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JP-2026514508-A - Crystal form of Ebenamide

JP2026514508AJP 2026514508 AJP2026514508 AJP 2026514508AJP-2026514508-A

Abstract

This 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.

Inventors

  • インボーデン，クリストフ
  • カステッリン，アンドレア

Assignees

  • ニューロン・ファーマシューティカルズ・ソチエタ・ペル・アチオニ

Dates

Publication Date
20260511
Application Date
20240424
Priority Date
20230428

Claims (20)

  1. This is the crystalline form of the evenamide salt, referred to as Form I, which exhibits 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; and 26.6 ± 0.2°²θ, measured using Cu Kα radiation.
  2. This is the crystalline form of the evenamid salt, referred to as Form II, which exhibits 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; Crystalline form of evenamide salt, selected from: - approximately 129.0°C, preferably cansylate; and - approximately 105.0°C, preferably mandelate.
  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. - Includes a step of recovering crystalline form I of everamide hydrochloride, 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 method comprising the step of obtaining crystalline form II of ebenamid hydrochloride and optionally recovering it.
  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 method comprising the step of obtaining crystalline form II of ebenamid hydrochloride and optionally recovering it.
  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 method comprising the step of obtaining and recovering crystalline form I of everamide hydrochloride.
  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 method comprising the step of obtaining and recovering crystalline form I of everamide hydrochloride.
  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, 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. The crystalline form of evenamide salt according to claims 1 to 6, for use as a pharmaceutical.
  18. The crystalline form of evenamide salt 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. The crystalline form of everamide salt according to claims 1 to 6, for use according to claim 19 in addition to one or more antipsychotic agents.

Description

Technical Field of the Invention The present invention relates to crystalline forms of evenamide salt, preferably hydrochloride salt, particularly forms I and II, their uses, methods for their preparation, and pharmaceutical compositions containing the novel crystalline forms. Background of the Invention Evenamide, 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide is a novel orally administered chemical entity having the following chemical formula (I) that specifically targets voltage-gated sodium channels (VGSCs): Ebenamide modulates persistent, repetitive firing without inducing impaired normal excitability. It normalizes glutamate release induced by abnormal sodium channel activity and is under clinical study as an adjunct therapy for the treatment of schizophrenia. Ebenamide has demonstrated potential benefits in a series of animal models predicting efficacy in schizophrenia and other mental disorders. In a phase 2 study in patients with schizophrenia, ebenamide provides preliminary evidence of efficacy, tolerability, and safety. International Publication No. 2008/151702 discloses the synthesis of 2-[2-(3-butoxyphenyl)-ethylamino]-N,N-dimethylacetamide and its hydrochloride salt, as summarized in the following scheme A, in the examples. International Publication No. 2020/212227 discloses methods for the preparation of everamide, its hydrochloride salt, and its deuterated derivatives. International Publication No. 2020/212352 discloses another method for the preparation of everamide, its hydrochloride salt, and its deuterated derivatives. IN201911052571 discloses a method for preparing amorphous everamide or a pharmaceutically acceptable salt thereof. The crystalline form of evenamide has not been disclosed or characterized to date. 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. 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 to methods for preparing them, and to pharmaceutical compositions containing at least one of the crystalline forms. Brief description and analysis method of the drawing XRPD spectrum of crystalline form I of everamide hydrochloride. DSC curves of everamide hydrochloride in crystalline forms I and II. DSC and TGA curves of everamide hydrochloride in crystalline forms I and II. 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. 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. Comparison of XRPD patterns of crystalline form I of everamide hydrochloride before and after heating/cooling treatment at room temperature. XRPD spectrum of everamide hydrochloride in crystalline form III. The crystalline morphology of evenamide hydrochloride was characterized by X-ray powder diffraction (XRPD). 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 of λ = 1.54 Å, generated at 30 kV and 15 mA. A lightly ground powder sample was packed into an aluminum sample holder, and the XRPD pattern was 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°. A Bruker BD5005 diffractometer, equipped with a Cu-Kα ray with wavelength λ = 1.54 Å, a nickel filter, and a position-sensitive detector (PSD), was used to measure samples in a TTK Anton Paar high-temperature apparatus, after light grinding in an Agata mortar, at 80°C and 110°C under the following conditions: 40 kV, 30 mA, step width 0.0 15° (2θ), step time 0.30 sec/step, angular range 4.5 < 2θ < 35. DSC patterns were obtained using a differential scanning calorimeter with a DSC2010 TA Instruments calorimeter under a nitrogen purge of 70 mL/min. The procedure was performed on 2–3 mg of sample in a non-airtightly sealed aluminum pan at a scanning speed of 10 K/min and 25–300°C. The TGA curve was recorded using a TG2050 TA Instruments thermogravimetric analyzer at a heating rate of 10 K/min and a nitrogen purge rate of 90 mL/min. HSM images were obtained by examining powder samples using a hot-stage microscope system consisting of a Mettler FP82HT cell, a Mettler FP 82HT control unit, and an optical microscope (Reichert Microstar I). Several crystals were suspended in silicon oil, placed on a microscope slide, covered with a coverslip, and he