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CN-117295735-B - Tolebrutinib crystal form, amorphous form, preparation method and application thereof

CN117295735BCN 117295735 BCN117295735 BCN 117295735BCN-117295735-B

Abstract

The present application provides a crystalline form, amorphous form, and methods of making and using tolebrutinib, the crystalline form of tolebrutinib provided herein has at least one of the following advantages: the stability is good, the hygroscopicity is low, the granularity distribution is uniform, the solubility meets the medicinal requirement, the storage is stable, the crystal transformation of the medicine in the development process and the storage is avoided, the preparation method is reliable, and the development value is great. The tolebrutinib amorphous form provided by the application has better solubility than the crystalline tolebrutinib, and meanwhile still has good placement stability and acceptable hygroscopicity, and has high medicinal value.

Inventors

  • SHENG XIAOHONG
  • SHENG XIAOXIA
  • DAI YU

Assignees

  • 杭州领业医药科技有限公司

Dates

Publication Date
20260512
Application Date
20220422
Priority Date
20210423

Claims (12)

  1. 1. Tolebrutinib crystal Form 1 with the structural formula shown in the specification, , Characterized in that the XRPD pattern of Form 1 has characteristic peaks at 10.4 ° ± 0.2 °, 11.4 ° ± 0.2 °, 20.6 ° ± 0.2 °, 16.7 ° ± 0.2 ° and 22.7 ° ± 0.2 °.
  2. 2. The Form tolebrutinib of claim 1, wherein the XRPD pattern of Form1 further has characteristic peaks at one or two of 2-theta values of 4.2 ° ± 0.2 °, 15.8 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.8 ° ± 0.2 ° and 24.8 ° ± 0.2 °.
  3. 3. The Form tolebrutinib of claim 1 or 2, wherein the XRPD pattern of Form 1 further has characteristic peaks at one or two of 2 theta values of 10.9 ° ± 0.2 °, 21.3 ° ± 0.2 °, 23.5±0.2°, 25.3±0.2° and 25.7±0.2° and above.
  4. 4. The Form tolebrutinib of claim 1 or 2, wherein the XRPD pattern of Form 1 has diffraction peaks at the positions of the 2Θ values in the following table: 。
  5. 5. the Form tolebrutinib of claim 1 or 2, wherein the XRPD pattern of Form 1 is substantially as shown in figure 7.
  6. 6. The Form tolebrutinib of claim 1 or 2, wherein the DSC profile of Form 1 begins to exhibit an endothermic peak at about 126 ℃.
  7. 7. The tolebrutinib crystalline Form 1 according to claim 1 or 2, the FT-IR spectrum of the crystalline Form 1 having a band at 840.7 ±2 cm -1 、978.3±2 cm -1 、1472.3±2 cm -1 、1492.5±2 cm -1 .
  8. 8. The process for the preparation of Form tolebrutinib of Form 1 according to any one of claims 1 to 7 wherein the process is selected from any one of the following processes: 1) Tolebrutinib is dissolved in a solvent 1 to Form a solution, and the solution is volatilized, crystallized, separated and dried to obtain a crystal Form 1; wherein the solvent 1 is acetone; 2) Tolebrutinib is dissolved in a good solvent to Form a solution, the solution is stirred (1), an anti-solvent is added, the solution is stirred (2), crystallization, separation and drying are carried out, and the crystal Form 1 is obtained; Wherein the good solvent is selected from single or mixed solvents of ethanol, acetone and tetrahydrofuran, and the anti-solvent is selected from single or mixed solvents of water, n-heptane and n-hexane; the stirring (1) and the stirring (2) are optional steps; 3) Tolebrutinib forming suspension in the solvent 2, stirring at room temperature, separating, and drying to obtain a crystal Form 1; wherein the solvent 2 is selected from one or a mixed solvent of ethanol or ethyl acetate; The mass-to-volume ratio (mg/mL) of tolebrutinib to solvent 2 is 20:1-100:1.
  9. 9. The method for preparing tolebrutinib Form 1 according to claim 8, wherein in method 1), the step of dissolving is performed at room temperature; In the method 2), the anti-solvent is a mixed solvent containing water, the volume ratio of the anti-solvent to the good solvent is more than or equal to 0.1:1, the dissolving step is carried out at room temperature, the stirring is carried out at a certain temperature which is less than or equal to 30 ℃, and the stirring time is more than or equal to 30min; in the method 3), the solvent 2 is ethanol, and the mass-to-volume ratio (mg/mL) of tolebrutinib to the solvent 2 is 25-50:1.
  10. 10. The method of claim 9, wherein in method 2), the volume ratio of the anti-solvent to the good solvent is 1:1-8:1.
  11. 11. A pharmaceutical composition comprising a Form 1 of tolebrutinib as defined in any one of claims 1-7, and at least one pharmaceutically acceptable carrier.
  12. 12. Use of the tolebrutinib crystalline Form 1 of any one of claims 1-7 or the pharmaceutical composition of claim 11 in the manufacture of a medicament for the treatment of an autoimmune disease.

Description

Tolebrutinib crystal form, amorphous form, preparation method and application thereof Citation of related application The present application claims the full benefit of the application patent application with application number 202110440552. X filed at day 23 of 2021 to the national intellectual property office of the people's republic of China and application number 202110479686.7 filed at day 30 of 2021 to the national intellectual property office of the people's republic of China, and is incorporated herein by reference in its entirety. Technical Field The present application relates to the field of pharmaceutical chemistry. In particular, the application relates to a crystalline form, amorphous form, and methods of making and using tolebrutinib. Background Polymorphism or polymorphism is a characteristic property of certain molecules and molecular compositions, and the same molecules may form different crystals due to different arrangements, and these crystals have different crystal structures and physical properties, such as solubility, stability, thermal properties, mechanical properties, purification ability, X-ray diffraction pattern, infrared absorption pattern, raman spectrum, solid-state nuclear magnetism, and the like. The discovery of new crystalline forms (including anhydrates, hydrates, solvates, etc.) of pharmaceutically active ingredients may result in more processing advantages or provide materials with better physicochemical properties, such as better bioavailability, storage stability, ease of processing, ease of purification, or as intermediate crystalline forms that facilitate conversion to other crystalline forms. Certain specific crystalline forms of certain compounds for use as pharmaceutically active ingredients may also help improve the performance of the drug. It expands the raw material types selected in the pharmacy, such as improving dissolution, improving shelf life, easier processing, etc. Tolebrutinib (research and development code SAR 442168), developed by prinspi (PRINCIPIA), which is later purchased by sirofii (Sanofi) and included in its product line, tolebrutinib is a BTK inhibitor for the treatment of cancer, autoimmune diseases such as multiple sclerosis and myasthenia gravis, inflammatory diseases, thromboembolic diseases, and the like, of the formula: no report on the crystal forms of the compound has been disclosed in the prior art. Thus, there is a need for a comprehensive systematic polymorphic screen for tolebrutinib to select crystalline forms with beneficial properties for product development of tolebrutinib. The inventors of the present application have surprisingly found the 2 crystalline forms of tolebrutinib during the course of the study. The tolebrutinib crystal form provided by the application has at least one of the following advantages of good stability, lower hygroscopicity, uniform particle size distribution, stable storage, capability of avoiding crystal transformation of the medicine in the development process and storage, reliable preparation method and great development value, and the solubility meets the medicinal requirement. At the same time, the inventors of the present application have surprisingly found an amorphous form of tolebrutinib. It is well known that solid powders have both amorphous and crystalline types of physical states. Generally amorphous solids have low stability and high hygroscopicity, which limits their pharmaceutical value. However, the inventors have found that tolebrutinib is amorphous, has better solubility than tolebrutinib in the crystalline state, and still has good placement stability and acceptable hygroscopicity, and has high medicinal value. Disclosure of Invention In view of the shortcomings of the prior art, the application aims to provide tolebrutinib crystal forms, amorphous forms, preparation methods and applications thereof. It is an object of the present application to provide tolebrutinib Form1 (hereinafter Form 1) having XRPD patterns with characteristic peaks at least about 10.4 ° ± 0.2 °, 11.4 ° ± 0.2 °, 20.6 ° ± 0.2 °, 16.7 ° ± 0.2 ° and 22.7 ° ± 0.2 °. Further, the tolebrutinib Form's XRPD pattern also has characteristic peaks at one or two of 2 theta values of 4.2 ° ± 0.2 °, 15.8 ° ± 0.2 °, 17.9 ° ± 0.2 °, 20.8±0.2° and 24.8 ° ± 0.2 ° or/and its XRPD pattern also has characteristic peaks at one or two of 2 theta values of 10.9 ° ± 0.2 °, 21.3 ° ± 0.2 °, 23.5±0.2 °, 25.3±0.2° and 25.7±0.2° or more. Still further, the XRPD pattern of tolebrutinib Form 1 has diffraction peaks at the 2θ values as set forth in the following table: 2θ±0.2°4.210.4 2θ±0.2°10.911.415.816.717.920.320.620.821.021.322.723.523.724.825.325.726.927.227.431.135.5 in a preferred embodiment of the application, the XRPD pattern for tolebrutinib Form 1 is substantially as shown in FIG. 7. In a preferred embodiment of the present application, the TGA profile of tolebrutinib Form is substantially as shown in figure 8. In a preferred