Tenofovir alafenamide hemifumarate compound, and pharmaceutical composition thereof

A technology for tenofovir alafenamide and fumarate compounds, which is applied in the fields of compounds of group 5/15 elements of the periodic table, organic chemistry, and pharmaceutical formulations, achieving excellent stability and simple preparation methods

Inactive Publication Date: 2018-03-13
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are no other relevant studies on the crystal form and stability of tenofovir alafenamide hemifumarate

Method used

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  • Tenofovir alafenamide hemifumarate compound, and pharmaceutical composition thereof
  • Tenofovir alafenamide hemifumarate compound, and pharmaceutical composition thereof
  • Tenofovir alafenamide hemifumarate compound, and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1: Preparation of Form C of tenofovir alafenamide hemifumarate

[0037] Take 500mg of tenofovir alafenamide hemifumarate, add 25mL of acetone and heat to 50°C to dissolve, and dry the solvent with nitrogen at room temperature to obtain the product.

[0038] XRD patterns such as figure 1 shown. The DSC spectrum shows that the melting point of the sample is about 105°C, and the melting is accompanied by exothermic crystallization, and the melting point of the sample after crystallization is about 130°C ( figure 2 ). The TGA spectrum shows that the weight loss is 0.8% before 120°C, the sample is anhydrous, and the decomposition temperature is about 178°C ( image 3 ).

Embodiment 2

[0039] Example 2: Preparation of E crystal form of tenofovir alafenamide hemifumarate

[0040] Take 100 mg of tenofovir alafenamide hemifumarate and diffuse it in a trifluoroethanol solvent atmosphere at room temperature for 4 hours.

[0041] XRD patterns such as Figure 4 shown. The DSC spectrum shows that there is a small and broad endothermic peak at 60-90°C, and the melting point of the sample after desolvation is 130°C, and crystal transformation occurs ( Figure 5). TGA spectrum shows 7.1% weight loss before 120 ℃, close to half trifluoroethanol molecule (theoretical weight ratio is 8.6%), sample is half trifluoroethanol solvate, and decomposition temperature is about 181 ℃ ( Figure 6 ).

Embodiment 3

[0042] Example 3: Preparation of H crystal form of tenofovir alafenamide hemifumarate

[0043] Take 100mg of tenofovir alafenamide hemifumarate, add 1,4-dioxane at room temperature, heat to 45°C to dissolve, filter, cool at 4°C for crystallization, a small amount of sample is precipitated, nitrogen blowing Can do it.

[0044] XRD patterns such as Figure 7 shown. The DSC pattern shows that desolvation is accompanied by melting, and the onset temperature is about 121 ° C ( Figure 8 ). The TGA spectrum shows a weight loss of 6.9% before 120°C, which is close to half of a 1,4-dioxane molecule (theoretical weight ratio is 7.6%). The sample is a half 1,4-dioxane solvate, and the decomposition temperature is about 180℃( Figure 9 ).

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Abstract

The invention provides a plurality of crystal forms of a tenofovir alafenamide hemifumarate compound, and especially a crystal form I of the tenofovir alafenamide hemifumarate. The tenofovir alafenamide hemifumarate crystal form I is excellent in stability, and is suitable for preparation of drugs. Characteristic peaks are observed at 2theta of 5.28+-0.2, 6.88+-0.2, 10.95+-0.2, 16.19+-0.2, 19.55+-0.2, 20.67+-0.2, 21.27+-0.2, and 26.59+-0.2 in an X-ray powder diffraction spectrum under Cu target radiation. Operation of a preparation of the crystal form I is simple, and the preparation method issuitable for industrialized production and applications.

Description

technical field [0001] The invention belongs to the field of medicine, and specifically relates to a new crystal form of tenofovir alafenamide hemifumarate compound and a preparation method thereof, and a compound containing the tenofovir alafenamide hemifumarate compound pharmaceutical composition. Background technique [0002] Tenofovir alafenamide (tenofovir alafenamide, the following structural formula), the chemical name is 9-[(R)-2-[[(S)-1-(isopropoxycarbonyl)ethyl]aminophenoxy Phosphinyl] methoxy] propyl] adenine] is a new type of nucleotide reverse transcriptase inhibitor developed by Gilead Sciences of the United States. It was launched in the United States in 2015 for the treatment of HIV infection in adults. The drug is also used to treat hepatitis B and is currently in Phase III clinical trials. This product is rapidly transformed into tenofovir after oral administration, and is phosphorylated into tenofovir diphosphate under the action of cellular kinases, wh...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6561A61K31/675A61P31/18A61P31/20
CPCC07B2200/13C07F9/65616
Inventor 陈庆财孙敏贾剑敏潘迅蔡开明
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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