WO2023143427A1 - Crystal form of arv-110 and preparation method therefor and use thereof - Google Patents

Crystal form of arv-110 and preparation method therefor and use thereof Download PDF

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Publication number
WO2023143427A1
WO2023143427A1 PCT/CN2023/073290 CN2023073290W WO2023143427A1 WO 2023143427 A1 WO2023143427 A1 WO 2023143427A1 CN 2023073290 W CN2023073290 W CN 2023073290W WO 2023143427 A1 WO2023143427 A1 WO 2023143427A1
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arv
crystal form
preparation
pharmaceutical composition
crystal
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PCT/CN2023/073290
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French (fr)
Chinese (zh)
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盛晓霞
盛晓红
曹雅晴
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杭州领业医药科技有限公司
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Publication of WO2023143427A1 publication Critical patent/WO2023143427A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • This application relates to the field of drug synthesis, especially the field of crystal form technology, and specifically relates to a crystal form of ARV-110 and its preparation method and application.
  • Polymorphism or polymorphism is a unique property of certain molecules and molecular compositions.
  • the same molecule may form different crystals due to different arrangements, and these crystals have different crystal structures and physical properties, such as solubility and stability. , thermal properties, mechanical properties, purification ability, X-ray diffraction spectrum, infrared absorption spectrum, Raman spectrum and solid-state NMR, etc.
  • ARV-110 is a small molecule compound developed by Arvinas for the treatment of prostate cancer, which is currently in phase 2 clinical research.
  • the chemical name of ARV-110 is N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[[4-[2-(2,6-dioxopiperidin-3-yl)-6- Fluoro-1,3-dioxoisoindol-5-yl] piperazin-1-yl] methyl] piperidin-1-yl] pyridazine-3-carboxamide, the structural formula is as shown in formula (I):
  • WO2021231174A1 discloses an amorphous form and two crystalline forms of ARV-110.
  • the amorphous form is prepared by spray drying, which will undergo crystal transformation in solution or under high temperature conditions, and has high hygroscopicity.
  • Form 4 is an ethanol solvate, which is generally not used as a pharmaceutical solid form, while Form 2 has poor solubility, only 1.2ug/ml in SIF medium. Therefore, further research is needed to find a solid form of ARV-110 suitable for formulation.
  • This application mainly provides a crystalline form of ARV-110, which has at least one of the following improved characteristics: good stability, low hygroscopicity, good solubility, high melting point, stable storage, and avoids drug development and storage. Crystal transformation, the preparation method is simple and reliable, and has great development value.
  • the first aspect of the present application provides an ARV-110 crystal form 1 with a structural formula as shown in formula (I),
  • ARV-110 crystal form 1 further has at least one characteristic diffraction peak selected from 13.88 ⁇ 0.2°, 21.27 ⁇ 0.2°, 21.83 ⁇ 0.2°, and 23.12 ⁇ 0.2°.
  • ARV-110 further has at least one characteristic diffraction peak selected from 17.82 ⁇ 0.2° and 25.75 ⁇ 0.2°.
  • the X-ray powder diffraction of the ARV-110 crystal form 1 has the following characteristic diffraction peak positions:
  • the X-ray powder diffraction of the ARV-110 crystal form 1 has the following characteristic diffraction peak positions:
  • the ARV-110 crystal form 1 has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the ARV-110 crystal form 1 has an X-ray powder diffraction pattern substantially as shown in FIG. 6 .
  • the ARV-110 crystal form 1 in the Fourier transform infrared spectrum (FT-IR), is selected from 744.25 ⁇ 2cm -1 , 826.95 ⁇ 2cm -1 , 1009.58 ⁇ 2cm -1 1039.18 ⁇ 2cm -1 , 1107.69 ⁇ 2cm -1 , 1124.91 ⁇ 2cm -1 , 1197.41 ⁇ 2cm -1 , 1238.10 ⁇ 2cm -1 , 1255.18 ⁇ 2cm -1 , 1272.03 ⁇ 2cm -1 , 1381.24 ⁇ 2cm -1 , 1448.522 At least one of ⁇ 2cm -1 , 1486.50 ⁇ 2cm -1 , 1640.91 ⁇ 2cm -1 and 1706.66 ⁇ 2cm -1 has a characteristic peak.
  • FT-IR Fourier transform infrared spectrum
  • the ARV-110 crystal form 1, in the Fourier transform infrared spectrum (FT-IR), at 1009.58 ⁇ 2cm -1 , 1039.18 ⁇ 2cm -1 , 1124.91 ⁇ 2cm -1 , 1197.41 There are characteristic peaks at ⁇ 2cm -1 , 1238.10 ⁇ 2cm -1 , 1448.52 ⁇ 2cm -1 , 1706.66 ⁇ 2cm -1 , There are characteristic peaks at 1255.18 ⁇ 2cm -1 , 1272.03 ⁇ 2cm -1 , 1381.24 ⁇ 2cm -1 , 1486.50 ⁇ 2cm -1 and 1640.91 ⁇ 2cm -1 .
  • FT-IR Fourier transform infrared spectrum
  • the ARV-110 crystal form 1 has a Fourier infrared spectrum substantially as shown in FIG. 5 .
  • the ARV-110 crystal form 1 is an anhydrate.
  • the ARV-110 crystal form 1 shows a weight loss of ⁇ 0.8% before 150° C. in the TGA spectrum.
  • the ARV-110 crystal form 1 shows a weight loss of about 0.4% before 150°C in the TGA spectrum.
  • the TGA characterization of the ARV-110 crystal form 1 is basically shown in FIG. 2 .
  • the melting point of the ARV-110 crystal form 1 is 288°C ⁇ 3°C; preferably 288°C ⁇ 2°C.
  • the DSC characterization of the ARV-110 crystal form 1 is basically shown in FIG. 3 .
  • the hygroscopicity of the ARV-110 crystal form 1 at 0%RH to 80%RH is ⁇ 1%.
  • the hygroscopicity of the ARV-110 crystal form 1 is 0.8%.
  • the isotherm adsorption curve of the ARV-110 crystal form 1 is basically shown in FIG. 4 .
  • the second aspect of the present application provides the preparation method of the ARV-110 crystal form 1 described in the first aspect:
  • Method (1) Weigh an appropriate amount of starting material ARV-110 and add a solvent to form a suspension, stir at room temperature to precipitate a solid, centrifuge or filter, and dry to obtain ARV-110 crystal form 1;
  • Method (2) Weigh an appropriate amount of starting material ARV-110, add 1,4-dioxane, heat to dissolve, add water, stir to precipitate solid, centrifuge or filter, and dry to obtain ARV-110 crystal form 1.
  • the solvent of the method (1) is selected from any one or a combination of methanol, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane and water.
  • the solvent of the method (1) is a mixed solvent of tetrahydrofuran and water; preferably, the volume ratio of tetrahydrofuran: water is 10:1-0.1:1, more preferably 2:1 -0.5:1.
  • the solvent of the method (1) is a mixed solvent of acetonitrile and water; preferably, the acetonitrile: water volume ratio is 20:1-1:1, more preferably 15:1 -5:1.
  • the ratio of starting material to solvent in the method (1) is ⁇ 1:1 (mg:ml), preferably ⁇ 5:1, more preferably 10:1-60:1.
  • the ratio of the starting material of the method (2): 1,4-dioxane is ⁇ 5:1 (mg:ml), preferably ⁇ 10:1; preferably, the method (2)
  • the ratio of 1,4-dioxane: water is 1:1-1:1.5.
  • the heating temperature in the method (2) is 40-80°C, preferably 50-70°C.
  • the stirring temperature of the preparation method (1) or (2) is room temperature.
  • the drying temperature of the preparation method (1) or (2) is ⁇ 30°C, more preferably 30-70°C.
  • the ARV-110 crystal form 1 described in this application has the following beneficial effects:
  • the ARV-110 crystal form 1 described in this application keeps the crystal form unchanged for 8 months under accelerated (40°C/75%RH), high temperature (50°C) and high humidity (97%RH) conditions, and has a good crystal structure. type stability.
  • the crystal form 1 of ARV-110 described in this application has a weight gain and hygroscopicity of about 0.8% under the environment of 0% RH to 80% RH, which is slightly hygroscopic.
  • the amorphous is 2.4%
  • Form 2 is 4.67%
  • the hygroscopicity is lower, it is more suitable for storage and transportation as the solid form of API, and it is convenient for the preparation of preparations.
  • the ARV-110 crystal form 1 described in this application has a melting point greater than 250° C., is stable at high temperatures, and is especially suitable for hot-melt extrusion processes.
  • the crystal form 1 of ARV-110 described in this application has a good chemical stability when stored for 30 days under high temperature (60°C) and accelerated (40°C/75%RH) conditions.
  • the preparation method is simple, highly repeatable, and suitable for industrial production.
  • the preparation method of ARV-110 crystal form 1 described in this application has few steps, is easy to operate, and has good industrialization prospects.
  • the third aspect of the present application provides a pharmaceutical composition, which comprises the ARV-110 crystal form 1 according to the first aspect and at least one pharmaceutically acceptable carrier.
  • the pharmaceutically acceptable carrier includes diluents or excipients or other additives, examples of which include but not limited to wetting agents, disintegrants, lubricants, binders, binders, surfactants wait.
  • additives include, but are not limited to, shellac, gum arabic, talc, titanium oxide, sugars (e.g., sucrose), gelatin, water, polysaccharides such as lactose or glucose, paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), and a pharmaceutically acceptable organic solvent Alcohols (e.g., ethanol or glycerin), natural mineral powders (e.g., kaolin, clay, talc, and chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), emulsifiers (e.g., lignin, Sulfite solution, methylcellulose, starch and polyvinylpyrrol
  • the pharmaceutical composition of the present application can be solid and semi-solid preparations for oral administration, including but not limited to tablets, coated agents, capsules, granules, powders, pills, powders, ointments, gels, emulsions, etc. . Tablets, coated formulations, capsules are preferred.
  • the pharmaceutical composition of the present application can also be other formulations, including but not limited to injections, such as intravenous drip formulations, intramuscular or subcutaneous injection formulations, suppositories for rectal administration, inhalation formulations for intranasal administration, or other topical formulations. Administration in the form of a transdermal patch.
  • the pharmaceutical composition can be prepared using known techniques in the art. When preparing the pharmaceutical composition, the ARV-110 crystal form 1 described in this application is mixed with at least one pharmaceutically acceptable carrier, or directly Mixing, granulating, tableting or dissolving processes to prepare the required preparations.
  • the filler or diluent is selected from lactose, D-mannitol, microcrystalline cellulose, starch, pregelatinized starch, calcium sulfate, phosphoric acid Any one or combination thereof in calcium hydrogen calcium carbonate;
  • the disintegrating agent is selected from sodium carboxymethyl starch, sodium hydroxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose , cross-linked polyvinylpyrrolidone or any combination thereof;
  • the lubricant/glidant is selected from magnesium stearate, talcum powder, micropowder silica gel or a combination thereof;
  • the binder is selected from starch pulp, sodium carboxymethyl cellulose (CMC-Na), hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, or any combination thereof.
  • the pharmaceutical composition comprises a therapeutically effective amount of the ARV-110 crystal form 1.
  • the therapeutically effective amount is in the range of about 10 ng-300 mg/kg, preferably 0.1-100 mg/kg, usually 0.5-25 mg/kg per day for the recipient/patient.
  • the unit dosage of ARV-110 crystal form 1 in the pharmaceutical composition is 5mg-1000mg; preferably 5mg-280mg; more preferably 5mg, 35mg, 70mg, 105mg, 140mg, 175mg, 210mg , any of 245mg or 280mg.
  • the preparation form of the pharmaceutical composition is a tablet.
  • the tablet comprises:
  • Form 1 of ARV-110 at about 1%-50% w/w;
  • the tablet comprises:
  • Form 1 of ARV-110 at about 1%-50% w/w;
  • magnesium stearate and about 0-1% magnesium stearate.
  • the tablet comprises:
  • the tablet comprises:
  • Form 1 of ARV-110 at about 1%-50% w/w;
  • the tablet comprises:
  • Form 1 of ARV-110 at about 1%-50% w/w;
  • magnesium stearate about 0.1-1% magnesium stearate.
  • the capsules comprise:
  • Form 1 of ARV-110 at about 1%-50% w/w;
  • Glidant or lubricant about 0-1% w/w.
  • the capsules comprise:
  • Form 1 of ARV-110 at about 1%-50% w/w;
  • the fourth aspect of the present application provides the use of the ARV-110 crystal form 1 described in the first aspect or the pharmaceutical composition described in the third aspect in the preparation of androgen receptor-related diseases.
  • the fifth aspect of the present application provides a method for treating diseases, the method comprising administering the ARV-110 crystal form 1 described in the first aspect or the drug combination described in the third aspect to a subject in need A substance, wherein the disease is an androgen receptor-related disease.
  • the method for treating diseases may be administered once a day, twice a day, or three times a day or more.
  • the androgen receptor-related disease is cancer; preferably prostate cancer.
  • the prostate cancer is castration-resistant prostate cancer; preferably metastatic castration-resistant prostate cancer (mCRPC).
  • mCRPC metastatic castration-resistant prostate cancer
  • the sixth aspect of the present application provides the combined use of the ARV-110 crystal form 1 described in the first aspect or the pharmaceutical composition or preparation thereof described in the third aspect and other drugs.
  • the other drugs may be other anti-cancer agents used to treat cancer or related conditions.
  • other drugs are selected from PARP inhibitors, CDK inhibitors, antacid drugs and the like.
  • the PARP inhibitor is selected from Olaparib, Niraparib, Rucaparib, Veliparib (ABT-888), Fluzoparib and Talazoparib (BMN-673) and the like.
  • the CDK inhibitor is selected from palbociclib, rebociclib, abeciclib, trilaciclib, dalcilib, triraciclib, G1T-38, SHR-6390, FLX-925 and the like.
  • the antacid drug may be selected from rabeprazole, omeprazole, aluminum magnesium carbonate, sodium bicarbonate, famotidine, ranitidine and the like.
  • other drugs can also be selected from abiraterone, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin , cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, or zlendronate.
  • Fig. 1 is the XRPD spectrum of ARV-110 crystal form 1 prepared according to Example 1;
  • Fig. 2 is the TGA spectrum of the ARV-110 crystal form 1 prepared according to Example 1;
  • Fig. 3 is the DSC spectrum of ARV-110 crystal form 1 prepared according to Example 1;
  • Fig. 4 is the isotherm adsorption curve of ARV-110 crystal form 1 prepared according to Example 1;
  • Fig. 5 is the Fourier transform infrared spectrum of ARV-110 crystal form 1 prepared according to Example 1;
  • Fig. 6 is the XRPD spectrum of ARV-110 crystal form 1 prepared according to Example 2;
  • Fig. 7 is the XRPD spectrum of the stability experiment of ARV-110 crystal form 1 in Example 7.
  • room temperature in the present invention refers to a temperature of 10-30°C.
  • the "separation" can use conventional methods in the art, such as centrifugation or filtration. Wherein, vacuum filtration is generally carried out with suction filtration at a pressure less than atmospheric pressure at room temperature.
  • drying can be accomplished using conventional techniques in the art, such as drying at room temperature, blast drying or reduced-pressure drying, and it can also be carried out under reduced pressure or without reduced pressure, and can be vacuum or non-vacuum.
  • the drying apparatus and method are not limited, and can be fume hood, blast oven, spray dryer, fluidized bed drying or vacuum oven; it can also be carried out under reduced or no reduced pressure.
  • crystal form refers to a certain lattice configuration of a crystalline substance. It is known in the art that crystal form is related to stability, dissolution and mechanical properties in pharmaceuticals. Different crystal forms of the same substance generally have different crystal lattices (eg, unit cells) with different physical properties characteristic of them. Different crystalline forms can be characterized by methods known in the art. For example, it can be identified by solid state characterization methods such as by X-ray powder diffraction (XRPD). Other characterization methods include Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Dynamic Vapor Sorption (DVS), Solid State NMR, etc. The crystalline form can be characterized by any one of the above methods, or by combining two or more methods.
  • XRPD X-ray powder diffraction
  • Other characterization methods include Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Dynamic Vapor Sorption (DVS), Solid State
  • the crystal form of the present invention is basically pure and single, basically without mixing any other crystal forms or amorphous states.
  • substantially pure when “substantially pure” is used to refer to a new crystal form, it means that this new crystal form occupies At least 80% by weight of the compound, more at least 90% by weight, especially at least 95% by weight, especially at least 99% by weight.
  • performance or “crystalline form performance” or “property” or “pharmaceutical property” includes its physical and chemical properties, and evaluation indicators include but are not limited to, for example, melting point, water solubility, dissolution rate, mechanical properties, stability Sex, pharmacokinetics or pharmacodynamics, hygroscopicity, fluidity, compressibility, competitiveness, etc.
  • the “relative strength” is expressed as a specific value in a specific XRPD pattern. Based on the anisotropic characteristics of crystals and the principle of X-ray powder diffraction, the relative intensity value of the diffraction peaks of the same crystal form will fluctuate with the preferred orientation of the sample. The common sense that this fluctuation does not affect the judgment of the same crystal form should be regarded as accepted by those skilled in the art.
  • the term "subject" as used herein includes mammals.
  • the mammal can be, for example, any mammal, eg, a human, primate, bird, mouse, rat, poultry, dog, cat, cow, horse, goat, camel, sheep, or pig.
  • the mammal is a human.
  • the term "effective” may mean, but is not limited to, the amount/dose of an active pharmaceutical ingredient which, when used in the context of its intended use, achieves or is sufficient to prevent a condition in a subject in need of such treatment or receiving such treatment , disease or disease state, inhibiting its occurrence, improving, delaying or treating its symptoms (to a certain extent, preferably relieving the symptoms completely).
  • effective encompasses all other effective amount or effective concentration terms such as "effective amount/dose”, “pharmaceutically effective amount/dose” or “therapeutically effective amount/dose” otherwise described or used in this application.
  • pharmaceutically acceptable or “pharmacologically acceptable” may mean, but are in no way limited to, entities and compositions that, as appropriate, do not produce adverse, allergic or other untoward reactions when administered to animals or humans.
  • ARV-110 is generally used as the starting material to prepare the crystal form of the present application, and the ARV-110 as the starting material can be purchased or prepared by the method in CN111892577A.
  • ARV-110 can be synthetic crude product, amorphous and other solid forms.
  • X-ray powder diffraction (XRPD) data were collected from a Bruker D8 Advance diffractometer. The parameters are as follows: Cu target; wavelength is Current and voltage: 40KV, 40mA; angle range: 3 ⁇ 40°2 ⁇ .
  • FT-IR Fourier transform infrared spectroscopy
  • DSC Differential thermal analysis
  • Thermogravimetric analysis (TGA) data were collected from a TA Instruments Q500 TGA.
  • the parameters are as follows: mode: high resolution mode; heating rate: 10°C/min; protective gas: N 2 ; sample plate: platinum crucible.
  • HPLC determination method chromatograph model: Ultimate3000, chromatographic column: C18 3 ⁇ m (150*4.6mm), column temperature: 45°C, flow rate 1.0mL/min, detection wavelength: 260nm, injection volume: 5 ⁇ L, running time: 32min, Mobile phase: mobile phase A: 0.1% TFA in H 2 O, mobile phase B: 0.1% TFA in CAN, the operating gradient is as follows:
  • ARV-110 weigh about 30 mg of ARV-110, add 1.0 mL of methanol to form a suspension, stir at room temperature for 1 day, a solid precipitates, filter, and vacuum dry at 30°C for 2 days to obtain ARV-110 crystal form 1.
  • Example 1 The samples of Example 1 were taken for characterization, as follows.
  • Figure 1 is the XRPD pattern of ARV-110 crystal form 1, and Table 1 shows the X-ray powder diffraction data of ARV-110 crystal form 1.
  • Table 1 X-ray powder diffraction data of ARV-110 Form 1
  • the TGA results are shown in Figure 2. It shows that the weight loss before 150°C is 0.4%, and the decomposition temperature is 334°C.
  • ARV-110 crystal form 1 has the following characteristic peaks: 744.25, 826.95, 1009.58, 1039.18, 1107.69, 1124.91, 1197.41, 1238.10, 1255.18, 1272.03, 1381.24, 1448.52, 1486.50, 1640.91 and 1706.66 cm - 1 .
  • ARV-110 weigh about 10 mg of ARV-110, add 0.5 mL of tetrahydrofuran, add 0.5 mL of water to form a suspension, stir at room temperature for 1 day, a solid precipitates, filter, and vacuum dry at 30°C for 2 days to obtain ARV-110 crystal form 1.
  • ARV-110 crystal form 1 was kept for 8 months under conditions of accelerated (40°C/75%RH/open), high temperature (50°C/open) and high humidity (room temperature/97%RH/open) The crystal form remains unchanged, and its XRPD spectrum is shown in Figure 7.
  • the tablet core components were mixed and compressed to obtain a tablet core, and then the tablet core was coated with the aqueous solution/suspension of the film coating of Example 10 to obtain the tablet.

Abstract

The present application relates to the field of drug synthesis, in particular to a crystal form of ARV-110 and a preparation method therefor and a use thereof. The crystal form of the ARV-110 at least has one of the following improved characteristics: the stability is good, the hygroscopicity is low, the solubility is good, the melting point is high, stable storage can be achieved, crystal transformation of a drug in a development process and storage is avoided, the preparation method is simple and reliable, and great development values are achieved.

Description

ARV-110的晶型及其制备方法和用途Crystal form of ARV-110 and its preparation method and use
相关申请的引用References to related applications
本申请要求于2022年1月27日向中华人民共和国国家知识产权局提交的第202210098471.5号中国发明专利申请的全部权益，并通过引用的方式将其全部内容并入本公开。This application claims all the rights and interests of the Chinese Invention Patent Application No. 202210098471.5 submitted to the State Intellectual Property Office of the People's Republic of China on January 27, 2022, and its entire content is incorporated into this disclosure by reference.
技术领域technical field
本申请涉及药物合成领域，特别是晶型技术领域，具体涉及一种ARV-110的晶型及其制备方法和用途。This application relates to the field of drug synthesis, especially the field of crystal form technology, and specifically relates to a crystal form of ARV-110 and its preparation method and application.
背景技术Background technique
多晶型或者多晶现象是某些分子和分子组合物的特有性质，相同的分子可能因不同的排列形式而形成不同晶体，而这些晶体具有不同的晶体结构和物理性质，如溶解度、稳定性、热性质、机械性质、纯化能力、X射线衍射图谱、红外吸收图谱、拉曼光谱和固态核磁等。Polymorphism or polymorphism is a unique property of certain molecules and molecular compositions. The same molecule may form different crystals due to different arrangements, and these crystals have different crystal structures and physical properties, such as solubility and stability. , thermal properties, mechanical properties, purification ability, X-ray diffraction spectrum, infrared absorption spectrum, Raman spectrum and solid-state NMR, etc.
发现药物活性成分新的晶型(包括无水物、水合物、溶剂化物等)可能会产生更具加工优势或提供具有更好理化特性的物质，比如更好的生物利用度、不易吸湿、储存稳定、易加工处理、易提纯或作为促进转化为其他晶型的中间体晶型。某些作为药学活性成分用的化合物的某特定晶型也可以帮助改善药物的性能。它扩大了制剂学上可选用的原料形态，例如改善溶出度、改善储藏期限、更容易加工等。Discovery of new crystal forms (including anhydrates, hydrates, solvates, etc.) Stable, easy to process, easy to purify or as an intermediate crystal form to promote transformation into other crystal forms. Certain crystal forms of certain compounds used as active pharmaceutical ingredients can also help improve the performance of the drug. It expands the form of raw materials that can be used in pharmacy, such as improving dissolution rate, improving shelf life, and easier processing.
ARV-110是由Arvinas公司研发的一种治疗***癌的小分子化合物，目前处于临床2期研究。ARV-110的化学名称为N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[[4-[2-(2,6-dioxopiperidin-3-yl)-6- fluoro-1,3-dioxoisoindol-5-yl]piperazin-1-yl]methyl]piperidin-1-yl]pyridazine-3-carboxamide，结构式如下式(I)所示：
ARV-110 is a small molecule compound developed by Arvinas for the treatment of prostate cancer, which is currently in phase 2 clinical research. The chemical name of ARV-110 is N-[4-(3-chloro-4-cyanophenoxy)cyclohexyl]-6-[4-[[4-[2-(2,6-dioxopiperidin-3-yl)-6- Fluoro-1,3-dioxoisoindol-5-yl] piperazin-1-yl] methyl] piperidin-1-yl] pyridazine-3-carboxamide, the structural formula is as shown in formula (I):
WO2021231174A1公开了ARV-110的无定型和2种晶型形式。其中，无定型经喷雾干燥制备，其在溶液或高温条件下会出现转晶现象，且引湿性较高。另外，在WO2021231174A1公开的2种晶型中，Form 4为乙醇溶剂合物，一般不作为药用固体形式，而Form 2溶解度欠佳，在SIF介质中只有1.2ug/ml。因此，仍需进一步研究寻找适合制备成制剂的ARV-110固态形式。WO2021231174A1 discloses an amorphous form and two crystalline forms of ARV-110. Among them, the amorphous form is prepared by spray drying, which will undergo crystal transformation in solution or under high temperature conditions, and has high hygroscopicity. In addition, among the two crystal forms disclosed in WO2021231174A1, Form 4 is an ethanol solvate, which is generally not used as a pharmaceutical solid form, while Form 2 has poor solubility, only 1.2ug/ml in SIF medium. Therefore, further research is needed to find a solid form of ARV-110 suitable for formulation.
背景技术中的信息仅仅在于说明本申请的总体背景，不应视为承认或以任何形式暗示这些信息构成本领域一般技术人员所公知的现有技术。The information in the background art is only to illustrate the general background of the application, and should not be regarded as an acknowledgment or any form of suggestion that the information constitutes the prior art known to those skilled in the art.
发明内容Contents of the invention
本申请主要提供一种ARV-110的晶型，其至少具有以下一种改进的特性：稳定性好，引湿性低，溶解度良好，熔点高，能稳定储存，避免药物在开发过程和储存中发生转晶，制备方法简单可靠，具有较大的开发价值。This application mainly provides a crystalline form of ARV-110, which has at least one of the following improved characteristics: good stability, low hygroscopicity, good solubility, high melting point, stable storage, and avoids drug development and storage. Crystal transformation, the preparation method is simple and reliable, and has great development value.
本申请的第一方面，提供一种结构式如式(I)所示的ARV-110晶型1，
The first aspect of the present application provides an ARV-110 crystal form 1 with a structural formula as shown in formula (I),
使用Cu-Kα辐射，在以衍射角2θ表示的X射线粉末衍射图谱中，具有选自16.28±0.2°、17.39±0.2°、18.63±0.2°、20.06±0.2°中的至少一个特征衍射峰；优选具有至少三个及其以上特征衍射峰。Using Cu-Kα radiation, in the X-ray powder diffraction pattern represented by diffraction angle 2θ, having at least one characteristic diffraction peak selected from 16.28±0.2°, 17.39±0.2°, 18.63±0.2°, 20.06±0.2°; It preferably has at least three or more characteristic diffraction peaks.
本申请优选技术方案中，ARV-110晶型1进一步具有选自13.88±0.2°、21.27±0.2°、21.83±0.2°、23.12±0.2°中的至少一个特征衍射峰。In the preferred technical solution of the present application, ARV-110 crystal form 1 further has at least one characteristic diffraction peak selected from 13.88±0.2°, 21.27±0.2°, 21.83±0.2°, and 23.12±0.2°.
本申请优选技术方案中，ARV-110进一步具有选自17.82±0.2°、25.75±0.2°中的至少一个特征衍射峰。In the preferred technical solution of the present application, ARV-110 further has at least one characteristic diffraction peak selected from 17.82±0.2° and 25.75±0.2°.
在本申请的一个具体的实施例中，所述的ARV-110晶型1的X射线粉末衍射具有以下特征衍射峰位置：
In a specific embodiment of the present application, the X-ray powder diffraction of the ARV-110 crystal form 1 has the following characteristic diffraction peak positions:
在本申请的另一个具体的实施例中，所述的ARV-110晶型1的X射线粉末衍射具有以下特征衍射峰位置：
In another specific embodiment of the present application, the X-ray powder diffraction of the ARV-110 crystal form 1 has the following characteristic diffraction peak positions:
在本申请的一个实施例中，所述的ARV-110晶型1具有基本如图1所示的X射线粉末衍射图谱。In one embodiment of the present application, the ARV-110 crystal form 1 has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
在本申请的一个实施例中，所述的ARV-110晶型1具有基本如图6所示的X射线粉末衍射图谱。In one embodiment of the present application, the ARV-110 crystal form 1 has an X-ray powder diffraction pattern substantially as shown in FIG. 6 .
本申请优选技术方案中，所述的ARV-110晶型1，在傅里叶红外光谱(FT-IR)中，在选自744.25±2cm-1、826.95±2cm-1、1009.58±2cm-1、1039.18±2cm-1、1107.69±2cm-1、1124.91±2cm-1、1197.41±2cm-1、1238.10±2cm- 1、1255.18±2cm-1、1272.03±2cm-1、1381.24±2cm-1、1448.52±2cm-1、1486.50±2cm-1、1640.91±2cm-1和1706.66±2cm-1中的至少之一处具有特征峰。In the preferred technical solution of the present application, the ARV-110 crystal form 1, in the Fourier transform infrared spectrum (FT-IR), is selected from 744.25±2cm -1 , 826.95±2cm -1 , 1009.58±2cm -1 1039.18 ± 2cm -1 , 1107.69 ± 2cm -1 , 1124.91 ± 2cm -1 , 1197.41 ± 2cm -1 , 1238.10 ± 2cm -1 , 1255.18 ± 2cm -1 , 1272.03 ± 2cm -1 , 1381.24 ± 2cm -1 , 1448.522 At least one of ±2cm -1 , 1486.50±2cm -1 , 1640.91±2cm -1 and 1706.66±2cm -1 has a characteristic peak.
本申请优选技术方案中，所述的ARV-110晶型1，在傅里叶红外光谱(FT-IR)中，在1009.58±2cm-1、1039.18±2cm-1、1124.91±2cm-1、1197.41±2cm-1、1238.10±2cm-1、1448.52±2cm-1、1706.66±2cm-1处具有特征峰；进一步，还可以在744.25±2cm-1、826.95±2cm-1、1107.69±2cm-1、1255.18±2cm-1、1272.03±2cm-1、1381.24±2cm-1、1486.50±2cm-1和1640.91±2cm- 1处具有特征峰。In the preferred technical solution of the present application, the ARV-110 crystal form 1, in the Fourier transform infrared spectrum (FT-IR), at 1009.58±2cm -1 , 1039.18±2cm -1 , 1124.91±2cm -1 , 1197.41 There are characteristic peaks at ±2cm -1 , 1238.10±2cm -1 , 1448.52 ± 2cm -1 , 1706.66±2cm -1 , There are characteristic peaks at 1255.18±2cm -1 , 1272.03±2cm -1 , 1381.24±2cm -1 , 1486.50± 2cm -1 and 1640.91±2cm -1 .
在本申请的一个实施例中，所述ARV-110晶型1具有基本如图5所示的傅里叶红外光谱。In an embodiment of the present application, the ARV-110 crystal form 1 has a Fourier infrared spectrum substantially as shown in FIG. 5 .
本申请优选技术方案中，所述的ARV-110晶型1为无水物。In the preferred technical solution of the present application, the ARV-110 crystal form 1 is an anhydrate.
本申请优选技术方案中，所述的ARV-110晶型1在TGA图谱中显示150℃前失重≤0.8％。In the preferred technical solution of the present application, the ARV-110 crystal form 1 shows a weight loss of ≤0.8% before 150° C. in the TGA spectrum.
在本申请的一个实施例中，所述的ARV-110晶型1在TGA图谱中显示150℃前失重约为0.4％。In an embodiment of the present application, the ARV-110 crystal form 1 shows a weight loss of about 0.4% before 150°C in the TGA spectrum.
在本申请的一个实施例中，所述ARV-110晶型1的TGA表征基本如图2所示。In an embodiment of the present application, the TGA characterization of the ARV-110 crystal form 1 is basically shown in FIG. 2 .
本申请优选技术方案中，所述的ARV-110晶型1熔点为288℃±3℃；优选为288℃±2℃。 In the preferred technical solution of the present application, the melting point of the ARV-110 crystal form 1 is 288°C±3°C; preferably 288°C±2°C.
在本申请的一个实施例中，所述ARV-110晶型1的DSC表征基本如图3所示。In one embodiment of the present application, the DSC characterization of the ARV-110 crystal form 1 is basically shown in FIG. 3 .
本申请优选技术方案中，所述ARV-110晶型1在0％RH至80％RH的引湿性为≤1％。In the preferred technical solution of the present application, the hygroscopicity of the ARV-110 crystal form 1 at 0%RH to 80%RH is ≤1%.
在本申请的一个实施例中，所述ARV-110晶型1的引湿性为0.8％。In one embodiment of the present application, the hygroscopicity of the ARV-110 crystal form 1 is 0.8%.
在本申请的一个实施例中，所述ARV-110晶型1的等温吸附曲线基本如图4所示。In an embodiment of the present application, the isotherm adsorption curve of the ARV-110 crystal form 1 is basically shown in FIG. 4 .
本申请的第二方面，提供第一方面所述的ARV-110晶型1的制备方法：The second aspect of the present application provides the preparation method of the ARV-110 crystal form 1 described in the first aspect:
方法(1)：称取适量的起始物料ARV-110加入溶剂形成悬浮液，室温搅拌析出固体，离心或过滤，干燥即得ARV-110晶型1；Method (1): Weigh an appropriate amount of starting material ARV-110 and add a solvent to form a suspension, stir at room temperature to precipitate a solid, centrifuge or filter, and dry to obtain ARV-110 crystal form 1;
方法(2)：称取适量的起始物料ARV-110加入1,4-二氧六环，加热溶清，加入水，搅拌析出固体，离心或过滤，干燥即得ARV-110晶型1。Method (2): Weigh an appropriate amount of starting material ARV-110, add 1,4-dioxane, heat to dissolve, add water, stir to precipitate solid, centrifuge or filter, and dry to obtain ARV-110 crystal form 1.
本申请优选技术方案中，所述方法(1)的溶剂选自甲醇、丙酮、乙腈、四氢呋喃、1,4-二氧六环和水中的任一种或其组合。In the preferred technical solution of the present application, the solvent of the method (1) is selected from any one or a combination of methanol, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane and water.
本申请的一些实施例中，所述方法(1)的溶剂为四氢呋喃和水的混合溶剂；优选地，所述四氢呋喃:水的体积比为10:1-0.1:1，更优选为2:1-0.5:1。In some embodiments of the present application, the solvent of the method (1) is a mixed solvent of tetrahydrofuran and water; preferably, the volume ratio of tetrahydrofuran: water is 10:1-0.1:1, more preferably 2:1 -0.5:1.
本申请的一些实施例中，所述方法(1)的溶剂为乙腈和水的混合溶剂；优选地，所述乙腈:水的体积比为20:1-1:1，更优选为15:1-5:1。In some embodiments of the present application, the solvent of the method (1) is a mixed solvent of acetonitrile and water; preferably, the acetonitrile: water volume ratio is 20:1-1:1, more preferably 15:1 -5:1.
本申请优选技术方案中，所述方法(1)的起始物料:溶剂的比例≥1:1(mg:ml)，优选≥5:1，更优选为10:1-60:1。In the preferred technical solution of the present application, the ratio of starting material to solvent in the method (1) is ≥1:1 (mg:ml), preferably ≥5:1, more preferably 10:1-60:1.
本申请优选技术方案中，所述方法(2)的起始物料:1,4-二氧六环的比例≥5:1(mg:ml)，优选≥10:1；优选地，所述方法(2)的1,4-二氧六环：水的比例为1:1-1:1.5。In the preferred technical solution of the present application, the ratio of the starting material of the method (2): 1,4-dioxane is ≥5:1 (mg:ml), preferably ≥10:1; preferably, the method (2) The ratio of 1,4-dioxane: water is 1:1-1:1.5.
本申请优选技术方案中，所述方法(2)所述的加热温度为40-80℃，优选为50-70℃。In the preferred technical solution of the present application, the heating temperature in the method (2) is 40-80°C, preferably 50-70°C.
本申请优选技术方案中，所述制备方法(1)或(2)的搅拌温度为室温。 In the preferred technical solution of the present application, the stirring temperature of the preparation method (1) or (2) is room temperature.
本申请优选技术方案中，所述制备方法(1)或(2)的干燥温度≥30℃，更优选为30-70℃。In the preferred technical solution of the present application, the drying temperature of the preparation method (1) or (2) is ≥30°C, more preferably 30-70°C.
特别说明的是，在本申请所述的制备方法(1)中，当选用混合溶剂作为溶剂使用时，可以分别加入，也可以混合后直接加入。In particular, in the preparation method (1) described in this application, when a mixed solvent is used as the solvent, it can be added separately, or directly added after mixing.
本申请所述ARV-110晶型1具有以下有益效果：The ARV-110 crystal form 1 described in this application has the following beneficial effects:
1.晶型稳定性好。本申请所述的ARV-110晶型1在加速(40℃/75％RH)、高温(50℃)和高湿(97％RH)条件下8个月保持晶型不变，具有良好的晶型稳定性。1. Good crystal stability. The ARV-110 crystal form 1 described in this application keeps the crystal form unchanged for 8 months under accelerated (40°C/75%RH), high temperature (50°C) and high humidity (97%RH) conditions, and has a good crystal structure. type stability.
2.引湿性低。本申请所述的ARV-110晶型1在0％RH至80％RH环境下增重吸湿约0.8％，为略有引湿性。相对于WO2021231174A1记载的无定型为2.4％、Form 2为4.67％，吸湿性更低，更适合作为API固态形式储存及运输，并且利于制剂的制备。2. Low humidity. The crystal form 1 of ARV-110 described in this application has a weight gain and hygroscopicity of about 0.8% under the environment of 0% RH to 80% RH, which is slightly hygroscopic. Compared with WO2021231174A1, the amorphous is 2.4%, Form 2 is 4.67%, the hygroscopicity is lower, it is more suitable for storage and transportation as the solid form of API, and it is convenient for the preparation of preparations.
3.溶解度良好。本申请所述的ARV-110晶型1在FaSSIF介质的溶解度为12ug/mL，是WO2021231174A1记载的相同介质中Form 2的10倍。3. Good solubility. The solubility of Form 1 of ARV-110 described in this application in FaSSIF medium is 12ug/mL, which is 10 times that of Form 2 in the same medium described in WO2021231174A1.
4.熔点高。本申请所述的ARV-110晶型1熔点大于250℃，高温稳定，特别适合热熔挤出工艺。4. High melting point. The ARV-110 crystal form 1 described in this application has a melting point greater than 250° C., is stable at high temperatures, and is especially suitable for hot-melt extrusion processes.
5.化学稳定性好。本申请所述的ARV-110晶型1在高温(60℃)和加速(40℃/75％RH)条件下放置30天纯度基本不变，具有良好的化学稳定性。5. Good chemical stability. The crystal form 1 of ARV-110 described in this application has a good chemical stability when stored for 30 days under high temperature (60°C) and accelerated (40°C/75%RH) conditions.
6.制备方法简单，重复性高，适合工业化生产。本申请所述的ARV-110晶型1制备方法步骤少，容易操作，具有良好的产业化前景。6. The preparation method is simple, highly repeatable, and suitable for industrial production. The preparation method of ARV-110 crystal form 1 described in this application has few steps, is easy to operate, and has good industrialization prospects.
本申请的第三方面，提供一种药物组合物，其包含根据第一方面所述的ARV-110晶型1以及至少一种药学上可接受的载体。The third aspect of the present application provides a pharmaceutical composition, which comprises the ARV-110 crystal form 1 according to the first aspect and at least one pharmaceutically acceptable carrier.
本申请中，所述药学上可接受的载体包括稀释剂或赋形剂或其他添加剂，其实例包括但不限于润湿剂、崩解剂、润滑剂、粘结剂、黏合剂、表面活性剂等。其他添加剂的实例包括但不限于紫胶、***树胶、滑石、氧化钛、糖(例如，蔗糖)、明胶、水、多糖诸如乳糖或葡萄糖、石蜡(例如，石油馏分)、植物油(例如，花生油或芝麻油)、以及药学上可接受的有机溶剂 如醇(例如，乙醇或甘油)、天然矿物粉末(例如，高岭土、粘土、滑石和白垩)、合成矿物粉末(例如，高度分散的硅酸和硅酸盐)、乳化剂(例如，木素、亚硫酸盐溶液、甲基纤维素、淀粉和聚乙烯基吡咯烷酮)、硬脂酸镁、硬脂酸、月桂基硫酸钠等。In the present application, the pharmaceutically acceptable carrier includes diluents or excipients or other additives, examples of which include but not limited to wetting agents, disintegrants, lubricants, binders, binders, surfactants wait. Examples of other additives include, but are not limited to, shellac, gum arabic, talc, titanium oxide, sugars (e.g., sucrose), gelatin, water, polysaccharides such as lactose or glucose, paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut oil or sesame oil), and a pharmaceutically acceptable organic solvent Alcohols (e.g., ethanol or glycerin), natural mineral powders (e.g., kaolin, clay, talc, and chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), emulsifiers (e.g., lignin, Sulfite solution, methylcellulose, starch and polyvinylpyrrolidone), magnesium stearate, stearic acid, sodium lauryl sulfate, etc.
本申请的药物组合物可以为口服给药的固体和半固体制剂，包括但不限于片剂、包衣剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、软膏剂、凝胶剂、乳剂等。优选为片剂、包衣剂、胶囊。本申请的药物组合物还可以为其他制剂，包括但不限于注射剂，例如静脉滴注制剂，肌肉或皮下注射制剂，经直肠给药的栓剂，经鼻内给药的吸入制剂，或另外的局部给药的透皮贴剂形式。所述药物组合物可以使用本领域的公知技术来制备，制备药物组合物时，将本申请所述的ARV-110晶型1与至少一种药学上可接受的载体相混合，也可通过直接混合、制粒、压片或溶解等工艺制备成所需制剂。The pharmaceutical composition of the present application can be solid and semi-solid preparations for oral administration, including but not limited to tablets, coated agents, capsules, granules, powders, pills, powders, ointments, gels, emulsions, etc. . Tablets, coated formulations, capsules are preferred. The pharmaceutical composition of the present application can also be other formulations, including but not limited to injections, such as intravenous drip formulations, intramuscular or subcutaneous injection formulations, suppositories for rectal administration, inhalation formulations for intranasal administration, or other topical formulations. Administration in the form of a transdermal patch. The pharmaceutical composition can be prepared using known techniques in the art. When preparing the pharmaceutical composition, the ARV-110 crystal form 1 described in this application is mixed with at least one pharmaceutically acceptable carrier, or directly Mixing, granulating, tableting or dissolving processes to prepare the required preparations.
本申请优选技术方案中，当所述制剂为口服固体制剂时，所述填充剂或稀释剂选自乳糖、D-甘露糖醇、微晶纤维素、淀粉、预胶化淀粉、硫酸钙、磷酸氢钙、碳酸钙中的任一种或其组合；所述崩解剂选自羧甲基淀粉钠、羟甲基纤维素钠、交联羧甲基纤维素钠、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮中的任一种或其组合；所述润滑剂/助流剂选自硬脂酸镁、滑石粉、微粉硅胶中的一种或其组合；所述黏合剂选自淀粉浆、羧甲基纤维素钠(CMC—Na)、羟丙基纤维素、甲基纤维素、乙基纤维素中的任一种或其组合。In the preferred technical solution of the present application, when the preparation is an oral solid preparation, the filler or diluent is selected from lactose, D-mannitol, microcrystalline cellulose, starch, pregelatinized starch, calcium sulfate, phosphoric acid Any one or combination thereof in calcium hydrogen calcium carbonate; the disintegrating agent is selected from sodium carboxymethyl starch, sodium hydroxymethyl cellulose, cross-linked sodium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose , cross-linked polyvinylpyrrolidone or any combination thereof; the lubricant/glidant is selected from magnesium stearate, talcum powder, micropowder silica gel or a combination thereof; the binder is selected from starch pulp, sodium carboxymethyl cellulose (CMC-Na), hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, or any combination thereof.
本申请优选技术方案中，所述药物组合物包含治疗有效量的所述ARV-110晶型1。优选地，所述治疗有效量的范围是接受者/患者每天约10ng-300mg/kg，优选0.1-100mg/kg，通常为0.5-25mg/kg。In the preferred technical solution of the present application, the pharmaceutical composition comprises a therapeutically effective amount of the ARV-110 crystal form 1. Preferably, the therapeutically effective amount is in the range of about 10 ng-300 mg/kg, preferably 0.1-100 mg/kg, usually 0.5-25 mg/kg per day for the recipient/patient.
本申请优选技术方案中，所述ARV-110晶型1在药物组合物中的单位剂量为5mg-1000mg；优选为5mg-280mg；进一步优选为5mg、35mg、70mg、105mg、140mg、175mg、210mg、245mg或280mg中的任一种。In the preferred technical solution of the present application, the unit dosage of ARV-110 crystal form 1 in the pharmaceutical composition is 5mg-1000mg; preferably 5mg-280mg; more preferably 5mg, 35mg, 70mg, 105mg, 140mg, 175mg, 210mg , any of 245mg or 280mg.
本申请优选技术方案中，所述药物组合物的制剂形式为片剂。In the preferred technical solution of the present application, the preparation form of the pharmaceutical composition is a tablet.
本申请优选技术方案中，按照重量百分比计，所述片剂包含： In the preferred technical solution of the present application, according to weight percentage, the tablet comprises:
约1％-50％w/w的ARV-110的晶型1；Form 1 of ARV-110 at about 1%-50% w/w;
约5-90％w/w的填充剂；about 5-90% w/w filler;
约1％-65％w/w的崩解剂；about 1%-65% w/w disintegrant;
约0-1％w/w的助流剂；about 0-1% w/w glidant;
以及约0-1％的润滑剂。and about 0-1% lubricant.
优选地，按照重量百分比计，所述片剂包含：Preferably, according to weight percentage, the tablet comprises:
约1％-50％w/w的ARV-110的晶型1；Form 1 of ARV-110 at about 1%-50% w/w;
约15-60％w/w的微晶纤维素；about 15-60% w/w microcrystalline cellulose;
约15-50％w/w的乳糖一水合物；about 15-50% w/w lactose monohydrate;
约1％-5％w/w的交联羧甲基纤维素钠；about 1%-5% w/w croscarmellose sodium;
约0-1％w/w的二氧化硅；about 0-1% w/w silica;
以及约0-1％的硬脂酸镁。and about 0-1% magnesium stearate.
进一步优选地，按照重量百分比计，所述片剂包含：Further preferably, according to weight percentage, the tablet comprises:
约5％w/w的ARV-110的晶型1；Form 1 of ARV-110 at about 5% w/w;
约40-50％w/w的微晶纤维素；about 40-50% w/w microcrystalline cellulose;
约40-50％w/w的乳糖一水合物；about 40-50% w/w lactose monohydrate;
约1-3％w/w的交联羧甲基纤维素钠；about 1-3% w/w croscarmellose sodium;
约0.1-1％w/w的二氧化硅；about 0.1-1% w/w silica;
约0.1-1％w/w的硬脂酸镁。About 0.1-1% w/w magnesium stearate.
本申请优选技术方案中，按照重量百分比计，所述片剂包含：In the preferred technical solution of the present application, according to weight percentage, the tablet comprises:
约1％-50％w/w的ARV-110的晶型1；Form 1 of ARV-110 at about 1%-50% w/w;
约10-90％w/w的填充剂；about 10-90% w/w filler;
约1％-30％w/w的崩解剂；about 1%-30% w/w disintegrant;
约1％-15％w/w的黏合剂；About 1%-15% w/w binder;
约0-1％w/w的助流剂；about 0-1% w/w glidant;
以及约0-1％的润滑剂。and about 0-1% lubricant.
优选地，按照重量百分比计，所述片剂包含： Preferably, according to weight percentage, the tablet comprises:
约1％-50％w/w的ARV-110的晶型1；Form 1 of ARV-110 at about 1%-50% w/w;
约15-30％w/w的微晶纤维素；about 15-30% w/w microcrystalline cellulose;
约15-40％w/w的乳糖一水合物；about 15-40% w/w lactose monohydrate;
约1％-10％w/w的交联聚乙烯吡咯烷酮；about 1%-10% w/w cross-linked polyvinylpyrrolidone;
约1％-10％w/w的羟丙基纤维素；about 1%-10% w/w hydroxypropyl cellulose;
约0.1-1％w/w的二氧化硅；about 0.1-1% w/w silica;
以及约0.1-1％的硬脂酸镁。and about 0.1-1% magnesium stearate.
本申请优选技术方案中，按照重量百分比计，所述胶囊剂包含：In the preferred technical solution of the present application, in terms of weight percentage, the capsules comprise:
约1％-50％w/w的ARV-110的晶型1；Form 1 of ARV-110 at about 1%-50% w/w;
约5-90％w/w的填充剂；about 5-90% w/w filler;
约0-1％w/w的助流剂或润滑剂。Glidant or lubricant about 0-1% w/w.
优选地，按照重量百分比计，所述胶囊剂包含：Preferably, by weight percentage, the capsules comprise:
约1％-50％w/w的ARV-110的晶型1；Form 1 of ARV-110 at about 1%-50% w/w;
约5-80％w/w的乳糖和/或微晶纤维素；about 5-80% w/w lactose and/or microcrystalline cellulose;
约0.1-1％w/w的硬脂酸镁。About 0.1-1% w/w magnesium stearate.
本申请的第四方面，提供第一方面所述的ARV-110晶型1或第三方面所述的药物组合物在制备用于雄激素受体相关疾病的用途。The fourth aspect of the present application provides the use of the ARV-110 crystal form 1 described in the first aspect or the pharmaceutical composition described in the third aspect in the preparation of androgen receptor-related diseases.
本申请的第五方面，提供一种用于治疗疾病的方法，所述方法包括向有需要的受试者给予第一方面所述的ARV-110晶型1或第三方面所述的药物组合物，其中所述疾病为雄激素受体相关疾病。The fifth aspect of the present application provides a method for treating diseases, the method comprising administering the ARV-110 crystal form 1 described in the first aspect or the drug combination described in the third aspect to a subject in need A substance, wherein the disease is an androgen receptor-related disease.
优选地，所述治疗疾病的方法可以是一天一次，一天两次，一天三次或以上给药。Preferably, the method for treating diseases may be administered once a day, twice a day, or three times a day or more.
本申请优选技术方案中，所述雄激素受体相关疾病为癌症；优选为***癌。In the preferred technical solution of the present application, the androgen receptor-related disease is cancer; preferably prostate cancer.
本申请的一些实施例中，所述***癌为去势抵抗性***癌；优选为转移性去势抵抗性***癌(mCRPC)。 In some embodiments of the present application, the prostate cancer is castration-resistant prostate cancer; preferably metastatic castration-resistant prostate cancer (mCRPC).
本申请的第六方面，提供第一方面所述的ARV-110晶型1或第三方面所述的药物组合物或其制剂与其他药物的联合应用。所述其他药物可以是用以治疗癌症或相关症状的其他抗癌剂。The sixth aspect of the present application provides the combined use of the ARV-110 crystal form 1 described in the first aspect or the pharmaceutical composition or preparation thereof described in the third aspect and other drugs. The other drugs may be other anti-cancer agents used to treat cancer or related conditions.
在本申请的一些实施例中，其他药物选自PARP抑制剂、CDK抑制剂、抗酸药物等。其中，所述PARP抑制剂选自奥拉帕利、尼拉帕利、Rucaparib、Veliparib(ABT-888)、Fluzoparib和Talazoparib(BMN-673)等。所述CDK抑制剂选自哌柏西利、瑞波西利、阿贝西利、Trilaciclib、达尔西利、曲拉西利、G1T-38、SHR-6390、FLX-925等。所述抗酸药物可以选自雷贝拉唑、奥美拉唑、铝碳酸镁、碳酸氢钠、法莫替丁、雷尼替丁等。In some embodiments of the present application, other drugs are selected from PARP inhibitors, CDK inhibitors, antacid drugs and the like. Wherein, the PARP inhibitor is selected from Olaparib, Niraparib, Rucaparib, Veliparib (ABT-888), Fluzoparib and Talazoparib (BMN-673) and the like. The CDK inhibitor is selected from palbociclib, rebociclib, abeciclib, trilaciclib, dalcilib, triraciclib, G1T-38, SHR-6390, FLX-925 and the like. The antacid drug may be selected from rabeprazole, omeprazole, aluminum magnesium carbonate, sodium bicarbonate, famotidine, ranitidine and the like.
在本申请的一些实施例中，其他药物还可以选自阿比特龙、雌氮芥、多烯紫杉醇、酮康唑、戈舍瑞林、组氨瑞林、曲普瑞林、布舍瑞林、环丙孕酮、氟他胺、比卡鲁胺、尼鲁米特、帕米膦酸盐、或左仑膦酸盐。In some embodiments of the present application, other drugs can also be selected from abiraterone, estramustine, docetaxel, ketoconazole, goserelin, histrelin, triptorelin, buserelin , cyproterone, flutamide, bicalutamide, nilutamide, pamidronate, or zlendronate.
附图说明Description of drawings
图1为根据实施例1制备得到的ARV-110晶型1的XRPD图谱；Fig. 1 is the XRPD spectrum of ARV-110 crystal form 1 prepared according to Example 1;
图2为根据实施例1制备得到的ARV-110晶型1的TGA图谱；Fig. 2 is the TGA spectrum of the ARV-110 crystal form 1 prepared according to Example 1;
图3为根据实施例1制备得到的ARV-110晶型1的DSC图谱；Fig. 3 is the DSC spectrum of ARV-110 crystal form 1 prepared according to Example 1;
图4为根据实施例1制备得到的ARV-110晶型1的等温吸附曲线；Fig. 4 is the isotherm adsorption curve of ARV-110 crystal form 1 prepared according to Example 1;
图5为根据实施例1制备得到的ARV-110晶型1的傅里叶红外光谱；Fig. 5 is the Fourier transform infrared spectrum of ARV-110 crystal form 1 prepared according to Example 1;
图6为根据实施例2制备得到的ARV-110晶型1的XRPD图谱；Fig. 6 is the XRPD spectrum of ARV-110 crystal form 1 prepared according to Example 2;
图7为实施例7的ARV-110晶型1稳定性实验的XRPD图谱。Fig. 7 is the XRPD spectrum of the stability experiment of ARV-110 crystal form 1 in Example 7.
具体实施方式Detailed ways
现详细说明本申请的多种示例性实施方式，该详细说明不应认为是对本申请的限制，而应理解为是对本申请的某些方面、特性和实施方案的更详细的描述。Various exemplary embodiments of the present application are now described in detail. The detailed description should not be considered as a limitation of the present application, but should be understood as a more detailed description of certain aspects, characteristics and embodiments of the present application.
应理解本申请中所述的术语仅仅是为描述特别的实施方式，并非用于限 制本申请。另外，对于本申请中的数值范围，应理解为具体公开了该范围的上限和下限以及它们之间的每个中间值。在任何陈述值或陈述范围内的中间值以及任何其他陈述值或在所述范围内的中间值之间的每个较小的范围也包括在本申请内。这些较小范围的上限和下限可独立地包括或排除在范围内。It should be understood that the terms described in this application are only used to describe specific embodiments, and are not used to limit Make this application. In addition, with regard to the numerical ranges in the present application, it should be understood that the upper and lower limits of the range and every intermediate value therebetween are specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated value or intervening value in a stated range is encompassed herein. The upper and lower limits of these smaller ranges may independently be included or excluded from the range.
除非另有说明，否则本文使用的所有技术和科学术语具有本申请所述领域的常规技术人员通常理解的相同含义。虽然本申请仅描述了优选的方法和材料，但是在本申请的实施或测试中也可以使用与本文所述相似或等同的任何方法和材料。本说明书中提到的所有文献通过引用并入，用以公开和描述与所述文献相关的方法和/或材料。在与任何并入的文献冲突时，以本说明书的内容为准。除非另有说明，否则“％”为基于重量的百分数。Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Although the preferred methods and materials are described herein, any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and/or materials in connection with which the documents are described. In case of conflict with any incorporated document, the contents of this specification control. "%" is a percentage by weight unless otherwise specified.
除非特殊注明，本发明所述的“室温”是指10-30℃的温度。Unless otherwise specified, "room temperature" in the present invention refers to a temperature of 10-30°C.
所述“分离”可以采用本领域的常规方法，例如离心或过滤。其中减压过滤，一般是在室温下以小于大气压的压力进行抽滤。The "separation" can use conventional methods in the art, such as centrifugation or filtration. Wherein, vacuum filtration is generally carried out with suction filtration at a pressure less than atmospheric pressure at room temperature.
所述“干燥”，可以采用本领域的常规技术完成，例如常温干燥、鼓风干燥或减压干燥，亦可以在减压或不减压下进行，可以为真空或非真空。干燥仪器和方法不受限制，可以是通风橱、鼓风烘箱、喷雾干燥器、流化床干燥或真空烘箱；亦可以在减压或不减压下进行。The "drying" can be accomplished using conventional techniques in the art, such as drying at room temperature, blast drying or reduced-pressure drying, and it can also be carried out under reduced pressure or without reduced pressure, and can be vacuum or non-vacuum. The drying apparatus and method are not limited, and can be fume hood, blast oven, spray dryer, fluidized bed drying or vacuum oven; it can also be carried out under reduced or no reduced pressure.
本申请中，术语“晶型”是指晶体物质的某种晶格构型。本领域已知的是，晶型在制药中和稳定性、溶出性和机械性有关。相同物质的不同晶型通常具有其特有的不同物理性质的不同的晶格(例如晶胞)。不同的晶型可通过本领域已知的方法进行表征。例如，可通过固态表征方法例如通过X射线粉末衍射(XRPD)来鉴定。其它表征方法包括示差扫描量热法(DSC)、热解重量分析(TGA)、动态蒸汽吸附(DVS)、固态NMR等。可以使用上述任一种方法对晶型进行表征，或者组合使用两种以上的方法进行表征。In this application, the term "crystal form" refers to a certain lattice configuration of a crystalline substance. It is known in the art that crystal form is related to stability, dissolution and mechanical properties in pharmaceuticals. Different crystal forms of the same substance generally have different crystal lattices (eg, unit cells) with different physical properties characteristic of them. Different crystalline forms can be characterized by methods known in the art. For example, it can be identified by solid state characterization methods such as by X-ray powder diffraction (XRPD). Other characterization methods include Differential Scanning Calorimetry (DSC), Thermogravimetric Analysis (TGA), Dynamic Vapor Sorption (DVS), Solid State NMR, etc. The crystalline form can be characterized by any one of the above methods, or by combining two or more methods.
本发明的晶型是基本纯的、单一的，基本没有混合任何其他晶型或非晶态。本发明中“基本纯的”当用来指新晶型时，指这个新晶型占所存在的化 合物的至少80％(重量)，更指至少90％(重量)，尤其指至少95％(重量)，特别是指至少99％(重量)。The crystal form of the present invention is basically pure and single, basically without mixing any other crystal forms or amorphous states. In the present invention, when "substantially pure" is used to refer to a new crystal form, it means that this new crystal form occupies At least 80% by weight of the compound, more at least 90% by weight, especially at least 95% by weight, especially at least 99% by weight.
本申请中，术语“性能”或“晶型性能”或“性质”或“药学性质”包括其物理和化学性质，评价指标包括但不限于，例如熔点、水溶性、溶出度、机械特性、稳定性、药动学或药效学、引湿性、流动性、可压性、竞争性等。In this application, the term "performance" or "crystalline form performance" or "property" or "pharmaceutical property" includes its physical and chemical properties, and evaluation indicators include but are not limited to, for example, melting point, water solubility, dissolution rate, mechanical properties, stability Sex, pharmacokinetics or pharmacodynamics, hygroscopicity, fluidity, compressibility, competitiveness, etc.
所述的“相对强度”，在具体的XRPD图谱中表现为具体数值。基于晶体的各向异性特性以及X-射线粉末衍射的原理，同一个晶型的衍射峰的相对强度数值随样品的择优取向现象会有波动，该波动不影响同一晶型的判断的常识应该被本领域的技术人员所接受。The "relative strength" is expressed as a specific value in a specific XRPD pattern. Based on the anisotropic characteristics of crystals and the principle of X-ray powder diffraction, the relative intensity value of the diffraction peaks of the same crystal form will fluctuate with the preferred orientation of the sample. The common sense that this fluctuation does not affect the judgment of the same crystal form should be regarded as accepted by those skilled in the art.
本文所用术语“受试者”包括哺乳动物。哺乳动物可为例如任何哺乳动物，例如，人、灵长类动物、鸟、小鼠、大鼠、家禽、狗、猫、牛、马、山羊、骆驼、绵羊或猪。优选哺乳动物为人。The term "subject" as used herein includes mammals. The mammal can be, for example, any mammal, eg, a human, primate, bird, mouse, rat, poultry, dog, cat, cow, horse, goat, camel, sheep, or pig. Preferably the mammal is a human.
术语“有效”可以意指但不限于活性医药成分的量/剂量，当在其预定用途的背景下使用时，其在需要此类治疗或接受此类治疗的受试者中实现或足以预防病状、病症或疾病状态，抑制其发生，改善、延迟或治疗其症状(在一定程度上，优选完全缓解症状)。术语有效包含所有其它有效量或有效浓度术语，例如“有效量/剂量”、“医药学有效量/剂量”或“治疗有效量/剂量”，其在本申请中另外描述或使用。The term "effective" may mean, but is not limited to, the amount/dose of an active pharmaceutical ingredient which, when used in the context of its intended use, achieves or is sufficient to prevent a condition in a subject in need of such treatment or receiving such treatment , disease or disease state, inhibiting its occurrence, improving, delaying or treating its symptoms (to a certain extent, preferably relieving the symptoms completely). The term effective encompasses all other effective amount or effective concentration terms such as "effective amount/dose", "pharmaceutically effective amount/dose" or "therapeutically effective amount/dose" otherwise described or used in this application.
术语“药学上可接受的”或“药理学上可接受”可以意指但决不局限于适当时当施用到动物或人类时不会产生不良、过敏或其它无不当反应的实体和组合物。The terms "pharmaceutically acceptable" or "pharmacologically acceptable" may mean, but are in no way limited to, entities and compositions that, as appropriate, do not produce adverse, allergic or other untoward reactions when administered to animals or humans.
本申请的方法中，一般以ARV-110作为起始物料制备本申请的晶型，作为起始物料的ARV-110可通过购买或通过CN111892577A中的方法制备得到。ARV-110可以为合成粗产物，无定型等其他固态形式。In the method of the present application, ARV-110 is generally used as the starting material to prepare the crystal form of the present application, and the ARV-110 as the starting material can be purchased or prepared by the method in CN111892577A. ARV-110 can be synthetic crude product, amorphous and other solid forms.
实施例中所用的各种试剂如无特别说明均为商购获得。除非另有说明，实施例均在室温下操作。 All reagents used in the examples are commercially available unless otherwise specified. The examples were run at room temperature unless otherwise stated.
除本申请特别说明外，其他实验方法均为本领域公知的方法，这些方法可参考例如《中华人民共和国药典》等。其中，进行检测的参数设置如下：Unless otherwise specified in this application, other experimental methods are methods known in the art, and these methods can refer to, for example, the Pharmacopoeia of the People's Republic of China. Among them, the parameters for detection are set as follows:
X-射线粉末衍射(XRPD)数据采自于BrukerD8 Advance diffractometer。参数如下：Cu靶；波长为电流电压：40KV，40mA；角度范围：3～40°2θ。X-ray powder diffraction (XRPD) data were collected from a Bruker D8 Advance diffractometer. The parameters are as follows: Cu target; wavelength is Current and voltage: 40KV, 40mA; angle range: 3~40°2θ.
傅里叶红外光谱(FT-IR)数据采自于Bruker Tensor27。参数如下：检测方法：ATR法；采集范围：600cm-1-4000cm-1；分辨率：4.0cm-1。Fourier transform infrared spectroscopy (FT-IR) data were collected from Bruker Tensor27. The parameters are as follows: detection method: ATR method; acquisition range: 600cm -1 -4000cm -1 ; resolution: 4.0cm -1 .
差热分析(DSC)数据采自于TA Instruments Q200 DSC。参数如下：升温速率：10℃/min；保护气体：N2；样品盘：加盖的铝坩埚。Differential thermal analysis (DSC) data were collected from TA Instruments Q200 DSC. The parameters are as follows: heating rate: 10°C/min; protective gas: N 2 ; sample tray: covered aluminum crucible.
热重分析(TGA)数据采自于TA Instruments Q500 TGA。参数如下：模式：高分辨模式；升温速率：10℃/min；保护气体：N2；样品盘：铂金坩埚。Thermogravimetric analysis (TGA) data were collected from a TA Instruments Q500 TGA. The parameters are as follows: mode: high resolution mode; heating rate: 10°C/min; protective gas: N 2 ; sample plate: platinum crucible.
动态水份吸附分析(DVS)数据和等温吸附分析数据采自于TA Instruments Q5000 TGA。参数如下：温度：25℃；相对湿度范围：0％RH-80％RH；dm/dt＝0.001％/min；平衡时间：90min；保护气体：N2；样品盘：铂金坩埚。Dynamic moisture sorption analysis (DVS) data and isothermal adsorption analysis data were collected from TA Instruments Q5000 TGA. The parameters are as follows: temperature: 25°C; relative humidity range: 0%RH-80%RH; dm/dt=0.001%/min; equilibration time: 90min; protective gas: N 2 ; sample tray: platinum crucible.
HPLC测定方法：色谱仪型号：Ultimate3000，色谱柱：C18 3μm(150*4.6mm)，柱温：45℃，流速1.0mL/min，检测波长：260nm，进样量：5μL，运行时间：32min，流动相：流动相A：0.1％TFA in H2O、流动相B：0.1％TFA in CAN，运行梯度如下：
HPLC determination method: chromatograph model: Ultimate3000, chromatographic column: C18 3μm (150*4.6mm), column temperature: 45°C, flow rate 1.0mL/min, detection wavelength: 260nm, injection volume: 5μL, running time: 32min, Mobile phase: mobile phase A: 0.1% TFA in H 2 O, mobile phase B: 0.1% TFA in CAN, the operating gradient is as follows:
实施例1 Example 1
称取约30mg ARV-110，加入1.0mL甲醇形成悬浮液，室温搅拌1天，析出固体，过滤，30℃真空干燥2天，制得ARV-110晶型1。Weigh about 30 mg of ARV-110, add 1.0 mL of methanol to form a suspension, stir at room temperature for 1 day, a solid precipitates, filter, and vacuum dry at 30°C for 2 days to obtain ARV-110 crystal form 1.
取实施例1的样品进行表征，具体如下。The samples of Example 1 were taken for characterization, as follows.
1、XRPD图谱1. XRPD pattern
图1为ARV-110晶型1的XRPD图谱，表1示出了ARV-110晶型1的X射线粉末衍射数据。Figure 1 is the XRPD pattern of ARV-110 crystal form 1, and Table 1 shows the X-ray powder diffraction data of ARV-110 crystal form 1.
表1：ARV-110晶型1的X射线粉末衍射数据
Table 1: X-ray powder diffraction data of ARV-110 Form 1
2、TGA图谱2. TGA spectrum
TGA结果如图2所示。显示150℃前失重为0.4％，分解温度为334℃。The TGA results are shown in Figure 2. It shows that the weight loss before 150°C is 0.4%, and the decomposition temperature is 334°C.
3、DSC图谱3. DSC spectrum
差示量热扫描结果如图3所示。在288℃附近有吸热峰。The results of differential calorimetry scanning are shown in Fig. 3 . There is an endothermic peak around 288°C.
4、等温吸附曲线图谱4. Isotherm adsorption curve
等温吸附曲线图谱测定结果如图4所示。在0％RH至80％RH环境下增重约吸湿约0.8％。The results of isotherm adsorption curve spectrum measurement are shown in Fig. 4 . In the environment of 0%RH to 80%RH, the weight gain is about 0.8% and the moisture absorption is about 0.8%.
5、FT-IR5. FT-IR
傅里叶红外光谱结果如图5所示。ARV-110晶型1存在如下特征峰：744.25、826.95、1009.58、1039.18、1107.69、1124.91、1197.41、1238.10、 1255.18、1272.03、1381.24、1448.52、1486.50、1640.91和1706.66cm- 1。考虑到不同条件下波数的变化，一般认为在±2cm-1的范围内是可接受的。The results of Fourier transform infrared spectroscopy are shown in Figure 5. ARV-110 crystal form 1 has the following characteristic peaks: 744.25, 826.95, 1009.58, 1039.18, 1107.69, 1124.91, 1197.41, 1238.10, 1255.18, 1272.03, 1381.24, 1448.52, 1486.50, 1640.91 and 1706.66 cm - 1 . Considering the variation of wavenumber under different conditions, it is generally considered acceptable within the range of ±2cm -1 .
实施例2Example 2
称取约30mg ARV-110，加入0.5mL丙酮，形成悬浮液，室温搅拌1天，析出固体，过滤，30℃真空干燥2天，制得ARV-110晶型1，X射线粉末衍射数据见表2，XRPD图谱详见附图6。Weigh about 30mg of ARV-110, add 0.5mL of acetone to form a suspension, stir at room temperature for 1 day, precipitate solid, filter, and vacuum dry at 30°C for 2 days to obtain ARV-110 crystal form 1. X-ray powder diffraction data are shown in the table 2. For the XRPD spectrum, please refer to the accompanying drawing 6.
表2：实施例2样品的X射线粉末衍射数据
Table 2: X-ray powder diffraction data of the sample of Example 2
实施例3Example 3
称取约10mg ARV-110，加入0.5mL四氢呋喃，加入0.5mL水形成悬浮液，室温搅拌1天，析出固体，过滤，30℃真空干燥2天，制得ARV-110晶型1。Weigh about 10 mg of ARV-110, add 0.5 mL of tetrahydrofuran, add 0.5 mL of water to form a suspension, stir at room temperature for 1 day, a solid precipitates, filter, and vacuum dry at 30°C for 2 days to obtain ARV-110 crystal form 1.
实施例4Example 4
称取约10mg ARV-110，加入1.0mL乙腈，加入0.1mL水形成悬浮液，室温搅拌1天；析出固体，过滤，30℃真空干燥2天，即得。Weigh about 10mg of ARV-110, add 1.0mL of acetonitrile, add 0.1mL of water to form a suspension, stir at room temperature for 1 day; precipitate solid, filter, and vacuum dry at 30°C for 2 days to obtain the product.
实施例5Example 5
称取约20mg ARV-110无定型，加入2.0mL水，1.5mL 1,4-二氧六环，室温搅拌1天，析出固体，过滤，30℃真空干燥2天，即得。Weigh about 20mg ARV-110 amorphous, add 2.0mL water, 1.5mL 1,4-dioxane, stir at room temperature for 1 day, precipitate solid, filter, and vacuum dry at 30°C for 2 days to obtain the product.
实施例6Example 6
称取约40mg ARV-110，加入3.0mL1,4-二氧六环，70℃溶清，加入4.0mL水，室温搅拌3天，析出固体，离心，即得。Weigh about 40 mg of ARV-110, add 3.0 mL of 1,4-dioxane, dissolve at 70°C, add 4.0 mL of water, stir at room temperature for 3 days, precipitate solids, and centrifuge to obtain the product.
实施例7晶型稳定性考察 Example 7 Crystal Form Stability Investigation
取实施例1制备的ARV-110晶型1样品，在加速(40℃/75％RH，敞口避光)、高温(50℃，敞口避光)和高湿(97％RH，敞口避光)条件下放置，结果显示：晶型1在加速、高温和高湿条件下保持14天晶型不变。Get the ARV-110 crystal form 1 sample prepared in Example 1, under accelerated (40°C/75%RH, open to light), high temperature (50°C, open to light) and high humidity (97%RH, open to light) Placed under the condition of avoiding light), the results showed that the crystal form 1 remained unchanged for 14 days under accelerated, high temperature and high humidity conditions.
进一步，ARV-110晶型1在加速(40℃/75％RH/敞口)、高温(50℃/敞口)和高湿(室温/97％RH/敞口)条件下放置8个月保持晶型不变，其XRPD图谱如图7所示。Further, ARV-110 crystal form 1 was kept for 8 months under conditions of accelerated (40°C/75%RH/open), high temperature (50°C/open) and high humidity (room temperature/97%RH/open) The crystal form remains unchanged, and its XRPD spectrum is shown in Figure 7.
实施例8化学稳定性考察Embodiment 8 chemical stability investigation
取实施例1制备的ARV-110晶型1样品适量，在高温(60℃/敞口)和加速(40℃/75％RH/敞口)条件下放置，分别于0天、14天、30天检测纯度(HPLC法)，结果如下：Take an appropriate amount of the ARV-110 crystal form 1 sample prepared in Example 1, place it under high temperature (60°C/open) and accelerated (40°C/75%RH/open) conditions, and place it on 0 day, 14 days, and 30 days, respectively. Day detection purity (HPLC method), the result is as follows:
表3：ARV-110晶型1的化学稳定性-纯度检测结果(A％)
Table 3: Chemical stability-purity test results of ARV-110 crystal form 1 (A%)
实施例9溶解度考察Embodiment 9 Solubility Investigation
取实施例1制备的ARV-110晶型1样品约15mg，在FaSSIF介质(制备方法：取3.95g磷酸二氢钾、1.61g牛磺胆酸钠、0.56g卵磷脂、7.7g氯化钾置于1000mL容量瓶中，用水溶解并定溶至1000mL，用10％磷酸与1％氢氧化钠调pH至6.5)中搅拌24h，取样测定，结果如下：About 15 mg of the ARV-110 crystal form 1 sample prepared in Example 1 was taken, and placed in a FaSSIF medium (preparation method: take 3.95 g of potassium dihydrogen phosphate, 1.61 g of sodium taurocholate, 0.56 g of lecithin, and 7.7 g of potassium chloride) In a 1000mL volumetric flask, dissolve it in water and fix the solution to 1000mL, adjust the pH to 6.5 with 10% phosphoric acid and 1% sodium hydroxide) and stir for 24 hours, take a sample for measurement, and the results are as follows:
表4：ARV-110晶型1在FaSSIF介质中的溶解度 Table 4: Solubility of ARV-110 Form 1 in FaSSIF media
实施例10片剂制备Embodiment 10 tablet preparation
按照下表的处方，将片芯组分混合，制粒，压制，得到片芯，然后将片芯用薄膜包衣的水溶液/悬浮液涂膜，即制备得到片剂。According to the prescription in the table below, mix the tablet core components, granulate, and compress to obtain a tablet core, and then coat the tablet core with a film-coated aqueous solution/suspension to prepare a tablet.
表5：片剂处方

Table 5: Tablet Prescription

实施例11片剂制备Embodiment 11 tablet preparation
按照下表的处方，将片芯组分混合压制，得到片芯，然后将片芯用实施例10薄膜包衣的水溶液/悬浮液涂膜，即得。According to the prescription in the table below, the tablet core components were mixed and compressed to obtain a tablet core, and then the tablet core was coated with the aqueous solution/suspension of the film coating of Example 10 to obtain the tablet.
表6：片剂处方
Table 6: Tablet Prescription
实施例12胶囊剂的制备The preparation of embodiment 12 capsules
按照下表处方，将各处方组分过筛并混合，装入硬明胶胶囊中，即得。According to the prescription in the table below, sieve and mix the components of the prescription, and put them into hard gelatin capsules.
表7：胶囊处方
Table 7: Capsule Prescription
尽管本申请已经参考示例性实施方案进行了描述，但应理解本申请不限于公开的示例性实施方案。在不背离本申请的范围或精神的情况下，可对本申请说明书的示例性实施方案做多种调整或变化。权利要求的范围应基于最宽的解释以涵盖所有修改和等同结构与功能。 While the present application has been described with reference to exemplary embodiments, it is to be understood that the application is not limited to the disclosed exemplary embodiments. Various adaptations or changes may be made to the exemplary embodiments described herein without departing from the scope or spirit of the application. The scope of the claims should be based on the broadest interpretation to cover all modifications and equivalent structures and functions.

Claims (17)

  1. 一种结构式如式(I)所示的ARV-110晶型1，
    A kind of ARV-110 crystal form 1 shown in formula (I),
    其特征在于，使用Cu-Kα辐射，在以衍射角2θ表示的X射线粉末衍射图谱中，具有选自16.28±0.2°、17.39±0.2°、18.63±0.2°、20.06±0.2°中的至少一个特征衍射峰；优选具有至少三个及其以上特征衍射峰。It is characterized in that, using Cu-Kα radiation, in the X-ray powder diffraction pattern represented by diffraction angle 2θ, there is at least one selected from 16.28±0.2°, 17.39±0.2°, 18.63±0.2°, 20.06±0.2° Characteristic diffraction peaks; preferably having at least three or more characteristic diffraction peaks.
  2. 根据权利要求1所述的ARV-110晶型1，其特征在于，所述ARV-110晶型1进一步具有选自13.88±0.2°、21.27±0.2°、21.83±0.2°、23.12±0.2°中的至少一个特征衍射峰。The ARV-110 crystal form 1 according to claim 1, wherein the ARV-110 crystal form 1 further has at least one characteristic diffraction peak.
  3. 根据权利要求1或2所述的ARV-110晶型1，其特征在于，所述ARV-110晶型1进一步具有选自17.82±0.2°、25.75±0.2°中的至少一个特征衍射峰。The ARV-110 crystal form 1 according to claim 1 or 2, characterized in that, the ARV-110 crystal form 1 further has at least one characteristic diffraction peak selected from 17.82±0.2° and 25.75±0.2°.
  4. 根据权利要求1-3任一项所述的ARV-110晶型1，其特征在于，所述ARV-110晶型1的X射线粉末衍射具有如下特征衍射峰位置：
    The ARV-110 crystal form 1 according to any one of claims 1-3, wherein the X-ray powder diffraction of the ARV-110 crystal form 1 has the following characteristic diffraction peak positions:
  5. 根据权利要求1-3任一项所述的ARV-110晶型1，其特征在于，所述ARV-110晶型1的X射线粉末衍射具有如下特征衍射峰位置：
    The ARV-110 crystal form 1 according to any one of claims 1-3, wherein the X-ray powder diffraction of the ARV-110 crystal form 1 has the following characteristic diffraction peak positions:
  6. 权利要求1-5任一项所述的ARV-110晶型1，其特征在于，所述ARV-110晶型1具有基本如图1或图6所示的X射线粉末衍射图谱。The ARV-110 crystal form 1 according to any one of claims 1-5, characterized in that the ARV-110 crystal form 1 has an X-ray powder diffraction pattern substantially as shown in FIG. 1 or FIG. 6 .
  7. 权利要求1-6任一项所述的ARV-110晶型1，其特征在于，所述ARV-110晶型1，在傅里叶红外光谱中，在选自744.25±2cm-1、826.95±2cm-1、1009.58±2cm-1、1039.18±2cm-1、1107.69±2cm-1、1124.91±2cm-1、1197.41±2cm-1、1238.10±2cm-1、1255.18±2cm-1、1272.03±2cm-1、1381.24±2cm-1、1448.52±2cm-1、1486.50±2cm-1、1640.91±2cm-1和1706.66±2cm-1中的至少之一处具有特征峰；优选地，所述ARV-110晶型1在傅里叶红外光谱(FT-IR)中，在1009.58±2cm-1、1039.18±2cm-1、1124.91±2cm-1、1197.41±2cm-1、1238.10±2cm-1、1448.52±2cm-1、1706.66±2cm-1处具有特征峰。The ARV-110 crystal form 1 according to any one of claims 1-6, characterized in that, in the Fourier transform infrared spectrum, the ARV-110 crystal form 1 is selected from 744.25±2 cm -1 , 826.95± 2cm -1 , 1009.58±2cm -1 , 1039.18±2cm -1 , 1107.69±2cm -1 , 1124.91±2cm -1 , 1197.41±2cm -1 , 1238.10±2cm -1 , 1255.18±2cm -1 , 1272.03±2cm -1 , 1272.03±2cm -1 1 , at least one of 1381.24±2cm -1 , 1448.52±2cm -1 , 1486.50±2cm -1 , 1640.91±2cm -1 and 1706.66±2cm -1 has a characteristic peak; preferably, the ARV-110 crystal Type 1 in Fourier transform infrared spectrum (FT-IR), at 1009.58±2cm -1 , 1039.18±2cm -1 , 1124.91±2cm -1 , 1197.41±2cm -1 , 1238.10±2cm -1 , 1448.52±2cm -1 , 1448.52±2cm -1 1. There is a characteristic peak at 1706.66±2cm -1 .
  8. 权利要求1-7任一项所述的ARV-110晶型1，其特征在于，所述ARV-110晶型1为无水物。The ARV-110 crystal form 1 according to any one of claims 1-7, characterized in that the ARV-110 crystal form 1 is an anhydrate.
  9. 权利要求1-8任一项所述的ARV-110晶型1，其特征在于，所述ARV-110晶型1在DSC图谱中显示的熔点为288℃±3℃；优选地，所述ARV-110晶型1在TGA图谱中显示150℃前失重≤0.8％；优选地，所述ARV-110晶型1在0％RH至80％RH的引湿性为≤1％。The ARV-110 crystal form 1 according to any one of claims 1-8, characterized in that, the melting point of the ARV-110 crystal form 1 shown in the DSC spectrum is 288°C±3°C; preferably, the ARV-110 crystal form 1 -110 crystal form 1 shows a weight loss before 150° C. of ≤0.8% in the TGA spectrum; preferably, the hygroscopicity of the ARV-110 crystal form 1 is ≤1% at 0% RH to 80% RH.
  10. 根据权利要求1-9任一项所述的ARV-110晶型1的制备方法，其特征在于，所述制备方法采用下列方法中的任一种： The preparation method of ARV-110 crystal form 1 according to any one of claims 1-9, wherein the preparation method adopts any of the following methods:
    方法(1)：称取适量的起始物料ARV-110加入溶剂形成悬浮液，室温搅拌析出固体，离心或过滤，干燥即得ARV-110晶型1；Method (1): Weigh an appropriate amount of starting material ARV-110 and add a solvent to form a suspension, stir at room temperature to precipitate a solid, centrifuge or filter, and dry to obtain ARV-110 crystal form 1;
    方法(2)：称取适量的起始物料ARV-110加入1,4-二氧六环，加热溶清，加入水，搅拌析出固体，离心或过滤，干燥即得ARV-110晶型1。Method (2): Weigh an appropriate amount of starting material ARV-110, add 1,4-dioxane, heat to dissolve, add water, stir to precipitate solid, centrifuge or filter, and dry to obtain ARV-110 crystal form 1.
  11. 根据权利要求10所述的ARV-110晶型1的制备方法，其特征在于，所述方法(1)的溶剂选自甲醇、丙酮、乙腈、四氢呋喃、1,4-二氧六环和水中的任一种或其组合；优选地，所述方法(1)的起始物料:溶剂的比例≥1:1(mg:ml)；The preparation method of ARV-110 crystal form 1 according to claim 10, is characterized in that, the solvent of described method (1) is selected from methanol, acetone, acetonitrile, tetrahydrofuran, 1,4-dioxane and water Any one or its combination; Preferably, the starting material of the method (1): the ratio of solvent ≥ 1:1 (mg:ml);
    优选地，所述方法(2)的起始物料:1,4-二氧六环的比例≥5:1(mg:ml)；优选地，所述方法(2)的1,4-二氧六环：水的比例为1:1-1:1.5；优选地，所述方法(2)的加热温度为40-80℃；Preferably, the starting material of the method (2): the ratio of 1,4-dioxane ≥ 5:1 (mg:ml); preferably, the 1,4-dioxane of the method (2) The ratio of six rings: water is 1:1-1:1.5; preferably, the heating temperature of the method (2) is 40-80°C;
    优选地，所述制备方法(1)或(2)的搅拌温度为室温；优选地，所述制备方法(1)或(2)的干燥温度≥30℃。Preferably, the stirring temperature of the preparation method (1) or (2) is room temperature; preferably, the drying temperature of the preparation method (1) or (2) is ≥30°C.
  12. 一种药物组合物，其特征在于，所述组合物包含根据权利要求1-9任一项所述的ARV-110晶型1以及至少一种药学上可接受的载体。A pharmaceutical composition, characterized in that the composition comprises ARV-110 crystal form 1 according to any one of claims 1-9 and at least one pharmaceutically acceptable carrier.
  13. 根据权利要求12所述的药物组合物，其特征在于，所述药物组合物选自适合口服给药的固体和半固体制剂；优选为片剂、包衣剂、胶囊；优选地，所述药物组合物中ARV-110晶型1的单位剂量为5mg-1000mg。The pharmaceutical composition according to claim 12, characterized in that, the pharmaceutical composition is selected from solid and semi-solid preparations suitable for oral administration; preferably tablets, coated agents, capsules; preferably, the drug The unit dosage of ARV-110 crystal form 1 in the composition is 5mg-1000mg.
  14. 根据权利要求1-9任一项所述的ARV-110晶型1或权利要求12-13任一项所述的药物组合物在制备用于雄激素受体相关疾病中的用途。Use of the ARV-110 crystal form 1 according to any one of claims 1-9 or the pharmaceutical composition according to any one of claims 12-13 in preparation for androgen receptor-related diseases.
  15. 根据权利要求1-9任一项所述的ARV-110晶型1或权利要求12-13任一项所述的药物组合物在用于治疗雄激素受体相关疾病的方法；优选地，所述疾病为***癌。The method for treating androgen receptor-related diseases according to the ARV-110 crystal form 1 described in any one of claims 1-9 or the pharmaceutical composition described in any one of claims 12-13; preferably, the The disease is prostate cancer.
  16. 一种用于治疗疾病的方法，所述方法包括向有需要的受试者给予权利要求1-9任一项所述的ARV-110晶型1或权利要求12-13任一项所述的药物组合物，其中，所述疾病为雄激素受体相关疾病。 A method for treating a disease, the method comprising administering the ARV-110 crystal form 1 described in any one of claims 1-9 or the crystal form 1 described in any one of claims 12-13 to a subject in need. A pharmaceutical composition, wherein the disease is an androgen receptor-related disease.
  17. 根据权利要求1-9任一项所述的ARV-110晶型1或权利要求12-13任一项所述的药物组合物与其他药物的联合应用。 The combined application of ARV-110 crystal form 1 according to any one of claims 1-9 or the pharmaceutical composition according to any one of claims 12-13 and other drugs.
PCT/CN2023/073290 2022-01-27 2023-01-20 Crystal form of arv-110 and preparation method therefor and use thereof WO2023143427A1 (en)

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