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New crystal form of lenvatinib mesylate, and preparation method thereof

A technology for lenvatinib mesylate and mesylate, which is applied to the new crystal form of lenvatinib mesylate and the field of preparation thereof, can solve the problem that the preparation process of crystal form M is difficult to control, difficult to purify, etc. question

Inactive Publication Date: 2020-03-24
CRYSTAL PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the research of the inventors of the present application, the preparation process of crystal form M is difficult to control and difficult to purify

Method used

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  • New crystal form of lenvatinib mesylate, and preparation method thereof
  • New crystal form of lenvatinib mesylate, and preparation method thereof
  • New crystal form of lenvatinib mesylate, and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0058] Example 1 The preparation method of lenvatinib mesylate salt crystal form 6

[0059] Put 1.0733 g of lenvatinib free base solid in a jacketed reaction flask, add 25 mL of acetonitrile and water mixed solvent (the volume ratio of acetonitrile and water is 99 / 1), and stir at 10°C. 155 μL of methanesulfonic acid (purity>99%) was added into 3 mL of acetonitrile, and the solution of methanesulfonic acid in acetonitrile was dropped into the reaction flask within 120 minutes. Stirring was continued for 22 hours at 10°C. After filtration, the filter cake was dried at room temperature to obtain a white solid.

[0060] After testing, the white solid obtained in this experiment is the crystal form 6 of lenvatinib mesylate. Its X-ray powder diffraction data are as follows figure 1 , shown in Table 1. DSC of Form 6 as figure 2 As shown, when heated to 71°C, dehydration begins. TGA of Form 6 as image 3 As shown, when heated to 125 ° C, there is about 4.3% weight loss.

[00...

Embodiment 2

[0065] Stability test of embodiment 2 mesylate crystal form 6

[0066] Samples of crystal form 6 of the mesylate salt of the present invention were taken respectively and placed under the conditions of room temperature / 22.5% relative humidity and room temperature / 43.2% relative humidity for 13 weeks, and samples were taken to detect changes in the crystal form. The results are shown in Table 2. XRPD comparison pictures of mesylate salt form 6 before and after placement Figure 5 shown. Figure 5 The upper picture is before storage, the middle one is after 13 weeks at room temperature / 22.5% relative humidity, and the lower picture is after 13 weeks at room temperature / 43.2% relative humidity.

[0067] Table 2

[0068] starting crystal form condition placement time Crystalline change Mesylate salt form 6 Room temperature / 22.5% relative humidity 13 weeks constant Mesylate salt form 6 Room temperature / 43.2% relative humidity 13 weeks constan...

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Abstract

The invention relates to a new crystal form of lenvatinib mesylate, and a preparation method thereof. The new crystal form of mesylate is good in stability, remarkable in process purification effect,simple in preparation method and low in cost, and has important value in optimizing and developing of medicine in the future.

Description

technical field [0001] The invention relates to the field of chemical medicine, in particular to a new crystal form of lenvatinib mesylate and a preparation method thereof. Background technique [0002] Lenvatinib is an oral multi-receptor tyrosine kinase (RTK) inhibitor developed by Japan's Eisai Company for the treatment of aggressive and differentiated thyroid cancer. It was obtained on February 13, 2015 Approved by the FDA, approved by the EMA on May 28, 2015, and the approved drug is lenvatinib mesylate crystal form C. The chemical name of lenvatinib is: 4-(3-chloro-4-(cyclopropylaminocarbonyl) aminophenoxy)-7-methoxy-6-quinolinecarboxamide, its structural formula is as formula (I ) shown. [0003] [0004] It is known that different crystal forms of solid chemical drugs can cause different solubility and stability, thereby affecting drug absorption and bioavailability, and leading to differences in clinical efficacy. Therefore, it is one of the important research...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/22C07C303/32C07C309/04A61K31/47A61P35/00
CPCA61P35/00C07B2200/13C07C303/32C07C309/04C07D215/22
Inventor 陈敏华张炎锋张龙黄春香杨朝惠张晓宇
Owner CRYSTAL PHARMA CO LTD
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