WO2021129589A1 - New crystal form of kd-025 and preparation method therefor - Google Patents

Abstract

Provided are various crystal forms of KD-025 and a preparation method therefor. The various crystal forms of the KD-025 are crystal form N1-crystal form N15. Also provided are an amorphous form of the KD-025 and a preparation method therefor. The crystal form N1, a crystal form N2, and the crystal form N15 all have good solubility or stability, are beneficial for storage, transfer, and operation in a production process, and are suitable for preparing into a preparation.

Description

New crystal form of KD-025 and its preparation method Technical field

The invention belongs to the field of medicinal chemistry, and relates to a new crystal form of KD-025 and a preparation method thereof.

Background technique

KD-025 is a selective ROCK2 (Rho-associated protein kinase 2, Rho-related protein kinase 2) inhibitor. It has multiple clinical indications such as the treatment of multiple sclerosis, psoriasis, rheumatoid arthritis, and Primary pulmonary fibrosis, atherosclerosis, non-alcoholic fatty liver, etc., among which many indications are in clinical phase I, and psoriasis and systemic sclerosis are in clinical phase II.

The structure of KD-025 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 KD-025, 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 KD-025 compound. The new crystal form has high solubility, good stability in water, stable under illumination, high temperature and high humidity, and the preparation process is simple and easy to operate. Superior properties, superiority in industrial production.

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. For this reason, an object of the present invention is to provide a new crystal form of KD-025 and a preparation method thereof, which crystal form has good water stability and good stability in influencing factor tests.

According to one aspect of the present invention, the present invention provides new crystal forms of KD-025: crystal form N1 and crystal form N15.

The above new crystal form of the present invention was studied, and it was found that the crystal form N1 and the crystal form N15 have good performance in water stability, influencing factor tests, etc., and can be used in the production of pharmaceutical preparations.

Said crystal form N1, 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, 7.7 , 9.6, 15.4, 17.8, 19.3, 25.2 and 25.9.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N1 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 3.9, 10.8, 11.6, 13.9, 14.9, 15.8, 16.4, 16.7, 17.2, 18.1,21.6, 22.6, 22.9, 24.6, 26.5, 27.1, 37.2 and 39.2.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N1 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peak: 3.9,5.8,7.7,9.6,10.8,11.6,13.9,14.9,15.4,15.8,16.4,16.7,17.2,17.8,18.1,19.3,21.6,22.6,22.9,24.6,25.2,25.9,26.5,27.1, 37.2 and 39.2.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N1 of KD-025 is shown in Figure 1, wherein the relative intensity of the peak at 7.7 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystal form N1 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 N1 has an endothermic peak at 232±2°C.

In some embodiments, the crystalline form N1 has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 2.

In some embodiments, the crystal form N1 has a thermogravimetric analysis curve (TGA) showing that the weight loss between 30°C and 160°C is less than 0.5%. In some embodiments, the crystalline form N1 has a thermogravimetric analysis curve (TGA) showing that there is a weight loss between 30°C and 160°C, and the weight loss is about 0.276%.

In some embodiments, the crystal form N1 has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 3.

Relative to KD-025, in some embodiments, the purity of the crystal form N1 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 KD-025, the purity of the crystal form N1 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

The crystalline form N15, 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: 8.2, 9.2 , 11.8, 16.6, 17.1,23.9, 26.1 and 27.4.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N15 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 8.4, 15.1, 18.6, 18.8, 20.9, 21.6, 22.4, 22.8, 25.5, 28.1,28.8, 34.4 and 36.0.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N15 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 8.2, 8.4, 9.2, 11.8, 15.1, 16.6, 17.1, 18.6, 18.8, 20.9, 21.6, 22.4, 22.8, 23.9, 25.5, 26.1,27.4, 28.1,28.8, 34.4 and 36.0.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N15 of KD-025 is shown in Figure 17, wherein the relative intensity of the peak at 17.1 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystal form N15 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 17.

In some embodiments, the differential scanning calorimetry (DSC) of the crystalline form N15 has an endothermic peak at 231±2°C.

In some embodiments, the crystalline form N15 has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 18.

In some embodiments, the crystalline form N15 has a thermogravimetric analysis curve (TGA) showing that the weight loss between 30°C and 150°C is less than 0.5%. In some embodiments, the crystalline form N15 has a thermogravimetric analysis curve (TGA) showing that there is a weight loss between 30°C and 150°C, and the weight loss is about 0.253%.

In some embodiments, the crystal form N15 has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 19.

Relative to KD-025, in some embodiments, the purity of the crystal form N15 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 KD-025, the purity of the crystalline form N15 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a new crystal form of KD-025: crystal form N2.

The crystalline form N2, through 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: 6.9, 10.4 , 18.3, 21.3, 24.6 and 28.2.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form N2 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 3.5, 14.0, 16.7, 19.7, 21.0, 31.8 and 39.1.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form N2 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 3.5, 6.9, 10.4, 14.0, 16.7, 18.3, 19.7, 21.0, 21.3, 24.6, 28.2, 31.8 and 39.1.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N2 of KD-025 is shown in Figure 4, wherein the relative intensity of the peak at 2θ of 6.9 degrees is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystalline form N2 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 4.

In some embodiments, the differential scanning calorimetry (DSC) of the crystalline form N2 has an exothermic peak at 179±2°C and an endothermic peak at 231±2°C.

In some embodiments, the crystalline form N2 has a differential scanning calorimetry curve (DSC spectrum) as shown in FIG. 24.

In some embodiments, the crystalline form N2 has a thermogravimetric analysis curve (TGA) showing that the weight loss between 30°C and 150°C is less than 0.5%.

In some embodiments, the crystalline form N2 has a thermogravimetric analysis curve (TGA) showing a weight loss of less than 0.5% and less than 1.0% in the temperature range of 30°C-150°C and 150°C-190°C, respectively .

In some embodiments, the crystalline form N2 has a thermogravimetric analysis curve (TGA pattern) substantially as shown in FIG. 25.

Relative to KD-025, in some embodiments, the purity of the crystalline form N2 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 KD-025, the purity of the crystalline form N2 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a new crystal form of KD-025: crystal form N3.

The crystal form N3, 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: 6.2, 6.9 , 9.3, 10.4, 15.6, 21.0, 24.5 and 25.1.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form N3 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 12.3, 13.9, 15.6, 16.2, 17.8, 18.7, 19.4, 20.1,21.9, 23.0, 26.5, 28.1, 31.6, 33.8 and 39.0.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form N3 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 6.2, 6.9, 9.3, 10.4, 12.3, 13.9, 15.6, 16.2, 17.8, 18.7, 19.4, 20.1,21.0, 21.9, 23.0, 24.5, 25.1,26.5, 28.1, 31.6, 33.8 and 39.0.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N3 of KD-025 is shown in Figure 5, wherein the relative intensity of the peak at 2θ of 6.9 degrees is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystalline form N3 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 5.

Relative to KD-025, in some embodiments, the purity of the crystalline form N3 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 KD-025, the purity of the crystalline form N3 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a new crystal form of KD-025: crystal form N4.

The crystalline form N4, through an X-ray powder diffractometer using Cu-Kα radiation, has an X-ray powder diffraction pattern in the following 2θ (unit:

Degrees, error ±0.2 degrees) have diffraction peaks at the angles: 6.8, 10.3, 13.7, 20.6, 24.1 and 27.6.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form N4 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 3.5, 15.9, 17.4, 18.8, 19.6, 22.8, 25.0, 31.1 and 38.3.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form N4 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 3.5, 6.8, 10.3, 13.7, 15.9, 17.4, 18.8, 19.6, 20.6, 22.8, 24.1,25.0, 27.6, 31.1 and 38.3.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N4 of KD-025 is shown in Figure 6, wherein the relative intensity of the peak at 2θ of 6.8 degrees is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystalline form N4 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 6.

Relative to KD-025, in some embodiments, the purity of the crystalline form N4 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 KD-025, the purity of the crystalline form N4 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a new crystal form of KD-025: crystal form N5.

The crystalline form N5, through an X-ray powder diffractometer using Cu-Kα radiation, has an X-ray powder diffraction pattern with diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle: 6.1, 6.8 , 10.3, 13.9, 18.6, 19.6, 21.0 and 25.8.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N5 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 12.6, 14.9, 15.8, 17.7, 18.2, 20.4, 22.9, 24.2, 25.0, 25.6, 27.3, 27, 6 and 37.2.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N5 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 6.1, 6.8, 10.3, 12.6, 13.9, 14.9, 15.8, 17.7, 18.2, 18.6, 19.6, 20.4, 21.0, 22.9, 24.2, 25.0, 25.6, 25.8, 27.3, 27, 6 and 37.2.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N5 of KD-025 is shown in Figure 7, wherein the relative intensity of the peak at 2θ of 6.8 degrees is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystalline form N5 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 7.

Relative to KD-025, in some embodiments, the purity of the crystalline form N5 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 KD-025, the purity of the crystalline form N5 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a new crystal form of KD-025: crystal form N6.

The crystalline form N6, through an X-ray powder diffractometer using Cu-Kα radiation, has an X-ray powder diffraction pattern with diffraction peaks at the following 2θ (unit: degree, error ±0.2 degree) angle: 7.0, 10.5 , 14.0, 15.6, 19.6, 21.2 and 24.8.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form N6 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 13.0, 18.0, 18.6, 20.1,21.8, 25.7, 28.0, 28.4, 32.0, 34.8, 37.8 and 39.4.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystalline form N6 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 7.0, 10.5, 13.0, 14.0, 15.6, 18.0, 18.6, 19.6, 20.1,21.2, 21.8, 24.8, 25.7, 28.0, 28.4, 32.0, 34.8, 37.8 and 39.4.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N6 of KD-025 is shown in Figure 8, wherein the relative intensity of the peak at 7.0 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystalline form N6 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 8.

Relative to KD-025, in some embodiments, the purity of the crystalline form N6 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 KD-025, the purity of the crystalline form N6 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a new crystal form of KD-025: crystal form N7.

The crystal form N7, 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: 6.5, 12.2 , 15.7, 19.3, 19.6, 26.3 and 27.6.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N7 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 8.4, 14.8, 16.0, 16.4, 16.9, 18.6, 18.8, 20.2, 20.4, 20.8, 21.4, 21.8, 22.5, 23.2, 24.5, 26.3, 26.6 and 27.1.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N7 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peak: 6.5, 8.4, 12.2, 14.8, 15.7, 16.0, 16.4, 16.9, 18.6, 18.8, 19.3, 19.6, 20.2, 20.4, 20.8, 21.4, 21.8, 22.5, 23.2, 24.5, 26.3, 26.6, 27.1,27.6, 30.2 and 36.2.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N7 of KD-025 is shown in Figure 9, wherein the relative intensity of the peak at 26.3 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystalline form N7 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 9.

Relative to KD-025, in some embodiments, the purity of the crystal form N7 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 KD-025, the purity of the crystalline form N7 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a new crystal form of KD-025: crystal form N8.

The crystalline form N8 is characterized in that, 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: 7.7, 9.4, 11.7, 15.6, 19.5 and 27.5.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N8 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 3.9, 6.4, 19.0, 23.5, 25.4, 31.5, 34.5 and 39.6.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N8 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 3.9, 6.4, 7.7, 9.4, 11.7, 15.6, 19.0, 19.5, 23.5, 25.4, 27.5, 31.5, 34.5 and 39.6.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N8 of KD-025 is shown in Figure 10, wherein the relative intensity of the peak at 7.7 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystalline form N8 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 10.

Relative to KD-025, in some embodiments, the purity of the crystalline form N8 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 KD-025, the purity of the crystalline form N8 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a new crystal form of KD-025: crystal form N9.

The crystal form N9, 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: 6.5, 16.0 , 16.7, 19.7, 19.8, 21.4, 26.3 and 27.5.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N9 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peak: 8.5, 13.4, 13.7, 14.6, 15.7, 18.8, 19.0, 19.4, 19.7, 19.8, 20.4, 20.6, 21.6, 22.6, 22.9, 24.5, 24.8, 27.0, 29.3, 30.7, 33.9, 34.2, 34.6, 36.3, 36.8 and 38.4.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N9 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peak: 6.5, 8.5, 13.4, 13.7, 14.6, 15.7, 16.0, 16.7, 18.8, 19.0, 19.4, 19.7, 19.8, 20.4, 20.6, 21.4, 21.6, 22.6, 22.9, 24.5, 24.8, 26.3, 27.0, 27.5, 29.3, 30.7, 33.9, 34.2, 34.6, 36.3, 36.8 and 38.4.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N9 of KD-025 is shown in Figure 11, wherein the relative intensity of the peak at 26.3 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystalline form N9 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 11.

Relative to KD-025, in some embodiments, the purity of the crystalline form N9 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 KD-025, the purity of the crystalline form N9 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a new crystal form of KD-025: crystal form N10.

Said crystal form N10, 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: 7.0, 10.5 , 12.5, 14.0, 18.0, 19.5, 21.1,24.6, 28.2 and 34.6.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N10 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 6.8, 9.9, 10.4, 15.5, 20.0, 21.5, 23.6, 25.7, 26.7, 27.7, 31.8 and 39.1.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N10 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 6.8, 7.0, 9.9, 10.5, 12.5, 14.0, 15.5, 18.0, 19.5, 20.0, 21.1,21.5, 23.6, 24.6, 25.7, 26.7, 27.7, 28.2, 31.8, 34.6 and 39.1.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N10 of KD-025 is shown in Figure 12, wherein the relative intensity of the peak at 7.0 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystal form N10 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 12.

Relative to KD-025, in some embodiments, the purity of the crystal form N10 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 KD-025, the purity of the crystalline form N10 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a new crystal form of KD-025: crystal form N11.

Said crystal form N11, 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: 6.5, 8.2 , 15.2, 16.3, 16.6, 19.0, 19.6, 19.8, 21.7, 21.9 and 26.4.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N11 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 11.4, 12.2, 14.6, 18.6, 20.3, 27.0, 28.1,28.3, 29.4, 32.4, 34.9 and 35.5.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N11 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 6.5, 8.2, 11.4, 12.2, 15.2, 16.3, 16.6, 19.0, 19.6, 19.8, 20.3, 21.7, 21.9, 26.4, 27.0, 28.1,28.3, 29.4, 32.4, 34.9 and 35.5.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N11 of KD-025 is shown in Figure 13, wherein the relative intensity of the peak at 6.5 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystal form N11 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 13.

Relative to KD-025, in some embodiments, the purity of the crystal form N11 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 KD-025, the purity of the crystal form N11 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a new crystal form of KD-025: crystal form N12.

The crystal form N12, 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: 6.7, 6.9 , 10.1, 17.0, 20.4 and 27.3.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N12 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 10.4, 14.2, 19.0, 21.3, 22.8, 24.8, 25.2, 25.6, 30.8 and 37.8.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N12 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 6.7, 6.9, 10.1, 10.4, 14.2, 17.0, 20.4, 21.3, 22.8, 24.8, 25.2, 25.6, 27.3, 30.8 and 37.8.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N12 of KD-025 is shown in Figure 14, wherein the relative intensity of the peak at 6.7 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystalline form N12 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 14.

Relative to KD-025, in some embodiments, the purity of the crystal form N12 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 KD-025, the purity of the crystalline form N12 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a new crystal form of KD-025: crystal form N13.

The crystal form N13, 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: 6.1, 12.8 , 14.7, 16.1, 16.7, 19.1 and 19.6.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N13 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 3.7, 9.4, 9.7, 11.0, 12.4, 21.7, 22.1,22.6, 25.8, 26.4, 29.6, 31.6 and 34.4.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N13 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 3.7, 6.1, 9.4, 9.7, 11.0, 12.4, 12.8, 14.7, 16.1, 16.7, 19.1, 19.6, 21.7, 22.1,22.6, 25.8, 26.4, 29.6, 31.6 and 34.4.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N13 of KD-025 is shown in Figure 15, wherein the relative intensity of the peak at 19.2 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystal form N13 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 15.

Relative to KD-025, in some embodiments, the purity of the crystal form N13 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 KD-025, the purity of the crystalline form N13 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a new crystal form of KD-025: crystal form N14.

The crystal form N14, 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: 6.5, 7.0 , 10.5, 15.3, 16.6, 18.6, 19.1, 19.6, 19.8, 20.3, 21.7, 22.0, 24.9 and 26.4.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N14 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peaks: 8.3, 11.5, 12.2, 14.0, 14.6, 16.3, 17.4, 18.0, 20.8, 22.9, 24.6, 25.8, 27.1,27.4, 28.1,28.3, 29.5, 32.5 and 35.6.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form N14 has diffraction at the following 2θ (unit: degree, error ±0.2 degree) angle Peak: 6.5,7.0,8.3,10.5,11.5,12.2,14.0,14.6,15.3,16.3,16.6,17.4,18.0,18.6,19.1,19.6,19.8,20.3,20.8,21.7,22.0,22.9,24.6,24.9, 25.8, 26.4, 27.1,27.4, 28.1,28.3, 29.5, 32.5 and 35.6.

In some embodiments, the X-ray powder diffraction pattern of the crystalline form N14 of KD-025 is shown in Figure 16, wherein the relative intensity of the peak at 26.4 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90%. %, or greater than 99%.

In some embodiments, the crystal form N14 has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 16.

Relative to KD-025, in some embodiments, the purity of the crystal form N14 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 KD-025, the purity of the crystalline form N14 is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention provides a crystal form of KD-025: crystal form A.

The crystal form A, 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, 7.0 , 9.6, 14.9, 15.8, 17.2, 18.3, 20.0 and 21.7.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form A has diffraction at the following 2θ (unit: degree, error ±0.2 degree) Peaks: 6.9, 7.7, 10.3, 15.5, 16.7, 17.8, 19.2, 20.6, 22.7, 24.8, 25.9, 26.5 and 27.1.

In some embodiments, by using an X-ray powder diffractometer using Cu-Kα radiation, the X-ray powder diffraction pattern of the crystal form A has diffraction at the following 2θ (unit: degree, error ±0.2 degree) Peaks: 5.8, 6.9, 7.0, 7.7, 9.6, 10.3, 14.9, 15.5, 15.8, 16.7, 17.2, 17.8, 18.3, 19.2, 20.0, 20.6, 21.7, 22.7, 24.8, 25.9, 26.5 and 27.1.

In some embodiments, the X-ray powder diffraction pattern of the crystal form A of KD-025 is shown in Figure 21, wherein the relative intensity of the peak at 7.7 degrees 2θ is greater than 70%, or greater than 80%, or greater than 90 %, or greater than 99%.

In some embodiments, the crystal form A has an X-ray powder diffraction pattern (XRPD pattern) substantially as shown in FIG. 21.

Relative to KD-025, in some embodiments, the purity of the crystal form A 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 KD-025, the purity of the crystal form A is at least 85%, or at least 90%, or at least 95%, or at least 99%.

According to one aspect of the present invention, the present invention also provides an amorphous form of KD-025. The powder X-ray diffraction pattern of the KD-025 amorphous form of the present invention at Cu-Kα rays is shown in FIG. 20.

The crystal forms N1, N15, and N2 provided by the present invention are crystal-free, good stability, good stability in water, not easy to deliquesce under high humidity conditions, and difficult to crystallize, which is beneficial to drug storage and transportation And the preparation of pharmaceutical preparations is beneficial to avoid changes in bioavailability and efficacy, and has strong economic value.

The crystal forms N3 and N8 provided by the present invention are trifluoroethanol solvates, the crystal form N4 is a dichloromethane solvate, the crystal form N5 is a butyl formate solvate, and the crystal form N6 is a n-heptane solvate. Crystal form N7 is tetrahydrofuran solvate, crystal form N9 is chloroform solvate, crystal form N10 is ethylene glycol monomethyl ether solvate, crystal form N11 is 1,4-dioxane solvate, crystal form N12 is dimethyl sulfoxide solvate, and crystal form N14 is n-heptane solvate.

The crystal form N13 provided by the present invention is easily transformed into an amorphous form when dried.

In the present invention, a more stable crystal form is of great significance for improving the quality of the drug, and the solvent-free crystal form is relatively more convenient in application than the solvent-containing crystal form.

The crystal forms N1, N15, N2, N3, N4, N5, N6, N7, N8, N9, N10, N11, N12, N13, N14 and amorphous forms of KD-025 described in the present invention can be used to treat multiple sclerosis Disease, psoriasis, rheumatoid arthritis, idiopathic pulmonary fibrosis, atherosclerosis, non-alcoholic fatty liver and other diseases/symptoms.

Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of any one or more of the crystal forms N1, N15, N2 and amorphous forms of KD-025 and pharmaceutically acceptable excipients or excipient. Generally, a therapeutically effective amount of any one or more of the crystal forms N1, N15, N2 and amorphous forms of KD-025 is mixed or contacted with one or more pharmaceutical excipients to prepare a pharmaceutical composition or preparation. The pharmaceutical composition or formulation can be prepared in a manner well known in the pharmaceutical field.

The pharmaceutical composition provided by the present invention may contain at least 0.1%-10% of the total weight of the composition of any one or more of the crystal forms N1, N15, N2 and amorphous forms. The pharmaceutical composition provided by the present invention may contain any one or more of the crystal forms N1, N15, N2, and amorphous forms at least 0.1% to 5% of the total weight of the composition. The pharmaceutical composition provided by the present invention may contain at least 0.1%-1% of the total weight of the composition of any one or more of the crystal forms N1, N15, N2, and amorphous forms. In some embodiments, the pharmaceutical composition provided by the present invention contains at least 0.1%-0.5% of any one or more of the crystal forms N1, N15, N2, and amorphous forms based on the total weight of the composition. .

In some embodiments, the pharmaceutical composition provided by the present invention contains at least 0.5%-10% of the total weight of the composition of any one or more of the crystalline forms N1, N15, N2, and amorphous forms. . In some embodiments, the pharmaceutical composition provided by the present invention contains at least 5%-10% of the total weight of the composition of any one or more of the crystalline forms N1, N15, N2, and amorphous forms. .

According to the mass ratio of the pharmaceutical composition provided by the present invention, at least 80% of KD-025 is any one or more of the crystal forms N1, N15, N2 and amorphous. In some embodiments, according to the mass ratio of the pharmaceutical composition, at least 90% of the KD-025 is any one or more of the crystal forms N1, N15, N2 and amorphous. In some embodiments, according to the mass ratio of the pharmaceutical composition, at least 95% of KD-025 is any one or more of the crystal forms N1, N15, N2 and amorphous. In some embodiments, according to the mass ratio of the pharmaceutical composition, at least 99% of KD-025 is any one or more of N1, N15, N2 and amorphous.

In some embodiments, the pharmaceutical composition further includes any one or more of crystal forms N3, N4, N5, N6, N7, N8, N9, N10, N11, N12, N13, and N14. In some embodiments, in the pharmaceutical composition, in terms of mass ratio, any one or more of crystal forms N3, N4, N5, N6, N7, N8, N9, N10, N11, N12, N13, and N14 The species is 0.1%-10%, or 0.5%-10%, or 5%-10%, or 0.5%-5% of KD-025. In some embodiments, in the pharmaceutical composition, in terms of mass ratio, any one or more of crystal forms N3, N4, N5, N6, N7, N8, N9, N10, N11, N12, N13, and N14 Species do not exceed 5%-10% of KD-025.

Relative to KD-025, in some embodiments, the purity of any one of the crystalline forms N1, N15, N2, and amorphous forms in the pharmaceutical composition is at least 80%. In some embodiments, relative to KD-025, in the pharmaceutical composition, the purity of any one of crystalline forms N1, N15, N2 and amorphous is at least 85%, or at least 90%, or at least 95%, Or at least 99%.

The pharmaceutical composition of the present invention can be used to prepare pharmaceutical preparations for the treatment of multiple sclerosis, psoriasis, rheumatoid arthritis, idiopathic pulmonary fibrosis, atherosclerosis, non-alcoholic fatty liver and other diseases . The pharmaceutical composition of the present invention can be used in methods for treating multiple sclerosis, psoriasis, rheumatoid arthritis, idiopathic pulmonary fibrosis, atherosclerosis, non-alcoholic fatty liver and other diseases.

According to the second aspect of the present invention, the present invention proposes a method for preparing the aforementioned crystal form N1 or crystal form N15 of KD-025, and provides a method for preparing crystal form N2-N14 and KD-025 amorphous form The preparation method.

A method for preparing the crystal form N1 of KD-025 includes: suspending KD-025 in a mixed solvent, stirring at a certain temperature, separating out solids, filtering, and drying to remove the solvent to obtain crystal form N1. The mixed solvent is selected from methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetone, acetonitrile, 1,4-dioxane, N-methyl One of the pyrrolidone is mixed with water. In the mixed solvent, the volume ratio of water to other solvents is 1:3 to 1:10; more preferably, it is 1:4 to 1:6. The certain temperature is 20°C to 80°C, more preferably 50°C to 70°C. When the mass of KD-025 is calculated in grams (g) and the volume of the mixed solvent is calculated in milliliters (mL), the mass-volume ratio of the KD-025 to the mixed solvent is 1:100 to 1:300; more preferably 1:150 ~ 1:250.

In some embodiments, a method for preparing the crystal form N1 of KD-025 includes: mixing KD-025 with a good solvent, stirring at room temperature until the dissolution is complete, adding water, continuing to stir to precipitate crystals, and drying to remove the solvent to obtain crystals. Type N1. The good solvent is methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, 1,4-dioxane, N-methylpyrrolidone One or more of. When the mass of KD-025 is calculated in grams (g) and the volume of the mixed solvent is calculated in milliliters (mL), the mass-volume ratio of the KD-025 to the good solvent is 1:10 to 1:30; more preferably 1:15 ~ 1:25. The volume ratio of the water to the good solvent is 1:0.5 to 1:10; more preferably, it is 1:2 to 1:5.

In some embodiments, a method for preparing the crystal form N1 of KD-025 includes: placing KD-025 in a mixed solvent, heating to completely dissolve, lowering to a certain temperature and then depositing solids, filtering, and drying to remove the solvent to obtain crystals. Type N1. The mixed solvent is selected from methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, 1,4-dioxane, N-methylpyrrolidone One of them is mixed with water. In the mixed solvent, the volume ratio of water to other solvents is 1:3 to 1:10; more preferably, it is 1:4 to 1:6. The certain temperature is 40°C-100°C. When the mass of KD-025 is calculated in grams (g) and the volume of the mixed solvent is calculated in milliliters (mL), the mass-volume ratio of the KD-025 to the mixed solvent is 1:10 to 1:200. The heating and dissolving temperature is 20 to 80°C, and the cooling and crystallization temperature is -10 to 15°C.

In some embodiments, a method for preparing the crystalline form N1 of KD-025 includes: placing KD-025 in a mixed solvent and stirring, dissolving completely at room temperature, leaving the solvent at room temperature to slowly evaporate the solvent, separating out the solid, filtering, and drying to remove the solvent , Get the crystal form N1. The mixed solvent is from methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, 1,4-dioxane, N-methylpyrrolidone One of them is mixed with water. In the mixed solvent, the volume ratio of water to other solvents is 1:3 to 1:10; more preferably, it is 1:4 to 1:6. When the mass of KD-025 is calculated in grams (g) and the volume of the mixed solvent is calculated in milliliters (mL), the mass-volume ratio of the KD-025 to the mixed solvent is 1:10 to 1:200.

In the method for preparing the crystal form N1 of KD-025, KD-025 is any one or more of the aforementioned crystal form and amorphous form. In some embodiments, in the method for preparing the crystal form N1 of KD-025, KD-025 is any one or more of the aforementioned crystal forms N2, A and amorphous.

A method for preparing the crystal form N15 of KD-025 includes: placing the solid of KD-025 in a mixed solvent of water and a good solvent, suspending and stirring, separating the solid, filtering, and drying to remove the solvent to obtain the crystal form N15. The good solvent is one or more selected from ethanol, isopropanol, acetone and acetonitrile. In the mixed solvent, the volume ratio of water to the good solvent is 1:3 to 1:10; more preferably, it is 1:4 to 1:6. When the mass of KD-025 is calculated in grams (g) and the volume of the mixed solvent is calculated in milliliters (mL), the mass-volume ratio of the KD-025 to the mixed solvent is 1:1 to 1:200. The solid of KD-025 is selected from one or more of KD-025 amorphous, KD-025 crystal form N1 and KD-025 crystal form N2.

In the method for preparing the crystal form N15, the KD-025 solid is any one or more of the aforementioned crystal form and amorphous form. In some embodiments, in the method for preparing crystal form N15, KD-025 is any one or more of the aforementioned crystal forms N1, N2 and amorphous.

A method for preparing the crystal form N2 of KD-025 includes: placing KD-025 in a solvent, suspending and stirring, separating out solids, filtering, and drying to remove the solvent to obtain crystal form N2. The solvent is selected from ethyl acetate, isopropanol, ethyl acetate, isopropyl acetate, ethyl formate, dimethyl carbonate, ethylene glycol dimethyl ether, acetone, methyl ethyl ketone, ethyl formate One or more of. When the mass of KD-025 is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of the KD-025 to the solvent is 1:1 to 1:200.

In some embodiments, a method for preparing the crystalline form N2 of KD-025 includes: placing KD-025 in a good solvent, dissolving it, and then adding an anti-solvent to precipitate the solid, filtering, and drying to remove the solvent to obtain the crystalline form N2. The good solvent is ethylene glycol monomethyl ether. The anti-solvent is at least one of cyclohexane or n-heptane. When the mass of KD-025 is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of the KD-025 to the good solvent is 1:1 to 1:200.

In the method for preparing the crystal form N2, the KD-025 solid is any one or more of the aforementioned crystal form and amorphous form.

A method for preparing the crystal form N3 of KD-025 includes: placing KD-025 in n-butanol at 20° C.-80° C., suspending and stirring, separating the solid, filtering, and drying to remove the solvent to obtain the crystal form N3. When the mass of KD-025 is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of the KD-025 to n-butanol is 1:1 to 1:200.

In some embodiments, a method for preparing the crystalline form N3 of KD-025 includes: placing KD-025 in trifluoroethanol at 20°C-80°C, dissolving it, slowly adding water dropwise to precipitate crystals, and filtering. The solvent was removed by drying to obtain the crystal form N3. When the mass of KD-025 is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of KD-025 to trifluoroethanol is 1:1 to 1:200. A method for preparing the crystal form N4 of KD-025 includes: placing KD-025 in methyl isobutyl ketone at 20°C-80°C, suspending and stirring or slowly volatilizing to precipitate crystals, filtering, and drying to remove the solvent , Get the crystal form N4. When the mass of KD-025 is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of the KD-025 to methyl isobutyl ketone is 1:1 to 1:200.

A method for preparing the crystal form N5 of KD-025 includes: placing KD-025 in butyl formate at 20° C.-80° C., suspending and stirring, precipitating crystals, filtering, and drying to remove the solvent to obtain crystal form N5. When the mass of KD-025 is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of KD-025 to butyl formate is 1:1 to 1:200.

A method for preparing the crystalline form N6 of KD-025 includes: placing KD-025 in 1,4-dioxane at 20°C-80°C, suspending and stirring or slowly volatilizing to precipitate crystals, filtering, and drying The solvent was removed to obtain the crystal form N6. When the mass of KD-025 is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of KD-025 to 1,4-dioxane is 1:1 to 1:200.

In some embodiments, a method for preparing the crystalline form N6 of KD-025 includes: placing KD-025 in 1,4-dioxane or acetone at 20°C-80°C, and slowly dripping it after dissolving. Add water or n-heptane to precipitate crystals, filter, and dry to remove the solvent to obtain crystal form N6. When the mass of KD-025 is calculated in grams (g) and the solvent volume is calculated in milliliters (mL), the mass-volume ratio of KD-025 to 1,4-dioxane or acetone is 1:1 to 1:200 .

A method for preparing the crystal form N7 of KD-025 includes: placing KD-025 in tetrahydrofuran at 20°C-80°C, suspending and stirring or slowly volatilizing to precipitate crystals, filtering, and drying to remove the solvent to obtain crystal form N7 . When the mass of KD-025 is calculated in grams (g) and the solvent volume is calculated in milliliters (mL), the mass-volume ratio of KD-025 to tetrahydrofuran is 1:1 to 1:200.

A method for preparing the crystal form N8 of KD-025 includes: placing KD-025 in trifluoroethanol, or a mixed solvent of trifluoroethanol and water, or a mixture of trifluoroethanol and ethanol at 20℃-80℃ In the mixed solvent, suspend and stir or evaporate slowly to precipitate crystals, filter, and dry to remove the solvent to obtain crystal form N8. When the mass of KD-025 is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of KD-025 to trifluoroethanol is 1:1 to 1:200.

A method for preparing the crystal form N9 of KD-025 includes: placing KD-025 in chloroform at 20°C-80°C, suspending and stirring or slowly volatilizing to precipitate crystals, filtering, and drying to remove the solvent to obtain crystal form N9 . When the mass of KD-025 is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of KD-025 to chloroform is 1:1 to 1:200.

A method for preparing the crystal form N10 of KD-025 includes: placing KD-025 in a solvent at 20°C-80°C, suspending and stirring or slowly volatilizing to precipitate crystals, filtering, and drying to remove the solvent to obtain crystal form N10 . The solvent is selected from one or more of ethylene glycol monomethyl ether and trifluoroethanol. The mass of KD-025 is calculated in grams (g), and when the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of the KD-025 to the solvent is 1:1 to 1:200. In some embodiments, a method for preparing the crystalline form N10 of KD-025 includes: placing KD-025 in a good solvent at 20°C-80°C, slowly adding water dropwise after dissolving, to precipitate crystals, filtering, and drying to remove Solvent to obtain crystal form N10. The good solvent is ethylene glycol monomethyl ether. The volume ratio of the good solvent to water is 1:0.5 to 1:10.

In the method for preparing crystal forms N3, N4, N5, N6, N7, N8, N9 and N10, KD-025 is any one or more of the aforementioned crystal forms and amorphous forms.

A method for preparing the crystal form N11 of KD-025 includes: placing KD-025 in 1,4-dioxane at 20°C-80°C, slowly adding anti-solvent dropwise after dissolving, and stirring to precipitate crystals. Filtering, drying and removing the solvent to obtain crystal form N11; the anti-solvent is selected from one or more of methyl tert-butyl ether and n-heptane.

In some embodiments, a method for preparing the crystal form N11 of KD-025 includes: placing KD-025 in 1,4-dioxane at 20°C-80°C, dissolving it, and slowly adding it dropwise to the reactor. Stir in the solvent to precipitate crystals, filter, and dry to remove the solvent to obtain crystal form N11; the anti-solvent is selected from one or more of cyclohexane, toluene, methyl tert-butyl ether, and n-heptane.

In some embodiments, a method for preparing the crystalline form N11 of KD-025 includes: placing KD-025 in a mixed solvent of 1,4-dioxane and ethanol at 20°C-80°C, lowering the temperature, The crystals were precipitated, filtered, and dried to remove the solvent to obtain crystal form N11. Said lowering temperature is lowering the temperature to -10°C-15°C. When the mass of KD-025 is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of the KD-025 to the mixed solvent is 1:10 to 1:200.

In the method for preparing crystal form N11, KD-025 is any one or more of the aforementioned crystal form and amorphous form.

A method for preparing the crystal form N12 of KD-025 includes: placing KD-025 in dimethyl sulfoxide at 20°C-80°C, dissolving it, adding ethyl acetate, evaporating the solvent, and depositing crystals, and filtering , Dry and remove the solvent to obtain crystal form N12.

In some embodiments, a method for preparing the crystalline form N12 of KD-025 includes: placing KD-025 in a mixed solvent of dimethyl sulfoxide and water at 20°C-80°C, lowering the temperature to precipitate crystals, Filter, dry and remove the solvent to obtain crystal form N12. Said lowering temperature is lowering the temperature to -10°C-15°C. When the mass of KD-025 is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of the KD-025 to the mixed solvent is 1:10 to 1:200.

In the method for preparing crystal form N12, KD-025 is any one or more of the aforementioned crystal form and amorphous form.

A method for preparing the crystal form N13 of KD-025 includes: placing KD-025 in trifluoroethanol at 20°C-80°C, slowly adding n-heptane dropwise after dissolving, stirring to precipitate crystals, filtering, and drying to remove Solvent to obtain crystal form N13. The volume ratio of n-heptane to trifluoroethanol is 1:0.5 to 1:10.

A method for preparing the crystalline form N14 of KD-025 includes: placing KD-025 in 1,4-dioxane at 20°C-80°C, dissolving it, slowly mixing with n-heptane, stirring, and depositing crystals , Filtered and dried to remove the solvent to obtain the crystal form N14. The volume ratio of n-heptane to 1,4-dioxane is 1:0.5 to 1:10.

A method for preparing KD-025 amorphous form includes: placing KD-025 in a good solvent at 20°C-80°C, dissolving it and adding water to separate out the solid, filtering, and drying to remove the solvent to obtain an amorphous form. The good solvent is selected from one or more of methanol, acetone, methyl ethyl ketone, dimethyl formamide, dimethyl sulfoxide, N-methylpyrrolidone, and ethylene glycol dimethyl ether.

In some embodiments, a method for preparing amorphous KD-025 includes: placing KD-025 in a good solvent at 20° C.-80° C., rotating rapidly, and removing the solvent to obtain an amorphous form. The good solvent is selected from one or more of methanol, acetone, methyl ethyl ketone, dimethyl formamide, dimethyl sulfoxide, N-methylpyrrolidone, and ethylene glycol dimethyl ether.

In the method for preparing an amorphous form, KD-025 is any one or more of the aforementioned crystal form and amorphous form.

In some embodiments, a method for preparing the amorphous form of KD-025 includes: heating the crystal form N13 of KD-025 at 50° C.-80° C. to obtain the amorphous form.

On the other hand, the present invention also provides a method for preparing the crystal form A of KD-025.

A method for preparing crystal form A of KD-025 includes: placing KD-025 in water or a mixed solvent of water and organic solvent at 20°C-80°C, suspending and stirring to precipitate crystals, filtering, and drying to remove the solvent , Get crystal form A. The organic solvent in the mixed solvent is selected from one or more of methanol, ethanol, isopropanol, n-propanol, dimethylformamide, dimethylsulfoxide, acetone, acetonitrile, and N-methylpyrrolidone Kind. When the mass of KD-025 is calculated in grams (g) and the volume of the solvent is calculated in milliliters (mL), the mass-volume ratio of the KD-025 to water or mixed solvent is 1:1 to 1:200. In some embodiments, the organic solvent is acetone.

In the method for preparing crystal form A, KD-025 is any one or more of the aforementioned crystal form and amorphous form.

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. The value of each number may differ by 1% or 2%.

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 difference may be less than or equal to 10°C, or 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 It is equal to 1°C, so the peak position or the value of the 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.

Description of the drawings

Figure 1: X-ray powder diffraction (XRPD) pattern of the crystal form N1 of KD-025.

Figure 2: Differential scanning calorimetry (DSC) graph of the crystalline form N1 of KD-025.

Figure 3: Thermogravimetric analysis (TGA) graph of the crystal form N1 of KD-025.

Figure 4: X-ray powder diffraction (XRPD) pattern of the crystalline form N2 of KD-025.

Figure 5: X-ray powder diffraction (XRPD) pattern of the crystalline form N3 of KD-025.

Figure 6: X-ray powder diffraction (XRPD) pattern of the crystalline form N4 of KD-025.

Figure 7: X-ray powder diffraction (XRPD) pattern of the crystalline form N5 of KD-025.

Figure 8: X-ray powder diffraction (XRPD) pattern of the crystalline form N6 of KD-025.

Figure 9: X-ray powder diffraction (XRPD) pattern of the crystalline form N7 of KD-025.

Figure 10: X-ray powder diffraction (XRPD) pattern of the crystalline form N8 of KD-025.

Figure 11: X-ray powder diffraction (XRPD) pattern of the crystalline form N9 of KD-025.

Figure 12: X-ray powder diffraction (XRPD) pattern of the crystalline form N10 of KD-025.

Figure 13: X-ray powder diffraction (XRPD) pattern of the crystalline form N11 of KD-025.

Figure 14: X-ray powder diffraction (XRPD) pattern of the crystalline form N12 of KD-025.

Figure 15: X-ray powder diffraction (XRPD) pattern of the crystalline form N13 of KD-025.

Figure 16: X-ray powder diffraction (XRPD) pattern of the crystalline form N14 of KD-025.

Figure 17: X-ray powder diffraction (XRPD) pattern of the crystalline form N15 of KD-025.

Figure 18: Differential scanning calorimetry (DSC) graph of the crystalline form N15 of KD-025.

Figure 19: Thermogravimetric analysis (TGA) graph of the crystal form N15 of KD-025.

Figure 20: Amorphous X-ray powder diffraction (XRPD) pattern of KD-025.

Figure 21: X-ray powder diffraction (XRPD) pattern of crystal form A of KD-025.

Figure 22: X-ray powder diffraction (XRPD) pattern of the 15-day influencing factor experimental product of the crystal form N1 of KD-025.

Figure 23: X-ray powder diffraction (XRPD) pattern of the 15-day influencing factor experimental product of the crystalline form N15 of KD-025.

Figure 24: Differential scanning calorimetry (DSC) graph of the crystalline form N2 of KD-025.

Figure 25: Thermogravimetric analysis (TGA) graph of the crystalline form N2 of KD-025.

Figure 26: X-ray powder diffraction (XRPD) pattern of the 15-day influencing factor experimental product of the crystalline form N2 of KD-025.

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 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.

In the present invention, the KD-025 solid in the examples contains any one or more of the aforementioned crystal forms and amorphous forms.

Example 1 Preparation method of crystal form N1 of KD-025

300mg of KD-025 solid was suspended and stirred in 10mL methanol at room temperature. After 22h, it was filtered, suction filtered and placed in a drying box at 50°C under vacuum overnight to obtain 262mg of powder. The obtained crystal was detected by XPRD and confirmed to be the crystal form N1 of KD-025; 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 2 Preparation method of crystal form N1 of KD-025

50mg of KD-025 solid was suspended and stirred in 2mL purified water at 70°C. After 8h, it was filtered, suction filtered and placed in a drying oven at 50°C under vacuum overnight to obtain 40mg of powder. The obtained crystal was detected by XPRD and confirmed to be the crystal form N1 of KD-025; 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 3 Preparation method of crystal form N1 of KD-025

Put 200mg of KD-025 solid in 3.5mL dimethylformamide at room temperature. After stirring to dissolve it, 20mL of purified water was slowly added dropwise to precipitate a solid. After crystallization continued for 2h, it was filtered, filtered with suction, and placed in Dry in a vacuum oven at 50°C overnight to obtain 165 mg of powder. The obtained crystal was detected by XPRD and confirmed to be the crystal form N1 of KD-025; 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 Preparation method of crystal form N1 of KD-025

Put 500mg of KD-025 solid in 50mL acetone at 50℃. After stirring and dissolving, 50mL of purified water was slowly added dropwise to precipitate the solid. After crystallization continued for 2h, it was filtered, suction filtered and placed in a drying box. It was vacuum dried overnight at °C to obtain 424 mg of powder. The obtained crystal was detected by XPRD and confirmed to be the crystal form N1 of KD-025; 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 5 Preparation method of crystal form N1 of KD-025

Put 500mg of KD-025 solid in 10mL acetone and 2mL purified water at 70℃. After stirring to dissolve it, slowly cool to 0℃ to precipitate the solid. After cultivating the crystal for 5 hours, filter, suction filter and place in a dry box. Dry in vacuum at 50°C overnight to obtain 405 mg of powder. The obtained crystal was detected by XPRD and confirmed to be the crystal form N1 of KD-025; 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 6 Preparation method of crystal form N1 of KD-025

Put 100mg of KD-025 solid in 15mL acetonitrile at 70℃. After stirring and dissolving, slowly evaporate the solvent at room temperature and precipitate the solid. After crystallization continues for 5h, filter, suction and place in a drying box at 50℃ After drying under vacuum overnight, 74 mg of powder was obtained. The obtained crystal was detected by XPRD and confirmed to be the crystal form N1 of KD-025; 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 7 Preparation method of crystal form N15 of KD-025

Put 200mg of the amorphous product of KD-025 in a mixed solvent of 2mL of purified water and 8mL of acetone at 50℃. After mixing and stirring for 24h, filter, filter with suction and place it in a drying oven at 50℃ for vacuum drying overnight. 165 mg of powder was obtained. The obtained crystal was detected by XPRD and confirmed to be the crystal form N15 of KD-025; its X-ray powder diffraction pattern was basically consistent with FIG. 17, its DSC pattern was basically the same as FIG. 18, and its TGA pattern was basically the same as FIG. 19.

Example 8 Preparation method of crystal form N15 of KD-025

Put 500mg of KD-025 crystal form N1 product in a mixed solvent of 1mL purified water and 2mL acetonitrile at 50℃, mix and stir for 24h, filter, filter with suction, and place in a drying oven at 50℃ for vacuum drying overnight , To obtain 360mg of powder. The obtained crystal was detected by XPRD and confirmed to be the crystal form N15 of KD-025; its X-ray powder diffraction pattern was basically consistent with FIG. 17, its DSC pattern was basically the same as FIG. 18, and its TGA pattern was basically the same as FIG. 19.

Example 9 Preparation method of crystal form N2 of KD-025

300 mg of KD-025 solid was placed in 10 mL of ethanol at room temperature, mixed and stirred for 24 hours, filtered, filtered with suction and placed in a drying box at 50° C. and dried overnight under vacuum to obtain 251 mg of powder. The obtained crystal was detected by XPRD and confirmed to be the crystal form N2 of KD-025; its X-ray powder diffraction pattern was basically consistent with that in Fig. 4.

Example 10 Preparation method of crystal form N3 of KD-025

Put 200mg of KD-025 solid in 20mL trifluoroethanol at 50°C, slowly add 20mL of purified water dropwise after dissolving, and precipitate the solid, filter, suction filter and place in a drying box at 50°C and vacuum dry overnight to obtain Powder 145mg. The obtained crystal was tested by XPRD and confirmed to be KD-025 crystal form N3; its X-ray powder diffraction pattern was basically consistent with that in Fig. 5.

Example 11 Preparation method of crystal form N4 of KD-025

Put 300mg of KD-025 solid in 10mL methyl isobutyl ketone at room temperature, mix and stir for 24h, then the solid will be precipitated out, filtered, suction filtered and placed in a drying oven at 50℃ and dried overnight under vacuum to obtain 260mg of powder . The obtained crystal was detected by XPRD and confirmed to be KD-025 crystal form N4; its X-ray powder diffraction pattern was basically consistent with that in Fig. 6.

Example 12 Preparation method of crystal form N5 of KD-025

30 mg of KD-025 solid was placed in 1 mL of butyl formate at room temperature, and after mixing and stirring for 20 hours, the solid was precipitated, filtered, suction filtered and placed in a drying box at 50°C under vacuum overnight to obtain 20 mg of powder. The obtained crystal was detected by XPRD and confirmed to be KD-025 crystal form N5; its X-ray powder diffraction pattern was basically the same as that in Fig. 7.

Example 13 Preparation method of crystal form N6 of KD-025

Put 200mg of KD-025 solid in 10mL 1,4-dioxane at 80℃, slowly add 20mL water after dissolving, and then precipitate the solid, filter, suction filter and place it in a drying oven at 50℃ for vacuum drying Overnight, 158 mg of powder was obtained. The obtained crystal was detected by XPRD and confirmed to be KD-025 crystal form N6; its X-ray powder diffraction pattern was basically the same as that in Fig. 8.

Example 14 Preparation method of crystal form N7 of KD-025

100mg of KD-025 solid was placed in 4mL tetrahydrofuran at room temperature, suspended and stirred for 20h, the solid was precipitated, filtered, suction filtered and placed in a drying box at 50°C under vacuum overnight to obtain 75mg of powder. The obtained crystal was detected by XPRD and confirmed to be KD-025 crystal form N7; its X-ray powder diffraction pattern was basically consistent with FIG. 9.

Example 15 Preparation method of crystal form N8 of KD-025

Put 400mg of KD-025 solid in 40mL trifluoroethanol at 60°C, dissolve it and slowly reduce to 0°C, precipitate the solid, filter, suction filter and place it in a drying box and vacuum dry at 50°C overnight to obtain a powder 342mg. The obtained crystal was detected by XPRD and confirmed to be KD-025 crystal form N8; its X-ray powder diffraction pattern was basically consistent with FIG. 10.

Example 16 Preparation method of crystal form N9 of KD-025

Put 150mg of KD-025 solid in 3mL chloroform at room temperature, suspend and stir for 24h, then the solid precipitated out, filtered, suction filtered and placed in a drying oven at 50°C under vacuum overnight to obtain 103mg of powder. The obtained crystal was detected by XPRD and confirmed to be KD-025 crystal form N9; its X-ray powder diffraction pattern was basically consistent with that in FIG. 11.

Example 17 Preparation method of crystal form N10 of KD-025

Put 200 mg of KD-025 solid in 10 mL of ethylene glycol monomethyl ether at room temperature, dissolve it and evaporate slowly at room temperature, and precipitate the solid, filter, filter with suction and place it in a drying oven at 50°C and vacuum dry overnight. 164 mg of powder was obtained. The obtained crystal was tested by XPRD and confirmed to be KD-025 crystal form N10; its X-ray powder diffraction pattern was basically the same as that in Fig. 12.

Example 18 Preparation method of crystal form N11 of KD-025

Put 200mg of KD-025 solid in 15mL 1,4-dioxane at 80℃. After dissolving it, add 20mL methyl tert-butyl ether slowly at room temperature. The solid precipitated out, filtered, filtered and placed together. It was vacuum-dried at 50°C in a drying box overnight to obtain 138 mg of powder. The obtained crystal was detected by XPRD and confirmed to be the crystal form N11 of KD-025; its X-ray powder diffraction pattern was basically consistent with that in FIG. 13.

Example 19 Preparation method of crystal form N12 of KD-025

Put 200mg of KD-025 solid in 10mL dimethyl sulfoxide and 2mL purified water at 50℃. After dissolving it, it will slowly drop to 0℃, then the solid will be precipitated, filtered, suction filtered and placed in a dry box at 50℃ It was dried in vacuum overnight to obtain 120 mg of powder. The obtained crystal was tested by XPRD and confirmed to be KD-025 crystal form N12; its X-ray powder diffraction pattern was basically the same as that in Fig. 14.

Example 20 Preparation method of crystal form N13 of KD-025

Put 50mg of KD-025 solid in 5mL trifluoroethanol at 50℃. After dissolving it, slowly add 5mL n-heptane dropwise at room temperature to precipitate the solid, filter, suction and place in a dry box under 50℃ vacuum After drying overnight, 21 mg of powder was obtained. The obtained crystal was detected by XPRD and confirmed to be KD-025 crystal form N13; its X-ray powder diffraction pattern was basically consistent with that in FIG. 15.

Example 21 Preparation method of crystal form N14 of KD-025

300 mg of KD-025 crystal form N6 (prepared by the method described in Example 6) was placed in 23 mL 1,4-dioxane at 70°C, and 46 mL n-heptane was slowly added dropwise at room temperature after dissolving. Alkane precipitated solid, filtered, suction filtered and placed in a drying box at 50°C and dried overnight under vacuum to obtain 244 mg of powder. The obtained crystal was detected by XPRD and confirmed to be KD-025 crystal form N14; its X-ray powder diffraction pattern was basically consistent with FIG. 16.

Example 22 Preparation method of KD-025 amorphous

Put 150mg of KD-025 solid in 2.5mL dimethylformamide at room temperature. After dissolving, slowly add 10mL purified water dropwise at room temperature to separate out the solid, filter, suction filter and place in a dry box at 50℃ It was dried under vacuum overnight to obtain 72 mg of powder. The obtained crystal was confirmed to be KD-025 amorphous by XPRD detection; its X-ray powder diffraction pattern was basically consistent with that in Fig. 20.

Example 23 Preparation method of crystal form A of KD-025

Put 150mg of KD-025 solid in a mixed solvent of 10mL purified water and 2mL acetone at room temperature. After mixing and stirring for 22 hours, the solid was precipitated, filtered, filtered with suction and placed in a drying oven at 50°C under vacuum overnight to obtain Powder 122mg. The obtained crystal was detected by XPRD and confirmed to be KD-025 crystal form A; its X-ray powder diffraction pattern was basically consistent with FIG. 21.

Water stability experiment of KD-025 new crystal form

1) Take the crystal form A, crystal form N1 and crystal form N15 samples of KD-025 of the present invention, respectively put them in water and suspend them at room temperature and high temperature for 1 day. After filtering and drying, samples are taken to measure XRPD. The experimental results are as follows: Table 1 .

Table 1 Study on the stability of the new crystal form in water

Experiment number	Raw material crystal form	temperature	Stiring time	Product crystal form
01	Crystal Form A	25℃	1d	Crystal Form A
02	Crystal Form A	60℃	1d	Crystal Form N1
03	Crystal Form N1	25℃	1d	Crystal Form N1
04	Crystal Form N1	60℃	1d	Crystal Form N1
05	Crystal Form N15	25℃	1d	Crystal Form N15
06	Crystal Form N15	60℃	1d	Crystal Form N15

The above results show that the crystal forms of crystal form N1 and crystal form N15 remain unchanged after being suspended in water at high and low temperature for a certain period of time, while crystal form A will be converted to crystal form N1 after being suspended in water for a certain period of time at high temperature, indicating the crystal form Both N1 and crystal form N15 are more stable than crystal form A.

Experiment on the influencing factors of the new crystal form of KD-025

According to the guiding principles of stability test of pharmaceutical preparations, the influencing factors of crystal forms N1, N2 and N15 are tested, including high temperature test, high humidity test and strong light irradiation test, to investigate the stability conditions that affect the crystal form, as shown in Table 2 below 3 and Table 4.

High temperature test: Take appropriate amount of crystal form N1, N2 and N15 samples, lay them flat in a weighing bottle, place them in a constant temperature and humidity box at 60℃±5℃, RH 75±5%, and then store them for 0, 5 and 15 days respectively Take about 100 mg of the above sample and test its crystal form by powder X-ray powder diffraction (XRPD). The results are shown in Figures 22, 23 and 26.

High humidity test: Take appropriate amount of crystal form N1 and N15 samples, lay them flat in a weighing bottle, place them in a constant temperature and humidity box at 25°C, RH 92.5±5%, and then take the above samples for approximately 0, 5, and 15 days. 100mg, the crystal form was tested by powder X-ray powder diffraction (XRPD). The results are shown in Figures 22, 23 and 26.

Light test: Take an appropriate amount of crystal form N1 and N15 samples, spread them in a weighing bottle, and place them in a constant temperature and humidity box with visible light 4500Lux±500Lux (VIS) and ultraviolet light 1.7W*h/m2 (UV) (25℃, RH). 60%±5%), and then about 100 mg of the above sample was taken on 0, 5 and 15 days, and its crystal form was tested by powder X-ray powder diffraction (XRPD). The results are shown in Figures 22, 23 and 26.

Table 2: Stability test results of crystal form N1

Table 3: Stability test conditions of crystal form N15

Table 4: Stability test conditions of crystal form N2

Results: The powder X-ray diffraction (XRPD) spectra of the samples of crystal form N1, N2 and crystal form N15 under the test conditions of high temperature, high humidity and light exposure indicate that the crystal forms N1, N2 and N15 are under various influencing factors. No crystal conversion has occurred, and it has good stability.

Testing equipment and methods

(1) X-ray powder 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,

1.540598;

1.544426; Kα2/Kα1 intensity ratio: 0.50), where the voltage is set at 45KV, and the current is set at 40mN1. The beam divergence of X-rays, that is, the effective size of 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 DN1tA 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 TN1UniversN1l N1nN1lysis.

(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.

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 contradicting each other.

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. Those 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 (19)

1. The crystal form N1 of KD-025 is characterized by the use of Cu-Kα radiation and an X-ray powder diffraction spectrum expressed in 2θ (error ±0.2 degrees). The X-ray powder diffraction pattern of the crystal form N1 is 5.8 in 2θ. There are diffraction peaks at, 7.7, 9.6, 15.4, 17.8, 19.3, 25.2 and 25.9 degrees.
2. The crystal form N1 of KD-025 according to claim 1, wherein the X-ray powder diffraction pattern of the crystal form N1 is 3.9, 10.8, 11.6, 13.9, 14.9, 15.8, 16.4, 16.7, 17.2, 18.1, There are diffraction peaks at 21.6, 22.6, 22.9, 24.6, 26.5, 27.1, 37.2 and 39.2 degrees; or the X-ray powder diffraction pattern of crystal form N1 is 3.9, 5.8, 7.7, 9.6, 10.8, 11.6, 13.9 in 2θ ,14.9,15.4,15.8,16.4,16.7,17.2,17.8,18.1,19.3,21.6,22.6,22.9,24.6,25.2,25.9,26.5,27.1,37.2 and 39.2 degree positions have diffraction peaks; or crystal form N1 The X-ray powder diffraction pattern is shown in Figure 1.
3. The crystal form N1 of KD-025 according to claim 1, and the thermogravimetric analysis curve of the crystal form N1 shows a weight loss between 30°C and 160°C.
4. The crystal form N1 of KD-025 of claim 1 has a purity of at least 90% relative to KD-025.
5. The crystal form N15 of KD-025 is characterized in that the X-ray powder diffraction spectrum expressed in 2θ (error ±0.2 degrees) using Cu-Kα radiation, and the X-ray powder diffraction pattern of the crystal form N15 is at least 2θ There are diffraction peaks at 8.2, 9.2, 11.8, 16.6, 17.1,23.9, 26.1,27.4 degrees.
6. The crystal form N15 of KD-025 according to claim 5, wherein the X-ray powder diffraction pattern of the crystal form N15 is at least 8.4, 15.1, 18.6, 18.8, 20.9, 21.6, 22.4, 22.8, 25.5, 28.1 in 2θ. , 28.8, 34.4, 36.0 degrees, there are diffraction peaks; or the X-ray powder diffraction pattern of crystal form N15 is at least 8.2, 8.4, 9.2, 11.8, 15.1, 16.6, 17.1, 18.6, 18.8, 20.9, 21.6 in 2θ There are diffraction peaks at, 22.4, 22.8, 23.9, 25.5, 26.1,27.4, 28.1,28.8, 34.4, 36.0 degrees; or the X-ray powder diffraction pattern of crystal form N15 is shown in Figure 17.
7. The crystal form N15 of KD-025 according to claim 6, and the thermogravimetric analysis curve of the crystal form N15 shows a weight loss between 30°C and 160°C.
8. The crystal form N15 of KD-025 of claim 6 has a purity of at least 90% relative to KD-025.
9. The crystalline form N2 of KD-025 is characterized by the use of Cu-Kα radiation and an X-ray powder diffraction spectrum expressed in 2θ (error ±0.2 degrees). The X-ray powder diffraction pattern of the crystalline form N2 is 6.9 at 2θ. There are diffraction peaks at 10.4, 18.3, 21.3, 24.6 and 28.2 degrees.
10. The crystal form N2 of KD-025 according to claim 9, wherein the X-ray powder diffraction pattern of the crystal form N2 has diffraction peaks at the positions of 3.5, 14.0, 16.7, 19.7, 21.0, 31.8 and 39.1 degrees in 2θ; Or the X-ray powder diffraction pattern of crystal form N2 has diffraction peaks at the positions of 3.5, 6.9, 10.4, 14.0, 16.7, 18.3, 19.7, 21.0, 21.3, 24.6, 28.2, 31.8 and 39.1 degrees in 2θ; or crystal form The X-ray powder diffraction pattern of N2 is shown in Figure 4.
11. The crystal form N2 of KD-025 according to claim 9 or 10, and the thermogravimetric analysis curve of the crystal form N2 shows a weight loss between 30°C and 150°C and 150°C and 190°C.
12. The crystal form N2 of KD-025 according to any one of claims 9-11, with respect to KD-025, the purity of the crystal form N2 is at least 90%.
13. A method for preparing the crystal form N1 of KD-025 according to any one of claims 1-4, comprising: suspending KD-025 with a mixed solvent, stirring to precipitate solids, filtering, and drying to remove the solvent to obtain crystal form N1; wherein , The mixed solvent is selected from methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, 1,4-dioxane, N- One of the methylpyrrolidone is mixed with water;

    Or include: mixing KD-025 with a good solvent, stirring at room temperature until the dissolution is complete, adding water, continuing to stir to precipitate crystals, and drying to remove the solvent to obtain crystal form N1; wherein the good solvent is methanol, ethanol, and isopropanol One or more of, n-propanol, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, acetone, acetonitrile, 1,4-dioxane, and N-methylpyrrolidone;

    Or include: placing KD-025 in a mixed solvent, heating at 20°C to 80°C to completely dissolve, lowering to -10°C to 15°C to precipitate solids, filtering, and drying to remove the solvent to obtain crystal form N1; the mixed solvent is optional One selected from methanol, ethanol, isopropanol, n-propanol, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, 1,4-dioxane, and N-methylpyrrolidone Mixed with water

    Or include: KD-025 is placed in a mixed solvent and stirred to completely dissolve at room temperature, and the solvent is slowly volatilized by standing at room temperature to precipitate solids, filtered, and dried to remove the solvent to obtain crystal form N1; the mixed solvent is selected from methanol and ethanol One of isopropanol, n-propanol, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetone, acetonitrile, 1,4-dioxane, and N-methylpyrrolidone is mixed with water.
14. A method for preparing the crystal form N2 of KD-025 according to any one of claims 9-12, comprising: placing KD-025 in a solvent, suspending and stirring, separating out the solid, filtering, and drying to remove the solvent to obtain the crystal form N2; The solvent is selected from ethyl acetate, isopropanol, ethyl acetate, isopropyl acetate, ethyl formate, dimethyl carbonate, ethylene glycol dimethyl ether, acetone, methyl ethyl ketone, ethyl formate One or more of esters;

    Or include: placing KD-025 in a good solvent, adding an anti-solvent after dissolving, and separating out the solid, filtering, and drying to remove the solvent to obtain crystal form N2; the good solvent is ethylene glycol monomethyl ether. The anti-solvent is at least one of cyclohexane or n-heptane.
15. A method for preparing the crystal form N15 of KD-025 according to any one of claims 5-8, comprising: placing the KD-025 solid in a mixed solvent of water and a good solvent, suspending and stirring, separating the solid, filtering, and drying to remove Solvent to obtain crystal form N15; the good solvent is one or more selected from ethanol, isopropanol, acetone and acetonitrile; the KD-025 solid is selected from KD-025 amorphous, KD-025 crystal One or more of type N1 and KD-025 crystal form N2.
16. A pharmaceutical composition comprising a therapeutically effective amount of the crystal form N1 according to any one of claims 1-4 or the crystal form N15 according to any one of claims 5-8 or claims 9-12 Any of the crystalline form N2 or amorphous form and a pharmaceutically acceptable excipient.
17. The pharmaceutical composition of claim 16, wherein the crystal form N1, crystal form N2, crystal form N15, or amorphous form is at least 0.1%-10% of the total weight of the composition in terms of mass ratio.
18. The pharmaceutical composition according to claim 16 or 17, wherein at least 80% of the KD-025 is any one or more of the crystal forms N1, N15, N2 and amorphous according to the mass ratio. .
19. The pharmaceutical composition of any one of claims 16-18 is used in the preparation of drugs for the treatment of multiple sclerosis, psoriasis, rheumatoid arthritis, idiopathic pulmonary fibrosis, atherosclerosis, and non-alcoholic fatty liver In the use.

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