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Polymorphs of darunavir

A technology of darunavir and crystallization, which is applied in the field of application in the treatment of retrovirus infection, can solve unmet problems

Inactive Publication Date: 2011-12-28
MAPI PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] There remains an unmet need for additional solid state forms of darunavir with favorable physiochemical properties, desirable bioavailability and beneficial pharmaceutical parameters

Method used

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  • Polymorphs of darunavir
  • Polymorphs of darunavir
  • Polymorphs of darunavir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0086] Example 1: Preparation of crystalline tetrahydrofuran solvate of darunavir

[0087] The darunavir tetrahydrofuran solvate of the present invention is prepared by dissolving approximately 1 g of darunavir ethanolate in 5 ml of tetrahydrofuran solvent. The solvent was then evaporated at room temperature (approximately 25°C) until crystals formed.

[0088] Alternatively, the darunavir tetrahydrofuran solvate of the invention is prepared by dissolving darunavir ethanolate in a tetrahydrofuran solvent, followed by addition of the antisolvent isopropanol (IPA) to cause crystal precipitation.

[0089] Alternatively, darunavir ethanolate was dissolved in a 1:2 ratio of tetrahydrofuran (THF):isopropyl acetate (iPrOAc) or a 1:2 ratio of tetrahydrofuran (THF):methyl tert-butyl ether ( MTBE) the darunavir tetrahydrofuran solvate of the present invention was prepared by heating the mixture to 60°C followed by cooling using an ice bath to induce crystallization.

Embodiment 2

[0090] Example 2: Characterization of the crystalline tetrahydrofuran solvate of darunavir

[0091] This new polymorph exhibits an endothermic peak at -95°C in differential scanning calorimetry (DSC; Mettler Toledo DSC; 10°C / min). X-ray powder diffraction (XRPD; Rigaku D / MAX 2200, CuKα, 40kV, 40mA, DivSlit 1deg, DivH.L.Slit 10mm, SctSlit 1deg, RecSlit 0.3mm, 10deg / min) showed unique characteristic peaks ( figure 1 ;Table 1). The X-ray powder diffraction pattern of the tetrahydrofuran solvate of darunavir of the present invention has a unique fingerprint, which is different from the X-ray diffraction pattern of darunavir ethanolate API ( figure 2 ). Even after two weeks of storage at 25°C, the XRPD and DSC spectra remained unchanged, thus indicating the stability of the crystals.

[0092] Table 1: X-ray diffraction peaks of darunavir tetrahydrofuran solvate

[0093]

[0094]

[0095] * Relative intensities may vary between samples.

[0096] Thermogravimetric anal...

Embodiment 3

[0109] Example 3: Preparation of crystalline dimethyl sulfoxide solvate of darunavir

[0110] The darunavir dimethyl sulfoxide solvate of the present invention was prepared by dissolving darunavir ethoxide in dimethyl sulfoxide at 60°C, followed by cooling using an ice bath to induce crystallization.

[0111] Alternatively, the darunavir dimethyl sulfoxide solvate of the present invention is prepared by dissolving approximately 1 g of darunavir ethanolate in 2.5 ml of dimethyl sulfoxide at 80°C. Water (10ml) was then added to induce crystallization.

[0112] Alternatively, the darunavir dimethyl sulfoxide solvate of the invention was prepared by dissolving darunavir ethoxide in dimethyl sulfoxide, followed by addition of the antisolvent isopropanol (IPA) to cause crystal precipitation.

[0113] Alternatively, the darunavir dimethyl sulfoxide solvate of the present invention is prepared by dissolving darunavir ethanolate at 60°C in any one of the following solvent mixtures: ...

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Abstract

The present invention provides new pseudopolymorphic forms of darunavir and novel amorphous darunavir, pharmaceutical compositions comprising these compounds, their preparation methods and their use in the treatment of retrovirus infections, especially HIV infections Applications.

Description

technical field [0001] The present invention relates to novel darunavir (darunavir), its pharmaceutical composition and its application in treating retrovirus infection. Background technique [0002] Darunavir is a second-generation protease inhibitor used to treat human immunodeficiency virus (HIV) infection. In 2006, the FDA approved the simultaneous administration of darunavir and the antiretroviral drug ritonavir (ritonavir) to treat HIV patients who have been administered other antiretroviral drugs. [0003] The chemical name of darunavir is: [(1S,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(benzo yl)propyl]-carbamic acid (3R, 3aS, 6aR)-hexahydrofuro[2,3-b]furan-3-yl ester, and is represented by the following chemical structure: [0004] [0005] Darunavir and its preparation methods are disclosed in EP 715618, WO 99 / 67417, US 5,968,942, US 6,248,775 and Bioorganic and Chemistry Letters, 8, 687-690, 1998. [0006] Several pseudopolymorphic f...

Claims

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Application Information

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IPC IPC(8): A01N57/00
CPCC07D493/04A61K31/34A61K31/426A61P31/14A61P31/18A61K2300/00
Inventor E·马鲁姆
Owner MAPI PHARMA
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