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Darunavir novel crystal form as well as preparation method and application thereof

A crystal and amorphous technology, applied in the field of preparation of new crystal forms, can solve problems affecting bioavailability

Inactive Publication Date: 2018-11-02
YANCHENG DESANO PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] For the same drug, different crystal forms or different hydrates, as well as differences in its stability, fluidity, hygroscopicity, and compressibility, will have an important impact on the application of the drug, thereby greatly affecting the bioavailability

Method used

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  • Darunavir novel crystal form as well as preparation method and application thereof
  • Darunavir novel crystal form as well as preparation method and application thereof
  • Darunavir novel crystal form as well as preparation method and application thereof

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preparation example Construction

[0055] The present invention also provides a preparation method of D1-type darunavir crystals.

[0056] The preparation method of the crystal of the present invention, the preparation method comprises the following steps:

[0057] (1) Stir the amorphous darunavir crystals in a mixed solvent of alcohol and water for 5 to 15 hours at room temperature;

[0058] (2) Filter, collect crystals, and dry.

[0059] In another preferred example, the alcohol in step (1) is selected from one or more of methanol, ethanol, and isopropanol; the weight ratio of amorphous darunavir, alcohol, and water is 1:0.25-3.0 : 4.0~10.0; the drying temperature described in the step (2) is 30~45° C.

[0060] Pharmaceutical compositions and applications

[0061] The present invention also provides a pharmaceutical composition, which contains active ingredients in a safe and effective dose range, and a pharmaceutically acceptable carrier.

[0062] The "active ingredient" mentioned in the present inventio...

Embodiment 1

[0089] Weigh 100g of amorphous darunavir, add it to 1000ml of methanol and water mixed solvent (methanol content 5%), stir at room temperature for 12 hours, filter, and dry at 35-40°C for 12-16 hours to obtain 95.8g of solid .

[0090] Result: the obtained solid, i.e. the powder X-ray diffraction pattern of crystal form D1 is as follows figure 1 Characterized, the differential thermal scanning spectrum is shown in 2, and its TGA and DSC combined spectrum is shown in image 3 As shown, the total water loss can be seen intuitively.

[0091] The moisture content in the crystal was determined to be 2.9% by KF moisture method.

Embodiment 2

[0093] Take by weighing 100g darunavir ethanol compound, join in the 500ml dichloromethane solution, after dissolving, concentrate to get foamy solid (being Darunavir amorphous), join in the mixed solvent of 800ml methanol and water ( methanol content 10%), stirred at room temperature for 10 hours, filtered, and dried at 35-40° C. for 12-16 hours to obtain 89.2 g of solid.

[0094] Results: The XRPD, DSC and TGA spectra of the obtained solid were basically consistent with the crystal form D1.

[0095] The moisture content in the crystal was determined to be 3.0% by KF moisture method.

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Abstract

The invention relates to a darunavir novel crystal form as well as a preparation method and application thereof, in particular to a novel crystal form of [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxyl-1-(phenyl methyl)propyl]-carbamic acid (3R, 3aS, 6aS)hexahydrofuran[2,3-b]furan-3-yl ester and a preparation method thereof. The crystal form is stable, is easy to store, andis better in mobility. Moreover, the preparation method is simple, can be industrially applied, and has a wide drug prospect.

Description

technical field [0001] The present invention relates to the field of medicinal chemistry, in particular to a [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxyl-1 A new crystal form of -(phenylmethyl)propyl]-carbamic acid (3R, 3aS, 6aS) hexahydrofuro[2,3-b]furan-3-yl ester, as well as a preparation method of the new crystal form and use. Background technique [0002] Darunavir, English name: Darunavir, chemical name: [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy- 1-(phenylmethyl)propyl]-carbamic acid (3R,3aS,6aS)hexahydrofuro[2,3-b]furan-3-yl ester, its structural formula is as follows: [0003] [0004] Darunavir, a new protease inhibitor developed by Tibotec Ireland, a subsidiary of Johnson & Johnson, is a second-generation protease inhibitor for the treatment of human immunodeficiency virus (HIV) infection The drug has been listed in the United States, the European Union and other countries and regions, and the trade name i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D493/04A61K31/34A61P31/18
CPCC07B2200/13C07D493/04
Inventor 李金亮赵楠王锰
Owner YANCHENG DESANO PHARMA CO LTD
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