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CN-122010875-A - New crystal forms of braamesen and hydrochloride thereof and preparation method thereof

CN122010875ACN 122010875 ACN122010875 ACN 122010875ACN-122010875-A

Abstract

The invention provides a novel crystal form APTI-I of Blamesen and a preparation method thereof. The new crystalline form of APTI-I uses Cu-K alpha radiation, whose XRPD pattern expressed in terms of 2 theta has characteristic peaks at 7.4 DEG + -0.2 DEG, 11.0 DEG + -0.2 DEG, 11.6 DEG + -0.2 DEG, 12.1 DEG + -0.2 DEG, 20.7 DEG + -0.2 DEG, 22.8 DEG + -0.2 deg. The new crystalline form of APTI-II uses Cu-K alpha radiation, whose XRPD patterns expressed in terms of 2 theta have characteristic peaks at 10.9 DEG + -0.2 DEG, 11.5 DEG + -0.2 DEG, 13.7 DEG + -0.2 DEG, 17.1 DEG + -0.2 DEG, 19.8 DEG + -0.2 DEG, 21.6 DEG + -0.2 deg. The new crystal form has higher preparation yield and better impurity removal effect, and provides more choices for the medicinal preparation.

Inventors

  • WU YUZHUO
  • Huang Zongsui
  • GUO WANCHENG
  • FANG JIE
  • CHU DINGJUN
  • XIE XIAOQIANG
  • WANG HONGLIAN

Assignees

  • 奥锐特药业(天津)有限公司

Dates

Publication Date
20260512
Application Date
20241112

Claims (10)

  1. 1. A new crystalline form of bolamesen, APTI-I, characterized by using Cu-ka radiation whose XRPD pattern expressed in terms of 2Θ has characteristic peaks at 7.4 ° ± 0.2 °, 11.0 ° ± 0.2 °, 11.6 ° ± 0.2 °, 12.1 ° ± 0.2 °, 20.7 ° ± 0.2 °, 22.8 ° ± 0.2 °.
  2. 2. The new crystalline form of braamesen claimed in claim 1, wherein the new crystalline form of braamesen APTI-I further has one or more features selected from the group consisting of: (i) Its XRPD pattern also has characteristic peaks at one or more of the following 2θ angles: 10.2°±0.2°、15.1°±0.2°、16.4°±0.2°、17.4°±0.2°、19.6°±0.2°、21.4°±0.2°、22.2°±0.2°、24.6°±0.2°、26.6°±0.2°、27.2°±0.2°、28.3°±0.2°、31.8°±0.2°、33.6°±0.2°、37.2°±0.2°. (ii) Its differential scanning calorimetric profile has endothermic peaks at 84.5.+ -. 5 ℃ and 91.2.+ -. 5 ℃.
  3. 3. The preparation method of the novel crystalline form of the APTI-I of braamesen according to claim 1 or 2, characterized in that the preparation method comprises the following steps: adding the braamesen free base into an organic solvent, stirring until the solution is clear, volatilizing the solvent to be less than 1/3 of the original volume, precipitating crystals, filtering to obtain a new braamesen crystal form APTI-I, The solvent is selected from methanol, ethanol, dichloromethane or a combination thereof, more preferably methanol.
  4. 4. The process for preparing a novel crystalline form of aplti-I of claim 3, wherein the solvent is used in an amount such that the volume to weight ratio of the solvent to the free base of the aplamasen is 5ml to 50ml/1g, more preferably 10ml to 30ml/1g, and/or The solvent volatilizes at a temperature of 20 to 50 ℃, more preferably 25 to 35 ℃, and/or The solvent volatilization is carried out under normal pressure or under vacuum condition, and the vacuum degree under the vacuum condition is 0-0.1 mpa, more preferably 0.01-0.08 mpa.
  5. 5. A new crystalline form of braamesen hydrochloride, APTI-II, characterized by the use of Cu-ka radiation having an XRPD pattern expressed in terms of 2Θ with characteristic peaks at 10.9 ° ± 0.2 °, 11.5 ° ± 0.2 °, 13.7 ° ± 0.2 °, 17.1 ° ± 0.2 °, 19.8 ° ± 0.2 °, 21.6 ° ± 0.2 °.
  6. 6. The novel crystalline form of ailafaxine dihydrochloride, according to claim 5, wherein the crystalline form of aiti-II further has one or more characteristics selected from the group consisting of: (i) Its XRPD pattern also has characteristic peaks at one or more of the following 2θ angles: 10.5°±0.2°、12.5°±0.2°、14.0°±0.2°、14.9°±0.2°、15.1°±0.2°、16.0°±0.2°、18.4°±0.2°、19.1°±0.2°、22.0°±0.2°、23.2°±0.2°、23.6°±0.2°、24.0°±0.2°、25.1°±0.2°、25.5°±0.2°、26.2°±0.2°、26.5°±0.2°、28.0°±0.2°、30.5°±0.2°, (ii) The differential scanning calorimetric spectrum has endothermic peaks at 75.4+/-5 ℃ and 227.9 +/-5 ℃, (Iii) The thermogravimetric analysis spectrum is about 40-110 ℃ and the weight is reduced by about 9.5%.
  7. 7. The preparation method of the novel crystal form APTI-II of the Blamesen hydrochloride, which is characterized in that the preparation method comprises the steps of adding the free base of the Blamesen into an organic solvent, stirring until the solution is clear, adding an organic solvent diluent of concentrated hydrochloric acid into the solution, stirring for 0.5-36 h at 20-50 ℃, filtering, drying the obtained solid in vacuum to obtain the novel crystal form APTI-II of the Blamesen hydrochloride, The molar ratio of the hydrogen chloride molecules in the organic solvent diluent of the braamesen free base and the concentrated hydrochloric acid is 1:1.0-1.2.
  8. 8. The process according to claim 7, wherein the organic solvent used for dissolving the free base of bramesne and the organic solvent used for diluting the concentrated hydrochloric acid are the same, and the organic solvent is selected from toluene, acetonitrile, dibutyl ketone, methyl ethyl ketone, ethyl acetate or a combination thereof, more preferably toluene, and/or The solvent used for dissolving the brazison free base is used in an amount such that the volume to weight ratio of the solvent to the brazison free base is 5ml to 50ml/1g, more preferably 12ml to 30ml/1g.
  9. 9. The preparation method according to claim 7, wherein the molar ratio of hydrogen chloride molecules in the organic solvent diluent of the braamesen free base and the concentrated hydrochloric acid is 1:1.05-1.15, and/or Stirring at 25-35 ℃ for 4-8 hours, and/or The vacuum drying temperature is 20 ℃ to 45 ℃, more preferably 20 ℃ to 30 ℃.
  10. 10. Use of a new crystalline form of braamesen, apt I-I or a new crystalline form of braamesen hydrochloride, apt I-II, for the preparation of a medicament comprising braamesen or for the purification of braamesen or a salt thereof.

Description

New crystal forms of braamesen and hydrochloride thereof and preparation method thereof Technical Field The invention belongs to the field of pharmaceutical crystal chemistry, and in particular relates to a novel crystal form of Blamesen and a novel crystal form of hydrochloride thereof and a preparation method thereof. Background Alzheimer's disease (Alzheimer disease, AD) is the most common form of dementia and is the fifth leading cause of death in adults over 65 years of age. As the population ages, the elderly population increases and the number of patients increases year by year. Patients are in urgent need of new therapies to improve the condition and to improve survival and quality of life. Blamesen (blarcamesine) is an orally available small molecule activator of sigma-1 receptor (SIGMAR 1), and data indicate that it is critical for restoring neuronal cell homeostasis and promoting neuronal plasticity. The existing clinical data also show that the symptoms of the braamesen applied to patients suffering from Alzheimer's disease are significantly improved. The chemical name of the braamesen is tetrahydro-N, N-dimethyl-2, 2-diphenyl-3-furanmethanamine, the structural formula is shown as the following formula (I), and the structural formula of the hydrochloride is shown as the following formula (II): It is known that different spatial arrangements of drug molecules can form different crystal forms, and different crystal forms of drug molecules generally bring about obvious differences in physicochemical properties, and in chemical production, different crystal forms can also cause different impurity removal effects due to different precipitation modes. Currently, the following prior art has conducted related studies on the crystalline form of braamesen: The prior art WO2017013498A2 discloses 3 crystal forms of the Blamesen, but the 3 crystal forms are prepared by a supercritical fluid method, and the preparation method has high condition requirements and is not easy to scale-up production. The prior art WO2019200345A1 discloses the anhydrous crystal form and hydrate crystal forms I-VIII of the Blamesen hydrochloride, 8 crystal forms in total, wherein the anhydrous crystal form I is disclosed by the prior art WO 2018231216A 1 and is a crystal form used by a preparation. The published data also indicate that braamesen hydrochloride form I is the presently best form. In addition, this prior art also discloses that crystalline form I of the free base of braamesen has poor water solubility of the free base relative to the hydrochloride, but there is still a potential development value in medicinal absorption. The prior art WO2021158586A1 discloses the crystalline Form B3 of bramessen hydrochloride, which is an n-pentanol solvate, the n-pentanol content in the solvate is higher, and the possibility that it can be used for pharmaceutical purposes is not shown at present. Therefore, there is a need to develop new crystalline forms of braamesen or its salts that are more excellent, facilitate industrial mass production and can improve their existing physicochemical properties, making them more suitable for the preparation of pharmaceutical formulations. Disclosure of Invention It is an object of an aspect of the present invention to provide novel crystalline form APTI-I of Blamesen using Cu-K alpha radiation having an XRPD pattern expressed in terms of 2 theta angles with characteristic peaks at 7.4 DEG+ -0.2 DEG, 11.0 DEG+ -0.2 DEG, 11.6 DEG+ -0.2 DEG, 12.1 DEG+ -0.2 DEG, 20.7 DEG+ -0.2 DEG, 22.8 DEG+ -0.2 deg. In another preferred embodiment, the XRPD pattern of the new crystalline form of bolamesen, APTI-I, also has characteristic peaks at one or more of the following 2θ angles: 10.2°±0.2°、15.1°±0.2°、16.4°±0.2°、17.4°±0.2°、19.6°±0.2°、21.4°±0.2°、22.2°±0.2°、24.6°±0.2°、26.6°±0.2°、27.2°±0.2°、28.3°±0.2°、31.8°±0.2°、33.6°±0.2°、37.2°±0.2°. in another preferred embodiment, the thermal profile of the crystalline form of the budesonide-I differential scanning calorimetry has endothermic peaks at 84.5 ± 5 ℃ and 91.2 ± 5 ℃. The invention also provides a preparation method of the novel crystal form APTI-I of the Bramerisen, which comprises the following steps: Adding the braziman free base into an organic solvent, stirring until the solution is clear, volatilizing the solvent to be less than 1/3 of the original volume, separating out crystals, and filtering to obtain the novel braziman crystal form APTI-I, wherein the solvent is selected from methanol, ethanol, dichloromethane or a combination thereof. In another preferred embodiment, the solvent is selected from methanol. In another preferred embodiment, the solvent is volatilized to dryness of less than 1/4, 1/5, 1/10, 1/15, 1/20, or 1/30, etc. of the original volume to precipitate crystals. In another preferred embodiment, the solvent is volatilized to dryness to precipitate crystals. In another preferred embodiment, the solvent is used in an amount such that the volume