention.
  • the patient refers to a mammal including a human.
  • the hyperproliferative diseases include prostate cancer, benign prostatic hyperplasia, breast cancer, ovarian cancer, diseases associated with prostate-specific antigen mRNA transcription, diseases associated with androgen receptor protein nuclear translocation, and the like, especially metastatic castration Tolerant to prostate cancer.
  • the novel solid form of enzalutamide of the present invention is useful for preparing a medicament for treating and/or preventing metastatic castration-resistant prostate cancer, which can interfere with transcription of prostate specific antigen mRNA and prevent nuclear translocation of androgen receptor protein , the androgen receptor protein is unstable.
  • the dosage can be 0.00bu 100 mg
  • Figure 1 is an XRPD pattern of enzalutamide Form I prepared according to US7709517.
  • Figure 2 is a DSC map of enzalutamide Form I prepared according to US7709517.
  • Figure 3 is a TGA diagram of enzalutamide Form I prepared according to US7709517.
  • Figure 4 is an infrared spectrum of enzalutamide Form I prepared according to US7709517.
  • Figure 5 is a Raman spectrum of enzalutamide Form I prepared according to US7709517.
  • Figure 6 is an XRPD pattern of the amorphous enzalutamide of the present invention.
  • Figure 7 is a DSC chart of the amorphous enzalutamide of the present invention.
  • Figure 8 is a TGA diagram of the amorphous enzalutamide of the present invention.
  • Figure 9 is an infrared spectrum of the amorphous enzalutamide of the present invention.
  • Figure 10 is a Raman spectrum of the amorphous enzalutamide of the present invention.
  • Figure 11 is an XRPD diagram of the enzalutamide Form II of the present invention.
  • Figure 12 is a DSC diagram of the enzalutamide Form II of the present invention.
  • Figure 13 is a TGA map of enzalutamide Form II of the present invention.
  • Figure 14 is an infrared spectrum of enzalutamide Form II of the present invention.
  • Figure 15 is an XRPD pattern of enzalutamide Form III of the present invention.
  • Figure 16 is a DSC chart of enzalutamide Form III of the present invention.
  • Figure 17 is a TGA diagram of the enzalutamide Form III of the present invention.
  • Figure 18 is an infrared spectrum of enzalutamide Form III of the present invention.
  • Figure 19 is a Raman spectrum of m-enzolamide crystal form m of the present invention. detailed description
  • Diffractometer equipped with a ⁇ -2 ⁇ goniometer, Mo monochromator, Lynxeye detector.
  • the acquisition software is Diffrac Plus XRD Commander and the analysis software is MDI Jade 5.0.
  • the instrument is calibrated with the standard (usually corundum) supplied with the instrument before use.
  • the detection conditions are: 2 ⁇ scanning angle range 3 ⁇ 40. , step size 0.02°, speed 0.2 sec/step.
  • Detection process Ka X-ray with a copper target wavelength of 1.54 nm, Under 40 kV and 40 mA operating conditions, the samples were tested at room temperature and the samples to be tested were placed on organic slides. Samples were not ground prior to testing unless otherwise stated.
  • the differential thermal analysis (DSC) data was taken from the TA Instruments Q200 MDSC, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually take 1 ⁇ 10 mg of the sample in an uncoated (unless otherwise specified) aluminum crucible, and raise the sample from room temperature to 250 ⁇ at a heating rate of 1 CTC/min under the protection of 50 ml/min dry N 2 . At the same time, the TA software records the change in heat during the temperature rise of the sample.
  • Thermogravimetric analysis (TGA) data was taken from the TA Instruments Q500 TGA, the instrument control software was Thermal Advantage, and the analysis software was Universal Analysis. Usually the ear is 5 ⁇ : 15 mg sample is placed in the platinum crucible, and the sample is lifted from room temperature by the method of segmented high-resolution detection at a heating rate of 10 ° C / min under the protection of 50 ml / min dry N 2 To 30 CTC, the TA software records the change in weight of the sample during the heating process.
  • IR Fourier infrared spectroscopy
  • the device model used for Raman spectroscopy is the DXR780 laser micro-Raman spectrometer. In the 10 times mirror, the wave number range SO ⁇ Ocm- 1 , the sample was subjected to Raman spectroscopy with an exposure time of 1 second and an exposure frequency of 8 times.
  • the high performance liquid chromatograph was performed using a Waters 2695 injector and a Waters 2487 detector. The detection methods are shown in Table 1.
  • Example 1 N-Mercapto-2-fluoro-4-(1,1-didecyl-cyanoindolyl)aminobenzamide (3 g, 13 mmol) and 4-isothiocyanato-2-trifluoro Hydrylbenzonitrile (5.8g, 26mmol) was added to 100mL DMF, heated to 100 ° C for 1 hour under microwave irradiation, cooled to 50 ° C, 2000 mL methanol and 500 mLlN hydrochloric acid were added, and the temperature was refluxed for 1.5 hours.
  • the XRPD pattern is shown in Figure 1 and is shown as Form I.
  • the DSC spectrum is shown in Figure 2 and shows a melting point of 197 ⁇ 199 ° ( .
  • the TGA map is shown in Figure 3 and is shown as an anhydrate.
  • Example 1 100 mg of enzalutamide prepared in Example 1 was placed in a 30 mL single-necked flask, 10 mL of dichloromethane was added, and ultrasonication was carried out for 30 seconds at 40 KHz to ensure complete dissolution, and then placed on a rotary evaporator, and dried at 40 Torr to remove the solvent. The rate was about 15 ml/min to give an amorphous enzalutamide.
  • the XRPD graphic is shown in Figure 6. It is shown as amorphous and does not have any sharp diffraction peaks. .
  • the DSC spectrum is shown in Figure 7. It is shown as amorphous, with a glass transition temperature of 46 ° C and crystallization at 137 ° C. After detection, crystal form I is formed after crystal transformation.
  • the TGA map is shown in Figure 8.
  • the IR map is shown in Figure 9.
  • the Raman diagram "i ridge is shown in Figure 10.
  • Example 1 1 mg of enzalutamide prepared in Example 1 was placed in a 30 mL single-necked flask. ' Add 1 OmL of dichloromethane, and sonicate at 40 KHz for 20 seconds to ensure complete dissolution, and then placed on a rotary evaporator at 40 ° C. The rate of solvent removal was about 5 ml/min to give amorphous enzalutamide.
  • Example 1 80 mg of enzalutamide prepared in Example 1 was placed in a 30 mL single-necked flask, and 10 mL of dichloromethane was added thereto, and ultrasonication was carried out for 40 seconds at 40 KHz to ensure complete dissolution, and then placed on a rotary evaporator and spun at 40 ° C. The rate of removal of the solvent was about 10 ml/min to give an amorphous enzalutamide.
  • Example 2 Take 100 mg of enzalutamide prepared in Example 1 into a 20 mL vial, add 1 OmL of dichloromethane, and soak it at 40 KHz for 60 seconds to ensure complete dissolution. Place it on a nitrogen purifier and pass at 40 °C. The solvent was removed by a nitrogen purge, and the solvent was removed at a rate of about 15 ml/min to obtain an amorphous enzalutamide.
  • Example 1 100 mg of enzalutamide prepared in Example 1 was placed in a 20 mL vial, and 10 mL of dichloromethane was added.
  • the solvent removal rate is about 15 ml / min, to obtain crystalline enzalutamide.
  • Example 1 100 mg of enzalutamide prepared in Example 1 was placed in a 20 mL vial, 10 mL of acetonitrile was added, ultrasonically incubated at 40 KHz for 30 seconds to ensure complete dissolution, and then placed in a lyophilizer, and the solution was cooled to minus 50 ° C to solidify the solution. The mixture was vacuum dried at room temperature, and the solvent was removed at a rate of about 15 ml/min to obtain an amorphous enzalutamide.
  • the enzalutamide 100 mg prepared in Example 1 was placed in a 20 mL vial, added with 10 mL of dichloromethane, sonicated at 40 KHz for 30 seconds to ensure complete dissolution, and then placed in a spray dryer, spray dried at room temperature to remove the solvent. The rate was 15 ml/min to give an amorphous enzalutamide.
  • Example 2 The methylene chloride in Example 2 was replaced with decyl alcohol, and the other operation was the same as in Example 2 to obtain an amorphous enzalutamide.
  • Example 2 The dichlorodecane in Example 2 was replaced with ethanol, and the other operations were the same as in Example 2 to obtain an amorphous state. Enzolamide.
  • Example 2 The dichlorodecane in Example 2 was replaced with n-propanol, and the other operation was the same as in Example 2 to obtain an amorphous enzalutamide.
  • Example 2 The dichlorodecane in Example 2 was replaced with isopropanol, and the other operation was the same as in Example 2 to obtain an amorphous enzalutamide.
  • Example 2 The methylene chloride in Example 2 was replaced with acetone, and the other operation was the same as in Example 2 to obtain an amorphous enzalutamide.
  • Example 2 The dichlorosilane in Example 2 was replaced with acetophenone, and the other operation was the same as in Example 2 to obtain an amorphous enzalutamide.
  • Example 2 The dichlorodecane in Example 2 was replaced with diethyl ether, and the other operation was the same as in Example 2 to obtain an amorphous enzalutamide.
  • Example 2 The methylene chloride in Example 2 was replaced with ethyl acetate, and the other operation was the same as in Example 2 to give the non-crystalline enzalutamide.
  • Example 2 The dichlorodecane in Example 2 was replaced with mercapto tert-butyl ether, and the other operation was the same as in Example 2 to obtain an amorphous enzalutamide.
  • Example 2 The dichloromethane in Example 2 was replaced with tetrahydrofuran, and the other operation was the same as in Example 2 to obtain an amorphous enzalutamide.
  • Example 2 The dichlorodecane in Example 2 was replaced with acetonitrile, and the other operation was the same as in Example 2 to obtain an amorphous enzalutamide.
  • Example 2 The dichlorodecane in Example 2 was replaced with chloroform, and the other operation was the same as in Example 2 to obtain an amorphous enzalutamide.
  • the samples prepared in Examples 3 to 20 had the same or similar XRPD patterns, DSC patterns, TGA patterns, IR patterns, Raman patterns (not shown) as in Example 2. These examples were prepared to give the same materials as in Example 2.
  • Example 2 20 mg of enzalutamide prepared in Example 1 was placed in a 5 ml reaction flask, 0.8 ml of methanol was added to dissolve, and 2.5 ml of water was added to another 5 ml reaction flask to obtain the above-mentioned enzalutamide sterol solution. It was added dropwise to water, stirred at room temperature for 5 minutes, centrifuged, and vacuum dried at 45 ° C for 5 hours to obtain enzalutamide Form II.
  • the DSC spectrum is shown in Fig. 12. It shows a melting point of 113 ⁇ 130 ⁇ . After melting, the crystal transformation occurs at a temperature of 131-148 ° C. After melting, the melting point of the sample is 196 ° C, and the known crystal form I is detected.
  • the TGA map is shown in Figure 13 and is shown as an anhydrate.
  • Example 2 20 mg of enzalutamide prepared in Example 1 was placed in a 5 ml reaction flask, dissolved in 1.0 ml of ethanol, and 5 ml of water was added to another 10 ml reaction flask, and the above-mentioned enzalutamide ethanol solution was dropped. It was added to water, stirred at 40 ° C for 2 minutes, centrifuged, and vacuum-dried at 45 ° C for 5 hours to obtain enzalutamide Form II.
  • Example 2 20 mg of enzalutamide prepared in Example 1 was placed in a 10 ml reaction flask, dissolved in 8.0 ml of acetonitrile, and 24 ml of water was added to another 50 ml reaction flask, and the above-mentioned enzalutamide acetonitrile solution was dropped. It was added to water, stirred at 10 ° C for 10 minutes, centrifuged, and vacuum dried at 45 ° C for 5 hours to obtain enzalutamide Form II.
  • Example 2 20 mg of enzalutamide prepared in Example 1 was placed in a 5 ml reaction flask, 0.8 ml of tetrahydrofuran was added, dissolved, and 8.0 ml of water was added to another 10 ml reaction flask to prepare the above-mentioned enzalutamide tetrahydrofuran solution. It was added dropwise to water, stirred at room temperature for 3 minutes, centrifuged, and vacuum dried at 45 ° C for 5 hours to obtain enzalutamide Form II.
  • Example 22 The samples prepared in Examples 22 to 24 had the same or similar XRPD patterns, IR patterns, and DSC patterns (not shown) as in Example 21. These examples were prepared to give the same materials as in Example 21.
  • Example 25 The samples prepared in Examples 22 to 24 had the same or similar XRPD patterns, IR patterns, and DSC patterns (not shown) as in Example 21. These examples were prepared to give the same materials as in Example 21.
  • Example 25 The samples prepared in Examples 22 to 24 had the same or similar XRPD patterns, IR patterns, and DSC patterns (not shown) as in Example 21. These examples were prepared to give the same materials as in Example 21.
  • Example 25 Example 25
  • Example 1 100 mg of enzalutamide prepared in Example 1 was weighed into a 5 ml glass vial, 2 ml of isopropyl acetate was added, and ultrasonication was carried out at 40 KHz for 30 seconds to ensure complete dissolution, without capping, and naturally evaporated to dryness at room temperature. , obtaining enzalutamide Form III.
  • Example 1 100 mg of enzalutamide prepared in Example 1 was weighed into a 5 ml glass vial, 4 ml of isopropyl acetate was added, and ultrasonication was carried out at 40 KHz for 30 seconds to ensure complete dissolution. Isopropyl acetate was blown at 20 ° C with nitrogen. Dry, to obtain enzalutamide Form III.
  • Example 26 to 27 have XRPD patterns, DSC patterns, TGA patterns, IR patterns, and Raman patterns (not shown) similar to those of Example 25, indicating the preparation and implementation of the preparations of these examples.
  • Example 25 is the same.
  • the formulation of the capsules is shown in Table 2.
  • Amorphous enzalutamide 40 prepared by the present invention 26.67% Acacia 5 3.33% Corn starch 30 20% Sucrose 75 50% Preparation of capsules: According to the formulation of Table 2, The amorphous enzalutamide prepared by the invention is mixed with corn starch and sucrose, and the gum arabic is dissolved in water to form a 1% aqueous solution, and added to the above mixture to prepare wet granules. Hey. Example 29
  • Example 28 The "amorphous enzalutamide prepared by the present invention” in Example 28 was changed to "enzuramide form II prepared by the present invention", and the other operation was the same as in Example 28, and a capsule was prepared.
  • Example 28 The “amorphous enzalutamide prepared by the present invention” in Example 28 was changed to "the enzaluene crystal form prepared by the present invention, and the other operation was the same as in Example 28, and a capsule was prepared.
  • Amorphous enzalutamide 40 prepared by the invention 13.33%
  • CaHP0 4 , corn starch and sucrose are mixed into a mixture, and the gum arabic is dissolved in water to form a 1% aqueous solution, and added to the above mixture to prepare wet granules.
  • the wet granules are dried, and the magnesium stearate is added and mixed. Tableting.
  • Example 31 The “amorphous enzalutamide prepared by the present invention” in Example 31 was changed to "enzuramide form II prepared by the present invention", and the same procedure as in Example 31 was carried out to prepare a tablet.
  • Example 31 The "amorphous enzalutamide prepared by the present invention” in Example 31 was replaced by "the enzalutamide form of the present invention", and the same procedure as in Example 31 was carried out to prepare a tablet.

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Abstract

La présente invention concerne une nouvelle forme solide d'enzalutamide. Comparativement à l'art antérieur, la nouvelle forme solide d'enzalutamide dans la présente invention possède une ou plusieurs propriétés améliorées, par exemple une bonne solubilité et un bon taux de dissolution, une bonne stabilité, des propriétés de traitement favorables, et est adaptée à être appliquée dans des préparations solides. La présente invention concerne également un procédé de préparation de la nouvelle forme solide d'enzalutamide, des compositions pharmaceutiques la comprenant et des utilisations associées dans la préparation de médicaments pour le traitement de maladies telles que le cancer de la prostate métastatique tolérant à la castration.
PCT/CN2013/001235 2013-10-14 2013-10-14 Forme solide d'enzalutamide, procédé de préparation et utilisation associée WO2015054804A1 (fr)

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US10118899B2 (en) 2015-05-29 2018-11-06 Astellas Pharma, Inc. Production method of enzalutamide crystal form
WO2019106691A1 (fr) 2017-11-28 2019-06-06 Aarti Industries Limited Procédé de préparation d'enzalutamide à l'aide d'un nouvel intermédiaire
EP3572069A1 (fr) * 2018-05-21 2019-11-27 Zentiva K.S. Augmentation de la solubilité et de la biodisponibilité de l'enzalutamide
CN111303042A (zh) * 2020-03-25 2020-06-19 北京赛思源生物医药技术有限公司 一种恩杂鲁胺的新晶型

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CN105030685B (zh) * 2015-07-21 2018-02-27 福格森（武汉）生物科技股份有限公司 一种恩杂鲁胺固体分散体口服制剂
CN110981812A (zh) * 2019-11-25 2020-04-10 奥锐特药业股份有限公司 一种无定形恩杂鲁胺的制备方法
CN111217757B (zh) * 2020-01-06 2021-03-19 武汉大学 一种恩杂鲁胺化合物及其药物组合物制剂
CN114224832A (zh) * 2022-02-11 2022-03-25 明度智云(浙江)科技有限公司 一种恩杂鲁胺注射剂及其制备方法和应用

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US7709517B2 (en) * 2005-05-13 2010-05-04 The Regents Of The University Of California Diarylhydantoin compounds
CN103108549A (zh) * 2010-02-24 2013-05-15 梅迪维新***医疗股份有限公司 合成二芳基乙内酰硫脲和二芳基乙内酰脲化合物的方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10118899B2 (en) 2015-05-29 2018-11-06 Astellas Pharma, Inc. Production method of enzalutamide crystal form
WO2019106691A1 (fr) 2017-11-28 2019-06-06 Aarti Industries Limited Procédé de préparation d'enzalutamide à l'aide d'un nouvel intermédiaire
EP3572069A1 (fr) * 2018-05-21 2019-11-27 Zentiva K.S. Augmentation de la solubilité et de la biodisponibilité de l'enzalutamide
CN111303042A (zh) * 2020-03-25 2020-06-19 北京赛思源生物医药技术有限公司 一种恩杂鲁胺的新晶型

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