CN114478512A

CN114478512A - Crystal form of acid and preparation method thereof

Info

Publication number: CN114478512A
Application number: CN202111208757.6A
Authority: CN
Inventors: 徐巾超; 时少展; 杨柳鸿; 张�杰; 陈勇; 黄芳芳
Original assignee: Sunshine Lake Pharma Co Ltd
Current assignee: Sunshine Lake Pharma Co Ltd
Priority date: 2020-10-27
Filing date: 2021-10-18
Publication date: 2022-05-13

Abstract

The invention mainly provides a crystal 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 solubility, and can be applied to pharmaceutical preparations.

Description

Crystal form of acid and preparation method thereof

Technical Field

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

Background

The compound Lanifibranor has the structure shown in the following formula, is a pan-peroxisome proliferator-activated receptor (PPAR) agonist, can be used for treating NASH (non-alcoholic fatty liver disease), is currently in clinical trials, and achieves primary and secondary endpoints in a clinical phase II trial.

The patent CN101248044B discloses the preparation method and melting point information of lanifibraner, but does not disclose the specific crystal form information. Because the crystal 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 crystal forms may have differences in various aspects, and 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, the crystal form of the drug needs to be researched. The inventor carries out related research on the crystal form of the Lanifibraner and discovers a new crystal form which can be applied.

Disclosure of Invention

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 or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), 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 found in the descriptions of "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 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 "comprising" or "comprises" is open-ended, i.e. comprising what is specified in the present invention, but not excluding other aspects.

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, some diffraction peaks in an X-ray powder diffraction pattern of the sample, 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 first strong peak to the intensity of the other peaks when the intensity of the first strong peak in a set of diffraction peaks assigned to a certain crystal form 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 ascribe to background noise.

The X-ray powder diffraction peak of the crystal, the 2theta or diffraction peak of the X-ray powder diffraction pattern of which has experimental error, may be slightly different between one machine and another machine and between one sample and another, the 2theta or diffraction peak of the X-ray powder diffraction pattern may have error of ± 0.2 ° in 2theta, and thus the value of the 2theta or diffraction peak cannot be regarded as absolute.

The Differential Scanning Calorimetry (DSC) curve of the crystal has experimental errors, the position and peak value of the endothermic peak may be slightly different 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 that the value of the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute.

The thermogravimetric analysis curve (TGA) of the crystal has experimental errors, the endothermic curve or the weight loss rate may slightly differ between one machine and another and between one sample and another, the numerical 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%, and thus the thermogravimetric analysis curve or the weight loss rate 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 a +/-1%, +/-2%, or +/-5% difference in each number based on the disclosed number. When used to approximate the 2theta (also known as 2theta or diffraction peak) value used to describe the X-ray powder diffraction peak, approximately means that there may be a +/-0.2 unit or +/-0.1 unit or +/-0.05 unit difference in the 2theta value.

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 100 g/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

On one hand, the inventor develops new crystal forms of the Lanifibraner through research, including a crystal form A, a crystal form B, a crystal form C, a crystal form D, a crystal form E, a crystal form F, a crystal form G, a crystal form H and a crystal form 1; amorphous forms of lanifibranator have also been developed.

A crystalline form of Lanifibranor, designated form A, having an X-ray powder diffraction pattern having at least 3 diffraction peaks selected from the group consisting of 16.7, 17.8, 20.2, 22.2, 24.5 and 25.2 degrees 2 θ (units: degrees, °, error ± 0.2 °).

In some embodiments, the form a has an X-ray powder diffraction pattern having diffraction peaks at 16.7, 17.8, 20.2, 22.2, 24.5, and 25.2 degrees 2 Θ. In some embodiments, the form a has an X-ray powder diffraction pattern having diffraction peaks at positions 7.7, 8.3, 10.8, 14.0, 15.6, 16.7, 17.8, 19.1, 20.2, 21.1, 22.2, 24.0, 24.5, 25.2, and 28.2 degrees 2 Θ. In some embodiments, form a has an X-ray powder diffraction pattern having diffraction peaks at 7.7, 8.3, 10.8, 14.0, 15.6, 16.4, 16.7, 17.0, 17.8, 19.1, 20.2, 21.1, 22.2, 23.8, 24.0, 24.5, 25.2, 25.5, 27.7, 28.2, 32.2, and 33.0 degrees 2 Θ.

In some embodiments, form a has an X-ray powder diffraction pattern having at least 3 or6 or 9 or 12 diffraction peaks selected from 7.7, 8.3, 10.8, 14.0, 15.6, 16.4, 16.7, 17.0, 17.8, 19.1, 20.2, 21.1, 22.2, 22.5, 23.2, 23.8, 24.0, 24.5, 25.2, 25.5, 26.3, 27.4, 27.7, 28.2, 29.7, 32.2, 33.0, 33.9, 34.1, 35.8, and 36.1 degrees 2 Θ.

In some embodiments, the form a has an X-ray powder diffraction pattern having diffraction peaks at 2 Θ of 7.7, 8.3, 10.8, 14.0, 15.6, 16.4, 16.7, 17.0, 17.8, 19.1, 20.2, 21.1, 22.2, 22.5, 23.2, 23.8, 24.0, 24.5, 25.2, 25.5, 26.3, 27.4, 27.7, 28.2, 29.7, 32.2, 33.0, 33.9, 34.1, 35.8, and 36.1 degrees.

In some embodiments, form a has an X-ray powder diffraction (XRPD) pattern as shown in figure 1.

The crystal form A also has the following characteristics that an endothermic peak is provided in a Differential Scanning Calorimetry (DSC) curve in the range of 175-185 ℃. In some embodiments, form a has an endothermic peak at 180 ± 3 ℃ in a Differential Scanning Calorimetry (DSC) curve. In some embodiments, form a has an endothermic peak at 180 ± 3 ℃ in a Differential Scanning Calorimetry (DSC) curve with a peak top value of 180 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form a is shown in figure 2.

The thermogravimetric analysis curve of the crystal form A sample has weight loss between 115 ℃ and 200 ℃, and the weight loss is about 1.54%.

In some embodiments, the thermogravimetric analysis curve (TGA) of form a is as shown in figure 3.

According to the experimental study on the stability of influencing factors, the crystal form A is a relatively stable crystal form, is stable under the conditions of high temperature, high humidity or illumination and is not easy to generate crystal form transformation.

A method of preparing Lanifibranor form a, comprising: dissolving a compound Lanifibranor in a crystallization solvent, cooling to separate out crystals, filtering and drying to obtain a crystal form A; or comprises the following steps: dissolving the Lanifibranor in a crystallization solvent, and volatilizing to obtain a crystal form A product; or comprises the following steps: and dissolving the Lanifibranor in a good solvent, mixing the solution with an anti-solvent after the solution is clear, separating out crystals, filtering and drying to obtain the crystal form A.

The crystallization solvent may be at least one of methanol, ethanol, N-propanol, isopropanol, ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, butyl acetate, dimethyl carbonate, dimethylformamide, dimethyl sulfoxide, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, and N-methylpyrrolidone.

The crystallization solvent may be a mixed solvent of water and at least one of methanol, ethanol, N-propanol, isopropanol, dimethylformamide, dimethylsulfoxide, acetonitrile, acetone, N-methylpyrrolidone, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, and tetrahydrofuran. When the crystallization solvent is a mixed solvent, the ratio of water to the organic solvent in the crystallization solvent can be 100:1 to 1:100 in terms of volume ratio.

The good solvent can be at least one of methanol, ethanol, N-propanol, isopropanol, ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate, butyl acetate, dimethyl carbonate, dimethylformamide, dimethyl sulfoxide, acetone, butanone, methyl isobutyl ketone, acetonitrile, tetrahydrofuran, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether and N-methylpyrrolidone.

The antisolvent may be at least one of trifluoroethanol, n-heptane, n-hexane, cyclohexane, isopropyl ether, and water.

The crystallization solvent may be used in an amount of 1ml to 200ml, or 1ml to 150ml, or 1ml to 100ml, or 1ml to 50ml, or 1ml to 30ml, or 1ml to 10ml per gram of the compound lanifimorator. In some embodiments, the crystallization solvent may be used in an amount of 5ml to 200ml, or 5ml to 100ml, or 5ml to 50ml, or 5ml to 30ml per gram of the compound lanifilor. In some embodiments, the crystallization solvent may be used in an amount of 1ml, 3ml, 5ml, 8ml, 10ml, 15ml, 20ml, 25ml, 40ml, 60ml, 80ml, or 120ml per gram of the compound lanifinaror.

The amount of the good solvent used may be 1ml to 200ml, or 1ml to 150ml, or 1ml to 100ml, or 1ml to 50ml, or 1ml to 30ml, or 1ml to 10ml per gram of the compound lanifimbranor. In some embodiments, the amount of the good solvent used may be 5ml to 200ml, or 5ml to 100ml, or 5ml to 50ml, or 5ml to 30ml per gram of the compound lanifinaror. In some embodiments, the good solvent may be used in an amount of 1ml, 3ml, 5ml, 8ml, 10ml, 15ml, 20ml, 25ml, 40ml, 60ml, 80ml, or 120ml per gram of the compound lanifinarator.

The anti-solvent may be used in an amount of 1ml to 300ml, or 1ml to 200ml, or 1ml to 150ml, or 1ml to 100ml, or 1ml to 50ml, or 1ml to 30ml, or 1ml to 10ml per gram of the compound lanifimorator. In some embodiments, the anti-solvent may be used in an amount of 5ml to 300ml, or 5ml to 200ml, or 5ml to 100ml, or 5ml to 50ml, or 5ml to 30ml per gram of the compound lanifinarator. In some embodiments, the anti-solvent may be used in an amount of 1ml, 3ml, 5ml, 8ml, 10ml, 15ml, 20ml, 25ml, 40ml, 60ml, 80ml, 120ml, 140ml, 160ml, 180ml, 230ml, 250ml, or 280ml per gram of the compound lanifinarator.

On the other hand, a new crystal form of Lanifibranor is called form B.

Crystalline form B of Lanifibranor having an X-ray powder diffraction pattern having diffraction peaks at 2 θ (units: degrees, °, error ± 0.2 °) of 10.0, 16.3, 17.7, 24.2, 24.7 and 26.4 degrees.

In some embodiments, the form B has an X-ray powder diffraction pattern having diffraction peaks at 10.0, 16.3, 17.5, 17.7, 19.3, 19.5, 24.2, 24.7, 26.4, 28.9, and 30.5 degrees 2 Θ.

In some embodiments, the form B has an X-ray powder diffraction pattern having diffraction peaks at 8.7, 9.4, 10.0, 13.4, 16.3, 17.5, 17.7, 18.8, 19.3, 19.5, 20.1, 21.9, 23.7, 24.2, 24.7, 26.4, 28.9, 30.5, 31.4, and 31.8 degrees 2 Θ.

In some embodiments, the form B has an X-ray powder diffraction (XRPD) pattern as shown in figure 4.

The Differential Scanning Calorimetry (DSC) curve of the crystal form B has endothermic peaks in the ranges of 105-125 ℃ and 165-185 ℃. In some embodiments, form B has Differential Scanning Calorimetry (DSC) endothermic peaks in the range of 115 ℃ to 125 ℃ and 170 ℃ to 180 ℃ with peak tops of 121 ℃ and 177 ℃, respectively. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form B is shown in figure 5.

Form B can be prepared by dissolving Lanifibranor in 1, 4-dioxane, followed by evaporation to remove the solvent.

According to the research, the crystal form B contains 1, 4-dioxane, and the solvent can be lost and the crystal form B is converted into another crystal form after the crystal form B is heated under certain conditions.

Through research, the inventor also develops a new crystal form of the Lanifibraner, which is called as a crystal form C. Form C has diffraction peaks at 11.3, 17.2, 18.4, 22.4, 24.6, and 27.5 degrees 2 θ (unit: degree, ± 0.2 °).

In some embodiments, form C has an X-ray powder diffraction pattern having diffraction peaks at 6.8, 11.3, 12.8, 13.7, 17.2, 18.4, 19.5, 21.4, 22.4, 23.0, 24.3, 24.6, 24.8, 27.5, 29.7, and 30.7 degrees 2 Θ (units: degrees, °).

In some embodiments, form C has an X-ray powder diffraction pattern having diffraction peaks at positions 2 θ (units: degrees, °) of 6.8, 11.3, 12.8, 13.7, 17.2, 17.7, 18.4, 19.5, 20.6, 21.4, 22.0, 22.4, 23.0, 23.5, 24.3, 24.6, 24.8, 25.2, 25.4, 27.5, 29.7, 30.7, 32.1, 34.0, and 37.5 degrees.

In some embodiments, form C has an X-ray powder diffraction (XRPD) pattern as shown in figure 6.

The crystal form C also has the following characteristics that the Differential Scanning Calorimetry (DSC) curve thereof has endothermic peaks in the range of 125-135 ℃ and 177-185 ℃. In some embodiments, form C has Differential Scanning Calorimetry (DSC) endothermic peaks in the range of 125 ℃ to 130 ℃ and 175 ℃ to 183 ℃, with peak tops of 129 ℃ and 180 ℃, respectively. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form C is shown in figure 7.

According to research, the crystal form C contains 1, 4-dioxane, has instability under certain conditions, and can lose the solvent and generate crystal transformation after being heated.

According to the embodiment of the invention, the crystal form C can be obtained by dissolving the Lanifibrane in 1, 4-dioxane, or in a mixed solvent of the 1, 4-dioxane and n-heptane, or in a mixed solvent of the 1, 4-dioxane and trifluoroethanol, then cooling to-5-20 ℃, precipitating crystals, and removing the solvent.

According to the embodiment of the invention, the Lanifinaror can be dissolved in 1, 4-dioxane, after the solution is clear, the anti-solvent is added, crystals are separated out, and the crystal form C is obtained by filtering and drying; the antisolvent may be at least one of n-heptane, cyclohexane, isopropyl ether.

In the method for preparing the crystal form C, the mass-to-volume ratio of the Lanifibranor to the 1, 4-dioxane can be 1g:1ml-1g:50ml, or 1g:35ml, or 1g:25ml, or 1g:15ml, or 1g:10ml, or 1g:5ml, or 1g:2.5 ml.

In the method for preparing the crystal form C, the mass-to-volume ratio of the Lanifibraner to the antisolvent can be 1g:1ml-1g:200ml, or 1g:1ml-1g:150ml, or 1g:1ml-1g:100ml, or 1g:1ml-1g:80ml, or 1g:1ml-1g:50 ml. In some embodiments, the method of preparing form C comprises a mass to volume ratio of Lanifibranor to the antisolvent of 1g:35ml, or 1g:25ml, or 1g:15ml, or 1g:10ml, or 1g:5ml, or 1g:2.5 ml.

The inventor researches and develops a new crystal form of the Lanifibraner, which is called as a crystal form D. Form D has an X-ray powder diffraction pattern having diffraction peaks at positions 2 θ (unit: degree, °, error ± 0.2 °) of 5.7, 9.0, 16.2, 20.2 and 20.5 degrees.

In some embodiments, form D has an X-ray powder diffraction pattern having diffraction peaks at positions 5.7, 8.0, 9.0, 12.7, 14.5, 16.2, 18.0, 20.2, 20.5, 26.0 degrees 2 Θ (units: degrees, °).

In some embodiments, form D has an X-ray powder diffraction pattern having diffraction peaks at 5.7, 8.0, 9.0, 12.7, 14.5, 16.2, 16.7, 18.0, 20.2, 20.5, 23.6, 25.5, 26.0, and 30.9 degrees 2 Θ (units: degrees, °).

In some embodiments, form D has an X-ray powder diffraction (XRPD) pattern as shown in figure 8.

The crystal form D also has the following characteristics that a Differential Scanning Calorimetry (DSC) curve thereof has endothermic peaks in the range of 110-125 ℃ and in the range of 170-183 ℃. In some embodiments, form D has a Differential Scanning Calorimetry (DSC) curve with endothermic peaks in the range of 110 ℃ to 120 ℃ and 173 ℃ to 181 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form D has endothermic peaks with peak tops of 119 ℃ and 179 ℃, respectively. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form D is shown in figure 9.

According to some embodiments of the invention, the crystal form D can be obtained by dissolving the Lanifibranor in a mixed solvent of 1, 4-dioxane and water, cooling to-5-10 ℃, precipitating crystals, filtering and drying. The volume ratio of the 1, 4-dioxane to water can be 0.1:1-10:1, or 1:1-5:1, or 2: 1. The mass-volume ratio of the Lanifibranor to the 1, 4-dioxane can be 1g:1ml-1g:50ml, or 1g:35ml, or 1g:25ml, or 1g:15ml, or 1g:10ml, or 1g:5 ml.

According to some embodiments of the invention, the crystal form D can be obtained by dissolving the Lanifinaror in 1, 4-dioxane, adding the solution into a counter solvent at 0 ℃ after the solution is clear, precipitating crystals, filtering and drying; the antisolvent is at least one selected from the group consisting of n-heptane, cyclohexane, and n-hexane. The volume ratio of the antisolvent to 1, 4-dioxane can be 50:1 to 1:1, or 30:1 to 1:1, or 25:1, or 20:1, or 15:1, or 10:1, or 5: 1.

According to the research, the crystal form D contains 1, 4-dioxane, and can lose the solvent and be converted into another crystal form after being heated under certain conditions.

The inventor researches and develops a new crystal form of the Lanifibraner, namely the crystal form E. Form E has an X-ray powder diffraction pattern having diffraction peaks at 9.9, 15.9, 17.4, 23.8, 24.2, and 24.9 degrees 2 θ (units: degrees, °, error ± 0.2 ℃).

In some embodiments, the crystalline form E has an X-ray powder diffraction pattern having diffraction peaks at 9.9, 15.9, 17.4, 17.8, 20.2, 21.2, 23.8, 24.2, 24.9, 26.4, 26.8, 28.1, and 31.0 degrees 2 Θ (units: degrees, °).

In some embodiments, form E has an X-ray powder diffraction pattern having diffraction peaks at positions 2 θ (units: degrees, °) of 9.9, 15.9, 17.4, 17.8, 19.2, 19.6, 20.2, 21.2, 23.8, 24.2, 24.9, 26.4, 26.8, 28.1, 31.0, and 38.9.

In some embodiments, form E has an X-ray powder diffraction (XRPD) pattern as shown in figure 10.

The crystal form E also has the following characteristics that the crystal form E has an endothermic peak at 90-105 ℃ in a Differential Scanning Calorimetry (DSC) curve. In some embodiments, form E has an endothermic peak at 165 ℃ to 182 ℃ in a Differential Scanning Calorimetry (DSC) curve. In some embodiments, the form E has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve with peak tops at 102 ℃ and 178 ℃, respectively. In some embodiments, a Differential Scanning Calorimetry (DSC) curve of form E is shown in figure 11.

It was found that form E can be obtained by drying the aforementioned form B at 60 ℃ for 18h under vacuum.

The inventor researches and develops a new crystal form of the Lanifibranor, which is called as a crystal form F.

According to some embodiments of the invention, form F has an X-ray powder diffraction pattern having diffraction peaks at 11.4, 15.3, 20.1, 20.9, 22.2, 24.6, 25.8, and 27.6 degrees 2 Θ (units: degrees, °, error ± 0.2 °). According to some embodiments of the invention, form F, having an X-ray powder diffraction pattern with diffraction peaks at 11.4, 15.3, 17.2, 17.8, 24.3, 24.6, 25.8, and 27.6 degrees 2 Θ.

In some embodiments, the crystalline form F, has an X-ray powder diffraction pattern with diffraction peaks at 8.9, 11.4, 15.3, 15.9, 17.2, 17.8, 18.8, 20.1, 20.9, 22.2, 24.3, 24.6, 25.8, and 27.6 degrees 2 Θ.

In some embodiments, form F has an X-ray powder diffraction pattern having diffraction peaks at 7.3, 8.9, 9.4, 11.4, 11.7, 14.3, 14.8, 15.3, 15.9, 17.2, 17.5, 17.8, 18.1, 18.8, 20.1, 20.9, 22.2, 22.8, 23.6, 24.3, 24.6, 25.8, 27.6, 29.0, and 30.7 degrees 2 Θ.

In some embodiments, an X-ray powder diffraction (XRPD) pattern of form F is shown in figure 12.

The crystal form F also has the following characteristics that the Differential Scanning Calorimetry (DSC) curve thereof has an endothermic peak at 165-175 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form F has an endothermic peak at 176 ℃ to 183 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form F has endothermic peaks at 165 ℃ -175 ℃ and 176 ℃ -183 ℃. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form F has endothermic peaks at 166 ℃ to 170 ℃ and 177 ℃ to 180 ℃. In some embodiments, the form F has a Differential Scanning Calorimetry (DSC) curve with endothermic peaks at 169 ℃ and 179 ℃, respectively. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form F is shown in figure 13.

The crystal form F also has the following characteristics that the thermogravimetric analysis curve (TGA) thereof has weight loss between 110 ℃ and 200 ℃, and the weight loss is about 0.89%. In some embodiments, the thermogravimetric analysis curve (TGA) of form F is as shown in figure 14.

In some embodiments, the form F contains an amorphous form with an amorphous content of less than 10% or less than 5%.

Researches show that the crystal form F is stable, crystal transformation is not easy to occur under the conditions of high temperature, high humidity or illumination, and the crystal form is not changed. Therefore, the crystal form F can be used for preparing pharmaceutical preparation compositions, and has good operability and quality controllability due to stable performance in the preparation process of the pharmaceutical preparation compositions.

A method of preparing form F comprising: and (3) placing the Lanifibranor amorphous or the crystal form C under high-humidity conditions or high-temperature conditions to obtain the crystal form F. In some embodiments, the Lanifibranor amorphous form is placed in an incubator at 60 ℃ for 1 day to give form F.

A method of preparing form F comprising: dissolving the Lanifibraner in dimethyl sulfoxide to obtain a dimethyl sulfoxide solution of the Lanifibraner; preparing crystal form F seed crystal and water into suspension; and then adding the suspension into the dimethyl sulfoxide solution at the temperature of-5-40 ℃, separating out a solid, filtering and drying to obtain a crystal form F.

The mass-volume ratio of the Lanifibrane to the dimethyl sulfoxide can be 1g:1ml-1g:200ml, or 1g:1ml-1g:100ml, or 1g:1ml-1g:50ml, or 1g:1ml-1g:25ml, or 1g:1ml-1g:10ml, or 1g:5ml, or 1g:20ml, or 1g:15 ml.

In the suspension, the mass ratio of the seed crystal to the water can be 0.1:1000-1:10, or 0.1:1000-1:100, or 0.1:1000-1:1000, or 5: 1000.

A novel crystalline form of Lanifibranor, designated form G, has diffraction peaks at 2 θ (units: degrees, °, error ± 0.2 °) of 9.7, 15.3, 17.8, 24.1, 24.5, 25.1 and 26. degree 1 in its X-ray powder diffraction pattern.

In some embodiments, form G has an X-ray powder diffraction pattern having diffraction peaks at 9.7, 10.2, 15.3, 16.3, 16.7, 17.8, 18.9, 20.5, 24.1, 24.5, 25.1, 26.1, 26.6, and 27.5 degrees 2 Θ.

In some embodiments, form G has an X-ray powder diffraction pattern having diffraction peaks at positions 7.8, 9.7, 10.2, 10.5, 10.9, 15.3, 15.9, 16.3, 16.7, 17.0, 17.8, 18.9, 20.5, 21.0, 21.8, 22.2, 23.0, 24.1, 24.5, 25.1, 26.1, 26.6, 27.0, 27.5, 28.1, and 30.2 degrees 2 Θ.

In some embodiments, form G has an X-ray powder diffraction (XRPD) pattern as shown in figure 15.

The crystal form G also has the following characteristics that the Differential Scanning Calorimetry (DSC) curve thereof has an endothermic peak within the range of 105-127 ℃. In some embodiments, form G has a Differential Scanning Calorimetry (DSC) curve with an endothermic peak in the range of 160 ℃ to 180 ℃. In some embodiments, form G has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve with peak tops of 125 ℃ and 177 ℃, respectively. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form G is shown in figure 16.

Form G can be prepared by dissolving Lanifibranor in a mixed solvent of n-propanol and toluene, and then volatilizing to remove the solvent.

The crystal form G has instability to heat, and is easy to generate crystal transformation after being heated under certain conditions, so that the crystal form G is transformed into other crystal forms.

A novel crystal form of Lanifibranor, called form H, has X-ray powder diffraction pattern having diffraction peaks at 9.4, 9.8, 17.8 and 19.0 degrees 2theta (unit: degree, °, error + -0.2 ℃).

In some embodiments, form H, when taken in an X-ray powder diffraction pattern, has diffraction peaks at 9.4, 9.8, 10.2, 17.8, 19.0, 23.5, and 24.9 degrees 2 Θ.

In some embodiments, form H has an X-ray powder diffraction pattern with diffraction peaks at 9.4, 9.8, 10.2, 15.8, 16.4, 17.8, 19.0, 20.2, 23.5, 24.9, and 37.5 degrees 2 Θ.

In some embodiments, form H has an X-ray powder diffraction (XRPD) pattern as shown in figure 17.

The crystal form H also has the following characteristics that the Differential Scanning Calorimetry (DSC) curve thereof has endothermic peaks in the ranges of 104-120 ℃, 163-172 ℃ and 175-183 ℃. In some embodiments, form H has endothermic peaks in the Differential Scanning Calorimetry (DSC) curve in the range of 105 ℃ to 118 ℃, 165 ℃ to 170 ℃, and 176 ℃ to 182 ℃. In some embodiments, form H has endothermic peaks in a Differential Scanning Calorimetry (DSC) curve with peak tops at 116 ℃, 168 ℃, and 180 ℃ respectively. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form H is shown in figure 18.

The crystal form H has instability to heat, and is easy to generate crystal transformation after being heated under certain conditions, so that the crystal form H is converted into other crystal forms.

According to an embodiment of the invention, a method of preparing form H comprises: dissolving Lanifibrano in at least one solvent selected from tetrahydrofuran, 1, 4-dioxane and ethylene glycol monomethyl ether, adding the solution into trifluoroethanol at the temperature of 0 ℃ after the solution is clear, precipitating crystals, and filtering to obtain the crystal form H.

On the other hand, the invention also provides a crystal form of the Lanifibranor, which is called as a crystal form 1.

The crystal form 1 has diffraction peaks at positions where 2theta (unit: degree, error + -0.2 degree) is 9.9, 15.7, 24.0, 25.1, 26.8 and 28.4 degrees in an X-ray powder diffraction pattern.

In some embodiments, form 1, having an X-ray powder diffraction pattern with diffraction peaks at 9.9, 10.1, 15.7, 17.3, 20.1, 20.6, 21.6, 22.3, 24.0, 25.1, 26.8, 27.1, 28.4, and 30.5 degrees 2 Θ.

In some embodiments, form 1, having an X-ray powder diffraction pattern with diffraction peaks at 7.8, 9.9, 10.1, 11.8, 15.7, 17.3, 18.1, 18.6, 20.1, 20.6, 21.6, 22.3, 22.7, 23.5, 24.0, 25.1, 26.1, 26.8, 27.1, 27.4, 28.4, 29.1, 30.5, 35.7 and 37.5 degrees 2 Θ.

In some embodiments, an X-ray powder diffraction (XRPD) pattern of form 1 is shown in figure 19.

The crystal form 1 also has the following characteristics that the Differential Scanning Calorimetry (DSC) curve thereof has endothermic peaks in the ranges of 111-125 ℃ and 170-185 ℃. In some embodiments, form 1 has endothermic peaks in the Differential Scanning Calorimetry (DSC) curve in the range of 115 ℃ to 123 ℃ and 177 ℃ to 183 ℃. In some embodiments, form 1 has an endothermic peak in a Differential Scanning Calorimetry (DSC) curve with peak tops at 121 ℃ and 180 ℃, respectively. In some embodiments, the Differential Scanning Calorimetry (DSC) curve of form 1 is shown in figure 20.

The crystal form 1 also has the following characteristics that the thermogravimetric analysis curve (TGA) thereof has weight loss of about 0.83 percent in the temperature range of 30-200 ℃.

Researches show that the crystal form 1 has instability under certain conditions and can generate crystal transformation; after the crystal form is placed for 15 days under the conditions of high temperature of 60 ℃, illumination, high humidity and the like, the crystal form is converted into a mixture of the crystal form 1 and the crystal form A.

A method of preparing crystalline form 1, comprising: dissolving Lanifibrano in at least one solvent selected from butanone, N-methylpyrrolidone, ethylene glycol dimethyl ether and butaneketone, adding the solution into trifluoroethanol at 0 ℃ after dissolving, separating out crystals, filtering and drying to obtain the crystal form 1.

A method of preparing crystalline form 1, comprising: the Lanifibranor is dissolved in ethyl formate, and after the solution is clear, the solution is added into n-heptane at the temperature of 0 ℃, crystals are separated out, and the crystals are filtered and dried to obtain the crystal form 1.

A method of preparing crystalline form 1, comprising: the Lanifibranor form H is dried under vacuum at 60 ℃ to obtain form 1.

In another aspect, the invention also provides an amorphous Lanifinaror, wherein the X-ray powder diffraction pattern of the amorphous Lanifinaror is shown in FIG. 21.

Researches show that the amorphous form has instability to illumination, high temperature and high humidity, and can be converted into the crystal form F under the conditions of high temperature, high humidity or illumination.

According to the embodiment of the invention, amorphous can be obtained by dissolving the Lanifibranor in an organic solvent and performing reduced pressure rotary evaporation; the organic solvent can be at least one of methanol, ethanol, tetrahydrofuran, ethylene glycol monomethyl ether, ethylene glycol dimethyl ether, ethyl acetate and acetone. In some embodiments, the Lanifibranor is dissolved in an organic solvent and rotary evaporated under reduced pressure at 40 ℃ to 60 ℃ to give amorphous form. In some embodiments, the organic solvent is acetone, resulting in an amorphous form.

The crystal form A and the crystal form F have better stability, are beneficial to operation in storage, transfer and production processes, and can be prepared into a medicinal composition together with a pharmaceutically acceptable carrier.

In another aspect, the present invention also provides a composition.

A composition, comprising: at least one selected from the aforementioned form a and form F, and a pharmaceutically acceptable excipient, optionally including an amorphous form.

In some embodiments, a composition comprises the aforementioned crystalline form F and a pharmaceutically acceptable excipient. In some embodiments, a composition comprising form F of the foregoing and a pharmaceutically acceptable adjuvant; at least one selected from the group consisting of the aforementioned form a, form B, form C, form D, form E, form G, form H, form 1 and amorphous form may also be included. In some embodiments, a composition comprising the aforementioned crystalline form F and a pharmaceutically acceptable excipient; also included is at least one selected from the group consisting of form a, form 1 and amorphous form described previously. In some embodiments, a composition comprises the aforementioned crystalline form F and a pharmaceutically acceptable excipient; also included is at least one selected from the aforementioned form a and amorphous form. In some embodiments, a composition comprising form F of the foregoing and a pharmaceutically acceptable adjuvant; also included are the aforementioned form a and amorphous forms. In some embodiments, a composition comprising form F of the foregoing and a pharmaceutically acceptable adjuvant; also included are the aforementioned form a. In some embodiments, a composition comprising form F of the foregoing and a pharmaceutically acceptable adjuvant; also included are the aforementioned amorphous forms.

In some embodiments, the crystalline form is at least 80%, or at least 85%, or at least 90% or at least 95% of the lanifibrator, calculated as a mass ratio, in the composition. In some embodiments, the crystalline form is at least 97% of the lanifibraner in the composition, calculated as a mass ratio. In some embodiments, the crystalline form is at least 99% of the lanifibraner in the composition, calculated as a mass ratio.

In some embodiments, the crystalline form is at least 10%, or at least 5% of Lanifibranor, calculated as a mass ratio in the composition. In some embodiments, the crystalline form is at least 1% or at least 0.5% of Lanifibranor, calculated as a mass ratio, in the composition.

In some embodiments, the crystalline form is no more than 10% of Lanifibranor, calculated as mass ratio, in the composition. In some embodiments, the crystalline form is not more than 6% of the Lanifibranor, calculated as a mass ratio, in the composition. In some embodiments, the crystalline form is not more than 5% of the Lanifibranor, calculated as a mass ratio, in the composition. In some embodiments, the crystalline form is not more than 3% of the Lanifibranor, calculated as a mass ratio, in the composition. In some embodiments, the crystalline form is not more than 1% of the Lanifibranor by mass of the composition. In some embodiments, the crystalline form is not more than 0.5% by mass of the Lanifibranor in the composition.

A composition comprising at least one of the aforementioned crystalline forms and a pharmaceutically acceptable excipient, and may further comprise the aforementioned amorphous form; the amorphous form is not more than 40% or 30% or 20% or 15% of the Lanifinaror calculated according to the mass ratio. In some embodiments, the amorphous form is not more than 10% of the lanifibrand in the composition, calculated as a mass ratio. In some embodiments, the amorphous form is not more than 6% of the lanifibrand in the composition, calculated as a mass ratio. In some embodiments, the amorphous form is not more than 5% of the lanifibrand in the composition, calculated as a mass ratio. In some embodiments, the amorphous form does not exceed 3% of the lanifibrand in the composition, calculated as a mass ratio. In some embodiments, the amorphous form is not more than 1% of the lanifibrand by mass in the composition. In some embodiments, the amorphous form is not more than 0.5% of the lanifibrand in the composition, calculated as a mass ratio.

In some embodiments, the crystalline form is at least 0.05% to 95%, 0.1% to 95%, 1% to 95%, 5% to 95%, or 1% to 50% by mass of the total mass of the composition, calculated as a mass ratio.

In some embodiments, the amorphous form is at least 0.05% to 95%, 0.1% to 95%, 1% to 95%, 5% to 95%, or 1% to 50% by mass of the total mass of the composition, calculated as a mass ratio. In some embodiments, the amorphous form is at least 0.05% to 10% of the total mass of the composition, calculated as a mass ratio. In some embodiments, the amorphous form is at least 5% to 10% of the total mass of the composition, calculated as mass ratio.

In some embodiments, the amorphous form is not more than 1% to 10% of the total mass of the composition, or not more than 5% of the total mass of the composition, calculated as a mass ratio.

In some embodiments, the composition, comprising the aforementioned crystalline form F and a pharmaceutically acceptable excipient; the crystal form F is at least 0.5-10%, or at least 0.5-5%, or at least 5-10%, or at least 90% or at least 95% of the Lanifibror by mass ratio; or said form F does not exceed 10%, or 5% or 1% of Lanifibranor.

The pharmaceutically acceptable auxiliary materials comprise a diluent, a disintegrating agent, an adhesive, a lubricant or the like.

The various crystal forms or amorphous forms can be used for preparing medicaments for treating NASH (non-alcoholic fatty liver disease).

The composition can be used for preparing a medicament for treating NASH (non-alcoholic fatty liver disease).

Drawings

Figure 1 shows an X-ray powder diffraction pattern (XRPD) of form a; FIG. 2 shows a Differential Scanning Calorimetry (DSC) curve of form A; figure 3 shows a thermogravimetric analysis plot (TGA) of form a.

Figure 4 shows an X-ray powder diffraction pattern (XRPD) of form B; figure 5 shows the Differential Scanning Calorimetry (DSC) curve of form B.

Figure 6 shows an X-ray powder diffraction pattern (XRPD) of form C; figure 7 shows the Differential Scanning Calorimetry (DSC) curve of form C.

Figure 8 shows an X-ray powder diffraction pattern (XRPD) of form D; figure 9 shows the Differential Scanning Calorimetry (DSC) curve of form D.

Figure 10 shows an X-ray powder diffraction pattern (XRPD) of form E; figure 11 shows the Differential Scanning Calorimetry (DSC) curve for form E.

Figure 12 shows an X-ray powder diffraction pattern (XRPD) of form F; FIG. 13 shows a Differential Scanning Calorimetry (DSC) curve of form F; fig. 14 shows a thermogravimetric analysis plot (TGA) of crystalline form F.

Figure 15 shows an X-ray powder diffraction pattern (XRPD) of form G; figure 16 shows the Differential Scanning Calorimetry (DSC) curve of form G.

Figure 17 shows an X-ray powder diffraction pattern (XRPD) of form H; figure 18 shows a Differential Scanning Calorimetry (DSC) curve for form H.

Figure 19 shows an X-ray powder diffraction pattern (XRPD) of form 1; figure 20 shows a Differential Scanning Calorimetry (DSC) curve for form 1.

FIG. 21 shows an amorphous X-ray powder diffraction pattern.

Figure 22 shows the powder dissolution profiles of form F and form a in phosphate buffer at pH 6.8.

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.

In the present invention, mg means mg, mL means mL, rpm means rpm, h means hour, and RH means relative humidity; SDS represents sodium dodecyl sulfate.

Parameters of the instrument

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

X-ray powder diffraction (XRPD) study

X-ray powder diffraction (XRPD) 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,

：1.540598；

: 1.544426, respectively; the K alpha 2/K alpha 1 intensity ratio: 0.50) with the voltage set at 45KV and the current set at 40 ma.the beam divergence of the X-rays, i.e. the effective size of the X-ray confinement on the sample, is 6.6 mm.a theta-theta continuous scan mode is used to obtain an effective 2theta range of 3 deg. -60 deg.. Taking a proper amount of sample at the position of the circular groove of the zero-background sample holder 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 holder. The sample was scanned at a scan step of 0.0167 ° in the range of 3-60 ° 2 θ ± 0.2 ° to produce a conventional XRPD 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 apparatus was purged with nitrogen at 50 mL/min. Data were 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 is 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 in percentage (Weight (%)).

EXAMPLE 1 preparation of form A

Dissolving 100mg of Lanifibranor in 15mL of methanol at 60 ℃, cooling to 0 ℃ to precipitate a solid, filtering and drying to obtain 65mg of crystal form A, detecting, and performing X-ray powder diffraction, DSC and TGA, wherein the results are shown in figure 1-figure 3.

Example 2 preparation of form a

200mg of Lanifibranor is dissolved in 2mL of tetrahydrofuran, the solution is slowly volatilized at room temperature after being dissolved clearly, solid is separated out and dried to obtain 180mg of solid, and the detection proves that the crystal form A is the crystal form A.

EXAMPLE 3 preparation of form A

500mg of Lanifibranor is dissolved in 15mL of acetone at 50 ℃,40 mL of trifluoroethanol is dripped in, solid is separated out, and the mixture is filtered and dried to obtain 450mg of crystal form A.

Example 4 preparation of form a

400mg of Lanifibranor is dissolved in 4mL of 1, 4-dioxane at room temperature, after the solution is clear, the Lanifibranor is slowly added into 40mL of water, solid is separated out, and the crystal form A is filtered and dried to obtain 366 mg.

EXAMPLE 5 preparation of form B

Dissolving 200mg of Lanifibranor in 2mL of 1, 4-dioxane at room temperature, slowly volatilizing at room temperature after dissolving to obtain a solid, and obtaining 174mg of a product, namely a crystal form B; x-ray powder diffraction, DSC and TGA were measured, and the results were shown in FIGS. 4 to 5.

EXAMPLE 6 preparation of form C

Dissolving 400mg of Lanifibranor in 2mL of 1, 4-dioxane at room temperature, slowly cooling to 10 ℃ after dissolving to be clear, separating out a solid, filtering, and drying to obtain 340mg of a product, wherein the XRPD and the DSC of the product are basically consistent with those in figures 6 and 7 through detection.

EXAMPLE 7 preparation of form C

200mg of Lanifibranor is dissolved in 2mL of 1, 4-dioxane at room temperature, 20mL of n-heptane is dripped, solid is separated out, and the crystal form C183 mg is obtained after filtration and drying.

Example 8 preparation of form D

200mg of Lanifibrane is dissolved in 2mL of 1, 4-dioxane at room temperature, and then slowly added into 40mL of n-heptane at 0 ℃ after dissolution, solid is separated out, the filtration and the drying are carried out, 160mg of solid is obtained, the solid is detected to be crystal form D, and XRPD and DSC spectrums of the crystal form D are respectively consistent with those in figures 8 and 9.

Example 9 preparation of form D

100mg of Lanifibraner is dissolved in a mixed solvent of 2mL of 1, 4-dioxane and 1mL of water at room temperature, and then the temperature is slowly reduced to 5 ℃ after the solution is clear, solid is separated out, filtered and dried, and 65mg of crystal form D is obtained.

EXAMPLE 10 preparation of form E

Vacuum drying 50mg of Lanifibranor crystal form B solid at 60 ℃ for 18h to obtain 45mg of crystal form E, wherein XRPD and DSC spectrums of the crystal form E are basically consistent with those in figure 10 and figure 11 respectively through detection.

Example 11 preparation of form F

300mg of the Lanifibranor amorphous form was placed in a 60 ℃ incubator for 1 day to obtain 280mg of the crystalline form F, and the XRPD, DSC, and TGA patterns thereof were detected to be substantially consistent with fig. 12, fig. 13, and fig. 14, respectively.

Example 12 preparation of form F

200mg of Lanifibraner is put in 2mL of dimethyl sulfoxide at room temperature, 20mg of crystal form F crystal seed is added into 20mL of water to prepare a suspension solution, and then the suspension solution is slowly added into the dimethyl sulfoxide solution; solid was precipitated, filtered and dried to obtain 150mg of form F.

EXAMPLE 13 preparation of form G

Dissolving 100mg of Lanifibraner in a mixed solvent of 12mL of n-propanol and 25mL of toluene at room temperature, slowly volatilizing at room temperature after dissolving to obtain 80mg of crystal form G, and detecting that XRPD and DSC spectrums of the crystal form G are basically consistent with those in figures 15 and 16 respectively.

Example 14 preparation of form H

200mg of Lanifibranor is dissolved in 2mL of 1, 4-dioxane at room temperature, after the Lanifibranor is dissolved clearly, the Lanifibranor is slowly added into 20mL of trifluoroethanol at 0 ℃, solid is separated out, the filtration and the drying are carried out, 176mg of crystal form H is obtained, and the XRPD and the DSC of the crystal form H are basically consistent with those in figures 17 and 18 respectively through detection.

Example 15 preparation of form 1

100mg of Lanifibraner 60 ℃ is dissolved in 10mL of ethyl formate, the obtained solution is slowly added into 20mL of n-heptane at 0 ℃ after being dissolved, solid is separated out, the obtained product is filtered and dried to obtain 60mg of crystal form 1, and the XRPD and DSC spectrums of the crystal form 1 are basically consistent with those of figure 19 and figure 20 respectively through detection.

EXAMPLE 16 preparation of amorphous form

300mg of Lanifibraner 50 ℃ is dissolved in 15mL of acetone at room temperature, after the solution is clear, the solution is subjected to decompression rotary evaporation at 50 ℃ until no solvent exists, 260mg of product is obtained, and the XRPD pattern of the product is basically consistent with that of figure 21 through detection, and the product is amorphous.

Example 17 stability testing

According to the guiding principle of the stability test of the bulk drugs, the influence factor test is carried out on the sample, including a high temperature test, a high humidity test and a strong light irradiation test, and the stability condition of each crystal form under different conditions is inspected.

The experimental conditions are as follows:

light test (light UV + VIS): appropriate amount of samples were taken, spread in weighing bottles, opened, placed in a constant temperature and humidity chamber (25 ℃, RH 60% +/-5%) of 4500Lux + -500 Lux (VIS) and ultraviolet 1.7W × h/m2(UV), and then about 20mg of the samples were taken at 0, 5 and 15 days, respectively, and the crystal form condition was tested by X-ray powder diffraction (XRPD).

High humidity test (high humidity 25 ℃ + 92.5% RH): appropriate amount of samples are respectively taken, laid in a weighing bottle, opened, placed in a constant temperature and humidity box with the temperature of 25 ℃ and RH of 92.5 +/-5 percent, and then about 20mg of samples are respectively taken in 0, 5 and 15 days, and the crystal form condition is tested by adopting X-ray powder diffraction (XRPD).

High temperature test (high temperature 60 ℃): appropriate amount of samples are respectively taken, laid in a weighing bottle, opened, placed in a thermostat at 60 +/-5 ℃ without controlling humidity, and then about 20mg of samples are respectively taken at 0, 5 and 15 days, and the crystal form condition is tested by X-ray powder diffraction (XRPD).

High temperature high humidity test (high temperature 60 ℃ + 75% RH): a proper amount of samples are respectively taken, laid in a weighing bottle, opened, placed in a constant temperature and humidity box with the temperature of 60 +/-5 ℃ and the RH of 75 +/-5 percent, then samples of about 20mg are respectively taken on 0, 5 and 15 days, and the crystal form condition is tested by adopting X-ray powder diffraction (XRPD).

The experimental results are as follows: the results of the measurements for each sample are shown in Table 1.

Table 1: results of stability experiments

According to the stability research results, the crystal form F and the crystal form A are more stable than other crystal forms or amorphous forms.

Example 18 solubility test

Samples were taken from 2 flasks, and 100mL of 1% SDS phosphate buffer pH 6.8 was added to each flask; placing the flask in a constant-temperature trap at 37 ℃, and stirring for 23 hours; the solubility was measured by an ultraviolet spectrophotometer at 5min, 30min, 1h, 2h, 4h, 6h, 8h, 10h and 23h from the start of adding the sample to the buffer solution, and the powder elution curve was plotted, and the results are shown in FIG. 22.

According to FIG. 22, the equilibrium solubility of form F is 15.3. mu.g/mL, and the equilibrium solubility of form A is 9.4. mu.g/mL; the dissolution rate of form F is greater than form a and the equilibrium solubility is greater than form a in a buffer at pH 6.8. The crystal form F has better solubility than the crystal form A, and is beneficial to the preparation and application of pharmaceutical preparations.

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 variations and combinations of the techniques described herein, may be made and used without departing from the spirit and scope of the invention. Those skilled in the art can implement and apply the present technology by appropriately modifying the process parameter implementations in view of the present disclosure. 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 crystalline form of Lanifibranor having an X-ray powder diffraction pattern with diffraction peaks at 11.4, 15.3, 20.1, 20.9, 22.2, 24.6, 25.8 and 27.6 degrees 2 Θ or 11.4, 15.3, 17.2, 17.8, 24.3, 24.6, 25.8 and 27.6 degrees 2 Θ.

2. The crystalline form of claim 1 having an X-ray powder diffraction pattern with diffraction peaks, in terms of 2 θ, at 8.9, 11.4, 15.3, 15.9, 17.2, 17.8, 18.8, 20.1, 20.9, 22.2, 24.3, 24.6, 25.8, and 27.6 degrees; or an X-ray powder diffraction pattern having diffraction peaks at 7.3, 8.9, 9.4, 11.4, 11.7, 14.3, 14.8, 15.3, 15.9, 17.2, 17.5, 17.8, 18.1, 18.8, 20.1, 20.9, 22.2, 22.8, 23.6, 24.3, 24.6, 25.8, 27.6, 29.0, and 30.7 degrees 2 θ; or an X-ray powder diffraction pattern thereof as shown in FIG. 12.

3. The crystalline form of claim 1 having endothermic peaks in a differential scanning calorimetry curve at 165 ℃ -175 ℃ and 176 ℃ -183 ℃; and/or the thermogravimetric analysis curve of the crystal form has weight loss between 110 ℃ and 200 ℃, and the weight loss is 0.89%.

4. A composition comprising the crystalline form of any one of claims 1-3 and a pharmaceutically acceptable carrier.

5. The composition according to claim 4, wherein the crystalline form is at least 90% of the Lanifidor, or the crystalline form is at least 0.5% of the Lanifidor, or the crystalline form is not more than 10% of the Lanifidor, calculated as a mass ratio.

6. The composition according to claim 4 or5, wherein the crystal form accounts for at least 0.05-95% of the total mass of the composition according to the mass ratio.

7. A method of preparing the crystalline form of any one of claims 1-3, comprising: dissolving the Lanifibraner in dimethyl sulfoxide to obtain a dimethyl sulfoxide solution of the Lanifibraner; preparing the crystal seeds of the crystal form and water into suspension; and then adding the suspension into the dimethyl sulfoxide solution at the temperature of-5-40 ℃, separating out a solid, filtering and drying to obtain the crystal form.

8. The method of claim 7, wherein the mass to volume ratio of the Lanifinaror to the dimethylsulfoxide is between 1g:1ml and 1g:200 ml.

9. The process according to claim 7 or 8, wherein the mass ratio of the seed crystals to the water in the suspension is from 0.1:1000 to 1: 10.

10. Use of the crystalline form of any one of claims 1-3 or the composition of any one of claims 4-6 in the manufacture of a medicament for the treatment of non-alcoholic fatty liver disease.