A crystalline form of salinosporamide a and a process for its preparation

Abstract

The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a crystal form of salicylic acid larsamiditan and a preparation method thereof. The crystal form has an X-ray diffraction spectrum expressed by 2theta using Cu-Kalpha radiation, and has characteristic peaks at least at 10.98+0.2°, 15.95+0.2°, 18.70+0.2°, 18.89+0.2°, 23.48+0.2° and 26.30+0.2°. The crystal form is composed of a basic unit of one molecule of larsamiditan and one molecule of salicylic acid. The crystal form has excellent solubility and good dissolution characteristics, can break through the limitation of the physicochemical properties of the existing salt type, and better meets the needs of subsequent preparation development and clinical application.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a crystal form of lasmidestan salicylate and its preparation method. Background Technology

[0002] Migraine is a common chronic neurovascular disease, often accompanied by severe headaches, nausea, and vomiting, significantly impacting patients' quality of life. Lasmiditan (also known as COL-144 or LY573144) is a selective 5-HT1F receptor agonist, chemically named 2,4,6-trifluoro-N-[6-[(1-methylpiperidin-4-yl)carbonyl]-pyridin-2-yl]-benzamide, with the chemical structure shown below: .

[0003] Studies have shown that lacmisitan can inhibit neuronal protein extravasation by enhancing 5-HT1F receptor activation, while not causing vasoconstriction at therapeutic doses, effectively reducing cardiovascular risk. Lasmiditan is widely used in the treatment and prevention of migraines, such as migraine neuralgia and neurovascular headaches, and also has potential therapeutic value for diseases related to 5-HT1F receptors, such as general pain, trigeminal neuralgia, anxiety, panic disorder, depression, post-traumatic stress disorder, and dementia.

[0004] Rasmiditan is marketed as an oral tablet, which has become a primary treatment for migraines due to its convenient administration and high patient compliance. However, the drug has extremely low solubility in water. This low solubility results in a slow dissolution rate in the gastrointestinal tract, making it difficult to fully dissolve within the limited gastrointestinal residence time. This leads to low oral bioavailability and affects the onset of therapeutic effect. At the same time, to overcome the low solubility problem, existing formulation technologies often require complex processes such as micronization and solid dispersions or the addition of large amounts of solubilizers, which significantly increases the difficulty of formulation development and production costs, and can easily lead to unstable product quality and large individual differences in absorption.

[0005] Currently, existing technologies mainly focus on the research of lacmidettan hemisuccinate. US8697876B discloses crystalline forms A, B, C, and amorphous forms of lacmidettan hemisuccinate, as well as pharmaceutical compositions containing crystalline form A. CN201780075750 discloses crystalline form D (dihydrate), crystalline form F (trihydrate), and crystalline form E (dehydrated form of crystalline form D) of lacmidettan hemisuccinate. Indian patent IN201941034052 also discloses crystalline form A, amorphous form, and solid dispersions of lacmidettan hemisuccinate. However, the above-mentioned crystalline forms have stability defects: crystalline form A is only stable under anhydrous conditions, such as in anhydrous ethanol; crystalline form E is a metastable form; and crystalline forms D and F are unstable under low relative humidity conditions and are prone to crystal transformation.

[0006] CN202510581608.6 discloses a method for preparing lasmididant hemisuccinate and acetate, as well as key intermediates therein. Although the acetate form offers some improvement in solubility compared to the hemisuccinate, the bottleneck of poor water solubility of lasmididant remains, and its solubility performance needs further improvement to meet the requirements of subsequent formulation development. Summary of the Invention

[0007] In view of the deficiencies in the prior art, the present invention provides a crystalline form of lasmiditan salicylate and its preparation method. This crystalline form has both excellent solubility and good dissolution characteristics, which can overcome the limitations of the existing physicochemical properties of salt forms and better meet the needs of subsequent formulation development and clinical application.

[0008] The technical solution of the present invention is as follows:

[0009] In a first aspect, the present invention provides a rasmidetan salicylate crystal form, wherein the X-ray diffraction pattern expressed in 2θ using Cu-Kα radiation has characteristic peaks at least at 10.98±0.2°, 12.41±0.2°, 15.95±0.2°, 18.70±0.2°, 18.89±0.2°, 19.92±0.2°, 23.48±0.2°, and 26.30±0.2°.

[0010] Preferably, the rasmidetan salicylate crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (expressed as 2θ) at at least 8.31±0.2°, 9.88±0.2°, 10.98±0.2°, 12.41±0.2°, 15.95±0.2°, 18.70±0.2°, 18.89±0.2°, 19.34±0.2°, 19.92±0.2°, 23.48±0.2°, and 26.30±0.2°.

[0011] Preferably, the characteristic peaks of the lacmidetane salicylate crystal form, when subjected to Cu-Kα radiation, conform to the following...Figure 1 The X-ray powder diffraction pattern shown is shown.

[0012] Preferably, the lacmidetane salicylate crystal form is composed of a basic unit consisting of one molecule of lacmidetane and one molecule of salicylic acid.

[0013] Preferably, the crystal form of the rasmidetan salicylate has the following crystallographic parameters: monoclinic crystal system, space group P21 / c; cell parameters: a = 10.2739(2) Å, b = 13.3174(3) Å, c = 18.1104(3) Å, α = 90°, β = 97.441(2)°, γ = 90°, z = 4, and cell volume V = 2457.03(8) Å. 3 .

[0014] In a second aspect, the present invention provides a method for preparing rasmidetam salicylate crystal form, comprising the following steps: adding an organic solvent of salicylic acid to rasmidetam solid powder, stirring and refluxing, and after the reaction is complete, cooling to crystallize, filtering, and vacuum drying to obtain the product.

[0015] Preferably, in the method, the organic solvent is selected from one or more of ethanol, isopropanol, and 2-butanol.

[0016] Preferably, in the method, the mass-to-volume ratio of raspirudine to organic solvent is 38:3~10, more preferably 38:4~8; wherein the mass is expressed in mg and the volume in mL.

[0017] Preferably, in the method, the molar ratio of lasmidetane to salicylic acid is 1:1 to 4; more preferably, it is 1:1.2 to 2.5.

[0018] Preferably, in the method, the cooling temperature for crystallization is 0~30℃; more preferably, it is 15~20℃.

[0019] Preferably, in the method, the crystallization time is 8~36h.

[0020] Preferably, in the method, the drying temperature is 50~60℃ and the drying time is 8~16h.

[0021] A third aspect of the present invention provides a pharmaceutical composition comprising the aforementioned lasmidettan crystal form and pharmaceutically acceptable excipients; wherein the lasmidettan crystal form is present in the pharmaceutical composition in a therapeutically effective amount. The pharmaceutically acceptable excipients may be conventional pharmaceutical excipients in the art. In solid dosage forms, the excipients include, but are not limited to, one or more of diluents, binders, disintegrants, lubricants, flow aids, release rate controllers, plasticizers, preservatives, and antioxidants. The pharmaceutical composition can be formulated into various dosage forms suitable for human consumption, including but not limited to tablets, capsules, granules, powders, or pills; preferably, the dosage form is selected from tablets, capsules, granules, sustained-release tablets, or controlled-release tablets. The pharmaceutical composition can be prepared using methods well known in the art, for example, by mixing a therapeutically effective amount of the lasmidettan crystal form with one or more pharmaceutical excipients to formulate a dosage form suitable for human consumption. Furthermore, the present invention also provides the use of the lasmidettan crystal form or the pharmaceutical composition in the preparation of a medicament for the prevention and / or treatment of acute migraines.

[0022] Crystal structure confirmed:

[0023] The lacmidetane salicylate crystal form provided by this invention is analyzed using X-ray single-crystal diffraction. The testing conditions are as follows: X-ray crystal data are collected on a Rigaku XtaLAB Synergy instrument (Japan), at a test temperature of 293(2) K, using CuKa radiation, and data is collected and analyzed using an ω-scan method. L p-correction. The structure was analyzed using the direct method, and all non-hydrogen atoms were identified using the difference Fourier method. All hydrogen atoms on carbon and nitrogen were obtained by theoretical hydrogenation. The structure was then refined using the least squares method.

[0024] The crystallographic parameters of the lacmidetane salicylate crystal form provided by this invention are: monoclinic crystal system, space group P21 / c; cell parameters are: a = 10.2739(2) Å, b = 13.3174(3) Å, c = 18.1104(3) Å, α = 90°, β = 97.441(2)°, γ = 90°, z = 4, cell volume V = 2457.03(8) ų, as shown in Table 1. The ORTEP diagram of the lacmidetane salicylate crystal form of this invention shows that the crystal is composed of one molecule of lacmidetane and one molecule of salicylic acid as the basic unit, as shown in the attached diagram. Figure 2 As shown. The packing diagram of the lacmidetane-salicylic acid of the present invention is attached. Figure 3 As shown.

[0025] Table 1. Main crystallographic data of lacmidetane salicylate crystal forms

[0026] The X-ray powder diffraction testing instrument and conditions for the lacmidetane salicylate crystal form in this invention are as follows: PANalytical Empyrean X-ray powder diffractometer; Cu target as the light source; flat sample stage; incident light path: BBHD; diffraction light path: PIXCEL; voltage: 45 kV; current: 40 mA; divergence slit: 1 / 4°; antiscattering slit: 1°; Solar slit: 0.04 rad; counting time per step: 0.5 s; scanning range: 3–50°. Based on crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are detailed in the appendix. Figure 1 And Table 2.

[0027] Table 2. Main XRD peaks of lacmidetam salicylate crystal form

[0028]

[0029] The crystal forms of lacmidetane salicylate prepared in the embodiments of the present invention all conform to... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0030] The TGA / DSC thermal analysis instrument and test conditions in this invention are as follows: TGA / DSC thermal analyzer: METTLER TOLEDOTGA / DSC3+; dynamic temperature range: 30~300℃; heating rate: 10℃ / min; program segment: gas N2; gas flow rate: 50 mL / min; crucible: 40μL aluminum crucible.

[0031] The TGA / DSC test results of the crystalline form of lacmidetane salicylate prepared in this invention are as follows: Figure 4 As shown in the figure. The differential thermal analysis results indicate that lacmidetane salicylate crystals exhibit an endothermic melting peak at approximately 233.35℃.

[0032] The beneficial effects of this invention are:

[0033] This invention provides a crystalline form of lasmiditan salicylate with good solubility, dissolution properties, and high stability, which helps to improve its bioavailability. This crystalline form can significantly improve the limitations of the physicochemical properties of existing crystalline forms, laying the foundation for the development of convenient and quality-controllable formulations, and better meeting the needs of clinical applications. Attached Figure Description

[0034] Figure 1 X-ray powder diffraction pattern of lacmidetane salicylate crystal form.

[0035] Figure 2 ORTEP diagram of the crystal form of lacmidetane salicylate.

[0036] Figure 3Packing diagram of the crystal forms of lacmidetane salicylate.

[0037] Figure 4 TGA / DSC spectra of lacmidetane salicylate crystal form. Detailed Implementation

[0038] The following specific embodiments further illustrate the present invention, but do not limit the scope of the present invention in any way. Those skilled in the art can make various modifications or improvements based on the basic idea of ​​the present invention, but as long as they do not depart from the basic idea of ​​the present invention, they are all within the scope of the present invention.

[0039] Example 1

[0040] 100.0 mg of salicylic acid was added to 28.8 mL of isopropanol and stirred to dissolve, resulting in an organic solution of salicylic acid. The resulting organic solution of salicylic acid was added to 136.6 mg of rasmiditan solid powder, stirred and refluxed. After the reaction was complete, the mixture was cooled to 15-20 °C for 24 h to crystallize. After filtration, the product was dried under vacuum at 60 °C for 12 h to obtain the crystalline product of rasmiditan salicylate, with a yield of 90.56% and an HPLC purity of 99.80%.

[0041] Example 2

[0042] 50.0 mg of salicylic acid was added to 10.8 mL of anhydrous ethanol and stirred to dissolve, thus obtaining an organic solution of salicylic acid. The resulting organic solution of salicylic acid was added to 136.6 mg of rasmiditan solid powder, stirred and refluxed. After the reaction was completed, the mixture was cooled to 0-10 °C for 8 h to crystallize. After filtration, the product was dried under vacuum at 50 °C for 8 h to obtain the crystalline product of rasmiditan salicylate, with a yield of 90.12% and an HPLC purity of 99.79%.

[0043] Example 3

[0044] 200.0 mg of salicylic acid was added to a mixed solvent of 35.9 mL of 2-butanol and anhydrous ethanol (volume ratio 1:1), and stirred to dissolve to obtain an organic solution of salicylic acid. The obtained organic solution of salicylic acid was added to 136.6 mg of lasmidetane solid powder, stirred and refluxed. After the reaction was completed, the mixture was cooled to 20-30 °C to crystallize, filtered, and vacuum dried at 70 °C for 16 h to obtain the crystalline product of lasmidetane salicylate, with a yield of 89.87% and an HPLC purity of 99.81%.

[0045] Example 4

[0046] 350.0 mg of salicylic acid was added to 10.8 mL of anhydrous ethanol and stirred to dissolve, thus obtaining an organic solution of salicylic acid. The resulting organic solution of salicylic acid was added to 136.6 mg of rasmiditan solid powder, stirred and refluxed. After the reaction was completed, the mixture was cooled to 0-10 °C for 8 h to crystallize. After filtration, the mixture was dried under vacuum at 50 °C for 8 h to obtain the crystalline product of rasmiditan salicylate, with a yield of 81.64% and an HPLC purity of 99.65%.

[0047] Example 5

[0048] 50.0 mg of salicylic acid was added to 71.8 mL of anhydrous ethanol and stirred to dissolve, thus obtaining an organic solution of salicylic acid. The resulting organic solution of salicylic acid was added to 136.6 mg of rasmiditan solid powder, stirred and refluxed. After the reaction was completed, the mixture was cooled to 0-10 °C for 8 h to crystallize. After filtration, the product was dried under vacuum at 50 °C for 8 h to obtain the crystalline product of rasmiditan salicylate, with a yield of 79.45% and an HPLC purity of 99.78%.

[0049] Comparative Example 1

[0050] 2,4,6-Trifluoro-N-(6-(piperidin-4-formyl)pyridin-2-yl)benzamide trifluoroacetate (200 g) was dissolved in formic acid (600 mL), and 37% formaldehyde (46 mL) was added with stirring. The reaction was carried out at about 90 °C until complete. Water was then added at about 30 °C, and the mixture was extracted with dichloromethane and washed with sodium hydroxide aqueous solution. Dichloromethane was evaporated and replaced with acetone. 4-hydroxybenzoic acid (61 g) was added and refluxed with stirring. The mixture was filtered and separated, and dried at 50 °C to obtain rasmiditan 4-hydroxybenzoic acid product with a yield of 62.54% and an HPLC purity of 99.69%.

[0051] Comparative Example 2

[0052] A 1.00-weight corrected ethanol solution of lacmidettan free base (approximately 4.5 volumes, 183 g) was added to a clean reactor through an online filter. The reactor was rinsed online with ethanol (0.5 volumes, 0.4 weight, 91 mL), and then heated to 75-80°C under a nitrogen atmosphere. Succinic acid (0.16 parts, 0.53 parts, 29.3 g) and ethanol (3.0 parts, 2.4 parts, 550 mL) were added to a second container and stirred at 20-25°C for 40-50 minutes under a nitrogen atmosphere. After dissolution, the solution was added to the reactor containing the lacmidettan ethanol solution. The reactor was maintained at 75-80°C and rinsed online with ethanol (1.0 volume, 0.8 weight, 183 mL). The reactor was cooled to 60-63°C, and the crystallization process was visually inspected and the crystallization temperature was recorded. The reactor was stirred for 50-60 minutes. The contents of the reaction vessel were cooled to 20-25°C within 40-60 minutes (approximately 1°C / minute), stirred for 4-6 hours, the solid was collected, washed with ethanol, and dried under vacuum at 45°C to obtain rasmidetane hemisuccinate crystal form A product with HPLC purity of 99.44%.

[0053] Comparative Example 3

[0054] Rasmidettan (541 mg, 1.6 mmol) was placed in isopropyl acetate (5 mL) and stirred at 1000 rpm at room temperature. Acetic acid (100 μL) was added. After stirring for about two minutes, a white solid precipitated from the solution. After 10 minutes, stirring was stopped, and the white solid was collected by vacuum filtration through Whatman filter paper and dried in situ under air for 10 minutes to obtain rasmidettan acetate crystals with an HPLC purity of 99.58%.

[0055] Verification Example:

[0056] 1. Product nature assessment

[0057] Rasmidetane crystal forms obtained in Example 1 and Comparative Examples 1-3 were used as test samples. Purified water, acetate buffer solution with pH 4.5, and phosphate buffer solution with pH 6.8 (potassium dihydrogen phosphate and disodium hydrogen phosphate, simulating the human intestinal environment) were used as dissolving media. 900 mL of the media was placed in a vial, and an excess of the test sample was added. After sealing, the solution was stirred at a constant temperature of 37°C in a water bath until dissolution equilibrium was reached. The solution was filtered through a filter membrane, and the filtrate was collected and diluted. The content was determined by HPLC and the solubility was calculated. Each group of experiments was measured in parallel three times, and the average value of the results was taken.

[0058] Table 3. Solubility determination results of various crystal forms of raspiridetan

[0059] The results showed that the salicylate lacmidetane crystal form prepared in this invention had significantly higher solubility in acetate buffer solution at pH 4.5, purified water, and phosphate buffer solution at pH 6.8 than the existing crystal forms.

[0060] Investigations revealed that the rasmiditan salicylate crystal form obtained by this invention exhibits good stability under high temperature and high humidity conditions, and its total impurity content is basically consistent with the value measured on day 0.

[0061] 2. Determination of in vitro dissolution properties of tablets obtained from different crystal forms

[0062] Rasmidettan Tablets: The crystalline forms of rasmidettan obtained in Example 1 and Comparative Examples 1-3 were used as APIs (50 mg by weight based on rasmidettan). The following excipients were then added: 30.86 mg microcrystalline cellulose, 7.5 mg pregelatinized starch, 5.63 mg + 7.88 mg croscarmellose sodium (LCMS), 0.56 mg sodium dodecyl sulfate, and 2.25 mg magnesium stearate. Preparation Method: LMS was passed through a safety sieve and added to purified water to form a granulation liquid. The API and the excipients to be wet-granulated (microcrystalline cellulose, pregelatinized starch, and croscarmellose sodium) were passed through a safety sieve and mixed in a granulator. Before adding the granulation liquid, the materials were mixed using the main impeller of the granulator. While mixing the powder, the powder blend was granulated in the granulator by adding the granulation liquid. The mixture was then fluidized bed dried, blended, and compressed to obtain tablets.

[0063] The dissolution rate of the lasmidettan tablets obtained in the examples and comparative examples was determined using the following method. Take the product and dissolve it according to the dissolution test method, using 900 mL of pH 6.8 phosphate buffer solution as the dissolution medium and a rotation speed of 75 rpm. At 10, 30, 60, and 120 minutes, take 10 mL of the solution, filter, and collect the filtrate as the test solution. Separately, take an appropriate amount of lasmidettan reference standard, place it in a 10 mL volumetric flask, dissolve and dilute to the mark with methanol, accurately measure 1 mL, place it in a 10 mL volumetric flask, dilute to the mark with the dissolution medium, and shake well to prepare the reference solution. Inject 10 μL each of the test solution and the reference solution into the liquid chromatograph, record the chromatogram, and calculate the dissolution rate per tablet using the external standard method based on the peak area. The limit is 80% of the labeled amount and should comply with regulations. The test results are shown in Table 4.

[0064] Table 4. Results of tablet appearance and dissolution test

[0065] The results showed that, compared with existing crystal forms, the tablets obtained using the lacmidetam salicylate crystal form prepared by the present invention have a moderate dissolution rate, significantly improve drug release behavior, effectively overcome the burst release phenomenon that is prone to occur in existing crystal form tablets, and help to develop safe, effective and clinically suitable formulations. At the same time, the crystal form obtained by the present invention has strong compressibility, resulting in tablets with moderate hardness and smooth surfaces without cracks. In contrast, the crystal forms obtained in Comparative Example 1 and Comparative Example 3 have poor compressibility, resulting in tablets with lower hardness and a few cracks.

Claims

1. A crystalline form of salinosporamide A characterized by, The crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 10.98±0.2°, 12.41±0.2°, 15.95±0.2°, 18.70±0.2°, 18.89±0.2°, 19.92±0.2°, 23.48±0.2°, and 26.30±0.2°.

2. The crystal form as described in claim 1, characterized in that, The crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (denoted as 2θ) at at least 8.31±0.2°, 9.88±0.2°, 10.98±0.2°, 12.41±0.2°, 15.95±0.2°, 18.70±0.2°, 18.89±0.2°, 19.34±0.2°, 19.92±0.2°, 23.48±0.2°, and 26.30±0.2°.

3. The crystal form as described in claim 1, characterized in that, The crystal form was subjected to Cu-Kα radiation, and its characteristic peaks conformed to the X-ray powder diffraction pattern shown in Figure 1.

4. The crystal form as described in claim 1, characterized in that, The crystal form, its crystallographic parameters are: monoclinic crystal system, space group P21 / c; the unit cell parameters are: a = 10.2739(2) A, b = 13.3174(3) A, c = 18.1104(3) A, a = 90°, b = 97.441(2)°, g = 90°, z = 4, the unit cell volume V = 2457.03(8) A 3 .

5. A crystal form as described in claim 1, characterized in that, The crystal of the described crystal form consists of a basic unit composed of one molecule of lasmiditane and one molecule of salicylic acid.

6. A method for preparing the crystal form as described in any one of claims 1 to 5, characterized in that, The method includes the following steps: adding the organic solvent of salicylic acid to the solid powder of lasmiditan, stirring and refluxing, and after the reaction is complete, cooling to crystallize, filtering, and vacuum drying to obtain the product.

7. The preparation method according to claim 6, characterized in that, In the method, the organic solvent is selected from one or more of ethanol, isopropanol, and 2-butanol.

8. The preparation method according to claim 6, characterized in that, In the method, the mass-to-volume ratio of raspirudine to organic solvent is 38:3~10, preferably 38:4~8; wherein the mass is expressed in mg and the volume in mL.

9. The preparation method according to claim 6, characterized in that, In the method, the molar ratio of lasmiditan to salicylic acid is 1:1 to 4; preferably 1:1.2 to 2.

5.

10. The preparation method according to claim 6, characterized in that, In the method, the cooling temperature for crystallization is 0~30℃; preferably 15~20℃.

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