CN113831283B - Preparation method of lenvatinib salt amorphous substance - Google Patents
Preparation method of lenvatinib salt amorphous substance Download PDFInfo
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- CN113831283B CN113831283B CN202111296789.6A CN202111296789A CN113831283B CN 113831283 B CN113831283 B CN 113831283B CN 202111296789 A CN202111296789 A CN 202111296789A CN 113831283 B CN113831283 B CN 113831283B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 30
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- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
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- JTEGQNOMFQHVDC-NKWVEPMBSA-N lamivudine Chemical compound O=C1N=C(N)C=CN1[C@H]1O[C@@H](CO)SC1 JTEGQNOMFQHVDC-NKWVEPMBSA-N 0.000 description 1
- 229960001627 lamivudine Drugs 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of pharmaceutical chemistry, and particularly discloses a preparation method of a cerivatinib mesylate amorphous substance, which comprises the steps of dissolving a cerivatinib mesylate C crystal form in purified water by adopting pure water as a solvent, and preparing the cerivatinib mesylate amorphous substance through stirring, cooling, freeze-drying and drying processes, wherein the method does not use any organic solvent, is environment-friendly, saves cost, has low energy consumption and is simple to operate, and can freeze-dry and vacuum-dry to prepare high-purity cerivatinib mesylate salt within 24 hours, meanwhile, the risk of rising of genotoxic impurities in the prior patent is avoided, no impurity is generated in the preparation process, and the prepared cerivatinib mesylate has high purity, less water content and water content, increased solubility and accords with the pharmaceutical standard; the pharmaceutical compositions prepared using the amorphous forms of the present invention have significant dissolution advantages.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and relates to a preparation method of an amorphous substance of a lenvatinib salt, in particular to a preparation method of an amorphous substance of 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide mesylate.
Background
Lenvatinib mesylate (Lenvatinib Mesilate), chemical name: 4- [ 3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy ] -7-methoxy-6-quinolinecarboxamide mesylate is an orally effective multi-kinase inhibitor developed by the Japanese health company, and mainly acts on a plurality of targets such as c-Kit, ret and VEGFR-2, and is used for treating solid tumors such as glioma, thyroid tumor, renal cancer, liver cancer and ovarian cancer. The U.S. FDA orphan drug was obtained 2 months 2013 and was approved clinically for the treatment of follicular, medullary, undifferentiated metastatic or locally advanced papillary thyroid cancer.
Amorphous is one of the most favorable forms of drug administration in the metastable state of the drug. Amorphous is a special crystalline state. In commercial processes, the surface of the compound may undergo a small amount of structural damage to become amorphous. The conventional instrument can hardly detect a small amount of amorphous substances, the physical properties of the amorphous structures of the medicines are greatly different from those of the crystal forms, the amorphous structures can greatly influence the stability, compatibility, dissolution speed, hygroscopicity, solvent adsorption tendency and other properties of products, and the existence of the amorphous substances can extremely influence the stability of the medicines in the production and storage processes, so that the whole new medicine development fails. The phenomenon that the medicinal crystal form C is converted into an amorphous substance exists in the preparation process of the lenvatinib mesylate, so that two crystal forms of the crystal form C and the amorphous substance exist in a tablet of the lenvatinib mesylate at the same time; in addition, the published report shows that the lenvatinib mesylate salt can not gel in an amorphous state, and can be rapidly dissolved out without adding alkaline auxiliary materials in the preparation process of the preparation. Therefore, the stable amorphous compound of the lenvatinib mesylate is provided, is not only important for researching qualitative and quantitative analysis of the amorphous compound in the lenvatinib mesylate tablet and improving the safety and stability of medicines, but also can be used as a raw material medicine to improve the dissolution performance of the medicinal preparation of the lenvatinib mesylate.
The original patent CN101233111A, CN104755463a discloses an amorphous crystal of lenvatinib mesylate and a preparation method thereof, but the preparation method is not suitable for process magnification. In the patent, alcohol solvents are used for freeze-drying, the solubility of alcohols to salt of the lenvatinib is low, meanwhile, the complete system is difficult to pre-freeze, extremely low temperature is needed, and the requirement on equipment is high; and the alcohol solvent is easy to react with methanesulfonic acid in the lenvatinib mesylate to generate genotoxic impurity methanesulfonate, which is not beneficial to the safety and quality control of the medicine. Meanwhile, the method uses reduced pressure concentration distillation and heating reflux, and the method can lead to degradation of the lenvatinib mesylate, so that the impurity content is increased, and the safety and quality control of the medicine are also not facilitated.
Patent CN113087666A discloses a method for preparing amorphous form of the lamivudine mesylate by using an alcohol/water mixed solvent such as tertiary butanol/water for dissolution, filtering, pre-freezing the filtrate at-45 ℃, and freeze-drying at-45 to-10 ℃ to obtain the amorphous form. The method avoids high temperature and reduces the generation of degradation impurities; however, since the method uses alcohols, the risk of the production of the genotoxic impurity mesylate is increased. In addition, the method disclosed by the patent is used for preparing the amorphous lenvatinib compound, although the freezing point of the mixed solvent of the alcohol and the water is higher than that of the alcohol, the mixed solvent still needs a very low temperature (-45 to-10 ℃), the freeze-drying time is long, the preparation condition requirement is high, the energy consumption is high, and the environment is not protected.
Therefore, the research on the preparation process of the amorphous lenvatinib mesylate, which is environment-friendly, low in energy consumption and simple to operate, can stably prepare the high-purity amorphous lenvatinib mesylate compound, reduce the risk of generating genotoxic impurities in the preparation process, and stably provide the amorphous substance of the lenvatinib mesylate for qualitative and quantitative analysis of the amorphous substance in the preparation and preparation of the preparation, and has important significance.
Disclosure of Invention
The invention aims to provide a preparation method of an amorphous substance of high-purity lenvatinib salt, which is environment-friendly, simple and convenient to operate and easy for industrial production, in particular to provide a preparation method of an amorphous substance of lenvatinib mesylate, and the preparation method is used for qualitative and quantitative analysis or preparation of the amorphous substance in a product of the lenvatinib mesylate.
In order to achieve the above purpose, the invention discloses a preparation method of an amorphous substance of lenvatinib mesylate, which comprises the following specific steps:
Dissolving the lenvatinib mesylate crystal form C by using purified water at 20-30 ℃, cooling the lenvatinib mesylate solution after stirring and clearing, setting the freeze-drying temperature and freeze-drying time when the solution is completely solidified into solid, and placing the solid in a freeze-dryer for freeze-drying to be in a powder state; and taking out the powdery solid, placing the powdery solid in a vacuum drying oven for vacuum drying, and controlling the temperature of the vacuum drying oven to be 50-55 ℃ and the vacuum degree to be less than-0.09 MPa for vacuum drying for 10-12 hours to obtain the lenvatinib mesylate amorphous substance.
According to an embodiment of the present invention, acetonitrile, ethanol, purified water, tert-butanol/water are used as solvents to dissolve lenvatinib mesylate, respectively. Studies show that the lenvatinib mesylate can be dissolved in purified water and tertiary butanol/water systems at 20-30 ℃, can not be dissolved in ethanol and acetonitrile, and can not be dissolved in acetonitrile with 400 times of volume under reflux. The invention preferably uses purified water as a solvent for dissolving the lenvatinib mesylate, and the dissolution temperature is selected from 20-30 ℃. The solvent may also be drinking water or distilled water.
According to an embodiment of the invention, the mass to volume ratio of the lenvatinib mesylate to the purified water in which the lenvatinib mesylate is dissolved is selected from 1:100 to 1:200, preferably 1:110. The inventor researches find that when the mass-volume ratio of the lenvatinib mesylate to the purified water for dissolving the lenvatinib mesylate is higher than 1:100, the lenvatinib mesylate cannot be completely dissolved, and a large amount of colloidal solids are generated; when the mass volume ratio of the lenvatinib mesylate to the purified water is 1:100-1:200, the lenvatinib mesylate can be completely dissolved, and the system is clear without obvious colloidal solids.
According to the embodiment of the invention, when preparing the amorphous substance of the lenvatinib mesylate, purified water is added to stir and dissolve the lenvatinib mesylate at 20-30 ℃, and then the mixture can be completely solidified at-10-0 ℃ without obvious liquid or colloidal solid, preferably at-5-0 ℃.
According to the embodiment of the invention, when preparing the lenvatinib mesylate amorphous substance, the water system of the lenvatinib mesylate which is solidified into a solid can be freeze-dried at the temperature below 0 ℃ in consideration of the freezing point of water, the freeze-drying temperature is preferably-5-0 ℃, and a vacuum pump is started to freeze-dry until the water system is in a powder state. The study shows that a small amount of ice cubes exist in a system with the freeze-drying time less than 9 hours, a large amount of foam-like solids appear, and the freeze-drying time is preferably 9-12 hours.
According to an embodiment of the present invention, the amorphous form of lenvatinib mesylate prepared by the method disclosed by the present invention has no sharp diffraction peak in the X-ray powder diffraction spectrum expressed in 2θ by cu—kα radiation; the infrared absorption spectrum obtained by KBr pellet measurement has an absorption peak at 1050.384cm-1、1192.971cm-1、1454.558 cm-1、1647.389 cm-1、3304.492 cm-1.
Compared with the prior art, the invention provides a method for preparing the stable amorphous substance of the lenvatinib mesylate, which can be used for researching the crystal form of the preparation, the preparation process of the amorphous substance of the lenvatinib mesylate disclosed by the invention does not use any organic solvent, is environment-friendly, low in energy consumption and simple in operation, and can be used for preparing the high-purity lenvatinib mesylate salt by freeze-drying and vacuum drying within 24 hours, meanwhile, the risk of increasing genotoxic impurities in the prior patent is avoided, no impurities are generated in the preparation process, and the prepared lenvatinib mesylate is high in purity, less in water content and increased in solubility and accords with the medicinal standard; the pharmaceutical compositions prepared using the amorphous forms of the present invention have significant dissolution advantages.
Drawings
Fig. 1 is an HPLC profile of crystalline form C of lenvatinib mesylate prior to lyophilization.
FIG. 2 is an X-ray powder diffraction spectrum of the amorphous form of lenvatinib mesylate of example 2.
FIG. 3 is an infrared spectrum of the amorphous form of lenvatinib mesylate of example 2.
Fig. 4 is an HPLC profile of the amorphous form of lenvatinib mesylate of example 2.
FIG. 5 is an X-ray powder diffraction spectrum of the amorphous form of lenvatinib mesylate of example 3.
Fig. 6 is an HPLC profile of the amorphous form of lenvatinib mesylate of example 3.
FIG. 7 is an X-ray powder diffraction spectrum of the amorphous form of lenvatinib mesylate of example 4.
Fig. 8 is an HPLC profile of the amorphous form of lenvatinib mesylate of example 4.
FIG. 9 is an X-ray powder diffraction spectrum of the amorphous form of lenvatinib mesylate of example 5.
Fig. 10 is an HPLC profile of the amorphous form of lenvatinib mesylate of example 5.
FIG. 11 is an HPLC plot of an amorphous form of lenvatinib mesylate of comparative example 1.
Detailed Description
EXAMPLE 1 investigation of the reaction conditions
The method comprises the steps of adding the lenvatinib mesylate crystal C (5 g) into a three-neck flask, and adding a solvent, wherein each parameter is selected from the following steps:
(1) Solvent screening
TABLE 1 solvent screening
Conclusion: purified water is selected as a solvent, and the C crystal form of the lenvatinib mesylate can be completely dissolved at 20-30 ℃, so that an organic solvent is not needed, the environment is protected, and the cost is saved.
(2) Screening of purified Water quantity
TABLE 2 purified water dosage screening
Conclusion: every 1g of the lenvatinib mesylate can select 100-200 mL of purified water as a solvent, and 5g of the lenvatinib mesylate preferably selects 550mL of purified water.
(3) Temperature reduction and selection of solution
Stirring at 20-30 ℃ for 2-3 hours until the solution is clear, and starting to cool after the solution is clear, wherein the cooling temperature is selected as follows:
TABLE 3 Cooling temperature screening
Conclusion: the system after the solution is clear can be completely solidified at the temperature of-5~0 ℃ without obvious liquid or mucilage binding solid.
(4) Freeze-drying time and temperature selection:
When all the solvent in the system is solidified into solid, the solid is placed in a freeze dryer, the temperature of the freeze dryer is set to be-5~0 ℃ according to the freezing point of water and the solidification temperature of the solvent system, and a vacuum pump is started until the solid is in powder form.
Table 4 lyophilization time screen
Conclusion: the freeze-drying time is less than 9 hours, a small amount of ice cubes exist in the system, a large amount of foam-like solids appear, and freeze-drying cannot be performed. Therefore, the freeze-drying time is set to 9-12 hours to finish freeze-drying.
Example 2
Adding the lenvatinib mesylate crystal C (5 g) into a three-neck flask, adding 550ml of purified water, stirring for 2-3 hours at 20-30 ℃ until the solution is clear, cooling to-5~0 ℃ after the solution is clear, placing the solid into a freeze dryer when the solvent in the system is completely solidified into solid, setting the temperature of the freeze dryer to-5~0 ℃, starting a vacuum pump, and freeze-drying for 9-12 hours until the solid is powdery. And after the freeze-drying is finished, taking out the solid powder, placing the solid powder in a vacuum drying oven, setting the temperature of the drying oven to be 50-55 ℃, controlling the vacuum degree to be less than-0.09 MPa, and vacuum drying for 10-12 hours, and collecting 4.8g of the amorphous substance of the lenvatinib mesylate. The purity is 99.796% and the water content is 0.32%. The powder X-ray diffraction diagram is shown in FIG. 2, the infrared absorption spectrum is shown in FIG. 3, and the HPLC spectrum is shown in FIG. 4.
Example 3
Adding the lenvatinib mesylate crystal C (5 g) into a three-neck flask, adding 550ml of purified water, stirring for 2-3 hours at 20-30 ℃ until the solution is clear, cooling to-10-5 ℃ after the solution is clear, placing the solid into a freeze dryer when all solvents in the system are solidified into solid, setting the temperature of the freeze dryer to-5~0 ℃, starting a vacuum pump, and freeze-drying for 9-12 hours until the solid is powdery. And after the freeze-drying is finished, taking out the solid powder, placing the solid powder in a vacuum drying oven, setting the temperature of the drying oven to be 50-55 ℃, controlling the vacuum degree to be less than-0.09 MPa, and vacuum drying for 10-12 hours, and collecting 4.7g of the amorphous substance of the lenvatinib mesylate. The purity is 99.797% and the water content is 0.35%. The powder X-ray diffraction pattern is shown in FIG. 5, and the HPLC pattern is shown in FIG. 6.
Example 4
Adding the lenvatinib mesylate crystal C (5 g) into a three-neck flask, adding 1100ml of purified water, stirring for 2-3 hours at 20-30 ℃ until the solution is clear, cooling to-10 to-5 ℃ after the solution is clear, placing the solid into a freeze dryer when the solvent in the system is completely solidified into solid, setting the temperature of the freeze dryer to-5~0 ℃, starting a vacuum pump, and freeze-drying for 9-12 hours until the solid is powdery. And after the freeze-drying is finished, taking out the solid powder, placing the solid powder in a vacuum drying oven, setting the temperature of the drying oven to be 50-55 ℃, controlling the vacuum degree to be less than-0.09 MPa, and vacuum drying for 10-12 hours, and collecting 4.8g of the amorphous substance of the lenvatinib mesylate. The purity is 99.795% and the water content is 0.34%. The powder X-ray diffraction pattern is shown in FIG. 7, and the HPLC pattern is shown in FIG. 8.
Example 5
Adding the lenvatinib mesylate crystal C (5 g) into a three-neck flask, adding 1000ml of purified water, stirring for 2-3 hours at 20-30 ℃ until the solution is clear, cooling to-5~0 ℃ after the solution is clear, placing the solid into a freeze dryer when the solvent in the system is completely solidified into solid, setting the temperature of the freeze dryer to-5~0 ℃, starting a vacuum pump, and freeze-drying for 9-12 hours until the solid is powdery. And after the freeze-drying is finished, taking out the solid powder, placing the solid powder in a vacuum drying oven, setting the temperature of the drying oven to be 50-55 ℃, controlling the vacuum degree to be less than-0.09 MPa, and vacuum drying for 10-12 hours, and collecting 4.6g of the amorphous substance of the lenvatinib mesylate. The purity is 99.793% and the water content is 0.38%. The powder X-ray diffraction pattern is shown in FIG. 9, and the HPLC pattern is shown in FIG. 10.
Comparative example 1 reference CN113087666a example 4 method for preparing amorphous form
50G of lenvatinib mesylate in crystal form C is added into 3.5L of mixed solution of tertiary butanol/water=1:2, stirred and dissolved at 15-25 ℃, filtered, and the filtrate is collected for freeze-drying, pre-frozen at-45 ℃ for 4 hours, dried once for 10 Pa for 4 hours, heated to-10 ℃, maintained at 12 hours, heated to 0 ℃ for 2 hours, maintained at 12 hours, heated to 10 ℃ for 24 hours, analyzed for 10 Pa for 20 ℃ for 4 hours, heated to 35 ℃ for 4 hours, and finally 48g of light yellow spongy solid with water content of 0.40% and related purity of 99.764% is obtained. The HPLC profile is shown in FIG. 11.
EXAMPLE 6 dissolution investigation
The amorphous forms obtained in example 2 and comparative example 1 were used as raw materials to prepare lamentatinib mesylate capsules, the dissolution rates were measured, and the compositions of the formulations are shown in table 5.
Table 5 capsule prescription
Group A: the amorphous substance of the lenvatinib mesylate example 2, calcium carbonate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, mannitol and microcrystalline cellulose pH101 are added into a self-sealing bag and manually mixed for 5min, the materials are poured into a tray, the prescribed amount of purified water is added into the tray, the materials are manually granulated, the wet soft material is placed into a blast drying box and dried at 65 ℃ until the water content is less than or equal to 3.0%, the wet soft material is taken out and is sieved by a 20-mesh screen to be granulated, the granules are filled into the self-sealing bag, the prescribed amount of talcum powder and microcrystalline cellulose pH102 are added into the self-sealing bag, the mixture is manually mixed for 5min, and the mixture is filled into No. 4 HPMC hollow capsules.
Group B: the amorphous substance of the lenvatinib mesylate in the comparative example 1, calcium carbonate, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, mannitol and microcrystalline cellulose pH101 are added into a self-sealing bag and manually mixed for 5min, the materials are poured into a tray, the prescribed amount of purified water is added, the materials are manually granulated, the wet soft material is placed into a blast drying box and dried at 65 ℃ until the water content is less than or equal to 3.0%, the wet soft material is taken out and is sieved by a 20-mesh screen for granulation, the granules are filled into the self-sealing bag, the prescribed amount of talcum powder and microcrystalline cellulose pH102 are added, the materials are manually mixed for 5min, and the materials are filled into No. 4 HPMC hollow capsules.
The above samples were each examined for dissolution according to the following method, and the results are shown in Table 6.
Dissolution medium: pH4.5 (1L Medium preparation mode: 2.99g sodium acetate trihydrate and 14ml2mol/L acetic acid solution, adding water to 1000ml, measuring pH, adjusting pH to 4.5 with acetic acid)
Volume of medium: 900ml
The method comprises the following steps: paddle method+sedimentation basket
Rotational speed: 75rpm
Sampling time points: 10min, 15min, 20min, 30min, 45min, 60min, 90min, 120min
Liquid phase sampling mode: 5ml of the filtrate was filtered through a 0.45 umPP-filter, and 4ml of the primary filtrate was discarded, and the subsequent filtrate was taken. Fluid infusion 5ml
Ultraviolet sampling mode: 10ml of the filtrate was filtered through a 0.45umPP filter head, and 4ml of the primary filtrate was discarded, and the subsequent filtrate was taken. Fluid infusion 10ml
TABLE 6 dissolution data statistics
EXAMPLE 7 solubility investigation
The amorphous materials obtained in example 2 and comparative example 1 were examined for solubility in order with reference to the chinese pharmacopoeia 2020 edition general examples, and the examination results are shown in table 7.
Table 7 solubility data statistics
Conclusion: comparing tables 6 and 7, compared with the sample obtained by the existing preparation method of the amorphous substance of the lenvatinib mesylate, the amorphous substance prepared by the invention has improved dissolution rate and solubility, and is beneficial to improving bioavailability.
The invention discloses a preparation method of an amorphous substance of a lamentatinib salt. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is specifically noted that all similar substitutions and modifications will be apparent to those skilled in the art, and are intended to be included in the present invention. While the present invention has been described with reference to the preferred embodiments, it will be apparent to one skilled in the art that variations and modifications can be made to the methods described herein, and the techniques of the invention can be implemented and practiced without departing from the spirit and scope of the invention.
Claims (2)
1. A process for the preparation of an amorphous form of lenvatinib mesylate, characterized in that: dissolving the crystalline form C of the lenvatinib mesylate by using purified water at 20-30 ℃, wherein the mass volume ratio of the lenvatinib mesylate to the purified water for dissolving the lenvatinib mesylate is selected from 1:110, cooling the solution of the lenvatinib mesylate at-10-0 ℃ after stirring and clearing, setting the freeze-drying temperature at-5~0 ℃ and the freeze-drying time for 9-12 hours when the solution is completely solidified into solid, and placing the solid in a freeze-dryer for freeze-drying to be in a powder state; and taking out the powdery solid, placing the powdery solid in a vacuum drying oven for vacuum drying, setting the temperature of the drying oven to be 50-55 ℃, controlling the vacuum degree to be less than-0.09 MPa, and vacuum drying for 10-12 hours to obtain the lenvatinib mesylate amorphous substance, wherein the lenvatinib mesylate amorphous substance is irradiated by Cu-K alpha, no sharp diffraction peak exists in an X-ray powder diffraction spectrum expressed by 2 theta, and an infrared absorption spectrum obtained by KBr tabletting has an absorption peak at a position of 1050.384cm -1、1192.971cm-1、1454.558cm-1、1647.389cm-1、3304.492cm-1.
2. A process for the preparation of an amorphous form of lenvatinib mesylate according to claim 1, characterized in that the solution of lenvatinib mesylate after the dissolution is stirred is cooled at-5~0 ℃.
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