WO2022036782A1 - Crystal form csvi of androgen receptor antagonist drug, and preparation method therefor and use thereof - Google Patents

Abstract

A new crystal form of an androgen receptor antagonist compound I and a preparation method therefor, a pharmaceutical composition containing the crystal form, and the use of the crystal form in the preparation of a drug for treating prostate cancer. Compared with the prior art, the new crystal form of an androgen receptor antagonist has one or more improved properties, thereby having a significant value in the optimization and development drugs in the future.

Description

Crystal form CSVI of an androgen receptor antagonist drug and its preparation method and use technical field

The present invention relates to the technical field of drug crystals. Specifically, it relates to a crystal form of an androgen receptor antagonist drug and its preparation method and use.

Background technique

Prostate cancer has become an important disease threatening men's health. Androgens are closely related to the growth of the prostate and the occurrence of prostate cancer. Blocking androgens has become an effective way to treat prostate cancer. According to the receptor theory, androgen must bind with androgen receptor (AR) to cause subsequent physiological and pathological effects, which lays a theoretical foundation for the application of androgen receptor (AR) antagonists in the treatment of prostate cancer. AR can be divided into steroidal and non-steroidal AR antagonists according to chemical structure. Non-steroidal drugs have better anti-androgen activity and are more suitable for the treatment of prostate cancer.

ODM-201 (BAY-1841788) is a non-steroidal oral androgen receptor (AR) antagonist clinically studied for the treatment of prostate cancer. ODM-201 has a high affinity and inhibitory effect on AR, and does not cross the blood-brain barrier, which can reduce neurological-related side effects such as epilepsy.

The chemical name of ODM-201 is: 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 number is 1297538-32-9, the structural formula of ODM-201 (hereinafter referred to as "Compound I") is as follows:

A crystal is a solid material whose constituent components are highly ordered in the microstructure, forming a lattice of crystals extending in all directions. Drug polymorphism refers to the existence of two or more different crystal forms of a drug. Due to different physical and chemical properties, different crystal forms of drugs may have different dissolution and absorption in the body, thereby affecting the clinical efficacy and safety of drugs to a certain extent; especially for poorly soluble solid drugs, the crystal form will have a greater impact. Therefore, drug crystal form must be an important content of drug research and also an important content of drug quality control.

The inventors of the present application have discovered the crystalline form CSVI of Compound I, which has advantages in physicochemical properties, preparation processability, and bioavailability, such as melting point, solubility, hygroscopicity, purification, stability, adhesion, bioavailability, etc. There are advantages in at least one aspect of compressibility, fluidity, dissolution in vitro and in vivo, bioavailability, etc., which provides a new and better choice for the development of drugs containing ODM-201, which is of great significance.

SUMMARY OF THE INVENTION

The main purpose of the present invention is to provide a new crystal form of ODM-201 and its preparation method and use.

According to the purpose of the present invention, the present invention provides the crystal form CSVI of ODM-201 (hereinafter referred to as "crystal form CSVI").

In one aspect, using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form CSVI has characteristic peaks at diffraction angles 2θ of 11.6°±0.2°, 12.7°±0.2°, 15.9°±0.2°.

Further, the X-ray powder diffraction of the crystalline form CSVI is characterized at one, or two, or three of the diffraction angles 2θ of 9.0°±0.2°, 17.0°±0.2°, 21.4°±0.2° Peak; preferably, the X-ray powder diffraction of the crystalline form CSVI has characteristic peaks at 3 positions in the diffraction angle 2θ value of 9.0°±0.2°, 17.0°±0.2°, and 21.4°±0.2°.

Further, the X-ray powder diffraction of the crystal form CSVI has characteristic peaks at 1 or 2 places in the diffraction angle 2θ of 25.8°±0.2°, 26.9°±0.2°; preferably, the crystal form CSVI There are characteristic peaks at 2 places in the diffraction angle 2θ value of 25.8°±0.2° and 26.9°±0.2° in the X-ray powder diffraction of .

On the other hand, using Cu-Kα radiation, the X-ray powder diffraction of the crystalline form CSVI has diffraction angle 2θ values of 9.0°±0.2°, 11.6°±0.2°, 12.7°±0.2°, 15.9°±0.2°, 17.0°±0.2°, 18.8°±0.2°, 21.4°±0.2°, 25.8°±0.2°, 26.9°±0.2° any 3 places, or 4 places, or 5 places, or 6 places, or 7 places , or 8, or 9 with characteristic peaks.

Without limitation, the X-ray powder diffraction pattern of the crystalline form CSVI is substantially as shown in FIG. 1 .

According to the purpose of the present invention, the present invention also provides a preparation method of the crystal form CSVI, the preparation method comprises: dissolving ODM-201 in tetrahydrofuran, adding an alkane solvent as an anti-solvent, stirring, centrifuging and drying to obtain a crystal Type CSVI.

Further, the alkane solvent is preferably n-heptane.

According to the purpose of the present invention, the present invention also provides a pharmaceutical composition comprising an effective therapeutic amount of the crystal form CSVI and a pharmaceutically acceptable carrier, diluent or adjuvant.

Further, the present invention provides the use of crystal form CSVI in the preparation of androgen receptor antagonist medicine.

Further, the present invention provides the use of the crystalline form CSVI in the preparation of a drug for the treatment of cancer.

Further, the present invention provides the use of crystal form CSVI in the preparation of a medicament for the treatment of prostate cancer.

In the present invention, the "stirring" is accomplished by conventional methods in the field, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein, the magnetic stirring is preferably 300-900 rev/min, and the mechanical stirring Preferably it is 100-300 rpm.

The "drying" can be carried out at room temperature or higher. The drying temperature is room temperature to about 60°C, or to 50°C, or to 40°C. Drying time can be 2-48 hours. Drying takes place in a fume hood, blast oven or vacuum oven.

In the present invention, "crystalline" or "polymorphic form" refers to those confirmed by X-ray powder diffraction pattern characterization. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized with experimental error depending on the conditions of the instrument, the preparation of the sample, and the purity of the sample. In particular, it is well known to those skilled in the art that X-ray powder diffraction patterns generally vary with instrument conditions. In particular, it should be pointed out that the relative intensities of diffraction peaks in X-ray powder diffraction patterns may also vary with experimental conditions, so the order of diffraction peak intensities cannot be used as the only or decisive factor. In fact, the relative intensities of diffraction peaks in X-ray powder diffraction patterns are related to the preferred orientation of the crystals, and the diffraction peak intensities shown here are illustrative and not for absolute comparison. In addition, the experimental error of the diffraction 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. In addition, due to the influence of experimental factors such as sample thickness, the overall shift of the diffraction peak angle will be caused, and a certain shift is usually allowed. Therefore, those skilled in the art can understand that the X-ray powder diffraction pattern of a crystal form in the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to here, and any X-ray powder diffraction pattern with characteristic peaks in these patterns Crystal forms with the same or similar X-ray powder diffraction patterns all fall within the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with an X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of images reflect the same or different crystal forms.

In some embodiments, the crystalline form CSVI of the present invention is pure, substantially free from admixture with any other crystalline forms. In the present invention, "substantially free" when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.

The term "about" in the present invention, when used to refer to measurable values, such as the quality of compounds and preparations, time, temperature, etc., means that there may be a certain range around the specific value, and the range may be ±10% , ±5%, ±1%, ±0.5%, or ±0.1%.

Description of drawings

1 is an XRPD pattern of the crystalline form CSVI obtained according to Example 1.

FIG. 2 is the XRPD pattern of the crystalline form CSVI obtained according to Example 2. FIG.

detailed description

The present invention will be described in detail with reference to the following examples, which describe in detail the preparation and use methods of the crystal forms of the present invention. It will be apparent to those skilled in the art that many changes in both materials and methods can be practiced without departing from the scope of the present invention.

The abbreviations used in the present invention are explained as follows:

XRPD: X-ray Powder Diffraction.

DSC: Differential Scanning Calorimetry

TGA: Thermogravimetric Analysis

Instruments and methods used to collect data:

The X-ray powder diffraction pattern of the present invention was collected on a Bruker D8 X-ray powder diffractometer. The method parameters of X-ray powder diffraction of the present invention are as follows:

X-ray reflection parameters: Cu, Kα

1.54056;

1.54439

Kα2/Kα1 intensity ratio: 0.50

Voltage: 45 thousand volts (kV)

Current: 40 milliamps (mA)

Scanning range: from 4.0 to 40.0 degrees

Differential Scanning Calorimetry (DSC) graphs according to the present invention were collected on a TA Q2000. The method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:

Scanning rate: 10°C/min unless otherwise specified

Shielding gas: N ₂

Thermogravimetric analysis (TGA) plots described in the present invention were collected on a TA Q500. The method parameters of thermogravimetric analysis (TGA) of the present invention are as follows:

Scan rate: 10°C/min

Shielding gas: N ₂

Unless otherwise specified, the following examples are operated at room temperature. The "room temperature" is not a specific temperature value, but refers to a temperature range of 10-30°C.

According to the present invention, the ODM-201 as a raw material is in the form of solid (crystalline or amorphous), semi-solid, wax or oil. Preferably, the ODM-201 as a raw material is in the form of solid powder.

The ODM-201 used in the following examples can be prepared according to the prior art, for example, according to the method described in CN102596910B.

detailed description

Examples 1-2: Preparation method of crystal form CSVI

Example 1

Weigh 501mg of solid ODM-201 into 10.0mL of tetrahydrofuran solvent, dissolve at 50°C, cool to -5°C and add 5mL of n-heptane, add seed crystals, then slowly add 15mL of n-heptane, stir at -5°C for 2 hours , centrifugation, and vacuum drying at 30° C. to obtain the crystal form CSVI of the present invention.

The XRPD diagram of the crystal form CSVI obtained in this example is shown in FIG. 1 , and the XRPD data is shown in Table 1.

Table 1

Diffraction angle 2θ	d value	strength%
8.46	10.46	3.18
8.95	9.88	22.68
11.62	7.62	100.00
12.73	6.95	32.46
15.87	5.59	56.50
16.46	5.38	8.23
17.03	5.21	70.06
18.01	4.93	19.64
18.82	4.72	38.78
20.74	4.28	11.33
21.35	4.16	60.32
22.38	3.97	9.59
22.82	3.90	27.51
23.67	3.76	19.35
24.40	3.65	12.03
24.99	3.56	17.12
25.77	3.46	42.99
26.89	3.32	28.02
27.82	3.21	7.87
30.11	2.97	5.15
32.42	2.76	5.17
34.23	2.62	2.27
35.44	2.53	3.24
39.03	2.31	1.35

Example 2

Weigh 501 mg of ODM-201 solid and add it to 6.0 mL of tetrahydrofuran solvent and dissolve it at room temperature, pre-cool 12 mL of n-heptane at 5 °C and add seed crystals, slowly add the tetrahydrofuran solution dissolved in ODM-201, and stir at 5 °C for 1 hour, Centrifuge and vacuum dry at 30° C. to obtain the crystal form CSVI of the present invention.

The XRPD diagram of the crystal form CSVI obtained in this example is shown in FIG. 2 , and the XRPD data is shown in Table 2.

Table 2

Diffraction angle 2θ	d value	strength%
9.00	9.83	23.98
11.62	7.62	100.00
12.72	6.96	20.75
15.87	5.58	66.20
17.02	5.21	49.07
18.04	4.92	22.53
18.79	4.72	42.98
21.39	4.15	54.20
22.81	3.90	36.22
25.74	3.46	47.16
26.86	3.32	35.32
32.47	2.76	5.79

Example 3: Dynamic Solubility of Crystal Form CSVI

Simulated gastrointestinal fluids such as SGF (simulated gastric fluid), FaSSIF (simulated fasting state intestinal fluid), FeSSIF (simulated fed state intestinal fluid) are biologically relevant media, which can better reflect the physiological environment of the gastrointestinal tract on drug release. The solubility tested in such media is closer to that in the human environment.

Take about 20 mg of the crystal form CSVI of the present invention and be suspended in 1.5 mL of SGF, 1.5 mL of FaSSIF, 1.5 mL of FeSSIF and 1.5 mL of water to prepare a suspension, equilibrate for 1 hour, 4 hours and 24 hours, respectively, use high-efficiency liquid The content (mg/mL) of the sample in the solution was tested by phase chromatography.

High solubility is beneficial to improve the absorption of drugs in the human body, improve bioavailability, and make drugs play a better therapeutic role; in addition, high solubility can reduce the dosage of drugs while ensuring the efficacy of drugs, thereby reducing the side effects of drugs and improve the safety of medicines.

Example 4: Intrinsic Dissolution Rate of Form CSVI

About 100 mg of the crystalline form CSVI was weighed, poured into the inherent dissolution mold, and held at a pressure of 5 kN for 1 min to make a sheet with a surface area of 0.5 cm ² , and the mold with the sheet was transferred to a dissolution apparatus to test the inherent dissolution rate.

Different crystal forms may lead to different dissolution rates of drugs in the body, which directly affect the absorption, distribution, metabolism, and excretion of drugs in the body, and ultimately lead to differences in clinical efficacy due to their different bioavailability. Dissolution rate is an important prerequisite for drug absorption. The high dissolution rate enables the drug to reach the highest concentration value in the plasma quickly after administration, thereby ensuring the rapid onset of the drug.

Example 5: Stability of Crystal Form CSVI

Weigh about 5 mg of the crystalline form CSVI prepared by the present invention, and place them under the conditions of 25°C/60%RH, 40°C/75%RH, 60°C/75%RH, and 80°C, respectively, and measure the purity and purity by HPLC and XRPD methods. crystal form.

The stability of the API under long-term conditions is beneficial to the storage of the drug. The stability of the drug substance under accelerated and more severe conditions is also critical to the drug. During the storage, transportation and production of APIs, high temperature and high humidity conditions will be encountered due to weather and seasonal differences, and climate differences in different regions. Stability under harsh conditions is beneficial to avoid the impact of deviation from the storage conditions on the label on the quality of the drug.

Example 6: Mechanical stability of crystalline form CSVI

Take an appropriate amount of crystal form CSVI, select a suitable tableting die, press and form under different pressures, and perform XRPD test before and after tableting.

The crystalline form CSVI was placed in a mortar and manually ground for 5 minutes, and XRPD tests were performed before and after grinding.

In the process of preparation processing, grinding, crushing and tableting of the API are often required. The physical stability of the crystal form under grinding and tableting conditions can reduce the risk of crystallinity change and crystal transformation of the API during the preparation process. The transformation of the crystal form will lead to changes in the absorption of the drug, affect the bioavailability, and even cause the toxic and side effects of the drug. Good chemical stability can ensure that basically no impurities are generated during storage. The crystal form has good physical and chemical stability, which can ensure the consistent and controllable quality of the raw material drug and the preparation, and minimize the drug quality change and bioavailability change caused by the crystal form change or the generation of impurities.

Example 7: Hygroscopicity of crystalline form CSVI

The hygroscopicity directly affects the physicochemical stability of the drug, and high hygroscopicity can easily cause chemical degradation and crystal transformation. In addition, high hygroscopicity will reduce the fluidity of the drug, thereby affecting the processing technology of the drug. Not only that, drugs with high hygroscopicity need to maintain low humidity during the production and storage process, which puts forward higher requirements for production and requires high costs. More importantly, high hygroscopicity can easily cause changes in the content of active ingredients in medicines, affecting the quality of medicines. The low hygroscopic crystal form does not have harsh environmental requirements, reduces the cost of material production, storage and quality control, and has strong economic value.

In accordance with the 2015 edition of the Chinese Pharmacopoeia General Chapter 9103, the hygroscopicity test of drugs, the hygroscopicity test experiment of crystal form CSVI was carried out. The experimental method is as follows:

1. Take a dry stoppered glass weighing bottle (outer diameter is 50mm, height is 15mm), and place it in a suitable 25℃±1℃ constant temperature desiccator one day before the test (the lower part is placed with ammonium chloride or ammonium sulfate saturated solution) Or in an artificial climate box (the set temperature is 25°C±1°C, and the relative humidity is 80%±2%), and the weight (m ₁ ) is precisely weighed.

2. Take an appropriate amount of the test product and spread it in the above weighing bottle. The thickness of the test product is generally about 1 mm, and the weight (m ₂ ) is precisely weighed.

3. Open the weighing bottle and place it together with the bottle cap under the above constant temperature and humidity conditions for 24 hours.

4. Close the lid of the weighing bottle and accurately measure the weight (m ₃ ).

Dynamic Moisture Sorption (DVS) Test Method:

Weigh about 10 mg of the crystal form CSVI of the present invention and use a dynamic moisture adsorption (DVS) instrument to test its hygroscopicity, cycle once under 0-95%-0 relative humidity, and record the mass change under each humidity.

About the description of hygroscopicity characteristics and the definition of hygroscopicity weight gain (Chinese Pharmacopoeia 2015 edition general rule 9103 Drug hygroscopicity test guidelines, experimental conditions: 25℃±1℃, 80% relative humidity):

Deliquescence: Absorbs sufficient water to form a liquid

Extremely hygroscopic: wet weight gain is not less than 15.0%

Moisture: Moisture gain is less than 15.0% but not less than 2.0%

Slightly hygroscopic: wet weight gain is less than 2.0% but not less than 0.2%

No or almost no hygroscopicity: wet weight gain is less than 0.2%

(The definition of hygroscopicity in 5.11 of the ninth edition of the European Pharmacopoeia is consistent with the Chinese Pharmacopoeia)

Example 8: Particle size distribution of crystal form CSVI

Take 10-30 mg of the prepared crystalline form CSVI, then add 10 mL of Isopar G (containing 0.2% lecithin), mix the sample to be tested well and add it into the SDC sampling system, make the sample size indicator reach the appropriate position, start In the experiment, the particle size distribution test was carried out to obtain the average particle size calculated by volume, the particle size corresponding to 10% in the particle size distribution (volume distribution), and the particle size distribution (volume distribution) corresponding to 50%. particle size.

Uniform particle size helps ensure content uniformity and reduces in vitro dissolution variability. At the same time, the preparation process can be simplified, no pretreatment of raw materials is required, cost is saved, and the risk of crystallinity reduction and crystal transformation that may be caused by grinding is also reduced.

Example 9: Flowability of Form CSVI

During the preparation process, the compressibility index or Carr index can usually be used to evaluate the fluidity of powder or intermediate particles. The measurement method is to gently load a certain amount of crystalline CSVI powder. Measure the initial loose volume after measuring the cylinder; use the tapping method to make the powder in the tightest state, and measure the final volume; calculate the bulk density ρ ₀ and tap density ρ _f ; According to the formula c=(ρ _f -ρ ₀ )/ρ _f Calculate the compressibility factor.

Refer to USP <1174> for the definition standard of compressibility coefficient for powder fluidity, see Table 5 for details.

table 5

Compressibility coefficient (%)	fluidity
≦10	excellent

11-15	Okay
16-20	generally
21-25	acceptable
26-31	Difference
32-37	very poor
>38	very poor

Example 10: Adhesion of Form CSVI

About 30 mg of crystalline form CSVI was added to an 8 mm round flat punch, and the tableting process was performed with a pressure of 10 kN. After tableting, it was held for about half a minute, and the amount of powder absorbed by the punch was weighed. After two consecutive pressings using this method, the accumulated final sticking amount of the punch, the highest sticking amount and the average sticking amount during the pressing process were recorded.

Good adhesion can effectively improve or avoid the sticking wheel, sticking and punching caused by dry granulation and tablet pressing, etc., which is beneficial to improve the appearance and weight difference of the product. Good adhesion can also effectively reduce the agglomeration of raw materials, facilitate the dispersion of raw materials and the mixing with other auxiliary materials, and ensure the mixing uniformity and content uniformity of the preparation.

Example 11: Formulation preparation of crystalline form CSVI

Tablet: Take an appropriate amount of crystal form CSVI, mix it evenly with the auxiliary materials, press it into flakes and pulverize it into granules, mix it evenly with the external auxiliary materials, and use a suitable mold to press and form.

Capsule: Take an appropriate amount of crystal form CSVI, mix it evenly with excipients, press it into flakes and pulverize it into granules, mix it evenly with external excipients, and fill it into capsules of suitable size.

Example 12: Stability in Form CSVI Formulations

The crystalline form CSVI preparation was packaged in HDPE bottles, placed under the conditions of 25°C/60%RH and 40°C/75%RH, and sampled to detect the crystalline form and impurities, and to investigate the formulation stability of the crystalline form CSVI.

Example 13: In vitro dissolution of crystalline form CSVI formulations

Tablets containing crystalline form CSVI were tested for dissolution in vitro, and the dissolution rate was determined according to the Chinese Pharmacopoeia 2015 Edition 0931 Dissolution and Release Determination Method.

Different crystal forms may lead to different dissolution rates of drugs in the body, which directly affect the absorption, distribution, metabolism, and excretion of drugs in the body, and ultimately lead to differences in clinical efficacy due to their different bioavailability. Dissolution is an important prerequisite for drug absorption. A good in vitro dissolution rate indicates that the drug has a higher degree of in vivo absorption and better in vivo exposure characteristics, thereby improving bioavailability and improving the efficacy of the drug.

The above-mentioned embodiments are only intended to illustrate the technical concept and characteristics of the present invention, and the purpose is to enable those who are familiar with the art to understand the content of the present invention and implement accordingly, and cannot limit the protection scope of the present invention by this. All equivalent changes or modifications made according to the spirit of the present invention should be included within the protection scope of the present invention.

Claims (9)

1. A crystal form CSVI of ODM-201, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has features at 2theta values of 11.6°±0.2°, 12.7°±0.2°, 15.9°±0.2° peak.
2. The crystalline form CSVI according to claim 1, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has 2 theta values of 9.0°±0.2°, 17.0°±0.2°, 21.4°±0.2° There are characteristic peaks at 1, 2, or 3 locations.
3. The crystalline form CSVI according to claim 1, characterized in that, using Cu-Kα radiation, its X-ray powder diffraction pattern has a 2 theta value of 25.8°±0.2°, 26.9°±0.2° at one or two locations has characteristic peaks.
4. A method for preparing crystal form CSVI according to claim 1, wherein the method comprises: dissolving ODM-201 in tetrahydrofuran, adding an alkane solvent as an anti-solvent, stirring, centrifuging and drying to obtain a white solid.
5. The preparation method according to claim 4, wherein the alkane solvent is n-heptane.
6. A pharmaceutical composition comprising an effective therapeutic amount of the crystal form CSVI described in claim 1 and a pharmaceutically acceptable carrier, diluent or adjuvant.
7. Use of the crystalline form CSVI according to claim 1 in the preparation of androgen receptor antagonist medicines.
8. Use of the crystal form CSVI of claim 1 in the preparation of a drug for treating cancer.
9. Use of the crystal form CSVI of claim 1 in the preparation of a medicament for the treatment of prostate cancer.

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