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Novel crystal form of lometapide mesylate and preparation method thereof

A technology of lometapide mesylate and lomitapide, which is applied in the field of new crystal forms of drugs, and can solve problems such as increased impurities, color changes, and decreased content

Active Publication Date: 2018-09-25
南京西默思博检测技术有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the amorphous powder may have stability problems in pharmaceutical preparations, color changes will occur during storage, and the content is prone to decrease and impurities increase, resulting in poor long-term stability.

Method used

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  • Novel crystal form of lometapide mesylate and preparation method thereof
  • Novel crystal form of lometapide mesylate and preparation method thereof
  • Novel crystal form of lometapide mesylate and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0051] The preparation of embodiment 2 lometapide mesylate crystal form I

[0052] Add 10 g of lomitapide to 120 ml of isopropyl acetate, and heat above 50° C. to dissolve. Add 1.49g of methanesulfonic acid and stir the reaction for about 1h, then cool down to 0-5°C for cooling and crystallization for 2-3h. After suction filtration, the collected crystals were vacuum-dried at 50° C. for 24 hours to obtain 10.3 g of lometapide mesylate powder solid, which was detected as crystal form I by XRD (yield 90%). The purity by HPLC is 99.93%.

[0053] 1 H-NMR (400MHz, CDCl3) δ0.811 (2H, m), 1.69 (2H, m), 1.78 (2H, d), 2.43 (2H, m), 2.56 (2H, m), 2.69 (2H, s ), 3.42(2H,d), 3.70(2H,m), 3.95(2H,m), 5.38(2H,t), 6.19(2H,d), 7.38(2H,m), 7.65(2H,d) , 7.79 (2H, d), 10.34 (2H, s).

Embodiment 3

[0054] Embodiment 3 Preparation of lometapide mesylate crystal form II

[0055] Add the lometapide mesylate (1 g) obtained in Example 2 into 10 ml of toluene solvent, heat to about 80°C and stir to dissolve; cool down to 0-5°C; stir for 3 hours, and a solid precipitates. After suction filtration, the filter cake was washed with toluene, and vacuum-dried at 50°C for 24 hours to obtain a white solid (0.95 g), which was detected as crystal form II by XRD. The purity by HPLC is 99.94%.

Embodiment 4

[0057] Mix 0.1 g of lometapide mesylate powder obtained in Example 2 with 1 mL of tert-butanol, heat above 50° C. to dissolve, freeze, and lyophilize for 24 hours to obtain 0.1 g of a solid product. Melting point: 111.3-114.6°C. The obtained solid has no characteristic absorption peak through XRD detection, and the powder is an amorphous solid.

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Abstract

The invention provides a new crystal form I and a new crystal form II of lomitapide mesylate and a preparation method thereof. An X-ray diffraction diagram of the crystallization form of the crystal form I contains diffraction peaks at the diffraction angles 2 theta of 6.269 degrees, 7.130 degrees, 11.479 degrees, 12.540 degrees, 14.019 degrees, 14.318 degrees, 17.104 degrees, 17.703 degrees, 17.977 degrees, 21.627 degrees and 21.877 degrees. An X-ray diffraction diagram of the crystallization form of the crystal form II contains diffraction peaks at the diffraction angles 2 theta of 7.108 degrees, 8.750 degrees, 11.407 degrees, 12.187 degrees, 13.389 degrees, 14.237 degrees, 15.927 degrees, 16.419 degrees, 17.049 degrees, 17.396 degrees, 19.963 degrees, 20.514 degrees, 20.865 degrees, 21.821 degrees, 22.519 degrees and 23.103 degrees. The crystal forms are high in purity and good in stability and can be well used as medicinal active constituents.

Description

technical field [0001] The present invention relates to a new crystal form of medicine, in particular to N-(2,2,2-trifluoroethyl)-9-[4-[4-[4,-(trifluoromethyl)[1 ,1,-Biphenyl-2-yl]formamido]piperidin-1-yl]butyl]-9-H-fluorenyl-9-carboxamide mesylate (lomitapide mesylate) New crystal form and its preparation method. Background technique [0002] Lomitapide mesylate (Lomitapide mesylate) is an oral small molecule microsomal triglyceride transfer protein (MTP) inhibitor developed by Aegerion Company. It was approved for listing by the U.S. FDA in December 2012. Its trade name is Lojuxda. Treatment is used to treat excess cholesterol, including primary hypercholesterolemia and familial hypercholesterolemia. Its chemical name is N-(2,2,2-trifluoroethyl)-9-[4-[4-[4,-(trifluoromethyl)[1,1,-biphenyl-2-yl] Formamido]piperidin-1-yl]butyl]-9-H-fluorenyl-9-carboxamide methanesulfonate, the structural formula is shown in (I) below. [0003] [0004] Invention patent WO2015121877 de...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D211/58
CPCC07B2200/13C07D211/58
Inventor 张孝清徐洪根汪飞邹正才包金远
Owner 南京西默思博检测技术有限公司
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