KR102581450B1 - Crystalline Form XI of lenvatinib mesylate and method for preparing the same - Google Patents

Abstract

It relates to crystalline Form Crystalline Form It is simple and has excellent stability.

Description

Crystalline Form XI of lenvatinib mesylate and method for preparing the same

This application relates to the field of drug crystalline forms, and in particular to crystalline forms of lenvatinib mesylate and methods for their preparation.

Lenvatinib's chemical name is 4-[3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy]-7-methoxy-6-quinolinecarboxamide, and its structural formula is the following formula (I ) as shown in

Lenvatinib is a treatment for thyroid cancer and liver cancer developed by Eisai Co., Ltd. of Japan. Lenvatinib is an oral multi-receptor tyrosine kinase (RTK) inhibitor that binds to its receptors in a novel manner, thereby inhibiting other angiogenesis-promoting and oncogenic signaling pathway-related RTKs involved in tumor proliferation, as well as vascular endothelial growth factor (RTK). It can selectively inhibit the kinase activity of the VEGF) receptor. It was approved by the FDA on February 13, 2015 as a treatment for patients with locally recurrent or metastatic advanced differentiated thyroid cancer that does not respond to radioactive iodine, and was later approved for marketing in the European Union and Japan, and on September 5, 2018, it was approved as a Chinese drug. It has been approved by the Regulatory Agency for the treatment of patients with unresectable liver cancer who have not previously received systemic therapy.

Patents CN100569753C, CN101337931B, CN101337932B and CN101337933B disclose crystalline forms A, B, C, F and I of lenvatinib mesylate. Here, anhydrous crystalline Form B transforms into crystalline Form C or a hybrid crystal thereof under different humidity conditions, and Form I also transforms into crystalline Form C or a hybrid crystal thereof under different humidity conditions, so Form B and Form I are less stable.

As can be seen, there is still a need in the art to provide a crystalline form of lenvatinib mesylate and a method for its preparation that have good stability, better product quality, simple manufacturing process, and are suitable for industrial production.

The purpose of the present invention is to provide a crystalline form of lenvatinib mesylate, which solves the problems of poor stability, unstable product quality, cumbersome manufacturing process, and impossibility of mass production in the crystalline form of lenvatinib mesylate in the prior art. there is.

The technical solution of the present invention to solve the above-described technical problem is as follows.

The X-ray powder diffraction pattern has diffraction angles (2θ) of approximately 5.73 ^o ±0.2 ^o , 8.03 ^o ±0.2 ^o , 11.45 ^o ±0.2 ^o , 12.75 ^o ±0.2 ^o , 16.15 ^o ±0.2 ^o , 17.24 ^o ±0.2 ^o , 18.16 ^o ±0.2 ^o , 19.69 ^o ±0.2 ^o , 20.68 ^o ±0.2 ^o , 22.15 ^o ±0.2 ^o , 22.96 ^o ±0.2 ^o , 23.76 ^o ±0.2 ^o , 24.32 ^o ±0.2 ^o , 25.13 ^o ±0.2 ^o , 26.32 ^o ±0.2 ^{Provided is crystalline Form _ _ _ _ _}

Preferably, the crystal form XI has an X-ray powder diffraction pattern basically as shown in FIG. 1.

Preferably, the crystalline Form

Preferably, the crystalline Form

Preferably, Form XI has a moisture content of 6.5%.

Preferably, Form XI is lenvatinib mesylate dihydrate containing two water of crystallization.

The present invention also,

Step (1) of uniformly stirring and mixing ethyl acetate and purified water at room temperature at a constant volume ratio;

Step (2) of adding lenvatinib mesylate to the mixed solvent of step (1); and

After the suspension in step (2) is uniformly dispersed, a certain amount of seed crystals of Form A method for preparing crystalline Form XI of lenvatinib mesylate is provided, comprising the step (3) of obtaining crystalline Form XI of mesylate.

Preferably, the constant volume ratio of ethyl acetate and purified water in step (1) is 100mL:(2-10)mL, more preferably, the constant volume ratio of ethyl acetate and purified water is 100mL:(2-5)mL, most preferably. The ratio is 100mL:3mL.

Preferably, the mass volume ratio of lenvatinib mesylate in step (2) and ethyl acetate in the mixed solvent of step (1) is 1g:(10-30)mL, more preferably, lenvatinib mesylate and ethyl acetate in the mixed solvent of step (1) are 1g:(10-30)mL. The mass volume ratio of ethyl acetate in the mixed solvent in step (1) is 1g:(15-25)mL, most preferably 1g:20mL.

Preferably, in step (3), the mass fraction of the seed crystals of Form The mass fraction is 2-6%, most preferably 5%, relative to the mesylate dosage.

Preferably the reaction temperature is 20 to 30°C, more preferably 20 to 25°C, and most preferably 25°C.

Preferably the stirring time is 6 to 12 hours, more preferably 6 to 10 hours, and most preferably 8 hours.

More preferably, the method for preparing lenvatinib mesylate crystalline Form

Step (1) of uniformly stirring and mixing ethyl acetate and purified water at room temperature - the volume ratio of ethyl acetate and purified water is 100mL:3mL - ;

Step (2) of adding lenvatinib mesylate to the mixed solvent of step (1) - the mass volume ratio of lenvatinib mesylate and ethyl acetate is 1g:20mL; and

After the suspension in step (2) is uniformly dispersed, seed crystals of Form and step (3) of obtaining a solid powder, that is, crystalline Form XI of lenvatinib mesylate.

Crystalline Form XI of lenvatinib mesylate prepared by the present invention has the following advantages.

1. Crystalline Form

2. Crystalline form XI of lenvatinib mesylate of the present invention can maintain a stable crystalline form under high temperature, high humidity, and light conditions.

3. Crystalline Form

4. Crystalline Form

5. The method for preparing lenvatinib mesylate crystalline Form Therefore, it is easy to recover, simple to operate, and has excellent stability, allowing kilogram-level products to be stably manufactured and advantageous for large-scale industrial production.

Figure 1 shows the XRD spectrum of crystalline Form XI of lenvatinib mesylate according to Example 1.
Figure 2 shows the DSC spectrum of crystalline Form XI of lenvatinib mesylate according to Example 1.
Figure 3 shows the TGA spectrum of crystalline Form XI of lenvatinib mesylate according to Example 1.
Figure 4 shows the DVS spectrum of crystalline Form XI of lenvatinib mesylate according to Example 1.
Figure 5 shows comparative XRD spectra of crystalline Form XI of lenvatinib mesylate according to Example 11 under different storage conditions.

Hereinafter, the present application will be described in more detail with reference to examples. The examples of this application are merely for illustrating the technical solutions of this application, and the substance and scope of this application are not limited thereto.

A description of the abbreviations used in this application is as follows.

XRD: X-ray powder diffraction

X-ray powder diffraction (XRD) measurements according to this application were collected using a DX-2700B powder diffractometer from Liaoning Dandong Haoyuan, and the specific parameters are as follows.

DSC: Differential scanning calorimetry

The measurements of differential scanning calorimetry (DSC) according to this application were collected using a METTLER TOLEDO model name DSC-1, with a temperature increase rate of 10°C/min, a temperature range of 25 to 250°C, and a nitrogen purge rate during the test process. is 60mL/min.

TGA: Thermogravimetric Analyzer

The measurements of thermogravimetric analysis (TGA) according to this application were collected using a METTLER TOLEDO model name TGA-2, the temperature rise rate was 10°C/min, the temperature range was 30~250°C, and the nitrogen purge rate during the test process was It is 20mL/min.

DVS: Dynamic Vapor Sorption Analyzer

Dynamic vapor sorption analysis (DVS) measurements according to the present application were collected using TA model name Q5000SA, the equilibrium temperature was 25°C, and the specific test parameters are as shown in the table below.

KF: Karl Fischer Moisture Meter

The moisture according to this application was measured with a Karl Fischer moisture meter of Metrohm (Swiss Metrohm) model name 870KF Titrino plus.

GC: gas chromatograph

The solvent residue according to the present application was measured with an Agilent model number 7890B gas chromatograph, and the specific parameters are as shown in the table below.

HPLC: High Performance Liquid Chromatography

Measurement of the HPLC spectrum was performed with an Agilent 1260DAD liquid chromatograph. In the present application, HPLC purity of lenvatinib mesylate is performed by the following method.

(1) Column filled with octadecylsilane bonded silica gel

(2) Detector: UV detector (wavelength 252nm and 205nm)

(3) Flow rate: 1mL per minute

(4) Run time: starting from the solvent peak, approximately 2.7 times the retention time of the lenvatinib peak

(5) Test solution: Accurately weigh 12.5 mg of this sample, dissolve in a solvent, and dilute to a solution containing approximately 0.5 mg per 1 mL to use as the test solution.

(6) Injection volume: 10 μL, measure the sample solution by automatic integration method and calculate the purity of lenvatinib in the sample according to the peak area.

Solvent screening experiment

In order to discover a new crystalline form of lenvatinib mesylate, the present inventors suspended a certain amount of lenvatinib mesylate in a reaction solvent, stirred at 25°C for 6 to 8 hours, and formed a new crystalline form by filtration and drying under reduced pressure. Screened.

As a result of screening the reaction solvent, it was surprisingly confirmed that when the reaction solvent was a mixed solvent of ethyl acetate and water, new crystalline Form

As shown in Table 1, when a pure organic solvent such as methanol, ethanol, acetone, etc. is used as a reaction solvent, the product obtained is crystalline form A or crystalline form C, and other mixed solvents, such as a mixed solvent of ethanol and water, are used as the reaction solvent. The product obtained upon use is crystalline Form A. As shown in Table 1, crystalline Form

Example 1: Preparation of lenvatinib mesylate crystalline Form XI

After stirring and mixing 200 mL ethyl acetate and 10 mL purified water uniformly at room temperature, add 10.0 g of lenvatinib mesylate to the mixed solvent of ethyl acetate and purified water, wait until the suspension is uniformly dispersed, and then incubate at 25°C for 24 hours. After stirring, it was filtered and dried under reduced pressure to obtain 9.1 g of solid powder. The yield is 91.0% and purity is 99.73%.

¹ H-NMR data is as follows:

X-ray powder measurement was performed on the obtained crystalline form XI of lenvatinib mesylate using Cu-ka rays, and the obtained .

As a result of performing DSC analysis on the obtained crystalline form

As a result of performing TGA analysis on the obtained crystalline form

As a result of moisture measurement on the obtained crystalline form XI of lenvatinib mesylate, the moisture content was 6.5%.

As a result of measuring the residual amount of ethyl acetate solvent for the obtained crystalline form XI of lenvatinib mesylate, the residual amount of ethyl acetate solvent was 0.068%.

Referring to the TGA weight loss, moisture and residual solvent data, it can be seen that Form

Example 2: Preparation of lenvatinib mesylate crystalline Form XI

After uniformly stirring and mixing 200 mL of ethyl acetate and 4 mL of purified water at room temperature, 10.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, and after the suspension was uniformly dispersed, 0.3 g of seed crystals of crystal form XI were added. After stirring at 25°C for 8 hours, 9.2 g of solid powder was obtained by filtration and drying under reduced pressure. The yield was 92.0%, purity was 99.77%, and the XRD data was basically consistent with Example 1.

Example 3: Preparation of lenvatinib mesylate crystalline Form XI

After uniformly stirring and mixing 2000 mL of ethyl acetate and 60 mL of purified water at room temperature, 100.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, and after the suspension was uniformly dispersed, 5.0 g of seed crystals of crystal form XI were added. After stirring at 25°C for 8 hours, 93.0 g of solid powder was obtained by filtration and drying under reduced pressure. The yield was 93.0%, purity was 99.76%, and the XRD data was basically consistent with Example 1.

Example 4: Preparation of lenvatinib mesylate crystalline Form XI

After uniformly stirring and mixing 200 mL of ethyl acetate and 20 mL of purified water at room temperature, 10.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, and after the suspension was uniformly dispersed, 1.0 g of seed crystals of crystal form XI were added. After stirring at 20°C for 8 hours, 9.2 g of solid powder was obtained by filtration and drying under reduced pressure. The yield was 92.0%, purity was 99.75%, and the XRD data was basically consistent with Example 1.

Example 5: Preparation of lenvatinib mesylate crystalline Form XI

After uniformly stirring and mixing 100 mL of ethyl acetate and 2 mL of purified water at room temperature, 10.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, and after the suspension was uniformly dispersed, 0.5 g of seed crystals of crystal form XI were added. After stirring at 15°C for 8 hours, 9.3 g of solid powder was obtained by filtration and drying under reduced pressure. The yield was 93.0%, purity was 99.73%, and the XRD data was basically consistent with Example 1.

Example 6: Preparation of lenvatinib mesylate crystalline Form XI

After uniformly stirring and mixing 100 mL of ethyl acetate and 10 mL of purified water at room temperature, 10.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, and after the suspension was uniformly dispersed, 0.5 g of seed crystals of crystal form XI were added. After stirring at 30°C for 8 hours, 9.1 g of solid powder was obtained by filtration and drying under reduced pressure. The yield was 91.0%, purity was 99.71%, and the XRD data was basically consistent with Example 1.

Example 7: Preparation of lenvatinib mesylate crystalline Form XI

After stirring and mixing 300 mL of ethyl acetate and 6 mL of purified water uniformly at room temperature, 10.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, and after the suspension was uniformly dispersed, 0.2 g of seed crystals of crystal form XI were added. After stirring at 40°C for 4 hours, 9.0 g of solid powder was obtained by filtration and drying under reduced pressure. The yield was 90.0%, purity was 99.69%, and the XRD data was basically consistent with Example 1.

Example 8: Preparation of lenvatinib mesylate crystalline Form XI

After stirring and mixing 300 mL of ethyl acetate and 30 mL of purified water uniformly at room temperature, 10.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, and after the suspension was uniformly dispersed, 0.6 g of seed crystals of crystal form XI were added. After stirring at 25°C for 8 hours, 9.1 g of solid powder was obtained by filtration and drying under reduced pressure. The yield was 91.0%, purity was 99.76%, and the XRD data was basically consistent with Example 1.

Example 9: Preparation of lenvatinib mesylate crystalline Form XI

After uniformly stirring and mixing 150 mL of ethyl acetate and 3 mL of purified water at room temperature, 10.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, and after the suspension was uniformly dispersed, 0.5 g of seed crystals of crystal form XI were added. After stirring at 25°C for 6 hours, 9.2 g of solid powder was obtained by filtration and drying under reduced pressure. The yield was 92.0%, purity was 99.72%, and the XRD data was basically consistent with Example 1.

Example 10: Preparation of lenvatinib mesylate crystalline Form XI

After stirring and mixing 250 mL of ethyl acetate and 5 mL of purified water uniformly at room temperature, 10.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, and after the suspension was uniformly dispersed, 0.5 g of seed crystals of crystal form XI were added. After stirring at 25°C for 12 hours, 9.1 g of solid powder was obtained by filtration and drying under reduced pressure. The yield was 91.0%, purity was 99.73%, and the XRD data was basically consistent with Example 1.

Example 11: Preparation of lenvatinib mesylate crystalline Form XI

After stirring and mixing 5000 mL of ethyl acetate and 150 mL of purified water uniformly at room temperature, 250.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, and after the suspension was uniformly dispersed, 12.50 g of seed crystals of crystal form XI were added. After stirring at 25°C for 8 hours, 232.8 g of solid powder was obtained by filtration and drying under reduced pressure. The yield was 93.1%, purity was 99.78%, and the XRD data was basically consistent with Example 1.

Example 12: Preparation of lenvatinib mesylate crystalline Form XI

After stirring and mixing 30L of ethyl acetate and 750mL of purified water uniformly at room temperature, 1.5kg of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, stirred at 25°C for 10 hours, filtered under reduced pressure, and dried to obtain a solid powder of 1.4%. kg was obtained. The yield was 93.3%, purity was 99.95%, and the XRD data was basically consistent with Example 1.

Experimental Example 1: Hygroscopicity test of crystalline form XI of lenvatinib mesylate

The results of DVS analysis performed on crystalline form XI of lenvatinib mesylate prepared in Example 1 are shown in FIG. 4. As shown in Figure 4, the weight loss is about 0.33% in the relative humidity range of 0 to 40%, which explains that the crystalline form is relatively stable and does not lose crystal water even when the relative humidity drops to 0%. In addition, the weight increase due to moisture absorption is about 0.25% in the relative humidity range of 40 to 80%, which explains that the hygroscopicity of the crystalline form is very small and that even if the relative humidity is as high as 80%, the weight increase due to moisture absorption is still very small. .

Experimental Example 2: Stability test of crystalline form XI of lenvatinib mesylate

Crystalline Form did. The results are shown in Table 3, and the XRD spectrum is shown in Figure 5.

Under the above conditions, as shown in FIG. 5, crystalline form

Under the above conditions, as can be seen from the data in Table 3, the purity of crystalline Form

In summary, crystalline Form

Experimental Example 3: Fluidity test of lenvatinib mesylate type XI powder

A powder rheology test was performed on crystalline Form

According to <Encyclopedia of Formulation Technology>, Volume 1, 2nd Edition, "Rheology of Solid Materials", in the tap density experiment, the harder the material is compressed, the worse the fluidity becomes, so the compression coefficient is used (compression coefficient (%) = 100% ( Fluidity can be evaluated by measuring (tap density - bulk density) / tap density). The larger the compression coefficient, the worse the fluidity of the powder, which is more disadvantageous for uniform mixing of the powder, which ultimately affects the tableting die or capsule filling. It affects the quality, content uniformity, hardness, and disintegration and dissolution of the formulation product. As shown in Table 4, the compression coefficient of Form C is much higher than that of Form XI, which means that the fluidity of Form

Experimental Example 4: Crystalline Form XI pharmacokinetic experiment of lenvatinib mesylate in rats

1. Purpose of experiment

After oral administration of crystalline Form

2. Materials and Methods

2.1 Experimental drug: Crystalline Form XI of lenvatinib mesylate prepared in Example 12

2.2 Experimental animals

Three male SD rats weighing 220-240 g were purchased from Hunan SJA Laboratory Animal (license number: SCXK (Xiang) 2019-0004) through Chengdu Byrness Weil biotech.

2.3 Experimental method

The experimental drug was prepared as a uniform suspension of 1.25 mg/kg in corn oil and then orally administered to rats at a volume of 4 mL/kg immediately for 15 minutes, 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, After 6 hours, 7 hours, 8 hours, and 24 hours, 0.1 mL of blood was collected from the jugular vein, placed in an EDTA-K2 tube, centrifuged at 3000 r/min for 10 minutes to separate the plasma, and stored frozen in an icebox at -80°C.

2.4 LC/MS/MS biological sample analysis

Mix 50 μL of plasma with 5 μL of working solution or blank diluent, add 150 μL of acetonitrile precipitant containing internal standard, shake with rotation for 2 minutes, centrifuge at 12000 r/min for 10 minutes, then 2 μL The supernatant was taken and mixed uniformly with 200 μL of purified water: acetonitrile (1:1), and the sample was injected and analyzed in a volume of 3 μL.

3. Experimental results

After all blood collections were completed, the blood drug concentration of each blood sample was independently analyzed and measured, and the parameters of the experimental drug (time to reach peak plasma concentration Tmax, peak plasma concentration Cmax, AUClast) were calculated. The average value and standard deviation were calculated based on the obtained parameters, and the specific results are shown in Table 5.

As shown in _Table 5, the time taken for crystalline Form This explains that crystalline form

Experimental Example 5: Dissolution experiment of crystalline form XI of lenvatinib mesylate

Crystalline Form The solution was taken at 15 minutes, 20 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes, and 120 minutes, and then the absorbance was measured at a wavelength of 250 nm using UV spectrophotometry to calculate each elution amount. The experimental results are shown in Table 6 below.

As can be seen from the data in the table above, crystalline Form

It will be apparent to those skilled in the art that various modifications and changes can be made to the compounds of the present application and their preparation methods without departing from the spirit or scope of the present application. Accordingly, various modifications and changes to the present application are included in the protection scope of the present application as long as they are within the scope covered by the claims and equivalent embodiments.

Claims (20)

The X-ray powder diffraction pattern has diffraction angles (2θ) of 5.73 ^o ±0.2 ^o , 8.03 ^o ±0.2 ^o , 11.45 ^o ±0.2 ^o , 12.75 ^o ±0.2 ^o , 16.15 ^o ±0.2 ^o , 17.24 ^o ±0.2 ^o , 18.16 ^o ± 0.2 ^o , 19.69 ^o ±0.2 ^o , 20.68 ^o ±0.2 ^o , 22.15 ^o ±0.2 ^o , 22.96 ^o ±0.2 ^o , 23.76 ^o ±0.2 ^o , 24.32 ^o ±0.2 ^o , 25.13 ^o ±0.2 ^o , 26.32 ^o ±0.2 ^o , including peaks at 27.00 ^o ±0.2 ^o , 28.87 ^o ±0.2 ^o , 29.51 ^o ±0.2 ^o and 34.90 ^o ±0.2 ^o ,
Crystalline form XI of lenvatinib mesylate. In claim 1,
The X-ray powder diffraction pattern has diffraction angles (2θ) of 20.30 ^o ±0.2 ^o , 25.63 ^o ±0.2 ^o , 28.34 ^o ±0.2 ^o , 31.08 ^o ±0.2 ^o , 31.70 ^o ±0.2 ^o , 36.23 ^o ±0.2 ^o , 36.72 ^o further comprising peaks at ±0.2 ^o and 37.98 ^o ±0.2 ^o ,
Crystalline form XI of lenvatinib mesylate. In claim 1 or claim 2,
The crystalline form
Crystalline form XI of lenvatinib mesylate. A method for preparing crystalline Form XI of lenvatinib mesylate according to claim 1, comprising:
Step (1) of uniformly stirring and mixing ethyl acetate and purified water at room temperature at a constant volume ratio;
Step (2) of adding lenvatinib mesylate to the mixed solvent of step (1); and
After the suspension in step (2) is uniformly dispersed, a certain amount of seed crystals of crystalline Form Comprising step (3) of obtaining crystalline Form XI of nib mesylate,
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
In step (1), the constant volume ratio of ethyl acetate and purified water is 100 mL: (2-10) mL,
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
In step (1), the constant volume ratio of ethyl acetate and purified water is 100 mL: (2-5) mL,
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
In step (1), the constant volume ratio of ethyl acetate and purified water is 100mL:3mL,
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
In step (2), the mass volume ratio of lenvatinib mesylate and ethyl acetate in the mixed solvent of step (1) is 1 g: (10-30) mL,
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
In step (2), the mass volume ratio of lenvatinib mesylate and ethyl acetate in the mixed solvent of step (1) is 1 g: (15-25) mL,
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
In step (2), the mass volume ratio of lenvatinib mesylate and ethyl acetate in the mixed solvent of step (1) is 1g:20mL,
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
In step (3), a certain amount of seed crystals of Form
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
In step (3), a certain amount of seed crystals of Form
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
In step (3), a certain amount of seed crystals of Form
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
The reaction temperature is 20-30°C, and the stirring time is 6-12 hours.
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
The reaction temperature is 20-25°C, and the stirring time is 6-10 hours.
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
The reaction temperature was 25°C and the stirring time was 8 hours.
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
Step (1) of uniformly stirring and mixing ethyl acetate and purified water at room temperature - the volume ratio of ethyl acetate and purified water is 100mL:3mL - ;
Step (2) of adding lenvatinib mesylate to the mixed solvent of step (1) - the mass volume ratio of lenvatinib mesylate and ethyl acetate is 1g:20mL; and
After the suspension in step (2) is uniformly dispersed, seed crystals of Form comprising step (3) of obtaining a solid powder, i.e., crystalline Form XI of lenvatinib mesylate,
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
After uniformly stirring and mixing 200 mL ethyl acetate and 20 mL purified water at room temperature, 10.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, and after the suspension was uniformly dispersed, 1.0 g of seed crystals of crystal form XI were added. Stirring at 20°C for 8 hours, followed by filtration and drying under reduced pressure to obtain 9.2 g of solid powder - the yield is 92.0% and the purity is 99.75%.
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
After uniformly stirring and mixing 5000 mL ethyl acetate and 150 mL purified water at room temperature, 250.0 g of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, and after the suspension was uniformly dispersed, 12.5 g of seed crystals of crystal form XI were added. Stirring at 25° C. for 8 hours, followed by filtration and drying under reduced pressure to obtain 232.8 g of solid powder - the yield is 93.1% and the purity is 99.78%.
Method for preparing lenvatinib mesylate crystalline Form XI. In claim 4,
After stirring and mixing 30L of ethyl acetate and 750mL of purified water uniformly at room temperature, 1.5kg of lenvatinib mesylate was added to the mixed solvent of ethyl acetate and purified water, stirred at 25°C for 10 hours, filtered under reduced pressure, and dried to obtain a solid powder of 1.4%. Obtaining kg - yield is 93.3%, purity is 99.95%,
Method for preparing lenvatinib mesylate crystalline Form XI.