New Lorlatinib crystal form and preparation method thereof

A lorlatinib crystal form and lorlatinib technology, which are applied in organic chemistry methods, organic chemistry and other directions, can solve the problems of low product purity, lack of druggability, incomplete crystallisation and the like, and achieve a simple preparation process, Improves bioavailability in vivo and facilitates dispersion

Pending Publication Date: 2022-02-18
LUOXIN PHARM SHANGHAI CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, in its disclosed Example 1, it can be seen that the isopropyl acetate solvate is obtained through the crystal form Form 7 beating experiment, and there is a risk of incomplete crystal transformation in the solid-solid transition process.
Form 24 is obtained by slurrying isopropyl acetate solvate in toluene solvent. The slurrying temperature is 80°C and the slurrying time is 72h. There is a problem of solution stability, which may easily lead to the risk of low product purity.
[0006] Chinese patent CN110483551A discloses a (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15,16,17-tetrahydro-2H-8,4 Crystals of -(methine bridge)pyrazolo[4,3-h][2,5,11]benzoxadiazatetradecylcyclo-3-carbonitrile (lorlatinib) free base , the X-ray powder diffraction pattern of the crystal measured by Cu-Ka rays contains at least the following characteristic peaks: the diffraction angle 2θ value is 7.85±0.2°, 12.21±0.2°, 17.16±0.2°, 17.92±0.2°, 20.59±0.2° and 23.44±0.2°, but the crystal form obtained in the disclosed Example 1, after TGA characterization, its weight loss is the weight of one molecule of 1.4-dioxane, so it is speculated that it is a solvate and does not have the ability to be used as a drug sex

Method used

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  • New Lorlatinib crystal form and preparation method thereof
  • New Lorlatinib crystal form and preparation method thereof
  • New Lorlatinib crystal form and preparation method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0124] Preparation of lorlatinib crystal form LX-1

[0125] Dissolve 20 mg of lorlatinib (Form 24 or amorphous) in dimethyl sulfoxide at room temperature at a concentration of 200 mg / ml-250 mg / ml. In this example, lorlatinib (Form 24 or amorphous) is controlled The concentration is 200mg / ml, and the solid powder is obtained by rapid volatilization at room temperature and placed in a 60°C oven for 2 hours to obtain the crystal form LX-1. The XRD spectrum is shown in the appendix figure 1 , DSC spectrum see attached figure 2 , 1 See attached for HNMR spectrum image 3 .

Embodiment 2

[0127] Preparation of lorlatinib crystal form LX-1

[0128] Dissolve 20 mg of lorlatinib (Form 24 or amorphous) in dimethyl sulfoxide at 60°C with a concentration of 300 mg / ml-500 mg / ml. In this example, the control of lorlatinib (Form 24 or amorphous ) at a concentration of 350 mg / ml, dissolved and filtered, cooled at -20°C, and the obtained solid powder was placed at 80°C and continuously vacuumed for 0.5h, which was Lorlatinib crystal form LX-1, and its identification data With embodiment 1.

Embodiment 3

[0130] Preparation of lorlatinib crystal form LX-1

[0131] Dissolve 20 mg of lorlatinib (Form 24 or amorphous) in dimethyl sulfoxide at room temperature, and its concentration is 200 mg / ml-250 mg / ml. In this example, lorlatinib (Form 24 or amorphous ) at a concentration of 200 mg / ml, liquid-liquid diffusion and gas-liquid diffusion at room temperature in the antisolvent, wherein the antisolvent is 5 times that of the good solvent dimethyl sulfoxide, and the obtained solid powder is placed at 60 ° C for 1 hour to continuously vacuumize, which is Lorlatinib crystal form LX-1, wherein the anti-solvent used is isopropyl ether or methyl tert-butyl ether, and its identification data are the same as in Example 1.

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Abstract

The invention discloses a novel Lorlatinib crystal form and a preparation method thereof. The Lorlatinib crystal form LX-1 has diffraction peaks at 6.1 + / -0.2 degrees, 7.3 + / -0.2 degrees, 8.4 + / -0.2 degrees, 9.9 + / -0.2 degrees, 12.0 + / -0.2 degrees, 14.9 + / -0.2 degrees, 16.0 + / -0.2 degrees, 17.2 + / -0.2 degrees, 18.2 + / -0.2 degrees, 19.4 + / -0.2 degrees, 20.0 + / -0.2 degrees, 20.9 + / -0.2 degrees, 21.8 + / -0.2 degrees, 22.8 + / -0.2 degrees and 25.8 + / -0.2 degrees in an X-ray powder diffraction pattern represented by a 2 theta angle, and has an endothermic peak at 205 + / -5 DEG C in a differential scanning heat map, and Karl Fischer moisture detection is 0.03%. The crystal form has good stability and solubility, the preparation process is simple and controllable, and the crystal form has good patent medicine prospects.

Description

technical field [0001] The invention relates to a medicine and a preparation method thereof, in particular to a new crystal form of lorlatinib and a preparation method thereof. Background technique [0002] Lorlatinib, English name: Lorlatinib, the drug is an ALK inhibitor modified by Pfizer of the United States through Crizotinib. It entered clinical trials in 2014 for the treatment of lung cancer, mainly for the first For non-small cell lung cancer patients resistant to the first-generation ALK inhibitor crizotinib and the second-generation ALK inhibitors Ceritinib and Alectinib, the chemical formula is as follows: [0003] [0004] Chinese patent CN107849060A discloses a crystalline form of lorlatinib free base, which discloses (10R)-7-amino-12-fluoro-2,10,16-trimethyl-15-oxo-10,15 ,16,17-tetrahydro-2H-8,4-(methine bridge)pyrazolo[4,3-h][2,5,11]benzoxadiazatetradecylcyclo-3 - A new crystalline form (Form 7) of carbonitrile (lorlatinib) free base having a powder X-ray...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D498/18
CPCC07D498/18C07B2200/13
Inventor 李庆秋黄继霆唐伟
Owner LUOXIN PHARM SHANGHAI CO LTD
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