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Lenvatinib-3,5-dihydroxybenzoic acid eutectic crystal and application thereof

A technology of dichloromethane and methanol, applied in the field of lenvatinib-3,5-dihydroxybenzoic acid co-crystal, which can solve the problem of less research on lenvatinib co-crystal

Inactive Publication Date: 2020-08-25
NOVAGENESIS THERAPEUTIX SUZHOU LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] At present, there are few studies on lenvatinib co-crystal, so lenvatinib co-crystal still needs to be developed

Method used

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  • Lenvatinib-3,5-dihydroxybenzoic acid eutectic crystal and application thereof
  • Lenvatinib-3,5-dihydroxybenzoic acid eutectic crystal and application thereof
  • Lenvatinib-3,5-dihydroxybenzoic acid eutectic crystal and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0073] The preparation method of LVB-3,5-DBA co-crystal: 500mg LVB+180mg 3,5-DBA+5ml methanol-dichloromethane (1:1) stirred for 48h, then centrifuged or filtered to separate and dry.

[0074] Characterization of co-crystals by PXRD

[0075] The prepared co-crystal and bulk drug were analyzed by powder X-ray (PXRD) as follows: image 3 As shown, it can be seen from the results that the newly prepared LVB-3,5-DBA co-crystal has significantly different diffraction from the raw drug lenvatinib (LVB) and the co-crystal former 3,5-dihydroxybenzoic acid pattern, indicating that a new co-crystal was successfully prepared.

[0076] Characterization of co-crystals by DSC

[0077] The prepared eutectic powder was characterized by differential scanning calorimetry (DSC) with a heating rate of 20°C / min and nitrogen as a protective gas. The results are as follows: Figure 4 shown. from Figure 4 It can be seen that the peak melting points of 3,5-DBA, LVB-3,5-DBA and lenvatinib free bas...

Embodiment 2

[0079] Intrinsic dissolution test of LVB-3,5-DBA and LVB mesylate salt already on the market

[0080] Experiments were carried out with an inherent dissolution device (Fucus Analytical Instrument Co., Ltd., China). LVB-3,5-DBA or LVB methanesulfonate and water-soluble starch are physically mixed in a weight ratio of 7 / 3, and then pressed at 300kgf for 2 minutes to prepare tablets for dissolution. Intrinsic dissolution conditions: 500ml 0.1M HCl (0.1% Tween 80) dissolution medium, rotating speed 300RPM. Take 1 ml of samples at 2, 4, 6, 8, and 10 min, respectively, and centrifuge at 13000 RPM for 2 min to measure the LVB concentration in the supernatant. The results are as follows Figure 5 shown. The results demonstrate that the LVB-3,5-DBA co-crystal has a faster intrinsic dissolution rate than the marketed LVB mesylate.

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Abstract

The invention discloses a lenvatinib-3,5-dihydroxybenzoic acid eutectic crystal and application of thereof. The eutectic crystal is composed of a compound shown as a formula (I) and a compound shown as a formula (II). In an X-ray powder diffraction pattern of the crystal form of the eutectic crystal, diffraction peaks occur when an 2theta angle is equal to 6.4 degrees + / - 0.2 degree, 8.0 degrees + / - 0.2 degree, 10.3 degrees + / - 0.2 degree, 11.6 degrees + / - 0.2 degree, 12.4 degrees + / - 0.2 degree, 16.0 degrees + / - 0.2 degree, 16.5 degrees + / - 0.2 degree, 19.4 degrees + / - 0.2 degree, 21.7 degrees + / - 0.2 degree, 23.2 degrees + / - 0.2 degree, 25.1 degrees + / - 0.2 degree and 25.7 degrees + / - 0.2 degree. The eutectic crystal can be used for inhibiting vascular endothelial growth factor receptors, fibroblast growth factor receptors, platelet-derived growth factor receptors and proto-oncogenes, and can be used for preventing and / or treating thyroid cancer or liver cancer.

Description

technical field [0001] The invention relates to the field of biomedicine, in particular, the invention relates to lenvatinib-3,5-dihydroxybenzoic acid co-crystal and application thereof. Background technique [0002] Lenvatinib is an anticancer drug developed and marketed by Japan's Eisai Company, which is approved for the treatment of thyroid cancer and liver cancer. Lenvatinib is a multi-enzyme inhibitor that can inhibit three vascular endothelial growth factor receptors (VEGFR1,2,3), fibroblast growth factor receptors (FGFR 1,2,3,4), platelet-derived growth factor receptor (PDGFR) and proto-oncogene. [0003] The co-crystal in pharmacy refers to the crystal formed by the combination of active pharmaceutical ingredient (active pharmaceutical ingredient, API) and cocrystal former (cocrystal former, CCF) under the action of hydrogen bond or other non-covalent bonds, in which API The pure states of CCF and CCF are solid at room temperature, and there is a fixed stoichiometr...

Claims

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Application Information

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IPC IPC(8): C07D215/48C07C65/03A61K31/47A61P35/00
CPCA61P35/00C07B2200/13C07C65/03C07D215/48
Inventor 钱锋刘程宇
Owner NOVAGENESIS THERAPEUTIX SUZHOU LTD