WO2019080811A1 - 一种选择性孕酮受体调节剂的晶型及其制备方法 - Google Patents

一种选择性孕酮受体调节剂的晶型及其制备方法

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WO2019080811A1
WO2019080811A1 PCT/CN2018/111270 CN2018111270W WO2019080811A1 WO 2019080811 A1 WO2019080811 A1 WO 2019080811A1 CN 2018111270 W CN2018111270 W CN 2018111270W WO 2019080811 A1 WO2019080811 A1 WO 2019080811A1
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Prior art keywords
solvent
crystal form
bay
crystalline form
crystal
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PCT/CN2018/111270
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English (en)
French (fr)
Inventor
陈敏华
张炎锋
张婧
张晓宇
刘凯
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苏州科睿思制药有限公司
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Application filed by 苏州科睿思制药有限公司 filed Critical 苏州科睿思制药有限公司
Priority to EP18869512.6A priority Critical patent/EP3701951A4/en
Priority to US16/759,066 priority patent/US20210171568A1/en
Priority to JP2020522371A priority patent/JP2021500359A/ja
Priority to CN201880067056.5A priority patent/CN111225671A/zh
Publication of WO2019080811A1 publication Critical patent/WO2019080811A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A61P5/36—Antigestagens
    • 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 chemistry.
  • it relates to a crystalline form of a selective progesterone receptor modulator and a process for its preparation.
  • Uterine fibroids are the most common benign tumors in women, with a recurrence rate of approximately 40% after surgery. Endometriosis is a common disease in women of childbearing age, and the incidence is increasing year by year in women. At present, effective drugs can only be used for short-term use and treatment, and long-term medication can have systemic adverse reactions.
  • Selective progesterone receptor modulators are a new class of ligands for progesterone receptors that, when combined with progesterone receptors, exhibit partial progesterone agonism and antagonistic activity in vivo, with high receptors and targets.
  • Selective specificity can effectively alleviate the clinical symptoms of uterine fibroids, reduce the volume of uterine fibroids, but does not affect the secretion of ovarian estrogen, and has no androgenic activity, so long-term use without masculinity, osteoporosis and increase cardiovascular Adverse reactions such as illness.
  • BAY-1002670 (Vilaprisan), developed by Bayer, is a small molecule selective progesterone receptor modulator. BAY-1002670 is expected to be the first drug that can be used for long-term oral treatment of uterine fibroids. In addition, studies have shown that BAY-1002670 can also be used as a potential drug for the treatment of endometriosis.
  • BAY-1002670 (11 ⁇ , 17 ⁇ )-17-hydroxy-11-[4-(methylsulfonyl)phenyl]-17-(pentafluoroethyl)est-4,9-diene- 3-ketone (hereinafter referred to as "compound (I)”), which has the following structural formula:
  • the crystal form is a different solid form formed by the arrangement of the compound molecules in the crystal lattice, and the drug polymorph refers to the presence of two or more different crystal forms of the drug.
  • the prior art CN102482317A discloses a preparation method of BAY-1002670, and the inventors obtained amorphous BAY-1002670 according to the preparation method of the compound (I) disclosed in CN102482317A.
  • the molecules in the amorphous material are disorderly arranged, so they are in a thermodynamically unstable state.
  • the inventors found in the study that the amorphous form of BAY-1002670 is unstable under the conditions of 25 ° C / 60% relative humidity, 40 ° C / 75% relative humidity and 60 ° C / 75% relative humidity.
  • amorphous preparation is usually a rapid process of kinetic solid precipitation.
  • the inventors of the present application unexpectedly discovered the crystalline form CS2 and the crystalline form CS4 of BAY-1002670 with excellent performance in stability, melting point, solubility, dissolution in vitro and in vivo, hygroscopicity, and bioavailability.
  • Advantages in at least one of adhesion, compressibility, fluidity, processing property, purification, formulation production, etc., especially physical, chemical stability, non-degradability, small particle size, uniform particle size distribution Low hygroscopicity and low solvent residue provide a new and better choice for the development of drugs containing BAY-1002670, which is of great significance.
  • the main object of the present invention is to provide a crystal form of BAY-1002670, a preparation method and use thereof.
  • the present invention provides a crystal form CS2 of BAY-1002670 (hereinafter referred to as "crystal form CS2").
  • the X-ray powder diffraction of the crystal form CS2 has characteristic peaks at diffraction angle 2 ⁇ values of 4.0° ⁇ 0.2°, 15.9° ⁇ 0.2°, and 17.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 19.0° ⁇ 0.2°, 20.4° ⁇ 0.2°, and 21.4° ⁇ 0.2°. peak.
  • the X-ray powder diffraction of the crystal form CS2 has a characteristic peak at three points in the diffraction angle 2 ⁇ value of 19.0° ⁇ 0.2°, 20.4° ⁇ 0.2°, and 21.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 11.8° ⁇ 0.2°, 15.0° ⁇ 0.2°, and 25.1° ⁇ 0.2°. peak.
  • the X-ray powder diffraction of the crystal form CS2 has a characteristic peak at three points in the diffraction angle 2 ⁇ value of 11.8° ⁇ 0.2°, 15.0° ⁇ 0.2°, and 25.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS2 has diffraction angles 2 ⁇ of 4.0° ⁇ 0.2°, 15.9° ⁇ 0.2°, 17.9° ⁇ 0.2°, 19.0° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.4° ⁇ 0.2°, 11.8° ⁇ 0.2°, 15.0° ⁇ 0.2°, 25.1° ⁇ 0.2°, 14.5° ⁇ 0.2°, 16.9° ⁇ 0.2°, 17.3° ⁇ 0.2°, 18.5° Any three, or four, or five, or six, or seven, or eight, or nine, or ten, or eleven, or twelve, or 13 of ⁇ 0.2° peak.
  • the X-ray powder diffraction pattern of Form CS2 is as shown in FIG.
  • the unit cell parameters of the crystalline CS2 single crystal are substantially as shown in the following table:
  • the present invention also provides a method for preparing a crystalline form CS2, characterized in that the method comprises:
  • BAY-1002670 was dissolved in a ketone solvent system, and then placed in an atmosphere containing n-heptane, which was obtained by gas-liquid permeation.
  • the ketone solvent in the method (1) is preferably acetone.
  • the alcohol solvent in the method (2) is preferably methanol
  • the ester solvent is preferably ethyl acetate
  • the ketone solvent is preferably butanone.
  • the ketone solvent in the method (3) is preferably methyl isobutyl ketone.
  • the present invention also provides a crystal form CS4 of BAY-1002670 (hereinafter referred to as "crystal form CS4").
  • the X-ray powder diffraction of the crystal form CS4 has characteristic peaks at diffraction angle 2 ⁇ values of 16.0° ⁇ 0.2°, 16.6° ⁇ 0.2°, and 14.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS4 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 18.9° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 10.1 ⁇ 0.2°. peak.
  • the X-ray powder diffraction of the crystal form CS4 has a characteristic peak at three points in the diffraction angle 2 ⁇ value of 18.9° ⁇ 0.2°, 21.5° ⁇ 0.2°, and 10.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form CS4 has characteristics at one, or two, or three of the diffraction angle 2 ⁇ values of 13.2° ⁇ 0.2°, 23.5° ⁇ 0.2°, and 17.9° ⁇ 0.2°. peak.
  • the X-ray powder diffraction of the crystalline form CS4 has a characteristic peak at three points in the diffraction angle 2 ⁇ value of 13.2° ⁇ 0.2°, 23.5° ⁇ 0.2°, and 17.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form CS4 has a diffraction angle 2 ⁇ value of 16.0° ⁇ 0.2°, 16.6° ⁇ 0.2°, 14.1° ⁇ 0.2°, 18.9° ⁇ 0.2°, 21.5° ⁇ 0.2°, 10.1° ⁇ 0.2°, 13.2° ⁇ 0.2°, 23.5° ⁇ 0.2°, 17.9° ⁇ 0.2°, 19.6° ⁇ 0.2°, 19.8° ⁇ 0.2°, 20.2° ⁇ 0.2°, 20.6° Any three, or four, or five, or six, or seven, or eight, or nine, or ten, or eleven, or twelve, or 13 of ⁇ 0.2° peak.
  • the X-ray powder diffraction pattern of Form CS4 is as shown in FIG.
  • the present invention also provides a method for preparing a crystalline form CS4, characterized in that the method comprises:
  • the BAY-1002670 raw material is placed in an ether solvent system and stirred at 40 ° C - 60 ° C; or
  • the BAY-1002670 raw material is placed in a closed environment containing an alcohol solvent or an ester solvent atmosphere, and is obtained by gas-solid permeation.
  • the ether solvent in the method (1) is preferably methyl tert-butyl ether; and the stirring temperature is preferably 50 °C.
  • the heating temperature in the method (2) is from 150 ° C to 200 ° C, preferably 160 ° C.
  • the alcohol solvent in the method (3) is preferably ethanol; and the ester solvent is preferably isopropyl acetate.
  • the crystalline form CS2 and the crystalline form CS4 provided by the present invention have the following beneficial effects:
  • the crystal form provided by the present invention has lower hygroscopicity than the prior art.
  • the test results show that the wettability of the crystalline form CS2 of the present invention is less than 15% of the prior art solid, and the wettability of the crystalline form CS4 is less than 10% of the prior art solid.
  • the weight gain of Form CS2 and Form CS4 at 80% relative humidity were 0.23% and 0.12%, respectively, while the prior art amorphous weight gain reached 1.89%.
  • Humidity affects the stability of the drug, fluidity and uniformity during processing, and ultimately affects the quality of the drug formulation. Humidity also affects the preparation, post-treatment and storage of the drug.
  • the low moisture absorbing crystal form has strict requirements on storage conditions, reduces material storage and quality control costs, and has strong economic value.
  • the crystal form provided by the present invention is more physically stable than the prior art.
  • the crystalline forms CS2 and CS4 of the present invention are left at a temperature of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for at least 6 months without change, and at least 2 at 60 ° C / 75% relative humidity.
  • the weekly crystal form did not change.
  • the prior art solids were partially converted to the crystalline form CS2 after being left at 40 ° C / 75% relative humidity for 6 months, and partially converted to the crystalline form CS2 after being left at 60 ° C / 75% relative humidity for 2 weeks.
  • the physical stability of the drug substance is critical to the drug. From bulk drugs to drugs, they need to go through storage, transportation, and formulation processes. These processes often encounter harsh conditions, most often high temperatures and high humidity. Such as the collision of raw materials in storage and transportation, the wet granulation process in the production of the preparation, the seasonal and regional climate differences, and weather factors.
  • the prior art solids are partially converted to a crystalline form after being placed under high temperature and high humidity conditions, while the crystalline form of the present invention is not converted.
  • the transformation of the crystal form causes a change in the absorption of the drug, causing toxic side effects of the drug.
  • the crystalline form CS2 and the crystalline form CS4 have good physical stability, ensuring consistent controllable quality of the drug substance and the preparation, and maximally reducing the toxicity of the drug due to the change of the crystal form, and ensuring the therapeutic effect of the drug.
  • the crystal form provided by the present invention is more chemically stable than the prior art.
  • the crystalline forms CS2 and CS4 of the present invention are allowed to stand under the condition of 25 ° C / 60% relative humidity for 6 months, the purity is only reduced by 0.06% and 0.13%, respectively, and the purity remains substantially unchanged, while the amorphous purity of the prior art is reduced by 0.80%.
  • the crystal forms CS2 and CS4 of the present invention are kept substantially unchanged under the condition of 40 ° C / 75% relative humidity for 3 months, and the purity is only reduced by 0.27% and 0.02%, respectively, while the amorphous purity of the prior art is reduced by 1.08%.
  • the chemical purity of the drug is of great significance for ensuring the efficacy and safety of the drug and preventing the occurrence of adverse drug reactions.
  • Impurities in drugs are the main factors affecting purity. For example, if the drug contains more than a limited amount of impurities, it may change the physical and chemical constants, the appearance traits will mutate, and affect the stability of the drug. The increase of impurities also makes the drug content significantly lower or The activity is reduced and the side effects are significantly increased.
  • the crystal form CS2 and the crystal form CS4 of the present invention have small change in purity after being placed, are not easy to be degraded, and have substantially no purity in drug storage, and effectively overcome the disadvantages of reduction in drug purity, poor efficacy, and increased toxicity. .
  • the crystalline form CS2 and the crystalline form CS4 of the present invention have almost no solvent residue and meet the medicinal requirements, while the residual amount of the solid solvent in the prior art exceeds the standard and cannot be directly used as a pharmaceutical raw material.
  • Many organic solvents have certain harm to the environment and the human body. Therefore, in order to ensure the safety of the drug and control the quality of the product, it is necessary to strictly control and control the organic solvent residue of the drug substance.
  • crystal forms CS2 and CS4 provided by the present invention have the following beneficial effects:
  • the crystal forms CS2 and CS4 of the present invention have a uniform particle size distribution. Its uniform particle size helps to ensure uniformity of content and uniformity of dissolution in vitro. At the same time, the preparation process can be simplified, the pretreatment of the raw material medicine is not required, the cost is saved, and the crystallinity change and the risk of crystal transformation which may be brought about by the grinding are also reduced.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the crystalline form CS2 or the crystalline form CS4 of the present invention or any mixture thereof, and at least one A pharmaceutically acceptable carrier, diluent or excipient.
  • crystalline form CS2 or the crystalline form CS4 provided by the present invention or any mixture thereof in the production of a pharmaceutical preparation containing a progestogen receptor modulator.
  • the "gas-liquid permeation" crystallization method generally means that a solid is dissolved in a good solvent to form a clear solution, and the solution is placed in a closed environment containing a poor solvent atmosphere, and the solid phase is precipitated by gas phase diffusion.
  • the method of crystals generally means that a solid is dissolved in a good solvent to form a clear solution, and the solution is placed in a closed environment containing a poor solvent atmosphere, and the solid phase is precipitated by gas phase diffusion.
  • the "gas-solid permeation" crystallization method generally refers to a method in which a solid raw material is placed in a closed environment containing a solvent atmosphere, and a solvent is contacted with a solid raw material by gas phase diffusion to obtain a crystal.
  • crystal or “polymorph” means confirmed by the X-ray diffraction pattern characterization shown.
  • X-ray diffraction pattern will generally 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 fact, the relative intensity of the diffraction peaks in the XRPD pattern is related to the preferred orientation of the crystal.
  • the peak intensities shown here are illustrative and not for absolute comparison.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall offset of the peak angle is caused, and a certain offset is usually allowed.
  • the X-ray diffraction pattern of one crystal form in the present invention is not necessarily identical to the X-ray diffraction pattern in the example referred to herein, and the "XRPD pattern is the same" as used herein does not mean absolutely the same.
  • the same peak position can differ by ⁇ 0.2° and the peak intensity allows for some variability.
  • Any crystal form having a map identical or similar to the characteristic peaks in these maps is within the scope of the present invention.
  • One skilled in the art will be able to compare the maps listed herein with a map of an unknown crystal form to verify whether the two sets of maps reflect the same or different crystal forms.
  • the crystalline form CS2 or crystalline form CS4 of the present invention is pure, substantially free of any other crystalline form.
  • substantially free when used to refer to a new crystalline form means that the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more Other crystal forms of 5% by weight, more preferably less than 1% by weight of other crystal forms.
  • Figure 1 is an XRPD pattern of a crystal form CS2 obtained according to Example 1 of the present invention.
  • Example 2 is a DSC chart of a crystalline form CS2 obtained according to Example 1 of the present invention.
  • Figure 3 is a TGA diagram of a crystalline form CS2 obtained according to Example 1 of the present invention.
  • Example 4 is an XRPD pattern of a crystal form CS2 obtained according to Example 2 of the present invention.
  • Figure 5 is an XRPD pattern of a crystalline form CS4 obtained in accordance with Example 6 of the present invention.
  • Figure 6 is a DSC chart of a crystalline form CS4 obtained in accordance with Example 6 of the present invention.
  • Figure 7 is a TGA diagram of a crystalline form CS4 obtained in accordance with Example 6 of the present invention.
  • Figure 8 is an XRPD pattern of a crystalline form CS4 obtained according to Example 7 of the present invention.
  • Figure 9 is an XRPD pattern of a crystalline form CS4 obtained in accordance with Example 8 of the present invention.
  • Figure 10 is an XRPD overlay of the crystalline CS2 placed at 25 ° C / 60% relative humidity for 6 months (the top image is before placement and the lower panel is after placement).
  • Figure 11 is an XRPD overlay of the crystalline CS4 placed at 25 ° C / 60% relative humidity for 6 months (the top image is before placement and the lower panel is after placement).
  • Figure 12 is an XRPD overlay of prior art solids placed at 25 ° C / 60% relative humidity for 6 months (the top view is before placement and the lower figure is after placement).
  • Figure 13 is an XRPD overlay of the crystalline CS2 placed at 40 °C / 75% relative humidity for 6 months (the top image is before placement and the lower panel is after placement).
  • Figure 14 is an XRPD overlay of the crystalline CS4 placed at 40 ° C / 75% relative humidity for 6 months (the top image is before placement and the lower panel is after placement).
  • Figure 15 is an XRPD overlay of prior art solids placed at 40 ° C / 75% relative humidity for 6 months (top panel before placement, bottom panel after placement).
  • Figure 16 is an XRPD overlay of the crystalline CS2 placed at 60 ° C / 75% relative humidity for 2 weeks (the top image is before placement and the lower panel is after placement).
  • Figure 17 is an XRPD overlay of the crystalline CS4 placed at 60 ° C / 75% relative humidity for 2 weeks (the top image is before placement and the lower panel is after placement).
  • Figure 18 is an XRPD overlay of prior art solids placed at 60 ° C / 75% relative humidity for 2 weeks (the top image is before placement and the lower panel is after placement).
  • Figure 19 is a PSD diagram of a crystalline form CS2 of the present invention.
  • Figure 20 is a PSD diagram of a crystalline form CS4 of the present invention.
  • PSD particle size distribution
  • the X-ray powder diffraction pattern of the present invention was collected on a Bruker D2 PHASER X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software
  • the analysis software is DVS-Intrinsic Analysis software.
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • room temperature is not an accurate temperature value and refers to a temperature range of 10 to 30 °C.
  • the BAY-1002670 as a raw material means a solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compound (I) as a raw material is in the form of a solid powder.
  • the BAY-1002670 starting material used in the following examples can be prepared according to the methods described in the prior art, for example, CN102482317A.
  • BAY-1002670 raw material 1022.4 mg was weighed, added to a mixed solvent system of water and acetone in a volume ratio of 4:1, stirred at room temperature for 2 days, filtered, and dried in vacuo to give a solid.
  • Example 1 The solid obtained in Example 1 was found to be crystalline form CS2, and its X-ray powder diffraction data is shown in Table 1, Table 1.
  • the DSC of the crystalline form CS2 obtained in Example 1 is as shown in FIG. 2, and the first endothermic peak starts to appear when heated to around 65 ° C.
  • the endothermic peak is the dehydration endothermic peak of the crystalline form CS2, and is heated to around 206 ° C.
  • a second endothermic peak begins to appear, which is the melting endothermic peak of Form CS2.
  • the TGA of the form CS2 obtained in Example 1 was as shown in Fig. 3, and when heated to around 100 ° C, it had a mass loss gradient of about 2.9%.
  • samples 2 to 4 were all crystalline form CS2.
  • Sample 2 was selected for test characterization, and the X-ray powder diffraction data is shown in Fig. 4 and Table 3.
  • the DSC of the crystalline form CS4 obtained in Example 6 is as shown in Fig. 6.
  • the first endothermic peak began to appear, and this endothermic peak is the melting endothermic peak of the crystalline form CS4.
  • the TGA of the crystal form CS4 obtained in Example 6 was as shown in Fig. 7, and when heated to around 170 ° C, it had a mass loss gradient of about 1.7%.
  • BAY-1002670 solid raw material 53.4 mg was weighed, dissolved in 2.5 mL of a 2-methyltetrahydrofuran solvent system, and volatilized at room temperature to obtain a solid.
  • the solid obtained by volatilization was heated to 160 ° C at a rate of 10 ° C / min, and equilibrated at 160 ° C for 10 min to give a solid.
  • the obtained solid was crystalline form CS4, and its X-ray powder diffraction data is shown in Fig. 8 and Table 6.
  • Sample 8 was selected for test characterization, and its X-ray powder diffraction data is shown in Figure 9, Table 8.
  • Example 10 Comparative study on the wettability of crystalline CS2, crystalline CS4 and prior art amorphous
  • Example 11 Study on the stability of crystalline CS2, crystalline CS4 and prior art amorphous
  • the crystalline form CS2 and the crystalline form CS4 of the present invention remain unchanged at a temperature of 25 ° C / 60% relative humidity for at least 6 months.
  • the crystalline forms CS2 and CS4 of the present invention are allowed to stand under the condition of 25 ° C / 60% relative humidity for 6 months, the purity remains substantially unchanged, the purity is only reduced by 0.06% and 0.13%, respectively, and the amorphous purity of the prior art is reduced by 0.80%. .
  • the crystalline form CS2 and the crystalline form CS4 of the present invention remain unchanged after being left for at least 6 months under conditions of 40 ° C / 75% relative humidity.
  • the prior art amorphous form was partially converted into the crystalline form CS2 of the present invention after being left for 6 months at 40 ° C / 75% relative humidity.
  • the crystalline forms CS2 and CS4 of the present invention are allowed to stand under the condition of 40 ° C / 75% relative humidity for 3 months, the purity remains substantially unchanged, the purity is only reduced by 0.27% and 0.02%, respectively, and the amorphous purity of the prior art is reduced by 1.08%. .
  • the above results show that the crystalline form CS2 and the crystalline form CS4 of the present invention have better physical and chemical stability than the prior art amorphous.
  • the crystalline form CS2, the crystalline form CS4 of the present invention and the amorphous amorphous material of the prior art were respectively placed at 60 ° C / 75% relative humidity to test the crystal form and purity change, and the results are shown in Table 14 and Table 15:
  • the crystal form CS2 and the crystalline form CS4 of the present invention After the crystalline form CS2 and the crystalline form CS4 of the present invention are left at a temperature of 60 ° C / 75% relative humidity for at least 2 weeks, the crystal form remains unchanged.
  • the prior art amorphous form was partially converted into the crystalline form CS2 of the present invention after being left for 2 weeks at 60 ° C / 75% relative humidity.
  • the crystal forms CS2 and CS4 of the present invention are placed under the condition of 60 ° C / 75% relative humidity for 2 weeks, the purity is substantially unchanged, and the purity is only changed by 0.05% and 0.03%, respectively, while the amorphous purity of the prior art is reduced. 0.98%.
  • the above results indicate that the crystalline form CS2 and the crystalline form CS4 of the present invention have better physical and chemical stability than the prior art amorphous.
  • Example 12 Form CS2, Form CS4 and Prior Art Amorphous Solvent Residues
  • the solvent residual amounts of the crystalline form CS2, the crystalline form CS4 of the present invention and the prior art amorphous solid were tested separately.
  • the test results show that the crystalline form CS2 and the crystalline form CS4 of the present invention have almost no solvent residue, and the solvent residual amount of methylene chloride in the amorphous solid is 64185 ppm.
  • methylene chloride is the second type of solvent in pharmaceuticals and the solvent residue must not exceed 600 ppm. It can be seen that the residual amount of methylene chloride solvent in the amorphous solid significantly exceeds the limit specified by ICH, and is not suitable for direct use as a pharmaceutical raw material.
  • the crystal forms CS2 and CS4 of the present invention are weighed, and then 10 mL of Isopar G (containing 0.2% lecithin) is added, and the sample to be tested is thoroughly mixed and added to the SDC sample introduction system to make the sample amount indication map reach a suitable position.
  • the particle size distribution was tested to obtain an average particle diameter calculated by volume, a particle size distribution (volume distribution), a particle diameter corresponding to 10%, and a particle size distribution (volume distribution) corresponding to 50%. Particle size.
  • the particle size distribution (volume distribution) accounts for 90% of the corresponding particle size and crystal size distribution map.
  • the particle size distribution results are shown in Table 16.
  • D10 indicates the particle size distribution (volume distribution) accounts for 10% of the particle size
  • D50 indicates the particle diameter corresponding to the particle size distribution (volume distribution), which is also called the median diameter.
  • D90 indicates the particle size distribution (volume distribution) accounts for 90% of the particle size
  • the particle size distribution (PSD) patterns of the crystal forms CS2 and CS4 are as shown in Figs. 19 and 20, respectively. It can be seen from the figure that the particle sizes of the crystal forms CS2 and CS4 are monodisperse normal distribution, the particle size distribution is uniform, and the particle size is small.
  • the uniform and small particle size of the crystalline forms CS2 and CS4 of the present invention helps to simplify the post-treatment process of the formulation process, such as reducing the grinding of the crystal form and saving cost.
  • the uniform particle size distribution of the crystal forms CS2 and CS4 can improve the uniformity of the drug substance components in the preparation, and the smaller crystal grain size can increase the specific surface area of the drug, increase the dissolution rate of the drug, facilitate drug absorption, and thereby improve bioavailability.

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Abstract

本发明涉及化合物(I)的晶型及其制备方法，含有该晶型的药物组合物，以及该晶型在制备含孕酮受体调节剂和治疗子宫肌瘤和/或子宫内膜异位药物制剂中的用途。本发明提供的化合物(I)的晶型比现有技术具有一种或多种改进的特性，对未来该药物的优化和开发具有重要价值。

Description

一种选择性孕酮受体调节剂的晶型及其制备方法 技术领域
本发明涉及药物化学领域。具体而言，涉及一种选择性孕酮受体调节剂的晶型及其制备方法。
背景技术
子宫肌瘤是女性中最常见的良性肿瘤，手术后复发率约为40％。子宫内膜异位症是育龄妇女的常见病，在女性中发病率逐年上升。目前，有效的药物只能用于短期服用和治疗，长期用药会有全身性不良反应。选择性孕酮受体调节剂为一类较新的孕酮受体的配体，与孕酮受体结合后，在体内可表现出部分孕酮激动和拮抗活性，具有高度的受体和靶向选择性特异性，能有效缓解子宫肌瘤临床症状，缩小子宫肌瘤体积，但不会影响卵巢雌激素分泌，本身无雄激素活性，因此长期使用无男性化、骨质疏松及增加心血管患病等不良反应。
由拜耳公司研发的BAY-1002670(Vilaprisan)是一种小分子选择性孕酮受体调节剂。BAY-1002670有望成为第一个可用来长期口服治疗子宫肌瘤的药物。此外，研究表明，BAY-1002670也可作为潜在治疗子宫内膜异位的候选药物。
BAY-1002670的化学名称为：(11β，17β)-17-羟基-11-[4-(甲基磺酰基)苯基]-17-(五氟乙基)雌-4，9-二烯-3-酮(以下称为“化合物(I)”)，其结构式如下：
Figure PCTCN2018111270-appb-000001
晶型是化合物分子在晶格中的排列不同而形成的不同固体形态，药物多晶型是指药物存在两种或两种以上的不同晶型。
由于不同晶型的药物可能会影响其在体内的溶出、吸收，进而可能在一定程度上影响药物的临床疗效和安全性；特别是对一些难溶性口服固体或半固体药物，晶型的影响会更大。因此，在研制固体口服制剂时，对晶型的研究有利于选择一种在临床治疗上有意义且稳定可 控的晶型。药物晶型是药物研究、检测和监管的重要内容，也是药物质量控制的重要内容。
现有技术CN102482317A公开了BAY-1002670的制备方法，本发明人根据CN102482317A公开的化合物(I)的制备方法，得到无定形的BAY-1002670。无定形物质中分子属无序排列，故处于热力学的不稳定状态。发明人在研究中发现，BAY-1002670的无定形在25℃/60％相对湿度、40℃/75％相对湿度和60℃/75％相对湿度条件下不稳定。另外，无定形的制备通常是一个快速的动力学固体析出的过程。研究中发现，无定形残留溶剂显著超标，且其颗粒属性很难通过工艺进行控制，使之在药物的实际应用中面临一定挑战。因此，有必要寻找BAY-1002670的晶体形态进行药物开发。目前尚无BAY-1002670的晶型信息公开。
为克服现有技术的缺点，本申请的发明人意外发现了性能优异的BAY-1002670的晶型CS2和晶型CS4，其在稳定性、熔点、溶解度、体内外溶出、引湿性、生物有效性、黏附性、可压性、流动性以及加工性能、提纯作用、制剂生产等方面中的至少一方面上存在优势，特别是物理、化学稳定性好，不易降解，粒径较小，粒度分布均匀，引湿性低且溶剂残留量低，为含BAY-1002670的药物开发提供了新的更好的选择，具有非常重要的意义。
发明内容
本发明的主要目的是提供BAY-1002670的晶型及其制备方法和用途。
根据本发明的目的，本发明提供BAY-1002670的晶型CS2(以下称作“晶型CS2”)。
一方面，使用Cu-Kα辐射，所述晶型CS2的X射线粉末衍射在衍射角2θ值为4.0°±0.2°、15.9°±0.2°、17.9°±0.2°处有特征峰。
进一步的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为19.0°±0.2°、20.4°±0.2°、21.4°±0.2°中的1处、或2处、或3处有特征峰。优选的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为19.0°±0.2°、20.4°±0.2°、21.4°±0.2°中的3处有特征峰。
进一步的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为11.8°±0.2°、15.0°±0.2°、25.1°±0.2°中的1处、或2处、或3处有特征峰。优选的，所述晶型CS2的X射线粉末衍射在衍射角2θ值为11.8°±0.2°、15.0°±0.2°、25.1°±0.2°中的3处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CS2的X射线粉末衍射在衍射角2θ值为4.0°±0.2°、15.9°±0.2°、17.9°±0.2°、19.0°±0.2°、20.4°±0.2°、21.4°±0.2°、11.8°±0.2°、15.0°±0.2°、25.1°±0.2°、14.5°±0.2°、16.9°±0.2°、17.3°±0.2°、18.5°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处、或10处、或11处、或12处、或13处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS2的X射线粉末衍射谱图如附图1所示。
非限制性地，在本发明的一个具体实施方案中，晶型CS2单晶的晶胞参数基本上如下表所示：
Figure PCTCN2018111270-appb-000002
根据本发明的目的，本发明还提供晶型CS2的制备方法，其特征在于，所述方法包括：
(1)将BAY-1002670原料置于酮类溶剂和水的混合溶剂中，搅拌得到；或
(2)将BAY-1002670溶解于醇类溶剂、酯类溶剂或酮类溶剂体系中，后置于含有水气氛的密闭环境中，通过气液渗透得到；或
(3)将BAY-1002670溶解于酮类溶剂体系中，后置于含有正庚烷气氛中，通过气液渗透得到。
进一步的，方法(1)中所述酮类溶剂优选为丙酮。
进一步的，方法(2)中所述醇类溶剂优选为甲醇，所述酯类溶剂优选为乙酸乙酯，所述酮类溶剂优选为丁酮。
进一步的，方法(3)中所述酮类溶剂优选为甲基异丁基酮。
根据本发明的目的，本发明还提供BAY-1002670的晶型CS4(以下称作“晶型CS4”)。
一方面，使用Cu-Kα辐射，所述晶型CS4的X射线粉末衍射在衍射角2θ值为16.0°±0.2°、16.6°±0.2°、14.1°±0.2°处有特征峰。
进一步的，所述晶型CS4的X射线粉末衍射在衍射角2θ值为18.9°±0.2°、21.5°±0.2°、10.1°±0.2°中的1处、或2处、或3处有特征峰。优选的，所述晶型CS4的X射线粉末衍射在衍射角2θ值为18.9°±0.2°、21.5°±0.2°、10.1°±0.2°中的3处有特征峰。
进一步的，所述晶型CS4的X射线粉末衍射在衍射角2θ值为13.2°±0.2°、23.5°±0.2°、17.9°±0.2°中的1处、或2处、或3处有特征峰。优选的，所述晶型CS4的X射线粉末衍射在衍射角2θ值为13.2°±0.2°、23.5°±0.2°、17.9°±0.2°中的3处有特征峰。
另一方面，使用Cu-Kα辐射，所述晶型CS4的X射线粉末衍射在衍射角2θ值为16.0°±0.2°、16.6°±0.2°、14.1°±0.2°、18.9°±0.2°、21.5°±0.2°、10.1°±0.2°、13.2°±0.2°、23.5°±0.2°、 17.9°±0.2°、19.6°±0.2°、19.8°±0.2°、20.2°±0.2°、20.6°±0.2°中的任意3处、或4处、或5处、或6处、或7处、或8处、或9处、或10处、或11处、或12处、或13处有特征峰。
非限制性地，在本发明的一个具体实施方案中，晶型CS4的X射线粉末衍射谱图如附图5所示。
根据本发明的目的，本发明还提供晶型CS4的制备方法，其特征在于，所述方法包括：
(1)将BAY-1002670原料置于醚类溶剂体系中，40℃-60℃下搅拌得到；或
(2)将BAY-1002670原料溶解于2-甲基四氢呋喃溶剂体系中，挥发得到固体，加热此固体得到晶型CS4；或
(3)将BAY-1002670原料置于含有醇类溶剂或酯类溶剂气氛的密闭环境中，通过气固渗透得到。
进一步的，方法(1)中所述醚类溶剂优选为甲基叔丁基醚；所述搅拌温度优选50℃。
进一步的，方法(2)中所述加热温度为150℃-200℃，优选为160℃。
进一步的，方法(3)中所述醇类溶剂优选为乙醇；所述酯类溶剂优选为乙酸异丙酯。
本发明提供的晶型CS2和晶型CS4具有以下有益效果：
(1)与现有技术相比，本发明提供的晶型具有更低的引湿性。测试结果表明，本发明晶型CS2的引湿性不到现有技术固体的15％，晶型CS4的引湿性不到现有技术固体的10％。晶型CS2和晶型CS4在80％相对湿度下的增重量分别为0.23％和0.12％，而现有技术无定形的增重量达到了1.89％。
引湿性会影响药物的稳定性、加工时的流动性和均匀性等，最终影响药物制剂的质量。引湿性也会影响药物的制备、后处理与储存。低引湿性晶型对储存条件要求不苛刻，降低了物料储存以及质量控制成本，具有很强的经济价值。
(2)与现有技术相比，本发明提供的晶型物理稳定性更好。本发明的晶型CS2和CS4在25℃/60％相对湿度和40℃/75％相对湿度条件下放置至少6个月晶型未发生改变，在60℃/75％相对湿度条件下放置至少2周晶型未发生变化。而现有技术固体在40℃/75％相对湿度条件下放置6个月后部分转变为晶型CS2，在60℃/75％相对湿度条件下放置2周后部分转变为晶型CS2。
原料药的物理稳定性对于药物至关重要。从原料药到药物需要经历储存、运输和制剂工艺过程，这些过程往往会遇到苛刻的条件，最常见为高温高湿。如原料药在储存和运输过程中的碰撞、制剂生产中的湿法制粒过程、季节和不同地区气候差异、及天气因素等带来的苛刻条件。现有技术固体在高温高湿条件下放置后部分转变为晶型，而本发明的晶型未发生转变。
晶型的转变会导致药物的吸收发生变化，引起药物的毒副作用。晶型CS2和晶型CS4具有良好的物理稳定性，保证原料药和制剂质量一致可控，最大可能地减少药物由于晶型改变引起的毒性增加，保证药物疗效发挥。
(3)与现有技术相比，本发明提供的晶型化学稳定性更好。本发明的晶型CS2和CS4在25℃/60％相对湿度条件下放置6个月，纯度分别仅降低0.06％和0.13％，纯度基本保持不变，而现有技术无定形纯度降低达0.80％；本发明的晶型CS2和CS4在40℃/75％相对湿度条件下放置3个月纯度基本保持不变，纯度分别仅降低0.27％和0.02％，而现有技术无定形纯度降低达1.08％；本发明的晶型CS2和CS4在60℃/75％相对湿度条件下放置2周纯度基本保持不变，纯度分别仅降低0.05％和0.03％，而现有技术无定形纯度降低达0.98％。
药物的化学纯度对于保证药物的疗效和安全性，防止药物不良反应的发生具有重要意义。药物中的杂质是影响纯度的主要因素，如药物中含有超过限量的杂质，就有可能使理化常数变化，外观性状产生变异，并影响药物的稳定性；杂质增多也使药物含量明显偏低或活性降低，毒副作用显著增加。与现有技术相比，本发明晶型CS2和晶型CS4放置后纯度变化小，不易降解，在药物储存中纯度基本不变，有效的克服了药物纯度降低、疗效变差、毒性增加等缺点。
(4)本发明晶型CS2和晶型CS4几乎没有溶剂残留，符合药用要求，而现有技术固体溶剂残留量超标，不能直接作为药用原料药。很多有机溶剂对环境、人体有一定危害，因此，为保障药物的用药安全，控制产品质量，需要严格对药物原料药的有机溶剂残留量进行要求和控制。
进一步地，本发明提供的晶型CS2和CS4还具有以下有益效果：
本发明的晶型CS2和CS4具有均一的粒径分布。其均匀的粒径有助于保证含量均匀度及体外溶出度的均一性。同时可简化制剂工艺，无需对原料药进行前处理，节约成本，也降低研磨可能带来的晶型结晶度变化和转晶的风险。
根据本发明的目的，本发明还提供一种药物组合物，所述药物组合物包含治疗和/或预防有效量的本发明的晶型CS2或晶型CS4或它们的任意混合，以及至少一种药学上可接受的载体、稀释剂或赋形剂。
进一步的，本发明提供的晶型CS2或晶型CS4或它们的任意混合在生产制备含孕激素受体调节剂的药物制剂中的用途。
进一步地，本发明提供的晶型CS2或晶型CS4或它们的任意混合在生产制备治疗子宫肌瘤和/或子宫内膜异位药物制剂中的用途。
本发明中，所述“气液渗透”的结晶方法通常指：将固体溶解在良溶剂中配成澄清溶液，将溶液置于含有不良溶剂气氛的密闭环境中，通过气相扩散以使固体析出得到晶体的方法。
所述“气固渗透”的结晶方法通常指：将固体原料置于含有一定溶剂气氛的密闭环境中，溶剂通过气相扩散与固体原料接触以得到晶体的方法。
本发明中，“晶体”或“多晶型”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，这里所讨论的理化性质可以被表征，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。事实上，XRPD图谱中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。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±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，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“XRPD图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些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。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。
在一些实施方案中，本发明的晶型CS2或晶型CS4是纯的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。
需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。
附图说明
图1为根据本发明实施例1所得晶型CS2的XRPD图。
图2为根据本发明实施例1所得晶型CS2的DSC图。
图3为根据本发明实施例1所得晶型CS2的TGA图。
图4为根据本发明实施例2所得晶型CS2的XRPD图。
图5为根据本发明实施例6所得晶型CS4的XRPD图。
图6为根据本发明实施例6所得晶型CS4的DSC图。
图7为根据本发明实施例6所得晶型CS4的TGA图。
图8为根据本发明实施例7所得晶型CS4的XRPD图。
图9为根据本发明实施例8所得晶型CS4的XRPD图。
图10为晶型CS2在25℃/60％相对湿度条件下放置6个月前后的XRPD叠图(上图为放置前，下图为放置后)。
图11为晶型CS4在25℃/60％相对湿度条件下放置6个月前后的XRPD叠图(上图为放置前，下图为放置后)。
图12为现有技术固体在25℃/60％相对湿度条件下放置6个月前后的XRPD叠图(上图为放置前，下图为放置后)。
图13为晶型CS2在40℃/75％相对湿度条件下放置6个月前后的XRPD叠图(上图为放置前，下图为放置后)。
图14为晶型CS4在40℃/75％相对湿度条件下放置6个月前后的XRPD叠图(上图为放置前，下图为放置后)。
图15为现有技术固体在40℃/75％相对湿度条件下放置6个月前后的XRPD叠图(上图为放置前，下图为放置后)。
图16为晶型CS2在60℃/75％相对湿度条件下放置2周前后的XRPD叠图(上图为放置前，下图为放置后)。
图17为晶型CS4在60℃/75％相对湿度条件下放置2周前后的XRPD叠图(上图为放置前，下图为放置后)。
图18为现有技术固体在60℃/75％相对湿度条件下放置2周前后的XRPD叠图(上图为放置前，下图为放置后)。
图19为本发明晶型CS2的PSD图。
图20为本发明晶型CS4的PSD图。
具体实施方式
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的制备和使用方法。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。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
PSD：粒径分布
采集数据所用的仪器及方法：
本发明所述的X射线粉末衍射图在Bruker D2 PHASER X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线光源：Cu,Kα
Figure PCTCN2018111270-appb-000003
1.54060；
Figure PCTCN2018111270-appb-000004
1.54439
Kα2/Kα1强度比例：0.50
电压：30仟伏特(kV)
电流：10毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：如无特别说明为10℃/min
保护气体：N 2
本发明所述的热重分析(TGA)图在TA Q500上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：N 2
本发明所述动态水分吸附(DVS)图在由SMS公司(Surface Measurement Systems Ltd.)生产的Intrinsic动态水分吸附仪上采集。仪器控制软件是DVS-Intrinsic control software，分析软件是DVS-Intrinsic Analysis software。所述的动态水分吸附仪的方法参数如下：
温度：25℃
载气，流速：N 2,200毫升/分钟
单位时间质量变化：0.002％/分钟
相对湿度范围：0％RH-95％RH
除非特殊说明，以下实施例均在室温条件下操作。所述“室温”不是精确的温度值，是指10～30℃温度范围。
根据本发明，作为原料的所述BAY-1002670指其固体(晶型或无定形)、半固体、蜡或油形式。优选地，作为原料的所述化合物(I)为固体粉末形式。
以下实施例中所使用的BAY-1002670原料可根据现有技术例如CN102482317A中所记载的方法制备获得。
实施例1～5：晶型CS2的制备
实施例1：
称取1022.4mg的BAY-1002670原料，加入体积比为4:1的水和丙酮的混合溶剂体系中，室温下搅拌2天，过滤，真空干燥得到固体。
经检测，实施例1所得固体为晶型CS2，其X射线粉末衍射数据如图1，表1所示。
表1
衍射角2θ d值 强度％
4.00 22.10 28.00
7.94 11.14 6.02
8.62 10.26 2.83
9.20 9.61 5.56
9.76 9.07 6.80
10.27 8.61 5.61
11.76 7.53 27.38
12.29 7.20 9.38
13.46 6.58 6.45
14.53 6.10 15.88
14.95 5.93 48.82
15.55 5.70 20.49
15.91 5.57 98.65
16.51 5.37 16.36
16.92 5.24 34.11
17.31 5.12 29.47
17.87 4.96 100.00
18.47 4.80 26.49
18.96 4.68 72.28
19.59 4.53 17.53
20.43 4.35 66.46
21.39 4.15 40.32
22.16 4.01 14.70
23.25 3.83 18.68
24.24 3.67 7.77
25.06 3.55 22.49
26.28 3.39 8.06
26.94 3.31 12.06
28.86 3.09 9.18
29.40 3.04 6.67
30.13 2.97 12.15
31.91 2.81 6.07
32.58 2.75 8.26
33.54 2.67 4.31
38.46 2.34 4.93
实施例1所得晶型CS2的DSC如图2所示，加热至65℃附近时开始出现第一个吸热峰，该吸热峰为晶型CS2的脱水吸热峰，加热至206℃附近时开始出现第二个吸热峰，该吸热峰为晶型CS2的熔化吸热峰。
实施例1所得晶型CS2的TGA如图3所示，加热至100℃附近时，具有约2.9％的质量损失梯度。
实施例2～4：
称取一定质量的BAY-1002670原料置于玻璃容器内，加入如下表2中所示的正溶剂，搅拌溶解后，将此玻璃容器敞口置于装有表2所示的反溶剂的大玻璃容器内，密闭放置直至有固体析出。实施例2～4所得样品分别标记为样品2～4。
经检测，样品2～4所得固体均为晶型CS2。选取样品2进行测试表征，其X射线粉末衍射数据如图4、表3所示。
表2
Figure PCTCN2018111270-appb-000005
表3
衍射角2θ d值 强度％
4.07 21.69 29.08
7.93 11.15 3.41
11.71 7.56 17.65
12.34 7.18 5.15
13.48 6.57 7.94
14.56 6.08 15.36
15.02 5.90 28.13
15.56 5.70 13.09
15.98 5.55 73.94
16.98 5.22 22.11
17.39 5.10 32.32
17.87 4.96 100.00
18.50 4.80 18.08
19.01 4.67 62.80
19.60 4.53 14.19
20.49 4.34 68.77
21.37 4.16 46.98
22.31 3.99 11.26
22.98 3.87 17.31
23.30 3.82 15.19
24.13 3.69 10.13
25.09 3.55 21.79
26.63 3.35 10.57
26.99 3.30 8.61
28.25 3.16 9.67
28.91 3.09 12.01
29.40 3.04 6.49
30.22 2.96 9.03
31.85 2.81 6.55
32.66 2.74 9.37
33.58 2.67 6.02
34.88 2.57 4.50
37.53 2.40 4.94
38.50 2.34 5.86
实施例5：
称取约9.9mg的BAY-1002670原料置于玻璃容器内，加入0.5mL甲基异丁基酮，搅拌溶解后，将此玻璃容器敞口置于装有正庚烷的大玻璃容器内，放置直至有固体析出。经检测，所得固体为晶型CS2。本实施例得到晶型CS2的单晶，单晶衍射及结构解析数据如表4所示，单晶结构表明晶型CS2为单水合物。
表4
Figure PCTCN2018111270-appb-000006
实施例6～9：晶型CS4的制备
实施例6：
称取102.8mg的BAY-1002670原料，加入4.0mL甲基叔丁基醚溶剂，50℃下搅拌18小时，离心收集固体，干燥后得到白色结晶。
经检测，所得白色结晶为晶型CS4，其X射线衍射数据如图5，表5所示。
实施例6所得晶型CS4的DSC如图6所示，加热至217℃附近时开始出现第一个吸热峰，该吸热峰为晶型CS4的熔化吸热峰。
实施例6所得晶型CS4的TGA如图7所示，加热至170℃附近时，具有约1.7％的质量损失梯度。
表5
衍射角2θ d值 强度％
10.05 8.80 18.06
13.20 6.71 35.97
13.48 6.57 22.59
14.17 6.25 22.27
15.95 5.56 100.00
16.65 5.32 41.84
17.82 4.98 19.14
18.59 4.77 12.72
18.95 4.68 26.26
19.60 4.53 38.47
19.84 4.47 34.38
20.18 4.40 16.47
20.58 4.32 19.66
21.48 4.14 30.48
22.15 4.01 18.86
23.51 3.78 17.20
24.87 3.58 12.33
26.43 3.37 5.73
27.05 3.30 6.20
28.83 3.10 9.90
30.73 2.91 7.81
33.11 2.71 5.13
33.71 2.66 3.90
34.29 2.62 3.36
36.66 2.45 6.57
37.83 2.38 2.37
实施例7：
称取53.4mg的BAY-1002670固体原料，溶解于2.5mL的2-甲基四氢呋喃溶剂体系中，室温下挥发得到固体。将挥发得到的固体以10℃/min的速率加热至160℃，在160℃下平衡10min得到固体。经检测，所得固体为晶型CS4，其X射线粉末衍射数据如图8，表6所示。
表6
衍射角2θ d值 强度％
10.04 8.81 16.52
13.16 6.73 72.27
13.40 6.61 36.36
14.09 6.29 34.81
15.97 5.55 100.00
16.59 5.34 47.55
17.80 4.98 30.66
18.57 4.78 12.59
18.87 4.70 25.32
19.54 4.54 36.21
19.83 4.48 25.81
20.22 4.39 20.09
20.50 4.33 14.51
21.47 4.14 28.46
22.11 4.02 10.92
23.49 3.79 21.95
24.82 3.59 15.85
27.00 3.30 5.50
28.76 3.10 12.04
30.74 2.91 8.60
33.06 2.71 7.49
33.67 2.66 4.48
34.27 2.62 2.97
36.56 2.46 5.38
37.84 2.38 2.59
实施例8～9：
称取一定质量的BAY-1002670原料置于小玻璃瓶中，将此小玻璃瓶敞口置于装有如下表7中所示的溶剂的大玻璃瓶中，封闭放置。溶剂通过气相扩散与小玻璃瓶中BAY-1002670原料接触。经检测，所得固体均为晶型CS4。
选取样品8进行测试表征，其X射线粉末衍射数据如图9，表8所示。
表7
实施例 原料质量(mg) 溶剂 溶剂体积(mL) 样品标记
8 7.5 乙醇 5.0 8
9 6.2 乙酸异丙酯 5.0 9
表8
衍射角2θ d值 强度％
10.08 8.78 18.80
13.23 6.69 37.24
13.47 6.57 25.59
14.17 6.25 27.35
15.97 5.55 100.00
16.67 5.32 34.80
17.80 4.98 17.22
18.61 4.77 13.34
18.94 4.69 22.74
19.63 4.52 33.62
19.87 4.47 31.33
20.25 4.39 18.05
20.61 4.31 12.96
21.53 4.13 28.55
22.20 4.00 14.07
23.58 3.77 16.21
24.88 3.58 12.52
26.46 3.37 4.72
26.98 3.31 5.54
27.18 3.28 4.96
28.85 3.09 8.24
30.77 2.91 8.11
33.12 2.70 5.30
33.71 2.66 3.75
34.34 2.61 2.81
36.65 2.45 6.02
38.07 2.36 3.02
实施例10：晶型CS2、晶型CS4和现有技术无定形的引湿性对比研究
取本发明晶型CS2、晶型CS4和现有技术无定形各约10mg，采用动态水分吸附仪(DVS)测试其引湿性，实验结果如表9所示。
表9
Figure PCTCN2018111270-appb-000007
结果表明，本发明的晶型CS2和晶型CS4与现有无定形相比具有更低的引湿性。
实施例11：晶型CS2、晶型CS4和现有技术无定形的稳定性研究
1. 25℃/60％相对湿度下的物理、化学稳定性研究
分别取本发明晶型CS2、晶型CS4和现有技术无定形置于25℃/60％相对湿度下敞口放置，测试晶型和纯度变化，结果如表10和表11所示：
表10
Figure PCTCN2018111270-appb-000008
表11
晶型 起始纯度 6个月纯度 纯度变化
CS2 98.64％ 98.58％ 0.06％
CS4 99.44％ 99.31％ 0.13％
无定形 98.68％ 97.88％ 0.80％
本发明晶型CS2和晶型CS4在25℃/60％相对湿度条件下，至少放置6个月后晶型保持不变。本发明的晶型CS2和CS4在25℃/60％相对湿度条件下放置6个月，纯度基本保持不变，纯度分别仅降低0.06％和0.13％，而现有技术无定形纯度降低达0.80％。
上述结果表明，本发明晶型CS2和晶型CS4的物理、化学稳定性好，在药物储存中纯度基本不变，更适合药用。而现有技术无定形在储存过程中杂质含量增加，从而导致药物含量明显偏低或活性降低，毒副作用显著增加。
2. 加速条件40℃/75％相对湿度下的物理、化学稳定性研究
分别取本发明晶型CS2、晶型CS4和现有技术无定形置于40℃/75％相对湿度下敞口放置，测试晶型和纯度变化，结果如表12和表13所示：
表12
Figure PCTCN2018111270-appb-000009
表13
晶型 起始纯度 3个月纯度 纯度变化
CS2 98.64％ 98.37％ 0.27％
CS4 99.44％ 99.42％ 0.02％
无定形 98.68％ 97.60％ 1.08％
本发明晶型CS2和晶型CS4在40℃/75％相对湿度条件下至少放置6个月后，晶型保持不变。而现有技术无定形在40℃/75％相对湿度条件下放置6个月后部分转变为本发明的晶型CS2。本发明的晶型CS2和CS4在40℃/75％相对湿度条件下放置3个月，纯度基本保持不变，纯度分别仅降低0.27％和0.02％，而现有技术无定形纯度降低达1.08％。上述结果表 明，相比现有技术无定形，本发明晶型CS2和晶型CS4具有更好的物理、化学稳定性。
3. 加速条件60℃/75％相对湿度下的物理、化学稳定性研究
分别取本发明晶型CS2、晶型CS4和现有技术无定形置于60℃/75％相对湿度下敞口放置测试晶型和纯度变化，结果如表14和表15所示：
表14
Figure PCTCN2018111270-appb-000010
表15
晶型 起始纯度 2周后纯度 纯度变化
CS2 98.64％ 98.59％ 0.05％
CS4 99.44％ 99.47％ 0.03％
无定形 98.68％ 97.70％ 0.98％
本发明晶型CS2和晶型CS4在60℃/75％相对湿度条件下至少放置2周后，晶型保持不变。而现有技术无定形在60℃/75％相对湿度条件下放置2周后部分转变为本发明的晶型CS2。本发明的晶型CS2和CS4在60℃/75％相对湿度条件下放置2周，纯度基本保持不变，纯度分别仅具有0.05％和0.03％的变化量，而现有技术无定形纯度降低达0.98％。上述结果表明，相比现有技术无定形，本发明晶型CS2和晶型CS4具有更好的物理、化学稳定性。
实施例12：晶型CS2、晶型CS4和现有技术无定形的溶剂残留
分别测试本发明晶型CS2、晶型CS4和现有技术无定形固体的溶剂残留量。测试结果表明，本发明晶型CS2和晶型CS4几乎无溶剂残留，而无定形固体中二氯甲烷的溶剂残留量为64185ppm。根据国际协调会(ICH)关于残留溶剂的指导原则，二氯甲烷属于药品中第二类溶剂，溶剂残留量不得超过600ppm。可见无定形固体中二氯甲烷溶剂的残留量明显超过ICH规定的限度，不适合直接作为药用原料药。
实施例13：粒径分布研究
称取本发明的晶型CS2和CS4，然后各加入10mL Isopar G(含有0.2％卵磷脂)，将待测 样品充分混合均匀后加入SDC进样系统中，使样品量指示图达到合适位置，开始实验，进行粒径分布的测试，从而得到按照体积计算的平均粒径、粒径分布中(体积分布)占10％所对应的粒径、粒径分布中(体积分布)占50％所对应的粒径。粒径分布中(体积分布)占90％所对应的粒径以及晶型粒度分布图。粒径分布结果见表16。
表16
晶型 MV(μm) D10(μm) D50(μm) D90(μm)
晶型CS2 13.16 3.09 8.41 27.45
晶型CS4 11.41 2.32 6.20 23.12
注：
MV：按照体积计算的平均粒径
D10：表示粒径分布中(体积分布)占10％所对应的粒径
D50：表示粒径分布中(体积分布)占50％所对应的粒径，又称中位径
D90：表示粒径分布中(体积分布)占90％所对应的粒径
晶型CS2和CS4的粒径分布(PSD)图分别如图19和图20。由图中可以看出，晶型CS2和CS4的粒径呈单分散正态分布，粒径分布均匀，且粒径小。
本发明晶型CS2和CS4均匀且较小的粒径有助于简化制剂过程的后处理工艺，如可减少对晶型的研磨，节约成本。此外，晶型CS2和CS4均匀的粒径分布可提高制剂中原料药组分的均一度，其更小的晶体粒径可增加药物比表面积，提高药物的溶出速率，有利于药物吸收，进而提高生物利用度。
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。

Claims (14)

  1. 一种BAY-1002670的晶型CS2，其特征在于，使用Cu-Kа辐射，其X射线粉末衍射在衍射角2θ值为4.0°±0.2°、15.9°±0.2°、17.9°±0.2°处有特征峰。
  2. 根据权利要求1所述的晶型CS2，其特征还在于，其X射线粉末衍射在衍射角2θ值为19.0°±0.2°、20.4°±0.2°、21.4°±0.2°中的1处、或2处、或3处有特征峰。
  3. 根据权利要求1所述的晶型CS2，其特征还在于，其X射线粉末衍射在衍射角2θ值为11.8°±0.2°、15.0°±0.2°、25.1°±0.2°中的1处、或2处、或3处有特征峰。
  4. 根据权利要求1-3任意一项所述的晶型CS2，其特征在于，所述晶型CS2为单斜晶系，C2空间群，其晶轴：
    Figure PCTCN2018111270-appb-100001
    晶面间夹角：α＝90°，β＝98.346(3)°，γ＝90°。
  5. 一种权利要求1所述的BAY-1002670晶型CS2的制备方法，其特征在于，所述方法为：
    (1)将BAY-1002670原料置于酮类溶剂和水的混合溶剂中，搅拌得到；或
    (2)将BAY-1002670原料溶解于醇类溶剂、酯类溶剂或酮类溶剂体系中，后置于含有水气氛的密闭环境中，通过气液渗透得到；或
    (3)将BAY-1002670溶解于酮类溶剂体系中，后置于含有正庚烷气氛的密闭环境中，通过气液渗透得到。
  6. 根据权利要求5所述的制备方法，方法(1)中所述酮类溶剂为丙酮；方法(2)中所述醇类溶剂为甲醇，所述酯类溶剂为乙酸乙酯，所述酮类溶剂为丁酮；方法(3)中所述酮类溶剂为甲基异丁基酮。
  7. 一种BAY-1002670的晶型CS4，其特征在于，使用Cu-Kа辐射，其X射线粉末衍射在衍射角2θ值为16.0°±0.2°、16.6°±0.2°、14.1°±0.2°处有特征峰。
  8. 根据权利要求7所述的晶型CS4，其特征还在于，其X射线粉末衍射在衍射角2θ值为18.9°±0.2°、21.5°±0.2°、10.1°±0.2°中的1处、或2处、或3处有特征峰。
  9. 根据权利要求7所述的晶型CS4，其特征还在于，其X射线粉末衍射在衍射角2θ值为13.2°±0.2°、23.5°±0.2°、17.9°±0.2°中的1处、或2处、或3处有特征峰。
  10. 一种权利要求7所述的BAY-1002670晶型CS4的制备方法，其特征在于，所述方法为：
    (1)将BAY-1002670原料置于醚类溶剂体系中，40℃-60℃下搅拌得到；或
    (2)将BAY-1002670原料溶解于2-甲基四氢呋喃溶剂体系中，挥发得到固体，将此固体加热至150℃-200℃得到晶型CS4；或
    (3)将BAY-1002670原料置于含有醇类溶剂或酯类溶剂气氛的密闭环境中，通过气固渗透得到。
  11. 根据权利要求10所述的制备方法，方法(1)中所述醚类溶剂为甲基叔丁基醚，所述搅拌温度为50℃；方法(2)中所述加热温度为160℃；方法(3)中所述醇类溶剂为乙醇，所述酯类溶剂为乙酸异丙酯。
  12. 一种药物组合物，所述药物组合物包含有效治疗量的权利要求1所述的晶型CS2或权利要求7所述的晶型CS4或它们的任意混合及药学上可接受的载体、稀释剂或赋形剂。
  13. 权利要求1所述的晶型CS2或权利要求7所述的晶型CS4或它们的任意混合在生产制备含孕激素受体调节剂的药物制剂中的用途。
  14. 权利要求1所述的晶型CS2或权利要求7所述的晶型CS4或它们的任意混合在生产制备治疗子宫肌瘤和/或子宫内膜异位药物制剂中的用途。
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