WO2015054804A1 - Solid form of enzalutamide, preparation method and use thereof - Google Patents

Solid form of enzalutamide, preparation method and use thereof 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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French (fr)
Chinese (zh)
Inventor
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/en
Priority to PCT/CN2013/001235 priority patent/WO2015054804A1/en
Priority to CN201610953259.7A priority patent/CN106543085A/en
Publication of WO2015054804A1 publication Critical patent/WO2015054804A1/en

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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.

Abstract

The present invention relates to a novel solid form of Enzalutamide. In comparison with the prior art, the new solid form of Enzalutamide in the present invention has one or more improved properties, such as good solubility and dissolution rate, good stability, favorable processing properties, and suitability for solid preparation application. The present invention also relates to a preparation method for the new solid form of Enzalutamide, pharmaceutical compositions thereof and uses thereof in preparing drugs for treating diseases such as metastatic castration-tolerant prostate cancer.

Description

恩杂鲁胺的固态形式及其制备方法和用途  Solid form of enzalutamide and preparation method and use thereof
技术领域  Technical field
本发明涉及药物化学结晶技术领域。 具体而言， 涉及恩杂鲁胺的新固态 形式， 以及所述新固态形式的制备方法、 其药物组合物和用途。 背景技术  The invention relates to the field of medicinal chemical crystallization technology. In particular, 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
恩杂鲁胺的化学名称为 4-{3-[4-氰基 -3- (三氟曱基） 苯基] 5，5-二曱基 -4- 氧代 -2-硫代咪唑烷 -1-基}-2 氟 -N-曱基苯曱酰胺， 英文名称为 Enzalutamide, 又称为 MDV-3100, 分子式 C lHl6F4N402S, 化学结构式如下所示： The chemical name of 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:
Figure imgf000002_0001
恩杂鲁胺是一种雄性激素受体拮抗剂， 由梅迪维新（Medivation )公司和 安斯泰来（ Astdlas Pharma )公司合作开发。 2012年 8月 31 日， 获得美国食 品药品管理局 (FDA)批准， 用于治疗已扩散或复发的晚期（转移性）去势耐受 前列腺癌， 即使患者既往接受过多西紫杉醇化疗或减少睾酮的药物或手术治 疗。 恩杂鲁胺的商品名为 Xtandi, 剂型为口服明胶软胶嚢， 规格 40毫克， 推 荐剂量为每日一次 160毫克。 研究结果显示， 接受 Xtandi治疗的患者中位总 生存期为 18.4个月 , 比接受安慰剂治疗的患者延长约 6个月的生存期。
Figure imgf000002_0001
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. The trade name of enzalutamide is Xtandi, and 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.
专利文献 US7709517 公开了恩杂鲁胺化合物及其制备方法， 具体的， Patent document US7709517 discloses an enzalutamide compound and a preparation method thereof, specifically,
US7709517实施例 56公开了用二氧化硅柱层析纯化含有恩杂鲁胺的乙酸乙酯 萃取液， 得到该化合物， 公开了其核磁共振氢谱（ 1H NMR )数据， 但未公开 该化合物的晶型表征数据。 经本发明人的重复实验及研究发现， 通过上述专 利文献方法获得的恩杂鲁胺化合物为晶态。 为便于区分， 以下称上述专利方 法制得的恩杂鲁胺晶态物质为 "晶型 Γ 。 恩杂鲁胺晶型 I溶解度较低， 例如 室温下晶型 I在水中的溶解度为 2.16微克 /克， 不利于药物的溶出， 进而影响 其生物利用度。 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. For ease of distinction, the crystalline material of enzalutamide prepared by the above patented method is referred to as "crystalline Γ. The solubility of enzalutamide Form I is low, for example The solubility of Form I in water at room temperature is 2.16 μg/g, which is not conducive to the dissolution of the drug, which in turn affects its bioavailability.
专利文献 WO201 1106570A1 公开了恩杂鲁胺的固态形式。 具体的， WO201 1 106570A1 实施例 5 中， 将恩杂鲁胺在异丙醇与乙酸异丙酯混合溶剂 中的溶液（混合溶剂中含 7.3%摩尔百分比的乙酸异丙酯）冷却析晶， 得到白 色粉末状产物。 WO2011 106570A1 实施例 8中， 将恩杂鲁胺的二氯曱烷溶液 蒸发， 粗品再通过柱层析纯化， 得到成品。 WO201 1 106570A1 没有公开上述 恩杂鲁胺固体的晶型数据。 经本发明人的重复实验及研究发现， WO201 1 106570 A1所得的恩杂鲁胺固体也是上述晶型 I。  The solid state form of enzalutamide is disclosed in the patent document WO 201 1106570 A1. Specifically, in Example 5 of WO201 1 106570A1, 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.
因此， 已知的恩杂鲁胺的固态形式存在一定的缺陷， 开发具有更多优越 性能的恩杂鲁胺的新固态形式很必要。 发明内容  Therefore, the known solid form of enzalutamide has certain drawbacks, and it is necessary to develop a new solid form of enzalutamide having more superior properties. Summary of the invention
针对现有技术的不足， 本发明的目的是开发溶解度好、 稳定性好、 适合 固体制剂应用的恩杂鲁胺的新固态形式， 以及其制备方法、 其药物组合物和 用途。  In view of the deficiencies of the prior art, it is an object of the present invention to develop a novel solid form of enzalutamide which has good solubility, good stability, and is suitable for solid formulation applications, as well as a process for its preparation, a pharmaceutical composition thereof and use thereof.
本发明的内容之一是提供具有如下结构式的非晶态恩杂鲁胺及其制备方 法。  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.
Figure imgf000003_0001
Figure imgf000003_0001
所述非晶态恩杂鲁胺的 X射线粉末衍射图基本上如图 6所示， 没有任何尖 锐的衍射峰。  The X-ray powder diffraction pattern of the amorphous enzalutamide is substantially as shown in Fig. 6, without any sharp diffraction peaks.
所述非晶态恩杂鲁胺的傅里叶红外光谱在波数为 3413、 2944、 2235、 1756、 1658、 1620、 1537、 1499、 1410、 1310、 1218、 1 177、 961、 922、 896、 861、 841 cm 处具有特征峰。  The Fourier transform infrared spectroscopy of the amorphous enzalutamide at wave numbers of 3413, 2944, 2235, 1756, 1658, 1620, 1537, 1499, 1410, 1310, 1218, 1 177, 961, 922, 896, 861 Characteristic peak at 841 cm.
所述非晶态恩杂鲁胺的拉曼光谱在波数为 3081、 2994、 2950、 2240、 1760 、 The Raman spectrum of the amorphous enzalutamide is at a wave number of 3081, 2994, 2950, 2240, 1760,
1623、 1377、 1203、 1034、 754、 735、 508cm-1处具有特征峰。 所述非晶态恩杂鲁胺的差式扫描量热图 （DSC )显示其玻璃化温度为 46°C , 转晶溫度为 137°C， 转晶后可形成已知晶型 I。 There are characteristic peaks at 1623, 1377, 1203, 1034, 754, 735, and 508 cm- 1 . 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.
室温下， 所述非晶态恩杂鲁胺在水中的溶解度为 7.85微克 /克， 较已知晶 型 I ( 2.16微克 /克） 高。  The solubility of the amorphous enzalutamide in water at room temperature is 7.85 μg / gram, which is higher than the known Form I ( 2.16 μg / gram).
通过增溶实验可知， 其在增溶剂十二烷基硫酸钠（ SDS )存在下的溶解度 为 455.8微克 /克， 仍比同条件下已知晶型 I的溶解度（179.9微克 /克） 高。  It was found by a solubilization experiment that the solubility in the presence of the solubilized sodium lauryl sulfate (SDS) was 455.8 μg/g, which was still higher than the solubility of the known Form I under the same conditions (179.9 μg/g).
所迷非晶态恩杂鲁胺放置于室温下、 各种相对湿度环境中一个月以上， 晶型均没有变化， 仍为非晶态， 没有结晶物质生成。  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.
所述非晶态恩杂鲁胺的制备方法， 包括如下步骤： 形成恩杂鲁胺在可溶溶 剂中的溶液， 以至少为 5毫升 /分钟的速率去除溶剂，得到所述非晶态恩杂鲁胺。  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.
优选地， 所述可溶溶剂选自 C C3醇、 (^-(^ 代烷烃、 C3-C4酮、 CrC5醚、 C3-C5酯、 C2-C3腈或其混合物， 更优选地， 所述可溶溶剂选自曱醇、 乙醇、 正 丙醇、 异丙醇、 二氯曱烷、 氯仿、 丙酮、 曱乙酮、 乙醚、 曱基叔丁基醚、 四 氢呋喃、 乙酸乙酯、 乙腈或其混合物。 优选地， 所述去除溶剂的方式选自旋 转蒸发、 真空蒸发、 氮吹蒸发、 冻干或喷雾干燥； 优选地， 所述去除溶剂的 速率为 5〜15毫升 /分钟。 Preferably, 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. Preferably, 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.
优选地， 所述恩杂鲁胺在可溶溶剂中的溶液浓度为在该溶液溫度下恩杂 鲁胺在可溶溶剂中溶解度的 0.1〜1.0倍， 更优选为 0.8〜1.0倍， 例如， 在室温下 恩杂鲁胺在可溶溶剂中的溶液浓度为 200〜300毫克 /毫升。  Preferably, 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.
本发明的非晶态恩杂鲁胺具有以下有益效果：  The amorphous enzalutamide of the present invention has the following beneficial effects:
与已知的恩杂鲁胺晶型 I相比， 本发明的非晶态恩杂鲁胺具有一种或多种 有利的性质， 例如： 溶解度、 溶出速度， 好的储存稳定性、 低吸湿性、 有利 的加工与处理特性、 适于固体制剂应用等。 特别是， 本发明的非晶态恩杂鲁 胺比恩杂鲁胺晶型 I的溶解度高。  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. In particular, the amorphous enzalutamide of the present invention has a higher solubility than the crystal form of enzalutamide.
本发明的内容之二是提供具有如下结构式的恩杂鲁胺晶型 II (以下称作 A second aspect of the present invention provides an enzalutamide form II having the following structural formula (hereinafter referred to as
"晶型 Π" ) 及其制备方法。 "Crystal form" and its preparation method.
Figure imgf000004_0001
所述晶型 Π的 X-射线粉末衍射图在以下衍射角 2Θ处具有特征峰： 4.9土 0.2°、 9.8士0.2。、 11.4土 0.2°、 13.6±0.2°、 15.7士 0.2°和 17.1士 0.2°。
Figure imgf000004_0001
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°.
优选地， 所述晶型 II的 X-射线粉末衍射图在以下衍射角 2Θ处具有特征峰： 4.9士 0.2°、 7.9土 0.2°、 9.8土0.2°、 11.4±0.2\ 12.7±0.2°、 13.6士 0.2。、 14.5士 0.2°、 15.4土 0.2°、 15.7士 0.2°、 17.1±0.2°、 18.6士 0.2° 口 25.7士 0.2°。  Preferably, the X-ray powder diffraction pattern of the Form II has characteristic peaks at the following diffraction angle 2Θ: 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 °.
进一步地，所述晶型 II的 X-射线粉末衍射图在以下衍射角 2Θ处具有特征峰 及其相对强度：  Further, the X-ray powder diffraction pattern of Form II has characteristic peaks and relative intensities at the following diffraction angles 2Θ:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
4.9±0.2° 100.0  4.9±0.2° 100.0
7.9士 0.2。 15.3  7.9 ± 0.2. 15.3
9.8士 0.2。 23.8  9.8 ± 0.2. 23.8
1 1.4±0.2° 22.3  1 1.4±0.2° 22.3
12.7土 0.2。 14.5  12.7 soil 0.2. 14.5
13.6士 0.2。 30.8  13.6 ± 0.2. 30.8
14.5±0.2° 20.9  14.5±0.2° 20.9
15.4±0.2° 15.7  15.4±0.2° 15.7
15.7士 0.2。 35.8  15.7 ± 0.2. 35.8
17.1±0.2° 34.7  17.1±0.2° 34.7
18.6±0.2° 16.8  18.6±0.2° 16.8
21.2±0.2° 1 1.0  21.2 ± 0.2 ° 1 1.0
23.0士 0.2。 14.4  23.0 ± 0.2. 14.4
23.5士 0.2。 18.8  23.5 ± 0.2. 18.8
24.5±0.2° 14.9  24.5±0.2° 14.9
25.7士 0.2。 24.6  25.7 ± 0.2. 24.6
27.1±0.2° 14.2  27.1±0.2° 14.2
非限制性地，所述晶型 II的一个典型实例具有如图 11所示 X-射线粉末衍射 图。  Without limitation, a typical example of the crystal form II has an X-ray powder diffraction pattern as shown in Fig. 11.
所述晶型 II的傅里叶红外光谱在波数为 1768、 1644、 1619、 1553、 1444、 The Fourier transform infrared spectrum of the crystal form II is 1768, 1644, 1619, 1553, 1444,
1412、 1373、 1311、 1283、 1221、 1188、 1108、 843、 827、 810、 777cm-1处具 有特征峰。 1412, 1373, 1131, 1283, 1221, 1188, 1108, 843, 827, 810, 777 cm -1 have characteristic peaks.
所述晶型 II的热重分析（TGA ) 图谱显示： 为无水物。  The thermogravimetric analysis (TGA) pattern of Form II shows: an anhydrate.
所述晶型 Π的差式扫描量热图 （DSC )显示熔点为 1 13 ~ 130°C , 熔融后发 生转晶，转晶温度为 131-148 C ,转晶后样品熔点为 196°C ,经检测为已知晶型 I。  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.
室温下， 所述晶型 II在水中的溶解度为 4.57微克 /克。 较已知晶型 1 ( 2.16 微克 /克） 高。 通过增溶实验可知， 晶型 II在增溶剂十二烷基硫酸钠（SDS )存在下溶解 度为 420.1微克 /克， 仍比同条件下已知晶型 I的溶解度（ 179.9微克 /克） 高。 The solubility of Form II in water was 4.57 μg/g at room temperature. Higher than known Form 1 (2.66 μg/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 μg/g, which was still higher than the solubility of the known Form I under the same conditions (179.9 μg/g).
所述晶型 II于室温、 60%相对湿度下放置一个月， 晶型和熔点不变。  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.
本发明所述恩杂鲁胺晶型 II的制备方法， 包括以下步骤： 将恩杂鲁胺的溶 液加入到水中， 然后于析晶温度下搅拌析晶， 将析出的固体分离、 干燥， 得 到所述恩杂鲁胺晶型 II, 其中所述溶液的溶剂选自 d-C3醇、 c2-c3腈、 c2-c6 醚或其混合物。 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.
所述析晶温度为 10°C ~ 40°C , 优选为室温； 所述析晶时间为 2分钟 ~ 10分 钟， 优选为 2分钟〜 5分钟；  The crystallization temperature is 10 ° C ~ 40 ° C, preferably room temperature; the crystallization time is 2 minutes ~ 10 minutes, preferably 2 minutes ~ 5 minutes;
优选地， 所述溶剂选自曱醇、 乙醇、 乙腈、 四氢呋喃或其混合物； 所述恩杂鲁胺溶液的浓度是该溶液温度下恩杂鲁胺在该溶剂中溶解度的 Preferably, 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.
0.1 ~ 1.0倍， 优选为 0.8 ~ 1.0倍。 0.1 to 1.0 times, preferably 0.8 to 1.0 times.
所述水的体积为溶剂体积的 3 ~ 10倍， 优选为 3 ~ 5倍。  The volume of the water is 3 to 10 times the volume of the solvent, preferably 3 to 5 times.
本发明恩杂鲁胺晶型 II的制备方法中， 所述千燥可以采用本领域的常规 方法， 如鼓风干燥、 减压干燥等。 干燥温度为 20-60°C , 优选为 30-50°C ; 干 燥时间为 1-10小时， 优选为 1-5小时， 更优选为 1-2小时。 减压千燥时优选 压力小于 0.09Mpa。 干燥可以在通风橱、 鼓风烘箱或真空烘箱里进行。  In the preparation method of the enzalutamide form II of the present invention, 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. When the pressure is reduced, 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.
本发明的恩杂鲁胺晶型 II具有以下有益效果：  The enzalutamide Form II of the present invention has the following beneficial effects:
与已知的恩杂鲁胺固态形式相比，本发明的恩杂鲁胺晶型 II具有一种或多 种有利的性质， 例如： 更高的结晶度、 溶解度、 溶出速度， 好的颗粒形态、 好的储存稳定性、 低吸湿性、 有利的加工与处理特性、 适于固体制剂应用等。 特别是， 恩杂鲁胺晶型 II比恩杂鲁胺已知晶型 I的溶解度高。  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. In particular, enzalutamide Form II has a higher solubility in Form I than enzalutamide.
本发明的内容之三是提供具有如下结构式的恩杂鲁胺晶型 m (以下称作 "晶型 ΠΓ )及其制备方法。  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.
Figure imgf000006_0001
Figure imgf000006_0001
所述晶型 III是恩杂鲁胺的乙酸异丙酯溶剂化物， 每分子恩杂鲁胺结合 0.5 分子乙酸异丙酯。 The crystalline form III is an isopropyl acetate solvate of enzalutamide, and each molecule of enzalutamide is combined with 0.5. Molecular isopropyl acetate.
所述晶型 III的 X-射线粉末衍射图在以下衍射角 2Θ处具有特征峰：  The X-ray powder diffraction pattern of Form III has characteristic peaks at the following diffraction angle 2Θ:
5.2士 0.2。、 10.0士 0.2。、 10.2±0.2。、 13.9±0.2°、 15.3±0.2。和 16.8土 0.2。。 5.2 ± 0.2. , 10.0 ± 0.2. , 10.2 ± 0.2. , 13.9 ± 0.2 °, 15.3 ± 0.2. And 16.8 soil 0.2. .
优选地， 所述晶型 III的 X-射线粉末衍射图在以下衍射角 2Θ处具有特征峰: 5.2士 0,2°、 10.0士 0.2。、 10.2士 0.2。、 13.3士 0.2。、 13.9士 0.2ο、 15.3±0.2ο、 16.8±0.2ο、 17.5士 0.2。、 20.2士 0.2。、 22.0士 0.2。、 23.4士 0.2。和 25.6士 0.2。。 Preferably, the X-ray powder diffraction pattern of Form III has a characteristic peak at the following diffraction angle 2Θ: 5.2 ± 0, 2°, 10.0 ± 0.2. , 10.2 ± 0.2. 13.3 ± 0.2. , 13.9 ± 0.2 ο , 15.3 ± 0.2 ο , 16.8 ± 0.2 ο , 17.5 ± 0.2 . 20.2 ± 0.2. 22.0 ± 0.2. 23.4 ± 0.2. And 25.6 ± 0.2. .
进一步地， 所述晶型 ΠΙ的 X-射线粉末衍射图在以下衍射角 2Θ处具有特征 峰及其相对强度：  Further, the X-ray powder diffraction pattern of the crystalline form has characteristic peaks and relative intensities at the following diffraction angles 2Θ:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
5.2士 0.2° 100.0  5.2 ± 0.2° 100.0
10.0±0.2° 22.2  10.0 ± 0.2 ° 22.2
10.2士 0.2。 25.2  10.2 ± 0.2. 25.2
13.3±0.2° 12.9  13.3±0.2° 12.9
13.9士 0.2Q 19.3 13.9 ± 0.2 Q 19.3
15.3士 0.2° 72.5  15.3 ± 0.2 ° 72.5
16.8土 0.2。 27.4  16.8 soil 0.2. 27.4
17.5士 0.2° 13.7  17.5 ± 0.2 ° 13.7
20.0士 0.2° 11.3  20.0 ± 0.2° 11.3
20.2士 0.2° 28.5  20.2 ± 0.2 ° 28.5
22.0±0.2° 21.4  22.0±0.2° 21.4
23.4土 0.2。 16.2  23.4 soil 0.2. 16.2
25.6±0.2° 30.7  25.6 ± 0.2 ° 30.7
27.9士 0.2° 1 1.7  27.9 ± 0.2° 1 1.7
非限制性地， 所述晶型 III的一个典型实例具有如图 15所示的 X-射线粉末 衍射图。  Without limitation, a typical example of the crystal form III has an X-ray powder diffraction pattern as shown in Fig. 15.
所述晶型 III的傅里叶红外光 在波数为 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、 747cm— 1处具有特征峰。 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.
所述晶型 III的拉曼光谱在波数为 2239、 1781、 1625、 1531、 1378、 1284、 1 183、 1031、 705 、 507、 158cm 处具有特征峰。  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.
所述晶型 ΙΠ的热重分析图（TGA )显示： 在 42°C〜57°C失重为 8.5%, 约合 0.5 个乙酸异丙酯分子的理论失重量， 判定为带 0.5个乙酸异丙酯分子的溶剂化物。  The thermogravimetric analysis chart (TGA) 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.
所述晶型 III的差式扫描量热图 （DSC ) 显示在 55°C失溶剂。 晶型 III经高 温转晶后形成已知晶型 I。 室温下， 所述晶型 III在水中的溶解度为 3.46微克 /克。 较已知晶型 1 ( 2.16 微克 /克） 高。 The differential scanning calorimetry (DSC) of Form III showed solvent loss at 55 °C. Form III is crystallized at a high temperature to form a known Form I. The solubility of Form III in water at room temperature was 3.46 μg/g. Higher than known Form 1 (2.66 μg/g).
通过增溶实验可知， 晶型 III在增溶剂十二烷基硫酸钠（ SDS )存在下的溶 解度为 392.4微克 /克， 仍比同条件下已知晶型 I的溶解度（179.9微克 /克） 高。  It was found by solubilization experiments that the solubility of Form III in the presence of solubilized sodium lauryl sulfate (SDS) was 392.4 μg/g, which was still higher than the solubility of known Form I (179.9 μg/g) under the same conditions. .
所述晶型 III的制备方法， 包括如下步骤： 将恩杂鲁胺的乙酸异丙酯溶液 去除溶剂至干， 得到所述的恩杂鲁胺晶型 III。  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.
所述去除溶剂的温度为 5〜35°C , 优选为 15〜20°C。  The temperature at which the solvent is removed is 5 to 35 ° C, preferably 15 to 20 ° C.
所述去除溶剂的方法优选为将恩杂鲁胺的乙酸异丙酯溶液自然挥发至千 且所用容器不加盖或者加盖并打孔， 或者将恩杂鲁胺的乙酸异丙酯溶液使用 氮气吹干。 具体操作如下： 将样品澄清溶液放在敞口的或加盖打孔的 5毫升玻 璃小瓶中， 自然挥发或小孔挥发或敞口氮气吹扫， 去除溶剂至干。  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.
所述恩杂鲁胺乙酸异丙酯溶液的浓度为在该溶液温度下恩杂鲁胺在乙酸 异丙酯中溶解度的 0.1〜1.0倍， 优选为 0.8〜1.0倍， 例如， 室温下该溶液的浓度 为 25〜50毫克 /毫升。  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.
本发明的恩杂鲁胺晶型 ΙΠ具有以下有益效果：  The enzalutamide form of the present invention has the following beneficial effects:
与已知的恩杂鲁胺固体形式相比， 本发明的恩杂鲁胺晶型 m具有一种或 多种有利的性质， 例如： 更高的结晶度、 溶解度、 溶出速度， 好的颗粒形态、 好的储存稳定性、 低吸湿性、 有利的加工与处理特性、 适于固体制剂应用等。 特别是， 恩杂鲁胺晶型 in比恩杂鲁胺已知晶型 I的溶解度高。  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. In particular, the solubility of the enzaluene form in intrinsic crystal form I is higher than that of enzalutamide.
本发明上述恩杂鲁胺的新固态形式是纯的、 单一的， 基本没有混合任何 其他晶型或其他非晶态。 本发明中， "基本没有"当用来指新的固态形式时， 指 这个新固态形式中含有的其他晶型或其他非晶态少于 20% (重量） ， 更指少 于 10% (重量） ， 尤其指少于 5% (重量） ， 特别是指少于 1% (重量） 。  The 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. In the present invention, "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.
本发明中， "晶体"、 "晶型 "或"非晶态 "指的是被所示的 X射线衍射图表征 所证实的。 本领域技术人员能够理解， 其中的实验误差取决于仪器的条件、 样品的准备和样品的纯度。 特别是， 本领域技术人员公知， X射线衍射图通 常会随着仪器的条件而有所改变。 特别需要指出的是， X射线衍射图的相对 强度也可能随着实验条件的变化而变化， 所以峰强度的顺序不能作为唯一或 决定性因素。 另外， 峰角度的实验误差通常在 5%或更少， 这些角度的误差也 应该被考虑进去， 通常允许有士 0.2 的误差。 另外， 由于样品高度等实验因素 的影响， 会造成峰角度的整体偏移， 通常允许一定的偏移。 因而， 本领域技 术人员可以理解的是， 任何具有和本发明图谱中的特征峰相同或相似的图的 晶型均属于本发明的范畴之内。 所述"单一晶型"是指经 X-射线粉末衍射检测 是单一晶型。 In the present invention, "crystal", "crystal form" or "amorphous state" means that it is confirmed by the X-ray diffraction pattern characterization shown. Those skilled in the art will appreciate that the experimental error therein depends on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that 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. In addition, 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. In addition, due to experimental factors such as sample height, the overall offset of the peak angle is caused, and a certain offset is usually allowed. Thus, the art It will be understood by the skilled person that any crystal form having the same or similar features as the characteristic peaks in the map of the present invention is within the scope of the present invention. The "single crystal form" means a single crystal form as detected by X-ray powder diffraction.
本发明的各制备方法中： 所述"室温，，是指 10-30° (：。  In each preparation method of the present invention: the "room temperature" means 10-30 ° (:.
所述搅拌， 可以采用本领域的常规方法， 例如搅拌方式包括磁力搅拌、 机械搅拌， 搅拌速度为 50〜1800转 /分， 优选 300〜900转 /分。  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.
所述分离， 可以采用本领域的常规方法， 例如过滤、 离心等。 过滤的具 体操作为： 将欲分离的样品置于滤纸上， 减压抽滤。 离心的具体操作为： 将 欲分离的样品置于离心管中， 之后高速旋转直至固体全部沉至离心管底部， 离心速率例如为 6000转 /分。  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.
所述"超声"， 可促进样品的溶解， 具体操作是： 将装有样品溶液或悬浊液 的容器置于超声波清洗器中， 一般以 40Khz的频率超声处理 20 ~ 60秒。  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.
所述"无水物"是指产物经热重分析（TGA )测量含有不多于 1.5% (重量比)， 或不多于 1% (重量比)的水。  The "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).
本发明的起始原料恩杂鲁胺，可根据专利文献 US7709517实施例 56公开的 方法制备。  The starting material enzalutamide of the present invention can be produced according to the method disclosed in Example 56 of Patent Document US7779517.
进一步地， 本发明提供了一种药物组合物， 所述药物组合物包含治疗和 / 或预防有效量的一种或多种选自本发明的恩杂鲁胺新的固态形式或者由本发 明制备方法得到的恩杂鲁胺新的固态形式， 以及至少一种药学上可接受的赋 形剂； 所述恩杂鲁胺新的固态形式包括本发明的非晶态恩杂鲁胺、 恩杂鲁胺 晶型 II或恩杂鲁胺晶型 III。所述药物组合物还可以包含可药用恩杂鲁胺的其它 的晶型、 非晶态或盐型， 包括但不限于 US7709517所述的晶型 I。 任选地， 所 述药物组合物还可以包含一种或多种其他的药物活性成分。  Further, the present invention provides 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. Optionally, the pharmaceutical composition may also comprise one or more additional pharmaceutically active ingredients.
上述药物组合物可为固态或液态， 例如固体口服剂型， 包括片剂、 颗粒 剂、 散剂、 丸剂、 粉末和胶嚢剂； 液体口服剂型， 包括溶液剂、 糖浆剂、 混 悬剂、 分散剂和乳剂； 可注射制剂， 包括溶液剂、 分散剂和冻干剂。 配方可 适于活性成分的快速释放、 延迟释放或调节释放。 可以是常规的、 可分散的、 可咀嚼的、 口腔溶解的或快速熔化的制剂。 给药途径包括口服、 静脉皮下注 射、 注射入组织给药、 透皮给药、 直肠给药、 滴鼻给药等。  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.
本发明所述药学上可接受的赋形剂包括但不限于： 稀释剂， 例如淀粉、 预胶化淀粉、 乳糖、 粉状纤维素、 微晶纤维素、 磷酸氢钙、 磷酸三钙、 甘露 醇、 山梨醇、 糖等； 粘合剂， 例如阿拉伯胶、 瓜尔胶、 明胶、 聚乙烯吡咯烷 酮、 羟丙基纤维素、 羟丙基曱基纤维素、 聚乙二醇等； 崩解剂， 例如淀粉、 羟基乙酸淀粉钠、 预胶化淀粉、 交联聚维酮、 交联羧曱基纤维素钠、 胶体二 氧化硅等； 润滑剂， 例如硬脂酸、 硬脂酸镁、 硬脂酸锌、 苯曱酸钠、 乙酸钠、 辛酰己酰聚氧甘油酯等； 助流剂， 例如胶体二氧化硅等； 复合物形成剂， 例 如各种级别的环糊精和树脂； 释放速度控制剂， 例如羟丙基纤维素、 羟曱基 纤维素、 羟丙基曱基纤维素、 乙基纤维素、 曱基纤维素、 曱基丙烯酸曱酯、 蜡等； 抗氧化剂， 例如丁基羟基茴香醚， 二丁基羟基曱苯等。 可用的其他药 学上可接受的载体包括但不限于成膜剂、 增塑剂、 着色剂、 调味剂、 粘度调 节剂、 防腐剂等。 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, such as various grades of cyclodextrin and resin; release rate control Agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl decyl cellulose, ethyl cellulose, decyl cellulose, decyl methacrylate, wax, etc.; antioxidants such as butyl hydroxy fen Ether, dibutyl hydroxy fluorene, 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, and the like.
所述药物组合物可以使用本领域技术人员公知的方法来制备。 制备药物 组合物时， 本发明的恩杂鲁胺新的固态形式或其组合与一种或多种药学上可 接受的赋形剂相混合， 任选地， 与可药用恩杂鲁胺的其它的晶型、 非晶态或 盐型相混合， 任选地， 与一种或多种其他的药物活性成分相混合。 固体制剂 可以通过直接混合、 制粒等工艺来制备。  The pharmaceutical composition can be prepared using methods well known to those skilled in the art. When preparing a pharmaceutical composition, 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.
进一步地， 本发明提供了本发明的非晶态恩杂鲁胺、 恩杂鲁胺晶型 II或恩 杂鲁胺晶型 ΠΙ在制备治疗和 /或预防过度增生疾病的药物中的用途。  Further, 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.
进一步地， 本发明提供了一种治疗和 /或预防过度增生疾病的方法， 所述 方法包括给予需要的患者治疗和 /或预防有效量的一种或多种的选自本发明的 非晶态恩杂鲁胺、 恩杂鲁胺晶型 II、 恩杂鲁胺晶型 III或其药物组合物。 所述患 者是指包括人类在内的哺乳动物。  Further, 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. Enzalutamide, enzalutamide Form II, enzalutamide Form III or a pharmaceutical composition thereof. The patient refers to a mammal including a human.
所述过度增生疾病包括前列腺癌、 良性前列腺增生、 乳腺癌、 卵巢癌、 与前列腺特异性抗原 mRNA转录相关的疾病，与雄激素受体蛋白质核易位相关 的疾病等， 尤其是转移性去势耐受前列腺癌。  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.
本发明的恩杂鲁胺新固态形式用于制备治疗和 /或预防转移性去势耐受前 列腺癌的药物中，可干扰前列腺特异性抗原 mRNA的转录， 防止雄激素受体蛋 白质的核易位， 使雄激素受体蛋白质不稳定。 使用剂量可以是 0.00卜 100毫克 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
/公斤体重 /天、 0.01〜 100毫克 /公斤体重 /天、 0.卜 10毫克 /公斤体重 /天或 1毫克 / 公斤体重 /天。 附图说明 /kg body weight / day, 0.01 ~ 100 mg / kg body weight / day, 0. Bu 10 mg / kg body weight / day or 1 mg / kg body weight / day. DRAWINGS
图 1为根据 US7709517制备的恩杂鲁胺晶型 I的 XRPD图谱。  Figure 1 is an XRPD pattern of enzalutamide Form I prepared according to US7709517.
图 2为根据 US7709517制备的恩杂鲁胺晶型 I的 DSC图谱。  Figure 2 is a DSC map of enzalutamide Form I prepared according to US7709517.
图 3为根据 US7709517制备的恩杂鲁胺晶型 I的 TGA图。  Figure 3 is a TGA diagram of enzalutamide Form I prepared according to US7709517.
图 4为根据 US7709517制备的恩杂鲁胺晶型 I的红外图谱。  Figure 4 is an infrared spectrum of enzalutamide Form I prepared according to US7709517.
图 5为根据 US7709517制备的恩杂鲁胺晶型 I的拉曼图谱。  Figure 5 is a Raman spectrum of enzalutamide Form I prepared according to US7709517.
图 6为本发明非晶态恩杂鲁胺的 XRPD图谱。  Figure 6 is an XRPD pattern of the amorphous enzalutamide of the present invention.
图 7为本发明非晶态恩杂鲁胺的 DSC图谱。  Figure 7 is a DSC chart of the amorphous enzalutamide of the present invention.
图 8为本发明非晶态恩杂鲁胺的 TGA图语。  Figure 8 is a TGA diagram of the amorphous enzalutamide of the present invention.
图 9为本发明非晶态恩杂鲁胺的红外图谱。  Figure 9 is an infrared spectrum of the amorphous enzalutamide of the present invention.
图 10为本发明非晶态恩杂鲁胺的拉曼图谱。  Figure 10 is a Raman spectrum of the amorphous enzalutamide of the present invention.
图 1 1为本发明恩杂鲁胺晶型 II的 XRPD图 i普。  Figure 11 is an XRPD diagram of the enzalutamide Form II of the present invention.
图 12为本发明恩杂鲁胺晶型 II的 DSC图普。  Figure 12 is a DSC diagram of the enzalutamide Form II of the present invention.
图 13为本发明恩杂鲁胺晶型 II的 TGA图谱。  Figure 13 is a TGA map of enzalutamide Form II of the present invention.
图 14为本发明恩杂鲁胺晶型 II的红外图谱。  Figure 14 is an infrared spectrum of enzalutamide Form II of the present invention.
图 15为本发明恩杂鲁胺晶型 III的 XRPD图谱。  Figure 15 is an XRPD pattern of enzalutamide Form III of the present invention.
图 16为本发明恩杂鲁胺晶型 III的 DSC图谱。  Figure 16 is a DSC chart of enzalutamide Form III of the present invention.
图 17为本发明恩杂鲁胺晶型 III的 TGA图语。  Figure 17 is a TGA diagram of the enzalutamide Form III of the present invention.
图 18为本发明恩杂鲁胺晶型 III的红外图谱。  Figure 18 is an infrared spectrum of enzalutamide Form III of the present invention.
图 19为本发明恩杂鲁胺晶型 m的拉曼图谱。 具体实施方式  Figure 19 is a Raman spectrum of m-enzolamide crystal form m of the present invention. detailed description
本发明进一步参考以下实施例限定， 所述实施例详细描述本发明的晶型、 其制备方法和应用。 对本领域技术人员显而易见的是， 对于材料和方法两者 的许多改变可在不脱离本发明范围的情况下实施。  The invention is further defined by the following examples, which describe in detail the crystal form of the invention, its method of preparation and its use. It will be apparent to those skilled in the art that many changes in the materials and methods can be practiced without departing from the scope of the invention.
检测仪器及方法：  Testing equipment and methods:
X射线粉末衍射 （ XPRD ) 所使用的仪器为 Bmker D8 Advance  The instrument used for X-ray powder diffraction ( XPRD ) is Bmker D8 Advance
Diffractometer, 配置有 Θ-2Θ测角仪、 Mo单色仪、 Lynxeye探测器。 采集软件是 Diffrac Plus XRD Commander,分析软件是 MDI Jade 5.0。仪器在使用前用仪器 自带的标准品 （一般为刚玉）校准。 检测条件为： 2Θ扫描角度范围 3〜40。， 步 长 0.02°， 速度 0.2秒 /步。 检测过程： 采用铜靶波长为 1.54nm的 Ka X-射线， 在 40 kV和 40 mA的操作条件下， 样品在室温条件下测试， 把需要检测的样品放 在有机玻片上。 除非特别说明， 样品在检测前未经研磨。 Diffractometer, equipped with a Θ-2Θ 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: 2Θ 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.
差热分析（ DSC )数据采自于 TA Instruments Q200 MDSC , 仪器控制软件 是 Thermal Advantage, 分析软件是 Universal Analysis。 通常取 1~10毫克的样品 放置于未加盖 （除非特别说明） 的铝坩埚内， 以 1CTC/分钟的升温速度在 50毫 升 /分钟千燥 N2的保护下将样品从室温升至 250Ό , 同时 TA软件记录样品在升 温过程中的热量变化。 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 保护 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.
热重分析（ TGA )数据采自于 TA Instruments Q500 TGA, 仪器控制软件 是 Thermal Advantage, 分析软件是 Universal Analysis。 通常耳又 5〜： 15 mg样品放 置于白金坩埚内， 采用分段高分辨检测的方式， 以 10°C/分钟的升温速度在 50 毫升 /分钟千燥N2保护下将样品从室温升至 30CTC , 同时 TA软件记录样品在升 温过程中的重量变化。 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.
傅里叶红外光谱（ IR ) 采用 ATR设备， 设备型号是 Bruker Tensor 27在 ^OO^OOcm-1范围内， 对红外吸收光谱采集， 其中样品和空白背景的扫描时间 均为 16秒， 仪器分辨率为
Figure imgf000012_0001
Fourier infrared spectroscopy (IR) is performed on the ATR device. The device model is Bruker Tensor 27 in the range of ^OO^OOcm- 1 , and the infrared absorption spectrum is collected. The scanning time of the sample and the blank background is 16 seconds. for
Figure imgf000012_0001
拉曼光谱采用的设备型号是 DXR780激光显微拉曼光谱仪。 在 10倍镜下， 波数范围 SO^^Ocm-1内， 以曝光时间 1秒、 曝光次数 8次对样品进行拉曼光谱 采集。 高效液相色谱仪采用 Waters2695进样器及 Waters2487检测器， 检测方法 如表 1所示。 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.
表 1 检测方法  Table 1 Test method
色谱柱 Welch Xtimate C 18, 5 μιη, 150 χ 4.6 mm  Column Welch Xtimate C 18, 5 μιη, 150 χ 4.6 mm
柱溫 r至> Column temperature r to >
M.  M.
流速 1.0 ml/min  Flow rate 1.0 ml/min
检测波长 220nm  Detection wavelength 220nm
进样量 5μL  Injection volume 5μL
溶剂 乙腈  Solvent acetonitrile
流动相 A 水  Mobile phase A water
流动性 B 乙腈  Fluidity B acetonitrile
时间 （分钟） 流动相 B百分比  Time (minutes) mobile phase B percentage
0 30  0 30
8 90  8 90
13 90 13.01 30 13 90 13.01 30
15 30  15 30
如无特别说明， 实施例均在室温条件下操作。  The examples were all operated at room temperature unless otherwise stated.
如无特别说明， 实施例中所用的各种试剂均为市售购买。 实施例 1 将 N-曱基 -2-氟 -4- ( 1， 1 -二曱基 -氰基曱基）氨基苯曱酰胺（3g, 13mmol ) 和 4-异硫氰基 -2-三氟曱基苯曱腈（5.8g， 26mmol)加入到 lOOmL DMF中， 在微 波照射下升温到 100°C保温 11小时，降温到 50°C ,加入 2000mL甲醇和 500mLlN 盐酸， 再升温回流 1.5小时， 冷却到室温， 倒入 5000mL冷水中， 用 5000mL乙 酸乙酯萃取， 有机相加硫酸镁干燥， 过滤， 滤液浓缩， 得到的残余物柱层析 (展开剂为二氯曱烷： 丙酮 =95: 5 )， 得到 1.5g恩杂鲁胺白色固体，摩尔收率： 25%。  Unless otherwise stated, the various reagents used in the examples were commercially available. 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. To room temperature, pour into 5000 mL of cold water, extract with 5000 mL of ethyl acetate, dry with organic sodium sulfate, filter, and concentrate the filtrate, and the residue obtained by column chromatography (dichloromethane: acetone = 95: 5) , 1.5 g of enzalutamide white solid was obtained in a molar yield: 25%.
Ή-NMR (300 MHz, DMSO-d6)： 1.61 (s,6H),3.07(d,3H,J=4.1 Hz),6.71 (m, 1 H 7.15(dd, 1 H,J=11.7Hz),7.24(dd, 1 H, J-8.4Hz), 7.83 (dd, 1 H, J=8.2Hz),7.95 (d, 1 H, J=2.1 Hz),7.99(d， 1 H,J=8.2Hz),8.28(dd, 1 H，J=8.4Hz)。  Ή-NMR (300 MHz, DMSO-d6): 1.61 (s, 6H), 3.07 (d, 3H, J = 4.1 Hz), 6.71 (m, 1 H 7.15 (dd, 1 H, J = 11.7 Hz), 7.24 (dd, 1 H, J-8.4 Hz), 7.83 (dd, 1 H, J = 8.2 Hz), 7.95 (d, 1 H, J = 2.1 Hz), 7.99 (d, 1 H, J = 8.2 Hz) ), 8.28 (dd, 1 H, J = 8.4 Hz).
XRPD图谱如图 1所示， 显示为晶型 I。  The XRPD pattern is shown in Figure 1 and is shown as Form I.
DSC图谱如图 2所示， 显示熔点为 197 ~ 199° ( 。  The DSC spectrum is shown in Figure 2 and shows a melting point of 197 ~ 199 ° ( .
TGA图谱如图 3所示， 显示为无水物。  The TGA map is shown in Figure 3 and is shown as an anhydrate.
IR图谱如图 4所示。  The IR spectrum is shown in Figure 4.
拉曼图谱如图 5所示。  The Raman spectrum is shown in Figure 5.
实施例 2 Example 2
取实施例 1制备的恩杂鲁胺 lOOmg放入 30mL单口烧瓶中， 加入 10mL二氯 曱烷， 40KHz超声 30秒保证其完全溶清， 再置于旋转蒸发仪上， 于 40Ό旋干， 去除溶剂的速率约为 15毫升 /分钟， 得到非晶态恩杂鲁胺。  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.
XRPD图语如图 6所示， 显示为无定形， 没有任何尖锐的衍射峰。 。  The XRPD graphic is shown in Figure 6. It is shown as amorphous and does not have any sharp diffraction peaks. .
DSC图谱如图 7所示， 显示为无定形， 玻璃化温度为 46°C , 137°C发生转 晶。 经检测， 转晶后形成晶型 I。  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.
TGA图谱如图 8所示。  The TGA map is shown in Figure 8.
IR图潘如图 9所示。 拉曼图 "i脊如图 10所示。 The IR map is shown in Figure 9. The Raman diagram "i ridge is shown in Figure 10.
实施例 3 Example 3
取实施例 1制备的恩杂鲁胺 1 Omg放入 30mL单口烧瓶中' 加入 1 OmL二氯曱 烷， 40KHz超声 20秒保证其完全溶清， 再置于旋转蒸发仪上， 于 40°C旋干' 去 除溶剂的速率约为 5毫升 /分钟， 得到非晶态恩杂鲁胺。 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.
实施例 4 Example 4
取实施例 1制备的恩杂鲁胺 80mg放入 30mL单口烧瓶中， 加入 1 OmL二氯甲 烷， 40KHz超声 40秒保证其完全溶清， 再置于旋转蒸发仪上， 于 40°C旋干， 去 除溶剂的速率约为 10毫升 /分钟， 得到非晶态恩杂鲁胺。  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.
实施例 5 Example 5
取实施例 1制备的恩杂鲁胺 1 OOmg放入 20mL小瓶中， 加入 1 OmL二氯曱烷， 40KHz超声 60秒保证其完全溶清，再置于氮气吹扫仪上， 于 40°C通氮气吹扫去 除溶剂， 去除溶剂的速率约为 15毫升 /分钟， 得到非晶态恩杂鲁胺。  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.
实施例 6 Example 6
取实施例 1制备的恩杂鲁胺 lOOmg放入 20mL小瓶中， 加入 10mL二氯曱烷， 100 mg of enzalutamide prepared in Example 1 was placed in a 20 mL vial, and 10 mL of dichloromethane was added.
40KHz超声 30秒保证其完全溶清，再置于真空干燥器中，于 45 °C真空烘干溶剂， 去除溶剂的速率约为 15毫升 /分钟， 得到 晶态恩杂鲁胺。 40KHz ultrasonic for 30 seconds to ensure complete dissolution, and then placed in a vacuum desiccator, drying the solvent under vacuum at 45 ° C, the solvent removal rate is about 15 ml / min, to obtain crystalline enzalutamide.
实施例 7 Example 7
取实施例 1制备的恩杂鲁胺 lOOmg放入 20mL小瓶中， 加入 10mL乙腈， 40KHz超声 30秒保证其完全溶清，再置于冻干机中， 降温至零下 50°C使溶液凝 固， 于室温抽真空干燥， 去除溶剂的速率约为 15毫升 /分钟， 得到非晶态恩杂 鲁胺。  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.
实施例 8  Example 8
取实施例 1制备的恩杂鲁胺 l OOmg放入 20mL小瓶中， 加入 10mL二氯甲烷， 40KHz超声 30秒保证其完全溶清， 再置于喷雾千燥机中， 于室温喷雾干燥， 去 除溶剂的速率为 15毫升 /分钟， 得到非晶态恩杂鲁胺。  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.
实施例 9  Example 9
将实施例 2中的二氯甲烷替换为曱醇， 其他操作同实施例 2, 得到非晶态 恩杂鲁胺。  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.
实施例 10  Example 10
将实施例 2中的二氯曱烷替换为乙醇， 其他操作同实施例 2, 得到非晶态 恩杂鲁胺。 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.
实施例 1 1 Example 1 1
将实施例 2中的二氯曱烷替换为正丙醇， 其他操作同实施例 2 , 得到非晶 态恩杂鲁胺。  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.
实施例 12 Example 12
将实施例 2中的二氯曱烷替换为异丙醇， 其他操作同实施例 2 , 得到非晶 态恩杂鲁胺。  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.
实施例 13 Example 13
将实施例 2中的二氯曱烷替换为丙酮， 其他操作同实施例 2 , 得到非晶态 恩杂鲁胺。  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.
实施例 14 Example 14
将实施例 2中的二氯曱烷替换为曱乙酮， 其他操作同实施例 2， 得到非晶 态恩杂鲁胺。  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.
实施例 15 Example 15
将实施例 2中的二氯曱烷替换为乙醚， 其他操作同实施例 2， 得到非晶态 恩杂鲁胺。  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.
实施例 16  Example 16
将实施例 2中的二氯甲烷替换为乙酸乙酯， 其他操作同实施例 2， 得到非 晶态恩杂鲁胺。  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.
实施例 17  Example 17
将实施例 2中的二氯曱烷替换为曱基叔丁基醚， 其他操作同实施例 2, 得 到非晶态恩杂鲁胺。  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.
实施例 18  Example 18
将实施例 2中的二氯甲烷替换为四氢呋喃， 其他操作同实施例 2， 得到非 晶态恩杂鲁胺。  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.
实施例 19  Example 19
将实施例 2中的二氯曱烷替换为乙腈， 其他操作同实施例 2 , 得到非晶态 恩杂鲁胺。  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.
实施例 20  Example 20
将实施例 2中的二氯曱烷替换为氯仿， 其他操作同实施例 2 , 得到非晶态 恩杂鲁胺。 实施例 3 ~ 20制备的样品具有与实施例 2相同或相似的 XRPD图谱、 DSC图 谱、 TGA图谱、 IR图语、 拉曼图谱（未示出） 。 说明这些实施例制备得到的 是和实施例 2相同的物质。 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.
实施例 21 Example 21
取实施例 1制备的恩杂鲁胺 20毫克放入 5毫升反应瓶中， 加入 0.8毫升甲醇 溶清， 另将 2.5毫升水加入另一个 5毫升反应瓶中， 将上述恩杂鲁胺曱醇溶液滴 加至水中， 室温下搅拌 5分钟， 离心， 45°C真空干燥 5小时， 得到恩杂鲁胺晶 型 II。  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.
XRPD图语如图 11所示。  The XRPD graphics are shown in Figure 11.
DSC图谱如图 12所示， 显示熔点为 113 ~ 130Ό， 熔融后发生转晶， 转晶 温度为 131-148°C， 转晶后样品熔点为 196°C , 经检测为已知晶型 I。  The DSC spectrum is shown in Fig. 12. It shows a melting point of 113 ~ 130 Ό. 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.
TGA图谱如图 13所示， 显示为无水物。  The TGA map is shown in Figure 13 and is shown as an anhydrate.
IR图谱如图 14所示。  The IR spectrum is shown in Figure 14.
实施例 22 Example 22
取实施例 1制备的恩杂鲁胺 20毫克放入 5毫升反应瓶中， 加入 1.0毫升乙醇 溶清， 另将 5毫升水加入另一个 10毫升反应瓶中， 将上述恩杂鲁胺乙醇溶液滴 加至水中， 40°C下搅拌 2分钟， 离心， 45°C真空千燥 5小时， 得到恩杂鲁胺晶 型 II。  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.
实施例 23 Example 23
取实施例 1制备的恩杂鲁胺 20毫克放入 10毫升反应瓶中，加入 8.0毫升乙腈 溶清， 另将 24毫升水加入另一个 50毫升反应瓶中， 将上述恩杂鲁胺乙腈溶液 滴加至水中， 10°C下搅拌 10分钟， 离心， 45°C真空干燥 5小时， 得到恩杂鲁胺 晶型 II。  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.
实施例 24 Example 24
取实施例 1制备的恩杂鲁胺 20毫克放入 5毫升反应瓶中， 加入 0.8毫升四氢 呋喃， 溶清， 另将 8.0毫升水加入另一个 10毫升反应瓶中， 将上述恩杂鲁胺四 氢呋喃溶液滴加至水中， 室温下搅拌 3分钟， 离心， 45°C真空干燥 5小时， 得 到恩杂鲁胺晶型 II。  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.
实施例 22 ~ 24制备的样品具有与实施例 21相同或相似的 XRPD图谱、 IR图 谱、 DSC图谱（未示出） 。 说明这些实施例制备得到的是和实施例 21相同的 物质。 实施例 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
称取实施例 1制备的恩杂鲁胺 100毫克于 5毫升玻璃瓶中， 加入 2毫升乙酸 异丙酯， 40KHz超声 30秒保证其完全溶清，不加盖，置于室温下自然挥发至干， 得到恩杂鲁胺晶型 III。  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.
XRPD图谱如图 15所示。  The XRPD map is shown in Figure 15.
DSC图谱如图 16所示， 显示在 55°C失溶剂。  The DSC spectrum is shown in Figure 16, which shows the loss of solvent at 55 °C.
TGA图谱如图 17所示， 显示在 42°C〜57°C失重为 8.5%, 约合 0.5个乙酸异 丙酯分子的理论失重量相符， 判定为带 0.5个乙酸异丙酯分子的溶剂化物； 经 检测， 该晶型脱去乙酸异丙酯后， 形成已知晶型 I。  The TGA spectrum is shown in Figure 17, which shows a weight loss of 8.5% at 42 °C to 57 °C, which is equivalent to the theoretical weight loss of 0.5 isopropyl acetate molecules, and is determined to be a solvate with 0.5 isopropyl acetate molecules. After the crystal form is removed, isopropyl acetate is removed to form a known crystal form I.
IR图谱如图 18所示。  The IR spectrum is shown in Figure 18.
拉曼图语如图 19所示。  The Raman language is shown in Figure 19.
实施例 26 Example 26
将实施例 25中的"不加盖 "条件替换为 "加盖打孔"条件，其他操作同实施例 Replace the "uncapped" condition in the embodiment 25 with the "capped punch" condition, and the other operations are the same as the embodiment.
25, 得到恩杂鲁胺晶型 m。 25, obtaining m-enzolamide crystal form m.
实施例 27 Example 27
称取实施例 1制备的恩杂鲁胺 100毫克于 5毫升玻璃瓶中， 加入 4毫升乙酸 异丙酯， 40KHz超声 30秒保证其完全溶清， 20°C下用氮气将乙酸异丙酯吹干， 得到恩杂鲁胺晶型 III。  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.
实施例 26〜27制备的样品具有与实施例 25相似的 XRPD图谱、 DSC图傳、 TGA图语、 IR图语、 拉曼图语（未示出） ， 说明这些实施例制备得到的物质 与实施例 25相同。  The samples prepared in Examples 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.
实施例 28  Example 28
胶嚢剂配方如表 2所示。  The formulation of the capsules is shown in Table 2.
表 2 胶嚢剂配方  Table 2 Gelatin formula
成 分 剂量（毫克 /粒） 兮里 本发明制备的非晶态恩杂鲁胺 40 26.67% 阿拉伯胶 5 3.33% 玉米淀粉 30 20% 蔗糖 75 50% 胶嚢剂的制备方法： 按照表 2配方， 本发明制备的非晶态恩杂鲁胺与玉米 淀粉、 蔗糖混勾成混合物， 将阿拉伯胶溶于水形成 1%的水溶液， 加入到上述 混合物中， 制备得到湿颗粒， 将颗粒干燥后装入胶嚢。 实施例 29 Ingredient Dose (mg/granule) 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
将实施例 28中的 "本发明制备的非晶态恩杂鲁胺"换为 "本发明制备的恩杂 鲁胺晶型 II", 其他操作同实施例 28, 制备胶嚢剂。  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.
实施例 30 Example 30
将实施例 28中得"本发明制备的非晶态恩杂鲁胺"换为"本发明制备的恩杂 鲁胺晶型 ΠΓ, 其他操作同实施例 28， 制备胶嚢剂。  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.
实施例 31 Example 31
片剂配方如表 3所示。  Tablet formulations are shown in Table 3.
表 3 片剂配方  Table 3 Tablet Formulation
成分 剂量（毫克 /片 ) 入 ^Ξ- 里  Ingredient dose (mg/tablet) into ^Ξ-
本发明制备的非晶态恩杂鲁胺 40 13.33%  Amorphous enzalutamide 40 prepared by the invention 13.33%
CaHP04 80 26.67% CaHP0 4 80 26.67%
阿拉伯胶 5 1.67%  Gum arabic 5 1.67%
玉米淀粉 60 20%  Corn starch 60 20%
蔗糖 1 13 37.66%  Sucrose 1 13 37.66%
硬脂酸镁 2 0.67%  Magnesium stearate 2 0.67%
片剂的制备方法： 按照表 3配方， 将本发明制备的非晶态恩杂鲁胺与  Method for preparing tablets: According to the formulation of Table 3, the amorphous enzalutamide prepared by the invention is
CaHP04、玉米淀粉、蔗糖混勾成混合物，将阿拉伯胶溶于水形成 1%的水溶液， 加入到上述混合物中， 制备得到湿颗粒， 将湿颗粒千燥， 加入硬脂酸镁混匀 后进行压片。 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.
实施例 32 Example 32
将实施例 31中得"本发明制备的非晶态恩杂鲁胺"换为 "本发明制备的恩杂 鲁胺晶型 II", 其他操作同实施例 31 , 制备片剂。  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.
实施例 33  Example 33
将实施例 31中得"本发明制备的非晶态恩杂鲁胺 "换为 "本发明制备的恩杂 鲁胺晶型 ΙΠ", 其他操作同实施例 31 , 制备片剂。 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.
†比例 1  † ratio 1
分别称取各 20.0毫克本发明制备的非晶态恩杂鲁胺、 恩杂鲁胺的晶型 II和 晶型 III以及实施例 1制备的恩杂鲁胺晶型 1, 各加入 100毫升水， 搅拌 1.5小时， 过滤， 称取滤液重量， 然后滤液旋干， 加入乙腈溶清并转移至 10毫升容量瓶 定容， 称重后进行高效液相色谱检测， 各晶型的溶解度结果见表 4, 显示： 本 发明的非晶态恩杂鲁胺、 恩杂鲁胺晶型 II和晶型 III的溶解度均比晶型 I高。  20.0 mg of each of the amorphous enzalutamide prepared by the present invention, the crystalline form II and the crystalline form III of enzalutamide, and the enzalutamide form 1 prepared in Example 1 were each weighed, and 100 ml of water was added thereto. After stirring for 1.5 hours, the mixture was filtered, and the filtrate was weighed. Then the filtrate was spun dry, dissolved in acetonitrile and transferred to a 10 ml volumetric flask for constant volume. After weighing, high performance liquid chromatography was performed. The solubility of each crystal form is shown in Table 4. It is shown that the solubility of the amorphous enzalutamide, enzalutamide Form II and Form III of the present invention is higher than that of Form I.
再分别量取 100毫升水至四个烧杯中， 并在其中各加入 160毫克十二烷基 硫酸钠（SDS ) ， 配置成十二烷基硫酸钠水溶液， 称取各 20,0毫克本发明制备 的非晶态恩杂鲁胺、 恩杂鲁胺晶型 II和晶型 III以及实施例 1制备的恩杂鲁胺晶 型 I， 分别加入上述十二烷基硫酸钠水溶液中， 搅拌 10分钟， 过滤， 称取滤液 重量， 然后滤液旋干， 加入乙腈溶清并转移至 10毫升容量瓶定容， 称重后进 行高效液相色谱检测， 各晶型的溶解度结果见表 4, 显示： 本发明的非晶态恩 杂鲁胺、 恩杂鲁胺的晶型 II和晶型 ΠΙ在增溶条件下溶解度均比晶型 I高。 Then, 100 ml of water was separately weighed into four beakers, and 160 mg of sodium dodecyl sulfate (SDS) was added thereto to prepare an aqueous solution of sodium lauryl sulfate, and 20 mg of each of the preparations were prepared. The amorphous enzalutamide, enzalutamide Form II and Form III, and the enzalutamide Form I prepared in Example 1, were respectively added to the above aqueous sodium lauryl sulfate solution, and stirred for 10 minutes. Filtration, weighed the filtrate, then the filtrate was spun dry, dissolved in acetonitrile and transferred to a 10 ml volumetric flask to determine the volume, and then weighed and then tested by high performance liquid chromatography. The solubility results of each crystal form are shown in Table 4, showing: The amorphous enzalutamide, the crystalline form II of enzalutamide and the crystalline form have higher solubility under the solubilization conditions than the crystalline form I.
表 4 不同晶型的溶解度结果  Table 4 Solubility results for different crystal forms
Figure imgf000019_0001
Figure imgf000019_0001

Claims

Figure imgf000020_0001
其特征在于， 所述非晶态恩杂鲁胺具有至少一种如下的特性： 所述非晶 态恩杂鲁胺的 X-射线粉末衍射图基本上如图 6所示； 或者所述非晶态恩杂鲁胺 的玻璃化温度为 46°C。
Figure imgf000020_0001
Characterizing in that the amorphous enzalutamide has at least one of the following characteristics: an X-ray powder diffraction pattern of the amorphous enzalutamide is substantially as shown in FIG. 6; or the amorphous The emidamide has a glass transition temperature of 46 °C.
2、 一种权利要求 1所述非晶态恩杂鲁胺的制备方法， 其特征在于， 包括 如下步骤： 形成恩杂鲁胺在可溶溶剂中的溶液， 以至少为 5毫升 /分钟的速率去 除溶剂， 得到所述非晶态的恩杂鲁胺；  2. A process for the preparation of amorphous enzalutamide according to claim 1, comprising the steps of: forming a solution of enzalutamide in a soluble solvent at a rate of at least 5 ml/min Removing the solvent to obtain the amorphous enzalutamide;
所述可溶溶剂选自 C,-C3醇、 C(-C2|¾代烷烃、 CrC4酮、 C2-C5醚、 C3-C5酯、 c2-c3腈或其混合物， 优选自曱醇、 乙醇、 正丙醇、 异丙醇、 二氯曱烷、 氯仿、 丙酮、 曱乙酮、 乙醚、 曱基叔丁基醚、 四氢呋喃、 乙酸乙酯、 乙腈或其混合 物； 所述恩杂鲁胺在可溶溶剂中的溶液浓度为在该溶液温度下恩杂鲁胺在可 溶溶剂中溶解度的 0.1〜1.0倍， 优选为 0.8〜1.0倍； 所述去除溶剂的速率优选为 5~15毫升 /分钟； 所述去除溶剂的方式选自旋转蒸发、 真空蒸发、 氮吹蒸发、 冻干或喷雾干燥。 The soluble solvent is selected from the group consisting of C,-C 3 alcohol, C ( -C 2 | 3⁄4 alkane, C r C 4 ketone, C 2 -C 5 ether, C 3 -C 5 ester, c 2 -c 3 nitrile) Or a mixture thereof, preferably from decyl alcohol, ethanol, n-propanol, isopropanol, dichlorodecane, chloroform, acetone, ethyl ketone, diethyl ether, decyl tert-butyl ether, tetrahydrofuran, ethyl acetate, acetonitrile or a mixture; the solution concentration of the enzalutamide in a soluble solvent is 0.1 to 1.0 times, preferably 0.8 to 1.0 times, the solubility of enzalutamide in the soluble solvent at the solution temperature; The rate is preferably from 5 to 15 ml/min; the solvent removal is selected from the group consisting of rotary evaporation, vacuum evaporation, nitrogen blow evaporation, lyophilization or spray drying.
3、 结构式如下所示的恩杂鲁胺晶型 II,  3. The structure of enzalutamide II as shown below,
其特征在于，所述晶型 II的 X-射线粉末衍射图在以下衍射角 2Θ处具有特征 峰： 4.9士 0.2。、 9.8士 0·2°、 1 1.4±0.2°、 13.6士 0.2°、 15.7士 0.2°和 17.1士 0.2°。 Characterized in that the X-ray powder diffraction pattern of the Form II has characteristics at the following diffraction angle 2Θ Peak: 4.9 ± 0.2. 9.8 ± 0 · 2 °, 1 1.4 ± 0.2 °, 13.6 ± 0.2 °, 15.7 ± 0.2 ° and 17.1 ± 0.2 °.
4、 根据权利要求 3所述的恩杂鲁胺晶型 Π, 其特征在于， 所述晶型 II的 X- 射线粉末衍射图在以下衍射角 2Θ处具有特征峰: 4.9±0.2°、 7.9±0·2°、 9.8±0.2°、 1 1.4±0.2°、 12.7±0.2。、 13.6士 0.2°、 14.5±0.2°、 15.4士 0.2°、 15.7士 0.2°、 17.1士 0.2°、 18.6士 0.2°和 25.7士 0.2°。  4. The enzalutamide crystalline form according to claim 3, wherein the X-ray powder diffraction pattern of the crystalline form II has a characteristic peak at a diffraction angle of 2 以下: 4.9 ± 0.2°, 7.9 ± 0·2°, 9.8±0.2°, 1 1.4±0.2°, 12.7±0.2. 1,3.6 ± 0.2 °, 14.5 ± 0.2 °, 15.4 ± 0.2 °, 15.7 ± 0.2 °, 17.1 ± 0.2 °, 18.6 ± 0.2 ° and 25.7 ± 0.2 °.
5、 根据权利要求 4所述的恩杂鲁胺晶型 Π, 其特征在于， 所述晶型 II的 X 射线粉末衍射图在以下衍射角 2Θ处具有特征峰及其相对强度：  The enzalutamide crystalline form according to claim 4, wherein the X-ray powder diffraction pattern of the crystalline form II has characteristic peaks and relative intensities at the following diffraction angles 2:
衍射角 2Θ 相对强度 °/。  Diffraction angle 2Θ Relative intensity °/.
4.9土 0.2° 100.0  4.9 soil 0.2° 100.0
7.9士 0.2° 15.3  7.9 ± 0.2° 15.3
9.8士 0.2° 23.8  9.8 ± 0.2° 23.8
1 1.4士 0.2° 22.3  1 1.4 ± 0.2° 22.3
12.7±0.2° 14.5  12.7±0.2° 14.5
13.6士 0.2° 30.8  13.6 ± 0.2° 30.8
14.5±0.2° 20.9  14.5±0.2° 20.9
15.4士 0.2Q 15.7 15.4士0.2 Q 15.7
15.7士 0.2° 35.8  15.7 士 0.2° 35.8
17.1士 0.2° 34.7  17.1 ± 0.2° 34.7
18.6±0.2° 16.8  18.6±0.2° 16.8
21.2士 0.2° 1 1.0  21.2 ± 0.2° 1 1.0
23.0士 0.2。 14.4  23.0 ± 0.2. 14.4
23.5士 0.2° 18.8  23.5 ± 0.2° 18.8
24.5±0.2° 14.9  24.5±0.2° 14.9
25.7±0.2° 24.6  25.7±0.2° 24.6
27.1士 0.2° 14.2  27.1 ± 0.2° 14.2
6、权利要求 3-5中任一项所述的恩杂鲁胺晶型 II的制备方法，其特征在于， 所述制备方法包括如下步骤： 将恩杂鲁胺溶液加入到水中， 然后于析晶温度 下搅拌析晶， 将析出的固体分离、 干燥， 得到所述恩杂鲁胺晶型 Π, 其中所述 溶液的溶剂选 d-Cg醇、 c2-c3腈、 c2-c6醚或其混合物； The method for preparing enzalutamide form II according to any one of claims 3 to 5, wherein the preparation method comprises the steps of: adding an enzalutamide solution to water, and then analyzing The crystal is stirred and stirred at a crystal temperature, and the precipitated solid is separated and dried to obtain the enzalutamide crystal form, wherein the solvent of the solution is selected from d-Cg alcohol, c 2 -c 3 nitrile, c 2 -c 6 Ether or a mixture thereof;
所述析晶温度为 10°C ~ 40°C , 优选为室温； 所述析晶时间为 2分钟〜 10分 钟， 优选为 2分钟〜 5分钟； 所述溶剂选自曱醇、 乙醇、 乙腈、 四氢呋喃或其 度的 0.1 ~ 1.0倍， 优选为 0.8 ~ 1.0倍； 所述水的体积为溶剂体积的 3 ~ 10倍， 优 选为 3 ~ 5倍。 The crystallization temperature is 10 ° C ~ 40 ° C, preferably room temperature; the crystallization time is 2 minutes to 10 minutes, preferably 2 minutes to 5 minutes; the solvent is selected from the group consisting of decyl alcohol, ethanol, acetonitrile, Tetrahydrofuran or a degree thereof is 0.1 to 1.0 times, preferably 0.8 to 1.0 times; the volume of the water is 3 to 10 times the volume of the solvent, preferably Choose 3 to 5 times.
7、 结构式如下所示的恩杂鲁胺晶型 m: 7. The structure of enzalutamide as shown below: m:
Figure imgf000022_0001
Figure imgf000022_0001
其特征在于， 所述晶型 III的 X-射线粉末衍射图在以下衍射角 2 Θ处具有特 征峰： 5.2士 0.2°、 10.0士 0.2°、 10.2士 0.2。、 13.9士 0.2°、 15.3±0.2°和 16.8±0.2°。  It is characterized in that the X-ray powder diffraction pattern of the crystal form III has a characteristic peak at the following diffraction angle 2 :: 5.2 ± 0.2°, 10.0 ± 0.2°, 10.2 ± 0.2. , 13.9 ± 0.2 °, 15.3 ± 0.2 ° and 16.8 ± 0.2 °.
8、 根据权利要求 7所述的恩杂鲁胺晶型 III, 其特征在于， 所述晶型 III的 X-射线粉末衍射图在以下衍射角 2Θ处具有特征峰： 5.2±0.2°、 10.0±0.2°、 10.2±0.2°、 13.3士 0.2°、 13.9士 0.2。、 15.3±0·2。、 16.8士 0.2°、 17.5±0.2°、 20.2士 0.2°、 22.0士 0.2°、 23.4土 0.2°和 25.6土 0.2°。  The enzalutamide crystal form III according to claim 7, wherein the X-ray powder diffraction pattern of the crystal form III has a characteristic peak at a diffraction angle of 2 以下: 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 °.
9、 根据权利要求 8所述的恩杂鲁胺晶型 ΙΠ, 其特征在于， 所述晶型 III的 X-射线粉末衍射图在以下衍射角 2Θ处具有特征峰及其相对强度：  9. The enzalutamide crystalline form according to claim 8, wherein the X-ray powder diffraction pattern of Form III has a characteristic peak and its relative intensity at the following diffraction angle 2:
衍射角 2Θ 相对强度％  Diffraction angle 2Θ relative intensity%
5.2±0.2° 100.0  5.2±0.2° 100.0
10.0土 0.2。 22.2  10.0 soil 0.2. 22.2
10.2±0.2° 25.2  10.2±0.2° 25.2
13.3士 0.2Q 12.9 13.3士0.2 Q 12.9
13.9±0.2° 19.3  13.9±0.2° 19.3
15.3士 0.2° 72.5  15.3 ± 0.2 ° 72.5
16.8士 0.2。 27.4  16.8 ± 0.2. 27.4
17.5士 0.2° 13.7  17.5 ± 0.2 ° 13.7
20.0士 0.2。 1 1.3  20.0 ± 0.2. 1 1.3
20.2土 0.2° 28.5  20.2 soil 0.2° 28.5
22.0土 0.2。 21.4  22.0 soil 0.2. 21.4
23.4±0.2° 16.2  23.4 ± 0.2 ° 16.2
25.6士 0.2° 30.7  25.6 ± 0.2° 30.7
27.9士 0.2° 11.7  27.9 ± 0.2° 11.7
10、 权利要求 7〜9中任一项所述的恩杂鲁胺晶型 III的制备方法， 其特征在 包括如下步骤： 将恩杂鲁胺的乙酸异丙酯溶液去除溶剂至干， 得到所述 的恩杂鲁胺晶型 III; The method for preparing the crystal form of enzalutamide according to any one of claims 7 to 9, which comprises the steps of: removing the solvent of isopropyl acetate from isopropyl acetate to dryness; Description Entamtamide Form III;
所述去除溶剂的方法优选为将恩杂鲁胺的乙酸异丙酯溶液自然挥发至干 且所用容器不加盖或者加盖并打孔， 或者将恩杂鲁胺的乙酸异丙酯溶液使用 氮气吹干； 所述恩杂鲁胺乙酸异丙酯溶液的浓度是在该溶液温度下恩杂鲁胺 在乙酸异丙酯中溶解度的 0.1〜1.0倍， 优选为 0.8〜： 1.0倍； 所述去除溶剂的温度 为 5〜35°C , 优选为 15〜20°C。  The method for removing the solvent is preferably that the isopropyl acetate solution of enzalutamide is naturally evaporated to dryness and the container used is not capped or capped and perforated, or the isopropyl acetate solution of enzalutamide is used with nitrogen. Drying; the concentration of the isopropyl acetate 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; The temperature of the solvent is 5 to 35 ° C, preferably 15 to 20 ° C.
11、 一种药物组合物， 其特征在于， 所述药物组合物包含治疗和 /或预防 有效量的一种或多种的选自权利要求 1所述的非晶态恩杂鲁胺、 权利要求 3〜5 中任一项所述的恩杂鲁胺晶型 II或者权利要求 7~9中任一项所述的恩杂鲁胺晶 型 III, 以及至少一种药学上可接受的赋形剂。  A pharmaceutical composition, comprising: a therapeutically and/or prophylactically effective amount of one or more selected from the group consisting of the amorphous enzalutamide of claim 1, claim The enzalutamide Form II of any one of 3 to 5, or the enzalutamide Form III according to any one of claims 7 to 9, and at least one pharmaceutically acceptable excipient .
12、 根据权利要求 1 1所述的药物组合物， 其特征在于， 所述药物组合物 可为固态或液态， 包括选自片剂、 颗粒剂、 散剂、 丸剂、 粉末或胶囊剂的固 体口服剂型， 或者选自溶液剂、 糖浆剂、 混悬剂、 分散剂或乳剂的液体口服 剂型， 或者选自溶液剂、 分散剂或冻干剂的可注射制剂， 或者选自适于活性 成分的快速释放剂、 延迟鋒放剂或调节释放剂， 或者选自常规的、 可分散的、 可咀嚼的、 口腔溶解的或快速熔化的剂型， 或者其给药途径选自口服、 静脉 皮下注射、 注射入组织给药、 透皮给药、 直肠给药或滴鼻给药。  The pharmaceutical composition according to claim 11, wherein the pharmaceutical composition is solid or liquid, and comprises a solid oral dosage form selected from the group consisting of a tablet, a granule, a powder, a pill, a powder or a capsule. Or a liquid oral dosage form selected from the group consisting of a solution, a syrup, a suspension, a dispersing agent or an emulsion, or an injectable preparation selected from the group consisting of a solution, a dispersing agent or a lyophilizate, or selected from a rapid release suitable for the active ingredient Agent, delayed release agent or modified release agent, or selected from a conventional, dispersible, chewable, orally dissolved or rapidly melted dosage form, or the route of administration thereof is selected from oral, intravenous subcutaneous injection, injection into tissue Administration, transdermal administration, rectal administration or intranasal administration.
13、 权利要求 1所述的非晶态恩杂鲁胺、 权利要求 3〜5中任一项所述的恩 杂鲁胺晶型 II或权利要求 7〜9中任一项所述的恩杂鲁胺晶型 III在制备治疗和 / 或预防过度增生疾病的药物中的用途； 所述过度增生疾病选自前列腺癌、 良 性前列腺增生、 乳腺癌、 卵巢癌、 与前列腺特异性抗原 mRNA转录相关的疾病 或与雄激素受体蛋白质核易位相关的疾病， 优选转移性去势耐受前列腺癌。  The amorphous enzalutamide according to claim 1, the enzalutamide crystal form II according to any one of claims 3 to 5, or the end of any one of claims 7 to 9. Use of sulphate form III in the preparation of a medicament for treating and/or preventing a hyperproliferative disease; the hyperproliferative disease selected from the group consisting of prostate cancer, benign prostatic hyperplasia, breast cancer, ovarian cancer, and transcription associated with prostate specific antigen mRNA A disease or a disease associated with a nuclear translocation of androgen receptor protein, preferably metastatic castration tolerant prostate cancer.
14、 一种治疗和 /或预防过度增生疾病的方法， 其特征在于， 所述方法包 括给予需要的患者治疗和 /或预防有效量的权利要求 1所述的非晶态恩杂鲁胺、 权利要求 3〜5中任一项所述的恩杂鲁胺晶型 II、权利要求 7〜9中任一项所述的恩 杂鲁胺晶型 III或者权利要求 1 1或 12所述的药物组合物； 所述过度增生疾病选 自前列腺癌、 良性前列腺增生、 乳腺癌、 卵巢癌、 与前列腺特异性抗原 mRNA 转录相关的疾病或与雄激素受体蛋白质核易位相关的疾病， 优选转移性去势 耐受前列腺癌； 所迷剂量选自 0.001〜 00毫克 /公斤体重 /天、 0.01〜100毫克 /公 斤体重 /天、 0.1~10毫克 /公斤体重 /天或 1毫克 /公斤体重 /天。  14. A method of treating and/or preventing a hyperproliferative disorder, the method comprising administering to a patient in need thereof a therapeutically and/or prophylactically effective amount of the amorphous enzalutamide of claim 1, right The enzalutamide crystal form II according to any one of claims 3 to 5, the enzalutamide crystal form III according to any one of claims 7 to 9 or the pharmaceutical composition according to claim 1 or 12 The hyperproliferative disease is selected from the group consisting of prostate cancer, benign prostatic hyperplasia, breast cancer, ovarian cancer, a disease associated with prostate-specific antigen mRNA transcription, or a disease associated with androgen receptor protein nuclear translocation, preferably metastatic. Potentially resistant to prostate cancer; the dose is selected from 0.001 to 00 mg/kg body weight/day, 0.01 to 100 mg/kg body weight/day, 0.1 to 10 mg/kg body weight/day or 1 mg/kg body weight/day.
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