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Lenvatinib mesilatee polymorph and preparation method thereof

A polymorphic form, lenvatinib technology, applied in the field of medicine, can solve problems such as not being able to be used as a pharmaceutical crystal form, thermodynamic instability, etc.

Inactive Publication Date: 2019-06-11
ANLITE SHANGHAI PHARMA TECH CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

WO2018054792 discloses various solvates and anhydrates of lenvatinib mesylate, including dimethyl sulfoxide solvates DMSO-1 and DMSO-2, acetic acid solvates ACA-1, anhydrous ACA-1HTDRY , acetic acid / chloroform solvate CHF-1, formic acid / ethyl acetate solvate FOA-1 and anhydrous H 2 O-1, CHF-1 obviously cannot be used as a pharmaceutical crystal form, because chloroform belongs to the second-class solvent with restricted use; formic acid is too acidic, so FOA-1 is not suitable for pharmaceutical preparations; the Onset temperature of ACA-1 is only 91.2°C, H 2 The onset temperature of O-1 is lower, only 34.6°C, and is thermodynamically unstable; ACA-1HT DRY is easy to absorb moisture

Method used

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  • Lenvatinib mesilatee polymorph and preparation method thereof
  • Lenvatinib mesilatee polymorph and preparation method thereof
  • Lenvatinib mesilatee polymorph and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0104] Embodiment 1: Preparation of crystal form AZT-15

[0105]Weigh 2.0 g of lenvatinib free base and add it into 20 mL of DMSO:acetone=3:1 mixed solvent, heat and stir at 50°C. After the solution was clear, 0.5 g of methanesulfonic acid was added and stirred for 10 minutes. Add 20 mL of MTBE dropwise for 30 minutes. After the dropwise addition, the temperature was lowered to 10-15° C., and the stirring was continued for 24 hours. Filter and dry under vacuum at 25°C to obtain flaky light yellow crystals. Gained crystal is tested by XRPD, and its X-ray powder diffraction pattern is as follows figure 1 As shown; by TGA test, the TGA figure of crystal form AZT-15 appears a weight loss peak at 181 ° C, and its spectrum is as follows figure 2 As shown; after the DSC test, the DSC diagram of the crystal form AZT-15 has a desolvation endothermic peak at 174 ° C, and the Onset temperature is 174 ± 2 ° C. The spectrum is as follows image 3 shown by 1 H-NMR test, the spectrum ...

Embodiment 2

[0110] Embodiment 2: Preparation of crystal form AZT-15

[0111] Weigh 2.0 g of lenvatinib free base and add it into 30 mL of DMSO:ethanol=4:1 mixed solvent, heat and stir at 50°C. After the solution was clear, 0.5 g of methanesulfonic acid was added and stirred for 10 minutes. Slowly add 30 mL of MTBE dropwise for 30 minutes. After the dropwise addition, the temperature was lowered to 10-15° C., and the stirring was continued for 24 hours. Filter and dry under vacuum at 25°C to obtain flaky light yellow crystals. The obtained crystals were subjected to XRPD, TGA, DSC, 1 H-NMR test, the obtained spectrograms are all substantially consistent with that of Example 1.

Embodiment 3

[0112] Embodiment 3: Preparation of crystal form AZT-15

[0113] Weigh 2.0 g of lenvatinib free base and add it into 20 mL of DMSO, heat and stir at 60°C. After the solution was clear, 0.5 g of methanesulfonic acid was added and stirred for 10 minutes. Cool down to 20° C., add 0.02 g of the crystal form AZT-15 obtained in Example 1, and stir for 10 minutes. Slowly add 20 mL of MTBE dropwise for 30 minutes. After the dropwise addition, the temperature was lowered to 10-15° C., and the stirring was continued for 24 hours. Filter and dry in a vacuum oven at 25°C to obtain flaky light yellow crystals. The obtained crystals were subjected to XRPD, TGA, DSC, 1 H-NMR test, the obtained spectrograms are all substantially consistent with that of Example 1.

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Abstract

The invention relates to a lenvatinib mesilatee polymorph and a preparation method thereof. In particular, the present invention provides a novel crystalline form of a lenvatinib mesilatee dimethyl sulfoxide solvate and a preparation method of the novel crystalline form. The novel crystalline form of the present invention has an excellent crystal form and chemical stability, and better flowability.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a lenvatinib mesylate dimethyl sulfoxide solvate polymorph and a preparation method thereof. Background technique [0002] The chemical name of lenvatinib mesylate is 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7-methoxy-6-quinolinecarboxamide mesylate, Its structural formula is as follows: [0003] [0004] Lenvatinib mesylate was developed by Japan's Eisai Co., Ltd. in February 2015 and was approved by the FDA for the treatment of advanced radioactive-iodine refractory differentiated thyroid cancer. In July, it was approved by Japan and the European Union. In July of the same year, the FDA further granted lenvatinib the breakthrough drug qualification for the treatment of advanced or metastatic renal cell carcinoma. [0005] CN100569753C discloses crystal forms A, B, C, F (hydrate), I (acetate), dimethylsulfoxide solvate (DMSO) of lenvatinib mesylate and a preparation met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48C07C303/32C07C309/04A61K31/47A61P35/00
Inventor 刘天杰申淑匣张良
Owner ANLITE SHANGHAI PHARMA TECH CO LTD
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