CN112300076B - Crystal form of androgen receptor inhibitor and preparation method thereof - Google Patents
Crystal form of androgen receptor inhibitor and preparation method thereof Download PDFInfo
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- CN112300076B CN112300076B CN202011180867.1A CN202011180867A CN112300076B CN 112300076 B CN112300076 B CN 112300076B CN 202011180867 A CN202011180867 A CN 202011180867A CN 112300076 B CN112300076 B CN 112300076B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
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- C—CHEMISTRY; METALLURGY
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- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention relates to a crystal form of an androgen receptor inhibitor and a preparation method thereof. In particular to a crystal form of an androgen receptor inhibitor shown in a formula (I) and a preparation method thereof. The novel crystal form has good stability and can be better used for clinical treatment.
Description
The application is a divisional application of Chinese patent application with the application number of 201811514940.7, the application date of 2018, 12 months and 12 days, and the name of the invention is 'a crystal form of an androgen receptor inhibitor and a preparation method thereof'.
Technical Field
The present invention relates to a novel crystalline form of an androgen receptor inhibitor and a process for its preparation.
Background
Prostate cancer (PCa) is a malignant tumor that occurs in the prostate tissue of men and is the result of abnormal, disordered growth of prostate acinar cells. Differentiation and growth of normal prostate epithelial cells and the development of prostate cancer are dependent on androgens, which are mainly synthesized in the testes, accounting for approximately 80-90%. Synthetic androgens bind to the Androgen Receptor (AR) upon entry into the cell, causing dissociation of Heat Shock Proteins (HSP) from the AR and entry of the AR into the nucleus, activating a number of downstream genes, including Prostate Specific Antigen (PSA). Early stage prostate cancer is androgen sensitive and orchiectomy (castration) can significantly inhibit the development of prostate cancer. However, castration has a certain timeliness, many patients undergo a transition from androgen-dependent to androgen-independent for a while after castration, are no longer effective for anti-androgen therapy, and develop androgen-independent prostate cancer (AIPC), while the occurrence of AlPC is still important in connection with the activation of AR signaling pathway in PCa cells.
WO2014036897 discloses a new class of AR antagonists, including compounds of formula (I), which have superior activity and fewer side effects, and thus have broad clinical prospects.
WO2017041622 discloses crystalline form I of a compound of formula (I); CN106518773A discloses a crystalline form II of the compound of formula (I).
It is well known that compounds may exist in a variety of crystalline forms. The crystal structure of the compound used as a medicinal active ingredient usually affects the chemical and physical stability of the medicament, and the difference of the crystal form, the preparation method and the storage condition may cause the change of the crystal structure of the compound and sometimes cause the generation of other forms of crystal forms. The physicochemical properties of different crystal forms are slightly different, and the drug effect and stability of the final finished medicine are also influenced. Therefore, it is necessary to improve various properties of the compound, and intensive research is needed to find a new crystal form with high purity and good physical and chemical stability.
Disclosure of Invention
The invention aims to provide a novel crystal form of a compound shown in a formula (I), which has good crystal form stability and chemical stability and can be better applied to clinic.
The invention provides a B crystal form of a compound shown as a formula (I), which is characterized in that: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 4.52, 9.215, 13.92, 14.98, 18.62, 23.99, and 32.822.
In a preferred embodiment, the present invention provides a crystalline form B of a compound of formula (I) characterized by: using Cu-K alpha radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 theta angles, having characteristic peaks at 2 theta angles of 4.52, 9.215, 13.92, 14.98, 18.62, 23.28, 23.99, 28.63, 32.822 and 33.33.
In a preferred embodiment, the present invention provides a compound of formula (I) in form B, characterized in that: using Cu-ka radiation, an X-ray powder diffraction pattern expressed in diffraction angle 2 θ angles was obtained with characteristic peaks at 2 θ angles of 4.52, 9.215, 13.92, 14.98, 18.62, 19.47, 23.28, 23.99, 28.63, 32.822, 33.33, 37.825, and 38.31.
In a preferred embodiment, the present invention provides a compound of formula (I) in form B, characterized in that: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 1.
The present invention further provides a process for preparing form B of a compound of formula (I), said process comprising:
(1) Dissolving a compound shown in a formula (I) in a proper amount of solvent, and volatilizing and crystallizing to obtain a target crystal form B, wherein the solvent can be one or more of methanol, ethanol, isopropanol and water; or
(2) And secondly, dissolving the compound shown in the formula (I) in a proper amount of good solvent, adding anti-solvent for crystallization, filtering and crystallizing to obtain the target B crystal form, wherein the good solvent can be one or more of acetic acid, ethanol and isopropanol, and the anti-solvent can be one or more of petroleum ether, cyclohexane, n-heptane and n-hexane.
In another aspect, the present invention provides a crystalline form C of a compound of formula (I), wherein: using Cu-K alpha radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 theta angles with characteristic peaks at 2 theta angles of 8.735, 9, 15.04, 15.66, 17.79, 18.992 and 20.365.
In a preferred embodiment, the present invention provides a crystalline form C of a compound of formula (I) characterized by: using Cu-K α radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 8.735, 9, 15.04, 15.66, 17.79, 18.992, 20.365, 22.837, 23.975, 24.433, 27.517, 29.48 and 30.274.
In a preferred embodiment, the present invention provides a crystalline form C of a compound of formula (I) characterized by: using Cu-ka radiation, an X-ray powder diffraction pattern expressed in diffraction angle 2 θ degrees was obtained with characteristic peaks at 2 θ angles of 8.735, 9, 15.04, 15.66, 17.79, 18.992, 20.365, 22.145, 22.837, 23.975, 24.433, 27.517, 29.48, 30.274, 30.735, 31.688, 33.19, 35.715 and 44.893.
In a preferred embodiment, the present invention provides a crystalline form C of the compound of formula (I) characterized in that: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 2.
The present invention further provides a process for preparing form C of the compound of formula (I), the process comprising:
dissolving the compound shown in the formula (I) in a proper amount of good solvent, adding anti-solvent for crystallization, filtering and crystallizing to obtain the target C crystal form, wherein the good solvent can be dioxane, and the anti-solvent can be one or more of petroleum ether, cyclohexane, n-heptane and n-hexane.
In another aspect, the present invention provides a crystalline form D of a compound of formula (I), wherein: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 theta angles, with characteristic peaks at 2 theta angles of 6.715, 10.109, 13.515, 13.925, 14.78 and 16.28.
In a preferred embodiment, the present invention provides a crystalline form D of a compound of formula (I) characterized in that: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 theta angles with characteristic peaks at 2 theta angles of 6.715, 10.109, 13.515, 13.925, 14.78, 16.28, 20.815, 23.255 and 24.695.
In a preferred embodiment, the present invention provides a crystalline form D of a compound of formula (I) characterized in that: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ angles, with characteristic peaks at 2 θ angles of 6.715, 10.109, 13.515, 13.925, 14.78, 16.28, 16.96, 20.815, 23.255, 24.695, 26.23 and 26.714.
In a preferred embodiment, the present invention provides a crystalline form D of a compound of formula (I) characterized in that: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 3.
The present invention further provides a process for preparing form D of a compound of formula (I), said process comprising:
dissolving the compound shown in the formula (I) in a proper amount of good solvent, adding an anti-solvent for crystallization, filtering and crystallizing to obtain a target D crystal form, wherein the good solvent can be one or more of tetrahydrofuran, dichloromethane, acetone, dioxane, acetonitrile, N-dimethylformamide, acetic acid, methyl isobutyl ketone, ethyl acetate, methanol, ethanol and isopropanol, and the anti-solvent can be one or more of water, petroleum ether, cyclohexane, N-heptane and N-hexane.
In another aspect, the present invention provides a crystalline form E of a compound of formula (I), wherein: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 7.29, 10.985, 12.425, 14.765, 15.855, 19.42 and 21.89.
In a preferred embodiment, the present invention provides a crystalline form E of a compound of formula (I) characterized by: using Cu-ka radiation, an X-ray powder diffraction pattern expressed in diffraction angle 2 theta angles was obtained with characteristic peaks at 2 theta angles of 6.705, 7.29, 10.985, 12.425, 14.765, 15.855, 18.555, 19.42, 21.89, 22.98 and 26.725.
In a preferred embodiment, the present invention provides a crystalline form E of a compound of formula (I) characterized by: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 6.705, 7.29, 10.985, 12.425, 14.765, 15.855, 17.76, 18.555, 19.42, 21.89, 22.98, 26.725, 28.48 and 38.12.
In a preferred embodiment, the present invention provides a crystalline form E of a compound of formula (I) characterized in that: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 4.
The present invention further provides a process for preparing form E of the compound of formula (I), comprising:
the target E crystal form is obtained by dissolving the compound shown in the formula (I) in ethanol, cooling and crystallizing, and filtering.
In certain embodiments, the reduced temperature crystallization temperature is less than 10 ℃.
In another aspect, the present invention provides a crystalline form F of a compound of formula (I), characterized in that: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ angles, having characteristic peaks at 2 θ angles of 6.24, 12.52, 15.43, 15.885, 18.44, and 21.59.
In a preferred embodiment, the present invention provides a crystalline form F of a compound of formula (I) characterized by: using Cu-K α radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, having characteristic peaks at 2 θ angles of 6.24, 9.436, 12.52, 13.895, 15.43, 15.885, 18.44, 21, 21.59, and 37.705.
In a preferred embodiment, the present invention provides a crystalline form F of a compound of formula (I) characterized in that: using Cu — K α radiation, an X-ray powder diffraction pattern expressed in diffraction angle 2 θ degrees was obtained, which had characteristic peaks at 2 θ angles of 6.24, 9.436, 12.52, 13.895, 15.43, 15.885, 16.912, 18.44, 21, 21.59, 22.47, 31.084, 37.705, and 39.28.
In a preferred embodiment, the present invention provides a crystalline form F of a compound of formula (I) characterized by: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 5.
The present invention further provides a process for preparing form F of the compound of formula (I), which process comprises:
the target F crystal form is obtained by dissolving the compound shown in the formula (I) in ethyl acetate, cooling and crystallizing, and filtering.
In certain embodiments, the reduced temperature crystallization temperature is less than 10 ℃.
In another aspect, the invention provides a crystal form G of a compound of formula (I), wherein: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 theta angles, with characteristic peaks at 2 theta angles of 7.889, 8.832, 13.375, 14.58, 15.9, 17.834 and 18.865.
In a preferred embodiment, the present invention provides in a further aspect a crystalline form G of a compound of formula (I) characterized in that: using Cu-ka radiation, an X-ray powder diffraction pattern expressed in diffraction angle 2 θ angles was obtained with characteristic peaks at 2 θ angles of 7.889, 8.832, 13.375, 14.58, 15.9, 17.834, 18.865, 20.545, 21.265, 23.005 and 25.156.
In a preferred embodiment, the present invention provides a crystalline form G of a compound of formula (I) characterized by: using Cu-ka radiation, an X-ray powder diffraction pattern is obtained expressed in terms of diffraction angle 2 θ, having characteristic peaks at 2 θ angles of 7.889, 8.832, 13.375, 14.58, 15.9, 17.834, 18.865, 20.545, 21.265, 23.005, 25.156, 25.975 and 26.784.
In a preferred embodiment, the present invention provides a crystalline form G of a compound of formula (I) characterized in that: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 6.
The present invention further provides a process for preparing crystalline form G of a compound of formula (I), said process comprising:
dissolving the compound shown in the formula (I) in dimethyl sulfoxide, and volatilizing and crystallizing to obtain a target G crystal form.
In another aspect, the present invention provides a crystalline form H of a compound of formula (I), characterized in that: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 6.48, 13.165, 15.68, 16.535, 18.96, 22.2 and 22.65.
In a preferred embodiment, the present invention provides in a further aspect a crystalline form H of a compound of formula (I) characterized in that: using Cu-K α radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 6.48, 9.815, 13.165, 15.68, 16.535, 18.96, 19.879, 20.975, 22.2, 22.65, 25.489 and 26.655.
In a preferred embodiment, the present invention provides a crystalline form H of a compound of formula (I) characterized in that: using Cu-K α radiation, an X-ray powder diffraction pattern was obtained, expressed in terms of diffraction angle 2 θ, having characteristic peaks at 2 θ angles of 6.48, 9.815, 13.165, 15.68, 16.535, 18.96, 19.879, 20.975, 22.2, 22.65, 24.454, 25.489, 26.655, 27.982, 28.75 and 31.635.
In a preferred embodiment, the present invention provides a crystalline form H of a compound of formula (I) characterized in that: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 7.
The present invention further provides a process for preparing the H crystalline form of the compound of formula (I), which process comprises:
the D crystal form of the compound shown in the formula (I) is placed in water for crystal transformation to obtain a target H crystal form.
The invention further relates to a pharmaceutical composition, which comprises one or more of crystal forms B, C, D, E, F, G and H of the compound shown in the formula (I), and one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to a pharmaceutical composition, which is prepared by mixing one or more crystal forms of B, C, D, E, F, G and H of the compound shown in the formula (I) with one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to a preparation method of a pharmaceutical composition containing the compound shown in the formula (I) or pharmaceutically acceptable salts thereof, which comprises the step of mixing one or more crystal forms of B, C, D, E, F, G and H of the compound shown in the formula (I) with one or more pharmaceutically acceptable carriers, diluents or excipients.
The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. For example, the crystalline form or pharmaceutical preparation of the present invention may be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated solutions for injection), suppositories, inhalants or sprays.
The invention further relates to the application of the crystal forms B, C, D, E, F, G and H of the compound shown in the formula (I) or the pharmaceutical composition in the preparation of medicines for treating diseases related to androgen receptors; the disease is preferably prostate cancer.
The crystal form obtained by the invention is subjected to structure determination and crystal form research through X-ray powder diffraction pattern (XRPD) and Differential Scanning Calorimetry (DSC).
The crystallization method of the crystal form in the invention is conventional, such as volatile crystallization, cooling crystallization or room temperature crystallization.
The starting materials used in the preparation method of the crystal form of the invention can be compounds represented by formula (I) in any form, and specific forms include but are not limited to: amorphous, random crystalline, and the like.
In the description and claims of this application, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The 'pulping' in the invention refers to a method for purifying by utilizing the characteristics that a substance has poor solubility in a solvent but impurities have good solubility in the solvent, and the pulping purification can remove color, change crystal forms or remove a small amount of impurities.
The "X-ray powder diffraction pattern or XRPD" according to the present invention refers to a pattern obtained by dividing the X-ray powder according to bragg formula 2d sin θ = n λ (where λ is the wavelength of X-rays,
the order n of diffraction is any positive integer, typicallyTaking the first-order diffraction peak, n = 1), when the X-ray is incident on an atomic plane with d lattice plane spacing of a crystal or a part of a crystal sample at a grazing angle θ (complementary angle of incidence, also called bragg angle), the bragg equation is satisfied, and the set of X-ray powder diffraction patterns is measured.
The differential scanning calorimetry or DSC in the invention refers to measuring the temperature difference and the heat flow difference between a sample and a reference substance in the process of heating or keeping constant temperature of the sample so as to represent all physical changes and chemical changes related to the heat effect and obtain the phase change information of the sample.
The 2 theta or 2 theta angle refers to a diffraction angle, theta is a Bragg angle and has the unit of DEG or degree, and the error range of 2 theta is +/-0.3 or +/-0.2 or +/-0.1.
The "interplanar spacing or interplanar spacing (d value)" referred to herein means that the spatial lattice selects 3 non-parallel unit vectors a, b, c connecting two adjacent lattice points, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. The space lattice is divided according to the determined parallelepiped unit connecting lines to obtain a set of linear grids called space lattice or lattice. The lattice and the crystal lattice respectively reflect the periodicity of the crystal structure by using geometrical points and lines, and the surface spacing (namely the distance between two adjacent parallel crystal surfaces) of different crystal surfaces is different; has a unit of
Or angstroms.
Advantageous effects of the invention
The compound shown in the formula (I) prepared by the invention has high purity of crystal forms B, C, D, E, F, G and H, and good stability of the crystal forms under the conditions of illumination, high temperature and high humidity; the HPLC purity change is small, the chemical stability is high, the dissolution rate in a solvent is higher than that of the existing crystal form, and the effect of the medicine is better played; the B, C, D, E, F, G and H crystal forms of the compound shown in the formula (I) can meet the medicinal requirements of production, transportation and storage, the production process is stable, repeatable and controllable, and the method can be suitable for industrial production.
Drawings
FIG. 1 is an XRPD pattern for form B of compound represented by formula (I);
FIG. 2 is an XRPD pattern for crystalline form C of compound represented by formula (I);
FIG. 3 is an XRPD pattern for form D of compound of formula (I);
FIG. 4 is an XRPD pattern for crystalline form E of compound represented by formula (I);
FIG. 5 is an XRPD pattern for crystalline form F of compound represented by formula (I);
FIG. 6 is an XRPD pattern for crystalline form G of compound represented by formula (I);
FIG. 7 is an XRPD pattern for form H of compound represented by formula (I);
FIG. 8 is a DSC of crystalline form B of compound represented by formula (I);
FIG. 9 is a DSC of crystalline form C of compound represented by formula (I);
FIG. 10 is a DSC of crystalline form D of compound represented by formula (I);
FIG. 11 is a DSC of crystalline form E of compound represented by formula (I);
FIG. 12 is a DSC spectrum of crystalline form F of compound represented by formula (I);
FIG. 13 is a DSC of crystalline form G of compound represented by formula (I);
FIG. 14 is a DSC of the crystal form H of the compound of formula (I).
FIG. 15 is the dissolution curves of crystal forms B, D, H and I SGF physiological medium
FIG. 16 is the dissolution curve of FESSIF physiological medium in crystal form B, D, H and I
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Test conditions of the apparatus used for the test:
1. differential Scanning Calorimeter (DSC)
The instrument model is as follows: mettlerToledo DSC 3 + STAR e System
And (3) purging gas: nitrogen gas
The heating rate is as follows: 10.0 ℃/min
Temperature range: 25-300 deg.C
2. X-ray Diffraction Spectroscopy (XRPD)
The instrument model is as follows: bruker D8 Discover A25X-ray powder diffractometer
Ray: monochromatic Cu-ka radiation (λ = 1.5406)
The scanning mode comprises the following steps: θ/2 θ, scan range: 4-60 degree
Voltage: 40KV, current: 40mA of
Example 1
Weighing 150mg of the I crystal form of the compound shown in the formula (I) (prepared according to the method disclosed in WO 2017041622) and placing the I crystal form into a reaction bottle, adding 6ml of ethanol for dissolving, then adding 30ml of petroleum ether, standing for 30min at room temperature, and filtering to obtain the B crystal form of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 1, the DSC pattern is shown in figure 8, and the characteristic peak positions are shown in the following table:
TABLE 1 characteristic peaks of form B
Example 2
Weighing 150mg of the crystal form I of the compound shown in the formula (I), putting the crystal form I into a reaction bottle, adding 0.5ml of dioxane for dissolving, adding 5ml of n-hexane, standing at room temperature for 6 hours, and filtering to obtain the crystal form C of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 2, the DSC pattern is shown in figure 9, and the characteristic peak positions are shown in the following table:
TABLE 2C Crystal form characteristic peaks
Example 3
Weighing 150mg of the crystal form I of the compound shown in the formula (I), putting the crystal form I into a reaction bottle, adding 0.5ml of acetonitrile, dissolving, adding 5ml of water, standing for 1h at room temperature, and filtering to obtain the crystal form D of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 3, the DSC pattern is shown in figure 10, and the characteristic peak positions are shown in the following table:
TABLE 3 characteristic peaks of the D crystal form
Example 4
Weighing 100mg of the crystal form I of the compound shown in the formula (I) and placing the crystal form I into a reaction bottle, adding 3ml of ethanol, stirring and dissolving at room temperature, cooling to-5 ℃ for crystallization, and filtering to obtain the crystal form E of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 4, the DSC pattern is shown in figure 11, and the characteristic peak positions are shown in the following table:
TABLE 4 characteristic peaks of the E crystal form
Example 5
Weighing 180mg of crystal form I of the compound shown in the formula (I) and placing the crystal form I into a reaction bottle, adding 1.1ml of ethyl acetate, stirring and dissolving at room temperature, cooling to-5 ℃ for crystallization, and filtering to obtain the crystal form F of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 5, the DSC pattern is shown in figure 12, and the characteristic peak positions are shown in the following table:
TABLE 5 characteristic peaks of the F crystal form
Example 6
Weighing 100mg of the crystal form I of the compound shown in the formula (I) and placing the crystal form I into a reaction bottle, adding 0.3ml of DMSO, dissolving, and placing the mixture at room temperature in an open manner until the solvent is completely volatilized to obtain the crystal form G of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 6, the DSC pattern is shown in figure 13, and the characteristic peak positions are shown in the following table:
TABLE 6 characteristic peaks of the G crystal form
Example 7
100mg of the crystal form D of the compound represented by the formula (I) obtained in example 3 is weighed and placed into a reaction bottle, 3ml of water is added, stirring is carried out at room temperature overnight, and filtering is carried out, so as to obtain the crystal form H of the compound represented by the formula (I). The X-ray diffraction pattern is shown in figure 7, the DSC pattern is shown in figure 14, and the characteristic peak positions are shown in the following table:
TABLE 7 characteristic peaks of the H crystal form
Example 8
And carrying out physical stability tests on the samples of the crystal forms B, C, D, E, F and H under different standing conditions. The placing conditions are as follows:
1. opening at 40 ℃ and humidity of 75 percent;
2. opening at 25 ℃ and humidity of 60%;
3. sealing at 5 ℃;
4. lighting and opening.
The test results are shown in Table 8.
TABLE 8 physical stability of the respective forms
Note: v represents that the crystal form is not changed; and x represents the change of the crystal form.
As can be seen from the table: the crystal forms C, E and F are transformed at 1 week, and the physical stability is poor; the stability of the crystal forms B, D and H is not changed within 1 month, and the physical stability is good.
Example 9
The samples of the three crystal forms B, D and H were placed under different humidity conditions to test chemical stability, and the results are shown in Table 9. The purity of the crystal form is detected by HPLC, the detection condition is Kromasil 100-5C18 (4.6 mm multiplied by 25cm,5 mu m), and the mobile phase: methanol/water, detection wavelength: 230nm.
TABLE 9 chemical stability of the respective forms
As can be seen from Table 9, the purity of the B, D and H crystal forms is high, and the purity is not reduced basically under various conditions, and the stability is good.
Example 10
Respectively weighing 20mg of B, D, H and I crystal forms of samples, placing the B, D, H and I crystal forms in an inherent dissolution rate metal module, keeping the temperature for 30s under the condition of 20 pounds of pressure, respectively adding 20ml of SGF (simulated gastric juice)/FESSIF (simulated feeding state intestinal juice) physiological medium, keeping the temperature at 37 ℃ and keeping the whole process at 100rpm, then respectively taking 0.5ml of solution and filtering the solution by using a 0.22um water phase microfiltration membrane for 5 min, 15 min, 30min, 45 min, 60 min, 90 min and 120min, simultaneously supplementing 0.5ml of the same physiological medium, and measuring the concentration according to an HPLC content measurement method. The results are shown in FIGS. 15 and 16.
The results show that: D. the dissolution rate of the H crystal form is basically the same as that of the I crystal form in SGF, and the dissolution rate of the B crystal form is obviously higher than that of the I crystal form. The dissolution rates of the crystal forms B, D and H are obviously faster than those of the crystal form I in FESSIF physiological medium, the dissolution rates of the crystal form D and the crystal form H are very close, and the dissolution rate of the crystal form B is higher than those of the crystal form D and the crystal form H.
Claims (11)
1. A crystalline form D of a compound of formula (I), characterized in that: using Cu-Ka radiation, an X-ray powder diffraction pattern expressed in diffraction angle 2 theta angles is obtained, which has characteristic peaks at 2 theta angles of 6.715, 10.109, 13.515, 13.925, 14.78 and 16.28,
2. form D according to claim 1, characterized in that: using Cu-Ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 6.715, 10.109, 13.515, 13.925, 14.78, 16.28, 20.815, 23.255 and 24.695.
3. Form D according to claim 1, characterized in that: using Cu-Ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, having characteristic peaks at 2 θ angles of 6.715, 10.109, 13.515, 13.925, 14.78, 16.28, 16.96, 20.815, 23.255, 24.695, 26.23, and 26.714.
4. Form D according to claim 1, characterized in that: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 3.
5. A crystalline form of the compound of formula (I) according to any one of claims 1 to 4, characterized in that: the error range of the 2 theta angle is +/-0.2.
6. A pharmaceutical composition comprising the crystalline form D of the compound of formula (I) as claimed in claims 1-5, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
7. A pharmaceutical composition prepared by mixing the form D of the compound of formula (I) as described in claims 1-5 with one or more pharmaceutically acceptable carriers, diluents or excipients.
8. A process for the preparation of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises mixing form D of a compound of formula (I) as claimed in claims 1-5 with one or more pharmaceutically acceptable carriers, diluents or excipients.
9. A process for preparing form D of the compound of formula (I) as claimed in claims 1-5, comprising: dissolving the compound shown in the formula (I) in a proper amount of good solvent, adding an anti-solvent for crystallization, and filtering and crystallizing, wherein the good solvent is selected from one or more of tetrahydrofuran, dichloromethane, acetone, dioxane, acetonitrile, N-dimethylformamide, acetic acid, methyl isobutyl ketone, ethyl acetate, methanol, ethanol and isopropanol, and the anti-solvent is selected from one or more of water, petroleum ether, cyclohexane, N-heptane and N-hexane.
10. Use of the crystalline form D of the compound of formula (I) according to claims 1 to 5 or the pharmaceutical compositions according to claims 6 and 7 for the preparation of a medicament for the treatment of diseases related to androgen receptors.
11. The use according to claim 10, wherein the disease is selected from prostate cancer.
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| CN106518773A (en) * | 2015-09-10 | 2017-03-22 | 江苏恒瑞医药股份有限公司 | Crystalline form of androgen receptor inhibitor and preparation method thereof |
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| CN106518773A (en) * | 2015-09-10 | 2017-03-22 | 江苏恒瑞医药股份有限公司 | Crystalline form of androgen receptor inhibitor and preparation method thereof |
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| CN112300076A (en) | 2021-02-02 |
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