Crystal form of Ebenamide

Abstract

The present invention relates to novel crystalline forms of evenamide salt, particularly forms I and II, their uses, methods for their preparation, and pharmaceutical compositions containing the novel crystalline forms.

Description

Technical Field

[0001] Technical Field of the Invention The present invention relates to crystalline forms of ebenamide salts, preferably hydrochloride salts, particularly Form I and Form II, their use, methods for their preparation, and pharmaceutical compositions containing said novel crystalline forms.

[0002] Background of the Invention Ebenamide, 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide, is a novel chemical entity with the following chemical formula (I) that specifically targets voltage-gated sodium channels (VGSCs) and is orally administrable:

Chem.

[0003] Ebenamide regulates sustained repetitive firing without inducing disorders of normal excitability. It normalizes glutamate release induced by abnormal sodium channel activity and is under clinical investigation as an add-on therapy for the treatment of schizophrenia.

[0004] Ebenamide has demonstrated potential benefits in a series of animal models that predict efficacy in schizophrenia and other mental disorders. In a Phase 2 study in patients with schizophrenia, ebenamide has provided preliminary evidence of efficacy, tolerability, and safety.

[0005] WO 2008 / 151702 discloses the synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide and its hydrochloride salt, as summarized in Scheme A below, in the Examples.

Chem.

[0006] International Publication No. 2020 / 212227 discloses methods for the preparation of everamide, its hydrochloride salt, and its deuterated derivatives.

[0007] International Publication No. 2020 / 212352 discloses another method for the preparation of everamide, its hydrochloride, and its deuterated derivatives.

[0008] IN201911052571 discloses a method for preparing amorphous form of everamide or a pharmaceutically acceptable salt thereof.

[0009] The crystalline form of evenamide has not been disclosed or characterized to date.

[0010] Therefore, there is a need to provide a crystalline form of everamide that is stable, non-hygroscopic, particularly soluble in water and body fluids, possesses optimal characteristics for formulation in pharmaceutical technology, and is also advantageously usable as an intermediate for the preparation of the crystalline form of everamide, especially in salt form.

[0011] Summary of the Invention The present invention relates to crystalline forms of evenamide salt, preferably hydrochloride salt, and more specifically to crystalline forms of evenamide hydrochloride salt as defined herein hereafter as crystalline forms I and II and crystalline form III, as well as methods for preparing them, and pharmaceutical compositions containing at least one of the crystalline forms. [Brief explanation of the drawing]

[0012] Brief description and analysis method of the drawing [Figure 1] XRPD spectrum of everamide hydrochloride in crystalline form I. [Figure 2] DSC curves of everamide hydrochloride in crystalline forms I and II. [Figure 3] DSC and TGA curves of crystalline morphology I and morphology II of everamide hydrochloride. [Figure 4]HSM images of evenamide hydrochloride in crystalline forms I and II. A: obtained at T=25°C; B: obtained at T=80°C; C: obtained at T=110°C; D: obtained at T=140°C. [Figure 5] Comparison of the XRPD patterns of everamide hydrochloride in crystalline form I at 80°C and everamide hydrochloride in crystalline form II at 110°C. [Figure 6] Comparison of XRPD patterns of crystalline form I of everamide hydrochloride before and after heating / cooling treatment at room temperature. [Figure 7] XRPD spectrum of crystalline form III of everamide hydrochloride.

[0013] The crystalline morphology of evenamide hydrochloride was characterized by X-ray powder diffraction (XRPD).

[0014] The X-ray powder diffraction (XRPD) patterns in Figures 1 and 7 were collected using a Rigaku Miniflex diffractometer with Cu-Kα rays having a wavelength λ=1.54 Å, generated at 30 kV and 15 mA. Powder samples lightly ground in a mortar were packed into an aluminum sample holder, and the XRPD patterns were recorded using a step scan mode with a scan speed of 1.0°²θ / min and a 2θ angle in the range of 5–35°.

[0015] XRPD patterns shown in Figures 5 and 6 were obtained by measuring samples in a TTK Anton Paar high-temperature apparatus at 80°C and 110°C, after light grinding in an Agata mortar, using a Bruker BD5005 diffractometer equipped with a Cu-Kα line with wavelength λ=1.54Å, a nickel filter, and a position-sensitive detector (PSD), under the following conditions: 40kV, 30mA, step width 0.0 15°(2θ), step time 0.30 sec / step, angle range 4.5<2θ<35.

[0016] The DSC pattern was obtained using a differential scanning calorimeter with a DSC 2010 TA Instruments calorimeter under a nitrogen purge of 70 mL / min. The runs were carried out on 2 - 3 mg of sample in a non - hermetically sealed aluminum pan at a scan rate of 10 K / min from 25 to 300 °C.

[0017] The TGA curve was recorded using a thermogravimetric analyzer of TG2050 TA Instruments at a heating rate of 10 K / min and a nitrogen purge of 90 mL / min.

[0018] The HSM images were obtained by examining a powder sample with a hot - stage microscope apparatus consisting of a Mettler FP82HT cell, a Mettler FP 82HT control unit, and an optical microscope (Reichert Microstar I).

[0019] Some crystals were suspended in silicone oil, placed on a microscope slide, covered with a cover glass, and heated from 25 °C to 160 °C at a scan rate of 5 K / min. Microscopic photographs were taken at predetermined temperatures.

[0020] Detailed Description of the Invention The present invention relates to solid crystalline forms of salts of 2 - [2 - (3 - butoxyphenyl) - ethylamino] - N,N - dimethylacetamide, also known as evenamide, represented by formula (I), preferably hydrochloride salts, selected from the following: · Evenamide in a crystalline form defined herein as Form I, having an XRPD spectrum as shown, for example, in Figure 1. Characteristic peaks are found at approximately 12.1; 13.4; 16.2; 16.7; 18.2; 18.7; 19.4; 21.7; 22.4; 22.8; 23.3; 23.7; 24.2; 24.4; 25.4; 26.0; 26.6 ± 0.2° 2θ; · Evenamide in a crystalline form defined herein as Form II (at 110 °C), having an XRPD spectrum as shown, for example, in Figure 5. Characteristic peaks are found at approximately 12.7; 17.7; 20.0; 20.4; 20.7 ± 0.2° 2θ.

[0021] The present invention also discloses an everamide hydrochloride in a crystalline form defined herein as form III, characterized by the XRPD spectrum shown in Figure 7, where characteristic peaks are found at approximately 15.6;18.3;21.6;23.4;25.2;26.2±0.2°2θ. The everamide in crystalline form III was determined to be the 1,4-dioxane solvate of the monoHCl salt.

[0022] Preferably, the salt of evenamide, more preferably the hydrochloride salt, is in crystalline form I.

[0023] Another object of the present invention is the crystalline form of the salt of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide represented by formula (I), where the salt of evenamide is as follows: • A salt that exhibits a main endothermic peak at approximately 119°C, preferably a sulfate; • A salt that exhibits a main endothermic peak at approximately 132.6°C, preferably a maleate; • A salt, preferably a phosphate, that exhibits a main endothermic peak at approximately 105.6°C; • A salt that exhibits a main endothermic peak at approximately 118.3°C, preferably a pyruvate; • A salt, preferably a fumarate, that exhibits a main endothermic peak at approximately 114.6°C; • A salt, preferably a mucoate, that exhibits a main endothermic peak at approximately 154.8°C; • A salt, preferably a citrate, that exhibits a main endothermic peak at approximately 140.7°C; • A salt that exhibits a main endothermic peak at approximately 101.2°C, preferably L-malate; • A salt, preferably a succinate, that exhibits a main endothermic peak at approximately 85.8°C; • A salt that exhibits a main endothermic peak at approximately 91.4°C, preferably a glutarate; • A salt that exhibits a main endothermic peak at approximately 147.9°C, preferably napadisylate; • A salt that exhibits a main endothermic peak at approximately 197.8°C, preferably an edisylate; • A salt that exhibits a main endothermic peak at approximately 120.0°C, preferably an esylate; • A salt, preferably a tosylate, that exhibits a main endothermic peak at approximately 161.8°C; • A salt, preferably a mesylate, that exhibits a main endothermic peak at approximately 139.5°C; • A salt that exhibits a main endothermic peak at approximately 184.5°C, preferably a napsylate; • A salt, preferably a besylate, that exhibits a main endothermic peak at approximately 107.0°C; • A salt, preferably an oxalate, that exhibits a main endothermic peak at approximately 198.3°C; • A salt, preferably a malonate, that exhibits a main endothermic peak at approximately 96.6°C; • A salt that exhibits a main endothermic peak at approximately 150.1°C, preferably a saccharin salt; • Salts that exhibit a main endothermic peak at approximately 129.0°C, preferably cansylates; and • A salt that exhibits a main endothermic peak at approximately 105.0°C, preferably a mandelate salt. More selected, More preferably, the salt is selected from the group comprising maleate, mucoate, citrate, edisylate, mesylate, napsylate, oxalate, saccharinate, and cansylate, and even more preferably, mucoate, citrate, edisylate, mesylate, napsylate, and saccharinate.

[0024] In a more preferred embodiment, the salt is selected from the group listed in Table 1. [Table 1] TIFF2026514508000004.tif247165 TIFF2026514508000005.tif73165 More preferably, the salt is selected from the group listed in Table 2. [Table 2] More preferably, the salt is selected from the group listed in Table 3. [Table 3]

[0025] A preferred salt according to the present invention is a salt having a melting point of 120°C or higher, and being neither a solvate nor a hydrate.

[0026] A more preferred salt according to the present invention is a salt having a melting point of 130°C or higher.

[0027] The most preferred salt is a polymorph that is stable at room temperature, i.e., about 20-25°C.

[0028] The comparison salts are reported in Table 4. [Table 4]

[0029] The term "crystalline form of evenamide" according to the present invention means the solid crystalline form of evenamide as a salt, and includes polymorphs, tautomers, and solvates.

[0030] As used herein, the term “solvate” refers to a crystalline form in which the solvent is incorporated into the crystalline structure. When the solvent is water, the solvate is called a “hydrate.” The solvent in the solvate may be present in stoichiometric or non-stoichiometric amounts.

[0031] As previously defined, the crystalline forms I and II of evenamide hydrochloride are further characterized by the DSC curves shown in Figure 2.

[0032] As previously defined, the crystalline forms I and II of evenamide hydrochloride are further characterized by the DSC and TGA curves shown in Figure 3.

[0033] As previously defined, the crystalline forms I and II of evenamide hydrochloride are further characterized by the HSM images shown in Figure 4.

[0034] Another object of the present invention is a method for preparing crystalline form I of everamide hydrochloride according to the present invention, which is as follows: - A step of adding a solvent to free evenamid base and gaseous hydrochloric acid or an aqueous hydrochloric acid solution, preferably gaseous hydrochloric acid, as a chlorine reagent; • A process of crystallization at a temperature of 94°C or lower; • Process for recovering crystalline form I of everamide hydrochloride Includes, Here, the solvent is selected from the group comprising or consisting of acetone, water, methyl alcohol, isopropyl alcohol, methyl ethyl ketone / water, ethyl acetate, methyl isobutyl ketone, methyl isobutylcarbinol, dimethylformamide, heptane, or a mixture of the above solvents, preferably the solvent is acetone (Scheme 1).

[0035] Scheme 1 Preparation of crystalline form I of ebenamide hydrochloride from free ebenamide base [ka]

[0036] According to the present invention, the evenamide used as a starting material may be in any form, crystalline or amorphous; it may be an anhydrous, hydrate or solvate, and is characterized by a high purity of at least 99.0%, preferably 99.5%, 99.6%, 99.7%, 99.8%, and more preferably 99.9%.

[0037] The molar ratio between the chloride reagent and evenamide in the starting solution may be in the range of 10:1 to 0.5:1, and preferably, the chloride reagent and evenamide are used in a stoichiometric molar ratio.

[0038] Solutions of evenamide are typically formed at temperatures between -20°C and 90°C, preferably between 20°C and 30°C, and more preferably at 25°C (room temperature).

[0039] The chlorine reagent according to the present invention may be selected from gaseous hydrochloric acid and aqueous hydrochloric acid, and gaseous hydrochloric acid is preferred.

[0040] According to the present invention, the solvent is selected from the group comprising or consisting of acetone, water, methyl alcohol, isopropyl alcohol, methyl ethyl ketone / water, ethyl acetate, methyl isobutyl ketone, methyl isobutylcarbinol, dimethylformamide, heptane, or a mixture of the above solvents, and preferably the solvent is acetone.

[0041] In a preferred embodiment, the solvent is acetone, and the chlorine reagent is gaseous hydrochloric acid.

[0042] Crystallization may be carried out by methods known in the art, for example, by solvent evaporation, by suspension equilibrium (slurry method), by cooling the solution, by precipitation, by vapor diffusion, by crystallization from molten material, by thermally induced transformation, by sublimation, by desolvation of solvates, by salting out, by pH change, preferably by solvent evaporation, or by suspension equilibrium (slurry method).

[0043] In the crystallization by solvent evaporation according to the present invention, the solvent may be selected from the group consisting of methyl ethyl ketone, methyl isobutyl ketone, methyl alcohol, ethyl alcohol, water, and acetone, and preferably the solvent is acetone.

[0044] In the crystallization by suspension equilibrium (slurry method) according to the present invention, the solvent may be selected from the group consisting of methyl ethyl ketone, methyl isobutyl ketone, acetone, and isopropyl alcohol, and preferably the solvent is acetone.

[0045] The crystalline form I of everamide, preferably hydrochloride, obtained in this manner can be advantageously used to prepare crystalline form II of everamide, preferably hydrochloride.

[0046] A further object of the present invention is a method for preparing crystalline form II of everamide hydrochloride according to the present invention, which is as follows: • Adding a solvent, preferably methyl isobutyl ketone, to free everamide base; • A step of heating the solution / dispersion to a temperature between 99 and 147°C; • A process of crystallization by adding a chloride reagent; • A step to obtain and selectively recover crystalline form II of ebenamid hydrochloride. This is a method that includes (Scheme 2).

[0047] Scheme 2 Method for preparing crystalline form II of ebenamide hydrochloride from free ebenamide base. [ka]

[0048] A further object of the present invention is a method for preparing crystalline form II of everamide hydrochloride according to the present invention, which is as follows: • The step of adding a solvent to the free base of everamide and the chloride reagent to form everamide hydrochloride in crystalline form I; • A step of heating the solution / dispersion to a temperature between 99 and 147°C; • A step to obtain and selectively recover crystalline form II of ebenamid hydrochloride. This method includes (Scheme 3).

[0049] Scheme 3 Preparation of crystalline form II of everamide hydrochloride from free everamide base via crystalline form I of everamide hydrochloride. [ka]

[0050] The crystalline form II of everamide, preferably hydrochloride, obtained in this manner can be advantageously used to prepare crystalline form I of everamide, preferably hydrochloride.

[0051] A further object of the present invention is a method for preparing crystalline form I of everamide hydrochloride according to the present invention, which is as follows: • Adding the solvent to the free base of everamide; • A step of heating the solution / dispersion to a temperature between 99 and 147°C; • A process of crystallization by adding gaseous hydrochloric acid as a chlorination reagent; • The process of obtaining crystalline form II of ebenamid hydrochloride, A step of cooling to a temperature between 0 and 94°C, preferably between 20 and 30°C, more preferably to 25°C (room temperature); - Process to obtain and recover crystalline form I of ebenamid hydrochloride. This method includes (Scheme 4).

[0052] Scheme 4 Preparation of crystalline form I of ebenamide hydrochloride from free ebenamide base via crystalline form II of ebenamide hydrochloride. [ka]

[0053] A further object of the present invention is a method for preparing crystalline form I of everamide hydrochloride according to the present invention, which is as follows: • A step of adding a solvent to free everamide base and gaseous hydrochloric acid as a chlorine reagent; • A step of heating the solution / dispersion to a temperature between 99 and 147°C; • The process of obtaining crystalline form II of ebenamid hydrochloride; A step of cooling to a temperature between 0 and 94°C, preferably between 20 and 30°C, more preferably to 25°C (room temperature); - Process to obtain and recover crystalline form I of ebenamid hydrochloride. This method includes (Scheme 5).

[0054] Scheme 5 Preparation of crystalline form I of everamide hydrochloride by heating crystalline form I of everamide hydrochloride obtained from everamide free base, and then cooling the crystalline form II of everamide hydrochloride obtained from that crystalline form. [ka]

[0055] A further object of the present invention is a method for preparing crystalline form II of everamide hydrochloride according to the present invention, comprising the step of heating crystalline form I of everamide hydrochloride at a temperature between 99°C and 147°C, and a method for preparing crystalline form I of everamide hydrochloride according to the present invention, comprising the step of cooling crystalline form II of everamide hydrochloride at a temperature of 94°C or lower (Scheme 6).

[0056] Scheme 6 A method for preparing crystalline form II of crystalline form II of crystalline form I of crystalline form I of crystalline form I of crystalline form I of crystalline form I of crystalline form I of crystalline form II [ka]

[0057] Ebenamide in crystalline form I can be recovered by concentrating the resulting dispersion using methods known in the art, such as filtration and / or centrifugation.

[0058] The crystalline form II of ebenamid can be recovered by concentrating the resulting dispersion by methods known in the art, for example, by filtration and / or centrifugation at a temperature above 94°C, preferably between 99 and 147°C.

[0059] All embodiments disclosed in this invention may be combined with each other.

[0060] Remarkably, the inventors of the present invention have discovered that crystalline forms I and II of evenamide obtained according to the present invention maintain their crystalline form even in the presence of moisture, as can be seen, for example, by the XRPD spectrum in Figure 5. This characteristic of the crystalline forms of evenamide of the present invention makes it more stable than any other known form of evenamide, and allows for the long-term storage of pharmaceutical formulations incorporating it as an active pharmaceutical ingredient.

[0061] Ebenamide of crystalline form I as defined herein is preferably the anhydrous crystalline form of ebenamide.

[0062] The crystalline form of everamide according to the present invention is characterized by a high level of crystallinity. The term "high level of crystallinity" refers to a crystalline form in which the percentage of crystallinity, as determined by standard analytical methods such as powder X-ray diffraction or microcalorimetry, is 90% or higher, preferably exceeding 95% w / w.

[0063] The chemical purity of the crystalline form of evenamide according to the present invention, as evaluated as area % (A%) by HPLC analysis, is 98% or higher, preferably 99.5% or higher.

[0064] A further object of the present invention is a pharmaceutical composition comprising everamide in the crystalline form as defined above, preferably form I or II, preferably its hydrochloride, and pharmaceutically acceptable excipients and / or carriers.

[0065] The pharmaceutical composition may be prepared into pharmaceutical form by known methods. The dose of the active ingredient present in the composition may be the dose commonly used in clinical practice for everamide.

[0066] A further object of the present invention is everamide, preferably in the crystalline form I and / or form II, as previously defined, preferably its hydrochloride, for use as a pharmaceutical, preferably in the prevention and / or treatment of neurological, cognitive, psychiatric, inflammatory, genitourinary, and gastrointestinal diseases, wherein a mechanism of action implying abnormal sodium channel activity plays a pathological role, more preferably in the prevention and / or treatment of cognitive and / or psychiatric disorders such as schizophrenia.

[0067] A further object of the present invention is a crystalline form, preferably form I and / or form II, of ebenamide, preferably its hydrochloride, as previously defined, for use in addition to one or more typical or atypical antipsychotics as a fixed or loose combination, in the prevention and / or treatment of schizophrenia, wherein the antipsychotic is preferably selected from the group comprising or consisting of risperidone, olanzapine, aripiprazole, clozapine, quetiapine, paliperidone, trifluoperazine, haloperidol, amisulpride, and blonanserin; more preferably, the typical antipsychotic is haloperidol, and the atypical antipsychotic is selected from risperidone and clozapine.

[0068] A further object of the present invention is the use of everamide in the crystalline form, preferably form I and / or form II, as previously defined, preferably its hydrochloride, for the preparation of pharmaceuticals for the prevention and / or treatment of cognitive and / or mental disorders such as schizophrenia.

[0069] A further object of the present invention is the use of the crystalline form, preferably form I and / or form II, of ebenamide, preferably its hydrochloride, as previously defined, in addition to the typical or atypical antipsychotics as previously defined, in fixed or loose combinations, for the preparation of a medicament for the prevention and / or treatment of schizophrenia.

[0070] A further object of the present invention is the use of the crystalline form, preferably form I and / or form II, of everamide, preferably its hydrochloride, as previously defined, for preparing a medicament for the prevention and / or treatment of schizophrenia, in addition to a typical or atypical antipsychotic, either in a fixed or loose combination, where the typical antipsychotic is haloperidol and the atypical antipsychotic is selected from risperidone and clozapine.

[0071] A further object of the present invention is a method for treating schizophrenia, comprising administering a therapeutically effective amount of everamide in the crystalline form as defined above, preferably form I and / or form II, preferably its hydrochloride, to a patient in need.

[0072] A further object of the present invention is a method for treating schizophrenia, comprising administering a therapeutically effective amount of everamide in the crystalline form as defined above, preferably form I and / or form II, preferably its hydrochloride, to a patient in need, in addition to a typical or atypical antipsychotic as defined above, in a fixed or loose combination.

[0073] A further object of the present invention is a method for treating schizophrenia, comprising administering a therapeutically effective amount of everamide, preferably in the crystalline form as defined above, preferably form I and / or form II, preferably its hydrochloride, to a patient in need, in addition to a typical or atypical antipsychotic, in a fixed or loose combination, where the typical antipsychotic is haloperidol and the atypical antipsychotic is selected from risperidone and clozapine.

[0074] The following embodiments further illustrate the present invention.

[0075] Example 1 - Preparation of crystalline form I of ebenamid hydrochloride In a standard jacketed reactor (1 L), 84.3 g of crude free base of evenamide, as a yellowish, viscous oil with HPLC purity of 90% (area %, A%), was added to acetone (320 ml) under mechanical stirring and a nitrogen atmosphere, and the temperature was maintained at 25-30°C. Next, the amount of HCl gas required for stoichiometric salt formation was added below the surface of the mixture. During the acid addition, the temperature was raised by 5°C, and the formation of a white to yellow precipitate was observed. Next, the suspension was cooled to 0°C and maintained at this temperature for a further 1 hour. The suspension was filtered and washed with acetone (2 × 40 ml). Next, the white cake was dried under reduced pressure at 30°C to provide evenamide HCl salt form I as a white needle-shaped solid (chromatographic purity 99%, A%).

[0076] Example 2 - Preparation of crystalline form I of ebenamid hydrochloride In a glass reactor, a solution of free evenamide base (1.5 kg, purity 88% (A%), approximately 4.74 mol) in acetone (5.7 L) was prepared, heated to 50°C, and then HCl gas (0.22 kg, 6.03 mol) was bubbling over it for approximately 1 hour. The mixture was maintained at 20°C for a further 2 hours, and then cooled to 0°C over 4 hours. Finally, the mixture was maintained at 0°C for 3 hours and then filtered on a glass filter. Next, the white cake was washed twice with acetone (2 × 1.5 L) and then dried under reduced pressure at 40°C to provide everamide HCl salt form I (1.16 kg, purity 99.5 (A%), assay 99.5%, 3.50 mol, molar yield 74%).

[0077] Example 3 - Recrystallization of Ebenamide HCl salt form I by solvent evaporation method 1. Recrystallization solvent: Methyl ethyl ketone Evenamide HCl salt (650 mg) was dissolved in an aqueous solution of H2O (0.25 g) in methyl ethyl ketone (35 ml) at room temperature. The solution was stored under reduced pressure to evaporate the water and methyl ethyl ketone, providing a residue consisting of evenamide HCl salt form I. 2. Recrystallization solvent: Methyl isobutyl ketone Evenamide HCl salt (650 mg) was dissolved in methyl isobutyl ketone (15 ml) and moistened with H2O (0.125 g) at room temperature. Water and methyl isobutyl ketone were evaporated under reduced pressure to provide a residue consisting of evenamide HCl salt form I. 3. Recrystallization solvent: Methyl alcohol 650 mg of evenamide HCl salt was dissolved in 5 ml of methyl alcohol at room temperature. Evaporation was carried out under reduced pressure, and a residue consisting of evenamide HCl salt form I was provided. 4. Recrystallization solvent: Acetone Evenamide HCl salt (650 mg) was dissolved in acetone (5 ml) at room temperature. Evaporation was carried out under reduced pressure, and a residue consisting of evenamide HCl salt form I was provided.

[0078] Example 4 - Recrystallization of evenamide HCl salt by slurry method 1. Recrystallization solvent: Methyl ethyl ketone A heterogeneous mixture of evenamide HCl (1.5 g) and methyl ethyl ketone (20 ml) was stirred in a round-bottom glass flask (50 ml) at 83°C for 12 hours. Next, the warm suspension was filtered over a glass filter. The solid was left under reduced pressure at room temperature to remove the solvent, yielding 1.3 g of pure everamide HCl salt form I. Yield 84% (amount of solid recovered / initial amount of solid). 2. Recrystallization solvent: Acetone A heterogeneous mixture of 1.5 g of evenamide HCl and 20 ml of acetone was stirred in a 50 ml round-bottom glass flask at 52°C for 12 hours. Next, the warm suspension was filtered over a glass filter. The solid was left under reduced pressure at room temperature to remove the solvent and provide 0.15 g of pure everamide HCl salt form I. 3. Recrystallization solvent: Methyl isobutyl ketone A heterogeneous mixture of evenamide HCl (1.5 g) and methyl isobutyl ketone (20 ml) was stirred in a round-bottom glass flask (50 ml) at 111°C (boiling point 116°C) for 12 hours. Next, the warm suspension was filtered over a glass filter. The solid was left under reduced pressure at room temperature to remove the solvent, yielding 0.69 g of pure evenamide salt HCl form I. 4. Recrystallization solvent: Isopropyl alcohol A heterogeneous mixture of evenamide HCl (1.5 g) and isopropyl alcohol (20 ml) was stirred in a round-bottom glass flask (50 ml) at 77°C for 12 hours. Next, the warm suspension was filtered over a glass filter. The solid was left under reduced pressure at room temperature to remove the solvent, yielding 0.66 g of pure everamide HCl salt form I.

[0079] Example 5 - XRPD measurement of an everamide HCl sample XRPD measurements of evenamide HCl samples obtained according to Examples 1-4 were obtained using a Bruker D5005 diffractometer equipped with CuKα, radiation, Ni filter, and position-sensitive detector in a TTK Anton Paar high-temperature apparatus, after light grinding in an Agata mortar. The XRPD measurements were obtained under the following conditions: 40kV, 30mA, step width 0.015°(2θ), step time 0.30 sec / step, angle range 4.5<2θ<35.

[0080] Patterns were collected at 25°, 80°, and 110°C with a heating rate of 3°C / min and a 20-minute delay before each measurement.

[0081] Finally, the sample was cooled to room temperature, and the final pattern was collected at 25°C. Next, the sample was heated to 110°C.

[0082] All patterns at 110°C belong to morphology II, but they are very different from those of morphology I collected at temperatures below 80°C.

[0083] The comparison shows a high degree of similarity between the crystalline phases of the samples in terms of both the angular position and intensity of reflections for patterns collected within the temperature range of 25–80°C. As the temperature increases, a slight angular decrease in the peaks is observed, as expected due to thermal expansion.

[0084] Example 6 - Preparation of crystalline form III of ebenamid HCl salt Slurry at room temperature Approximately 20 mg of evenamide HCl salt was used as the starting material and suspended in 0.2–0.5 mL of a mixture of dioxane and aqueous dioxane in an HPLC vial. The suspension was then magnetically stirred at room temperature for approximately 5 days. Morphology III was observed from a slurry in a 1,4-dioxane(H2O) solvent system. Morphology III samples were obtained by drying under N2 at room temperature, and no morphological change was observed before / after drying, which was confirmed by XRPD (Figure 7).

[0085] The TGA results showed a 3.7% weight loss from room temperature to 100°C, and a 7.7% weight loss from 100°C to 160°C.

[0086] The DSC results showed four endothermic peaks at 56.6°C, 88.0°C, 98.6°C, and 149.4°C (peak).

[0087] 1 The 1H NMR spectrum showed that the molar ratio of 1,4-dioxane / evenamide HCl was 0.5 (12.3 wt%).

[0088] Further heating of morphology III was investigated to study the thermal events, and XRPD results showed that morphology I was formed after heating to 70°C. PLM images showed that morphology III consisted of plate-like crystals and aggregates.

[0089] The residual solid was isolated before XRPD analysis. The results are reported in Table 5.

[0090] [Table 5] Based on the characterization results, form III was determined to be the 1,4-dioxane solvate of the monoHCl salt.

[0091] Example 7 - Preparation of everamide mucinate ((2S,3R,4S,5R)-2,3,4,5-tetrahydroxyhexanediate of everamide) Evenamide mucoate was prepared by reaction crystallization. Mucoic acid ((2S,3R,4S,5R)-2,3,4,5-tetrahydroxyhexanodic acid) was added in a 1:1 molar ratio to a 50 mg / ml solution of free evenamide base in methyl ethyl ketone.

[0092] The mixture was stirred at room temperature for 3 days, and the solid was isolated by centrifugation. The solid was then dried under nitrogen. Polarizing microscope observation revealed that the solid was a birefringent crystal.

[0093] TGA / DSC indicated a very slight weight loss up to 150°C and a single endothermic peak at 154.8°C (melting point). 1 ¹H NMR results were obtained in DMSO-d6, confirming an acid / base stoichiometry of 1.0 and the absence of residual solvent. HPLC purity was 99.6 area%. Based on the characteristic data, the mucinous salt was evaluated as a monosal anhydride. Crystallinity was confirmed and characterized by XRPD.

[0094] Example 8 - Preparation of 2-hydroxypropane-1,2,3-tricarboxylate of everamide citrate, which is everamide. Evenamide citrate was prepared by reaction crystallization. Citric acid (2-hydroxypropane-1,2,3-tricarboxylic acid) was added in a 1:1 molar ratio to a 50 mg / ml solution of free evenamide base in 2-methyltetrahydrofuran. The mixture was stirred at room temperature for 5 days, and the solid was isolated by centrifugation. The solid was then dried under nitrogen. PLM showed that the solid was a birefringent crystal.

[0095] TGA / DSC indicated a 0.22% weight loss up to 120°C and a single endothermic peak at 140.7°C (melting point). 1¹H NMR results were obtained in DMSO-d6, confirming an acid / base stoichiometry of 1.1 and the absence of residual solvent. HPLC showed a purity of 100.0 area%. Based on the characteristic data, the citrate was evaluated as a mono-salt anhydride. Crystallinity was confirmed by XRPD.

[0096] Example 9 - Preparation of everamide hemyedisylate (1,2-ethane disulfonate) Edisylate type A was prepared by reaction crystallization. 1,2-Ethanedisulfonic acid was added to a 50 mg / ml solution of free evenamide base in isopropanol / n-heptane (1:5, v / v) in a molar acid-base ratio of 0.5:1. The mixture was stirred at room temperature for 3 days, then stirred overnight at 5°C. The solid product was isolated by centrifugation and dried under nitrogen. PLM images of the solid showed birefringent crystals.

[0097] TGA / DSC indicated a weight loss of 0.15% up to 120°C. DSC indicated three endothermic peaks at 115.0°C, 148.0°C, and 197.8°C. ¹H NMR in DMSO-d6 determined the acid / base stoichiometry to be 0.5. HPLC purity was 99.3 area%.

[0098] A heating experiment was performed on edisylate type A. After heating to 120°C, edisylate type A changed to edisylate type B. Based on the characteristic data, edisylate type A is likely the anhydrous form of the hemi salt, and edisylate type B is a different crystalline form.

[0099] Edisylate type B was directly prepared by reaction crystallization in 2-Me-THF. 1,2-Ethandisulfonic acid was added to a 50 mg / ml solution of free evenamide base in 2-methyltetrahydrofuran at a molar ratio (acid / base) of 0.5. The mixture was stirred at room temperature for 3 days, then stirred overnight at 5°C. The solid product was isolated by centrifugation and dried under nitrogen. PLM images showed birefringent crystals.

[0100] The TGA / DSC showed a weight loss of 0.21% up to 120°C, and two endothermic peaks at 148.3°C and 200.3°C (peak temperature). 1 ¹H NMR results were obtained in DMSO-d6, which showed an acid / base stoichiometry of 0.5. HPLC purity was 98.7% area.

[0101] The obtained edisylate B-type was characterized by VT-XRPD. After heating to 150°C, edisylate B-type transformed into a new crystalline form named edisylate C-type, and then transformed back to edisylate B-type upon returning to room temperature. Based on VT-XRPD and characterization data, edisylate B / C-type is likely an anhydride of an enantiotropic hemi salt. XRPD indicated different crystalline structures for A-type and B-type.

[0102] Example 10 - Preparation of everamide mesylate The mesylate was prepared by reaction crystallization. A 50 mg / ml solution of free everamide base in ethyl acetate was reacted with methanesulfonic acid in a 1:1 molar ratio. The mixture was stirred at room temperature for 3 days, then stirred overnight at 5°C. The solid was isolated by centrifugation and dried under nitrogen. PLM images showed plate-like birefringent crystals.

[0103] TGA / DSC indicated a very slight weight loss up to 150°C and a single endothermic peak at 139.5°C (peak temperature). ¹H NMR results obtained in DMSO-d6 indicated an acid / base stoichiometry of 0.9 and no residual solvent.

[0104] HPLC showed a purity of 100.0 area%. Based on the characteristic data, the mesylate type A was determined to be a monosalt anhydrous.

[0105] Example 11 - Preparation of evenamide napsylate Napsylates were prepared by reaction crystallization at room temperature. A 50 mg / ml solution of free everamide base in 2-methyltetrahydrofuran was reacted with methanesulfonic acid at room temperature for 3 days, and then cooled overnight to 5°C. The solid was isolated by centrifugation and dried under nitrogen. PLM images showed birefringent crystals.

[0106] TGA / DSC indicated a 0.05% weight loss up to 130°C and one endothermic peak at 184.5°C (peak temperature). 1 ¹H NMR results were obtained in DMSO-d6, and it was noted that the acid / base stoichiometry was 0.9, indicating the absence of residual solvent.

[0107] HPLC showed a purity of 98.8% by area. The water content was 0.02% as measured by KF. Based on the characteristic data, napsylate type A was an anhydrous monosalt.

[0108] Example 12 - Ebenamide saccharate (1H-1λ 6 Preparation of 2-benzothiazole-1,1,3(2H)-trione salt Saccharin salts were prepared by reaction crystallization. A 50 mg / ml solution of free everamide base in isopropanol / n-heptane (1:5, v / v) was prepared using 1H-1λ 6 The mixture was stirred at room temperature for 3 days with 2-benzothiazole-1,1,3(2H)-trione in a 1:1 molar ratio. The resulting solid was isolated by centrifugation and dried under nitrogen. PLM imaging showed birefringent crystals.

[0109] TGA / DSC indicated a very slight weight loss up to 150°C and a single endothermic peak at 150.1°C (peak temperature). 1 ¹H NMR results were obtained in DMSO-d6, which indicated an acid / base stoichiometry of 0.9 and the absence of residual solvent.

[0110] The purity measured by HPLC was 100.0 area%. Based on the characteristic data, the saccharin salt was determined to be an anhydrous monosalt.

[0111] Final observations Evenamide hydrochloride was found to exist in at least three enantiotropic polymorphs: form I, which is stable at room temperature; form II, which is stable at temperatures above the transition temperature (94°C to 99°C); and form III, which is a 1,4-dioxane solvate that is stable at room temperature.

[0112] It was observed that morphology I reversibly transforms into morphology II when heated to over 99°C (DSC and XRPD).

[0113] It is noteworthy that DSC and XRPD diagrams were recorded on the solid product in the absence of a solvent.

Claims

1. This is a crystalline form of the evenamid salt, referred to as morphology I, which has an XRPD spectrum with characteristic peaks occurring at approximately 12.1; 13.4; 16.2; 16.7; 18.2; 18.7; 19.4; 21.7; 22.4; 22.8; 23.3; 23.7; 24.2; 24.4; 25.4; 26.0; 26.6 ± 0.2°²θ, measured using Cu Kα radiation (λ = 1.54 Å).

2. This is the crystalline form of the evenamid salt, referred to as morphology II, which has an XRPD spectrum with characteristic peaks occurring at approximately 12.7; 17.7; 20.0; 20.4; and 20.7 ± 0.2°²θ, measured using Cu Kα radiation (λ = 1.54 Å).

3. The crystalline form of the evenamide salt according to claim 1 or 2, wherein the salt is a hydrochloride salt.

4. The following salts exhibit the main endothermic peaks: Approximately 119°C, preferably sulfates; Approximately 132.6°C, preferably maleate; Approximately 105.6°C, preferably phosphate; Approximately 118.3°C, preferably pyruvate; Approximately 114.6°C, preferably fumarate; Approximately 154.8°C, preferably a mucinous salt; Approximately 140.7°C, preferably citrate; • Approximately 101.2°C, preferably L-malate; Approximately 85.8°C, preferably succinate; Approximately 91.4°C, preferably glutarate; Approximately 147.9°C, preferably napadisylate; Approximately 197.8°C, preferably edisylate; - Approximately 120.0°C, preferably esylates; Approximately 161.8°C, preferably tosylate; Approximately 139.5°C, preferably a mesylate; Approximately 184.5°C, preferably napsylate; Approximately 107.0°C, preferably besylate; Approximately 198.3°C, preferably oxalate; Approximately 96.6°C, preferably malonate; - Approximately 150.1°C, preferably saccharin salt; - Approximately 129.0°C, preferably cansylate; and - Approximately 105.0°C, preferably mandelate salt More selected crystalline forms of evenamide salt.

5. The crystalline form of the everamide salt according to claim 4, wherein the salt is selected from maleate, mucoate, citrate, edisylate, mesylate, napsylate, oxalate, saccharinate, and cansylate.

6. The crystalline form of the everamide salt according to claim 5, wherein the salt is selected from mucoate, citrate, edisylate, mesylate, napsylate, and saccharinate.

7. A method for preparing evenamide in crystalline form I as defined in claim 1, the following: - A step of adding a solvent to free everamide base and gaseous hydrochloric acid or an aqueous hydrochloric acid solution as a chloride reagent, preferably gaseous hydrochloric acid. - A process of crystallization at a temperature of 94°C or lower. - Process for recovering crystalline form I of everamide hydrochloride Includes, The method wherein the solvent is selected from acetone, water, methyl alcohol, isopropyl alcohol, methyl ethyl ketone / water, ethyl acetate, methyl isobutyl ketone, methyl isobutylcarbinol, dimethylformamide, heptane, or a mixture of the above solvents, and preferably the solvent is acetone.

8. A method for preparing crystalline form II of everamide hydrochloride according to claim 2, the following: - The step of adding a solvent to free everamide base, - A step of heating the solution / dispersion to a temperature between 99 and 147°C. - A process of crystallization by adding a chloride reagent. - A step to obtain and selectively recover crystalline form II of ebenamid hydrochloride. Methods that include...

9. A method for preparing crystalline form II of everamide hydrochloride according to claim 2 or 3, the following: - A step of adding a solvent to the free base of evenamide and the chloride reagent in order to form the crystalline form I of evenamide hydrochloride. - A step of heating the solution / dispersion to a temperature between 99 and 147°C. - A step to obtain and selectively recover crystalline form II of ebenamid hydrochloride. Methods that include...

10. A method for preparing crystalline form I of everamide hydrochloride according to claim 1, the following: - The step of adding the solvent to the free base of everamide, - A step of heating the solution / dispersion to a temperature between 99 and 147°C. - A process of crystallization by adding gaseous hydrochloric acid as a chlorination reagent. - Steps to obtain crystalline form II of ebenamid hydrochloride, - A step of cooling to a temperature within the range of 0 to 94°C, preferably within the range of 20 to 30°C, more preferably to 25°C (room temperature). - A step to obtain and recover crystalline form I of ebenamid hydrochloride. Methods that include...

11. A method for preparing crystalline form I of everamide hydrochloride according to claim 1, the following: - A step of adding a solvent to free evenamid base and gaseous hydrochloric acid as a chloride reagent. - A step of heating the solution / dispersion to a temperature between 99 and 147°C. - Steps to obtain crystalline form II of ebenamid hydrochloride, - A step of cooling to a temperature between 0 and 94°C, preferably between 20 and 30°C, more preferably 25°C (room temperature). - A step to obtain and recover crystalline form I of ebenamid hydrochloride. Methods that include...

12. The method according to claims 4 to 7, wherein the solvent is selected from acetone, water, methyl alcohol, isopropyl alcohol, methyl ethyl ketone / water, ethyl acetate, methyl isobutyl ketone, dimethylformamide, heptane, or a mixture of the said solvents, preferably the solvent being acetone.

13. The method according to claims 4 to 8, wherein the chlorinating reagent is selected from gaseous hydrochloric acid and aqueous hydrochloric acid solution, and is preferably gaseous hydrochloric acid.

14. The use of crystalline form I of evenanamide as defined in claim 1 or 3 in the preparation of crystalline form II of evenanamide as defined in claim 2 or 3, by heating crystalline form I of evenanamide at a temperature between 99°C and 147°C to obtain crystalline form II of evenanamide.

15. The use of crystalline form II of evenanamide as defined in claim 2 or 3 in the preparation of crystalline form I of evenanamide as defined in claim 1 or 3, by cooling crystalline form II of evenanamide at a temperature of 94°C or lower to obtain crystalline form I of evenanamide.

16. A pharmaceutical composition comprising a crystalline salt of everamide according to claims 1 to 6 as an active pharmaceutical ingredient, and a pharmaceutically acceptable excipient and / or carrier.

17. Evenamide salts in crystalline form according to claims 1 to 6, for use as pharmaceuticals.

18. Evenamide salts in crystalline form according to claims 1 to 6, for use in the prevention and / or treatment of neurological, cognitive, psychiatric, inflammatory, genitourinary, and gastrointestinal diseases in which abnormal sodium channel activity plays a pathological role.

19. The crystalline form of the everamide salt according to claims 1 to 6 for use according to claim 18, wherein the disease is a mental disorder such as schizophrenia.

20. Ebenamide salts in crystalline form according to claims 1 to 6, for use according to claim 19 in addition to one or more antipsychotic drugs.

21. An everamide salt in crystalline form according to claims 1 to 6 for use according to claim 20, wherein the antipsychotic agent is selected from the group comprising or including risperidone, olanzapine, aripiprazole, clozapine, quetiapine, paliperidone, trifluoperazine, haloperidol, amisulpride, and blonanserin.

22. an everamide salt in crystalline form according to claims 1 to 6 for use according to claim 20 in addition to one or more typical or atypical antipsychotics, wherein the typical antipsychotic is haloperidol and the atypical antipsychotic is selected from risperidone and clozapine.

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