New crystalline forms of 5-ht1f receptor agonists and methods of making the same

Abstract

The present application belongs to the technical field of crystal form of drug molecules, and particularly relates to a new crystal form of 5-HT1F receptor agonist, i.e. hemisuccinate lasmiditan. The crystal form of hemisuccinate lasmiditan provided by the present application has characteristic peaks at 4.95±0.2°, 15.83±0.2°, 16.38±0.2°, 18.53±0.2°, 20.01±0.2° and 26.11±0.2° in an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation. The obtained crystal form has good stability, does not have crystal transformation phenomenon, is suitable for long-term storage of drug preparations, has high solubility and bioavailability, provides a new option for drug preparations, has a simple preparation process, good repeatability and is suitable for industrialized production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and particularly relates to a new crystal form of a 5-HT1F receptor agonist. BACKGROUND

[0002] Migraine is a common, periodic recurrent neurovascular disease, accompanied by moderate to severe throbbing headache during the attack, usually unilateral, or bilateral alternately or involving bilateral, accompanied by some autonomic symptoms, such as fear, nausea, vomiting, photophobia, etc., with long duration, prolonged illness, and difficult to cure. Migraine has a great impact on the quality of life. In 2001, WHO published a report on common diseases according to the health life loss year, and migraine ranked in the top 20, and severe migraine was defined as the most disabling disease, similar to dementia, paralysis and severe mental illness.

[0003] The effective component of a new drug for treating acute migraine is Lasmiditan, which is temporarily translated as Lasmiditan, and also translated as Lasmiditan, Lasmiditan, Lasmiditan, Lasmiditan, Lasmiditan and Lasmiditan. Code COL-144 and LY573144. The English name is 2,4,6-trifluoro-N-[6-(1-methylpiperidine-4-carbonyl)pyridin-2-yl]benzamide, and the Chinese name is 2,4,6-trifluoro-N-[6-[(1-methyl-4-piperidyl) carbonyl]-2-pyridyl] benzamide. According to the research results of cloning human 5-hydroxytryptamine 1F subtype (5-HT1F) receptor of Synaptic Biopharmaceutical Company of the United States, Lasmiditan was first successfully developed by Eli Lilly Company in March 2003. In December 2005, Eli Lilly Company signed an agreement with CoLucid Pharmaceutical Company, granting the company exclusive development license worldwide. In October 2013, CoLucid Company signed an agreement with Yedong Pharmaceutical Company of South Korea, granting the company sales and operation rights in South Korea and Southeast Asia. In February 2015, Eli Lilly Company and CoLucid Pharmaceutical Company signed a revised agreement, Eli Lilly Company has or retains the exclusive right to research Lasmiditan, and in March 2017, Eli Lilly Company completed the acquisition of CoLucid Pharmaceutical Company, which became its wholly-owned subsidiary.

[0004] Eli Lilly Company submitted a new drug application to the US Food and Drug Administration (FDA) on November 14, 2018, and was approved for marketing on October 11, 2019. The trade name of Lasmiditan hemisuccinate tablets (hereinafter referred to as Lasmiditan tablets) is Lasmiditan is an orally, centrally penetrant, selective, 5-HT1F agonist with a mechanism of action that is different from the triptans currently approved for the treatment of migraine, and does not have vasoconstrictor effects, making it safer for migraine patients with or at risk for cardiovascular disease, and the only approved acute treatment for adult migraine in 20 years.

[0005] CN100352817C discloses lasmiditan, lasmiditan hemisuccinate and hydrochloride and a preparation method thereof, and also discloses their mass spectrum, 1H-NMR, 13C-NMR and melting point characterization data, according to the reports in the existing literature, amorphous lasmiditan is prepared. US20190233393 discloses crystal forms A, B, C, F, G of lasmiditan Form 1, Form 2, Form 3 and lasmiditan hydrochloride, wherein the crystal forms A, B, C of lasmiditan Form 1, Form 2, Form 3 and lasmiditan hydrochloride have good solid state stability and chemical stability within 10 days. For lasmiditan hemisuccinate, US8697876B2 discloses crystal forms A, B, C, amorphous and pharmaceutical compositions of crystal form A of lasmiditan hemisuccinate, wherein crystal form C is only observed by naked eye without any change after 2 days and 3 days of storage at 75% RH; CN201780075750 discloses crystal form D (dihydrate), crystal form F (trihydrate), crystal form E (dehydrated hydrate of crystal form D) of lasmiditan hemisuccinate and a preparation method thereof, crystal form D can be prepared by wet granulation starting from crystal form A, crystal form A is stored at 25 DEG 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; Indian patent IN201941034052 discloses crystal form A, amorphous and solid dispersions of lasmiditan hemisuccinate.

[0006] In view of the above-mentioned technical problems that the system research on the crystal forms of lasmiditan reported in the literature is not perfect, and the stability of the existing crystal forms needs to be improved, it is an urgent problem for those skilled in the art to provide a new crystal form of lasmiditan hemisuccinate with good solubility, stability and high bioavailability. SUMMARY

[0007] In order to overcome the shortcomings of the prior art, the present application provides a new crystal form of 5-HT1F receptor agonist, i.e. 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] In one aspect, the present application provides a crystalline form of 5-HT1F receptor agonist, i.e. lasmiditan hemisuccinate, having an X-ray diffraction pattern, expressed in terms of 2-theta, using Cu-K alpha radiation, with characteristic peaks at 4.95±0.2°, 15.83±0.2°, 16.38±0.2°, 18.53±0.2°, 20.01±0.2°, 26.11±0.2°.

[0010] Preferably, the crystalline form has an X-ray diffraction pattern, expressed in terms of 2-theta, using Cu-K alpha radiation, with characteristic peaks at 4.95±0.2°, 9.89±0.2°, 13.54±0.2°, 15.83±0.2°, 16.38±0.2°, 17.71±0.2°, 18.53±0.2°, 19.39±0.2°, 20.02±0.2°, 23.76±0.2°, 26.11±0.2°.

[0011] Preferably, the crystalline form has Figure 1 the X-ray powder diffraction pattern shown.

[0012] Preferably, the crystalline form has Figure 2 the TGA / DSC pattern shown.

[0013] In another aspect, the present application provides a method for preparing the crystalline form of lasmiditan hemisuccinate, comprising the following steps: adding lasmiditan and succinic acid into a mixed solution of xylene and a second organic solvent, respectively, stirring at an elevated temperature, cooling and crystallizing, filtering, collecting the solid, and drying.

[0014] Preferably, the second organic solvent is selected from one of dichloromethane and ethanol.

[0015] Preferably, the volume ratio of xylene to the second organic solvent is 1:0.2-1.

[0016] Preferably, the molar ratio of lasmiditan to succinic acid is 1:0.5-1.0, and further preferably 1:0.7.

[0017] Preferably, the ratio of lasmiditan to xylene is 1:2-8, g / ml.

[0018] Preferably, the stirring temperature is 30-40℃.

[0019] Preferably, the stirring time is 1-2h.

[0020] Preferably, the cooling rate is 0.2-1℃ / min, and further preferably 0.5℃ / min.

[0021] Preferably, the crystallization temperature is 0-5℃.

[0022] Preferably, the crystallization time is 1-2h.

[0023] Preferably, the drying is vacuum drying at 50-60℃.

[0024] Preferably, the drying time is 12-16h.

[0025] In another aspect, the present application also provides a pharmaceutical composition comprising the crystalline form of lasmiditan hemisuccinate and a pharmaceutically acceptable excipient. The crystalline form can be in a therapeutically effective amount. The pharmaceutically acceptable excipient can be an excipient well known in the art, including but not limited to diluents, binders, disintegrants, lubricants, glidants, release rate controlling agents, plasticizers, preservatives, antioxidants, etc. in the case of solid formulations.

[0026] The pharmaceutical composition can be in a dosage form suitable for human consumption, such as tablets, capsules, granules, powders, or pills, preferably tablets, capsules, granules, disintegrating tablets, sustained-release or controlled-release tablets.

[0027] The pharmaceutical composition of the present application can be prepared by methods well known in the art by mixing a therapeutically effective amount of the crystalline form with various pharmaceutical excipients to form a dosage form suitable for human consumption, such as tablets, capsules, granules, which can be prepared by mixing, granulating, pelletizing, tabletting, or filling capsules.

[0028] Crystal structure confirmation

[0029] (1) X-ray powder diffraction detection

[0030] The X-ray powder diffraction testing instrument and testing conditions for the crystalline form of the present application: X-ray powder diffractometer: PANalytical EMPYREAN; Cu-Kα; sample stage: flat plate; incident light path: BBHD; diffracted light path: PLXCEL; voltage 45kv, current 40mA; divergence slit: 1 / 4°; anti-scattering slit: 1°; soller slit: 0.04 rad; step size: 0.5s; scan range: 3-50°.

[0031] The main X-ray powder diffraction characteristic peaks of the crystalline form of lasmiditan hemisuccinate are shown in Table 1.

[0032] Table 1 Main X-ray powder diffraction characteristic peaks of the crystalline form of lasmiditan hemisuccinate

[0033]

[0034]

[0035] (2) TGA / DSC analysis

[0036] The TGA / DSC thermal analysis instrument and test conditions of the crystal form of the application 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 crystal form of the application are shown in Figure 2 .

[0038] Structure confirmation:

[0039] 1 H NMR (600 MHz, DMSO-d6) δ: 1.56 (d, J = 12.1 Hz, 2H), 1.89 (d, J = 12.6 Hz, 2H), 2.10 (t, J = 10.9 Hz, 2H), 2.24 (s, 3H), 2.38 (s, 2H), 2.89 (d, J = 13.1 Hz, 2H), 3.70 (s, 1H), 7.42 (dd, J = 9.4, 7.7 Hz, 2H), 7.79 (d, J = 7.7 Hz, 1H), 8.10 (t, J = 8.0 Hz, 1H), 8.39 (d, J = 8.2 Hz, 1H), 11.46 (s, 1H).

[0040] The application provides a new semisuccinic acid lasmiditan crystal form, which has good stability, does not have a crystal transformation phenomenon, is suitable for long-term storage of a drug preparation, has high solubility and bioavailability, and provides a new selection for a drug preparation, has a simple preparation process, good repeatability, and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0041] Figure 1 : PXRD spectrum of the semisuccinic acid lasmiditan crystal form;

[0042] Figure 2 : TGA / DSC graph of the semisuccinic acid lasmiditan crystal form. DETAILED DESCRIPTION

[0043] The application is further described below through the description of specific embodiments, and it should be correctly understood that: the embodiments of the application are only used to illustrate the application, and are not a limitation on the application. Therefore, simple improvements on the method of the application are all within the protection scope of the application.

[0044] Example 1

[0045] 3.00 g of rasmiditan and 0.66 g of succinic acid were added to a mixed solution of xylene and 9 ml of dichloromethane. The solution was heated to 35 °C and stirred for 1 h. The temperature was then lowered to 0–5 °C at a rate of 0.5 °C / min, and crystallization was allowed to occur for 1.5 h. The solution was filtered, and the filter cake was dried under reduced pressure at 50–60 °C for 12 h to obtain the crystalline form of hemisuccinic acid rasmiditan, with a yield of 90.42% and an HPLC purity of 99.79%.

[0046] Example 2

[0047] 3.00 g of rasmiditan and 0.47 g of succinic acid were added to a mixed solution of xylene and dichloromethane in 6 ml. The solution was heated to 30 °C and stirred for 1.5 h. The solution was then cooled to 0–5 °C at a rate of 1 °C / min and allowed to crystallize for 1.5 h. The solution was filtered, and the filter cake was dried under reduced pressure at 50–60 °C for 12 h to obtain the crystalline form of rasmiditan hemisuccinate, with a yield of 87.51% and an HPLC purity of 99.75%.

[0048] Example 3

[0049] 3.00 g of lasmidetane and 0.94 g of succinic acid were added to a mixed solution of 24 ml xylene and 5 ml ethanol. The solution was heated to 40 °C and stirred for 2 h. The solution was then cooled to 0–5 °C at a rate of 0.2 °C / min and allowed to crystallize for 2 h. The solution was filtered, and the filter cake was dried under reduced pressure at 50–60 °C for 16 h to obtain the crystalline form of hemisuccinic acid lasmidetane, with a yield of 86.42% and an HPLC purity of 99.73%.

[0050] Example 4

[0051] 3.00 g of rasmiditan and 0.75 g of succinic acid were added to a mixed solution of 9 ml xylene and 6 ml dichloromethane. The solution was heated to 35 °C and stirred for 1.5 h. The temperature was then lowered to 0–5 °C at a rate of 0.8 °C / min, and crystallization was allowed to occur for 1.5 h. The solution was filtered, and the filter cake was dried under reduced pressure at 50–60 °C for 14 h to obtain the crystalline form of hemisuccinic acid rasmiditan, with a yield of 89.01% and an HPLC purity of 99.76%.

[0052] Example 5

[0053] 3.00 g of lasmidetane and 0.66 g of succinic acid were added to a mixed solution of 15 ml xylene and 6 ml ethanol. The solution was heated to 40 °C and stirred for 2 h. The solution was then cooled to 0–5 °C at a rate of 2 °C / min and allowed to crystallize for 2 h. The solution was filtered, and the filter cake was dried under reduced pressure at 50–60 °C for 12 h to obtain the crystalline form of hemisuccinic acid lasmidetane, with a yield of 74.58% and an HPLC purity of 99.31%.

[0054] Example 6

[0055] Add 3.00 g of lasmiditan, 0.84 g of succinic acid into 18 ml of a mixed solution of xylene and 7 ml of ethanol, heat to 50 °C, stir for 1.5 h, cool to 0-5 °C at 0.5 °C / min, crystallize for 1.5 h, filter, and the filter cake is dried under reduced pressure at 50-60 °C for 12 h to obtain semisuccinic acid lasmiditan crystal form, with a yield of 80.47% and an HPLC purity of 99.70%.

[0056] Example 7

[0057] Add 3.00 g of lasmiditan, 0.66 g of succinic acid into 30 ml of a mixed solution of xylene and 6 ml of dichloromethane, heat to 35 °C, stir for 1 h, cool to 0-5 °C at 0.5 °C / min, crystallize for 2 h, filter, and the filter cake is dried under reduced pressure at 50-60 °C for 16 h to obtain semisuccinic acid lasmiditan crystal form, with a yield of 83.82% and an HPLC purity of 99.64%.

[0058] Comparative Example 1

[0059] Referring to the method disclosed in US8697876, semisuccinic acid lasmiditan crystal form A is prepared: an ethanol solution (1.00 weight correction, about 4.5 volumes, 183 g) of lasmiditan free base is added to a clean reactor through an online filter, ethanol (0.5 volumes, 0.4 weight, 91 ml) is online rinsed, 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) are 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, visually inspected for crystallization in the reactor and recorded the crystallization temperature, and stirred for 50-60 minutes. The contents of the reaction vessel are cooled to 20-25 °C in 40-60 minutes (about 1 °C / min), stirred for 4-6 hours, the solid is 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%.

[0060] Comparative Example 2

[0061] Referring to the method disclosed in patent CN2017800757507, semisuccinic acid lasmiditan dihydrate crystal form D is prepared: prepared by wet granulation using a high-shear granulator, 200 g of semisuccinic acid lasmiditan crystal form A is mixed with water in a 4 liter tank at a rate of 87% (w / v), the spray rate is 20 g*kg / min, the stirring paddle speed is 400 rpm, and the granulation time is 2 minutes, and the prepared granules are dried in a fluidized bed system (inlet air amount 60 m3 / h, inlet temperature 70°C, outlet product temperature 22→34°C, product temperature 23→50°C) to obtain semi-succinic acid ramucirumab dihydrate Form D with HPLC purity of 99.61%.

[0062] Comparative Example 3

[0063] Referring to the method disclosed in the patent CN2017800757507, semi-succinic acid ramucirumab Form F trihydrate was prepared: 913 mg of amorphous semi-succinic acid ramucirumab 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, and stirring (300 rpm) was continued at 5°C for 3 days, filtered, air-dried, and dried to obtain semi-succinic acid ramucirumab Form F trihydrate with HPLC purity of 99.90%.

[0064] Verification Example 1 Physical Stability Test

[0065] 1. Test material: semi-succinic acid ramucirumab crystal forms prepared in Example 1 and Comparative Examples 1-3.

[0066] 2. Test method: 20 mg of each semi-succinic acid ramucirumab crystal form was respectively placed in a glass vial, and the vial was placed in a constant temperature and humidity chamber at 40°C / 75% relative humidity without a cap. At 7 days, 14 days, 30 days, 45 days, and 60 days, XRPD sampling was performed, and the above XRPD method was used for identification test to test the physical stability.

[0067] 3. Test results: see Table 2.

[0068] Table 2 Physical stability test results of semi-succinic acid ramucirumab crystal forms

[0069]

[0070] Note: NA is not detected.

[0071] The semi-succinic acid ramucirumab crystal form provided by the present application does not undergo crystal form conversion after being stored at 40°C / 75% relative humidity for 60 days, which proves that the crystal form has excellent physical stability.

[0072] Verification Example 2 Solubility Test

[0073] 1. Test material: semi-succinic acid ramucirumab crystal forms prepared in Example 1 and Comparative Examples 1-3.

[0074] 2. Test method: solubility test refers to the relevant contents of Chinese Pharmacopoeia (2020 edition), with water, pH = 6.8 phosphate buffer solution (simulating human intestinal environment) as the dissolution medium. 900ml water or pH 6.8 phosphate buffer solution was taken in a vial, and an excess of the above semisuccinic acid larsamiditan crystal form was added, and the vial was sealed and placed in a 37℃ water bath constant temperature stirring, filtered with filter membrane, diluted with filter liquid, and the content was detected by HPLC detection purity method, and the solubility was obtained. Three parallel tests were carried out, and the results were averaged.

[0075] 3. Test results: the test results are shown in Table 3.

[0076] Table 3 Solubility of semisuccinic acid larsamiditan crystal form

[0077]

[0078] Bioavailability test of verification example 3

[0079] 1. Test material: semisuccinic acid larsamiditan crystal form prepared in example 1, comparative examples 1-3.

[0080] 2. Test method: 20 healthy SD rats, half male and half female, weighing 200-240g, were randomly divided into 4 groups, and fasted for 12 hours before administration, and free water. The above semisuccinic acid larsamiditan crystal form 10mg / kg was given by gavage (preparation solution) respectively; 10min, 20min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 8h, 12h, 24h after administration, 300ul of blood was taken from the rat from the fundus plexus, and placed in a heparinized test tube, and analyzed by LC-MS / MS.

[0081] 3. Test results: the test results are shown in Table 4.

[0082] Table 4 Pharmacokinetic test results of semisuccinic acid larsamiditan crystal form

[0083]

[0084] From the data of table 3 and table 4, it can be seen that the solubility and bioavailability of the semisuccinic acid larsamiditan crystal form prepared by the present application are high, which is better than the existing crystal form, and can better meet the requirements of drug preparation, and provide a better basis for its application in drug treatment.

Claims

1. A novel crystalline form of lasmidetane hemisuccinate, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, has characteristic peaks at 4.95±0.2°, 15.83±0.2°, 16.38±0.2°, 18.53±0.2°, 20.01±0.2°, and 26.11±0.2°.

2. The crystal form as described in claim 1, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, shows characteristic peaks at 4.95±0.2°, 9.89±0.2°, 13.54±0.2°, 15.83±0.2°, 16.38±0.2°, 17.71±0.2°, 18.53±0.2°, 19.39±0.2°, 20.02±0.2°, 23.76±0.2°, and 26.11±0.2°.

3. The crystal form as described in claim 1, characterized in that, The crystal form has an X-ray powder diffraction pattern as shown in Figure 1.

4. A method for preparing the crystal form according to any one of claims 1-3, characterized in that, Includes the following steps: Rasmiditan and succinic acid were added sequentially to a mixed solution of xylene and a second organic solvent. The mixture was heated and stirred, then cooled to allow crystals to precipitate. The crystals were filtered, the solid was collected, and dried to obtain the final product. The second organic solvent was selected from dichloromethane and ethanol.

5. The preparation method according to claim 4, characterized in that, The volume ratio of xylene to the second organic solvent is 1:0.2~1.

6. The preparation method according to claim 4, characterized in that, The molar ratio of raspirin to succinic acid is 1:0.5~1.0; the molar ratio of raspirin to xylene is 1:2~8, g / ml.

7. The preparation method according to claim 4, characterized in that, The heating and stirring temperature is 30~40℃.

8. The preparation method according to claim 4, characterized in that, The cooling rate is 0.2~1℃ / min.

9. The preparation method according to claim 8, characterized in that, The cooling rate is 0.5℃ / min.

10. The preparation method according to claim 4, characterized in that, The crystallization temperature is 0~5℃.

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