Acid salts of lasmiditan and methods of making the same

Abstract

The present application belongs to the technical field of medicine crystal form, and particularly relates to acid salts of lasmiditan, in particular, 2,3-dihydroxybenzoic acid salt of lasmiditan and 3,5-dihydroxybenzoic acid salt of lasmiditan. The new salt type of lasmiditan has high solubility, in particular, the solubility of 2,3-dihydroxybenzoic acid salt of lasmiditan in 37°C water, pH6.8 phosphate buffer is as high as 73.85, 79.22 mg / ml, which is beneficial to better therapeutic effect of the medicine; meanwhile, the stability is excellent, the crystal form does not change in the influencing factor test, and the purity change is relatively small, and the mechanical stability is good, which is convenient for preparation processing.

Description

Technical Field

[0001] This invention belongs to the technical field of drug crystal forms, specifically relating to the acid salt of lasmiditan and its preparation method. Background Technology

[0002] Lasmiditan, also known as COL-144 or LY573144, works by selectively inhibiting the calcitonin gene-related peptide (CGRP) receptor. CGRP is a key neurotransmitter involved in the pathological process of migraine; binding to its receptor triggers vasodilation and inflammation, leading to symptoms such as headache and nausea. As the first approved new drug for the treatment of acute migraine in adults in 20 years, lacmiditan has reshaped the migraine treatment landscape with its unique mechanism and significant advantages. Its core advantages lie in three dimensions: innovative mechanism, breakthrough safety, and reliable efficacy. As a selective serotonin 1F receptor agonist, it avoids the vasoconstrictive effects of traditional drugs, instead targeting the trigeminal nerve pathway in the central nervous system to block the release of pain-inducing substances such as CGRP and glutamate, relieving pain at its source and avoiding cardiovascular risks. It is particularly suitable for individuals with cardiovascular disease or those at high risk. In terms of efficacy, it penetrates the central nervous system rapidly after oral administration, with most patients experiencing pain relief within 2 hours. It also improves accompanying symptoms such as photophobia, phonophobia, and nausea, significantly enhancing quality of life.

[0003] Rasmiditan, chemically named 2,4,6-trifluoro-N-[6-[(l-methyl-piperidin-4-yl)carbonyl]-pyridin-2-yl]-benzamide, has the following chemical structural formula: .

[0004] Crystal form refers to the different solid forms formed by the different arrangements of molecules or atoms in a crystal lattice. Crystalline drugs refer to solid drugs in which the active ingredient exists in a specific crystal form. Polymorphic drugs refer to drugs that exist in two or more different crystal forms. Because different crystal forms can affect a drug's dissolution and absorption in the body, they may, to some extent, affect its clinical efficacy and safety; this is especially true for some poorly soluble oral solid or semi-solid drugs, where the impact of crystal form is even greater. Therefore, when developing solid oral dosage forms, studying crystal form is beneficial for selecting a clinically significant and stable crystal form that is controllable. From the perspective of drug quality supervision, drug crystal form is inevitably an important aspect of drug research, testing, and regulation, and also a crucial element of drug quality control.

[0005] CN03807363.3 discloses amorphous forms of lacmidetane hemisuccinate and hydrochloride; US8697876 discloses crystal form A of lacmidetane hemisuccinate for commercial use, as well as crystal forms B, C and amorphous forms of lacmidetane hemisuccinate; CN201780075750.7 discloses crystal forms D (dihydrate), F (trihydrate), and E (dehydrated form of crystal form D) of lacmidetane hemisuccinate, wherein crystal form E is a metastable form; CN202080049829.4 discloses lacmidetane acetate. IN202021049451A discloses bis(2,4,6-trifluorobenzoate) of lasmididan as an intermediate for the preparation of high-purity lasmididan or its hemisuccinate. This bis(2,4,6-trifluorobenzoate) requires a multi-step preparation process, and experiments showed that the stability, especially hygroscopicity, of the bis(2,4,6-trifluorobenzoate) prepared by this method was not improved compared to crystal form A of lasmididan hemisuccinate. DVS testing showed a 6.65% weight gain due to hygroscopic absorption at 25°C / 80%RH. WO2023152081A discloses addition salts of lasmididan with hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, oxalic acid, L-tartaric acid, formic acid, and acetic acid, also used for the preparation of high-purity lasmididan or its hemisuccinate. Studies on its basic physicochemical properties, stability, and hygroscopicity revealed that the SF2 sulfate of lasmididan exhibits the best overall physicochemical properties.

[0006] Although numerous crystal forms of lasmiditant have been published in existing literature, systematic research on its crystal forms still needs improvement. For generic drug companies, developing new crystal forms of drugs to break through the patent protection of original drug companies for crystal forms both domestically and internationally, and to bring generic drugs to market earlier, has become a crucial issue in recent years, directly impacting the market and international competitiveness of both generic drug and API companies.

[0007] This invention provides a rasolmidat crystal form that is easy to prepare and has good physicochemical properties, providing a better basis for the application of rasolmidat in drug therapy, thereby maximizing its medicinal value. Summary of the Invention

[0008] In view of the shortcomings of the prior art, the present invention provides a new acid salt of lasmididan, which has advantages in at least one aspect of stability, melting point, solubility, in vitro and in vivo dissolution, hygroscopicity, bioavailability, adhesion, and compressibility, especially low hygroscopicity, high solubility, and good stability. This provides a new and better option for the development of drugs containing lasmididan and is of great significance.

[0009] Current research focuses on conventional ligands such as succinic acid, hydrochloric acid, and acetic acid, without exploring salt-forming reagents with low toxicity and high buffering capacity, such as 2,3-dihydroxybenzoic acid. The inventors discovered that lasmidetam and 2,3-dihydroxybenzoic acid / 3,5-dihydroxybenzoic acid can form a stable crystal form with excellent physicochemical properties, such as significantly improved solubility and stability.

[0010] The specific technical content of this invention is as follows:

[0011] On one hand, the present invention provides an acid salt of raspireditamine, wherein the acid salt is 2,3-dihydroxybenzoate or 3,5-dihydroxybenzoate of raspireditamine.

[0012] The 2,3-dihydroxybenzoate of raspiridant, as represented by 2θ, has characteristic peaks at least at 15.91±0.2°, 19.04±0.2°, 19.49±0.2°, 21.75±0.2°, 28.90±0.2°, and 32.22±0.2° in its X-ray diffraction pattern.

[0013] Preferably, the 2,3-dihydroxybenzoate of the raspiridant has characteristic peaks at least at 15.91±0.2°, 16.87±0.2°, 19.04±0.2°, 18.42±0.2°, 19.49±0.2°, 21.75±0.2°, 28.90±0.2°, and 32.22±0.2° in its X-ray diffraction pattern (denoted as 2θ).

[0014] Preferably, the characteristic peaks of the 2,3-dihydroxybenzoate of the raspiridant conform to the following... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0015] Preferably, the crystallographic parameters of the 2,3-dihydroxybenzoate of raspiride are: monoclinic crystal system, space group Pc; cell parameters: a=10.3687(5) Å, b=13.0581(7) Å, c=18.5128(9) Å, α=90°, β=97.975(4)°, γ=90°, cell volume V=2482.3(2) Å. 3 .

[0016] Preferably, the 2,3-dihydroxybenzoate of the raspiriditan has Figure 2 The TGA / DSC diagram shown.

[0017] The 3,5-dihydroxybenzoate of the raspiriditan, as expressed in 2θ, has characteristic peaks at least at 10.03±0.2°, 12.11±0.2°, 17.97±0.2°, 23.75±0.2°, 20.99±0.2°, 26.69±0.2°, and 32.95±0.2° in its X-ray diffraction pattern.

[0018] Preferably, the 3,5-dihydroxybenzoate of the raspiriditan has characteristic peaks at least at 10.03±0.2°, 12.11±0.2°, 13.79±0.2°, 16.99±0.2°, 17.97±0.2°, 20.99±0.2°, 22.02±0.2°, 23.75±0.2°, 24.42±0.2°, and 26.69±0.2° in its X-ray diffraction pattern (denoted as 2θ).

[0019] Preferably, the characteristic peaks of the 3,5-dihydroxybenzoate of the raspiridant conform to the following... Figure 5 The X-ray powder diffraction pattern shown is shown.

[0020] Preferably, the crystallographic parameters of the 3,5-dihydroxybenzoate of rasmiditan are: monoclinic crystal system, space group P21 / c; cell parameters are: a = 8.8372(4) Å, b = 12.8723(6) Å, c = 26.8364(11) Å, α = 90.00°, β = 91.716(4) °, γ = 90.00°, and cell volume V = 3051.4(2) Å. 3 .

[0021] Secondly, the present invention provides a method for preparing the lasmididan acid salt, comprising the following steps: adding lasmididan and an acid to a solvent, stirring to dissolve, allowing to stand to crystallize, filtering, and drying to obtain the salt.

[0022] Preferably, the acid is 2,3-dihydroxybenzoic acid or 3,5-dihydroxybenzoic acid.

[0023] Preferably, the organic solvent is selected from one or more of methanol, ethanol, acetone, acetonitrile, isopropanol, n-butanol, n-propanol, and DMF.

[0024] Preferably, the molar ratio of rasmidetane to acid is 1:1 to 6.

[0025] In one embodiment, the present invention provides a method for preparing the 2,3-dihydroxybenzoic acid salt of lasmididan, comprising the following steps: adding lasmididan and 2,3-dihydroxybenzoic acid to solvent A, stirring to dissolve, allowing to stand to crystallize, filtering, and drying to obtain the product.

[0026] Preferably, solvent A is selected from one or more of ethanol, acetone, methanol, isopropanol and DMF.

[0027] More preferably, solvent A is selected from one or a combination of methanol, acetone and isopropanol.

[0028] Preferably, the mass-to-volume ratio of lasmidetane to solvent A is 5-20:1, wherein the mass is expressed in mg and the volume in ml.

[0029] More preferably, the mass-to-volume ratio of the lasmidetane to solvent A is 10-20:1, wherein the mass is expressed in mg and the volume in ml.

[0030] Preferably, the molar ratio of rasmidetane to 2,3-dihydroxybenzoic acid is 1:1 to 6.

[0031] More preferably, the molar ratio of rasmidetane to 2,3-dihydroxybenzoic acid is 1:1~3.

[0032] Preferably, the dissolution temperature is 40~50℃.

[0033] More preferably, the dissolution temperature is 50°C.

[0034] Preferably, the static crystallization temperature is room temperature.

[0035] Preferably, the crystallization time is 48 to 96 hours.

[0036] Preferably, the drying temperature is 38–55°C and the drying time is 8–12 hours.

[0037] Crystal structure of 2,3-dihydroxybenzoate of raspiridant confirmed

[0038] The X-ray single-crystal diffraction analysis conditions were as follows: Rigaku XtaLAB Synergy X-ray single-crystal diffractometer; copper target as the light source; temperature 293 K; voltage 50 kV; current 1 mA; data were collected in ω-scan mode and Lp correction was performed. The structure was resolved 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, and the structure was refined using the least squares method.

[0039] Its crystallographic parameters are: monoclinic crystal system, space group Pc; cell parameters are: a=10.3687(5)Å, b=13.0581(7)Å, c=18.5128(9)Å, α=90°, β=97.975(4)°, γ=90°, z=2, cell volume V= 2482.3(2)Å. 3The ORTEP plot of the 2,3-dihydroxybenzoic acid salt of lasmididan of this invention shows that the crystal contains two molecules of lasmididan and two molecules of 2,3-dihydroxybenzoic acid, as shown in the attached figure. Figure 3 As shown. The hydrogen bond diagram of the 2,3-dihydroxybenzoate of raspiridant of the present invention is attached. Figure 4 As shown.

[0040] Table 1. Key crystallographic data of 2,3-dihydroxybenzoate of rasmiditan

[0041] X-ray powder diffraction testing instrument and testing conditions: X-ray powder diffractometer: PANalyticalEmprem; Cu-Kα; Sample stage: flat plate; Incident light path: BBHD; Diffraction light path: PLXCEL; Voltage 45 kV, Current 40 mA; Divergence slit: 1 / 4; Anti-scattering slit: 1; Solar slit: 0.04 rad; Step size: 0.5 s; Scanning range: 3~50°.

[0042] 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.

[0043] Table 2. Major PXRD peaks of 2,3-dihydroxybenzoate of raspiridin

[0044] The 2,3-dihydroxybenzoate samples of lasmididan prepared in the examples all met the requirements of Appendix Figure 1 X-ray powder diffraction pattern.

[0045] The TGA / DSC thermal analysis instrument and testing conditions in this invention: TGA / DSC thermal analyzer: METTLER TOLEDOTGA / DSC 3+ Dynamic temperature range: 30~300℃; heating rate: 10℃ / min; programmed gas N2; gas flow rate: 50 mL / min; crucible: 40 μl aluminum crucible.

[0046] The TGA / DSC test results of the 2,3-dihydroxybenzoate of raspiridant of this invention are as follows: Figure 2 As shown, differential thermal analysis results indicate that an endothermic melting peak appears at around 222.69℃.

[0047] In one embodiment, the present invention provides a method for preparing the 3,5-dihydroxybenzoic acid salt of lasmididan, comprising the following steps: adding lasmididan and 3,5-dihydroxybenzoic acid to solvent B, stirring to dissolve, allowing to stand to crystallize, filtering, and drying to obtain the product.

[0048] Preferably, solvent B is n-propanol and a mixture of one or more solvents selected from methanol, ethanol, acetone, acetonitrile, isopropanol, n-butanol, and DMF.

[0049] More preferably, solvent B is a mixture of n-propanol and one or more selected from n-butanol, methanol, and ethanol.

[0050] Preferably, the mass-to-volume ratio of lasmidetane to solvent B is 5-20:1, wherein the mass is expressed in mg and the volume in ml.

[0051] More preferably, the mass-to-volume ratio of lasmidetane to solvent B is 10-15:1, wherein the mass is expressed in mg and the volume in ml.

[0052] Preferably, the volume percentage of n-propanol in the mixed solvent is 20-50%.

[0053] Preferably, the molar ratio of rasmidetane to 3,5-dihydroxybenzoic acid is 1:1 to 6.

[0054] More preferably, the molar ratio of lasmidetane to 3,5-dihydroxybenzoic acid is 1:3~6.

[0055] Preferably, the dissolution temperature is 40~50℃.

[0056] More preferably, the dissolution temperature and the static crystallization temperature are room temperature.

[0057] Preferably, the crystallization time is 48 to 96 hours.

[0058] Preferably, the drying temperature is 38–55°C and the drying time is 8–12 hours.

[0059] Crystal structure of 3,5-dihydroxybenzoate of raspiridant confirmed

[0060] The X-ray single crystal diffraction and X-ray powder diffraction analysis conditions are the same as those for raspiridine 3,5-dihydroxybenzoate.

[0061] The crystallographic parameters of rasmiditan 3,5-dihydroxybenzoate are: monoclinic system, space group P21 / c; cell parameters are: a = 8.8372(4) Å, b = 12.8723(6) Å, c = 26.8364(11) Å, α = 90.00°, β = 91.716(4) °, γ = 90.00°, z = 4, cell volume V = 3051.4(2) Å. 3 .

[0062] The ORTEP diagram of the 3,5-dihydroxybenzoic acid salt crystal of lasmididan of this invention shows that one molecule of lasmididan, one molecule of 3,5-dihydroxybenzoic acid, and one molecule of n-propanol are linked together by hydrogen bonds in this crystal, as shown in the attached diagram. Figure 6 As shown. The hydrogen bond diagram of the 3,5-dihydroxybenzoate of raspiridant of the present invention is attached. Figure 7 As shown.

[0063] Table 3. Key crystallographic data of 3,5-dihydroxybenzoate of raspiridant

[0064] Based on crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are detailed in the appendix. Figure 5 And Table 4.

[0065] Table 4. Major PXRD peaks of 3,5-dihydroxybenzoate of lacmidetin

[0066] The 3,5-dihydroxybenzoate samples of lasmididan prepared in the examples all met the requirements of Appendix Figure 5 X-ray powder diffraction pattern.

[0067] Thirdly, the present invention provides the use of the lasmiditan acid salt in the preparation of a medicament for treating migraines.

[0068] Fourthly, the present invention provides a pharmaceutical composition comprising the lasmiditan acid salt of the present invention and other pharmaceutically feasible components.

[0069] Other pharmaceutically feasible components may be co-operable active pharmaceutical ingredients and / or pharmaceutically acceptable excipients.

[0070] Preferred pharmaceutically acceptable excipients include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers, wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, etc.

[0071] There are no particular limitations on the administration method of the active ingredients or pharmaceutical compositions of the present invention. Representative administration methods include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), etc. The compounds of the present invention can be administered alone or in combination with other pharmaceutically acceptable compounds.

[0072] Compared with the prior art, the technical effects achieved by the present invention are as follows:

[0073] (1) This invention provides for the first time 2,3-dihydroxybenzoate and 3,5-dihydroxybenzoate of rasmiditan.

[0074] (2) The new salt form of lasmidestan of the present invention has high solubility. In particular, the solubility of 2,3-dihydroxybenzoate of lasmidestan is as high as 73.85 and 79.22 mg / ml in water at 37°C and phosphate buffer at pH 6.8, respectively. This is beneficial to improve the speed and extent of drug absorption in the human body and enable the drug to exert a better therapeutic effect. In addition, higher solubility can reduce the dosage of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.

[0075] (3) The new salt form of raspiridiltan provided by the present invention has good stability, the crystal form did not change in the influencing factor test, and the purity changed little.

[0076] (4) The new salt form of raspiridil provided by the present invention has good mechanical stability and is easy to process into formulations. Attached Figure Description

[0077] Figure 1 PXRD pattern of 2,3-dihydroxybenzoate of raspiridant.

[0078] Figure 2 TGA / DSC plot of 2,3-dihydroxybenzoate of raspiridant.

[0079] Figure 3 ORTEP plot of 2,3-dihydroxybenzoate of raspiridant.

[0080] Figure 4 Hydrogen bond diagram of 2,3-dihydroxybenzoate of raspiridant.

[0081] Figure 5 PXRD pattern of 3,5-dihydroxybenzoate of raspiridant.

[0082] Figure 6 ORTEP plot of 3,5-dihydroxybenzoate of raspiridant.

[0083] Figure 7 Hydrogen bond diagram of 3,5-dihydroxybenzoate of raspiridant. Detailed Implementation

[0084] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection claimed by the present invention.

[0085] Example 1

[0086] 37.7 mg of rasolvidin and 38.5 mg of 2,3-dihydroxybenzoic acid were added to 2 ml of methanol, ultrasonically heated to 50 °C, stirred until dissolved, filtered, allowed to cool naturally to room temperature, allowed to stand for crystallization for 48 h, filtered, and dried at 55 °C for 8 h to obtain 2,3-dihydroxybenzoic acid salt of rasolvidin, with a yield of 91.28% and a purity of 99.90%.

[0087] Example 2

[0088] 37.7 mg of rasolvidin and 15.4 mg of 2,3-dihydroxybenzoic acid were added to a mixed solution of 2 ml isopropanol and 1 ml methanol. The solution was ultrasonically heated to 45 °C, stirred until dissolved, filtered, allowed to cool naturally to room temperature, and allowed to stand for crystallization for 72 h. After filtration, the solution was dried at 55 °C for 8 h to obtain 2,3-dihydroxybenzoic acid salt of rasolvidin, with a yield of 87.59% and a purity of 99.72%.

[0089] Example 3

[0090] 37.7 mg of rasolvidin and 46.2 mg of 2,3-dihydroxybenzoic acid were added to 3.5 ml of isopropanol, sonicated to 50 °C, stirred until dissolved, filtered, allowed to cool naturally to room temperature, allowed to stand for crystallization for 72 h, filtered, and dried at 55 °C for 12 h to obtain 2,3-dihydroxybenzoic acid salt of rasolvidin, with a yield of 89.35% and a purity of 99.84%.

[0091] Example 4

[0092] 37.7 mg of rasolvidin and 30.8 mg of 2,3-dihydroxybenzoic acid were added to a mixed solvent of 2 ml acetone and 1 ml methanol. The mixture was ultrasonically heated to 50 °C, stirred until dissolved, filtered, allowed to cool naturally to room temperature, and allowed to stand for crystallization for 48 h. After filtration, the mixture was dried at 55 °C for 8 h to obtain 2,3-dihydroxybenzoic acid salt of rasolvidin, with a yield of 72.66% and a purity of 99.43%.

[0093] Example 5

[0094] 37.7 mg of lasmidetane and 38.5 mg of 2,3-dihydroxybenzoic acid were added to 2 ml of trifluoroethanol, ultrasonically heated to 50°C, stirred until dissolved, filtered, allowed to cool naturally to room temperature, and allowed to stand for crystallization for 48 h. The crystals were then filtered again and dried at 55°C for 8 h. No crystals with the desired properties were obtained. Figure 1The PXRD pattern shown is of 2,3-dihydroxybenzoate of raspiridetan.

[0095] Example 6

[0096] 37.0 mg of rasolvidin and 86.4 mg of 3,5-dihydroxybenzoic acid were added to a mixed solvent of 2 ml n-butanol and 1 ml n-propanol. The mixture was sonicated at room temperature until dissolved, filtered, allowed to stand for crystallization for 48 h, filtered again, and dried at 55°C for 8 h to obtain rasolvidin-3,5-dihydroxybenzoic acid salt with a yield of 92.21% and a purity of 99.66%.

[0097] Example 7

[0098] 37.0 mg of rasolvidin and 45.4 mg of 3,5-dihydroxybenzoic acid were added to a mixed solvent of 2 ml methanol and 1.5 ml n-propanol. The mixture was ultrasonically stirred at room temperature until dissolved, filtered, allowed to stand for crystallization for 72 h, filtered again, and dried at 55°C for 12 h to obtain rasolvidin-3,5-dihydroxybenzoic acid salt with a yield of 92.06% and a purity of 99.54%.

[0099] Example 8

[0100] 37.0 mg of lasmidetane and 60.5 mg of 3,5-dihydroxybenzoic acid were added to a mixed solvent of 2 ml ethanol and 0.5 ml n-propanol. The mixture was sonicated at room temperature until dissolved, filtered, allowed to stand for crystallization for 48 h, filtered again, and dried at 55°C for 12 h to obtain lasmidetane-3,5-dihydroxybenzoic acid salt with a yield of 90.44% and a purity of 99.62%.

[0101] Example 9

[0102] 37.0 mg of rasolvidin and 75.6 mg of 3,5-dihydroxybenzoic acid were added to a mixed solvent of 2 ml n-butanol and 1 ml n-propanol. The mixture was sonicated at room temperature until dissolved, filtered, allowed to stand for crystallization for 48 h, filtered again, and dried at 55°C for 12 h to obtain rasolvidin-3,5-dihydroxybenzoic acid salt with a yield of 85.71% and a purity of 99.37%.

[0103] Example 10

[0104] 37.0 mg of lasmidetane and 30.2 mg of 3,5-dihydroxybenzoic acid were added to a mixed solvent of 1.5 ml n-butanol and 1.5 ml n-propanol. The mixture was sonicated at room temperature until dissolved, filtered, allowed to stand for crystallization for 48 h, filtered again, and dried at 55°C for 12 h to obtain lasmidetane-3,5-dihydroxybenzoic acid salt with a yield of 82.35% and a purity of 99.57%.

[0105] Example 11

[0106] 37.0 mg of lasmidetane and 86.4 mg of 3,5-dihydroxybenzoic acid were added to 3 ml of n-propanol, and the mixture was sonicated at room temperature until dissolved. The solution was filtered, allowed to stand for crystallization for 48 hours, filtered again, and dried at 55°C for 8 hours. No crystals were obtained. Figure 5 The PXRD pattern shown is of 3,5-dihydroxybenzoate of raspiridetan.

[0107] Comparative Example 1

[0108] 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 dried at 50 °C to obtain 4-hydroxybenzoic acid lasmiditan, with a yield of 62.54% and an HPLC purity of 99.69%.

[0109] Comparative Example 2

[0110] 30.0 mg of lasmiditan was added to 0.5 ml of methanol and stirred to dissolve. Then, 40 μl of 1 M sulfuric acid aqueous solution was added and stirred for 30 min. The solvent was evaporated to dryness under vacuum to obtain the residue. Then, 3 ml of isopropanol (0.5 ml each time) was added in 6 portions and refluxed to dissolve. The solution was slowly cooled to room temperature, allowed to stand for crystallization for 48 h, and dried at 55°C for 8 h to obtain the product. The yield was 75.6% and the purity was 99.32%.

[0111] Influencing Factors Experiment

[0112] Appropriate amounts of each crystal form of rasmiditant prepared in Examples 1 and 6 and Comparative Examples 1 and 2 were taken and placed in an open environment under light (4500 Lux), high temperature (60°C), and high humidity (RH 90%). Samples were taken on days 10 and 30, and the total impurities (%) were determined by HPLC. The experiment was performed in triplicate, and the average value was taken. X-ray powder diffraction was performed on day 30. The experimental results are shown in Table 5.

[0113] Table 5. Results of the experiment on influencing factors

[0114] Solubility test

[0115] Using water and pH 6.8 phosphate buffer as the dissolving medium, excess of the test crystal form was dispersed in the above medium at 25℃ / 37℃, and stirred 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 and solubility (mg / ml, based on lasmiditant) were determined by HPLC. Three parallel experiments were performed, and the average value was taken. The experimental results are shown in Table 6.

[0116] Table 6 Solubility Test Results

[0117] Hygroscopicity test

[0118] Ten mg of each of the raspireditrin crystal forms prepared in Examples 1 and 6 and Comparative Examples 1 and 2 were taken, and their hygroscopicity was tested using a dynamic moisture adsorption (DVS) instrument. The relative humidity test range was 0-95%RH, and the test temperature was 25°C. The change in crystal form of the samples after DVS was measured, and the hygroscopicity test results at 80%RH are shown in Table 7.

[0119] Table 7 Results of hygroscopicity test

[0120] Grinding stability test

[0121] The crystal forms prepared in Examples 1 and 6 of the present invention and Comparative Examples 1 and 2 were placed in a mortar and manually ground for 10 minutes. XRPD tests were performed before and after grinding. The results showed that the crystal forms and crystallinity of the 2,3-dihydroxybenzoate and 3,5-dihydroxybenzoate of lacmidetane of the present invention did not change, indicating that they have good mechanical stability and are easy to process into formulations. The crystal form of Comparative Example 1 did not change, while the crystal form of Comparative Example 2 did change.

Claims

1. An acid salt of rasmidetane, characterized in that, The acid salt is 2,3-dihydroxybenzoate or 3,5-dihydroxybenzoate of rasmidetane.

2. The acid salt according to claim 1, characterized in that, The 2,3-dihydroxybenzoate of raspiridant, as represented by 2θ, has characteristic peaks at least at 15.91±0.2°, 19.04±0.2°, 19.49±0.2°, 21.75±0.2°, 28.90±0.2°, and 32.22±0.2° in its X-ray diffraction pattern.

3. The acid salt according to claim 2, characterized in that, The characteristic peaks of the 2,3-dihydroxybenzoate of raspiridant conform to the X-ray powder diffraction pattern shown in Figure 1.

4. The acid salt according to claim 1, characterized in that, The 3,5-dihydroxybenzoate of the raspiridant, as represented by 2θ, has characteristic peaks at least at 10.03±0.2°, 12.11±0.2°, 17.97±0.2°, 20.99±0.2°, 23.75±0.2°, and 26.69±0.2° in its X-ray diffraction pattern.

5. The acid salt according to claim 4, characterized in that, The characteristic peaks of the 3,5-dihydroxybenzoate of raspiridant conform to the X-ray powder diffraction pattern shown in Figure 5.

6. A method for preparing the rasmidetane acid salt according to any one of claims 1 to 4, characterized in that, The process includes the following steps: adding raspiridetan and acid to a solvent, stirring to dissolve, allowing to stand and crystallize, filtering, and drying to obtain the final product.

7. The preparation method according to claim 6, characterized in that, The acid is 2,3-dihydroxybenzoic acid or 3,5-dihydroxybenzoic acid; the solvent is selected from one or more of methanol, ethanol, acetone, acetonitrile, isopropanol, n-butanol, n-propanol, and DMF.

8. The preparation method according to claim 7, characterized in that, The mass-to-volume ratio of raspiridant to solvent is 5-20:1, where mass is expressed in mg and volume in ml.

9. The preparation method according to claim 5, characterized in that, The molar ratio of raspirine to acid is 1:1 to 6.

10. Use of the lasmidetane acid salt according to any one of claims 1 to 4 in the preparation of a medicament for treating migraines.

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