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Tenofovir alafenamide fumarate compound and pharmaceutical composition thereof

A technology of alafenamide fumarate compound and alafenamide fumarate is applied in the field of pharmaceutical compositions containing the tenofovir alafenamide fumarate compound, which can solve the problem of Issues such as crystal form and data are disclosed to achieve the effect of simple preparation method and good stability

Inactive Publication Date: 2017-10-03
JIANGSU AOSAIKANG PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] CN1291994C discloses the preparation method of tenofovir alafenamide fumarate, but does not disclose any relevant crystal forms and data
[0005] At present, there is no relevant research on the crystal form and stability of tenofovir alafenamide fumarate

Method used

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  • Tenofovir alafenamide fumarate compound and pharmaceutical composition thereof
  • Tenofovir alafenamide fumarate compound and pharmaceutical composition thereof
  • Tenofovir alafenamide fumarate compound and pharmaceutical composition thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] Example 1: Preparation of Form I of tenofovir alafenamide fumarate

[0056] Method 1: Take 500 mg of tenofovir alafenamide fumarate, add 10 mL of methanol at room temperature, add dropwise 200 mL of isopropyl ether under stirring, a large amount of solid is precipitated, centrifugally filtered, and vacuum dried overnight at room temperature to obtain.

[0057] Method 2: Take 500 mg of tenofovir alafenamide fumarate, add 8 ml of methyl tert-butyl ether at room temperature, stir and crystallize, centrifuge and filter, and dry in vacuum at room temperature.

[0058] Method 3: Take 500mg of tenofovir alafenamide fumarate, add 15ml of tetrahydrofuran to obtain a solution, add the solution to 200ml of methyl isopropyl ether, crystallize, centrifugal filter, and vacuum dry overnight at room temperature to obtain .

[0059] The XRD patterns measured using Cu-Kα radiation are as Figure 5 As shown, the spectral data are listed in Table 2 below. TGA test shows that the weight ...

Embodiment 2

[0062] Example 2: Preparation of Form II of tenofovir alafenamide fumarate

[0063] Take 500 mg of tenofovir alafenamide fumarate, add 5 mL of chloroform at room temperature, stir magnetically at room temperature for 3 days, centrifuge, and dry in vacuo overnight.

[0064] The XRD patterns measured using Cu-Kα radiation are as Figure 9 As shown, the spectral data are listed in Table 3 below. TAG detection shows that the weight loss is 3.2% before 100°C, which is about one water molecule (theoretical weight ratio is 3.0%), and the decomposition temperature is about 174°C. The crystal form is a monohydrate ( Figure 10 ). DSC detection shows that the sample has a broad absorption peak between 40°C and 85°C, and a crystal transformation exothermic peak between 90°C and 105°C, and the crystal transformation ( Figure 11 ).

[0065] Table 3. XRD pattern data of the crystal form II of tenofovir alafenamide fumarate

[0066] serial number

Embodiment 3

[0067] Example 3: Preparation of Form III of tenofovir alafenamide fumarate

[0068] Take 500 mg of tenofovir alafenamide fumarate, diffuse it in a trifluoroethanol solvent atmosphere at room temperature for 1 day, take it out and dry it at room temperature for 2 minutes.

[0069] The XRD patterns measured using Cu-Kα radiation are as Figure 12 As shown, the spectral data are listed in Table 4 below. The TGA spectrum shows that there is about 14.0% weight loss before 120°C, which is about one trifluoroethanol molecule, and the decomposition temperature is about 171°C ( Figure 13 ). The DSC spectrum shows that there is a desolvation endothermic peak between 50 and 105 ° C, and the melting point is about 120 ° C ( Figure 14 ).

[0070] Table 4. XRD pattern data of the crystal form III of tenofovir alafenamide fumarate

[0071]

[0072]

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Abstract

The invention provides a plurality of crystal forms of a tenofovir alafenamide fumarate compound, which comprise crystal forms I, II, III, IV and V, wherein the crystal forms I, II and V have higher stability, and especially the crystal form I has the highest stability and is very suitable for producing preparations. Under the Cu-Kalpha radiation, the crystal form I has characteristic peaks in an X-ray powder diffraction spectrum when the 2theta angle is 6.724+ / -0.2, 8.347+ / -0.2, 10.785+ / -0.2, 16.068+ / -0.2, 17.446+ / -0.2, 18.150+ / -0.2, 20.028+ / -0.2 and 20.606+ / -0.2 degrees. The invention also provides preparation methods of the crystal forms. The preparation methods are simple to operate and applicable to industrial production.

Description

technical field [0001] The invention belongs to the field of medicine, and specifically relates to a new crystal form of tenofovir alafenamide fumarate and a preparation method thereof, and a pharmaceutical composition containing the tenofovir alafenamide fumarate compound . Background technique [0002] Tenofovir alafenamide (tenofovir alafenamide, the structural formula is shown below), the chemical name is 9-[(R)-2-[[(S)-1-(isopropoxycarbonyl)ethyl]aminobenzene Oxyphosphinyl] 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, which inhibits vira...

Claims

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Application Information

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IPC IPC(8): C07F9/6561C07C57/15C07C51/41A61K31/675A61P31/18A61P31/20
CPCC07B2200/13C07F9/65616
Inventor 陈庆财孙敏贾剑敏田帅华潘迅蔡开明
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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