Process for preparing darunavir amorphous

Abstract

The present invention relates to medical chemistry technique field, particularly relates to a preparation method for amorphous darunavir crystal, ##STR00001## The present invention provides a preparation method for preparing amorphous form of darunavir using an anti-solvent method. It can be a different method compared to the evaporation and concentration process disclosed in WO2011048604. Although the same with WO2013114382, anti-solvent are used, the target crystal form are truly different. The crystal form of WO2013114382 is solvent-free darunavir crystal, while an amorphous form of darunavir in the present application.

Claims

1. A preparation method of an amorphous darunavir crystal, wherein, comprising the following steps: a. Adding darunavir into the soluble solvent, b. after dissolved, take it into anti-solvent, c. isolated to obtain amorphous darunavir crystal; the anti-solvent is C5C12 alkanes.

2. The preparation method of an amorphous darunavir crystal according to claim 1, wherein, comprising the following steps: a. Adding darunavir into the soluble solvent, b. after dissolved, take it into anti-solvent at a certain temperature, c. isolated to obtain amorphous darunavir crystal; the anti-solvent is C5C12 alkanes.

3. The preparation method of an amorphous darunavir crystal according to claim 1, wherein, comprising the following steps: a. Adding darunavir into the soluble solvent, b. after dissolved to be a clear solution, take it into anti-solvent at a certain temperature, c. isolated to obtain amorphous darunavir crystal; the anti-solvent is C5C12 alkanes.

4. The preparation method of an amorphous darunavir crystal according to claim 1, wherein, comprising the following steps: a. Adding darunavir into the soluble solvent, b. after dissolved to be a clear solution at the temperature of room temperature to the boiling of the solvent, take it into anti-solvent at a certain temperature, c. isolated to obtain amorphous darunavir crystal; the anti-solvent is C5C12 alkanes.

5. The preparation method according to claim 1, 2, 3 or 4, wherein, the said soluble solvent is selected from any one of esters or ketones or mixture of them; the said anti-solvent is hydrocarbon solvent or ethers.

6. The preparation method according to claim 5, wherein, said ester solvent is ethyl formate, acetate ester or isopropyl acetate; the said ketones is acetone, methyl ethyl ketone, MIBK or methyl n-butyl ketone.

7. The preparation method according to claim 1, 2, 3 or 4, wherein, the C5C12 alkanes is selected from one of heptane, hexane, cyclohexane, methyl cyclohexane or mixture of them.

8. The preparation method according to claim 2, 3 or 4, wherein, the temperature is 30 C.30 C.

9. The preparation method according to claim 1, 2, 3 or 4, wherein, the quality ratio of darunavir soluble solvent with anti-solvent is 1:150.

Description

DRAWINGS

(1) FIG. 1 illustrates the XRPD spectrum of amorphous darunavir crystal prepared from the Example 1;

(2) FIG. 2 illustrates the XRPD spectrum of amorphous darunavir crystal prepared from the Example 2.

SPECIFIC EMBODIMENT

(3) To better understand the contents of the present invention, further description incorporated with the specific examples are described. It should be noted that the specific embodiment is not to form a limit to the contents of the present invention.

(4) The examining condition of the present invention

(5) Instrument: Bruker D2 Phaser X-ray powder diffraction instrument

(6) X-ray powder diffraction target material: Cu K (1.54184 A);

(7) Tube pressure: 30 kV;

(8) Tube flow: 10 mA;

(9) 2 scanning scope: 2-40;

(10) Scanning rate (chasse) 0.2 s/step;

(11) Step size: 0.02.

Example 1

(12) Into the 250 ml quadrangle bottle, 50 g isopropyl acetate and 10 g darunavir were added, stirred, the mixture was heated to 50-60 C.; after the solution was clear, take the solution into n-heptane at a temperature of 05 C., after the adding, keep the temperature for 1-3 hours. Suction filtrated, the mixture was eluted by n-heptane. The wet product was dried on a vacuum oven at the temperature of 60 C. The amorphous darunavir crystal was obtained with the yield of 9.3 g (93.0%), the purity is 100.0%. The XPRD spectrum is shown by FIG. 1.

Example 2

(13) Into the 250 ml quadrangle bottle, 4 g acetone and 1 g darunavir were added, stirred, the mixture was heated to 50-60 C.; after the solution was clear, take the solution into n-heptane at a temperature of 05 C., after the adding, keep the temperature for 1-3 hours. Suction filtrated, the mixture was eluted by n-heptane. The wet product was dried on a vacuum oven at the temperature of 60 C. The amorphous darunavir crystal was obtained with the yield of 0.95 g (95.0%), the purity is 99.9%. The XPRD spectrum is shown by FIG. 2.

Example 3

(14) Into the 250 ml quadrangle bottle, 50 g isopropyl acetate and 10 g darunavir were added, stirred, the mixture was heated to 50-60 C.; after the solution was clear, take the solution into n-heptane at a temperature of 100 C., Suction filtrated, the mixture was eluted by n-heptane. The wet product was dried on a vacuum oven at the temperature of 60 C. The amorphous darunavir crystal was obtained with the yield of 9.3 g (93.0%), the purity is 100.0%.

Example 4

(15) Into the 250 ml quadrangle bottle, 50 g isopropyl acetate and 10 g darunavir were added, stirred, the mixture was heated to 50-60 C.; after the solution was clear, take the solution into n-heptane at a temperature of 510 C., Suction filtrated, the mixture was eluted by n-heptane. The wet product was dried on a vacuum oven at the temperature of 60 C. The amorphous darunavir crystal was obtained with the yield of 9.3 g (93.0%), the purity is 100.0%.