Preparation method of amorphous quinoline carboxamide derivative

An amorphous, methanesulfonic acid technology, applied in the field of medicinal chemistry, can solve the problems of easy agglomeration of amorphous form, unfavorable drug safety and quality control, and unsuitable for mass scale-up production.

Active Publication Date: 2021-07-09
NANJING CHIA TAI TIANQING PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] CN101233111A and CN104755463A record decompression concentration distillation, heating and boiling and other operations will lead to the degradation of lenvatinib mesylate, and the impurity content will increase, which is not conducive to the safety and quality control of the drug, and the obtained amorphous is easy to agglomerate, Not suitable for mass scale-up production

Method used

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  • Preparation method of amorphous quinoline carboxamide derivative
  • Preparation method of amorphous quinoline carboxamide derivative
  • Preparation method of amorphous quinoline carboxamide derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0051] The investigation of embodiment 1 freeze-drying solvent

[0052] Dissolve lenvatinib mesylate crystal form C (5g) in different solvent systems, stir and dissolve at 20±5°C, filter, collect the filtrate and freeze-dry, the specific freeze-drying method is as follows:

[0053] 1) Pre-freezing

[0054] The temperature of the heat transfer oil reaches -40°C in 1.5h and keeps for 4h;

[0055] 2) Once dry

[0056] In the first stage, the temperature of the heat transfer oil reaches -10°C in 4 hours, the vacuum degree is 10 Pa, and it is kept for 24 hours;

[0057]In the second stage, the temperature of the heat transfer oil reaches 10°C in 2 hours, and the vacuum degree is 10 Pa, and it is kept for 24 hours;

[0058] 3) Analytical drying

[0059] In the first stage, the temperature of the heat transfer oil reaches 20°C in 2 hours, and the vacuum degree is 10 Pa, and it is kept for 4 hours;

[0060] In the second stage, the temperature of the heat transfer oil reaches 35°...

Embodiment 2

[0065] Embodiment 2 tert-butanol / water system investigation

[0066] In order to dissolve more effectively, the influence of different proportions of tert-butanol / water system on the solubility was investigated, and the experimental data are shown in Table 2.

[0067] Table 2 The influence of different proportions of tert-butanol / water system on solubility

[0068] Numbering Solvent ratio (volume ratio) melting temperature dissolved volume dissolution phenomenon 1. tert-butanol / water=2:1 20±5℃ 18 times form a transparent gel 2. tert-butanol / water=1:1 20±5℃ 45 times Forms a low viscosity clear solution 3. tert-butanol / water=1:2 20±5℃ 70 times Forms a low viscosity clear solution 4. tert-butanol / water=1:3 20±5℃ 129 times Forms a low viscosity clear solution

[0069] Conclusion: The ratio of tert-butanol / water in the range of 1:1 to 1:3 can form a low-viscosity transparent solution with uniform dissolution. Conside...

Embodiment 3

[0070] Embodiment 3 lyophilization curve optimization

[0071] For more effective freeze-drying, a freeze-drying solvent of tert-butanol / water with a volume ratio of 1:1 was selected, and the temperature and time of the pre-freezing stage, sublimation stage, and desorption stage were investigated, and the freeze-drying curve was studied. The experimental results As shown in Table 3, the vacuum degree is 10 Pa.

[0072] Table 3 freeze-drying curve optimization experimental results

[0073]

[0074]

[0075] Conclusion: The tert-butanol / water system lyophilization adopts slow temperature rise and step-by-step analysis drying in the first drying stage, which can ensure the appearance of the drug is fluffy and not collapsed, the sample has low moisture content and low residual solvent.

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Abstract

The invention relates to a preparation method of an amorphous quinoline carboxamide derivative, which comprises the following steps: dissolving a crystal form C of lenvatinib mesylate in a tert-butyl alcohol/water mixed solvent, stirring, filtering, collecting filtrate, and freeze-drying to obtain the amorphous quinoline carboxamide derivative. The amorphous form obtained by the method is high in purity, uniform in freeze-drying, fluffy in sample appearance, low in water content, qualified in solvent residue, small in damage of a freeze-drying solvent to instruments and equipment, safe to operate and suitable for industrial production, the obtained amorphous form does not generate a gel phenomenon in a preparation process, and capsules prepared from the amorphous form as a raw material have the advantage of being fast in dissolution.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a preparation method of amorphous quinoline formamide derivatives. Background technique [0002] 4-[3-Chloro-4-(N'-cyclopropylureido)phenoxy]-7-methoxyquinoline-6-carboxamide methanesulfonate, namely lenvatinib mesylate, It is a multi-target receptor tyrosine kinase inhibitor, which is used for the treatment of aggressive, locally advanced or metastatic differentiated thyroid cancer, advanced renal cell carcinoma, liver cancer, etc., and its structure is shown in formula I: [0003] [0004] CN102470133A discloses A of 4-[3-chloro-4-(N'-cyclopropylureido) phenoxy]-7-methoxyquinoline-6-formamide methanesulfonate (formula I for short). , B, C crystal forms and various crystal forms of hydrates or other salt forms. CN101233111A and CN104755463A disclose amorphous crystals and preparation methods thereof. [0005] CN102470133A discloses the pharmaceutical preparation of the f...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/48C07C303/44C07C309/04
CPCC07D215/48C07C309/04
Inventor 朱春霞吴晶张道俊马雪龙徐丹柴雨柱王华萍宋洁梅江宁赵炎磊龚彦春刘永强
Owner NANJING CHIA TAI TIANQING PHARMA
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