A new crystalline form of semisuccinic acid larimidotan

Abstract

The present application belongs to the technical field of crystal form of drug molecules, and particularly relates to a new crystal form of semisuccinic acid lasmiditan. The X-ray diffraction spectrum of the semisuccinic acid lasmiditan crystal form provided by the present application has characteristic peaks at 14.22±0.2°, 16.33±0.2°, 17.05±0.2°, 19.34±0.2°, 19.54±0.2° and 23.54±0.2° in terms of 2θ. The crystal form has good stability, small hygroscopicity and high solubility, is helpful to improve the bioavailability of lasmiditan and improve the clinical curative effect, and has important value for optimization and development of lasmiditan preparations.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a semisuccinic acid lasmiditan crystal form. BACKGROUND

[0002] Migraine is characterized by recurrent attacks of moderate to severe headache, usually with nausea, anxiety, depression, etc., which seriously affect sleep quality, social skills and learning performance of adolescents, and directly lead to decreased labor capacity of adults, affecting about 10% of the global population, and the incidence of women is 3 times that of men. At present, there is still no drug that can completely cure migraine. In 2017, there were more than 3600 million cases of migraine patients in the United States, 800 million cases in Japan, and about 1300 million cases in China. The annual medical and health expenditure and economic loss caused by migraine in the United States reached tens of billions of dollars.

[0003] Lasmiditan, namely 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide, is the first innovative drug for emergency treatment of migraine in the past 20 years, the first drug with a new mechanism of action, which acts on 5-HT1F receptors in the trigeminal nerve pathway, penetrates the central nervous system, blocks the sensation of pain, and relieves the symptoms of migraine. For migraine patients who have no relief from triptans or other existing therapies, lasmiditan is expected to meet the clinical treatment needs of 40% of these patients. Compared with traditional triptans, it does not constrict blood vessels, thereby not increasing the risk of cardiovascular disease, and for this part of patients with or likely to have cardiovascular disease, lasmiditan provides a better solution. 1f For this part of patients with or likely to have cardiovascular disease, lasmiditan provides a better solution.

[0004] The crystallinity of a drug affects its solubility, dissolution rate, hardness, compressibility and melting point, and other physical and mechanical properties, which can affect the manufacture and utility of the drug, and in cases where two or more polymorphs can be produced, the properties of the polymorphs must be compared and the preferred polymorph selected based on the physical property variables, with certain aspects, such as ease of preparation, stability, etc., being considered critical, and can also be preferred due to higher or lower solubility and / or more optimal pharmacokinetics, which can significantly affect the pharmaceutical processing of the compound, particularly when the compound is prepared or used on a commercial scale.

[0005] US8697876B2 discloses crystal form A, B, C, amorphous of Lasmiditan hemisuccinate and pharmaceutical composition of crystal form A, wherein crystal form C is stored at 75% RH for 2 days and 3 days, and no change is found in the sample by visual observation; CN201780075750 discloses crystal form D (dihydrate), crystal form F (trihydrate), crystal form E (dehydrated hydrate of crystal form D) of Lasmiditan hemisuccinate and preparation method thereof, crystal form D can be prepared by wet granulation starting from crystal form A, crystal form A is stored at 25°C and 96% relative humidity (RH), wherein crystal form E is a metastable form, crystal forms D, F are not completely stable at low relative humidity and are prone to crystal transformation; IN201941034052 discloses crystal form A, amorphous and solid dispersion thereof of Lasmiditan hemisuccinate.

[0006] In summary, the prior art does not systematically study the known crystal forms of Lasmiditan hemisuccinate in terms of solubility, stability, hygroscopicity, etc., and cannot well meet the requirements of pharmaceutical preparations, so it is necessary to develop more crystal forms, on the one hand to provide more crystal forms of Lasmiditan hemisuccinate for drug application, and on the other hand to develop crystal forms of Lasmiditan hemisuccinate that are more suitable for industrial production and have high economic benefits. SUMMARY

[0007] In order to overcome the shortcomings of the prior art, the present application provides a crystal form of Lasmiditan hemisuccinate and a preparation method thereof, which has good stability and high solubility, and can better meet the requirements of pharmaceutical preparations.

[0008] The specific technical content of the present application is as follows:

[0009] The present application first provides a crystal form of Lasmiditan hemisuccinate, which has characteristic peaks at 14.22±0.2°, 16.33±0.2°, 17.05±0.2°, 19.34±0.2°, 19.54±0.2°, 23.54±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0010] Preferably, the crystal form of Lasmiditan hemisuccinate has characteristic peaks at 9.74±0.2°, 14.22±0.2°, 15.26±0.2°, 16.33±0.2°, 16.56±0.2°, 17.05±0.2°, 18.64±0.2°, 19.34±0.2°, 19.54±0.2°, 23.54±0.2°, 25.92±0.2° in the X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation.

[0011] Preferably, the crystal form of Lasmiditan hemisuccinate has the X-ray powder diffraction spectrum shown in the figure. Figure 1 Preferably, the crystal form of Lasmiditan hemisuccinate has the X-ray powder diffraction spectrum shown in the figure.

[0012] Preferably, the semisuccinic acid larimidotan crystal form has Figure 3 TGA / DSC pattern shown.

[0013] The present application further provides a preparation method of the semisuccinic acid larimidotan crystal form, which comprises the following steps: adding succinic acid and larimidotan into a mixed solution of water and an organic solvent in sequence, stirring and refluxing, cooling and crystallizing after the reaction is completed, filtering, and drying to obtain the semisuccinic acid larimidotan crystal form.

[0014] Preferably, the organic solvent is one or a combination of glycerol, isopropyl alcohol, and tetrahydrofuran.

[0015] Preferably, the volume ratio of the water to the organic solvent is 1:5-10, and more preferably 1:8.

[0016] Preferably, the mass-volume ratio of the larimidotan to the mixed solution is 1:10-20 g / ml, and more preferably 1:10-15 g / ml.

[0017] Preferably, the molar ratio of the larimidotan to the succinic acid is 1:0.7-1.1, and more preferably 1:0.8.

[0018] Preferably, the stirring and refluxing time is 2-5 h.

[0019] Preferably, the cooling and crystallizing temperature is 0-15℃, and more preferably 5-10℃.

[0020] Preferably, the crystallizing time is 3-6 h.

[0021] Preferably, the drying is vacuum drying at 50-60℃.

[0022] Preferably, the drying time is 6-12 h.

[0023] The present application further provides a pharmaceutical composition comprising the semisuccinic acid larimidotan crystal form and pharmaceutically acceptable excipients. The semisuccinic acid larimidotan crystal form can be a therapeutically effective amount. The pharmaceutically acceptable excipients can be excipients known in the art, including but not limited to diluents, binders, disintegrants, lubricants, glidants, release rate control agents, plasticizers, preservatives, antioxidants, etc. in the case of solid preparations.

[0024] The pharmaceutical composition can be in a dosage form suitable for human administration, such as tablets, capsules, granules, powders, or pills, and preferably tablets, capsules, granules, disintegrating tablets, sustained-release or controlled-release tablets.

[0025] The pharmaceutical composition of the present application can be prepared by mixing a therapeutically effective amount of the semisuccinic acid lasmiditan crystal form and various pharmaceutical adjuvants in a manner known in the art, and can be prepared into a dosage form suitable for human consumption, such as tablets, capsules, granules, etc. by mixing, granulating, tabletting, or filling capsules, etc.

[0026] The present application also provides a use of the above-mentioned semisuccinic acid lasmiditan crystal form or the above-mentioned pharmaceutical composition in the preparation of a drug for preventing and / or treating acute migraine.

[0027] Crystal structure confirmation

[0028] (1) X-ray powder diffraction detection

[0029] The X-ray powder diffraction testing instrument and testing conditions for the semisuccinic acid lasmiditan crystal form of the present application: X-ray powder diffraction instrument: PANalytical EMPYREAN; Cu-Kα; sample stage: flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv, current 40mA; divergence slit: 1 / 4°; anti-scattering slit: 1°; soller slit: 0.04 rad; step size: 0.5s; scanning range: 3-50°.

[0030] The main X-ray powder diffraction characteristic peaks of the semisuccinic acid lasmiditan crystal form are shown in Table 1.

[0031] Table 1 Main X-ray powder diffraction characteristic peaks of the semisuccinic acid lasmiditan crystal form

[0032]

[0033]

[0034] The PXRD pattern of the crystal form A reported in US8697876B2 is shown in Figure 2 For the crystal form A, note the characteristic peaks at 15.32° ± 0.1°, 16.15° ± 0.10°, 23.18° ± 0.10°, 23.39° ± 0.10°, 24.77° ± 0.10°, for the crystal form of the present application, the characteristic peaks are at 19.54 ± 0.2°, 24.02 ± 0.2°, 25.19 ± 0.2°, as the above data confirm, the crystal form of the present application can be distinguished from the crystal form A.

[0035] (2) TGA / DSC analysis

[0036] The TGA / DSC thermal analysis instrument and test conditions used for the semi-succinic acid lassirmitan crystal form are as follows: Mettler-Toledo TGA / DSC thermal analyzer (TGA / DSC3+); dynamic temperature section: 30-300℃; heating rate: 10K / min; program section gas N2; gas flow: 50ml / min; crucible: aluminum crucible 40ul.

[0037] The TGA / DSC test results of the semi-succinic acid lassirmitan crystal form are shown in the following table: Figure 3 An endothermic peak appears in the range of 59.58-113.05℃ and 154.77-188.45℃, and there is a 10wt% loss in the range of 56.75-109.47℃.

[0038] Structure confirmation:

[0039] 1 H NMR (600MHz, DMSO-d6) δ: 1.57 (d, J = 12.2 Hz, 2H), 1.84 (d, J = 12.8 Hz, 2H), 2.06 (t, J = 11.5 Hz, 2H), 2.24 (s, 3H), 2.38 (s, 2H), 2.89 (d, J = 13.3 Hz, 2H), 3.70 (s, 1H), 7.40 (dd, J = 9.5, 7.8 Hz, 2H), 7.80 (d, J = 7.6 Hz, 1H), 8.08 (t, J = 7.9 Hz, 1H), 8.40 (d, J = 8.2 Hz, 1H), 11.51 (s, 1H).

[0040] Advantages of the present application:

[0041] The present application first provides a new crystal form of semi-succinic acid lassirmitan, which has good stability, small hygroscopicity, and high solubility, which helps to improve the bioavailability of semi-succinic acid lassirmitan, improve the clinical efficacy, and has important value for the optimization and development of semi-succinic acid lassirmitan preparation. BRIEF DESCRIPTION OF DRAWINGS

[0042] Figure 1 : PXRD spectrum of semi-succinic acid lassirmitan crystal form;

[0043] Figure 2 : PXRD spectrum of crystal form A in US8697876B2;

[0044] Figure 3 : TGA / DSC graph of semi-succinic acid lassirmitan crystal form. DETAILED DESCRIPTION

[0045] The application will be further described in the following description with specific reference being made to the figures. It is to be understood that the examples of the application are merely illustrative of the application and do not limit the scope of the application. Simple modifications to the application described herein will be apparent to those skilled in the art and, where permitted, remain within the scope of the application.

[0046] The raw materials used in the application, lasmiditan and succinic acid, are commercially available.

[0047] Example 1

[0048] 3.00 g of lasmiditan and 0.75 g of succinic acid were sequentially added to a mixed solution of 5 ml of water and 40 ml of glycerol, stirred and refluxed for 4 h, cooled and crystallized at 5-10 °C for 5 h, and dried at 55 °C under reduced pressure and vacuum for 8 h to obtain the semisuccinic acid lasmiditan crystal form, with a yield of 89.7% and an HPLC purity of 99.84%.

[0049] Example 2

[0050] 3.00 g of lasmiditan and 0.66 g of succinic acid were sequentially added to a mixed solution of 5 ml of water and 25 ml of isopropanol, stirred and refluxed for 5 h, cooled and crystallized at 5-10 °C for 5 h, and dried at 50 °C under reduced pressure and vacuum for 12 h to obtain the semisuccinic acid lasmiditan crystal form, with a yield of 86.9% and an HPLC purity of 99.79%.

[0051] Example 3

[0052] 3.00 g of lasmiditan and 1.03 g of succinic acid were sequentially added to a mixed solution of 10 ml of water and 50 ml of tetrahydrofuran, stirred and refluxed for 2 h, cooled and crystallized at 0-5 °C for 6 h, and dried at 55 °C under reduced pressure and vacuum for 10 h to obtain the semisuccinic acid lasmiditan crystal form, with a yield of 85.5% and an HPLC purity of 99.80%.

[0053] Example 4

[0054] 3.00 g of lasmiditan and 0.75 g of succinic acid were sequentially added to a mixed solution of 9 ml of water and 36 ml of isopropanol, stirred and refluxed for 4 h, cooled and crystallized at 5-10 °C for 4 h, and dried at 50 °C under reduced pressure and vacuum for 8 h to obtain the semisuccinic acid lasmiditan crystal form, with a yield of 81.9% and an HPLC purity of 99.69%.

[0055] Example 5

[0056] 3.00 g of lasmiditan and 0.84 g of succinic acid were sequentially added to a mixed solution of 3 ml of water and 42 ml of glycerol, stirred and refluxed for 4 h, cooled and crystallized at 5-10 °C for 5 h, and dried at 60 °C under reduced pressure and vacuum for 8 h to obtain the semisuccinic acid lasmiditan crystal form, with a yield of 80.5% and an HPLC purity of 99.72%.

[0057] Example 6

[0058] To the mixture solution of 3 ml water and 21 ml ethanol, 3.00 g of lasmiditan, 0.75 g of succinic acid were added in sequence, stirred and refluxed for 3 h, cooled and crystallized for 6 h at 5-10 °C, and dried under reduced pressure at 50 °C for 12 h to obtain semisuccinic acid lasmiditan crystal form, with a yield of 77.6% and an HPLC purity of 99.70%.

[0059] Comparative Example 1

[0060] Referring to the method disclosed in US patent US8697876, semisuccinic acid lasmiditan crystal form A was prepared: an ethanol solution of lasmiditan free base (1.00 weight correction, about 4.5 volumes, 183 g) was added to a clean reactor through an online filter, ethanol (0.5 volumes, 0.4 weight, 91 ml) was rinsed online, 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 loaded into a second container and stirred at 20-25 °C for 40-50 minutes under a nitrogen atmosphere, and after dissolution, added to the reactor containing the ethanol solution of lasmiditan, maintained at 75-80 °C, and rinsed online with ethanol (1.0 volumes, 0.8 weight, 183 ml). Cooled to 60-63 °C, and the crystallization in the reactor was visually inspected and the crystallization temperature was recorded, and stirred for 50-60 minutes. The contents of the reaction vessel were cooled to 20-25 °C in 40-60 minutes (about 1 °C / min), stirred for 4-6 hours, the solid was collected, washed with ethanol, and dried under vacuum at 45 °C to obtain semisuccinic acid lasmiditan crystal form A with an HPLC purity of 99.45%.

[0061] Comparative Example 2

[0062] Referring to the method disclosed in patent CN2017800757507, semisuccinic acid lasmiditan dihydrate crystal form D was prepared: prepared by wet granulation using a high-shear granulator, 200 g of semisuccinic acid lasmiditan crystal form A was mixed with water in a 4 liter tank at a rate of 87% (w / v), the spray rate was 20 g*kg / min, the stirring paddle speed was 400 rpm, and the granulation time was 2 minutes, and the prepared granules were dried in a fluidized bed system (inlet air flow 60 m 3 / h, inlet air temperature 70 °C, outlet product temperature 22→34 °C, product temperature 23→50 °C) to obtain semisuccinic acid lasmiditan dihydrate crystal form D with an HPLC purity of 99.61%.

[0063] Comparative Example 3

[0064] Referring to the method disclosed in the patent CN2017800757507, the semisuccinic acid-larsamiditan crystal form trihydrate crystal form F was prepared: 913 mg of amorphous semisuccinic acid-larsamiditan was added to a glass reaction tube, cooled to 5°C and 12.5 ml of pre-cooled water was added to form a thick suspension, based on stirring (300 rpm) at 5°C for 3 days, filtered, air-dried, dried, and semisuccinic acid-larsamiditan crystal form trihydrate crystal form F was obtained, with a HPLC purity of 99.90%.

[0065] Verification of stability test of Example 1

[0066] 1. Test material: semisuccinic acid-larsamiditan crystal forms prepared in Example 1 and Comparative Examples 1-3.

[0067] 2. Test method: semisuccinic acid-larsamiditan crystal forms prepared in Example 1 and Comparative Examples 1-3 were respectively placed in light (4500 Lux), high temperature (60°C), and high humidity (RH 90%) environments, and samples were taken at 10 days and 30 days, respectively, for HPLC purity detection (%), and X-ray powder diffraction detection was performed at 30 days.

[0068] 3. Test results: the test results are shown in Table 2.

[0069] Table 2: Test results of semisuccinic acid-larsamiditan crystal form influencing factors

[0070]

[0071] From the data in Table 2, it can be seen that the semisuccinic acid-larsamiditan crystal form of the present application has good stability under light, high temperature, and high humidity conditions, with small changes in purity and no crystal form conversion.

[0072] Verification of hygroscopicity test of Example 2

[0073] 1. Test material: semisuccinic acid-larsamiditan crystal forms prepared in Example 1 and Comparative Examples 1-3.

[0074] 2. Test method: 10 mg of semisuccinic acid-larsamiditan crystal forms prepared in Example 1 and Comparative Examples 1-3 were respectively taken, and dynamic water adsorption (DVS) instrument was used to test the hygroscopicity of each. Three parallel tests were performed, and the results were averaged.

[0075] The moisture absorption characteristics are described in the following table: deliquescence: absorbs sufficient moisture to form a liquid. highly hygroscopic: moisture absorption weight gain is not less than 15%. hygroscopic: moisture absorption weight gain is less than 15% but not less than 2%. slightly hygroscopic: moisture absorption weight gain is less than 2% but not less than 0.2%. non- or almost non-hygroscopic: moisture absorption weight gain is less than 0.2%.

[0076] 3. Test results: the test results are shown in Table 3.

[0077] Table 3: hygroscopicity test results of the semisuccinic acid-larsimictan crystal form

[0078] Sample Relative moisture pick-up weight gain (%) Example 1 0.58 Comparative Example 1 5.25 Comparative Example 2 7.60 Comparative Example 3 8.95

[0079] The test results show that the semisuccinic acid-larsimictan crystal form of the present application has a weight gain of 0.58% after equilibrium at 80% humidity, and is slightly hygroscopic, which is significantly lower than the crystal forms of the comparative examples. It is found that Examples 1-6 have similar hygroscopicity test results.

[0080] Verification of the solubility test of Example 3

[0081] 1. Test materials: semisuccinic acid-larsimictan crystal forms prepared in Examples 1 and Comparative Examples 1-3.

[0082] 2. Test method: the solubility test is performed according to the relevant content of the Chinese Pharmacopoeia (2020 edition), with water and pH 6.8 phosphate buffer solution (simulating the human intestinal environment) as the dissolution medium. 900 ml of water or pH 6.8 phosphate buffer solution is weighed into a vial, and an excess of the above semisuccinic acid-larsimictan crystal form is added, and the vial is sealed and placed in a 37°C water bath for constant temperature stirring. The filtrate is filtered, diluted, and the content is detected by the HPLC detection purity method to obtain the solubility. Three parallel tests are performed, and the results are averaged.

[0083] 3. Test results: the test results are shown in Table 4.

[0084] Table 4: solubility of semisuccinic acid-larsimictan crystal form

[0085]

[0086] As shown in Table 4, the solubility of the semisuccinic acid-larsimictan crystal form of the present application in water and pH 6.8 phosphate buffer solution is significantly better than that of the crystal forms of the comparative examples.

Claims

1. A crystalline form of hemi-sesamorelin, characterized by, The crystal form has an X-ray powder diffraction pattern as shown in Figure 1 using Cu-Ka radiation.

2. The crystal form as described in claim 1, characterized in that, The crystal form has a TGA / DSC pattern as shown in Figure 3.

3. A process for preparing the semisuccinic acid larimidotan crystalline form according to any one of claims 1-2, characterized in that, The method comprises the following steps: succinic acid and lasmiditan are added into a mixed solution of water and an organic solvent in sequence, stirred and refluxed, the reaction is completed, cooled and crystallized, filtered and dried to obtain the product; the organic solvent is one or a combination of glycerol, isopropyl alcohol and tetrahydrofuran; the cooling and crystallization temperature is 0-15℃.

4. The production method according to claim 3, wherein The volume ratio of the water and the organic solvent is 1:5-10.

5. The production method according to claim 3, wherein The mass-volume ratio of the lasmiditan and the mixed solution is 1:10-20 g / ml.

6. The production method according to claim 5, wherein The mass-volume ratio of the lasmiditan and the mixed solution is 1:10-15 g / ml.

7. The production method according to claim 3, wherein The stirring and refluxing time is 2-5 h.

8. The production method according to claim 3, wherein The crystallization time is 3-6 h.

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