WO2012107889A1 - Process for the preparation of amorphous darunavir - Google Patents
Process for the preparation of amorphous darunavir Download PDFInfo
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- WO2012107889A1 WO2012107889A1 PCT/IB2012/050572 IB2012050572W WO2012107889A1 WO 2012107889 A1 WO2012107889 A1 WO 2012107889A1 IB 2012050572 W IB2012050572 W IB 2012050572W WO 2012107889 A1 WO2012107889 A1 WO 2012107889A1
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- darunavir
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- amorphous
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
Definitions
- the present invention relates to a process for the preparation of amorphous darunavir.
- Darunavir is chemically [(lS,2i?)-3-[[(4-aminophenyl)sulfonyl](2- methylpropyl)arnino]-2-hydroxy-l-(phenylmethyl)propy.l]-carbamic acid (3i?,3aS,6aJ?)- hexahydrofuro[2,3-b]furan-3-yl ester of Formula I.
- U.S. Publication No. 2007/0060642 provides processes for preparing darunavir in which darunavir is isolated as ethanolate.
- WO 2010/086844 mentions the preparation method for amorphous darunavir by slow precipitation from a saturated solution using various solvent systems.
- WO 2010/086844 also mentions that the amorphous darunavir is prepared in the following solvent/antisolvent systems: methyl ethyl ketone/methyl tert-butyl ether, dichloromethane/toluene, acetonitrile/water, 2-methyltetrahydrofuran/isopropanol and methyl isobutyl ketone/toluene.
- WO 2010/086844 also mentions that the amorphous form is prepared by dissolving darunavir ethanolate in dichloromethane and evaporating dichloromethane under ambient conditions until a precipitate is formed.
- WO 2010/086844 further provides processes for the preparation of tetrahydrofuran and dimethylsulfoxide solvates of darunavir.
- the present inventors have developed an easily reproducible method, which does not use spray drying or lyophilization, for preparing darunavir in pure amorphous form which is pure, stable and is suitable for developing pharmaceutical dosage forms.
- Figure 1 depicts the XRPD (X-Ray Powder Diffractogram) of amorphous darunavir obtained according to Example 1.
- Figure 2 depicts the XRPD (X-Ray Powder Diffractogram) of amorphous darunavir obtained according to Example 2.
- Figure 3 depicts the XRPD (X-Ray Powder Diffractogram) of amorphous darunavir obtained according to Example 3.
- Figure 4 depicts the XRPD (X-Ray Powder Diffractogram) of amorphous darunavir obtained according to Example 4.
- Figure 5 depicts the XRPD (X-Ray Powder Diffractogram) of amorphous darunavir obtained according to Example 1 and stored for 4 months.
- Figure 6 depicts the XRPD (X-Ray Powder Diffractogram) of amorphous darunavir obtained according to Example 2 and stored for 6 months.
- An aspect of the present invention provides a process for the preparation of amorphous darunavir, wherein the process comprises:
- step b) removing the solvent from the solution obtained in step a) to obtain a residue; c) treating the residue obtained in step b) with a hydrocarbon solvent; and d) isolating amorphous darunavir from the mixture thereof.
- the starting darunavir may be in any solid form and prepared according to the methods provided in the prior art, for example, Bioorganic & Medicinal Chemistry Letters, Vol. 8, p. 687-690 (1998), U.S. Patent No. 7,700,645 or U.S. Publication No. 2007/060642.
- ethyl acetate Prior to preparing the solution of darunavir in ethyl acetate,
- the darunavir may be subjected to treatment with an alcoholic solvent or water or a mixture thereof.
- darunavir may be dissolved and re-precipitated from an alcoholic solvent, for example, denatured spirit or ethanol, or isopropanol, or a mixture thereof, or water or a mixture thereof.
- the solution of darunavir in ethyl acetate, dichloromethane, or a mixture thereof may be prepared by dissolving darunavir in ethyl acetate, dichloromethane, or a mixture thereof.
- the solution of darunavir in ethyl acetate, dichloromethane, or a mixture thereof may be optionally filtered to remove any undissolved material.
- the solvent is completely or partially removed from the solution to obtain a residue.
- the solvent may be removed from the solution by methods including concentration, distillation, evaporation, or a combination thereof, for example, vacuum distillation.
- the residue may be solid or semisolid.
- the residue is treated with a hydrocarbon solvent.
- the hydrocarbon may be an aliphatic hydrocarbon or aromatic hydrocarbon or a mixture thereof.
- the hydrocarbon may be, for example, hexanes, pentane, hexane, heptane, cyclohexane or a mixture thereof.
- the treatment with the hydrocarbon solvent may be carried out by stirring of the mixture for about 1 minute to about 50 hours, for example about 10 minutes to about 1 hour. The stirring may be carried out at about 0°C to about 50°C, for example, at about 15°C to about 30°C.
- the amorphous darunavir so obtained may be isolated from the mixture by methods including filtration, evaporation, decantation, centrifugation or a combination thereof.
- the amorphous darunavir may be optionally washed with the hydrocarbon solvent and dried.
- the amorphous darunavir so obtained has a purity of about 98.5% or above.
- XRPD of the samples were determined by using Panalytical X'Pert Pro X-Ray Powder Diffractometer in the range 3 to 40° 2 ⁇ with a step size of 0.02 and under tube voltage and current of 45 Kv and 40 mA respectively. Copper radiation of wavelength 1.54 angstrom and Xceletor detector were used.
- a mixture of darunavir (2 g; HPLC purity: 96.11 %) and denatured spirit (20 mL) was heated to 60°C and stirred at 60°C to 65°C for 0.5 hour to obtain a solution.
- the solution was cooled to 15°C and was stirred at 15°C to 20°C for 0.5 hour.
- the precipitate obtained was filtered and washed with denatured spirit (5 mL).
- the precipitate was dissolved in dichloromethane (10 mL) and the resultant solution was subjected to vacuum distillation to obtain a residue by removing the solvent. Hexanes (20 mL) were added to the residue and the resultant slurry was stirred for 0.5 hour at 20°C to 25°C.
- the precipitate obtained was filtered, washed with hexanes (2 x 2 mL) and dried under vacuum at 40°C to 45 °C to obtain amorphous darunavir having an XRPD pattern as depicted in Figure 1.
- the amorphous darunavir prepared according to this method was stored at 25°C to 30°C for four months. There was no change in XRPD pattern after four months as depicted in Figure 5.
- a mixture of darunavir (1 g; HPLC purity 96.11%) and denatured spirit (10 mL) was heated to 60°C and stirred at 60°C to 65°C for 0.5 hour to obtain a solution.
- the solution was cooled to 10°C and stirred at 5°C to 10°C for 0.5 hour.
- the precipitate obtained was filtered and washed with denatured spirit (5 mL).
- the precipitate was dissolved in ethyl acetate (8 mL) and the resultant solution was subjected to vacuum distillation to obtain a residue by removing the solvent. Hexanes (10 mL) were added to the residue and the resultant slurry was stirred for 15 minutes at 25°C to 30°C.
- the precipitate obtained was filtered, washed with hexanes (2 x 1 mL) and dried under vacuum at 40°C to 45°C to obtain amorphous darunavir having an XRPD pattern as depicted in Figure 2.
- the amorphous darunavir prepared according to this method was stored at 25°C to 30°C for six months. There was no change in XRPD pattern after six months as depicted in Figure 6.
- a mixture of darunavir (2 g; HPLC purity 96.11%) and isopropyl alcohol (20 mL) was heated to 80°C and stirred at 80°C to 85°C for 0.5 hour to obtain a solution.
- the solution was cooled to 10°C and stirred at 10°C to 15°C for 0.5 hour.
- the precipitate obtained was filtered and washed with isopropyl alcohol (5 mL).
- the precipitate was dissolved in dichloromethane (25 mL) and the resultant solution was subjected to vacuum distillation to obtain a residue by removing the solvent. Hexanes (20 mL) were added to the residue and the resultant slurry was stirred for 0.5 hour at 20°C to 25°C.
- the precipitate obtained was filtered, washed with hexanes (2 x 2 mL) and dried under vacuum at 40°C to 45°C to obtain amorphous darunavir having an XRPD pattern as depicted in Figure 3.
- Darunavir ethanolate (0.8 g) was dissolved in dichloromethane (10 ml) at 25 °C to 30°C. The resultant solution was subjected to vacuum distillation at 40°C to 45°C to obtain a residue by removing the solvent. Hexanes (10 mL) were added to the residue and the resultant slurry was stirred for 0.5 hour at 20°C to 25°C. The precipitate obtained was filtered, washed with hexanes (2 x 1 mL) and dried under vacuum at 40°C to 45°C to obtain amorphous darunavir having an XRPD pattern as depicted in Figure 4.
- the solid was treated with a mixture of water (6 mL) and isopropanol (54 mL) and the resultant mixture was stirred at 70°C to 75°C for 20 minutes and cooled to 5°C to 10°C. It was further stirred for 20 minutes at 5°C to 10°C to obtain a solid precipitate.
- the solid precipitate was filtered and washed with isopropano water mixture (10 mL, 10% water in isopropanol).
- the wet material was dissolved in dichloromethane (40 mL) at 25°C to 30°C and the resulting solution was subjected to vacuum distillation at 40°C to 45°C to obtain a residue.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention relates to a process for the preparation of amorphous darunavir.
Description
PROCESS FOR THE PREPARATION OF AMORPHOUS DARUNAVIR
Field of the Invention
The present invention relates to a process for the preparation of amorphous darunavir. Background of the Invention
Darunavir is chemically [(lS,2i?)-3-[[(4-aminophenyl)sulfonyl](2- methylpropyl)arnino]-2-hydroxy-l-(phenylmethyl)propy.l]-carbamic acid (3i?,3aS,6aJ?)- hexahydrofuro[2,3-b]furan-3-yl ester of Formula I.
comparative purposes. U.S. Publication No. 2007/0060642 provides processes for preparing darunavir in which darunavir is isolated as ethanolate.
WO 2010/086844 mentions the preparation method for amorphous darunavir by slow precipitation from a saturated solution using various solvent systems.
WO 2010/086844 also mentions that the amorphous darunavir is prepared in the following solvent/antisolvent systems: methyl ethyl ketone/methyl tert-butyl ether, dichloromethane/toluene, acetonitrile/water, 2-methyltetrahydrofuran/isopropanol and methyl isobutyl ketone/toluene.
WO 2010/086844 also mentions that the amorphous form is prepared by dissolving darunavir ethanolate in dichloromethane and evaporating dichloromethane under ambient conditions until a precipitate is formed. WO 2010/086844 further provides processes for the preparation of tetrahydrofuran and dimethylsulfoxide solvates of darunavir.
Summary of the Invention
The present inventors have developed an easily reproducible method, which does not use spray drying or lyophilization, for preparing darunavir in pure amorphous form which is pure, stable and is suitable for developing pharmaceutical dosage forms.
Brief Description of the Drawings
Figure 1 depicts the XRPD (X-Ray Powder Diffractogram) of amorphous darunavir obtained according to Example 1.
Figure 2 depicts the XRPD (X-Ray Powder Diffractogram) of amorphous darunavir obtained according to Example 2.
Figure 3 depicts the XRPD (X-Ray Powder Diffractogram) of amorphous darunavir obtained according to Example 3.
Figure 4 depicts the XRPD (X-Ray Powder Diffractogram) of amorphous darunavir obtained according to Example 4.
Figure 5 depicts the XRPD (X-Ray Powder Diffractogram) of amorphous darunavir obtained according to Example 1 and stored for 4 months.
Figure 6 depicts the XRPD (X-Ray Powder Diffractogram) of amorphous darunavir obtained according to Example 2 and stored for 6 months.
Detailed Description of the Invention
An aspect of the present invention provides a process for the preparation of amorphous darunavir, wherein the process comprises:
a) providing a solution of darunavir in ethyl acetate, dichloromethane, or a
mixture thereof;
b) removing the solvent from the solution obtained in step a) to obtain a residue; c) treating the residue obtained in step b) with a hydrocarbon solvent; and d) isolating amorphous darunavir from the mixture thereof.
The starting darunavir may be in any solid form and prepared according to the methods provided in the prior art, for example, Bioorganic & Medicinal Chemistry Letters, Vol. 8, p. 687-690 (1998), U.S. Patent No. 7,700,645 or U.S. Publication No. 2007/060642. Prior to preparing the solution of darunavir in ethyl acetate,
dichloromethane, or a mixture thereof, the darunavir may be subjected to treatment with an alcoholic solvent or water or a mixture thereof. For example, darunavir may be dissolved and re-precipitated from an alcoholic solvent, for example, denatured spirit or ethanol, or isopropanol, or a mixture thereof, or water or a mixture thereof.
The solution of darunavir in ethyl acetate, dichloromethane, or a mixture thereof may be prepared by dissolving darunavir in ethyl acetate, dichloromethane, or a mixture thereof. The solution of darunavir in ethyl acetate, dichloromethane, or a mixture thereof may be optionally filtered to remove any undissolved material. The solvent is completely or partially removed from the solution to obtain a residue. The solvent may be removed from the solution by methods including concentration, distillation, evaporation, or a combination thereof, for example, vacuum distillation. The residue may be solid or semisolid. The residue is treated with a hydrocarbon solvent. The hydrocarbon may be an aliphatic hydrocarbon or aromatic hydrocarbon or a mixture thereof. The hydrocarbon may be, for example, hexanes, pentane, hexane, heptane, cyclohexane or a mixture thereof. The treatment with the hydrocarbon solvent may be carried out by stirring of the mixture for about 1 minute to about 50 hours, for example about 10 minutes to about 1
hour. The stirring may be carried out at about 0°C to about 50°C, for example, at about 15°C to about 30°C. The amorphous darunavir so obtained may be isolated from the mixture by methods including filtration, evaporation, decantation, centrifugation or a combination thereof. The amorphous darunavir may be optionally washed with the hydrocarbon solvent and dried. The amorphous darunavir so obtained has a purity of about 98.5% or above.
XRPD of the samples were determined by using Panalytical X'Pert Pro X-Ray Powder Diffractometer in the range 3 to 40° 2Θ with a step size of 0.02 and under tube voltage and current of 45 Kv and 40 mA respectively. Copper radiation of wavelength 1.54 angstrom and Xceletor detector were used.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Example 1 : Preparation of Amorphous Darunavir
A mixture of darunavir (2 g; HPLC purity: 96.11 %) and denatured spirit (20 mL) was heated to 60°C and stirred at 60°C to 65°C for 0.5 hour to obtain a solution. The solution was cooled to 15°C and was stirred at 15°C to 20°C for 0.5 hour. The precipitate obtained was filtered and washed with denatured spirit (5 mL). The precipitate was dissolved in dichloromethane (10 mL) and the resultant solution was subjected to vacuum distillation to obtain a residue by removing the solvent. Hexanes (20 mL) were added to the residue and the resultant slurry was stirred for 0.5 hour at 20°C to 25°C. The precipitate obtained was filtered, washed with hexanes (2 x 2 mL) and dried under vacuum at 40°C to 45 °C to obtain amorphous darunavir having an XRPD pattern as depicted in Figure 1. The amorphous darunavir prepared according to this method was stored at 25°C to 30°C for four months. There was no change in XRPD pattern after four months as depicted in Figure 5.
Yield: 1.82 g
Purity: 99.18%
Example 2: Preparation of Amorphous Darunavir
A mixture of darunavir (1 g; HPLC purity 96.11%) and denatured spirit (10 mL) was heated to 60°C and stirred at 60°C to 65°C for 0.5 hour to obtain a solution. The solution was cooled to 10°C and stirred at 5°C to 10°C for 0.5 hour. The precipitate obtained was filtered and washed with denatured spirit (5 mL). The precipitate was dissolved in ethyl acetate (8 mL) and the resultant solution was subjected to vacuum distillation to obtain a residue by removing the solvent. Hexanes (10 mL) were added to the residue and the resultant slurry was stirred for 15 minutes at 25°C to 30°C. The precipitate obtained was filtered, washed with hexanes (2 x 1 mL) and dried under vacuum at 40°C to 45°C to obtain amorphous darunavir having an XRPD pattern as depicted in Figure 2. The amorphous darunavir prepared according to this method was stored at 25°C to 30°C for six months. There was no change in XRPD pattern after six months as depicted in Figure 6.
Yield: 0.7 g Purity: 98.52%
Example 3: Preparation of Amorphous Darunavir
A mixture of darunavir (2 g; HPLC purity 96.11%) and isopropyl alcohol (20 mL) was heated to 80°C and stirred at 80°C to 85°C for 0.5 hour to obtain a solution. The solution was cooled to 10°C and stirred at 10°C to 15°C for 0.5 hour. The precipitate obtained was filtered and washed with isopropyl alcohol (5 mL). The precipitate was dissolved in dichloromethane (25 mL) and the resultant solution was subjected to vacuum distillation to obtain a residue by removing the solvent. Hexanes (20 mL) were added to the residue and the resultant slurry was stirred for 0.5 hour at 20°C to 25°C. The precipitate obtained was filtered, washed with hexanes (2 x 2 mL) and dried under vacuum at 40°C to 45°C to obtain amorphous darunavir having an XRPD pattern as depicted in Figure 3.
Yield: 1.35 g
Purity: 99.18%
Example 4: Preparation of Amorphous Darunavir
Darunavir ethanolate (0.8 g) was dissolved in dichloromethane (10 ml) at 25 °C to 30°C. The resultant solution was subjected to vacuum distillation at 40°C to 45°C to obtain a residue by removing the solvent. Hexanes (10 mL) were added to the residue and the resultant slurry was stirred for 0.5 hour at 20°C to 25°C. The precipitate obtained was filtered, washed with hexanes (2 x 1 mL) and dried under vacuum at 40°C to 45°C to obtain amorphous darunavir having an XRPD pattern as depicted in Figure 4.
Yield: 0.75 g
Purity: 99.06%
Example 5: Preparation of Amorphous Darunavir
A mixture of darunavir isopropanolate (8 g) and denatured spirit (80 mL) was heated to 70°C and stirred at 70°C to 75°C for 0.5 hour to obtain a solution. The solution was cooled to 10°C and further stirred for 0.5 hour. The precipitate obtained was filtered and denatured spirit (65 mL) was added to the wet solid. The resultant mixture was stirred at 70°C to 75°C for 20 minutes and cooled to 5°C to 10°C. It was further stirred for 20 minutes at 5°C to 10°C to obtain a solid precipitate. The solid precipitate was filtered to obtain a solid. The solid was treated with a mixture of water (6 mL) and isopropanol (54 mL) and the resultant mixture was stirred at 70°C to 75°C for 20 minutes and cooled to 5°C to 10°C. It was further stirred for 20 minutes at 5°C to 10°C to obtain a solid precipitate. The solid precipitate was filtered and washed with isopropano water mixture (10 mL, 10% water in isopropanol). The wet material was dissolved in dichloromethane (40 mL) at 25°C to 30°C and the resulting solution was subjected to vacuum distillation at 40°C to 45°C to obtain a residue. Hexanes (80 mL) were added to the residue and the resultant slurry was stirred for 0.5 hour at 20°C to 25°C. The white precipitate obtained was filtered, washed with hexanes and dried under vacuum at 40°C to 45 °C to obtain amorphous darunavir.
Yield: 4.85 g
Purity: 99.72%
Claims
1. A process for the preparation of amorphous darunavir, wherein the process comprises:
a) providing a solution of darunavir in ethyl acetate, dichloromethane, or a
mixture thereof;
b) removing the solvent from the solution obtained in step a) to obtain a residue; c) treating the residue obtained in step b) with a hydrocarbon solvent; and d) isolating amorphous darunavir from the mixture thereof.
2. The process according to claim 1, wherein darunavir is optionally treated with an alcoholic solvent or water or a mixture thereof prior to step a).
3. The process according to claim 2, wherein the alcoholic solvent is denatured spirit, ethanol, isopropanol, or a mixture thereof.
4. The process according to claim 1, wherein the solvent is completely or partially removed from the solution obtained in step a) to obtain a residue.
5. The process according to claim 1, wherein the hydrocarbon solvent is aliphatic hydrocarbon, aromatic hydrocarbon, or a mixture thereof.
6. The process according to claim 5, wherein the hydrocarbon solvent is hexanes, pentane, hexane, heptane, cyclohexane, or a mixture thereof.
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| WO2012107889A9 WO2012107889A9 (en) | 2012-10-11 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017096690A1 (en) * | 2015-12-08 | 2017-06-15 | 浙江九洲药业股份有限公司 | Method for preparing amorphous form of darunavir |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0715618A1 (en) | 1993-08-24 | 1996-06-12 | G.D. Searle & Co. | Hydroxyethylamino sulphonamides useful as retroviral protease inhibitors |
| US6248775B1 (en) | 1992-08-25 | 2001-06-19 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| US20070060642A1 (en) | 2003-12-23 | 2007-03-15 | Goyvaerts Nicolaas Martha Feli | Process for the preparation of (3r,3as,6ar)-hexahydrofuro [2,3-b] furan-3-yl (1s,2r)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate |
| US7700645B2 (en) | 2002-05-16 | 2010-04-20 | Tibotec Pharmaceuticals Ltd. | Pseudopolymorphic forms of a HIV protease inhibitor |
| WO2010086844A1 (en) | 2009-01-29 | 2010-08-05 | Mapi Pharma Hk Limited | Polymorphs of darunavir |
| WO2011048604A2 (en) * | 2009-09-17 | 2011-04-28 | Matrix Laboratories Limited | An improved process for the preparation of darunavir |
| WO2011073993A1 (en) * | 2009-12-16 | 2011-06-23 | Hetero Research Foundation | Polymorphs of darunavir |
-
2012
- 2012-02-08 WO PCT/IB2012/050572 patent/WO2012107889A1/en active Application Filing
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6248775B1 (en) | 1992-08-25 | 2001-06-19 | G. D. Searle & Co. | α- and β-amino acid hydroxyethylamino sulfonamides useful as retroviral protease inhibitors |
| EP0715618A1 (en) | 1993-08-24 | 1996-06-12 | G.D. Searle & Co. | Hydroxyethylamino sulphonamides useful as retroviral protease inhibitors |
| US7700645B2 (en) | 2002-05-16 | 2010-04-20 | Tibotec Pharmaceuticals Ltd. | Pseudopolymorphic forms of a HIV protease inhibitor |
| US20070060642A1 (en) | 2003-12-23 | 2007-03-15 | Goyvaerts Nicolaas Martha Feli | Process for the preparation of (3r,3as,6ar)-hexahydrofuro [2,3-b] furan-3-yl (1s,2r)-3-[[(4-aminophenyl) sulfonyl] (isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate |
| WO2010086844A1 (en) | 2009-01-29 | 2010-08-05 | Mapi Pharma Hk Limited | Polymorphs of darunavir |
| WO2011048604A2 (en) * | 2009-09-17 | 2011-04-28 | Matrix Laboratories Limited | An improved process for the preparation of darunavir |
| WO2011073993A1 (en) * | 2009-12-16 | 2011-06-23 | Hetero Research Foundation | Polymorphs of darunavir |
Non-Patent Citations (1)
| Title |
|---|
| BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 8, 1998, pages 687 - 690 |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017096690A1 (en) * | 2015-12-08 | 2017-06-15 | 浙江九洲药业股份有限公司 | Method for preparing amorphous form of darunavir |
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| WO2012107889A9 (en) | 2012-10-11 |
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