CN115246830A

CN115246830A - Solid form of acid and preparation method thereof

Info

Publication number: CN115246830A
Application number: CN202110468365.7A
Authority: CN
Inventors: 时少展; 徐巾超; 张�杰; 陈勇; 黄芳芳
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2021-04-28
Filing date: 2021-04-28
Publication date: 2022-10-28

Abstract

The invention mainly provides a solid form of acid and a preparation method thereof, belonging to the technical field of medicines. The crystal form provided by the invention has better stability and can be applied to pharmaceutical preparations.

Description

Solid form of an acid and process for its preparation

Technical Field

The invention belongs to the technical field of medicines, and relates to a solid form of acid and a preparation method thereof.

Background

Enarodusat is an orally active hypoxia inducible factor prolyl hydroxylase inhibitor (HIF-PHI) and has been developed for the indication renal anemia.

Enarodusat is a substance which is difficult to dissolve in water, the solubility of the Enarodusat is less than 20 mu g/ml in water, and because the solid form of the drug has important influence on the preparation of the drug, the preparation, the storage, the application, the dissolution, the bioavailability and the like of the pharmaceutical preparation, different solid forms can have difference in various aspects, the problems that the drug effect, the safety and the application of the pharmaceutical preparation are obviously different or the quality requirements are easily not met are caused, and the solid form of the drug needs to be researched. The inventors have conducted a related study on the solid form of Enarodustat and found new co-crystals and new salt forms that can be applied.

Disclosure of Invention

The present invention relates primarily to solid forms of Enarodustat. The solid form provided by the invention has the characteristics of stability, high solubility and convenience for implementation and application.

In another aspect, the invention also provides methods and compositions for preparing solid forms of Enarodustat, and the like. The preparation method of the Enaroustistat in a solid form, which is provided by the invention, is simple to operate, high in yield and easy for industrial production.

In a first aspect, the present invention provides a solid form of Enarodustat.

A solid form of enamustat comprising an enamustat eutectic or an enamustat salt form.

The Enarodusat eutectic comprises: enarodusat-isonicotinine co-crystal, enarodusat-nicotinamide co-crystal type 2, enarodusat-benzamide co-crystal, enarodusat-cinnamamide co-crystal, enarodusat-nicotinamide co-crystal type 3 or Enarodusat-nicotinamide co-crystal type 1. The Enaroustistat salt type is Enaroustistat-isoniazid salt type.

The molar ratio of Enaroustistat to isonicotin in the Enaroustistat-isonicotin eutectic is 1.

The molar ratio of Enaroustistat to nicotinamide in the Enaroustistat-nicotinamide eutectic type 2 is 1.

The molar ratio of Enaroustistat to benzamide in the Enaroustistat-benzamide eutectic is 1.

The molar ratio of Enaroustiat to cinnamamide in the Enaroustiat-cinnamamide eutectic is 1.

The molar ratio of Enaroustistat to nicotinamide in the Enaroustistat-nicotinamide eutectic type 3 is 2.

The molar ratio of Enaroustiat to nicotinamide in the Enaroustiat-nicotinamide eutectic type 1 is 2.

The molar ratio of Enaroustistat to isoniazid in the Enaroustistat-isoniazid salt form is 1.

The X-ray powder diffraction pattern of the Enaroustistat-isonicotin eutectic has characteristic peaks at diffraction angles 2theta of 5.5 +/-0.2 degrees, 8.3 +/-0.2 degrees, 14.0 +/-0.2 degrees and 19.6 +/-0.2 degrees. In some embodiments, the enariodustat-isonicotin co-crystal has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 5.5 ± 0.2 °,8.3 ± 0.2 °,11.1 ± 0.2 °,14.0 ± 0.2 °,15.9 ± 0.2 °,16.8 ± 0.2 °,17.9 ± 0.2 °,19.6 ± 0.2 °,22.5 ± 0.2 °,22.9 ± 0.2 °,24.7 ± 0.2 °,26.7 ± 0.2 °,28.2 ± 0.2 °,31.1 ± 0.2 °,32.4 ± 0.2 °,34.9 ± 0.2 °,37.0 ± 0.2 ° and 37.9 ± 0.2 °. In some embodiments, the earodustat-isonicotin co-crystal has an X-ray powder diffraction pattern substantially as shown in figure 1.

The Enarodusat-isonicotine eutectic has an endothermic peak at 140 ℃ -170 ℃ in a differential scanning calorimetry curve. In some embodiments, the differential scanning calorimetry curve of the Enarodustat-isonicotin co-crystal is substantially as shown in figure 2.

The peak value of the endothermic peak of the Enarodusat-isonicotine eutectic is within 150-160 ℃.

The weight loss of the Enarodusat-isonicotin eutectic in a thermogravimetric analysis curve at 30-125 ℃ is not more than 1%. In some embodiments, the enariodustat-isonicotin co-crystal has a weight loss of 0.4% to 0.9% in the thermogravimetric analysis curve at 30 ℃ to 125 ℃. In some embodiments, the enariodustat-isonicotin co-crystal has a weight loss of 0.5% to 0.8% in the thermogravimetric analysis curve at 30 ℃ to 125 ℃. In some embodiments, the thermogravimetric analysis curve of the Enarodustat-isonicotin co-crystal is substantially as shown in figure 3.

The X-ray powder diffraction pattern of the Enaroustistat-nicotinamide eutectic type 2 has characteristic peaks at diffraction angles 2theta of 7.1 +/-0.2 degrees, 7.6 +/-0.2 degrees, 15.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.5 +/-0.2 degrees and 17.8 +/-0.2 degrees. In some embodiments, the enariodustat-nicotinamide eutectic pattern 2 has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 7.1 ± 0.2 °,7.6 ± 0.2 °,15.3 ± 0.2 °,16.2 ± 0.2 °,17.5 ± 0.2 °,17.8 ± 0.2 °,18.5 ± 0.2 °,19.5 ± 0.2 °,20.0 ± 0.2 °,23.2 ± 0.2 °,23.9 ± 0.2 ° and 25.1 ± 0.2 °. In some embodiments, the enariodustat-nicotinamide eutectic pattern 2 has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 7.1 ± 0.2 °,7.6 ± 0.2 °,8.8 ± 0.2 °,9.7 ± 0.2 °,14.3 ± 0.2 °,15.3 ± 0.2 °,16.2 ± 0.2 °,17.5 ± 0.2 °,17.8 ± 0.2 °,18.5 ± 0.2 °,19.5 ± 0.2 °,20.0 ± 0.2 °,21.9 ± 0.2 °,23.2 ± 0.2 °,23.9 ± 0.2 °,25.1 ± 0.2 °,25.8 ± 0.2 °,27.0 ± 0.2 °,27.4 ± 0.2 °,27.8 ± 0.2 °,28.3 ± 0.2 °,28.9 ± 0.2 °,30.2 ± 0.2 °,31.5 ± 0.2 °, 27.32.32 ± 0.34 ± 0.2 °, and 37.9 ± 0.2 ° 2 ± 0.2 °. In some embodiments, the earodustat-nicotinamide eutectic pattern 2 has an X-ray powder diffraction pattern substantially as shown in figure 4.

The Enarodustat-nicotinamide eutectic type 2 has an endothermic peak at 130 ℃ to 160 ℃ in a differential scanning calorimetry curve. In some embodiments, the Enarodustat-nicotinamide eutectic pattern 2 has a differential scanning calorimetry curve substantially as shown in fig. 5.

The peak of the endothermic peak of said enamodustat-nicotinamide eutectic form 2 is within 140 ℃ to 150 ℃.

The weight loss at 30-125 ℃ in the thermogravimetric analysis curve of the Enaroustistat-nicotinamide eutectic type 2 is not more than 0.6%. In some embodiments, the enariodustat-nicotinamide eutectic pattern 2 has a weight loss of 0.1% to 0.6% in the thermogravimetric analysis curve at 30 ℃ to 125 ℃. In some embodiments, the enariodustat-nicotinamide eutectic pattern 2 has a weight loss of 0.2% to 0.5% in the thermogravimetric analysis curve at 30 ℃ to 125 ℃. In some embodiments, the thermogravimetric analysis curve of the enariodustat-nicotinamide eutectic pattern 2 is substantially as shown in fig. 6.

The X-ray powder diffraction pattern of the Enaroustistat-benzamide eutectic has characteristic peaks at diffraction angles 2theta of 7.5 +/-0.2 degrees, 9.3 +/-0.2 degrees, 15.2 +/-0.2 degrees, 16.3 +/-0.2 degrees, 16.9 +/-0.2 degrees, 18.7 +/-0.2 degrees, 21.9 +/-0.2 degrees, 25.7 +/-0.2 degrees, 31.5 +/-0.2 degrees and 17.8 +/-0.2 degrees. In some embodiments, the enariodustat-benzamide co-crystal has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 4.8 ± 0.2 °,7.5 ± 0.2 °,9.3 ± 0.2 °,9.6 ± 0.2 °,15.2 ± 0.2 °,15.8 ± 0.2 °,16.3 ± 0.2 °,16.9 ± 0.2 °,18.7 ± 0.2 °,21.2 ± 0.2 °,21.4 ± 0.2 °,21.9 ± 0.2 °,23.0 ± 0.2 °,24.0 ± 0.2 °,25.3 ± 0.2 °,25.7 ± 0.2 °,26.5 ± 0.2 °,27.8 ± 0.2 ° and 31.5 ± 0.2 °. In some embodiments, the X-ray powder diffraction pattern of the enarodust at-benzamide co-crystal has characteristic peaks at diffraction angles 2 θ of 4.8 ± 0.2 °,7.5 ± 0.2 °,8.6 ± 0.2 °,9.3 ± 0.2 °,9.6 ± 0.2 °,11.8 ± 0.2 °,14.5 ± 0.2 °,15.2 ± 0.2 °,15.8 ± 0.2 °,16.3 ± 0.2 °,16.9 ± 0.2 °,17.4 ± 0.2 °,18.7 ± 0.2 °,21.2 ± 0.2 °,21.4 ± 0.2 °,21.9 ± 0.2 °,23.0 ± 0.2 °,24.0 ± 0.2 °,24.9 ± 0.2 °,25.3 ± 0.2 °,25.7 ± 0.2 °,26.5 ± 0.2 °,27.8 ± 0.2 °,24.8 ± 0.2 °,24.9 ± 0.2 °,25.3 ± 0.2 °,25.7 ± 0.2 °, and 2.34 ± 0.35 ± 0.2 ° 2 ° 2.2 °. In some embodiments, the araodustat-benzamide co-crystal has an X-ray powder diffraction pattern substantially as shown in figure 7.

The Enarodusat-benzamide eutectic has an endothermic peak at 140-160 ℃ in a differential scanning calorimetry curve. In some embodiments, the differential scanning calorimetry curve of the Enarodustat-benzamide co-crystal is substantially as shown in fig. 8.

The peak value of the endothermic peak of the Enaroustistat-benzamide eutectic is within 145-155 ℃.

The weight loss of the Enaroustistat-benzamide eutectic at 30-125 ℃ in a thermogravimetric analysis curve is not more than 0.6%. In some embodiments, the enariodustat-benzamide co-crystal has a weight loss of 0.1% to 0.6% in the thermogravimetric analysis curve from 30 ℃ to 125 ℃. In some embodiments, the enariodustat-benzamide co-crystal has a weight loss of 0.2% to 0.5% in the thermogravimetric analysis curve from 30 ℃ to 125 ℃. In some embodiments, the thermogravimetric analysis curve of the enariodustat-benzamide co-crystal is substantially as shown in fig. 9.

The X-ray powder diffraction pattern of the Enaroustitat-cinnamamide eutectic has characteristic peaks at diffraction angles 2theta of 7.5 +/-0.2 degrees, 11.4 +/-0.2 degrees, 14.9 +/-0.2 degrees, 17.2 +/-0.2 degrees, 19.3 +/-0.2 degrees, 23.3 +/-0.2 degrees, 24.3 +/-0.2 degrees and 25.7 +/-0.2 degrees. In some embodiments, the X-ray powder diffraction pattern of the Enarodustat-cinnamamide co-crystal has characteristic peaks at diffraction angles 2 Θ of 7.5 ± 0.2 °,10.0 ± 0.2 °,11.4 ± 0.2 °,13.1 ± 0.2 °,13.7 ± 0.2 °,14.9 ± 0.2 °,15.2 ± 0.2 °,16.5 ± 0.2 °,17.2 ± 0.2 °,19.3 ± 0.2 °,20.2 ± 0.2 °,20.7 ± 0.2 °,21.0 ± 0.2 °,21.3 ± 0.2 °,21.7 ± 0.2 °,22.4 ± 0.2 °,23.3 ± 0.2 °,23.8 ± 0.2 °,24.3 ± 0.2 °,25.7 ± 0.2 °,26.2 ± 0.2 °,26.5 ± 0.2 °,27.7 ± 0.2 °,30.1 ± 0.2 °, and 37.2 ± 0.2 °. In some embodiments, the Enaroustistat-cinnamamide co-crystal has an X-ray powder diffraction pattern at diffraction angle 2 θ of 7.5 ± 0.2 °,10.0 ± 0.2 °,11.4 ± 0.2 °,12.0 ± 0.2 °,12.4 ± 0.2 °,13.1 ± 0.2 °,13.7 ± 0.2 °,14.9 ± 0.2 °,15.2 ± 0.2 °,16.0 ± 0.2 °,16.5 ± 0.2 °,17.2 ± 0.2 °,19.3 ± 0.2 °,19.7 ± 0.2 °,20.2 ± 0.2 °,20.7 ± 0.2 °,21.0 ± 0.2 °,21.3 ± 0.2 °,21.7 ± 0.2 °,22.4 +/-0.2 degrees, 22.9 +/-0.2 degrees, 23.3 +/-0.2 degrees, 23.8 +/-0.2 degrees, 24.3 +/-0.2 degrees, 24.6 +/-0.2 degrees, 25.2 +/-0.2 degrees, 25.7 +/-0.2 degrees, 26.2 +/-0.2 degrees, 26.5 +/-0.2 degrees, 27.1 +/-0.2 degrees, 27.7 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.1 +/-0.2 degrees, 29.7 +/-0.2 degrees, 30.1 +/-0.2 degrees, 30.8 +/-0.2 degrees, 31.6 +/-0.2 degrees, 33.3 +/-0.2 degrees, 34.2 +/-0.2 degrees, 35.1 +/-0.2 degrees, 35.7 +/-0.2 degrees, 37.2 +/-0.2 degrees, 38.2 +/-0.2 degrees and 39.2 +/-0.2 degrees have characteristic peaks. In some embodiments, the earodustat-cinnamamide co-crystal has an X-ray powder diffraction pattern substantially as shown in figure 10.

The Enarodusat-cinnamamide eutectic has an endothermic peak at 150-180 ℃ in a differential scanning calorimetry curve. In some embodiments, the Enarodustat-cinnamamide co-crystal has a differential scanning calorimetry curve substantially as shown in figure 11.

The peak value of the endothermic peak of the Enaroustistat-cinnamamide eutectic is within 160-170 ℃.

The weight loss of the Enaroustistat-cinnamamide eutectic at 30-125 ℃ in a thermogravimetric analysis curve is not more than 0.6%. In some embodiments, the enariodustat-cinnamamide co-crystal has a weight loss of 0.1% to 0.6% in a thermogravimetric analysis curve at 30 ℃ to 125 ℃. In some embodiments, the enariodustat-cinnamamide co-crystal has a weight loss of 0.2% to 0.5% in a thermogravimetric analysis curve at 30 ℃ to 125 ℃. In some embodiments, the thermogravimetric analysis curve of the earodustat-cinnamamide co-crystal is substantially as shown in figure 12.

The X-ray powder diffraction pattern of the Enaroustistat-nicotinamide eutectic pattern 3 has characteristic peaks at diffraction angles 2theta of 6.1 +/-0.2 degrees, 12.3 +/-0.2 degrees and 17.8 +/-0.2 degrees. In some embodiments, the enariodustat-nicotinamide eutectic pattern 3 has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 6.1 ± 0.2 °,12.3 ± 0.2 °,15.4 ± 0.2 °,17.8 ± 0.2 °,21.3 ± 0.2 °,21.7 ± 0.2 °,29.2 ± 0.2 °,34.5 ± 0.2 ° and 38.6 ± 0.2 °. In some embodiments, the Enaroustistat-nicotinamide eutectic pattern 3 has an X-ray powder diffraction pattern at diffraction angle 2 θ of 6.1 ± 0.2 °,9.2 ± 0.2 °,11.5 ± 0.2 °,12.3 ± 0.2 °,13.5 ± 0.2 °,15.2 ± 0.2 °,15.4 ± 0.2 °,15.9 ± 0.2 °,16.2 ± 0.2 °,17.8 ± 0.2 °,18.5 ± 0.2 °,20.8 ± 0.2 °,21.3 ± 0.2 °,21.7 ± 0.2 °,22.0 ± 0.2 °,22.3 +/-0.2 degrees, 23.4 +/-0.2 degrees, 24.1 +/-0.2 degrees, 24.8 +/-0.2 degrees, 25.4 +/-0.2 degrees, 26.8 +/-0.2 degrees, 28.1 +/-0.2 degrees, 28.8 +/-0.2 degrees, 29.2 +/-0.2 degrees, 30.1 +/-0.2 degrees, 30.7 +/-0.2 degrees, 31.9 +/-0.2 degrees, 32.5 +/-0.2 degrees, 34.5 +/-0.2 degrees, 34.9 +/-0.2 degrees, 35.5 +/-0.2 degrees, 36.5 +/-0.2 degrees, 37.7 +/-0.2 degrees, 38.6 +/-0.2 degrees, 38.8 +/-0.2 degrees and 39.5 +/-0.2 degrees have characteristic peaks. In some embodiments, the earodustat-nicotinamide eutectic pattern 3 has an X-ray powder diffraction pattern substantially as shown in figure 13.

The enariodusat-nicotinamide eutectic type 3 has an endothermic peak at 130-160 ℃ in a differential scanning calorimetry curve. In some embodiments, the differential scanning calorimetry curve of the enarodust at-nicotinamide eutectic pattern 3 is substantially as shown in fig. 14.

The peak value of the endothermic peak of the Enarodusat-nicotinamide eutectic type 3 is within 140-150 ℃.

The weight loss at 30-125 ℃ in the thermogravimetric analysis curve of the Enaroustistat-nicotinamide eutectic type 3 is not more than 1.5%. In some embodiments, the enariodustat-nicotinamide eutectic pattern 3 has a weight loss of 0.5% to 1.2% in the thermogravimetric analysis curve at 30 ℃ to 125 ℃. In some embodiments, the enariodustat-nicotinamide eutectic pattern 3 has a weight loss of 0.6% to 1.0% at 30 ℃ to 125 ℃ in a thermogravimetric analysis curve. In some embodiments, the enariodustat-nicotinamide eutectic pattern 3 has a weight loss of 0.7% to 0.9% in a thermogravimetric analysis curve at 30 ℃ to 125 ℃. In some embodiments, the thermogravimetric analysis curve of the enariodustat-nicotinamide eutectic pattern 3 is substantially as shown in fig. 15.

The X-ray powder diffraction pattern of the Enarodustat-nicotinamide eutectic mode 1 has characteristic peaks at diffraction angles 2theta of 5.5 +/-0.2 degrees, 16.8 +/-0.2 degrees and 18.3 +/-0.2 degrees. In some embodiments, the enariodustat-niacinamide eutectic pattern 1 has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 5.5 ± 0.2 °,10.0 ± 0.2 °,11.1 ± 0.2 °,16.8 ± 0.2 °,18.3 ± 0.2 °,19.6 ± 0.2 ° and 20.2 ± 0.2 °. In some embodiments, the enariodustat-niacinamide eutectic pattern 1 has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 5.5 ± 0.2 °,8.3 ± 0.2 °,9.1 ± 0.2 °,10.0 ± 0.2 °,11.1 ± 0.2 °,13.3 ± 0.2 °,14.0 ± 0.2 °,14.5 ± 0.2 °,15.7 ± 0.2 °,16.8 ± 0.2 °,17.5 ± 0.2 °,18.3 ± 0.2 °,19.6 ± 0.2 °,20.2 ± 0.2 °,22.4 ± 0.2 °,23.3 ± 0.2 °,25.1 ± 0.2 °,25.4 ± 0.2 °,26.5 ± 0.2 °,26.9 ± 0.2 °,27.8 ± 0.2 °,29.1 ± 0.2 °,31.2 ± 0.2 °, 35.0.2 ± 0.3 ± 0.2 °,37.3 ± 0.2 ° and 38.0 ± 0 ± 0.2 °. In some embodiments, the enariodustat-nicotinamide eutectic pattern 1 has an X-ray powder diffraction pattern substantially as shown in figure 16.

The enarodust at-nicotinamide eutectic type 1 has an endothermic peak at 140 ℃ -160 ℃ in a differential scanning calorimetry curve. In some embodiments, the differential scanning calorimetry curve of the enarodust at-nicotinamide eutectic pattern 1 is substantially as shown in fig. 17.

The peak of the endothermic peak of said Enarodusat-nicotinamide eutectic form 1 is within 145 ℃ -150 ℃.

The weight loss at 30-125 ℃ in the thermogravimetric analysis curve of the Enaroustistat-nicotinamide eutectic type 1 is not more than 1.0%. In some embodiments, the enariodustat-nicotinamide eutectic pattern 1 has a weight loss of 0.2% to 0.9% at 30 ℃ to 125 ℃ in a thermogravimetric analysis curve. In some embodiments, the enariodustat-nicotinamide eutectic pattern 1 has a weight loss of 0.3% to 0.8% at 30 ℃ to 125 ℃ in a thermogravimetric analysis curve. In some embodiments, the enariodustat-nicotinamide eutectic pattern 1 has a weight loss of 0.4% to 0.7% at 30 ℃ to 125 ℃ in a thermogravimetric analysis curve. In some embodiments, the thermogravimetric analysis curve of the enariodustat-nicotinamide eutectic pattern 1 is substantially as shown in fig. 18.

The X-ray powder diffraction pattern of the Enarodustat-isoniazid salt type has characteristic peaks at diffraction angles 2theta of 7.0 +/-0.2 degrees, 18.6 +/-0.2 degrees, 21.4 +/-0.2 degrees, 26.6 +/-0.2 degrees and 27.6 +/-0.2 degrees. In some embodiments, the Enarodustat-isoniazid salt form has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 θ of 7.0 + 0.2 °,9.9 + 0.2 °,13.4 + 0.2 °,16.6 + 0.2 °,18.4 + 0.2 °,18.6 + 0.2 °,19.4 + 0.2 °,21.4 + 0.2 °,23.0 + 0.2 °,25.2 + 0.2 °,26.6 + 0.2 ° and 27.6 + 0.2 °. In some embodiments, the enariodustat-isoniazid salt form of the X-ray powder diffraction pattern has characteristic peaks at diffraction angles 2 θ of 7.0 ± 0.2 °,9.1 ± 0.2 °,9.9 ± 0.2 °,13.4 ± 0.2 °,13.7 ± 0.2 °,14.6 ± 0.2 °,15.0 ± 0.2 °,15.5 ± 0.2 °,16.6 ± 0.2 °,18.4 ± 0.2 °,18.6 ± 0.2 °,18.9 ± 0.2 °,19.4 ± 0.2 °,19.8 ± 0.2 °,20.0 ± 0.2 °,20.8 ± 0.2 °,21.4 ± 0.2 °,22.2 ± 0.2 °,23.0 ± 0.2 °,23.5 ± 0.2 °,24.1 ± 0.2 °,25.2 ± 0.2 °,26.6 ± 0.2 °, 22.27 ± 0.1 ± 0.2 °,23.0 ± 0.2 °,23.5 ± 0.2 °,23.2 ± 0.2 °,37 ± 0.2 °, and 37 ± 0.2 ° 2 ± 0.2 °. In some embodiments, the Enarodustat-isoniazid salt form has an X-ray powder diffraction pattern substantially as shown in figure 19.

The differential scanning calorimetry curve of the Enarodusat-isoniazid salt type has an endothermic peak at 110 ℃ to 150 ℃. In some embodiments, the Enarodustat-isoniazid salt form has a differential scanning calorimetry curve substantially as shown in figure 20.

The peak value of the endothermic peak of the Enarodustat-isoniazid salt form is within 120 ℃ to 130 ℃.

The weight loss of the Enarodustat-isoniazid salt type thermogravimetric analysis curve at 30-125 ℃ is not more than 0.7%. In some embodiments, the enariodustat-cinnamamide co-crystal has a weight loss of 0.2% to 0.7% in a thermogravimetric analysis curve at 30 ℃ to 125 ℃. In some embodiments, the enariodustat-cinnamamide co-crystal has a weight loss of 0.3% to 0.6% in a thermogravimetric analysis curve at 30 ℃ to 125 ℃. In some embodiments, the thermogravimetric analysis curve of the Enarodustat-isoniazid salt form is substantially as shown in figure 21.

On the other hand, the invention also provides an Enarodustat crystal form N6.

A crystalline form of Enarodustat, designated form N6 Enarodustat, having an X-ray powder diffraction pattern having at least 3 characteristic peaks selected from 2 θ at 6.8 + 0.2 °,8.7 + 0.2 °,10.2 + 0.2 °,13.8 + 0.2 °,17.3 + 0.2 °,17.7 + 0.2 °,22.7 + 0.2 °,24.0 + 0.2 °,25.8 + 0.2 °,26.3 + 0.2 ° and 27.8 + 0.2 °. In some embodiments, the enariodustat form N6 has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 6.8 ± 0.2 °,8.7 ± 0.2 °,10.2 ± 0.2 °,13.8 ± 0.2 °,17.3 ± 0.2 °,17.7 ± 0.2 °,22.7 ± 0.2 °,24.0 ± 0.2 °,25.8 ± 0.2 °,26.3 ± 0.2 ° and 27.8 ± 0.2 °. In some embodiments, the enariodustat form N6 has an X-ray powder diffraction pattern at diffraction angle 2 Θ of 6.8 ± 0.2 °,8.7 ± 0.2 °,8.9 ± 0.2 °,10.2 ± 0.2 °,10.3 ± 0.2 °,11.8 ± 0.2 °,13.0 ± 0.2 °,13.2 ± 0.2 °,13.8 ± 0.2 °,14.3 ± 0.2 °,15.0 ± 0.2 °,15.4 ± 0.2 °,15.7 ± 0.2 °,16.6 ± 0.2 °, the characteristic peaks are at 17.3 + -0.2 degrees, 17.7 + -0.2 degrees, 18.4 + -0.2 degrees, 19.2 + -0.2 degrees, 19.6 + -0.2 degrees, 20.5 + -0.2 degrees, 21.5 + -0.2 degrees, 22.0 + -0.2 degrees, 22.4 + -0.2 degrees, 22.7 + -0.2 degrees, 23.4 + -0.2 degrees, 24.0 + -0.2 degrees, 25.8 + -0.2 degrees, 26.3 + -0.2 degrees, 27.2 + -0.2 degrees, 27.8 + -0.2 degrees, 28.9 + -0.2 degrees and 31.7 + -0.2 degrees. In some embodiments, the Enarodustat form N6 has an X-ray powder diffraction pattern substantially as shown in figure 22.

The differential scanning calorimetry curve of Enaroustistat crystal form N6 has an endothermic peak at 171-177 ℃. In some embodiments, the Enarodustat form N6 has a differential scanning calorimetry curve substantially as shown in figure 23.

The thermogravimetric analysis curve of Enarodustat crystal form N6 has no more than 1% weight loss at 30-150 ℃. In some embodiments, the enariodustat form N6 has a weight loss in the thermogravimetric analysis curve of no more than 0.7% at 30 ℃ to 150 ℃. In some embodiments, the enariodustat form N6 has a weight loss in the thermogravimetric analysis curve of 0.3% to 0.7% at 30 ℃ to 150 ℃. In some embodiments, the enariodustat form N6 has a weight loss in the thermogravimetric analysis curve of 0.4% to 0.6% at 30 ℃ to 150 ℃. In some embodiments, the enariodustat form N6 has a weight loss of about 0.53% in the thermogravimetric analysis curve from 30 ℃ to 150 ℃. In some embodiments, the thermogravimetric analysis curve of Enarodustat form N6 is substantially as shown in figure 24.

On the other hand, the invention also provides an Enarodustat crystal form N1.

A crystalline form of Enarodustat, designated form N1 Enarodustat, having an X-ray powder diffraction pattern having at least 3 characteristic peaks, selected from 5.1 + -0.2 °,9.2 + -0.2 °,11.7 + -0.2 °,17.7 + -0.2 °,25.7 + -0.2 ° and 26.8 + -0.2 ° 2 θ. In some embodiments, the enariodustat form N1 has an X-ray powder diffraction pattern having characteristic peaks at diffraction angles 2 Θ of 5.1 ± 0.2 °,9.2 ± 0.2 °,11.7 ± 0.2 °,17.7 ± 0.2 °,25.7 ± 0.2 ° and 26.8 ± 0.2 °. In some embodiments, the earodustat form N1 has an X-ray powder diffraction pattern substantially as shown in figure 25.

The differential scanning calorimetry curve of the Enaroustistat crystal form N1 has endothermic peaks at 113 ℃ -119 ℃ and 168 ℃ -174 ℃. In some embodiments, the Enarodustat form N1 has a differential scanning calorimetry curve substantially as shown in fig. 26.

In a second aspect, the present invention provides a composition.

A composition comprising the solid form of the first aspect and a pharmaceutically acceptable excipient.

The solid form may be at least 0.05% to 95% by mass of the total mass of the composition.

In a third aspect, the present invention provides a process for preparing the solid form of the first aspect.

A method of preparing the solid form of the first aspect, comprising: mixing Enaroustistat crystal form N6, a ligand A and a solvent I, wherein the ligand A is isonicotin, nicotinamide, benzamide or cinnamamide, suspending and pulping, filtering to obtain a filter cake, and drying the filter cake to obtain the solid form; or comprises the following steps: dissolving Enaroustistat solid and a ligand B in a solvent II, wherein the ligand B is isonicotine, nicotinamide, benzamide, cinnamamide or isoniazid, adding an anti-solvent, stirring, filtering to obtain a filter cake, and drying the obtained filter cake to obtain the solid form; or comprises the following steps: dissolving Enaroustistat solid and a ligand C in a solvent III, wherein the ligand C is isonicotine, nicotinamide, benzamide or cinnamamide, and volatilizing to obtain the solid form.

The enoodustat solid may be enoodustat in any solid form and does not include any of co-crystals, hydrates, solvates, and salt forms. In some embodiments, the enoodustat solid is enoodustat in amorphous or crystalline form, and the enoodustat solid does not include any of a co-crystal, a hydrate, a solvate, and a salt form. In some embodiments, the enamustiat solid is enamustiat form N1. In some embodiments, the enariodustat solid is enariodustat form N6.

The solvent I comprises at least one of ethyl acetate, acetonitrile and methanol, the ligand A is isonicotin, and the Enaroustistat-isonicotin eutectic crystal is obtained. In some embodiments, the solvent I is ethyl acetate, acetonitrile or methanol and the ligand a is isonicotin, resulting in an enarodust at-isonicotin co-crystal.

The solvent I can comprise or be ethyl acetate, the ligand A is nicotinamide, and the Enaroustistat-nicotinamide eutectic type 2 is obtained.

The solvent I can comprise at least one selected from ethyl acetate, acetonitrile and methanol, and the ligand A is benzamide, so that an Enaroustistat-benzamide eutectic is obtained. In some embodiments, the solvent I is ethyl acetate and the ligand a is benzamide, resulting in an Enarodustat-benzamide co-crystal.

The solvent I can comprise at least one selected from ethyl acetate, acetonitrile and methanol, and the ligand A is cinnamamide, so that the Enaroustistat-cinnamamide eutectic is obtained. In some embodiments, the solvent I is methanol and the ligand a is cinnamamide, resulting in an Enarodustat-cinnamamide co-crystal.

The solvent I can be ethanol, the ligand A is nicotinamide, and the drying is drying by nitrogen blow at 20-30 ℃ to obtain the Enaroustistat-nicotinamide eutectic type 1.

The solvent II can comprise at least one selected from tetrahydrofuran, ethanol and acetone, the ligand B is isonicotin, and the Enaroustitat-isonicotin eutectic crystal is obtained. In some embodiments, the solvent II is ethanol and the ligand B is isonicotin, resulting in an Enarodustat-isonicotin co-crystal.

The solvent II can comprise at least one selected from tetrahydrofuran and acetone, the ligand B is nicotinamide, and the Enaroustistat-nicotinamide eutectic type 2 is obtained.

The solvent II can comprise at least one selected from tetrahydrofuran, ethanol and acetone, and the ligand B is benzamide, so that an Enaroustistat-benzamide eutectic is obtained. In some embodiments, the solvent II is acetone and the ligand B is benzamide, resulting in an Enarodustat-benzamide co-crystal.

The solvent II can comprise at least one selected from tetrahydrofuran, ethanol and acetone, and the ligand B is cinnamamide, so that the Enaroustistat-cinnamamide eutectic is obtained. In some embodiments, the solvent II is tetrahydrofuran and the ligand B is cinnamamide, resulting in an Enarodustat-cinnamamide co-crystal.

The solvent II can comprise or be acetone, and the ligand B is isoniazid, so that the Enaroustistat-isoniazid salt type is obtained.

The solvent II can be ethanol, the ligand B is nicotinamide, and the Enaroustistat-nicotinamide eutectic type 3 is obtained.

The solvent III can be tetrahydrofuran, the ligand C is isonicotine, and the Enaroustistat-isonicotine eutectic crystal is obtained.

The solvent III may be tetrahydrofuran, the ligand C nicotinamide, to give enarodustt-nicotinamide eutectic form 2.

The solvent III can be tetrahydrofuran, and the ligand C is benzamide, so that an Enaroustistat-benzamide eutectic is obtained.

The solvent III can be tetrahydrofuran, and the ligand C is cinnamamide, so that the Enaroustistat-cinnamamide eutectic is obtained.

The anti-solvent may comprise or be n-heptane.

The temperature of the suspension and the pulping can be 20-35 ℃.

The temperature of the dissolution may be 40 ℃ to 80 ℃.

The suspension and pulping time can be 24-48 h.

The stirring time can be 24-48 h.

The charging mass ratio of the Enaroustistat crystal form N6 to the ligand A can be 1.

The charging mass ratio of the Enaroustistat solid to the ligand B can be 1.

The feeding mass ratio of the Enaroustistat to the ligand C can be 1.

The ratio of the charging mass of the Enaroustistat crystal form N6 to the charging volume of the solvent I can be 20 mg-10 mg.

The ratio of the charged mass of Enaroustistat to the charged volume of solvent II may be from 20mg to 501mg.

The ratio of the charged mass of Enaroustistat to the charged volume of solvent III may be 25mg to 1ml to 35mg.

In some embodiments of the invention, a method of preparing an Enarodustat-isonicotin co-crystal comprises: mixing Enaroustistat crystal form N6, a ligand A and a solvent I, wherein the ligand A is isonicotin, the solvent I comprises at least one selected from ethyl acetate, acetonitrile and methanol, suspending and pulping, filtering to obtain a filter cake, and drying the obtained filter cake to obtain the Enaroustistat-isonicotin eutectic crystal.

In some embodiments of the invention, a method of making an Enarodustat-isonicotin co-crystal comprises: dissolving Enaroustistat solid and a ligand B in a solvent II, wherein the ligand B is isonicotin, the solvent II comprises at least one of tetrahydrofuran, ethanol and acetone, adding an anti-solvent, the anti-solvent is n-heptane, stirring, filtering to obtain a filter cake, and drying the filter cake to obtain the Enaroustistat-isonicotin eutectic crystal.

In some embodiments of the invention, a method of making an Enarodustat-isonicotin co-crystal comprises: dissolving Enaroustistat solid and a ligand C in a solvent III, wherein the ligand C is isonicotin, and the solvent III is tetrahydrofuran, and volatilizing to obtain the Enaroustistat-isonicotin eutectic crystal.

In some embodiments of the invention, a method of preparing enarodust at-nicotinamide eutectic form 2, comprises: mixing the Enaroustistat crystal form N6, a ligand A and a solvent I, wherein the ligand A is nicotinamide, the solvent I is ethyl acetate, suspending and pulping, filtering to obtain a filter cake, and drying the filter cake to obtain the Enaroustistat-nicotinamide eutectic crystal form 2.

In some embodiments of the invention, a method of preparing enarodust at-nicotinamide eutectic form 2, comprises: dissolving Enaroustistat solid and a ligand B in a solvent II, wherein the ligand B is nicotinamide, the solvent II comprises at least one of tetrahydrofuran and acetone, adding an anti-solvent, the anti-solvent is n-heptane, stirring, filtering to obtain a filter cake, and drying the filter cake to obtain the Enaroustistat-nicotinamide eutectic type 2.

In some embodiments of the invention, a method of preparing enarodustt-nicotinamide eutectic form 2, comprises: dissolving Enaroustistat solid and a ligand C in a solvent III, wherein the ligand C is nicotinamide, the solvent III is tetrahydrofuran, and volatilizing to obtain the Enaroustistat-nicotinamide eutectic crystal form 2.

In some embodiments of the invention, a method of preparing an Enarodustat-benzamide co-crystal comprises: mixing the Enaroustistat crystal form N6, a ligand A and a solvent I, wherein the ligand A is benzamide, the solvent I comprises at least one of ethyl acetate, acetonitrile and methanol, suspending and pulping, filtering to obtain a filter cake, and drying the filter cake to obtain the Enaroustistat-benzamide eutectic crystal.

In some embodiments of the invention, a method of preparing an Enarodustat-benzamide co-crystal comprises: dissolving Enaroustistat solid and a ligand B in a solvent II, wherein the ligand B is benzamide, the solvent II comprises at least one of tetrahydrofuran, ethanol and acetone, adding an anti-solvent, the anti-solvent is n-heptane, stirring, filtering to obtain a filter cake, and drying the filter cake to obtain the Enaroustistat-benzamide eutectic crystal.

In some embodiments of the invention, a method of preparing an Enarodustat-benzamide co-crystal comprises: dissolving Enaroustistat solid and a ligand C in a solvent III, wherein the ligand C is benzamide, the solvent III is tetrahydrofuran, and volatilizing to obtain the Enaroustistat-benzamide eutectic.

In some embodiments of the invention, a method of making an enarodustt-cinnamamide co-crystal comprises: mixing Enaroustistat crystal form N6, a ligand A and a solvent I, wherein the ligand A is cinnamide, and the solvent I comprises at least one selected from ethyl acetate, acetonitrile and methanol, suspending and pulping, filtering to obtain a filter cake, and drying the filter cake to obtain the Enaroustistat-cinnamide eutectic crystal.

In some embodiments of the invention, a method of preparing an enarodust at-cinnamamide co-crystal comprises: dissolving Enaroustistat solid and a ligand B in a solvent II, wherein the ligand B is cinnamamide, the solvent II comprises at least one of tetrahydrofuran, ethanol and acetone, adding an anti-solvent, the anti-solvent is n-heptane, stirring, filtering to obtain a filter cake, and drying the filter cake to obtain the Enaroustistat-cinnamamide eutectic crystal.

In some embodiments of the invention, a method of making an enarodustt-cinnamamide co-crystal comprises: dissolving the Enaroustistat solid and the ligand C in a solvent III, wherein the ligand C is cinnamide, the solvent III is tetrahydrofuran, and volatilizing to obtain the Enaroustistat-cinnamide eutectic.

In some embodiments of the invention, a method of preparing an Enarodustat-isoniazid salt form, comprising: dissolving Enaroustistat solid and a ligand B in a solvent II, adding an antisolvent, stirring, filtering to obtain a filter cake, and drying the filter cake to obtain the Enaroustistat-isoniazid salt type, wherein the ligand B is isoniazid, the solvent II is acetone, the antisolvent is n-heptane.

In some embodiments of the invention, a method of preparing enarodust at-nicotinamide eutectic form 3, comprises: dissolving Enaroustistat solid and a ligand B in a solvent II, wherein the ligand B is nicotinamide, the solvent II is ethanol, adding an anti-solvent, the anti-solvent is n-heptane, stirring, filtering to obtain a filter cake, and drying the filter cake to obtain the Enaroustistat-nicotinamide eutectic type 3.

In some embodiments of the invention, a method of preparing enarodust at-nicotinamide eutectic form 1 comprises: mixing Enaroustistat crystal form N6, a ligand A and a solvent I, wherein the ligand A is nicotinamide, the solvent I is ethanol, suspending and pulping, filtering to obtain a filter cake, and drying the filter cake to obtain the Enaroustistat-nicotinamide eutectic crystal form 1.

On the other hand, the invention provides a preparation method of Enarodustat crystal form N6.

A method for preparing Enarodustat crystal form N6, comprising: dissolving Enaroustistat solid in ethylene glycol monomethyl ether, wherein the Enaroustistat solid can be Enaroustistat in any solid form, does not contain any one of eutectic, hydrate, solvate and salt form, dissolving the Enaroustistat solid clearly, adding water, precipitating crystals, filtering to obtain a filter cake, and drying the filter cake to obtain the crystal form N6.

The amount of ethylene glycol monomethyl ether used may range from 20ml to 150ml per gram of Enaroustistat solid.

The amount of water may be from 100ml to 250ml per gram of Enaroustistat solid.

The temperature of the ethylene glycol monomethyl ether can be 40-70 ℃. In some embodiments, the temperature of the ethylene glycol monomethyl ether is from 50 ℃ to 60 ℃.

In a fourth aspect, the present invention provides a use of the aforementioned crystalline form or the aforementioned composition.

Use of a crystalline form of the first aspect or a composition of the second aspect in the manufacture of a medicament for treating renal anemia.

Advantageous effects

Compared with the prior art, the invention has at least one of the following beneficial effects:

(1) Novel co-crystals and novel salt forms of Enarodustat are provided.

(2) The Enaroustistat-benzamide eutectic, the Enaroustistat-cinnamamide eutectic, the Enaroustistat-isonicotinine eutectic, the Enaroustistat-nicotinamide eutectic type 2, the Enaroustistat-nicotinamide eutectic type 3 and the Enaroustistat-isonicotinate provided by the invention have the advantages that the crystal forms are unchanged after 15 days under the condition of influencing factors, and the crystal forms are good in stability.

(3) The eutectic and the salt form provided by the invention have good solubility, and the solubility of the eutectic-isonicotinite eutectic is 28.3 times of the solubility of an Enaroustiat crystal form N6 in a phosphate buffer solution with the pH value of 4.5 and the temperature of 37 ℃ by calculating the Enaroustiat; the solubility of the enariodustat-nicotinamide eutectic form 2 is 17.1 times that of enariodustat form N6; the solubility of the Enaroustitat-benzamide eutectic is 13.0 times that of Enaroustitat crystal form N6; the solubility of the Enaroustitat-cinnamamide eutectic is 4.6 times of the solubility of Enaroustitat crystal form N6; the solubility of the enariodustat-isoniazid salt form is 3.1 times that of enariodustat form N6; the solubility of the enariodustat-nicotinamide eutectic form 3 is 2.8 times the solubility of enariodustat form N6.

(4) The Enaroustistat-benzamide eutectic, the Enaroustistat-cinnamamide eutectic, the Enaroustistat-isonicotin eutectic, the Enaroustistat-nicotinamide eutectic type 2, the Enaroustistat-nicotinamide eutectic type 3 and the Enaroustistat-isoniazide salt provided by the invention can be used for preparing a pharmaceutical preparation.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of Enaroustitat-isonicotin eutectic.

FIG. 2 is a spectrum diagram of a differential scanning calorimetry curve of Enaroustitat-isonicotin eutectic.

FIG. 3 is a thermogravimetric analysis curve of the Enarodustat-isonicotin co-crystal.

Figure 4 is an X-ray powder diffraction pattern of Enarodustat-nicotinamide eutectic pattern 2.

FIG. 5 is a differential scanning calorimetry curve of Enarodusat-nicotinamide eutectic pattern 2.

FIG. 6 is a thermogravimetric analysis curve spectrum of Enaroustistat-nicotinamide eutectic pattern 2.

FIG. 7 is an X-ray powder diffraction pattern of Enaroustitat-benzamide co-crystal.

FIG. 8 is a spectrum of a differential scanning calorimetry curve of the Enarodusat-benzamide eutectic.

FIG. 9 is a thermogravimetric analysis curve spectrum of the Enaroustistat-benzamide eutectic.

Figure 10 is an X-ray powder diffraction pattern of the Enarodustat-cinnamamide co-crystal.

FIG. 11 is a differential scanning calorimetry curve of the Enaroustistat-cinnamamide co-crystal.

FIG. 12 is a thermogravimetric analysis curve spectrogram of the Enaroustitat-cinnamamide eutectic.

Figure 13 is an X-ray powder diffraction pattern of Enarodustat-nicotinamide eutectic pattern 3.

FIG. 14 is a differential scanning calorimetry curve of Enarodusat-nicotinamide eutectic form 3.

FIG. 15 is a thermogravimetric analysis curve of Enaroustistat-nicotinamide eutectic pattern 3.

Figure 16 is an X-ray powder diffraction pattern of enarodustt-nicotinamide eutectic pattern 1.

FIG. 17 is a spectrum of a differential scanning calorimetry curve of Enaroustistat-nicotinamide eutectic pattern 1.

FIG. 18 is a thermogravimetric analysis curve of Enaroustistat-nicotinamide eutectic pattern 1.

FIG. 19 is an X-ray powder diffraction pattern of Enarodustat-isoniazid salt form.

FIG. 20 is a chart of a differential scanning calorimetry curve of Enaroustistat-isoniazid salt type.

FIG. 21 is a thermogravimetric analysis curve of the Enarodustat-isoniazid salt form.

Figure 22 is an X-ray powder diffraction pattern of Enarodustat form N6.

FIG. 23 is a spectrum of a differential scanning calorimetry curve of Enaroustistat crystal form N6.

FIG. 24 is a thermogravimetric analysis curve of Enarodustat form N6.

Figure 25 is an X-ray powder diffraction pattern of Enarodustat form N1.

FIG. 26 is a differential scanning calorimetry curve of Enarodustat form N1.

FIG. 27 is a nuclear magnetic resonance spectrum of Enaroustistat, benzamide, and Enaroustistat-benzamide co-crystal.

FIG. 28 is a nuclear magnetic resonance spectrum of Enaroustitat, cinnamamide, and Enaroustitat-cinnamamide co-crystal.

Figure 29 is a nuclear magnetic resonance spectrum of Enarodustat, niacinamide, and Enarodustat-niacinamide eutectic pattern 1.

Figure 30 is a nuclear magnetic resonance spectrum of enarodust, nicotinamide and enarodust-nicotinamide eutectic pattern 2.

Figure 31 is a nuclear magnetic resonance spectrum of enarodust, nicotinamide and enarodust-nicotinamide eutectic pattern 3.

FIG. 32 is a nuclear magnetic resonance spectrum of Enaroustistat, isonicotin, and Enaroustistat-isonicotin cocrystal form.

FIG. 33 shows NMR spectra of Enaroustistat, isoniazid and Enaroustistat-isoniazid salt forms.

Definition of terms

The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including but not limited to defined terminology, terminology application, described techniques, and so on), this application controls.

It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of elements, and the 75 th version of the handbook of chemistry and Physics, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", thomas Sorrell, university Science Books, sausalito:1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, john Wiley & Sons, new York:2007, the entire contents of which are incorporated herein by reference.

The term "optional" means that the subsequently described event or circumstance may, but need not, occur. For example, "optional organic solvent" means that an organic solvent may or may not be present.

In the invention, g represents g; DEG C represents centigrade degree; l represents liter; mg means mg, mL means mL, rpm means rpm/min, h means hour, RH means relative humidity.

The term "co-crystal" refers to a crystalline substance composed of two or more different molecules in the same crystal lattice, typically a drug and a co-crystal ligand; they are different from salts and more like solvates, although all contain more than one component in a crystal lattice.

The term "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.

The term "clear" means to dissolve and become clear.

The term "substantially as shown in the figure" means that substantially pure certain "crystalline form" has at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in its X-ray powder diffraction pattern that appear in the X-ray powder diffraction pattern given. When the content of a certain crystal form in a sample is gradually reduced, diffraction peaks in an X-ray powder diffraction pattern of the crystal form, which are attributed to the crystal form, may be reduced due to the detection sensitivity of an instrument.

The term "relative intensity" refers to the ratio of the intensity of the other peaks to the intensity of the first strong peak in a set of diffraction peaks assigned to a certain crystal form, when the intensity of the first strong peak is defined as 100%.

In the context of the present invention, the 2 θ (also called 2theta or diffraction peak) values in the X-ray powder diffraction pattern are all in degrees (°).

The term "diffraction peak" when referring to a map and/or data in a map refers to a feature that one skilled in the art would not attribute to background noise.

The X-ray powder diffraction peak, the measurement of the 2theta or diffraction peak of the X-ray powder diffraction pattern thereof, has experimental error, and the measurement of the 2theta or diffraction peak of the X-ray powder diffraction pattern may be slightly different between one machine and another machine and between one sample and another sample, the error of the 2theta is ± 0.2 °, so that the value of the 2theta or diffraction peak cannot be regarded as absolute.

The Differential Scanning Calorimetry (DSC) curve has experimental errors, the position and peak value of the endothermic peak may slightly differ between one machine and another machine and between one sample and another sample, and the value of the experimental error or difference may be 4 ℃ or less, 3 ℃ or less, 2 ℃ or less, or 1 ℃ or less, so the value of the peak position or peak value of the endothermic peak of the DSC cannot be regarded as absolute.

The thermogravimetric analysis curve (TGA) has experimental errors, the endothermic curve or weight loss may differ slightly between one machine and another and between one sample and another, and the value of the experimental error or difference may be less than or equal to 0.004% or 0.003% or 0.002% or 0.001%, so the thermogravimetric analysis curve or weight loss thereof cannot be regarded as absolute.

In the context of the present invention, all numbers disclosed herein are approximate, whether or not the word "about" or "approximately" is used, and there may be +/-1%, +/-2%, or +/-5% differences in each number based on the disclosed numbers. When used to approximate the 2theta (also called 2theta or diffraction peak) value used to describe an X-ray powder diffraction peak, approximately means that the 2theta value may vary by +/-0.2 units or +/-0.1 units or +/-0.05 units.

By "room temperature" is meant a temperature of about 20 ℃ to 35 ℃ or about 23 ℃ to 28 ℃ or about 25 ℃.

The term "good solvent" may be a single solvent or a mixture of solvents, meaning that the solubility of the sample in the single solvent or mixture of solvents is greater than 1g/L, or greater than 2g/L, or greater than 3g/L, or greater than 4g/L, or greater than 5g/L, or greater than 6g/L, or greater than 7g/L, or greater than 8g/L, or greater than 9g/L, or greater than 10g/L, or greater than 15g/L, or greater than 20g/L, or greater than 30g/L, or greater than 40g/L, or greater than 50g/L, or greater than 60g/L, or greater than 70g/L, or greater than 80g/L, or greater than 100g/L. In some embodiments, the sample has greater solubility in the good solvent than the anti-solvent; in some embodiments, the difference in solubility of the good solvent and the anti-solvent for the sample is about 10%,20%,30%,40%,50%,60%,70%,80%, or 90%; in some embodiments, the good solvent is more soluble in the sample than the anti-solvent, greater than 10%,20%,30%,40%,50%,60%,70%,80%, or 90%.

Detailed Description

In order to make the technical solutions of the present invention better understood by those skilled in the art, the following further discloses some non-limiting examples to further explain the present invention in detail.

The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.

Parameters of the instrument

All analyses below were performed at room temperature unless otherwise specified in the parameters.

X-ray powder diffraction study

X-ray powder diffraction patterns were collected on a PANalytical Empyrean X-ray diffractometer in the netherlands equipped with a transmission-reflection sample stage with an automated 3X 15 zero background sample holder. The radiation source used was a source of radiation of (Cu, k α,

the K alpha 2/K alpha 1 intensity ratio: 0.50 Voltage is set at 45KV, current is set at 40ma, beam divergence of X-ray, i.e., the effective size of X-ray confinement on the sample, is 6.6mm, and a theta-theta continuous scanning mode is employed to obtain an effective 2theta range of 3 deg. to 40 deg.. Taking a proper amount of sample at the position of the circular groove of the zero-background sample rack under the environmental condition (about 18-32 ℃), lightly pressing the sample by using a clean glass slide to obtain a flat plane, and fixing the zero-background sample rack. The sample was scanned at a scanning step of 0.0168 ° in the range of 3-40 ° 2 θ ± 0.2 ° to produce a conventional X-ray powder diffraction pattern. The software used for Data collection was a Data Collector, and Data was analyzed and presented using Data Viewer and HighScore Plus.

Differential Scanning Calorimetry (DSC)

DSC measurements were performed in a TA instruments model Q2000 using a sealed tray apparatus. Samples (approximately 1-3 mg) were weighed in aluminum pans, capped with Tzero, precision recorded to one hundredth of a milligram, and transferred to the instrument for measurement. The instrument was purged with nitrogen at 50 mL/min. Data was collected between 30 ℃ and 300 ℃ at a heating rate of 10 ℃/min. The endothermic peak was plotted downward, and the data was analyzed and displayed using TA Universal Analysis.

Thermogravimetric analysis (TGA)

TGA data were collected on TA Instruments Q500. The temperature of the instrument was calibrated using certified nickel. Typically, 8-12mg of sample was loaded onto a pre-weighed platinum crucible and heated from 30 ℃ to 300 ℃ at 10 ℃/min. A nitrogen purge of 60mL/min was maintained over the sample. In the TGA chart, the abscissa represents Temperature (deg.C) and the ordinate represents Weight loss (Weight (%)).

Example 1: preparation of Enarodusat crystal form N6

Weighing 150mg of Enaroustistat crystal form N1, dissolving in 5mL of ethylene glycol monomethyl ether at 55 ℃, dropwise adding 15mL of water after dissolving to separate out a solid, filtering after 24 hours to obtain a solid, and drying the solid to obtain 135mg of Enaroustistat crystal form N6; and detecting the Enarodustat crystal form N6, wherein an X-ray powder diffraction pattern is basically consistent with that of a figure 22, a differential scanning calorimetry curve pattern is basically consistent with that of a figure 23, and a thermogravimetric analysis pattern is basically consistent with that of a figure 24.

Example 2: preparation of Enarodusat crystal form N1

Weighing 100mg of Enaroustistat crystal form N1, adding the Enaroustistat crystal form N1 into 4.5mL of water and 1.5mL of N-propanol, suspending and pulping for 24h at 25 ℃, filtering to obtain a solid, and drying the obtained solid to obtain 65mg of Enaroustistat crystal form N1; and detecting the Enarodustat crystal form N1, wherein the X-ray powder diffraction pattern is basically consistent with that of figure 25, and the differential scanning calorimetry curve pattern is basically consistent with that of figure 26.

Example 3: preparation of Enarodusat-benzamide eutectic

Weighing 100mg of Enaroustistat crystal form N6 and 60mg of benzamide, adding 5mL of ethyl acetate, suspending and pulping at 30 ℃ for 24h, filtering to obtain a filter cake, and drying the filter cake to obtain 141mg of Enaroustistat-benzamide eutectic crystal; the obtained Enarodusat-benzamide eutectic is detected, the X-ray powder diffraction pattern of the Enarodusat-benzamide eutectic is basically consistent with that in figure 7, the differential scanning calorimetry curve pattern of the Enarodusat-benzamide eutectic is basically consistent with that in figure 8, the thermogravimetric analysis pattern of the Enarodusat-benzamide eutectic is basically consistent with that in figure 9, and the nuclear magnetic resonance pattern of the Enarodusat-benzamide eutectic is basically consistent with that in figure 27.

Example 4: preparation of Enarodusat-benzamide eutectic

Weighing 100mg of Enaroustistat crystal form N1 and 60mg of benzamide, adding 5mL of acetone, dissolving at 60 ℃, adding 15mL of N-heptane, stirring at 30 ℃ for about 24 hours, filtering to obtain a filter cake, and drying the obtained filter cake to obtain 125mg of Enaroustistat-benzamide eutectic crystal; the obtained Enarodusat-benzamide eutectic is detected, the X-ray powder diffraction pattern of the Enarodusat-benzamide eutectic is basically consistent with that in figure 7, the differential scanning calorimetry curve pattern of the Enarodusat-benzamide eutectic is basically consistent with that in figure 8, the thermogravimetric analysis pattern of the Enarodusat-benzamide eutectic is basically consistent with that in figure 9, and the nuclear magnetic resonance pattern of the Enarodusat-benzamide eutectic is basically consistent with that in figure 27.

Example 5: preparation of Enarodusat-benzamide eutectic

Weighing 100mg of Enaroustistat crystal form N1 and 60mg of benzamide, adding 3mL of tetrahydrofuran, dissolving at 60 ℃, volatilizing at 30 ℃, and volatilizing to obtain 117mg of Enaroustistat-benzamide eutectic; the obtained Enarodusat-benzamide eutectic is detected, the X-ray powder diffraction pattern of the Enarodusat-benzamide eutectic is basically consistent with that in figure 7, the differential scanning calorimetry curve pattern of the Enarodusat-benzamide eutectic is basically consistent with that in figure 8, the thermogravimetric analysis pattern of the Enarodusat-benzamide eutectic is basically consistent with that in figure 9, and the nuclear magnetic resonance pattern of the Enarodusat-benzamide eutectic is basically consistent with that in figure 27.

Example 6: preparation of Enarodusat-cinnamamide eutectic

Weighing 100mg of Enaroustistat crystal form N6 and 70mg of cinnamamide, adding 5mL of methanol, suspending and pulping at 30 ℃ for 24h, filtering to obtain a filter cake, and drying the filter cake to obtain 149mg of Enaroustistat-cinnamamide eutectic; the obtained Enarodusat-cinnamamide eutectic is detected, the X-ray powder diffraction pattern is basically consistent with that of figure 10, the differential scanning calorimetry curve pattern is basically consistent with that of figure 11, the thermogravimetric analysis pattern is basically consistent with that of figure 12, and the nuclear magnetic resonance pattern is basically consistent with that of figure 28.

Example 7: preparation of Enarodusat-cinnamamide eutectic

Weighing 100mg of Enaroustistat crystal form N1 and 70mg of cinnamamide, adding 5mL of tetrahydrofuran, dissolving at 60 ℃, adding 15mL of N-heptane, stirring at 30 ℃ for 24 hours, filtering to obtain a filter cake, and drying the filter cake to obtain 141mg of Enaroustistat-cinnamamide eutectic; the obtained Enarodusat-cinnamamide eutectic is detected, the X-ray powder diffraction pattern is basically consistent with that in figure 10, the differential scanning calorimetry curve pattern is basically consistent with that in figure 11, the thermogravimetric analysis pattern is basically consistent with that in figure 12, and the nuclear magnetic resonance pattern is basically consistent with that in figure 28.

Example 8: preparation of Enarodusat-cinnamamide eutectic

Weighing 100mg of Enaroustistat crystal form N1 and 70mg of cinnamamide, adding 3mL of tetrahydrofuran, dissolving at 60 ℃, volatilizing at 30 ℃, and volatilizing to obtain 121mg of Enaroustistat-cinnamamide eutectic crystal; the obtained Enarodusat-cinnamamide eutectic is detected, the X-ray powder diffraction pattern is basically consistent with that of figure 10, the differential scanning calorimetry curve pattern is basically consistent with that of figure 11, the thermogravimetric analysis pattern is basically consistent with that of figure 12, and the nuclear magnetic resonance pattern is basically consistent with that of figure 28.

Example 9: preparation of Enarodusat-isonicotinine eutectic

Weighing 100mg of Enarodustat crystal form N6 and 60mg of isonicotin, adding 5mL of acetonitrile, suspending and pulping at 30 ℃ for 24h, filtering to obtain a filter cake, and drying the obtained filter cake to obtain 140mg of Enarodustat-isonicotin eutectic crystal; the obtained Enarodusat-isonicotine eutectic crystal is detected, the X-ray powder diffraction pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 1, the differential scanning calorimetry curve pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 2, the thermogravimetric analysis pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 3, and the nuclear magnetic resonance pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 32.

Example 10: preparation of Enarodustat-isonicotine eutectic

Weighing 100mg of Enaroustistat crystal form N6 and 60mg of isonicotin, adding 5mL of ethyl acetate, suspending and pulping at 30 ℃ for 24h, filtering to obtain a filter cake, and drying the filter cake to obtain 143mg of Enaroustistat-isonicotin eutectic crystal; the obtained Enarodusat-isonicotine eutectic crystal is detected, the X-ray powder diffraction pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 1, the differential scanning calorimetry curve pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 2, the thermogravimetric analysis pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 3, and the nuclear magnetic resonance pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 32.

Example 11: preparation of Enarodustat-isonicotine eutectic

Weighing 100mg of Enarodustat crystal form N6 and 60mg of isonicotin, adding 5mL of methanol, suspending and pulping at 30 ℃ for 24h, filtering to obtain a filter cake, and drying the obtained filter cake to obtain 148mg of Enarodustat-isonicotin eutectic crystal; the obtained Enarodusat-isonicotine eutectic crystal is detected, the X-ray powder diffraction pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 1, the differential scanning calorimetry curve pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 2, the thermogravimetric analysis pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 3, and the nuclear magnetic resonance pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 32.

Example 12: preparation of Enarodustat-isonicotine eutectic

Weighing 100mg of Enaroustistat crystal form N1 and 60mg of isonicotin, adding 5mL of ethanol, dissolving at 60 ℃, adding 15mL of N-heptane, stirring at 30 ℃ for 24 hours, filtering to obtain a filter cake, and drying the filter cake to obtain 131mg of Enaroustistat-isonicotin eutectic crystal; the obtained Enarodusat-isonicotine eutectic crystal is detected, the X-ray powder diffraction pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 1, the differential scanning calorimetry curve pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 2, the thermogravimetric analysis pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 3, and the nuclear magnetic resonance pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 32.

Example 13: preparation of Enarodustat-isonicotine eutectic

Weighing 100mg of Enaroustistat crystal form N6 and 60mg of isonicotin, adding 5mL of ethanol, dissolving at 60 ℃, adding 15mL of N-heptane, stirring at 30 ℃ for 24h, filtering to obtain a filter cake, and drying the filter cake to obtain 130mg of Enaroustistat-isonicotin eutectic crystal; the obtained Enarodusat-isonicotine eutectic crystal is detected, the X-ray powder diffraction pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 1, the differential scanning calorimetry curve pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 2, the thermogravimetric analysis pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 3, and the nuclear magnetic resonance pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 32.

Example 14: preparation of Enarodusat-isonicotinine eutectic

Weighing 100mg of Enaroustistat crystal form N1 and 60mg of isonicotin, adding 5mL of tetrahydrofuran, dissolving at 60 ℃, adding 15mL of N-heptane, stirring at 30 ℃ for 24h, filtering to obtain a filter cake, and drying the obtained filter cake to obtain 135mg of Enaroustistat-isonicotin eutectic crystal; the obtained Enarodusat-isonicotine eutectic crystal is detected, the X-ray powder diffraction pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 1, the differential scanning calorimetry curve pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 2, the thermogravimetric analysis pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 3, and the nuclear magnetic resonance pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 32.

Example 15: preparation of Enarodusat-isonicotinine eutectic

Weighing 100mg of Enaroustistat crystal form N1 and 60mg of isonicotin, adding 5mL of acetone, dissolving at 60 ℃, adding 15mL of N-heptane, stirring at 30 ℃ for 24 hours, filtering to obtain a filter cake, and drying the filter cake to obtain 128mg of Enaroustistat-isonicotin eutectic crystal; the obtained Enarodusat-isonicotine eutectic crystal is detected, the X-ray powder diffraction pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 1, the differential scanning calorimetry curve pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 2, the thermogravimetric analysis pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 3, and the nuclear magnetic resonance pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 32.

Example 16: preparation of Enarodusat-isonicotinine eutectic

Weighing 100mg of Enaroustistat crystal form N1 and 60mg of isonicotin, adding 3mL of tetrahydrofuran, dissolving and clearing at 60 ℃, volatilizing at 30 ℃, and volatilizing to obtain 116mg of Enaroustistat-isonicotin eutectic crystal; the obtained Enarodusat-isonicotine eutectic crystal is detected, the X-ray powder diffraction pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 1, the differential scanning calorimetry curve pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 2, the thermogravimetric analysis pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 3, and the nuclear magnetic resonance pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 32.

Example 17: preparation of Enarodusat-isonicotinine eutectic

Weighing 100mg of Enaroustistat crystal form N6 and 60mg of isonicotin, adding 3mL of tetrahydrofuran, dissolving and clearing at 60 ℃, volatilizing at 30 ℃, and volatilizing to obtain 120mg of Enaroustistat-isonicotin eutectic crystal; the obtained Enarodusat-isonicotine eutectic crystal is detected, the X-ray powder diffraction pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 1, the differential scanning calorimetry curve pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 2, the thermogravimetric analysis pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 3, and the nuclear magnetic resonance pattern of the Enarodusat-isonicotine eutectic crystal is basically consistent with that in figure 32.

Example 18: preparation of enariodusat-nicotinamide eutectic form 1

Weighing 100mg of Enaroustistat crystal form N6 and 60mg of nicotinamide, adding 5mL of ethanol, suspending and pulping at 30 ℃ for 24h, filtering to obtain a filter cake, and drying the filter cake, wherein the drying is drying at 20-30 ℃ by drying with nitrogen gas to obtain 110mg of Enaroustistat-nicotinamide eutectic form 1; the obtained Enarodusat-nicotinamide eutectic type 1 is detected, the X-ray powder diffraction pattern is basically consistent with that of figure 16, the differential scanning calorimetry curve pattern is basically consistent with that of figure 17, the thermogravimetric analysis pattern is basically consistent with that of figure 18, and the nuclear magnetic resonance pattern is basically consistent with that of figure 29. By adopting a drying mode of drying at a high temperature (such as a temperature of more than 50 ℃), the Enaroustistat-nicotinamide eutectic type 1 is unstable and crystal transformation can occur.

Example 19: preparation of Enarodustat-nicotinamide eutectic form 2

Weighing 100mg of Enaroustistat crystal form N6 and 60mg of nicotinamide, adding 5mL of ethyl acetate at 30 ℃, suspending and pulping for 24h at 30 ℃, filtering to obtain a filter cake, and drying the obtained filter cake to obtain 133mg of Enaroustistat-nicotinamide eutectic type 2; the obtained Enarodusat-nicotinamide eutectic type 2 is detected, the X-ray powder diffraction pattern is basically consistent with that of figure 4, the differential scanning calorimetry curve pattern is basically consistent with that of figure 5, the thermogravimetric analysis pattern is basically consistent with that of figure 6, and the nuclear magnetic resonance pattern is basically consistent with that of figure 30.

Example 20: preparation of Enarodustat-nicotinamide eutectic type 2

Weighing 100mg of Enaroustistat crystal form N6 and 60mg of nicotinamide, adding 5mL of acetone, dissolving at 60 ℃, adding 15mL of N-heptane, stirring at 30 ℃ for 24h, filtering to obtain a filter cake, and drying the obtained filter cake to obtain 125mg of Enaroustistat-nicotinamide eutectic form 2; and detecting the obtained Enarodusat-nicotinamide eutectic type 2, wherein the X-ray powder diffraction pattern is basically consistent with that in figure 4, the differential scanning calorimetry curve pattern is basically consistent with that in figure 5, the thermogravimetric analysis pattern is basically consistent with that in figure 6, and the nuclear magnetic resonance pattern is basically consistent with that in figure 30.

Example 21: preparation of Enarodustat-nicotinamide eutectic form 2

Weighing 100mg of Enaroustistat crystal form N6 and 60mg of nicotinamide, adding 5mL of tetrahydrofuran, dissolving at 60 ℃, adding 15mL of N-heptane, stirring at 30 ℃ for 24 hours, filtering to obtain a filter cake, and drying the obtained filter cake to obtain 123mg of Enaroustistat-nicotinamide eutectic crystal form 2; and detecting the obtained Enarodusat-nicotinamide eutectic type 2, wherein the X-ray powder diffraction pattern is basically consistent with that in figure 4, the differential scanning calorimetry curve pattern is basically consistent with that in figure 5, the thermogravimetric analysis pattern is basically consistent with that in figure 6, and the nuclear magnetic resonance pattern is basically consistent with that in figure 30.

Example 22: preparation of Enarodustat-nicotinamide eutectic form 2

Weighing 100mg of Enaroustistat crystal form N1 and 60mg of nicotinamide, adding 5mL of acetone, dissolving at 60 ℃, adding 15mL of N-heptane, stirring at 30 ℃ for 24h, filtering to obtain a filter cake, and drying the obtained filter cake to obtain 120mg of Enaroustistat-nicotinamide eutectic form 2; the obtained Enarodusat-nicotinamide eutectic type 2 is detected, the X-ray powder diffraction pattern is basically consistent with that of figure 4, the differential scanning calorimetry curve pattern is basically consistent with that of figure 5, the thermogravimetric analysis pattern is basically consistent with that of figure 6, and the nuclear magnetic resonance pattern is basically consistent with that of figure 30.

Example 23: preparation of Enarodustat-nicotinamide eutectic form 2

Weighing 100mg of Enaroustistat crystal form N1 and 60mg of nicotinamide, adding 5mL of tetrahydrofuran, dissolving at 60 ℃, adding 15mL of N-heptane, stirring at 30 ℃ for 24h, filtering to obtain a filter cake, and drying the obtained filter cake to obtain 120mg of Enaroustistat-nicotinamide eutectic form 2; the obtained Enarodusat-nicotinamide eutectic type 2 is detected, the X-ray powder diffraction pattern is basically consistent with that of figure 4, the differential scanning calorimetry curve pattern is basically consistent with that of figure 5, the thermogravimetric analysis pattern is basically consistent with that of figure 6, and the nuclear magnetic resonance pattern is basically consistent with that of figure 30.

Example 24: preparation of Enarodustat-nicotinamide eutectic type 2

Weighing 100mg of Enaroustistat crystal form N1 and 60mg of nicotinamide, adding 3mL of tetrahydrofuran, dissolving and cleaning at 60 ℃, volatilizing at 30 ℃, and volatilizing to obtain 118mg of Enaroustistat-nicotinamide eutectic crystal form 2; the obtained Enarodusat-nicotinamide eutectic type 2 is detected, the X-ray powder diffraction pattern is basically consistent with that of figure 4, the differential scanning calorimetry curve pattern is basically consistent with that of figure 5, the thermogravimetric analysis pattern is basically consistent with that of figure 6, and the nuclear magnetic resonance pattern is basically consistent with that of figure 30.

Example 25: preparation of Enarodustat-nicotinamide eutectic form 2

Weighing 100mg of Enaroustistat crystal form N6 and 60mg of nicotinamide, adding 3mL of tetrahydrofuran, dissolving and clearing at 60 ℃, volatilizing at 30 ℃, and volatilizing to obtain 115mg of Enaroustistat-nicotinamide eutectic crystal form 2; the obtained Enarodusat-nicotinamide eutectic type 2 is detected, the X-ray powder diffraction pattern is basically consistent with that of figure 4, the differential scanning calorimetry curve pattern is basically consistent with that of figure 5, the thermogravimetric analysis pattern is basically consistent with that of figure 6, and the nuclear magnetic resonance pattern is basically consistent with that of figure 30.

Example 26: preparation of Enarodustat-nicotinamide eutectic type 3

Weighing 100mg of Enaroustistat crystal form N1 and 60mg of nicotinamide, adding 5mL of ethanol, dissolving at 60 ℃, adding 15mL of N-heptane, stirring at 30 ℃ for 24h, filtering to obtain a filter cake, and drying the obtained filter cake to obtain 123mg of Enaroustistat-nicotinamide eutectic form 3; the obtained Enarodusat-nicotinamide eutectic type 3 is detected, the X-ray powder diffraction pattern is basically consistent with that of figure 13, the differential scanning calorimetry curve pattern is basically consistent with that of figure 14, the thermogravimetric analysis pattern is basically consistent with that of figure 15, and the nuclear magnetic resonance pattern is basically consistent with that of figure 31.

Example 27: preparation of Enarodusat-isoniazid salt form

Weighing 150mg of Enaroustistat crystal form N1 and 65mg of isoniazid, adding 3mL of acetone, dissolving at 60 ℃, adding 15mL of N-heptane, stirring at 30 ℃ for about 24 hours, and filtering to obtain 179mg of Enaroustistat-isoniazid salt form; the obtained Enarodustat-isoniazid salt type is detected, the X-ray powder diffraction pattern is basically consistent with figure 19, the differential scanning calorimetry curve pattern is basically consistent with figure 20, the thermogravimetric analysis pattern is basically consistent with figure 21, and the nuclear magnetic resonance pattern is basically consistent with figure 33.

Example 28: stability test

According to the guiding principle of the stability test of the raw material medicine, influence factor experiments are respectively carried out on the Enaroustistat crystal form N1, the Enaroustistat-benzamide eutectic, the Enaroustistat-cinnamamide eutectic, the Enaroustistat-isonicotin eutectic, the Enaroustistat-nicotinamide eutectic type 2, the Enaroustistat-nicotinamide eutectic type 3 and the Enaroustistat-isoniazid salt type, wherein the influence factor experiments comprise a high-temperature test, a high-humidity test and a strong light irradiation test, and the stability conditions of all crystal forms under different conditions are inspected.

The experimental conditions are as follows:

light test (light UV + VIS): taking appropriate amounts of Enaroustistat crystal form N1, enaroustistat-benzamide eutectic, enaroustistat-cinnamamide eutectic, enaroustistat-isonicotin eutectic, enaroustistat-nicotinamide eutectic type 2, enaroustistat-nicotinamide eutectic type 3 and Enaroustistat-isoniazide salt type respectively, tiling the obtained product into a weighing bottle, opening the weighing bottle, placing the obtained product in a constant temperature and humidity chamber (25 ℃, RH 60% +/-5%) with visible light 4500Lux +/-500 Lux (VIS) and ultraviolet light 1.7W X h/m2 (UV), taking about 20mg of the sample in 15 days respectively, and testing the crystal form condition by adopting X-ray powder diffraction (X-ray powder diffraction).

High humidity test (high humidity 25 ℃ +92.5% RH): taking proper amounts of Enaroustistat crystal form N1, enaroustistat-benzamide eutectic, enaroustistat-cinnamamide eutectic, enaroustistat-isonicotinite eutectic, enaroustistat-nicotinamide eutectic type 2, enaroustistat-nicotinamide eutectic type 3 and Enaroustistat-isoniazide salt type respectively, tiling the obtained materials in a weighing bottle, opening the weighing bottle, placing the weighing bottle in a constant temperature and humidity box with the temperature of 25 ℃ and the RH of 92.5 +/-5 percent, taking samples of about 20mg in 15 days respectively, and testing the crystal form conditions by adopting X-ray powder diffraction (X-ray powder diffraction).

High temperature test (high temperature 60 ℃): taking an appropriate amount of Enaroustistat crystal form N1, enaroustistat-benzamide eutectic, enaroustistat-cinnamamide eutectic, enaroustistat-isonicotinite eutectic, enaroustistat-nicotinamide eutectic type 2, enaroustistat-nicotinamide eutectic type 3 and Enaroustistat-isoniazide salt type respectively, tiling and placing in a weighing bottle, opening, placing in a constant temperature box at 60 +/-5 ℃ (without controlling humidity), then taking samples of about 20mg respectively in 15 days, and testing the crystal form condition by adopting X-ray powder diffraction (X-ray powder diffraction).

The experimental results are as follows: the results are shown in Table 1.

Table 1: results of stability experiment

And (4) conclusion: the Enaroustitat crystal form N1 can generate crystal transformation under the high-temperature condition, and the crystal form stability is poor, while the Enaroustitat-benzamide eutectic, the Enaroustitat-cinnamamide eutectic, the Enaroustitat-isonicotinite eutectic, the Enaroustitat-nicotinamide eutectic type 2, the Enaroustitat-nicotinamide eutectic type 3 and the Enaroustitat-isonicotinate provided by the invention can keep stable crystal forms and have good crystal form stability under the condition of influencing factors.

Example 29: solubility detection

Solubility assay of each solid form in phosphate buffer solution pH 4.5: weighing a flask and a stirrer in advance, respectively and accurately weighing an Enaroustiat crystal form N6, an Enaroustiat-benzamide eutectic, an Enaroustiat-cinnamamide eutectic, an Enaroustiat-isonicotinic eutectic, an Enaroustiat-nicotinamide eutectic type 2, an Enaroustiat-nicotinamide eutectic type 3 and an Enaroustiat-isoniazide proper amount, respectively adding into the small flask, dropwise adding a phosphate buffer solution with pH 4.5, magnetically stirring at a rotation speed of 200rpm, and stopping adding the buffer solution until the solid is completely dissolved. No visible particles were visible and considered to be completely dissolved. After dissolution, the total weight of the test tube, stirrer, and buffer was weighed, the weight of the buffer added was calculated, and then the solubility was calculated, and the results of the solubility test are shown in table 2. Wherein the Enarodustat crystal form N1 is unstable in a buffer solution with pH 4.5 and can be transformed into crystal form N6, so the solubility of the crystal form N6 is experimentally tested to be used as comparative data.

Table 2: solubility of each Enarodusat solid form

And (4) analyzing results: as can be seen from Table 2, enarodustat form N6 is in a non-wetting state in a phosphate buffer solution with pH 4.5, the solubility is extremely low, and is only 12.5. Mu.g/ml, and the solubilities of the obtained eutectic crystal and salt form in the phosphate buffer solution with pH 4.5 are greatly improved. The solubility of the enariostat-isonicotin co-crystal in phosphate buffer solution at pH 4.5 at 37 ℃, calculated as enariostat, is 28.3 times the solubility of enariostat form N6; the solubility of the Enarodustat-nicotinamide eutectic type 2 is 17.1 times of the solubility of the Enarodustat crystal form N6; the solubility of the enariodustat-benzamide co-crystal is 13.0 times of the solubility of enariodustat form N6; the solubility of the Enaroustitat-cinnamamide eutectic is 4.6 times of the solubility of Enaroustitat crystal form N6; the solubility of the enariodustat-isoniazid salt form is 3.1 times that of enariodustat form N6; the solubility of the Enarodustat-nicotinamide eutectic form 3 is 2.8 times the solubility of the Enarodustat form N6.

While the methods of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods and applications described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention within the intended scope, spirit and scope of the invention. Those skilled in the art can modify the process parameters appropriately in view of the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.

Claims

1. A solid form of Enarodusat comprising an Enarodusat co-crystal or Enarodusat salt form, said Enarodusat co-crystal comprising: an enodicat-isonicotine co-crystal, enodicat-nicotinamide co-crystal type 2, enodicat-benzamide co-crystal, enodicat-cinnamamide co-crystal or enodicat-nicotinamide co-crystal type 3; the Enaroustistat salt type is Enaroustistat-isoniazid salt type; wherein the molar ratio of Enaroustistat to isonicotin in the Enaroustistat-isonicotin eutectic is 1; the molar ratio of Enaroustistat to nicotinamide in the Enaroustistat-nicotinamide eutectic type 2 is 1; the molar ratio of Enaroustistat to benzamide in the Enaroustistat-benzamide eutectic is 1; the molar ratio of Enaroustistat to cinnamamide in the Enaroustistat-cinnamamide eutectic is 1; the molar ratio of Enaroustistat to nicotinamide in the Enaroustistat-nicotinamide eutectic type 3 is 2; the molar ratio of Enaroustistat to isoniazid in the Enaroustistat-isoniazid salt form is 1.

2. The solid form of claim 1, the Enarodustat-isonicotinic co-crystal having an X-ray powder diffraction pattern having characteristic peaks at diffraction angles, 2 θ, of 5.5 ± 0.2 °,8.3 ± 0.2 °,14.0 ± 0.2 ° and 19.6 ± 0.2 °; or the X-ray powder diffraction pattern of the Enaroustistat-isonicotin eutectic has characteristic peaks at diffraction angles 2theta of 5.5 +/-0.2 degrees, 8.3 +/-0.2 degrees, 11.1 +/-0.2 degrees, 14.0 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.8 +/-0.2 degrees, 17.9 +/-0.2 degrees, 19.6 +/-0.2 degrees, 22.5 +/-0.2 degrees, 22.9 +/-0.2 degrees, 24.7 +/-0.2 degrees, 26.7 +/-0.2 degrees, 28.2 +/-0.2 degrees, 31.1 +/-0.2 degrees, 32.4 +/-0.2 degrees, 34.9 +/-0.2 degrees, 37.0 +/-0.2 degrees and 37.9 +/-0.2 degrees.

3. The solid form of claim 1 or 2, having an endothermic peak at 140 ℃ -170 ℃ in a differential scanning calorimetry curve of the enarodust at-isonicotin co-crystal.

4. The solid form of claim 3, the Enarodustat-isonicotinic co-crystal having an endothermic peak within 150 ℃ -160 ℃.

5. The solid form of any one of claims 1-4, having a weight loss of no more than 1% in the thermogravimetric analysis curve of the Enarodustat-isonicotinic co-crystal between 30 ℃ and 125 ℃.

6. The solid form of claim 1, said Enarodustat-nicotinamide eutectic pattern 2 having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles, 2 θ, of 7.1 ± 0.2 °,7.6 ± 0.2 °,15.3 ± 0.2 °,16.2 ± 0.2 °,17.5 ± 0.2 ° and 17.8 ± 0.2 °; or the X-ray powder diffraction pattern of the Enaroustistat-nicotinamide eutectic pattern 2 has characteristic peaks at diffraction angles 2theta of 7.1 +/-0.2 degrees, 7.6 +/-0.2 degrees, 15.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.5 +/-0.2 degrees, 17.8 +/-0.2 degrees, 18.5 +/-0.2 degrees, 19.5 +/-0.2 degrees, 20.0 +/-0.2 degrees, 23.2 +/-0.2 degrees, 23.9 +/-0.2 degrees and 25.1 +/-0.2 degrees; or the X-ray powder diffraction pattern of the Enaroustistat-nicotinamide eutectic type 2 is 7.1 +/-0.2 degrees, 7.6 +/-0.2 degrees, 8.8 +/-0.2 degrees, 9.7 +/-0.2 degrees, 14.3 +/-0.2 degrees, 15.3 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.5 +/-0.2 degrees, 17.8 +/-0.2 degrees, 18.5 +/-0.2 degrees, 19.5 +/-0.2 degrees, 20.0 +/-0.2 degrees, 21.9 +/-0.2 degrees, characteristic peaks are at 23.2 + -0.2 deg., 23.9 + -0.2 deg., 25.1 + -0.2 deg., 25.8 + -0.2 deg., 27.0 + -0.2 deg., 27.4 + -0.2 deg., 27.8 + -0.2 deg., 28.3 + -0.2 deg., 28.9 + -0.2 deg., 30.2 + -0.2 deg., 31.5 + -0.2 deg., 32.5 + -0.2 deg., 32.9 + -0.2 deg., 33.8 + -0.2 deg., 34.8 + -0.2 deg., 35.5 + -0.2 deg., 37.6 + -0.2 deg. and 38.8 + -0.2 deg..

7. The solid form of claim 1 or 6, having an endothermic peak at 130 ℃ -160 ℃ in a differential scanning calorimetry curve of the Enarodustat-nicotinamide eutectic pattern 2.

8. The solid form of claim 7, the Enarodustat-nicotinamide eutectic pattern 2 having an endothermic peak within 140 ℃ -150 ℃.

9. The solid form of any one of claims 1 and 6-8, having a weight loss of no more than 0.6% in the thermogravimetric analysis curve of the enariodustat-nicotinamide eutectic pattern 2 from 30 ℃ to 125 ℃.

10. The solid form of claim 1, the Enarodustat-benzamide co-crystal having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles, 2 θ, of 7.5 ± 0.2 °,9.3 ± 0.2 °,15.2 ± 0.2 °,16.3 ± 0.2 °,16.9 ± 0.2 °,18.7 ± 0.2 °,21.9 ± 0.2 °,25.7 ± 0.2 °,31.5 ± 0.2 ° and 17.8 ± 0.2 °; or the X-ray powder diffraction pattern of the Enarodustat-benzamide eutectic has characteristic peaks at diffraction angles 2theta of 4.8 +/-0.2 degrees, 7.5 +/-0.2 degrees, 9.3 +/-0.2 degrees, 9.6 +/-0.2 degrees, 15.2 +/-0.2 degrees, 15.8 +/-0.2 degrees, 16.3 +/-0.2 degrees, 16.9 +/-0.2 degrees, 18.7 +/-0.2 degrees, 21.2 +/-0.2 degrees, 21.4 +/-0.2 degrees, 21.9 +/-0.2 degrees, 23.0 +/-0.2 degrees, 24.0 +/-0.2 degrees, 25.3 +/-0.2 degrees, 25.7 +/-0.2 degrees, 26.5 +/-0.2 degrees, 27.8 +/-0.2 degrees and 31.5 +/-0.2 degrees; or the X-ray powder diffraction pattern of the Enarodustat-benzamide eutectic has characteristic peaks at diffraction angles 2theta of 4.8 +/-0.2 degrees, 7.5 +/-0.2 degrees, 8.6 +/-0.2 degrees, 9.3 +/-0.2 degrees, 9.6 +/-0.2 degrees, 11.8 +/-0.2 degrees, 14.5 +/-0.2 degrees, 15.2 +/-0.2 degrees, 15.8 +/-0.2 degrees, 16.3 +/-0.2 degrees, 16.9 +/-0.2 degrees, 17.4 +/-0.2 degrees, 18.7 +/-0.2 degrees, 21.2 +/-0.2 degrees, 21.4 +/-0.2 degrees, 21.9 +/-0.2 degrees, 23.0 +/-0.2 degrees, 24.0 +/-0.2 degrees, 24.9 +/-0.2 degrees, 25.3 +/-0.2 degrees, 25.7 +/-0.2 degrees, 26.5 +/-0.2 degrees, 27.8 +/-0.2 degrees, 29.8 +/-0.2 degrees, 30.2 degrees, 30.9 +/-0.2 degrees, 25.3 +/-0.2 degrees, 33.2 degrees, 33.3 +/-0.2 degrees, and 2.5 +/-0.2 degrees, 2 degrees.

11. The solid form of claim 1 or 10, the enarodust at-benzamide co-crystal having an endothermic peak in a differential scanning calorimetry curve at 140 ℃ -160 ℃.

12. The solid form of claim 11, the Enarodustat-benzamide co-crystal having an endothermic peak within 145 ℃ -155 ℃.

13. The solid form of any one of claims 1 and 10-12, having a weight loss of no more than 0.6% in the thermogravimetric analysis curve of the enariodustat-benzamide co-crystal at 30 ℃ to 125 ℃.

14. The solid form of claim 1, the Enarodustat-cinnamamide co-crystal having an X-ray powder diffraction pattern having characteristic peaks at diffraction angles, 2 θ, of 7.5 ± 0.2 °,11.4 ± 0.2 °,14.9 ± 0.2 °,17.2 ± 0.2 °,19.3 ± 0.2 °,23.3 ± 0.2 °,24.3 ± 0.2 ° and 25.7 ± 0.2 °; or the X-ray powder diffraction pattern of the Enarodustat-cinnamamide eutectic has characteristic peaks at diffraction angles 2theta of 7.5 +/-0.2 degrees, 10.0 +/-0.2 degrees, 11.4 +/-0.2 degrees, 13.1 +/-0.2 degrees, 13.7 +/-0.2 degrees, 14.9 +/-0.2 degrees, 15.2 +/-0.2 degrees, 16.5 +/-0.2 degrees, 17.2 +/-0.2 degrees, 19.3 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.7 +/-0.2 degrees, 21.0 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.4 +/-0.2 degrees, 23.3 +/-0.2 degrees, 23.8 +/-0.2 degrees, 24.3 +/-0.2 degrees, 25.7 +/-0.2 degrees, 26.2 degrees, 26.5 +/-0.2 degrees, 27.7 +/-0.2.30.1 +/-0.2 degrees and 37.2 degrees; or the X-ray powder diffraction pattern of the Enaroustistat-cinnamamide eutectic crystal is 7.5 +/-0.2 degrees, 10.0 +/-0.2 degrees, 11.4 +/-0.2 degrees, 12.0 +/-0.2 degrees, 12.4 +/-0.2 degrees, 13.1 +/-0.2 degrees, 13.7 +/-0.2 degrees at the diffraction angle 2theta, 14.9 +/-0.2 degrees, 15.2 +/-0.2 degrees, 16.0 +/-0.2 degrees, 16.5 +/-0.2 degrees, 17.2 +/-0.2 degrees, 19.3 +/-0.2 degrees, 19.7 +/-0.2 degrees, 20.2 +/-0.2 degrees, 20.7 +/-0.2 degrees, 21.0 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.4 +/-0.2 degrees, characteristic peaks are arranged at 22.9 +/-0.2 degrees, 23.3 +/-0.2 degrees, 23.8 +/-0.2 degrees, 24.3 +/-0.2 degrees, 24.6 +/-0.2 degrees, 25.2 +/-0.2 degrees, 25.7 +/-0.2 degrees, 26.2 +/-0.2 degrees, 26.5 +/-0.2 degrees, 27.1 +/-0.2 degrees, 27.7 +/-0.2 degrees, 28.2 +/-0.2 degrees, 29.1 +/-0.2 degrees, 29.7 +/-0.2 degrees, 30.1 +/-0.2 degrees, 30.8 +/-0.2 degrees, 31.6 +/-0.2 degrees, 33.3 +/-0.2 degrees, 34.2 +/-0.2 degrees, 35.1 +/-0.2 degrees, 35.7 +/-0.2 degrees, 37.2 +/-0.2 degrees, 38.2 +/-0.2 degrees and 39.2 +/-0.2 degrees.

15. The solid form of claim 1 or 14, the Enarodustat-cinnamamide co-crystal having an endothermic peak at 150 ℃ -180 ℃ in a differential scanning calorimetry curve.

16. The solid form of claim 15, the enarodust at-cinnamamide co-crystal having an endothermic peak within 160 ℃ to 170 ℃.

17. The solid form of any one of claims 1 and 14-16, the enariodustat-cinnamamide co-crystal having a weight loss of no more than 0.6% in a thermogravimetric analysis curve at 30 ℃ to 125 ℃.

18. The solid form of claim 1, said Enarodustat-nicotinamide eutectic pattern 3 having an X-ray powder diffraction pattern with characteristic peaks at diffraction angles, 2 Θ, of 6.1 ± 0.2 °,12.3 ± 0.2 ° and 17.8 ± 0.2 °; or the X-ray powder diffraction pattern of the Enaroustistat-nicotinamide eutectic type 3 has characteristic peaks at diffraction angles 2theta of 6.1 +/-0.2 degrees, 12.3 +/-0.2 degrees, 15.4 +/-0.2 degrees, 17.8 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.7 +/-0.2 degrees, 29.2 +/-0.2 degrees, 34.5 +/-0.2 degrees and 38.6 +/-0.2 degrees; or the X-ray powder diffraction pattern of the Enaroustistat-nicotinamide eutectic type 3 has the characteristic that the diffraction angle 2theta has the peak values of 6.1 +/-0.2 degrees, 9.2 +/-0.2 degrees, 11.5 +/-0.2 degrees, 12.3 +/-0.2 degrees, 13.5 +/-0.2 degrees, 15.2 +/-0.2 degrees, 15.4 +/-0.2 degrees, 15.9 +/-0.2 degrees, 16.2 +/-0.2 degrees, 17.8 +/-0.2 degrees, 18.5 +/-0.2 degrees, 20.8 +/-0.2 degrees, 21.3 +/-0.2 degrees, 21.7 +/-0.2 degrees, 22.0 +/-0.2 degrees, 22.3 +/-0.2 degrees, 23.4 +/-0.2 degrees, 24.1 +/-0.2 degrees, 24.8 +/-0.2 degrees, 25.4 +/-0.2 degrees, 26.8 +/-0.2 degrees, 28.1 +/-0.2 degrees, 28.8 +/-0.2.2 degrees, 30.2 +/-0.2.2 degrees, 30.5 +/-0.2 degrees, 0.5 +/-0.2 degrees, 9.2 degrees, 2.2.2 degrees, 9 +/-0.2.2 degrees, 30.2.2.2 degrees, 9 +/-0.2 degrees, 9.2.2 degrees, 9 +/-0.2.2 degrees, 2.2.2.2.2 degrees, 30.2 degrees, 30.2.2 degrees, 30.2 degrees, 0.2.2 degrees, 9 +/-0.2.2.2 degrees, 9 +/-0.2 degrees, 2.2 degrees, 2 degrees, 2.2.2 degrees, 2 degrees, 2.2.2.2.2 degrees, 2.2.2.2.2.2 degrees, 9.

19. The solid form of claim 1 or 18, having an endothermic peak at 130 ℃ -160 ℃ in a differential scanning calorimetry curve of Enarodustat-nicotinamide eutectic pattern 3.

20. The solid form of claim 19, the peak of the endotherm of enariodustat-nicotinamide eutectic pattern 3 is within 140 ℃ -150 ℃.

21. The solid form of any one of claims 1 and 18-20, having a weight loss of no more than 1.5% in the thermogravimetric analysis curve of enariodustat-nicotinamide eutectic pattern 3 from 30 ℃ to 125 ℃.

22. The solid form of claim 1, having an X-ray powder diffraction pattern for the Enarodustat-isoniazid salt form having characteristic peaks at diffraction angles 2 Θ of 7.0 ± 0.2 °,18.6 ± 0.2 °,21.4 ± 0.2 °,26.6 ± 0.2 ° and 27.6 ± 0.2 °; or the X-ray powder diffraction pattern of the Enarodustat-isoniazid salt type has characteristic peaks at diffraction angles 2theta of 7.0 +/-0.2 degrees, 9.9 +/-0.2 degrees, 13.4 +/-0.2 degrees, 16.6 +/-0.2 degrees, 18.4 +/-0.2 degrees, 18.6 +/-0.2 degrees, 19.4 +/-0.2 degrees, 21.4 +/-0.2 degrees, 23.0 +/-0.2 degrees, 25.2 +/-0.2 degrees, 26.6 +/-0.2 degrees and 27.6 +/-0.2 degrees; or the diffraction angle 2theta of the X-ray powder diffraction pattern of the Enaroustistat-isoniazid salt type is 7.0 +/-0.2 degrees, 9.1 +/-0.2 degrees, 9.9 +/-0.2 degrees, 13.4 +/-0.2 degrees, 13.7 +/-0.2 degrees, 14.6 +/-0.2 degrees, 15.0 +/-0.2 degrees, 15.5 +/-0.2 degrees, 16.6 +/-0.2 degrees, 18.4 +/-0.2 degrees, 18.6 +/-0.2 degrees, 18.9 +/-0.2 degrees, 19.4 +/-0.2 degrees, 19.8 +/-0.2 degrees, 20.0 +/-0.2 degrees, 20.8 +/-0.2 degrees, 21.4 +/-0.2 degrees, 22.2 +/-0.2 degrees, 23.0 +/-0.2 degrees, 23.5 +/-0.2 degrees, 24.1 +/-0.2 degrees, 25.2 +/-0.2 degrees, 26.6 +/-0.2 degrees, 27.1 +/-0.2 degrees, 27.6 +/-0.2 degrees, 29.7 +/-0.2 degrees, 32.4 +/-0.2 degrees, 34.6 +/-0.2 degrees, 36.2 +/-0.2 degrees, 37.4 +/-0.2 degrees, 38.5 +/-0.2 degrees and 39.2 +/-0.2 degrees have characteristic peaks.

23. The solid form of claim 1 or 22, having an endothermic peak at 110 ℃ -150 ℃ in a differential scanning calorimetry curve for the Enarodustat-isoniazid salt form.

24. The solid form of claim 23, the peak of the endotherm of the Enarodustat-isoniazid salt form is within 120 ℃ -130 ℃.

25. The solid form of any one of claims 1 and 22-24, having a weight loss of no more than 0.7% in the thermogravimetric analysis curve of the Enarodustat-isoniazid salt form at 30 ℃ to 125 ℃.

26. A composition comprising the solid form of any one of claims 1-25 and a pharmaceutically acceptable excipient.

27. The composition according to claim 26, wherein the solid form is at least 0.05-95% by mass of the total mass of the composition.

28. A method of preparing the solid form of any one of claims 1-25, comprising: mixing Enaroustistat crystal form N6, a ligand A and a solvent I, wherein the ligand A is isonicotin, nicotinamide, benzamide or cinnamamide, suspending and pulping, filtering to obtain a filter cake, and drying the filter cake to obtain the solid form; or comprises the following steps: dissolving Enaroustistat solid and a ligand B in a solvent II, wherein the ligand B is isonicotine, nicotinamide, benzamide, cinnamamide or isoniazid, adding an anti-solvent, stirring, filtering to obtain a filter cake, and drying the obtained filter cake to obtain the solid form; or comprises the following steps: dissolving Enaroustistat solid and a ligand C in a solvent III, wherein the ligand C is isonicotin, nicotinamide, benzamide or cinnamamide, and volatilizing to obtain the solid form.

29. The process of claim 28, said solvent I comprising at least one selected from ethyl acetate, acetonitrile and methanol, said ligand a being isonicotin, resulting in an enarodust at-isonicotin co-crystal; or the solvent I comprises or is ethyl acetate, the ligand A is nicotinamide, and an Enaroustistat-nicotinamide eutectic type 2 is obtained; or the solvent I comprises at least one selected from ethyl acetate, acetonitrile and methanol, the ligand A is benzamide, and Enaroustistat-benzamide eutectic is obtained; or the solvent I comprises at least one selected from ethyl acetate, acetonitrile and methanol, and the ligand A is cinnamamide, so that the Enaroustistat-cinnamamide eutectic is obtained.

30. The method of claim 28, said solvent II comprising at least one selected from tetrahydrofuran, ethanol and acetone, said ligand B being isonicotin, resulting in an enarodust at-isonicotin co-crystal; or the solvent II comprises at least one of tetrahydrofuran and acetone, the ligand B is nicotinamide, and the Enaroustistat-nicotinamide eutectic type 2 is obtained; or the solvent II comprises at least one selected from tetrahydrofuran, ethanol and acetone, the ligand B is benzamide, and Enaroustistat-benzamide eutectic is obtained; or the solvent II comprises at least one selected from tetrahydrofuran, ethanol and acetone, the ligand B is cinnamamide, and Enaroustistat-cinnamamide eutectic is obtained; or the solvent II comprises or is acetone, the ligand B is isoniazid, and an Enaroustistat-isoniazid salt type is obtained; or the solvent II is ethanol, and the ligand B is nicotinamide, so that the Enaroustistat-nicotinamide eutectic type 3 is obtained.

31. The process according to claim 28, said solvent III being tetrahydrofuran, said ligand C being isonicotin, resulting in an enarodust at-isonicotin co-crystal; or the solvent III is tetrahydrofuran and the ligand C is nicotinamide, so that an Enaroustistat-nicotinamide eutectic type 2 is obtained; or the solvent III is tetrahydrofuran, and the ligand C is benzamide, so that an Enaroustistat-benzamide eutectic is obtained; or the solvent III is tetrahydrofuran, and the ligand C is cinnamamide, so that the Enaroustistat-cinnamamide eutectic is obtained.

32. The process of any one of claims 28 or 30, the anti-solvent comprising or being n-heptane.

33. The process of claim 28 or 29, wherein the suspension is slurried at a temperature of 20 ℃ -35 ℃.

34. The method of any one of claims 28 and 30-32, the temperature of dissolution being 40-80 ℃.

35. The process of any one of claims 28-30 and 32-34, wherein the time of slurrying of the suspension or the stirring is 24-48 h.

36. The process of any one of claims 28-35, wherein the charge mass ratio of Enarodustat form N6 to ligand a is 1; or the charging mass ratio of the Enarodustat solid to the ligand B is 1; or the charging mass ratio of the Enarodustat solid to the ligand C is 1.

37. The process of any one of claims 28 to 36, wherein the ratio of charged mass of enarodust form N6 to charged volume of solvent I is from 20mg to 11ml; or the ratio of the charging mass of the Enaroustistat solid to the charging volume of the solvent II is 20mg to 1ml; or the ratio of the feeding mass of the Enaroustistat solid to the feeding volume of the solvent III is 25mg.

38. Use of a solid form according to any one of claims 1 to 25 or a composition according to any one of claims 26 to 27 in the manufacture of a medicament for the treatment of renal anemia.