Polymorphs of elafibranor

Abstract

To provide crystalline forms of elafibranor capable of providing improved physicochemical properties.SOLUTION: The present invention provides novel forms B, C, D, and E of elafibranor.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to novel polymorphs of elafibranor, pharmaceutical compositions containing same, and methods for preparing the polymorphs. [Background technology]

[0002] 2-(2,6-Dimethyl-4-{3-[4-(methylsulfanyl)phenyl]-3-oxopropen-1-yl}phenoxy)-2-methylpropanoic acid (Elafibranor, or ELA, originally designated GFT505), disclosed in WO2004005233, is a PPAR-α / δ dual agonist with beneficial properties for the treatment of numerous diseases, including fibrotic, gastrointestinal, and hepatic disorders, particularly cholestatic diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), or liver diseases, particularly nonalcoholic fatty liver disease (NAFLD), such as nonalcoholic steatohepatitis (NASH). Elafibranor was evaluated for its clinical efficacy in NASH in a 1-year liver biopsy-based phase 2b trial (GFT505-2127), one of the largest interventional studies conducted in NASH to date. To date, elafibranor has been administered to over 800 patients and healthy volunteers. Its beneficial properties against NASH include, inter alia, improvement of markers of liver dysfunction, such as ALAT, ASAT, γGT, and ALP; improvement of insulin sensitivity and glucose homeostasis; favorable effects on plasma lipids, such as reductions in plasma triglycerides and LDL-C and increases in HDL-C levels; anti-inflammatory properties; and efficacy in histological NASH parameters (steatosis, inflammation, and fibrosis) in disease model animals, i.e., anti-fibrotic activity. A comprehensive toxicology package, including a two-year carcinogenicity study, has demonstrated no safety concerns. Elafibranor is currently being evaluated in a Phase 3 clinical trial for the treatment of NASH. Evaluation of this molecule for the treatment of PBC has also begun in a Phase 2 clinical trial.

[0003] Polymorphism occurs when substances of the same composition crystallize in different lattice arrangements, resulting in different thermodynamic properties and stabilities specific to each individual polymorphic form. When a chemical is a drug, the ability of that chemical to exist in multiple crystal forms can have a profound effect on the drug's shelf life, solubility, formulation properties, and / or processing characteristics. Therefore, from a quality perspective, it is very important to ensure that the manufacturing process results in the specific polymorphic form that has been approved by regulatory agencies for marketing, and that the formation of other polymorphic forms with different thermodynamic properties and stabilities is controlled.

[0004] Szokol (2018) (IP.com number IPCOM000252802D) describes a crystalline form of elafibranor. However, this form does not appear to be optimal, and there remains a need to provide improved polymorphic forms of elafibranor. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] WO2004005233 [Non-patent literature]

[0006] [Non-Patent Document 1] Szokol(2018)(IP.com number IPCOM000252802D) Summary of the Invention [Problem to be solved by the invention]

[0007] The present invention provides crystalline forms of elafibranor that can provide improved physicochemical properties. [Means for solving the problem]

[0008] Five crystalline forms of elafibranor have been identified, designated Form A, Form B, Form C, Form D, and Form E. Among these forms, Form A corresponds to the crystal already identified by Szokol. Accordingly, the present invention provides novel Forms B, C, D, and E of elafibranor. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 shows the X-ray diffraction profile of Form A. [Figure 2] FIG. 1 shows the X-ray diffraction profile of Form B. [Figure 3] FIG. 1 shows the X-ray diffraction profile of Form C (recrystallized in EtOH). [Figure 4] FIG. 1 shows the X-ray diffraction profile of Form D (recrystallized in MeOH). [Figure 5] FIG. 1 shows the X-ray diffraction profile of Form E (recrystallized in DMA). [Figure 6] FIG. 1 shows the HPLC profile of Form B at 350 nm. [Figure 7] FIG. 1 shows the HPLC profile at 350 nm of Form C (recrystallized in EtOH). [Figure 8] FIG. 1 shows the HPLC profile at 350 nm of Form D (recrystallized in MeOH). [Figure 9] FIG. 1 shows the HPLC profile at 350 nm of Form E (recrystallized in DMA). DETAILED DESCRIPTION OF THE INVENTION

[0010] definition Unless otherwise defined, 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 disclosure belongs.

[0011] In this disclosure, the singular forms "a," "an," and "the" include plural references, and reference to a particular numerical value includes at least that particular value unless the context clearly dictates otherwise. Thus, for example, reference to "a solvent" is a reference to one or more such solvents and equivalents thereof to those skilled in the art, and so forth.

[0012] The term "about" or "approximately" when referring to a numerical value means ±10% of that value, particularly ±5% of that value.

[0013] As used herein, the term "disease" refers to a disease, disorder, condition, symptom, or sign. This term is used synonymously with the phrase "disease or disorder."

[0014] As used herein, the terms "treatment" or "therapy" (or their different word forms) include preventative (e.g., disease prevention), curative, or palliative treatment. Such preventative, curative, or palliative treatment may be complete or partial. For example, the complete elimination of unwanted symptoms of a disease or the partial elimination of one or more unwanted symptoms of a disease would represent "treatment" as intended herein.

[0015] As used throughout this disclosure, the term "effective amount" refers to an amount effective, upon administration, for a period of time necessary to achieve the desired results for treating the relevant disorder, condition, or side effect. It will be understood that the effective amount of the components of the present invention will vary from patient to patient, depending not only on the specific compound, component, or composition selected, the route of administration, and the ability of the component to elicit the desired response in an individual, but also on factors such as the pathology or severity of the condition to be alleviated, hormone levels, age, sex, individual weight, patient condition, and the severity of the condition being treated, any concomitant medications or special diets a particular patient may be following, and other factors that would be recognized by one of ordinary skill in the art; ultimately, the appropriate dose will be determined by the attending physician. The dosing regimen may be adjusted to provide an improved therapeutic response. An effective amount is also one in which the therapeutically beneficial effects outweigh any toxic or harmful effects of the compound. For example, compounds useful in the present invention are administered at a dose and for a time such that the level of fibrosis or NASH activity, as measured, for example, by NAS score assessment, is reduced compared to the level of fibrosis or NASH activity before treatment began.

[0016] "Pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are suitable, within the scope of sound medical judgment, for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problematic complications, commensurate with a reasonable benefit / risk ratio.

[0017] Crystalline forms of elafibranor Provided herein are novel crystalline forms of elafibranor. While elafibranor has previously been known in its amorphous form and one crystalline form (hereinafter identified as "Form A"), the present disclosure provides other distinct crystalline forms of this molecule. Crystalline forms of elafibranor may have beneficial properties that make them more suitable for use in pharmaceutical compositions, such as chemical purity, flowability, solubility, morphology or morphology, and stability (e.g., storage stability, stability to dehydration, stability to light, stability to polymorphic transformation, low hygroscopicity, and low residual solvent content).

[0018] "Crystalline elafibranor" refers to a polymorphic or pseudopolymorphic form of elafibranor. phase (i.e., hydrate or solvate).

[0019] In certain embodiments, the crystalline form of elafibranor of the present invention is an anhydrous crystalline form.

[0020] The term "purity," when referring to one of the crystalline forms of elafibranor disclosed herein, means the extent to which a particular crystalline form is undiluted or unmixed with other crystalline forms and / or foreign matter, expressed as a weight percent (wt%). The term "purity," as used with respect to a formulation or dosage form of a crystalline form of elafibranor disclosed herein, means, when that formulation or dosage form contains a particular crystalline form as the active pharmaceutical agent (as well as one or more other ingredients, e.g., a pharmaceutically acceptable vehicle), the degree to which the active pharmaceutical agent in that formulation or dosage form contains that particular crystalline form of elafibranor and is free of other crystalline forms, also expressed as a percentage by weight (wt%). Those skilled in the art will understand that any measured purity level will exhibit some variability, as the weight percent of a particular crystalline form may vary with measurements made with different equipment, different calibrations, and / or different software packages. Due to these sources of variability, when referring to the percent purity of a crystalline form, it is common to describe purity using the words "about" or "at least."

[0021] Elafibranor has the structure represented by formula (I).

[0022] [ka]

[0023] The existence of various crystalline polymorphic forms of elafibranor has been investigated to determine the appropriate form of the compound for use in pharmaceutical compositions. In accordance with the present invention, five different crystalline forms of elafibranor have been identified.

[0024] According to the present invention, a first crystalline form, identified as Form A, has been prepared and corresponds to the crystals previously described in Szokol (2018) (IP.com number IPCOM000252802D). This Form A has an X-ray diffraction pattern including the following diffraction peaks (angles 2θ±0.2°): 8.3°, 10.7°, 11.6°, 15.1°, 20.7°, 26.9°, 27.6°, and 29°.

[0025] Form A may be obtained according to the method provided in Szokol, 2018. Alternatively, crystalline Form A may be prepared by crystallizing elafibranor from its solution in a solvent, such as DMF or THF / water, away from light at a temperature comprised between +4°C and +8°C for more than 4 weeks.

[0026] In another aspect, the present invention relates to crystalline form B of elafibranor having an X-ray diffraction pattern comprising the following characteristic diffraction peaks (angles 2θ±0.2°): 11.0°, 11.1°, 12.3°, 13.5°, 16.3°, 17.2° and 17.4°.

[0027] In certain embodiments, the X-ray diffraction pattern of Form B further comprises at least one of the following diffraction peaks (angles 2θ±0.2°): 7.9°, 15.7°, 15.9°, 16.6°, 22.8°, and 23.5°. In certain embodiments, the X-ray diffraction pattern of Form B comprises one, two, three, four, five, or six of these peaks. In certain embodiments, the X-ray diffraction pattern of Form B comprises the following diffraction peaks (angles 2θ±0.2°): 7.9°, 11.0°, 11.1°, 12.3°, 13.5°, 15.7°, 15.9°, 16.3°, 16.6°, 17.2°, 17.4°, 22.8°, and 23.5°.

[0028] In further embodiments, the X-ray diffraction pattern of Form B further comprises at least one of the following diffraction peaks (angles 2θ±0.2°): 12.6°, 19.0°, 20.0°, 20.3°, 23.8°, 24.4°, 25.2°, 25.4°, 26.3°, 26.7°, 27.2°, 27.8°, and 28.3°. In certain embodiments, the X-ray diffraction pattern of Form B comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 of these peaks.

[0029] In yet another embodiment, the X-ray diffraction pattern of Form B further comprises at least one of the following diffraction peaks (angles 2θ±0.2°): 7.9°, 11.0°, 11.1°, 12.3°, 12.6°, 13.5°, 15.7°, 15.9°, 16.3°, 16.6°, 17.2°, 17.4°, 19.0°, 20.0°, 20.3°, 22.8°, 23.5°, 23.8°, 24.4°, 25.2°, 25.4°, 26.3°, 26.7°, 27.2°, 27.8°, and 28.3°.

[0030] In a further particular embodiment, the X-ray diffraction pattern of Form B is as shown in FIG.

[0031] The preparation of Form B involves providing a solution of elafibranor dissolved in isopropyl alcohol. After partial distillation of the isopropyl alcohol (approximately half of the initial volume of the solution), the reaction mixture is cooled to 0° C. to crystallize, and purified elafibranor is obtained after filtration, washing with cold isopropyl alcohol, and drying.

[0032] In another aspect, the present invention relates to crystalline Form C of elafibranor, which is a 1:1 stoichiometric ethanol solvate of elafibranor. Form C has an X-ray diffraction pattern containing the following characteristic diffraction peaks (angles 2θ±0.2°): 17.7°, 23.3°, 27.3°, 34.3°, and 34.6°.

[0033] In certain embodiments of the present invention, the X-ray diffraction pattern of Form C further comprises the following diffraction peaks (angles 2θ±0.2°): 28.9°. In certain embodiments, the X-ray diffraction pattern of Form C further comprises the following diffraction peaks (angles 2θ±0.2°): 17.7°, 23.3°, 27.3°, 28.9°, 34.3°, and 34.6°.

[0034] In certain embodiments of the present invention, the X-ray diffraction pattern of Form C further comprises the following diffraction peaks (angles 2θ±0.2°): 8.9°, 10.1°, 10.7°, 11.3°, 32.0°, and 35.5°. In certain embodiments, the X-ray diffraction pattern of Form C comprises 1, 2, 3, 4, 5, or 6 of these peaks.

[0035] In yet another embodiment, the X-ray diffraction pattern of Form C comprises the following diffraction peaks (angles 2θ±0.2°): 8.9°, 10.1°, 10.7°, 11.3°, 17.7°, 23.3°, 27.3°, 28.9°, 32.0°, 34.3°, 34.6°, and 35.5°.

[0036] In a further particular embodiment, the X-ray diffraction pattern of Form C is as shown in FIG.

[0037] Crystalline form C may be prepared by crystallizing elafibranor in suspension from its solution in ethanol at a temperature comprised between +4°C and +8°C for more than 4 weeks, away from light.

[0038] In another aspect, the present invention relates to crystalline Form D of elafibranor, which is a 1:1 stoichiometric methanol solvate of elafibranor. Form D has an X-ray diffraction pattern containing the following characteristic diffraction peaks (angles 2θ±0.2°): 10.9°, 15.6°, 16.1°, 18.6°, 19.9°, and 20.7°.

[0039] In certain embodiments of the present invention, the X-ray diffraction pattern of Form D further comprises the following diffraction peaks (angles 2θ±0.2°): 7.8°, 17.7°, 18.1°, 21.9°, 22.3°, and 24.6°. In certain embodiments, the X-ray diffraction pattern of Form D comprises one, two, three, four, five, or six of these peaks. In certain embodiments, the X-ray diffraction pattern of Form D comprises the following diffraction peaks (angles 2θ±0.2°): 7.8°, 10.9°, 15.6°, 16.1°, 17.7°, 18.1°, 18.6°, 19.9°, 20.7°, 21.9°, 22.3°, and 24.6°.

[0040] In certain embodiments of the present invention, the X-ray diffraction pattern of Form D further comprises the following diffraction peaks (angles 2θ±0.2°): 9.3°, 12.9°, 13.4°, 14.7°, 24.1°, 25.1°, 25.5°, 25.8°, 26.1°, 27.3°, 28.0°, 28.4°, 29.2°, 29.9°, 32.3°, 32.9°, and 33.6°. In certain embodiments, the X-ray diffraction pattern of Form D comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 of these peaks.

[0041] In yet another embodiment, Form D has an X-ray diffraction pattern comprising the following diffraction peaks (angles 2θ±0.2°): 7.8°, 9.3°, 10.9°, 12.9°, 13.4°, 14.7°, 15.6°, 16.1°, 17.7°, 18.1°, 18.6°, 19.9°, 20.7°, 21.9°, 22.3°, 24.1°, 24.6°, 25.1°, 25.5°, 25.8°, 26.1°, 27.3°, 28.0°, 28.4°, 29.2°, 29.9°, 32.3°, 32.9°, and 33.6°.

[0042] In a further particular embodiment, the X-ray diffraction pattern of Form D is as shown in FIG.

[0043] Crystalline form D may be prepared by crystallizing elafibranor in suspension from its solution in methanol at a temperature comprised between +4°C and +8°C for more than 4 weeks, away from light.

[0044] In another aspect, the present invention relates to crystalline Form E of elafibranor, which is a 1:1 stoichiometric N,N-dimethylacetamide solvate of elafibranor. Form E has an X-ray diffraction pattern containing the following characteristic diffraction peaks (angles 2θ±0.2°): 13.3°, 15.1°, 17.1°, and 29.5°.

[0045] In certain embodiments of the present invention, the X-ray diffraction pattern of Form E further comprises the following diffraction peaks (at angles 2θ±0.2°): 18.1°, 25.2°, 25.9°, and 26.2°. In certain embodiments, the X-ray diffraction pattern of Form E comprises one, two, three, or four of these peaks. In certain embodiments, the X-ray diffraction pattern of Form E comprises the following diffraction peaks (at angles 2θ±0.2°): 13.3°, 15.1°, 17.1°, 18.1°, 25.2°, 25.9°, 26.2°, and 29.5°.

[0046] In certain embodiments of the present invention, the X-ray diffraction pattern of Form E further comprises the following diffraction peaks (angles 2θ±0.2°): 7.6°, 8.6°, 11.2°, 16.1°, 16.9°, 17.8°, and 22.8°. In certain embodiments, the X-ray diffraction pattern of Form E comprises 1, 2, 3, 4, 5, 6, or 7 of these peaks.

[0047] In yet another embodiment, Form E has an X-ray diffraction pattern comprising the following diffraction peaks (angles 2θ±0.2°): 7.6°, 8.6°, 11.2°, 13.3°, 15.1°, 17.1°, 16.1°, 16.9°, 17.8°, 18.1°, 22.8°, 25.2°, 25.9°, 26.2°, and 29.5°.

[0048] In a further particular embodiment, the X-ray diffraction pattern of Form E is as shown in FIG.

[0049] Crystalline form E can be recrystallized by natural evaporation of a solution of elafibranor in N,N-dimethylacetamide at room temperature and away from light.

[0050] Single crystal X-ray diffraction provides three-dimensional structural information regarding the positions of atoms and bonds in a crystalline form. However, it is not always possible or feasible to obtain such structures from crystalline forms, for example, due to insufficient crystal size or the difficulty of preparing crystals of sufficient quality for single crystal X-ray diffraction. However, structural identification information can be obtained from other solid-state techniques, such as X-ray powder diffraction and Raman spectroscopy. These techniques are used to generate data about the crystalline form of a solid. Once data is collected for a known crystalline form, the data can be used to identify the presence of that crystalline form in other materials. Thus, these data effectively characterize the crystalline form. For example, an X-ray powder diffraction pattern, or a portion thereof, can serve as a fingerprint to characterize the crystalline form. An X-ray powder diffractogram is an xy graph with the X-axis representing the scattering angle 2θ (diffraction) and the y-axis representing the intensity. Peaks in this diagram can be used to characterize the crystalline form. Although peaks across the diffractogram can be used to characterize the crystalline form, some of the more characteristic peaks can also be used to accurately characterize the crystalline form. Because peak intensities can vary with sample orientation, data are often represented by peak positions on the x-axis rather than peak intensities on the y-axis. There is also variability in peak positions on the x-axis. This variability has several sources, one of which is due to sample preparation.

[0051] Samples of the same crystalline material prepared under different conditions can produce slightly different diffractograms. Factors such as particle size, water content, solvent content, and orientation can affect how a sample diffracts X-rays. Another source of variability comes from instrument parameters. Different X-ray instruments operate using different parameters, which can result in slightly different diffraction parameters from the same crystalline form. Similarly, different software packages process X-ray data differently, which also results in variability. These and other sources of variability are known to those skilled in the art. Because of these sources of variability, it is common to describe X-ray diffraction peaks using the word "about" before the 2θ peak value. The word "about" encompasses this variability, which results in peak position variations of approximately plus or minus 0.2 scattering angles (2θ) across many sample preparation conditions, as well as many data collection and processing conditions. Thus, under many sample preparation, data collection and data processing conditions, when a peak is said to be at about 10.5 scattering angles (2θ), it is likely that the peak is somewhere between 10.3 (2θ) and 10.7 (2θ).

[0052] High performance liquid chromatography, or HPLC, is a chromatographic method used to separate compounds in a mixture, to identify each compound, and to quantify each compound. HPLC is a technique known in the art for determining the purity of compounds. The purity of elafibranor Forms A, B, C, D and E can be determined using HPLC as is well known to those skilled in the art.

[0053] In a preferred embodiment of the present invention, the crystalline form A, the crystalline form B, the crystalline form C, the crystalline form D and the crystalline form E are substantially free of impurities.

[0054] By "substantially free," it is meant in the present invention that crystalline form A, crystalline form B, crystalline form C, crystalline form D and crystalline form E contain less than 10%, preferably less than 5%, more preferably less than 2% of any impurity.

[0055] In certain embodiments, substantially free of impurities means substantially free of foreign matter, such as salt-forming acids, residual solvents, or any other impurities that may result from the preparation and / or isolation of the compound of Formula (I).

[0056] In certain embodiments, the crystalline forms have a purity of at least 85%, particularly at least 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or even at least 99%. In another aspect, the present invention relates to pharmaceutical compositions containing, as an active ingredient, a crystalline form of elafibranor of the present invention. These pharmaceutical compositions contain an effective amount of at least one crystalline form of elafibranor of the present invention and at least one pharmaceutically acceptable excipient. The excipient is selected from conventional excipients known to those skilled in the art according to the desired pharmaceutical form and method of administration.

[0057] In one embodiment, the pharmaceutical composition of the present invention contains as an active ingredient a crystalline form of elafibranor selected from the group consisting of Form A, Form B, Form C, Form D and Form E, in particular selected from the group consisting of Form B, Form C, Form D and Form E.

[0058] The compositions of the present invention can be formulated for any type of administration. For example, the compositions can be formulated for oral, topical, parenteral, or enteral administration, or for inhalation. The crystalline forms of elafibranor can be formulated for administration as is or in combination with conventional pharmaceutical carriers, diluents, or excipients, which can be liquid or solid. Applicable solid carriers, diluents, or excipients can function as, among other things, binders, disintegrants, fillers, lubricants, glidants, compression aids, processing aids, pigments, sweeteners, preservatives, suspending / dispersing agents, tablet disintegrants, encapsulating materials, film-forming or coating agents, flavoring agents, or printing inks. Any materials used in preparing any dosage unit form are preferably pharmaceutically pure and substantially non-toxic in the amounts used.

[0059] Additionally, the crystalline forms of elafibranor may be incorporated into sustained release preparations or formulations. In this regard, administration includes, inter alia, the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial, e.g., transdermal, intraocular, sublingual, and buccal; topical, e.g., intraocular, transdermal, intraocular, rectal, insufflation, and aerosol nasal inhalation, and rectal systemic administration.

[0060] In powders, the carrier, diluent, or excipient may be a finely divided solid mixed with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier, diluent, or excipient having the necessary compression properties in suitable proportions and compacted in the shape and size desired. For oral therapeutic administration, the active compound may be combined with the carrier, diluent, or excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. The amount of active compound in such therapeutically useful compositions is preferably such that a suitable dosage will be obtained. Liquid carriers, diluents, or excipients can be used in preparing solutions, suspensions, emulsions, syrups, elixirs, etc. The active ingredients of the present invention can be dissolved or suspended in a pharmaceutically acceptable liquid, such as water, an organic solvent, a mixture of both, or a pharmaceutically acceptable oil or fat. The liquid carriers, excipients, or diluents may contain other suitable pharmaceutical additives, such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, pigments, viscosity regulators, stabilizers, or osmotic pressure regulators.

[0061] Suitable solid carriers, diluents, and excipients may include, for example, calcium phosphate, silicon dioxide, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, ethyl cellulose, sodium carboxymethyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, low melting point waxes, ion exchange resins, croscarmellose, carbon, acacia, pregelatinized starch, crospovidone, HPMC, povidone, titanium dioxide, polycrystalline cellulose, aluminum metahydroxide, agar, tragacanth, or mixtures thereof.

[0062] Suitable examples of liquid carriers, diluents, and excipients include, for example, for oral, topical, or parenteral administration, water (especially those containing additives such as those described above, e.g., cellulose derivatives, preferably sodium carboxymethylcellulose solution), alcohols (e.g., monohydric and polyhydric alcohols, e.g., glycols) and derivatives thereof, and oils (e.g., fractionated coconut oil and peanut oil), or mixtures thereof.

[0063] For parenteral administration, the carrier, diluent, or excipient may also be an oily ester, such as ethyl oleate and isopropyl myristate. Sterile liquid carriers, diluents, or excipients for use in sterile liquid compositions for parenteral administration are also contemplated. Solutions of the active compound as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under ordinary conditions of storage and use, these preparations may contain preservatives to prevent the growth of microorganisms.

[0064] Pharmaceutical forms suitable for injectable use include, for example, sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form is preferably sterile and liquid for ease of syringability. It is preferably stable under the conditions of manufacture and storage and is preferably preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier, diluent, or excipient can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, the maintenance of the required particle size in the case of dispersions, and the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be achieved by the use of agents delaying absorption, for example, aluminum monostearate and gelatin.

[0065] Sterile injectable solutions can be prepared by adding a pharmaceutically appropriate amount of the above crystalline form of elafibranor to a suitable solvent, along with various other ingredients as listed above, as needed, followed by filtered sterilization. Typically, dispersions can be prepared by adding a sterilized active ingredient to a sterile vehicle containing a basic dispersion medium and the other required ingredients listed above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation include vacuum drying and freeze-drying, which yield powders of one or more active ingredients and any additional desired ingredients from a previously sterile-filtered solution thereof. Also disclosed are methods for preparing such pharmaceutical compositions, comprising combining any of the previously disclosed embodiments of the crystalline forms of elafibranor with a pharmaceutically acceptable excipient. Any acceptable method for combining an active agent with a pharmaceutically acceptable excipient can be used in accordance with the methods of the present invention, and those of skill in the art will readily recognize appropriate combination techniques. In some embodiments, the combining step can be as simple as adding a desired amount of the crystalline forms of elafibranor to an existing substance, such as a liquid beverage or powdered beverage mix. In other embodiments, the combining step includes any method conventionally used for mixing an active agent with an excipient for the preparation of a pharmaceutical dosage form (e.g., solid, semi-solid, liquid, or inhalable form), a cosmetic (e.g., powder, cream, lotion, or emollient), or a food product (e.g., solid, semi-solid, or liquid).

[0066] In another aspect, the present disclosure provides a therapeutic method for the treatment of a disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a crystalline form of elafibranor disclosed herein.

[0067] As used herein, the phrase "therapeutically effective amount" refers to that amount of active compound that elicits the biological or pharmaceutical response sought in a tissue, body, animal, individual or human by a researcher, veterinarian, physician or other clinician, which response includes one or more of the following: (1) Preventing a disease or condition, e.g., preventing a disease, condition, or disorder in an individual who may be predisposed to the disease, condition, or disorder but has not yet experienced or displayed the pathology or symptoms of the disease; (2) inhibiting a disease or condition, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder (i.e., including arresting further development of the pathology and / or symptoms); and (3) Ameliorating a disease or condition, e.g., ameliorating a disease, condition, or disorder (i.e., including reversing the pathology and / or symptoms) in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder.

[0068] The crystalline forms of elafibranor may be administered by any of the routes described above for the pharmaceutical compositions of the present invention. For example, the crystalline forms of elafibranor may be administered orally, topically, parenterally, enterally, or by inhalation. The crystalline forms of elafibranor may be administered in combination with a pharmaceutically acceptable excipient.

[0069] The subject is a mammalian subject, preferably a human subject. However, the subject may also be any animal, for example, a laboratory animal. Therefore, as can be easily understood by those skilled in the art, the method, crystalline form and composition of the present invention are particularly suitable for administration to any animal, particularly mammals, for example, domestic animals such as, but not limited to, humans, feline and canine subjects, farm animals such as, but not limited to, cattle, horses, goats, sheep and pigs, wild animals (whether in the wild or in zoos), research animals such as mice, rats, rabbits, goats, sheep, pigs, dogs, cats, and birds (i.e., for veterinary use), such as chickens, turkeys, songbirds, and other birds.

[0070] The crystalline forms of the present invention can be used in methods of treating a number of diseases or conditions, in particular, the pharmaceutical compositions of the present invention are administered to a subject in need thereof for the treatment of any of the diseases or conditions disclosed in WO2004 / 005233, WO2004 / 005243, WO2011 / 064350 or WO2014 / 111584.

[0071] In certain embodiments, the diseases to be treated are immune, inflammatory, metabolic, fibrotic, and cholestatic diseases. In certain embodiments, the diseases include metabolic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver disease, alcohol-induced liver disease, pathogen-induced liver disease, inflammatory liver disease, liver disease mediated by immune system dysfunction, dyslipidemia, cardiovascular disease, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathy (e.g., primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), biliary atresia, familial intrahepatic cholestasis type 3 (PFIC3)), inflammatory bowel disease, and cholangitis. Cancer, ulcerative colitis, keloid, old myocardial infarction, scleroderma / systemic sclerosis, inflammatory diseases, neurodegenerative diseases, cancer, liver cancer, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, meningioma associated with neurofibromatosis, pancreatic neuroendocrine tumors, pancreatic exocrine tumors, leukemia, myeloproliferative / myelodysplastic disorders, mastocytosis, dermatofibrosarcoma, solid tumors (e.g., breast cancer, lung cancer, thyroid cancer or colorectal cancer), prostate cancer, liver fibrosis or cirrhosis of any cause, metabolic disease-induced liver fibrosis or cirrhosis, NAFLD-induced fibrosis or cirrhosis, NASH-induced fibrosis or cirrhosis, Alcohol-induced liver fibrosis or cirrhosis, drug-induced liver fibrosis or cirrhosis, pathogen-induced liver fibrosis or cirrhosis, parasitic infection-induced liver fibrosis or cirrhosis, bacterial infection-induced liver fibrosis or cirrhosis, viral infection-induced fibrosis or cirrhosis, HBV infection-induced liver fibrosis or cirrhosis, HCV infection-induced liver fibrosis or cirrhosis, HIV infection-induced liver fibrosis or cirrhosis, both HCV and HIV infection-induced liver fibrosis or cirrhosis, radiation or chemotherapy-induced fibrosis or cirrhosis, biliary fibrosis, liver fibrosis or cirrhosis due to any chronic cholestatic disease , gastrointestinal fibrosis of any cause, Crohn's disease-induced fibrosis, ulcerative colitis-induced fibrosis, intestinal (e.g., small intestine) fibrosis, colonic fibrosis, gastric fibrosis, skin fibrosis, epidermal fibrosis, endothelial fibrosis, scleroderma / systemic sclerosis-induced skin fibrosis, pulmonary fibrosis, pulmonary fibrosis secondary to chronic inflammatory airway disease (e.g., COPD, asthma, emphysema, smoker's lung, tuberculosis), pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cardiac fibrosis, renal fibrosis, nephrogenic systemic fibrosis, muscle fibrosis, soft tissue (e.g., mediastinal or retroperitoneal) fibrosis, bone marrow fibrosis, arthrofibrosis, tendon fibrosis,Selected from the group consisting of cartilage fibrosis, pancreatic fibrosis, uterine fibrosis, nervous system fibrosis, testicular fibrosis, ovarian fibrosis, adrenal fibrosis, arterial fibrosis, venous fibrosis, ocular fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis (a complication of coal worker's pneumoconiosis), proliferative connective fibrosis, neoplastic fibrosis, peri-implant fibrosis, asbestosis, articular fibrosis, and adhesive capsulitis.

[0072] In a most preferred embodiment, the disease is metabolic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver disease, alcohol-induced liver disease, pathogen-induced liver disease, inflammatory liver disease, liver disease mediated by immune system dysfunction, dyslipidemia, cardiovascular disease, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathy (e.g., primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), biliary atresia, familial intrahepatic cholestasis type 3 (PFIC3)), inflammatory bowel disease, Crohn's disease, ulcerative colitis, liver cancer, hepatocellular carcinoma, gastrointestinal cancer, stomach cancer, colorectal cancer, metabolic disease-induced liver fibrosis or cirrhosis, NAFLD-induced fibrosis or cirrhosis, NASH-induced fibrosis or cirrhosis, alcohol-induced liver fibrosis or cirrhosis, drug-induced liver fibrosis or cirrhosis. liver fibrosis or cirrhosis induced by pathogens, liver fibrosis or cirrhosis induced by parasitic infection, liver fibrosis or cirrhosis induced by bacterial infection, liver fibrosis or cirrhosis induced by viral infection, liver fibrosis or cirrhosis induced by HBV infection, liver fibrosis or cirrhosis induced by HCV infection, liver fibrosis or cirrhosis induced by HIV infection, liver fibrosis or cirrhosis induced by both HCV and HIV infection, radiation or chemotherapy induced fibrosis or cirrhosis, biliary fibrosis, The present invention is selected from the group consisting of liver fibrosis or cirrhosis due to any chronic cholestatic disease, gastrointestinal fibrosis due to any cause, Crohn's disease-induced fibrosis, ulcerative colitis-induced fibrosis, intestinal (e.g., small intestinal) fibrosis, colonic fibrosis, gastric fibrosis, pulmonary fibrosis, pulmonary fibrosis secondary to chronic inflammatory airway disease (e.g., COPD, asthma, emphysema, smoker's lung, tuberculosis), pulmonary fibrosis, and idiopathic pulmonary fibrosis (IPF).

[0073] In a further embodiment, the pharmaceutical composition of the present invention is used to inhibit the proliferation and / or activation of fibroblasts, which are responsible for collagen fiber production and / or extracellular matrix production.

[0074] According to the present invention, the term "autoimmune disease" is used to refer to conditions resulting from an abnormal immune response of the body against substances and tissues normally present in the body. The disease may be limited to a certain organ (e.g., in type I diabetes or autoimmune thyroiditis) or may involve specific tissues in different locations (e.g., in Goodpasture's syndrome, a disease of the basement membrane in the lungs and kidneys).

[0075] The term "inflammation" is used to refer to a condition resulting from a defensive response involving host cells, blood vessels, and proteins and other mediators that can help to remove the cause of cell / tissue damage and the necrotic cells / tissue resulting from the initial injury and initiate the repair process. The inflammatory response can be manifested as pain, heat, redness, swelling, vasodilation, increased vascular flow, and decreased function.

[0076] According to the present invention, the terms "fibrosis," "fibrotic disease," "fibrotic disorder," and their variations (declinations) refer to a pathological condition in which excessive deposition of fibrous connective tissue occurs in an organ or tissue. More specifically, fibrosis is a pathological process defined by the formation of persistent fibrous scars and excessive production of extracellular matrix by connective tissue in response to tissue injury. Physiologically, the deposition of connective tissue can obliterate the structure and function of the underlying organ or tissue.

[0077] According to the present invention, the fibrosis or fibrotic disorder may relate to fibrosis of any organ or tissue. Illustrative, but non-limiting examples of fibrosis of specific organs include fibrosis of the liver, gastrointestinal tract, kidney, skin, epidermis, endothelium, muscle, tendon, cartilage, heart, pancreas, lung, uterus, nervous system, testes, penis, ovaries, adrenal glands, arteries, veins, colon, intestines (e.g., small intestine), biliary tract, soft tissue (e.g., mediastinum or retroperitoneum), bone marrow, joints, or stomach, in particular fibrosis of the liver, kidney, skin, epidermis, endothelium, muscle, tendon, cartilage, heart, pancreas, lung, uterus, nervous system, testes, ovaries, adrenal glands, arteries, veins, colon, intestines (e.g., small intestine), biliary tract, soft tissue (e.g., mediastinum or retroperitoneum), bone marrow, joints, eyes, or stomach.

[0078] According to the present invention, the terms "cholestasis" or "cholestatic disease" or "cholestatic disorder" and their variants refer to a pathological condition defined by a reduced bile flow due to impaired secretion by hepatocytes or obstruction of bile flow through the intrahepatic or extrahepatic bile ducts. Thus, the clinical definition of cholestasis is the retention of any substance normally excreted in bile.

[0079] In certain embodiments, the fibrotic disorder is selected from the group consisting of fibrosis of the liver, gastrointestinal tract, lung, heart, kidney, muscle, skin, soft tissue (e.g., mediastinal or retroperitoneum), bone marrow, intestinal tract, and joints (e.g., knee, shoulder, or other joints).

[0080] In a preferred embodiment, the fibrotic disorder is selected in the group consisting of liver, lung, skin, kidney and intestinal fibrosis.

[0081] In a more preferred embodiment of the present invention, the fibrotic disease to be treated is selected from the following non-exhaustive list of fibrotic diseases: non-alcoholic steatohepatitis (NASH), pulmonary fibrosis, idiopathic pulmonary fibrosis, cutaneous fibrosis, ocular fibrosis (e.g., capsular fibrosis), endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis (a complication of coal worker's pneumoconiosis), proliferative connective fibrosis, neoplastic fibrosis, pulmonary fibrosis secondary to chronic inflammatory airway disease (e.g., COPD, asthma, emphysema, smoker's lung, tuberculosis), alcohol- or drug-induced liver fibrosis, liver cirrhosis. , infection-induced liver fibrosis, radiation- or chemotherapy-induced fibrosis, nephrogenic systemic fibrosis, Crohn's disease, ulcerative colitis, keloids, old myocardial infarction, scleroderma / systemic sclerosis, joint fibrosis, some forms of adhesive capsulitis, chronic fibrosing cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC), biliary atresia, familial intrahepatic cholestasis type 3 (PFIC3), peri-transplant fibrosis, and asbestosis.

[0082] Cholestasis is defined as a decrease in bile flow due to impaired secretion by hepatocytes (hepatocellular cholestasis) or obstruction of bile flow through the intrahepatic or extrahepatic bile ducts (obstructive cholestasis).In clinical practice, cholestasis is any condition in which bile flow from the liver is delayed or blocked.According to certain embodiments of the present invention, the cholestatic disease is selected from the group consisting of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), intrahepatic cholestasis of pregnancy, progressive familial intrahepatic cholestasis, biliary atresia, cholelithiasis, infectious cholangitis, cholangitis associated with Langerhans cell histiocytosis, Alagille syndrome, asymptomatic cholangiopenia, drug-induced cholestasis, and cholestasis associated with total parenteral nutrition.In a preferred embodiment, the cholestatic disease is PBC or PSC, particularly PBC.

[0083] Examples of inflammatory, fibrotic, metabolic, and cholestatic diseases include metabolic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver disease, alcohol-induced liver disease, pathogen-induced liver disease, inflammatory liver disease, liver disease mediated by immune system dysfunction, dyslipidemia, cardiovascular disease, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathy (e.g., primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC), biliary atresia, familial intrahepatic cholestasis type 3 (PFIC3)), and inflammatory bowel disease. , Crohn's disease, ulcerative colitis, keloid, old myocardial infarction, scleroderma / systemic sclerosis, inflammatory diseases, neurodegenerative diseases, cancer, liver cancer, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, meningiomas associated with neurofibromatosis, pancreatic neuroendocrine tumors, pancreatic exocrine tumors, leukemia, myeloproliferative / myelodysplastic disorders, mastocytosis, dermatofibrosarcoma, solid tumors (e.g., breast cancer, lung cancer, thyroid cancer, or colorectal cancer), prostate cancer, liver fibrosis or cirrhosis of any cause, metabolic disease-induced liver fibrosis or cirrhosis, NAFLD-induced fibrosis or cirrhosis, NASH-induced fibrosis or cirrhosis, alcohol-induced liver cirrhosis fibrosis or cirrhosis, drug-induced liver fibrosis or cirrhosis, pathogen-induced liver fibrosis or cirrhosis, parasitic infection-induced liver fibrosis or cirrhosis, bacterial infection-induced liver fibrosis or cirrhosis, viral infection-induced fibrosis or cirrhosis, HBV infection-induced liver fibrosis or cirrhosis, HCV infection-induced liver fibrosis or cirrhosis, HIV infection-induced liver fibrosis or cirrhosis, both HCV and HIV infection-induced liver fibrosis or cirrhosis, radiation or chemotherapy-induced fibrosis or cirrhosis, biliary fibrosis, liver fibrosis or cirrhosis due to any chronic cholestatic disease, gastrointestinal fibrosis due to any cause, Crohn's disease induced fibrosis, ulcerative colitis-induced fibrosis, intestinal (e.g., small intestine) fibrosis, colonic fibrosis, gastric fibrosis, skin fibrosis, epidermal fibrosis, endothelial fibrosis, scleroderma / systemic sclerosis-induced skin fibrosis, pulmonary fibrosis, pulmonary fibrosis secondary to chronic inflammatory airway disease (e.g., COPD, asthma, emphysema, smoker's lung, tuberculosis), pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), cardiac fibrosis, renal fibrosis, nephrogenic systemic fibrosis, muscle fibrosis, soft tissue (e.g., mediastinal or retroperitoneal) fibrosis, bone marrow fibrosis, arthrofibrosis, tendon fibrosis, cartilage fibrosis, pancreatic fibrosis, uterine fibrosis, nervous system fibrosis, testicular fibrosis, ovarian fibrosis,These include adrenal fibrosis, arterial fibrosis, venous fibrosis, ocular fibrosis, endomyocardial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis (a complication of coal worker's pneumoconiosis), proliferative connective fibrosis, neoplastic fibrosis, peri-implant fibrosis, asbestosis, articular fibrosis, and adhesive capsulitis.

[0084] Preferably, the disease is a metabolic liver disease, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), drug-induced liver disease, alcohol-induced liver disease, pathogen-induced liver disease, inflammatory liver disease, liver disease mediated by immune system dysfunction, dyslipidemia, cardiovascular disease, restenosis, syndrome X, metabolic syndrome, diabetes, obesity, hypertension, chronic cholangiopathy (e.g., primary sclerosing cholangitis (PSC)), or ), primary biliary cholangitis (PBC), biliary atresia, familial intrahepatic cholestasis type 3 (PFIC3), inflammatory bowel disease, Crohn's disease, ulcerative colitis, liver cancer, hepatocellular carcinoma, gastrointestinal cancer, gastric cancer, colorectal cancer, metabolic disease-induced liver fibrosis or cirrhosis, NAFLD-induced fibrosis or cirrhosis, NASH-induced fibrosis or cirrhosis, alcohol-induced liver fibrosis or cirrhosis, drug-induced liver fibrosis or cirrhosis, pathogens induced liver fibrosis or cirrhosis, parasitic infection-induced liver fibrosis or cirrhosis, bacterial infection-induced liver fibrosis or cirrhosis, viral infection-induced fibrosis or cirrhosis, HBV infection-induced liver fibrosis or cirrhosis, HCV infection-induced liver fibrosis or cirrhosis, HIV infection-induced liver fibrosis or cirrhosis, both HCV and HIV infection-induced liver fibrosis or cirrhosis, radiation or chemotherapy-induced fibrosis or cirrhosis, biliary tract fibrosis, liver fibrosis or cirrhosis due to any chronic cholestatic disease, gastrointestinal fibrosis due to any cause, Crohn's disease-induced fibrosis, ulcerative colitis-induced fibrosis, intestinal (e.g., small intestine) fibrosis, colonic fibrosis, gastric fibrosis, pulmonary fibrosis, pulmonary fibrosis secondary to chronic inflammatory airway disease (e.g., COPD, asthma, emphysema, smoker's lung, tuberculosis), pulmonary fibrosis, and idiopathic pulmonary fibrosis (IPF).

[0085] The term "treatment" or "treating" refers to the curative or prophylactic treatment of a disorder in a subject in need thereof. Such treatment involves administering the compound, particularly the compound contained in a pharmaceutical composition, to a subject, i.e., a patient, with a declared disorder to cure, delay, reverse, or slow the progression of the disorder, thereby improving the condition of the subject. Such treatment may also result in the alleviation of symptoms associated with the disorder, or the halting of further progression or worsening of those symptoms. Treatment may also be administration to a healthy subject or a subject at risk of developing a cholestatic or fibrotic disorder to prevent or delay the disorder.

[0086] Thus, in accordance with the present invention, treatment of immune, inflammatory, metabolic, fibrotic and cholestatic disorders involves administering a therapeutically effective amount of elafibranor to a subject with a declared disorder to cure, delay, reverse or slow the progression of the disorder, thereby improving the condition of said patient, or to a healthy subject, particularly one at risk of developing such a disorder.

[0087] The present invention is further described by reference to the following examples which detail the preparation of the crystalline forms of the present invention. [Example]

[0088] X-ray powder diffraction (XRPD) analysis X-ray powder diffraction (XRPD) analyses were performed on a Bruker AXS D8 Advance instrument in the θ-θ configuration using a copper anticathode, a single-crystal silicon sample holder, and a Lynxeye detector. The instrument operating conditions for X-ray pattern acquisition are listed in TABLE 1.

[0089] [Table 1]

[0090] After aging, the powder sample was dispersed into the silicon sample holder, avoiding preferred orientation (rather than randomly orienting the crystals) and ensuring planarity of the sample surface. The X-ray diffraction patterns of Form A, Form B, Form C, Form D and Form E are shown in Figures 1, 2, 3, 4 and 5, respectively.

[0091] Thermogravimetric Analysis (TGA) and Infrared (IR) Thermogravimetric analysis (TGA) coupled with infrared (IR) was performed on a TA Instruments ATG 2950 equipped with an EGA oven and a ThermoNicolet Nexus FT-IR equipped with a cell and gas delivery lines for TGA gas analysis. The sample, placed in an aluminum capsule in the thermogravimetric analyzer, was heated from room temperature to 300°C. A ramp rate of 10°C / min was used. During heating, the thermogravimetric analyzer oven was continuously purged with a low nitrogen flow rate of 90 mL / min (Air Liquide gas, Alphagaz N2 quality). The gas generated by the TGA oven was delivered to the FT-IR instrument using a gas delivery line. The analytical cell and gas delivery line were maintained at 110°C. On the IR bench, the spectral resolution was 4 cm-1, the scan speed was 0.62329 cm / s, and IR spectra were recorded every 32 s.

[0092] HPLC analysis HPLC analysis was performed on a Waters, Symmetry Shield RP18, 4.5 x 150 mm column. Table 3 shows the HPLC parameters used to analyze the samples.

[0093] [Table 2]

[0094] Sample preparation Approximately 1 mg of the solid recrystallized residue was placed in a 10 mL volumetric flask and then dissolved to 10 mL with MeOH. Immediately after dissolution of the sample in MeOH, the solution was processed, packaged, and stored away from light. result All recrystallized samples (Forms A to E) corresponded to elafibranor and had similar retention times and percent purity of at least 98.9%, demonstrating that the samples corresponded to elafibranor and not degradation products.

[0095] Synthesis of the raw material elafibranor The tert-butyl ester of elafibranor ("Compound" in the experimental section below) was prepared according to the method described in WO2011144579. The ester (1 equivalent) was stirred in dichloromethane at room temperature, and trifluoroacetic acid (10 equivalents) was added. The reaction mixture was hydrolyzed and then washed with water. The dichloromethane was evaporated, and the resulting solid was then filtered to obtain crude elafibranor.

[0096] Crystallization method Different methods have been identified for producing specific crystalline forms of elafibranor.

[0097] Form A Form A can be obtained by crystallizing the elafibranor prepared above according to the method described in Z. Szokol (2018) (IP.com number IPCOM000252802D). This method gives elafibranor in 77.2% yield.

[0098] TABLE 4 lists the numerical values ​​of the XRPD peak positions in the diffractogram of FIG.

[0099] [Table 3]

[0100] Form B Elafibranor Form B was prepared according to the following method. The wet crude elafibranor prepared above was charged with isopropyl alcohol in a suitable reactor, and the mixture was heated to 70°C and stirred until dissolution was achieved. After partial distillation of the isopropyl alcohol (approximately half of the initial volume of the solution), the reaction mixture was cooled to 0°C to allow crystallization, yielding purified elafibranor after filtration, washing with cold isopropyl alcohol, and drying. Yield: 76%. TABLE 5 lists the numerical values ​​of the XRPD peak positions in the diffractogram of FIG.

[0101] [Table 4]

[0102] Form C The elafibranor (10.6 mg) prepared above was suspended at room temperature in ethanol (240 μL) previously saturated with elafibranor (28.7 mg / mL). For the crystallization step, the suspension was placed at a temperature between +4°C and +8°C to limit chemical decomposition prior to characterization of the insoluble compound by XRPD, followed by optical microscopy and differential scanning calorimetry. Analysis showed that Form C was an ethanol solvate with a 1:1 stoichiometry. HPLC confirmed that Form C was elafibranor (not a degradation product) (same retention time - 99% purity).

[0103] TABLE 6 lists the numerical values ​​of the XRPD peak positions in the diffractogram of FIG.

[0104] [Table 5]

[0105] Form D The elafibranor (13.4 mg) prepared above was suspended at room temperature in methanol (200 μL) previously saturated with elafibranor (17.7 mg / mL). For the crystallization step, the suspension was placed at a temperature between +4°C and +8°C to limit chemical decomposition prior to characterization of the insoluble compound by XRPD, followed by optical microscopy and differential scanning calorimetry. Analysis concluded that Form D is a methanol solvate with 1 / 1 stoichiometry. HPLC confirmed that Form D was elafibranor (not a degradation product) (same retention time - 99% purity). TABLE 7 lists the numerical values ​​of the XRPD peak positions in the diffractogram of FIG.

[0106] [Table 6]

[0107] Form E The above prepared elafibranor (10.7 mg) was suspended at room temperature in N,N-dimethylacetamide (DMA) (100 μL) previously saturated with elafibranor (11.9 mg / mL). For the crystallization step, the suspension was left at room temperature and away from light for 4 weeks before characterization of the insoluble compound by XRPD, followed by optical microscopy and differential scanning calorimetry. Analysis showed that Form E is a 1 / 1 stoichiometric N,N-dimethylacetamide solvate. HPLC confirmed that Form E was elafibranor (not a degradation product) (same retention time - 99% purity). TABLE 8 lists the numerical values ​​of the XRPD peak positions in the diffractogram of FIG.

[0108] [Table 7]

Claims

1. Crystalline form C of elafibranor having an X-ray diffraction pattern including the following diffraction peaks (angles 2θ±0.2°): 17.7°, 23.3°, 27.3°, 34.3° and 34.6°.

2. 2. The crystalline form of elafibranor of claim 1, wherein the X-ray diffraction pattern further comprises a diffraction peak at 28.9° (angle 2θ±0.2°).

3. 3. The crystalline form of elafibranor of claim 1 or 2, wherein the X-ray diffraction pattern comprises at least one peak selected from the group consisting of 8.9°, 10.1°, 10.7°, 11.3°, 32.0° and 35.5°.

4. 4. The crystalline form of elafibranor according to any one of claims 1 to 3, wherein the X-ray diffraction pattern comprises the following diffraction peaks (angles 2θ±0.2°): 8.9°, 10.1°, 10.7°, 11.3°, 17.7°, 23.3°, 27.3°, 28.9°, 32.0°, 34.3°, 34.6° and 35.5°.

5. Crystalline form D of elafibranor having an X-ray diffraction pattern including the following diffraction peaks (angles 2θ±0.2°): 10.9°, 15.6°, 16.1°, 18.6°, 19.9° and 20.7°.

6. 6. The crystalline form of elafibranor described in claim 5, wherein the X-ray diffraction pattern further comprises at least one more diffraction peak (angle 2θ±0.2°) selected from the group consisting of 7.8°, 17.7°, 18.1°, 21.9°, 22.3° and 24.6°.

7. 7. The crystalline form of elafibranor according to claim 5 or 6, wherein the X-ray diffraction pattern further comprises at least one more diffraction peak (angle 2θ±0.2°) selected from the group consisting of 9.3°, 12.9°, 13.4°, 14.7°, 24.1°, 25.1°, 25.5°, 25.8°, 26.1°, 27.3°, 28.0°, 28.4°, 29.2°, 29.9°, 32.3°, 32.9° and 33.6°.

8. 8. The crystalline form of elafibranor of any one of claims 5 to 7, wherein the X-ray diffraction pattern comprises the following diffraction peaks (angles 2θ±0.2°): 7.8°, 9.3°, 10.9°, 12.9°, 13.4°, 14.7°, 15.6°, 16.1°, 17.7°, 18.1°, 18.6°, 19.9°, 20.7°, 21.9°, 22.3°, 24.1°, 24.6°, 25.1°, 25.5°, 25.8°, 26.1°, 27.3°, 28.0°, 28.4°, 29.2°, 29.9°, 32.3°, 32.9°, and 33.6°.

9. Crystalline form E of elafibranor having an X-ray diffraction pattern comprising the following diffraction peaks (angles 2θ±0.2°): 13.3°, 15.1°, 17.1° and 29.5°.

10. 10. The crystalline form of elafibranor of claim 9, wherein the X-ray diffraction pattern further comprises at least one other diffraction peak (angle 2θ±0.2°) selected from the group consisting of 18.1°, 25.2°, 25.9° and 26.2°.

11. 11. The crystalline form of elafibranor according to claim 9 or 10, wherein the X-ray diffraction pattern further comprises at least one more diffraction peak (angle 2θ±0.2°) selected from the group consisting of 7.6°, 8.6°, 11.2°, 16.1°, 16.9°, 17.8° and 22.8°.

12. 12. The crystalline form of elafibranor according to any one of claims 9 to 11, wherein the X-ray diffraction pattern comprises the following diffraction peaks (angle 2θ±0.2°): 7.6°, 8.6°, 11.2°, 13.3°, 15.1°, 17.1°, 16.1°, 16.9°, 17.8°, 18.1°, 22.8°, 25.2°, 25.9°, 26.2° and 29.5°.

13. 13. A pharmaceutical composition comprising an effective amount of a crystalline form of elafibranor according to any one of claims 1 to 12, and at least one pharmaceutically acceptable excipient.

14. 14. The pharmaceutical composition according to claim 13, formulated in the form of a tablet, an injection suspension, a gel, an oil, a pill, a suppository, a powder, a gel cap, a capsule, an aerosol, or in a sustained or extended release galenic dosage form.

15. 13. The crystalline form of elafibranor according to any one of claims 1 to 12 for use in a method for the treatment of liver damage.

16. 16. The crystalline form of elafibranor for use according to claim 15, wherein the liver disorder is selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or cirrhosis.

17. 13. The crystalline form of elafibranor according to any one of claims 1 to 12 for use in a method for the treatment of a cholestatic disease.

18. 18. The crystalline form of elafibranor for use according to claim 17, wherein the cholestatic disease is PBC or PSC.

19. 15. A pharmaceutical composition according to claim 13 or 14 for use in a method for the treatment of liver damage.

20. 20. The pharmaceutical composition for use according to claim 19, wherein the liver disorder is selected from the group consisting of non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH) or cirrhosis.

21. 15. A pharmaceutical composition according to claim 13 or 14 for use in a method for the treatment of a cholestatic disease.

22. 22. The pharmaceutical composition for use according to claim 21, wherein the cholestatic disease is PBC or PSC.

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