CN116239568A

CN116239568A - New crystal forms of 5-HT1F receptor agonist and preparation method thereof

Info

Publication number: CN116239568A
Application number: CN202111490321.0A
Authority: CN
Inventors: 姚倩; 丁军
Original assignee: Shandong New Time Pharmaceutical Co Ltd
Current assignee: Shandong New Time Pharmaceutical Co Ltd
Priority date: 2021-12-08
Filing date: 2021-12-08
Publication date: 2023-06-09

Abstract

The invention belongs to the technical field of crystal form drug molecules, and particularly relates to a novel crystal form of 5-HT1F receptor agonist, namely lasemide hemisuccinate. The crystal form of the laslmidian hemisuccinate uses Cu-K alpha radiation, and an X-ray diffraction pattern expressed by 2 theta has characteristic peaks at the positions of 4.95+/-0.2 degrees, 15.83+/-0.2 degrees, 16.38+/-0.2 degrees, 18.53+/-0.2 degrees, 20.01+/-0.2 degrees and 26.11+/-0.2 degrees; the obtained crystal form has good stability, no crystal transformation phenomenon, and is suitable for long-term storage of pharmaceutical preparations; the solubility and the bioavailability are high, and a new choice is provided for the pharmaceutical preparation; the preparation process is simple, has good repeatability and is suitable for industrial production.

Description

New crystal forms of 5-HT1F receptor agonist and preparation method thereof

Technical Field

The invention belongs to the technical field of pharmaceutical chemistry, and particularly relates to a novel crystal form of a 5-HT1F receptor agonist.

Background

Migraine is a common and periodically recurrent neurovascular disease, is accompanied by moderately severe pulsating headache, is common on one side or alternately attacks or affects both sides on both sides, is accompanied by some autonomic nerve symptoms such as fear, nausea, vomiting, photophobia and the like, and has the characteristics of long onset time, lasting illness state, difficult healing and the like. Migraine has a great impact on quality of life, and WHO reported in 2001 to rank common diseases in the life loss of health, with migraine being the first 20, and severe migraine being the most disabling disease, like dementia, paralysis and severe psychosis.

The new medicine for treating acute migraine contains the effective component Lasmidinitan, named Lasmidinitan, lamidiutan, lamizotan Mi Tan, lasisight Mi Tan, lasmidiutan, and Limizotan. Code numbers COL-144 and LY573144. English chemical name is 2,4,6-trifluoro-N- [6- (1-methyl-4-carbonyl) pyridin-2-yl ] benzamide, and Chinese cultural name is 2,4,6-trifluoro-N- [6- [ (1-methyl-4-piperidinyl) carbonyl ] -2-pyridyl ] benzamide. The results of cloning of human 5-hydroxytryptamine subtype 1F (5-HT 1F) receptor by Gift corporation of America (Elilily) in 3 months 2003 were first developed. 12 months 2005, gift company signed an agreement with CoLucid pharmaceutical company in the United states, granting that company the right to develop exclusive rights worldwide. 10 months 2013, the CoLucid company has signed an agreement with the korean eastern pharmaceutical company, granting the company sales operations in korea and southeast asia. And 2 months 2015, the Gift company and the CoLucid pharmaceutical company re-sign modification agreement, wherein the Gift company owns or reserves the proprietary right to study the lamidetan, and 3 months 2017, the Gift company completes the purchase of the CoLucid pharmaceutical company, and the CoLucid pharmaceutical company becomes the full-resource subsidiary company.

The Gift company submits a new drug to the United states Food and Drug Administration (FDA) for marketing on 11.14.2018, and is approved for marketing on 11.10.2019. The trade name of the lasmiditant hemisuccinate tablet (abbreviated as the lasmiditant tablet) is

The masculine is an oral, central nervous system permeable, selective and 5-HT1F agonist, has a mechanism of action different from that of the currently available batch of 'desteine' medicines for treating migraine, does not have a vasoconstrictor effect, is safer for patients suffering from or at risk of cardiovascular diseases, and is the only approved medicine for treating adult acute migraine for 20 years.

CN100352817C discloses lasmidbody, lasmidbody hemisuccinate and hydrochloride and methods for preparing the same, and also discloses mass spectrum, 1H-NMR, 13C-NMR and melting point characterization data of the same, which are prepared into amorphous lasmidbody according to the report of the prior literature. US patent 20190233393 discloses forms A, B, C, F, G of lasmidbody Form1, form2, form3 and lasmidbody hydrochloride, wherein forms A, B, C of lasmidbody Form1, form2, form3 and lasmidbody hydrochloride have good solid state and chemical stability within 10 days. For lasmidbody hemisuccinate, U.S. patent No. 8697876B2 discloses pharmaceutical compositions of crystalline form A, B, C, amorphous form and crystalline form a of lasmidbody hemisuccinate, wherein after 2 days and 3 days of storage of form C at 75% rh, no change is found by visual inspection of the sample alone; CN201780075750 discloses form D (dihydrate), form F (trihydrate), form E (dehydrated hydrate of form D) of the lasmidbody hemisuccinate salt, and a process for its preparation, form D being prepared by a wet granulation process starting from form a, form a being stored at 25 ℃ and 96% Relative Humidity (RH), wherein form E is a metastable form, form D, F is not completely stable at low relative humidity, and seeding readily occurs; indian patent IN201941034052 discloses crystalline form a, amorphous form and solid dispersions of lasmidbody hemisuccinate.

In view of the problems that systematic research of the crystal form of the lamivudine reported in the above documents is not perfect enough, the stability of the existing crystal form is to be improved, and the like, the provision of a novel crystal form of the lamivudine hemisuccinate with good solubility, high stability and high bioavailability is a problem to be solved urgently by those skilled in the art.

Disclosure of Invention

In order to overcome the defects of the prior art, the invention provides a novel crystal form of a 5-HT1F receptor agonist, namely the laslmidian hemisuccinate and a preparation method thereof, and the crystal form has good stability and high solubility and can better meet the requirements of pharmaceutical preparations.

The specific technical content of the invention is as follows:

in one aspect, the invention provides a crystalline form of 5-HT1F receptor agonist, lamivudine hemisuccinate, having an X-ray diffraction pattern as expressed in2 theta 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 ° using Cu-K alpha radiation.

Preferably, the X-ray diffraction pattern of the crystal form expressed by 2 theta has characteristic peaks at 4.95+/-0.2 degrees, 9.89+/-0.2 degrees, 13.54+/-0.2 degrees, 15.83+/-0.2 degrees, 16.38+/-0.2 degrees, 17.71+/-0.2 degrees, 18.53+/-0.2 degrees, 19.39+/-0.2 degrees, 20.02+/-0.2 degrees and 23.76+/-0.2 degrees and 26.11+/-0.2 degrees.

Preferably, the crystalline form has an X-ray powder diffraction pattern as shown in figure 1.

Preferably, the crystalline form has a TGA/DSC profile as shown in FIG. 2.

In another aspect, the invention provides a method for preparing a crystalline form of lasmidbody hemisuccinate, comprising the steps of: sequentially adding the masidian and the succinic acid into the mixed solution of the dimethylbenzene and the second organic solvent, heating, stirring, cooling, crystallizing, filtering, collecting solids, and drying to obtain the externally applied agent.

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

Preferably, the dosage volume ratio of the xylene to the second organic solvent is 1:0.2 to 1.

Preferably, the dosage mole ratio of the masculine to the succinic acid is 1:0.5 to 1.0, more preferably 1:0.7.

preferably, the dosage ratio of the lamiditan to the dimethylbenzene is 1: 2-8,g/ml.

Preferably, the temperature of the heating and stirring is 30-40 ℃.

Preferably, the stirring time is 1-2 hours.

Preferably, the cooling rate is 0.2 to 1 ℃/min, more preferably 0.5 ℃/min.

Preferably, the crystallization temperature is 0-5 ℃.

Preferably, the crystallization time is 1-2h.

Preferably, the drying is reduced pressure vacuum drying at 50-60 ℃.

Preferably, the drying time is 12 to 16 hours.

On the other hand, the invention also provides a pharmaceutical composition which comprises the crystal form of the lasmidbody hemisuccinate and pharmaceutically acceptable auxiliary materials. The crystalline form may be in a therapeutically effective amount. The pharmaceutically acceptable excipients may be those well known in the art, and in the case of solid formulations, include, but are not limited to: diluents, binders, disintegrants, lubricants, glidants, release-rate controlling agents, plasticizers, preservatives, antioxidants, and the like.

The pharmaceutical composition may be selected from the dosage forms suitable for human administration, for example: tablets, capsules, granules, powders, or pills, etc., preferably tablets, capsules, granules, disintegrating tablets, sustained-release or controlled-release tablets.

The pharmaceutical compositions of the present invention may be prepared by methods well known in the art, which may be formulated into dosage forms suitable for human administration by mixing a therapeutically effective amount of the crystalline form with various pharmaceutical excipients, such as: the tablets, capsules and granules can be prepared by the processes of mixing, granulating, tabletting or filling capsules.

Crystal structure confirmation

(1) X-ray powder diffraction detection

The X-ray powder diffraction test instrument and test conditions for the crystal form provided by the invention are as follows: x-ray powder diffractometer: PANalytical EMPYREAN; cu-K alpha; sample stage: a flat plate; incident light path: BBHD; diffraction light path: PLXCEL; voltage 45kv and current 40mA; divergence slit: 1/4 °; anti-scatter slit: 1 DEG; a cable pull slit: 0.04rad; step size: 0.5s; scanning range: 3-50 deg.

The main X-ray powder diffraction characteristic peaks of the crystalline form of lasmidbody hemisuccinate are shown in table 1.

TABLE 1 principal X-ray powder diffraction characteristic peaks of the crystalline form of lasemifene hemisuccinate

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(2) TGA/DSC analysis

The TGA/DSC thermal analysis instrument and the test conditions for the crystal form are as follows: meltrele-tolidol TGA/DSC thermogram (TGA/DSC 3+); dynamic temperature section: 30-300 DEG CThe method comprises the steps of carrying out a first treatment on the surface of the Heating rate: 10K/min; procedure section gas N ₂ The method comprises the steps of carrying out a first treatment on the surface of the Gas flow rate: 50ml/min; crucible: 40 μl of aluminum crucible.

The results of the TGA/DSC test of the crystalline form of the present invention are shown in FIG. 2.

And (3) structural confirmation:

¹ H NMR(600MHz,DMSO-d ₆ )δ：1.56(d,J＝12.1Hz,2H),1.89(d,J＝12.6Hz,2H),2.10(t,J＝10.9Hz,2H),2.24(s,3H),2.38(s,2H),2.89(d,J＝13.1Hz,2H),3.70(s,1H),7.42(dd,J＝9.4,7.7Hz,2H),7.79(d,J＝7.7Hz,1H),8.10(t,J＝8.0Hz,1H),8.39(d,J＝8.2Hz,1H),11.46(s,1H).

the invention has the beneficial effects that: the invention provides a novel crystal form of the laslmidian hemisuccinate, which has good stability, does not generate crystal transformation phenomenon, and is suitable for long-term storage of pharmaceutical preparations; the solubility and the bioavailability are high, and a new choice is provided for the pharmaceutical preparation; the preparation process is simple, has good repeatability and is suitable for industrial production.

Drawings

Fig. 1: PXRD spectrum of the crystal form of lasmidbody hemisuccinate;

fig. 2: TGA/DSC of the crystalline form of lasmidbody hemisuccinate.

Detailed Description

The invention is further illustrated by the following description of specific embodiments with the understanding that: the examples of the present invention are merely illustrative of the present invention and are not intended to be limiting. Therefore, simple modifications to the invention, which are within the scope of the claimed invention, are possible with the method of the invention.

Example 1

3.00g of laslmidian and 0.66g of succinic acid are added into a mixed solution of 15ml of dimethylbenzene and 9ml of dichloromethane, the temperature is raised to 35 ℃, the mixture is stirred for 1h, the temperature is reduced to 0-5 ℃ at 0.5 ℃/min, crystallization is carried out for 1.5h, filtration is carried out, the filter cake is dried under reduced pressure and vacuum for 12h at 50-60 ℃, and the laslmidian hemisuccinate crystal form is obtained, the yield is 90.42%, and the HPLC purity is 99.79%.

Example 2

3.00g of laslmidian and 0.47g of succinic acid are added into a mixed solution of 6ml of dimethylbenzene and 6ml of dichloromethane, the temperature is raised to 30 ℃, the mixture is stirred for 1.5h, the temperature is reduced to 0-5 ℃ at 1 ℃/min, crystallization is carried out for 1.5h, filtration is carried out, a filter cake is dried under reduced pressure and vacuum for 12h at 50-60 ℃, and the laslmidian hemisuccinate crystal form is obtained, the yield is 87.51%, and the HPLC purity is 99.75%.

Example 3

3.00g of laslmidian and 0.94g of succinic acid are added into a mixed solution of 24ml of dimethylbenzene and 5ml of ethanol, the temperature is raised to 40 ℃, the mixture is stirred for 2 hours, the temperature is reduced to 0-5 ℃ at 0.2 ℃/min, crystallization is carried out for 2 hours, filtration and filter cake vacuum drying is carried out for 16 hours at 50-60 ℃ under reduced pressure, thus obtaining the laslmidian hemisuccinate crystal form, the yield is 86.42 percent, and the HPLC purity is 99.73 percent.

Example 4

3.00g of laslmidian and 0.75g of succinic acid are added into a mixed solution of 9ml of dimethylbenzene and 6ml of dichloromethane, the temperature is raised to 35 ℃, the mixture is stirred for 1.5h, the temperature is reduced to 0-5 ℃ at 0.8 ℃/min, crystallization is carried out for 1.5h, filtration is carried out, the filter cake is dried under reduced pressure and vacuum for 14h at 50-60 ℃, and the laslmidian hemisuccinate crystal form is obtained, the yield is 89.01%, and the HPLC purity is 99.76%.

Example 5

3.00g of laslmidian and 0.66g of succinic acid are added into a mixed solution of 15ml of dimethylbenzene and 6ml of ethanol, the temperature is raised to 40 ℃, the mixture is stirred for 2 hours, the temperature is reduced to 0-5 ℃ at 2 ℃/min, crystallization is carried out for 2 hours, filtration is carried out, a filter cake is dried under reduced pressure and vacuum for 12 hours at 50-60 ℃, and the laslmidian hemisuccinate crystal form is obtained, the yield is 74.58%, and the HPLC purity is 99.31%.

Example 6

3.00g of laslmidian and 0.84g of succinic acid are added into a mixed solution of 18ml of dimethylbenzene and 7ml of ethanol, the temperature is raised to 50 ℃, the mixture is stirred for 1.5h, the temperature is reduced to 0-5 ℃ at 0.5 ℃/min, crystallization is carried out for 1.5h, filtration is carried out, the filter cake is dried for 12h under reduced pressure and vacuum at 50-60 ℃, and the laslmidian hemisuccinate crystal form is obtained, the yield is 80.47%, and the HPLC purity is 99.70%.

Example 7

3.00g of laslmidian and 0.66g of succinic acid are added into a mixed solution of 30ml of dimethylbenzene and 6ml of dichloromethane, the temperature is raised to 35 ℃, the mixture is stirred for 1h, the temperature is reduced to 0-5 ℃ at 0.5 ℃/min, crystallization is carried out for 2h, filtration and filter cake vacuum drying is carried out for 16h under reduced pressure at 50-60 ℃ to obtain the laslmidian hemisuccinate crystal form, the yield is 83.82% and the HPLC purity is 99.64%.

Comparative example 1

Referring to the process disclosed in US patent 8697876, crystalline form a of lasmidbody hemisuccinate is prepared: an ethanol solution of the free base of lasmidbody (1.00 weight correction, about 4.5 volumes, 183 g) was added to a clean reactor through an in-line filter, ethanol (0.5 volumes, 0.4 weight, 91 ml) was flushed in-line, and then heated to 75-80 ℃ 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 under nitrogen at 20-25 ℃ for 40-50 minutes, after dissolution, added to a reactor containing an ethanol solution of lasmidbody, kept at 75-80 ℃ and rinsed in-line with ethanol (1.0 volume, 0.8 weight, 183 mL). Cooled to 60-63 ℃, the crystallization in the reactor is visually checked and the crystallization temperature is recorded and stirred for 50-60 minutes. The reaction vessel contents were cooled to 20-25 ℃ over 40-60 minutes (about 1 ℃/min), stirred for 4-6 hours, the solids were collected, washed with ethanol, and dried under vacuum at 45 ℃ to give crystalline form a of lasmidbody hemisuccinate with HPLC purity of 99.45%.

Comparative example 2

Referring to the process disclosed in patent CN2017800757507, crystalline form D of lasmidbody hemisuccinate dihydrate is prepared: prepared by wet granulation using a high shear granulator, 200 g of lamiditan hemisuccinate form a was mixed with 87% (w/v) of water in a 4 liter tank, spray rate 20g kg/min, stirring paddle speed 400rpm, granulation time 2 minutes, and the prepared granules were dried in a fluidized bed system (air intake 60m ³ And/h, the inlet air temperature is 70 ℃, the outlet product temperature is 22-34 ℃, the product temperature is 23-50 ℃), and the crystal form D of the lasmidbody hemisuccinate dihydrate is obtained, and the HPLC purity is 99.61%.

Comparative example 3

Referring to the process disclosed in patent CN2017800757507, the preparation of the crystalline form F of lasmidbody hemisuccinate, crystalline form trihydrate: 913 mg of the amorphous form of lasmidbody hemisuccinate was added to a glass reaction tube, cooled to 5 ℃ and 12.5ml of pre-cooled water was added to form a thick suspension, stirring (300 rpm) was continued at 5 ℃ for 3 days, filtration, air-drying, and drying to obtain the crystalline form F of lasmidbody hemisuccinate, crystalline form trihydrate, having an HPLC purity of 99.90%.

Verification example 1 physical stability test

1. Test materials: the crystalline forms of laslmidian hemisuccinate prepared in example 1, comparative examples 1-3.

2. The test method comprises the following steps: taking 20mg of the above-mentioned crystal form of lasmidbody hemisuccinate, respectively packaging into glass vials, placing the vials in a constant temperature and humidity box with a relative humidity of 40 ℃/75% under the condition of no cover, carrying out XRPD sampling at the time points of 7 days, 14 days, 30 days, 45 days and 60 days, and carrying out identification inspection by using the above-mentioned XRPD method to test physical stability.

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

TABLE 2 results of physical stability test of the crystalline form of lasmidbody hemisuccinate

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Note that: NA was undetected.

The crystal form of the lasmidbody hemisuccinate provided by the invention does not have crystal form transformation when being stored for 60 days in a relative humidity environment of 40 ℃/75%, and the physical stability of the crystal form of the invention is proved to be excellent.

Verification of example 2 solubility test

2. The test method comprises the following steps: the solubility test refers to the content of Chinese pharmacopoeia (2020 edition) and takes water and phosphoric acid buffer solution with pH=6.8 (simulating human intestinal environment) as dissolution medium. Measuring 900ml of water or phosphoric acid buffer solution with pH of 6.8 in a penicillin bottle, respectively adding excessive crystal forms of the lasmidbody hemisuccinate, sealing the penicillin bottle, placing in a 37 ℃ water bath, stirring at constant temperature, filtering with a filter membrane, diluting the filtrate, detecting the content by adopting an HPLC (high performance liquid chromatography) detection purity method, and obtaining the solubility. Three replicates were run and the results averaged.

3. Test results: the test results are shown in Table 3.

TABLE 3 solubility of the crystalline form of lasmidbody hemisuccinate

Verification of example 3 bioavailability test

2. The test method comprises the following steps: 20 healthy SD rats, each half of which is 200-240g in weight, were randomly divided into 4 groups and fasted for 12 hours before administration, and were freely drunk. Respectively administering 10mg/kg of the above-mentioned crystalline form of lasmidbody hemisuccinate and respectively administering intragastric administration (preparing solution); 300 μl of blood was continuously taken from the ocular fundus venous plexus via rats at 10min,20min,30min,1h,1.5h,2h,2.5h,3h,4h,8h,12h,24h after administration, respectively, and placed in heparinized tubes for LC-MS/MS analysis.

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

TABLE 4 results of pharmacokinetic experiments on the crystalline form of Lasmimiditant hemisuccinate

From the data in tables 3 and 4, the crystal form of the lamiditan hemisuccinate prepared by the invention has high solubility and bioavailability, is superior to the existing crystal form, can better meet the requirements of pharmaceutical preparations, and provides better basis for the application of the lamiditan hemisuccinate in the aspect of pharmaceutical treatment.

Claims

1. A novel crystalline form of a 5-HT1F receptor agonist, characterized by an X-ray diffraction pattern expressed in2Θ having a characteristic peak 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 ° using Cu-ka radiation.

2. The crystalline form of claim 1, wherein the X-ray diffraction pattern in2Θ has a characteristic peak 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° using Cu-ka radiation.

3. The crystalline form of claim 1, wherein the crystalline form has an X-ray powder diffraction pattern as shown in figure 1.

4. A process for preparing the crystalline form of any one of claims 1-3, comprising the steps of: sequentially adding the masidian and the succinic acid into the mixed solution of the dimethylbenzene and the second organic solvent, heating, stirring, cooling, crystallizing, filtering, collecting solids, and drying to obtain the externally applied agent.

5. The method according to claim 4, wherein the second organic solvent is selected from one of dichloromethane and ethanol.

6. The method according to claim 4, wherein the ratio of the xylene to the second organic solvent is 1:0.2 to 1.

7. The preparation method according to claim 4, wherein the molar ratio of the amount of the lamidian to the amount of the succinic acid is 1:0.5-1.0; the dosage ratio of the masmitriptan to the dimethylbenzene is 1: 2-8,g/ml.

8. The method according to claim 4, wherein the temperature is 30 to 40 ℃.

9. The process according to claim 4, wherein the cooling rate is 0.2 to 1 ℃/min, preferably 0.5 ℃/min.

10. The method according to claim 4, wherein the crystallization temperature is 0 to 5 ℃.