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Sofosbuvir monocrystals, and preparation and use thereof

A sofosbuvir single crystal technology, which is applied in the field of sofosbuvir single crystal and preparation, can solve the problems of curative effect impact, change of drug bioavailability, drug absorption, transport impact, etc., and achieve good application prospects

Inactive Publication Date: 2016-12-07
中科云和(北京)生物医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, since the crystal form of the drug has a major impact on the absorption and transport of the drug, it will change the bioavailability of the drug and have a greater impact on the efficacy

Method used

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  • Sofosbuvir monocrystals, and preparation and use thereof
  • Sofosbuvir monocrystals, and preparation and use thereof
  • Sofosbuvir monocrystals, and preparation and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: the preparation of sofosbuvir single crystal M

[0038] Dissolve 1g of Sofosbuvir in 20mL of 50°C chloroform-isopropanol (volume ratio 50:1) mixed solution, stir to dissolve, then cool the solution in which Sofosbuvir is dissolved to room temperature while stirring and crystallizing, Filter until no solid precipitates out, wash with a small amount of cold solvent (hexane or dichloromethane) (4°C), and send the sample for single crystal X-ray diffraction to determine the crystal structure. The obtained sofosbuvir is detected by HPLC, and the content is 99.9%; by gas chromatography, the residual solvent content is lower than 40ppm.

[0039] Its single crystal X-ray diffraction pattern has the following characteristics, the crystal belongs to the monoclinic system, the space group is P21, and the unit cell parameters: β = 108.96(3)°. unit cell volume The number of molecules in the unit cell is Z=2.

[0040]The drug used in the present invention is Sofos...

Embodiment 2

[0042] Embodiment 2: Preparation of Sofosbuvir single crystal

[0043] Dissolve 1g of Sofosbuvir in 6mL of dimethyl carbonate at 50°C, slowly crystallize under stirring, collect the crystals by filtration, wash with a small amount of cold solvent (hexane or dichloromethane), select the crystals and send them to the sample for determination Crystal X-ray diffraction to determine the three-dimensional structure of the new crystal form M of Sofosbuvir.

[0044] Its single crystal X-ray diffraction pattern has the following characteristics, the crystal belongs to the monoclinic system, the space group is P21, and the unit cell parameters: β = 108.96(3)°. unit cell volume The number of molecules in the unit cell is Z=2.

[0045] The drug used in the present invention is Sofosbuvir, and its chemical name is S-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-oxo-3, 4-Dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid iso ...

Embodiment 3

[0046] Embodiment 3: the preparation of sofosbuvir single crystal M

[0047] Dissolve 1 g of sofosbuvir in 10 mL of diethyl oxalate at 50°C, slowly cool to room temperature, and volatilize and crystallize. After no more solids were precipitated, the crystals were collected by filtration, washed with a small amount of cold solvent (hexane or dichloromethane), and then sent to determine single crystal X-ray diffraction.

[0048] Its single crystal X-ray diffraction pattern has the following characteristics, the crystal belongs to the monoclinic system, the space group is P21, and the unit cell parameters: β = 108.96(3)o. unit cell volume The number of molecules in the unit cell is Z=2.

[0049] The drug used in the present invention is Sofosbuvir, and its chemical name is S-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-oxo-3, 4-Dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propionic acid iso Propyl ester, molecular formula ...

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Abstract

The invention discloses sofosbuvir monocrystals, and a preparation and a use thereof. A sofosbuvir monocrystal M is a monoclinic system, the space group is P21, and crystal cell parameters are as follows: a is 1.3816(3) nm, b is 0.5973(2) nm, c is 1.7666(4) nm, beta is 108.96(3) DEG, the crystal cell volume is 1.3787(3)A<3>, and the quantity Z of molecules in the crystal cell is 2. The powder characteristic diffraction angles (2theta) of crystal form N comprise 8.2 + / - 0.2 DEG, 10.5 + / - 0.2 DEG, 12.6 + / - 0.2 DEG, 13.5 + / - 0.2 DEG, 16.4 + / - 0.2 DEG, 17.0 + / - 0.2 DEG, 17.3 + / - 0.2 DEG, 18.2 + / - 0.2 DEG, 19.0 + / - 0.2 DEG, 19.5 + / - 0.2 DEG, 20.2 + / - 0.2 DEG, 21.0 + / - 0.2 DEG, 22.2 + / - 0.2 DEG, 23.4 + / - 0.2 DEG, 23.8 + / - 0.2 DEG, 25.3 + / - 0.2 DEG, 25.5 + / - 0.2 DEG, 27.3 + / - 0.2 DEG and 28.2 + / - 0.2 DEG. The powder characteristic diffraction angles (2theta) of crystal form O comprise 8.6 + / -0.2 DEG, 9.2 + / - 0.2 DEG, 11.8 + / - 0.2 DEG, 14.2 + / - 0.2 DEG, 15.1 + / - 0.2 DEG, 15.6 + / - 0.2 DEG, 16.0 + / - 0.2 DEG, 16.5 + / - 0.2 DEG, 17.1 + / - 0.2 DEG, 17.5 + / - 0.2 DEG, 18.1 + / - 0.2 DEG, 19.8 + / - 0.2 DEG, 20.1 + / - 0.2 DEG, 22.2 + / - 0.2 DEG, 23.5 + / - 0.2 DEG, 25.8 + / - 0.2 DEG and 27.0 + / - 0.2 DEG. The novel crystal form sofosbuvir monocrystals have good stability.

Description

technical field [0001] The invention relates to a sofosbuvir single crystal, a preparation method and an application. Background technique [0002] Gilead's hepatitis C drug Sofosbuvir (trade name: Sovaldi, generic name: Sofosbuvir, formerly known as GS-7977, PSI-7977, 400mg tablet) was approved by the US Food and Drug Administration on December 6, 2013 FDA approved for the treatment of adult patients with genotype 1, 2, 3 and 4 chronic hepatitis C (Hepatitis C). Sofosbuvir is the first drug approved for the full oral treatment of hepatitis C. When used for the treatment of specific genotypes (type 2, type 3) of chronic hepatitis C, it can eliminate the need for traditional injection drug interferon ( IFN) demand. [0003] [0004] [0005] Sofosbuvir is an inhibitor of hepatitis C virus NS5B polymerase. For HCV genotype 2 (HCV GT2) and HCV genotype 3 (HCV GT3) infection, Sofosbuvir only needs to be combined with Ribavirin It is therefore the world's first all-oral ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H19/10C07H1/00A61K31/7072A61P31/14A61P1/16
CPCC07B2200/13C07H1/06C07H19/10
Inventor 汤律进周守明王彩琴冯汝宏
Owner 中科云和(北京)生物医药科技有限公司