WO2021104021A1

WO2021104021A1 - New crystal form of tropifexor and preparation method therefor

Info

Publication number: WO2021104021A1
Application number: PCT/CN2020/128084
Authority: WO
Inventors: 张�杰; 廖伟龙; 邝润桥; 徐巾超; 陈勇; 罗忠华; 黄芳芳
Original assignee: 广东东阳光药业有限公司
Priority date: 2019-11-29
Filing date: 2020-11-11
Publication date: 2021-06-03
Also published as: CN114728955A

Abstract

Provided in the present invention are a new crystal form of Tropifexor and a preparation method therefor, which fall within the field of medicinal chemistry. The crystal form is crystal form I. The XRPD pattern of crystal form I includes characteristic peaks having the following 2θ (errors ± 0.2 degrees) values: 5.8, 6.7, 8.3, 10.5, 11.5, 13.0, 14.9, 15.6, 16.5, 20.5, 21.1, 24.8, 26.2 and 26.7 degrees. Crystal form I has good solubility and stability, is conducive to storage, transferring, and production process operations, and is suitable for being prepared into preparations.

Description

New crystal form of Tropifexor and its preparation method

Technical field

The invention belongs to the field of medicinal chemistry, and relates to a new crystal form of Tropifexor and a preparation method thereof.

Background technique

Tropifexor was originally developed by Novartis and then licensed to Pfizer for collaborative development. It is a non-steroidal FXR (farnesoid receptor) agonist, currently in clinical phase II of indications for NASH (non-alcoholic steatohepatitis), fatty liver and primary biliary cholangitis.

The structure of Tropifexor is shown in the following formula (1):

Drug polymorphism is a common phenomenon in drug development and an important factor affecting drug quality. Different crystal forms of the same drug may have significant differences in physical and chemical properties such as appearance, fluidity, solubility, storage stability, bioavailability, etc., and there may be great differences, which will affect the storage transfer, application, stability, and efficacy of the drug. In order to obtain an effective crystal form that is beneficial to the production or pharmaceutical preparations, it is necessary to conduct a comprehensive investigation of the crystallization behavior of the drug to obtain a crystal form that meets the production requirements.

At present, there is no literature that discloses the crystal form of Tropifexor, and there is no related literature report.

The present invention obtains a new crystal form of the compound through a large number of experimental studies on the Tropifexor compound. The new crystal form has the advantages of high solubility, good stability, low moisture absorption, simple preparation process and easy operation, etc., and has excellent properties in industrial production. Superiority.

Summary of the invention

The present invention aims to solve one of the technical problems in the related art at least to a certain extent. To this end, an object of the present invention is to provide a new crystal form of Tropifexor and a preparation method thereof, which has good solubility and stability.

According to one aspect of the present invention, the present invention provides a new crystal form of Tropifexor: crystal form I.

The new crystal form of the present invention was studied, and it was found that the crystal form I has good performance in terms of stability, solubility, etc., and can be used in the production of pharmaceutical preparations.

The crystal form I, by using an X-ray powder diffractometer using Cu-Kα radiation, its X-ray powder diffraction pattern has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle: 5.8, 6.7, 8.3, 10.5, 11.5, 13.0, 14.9, 15.6, 16.5, 20.5, 21.1,24.8, 26.2 and 26.7.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) : 12.5, 13.4, 17.3, 17.9, 18.4, 18.6, 20.1,21.9, 22.5, 23.3, 23.6, 23.9, 27.4, 28.8, 29.6 and 31.6.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form I has diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) ：5.8,6.7,8.3,10.5,11.5,12.5,13.0,13.4,14.9,15.6,16.5,17.3,17.9,18.4,18.6,20.1,20.5,21.1,21.9,22.5,23.3,23.6,23.9,24.8,26.2 , 26.7, 27.4, 28.8, 29.6 and 31.6.

In some embodiments, in the X-ray powder diffraction pattern of Tropifexor crystal form I, the relative intensity of the peak at 15.6 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%, or greater than 99%.

In some embodiments, the crystal form I has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 1.

In some embodiments, the differential scanning calorimetry (DSC) of the crystalline form I has an endothermic peak at 150°C to 200°C, and the peak temperature of the endothermic peak is at 180°C to 190°C.

In some embodiments, the crystalline form I has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 2.

In some embodiments, the crystalline form I has a thermogravimetric analysis curve (TGA) showing that there is a weight loss between 30°C and 200°C, and the weight loss is about 0.4%.

In some embodiments, the crystal form I has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 3.

Relative to Tropifexor, in some embodiments, the purity of the crystalline form I is at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99%. In some embodiments, relative to Tropifexor, the purity of the crystalline form I is at least 85%, or at least 90%, or at least 95%, or at least 99%.

The Tropifexor crystal form I of the present invention can be used to treat diseases such as NASH, fatty liver and primary biliary cholangitis.

Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of Tropifexor crystal form I and pharmaceutically acceptable auxiliary materials or excipients. Generally, a therapeutically effective amount of Tropifexor crystal form I is mixed or contacted with one or more pharmaceutical excipients to prepare a pharmaceutical composition or preparation, and the pharmaceutical composition or preparation is prepared in a well-known manner in the pharmaceutical field. The pharmaceutical composition or preparation can be used to treat diseases such as NASH, fatty liver, and primary biliary cholangitis.

The present invention provides a pharmaceutical composition, which may contain at least 0.1%-10% of the crystal form I of the total weight of the composition. The present invention provides a pharmaceutical composition, which may contain at least 0.1%-5% of the crystal form I of the total weight of the composition. The present invention provides a pharmaceutical composition, which may contain at least 0.1%-1% of the crystal form I of the total weight of the composition. In some embodiments, the present invention provides a pharmaceutical composition, which contains at least 0.1%-0.5% of the crystal form I of the total weight of the composition.

The pharmaceutical composition provided by the present invention contains Tropifexor, and at least 80% of the Tropifexor is the Tropifexor crystal form I according to the mass ratio. In some embodiments, a pharmaceutical composition contains Tropifexor, and at least 90% of Tropifexor is the Tropifexor crystal form I according to the mass ratio. In some embodiments, a pharmaceutical composition contains Tropifexor, and at least 95% of the Tropifexor is the Tropifexor crystal form I according to the mass ratio. In some embodiments, a pharmaceutical composition contains Tropifexor, and at least 99% of Tropifexor is the Tropifexor crystal form I according to the mass ratio.

Relative to Tropifexor, in some embodiments, the purity of crystal form I in the pharmaceutical composition is at least 80%. In some embodiments, relative to Tropifexor, the purity of the crystalline form I in the pharmaceutical composition is at least 85%, or at least 90%, or at least 95%, or at least 99%.

The pharmaceutical composition containing Tropifexor crystal form I of the present invention can be used to prepare pharmaceutical preparations for NASH, fatty liver, primary biliary cholangitis and the like. The pharmaceutical composition containing Tropifexor crystal form I of the present invention can be used in methods for treating diseases such as NASH, fatty liver, and primary biliary cholangitis.

The crystal form I provided by the invention has good stability and solubility, is not easy to deliquesce under high humidity conditions, is convenient for long-term storage and placement of drugs, and can well avoid drug storage and crystal transformation during the development process, thereby avoiding bioavailability As well as the change of drug efficacy, it has strong economic value.

According to the second aspect of the present invention, the present invention proposes a method for preparing the aforementioned Tropifexor crystal form I.

A method for preparing Tropifexor crystal form I includes: mixing Tropifexor with a good solvent, heating to complete dissolution, mixing with an anti-solvent, stirring to precipitate crystals, collecting crystals, and removing the solvent to obtain crystal form I.

In some embodiments, a method for preparing Tropifexor crystal form I includes: mixing Tropifexor with a good solvent, heating to a certain temperature to completely dissolve, adding an anti-solvent to the solution dropwise, stirring to precipitate crystals, and collecting Crystals, removing the solvent, and obtaining crystal form I. In some embodiments, a method for preparing Tropifexor crystal form I includes: mixing Tropifexor with a good solvent, heating to 40°C-80°C to completely dissolve it; then adding an anti-solvent at room temperature, stirring to precipitate crystals, The crystals are collected and the solvent is removed to obtain crystal form I.

The good solvent is ethanol, acetone or a combination thereof.

In some embodiments, when the mass of the good solvent is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of the Tropifexor to the good solvent is 1:2 to 1:50; more preferably It is 1:10～1:30.

The certain temperature is 40°C-80°C.

The anti-solvent is one of water and n-heptane.

The "crystal form" of the present invention can be present in the sample at 0.0001%-100%. Therefore, as long as the sample contains trace amounts, for example, greater than 0.0001%, greater than 0.001%, greater than 0.001% or greater than 0.01% of the present invention The "crystal form" of should be understood as falling within the protection scope of the present invention. In order to describe the various parameters of the "crystal form" described in the present invention more clearly, the present invention tests various parameters on a sample containing a certain "crystal form" that is substantially pure and carries out the determination of the crystal form. Characterization and identification.

In the context of the present invention, regardless of whether the words "about" or "about" are used, all numbers disclosed herein are approximate values. Based on the public figures, the value of each figure may differ by 1%, 2%, or 5%.

The differential scanning calorimetry (DSC) of the crystal form has experimental errors and is slightly affected by the dryness of the sample. Between one machine and another machine and between one sample and another sample, the The position and peak value of the thermal peak may be slightly different. The experimental error or the value of the difference may be less than or equal to 5°C, or less than or equal to 4°C, or less than or equal to 3°C, or less than or equal to 2°C, or less than or equal to 1°C. The peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.

In the present invention, when calculating the mass-to-volume ratio, the mass unit is grams and the volume unit is milliliters.

In the present invention, "RH" means relative humidity.

In the present invention, the room temperature is in the range of 20°C-40°C.

Description of the drawings

Figure 1: X-ray powder diffraction (XRPD) pattern of the crystalline form I of the compound of formula (1).

Figure 2: Differential scanning calorimetry (DSC) curve diagram of the crystalline form I of the compound of formula (1).

Figure 3: Thermogravimetric analysis (TGA) graph of the crystalline form I of the compound of formula (1).

Figure 4: The isothermal adsorption equilibrium (DVS) curve diagram of the crystalline form I of the compound of formula (1).

Detailed ways

The embodiments of the present invention are described in detail below. Examples of the embodiments are shown in the accompanying drawings, wherein the same or similar reference numerals indicate the same or similar elements or elements with the same or similar functions. The embodiments described below with reference to the accompanying drawings are exemplary, and are intended to explain the present invention, but should not be construed as limiting the present invention.

In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further describe the present invention in detail.

The reagents used in the present invention can be purchased from the market or can be prepared by the method described in the present invention.

Example 1 Preparation method of Tropifexor crystal form I

50.0 mg of Tropifexor was added to ethanol (1.0 ml), heated to 60° C. and stirred to obtain a clear solution, and then water (3 ml) was added dropwise to the Tropifexor solution. Stir and precipitate solid product. It was filtered with suction and placed in a drying box at 50°C and vacuum dried to constant weight to obtain 38.5 mg of solid powder. The obtained crystal was detected by XPRD and confirmed to be Tropifexor crystal form I; its X-ray powder diffraction pattern was basically the same as that of Fig. 1, its DSC pattern was basically the same as that of Fig. 2, and the TGA pattern was basically the same as that of Fig. 3.

Example 2 Preparation method of Tropifexor crystal form I

50.0 mg of Tropifexor was added to ethanol (1.0 ml), heated to 60° C. and stirred to obtain a clear solution, and then n-heptane (3 ml) was added dropwise to the Tropifexor solution. Stir and precipitate solid product. It was filtered with suction and placed in a drying box at 50°C and vacuum dried to constant weight to obtain 39.7 mg of solid powder. The obtained crystal was detected by XPRD and confirmed to be Tropifexor crystal form I; its X-ray powder diffraction pattern was basically the same as that of Fig. 1, its DSC pattern was basically the same as that of Fig. 2, and the TGA pattern was basically the same as that of Fig. 3.

Example 3 Preparation method of Tropifexor crystal form I

50.0 mg of Tropifexor was added to acetone (1.0 ml), heated to 60° C. and stirred to obtain a clear solution, and then n-heptane (3 ml) was added dropwise to the Tropifexor solution. Stir and precipitate solid product. It was filtered with suction and placed in a drying box at 50°C and vacuum dried to constant weight to obtain 37.3 mg of solid powder. The obtained crystal was detected by XPRD and confirmed to be Tropifexor crystal form I; its X-ray powder diffraction pattern was basically consistent with FIG. 1, its DSC pattern was basically the same as FIG. 2, and its TGA pattern was basically the same as FIG. 3.

Example 4 Stability experiment of Tropifexor crystal form I

1) High temperature test

Take the Tropifexor crystal form I samples of the present invention and place them in a constant temperature and humidity box at 60°C (temperature deviation ±5°C)/75% relative humidity (humidity deviation ±5%), and then place them at 5, 10, and 15 respectively. About 10 mg of the above sample was taken every day, and the experimental results of the crystal form were tested as shown in Table 1.

Table 1 Stability study of crystal form I

The above results show that the sample is placed at a high temperature of 60°C (temperature deviation ±5°C)/75% relative humidity (humidity deviation ±5%) for 5 days, 10 days, and 15 days, respectively, the crystal form does not change and the stability is good.

2) High humidity test

Take the Tropifexor crystal form I sample of the present invention and place it flat in a weighing bottle, place it in a constant temperature and humidity box at 25°C/92.5% relative humidity (humidity deviation ±5%), and then take it on 5, 10, and 15 days respectively The above sample is about 10 mg, and the experimental results of testing its crystal form are shown in Table 2.

Table 2 Stability study of crystal form I

The above results show that after the samples are placed at 25°C/92.5% relative humidity (humidity deviation ±5%) for 5 days, 10 days, and 15 days, the crystal form remains unchanged and the stability is good.

3) Light test

Take the Tropifexor crystal form I sample of the present invention and place it flat in a weighing bottle, and place it in a constant temperature and humidity box (25°C, RH60±5%) with visible light 4500Lux±500Lux and ultraviolet light 1.7W*h/m2, Then, about 10 mg of the above sample was taken on 5, 10, and 15 days, and the crystal form was tested. The experimental results are shown in Table 3.

Table 3 Stability study of crystal form I

The above results show that the sample is placed in a constant temperature and humidity box (25℃, RH60±5%) of visible light 4500Lux±500Lux and ultraviolet light 1.7W*h/m ^{2 for 5 days, 10 days, and 15 days, the crystal form is not} Change and good stability.

Example 5 Solubility experiment of Tropifexor crystal form I

Weigh the flask and the stir bar in advance, accurately weigh the samples of Tropifexor new crystal form I, add them to the bottle separately, add water dropwise and stir until the solids are dissolved and stop adding water. When there are no visible particles, it is regarded as completely dissolved. After dissolution, weigh the total weight of the test tube, stir bar, and aqueous solution, calculate the weight of the added water, and then calculate the solubility; the density of the water is calculated according to 1.00g/mL, and the test crystal form I sample in 25 ℃ or 37 ℃ water The solubility and solubility test results are shown in Table 4.

Table 4 Experimental results of solubility test of Tropifexor crystal form I

温度temperature	Tropifexor晶型Tropifexor crystal form	溶解度Solubility
25℃25℃	晶型IForm I	0.120mg/ml0.120mg/ml
37℃37°C	晶型IForm I	0.129mg/ml0.129mg/ml

From the test solubility data in the above table, it can be seen that the crystal form I has good wettability in water and good solubility.

Example 6 Analysis of moisture absorption of Tropifexor crystal form I

Take 50mg of Tropifexor crystal form I solid, use DVS instrument to change with relative humidity (0%-95.0%-0%) at 25.0℃, start from 0% relative humidity, and reach with a 10% relative humidity step change 95% relative humidity, and then a 10% relative humidity step change to 0% relative humidity. When the absolute value of the sample weight change dm/dt per unit time is less than 0.1% under a certain relative humidity condition, it is considered to be in equilibrium, and then the next relative humidity is entered. Detect the change of hygroscopicity of the product under (0%-95.0%-0%) relative humidity cycle conditions. The results are shown in Figure 4.

It can be seen from Figure 4 that when the humidity of the DVS curve of the crystal form I is greater than 75%, the moisture attracting property rises sharply. When the humidity is 95%, the moisture attracting weight gain reaches the maximum, which is about 7.12%, indicating that the crystal form I has a higher moisture attracting property.

Testing equipment and methods

(1) Powder X-ray diffraction (XRPD) research

X-ray powder diffraction (XRPD) patterns were collected on a Dutch PANalytical Empyrean X-ray diffractometer equipped with an automated 3*15 zero background sample holder with a transflective sample stage. The radiation source used is (Cu, kα, Kα1

1.540598; Kα2

1.544426; Kα2/Kα1 intensity ratio: 0.50), where the voltage is set at 45KV, and the current is set at 40mA. The beam divergence of X-rays, that is, the effective size of the X-ray confinement on the sample, is 10mm. Using θ-θ Continuous scanning mode, get the effective 2θ range of 3°～40°. Take an appropriate amount of sample in the circular groove of the zero background sample holder under ambient conditions (about 18°C ~ 32°C), press lightly with a clean glass slide to obtain a flat surface, and fix the zero background sample holder. The sample is used to generate a traditional XRPD pattern in the range of 3-40°2θ with a scanning step of 0.0168°. The software used for data collection is Data Collector, and the data is analyzed and displayed with Data Viewer and HighScore Plus.

Using the above conditions, the crystal forms prepared in the examples were tested by XRPD.

(2) Differential scanning calorimetry (DSC) analysis

The DSC measurement was performed in TA Instruments ^TM model Q2000 with a sealed disk device. Weigh the sample (approximately 1 to 3 mg) in an aluminum pan, cover it with Tzero, accurately record it to one hundredth of a milligram, and transfer the sample to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data was collected between room temperature and 300°C at a heating rate of 10°C/min. The endothermic peak is drawn downward, and the data is analyzed and displayed by TA Universal Analysis.

(3) Thermogravimetric analysis (TGA) analysis

The TGA measurement was performed in TA Instruments ^TM model Q500. The operation step is to peel the empty crucible, take a solid sample of about 10 mg, place it in the peeled empty crucible, and spread it evenly. After the instrument runs stably, collect data at a heating rate of 10°C/min between room temperature and 300°C under nitrogen purge, and record the spectrum.

(4)Dynamic vapor adsorption analyzer DVS

DVS test isotherm adsorption equilibrium curve test method, instrument: DVS-INTRINSIC, with relative humidity (0%-95.0%-0%) at 25.0℃, starting from 0% relative humidity, with 10% relative humidity step The change reaches 95% relative humidity, and then a 10% relative humidity step change reaches 0% relative humidity. When the absolute value of the sample weight change dm/dt per unit time is less than 0.1% under a certain relative humidity condition, it is considered to be in equilibrium, and then the next relative humidity is entered. Detect the change of hygroscopicity of the product under (0%-95.0%-0%) relative humidity cycle conditions.

Regarding the description of hygroscopicity characteristics and the definition of hygroscopic weight gain (Chinese Pharmacopoeia 2010 edition appendix drug hygroscopicity test guidelines, experimental conditions: 25±0.2℃, 80% relative humidity):

Deliquescence: absorb enough water to form a liquid;

Extremely moisture-absorbing: weight gain by moisture-absorbing is not less than 15%;

Has moisture absorption: moisture absorption weight gain is less than 15% but not less than 2%;

Slight moisture absorption: weight gain by moisture absorption is less than 2% but not less than 0.2%;

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

In the description of this specification, descriptions with reference to the terms "one embodiment", "some embodiments", "examples", "specific examples", or "some examples" etc. mean specific features described in conjunction with the embodiment or example , Structures, materials or features are included in at least one embodiment or example of the present invention. In this specification, the schematic representations of the above terms do not necessarily refer to the same embodiment or example. Moreover, the described specific features, structures, materials or characteristics can be combined in any one or more embodiments or examples in a suitable manner. In addition, those skilled in the art can combine and combine the different embodiments or examples and the features of the different embodiments or examples described in this specification without mutual contradiction.

Although the embodiments of the present invention have been shown and described above, it can be understood that the above-mentioned embodiments are exemplary and should not be construed as limiting the present invention. A person of ordinary skill in the art can comment on the above-mentioned embodiments within the scope of the present invention. The embodiment undergoes changes, modifications, substitutions, and modifications.

Claims

The crystal form I of Tropifexor is characterized by an X-ray powder diffraction spectrum expressed in 2θ (error ±0.2 degrees) using Cu-Kα radiation. The X-ray powder diffraction pattern of the crystal form I is 5.8,6.7 in 2θ. There are diffraction peaks at 8.3, 10.5, 11.5, 13.0, 14.9, 15.6, 16.5, 20.5, 21.1,24.8, 26.2 and 26.7 degrees.
The X-ray powder diffraction pattern of the crystal form I of claim 1, and the 2θ of the crystal form I is 12.5, 13.4, 17.3, 17.9, 18.4, 18.6, 20.1,21.9, 22.5, 23.3, 23.6, 23.9, 27.4, There are diffraction peaks at 28.8, 29.6 and 31.6 degrees; or the X-ray powder diffraction pattern of crystal form I is 5.8, 6.7, 8.3, 10.5, 11.5, 12.5, 13.0, 13.4, 14.9, 15.6, 16.5, 17.3 in 2θ , 17.9, 18.4, 18.6, 20.1,20.5, 21.1,21.9, 22.5, 23.3, 23.6, 23.9, 24.8, 26.2, 26.7, 27.4, 28.8, 29.6 and 31.6 degree positions have diffraction peaks; or X- of crystal form I The X-ray powder diffraction pattern is shown in Figure 1.
The crystalline form I of Tropifexor according to claim 1, and the thermogravimetric analysis curve of the crystalline form I showed a weight loss between 30°C and 200°C.
The crystalline form I of Tropifexor according to claim 1, and the thermogravimetric analysis curve of the crystalline form I showed a weight loss between 30°C and 200°C, with a weight loss of about 0.4%.
The crystal form I of Tropifexor according to claim 1, and the purity of the crystal form I is at least 70%.
A method for preparing the crystal form I of Tropifexor according to any one of claims 1-5, comprising: mixing Tropifexor with a good solvent, heating to complete dissolution, mixing with an anti-solvent, stirring to precipitate crystals, collecting crystals, and removing the solvent to obtain Crystal form I; wherein the good solvent is at least one of ethanol and acetone; the anti-solvent is at least one of water and n-heptane.
The method according to claim 6, characterized in that the mass-volume ratio of the Tropifexor to the good solvent is 1:2 to 1:50.
A pharmaceutical composition comprising a therapeutically effective amount of the crystal form I according to any one of claims 1 to 5 and pharmaceutically acceptable excipients.
The pharmaceutical composition according to claim 8, wherein at least 80% of Tropifexor is crystalline form I in terms of mass ratio.
The pharmaceutical composition according to claim 8 or 9, wherein the crystal form I is at least 0.1%-10% of the total weight of the composition.
Use of the crystal form according to any one of claims 1-5 or the composition according to any one of claims 8-10 in the preparation of a medicament for the treatment of NASH, fatty liver and primary biliary cholangitis.