WO2010140156A2 - Novel polymorphs of raltegravir potassium - Google Patents
Novel polymorphs of raltegravir potassium Download PDFInfo
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- WO2010140156A2 WO2010140156A2 PCT/IN2009/000317 IN2009000317W WO2010140156A2 WO 2010140156 A2 WO2010140156 A2 WO 2010140156A2 IN 2009000317 W IN2009000317 W IN 2009000317W WO 2010140156 A2 WO2010140156 A2 WO 2010140156A2
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- WIPO (PCT)
- Prior art keywords
- raltegravir potassium
- raltegravir
- potassium
- crystalline form
- amorphous form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- Raltegravir can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
- novel amorphous form of raltegravir potassium is provided.
- a process for preparation of raltegravir potassium amorphous form which comprises freeze drying an aqueous solution of raltegravir potassium at - 170 to -180 deg C to obtain raltegravir potassium amorphous form.
- Freeze drying is the term used, freezing the material and then reducing the surrounding pressure and adding enough heat to allow the frozen water in the material to sublime directly from the solid phase to gas.
- a process for preparation of raltegravir potassium amorphous form which comprises freeze drying an aqueous solution of raltegravir potassium at - 170 to -180 deg C to obtain raltegravir potassium amorphous form.
- a process for the preparation of raltegravir potassium amorphous form which comprises: a) stirring raltegravir potassium in water; b) removing the water from the solution obtained in step (a) to obtain a solid; c) slurrying the solid obtained in step (b) with an organic solvent; and d) isolating raltegravir potassium amorphous form.
- the organic solvent used in step (c) is a solvent or a mixture of solvents and may be selected from the group consisting of a heptane, hexane, diethyl ether, cyclohexane, n-hexanol, n-octanol, 3-ethyl-3-pentanol, polyethylene glycol, isopropyl acetate, n-butyl acetate, glycerol triacetate, acetone, methyl isobutyl ketone, 2,4-dimethylpentanone, alpha-tetralone, methyl t-butyl ether,
- the pharmaceutical dosage form may preferably be in an oral dosage form.
- X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-K ⁇ radiation.
- sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 degrees to theta per step and a step of 52 seconds.
- the sample was simply placed on the sample holder.
- the sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.
- DSC Different Scanning Calorimetry
- measurements were performed with a DSC Q10 (TA Instruments, Inc.).
- About 2.3 mg of the powder was placed in an open aluminum pan and it was crimped with an aluminum lid. The crimped sample was then placed in the DSC cell opposite to empty aluminum pan (as reference) and the sample was scanned at 10 deg C/min from 50 deg C to 300 deg C.
- Raltegravir (10 gm) was dissolved in dimethylformamide (100 ml) at room temperature and cooled to 10 to 15 deg C. To the reaction mass was added slowly a mixture of potassium hydroxide (1.5 gm) and water (2 ml) at 10 to 15 deg C and the temperature was raised to 25 to 30 deg C, filtered. The solid obtained was washed with dimethylformamide and dried at 110 to 120 deg C for 48 hours to obtain 7 gm of raltegravir potassium crystalline form H1.
Abstract
The present invention provides novel polymorphs of raltegravir potassium, processes for their preparation and pharmaceutical compositions comprising them. Thus for example, raltegravir potassium was added to water and stirred for 15 minutes, the solution was filtered on hiflo bed and the bed washed with water, the resulting solution was subjected to freeze drying at -180 deg C for 13 hours to give raltegravir potassium amorphous form.
Description
NOVEL POLYMORPHS OF RALTEGRAVIR POTASSIUM
FIELD OF THE INVENTION
The present invention provides novel polymorphs of raltegravir potassium, processes for their preparation and pharmaceutical compositions comprising them.
BACKGROUND OF THE INVENTION
Inhibitors of human immunodeficiency virus (HIV) protease have been approved for use in the treatment of HIV infection for several years. A particularly effective HIV integrase inhibitor is N-(4-fluorobenzyl)-5-hydroxy-1- methyl-2-(1-methyl-1-{[(5-methyl-1 ,3,4-oxadiazol-2-yl)carbonyl]amino}ethyl)-6- oxo-1 ,6-dihydropyrimidine-4-carboxamide, also known as raltegravir and its pharmaceutically acceptable salts such as raltegravir potassium. Raltegravir is represented by the following structure.
Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and /or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline forms of the same pure substance in which the molecules have different arrangements and / or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties
of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining a crystalline form over the other.
Raltegravir can exist in different polymorphic forms, which differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
WO Patent Publication No. 03/035077 disclosed N-substituted 5- hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamides and pharmaceutically acceptable salts thereof. Processes for the preparations of raltegravir and related compounds were disclosed in WO Patent No. 03/035077. According to
WO Patent No. 03/035077, raltegravir is prepared by reacting 5-methyl-1 ,3,4- oxadiazole-2-carboxylic acid with 2-(1-amino-1-methylethyl)-N-(4-fluorobenzyl)- 5-hydroxy-1-methyl-6-oxo-1 ,6-dihydropyrimidine-4-carboxamide in acetonitrile in presence of triethyl amine and N,N-dimethylformamide.
WO Patent Publication No. 2006/060712 disclosed two crystalline forms of raltegravir potassium and processes for their preparation. The Publication described the formation of two crystalline forms of raltegravir potassium, which were designated raltegravir potassium salt of crystalline anhydrous Form 1 and hydrated Form 2.
According to the 712 patent publication, crystalline anhydrous form 1 of raltegravir potassium salt (characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at about 5.9, 12.5, 20.0, 20.6 and 25.6 degrees and further characterized by an differential scanning calorimetry exhibiting a single endotherm with a peak temperature of about 279 deg C) can be prepared by crystallization of raltegravir potassium from mixing an aqueous solution of a potassium base with a mixture comprising raltegravir, water and alcohol to form a basic solution of raltegravir and filtering the solution. The resulting solution was seeded to provide the crystalline potassium salt of raltegravir.
According to the 712 patent publication, crystalline hydrated form 2 of raltegravir potassium salt (characterized by an X-ray powder diffraction pattern having peaks expressed as 2Θ at about 7.9, 13.8, 15.7, 24.5 and 31.5 degrees and further characterized by an differential scanning calorimetry exhibiting two
broad endotherms with peak temperatures of about 146 deg C and 239 deg C and a third sharp endotherm with a peak temperature of about 276 deg C) can be prepared by crystallization of raltegravir potassium from solid potassium hydroxide and raltegravir were added to acetone, and the resulting solution was sonicated for several minutes until a precipitate formed. Then the resulting suction was filtered to dryness.
We have discovered that raltegravir can be prepared in well-defined and consistently reproducible amorphous form and crystalline form.
One object of the present invention is to provide a novel amorphous form of raltegravir potassium and a process for preparing it and pharmaceutical compositions comprising it.
Another object of the present invention is to provide a novel crystalline form of raltegravir potassium and a process for preparing it and pharmaceutical compositions comprising it.
SUMMARY OF THE INVENTION
In accordance with one aspect of the present invention, there is provided novel amorphous form of raltegravir potassium.
In accordance with another aspect of the present invention, there is provided a process for preparation of raltegravir potassium amorphous form, which comprises freeze drying an aqueous solution of raltegravir potassium at - 170 to -180 deg C to obtain raltegravir potassium amorphous form.
In accordance with another aspect of the present invention, there is provided a process for the preparation of raltegravir potassium amorphous form, which comprises: a) stirring raltegravir potassium in water; b) removing the water from the solution obtained in step (a) to obtain a solid; c) slurrying the solid obtained in step (b) with an organic solvent; and d) isolating raltegravir potassium amorphous form.
In accordance with another aspect of the present invention, there is provided a novel crystalline form of raltegravir potassium designated as form H1 characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.2, 6.9, 9.0, 13.9, 21.5 and 23.0 ± 0.2 degrees.
In accordance with another aspect of the present invention, there is provided a process for the preparation of raltegravir potassium crystalline form H1, which comprises: a) providing a solution of raltegravir potassium in dimethylformamide or dimethylacetamide or mixture thereof, optionally mixed with one or more other solvent; b) separating solid from the solution obtained in step (a); and c) isolating raltegravir potassium crystalline form H1.
In accordance with another aspect of the present invention, there is provided a pharmaceutical composition comprising a polymorphic form of raltegravir potassium selected from form H1 and amorphous form or a mixture thereof; and a pharmaceutically acceptable excipient.
DETAILED DESCRIPTION OF THE INVENTION In accordance with one aspect of the present invention, there is provided novel amorphous form of raltegravir potassium. The powdered x-ray diffractogram (PXRD) of raltegravir potassium amorphous form is shown in figure 1.
Raltegravir potassium amorphous form of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 2.
Freeze drying is the term used, freezing the material and then reducing the surrounding pressure and adding enough heat to allow the frozen water in the material to sublime directly from the solid phase to gas. In accordance with another aspect of the present invention, there is provided a process for preparation of raltegravir potassium amorphous form, which comprises freeze drying an aqueous solution of raltegravir potassium at - 170 to -180 deg C to obtain raltegravir potassium amorphous form.
In accordance with another aspect of the present invention, there is provided a process for the preparation of raltegravir potassium amorphous form, which comprises: a) stirring raltegravir potassium in water; b) removing the water from the solution obtained in step (a) to obtain a solid;
c) slurrying the solid obtained in step (b) with an organic solvent; and d) isolating raltegravir potassium amorphous form.
The organic solvent used in step (c) is a solvent or a mixture of solvents and may be selected from the group consisting of a heptane, hexane, diethyl ether, cyclohexane, n-hexanol, n-octanol, 3-ethyl-3-pentanol, polyethylene glycol, isopropyl acetate, n-butyl acetate, glycerol triacetate, acetone, methyl isobutyl ketone, 2,4-dimethylpentanone, alpha-tetralone, methyl t-butyl ether,
2,2,4,4-tetramethyltetrahydrofuran, toluene, tetralin, nitrobenzene, p-xylene, sulfolane and decalin. Preferable organic solvent is selected from heptane, hexane, diethyl ether and cyclohexane, still more preferable organic solvent is heptane.
Raltegravir potassium used in the process of the present invention may be in the form of hydrated and anhydrous. Thus, for example, raltegravir potassium anhydrous crystalline form 1 and raltegravir potassium hydrated crystalline form 2 may be used.
The water may be removed from the solution in step (b) by known methods, for example, distillation or spray drying.
The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may also preferably be carried out until the solvent is almost completely distilled off. .
The temperature at which slurrying is carried out is not critical and the slurrying may conveniently be carried out at room temperature.
The isolation of raltegravir potassium amorphous form may be performed by conventional techniques such as centrifugation and filtration. In accordance with another aspect of the present invention, there is provided a novel crystalline form of raltegravir potassium designated as form H1 characterized by peaks in the powder x-ray diffraction spectrum having 2Θ angle positions at about 5.2, 6.9, 9.0, 13.9, 21.5 and 23.0 ± 0.2 degrees. The powdered x-ray diffractogram (PXRD) of raltegravir potassium crystalline form H1 is shown in figure 3.
Raltegravir potassium crystalline form H1 of present invention is further characterized by a Differential Scanning Calorimetry (DSC) thermogram as shown in figure 4.
The raltegravir potassium crystalline form H1 may be identified and differentiated from the known polymorphs by its characteristic PXRD pattern. Thus, for example, a peak at 5.2 ± 0.2 degrees 2Θ is present and a peak at 12.5 ± 0.2 degrees 2Θ is absent in the PXRD of the raltegravir potassium crystalline form H1 of the present invention, but the peak at 5.2 ± 0.2 degrees 20 is absent and a peak at 12.5 ± 0.2 degrees 2Θ is present in the PXRD of the raltegravir potassium anhydrous crystalline form 1 disclosed in the WO Patent Publication No. 2006/060712.
In accordance with another aspect of the present invention, there is provided a process for the preparation of raltegravir potassium crystalline form H1 , which comprises: a) providing a solution of raltegravir potassium in dimethylformamide or dimethylacetamide or mixture thereof, optionally mixed with one or more other solvent; b) separating solid from the solution obtained in step (a); and c) isolating raltegravir potassium crystalline form H1.
Raltegravir potassium used in the process of the present invention may be in the form of hydrated, anhydrous and amorphous. Thus, for example, raltegravir potassium amorphous form, raltegravir potassium anhydrous crystalline form 1 and raltegravir potassium hydrated crystalline form 2 may be used. Preferable raltegravir potassium amorphous form is used.
The other solvent used in step (a) is an inorganic solvent or an organic solvent and may be selected from the group consisting of a water, dimethyl sulfoxide, liquid ammonia, cyclohexane and hexane. Preferable other solvent is water.
The isolation of raltegravir potassium crystalline form H1 may be performed by conventional techniques such as centrifugation and filtration.
In accordance with another aspect of the present invention, there is provided a pharmaceutical composition comprising a polymorphic form of raltegravir potassium selected from form H1 and amorphous form or a mixture thereof; and a pharmaceutically acceptable excipient.
The pharmaceutical dosage form may preferably be in an oral dosage form.
BRIEF DESCRIPTION OF THE DRAWING
Figure 1 is X-ray powder diffraction spectrum of raltegravir potassium amorphous form.
Figure 2 is Differential scanning calorimetry (DSC) thermogram of raltegravir potassium amorphous form. Figure 3 is X-ray powder diffraction spectrum of raltegravir potassium crystalline form H1.
Figure 4 is Differential scanning calorimetry (DSC) thermogram of raltegravir potassium crystalline form H1.
X-ray powder diffraction spectrum was measured on a bruker axs D8 advance X-ray powder diffractometer having a copper-Kα radiation.
Approximately 1gm of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two-theta, at 0.02 degrees to theta per step and a step of 52 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA. DSC (Differential Scanning Calorimetry) measurements were performed with a DSC Q10 (TA Instruments, Inc.). About 2.3 mg of the powder was placed in an open aluminum pan and it was crimped with an aluminum lid. The crimped sample was then placed in the DSC cell opposite to empty aluminum pan (as reference) and the sample was scanned at 10 deg C/min from 50 deg C to 300 deg C.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Examples Example 1 Raltegravir potassium (25 gm) was dissolved in water (350 ml), stirred for
15 minutes at room temperature. The solution was filtered on hiflo bed and the bed washed with water (25 ml). The resulting solution was subjected to freeze drying at -180 deg C for 13 hours to obtain 25 gm of raltegravir potassium amorphous form. Example 2
Raltegravir potassium anhydrous crystalline form 1 (10 gm) was dissolved in water (150 ml), stirred for 15 minutes at room temperature. The solution was filtered on hiflo bed, the bed washed with water and distilled off the water under vacuum at 55 to 60 deg C to obtain solid. To the solid was added
heptane (100 ml), distilled off the solvent and solid was collected. The solid was taken in heptane (100 ml), stirred for 2 hours at room temperature, filtered, washed the solid with heptane and dried the solid at 90 to 100 deg C for 5 hours to obtain 9.5 gm of raltegravir potassium amorphous form. Example 3
Raltegravir potassium amorphous form (10 gm) as obtained in example 2 was dissolved in dimethylformamide (100 ml) at room temperature. The solution was stirred for 1 hour at room temperature and separated the solid. The solid was stirred for 24 hours at room temperature, filtered, washed the solid with dimethylformamide and dried at 115 to 120 deg C for 48 hours to obtain 10 gm of raltegravir potassium crystalline form H1.
Example 4
Raltegravir (10 gm) was dissolved in dimethylformamide (100 ml) at room temperature and cooled to 10 to 15 deg C. To the reaction mass was added slowly a mixture of potassium hydroxide (1.5 gm) and water (2 ml) at 10 to 15 deg C and the temperature was raised to 25 to 30 deg C, filtered. The solid obtained was washed with dimethylformamide and dried at 110 to 120 deg C for 48 hours to obtain 7 gm of raltegravir potassium crystalline form H1.
Claims
1. A raltegravir potassium amorphous form, characterized by an x-ray powder diffractogram as shown in figure 1.
2. The raltegravir potassium amorphous form as claimed in claim 1, wherein the raltegravir potassium amorphous form is further characterized by a differential scanning calorimetry thermogram as shown in figure 2.
3. A process for the preparation of raltegravir potassium amorphous form as defined in claim 1, which comprises freeze drying an aqueous solution of raltegravir potassium at -170 deg C to -180 deg C to obtain raltegravir potassium amorphous form.
4. A process for the preparation of raltegravir potassium amorphous form as defined in claim 1, which comprises: a. stirring raltegravir potassium in a water; b. removing the water from the solution obtained in step (a) to obtain a solid. c. slurrying the solid obtained in step (b) with an organic solvent; and d. isolating raltegravir potassium amorphous form.
5. The process as claimed in claim 4, wherein the organic solvent used in step (c) is a solvent or a mixture of solvents and selected from the group consisting of a heptane, hexane, diethyl ether, cyclohexane, n-hexanol, n- octanol, 3-ethyl-3-pentanol, polyethylene glycol, isopropyl acetate, n-butyl acetate, glycerol triacetate, acetone, methyl isobutyl ketone, 2,4- dimethylpentanone, alpha-tetralone, methyl t-butyl ether, 2,2,4,4- tetramethyltetrahydrofuran, toluene, tetralin, nitrobenzene, p-xylene, sulfolane and decalin.
6. The process as claimed in claim 5, wherein the organic solvent used in step (c) is selected from heptane, hexane, diethyl ether and cyclohexane.
7. The process as claimed in claim 6, wherein the organic solvent used in step (c) is heptane.
8. The process as claimed in claim 4, wherein the raltegravir potassium used is in the form of hydrated and anhydrous.
9. The process as claimed in claim 8, wherein the raltegravir potassium used is in the form of raltegravir potassium anhydrous crystalline form 1 and raltegravir potassium hydrated crystalline form 2.
10. A raltegravir potassium crystalline form H1, characterized by an X-ray powder diffractogram having peaks expressed as 2Θ angle positions at about 5.2, 6.9, 9.0, 13.9, 21.5 and 23.0 ± 0.2 degrees.
11. A raltegravir potassium crystalline form H1, characterized by an x-ray powder diffractogram as shown in figure 3.
12. The raltegravir potassium crystalline form H1 as claimed in claim 10, wherein the raltegravir potassium crystalline form H1 is further characterized by a differential scanning calorimetry thermogram as shown in figure 4.
13. A process for the preparation of raltegravir potassium crystalline form H1 as defined in claim 10, which comprises: a. providing a solution of raltegravir potassium in dimethylformamide or dimethylacetamide or mixture thereof, optionally mixed with one or more other solvent; b. separating solid from the solution obtained in step (a); and c. isolating raltegravir potassium crystalline form H1.
14. The process as claimed in claim 13, wherein the raltegravir potassium used is in the form of hydrated, anhydrous and amorphous.
15. The process as claimed in claim 14, wherein the raltegravir potassium used is in the form of raltegravir potassium amorphous form, raltegravir potassium anhydrous crystalline form 1 and raltegravir potassium hydrated crystalline form 2.
16. The process as claimed in claim 15, wherein the raltegravir potassium used is in the form of raltegravir potassium amorphous form.
17. The process as claimed in claim 13, wherein the other solvent used in step (a) is an inorganic solvent or an organic solvent and selected from the group consisting of a water, dimethyl sulfoxide, liquid ammonia, cyclohexane and hexane.
18. The process as claimed in claim 17, wherein the other solvent used in step (a) is water.
19. A pharmaceutical composition comprising a polymorphic form of raltegravir potassium selected from form H1 and amorphous form or a mixture thereof and a pharmaceutically acceptable excipient.
20. The pharmaceutical composition as claimed in claim 19, wherein the pharmaceutical composition is used in an oral dosage form.
1. The pharmaceutical composition as claimed in claim 20, wherein the oral pharmaceutical dosage form is a tablet.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP09845466.3A EP2438062B1 (en) | 2009-06-02 | 2009-06-02 | Process for the preparation of amorphous raltegravir potassium |
| US13/375,575 US8742105B2 (en) | 2009-06-02 | 2009-06-02 | Polymorphs of raltegravir potassium |
| ES09845466.3T ES2549387T3 (en) | 2009-06-02 | 2009-06-02 | Preparation procedure for amorphous potassium raltegravir |
| PCT/IN2009/000317 WO2010140156A2 (en) | 2009-06-02 | 2009-06-02 | Novel polymorphs of raltegravir potassium |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2009/000317 WO2010140156A2 (en) | 2009-06-02 | 2009-06-02 | Novel polymorphs of raltegravir potassium |
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| WO2010140156A2 true WO2010140156A2 (en) | 2010-12-09 |
| WO2010140156A3 WO2010140156A3 (en) | 2012-09-27 |
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| PCT/IN2009/000317 WO2010140156A2 (en) | 2009-06-02 | 2009-06-02 | Novel polymorphs of raltegravir potassium |
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|---|---|
| US (1) | US8742105B2 (en) |
| EP (1) | EP2438062B1 (en) |
| ES (1) | ES2549387T3 (en) |
| WO (1) | WO2010140156A2 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011123754A1 (en) | 2010-04-01 | 2011-10-06 | Teva Pharmaceutical Industries Ltd. | Raltegravir salts and crystalline forms thereof |
| WO2012103105A1 (en) | 2011-01-24 | 2012-08-02 | Assia Chemical Industries Ltd. | Processes for preparing raltegravir and intermediates in the processes |
| WO2012137142A1 (en) | 2011-04-06 | 2012-10-11 | Lupin Limited | Novel salts of raltegravir |
| US20120270888A1 (en) * | 2011-04-25 | 2012-10-25 | Bandi Parthasaradhi Reddy | Pharmaceutical compositions of raltegravir, methods of preparation and use thereof |
| WO2013037731A1 (en) | 2011-09-16 | 2013-03-21 | Hexal Ag | Novel polymorphic form of raltegravir potassium |
| WO2013111100A1 (en) | 2012-01-25 | 2013-08-01 | Lupin Limited | Stable amorphous raltegravir potassium premix and process for the preparation thereof |
| US20140038992A1 (en) * | 2011-04-25 | 2014-02-06 | Hetero Research Foundation | Methods of administering raltegravir and raltegravir compositions |
| EP2818470A1 (en) * | 2013-06-27 | 2014-12-31 | Basf Se | Cocrystals of raltegravir potassium |
| US8962833B2 (en) | 2010-05-25 | 2015-02-24 | Hetero Research Foundation | Salts of raltegravir |
| WO2015114608A1 (en) | 2014-02-03 | 2015-08-06 | Mylan Laboratories Ltd | Processes for the preparation of intermediates of raltegravir |
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| US20150166520A1 (en) * | 2012-07-20 | 2015-06-18 | Merck Sharp & Dohme Corp. | Amido-substituted pyrimidinone derivatives useful for the treatment of hiv infection |
| WO2014064711A2 (en) * | 2012-10-22 | 2014-05-01 | Hetero Research Foundation | Methods of administering raltegravir and raltegravir compositions |
| JP2019529410A (en) * | 2016-09-15 | 2019-10-17 | ルピン・リミテッド | Method for producing pure and stable crystalline raltegravir potassium type 3 |
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| EP1441735B1 (en) | 2001-10-26 | 2006-02-22 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti S.P.A. | N-substituted hydroxypyrimidinone carboxamide inhibitors of hiv integrase |
| UA87884C2 (en) | 2004-12-03 | 2009-08-25 | Мерк Энд Ко., Инк. | Potassium salt of an hiv integrase inhibitor |
| JP2008521929A (en) * | 2004-12-03 | 2008-06-26 | メルク エンド カムパニー インコーポレーテッド | Pharmaceutical composition containing antinucleating agent |
| WO2011024192A2 (en) | 2009-07-27 | 2011-03-03 | Matrix Laboratories Ltd | Novel polymorphs of raltegravir |
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2009
- 2009-06-02 WO PCT/IN2009/000317 patent/WO2010140156A2/en active Application Filing
- 2009-06-02 EP EP09845466.3A patent/EP2438062B1/en active Active
- 2009-06-02 ES ES09845466.3T patent/ES2549387T3/en active Active
- 2009-06-02 US US13/375,575 patent/US8742105B2/en active Active
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| US8722722B2 (en) | 2010-04-01 | 2014-05-13 | Teva Pharmaceutical Industries Ltd | Raltegravir salts and crystalline forms thereof |
| WO2011123754A1 (en) | 2010-04-01 | 2011-10-06 | Teva Pharmaceutical Industries Ltd. | Raltegravir salts and crystalline forms thereof |
| EP2796458A1 (en) | 2010-04-01 | 2014-10-29 | Teva Pharmaceutical Industries Ltd. | Crystalline raltegravir sodium salts |
| US8962833B2 (en) | 2010-05-25 | 2015-02-24 | Hetero Research Foundation | Salts of raltegravir |
| WO2012103105A1 (en) | 2011-01-24 | 2012-08-02 | Assia Chemical Industries Ltd. | Processes for preparing raltegravir and intermediates in the processes |
| WO2012137142A1 (en) | 2011-04-06 | 2012-10-11 | Lupin Limited | Novel salts of raltegravir |
| US9163009B2 (en) | 2011-04-06 | 2015-10-20 | Lupin Limited | Salts of raltegravir |
| WO2012147101A2 (en) | 2011-04-25 | 2012-11-01 | Hetero Research Foundation | Pharmaceutical compositions of raltegravir, methods of preparation and use thereof |
| US20140038992A1 (en) * | 2011-04-25 | 2014-02-06 | Hetero Research Foundation | Methods of administering raltegravir and raltegravir compositions |
| US20120270888A1 (en) * | 2011-04-25 | 2012-10-25 | Bandi Parthasaradhi Reddy | Pharmaceutical compositions of raltegravir, methods of preparation and use thereof |
| US9968607B2 (en) | 2011-04-25 | 2018-05-15 | Hetero Research Foundation | Pharmaceutical compositions of raltegravir, methods of preparation and methods of use therof |
| WO2013037731A1 (en) | 2011-09-16 | 2013-03-21 | Hexal Ag | Novel polymorphic form of raltegravir potassium |
| CN104093400A (en) * | 2012-01-25 | 2014-10-08 | 鲁宾有限公司 | Stable amorphous raltegravir potassium premix and process for the preparation thereof |
| WO2013111100A1 (en) | 2012-01-25 | 2013-08-01 | Lupin Limited | Stable amorphous raltegravir potassium premix and process for the preparation thereof |
| JP2015504913A (en) * | 2012-01-25 | 2015-02-16 | ルピン・リミテッドＬｕｐｉｎ Ｌｉｍｉｔｅｄ | Stable amorphous raltegravir potassium premix and preparation method thereof |
| EP2818470A1 (en) * | 2013-06-27 | 2014-12-31 | Basf Se | Cocrystals of raltegravir potassium |
| WO2015114608A1 (en) | 2014-02-03 | 2015-08-06 | Mylan Laboratories Ltd | Processes for the preparation of intermediates of raltegravir |
Also Published As
| Publication number | Publication date |
|---|---|
| EP2438062A2 (en) | 2012-04-11 |
| EP2438062A4 (en) | 2013-07-31 |
| US8742105B2 (en) | 2014-06-03 |
| ES2549387T3 (en) | 2015-10-27 |
| WO2010140156A3 (en) | 2012-09-27 |
| US20120178930A1 (en) | 2012-07-12 |
| EP2438062B1 (en) | 2015-07-29 |
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