A crystalline form of lasmiditan-1-hydroxy-2-naphthoate and methods of making the same

Abstract

This invention belongs to the field of medicinal chemistry, specifically relating to a crystalline form of lasmidetane-1-hydroxy-2-naphthoic acid and its preparation method. The crystalline form exhibits characteristic peaks at least at 10.24±0.2°, 14.65±0.2°, 21.53±0.2°, 21.98±0.2°, 23.70±0.2°, 26.44±0.2°, and 27.09±0.2° in its 2θ X-ray diffraction pattern under Cu-Kα radiation. The crystalline form consists of two molecules of lasmidetane and two molecules of 1-hydroxy-2-naphthoic acid as its basic unit. This crystalline form improves the solubility of lasmidetane, solving the problem of limited formulation development due to its low solubility. It is suitable for the development of various formulations, providing a foundation for improving drug efficacy and patient compliance.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical chemistry technology, specifically relating to a crystalline form of lasmidetane-1-hydroxy-2-naphthoic acid salt and its preparation method. Background Technology

[0002] Rasmidetane is a selective 5-HT 1F 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] Pharmacological studies have shown that lasmidestan inhibits neuronal protein extravasation by enhancing 5-HT1F receptor activation, and does not cause vasoconstriction at therapeutic doses, thereby effectively reducing cardiovascular risk. Based on this mechanism of action, lasmidestan is widely used clinically for the treatment and prevention of migraines, such as migraine neuralgia and neurovascular headaches. It also has therapeutic and preventive effects on general pain, trigeminal neuralgia, anxiety, panic disorder, depression, post-traumatic stress disorder, and dementia, as well as other diseases related to 5-HT1F receptors.

[0004] Migraine is a common chronic neurovascular disease, often accompanied by severe headaches, nausea, and vomiting, significantly impacting patients' quality of life. Currently, lacmisitan is marketed as an oral tablet, which has become a primary treatment due to its convenient administration and high patient compliance. However, this drug has extremely low solubility in water, resulting in a slow dissolution rate in the gastrointestinal tract. It is difficult to fully dissolve within the limited gastrointestinal residence time, leading to low oral bioavailability and affecting the onset of therapeutic effect. Furthermore, 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. This increases the difficulty of formulation development and production costs, and can also lead to unstable product quality and significant individual differences in absorption.

[0005] In the research of crystalline drugs, existing technologies mainly focus on 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 its dihydrate crystalline form D, trihydrate crystalline form F, and crystalline form E (dehydrated form of crystalline form D); IN201941034052 also discloses crystalline form A, amorphous form, and solid dispersions of hemisuccinate. However, these crystalline forms not only have solubility issues but also stability defects: crystalline form A is stable only under anhydrous conditions (such as anhydrous ethanol), crystalline form E is a metastable form, while crystalline forms D and F are unstable under low relative humidity conditions and are prone to crystal transformation. In addition, although CN202510581608.6 discloses a method for preparing lasmidestan acetate, which has improved solubility compared to hemisuccinate, the problem of poor water solubility of lasmidestan still exists, limiting the development of formulations and their clinical application. Summary of the Invention

[0006] In view of the problems in the prior art, the present invention aims to provide a crystalline form of lasmidetane-1-hydroxy-2-naphthoic acid salt and a method for preparing the same. This crystalline form improves the solubility properties of lasmidetane, solves the problem of limited formulation development caused by its low solubility, and is suitable for the development of various formulations, providing a foundation for improving drug efficacy and patient compliance.

[0007] The technical solution of this invention is as follows:

[0008] In a first aspect, the present invention provides a crystalline form of lasmidetane-1-hydroxy-2-naphthocarboxylate, wherein the crystalline form exhibits characteristic peaks at least at 10.24±0.2°, 14.65±0.2°, 21.53±0.2°, 21.98±0.2°, 23.70±0.2°, 26.44±0.2°, and 27.09±0.2° when subjected to Cu-Kα radiation and displayed as 2θ X-ray diffraction patterns.

[0009] Preferably, the rasmidetan-1-hydroxy-2-naphthylcarbamate crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks in its X-ray diffraction pattern (expressed as 2θ) at at least 10.24±0.2°, 14.65±0.2°, 21.53±0.2°, 21.98±0.2°, 23.70±0.2°, 25.86±0.2°, 26.44±0.2°, 27.09±0.2°, 24.70±0.2°, and 16.03±0.2°.

[0010] Preferably, the lacmidetane-1-hydroxy-2-naphthocarboxylate crystal form, when subjected to Cu-Kα radiation, exhibits characteristic peaks conforming to the following... Figure 1 The X-ray powder diffraction pattern shown is shown.

[0011] Preferably, the rasmidetan-1-hydroxy-2-naphthoic acid crystal form is composed of two molecules of rasmidetan and two molecules of 1-hydroxy-2-naphthoic acid as basic units.

[0012] Preferably, the crystallographic parameters of the lasmidetan-1-hydroxy-2-naphthoate are: monoclinic crystal system, space group P21; cell parameters a = 13.1511(9) Å, b = 11.8460(11) Å, c = 17.2031(18) Å, α = 90°, β = 96.494(7)°, γ = 90°, z = 2, and cell volume V = 2662.8(4) Å. 3 .

[0013] In a second aspect, the present invention provides a method for preparing lacmidettan-1-hydroxy-2-naphthoic acid crystal form, the method comprising the following steps: simultaneously adding lacmidettan and 1-hydroxy-2-naphthoic acid to chloroform, heating and stirring until completely dissolved, then adding ethyl acetate or isopropyl acetate and stirring, cooling to crystallize, filtering, and vacuum drying to obtain lacmidettan-1-hydroxy-2-naphthoic acid crystal form.

[0014] Preferably, the molar ratio of lacmidetane to 1-hydroxy-2-naphthoic acid is 1:1.2 to 3.6; more preferably, the molar ratio of lacmidetane to 1-hydroxy-2-naphthoic acid is 1:1.2 to 2.5.

[0015] Preferably, the mass-to-volume ratio of raspiridine to chloroform is 37:4~9, wherein the mass is expressed in mg and the volume in mL.

[0016] Preferably, the heating temperature is 40~45℃.

[0017] Preferably, the volume ratio of ethyl acetate or isopropyl acetate to chloroform is 2-6:1, more preferably 3-4:1.

[0018] Preferably, the cooling and crystallization temperature is 0~10℃, and the time is 6~10h.

[0019] Preferably, the drying temperature is 45~55℃ and the drying time is 8~16h.

[0020] This invention also provides a pharmaceutical composition comprising the aforementioned crystalline form and pharmaceutically acceptable excipients. The crystalline 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 the following: 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 orally disintegrating tablets, capsules, granules, sustained-release tablets, or controlled-release tablets. The pharmaceutical composition can be prepared using methods well known in the art; specifically, a therapeutically effective amount of the aforementioned crystalline form can be mixed with one or more pharmaceutical excipients to prepare a dosage form suitable for human consumption. This invention also provides the use of the aforementioned crystalline form or the pharmaceutical composition in the preparation of medications for the prevention and / or treatment of acute migraines.

[0021] Crystal structure confirmed:

[0022] The crystal form of lasmidetane-1-hydroxy-2-naphthylcarboxylate provided by this invention was analyzed using X-ray single-crystal diffraction. The test conditions were: 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. The structure was refined using the least squares method; further structural analysis yielded the X-ray single-crystal diffraction pattern (SXRD), as shown below. Figure 2 As shown.

[0023] The crystallographic parameters of the lacmidetane-1-hydroxy-2-naphthoate crystal form provided by this invention are: monoclinic crystal system, space group P21; cell parameters are: a = 13.1511(9) Å, b = 11.8460(11) Å, c = 17.2031(18) Å, α = 90°, β = 96.494(7)°, γ = 90°, z = 2, cell volume V = 2662.8(4) Å. 3 As shown in Table 1, the ORTEP diagram of the lacmidetane-1-hydroxy-2-naphthoic acid crystal form of the present invention shows that the crystal consists of two molecules of lacmidetane and two molecules of 1-hydroxy-2-naphthoic acid as the basic unit, as shown in the attached diagram. Figure 2 As shown. A packing diagram of the crystal forms of lacmidetane-1-hydroxy-2-naphthoate of the present invention is attached. Figure 3 As shown.

[0024] Table 1. Main crystallographic data of lacmidetane-1-hydroxy-2-naphthocarbamate crystal forms

[0025] The X-ray powder diffraction testing instrument and conditions for the lacmidetane-1-hydroxy-2-naphthoate crystal form in this invention are as follows: X-ray powder diffractometer: PANalytical Emprem; 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°. Based on crystallographic data, the characteristic peaks in the corresponding X-ray powder diffraction pattern (Cu-Kα) are detailed in the appendix. Figure 1 As shown in Table 2.

[0026] Table 2. Main XRD peaks of lacmidetane-1-hydroxy-2-naphthocarbamate crystal form

[0027] All samples of the rasmiditan-1-hydroxy-2-naphthoic acid salt crystal form prepared in the examples conformed to X-ray powder diffraction patterns.

[0028] Compared with the prior art, the present invention has the following outstanding advantages:

[0029] 1. The 1-hydroxy-2-naphthoic acid salt crystal form of lasmididan prepared in this invention improves the lipid-water partition properties and solubility of lasmididan through salt-forming modification, thereby increasing the dissolution and absorption rate of the drug. While significantly improving bioavailability and clinical efficacy, it effectively reduces the difficulty of formulation development and production costs, providing a stable foundation for improving patient compliance.

[0030] 2. The preparation process of this invention is simple and easy to operate, requires no complex and harsh reaction conditions, is highly adaptable to production equipment, has high reproducibility and high batch-to-batch quality stability, which is conducive to realizing industrial production. Attached Figure Description

[0031] Figure 1 X-ray powder diffraction pattern of the crystal form of lacmidetane-1-hydroxy-2-naphthoic acid salt.

[0032] Figure 2 ORTEP diagram of the crystal form of lacmidetane-1-hydroxy-2-naphthoic acid salt.

[0033] Figure 3 Stacking diagram of the crystal form of lacmidetane-1-hydroxy-2-naphthoic acid salt. Detailed Implementation

[0034] 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.

[0035] Example 1

[0036] 37.7 mg of lasmidetane and 22.6 mg of 1-hydroxy-2-naphthoic acid were simultaneously added to 7 mL of chloroform, heated to 45 °C and stirred until completely dissolved. Then, 24 mL of ethyl acetate was added and stirred. The mixture was cooled to 0–10 °C and crystallized for 8 h. After filtration, the crystals were dried under vacuum at 45–55 °C for 12 h to obtain lasmidetane-1-hydroxy-2-naphthoic acid salt crystals with a yield of 88.79% and an HPLC purity of 99.87%.

[0037] Example 2

[0038] 37.7 mg of lasmidetane and 47.0 mg of 1-hydroxy-2-naphthoic acid were simultaneously added to 4 mL of chloroform, heated to 40 °C, and stirred until completely dissolved. Then, 8 mL of ethyl acetate was added and stirred. The mixture was cooled to 0–10 °C and crystallized for 6 hours. After filtration, the crystals were dried under vacuum at 45–55 °C for 8 hours to obtain lasmidetane-1-hydroxy-2-naphthoic acid salt crystals, with a yield of 87.85% and an HPLC purity of 99.79%.

[0039] Example 3

[0040] 37.7 mg of lasmidetane and 67.7 mg of 1-hydroxy-2-naphthoic acid were simultaneously added to 9 mL of chloroform, heated to 45 °C, and stirred until completely dissolved. Then, 54 mL of isopropyl acetate was added and stirred. The mixture was cooled to 0–10 °C and crystallized for 10 h. After filtration, the crystals were dried under vacuum at 45–55 °C for 16 h to obtain lasmidetane-1-hydroxy-2-naphthoic acid salt crystals, with a yield of 86.34% and an HPLC purity of 99.83%.

[0041] Example 4

[0042] 37.7 mg of rasolvidan and 112.9 mg of 1-hydroxy-2-naphthoic acid were simultaneously added to 7 mL of chloroform, heated to 45 °C and stirred until completely dissolved. Then, 24 mL of ethyl acetate was added and stirred. Crystallization was carried out at 0–10 °C for 8 h, filtered, and dried under vacuum at 45–55 °C for 12 h to obtain rasolvidan-1-hydroxy-2-naphthoic acid salt crystals, with a yield of 82.13% and an HPLC purity of 99.75%.

[0043] Example 5

[0044] 37.7 mg of lasmidetane and 22.6 mg of 1-hydroxy-2-naphthoic acid were simultaneously added to 7 mL of chloroform, heated to 45 °C, and stirred until completely dissolved. Then, 100 mL of ethyl acetate was added and stirred. Crystallization was carried out at 0–10 °C for 8 h, filtered, and dried under vacuum at 45–55 °C for 12 h to obtain lasmidetane-1-hydroxy-2-naphthoic acid crystal form, with a yield of 73.28% and an HPLC purity of 99.81%.

[0045] Comparative Example 1

[0046] 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%.

[0047] Comparative Example 2

[0048] Rasmidetam hemisuccinate crystal form A was prepared by wet granulation using a high-shear granulator. 200 g of rasmidetam hemisuccinate (crystal form A) was mixed with 87% (w / v) water in a 4-liter tank. The spray rate was 20 g / kg / min, the impeller speed was 400 rpm, and the granulation time was 2 minutes. The prepared particles were then dried in a fluidized bed system (air inlet flow rate 60 m³ / min). 3 The product was obtained by saturating the following conditions: (inlet temperature 70℃, outlet product temperature 22→34℃, product temperature 23→50℃) with an HPLC purity of 99.63% for the following conditions: (inlet temperature 70℃, outlet product temperature 22→34℃, product temperature 23→50℃).

[0049] Comparative Example 3

[0050] 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%.

[0051] Verification Example:

[0052] 1. Study on the quality characteristics of products of various crystal forms

[0053] Purified water, acetate buffer solution with a pH of 4.5, and potassium dihydrogen phosphate-disodium hydrogen phosphate buffer solution with a pH of 6.8 (simulating the human intestinal environment) were used as dissolving media. Rasmidettan crystal forms prepared in Example 1 and Comparative Examples 1-3 were used as test samples. 900 mL of each medium was accurately measured and placed in a vial. An excess of the test sample was added to bring the system to supersaturation. Each vial was sealed and placed in a 37°C constant temperature water bath with continuous stirring until dissolution equilibrium was reached. After standing, the supernatant was filtered through a filter membrane, the initial filtrate was discarded, and an appropriate amount of the subsequent filtrate was accurately measured and diluted. The content was determined by high-performance liquid chromatography (HPLC), and the solubility of each test sample in different media was calculated. Each experiment was performed in triplicate, and the average value was used as the final result.

[0054] Table 3. Results of solubility determination of various crystal forms of raspiridetan

[0055] The results showed that the latamiditant-1-hydroxy-2-naphthoic acid salt crystal form prepared in this invention has superior solubility characteristics. In three dissolution media, especially in the acetate buffer solution at pH 4.5, the solubility of the crystal form of this invention was significantly improved, indicating that the crystal form can effectively improve the solubility of the drug and is beneficial to improving the bioavailability of latamiditant.

[0056] The rasmiditan-1-hydroxy-2-naphthoic acid salt crystal form provided by this invention shows no significant difference in total impurity content of related substances compared with day 0 under high temperature and high humidity conditions, indicating that its crystal form quality is stable.

[0057] 2. Determination of the properties of orthotopic fragments obtained from different crystal forms

[0058] Using the crystalline form of latamidittan prepared in Example 1 and Comparative Examples 1-3, and commercially available latamidittan (unsalted) as raw materials, orally disintegrating tablets were prepared according to the preparation method of Example 3 in CN202110722510.X. The weights of each component in the prescription were as follows: latamidittan 6.25%, lactose 200 mesh 57.75%, microcrystalline cellulose 28%, croscarmellose sodium 10%, aspartame 1%, and magnesium stearate 2%. The preparation method was as follows: the active pharmaceutical ingredients latamidittan and aspartame were finely ground and passed through a 100-mesh sieve, the prescribed amounts were weighed, and the two were mixed evenly. Microcrystalline cellulose, croscarmellose sodium cellulose, and lactose were each sieved through a 60-mesh sieve, weighed out separately, and added to the above-mentioned mixed drugs in sequence and mixed evenly. Then, the prescribed amount of magnesium stearate was added, sieved, and mixed evenly. The intermediate content was detected, and after determining the tablet weight, the tablets were compressed using direct compression technology to obtain the final product.

[0059] Determination of disintegration time limit: Refer to the disintegration time limit method for orally disintegrating tablets in General Chapter 0921 of Part IV of the Chinese Pharmacopoeia 2020 edition.

[0060] Dissolution determination: The dissolution of the lasmidettan formulations obtained in the examples and comparative examples was determined using the following method. Take the product and perform the dissolution test according to the method, rotating at 75 rpm. At 5, 10, and 15 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 dissolution medium, and mix 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 peak area. The limit is 80% of the labeled amount and should comply with regulations.

[0061] Table 4. Properties of orally disintegrating tablets obtained from different crystal forms of lacmidetine.

[0062] The results show that the orally disintegrating tablets prepared using the crystal form obtained in the embodiments of the present invention have excellent appearance, moderate hardness, rapid disintegration, and rapid dissolution. Compared with the orally disintegrating tablets prepared in Example 1, the hardness of the formulation may be affected by the poor compressibility of the API crystal form, resulting in surface cracks and slower disintegration and dissolution. Compared with the orally disintegrating tablets prepared in Examples 2-3, the tablets have lower hardness and are easily fragmented, with slow disintegration and dissolution behavior. The orally disintegrating tablets prepared directly using lasmiditan have poor stability, obvious surface cracks, and poor disintegration and dissolution performance.

Claims

1. A crystalline form of lacmidetane-1-hydroxy-2-naphthocarboxylate, 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 10.24±0.2°, 14.65±0.2°, 21.53±0.2°, 21.98±0.2°, 23.70±0.2°, 26.44±0.2°, and 27.09±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 10.24±0.2°, 14.65±0.2°, 21.53±0.2°, 21.98±0.2°, 23.70±0.2°, 25.86±0.2°, 26.44±0.2°, 27.09±0.2°, 24.70±0.2°, and 16.03±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 consists of two molecules of lasmiditan and two molecules of 1-hydroxy-2-naphthoic acid as basic units.

5. The crystal form as described in claim 1, characterized in that, The crystallographic parameters of the crystal form are: monoclinic crystal system, space group P21; cell parameters are a = 13.1511(9) A, b = 11.8460(11) A, c = 17.2031(18) A, a = 90°, b = 96.494(7)°, g = 90°, z = 2, cell volume V = 2662.8(4) A 3 .

6. A method for preparing the crystal form as described in claim 1, characterized in that, The preparation method includes the following steps: Rasmidettan and 1-hydroxy-2-naphthoic acid are simultaneously added to chloroform, heated and stirred until completely dissolved, then ethyl acetate or isopropyl acetate is added and stirred, cooled to crystallize, filtered, and vacuum dried to obtain rasmidettan-1-hydroxy-2-naphthoic acid crystal form.

7. The method as described in claim 6, characterized in that, In the preparation method, the molar ratio of lasmidetane to 1-hydroxy-2-naphthoic acid is 1:1.2~3.6; preferably, the molar ratio of lasmidetane to 1-hydroxy-2-naphthoic acid is 1:1.2~2.

5.

8. The method as described in claim 6, characterized in that, In the preparation method, the mass-to-volume ratio of raspiridant to chloroform is 37:4~9, where mass is expressed in mg and volume in mL.

9. The method as described in claim 6, characterized in that, In the preparation method, the heating temperature is 40~45℃.

10. The method as described in claim 6, characterized in that, In the preparation method, the volume ratio of ethyl acetate or isopropyl acetate to chloroform is 2~6:1; preferably 3~4:1.

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