A semisuccinic acid larimidotan crystalline form and a process for its preparation

Abstract

The application belongs to the technical field of crystal form drug molecules, and particularly relates to a semisuccinic acid lasmiditan crystal form and a preparation method thereof. The semisuccinic acid lasmiditan crystal form provided by the application has characteristic peaks at 4.96+ / -0.2°, 9.91+ / -0.2°, 18.48+ / -0.2°, 19.87+ / -0.2° and 21.05+ / -0.2° in an X-ray diffraction spectrum expressed in 2θ using Cu-Kα radiation, and has excellent crystal form physical and chemical properties, high purity, good stability, high solubility, high bioavailability, helps to improve clinical efficacy, and has a simple and efficient preparation method and is suitable for industrialized production.

Description

TECHNICAL FIELD

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

[0002] Larimide, 2,4,6-trifluoro-N-[6-(1-methyl-piperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide, is a selective and highly effective 5-HT-1F receptor agonist for treating migraine, and the molecular formula is C 19 H 18 F3N3O2, CAS: 439239-90-4, and the structural formula is as follows:

[0003]

[0004] Larimide was first developed by Eli Lilly in March 2003, and a new drug marketing application was submitted to the US Food and Drug Administration (FDA) on November 14, 2018. It was approved for marketing on October 11, 2019, and the active ingredient is semisuccinic acid larimide, tablet, and the trade name is Its mechanism of action is different from the current new type of drug for treating migraine “dant”, and it does not have a vasoconstrictive effect. It is safer for migraine patients with cardiovascular disease or at risk of cardiovascular disease, and is the only drug approved for the treatment of acute migraine in adults in the past 20 years. The structural formula of semisuccinic acid larimide is as follows:

[0005]

[0006] In recent years, it has been found that different crystal forms of drugs have different physicochemical properties (density, hardness, solubility, stability, optical and electrical properties, etc.), dissolution rates, biological effects, and the like. Therefore, research on drug crystal forms has important practical value in medicine. Crystal drug molecules include polymorphs, hydrates, solvates and salts of drug molecules, etc. Through the crystallization of drugs, not only the crystallographic parameters of crystal drug molecules can be determined, but also the types and numbers of solvent molecules (such as crystallization water molecules) in the crystal can be determined. This is very important for understanding and mastering the spatial arrangement of drug molecules and physicochemical properties.

[0007] Patent US8697876 discloses crystal form A, B, C, amorphous and pharmaceutical composition of crystal form A of lassoside, 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 lassoside and its preparation method, crystal form D can be prepared by wet granulation method starting from crystal form A, crystal form A is stored at 25℃ and 96% relative humidity (RH), wherein crystal form E is a metastable form, crystal forms D and F are not completely stable at low relative humidity and are prone to crystallization; Indian patent IN201941034052 discloses crystal form A, amorphous and solid dispersion of lassoside.

[0008] The above reports are not comprehensive enough for the physicochemical properties of the crystal form of lassoside, and its solubility, stability and other aspects cannot meet the requirements of pharmaceutical preparations, so more crystal forms of lassoside are needed for drug application. SUMMARY

[0009] In order to overcome the shortcomings of the prior art, the present application provides a crystal form of lassoside and a preparation method thereof, which has good stability, high solubility and high bioavailability.

[0010] The specific technical content of the present application is as follows:

[0011] In the first aspect of the present application, a crystal form of lassoside is provided, which has characteristic peaks at 4.96±0.2°, 9.91±0.2°, 18.48±0.2°, 19.87±0.2°, 21.05±0.2° in the X-ray diffraction spectrum expressed by 2θ using Cu-Kα radiation.

[0012] Preferably, the crystal form of lassoside has characteristic peaks at 4.96±0.2°, 9.91±0.2°, 10.70±0.2°, 15.84±0.2°, 17.71±0.2°, 17.95±0.2°, 18.48±0.2°, 19.87±0.2°, 21.05±0.2°, 26.03±0.2° in the X-ray diffraction spectrum expressed by 2θ using Cu-Kα radiation.

[0013] Preferably, the semi-succinic acid larimidotan crystal form has an X-ray powder diffraction pattern as shown in Figure 1.

[0014] Preferably, the semi-succinic acid larimidotan crystal form has an X-ray powder diffraction pattern as shown in Figure 1. Figure 1 Preferably, the semi-succinic acid larimidotan crystal form has an X-ray powder diffraction pattern as shown in Figure 1.

[0015] Preferably, the semi-succinic acid larimidotan crystal form has a TGA / DSC pattern as shown in Figure 2. Figure 2 Preferably, the semi-succinic acid larimidotan crystal form has a TGA / DSC pattern as shown in Figure 2.

[0016] In the second aspect of the present application, a preparation method of the semi-succinic acid larimidotan crystal form is provided, which specifically comprises the following steps: adding larimidotan into an organic solvent, stirring, and reserving; then adding succinic acid into the same organic solvent, stirring under heating, adding the above-mentioned larimidotan organic solvent mixture after complete dissolution, continuing the reaction under heating, stirring under cooling, crystallizing, filtering, and drying, to obtain the semi-succinic acid larimidotan crystal form.

[0017] The organic solvent is one or a combination of n-hexane, methanol, and acetonitrile.

[0018] Preferably, the organic solvent is n-hexane.

[0019] The molar ratio of the amount of the larimidotan to the amount of the succinic acid is 1:0.6-1.

[0020] Preferably, the molar ratio of the amount of the larimidotan to the amount of the succinic acid is 1:0.8.

[0021] The reaction temperature is 40-55℃.

[0022] Preferably, the reaction temperature is 45-50℃.

[0023] The crystallization temperature is 0-10℃.

[0024] Preferably, the crystallization temperature is 5-10℃.

[0025] The ratio of the amount of the larimidotan to the amount of the organic solvent in the mixture is 1:8-15, g / mL.

[0026] Preferably, the ratio of the amount of lasmiditan and the organic solvent in the mixture is 1:12, g / mL.

[0027] The ratio of the amount of succinic acid and the organic solvent for dissolving succinic acid is 1:15-20, g / mL.

[0028] Preferably, the ratio of the amount of succinic acid and the organic solvent for dissolving succinic acid is 1:18, g / mL.

[0029] The heat preservation reaction time is 0.5-2 h.

[0030] In a third aspect of the present application, there is provided the use of the hemi-succinate lasmiditan crystal form as an active ingredient in the preparation of a drug for treating acute migraine.

[0031] In a fourth aspect of the present application, there is provided a pharmaceutical composition comprising the hemi-succinate lasmiditan crystal form and pharmaceutically acceptable other components.

[0032] The preparation method of the pharmaceutical composition is to use standard and conventional techniques to combine the hemi-succinate lasmiditan crystal form of the present application with pharmaceutically acceptable solid or liquid carriers, and optionally with pharmaceutically acceptable adjuvants and excipients to prepare a usable dosage form.

[0033] Preferably, the dosage form of the pharmaceutical composition includes but is not limited to tablets, capsules, granules, pills, injections, and patches, etc.

[0034] Crystal structure confirmation

[0035] (1) X-ray powder diffraction detection

[0036] The X-ray powder diffraction testing instrument and testing conditions for the hemi-succinate lasmiditan crystal form of the present application are as follows: X-ray powder diffractometer: 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°.

[0037] The main X-ray powder diffraction characteristic peaks of the hemi-succinate lasmiditan crystal form are shown in Table 1.

[0038] Table 1 Main X-ray powder diffraction characteristic peaks of the hemi-succinate lasmiditan crystal form

[0039]

[0040]

[0041] (2) TGA / DSC analysis

[0042] The TGA / DSC thermal analysis instrument and test conditions of the semi-succinic acid lasmiditan crystal form of the present application are as follows: Mettler Toledo TGA / DSC thermal analyzer (TGA / DSC3+); dynamic temperature section: 30-400℃; heating rate: 10K / min; program section gas N2; gas flow: 50ml / min; crucible: aluminum crucible 40ul.

[0043] The TGA / DSC test results of the semi-succinic acid lasmiditan crystal form of the present application are shown in Figure 2 .

[0044] Structure confirmation:

[0045]

[0046] The high-resolution mass spectrum and hydrogen spectrum of the semi-succinic acid lasmiditan crystal form of the present application are shown in Figure 3 , Figure 4 .

[0047] The present application has the following beneficial effects: the semi-succinic acid lasmiditan crystal form of the present application has good stability, high bioavailability, is suitable for the manufacture of pharmaceutical preparations and long-term storage; and the preparation process is simple, has good repeatability, and is suitable for industrial production. BRIEF DESCRIPTION OF DRAWINGS

[0048] Figure 1 : PXRD spectrum of semi-succinic acid lasmiditan crystal form;

[0049] Figure 2 : TGA / DSC graph of semi-succinic acid lasmiditan crystal form;

[0050] Figure 3 : High-resolution mass spectrum of semi-succinic acid lasmiditan crystal form;

[0051] Figure 4 : Hydrogen spectrum of semi-succinic acid lasmiditan crystal form. DETAILED DESCRIPTION

[0052] The present application will be further described below through the description of specific embodiments, and it should be correctly understood that: the embodiments of the present application are only used to illustrate the present application, and are not a limitation of the present application. Therefore, simple improvements of the present application under the premise of the method of the present application are within the scope of the present application.

[0053] Example 1

[0054] Stir 3.77 g (10 mmol) of ramucirumab in 45 ml of n-hexane to obtain a ramucirumab n-hexane mixture, which is ready for use; then stir 0.94 g (8 mmol) of succinic acid in 17 ml of n-hexane at 45-50 °C until completely dissolved, and then add the above-mentioned ramucirumab n-hexane mixture, continue to react for 1 h, and then stir at 5-10 °C until crystals are precipitated. After the precipitation is completed, perform suction filtration, and then dry the filter cake under reduced pressure and vacuum to obtain semi-succinic acid ramucirumab crystal form, with a yield of 96.1% and a purity of 99.89%.

[0055] Example 2

[0056] Stir 3.77 g (10 mmol) of ramucirumab in 30 ml of n-hexane to obtain a ramucirumab n-hexane mixture, which is ready for use; then stir 0.71 g (6 mmol) of succinic acid in 14 ml of n-hexane at 40-45 °C until completely dissolved, and then add the above-mentioned ramucirumab n-hexane mixture, continue to react for 1 h, and then stir at 5-10 °C until crystals are precipitated. After the precipitation is completed, perform suction filtration, and then dry the filter cake under reduced pressure and vacuum to obtain semi-succinic acid ramucirumab crystal form, with a yield of 94.9% and a purity of 99.82%.

[0057] Example 3

[0058] Stir 3.77 g (10 mmol) of ramucirumab in 57 ml of n-hexane to obtain a ramucirumab n-hexane mixture, which is ready for use; then stir 1.18 g (10 mmol) of succinic acid in 18 ml of n-hexane at 50-55 °C until completely dissolved, and then add the above-mentioned ramucirumab n-hexane mixture, continue to react for 2 h, and then stir at 0-5 °C until crystals are precipitated. After the precipitation is completed, perform suction filtration, and then dry the filter cake under reduced pressure and vacuum to obtain semi-succinic acid ramucirumab crystal form, with a yield of 93.5% and a purity of 99.81%.

[0059] Example 4

[0060] Stir 3.77 g (10 mmol) of ramucirumab in 38 ml of n-hexane to obtain a ramucirumab n-hexane mixture, which is ready for use; then stir 1.06 g (9 mmol) of succinic acid in 17 ml of n-hexane at 45-50 °C until completely dissolved, and then add the above-mentioned ramucirumab n-hexane mixture, continue to react for 0.5 h, and then stir at 5-10 °C until crystals are precipitated. After the precipitation is completed, perform suction filtration, and then dry the filter cake under reduced pressure and vacuum to obtain semi-succinic acid ramucirumab crystal form, with a yield of 95.6% and a purity of 99.85%.

[0061] Example 5

[0062] The 3.77 g (10 mmol) of ramucirumab was added to 23 ml of acetonitrile and stirred to obtain a ramucirumab-acetonitrile mixture, which was prepared for use; then 1.18 g (10 mmol) of succinic acid was added to 12 ml of acetonitrile and stirred at 45-50°C until completely dissolved, and then the above-mentioned ramucirumab-acetonitrile mixture was added, and the reaction was continued for 1 h at 45-50°C, and then the mixture was stirred at 5-10°C until crystals were precipitated, and then the mixture was filtered, and the filter cake was dried under reduced pressure to obtain the semi-succinic acid ramucirumab crystal form, with a yield of 90.4% and a purity of 99.65%.

[0063] Example 6

[0064] The 3.77 g (10 mmol) of ramucirumab was added to 23 ml of acetonitrile and stirred to obtain a ramucirumab-acetonitrile mixture, which was prepared for use; then 1.18 g (10 mmol) of succinic acid was added to 12 ml of acetonitrile and stirred at 45-50°C until completely dissolved, and then the above-mentioned ramucirumab-acetonitrile mixture was added, and the reaction was continued for 1 h at 45-50°C, and then the mixture was stirred at 5-10°C until crystals were precipitated, and then the mixture was filtered, and the filter cake was dried under reduced pressure to obtain the semi-succinic acid ramucirumab crystal form, with a yield of 90.4% and a purity of 99.65%.

[0065] Example 7

[0066] The 3.77 g (10 mmol) of ramucirumab was added to 45 ml of n-hexane and stirred to obtain a ramucirumab-n-hexane mixture, which was prepared for use; then 0.94 g (8 mmol) of succinic acid was added to 17 ml of n-hexane and stirred at 60-65°C until completely dissolved, and then the above-mentioned ramucirumab-n-hexane mixture was added, and the reaction was continued for 0.5 h at 60-65°C, and then the mixture was stirred at 5-10°C until crystals were precipitated, and then the mixture was filtered, and the filter cake was dried under reduced pressure to obtain the semi-succinic acid ramucirumab crystal form, with a yield of 87.2% and a purity of 99.73%.

[0067] Example 8

[0068] The 3.77 g (10 mmol) of ramucirumab was added to 45 ml of n-hexane and stirred to obtain a ramucirumab-n-hexane mixture, which was prepared for use; then 0.94 g (8 mmol) of succinic acid was added to 17 ml of n-hexane and stirred at 60-65°C until completely dissolved, and then the above-mentioned ramucirumab-n-hexane mixture was added, and the reaction was continued for 0.5 h at 60-65°C, and then the mixture was stirred at 5-10°C until crystals were precipitated, and then the mixture was filtered, and the filter cake was dried under reduced pressure to obtain the semi-succinic acid ramucirumab crystal form, with a yield of 87.2% and a purity of 99.73%. Figure 1 The X-ray powder diffraction pattern shown in the above-mentioned semi-succinic acid ramucirumab crystal form could not be obtained.

[0069] Comparative Example 1

[0070] Reference is made to the method disclosed in US Patent No. 8697876 for the preparation of Lasmiditan hemisuccinate Form A: An ethanol solution of Lasmiditan free base (1.00 parts by weight, about 4.5 volumes, 183 g) was charged into a clean reactor through an in-line filter, ethanol (0.5 volumes, 0.4 parts by weight, 91 mL) was flushed in-line and then heated to 75-80 °C under nitrogen atmosphere. Succinic acid (0.16 parts, 0.53 parts, 29.3 g) and ethanol (3.0 parts, 2.4 parts, 550 mL) were charged into a second vessel and stirred at 20-25 °C for 40-50 minutes under nitrogen atmosphere, dissolved and charged into the reactor containing the Lasmiditan ethanol solution maintaining 75-80 °C, flushed in-line with ethanol (1.0 volumes, 0.8 parts by weight, 183 mL). Cooled to 60-63 °C, checked the crystallization visually and recorded the crystallization temperature, stirred for 50-60 minutes. The reactor contents were cooled to 20-25 °C in 40-60 minutes (about 1 °C / minute), stirred for 4-6 hours, the solid was collected, washed with ethanol, dried under vacuum at 45 °C to get Lasmiditan hemisuccinate Form A with HPLC purity 99.45%.

[0071] Comparative Example 2

[0072] Reference is made to the method disclosed in US Patent No. 8697876 for the preparation of Lasmiditan hemisuccinate Form B: Lasmiditan hemisuccinate Form A (41.1 mg) was charged into 0.7 mL of water, stirred at 55 °C to get a light yellow clear solution, the solution was then filtered through a warm 0.2 pm nylon filter into a warm vial, the vial was capped and allowed to cool slowly to room temperature by turning off the heating mantle, sealed with parafilm and wrapped with aluminum foil to avoid exposure to light, the clear solution was still retained after 3 days of storage at room temperature. The vial wall was scratched with a sharp needle to promote nucleation, the vial containing the solution was sealed with parafilm, wrapped with aluminum foil and placed in a refrigerator at about 2 °C, stored for 3 weeks, filtered, air dried to get Lasmiditan hemisuccinate Form B with HPLC purity 99.87%.

[0073] Comparative Example 3

[0074] Reference is made to the method disclosed in US Patent No. 8697876 for the preparation of Lasmiditan hemisuccinate Form C: Amorphous Lasmiditan hemisuccinate was kept in a sealed environment at 25 °C, 75% RH for 1 day, wrapped with aluminum foil to avoid exposure to light, dried to get Lasmiditan hemisuccinate Form C with HPLC purity 99.70%.

[0075] Comparative Example 4

[0076] Reference to the method disclosed in patent CN2017800757507, prepare semi-succinic acid lassirmitan dihydrate crystal form D: by using high shear granulator wet granulation method, in 4 liter tank 200 grams of semi-succinic acid lassirmitan crystal form A is mixed with 87% (w / v) amount of water, spray rate 20g*kg / min, stirring paddle speed 400rpm, granulation time 2 minutes, the prepared granules are dried in a fluidized bed system (inlet air quantity 60m 3 / h, inlet air temperature 70℃, outlet product temperature 22→34℃, product temperature 23→50℃), semi-succinic acid lassirmitan dihydrate crystal form D is obtained, HPLC purity 99.61%.

[0077] Comparative example 5

[0078] Reference to the method disclosed in patent CN2017800757507, prepare semi-succinic acid lassirmitan crystal form trihydrate crystal form F: 913 milligrams of amorphous semi-succinic acid lassirmitan is added to a glass reaction tube, cooled to 5℃ and 12.5ml of pre-cooled water is added to form a thick suspension, continue to stir (300rpm) at 5℃ for 3 days, filter, air dry, dry, semi-succinic acid lassirmitan crystal form trihydrate crystal form F is obtained, HPLC purity 99.90%.

[0079] Stability test of verification example 1

[0080] 1. Test material: semi-succinic acid lassirmitan crystal form prepared in example 1 and comparative examples 1-5.

[0081] 2. Test method: take semi-succinic acid lassirmitan crystal form prepared in example 1 and comparative examples 1-5 respectively, place them in an environment with temperature 40℃ and humidity 75%±5% for 6 months, take samples at 1 month, 3 months and 6 months respectively, and detect total impurities (%) by HPLC. Three parallel tests are carried out, and the average value is taken.

[0082] 3. Test results: see table 2.

[0083] Table 2: results of semi-succinic acid lassirmitan crystal form solid state stability test

[0084]

[0085] From table 2, it can be seen that the semi-succinic acid lassirmitan crystal form of the application has good stability after 6 months of accelerated testing, and the purity changes little. It is found that examples 1-7 have similar stability test results.

[0086] Solubility test of verification example 2

[0087] 1. Test material: semi-succinic acid lassirmitan crystal form prepared in example 1 and comparative examples 1-5.

[0088] 2. Test method: solubility test refers to the relevant content of Chinese Pharmacopoeia (2020 edition). 900 ml of water was taken in a vial, and an excess of the above semi-succinic acid larsamiditan crystal form was added, the vial was sealed and placed in a 37℃ water bath constant temperature stirring for 1 hour, filtered through 0.2 μm filter membrane, the filtrate was diluted, the content was detected by HPLC detection purity method, and the solubility was obtained. Three parallel tests were carried out, and the average value was taken.

[0089] 3. Test results: the test results are shown in Table 3.

[0090] Table 3 Solubility test results of semi-succinic acid larsamiditan crystal form

[0091] Sample Solubility (mg / ml) Example 1 40.37 Comparative Example 1 35.12 Comparative Example 2 19.73 Comparative Example 3 20.18 Comparative Example 4 5.94 Comparative Example 5 28.63

[0092] The solubility test results show that the solubility of the semi-succinic acid larsamiditan crystal form prepared by the present application in water is better than that of the semi-succinic acid larsamiditan crystal form prepared by comparative examples 1-5.

[0093] Pharmacokinetic test of verification example 3

[0094] 1. Test material: semi-succinic acid larsamiditan crystal form prepared by example 1, comparative example 4 and comparative example 5.

[0095] 2. Test method: 30 healthy SD rats, half male and half female, weighing 200-240g, were randomly divided into 3 groups, and fasted for 12 hours before administration, and free water. 10 mg / kg of the above semi-succinic acid larsamiditan crystal form was given by gavage (preparation solution); 10 min, 20 min, 30 min, 1 h, 1.5 h, 2 h, 2.5 h, 3 h, 4 h, 8 h, 12 h, 24 h after administration, 300 μl of blood was taken from the rat from the fundus plexus, and placed in a heparinized test tube, and analyzed by LC-MS / MS.

[0096] 3. Test results: the test results are shown in Table 4.

[0097] Table 4 Pharmacokinetic test results of semi-succinic acid larsamiditan crystal form

[0098]

[0099] Through the study of the pharmacokinetics of semi-succinic acid larsamiditan crystal form, the experimental results confirm that the bioavailability of the semi-succinic acid larsamiditan crystal form provided by the present application is effectively improved, and significant progress has been made compared with the existing crystal form.

Claims

1. A crystal form of lacmidetane hemisuccinate, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, has characteristic peaks at 4.96±0.2°, 9.91±0.2°, 18.48±0.2°, 19.87±0.2°, and 21.05±0.2°.

2. The crystalline form of lacmidetane hemisuccinate as described in claim 1, characterized in that, Using Cu-Kα radiation, the X-ray diffraction pattern, expressed as 2θ, shows characteristic peaks at 4.96±0.2°, 9.91±0.2°, 10.70±0.2°, 15.84±0.2°, 17.71±0.2°, 17.95±0.2°, 18.48±0.2°, 19.87±0.2°, 21.05±0.2°, and 26.03±0.2°.

3. The crystalline form of lacmidetane hemisuccinate as described in claim 1, characterized in that, The crystal form has the X-ray powder diffraction pattern shown in Figure 1.

4. A method for preparing the crystalline form of lacmidetane hemisuccinate according to any one of claims 1-3, characterized in that, Includes the following steps: Rasmidetane was added to an organic solvent and stirred to obtain a rasmidetane-organic solvent mixture, which was set aside. Then, succinic acid was added to the same organic solvent, heated and stirred until completely dissolved, and then the above-mentioned rasmidetane-organic solvent mixture was added. The reaction was continued at a constant temperature, and then cooled and stirred to induce crystallization. After crystallization was complete, the mixture was filtered and dried to obtain the final product. The organic solvent was one or a combination of hexane, methanol, and acetonitrile. The crystallization temperature was 0~10℃.

5. The preparation method according to claim 4, characterized in that, The molar ratio of lasmiditan to succinic acid is 1:0.6~1.

6. The preparation method according to claim 4, characterized in that, The reaction temperature is 40~55℃.

7. The preparation method according to claim 6, characterized in that, The reaction temperature is 45~50℃.

8. The preparation method according to claim 4, characterized in that, The ratio of lasmidetane to organic solvent in the mixture is 1:8~15, g / mL; the ratio of succinic acid to organic solvent for dissolving succinic acid is 1:15~20, g / mL.

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

10. The use of the lacmidetane hemisuccinate crystal form according to any one of claims 1-3 as an active ingredient in the preparation of a medicament for treating acute migraine.

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