WO2018036558A1 - 一种雄激素受体拮抗剂药物的晶型及其制备方法和用途 - Google Patents

一种雄激素受体拮抗剂药物的晶型及其制备方法和用途 Download PDF

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WO2018036558A1
WO2018036558A1 PCT/CN2017/099036 CN2017099036W WO2018036558A1 WO 2018036558 A1 WO2018036558 A1 WO 2018036558A1 CN 2017099036 W CN2017099036 W CN 2017099036W WO 2018036558 A1 WO2018036558 A1 WO 2018036558A1
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preparation
odm
crystal form
present
solvent
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PCT/CN2017/099036
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English (en)
French (fr)
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陈敏华
张炎峰
李骄洋
鄢楷强
刘启月
张晓宇
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苏州科睿思制药有限公司
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Priority to SI201730734T priority Critical patent/SI3495352T1/sl
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 EP17842980.9A priority patent/EP3495352B1/en
Priority to JP2019511530A priority patent/JP6716023B2/ja
Priority to PL17842980T priority patent/PL3495352T3/pl
Priority to US16/328,249 priority patent/US10815221B2/en
Priority to DK17842980.9T priority patent/DK3495352T3/da
Priority to ES17842980T priority patent/ES2869882T3/es
Priority to CN201780048143.1A priority patent/CN109641851B/zh
Priority to LTEP17842980.9T priority patent/LT3495352T/lt
Priority to RS20210521A priority patent/RS61773B1/sr
Publication of WO2018036558A1 publication Critical patent/WO2018036558A1/zh
Priority to CY20211100367T priority patent/CY1124083T1/el
Priority to HRP20210667TT priority patent/HRP20210667T1/hr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non 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
    • 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 pharmaceutical crystal technology.
  • it relates to a crystalline form of an androgen receptor antagonist drug, a preparation method and use thereof.
  • Prostate cancer has become an important disease that threatens men's health. Its incidence is higher in Western countries and is increasing year by year. In Asian countries with low incidence in the past, the number of patients has increased in recent years.
  • Commonly used methods for clinical treatment of prostate cancer include surgical resection, radiation therapy, and endocrine therapy that blocks androgen. Androgen is closely related to the growth of prostate and the occurrence of prostate cancer, so endocrine therapy has become an effective way to treat prostate cancer.
  • the method includes orchiectomy, estrogen therapy, gonadotropin releasing hormone analog therapy, gonadotropin releasing hormone antagonist therapy, androgen antagonistic therapy, etc., wherein androgen antagonistic therapy can be used alone or in combination with early prostate cancer.
  • Surgery for adjuvant treatment is one of the main methods for clinical treatment of prostate cancer. Androgen receptors, as targets of the biological effects of androgens, have become an important part of biomedical research.
  • ODM-201 (BAY-1841788) is a non-steroidal oral androgen receptor (AR) antagonist used in the treatment of prostate cancer.
  • ODM-201 does not cross the blood-brain barrier and can reduce nervous system-related side effects such as epilepsy. Bayer has demonstrated the efficacy and safety of ODM-201 in clinical trials, demonstrating its potential for treating prostate cancer.
  • ODM-201 N-((S)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)- 3-(1-hydroxyethyl)-1H-pyrazole-5-carboxamide, well known to those skilled in the art, the chemical name includes its tautomer N-((S)-1-(3-(3- Chloro-4-cyanophenyl)-1H-pyrazol-1-yl)-propan-2-yl)-5-(1-hydroxyethyl)-1H-pyrazole-3-carboxamide, CAS No. 1297538-32-9, its structural formula is shown in formula (I):
  • Solid chemical drugs have different crystal forms that can cause differences in solubility, stability, fluidity, and compressibility, thereby affecting the safety and efficacy of pharmaceutical products containing the compound (see K. Knapman, Modern Drug Discovery, 3, 53). -54,57,2000.), resulting in differences in clinical efficacy.
  • New crystalline forms of pharmaceutically active ingredients (including anhydrates, hydrates, solvates, etc.) have been found to produce more processing advantages or to provide materials with better physicochemical properties, such as better bioavailability, storage stability, and ease of use. Processing, easy purification or as an intermediate for promoting conversion to other crystal forms Crystal form.
  • the new crystalline form of the pharmaceutically acceptable compound can help improve the performance of the drug and expand the formulation of the raw materials that can be used in the formulation.
  • Patent CN102596910B discloses a process for the preparation of ODM-201, but does not disclose any crystal form information.
  • Patent No. WO2016120530A1 discloses Form I of formula (I) (CAS No. 1297538-32-9), Form I' and Formula (Ib) of Formula (Ia) (CAS No.: 1976022-48-6) (CAS No.: 1976022-49-7) Form I".
  • the literature Expert Rev. Anticancer Ther. 15(9), (2015) has reported that ODM-201 is a ratio of 1:1 (Ia) And (Ib) two kinds of diastereomer compositions, that is, the structure represented by the formula (I). Therefore, the crystal form of the existing ODM-201 is only reported by the crystal form I.
  • Form I has low solubility and high wettability, and the preparation of Form I requires the use of a highly toxic acetonitrile solvent.
  • Acetonitrile is animal carcinogenic and is the second type of solvent that should be controlled during the process development stage.
  • the preparation method of the crystal form I is relatively complicated, the preparation cycle is long, heating is required in the process, and the industrial preparation cost is increased, which is disadvantageous for industrial production.
  • the inventors discovered the crystal form B and the crystal form C of the present invention through experiments, and found that the crystal form B and the form C of the present invention have more excellent properties than the prior art. Dissolution is a prerequisite for drug absorption, and the increase in solubility will help to improve the bioavailability of the drug, thereby improving the drug-forming properties of the drug. Compared with the prior art, the crystalline form B and the crystalline form C of the present invention have higher solubility and provide favorable conditions for drug development. Form B and Form C of the present invention also have lower wettability than the prior art. The crystal form of the drug with high hygroscopicity changes the weight due to the adsorption of more water, so that the content of the crystalline component of the raw material is not easy to determine.
  • the crystal form of the raw material drug has a high moisture absorbing property and absorbs agglomerates, thereby affecting the preparation process.
  • the particle size distribution of the sample and the uniformity of the drug substance in the preparation thereby affecting the dissolution and bioavailability of the sample.
  • the crystal form B and the crystal form C of the invention have substantially the same moisture content under different humidity conditions, overcome the disadvantages caused by high wettability, are more conducive to long-term storage of the medicine, and reduce material storage and quality control costs.
  • the present invention provides the crystal form B and the crystal form C of the ODM-201 represented by the formula (I), which has good stability, excellent fluidity, suitable particle size and uniform distribution.
  • the solvent used in the preparation method of the crystal form B and the crystal form C of the invention is less toxic, is advantageous for green industrial production, and avoids the pharmaceutical risk caused by the residue of the toxic solvent, and is more favorable for the preparation of the pharmaceutical preparation.
  • the new crystal form provided by the invention has simple preparation method, no heating, short preparation period, and is favorable for cost control in industrial production.
  • Form B and Form C of the present invention provide a new and better choice for the preparation of pharmaceutical preparations containing ODM-201, and are of great significance for drug development.
  • the main object of the present invention is to provide a crystal form of ODM-201 and a preparation method and use thereof.
  • the present invention provides a crystal form B of ODM-201 represented by the formula (I) (hereinafter referred to as "crystal form B").
  • the X-ray powder diffraction of the Form B has a characteristic peak at a diffraction angle 2 ⁇ of 16.2° ⁇ 0.2°, 9.0° ⁇ 0.2°, and 22.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form B has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ of 24.7° ⁇ 0.2°, 11.9° ⁇ 0.2°, and 18.1° ⁇ 0.2°;
  • the X-ray powder diffraction of the Form B has a characteristic peak at a diffraction angle 2 ⁇ of 24.7° ⁇ 0.2°, 11.9° ⁇ 0.2°, and 18.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form B is 14.7° ⁇ 0.2° at a diffraction angle 2 ⁇
  • One or two or three of 23.5 ° ⁇ 0.2 °, 27.8 ° ⁇ 0.2 ° have characteristic peaks; preferably, the X-ray powder diffraction of the crystal form B is 14.7 ° ⁇ 0.2 °, 23.5 at a diffraction angle 2 ⁇ There are characteristic peaks at ° ⁇ 0.2° and 27.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form B is 16.2° ⁇ 0.2°, 9.0° ⁇ 0.2°, 22.5° ⁇ 0.2°, 24.7° ⁇ 0.2°, 11.9° ⁇ at the diffraction angle 2 ⁇ . There are characteristic peaks at 0.2°, 18.1° ⁇ 0.2°, 14.7° ⁇ 0.2°, 23.5° ⁇ 0.2°, and 27.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form B is shown in FIG.
  • the present invention also provides a method for preparing the crystalline form B, which comprises: 1) dissolving ODM-201 in an alcohol or a ketone or a mixed solvent of the two, with water as the opposite The solvent is added dropwise to the presence of solids; or
  • the ODM-201 is dissolved in a mixed solvent of a halogenated hydrocarbon and an alcohol solvent or an ether and water at room temperature, and the clear solution is volatilized at room temperature until a solid precipitates.
  • the alcohol solvent is methanol, ethanol or a mixture thereof
  • the alcohol solvent is methanol
  • the halogenated hydrocarbon solvent is a chlorinated alkane
  • the chlorinated hydrocarbon solvent is dichloromethane
  • the ketone solvent is a saturated aliphatic ketone
  • the ketone solvent is acetone
  • the ether solvent is a cyclic ether compound
  • the ether solvent is tetrahydrofuran
  • reaction temperature or operating temperature is 10-40 ° C, more preferably room temperature;
  • the crystallization time is from 36 to 72 hours, more preferably 48 hours.
  • the present invention also provides a crystal form C of ODM-201 represented by the formula (I) (hereinafter referred to as For "Crystal C").
  • the X-ray powder diffraction of the Form C has characteristic peaks at diffraction angle 2 ⁇ values of 9.4 ° ⁇ 0.2 °, 14.1 ° ⁇ 0.2 °, and 12.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction of the Form C has a characteristic peak at one or two or three points in the diffraction angle 2 ⁇ value of 15.1° ⁇ 0.2°, 15.8° ⁇ 0.2°, and 19.9° ⁇ 0.2°;
  • the X-ray powder diffraction of the Form C has a characteristic peak at a diffraction angle 2 ⁇ of 15.1° ⁇ 0.2°, 15.8° ⁇ 0.2°, and 19.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form C has a characteristic peak at a diffraction angle 2 ⁇ value of 23.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the Form C is at a diffraction angle 2 ⁇ of 9.4° ⁇ 0.2°, 14.1° ⁇ 0.2°, 12.1° ⁇ 0.2°, 15.1° ⁇ 0.2°, 15.8°. There are characteristic peaks at ⁇ 0.2°, 19.9° ⁇ 0.2°, and 23.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form C is as shown in FIG.
  • the present invention also provides a method for preparing Form C, which comprises, but is not limited to, adding ODM-201 to a mixing system of acetic acid and other organic solvents in a certain volume ratio, after heating to a certain temperature, Cooling and crystallization were obtained.
  • the other organic solvent comprises isopropanol, methyl tert-butyl ether, toluene and ethyl acetate.
  • the other organic solvent is isopropanol or methyl tert-butyl ether;
  • the heating temperature comprises 40 to 60 ° C, preferably, the heating temperature is 50 ° C;
  • the volume ratio comprises 2:1 to 1:2;
  • the ODM-201 free base or ODM-201 refers to the solid, semi-solid, wax or oil form of the compound of formula (I).
  • room temperature is not an accurate temperature value and refers to a temperature range of 10-30 °C.
  • volatilization is carried out by a conventional method in the art.
  • the slow volatilization is to seal the container with a sealing film, puncture the hole, and let it stand for volatilization; the rapid volatilization is to place the container open and volatilize.
  • 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.
  • Crystal form and “polymorph” and other related terms are used in the present invention to mean that a solid compound exists in a specific crystalline state in a crystal structure.
  • the difference in physical and chemical properties of polymorphs can be reflected in storage stability, compressibility, density, dissolution rate and the like. In extreme cases, differences in solubility or dissolution rate can cause drug inefficiencies and even toxicity.
  • the novel Form B or Form C of the present invention is pure, unitary, and substantially free of any other crystalline form.
  • substantially no refers to this when used to refer to a new crystal form.
  • the crystalline form contains less than 20% by weight of other crystalline forms, especially less than 10% by weight of other crystalline forms, more preferably less than 5% by weight of other crystalline forms, more preferably less than 1% ( Other crystal forms of weight).
  • the crystalline form B and the crystalline form C of the present invention have the following advantages:
  • the crystal form B and the crystal form C of the present invention have a weight gain of 1.07% and 0.93% at 80% relative humidity, respectively, and are slightly wettable.
  • the crystal form of the present invention has low wettability, and can well resist the instability of crystal form in the process of pharmaceutical preparation and/or storage, and the unprocessability of the preparation caused by external factors such as environmental moisture. It facilitates accurate quantification and post-transportation and storage in the preparation of the preparation.
  • the crystalline form B of the present invention did not change under the conditions of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 3 months. Therefore, the crystalline form B of the present invention has good stability and is advantageous for preservation of the sample and stabilization of the preparation.
  • the crystalline form B and the crystalline form C of the present invention can significantly improve the solubility as compared with the crystalline form I disclosed in the prior art WO2016120530A1, thereby contributing to an increase in the bioavailability of the drug.
  • Form B of the present invention has a narrower particle size distribution and a smaller particle size than Form I.
  • Its uniform particle size helps to simplify the post-treatment process of the formulation process, such as reducing the grinding of the crystal, saving cost, reducing the crystallinity change and the risk of crystal transformation in the grinding, and improving the quality control.
  • Its narrower particle size distribution improves the uniformity of the drug substance components in the formulation, while making the difference between different batches of preparations smaller, such as more uniform dissolution; its smaller crystal size can increase the drug ratio.
  • the surface area increases the dissolution rate of the drug, which is beneficial to the absorption of the drug, thereby improving the bioavailability.
  • the crystal form C of the invention has higher polishing stability than the crystal form I, and is often used in the preparation process.
  • the grinding and pulverization of the raw material medicine is required, and the high grinding stability can reduce the risk of crystallinity change and crystal transformation of the raw material medicine during the processing of the preparation.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of Form B of the present invention, Form C or any mixture thereof, and at least one pharmaceutically acceptable carrier , diluent or excipient.
  • the present invention provides the use of Form B of Form ODM-201, Form C, or any mixture thereof in the preparation of a pharmaceutical formulation of an androgen receptor antagonist.
  • the present invention provides the use of Form B of Form ODM-201, Form C, or any mixture thereof in the preparation of a pharmaceutical pharmaceutical preparation.
  • the present invention provides the use of Form B of Form ODM-201, Form C, or any mixture thereof in the preparation of a pharmaceutical preparation for prostate cancer.
  • the new crystalline form B or crystalline form C of ODM-201 provided by the invention has the following advantageous properties: low wettability, good stability, excellent fluidity, good grinding stability, suitable particle size and uniform distribution, and The prior art has a higher solubility than the prior art.
  • Figure 1 is an X-ray powder diffraction pattern of Form B obtained in Example 1 according to the present invention.
  • Example 2 is an X-ray powder diffraction pattern of Form B obtained according to Example 2 of the present invention.
  • Figure 3 is a DSC chart of Form B obtained in accordance with Example 2 of the present invention.
  • Figure 5 is an X-ray powder diffraction pattern of Form B obtained according to Example 3 of the present invention.
  • Figure 6 is a hydrogen nuclear magnetic resonance diagram of Form B obtained according to Example 3 of the present invention.
  • Figure 7 is an X-ray powder diffraction pattern of Form B obtained according to Example 4 of the present invention.
  • Figure 8 is an X-ray powder diffraction pattern of Form C obtained according to Example 5 of the present invention.
  • Figure 9 is an X-ray powder diffraction pattern of Form C obtained according to Example 6 of the present invention.
  • Figure 10 is a DVS diagram of Form B of the present invention.
  • Figure 11 is a comparison of XRPD before and after DVS of Form B of the present invention (the figure below shows the XRPD pattern before DVS, and the figure above shows the XRPD pattern after DVS).
  • Figure 12 is a DVS diagram of Form C of the present invention.
  • Figure 13 is a comparison of XRPD before and after DVS of Form C of the present invention (the following figure is an XRPD diagram before DVS, and the above figure is an XRPD diagram after DVS).
  • Figure 14 is a DVS diagram of a prior art Form I.
  • Figure 15 is an XRPD pattern of Form B of the present invention before and after placement at 25 ° C / 60% relative humidity (the lower image shows the XRPD pattern before placement, and the upper view shows the XRPD pattern after placement).
  • Figure 16 is an XRPD pattern of Form B of the present invention before and after being placed under conditions of 40 ° C / 75% relative humidity (the lower graph is an XRPD pattern before placement, and the upper panel is an XRPD pattern after placement).
  • Figure 17 is an XRPD pattern of the Form C of the present invention before and after being placed at 25 ° C / 60% relative humidity (the lower image shows the XRPD pattern before placement, and the upper view shows the XRPD pattern after placement).
  • Figure 18 is a graph showing the particle size distribution of Form B of the present invention.
  • Figure 19 is a particle size distribution diagram of Form I disclosed in WO2016120530A1.
  • Fig. 20 is a comparison diagram of XRPD before and after the polishing of the crystal form C of the present invention (the lower graph is an XRPD pattern before polishing, and the upper graph is an XRPD pattern after grinding).
  • Figure 21 is a comparison of XRPD before and after polishing of Form I disclosed in WO2016120530A1 (the figure below shows the XRPD pattern before grinding, and the figure above shows the XRPD pattern after grinding).
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean 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:
  • Nuclear magnetic resonance spectroscopy data (1H NMR) were taken from a Bruker Avance II DMX 400M HZ NMR spectrometer. A sample of 1-5 mg was weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a solution of 2-10 mg/mL.
  • HPLC high performance liquid chromatography
  • DAD diode array detector
  • the elution gradient is as follows:
  • the particle size distribution results described in the present invention were collected on a Microtrac S3500 laser particle size analyzer.
  • the Microtrac S3500 is equipped with an SDC (Sample Delivery Controller) injection system.
  • SDC Sample Delivery Controller
  • This test uses a wet method and the test dispersion medium is Isopar G.
  • the method parameters of the laser particle size analyzer are as follows:
  • the flow rate is 60% of 60% of 65 ml/sec.
  • the starting material ODM-201 used in the following examples can be prepared according to the method described in the prior art, for example, the CN102596910B patent.
  • Form I used in the following examples was prepared according to the method disclosed in WO2016120530A1.
  • ODM-201 solid 29.5 mg was added to 1.0 mL of a mixed solvent of dichloromethane and methanol in a volume ratio of 1:1, and a solution was obtained at room temperature, and the clear solution was volatilized at room temperature for about 5 days to precipitate solids. .
  • the obtained crystalline solid is the crystalline form B of the present invention, and its X-ray powder diffraction data is shown in Table 1, Table 1.
  • ODM-201 solid 31.6 mg was added to 1.2 mL of a mixed solvent of dichloromethane and methanol in a volume ratio of 1:2, and a clear solution was obtained at room temperature, and the clear solution was volatilized at room temperature for about 5 days to precipitate solids. .
  • the DSC of this crystal form is shown in Fig. 3, which has an endothermic peak, and an endothermic peak begins to appear near 162 ° C, which is a melting endothermic peak.
  • the TGA of this crystalline form is shown in Figure 4 and has a mass loss gradient of about 1.0% when heated to 150 °C.
  • ODM-201 solid 20.3 mg was dissolved in 0.8 mL of acetone solution, and 4.0 mL of water was added dropwise to precipitate a solid.
  • ODM-201 solid 26.5 mg was added to a mixed solvent of 1.8 mL of tetrahydrofuran and water in a volume ratio of 4:1, a solution was obtained at room temperature, and the clear solution was volatilized at room temperature for about 5 days to precipitate a solid.
  • ODM-201 33.7 mg was added to 2.0 mL of a mixed solvent of acetic acid and isopropanol in a volume ratio of 1:2, and allowed to stand at 50 ° C for 5 hours, filtered and rapidly transferred to a low temperature of 4 ° C to be cooled to obtain white. Crystalline solid.
  • the obtained crystalline solid was the crystalline form C of the present invention, and its X-ray powder diffraction data is shown in Fig. 8 and Table 5.
  • ODM-201 29.5 mg was added to 2.0 mL of a mixed solvent of acetic acid and isopropyl alcohol in a volume ratio of 1:1, and allowed to stand at 50 ° C for 5 hours, filtered and rapidly transferred to a low temperature of 4 ° C to be cooled.
  • ODM-201 free base 12.45 mg was added to 0.2 mL of a mixed solvent of acetic acid and methyl tert-butyl ether in a volume ratio of 1:2, allowed to stand at 50 ° C for 5 hours, filtered and rapidly transferred to a low temperature of 4 ° C. Under cooling, a white crystalline solid was obtained. Upon examination, the solid obtained in this example was crystalline form C.
  • Example 8 Comparative test of wettability of Form B, Form C and Existing Form I
  • the wettability of the crystalline form B, the crystalline form C and the existing crystalline form I of the present invention was measured by a dynamic moisture adsorption (DVS) instrument.
  • the experimental results are shown in Table 7.
  • the DVS pattern of the wettability test of Form B is shown in Fig. 10, and the XRPD comparison chart before and after DVS is shown in Fig. 11.
  • the DVS pattern of the wettability test of Form C is shown in Fig. 12, and the XRPD comparison chart before and after DVS is shown in Fig. 13.
  • DVS diagram of existing crystal form I As shown in Figure 14.
  • Humidity is one of the key properties of the drug crystal form.
  • the drug form with high hygroscopicity changes the weight due to the adsorption of more water, making the content of the crystalline component of the raw material difficult to determine.
  • the crystal form of the raw material drug is easy to absorb and agglomerate due to high moisture absorbing property, thereby affecting the particle size distribution of the sample in the preparation process and the uniformity of the drug substance in the preparation, thereby affecting the dissolution and bioavailability of the sample.
  • the raw materials with high wettability are demanding on packaging and storage conditions, resulting in an increase in the production cost of the drug. Therefore, the preparation of low hygroscopic drug crystal forms is essential for drug production.
  • the drawbacks caused by the wettability simplify the preparation and post-treatment processes of the crystalline form B and the crystalline form C of the present invention, such as the need to control the environmental humidity during the preparation process, without special requirements for packaging and storage conditions, cost saving, and easy Industrial production and long-term storage of pharmaceuticals. Because the storage conditions are not demanding, the material storage and quality control costs will be greatly reduced, and it has strong economic value and is more suitable for medicinal use.
  • the wetting weight gain is not less than 15.0%
  • Humidity Wet weight gain is less than 15.0% but not less than 2.0%
  • wet weight gain is less than 2.0% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the crystalline form B of the present invention remained at a temperature of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity, and the crystal form remained unchanged for 3 months.
  • the above test results show that the crystalline form B of the present invention has good stability.
  • the crystal form C of the present invention remained unchanged under the condition of 25 ° C / 60% relative humidity for one month, indicating that the crystal form C had good stability.
  • the stability of the drug is very important, especially during the commercial period. Maintaining good stability can reduce the risk of drug dissolution rate and bio-profit change due to crystal form changes, and ensure the efficacy and safety of the drug.
  • the occurrence of adverse drug reactions is of great significance.
  • the more stable crystal form is more controllable during the crystallization process, and it is not easy to appear mixed crystal, and it is not easy to be converted into other crystal forms during the preparation process and storage process, thereby ensuring consistent and controllable sample quality and ensuring the preparation product.
  • the dissolution profile does not change as the storage time changes.
  • Solubility is one of the key properties of drugs, directly affecting the absorption of drugs in the human body.
  • the solubility of different crystal forms may be significantly different, and the absorption dynamics in the body may also change, resulting in differences in bioavailability, which ultimately affects the clinical safety and efficacy of the drug.
  • solubility is more important. Increased solubility will help improve the bioavailability of the drug, thereby increasing the drug's drug properties. In addition, the increase in solubility also reduces the difficulty of formulation process development. A sufficiently high solubility crystal form can be developed using a conventional formulation process, while for a less soluble crystal form, in order to achieve an ideal bioavailability, it is necessary to adopt a more Complex formulation process. In addition, the increase in solubility can reduce the dose of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.
  • the crystalline form B of the present invention and the crystalline form I sample disclosed in the patent WO2016120530A1 are respectively used with pH 1.8 SGF (simulated artificial gastric juice), pH 5.0 FeSSIF (simulated artificial intestinal juice in the fed state), pH 6.5 FaSSIF (simulated artificial intestinal juice in the fasting state)
  • pH 1.8 SGF simulated artificial gastric juice
  • pH 5.0 FeSSIF simulated artificial intestinal juice in the fed state
  • pH 6.5 FaSSIF simulated artificial intestinal juice in the fasting state
  • HPLC high performance liquid chromatography
  • Dissolution is the premise of drug absorption. From the experimental results, the solubility of crystal form I is low, so it is very important to increase the solubility of crystal form. Compared with the prior art, the solubility of the crystalline form B of the present invention is remarkably improved, providing favorable conditions for drug development.
  • the crystal form C of the present invention and the crystal form I sample disclosed in the patent WO2016120530A1 are respectively formulated into a saturated solution by using pH 5.0 FeSSIF (simulated intestinal juice in simulated feeding state), pH 6.5 FaSSIF (simulated intestinal liquid in simulated fasting state), in 1 hour. After 4 hours, the content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The experimental results are shown in Table 11.
  • Example 12 Comparison of particle size distribution between Form B of the present invention and existing Form I
  • 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) pattern of Form B is shown in Figure 18, and the particle size distribution (PSD) pattern of Form I disclosed in WO2016120530A1 is shown in Figure 19. It can be seen from the figure that the crystallite B has a monodisperse normal distribution, a uniform particle size and a narrow distribution. The particle size distribution of the existing crystal form I has a bimodal distribution, and the uniformity of the particle size distribution is poor.
  • Different crystal forms may exhibit different compressibility, bulk density, fluidity, and stability to grinding, pressure and pulverization due to their different particle properties, thereby affecting the process in the formulation.
  • a narrower particle size distribution can increase the homogeneity of the drug substance components in the formulation, while making the difference between different batches of the formulation smaller, such as more uniform dissolution; smaller crystal size can increase the specific surface area of the drug.
  • Improve the dissolution rate of the drug which is beneficial to the absorption of the drug, thereby improving the bioavailability.
  • Large clusters of crystals are often susceptible to entrapment of residual solvents or other impurities.
  • the bulk crystal powder cannot be uniformly dispersed, and it is difficult to mix uniformly with the auxiliary material, which is disadvantageous for the preparation of the preparation.
  • the shape of the crystal form B of the present invention is regular, and its uniform and small particle size helps to simplify the post-treatment process of the preparation process, such as reducing the grinding of the crystal form, saving cost, and reducing the crystallinity change and rotation in the grinding process.
  • the risk of crystals improves quality control.
  • the narrower particle size distribution of Form B 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 and improve the drug.
  • the dissolution rate is beneficial to the absorption of the drug, thereby improving bioavailability.
  • the crystalline form C of the present invention and the crystalline form I disclosed in the patent WO2016120530A1 were each about 20 mg, and were manually ground for 5 minutes in a mortar, and the samples were subjected to XRPD test before and after the grinding.
  • the test results of Form C are shown in Figure 20 (below the figure is before grinding, the figure above is after grinding), and the test result of Form I is shown in Figure 21 (below the figure before grinding, the figure above is after grinding). It can be seen from the figure that the crystal form of the present invention C remains fine after grinding, and the crystallinity of the crystal form I is significantly decreased, indicating that the polishing stability of the crystalline form C of the present invention is superior to the crystalline form I disclosed in the patent WO2016120530A1. .
  • Form C has better mechanical stability in the subsequent process and provides more options for subsequent formulation processes.
  • the crystal form C can be ground by a subsequent dry grinding means to obtain particles having a smaller particle size.

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Abstract

本发明公开了一种雄激素受体拮抗剂药物(式(I)所示的ODM-201)的晶型及其制备方法和用途。本发明提供的ODM-201的晶型B或晶型C的引湿性低、稳定性好、溶解度高、流动性优良、粒径大小合适并且分布较为均匀，为含ODM-201的药物制剂的制备提供了新的选择，对于药物开发具有非常重要的价值。

Description

一种雄激素受体拮抗剂药物的晶型及其制备方法和用途 技术领域
本发明涉及药物晶体技术领域。具体而言，涉及一种雄激素受体拮抗剂药物的晶型及其制备方法和用途。
背景技术
***癌已成为威胁男性健康的重要疾病，其发病率在西方国家较高且呈逐年上升的趋势，而在过去发病率较低的亚洲国家，近年来患病人数增长也在加快。临床治疗***癌常用的方法有手术切除、放射治疗以及阻断雄激素的内分泌疗法等。雄激素与***的生长以及***癌的发生密切相关，因此内分泌疗法已成为治疗***癌的有效途径。该方法包括睾丸切除法、***疗法、***释放激素类似物疗法、***释放激素拮抗剂疗法、雄激素拮抗疗法等，其中雄激素拮抗疗法既可单独治疗早期***癌也可配合手术进行辅助治疗，是当前临床治疗***癌的主要手段之一。而雄激素受体作为雄激素发挥生物学效应的靶点，已成为生物医学领域研究的重要内容。
临床实验表明，给予***癌病人外源性雄激素会导致患者的病情加重；但相反，若通过切除睾丸，降低患者体内雄激素水平则会使病情缓解，这表明雄激素对***癌的发展有重要影响。根据受体学说，雄激素必须与雄激素受体(AR)结合后才能引起后续的生理和病理效应，这就为应用雄激素受体(AR)拮抗剂治疗***癌奠定了理论基础。体外实验已证实，AR拮抗剂能抑制***细胞增殖，并促进其凋亡。根据AR拮抗剂的化学结构，可将其分为甾体类AR拮抗剂和非甾体类AR拮抗剂。非甾体类药物抗雄激素的活性较好，不存在甾体类药物的激素样副作用，所以更适合用于前列 腺癌的治疗。
ODM-201(BAY-1841788)是一种非甾体类口服雄激素受体(AR)拮抗剂，临床研究用于治疗***癌。ODM-201对AR具有很高的亲和力和抑制效果，其中Ki＝11nM，IC50＝26nM，Ki为ODM-201与AR复合物的解离常数，其值越小表示亲和能力越强；IC50(half maximal inhibitory concentration)是指被测量的半抑制浓度，能指示某一药物或者物质(抑制剂)在抑制某些生物程序的半量，该数值越低，药物的抑制能力越强。此外，ODM-201不穿过血脑屏障，能够减少癫痫等神经***相关的副作用。拜耳公司已在临床试验中证明了ODM-201的有效性和安全性，显示出其在治疗***癌方面的强大潜力。
ODM-201的化学名称为：N-((S)-1-(3-(3-氯-4-氰基苯基)-1H-吡唑-1-基)-丙烷-2-基)-3-(1-羟基乙基)-1H-吡唑-5-甲酰胺，本领域人员公知，该化学名称包含其互变异构体N-((S)-1-(3-(3-氯-4-氰基苯基)-1H-吡唑-1-基)-丙烷-2-基)-5-(1-羟基乙基)-1H-吡唑-3-甲酰胺，CAS号为1297538-32-9，其结构式如式(I)所示：
Figure PCTCN2017099036-appb-000001
固体化学药物晶型不同，可造成其溶解度、稳定性、流动性和压缩性等不同，从而影响含有该化合物的药物产品的安全性和有效性(参见K.Knapman,Modern Drug Discovery,3,53-54,57,2000.)，从而导致临床药效的差异。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、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。药学上化合物的新晶型可以帮助改善药物的性能，扩大制剂学上可选用的原料型态。
专利CN102596910B公开了ODM-201的制备方法，但并未公开任何的晶型信息。专利WO2016120530A1公开了式(I)(CAS号：1297538-32-9)所示的晶型I，式(Ia)(CAS号：1976022-48-6)所示的晶型I’和式(Ib)(CAS号：1976022-49-7)所示的晶型I”。文献Expert Rev.Anticancer Ther.15(9),(2015)已报道：ODM-201是由1:1比例的(Ia)和(Ib)两种非对应异构体组成，即为式(I)所示结构。因此，现有关于ODM-201的晶型只有晶型I报道。
Figure PCTCN2017099036-appb-000002
然而，晶型I的溶解度较低、引湿性高，并且晶型I的制备需用到毒性较强的乙腈溶剂，乙腈具有动物致癌性，是在工艺开发阶段应需控制的二类溶剂。晶型I的制备方法较为复杂，制备周期长，过程中需要加热，增加工业化制备成本，不利于工业化生产。为克服上述缺陷，本领域仍需要***全面的开发式(I)所示ODM-201的其它晶型，简化其制备工艺，从而实现其药物学上的发展并释放其潜能，并促进含该活性药物成分的更好的配方的制备。
发明人通过实验发现了本发明的晶型B和晶型C，并发现与现有技术相比，本发明的晶型B和晶型C具有更优良的性质。溶解是药物吸收的前提条件，溶解度的提高将有助于提高药物的生物利用度，从而提高药物的成药性。与现有技术相比，本发明的晶型B和晶型C溶解度更高，为药物开发提供有利条件。与现有技术相比，本发明的晶型B和晶型C还具有更低的引湿性。引湿性高的药物晶型因吸附较多水分导致重量发生变化，使原料晶型组份含量不易确定。此外，原料药晶型因引湿性高而吸水结块，从而影响制剂工艺 中样品的粒径分布和原料药在制剂中的均一度，进而影响样品的溶出及生物利用度。本发明的晶型B和晶型C在不同湿度条件下水分含量基本保持不变，克服高引湿性带来的弊端，更有利于药品的长期贮存，降低物料储存以及质量控制成本。
此外，本发明提供式(I)所示ODM-201的晶型B和晶型C，其稳定性好、流动性优良、粒径大小合适并且分布较为均匀。本发明晶型B和晶型C的制备方法中所用溶剂毒性更低，利于绿色化工业生产，且避免有毒溶剂残留带来的制药风险，更有利于药物制剂的制备。本发明提供的新晶型，制备方法操作简单，无需加热，制备周期短，有利于工业化生产中的成本控制。本发明的晶型B和晶型C为含ODM-201的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。
发明内容
发明要解决的问题
本发明的主要目的是提供ODM-201的晶型及其制备方法和用途。
用于解决问题的方案
根据本发明的目的，本发明提供式(I)所示ODM-201的晶型B(以下称为“晶型B”)。
使用Cu-Kα辐射，所述晶型B的X射线粉末衍射在衍射角2θ为16.2°±0.2°、9.0°±0.2°、22.5°±0.2°处有特征峰。
进一步的，所述晶型B的X射线粉末衍射在衍射角2θ为24.7°±0.2°、11.9°±0.2°、18.1°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型B的X射线粉末衍射在衍射角2θ为24.7°±0.2°、11.9°±0.2°、18.1°±0.2°处有特征峰。
更进一步的，所述晶型B的X射线粉末衍射在衍射角2θ为14.7°±0.2°、 23.5°±0.2°、27.8°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型B的X射线粉末衍射在衍射角2θ为14.7°±0.2°、23.5°±0.2°、27.8°±0.2°处有特征峰。
在一个优选的实施方案中，所述晶型B的X射线粉末衍射在衍射角2θ为16.2°±0.2°、9.0°±0.2°、22.5°±0.2°、24.7°±0.2°、11.9°±0.2°、18.1°±0.2°、14.7°±0.2°、23.5°±0.2°、27.8°±0.2°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B的X射线粉末衍射谱图如图1所示。
根据本发明的目的，本发明还提供所述晶型B的制备方法，所述制备方法包括：1)将ODM-201溶解于醇类或酮类或两者的混合溶剂中，以水作为反溶剂滴加至有固体析出；或
2)在室温下将ODM-201溶解于卤代烃与醇类溶剂或醚类与水的混合溶剂中，将该澄清溶液在室温下挥发至有固体析出。
其中：
所述醇类溶剂为甲醇、乙醇或者它们的混合物；
优选地，所述醇类溶剂为甲醇；
所述卤代烃类溶剂为氯代烷烃；
优选地，所述氯代烃类溶剂为二氯甲烷；
所述酮类溶剂为饱和脂肪酮；
优选地，所述酮类溶剂为丙酮；
所述醚类溶剂为环醚化合物；
优选地，所述醚类溶剂为四氢呋喃；
优选地，所述反应温度或操作温度为10-40℃，更优选为室温；
优选地，所述析晶时间为36-72小时，更优选为48小时。
根据本发明的目的，本发明还提供式(I)所示ODM-201的晶型C(以下称 为“晶型C”)。
使用Cu-Kα辐射，所述晶型C的X射线粉末衍射在衍射角2θ值为9.4°±0.2°、14.1°±0.2°、12.1°±0.2°处有特征峰。
进一步的，所述晶型C的X射线粉末衍射在衍射角2θ值为15.1°±0.2°、15.8°±0.2°、19.9°±0.2°中的一处或两处或三处有特征峰；优选地，所述晶型C的X射线粉末衍射在衍射角2θ为15.1°±0.2°、15.8°±0.2°、19.9°±0.2°处有特征峰。
更进一步的，所述晶型C的X射线粉末衍射在衍射角2θ值为23.7°±0.2°处有特征峰。
在一个优选的实施方案中，所述晶型C的X射线粉末衍射在衍射角2θ值为9.4°±0.2°、14.1°±0.2°、12.1°±0.2°、15.1°±0.2°、15.8°±0.2°、19.9°±0.2°、23.7°±0.2°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C的X射线粉末衍射谱图如图8所示。
根据本发明的目的，本发明还提供晶型C的制备方法，所述制备方法包括但不限于将ODM-201加入到一定体积比的乙酸与其它有机溶剂的混合体系，加热至一定温度后，冷却析晶获得。
其中：
所述其它有机溶剂包含异丙醇，甲基叔丁基醚，甲苯和乙酸乙酯，优选地，所述其它有机溶剂为异丙醇或甲基叔丁基醚；
所述加热温度包含40～60℃，优选地，所述加热温度为50℃；
所述体积比包含2:1～1:2；
在本发明的晶型B和晶型C的制备方法中：
所述ODM-201游离碱或ODM-201是指式(I)化合物的固体、半固体、蜡或油形式。
所述“室温”不是精确的温度值，是指10-30℃温度范围。
所述“挥发”采用本领域的常规方法完成，例如缓慢挥发是将容器封上封口膜，扎孔，静置挥发；快速挥发是将容器敞口放置挥发。
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。
“晶型”和“多晶型”以及其他相关词汇在本发明中指的是固体化合物在晶体结构中以特定的晶型状态存在。多晶型理化性质的不同可以体现在储存稳定性、可压缩性、密度、溶出速度等方面。在极端的情况下，溶解度或溶出速度的不同可以造成药物低效，甚至毒性。
在一些实施方案中，本发明的新晶型B或晶型C是纯的、单一的，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。
有益效果
与现有技术相比，本发明的晶型B和晶型C具有以下优势：
本发明的晶型B和晶型C在80％相对湿度下增重量分别为1.07％和0.93％，属于略有引湿性。与现有技术相比，本发明晶型的引湿性低，能够很好地对抗药物制剂和/或存储等过程中晶型不稳定以及由环境湿气等外来因素所引起的制剂不可加工等问题，有利于制剂制备中的准确定量和后期的运输和储存。
由稳定性试验可知，本发明的晶型B在25℃/60％相对湿度和40℃/75％相对湿度条件下放置3个月晶型未发生变化。因此，本发明的晶型B具有良好的稳定性，有利于样品的保存和制剂的稳定。
本发明的晶型B和晶型C与现有专利WO2016120530A1公开的晶型I相比，能显著改善溶解性，从而有助于提高药物的生物利用度。
本发明的晶型B与晶型I相比具有更窄的粒径分布和更小的粒径。其均匀的粒径有助于简化制剂过程的后处理工艺，如可减少对晶体的研磨，节约成本，也减小研磨中晶型结晶度变化和转晶的风险，提高质量控制。其更窄的粒径分布可提高制剂中原料药组分的均一度，同时使得不同批次制剂之间的差异性更小，如溶出更均一；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。
本发明的晶型C与晶型I相比具有更高的研磨稳定性，制剂加工过程中常 需要原料药的研磨粉碎，高的研磨稳定性能够减小制剂加工过程中发生原料药晶型结晶度改变和转晶的风险。
此外，本发明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晶型B、晶型C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ODM-201的晶型B、晶型C或它们的任意混合在制备雄激素受体拮抗剂药物制剂中的用途。
进一步的，本发明提供ODM-201的晶型B、晶型C或它们的任意混合在制备癌症药物制剂中的用途。
更进一步的，本发明提供ODM-201的晶型B、晶型C或它们的任意混合在制备***癌药物制剂中的用途。
本发明提供的ODM-201新的晶型B或晶型C具有以下有利性质：其引湿性低、稳定性好、流动性优良、研磨稳定性好、粒径大小合适并且分布较为均匀，且与现有技术相比溶解度更高。
附图说明
图1为根据本发明实施例1所得晶型B的X射线粉末衍射图。
图2为根据本发明实施例2所得晶型B的X射线粉末衍射图。
图3为根据本发明实施例2所得晶型B的DSC图。
图4为根据本发明实施例2所得晶型B的TGA图。
图5为根据本发明实施例3所得晶型B的X射线粉末衍射图。
图6为根据本发明实施例3所得晶型B的氢核磁共振图。
图7为根据本发明实施例4所得晶型B的X射线粉末衍射图。
图8为根据本发明实施例5所得晶型C的X射线粉末衍射图。
图9为根据本发明实施例6所得晶型C的X射线粉末衍射图。
图10为本发明晶型B的DVS图。
图11为本发明晶型B的DVS前后XRPD对比图(下图为DVS前的XRPD图，上图为DVS后的XRPD图)。
图12为本发明晶型C的DVS图。
图13为本发明晶型C的DVS前后XRPD对比图(下图为DVS前的XRPD图，上图为DVS后的XRPD图)。
图14为现有晶型I的DVS图。
图15为本发明晶型B在25℃/60％相对湿度条件下放置前后的XRPD图(下图为放置前的XRPD图，上图为放置后的XRPD图)。
图16为本发明晶型B在40℃/75％相对湿度条件下放置前后的XRPD图(下图为放置前的XRPD图，上图为放置后的XRPD图)。
图17为本发明晶型C在25℃/60％相对湿度条件下放置前后的XRPD图(下图为放置前的XRPD图，上图为放置后的XRPD图)。
图18为本发明晶型B的粒径分布图。
图19为WO2016120530A1公开的晶型I的粒径分布图。
图20为本发明晶型C研磨前后的XRPD对比图(下图为研磨前的XRPD图，上图为研磨后的XRPD图)。
图21为WO2016120530A1公开的晶型I研磨前后的XRPD对比图(下图为研磨前的XRPD图，上图为研磨后的XRPD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。
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Panalytical Empyrean 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射线反射参数：Cu，Kα
Kα1
Figure PCTCN2017099036-appb-000003
1.540598；Kα2
Figure PCTCN2017099036-appb-000004
1.544426
Kα2/Kα1强度比例：0.50
电压：45千伏特(kV)
电流：40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：N2
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：N2
核磁共振氢谱数据(1HNMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配成2-10mg/mL的溶液。
本发明中高效液相色谱(HPLC)数据采自于安捷伦1260，所用检测器为二极管阵列检测器(DAD)。本发明所述的测试溶解度的HPLC方法参数如下：
1、色谱柱：Agilent Infinity Lab Poroshell 120EC-C18 150*3.0mm，2.7μm
2、流动相：A：25mmol/L KH2PO4水溶液
B：乙腈溶液
洗脱梯度如下：
Time(min) ％B
0.0 30
6.0 45
7.0 80
10.0 80
10.1 30
12.0 30
3、流速：0.7ml/min
4、进样量：5μl
5、检测波长：220nm
6、柱温：40℃
7、稀释剂：50％乙腈
本发明中所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。Microtrac S3500配备SDC(Sample Delivery Controller)进样***。本测试采用湿法，测试分散介质为Isopar G。所述的激光粒度分析仪的方法参数如下：
Figure PCTCN2017099036-appb-000005
*：流速60％为65毫升/秒的60％。
除非特殊说明，以下实施例均在室温条件下操作。
以下实施例中所使用的原料ODM-201可根据现有技术例如CN102596910B专利所记载的方法制备获得。
以下实施例中所用晶型I为根据WO2016120530A1中公开的方法制备得到。
实施例1：晶型B的制备方法
将29.5mg的ODM-201固体加入到1.0mL二氯甲烷与甲醇体积比1:1的混合溶剂中，在室温下获得溶清溶液，将该澄清溶液在室温下挥发至约5天有固体析出。
经检测，所得结晶固体为本发明所述晶型B，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％
5.89 15.00 5.85
7.32 12.08 2.49
8.96 9.87 23.95
11.89 7.45 6.75
13.46 6.58 12.79
14.78 5.99 15.21
16.20 5.47 100.00
17.06 5.20 4.98
18.03 4.92 14.32
18.38 4.83 7.76
19.11 4.65 6.18
20.17 4.40 8.33
22.51 3.95 31.86
23.54 3.78 11.12
24.67 3.61 16.83
25.62 3.48 6.10
27.23 3.28 6.08
27.87 3.20 10.27
实施例2：晶型B的制备方法
将31.6mg的ODM-201固体加入到1.2mL二氯甲烷与甲醇体积比1:2的混合溶剂中，在室温下获得溶清溶液，将该澄清溶液在室温下挥发至约5天有固体析出。
经检测，本实施例得到固体为晶型B，其X射线粉末衍射数据如图2，表2所示。
表2
衍射角2θ d值 强度％
8.96 9.87 24.75
11.86 7.46 5.76
13.56 6.53 10.98
14.78 5.99 18.86
16.23 5.46 100.00
18.13 4.89 9.71
20.19 4.40 6.01
22.52 3.95 28.70
23.57 3.77 8.23
24.66 3.61 9.07
27.82 3.21 5.69
该晶型的DSC如图3所示，其有一个吸热峰，在162℃附近开始出现吸热峰，该吸热峰是熔化吸热峰。
该晶型的TGA如附图4所示，将其加热至150℃时，具有约1.0％的质量损失梯度。
实施例3：晶型B的制备方法
将20.3mg的ODM-201固体溶解于0.8mL丙酮溶液中，逐滴加入4.0mL水，有固体析出。
经检测，本实施例得到固体为晶型B，其X射线粉末衍射数据如图5，表3所示。采用液体核磁确定产物化学结构，其核磁数据为：1H NMR(400MHz,DMSO)δ13.10(s,1H),8.26(d,J＝8.6Hz,1H),8.15(s,1H),8.08–7.85(m,3H),7.00(d,J＝2.1Hz,1H),6.46(s,1H),5.48(d,J＝4.6Hz,1H),4.86(s,1H),4.55–4.31(m,3H),1.44(d,J＝6.4Hz,3H),1.17(d,J＝6.3Hz,3H)，其核磁共振氢谱如图6所示。
表3
衍射角2θ d值 强度％
5.88 15.02 12.07
8.96 9.87 39.59
10.11 8.75 2.63
11.91 7.43 16.39
13.70 6.46 15.35
14.74 6.01 15.50
16.20 5.47 100.00
17.02 5.21 5.92
18.05 4.91 15.51
19.03 4.66 6.54
20.16 4.40 7.43
22.52 3.95 31.50
23.52 3.78 11.99
24.72 3.60 19.12
25.55 3.49 6.12
27.83 3.21 8.69
实施例4：晶型B的制备方法
将26.5mg的ODM-201固体加入到1.8mL四氢呋喃与水体积比4:1的混合溶剂中，在室温下获得溶清溶液，将该澄清溶液在室温下挥发至约5天有固体析出。
经检测，本实施例得到固体为晶型B，其X射线粉末衍射数据如图7，表4所示。
表4
衍射角2θ d值 强度％
5.94 14.88 3.21
7.33 12.06 3.60
8.96 9.87 19.24
11.88 7.45 6.40
13.49 6.56 12.22
14.75 6.01 17.06
16.21 5.47 100.00
18.09 4.90 14.73
19.06 4.66 5.04
20.17 4.40 10.14
22.53 3.95 32.74
23.59 3.77 7.95
24.65 3.61 12.34
25.53 3.49 6.32
27.25 3.27 7.42
27.85 3.20 10.63
28.76 3.10 3.15
31.73 2.82 2.82
32.93 2.72 1.48
实施例5：晶型C的制备方法
将33.7mg ODM-201加入到2.0mL乙酸与异丙醇体积比为1:2的混合溶剂中，在50℃条件下静置5小时，过滤并迅速转移至低温4℃条件下冷却，得到白色结晶固体。
经检测，所得结晶固体为本发明晶型C，其X射线粉末衍射数据如图8，表5所示。
表5
衍射角2θ d值 强度％
4.50 19.62 7.28
9.40 9.41 69.13
12.06 7.34 100.00
14.14 6.26 74.33
15.07 5.88 33.33
15.78 5.61 37.25
17.95 4.94 7.11
18.91 4.69 10.70
19.93 4.46 31.90
20.39 4.36 24.61
21.32 4.17 18.11
22.51 3.95 7.52
23.20 3.83 18.32
23.68 3.76 44.42
25.04 3.56 17.65
25.78 3.46 7.02
26.86 3.32 26.38
27.26 3.27 21.55
29.50 3.03 15.43
30.44 2.94 12.15
34.43 2.60 4.21
实施例6：晶型C的制备方法
将29.5mg ODM-201加入至2.0mL体积比为1:1的乙酸与异丙醇的混合溶剂中，在50℃条件下静置5小时，过滤并迅速转移到低温4℃条件下冷却，得白色结晶固体。
经检测，本实施例得到固体为晶型C，其X射线粉末衍射数据如图9，表6所示。
表6
衍射角2θ d值 强度％
9.42 9.39 41.55
12.07 7.34 100.00
14.14 6.26 75.78
15.07 5.88 47.86
15.82 5.60 56.51
18.16 4.88 22.96
19.01 4.67 12.60
19.97 4.45 72.50
20.40 4.35 35.66
21.35 4.16 38.06
22.53 3.95 15.90
23.18 3.84 36.51
23.68 3.76 73.07
25.10 3.55 36.13
26.95 3.31 73.82
27.32 3.26 63.99
29.54 3.02 31.32
30.47 2.93 35.53
33.60 2.67 8.62
34.57 2.59 11.73
实施例7：晶型C的制备方法
将12.45mg ODM-201游离碱加入到0.2mL体积比为1:2的乙酸与甲基叔丁基醚的混合溶剂中，在50℃条件下静置5小时，过滤并迅速转移到低温4℃下冷却，得白色结晶固体。经检测，本实施例得到的固体为晶型C。
实施例8：晶型B、晶型C和现有晶型I的引湿性对比测试
分别取本发明晶型B、晶型C和现有晶型I各约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表7所示。晶型B的引湿性实验的DVS图如图10所示，DVS前后XRPD对比图如图11所示。晶型C的引湿性实验的DVS图如图12所示，DVS前后XRPD对比图如图13所示。现有晶型I的DVS图 如图14所示。
表7
Figure PCTCN2017099036-appb-000006
引湿性是药物晶型的关键性质之一，引湿性高的药物晶型因吸附较多水分导致重量发生变化，使原料晶型组份含量不易确定。此外，原料药晶型因引湿性高而易吸水结块，从而影响制剂工艺中样品的粒径分布和原料药在制剂中的均一度，进而影响样品的溶出及生物利用度。引湿性高的原料药对包装和贮存条件要求苛刻，导致药品的生产成本增加。因此，制备低引湿性的药物晶型对药物生产至关重要。
结果表明，本发明的晶型B和晶型C与现有晶型相比具有较低的引湿性，且DVS前后本发明晶型B和晶型C未发生改变，能够克服上述药物晶型高引湿性带来的弊端，简化含本发明晶型B和晶型C药物的制备与后处理工艺，如制剂过程中可不必控制环境湿度，对包装和贮存条件无特殊苛刻要求，节约成本，易于工业化生产和药品的长期贮存。由于对储存条件要求不苛刻，将大大降低物料储存以及质量控制成本，具有很强的经济价值，更适合药用。
关于引湿性特征描述与引湿性增重的界定(中国药典2015年版通则9103药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15.0％
有引湿性：引湿增重小于15.0％但不小于2.0％
略有引湿性：引湿增重小于2.0％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
实施例9：晶型B和晶型C的稳定性测试
取晶型B的样品分别置于25℃/60％相对湿度和40℃/75％相对湿度下敞口放置3个月，取样测其XRPD图，放置前后的XRPD图如图15和图16所示，结果如表8所示：
表8
Figure PCTCN2017099036-appb-000007
本发明晶型B在25℃/60％相对湿度和40℃/75％相对湿度条件下，放置3个月晶型保持不变。上述试验结果表明，本发明晶型B具有良好的稳定性。
取晶型C的样品置于25℃/60％相对湿度下敞口放置1个月，然后取样测XRPD图，放置前后的XRPD图如图17所示，结果如表9所示：
表9
Figure PCTCN2017099036-appb-000008
本发明晶型C在25℃/60％相对湿度条件下，放置1个月晶型保持不变，表明晶型C具有良好的稳定性。
药物的稳定性至关重要，尤其在市售有效期内，保持较好的稳定性能够减少药物由于晶型变化而导致药物溶出速率及生物利度改变的风险，对保证药物疗效和安全性，防止药物不良反应的发生具有重要意义。更稳定的晶型在结晶工艺过程中更加可控，不容易出现混晶，且在制剂工艺及储存过程中，不容易转变成其它晶型，从而保证样品的质量一致可控，并确保制剂产品的溶出曲线不会随着储存的时间变化而发生改变。
结果表明，本发明晶型B和晶型C具有良好的稳定性，符合药物应用及制剂工艺中对晶型的苛刻要求。
实施例10：本发明晶型B与现有晶型I的溶解度对比测试
溶解度是药物的关键性质之一，直接影响药物在人体内的吸收。不同晶型药物的溶解度可能会存在明显差异，体内吸收动态也会发生变化，造成生物利用度的差异，最终影响到药物的临床安全性和疗效。
尤其对一个难溶性药物而言，提高溶解度更为重要。溶解度的提高将有助于提高药物的生物利用度，从而提高药物的成药性。另外，溶解度的提高也降低了制剂工艺开发的难度，足够高溶解度的晶型可以采用传统的制剂工艺进行开发，而对于溶解度较低的晶型，为了达到理想的生物利用度，则需要采取更加复杂的制剂工艺。此外，溶解度升高能够在保证药物疗效的同时，降低药品的剂量，从而降低药品的副作用并提高药品的安全性。
为测试本发明晶型B的溶解性，发明人做了如下实验：
将本发明中的晶型B与专利WO2016120530A1公开的晶型I样品分别用pH1.8SGF(模拟人工胃液)，pH5.0FeSSIF(模拟进食状态下人工肠液)，pH6.5FaSSIF(模拟空腹状态下人工肠液)配制成饱和溶液，在1小时和4个小时后采用高效液相色谱(HPLC)测定饱和溶液中样品的含量。实验结果如表10所示。
表10
Figure PCTCN2017099036-appb-000009
结果表明，在SGF、FaSSIF、FeSSIF中放置1小时，4个小时后，本发明晶型B的溶解度显著高于现有专利WO2016120530A1所公开的晶型I的溶解度。
溶解是药物吸收的前提，从实验结果看，晶型I的溶解度较低，因此提高晶型溶解度显得至关重要。与现有技术相比，本发明的晶型B的溶解度显著提高，为药物开发提供有利条件。
实施例11：本发明晶型C与现有晶型I的溶解度对比测试
将本发明中的晶型C与专利WO2016120530A1公开的晶型I样品分别用pH5.0FeSSIF(模拟进食状态下人工肠液)，pH6.5FaSSIF(模拟空腹状态下人工肠液)配制成饱和溶液，在1小时和4个小时后采用高效液相色谱(HPLC)测定饱和溶液中样品的含量。实验结果如表11所示。
表11
Figure PCTCN2017099036-appb-000010
结果表明，在FeSSIF放置1小时，在FaSSIF放置1小时、4小时后，本发明晶型C的溶解度高于现有专利WO2016120530A1所公开的晶型I的溶解度。与现有技术相比，本发明的晶型C的溶解度更高，为药物开发提供有利条件。
实施例12：本发明晶型B与现有晶型I的粒径分布对比
取本发明晶型B与专利WO2016120530A1所公开晶型I的样品分别进行粒径分布测试。粒径分布结果见表12。
表12
晶型 MV(μm) D10(μm) D50(μm) D90(μm)
晶型B 3.12 1.20 2.73 5.49
晶型I 136.1 24.97 100.5 297.4
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B的粒径分布(PSD)图见图18，专利WO2016120530A1所公开的晶型I的粒径分布(PSD)图见图19。由图中可以看出，晶型B粒径呈单分散正态分布，粒径均匀，分布窄。现有晶型I的粒径分布成双峰分布，粒径分布均一性差。
不同晶型因其颗粒属性的不同，可能表现出不同的可压性，堆密度，流动性，及对研磨、压力和粉碎的稳定性，从而影响制剂中的工艺过程。例如：更窄的粒径分布可提高制剂中原料药组分的均一度，同时使得不同批次制剂之间的差异性更小，如溶出更均一；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。而大块成团的晶体通常容易包裹残留溶剂或其它杂质。并且在制备制剂时，大块晶体粉末不能均匀分散，与辅料难以混合均匀，不利于制剂的制备。
本发明晶型B形状规则，其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，也减少研磨中晶型结晶度变化和转晶的风险，提高质量控制。此外，晶型B更窄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。
实施例13：本发明晶型C研磨稳定性研究
取本发明晶型C和专利WO2016120530A1所公开的晶型I各约20毫克，分别用研钵手动研磨5分钟，研磨前后对样品进行XRPD测试。晶型C的测试结果见图20(下图为研磨前，上图为研磨后)，晶型I的测试结果见图21(下图为研磨前，上图为研磨后)。从图中可以看出，本发明晶型C经过研磨后结晶度保持良好，而晶型I的结晶度明显下降，说明本发明晶型C的研磨稳定性优于专利WO2016120530A1所公开的晶型I。
上述结果表明，晶型C在后续的工艺过程中具备更好的机械稳定性，为后续制剂工艺提供更多选择。例如，可以通过后续干法研磨手段对晶型C进行研磨从而得到粒径更小的颗粒。
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 (13)

  1. 一种式(I)所示ODM-201的晶型B，其特征在于，其X射线粉末衍射在衍射角2θ为16.2°±0.2°、9.0°±0.2°、22.5°±0.2°处有特征峰。
    Figure PCTCN2017099036-appb-100001
  2. 根据权利要求1所述的晶型B，其特征还在于，其X射线粉末衍射在衍射角2θ为24.7°±0.2°、11.9°±0.2°、18.1°±0.2°中的一处或两处或三处有特征峰。
  3. 根据权利要求1所述的晶型B，其特征还在于，其X射线粉末衍射在衍射角2θ为14.7°±0.2°、23.5°±0.2°、27.8°±0.2°中的一处或两处或三处有特征峰。
  4. 式(I)所示ODM-201的晶型B的制备方法，其特征在于，所述方法包括：
    1)将ODM-201溶解于醇类或酮类或两者的混合溶剂中，以水作为反溶剂滴加至有固体析出；或
    2)在室温下将ODM-201溶解于卤代烃与醇类溶剂或醚类与水的混合溶剂中，将该澄清溶液在室温下挥发至有固体析出。
  5. 根据权利要求4所述的制备方法，其特征在于，所述醇类溶剂为甲醇、乙醇或者它们的混合物；所述卤代烃类溶剂为氯代烷烃；所述酮类溶剂为饱和脂肪酮；所述醚类溶剂为环醚化合物。
  6. 一种式(I)所示ODM-201的晶型C，其特征在于，其X射线粉末衍射在衍射角2θ值为9.4°±0.2°、14.1°±0.2°、12.1°±0.2°处具有特征峰。
  7. 根据权利要求6所述的晶型C，其特征还在于，其X射线粉末衍射在衍射角2θ值为15.1°±0.2°、15.8°±0.2°、19.9°±0.2°中的一处或两处或三处具有特征峰
  8. 根据权利要求6所述的晶型C，其特征还在于，其X射线粉末衍射在衍 射角2θ值为23.7°±0.2°处具有特征峰
  9. 一种式(I)所示ODM-201的晶型C的制备方法，其特征在于，所述方法包括：将ODM-201加入到一定体积比的乙酸与其它有机溶剂的混合体系，加热至一定温度后，冷却析晶获得。
  10. 根据权利要求9所述的制备方法，其特征在于，所述其它有机溶剂为异丙醇或甲基叔丁基醚；所述加热温度为40～60℃；所述体积比为2:1～1:2。
  11. 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B或权利要求6所述的晶型C及药学上可接受的载体、稀释剂或赋形剂。
  12. 权利要求1所述的晶型B或权利要求6所述的晶型C在生产用于制备雄激素受体拮抗剂药物制剂中的用途。
  13. 权利要求1所述的晶型B或权利要求6所述的晶型C在生产用于制备***癌药物制剂中的用途。
PCT/CN2017/099036 2016-08-26 2017-08-25 一种雄激素受体拮抗剂药物的晶型及其制备方法和用途 WO2018036558A1 (zh)

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