US20060235008A1 - Novel polymorphs of efavirenz - Google Patents
Novel polymorphs of efavirenz Download PDFInfo
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- US20060235008A1 US20060235008A1 US10/568,904 US56890406A US2006235008A1 US 20060235008 A1 US20060235008 A1 US 20060235008A1 US 56890406 A US56890406 A US 56890406A US 2006235008 A1 US2006235008 A1 US 2006235008A1
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- XPOQHMRABVBWPR-ZDUSSCGKSA-N O=C1NC2=CC=C(Cl)C=C2[C@@](C#CC2CC2)(C(F)(F)F)O1 Chemical compound O=C1NC2=CC=C(Cl)C=C2[C@@](C#CC2CC2)(C(F)(F)F)O1 XPOQHMRABVBWPR-ZDUSSCGKSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
Definitions
- the present invention relates to novel polymorphs of efavirenz, processes for their preparation and pharmaceutical compositions containing them.
- the present invention relates to novel polymorphs of efavirenz, processes for their preparation and pharmaceutical compositions containing them.
- HIV reverse transcriptase (including its resistant varieties) inhibitors are described in U.S. Pat. No. 5,519,021.
- An especially important compound among those disclosed is efavirenz, (4S)-6-chloro-4-(cyclopropylethyny])-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-ben ⁇ oxazin-2-one.
- Efavirenz has the following structural formula:
- This compound is used for the preparation of a medicament having nonnucleoside HIV-1 reverse transcriptase inhibiting activity that is useful in the prevention or treatment of infection by HIV and the treatment of AIDS.
- Efavirenz is sold commercially as SUSTIVA® by Bristol Myers Squibb.
- WO patent application publication No. 98/33782 disclosed three crystalline forms, Form I (characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at 6.1, 6.4, 10.4, 10.9, 12.3, 13.2, 14.2, 15.2, 16.9, 18.4, 19.2, 20.1, 21.2, 22.3, 23.0, 24.9, 25.9, 26.3, 27.2, 28.1, 28.6, 29.1, 29.5, 30.7, 32.4 and 38.3 degrees), Form II (characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at 3.6, 6.3, 11.1, 12.8, 13.3, 14.3, 16.1, 16.9, 18.5, 19.2, 19.6, 20.6, 21.3, 22.6, 23.2, 24.4, 24.9, 26.0, 26.8, 27.6, 28.4, 29.2, 29.6, 30.6, 31.9 and 33.8 degrees) and Form III (characterized by an x-ray powder diffraction patterns having peaks expressed as 2 ⁇ at 7.2, 10.9, 13.7, 14.5, 16.7, 19.1, 19.
- WO patent application publication No. 99/64405 disclosed fivs crystalline forms, Form 1 (characterized by an x-ray powder diffraction patterns having peaks expressed as 26 at about 6.0, 6.3, 10.3, 10.8, 14.1, 16.8, 20.0, 20.5, 21.1 and 24.8 degrees), Form 2 (characterized by an x-ray powder diffraction patterns having peaks expressed as 26 at about 6.8, 9.2, 12.3, 16.2, 21.4, 22.7, 24.1 and 28.0 degrees), Form 3 (characterized by an x-ray powder diffraction patterns having peaks expressed as 26 at about 7.1, 7.3, 11.0, 13.8, 20.9, 23.3, 27.9 and 33.5 degrees), Form 4 (characterized by an x-ray powder diffraction patterns having peaks expressed as 26 at about 3.6, 6.3, 9.7, 11.0, 12.7, 13.2, 16.1, 19.2, 19.5/20.6 and 24.3 degrees) and Form 5 (characterized by an x-ray powder diffraction patterns having peaks expressed as 26 at about 10.2, 11.4, 11.6, 12.6, 19.1, 20
- the novel form is at least as stable as the reported forms (Form I, Form II, Form III, Form 1, Form 2, Form 3, Form 4 and Form 5).
- the novel crystalline form is stable over the time and has good flow properties and so, the novel crystalline form is suitable for formulating efavirenz.
- Amorphous form of efavirenz has not been reported in the prior art. So, there is a need for stable amorphous form of efavirenz for better pharmaceutical preparations.
- One object of the present invention is to provide a stable novel crystalline form of efavirenz, process for preparing it and a pharmaceutical composition containing it.
- Another object of the present invention is to provide a novel stable amorphous form of efavirenz, process for preparing it and a pharmaceutical composition containing it.
- amorphous form of efavirenz is characterized by having broad x-ray diffraction spectrum as in FIG. 1 .
- a process for preparation of amorphous efavirenz which comprises:
- the preferable ketonic solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone and diethyl ketone; more preferable ketonic solvent is selected from acetone and diethyl ketone; and still more preferable ketonic solvent is acetone.
- the solution of efavirenz in the ketonic solvent may be prepared by dissolving efavirenz in a known form or in crystalline form H1 described below in ths said ketonic solvent.
- crude efavirenz may also be used in the process.
- the precipitation is carried out at about 0° C.-10° C. and more preferably at about 2° C.-5° C.
- the precipitated solid may be collected by filtration or centrifugation.
- the preferable temperature range of drying is at about 50° C.-60° C. and more preferable temperature range is at about 55° C.-60° C.
- the process is carried out by precipitating from a solution of efavirenz in a C 3 -C 8 -ketonic solvent, preferably acetone, by adding the said solution to water at about 0° C.-10° C. and more preferably at about 2° C.-5° C.; collecting the precipitated solid by filtration or centrifugation; and drying the solid collected at about 40° C.-65° C., more preferably at about 55° C.-60° C. to obtain amorphous efavirenz.
- a solution of efavirenz in a C 3 -C 8 -ketonic solvent preferably acetone
- the novel amorphous efavirenz is found to have better dissolution properties when compared with the known forms.
- a novel crystalline form of efavirenz designated as form H1 characterized by an x-ray powder diffraction spectrum having peaks expressed as 2 ⁇ at about 5.4, 10.4, 11.6, 12.5, 15.3, 20.1, 20.8, 22.5, 23.1, 25.7, 27.9, 28.5, 28.8, 29.5, 30.2 and 38.2 degrees.
- FIG. 2 shows typical form H1 x-ray powder diffraction spectrum.
- a process for preparation of efavirenz form H1 which comprises:
- the preferable alcoholic solvent is selected from ethanol, n-propanol, n-butanol, isopropanol and methanol and more preferable alcoholic solvent is n-propanol.
- the preferable ketonic solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone and diethyl ketone; more preferable ketonic solvent is selected from acetone and diethyl ketone; and still more preferable ketonic solvent is acetone.
- the solution of efavirenz in the ketonic or alcoholic solvent may be prepared by dissolving efavirenz in a known form or in amorphous form in the said ketonic or alcoholic solvent.
- crude efavirenz may also be used in the process.
- the precipitation is carried out at about 0° C.-10° C. and more preferably at about 2° C.-5° C.
- the precipitated solid may be collected by filtration or centrifugation.
- step (b) is carried out until the water content falls in the range 2-5% of the solid by weight.
- the preferable temperature range of drying in step (c) is at about 40° C.-50° C. and more preferably at about 40° C.-45° C.
- the process is carried out by precipitating from a solution of efaviren ⁇ in a C 1 -C 6 -alcoholic solvent, preferably n-propanol or isopropanol, C 3 -C 3 -ketonic solvent, preferaly acetone or diethyl ketone, or a mixture thereof by adding the said solution to water at about 0° C.-10° C. and more preferably at about 2° C.-5° C.; collecting the precipitated solid by filtration or centrifugation; drying the precipitated solid at about 25° C.-35° C. until the water content is 2-5%; and drying the solid obtained at about 40° C.-55° C., preferably at about 40° C.-50° C., to obtain crystalline efaviren ⁇ form H1.
- a C 1 -C 6 -alcoholic solvent preferably n-propanol or isopropanol, C 3 -C 3 -ketonic solvent, preferaly acetone or diethyl ket
- alkyl portion of the C 1 to C 5 -alcohol and C 3 to C 8 -ketone used can be straight or branch, unsubstituted or substituted with for example alkoxy, halogen, nitro, cyano or hydroxy groups.
- the novel crystalline efavirenz form H1 is at least as stable as the reported forms (Form I, Form II, Form III, Form 1, Form 2, Form 3, Form 4 and Form 5).
- the novel crystalline form is stable over the time and has good flow properties and so, the novel crystalline form is suitable for formulating efavirenz.
- novel polymorphs of efavirenz are useful for the preparation of medicaments having nucleoside HIV-1 reverse transcriptase inhibiting activity thpt is, useful in the prevention or treatment of infection by HIV and the treatment of aids.
- the novel polymorphs of efavirenz can be used in pharmaceutical compositions generally in combination with at least one pharmaceutically acceptable excipient.
- FIG. 1 is a x-ray powder diffraction spectrum of amorphous form of efavirenz.
- FIG. 2 is a x-ray powder diffraction spectrum of efavirenz form H1.
- x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a copper-K ⁇ radiation.
- Efavirenz crude (5 gm, obtained by the process described in example 6, step A to step D, of U.S. Pat. No. 5,519,021) is dissolved in acetone (20 ml) at 23° C.-30° C., slowly added b water (200 ml) for 30 minutes at 0° C.-5° C. and stirred for 1 hour at the same temperature. Then the separated solid is filtered, washed with water (20 ml) and dried at 55° C.-60° C. for 5 hours to give 4.5 gm of amorphous efavirenz.
- Efavirenz form 1 (10 gm, obtained by the process described in example 8 of WO patent application publication No. 99/64405) is dissolved in diethylketone (50 ml) at 25° C.-30° C., slowly added to water (350 ml) for 45 minutes at 0° C.-5° C. and stirred for 2 hours at the same temperature. Then the separated solid is filtered, washed with water (50 ml) and dried at 55° C.-60° C. for 5 hours to give 9.5 gm of amorphous efavirenz.
- Efavirenz crude (5 gm) is dissolved in n-propanol (20 ml) at 25° C.-30° C., slowly added to water (200 ml) for 30 minutes at 0° C.-5° C. and stirred for 1 hour at the same temperature. Then the separated solid is filtered, washed with water (20 ml) and dried at 25° C.-30° C. for 18 hours to obtain efavirenz as wet solid (moisture content: 2.5% by Karl fisher method). The wet solid is dried at 40° C.-45° C. to give 4.4 gm of efavirenz form H1 (water content: 0.3%).
- Amorphous efavirenz (5 gm, obtained in example 1) is dissolved in isopropanol (25 ml) at 25° C.-30° C., slowly added to water (170 ml) for 30 minutes at 0° C.-5° C. and stirred for 1 hour. 30 minutes at the same temperature. Then the separated solid is filtered, washed with water (30 ml) and dried at 25° C.-30° C. for 20 hours to obtain efavirenz as wet solid (moisture content: 3.2% by Karl fisher method), The wet solid is dried at 40° C.-45° C. to give 4.3 gm of efavirenz form H1 (water content: 0.35%).
Abstract
Description
- The present invention relates to novel polymorphs of efavirenz, processes for their preparation and pharmaceutical compositions containing them.
- The present invention relates to novel polymorphs of efavirenz, processes for their preparation and pharmaceutical compositions containing them.
- Pharmaceutical products with HIV reverse transcriptase (including its resistant varieties) inhibitors are described in U.S. Pat. No. 5,519,021. An especially important compound among those disclosed is efavirenz, (4S)-6-chloro-4-(cyclopropylethyny])-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benΣoxazin-2-one. Efavirenz has the following structural formula:
- This compound is used for the preparation of a medicament having nonnucleoside HIV-1 reverse transcriptase inhibiting activity that is useful in the prevention or treatment of infection by HIV and the treatment of AIDS. Efavirenz is sold commercially as SUSTIVA® by Bristol Myers Squibb.
- WO patent application publication No. 98/33782 disclosed three crystalline forms, Form I (characterized by an x-ray powder diffraction patterns having peaks expressed as 2Θ at 6.1, 6.4, 10.4, 10.9, 12.3, 13.2, 14.2, 15.2, 16.9, 18.4, 19.2, 20.1, 21.2, 22.3, 23.0, 24.9, 25.9, 26.3, 27.2, 28.1, 28.6, 29.1, 29.5, 30.7, 32.4 and 38.3 degrees), Form II (characterized by an x-ray powder diffraction patterns having peaks expressed as 2Θ at 3.6, 6.3, 11.1, 12.8, 13.3, 14.3, 16.1, 16.9, 18.5, 19.2, 19.6, 20.6, 21.3, 22.6, 23.2, 24.4, 24.9, 26.0, 26.8, 27.6, 28.4, 29.2, 29.6, 30.6, 31.9 and 33.8 degrees) and Form III (characterized by an x-ray powder diffraction patterns having peaks expressed as 2Θ at 7.2, 10.9, 13.7, 14.5, 16.7, 19.1, 19.6, 20.8, 21.7, 22.3, 22.8, 23.2, 23.9, 24.5, 24.9, 25.8, 27.0, 27.6, 29.3, 30.3, 30.7, 31.3, 33.4, 38.4 and 39.2 degrees) of efaviren Σ.
- WO patent application publication No. 99/64405 disclosed fivs crystalline forms, Form 1 (characterized by an x-ray powder diffraction patterns having peaks expressed as 26 at about 6.0, 6.3, 10.3, 10.8, 14.1, 16.8, 20.0, 20.5, 21.1 and 24.8 degrees), Form 2 (characterized by an x-ray powder diffraction patterns having peaks expressed as 26 at about 6.8, 9.2, 12.3, 16.2, 21.4, 22.7, 24.1 and 28.0 degrees), Form 3 (characterized by an x-ray powder diffraction patterns having peaks expressed as 26 at about 7.1, 7.3, 11.0, 13.8, 20.9, 23.3, 27.9 and 33.5 degrees), Form 4 (characterized by an x-ray powder diffraction patterns having peaks expressed as 26 at about 3.6, 6.3, 9.7, 11.0, 12.7, 13.2, 16.1, 19.2, 19.5/20.6 and 24.3 degrees) and Form 5 (characterized by an x-ray powder diffraction patterns having peaks expressed as 26 at about 10.2, 11.4, 11.6, 12.6, 19.1, 20.6, 21.3, 22.8, 24.8, 27.4, 28.2 and 31.6 degrees) of efaviren Σ.
- We have discovered a stable novel crystalline form of efavirenz. The novel form is at least as stable as the reported forms (Form I, Form II, Form III, Form 1,
Form 2, Form 3, Form 4 and Form 5). The novel crystalline form is stable over the time and has good flow properties and so, the novel crystalline form is suitable for formulating efavirenz. - Amorphous form of efavirenz has not been reported in the prior art. So, there is a need for stable amorphous form of efavirenz for better pharmaceutical preparations.
- One object of the present invention is to provide a stable novel crystalline form of efavirenz, process for preparing it and a pharmaceutical composition containing it.
- Another object of the present invention is to provide a novel stable amorphous form of efavirenz, process for preparing it and a pharmaceutical composition containing it.
- In accordance with the present invention, there is provided a novel amorphous form of efavirenz. The amorphous efavirenz is characterized by having broad x-ray diffraction spectrum as in
FIG. 1 . - In accordance with the present invention, a process is provided for preparation of amorphous efavirenz, which comprises:
- a) precipitating from a solution of efavirenz in a C3-C8-ketonic solvent by using water as precipitating solvent at below about 15° C., and collecting the precipitated solid; and
- b) drying the solid collected at about 40° C.-65° C. to obtain amorphous efavirenz.
- The preferable ketonic solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone and diethyl ketone; more preferable ketonic solvent is selected from acetone and diethyl ketone; and still more preferable ketonic solvent is acetone.
- The solution of efavirenz in the ketonic solvent may be prepared by dissolving efavirenz in a known form or in crystalline form H1 described below in ths said ketonic solvent. Alternatively, crude efavirenz may also be used in the process.
- Preferably the precipitation is carried out at about 0° C.-10° C. and more preferably at about 2° C.-5° C.
- The precipitated solid may be collected by filtration or centrifugation.
- The preferable temperature range of drying is at about 50° C.-60° C. and more preferable temperature range is at about 55° C.-60° C.
- Preferably the process is carried out by precipitating from a solution of efavirenz in a C3-C8-ketonic solvent, preferably acetone, by adding the said solution to water at about 0° C.-10° C. and more preferably at about 2° C.-5° C.; collecting the precipitated solid by filtration or centrifugation; and drying the solid collected at about 40° C.-65° C., more preferably at about 55° C.-60° C. to obtain amorphous efavirenz.
- The novel amorphous efavirenz is found to have better dissolution properties when compared with the known forms.
- In accordance with the present invention, there is provided a novel crystalline form of efavirenz, designated as form H1, characterized by an x-ray powder diffraction spectrum having peaks expressed as 2Θ at about 5.4, 10.4, 11.6, 12.5, 15.3, 20.1, 20.8, 22.5, 23.1, 25.7, 27.9, 28.5, 28.8, 29.5, 30.2 and 38.2 degrees.
FIG. 2 shows typical form H1 x-ray powder diffraction spectrum. - In accordance with the present invention, a process is provided for preparation of efavirenz form H1, which comprises:
- si) precipitating from a solution of efavirenz in a c-, -c0-alcoholic, Cs-Gs-ketonic solvent or a mixture thereof by using water as precipitating solvent at below about 15° C., collecting the precipitated solid;
- b) drying the solid collected at about 25° C.-35° C. until the water content falls in the range 2-10% of the solid by weight; and
- c) drying the solid obtained in (b) at about 40° C.-55° C. to obtain crystalline efavirenz form H1.
- The preferable alcoholic solvent is selected from ethanol, n-propanol, n-butanol, isopropanol and methanol and more preferable alcoholic solvent is n-propanol.
- The preferable ketonic solvent is selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone and diethyl ketone; more preferable ketonic solvent is selected from acetone and diethyl ketone; and still more preferable ketonic solvent is acetone.
- The solution of efavirenz in the ketonic or alcoholic solvent may be prepared by dissolving efavirenz in a known form or in amorphous form in the said ketonic or alcoholic solvent. Alternatively, crude efavirenz may also be used in the process.
- Preferably the precipitation is carried out at about 0° C.-10° C. and more preferably at about 2° C.-5° C.
- The precipitated solid may be collected by filtration or centrifugation.
- It has been found that the drying of precipitated product in step (a) directly at higher temperature leads to known crystalline form 1 (WO patent application publication No. 99/64405).
- Preferably the drying in step (b) is carried out until the water content falls in the range 2-5% of the solid by weight.
- The preferable temperature range of drying in step (c) is at about 40° C.-50° C. and more preferably at about 40° C.-45° C.
- Preferably the process is carried out by precipitating from a solution of efaviren Σ in a C1-C6-alcoholic solvent, preferably n-propanol or isopropanol, C3-C3-ketonic solvent, preferaly acetone or diethyl ketone, or a mixture thereof by adding the said solution to water at about 0° C.-10° C. and more preferably at about 2° C.-5° C.; collecting the precipitated solid by filtration or centrifugation; drying the precipitated solid at about 25° C.-35° C. until the water content is 2-5%; and drying the solid obtained at about 40° C.-55° C., preferably at about 40° C.-50° C., to obtain crystalline efaviren Σform H1.
- Unless otherwise specified, the alkyl portion of the C1 to C5-alcohol and C3 to C8-ketone used can be straight or branch, unsubstituted or substituted with for example alkoxy, halogen, nitro, cyano or hydroxy groups.
- The novel crystalline efavirenz form H1 is at least as stable as the reported forms (Form I, Form II, Form III, Form 1,
Form 2, Form 3, Form 4 and Form 5). The novel crystalline form is stable over the time and has good flow properties and so, the novel crystalline form is suitable for formulating efavirenz. - The above novel polymorphs of efavirenz are useful for the preparation of medicaments having nucleoside HIV-1 reverse transcriptase inhibiting activity thpt is, useful in the prevention or treatment of infection by HIV and the treatment of aids. The novel polymorphs of efavirenz can be used in pharmaceutical compositions generally in combination with at least one pharmaceutically acceptable excipient.
- All the patents mentioned above are incorporated herein by reference.
-
FIG. 1 is a x-ray powder diffraction spectrum of amorphous form of efavirenz. -
FIG. 2 is a x-ray powder diffraction spectrum of efavirenz form H1. - x-Ray powder diffraction spectrum was measured on a Bruker axs D8 advance x-ray powder diffractometer having a copper-K α radiation.
- The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope or spirit of the invention.
- Efavirenz crude (5 gm, obtained by the process described in example 6, step A to step D, of U.S. Pat. No. 5,519,021) is dissolved in acetone (20 ml) at 23° C.-30° C., slowly added b water (200 ml) for 30 minutes at 0° C.-5° C. and stirred for 1 hour at the same temperature. Then the separated solid is filtered, washed with water (20 ml) and dried at 55° C.-60° C. for 5 hours to give 4.5 gm of amorphous efavirenz.
- Efavirenz form 1 (10 gm, obtained by the process described in example 8 of WO patent application publication No. 99/64405) is dissolved in diethylketone (50 ml) at 25° C.-30° C., slowly added to water (350 ml) for 45 minutes at 0° C.-5° C. and stirred for 2 hours at the same temperature. Then the separated solid is filtered, washed with water (50 ml) and dried at 55° C.-60° C. for 5 hours to give 9.5 gm of amorphous efavirenz.
- Efavirenz crude (5 gm) is dissolved in n-propanol (20 ml) at 25° C.-30° C., slowly added to water (200 ml) for 30 minutes at 0° C.-5° C. and stirred for 1 hour at the same temperature. Then the separated solid is filtered, washed with water (20 ml) and dried at 25° C.-30° C. for 18 hours to obtain efavirenz as wet solid (moisture content: 2.5% by Karl fisher method). The wet solid is dried at 40° C.-45° C. to give 4.4 gm of efavirenz form H1 (water content: 0.3%).
- Amorphous efavirenz (5 gm, obtained in example 1) is dissolved in isopropanol (25 ml) at 25° C.-30° C., slowly added to water (170 ml) for 30 minutes at 0° C.-5° C. and stirred for 1 hour. 30 minutes at the same temperature. Then the separated solid is filtered, washed with water (30 ml) and dried at 25° C.-30° C. for 20 hours to obtain efavirenz as wet solid (moisture content: 3.2% by Karl fisher method), The wet solid is dried at 40° C.-45° C. to give 4.3 gm of efavirenz form H1 (water content: 0.35%).
Claims (28)
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US13/540,987 US8466279B2 (en) | 2004-08-19 | 2012-07-03 | Polymorphs of efavirenz |
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Cited By (1)
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US20100274007A1 (en) * | 2007-12-24 | 2010-10-28 | Matrix Laboratories Limited | Process for preparing polymorphic forms of (s)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2h-3,1-benzoxazin-2-one |
Families Citing this family (8)
Publication number | Priority date | Publication date | Assignee | Title |
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US20060235008A1 (en) | 2004-08-19 | 2006-10-19 | Hetero Drugs Limited | Novel polymorphs of efavirenz |
WO2008108630A1 (en) * | 2007-03-02 | 2008-09-12 | Ultimorphix Technologies B.V. | Polymorphic forms of efavirenz |
WO2009011567A1 (en) * | 2007-07-16 | 2009-01-22 | Ultimorphix Technologies B.V. | Crystalline forms of efavirenz |
ES2445090T3 (en) | 2008-12-22 | 2014-02-28 | Hetero Research Foundation | Procedure to prepare an efavirenz polymorph |
DE102009041443A1 (en) | 2009-09-16 | 2011-03-31 | Archimica Gmbh | Salts of 6-chloro-4- (cyclopropylethynyl) -1,4-dihydro-4- (trifluoromethyl) -2H-3,1-benzoxazin-2-one and their synthesis, purification and use as precursors of efavirenz |
EP2496218A1 (en) | 2009-11-04 | 2012-09-12 | Hetero Research Foundation | Bioequivalent formulation of efavirenz |
EP2471783A1 (en) | 2010-12-23 | 2012-07-04 | Esteve Química, S.A. | Novel polymorphic form of efavirenz |
CN103508973B (en) * | 2012-06-25 | 2016-04-27 | 上海迪赛诺药业有限公司 | Prepare the method for efavirenz I type crystallization |
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RU2500679C2 (en) | 2006-08-07 | 2013-12-10 | Палау Фарма, С.А. | Antifungal crystalline compounds |
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- 2004-08-19 US US10/568,904 patent/US20060235008A1/en not_active Abandoned
- 2004-08-19 WO PCT/IN2004/000250 patent/WO2006018853A2/en active Application Filing
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2011
- 2011-07-01 US US13/174,893 patent/US8242267B2/en not_active Expired - Fee Related
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US5665720A (en) * | 1992-08-07 | 1997-09-09 | Merck & Co., Inc. | Benzoxazinones as inhibitors of HIV reverse transcriptase |
US6639071B2 (en) * | 1997-02-05 | 2003-10-28 | Merck & Co., Inc. | Crystal Forms of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one |
US20040102523A1 (en) * | 2002-08-09 | 2004-05-27 | Michel Broquaire | Modafinil polymorphic forms |
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US20100274007A1 (en) * | 2007-12-24 | 2010-10-28 | Matrix Laboratories Limited | Process for preparing polymorphic forms of (s)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2h-3,1-benzoxazin-2-one |
US8318930B2 (en) | 2007-12-24 | 2012-11-27 | Matrix Laboratories Limited | Process for preparing polymorphic forms of (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one |
Also Published As
Publication number | Publication date |
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WO2006018853A2 (en) | 2006-02-23 |
US8466279B2 (en) | 2013-06-18 |
US20120271047A1 (en) | 2012-10-25 |
US20120115857A1 (en) | 2012-05-10 |
WO2006018853A3 (en) | 2008-04-10 |
US8242267B2 (en) | 2012-08-14 |
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