WO2013105106A1 - Procédé amélioré pour la préparation d'étoricoxibe et de polymorphes de celui-ci - Google Patents
Procédé amélioré pour la préparation d'étoricoxibe et de polymorphes de celui-ci Download PDFInfo
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- WO2013105106A1 WO2013105106A1 PCT/IN2012/000720 IN2012000720W WO2013105106A1 WO 2013105106 A1 WO2013105106 A1 WO 2013105106A1 IN 2012000720 W IN2012000720 W IN 2012000720W WO 2013105106 A1 WO2013105106 A1 WO 2013105106A1
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- Prior art keywords
- etoricoxib
- crystalline form
- acetate
- solvents
- formula
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- MNJVRJDLRVPLFE-UHFFFAOYSA-N Cc(cc1)ncc1-c(c(-c(cc1)ccc1S(C)(=O)=O)c1)ncc1Cl Chemical compound Cc(cc1)ncc1-c(c(-c(cc1)ccc1S(C)(=O)=O)c1)ncc1Cl MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
Definitions
- the invention relates to an improved process for the preparation of etoricoxib and polymorphs thereof.
- the invention relates to a process for the preparation of stable crystalline Form-I of etoricoxib.
- the invention also relates to a process for the preparation of amorphous form of etoricoxib.
- the invention also relates to pharmaceutical compositions that include the stable crystalline Form-I of etoricoxib.
- Etoricoxib is a selective COX-2 inhibitor which has been shown to be as effective as non-selective non-steroidal anti-inflammatory drugs in the management of chronic pain in rheumatoid arthritis, osteoarthritis and other COX-2 mediated disorders.
- Etoricoxib is -chloro-3-(4-methanesulfonylphenyI)-6' : methyl- [2,3 'jbipyridinyl having structural Formula (I).
- Etoricoxib belongs to a class of drugs known as COX-2 inhibitors that are used in the treatment of COX-2 mediated disorders.
- the therapeutic application of etoricoxib as a COX-2 inhibitor is disclosed in International (PCT) Publication No. WO 96/10012 Al and WO 96/16934 Al .
- U.S. Patent No. 5,861,419 discloses a process for the preparation of etoricoxib.
- Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular Formula, yet each polymorph may have distinct physical properties.
- a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different x-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state 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 a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry.
- the WO '230 Al discloses a process for the preparation of Form V by heating etoricoxib in isopropyl acetate at 55°C. The suspension was cooled at ambient temperature and the solids were isolated by filtration. The solids were washed with IPAC and dried in vacuum to give the Form V polymorph as a colorless solid.
- International (PCT) Publication No. WO 2001 /037833 Al discloses polymorphic Form V of etoricoxib and process for its preparation.
- International (PCT) Publication No. WO 2002/096877 Al discloses a pharmaceutical composition comprising 1 -50% of polymorphic Form V of etoricoxib and remainder of the compound comprising at least one polymorph selected from Forms I, II, III and IV.
- the WO '833 application discloses a process for the preparation of crystalline Form-I of etoricoxib by recrystallizing Form II obtained using ethyl acetate or from a solvent mixture of isopropanol/hexane.
- the present invention provides processes for the preparation of etoricoxib and crystalline Form-I thereof, which is easily scalable and industrially applicable.
- the invention also provides an improved process for the preparation of etoricoxib which avoids the use of potassium tert-butoxide.
- a stable etoricoxib crystalline Form-I having a particle size distribution dO. l ⁇ 5 ⁇ , d0.5 ⁇ 12 ⁇ and d0.9 ⁇ 50 ⁇ .
- Form-I substantially free from Form-V, characterized by having no peak at about 13.7 A by X-ray powder diffraction.
- a stable etoricoxib crystalline Form-I substantially free from Form-IV characterized by having no peak at about 8.7 A by X-ray powder diffraction.
- a stable etoricoxib crystalline Form-I substantially free from hemihydrate characterized by having no peak at about 5.3 A by X-ray powder diffraction.
- the process includes:
- the process includes:
- the process includes:
- the process includes:
- the process includes:
- the process includes:
- R 2 through R 5 are independently C] -6 alkyl, aryl, aralkyl.
- R 2 and R 3 together as well as R4 and R 5 together represents a cyclic group, optionally containing one or more heteroatom selected from N, O or S,
- a pharmaceutical composition comprising a therapeutically effective amount of stable crystalline Form-I of etoricoxib having a particle size d0.9 ⁇ 50 ⁇ .
- FIG 1. shows the X-ray diffractogram (XRD) of Etoricoxib crystalline Form-I prepared by the process of present invention.
- FIG 2. shows the differential scanning calorimetry (DSC) of Etoricoxib crystalline Form-I prepared by the process of present invention.
- FIG 3. shows the X-ray diffractogram (XRD) of Etoricoxib amorphous form prepared by the process of present invention.
- stable refers to crystalline etoricoxib Form-I that includes either of the following:
- crystalline Form-I does not convert to Form-V or hydrates or other known crystalline forms, when stored at a temperature of up to about 40°C and a relative humidity of up to about 75% for atleast 6 months, or
- crystalline Form-I does not convert to Form-V or hydrates or other known crystalline forms when stored at a temperature of up to about 25°C and a relative humidity of up to about 60% for atleast 6 months.
- the stable crystalline Form-I does not show an X-ray powder diffraction peak at a diffraction angle (2 ⁇ ) of about 8.7 A for Form-IV or 13.7 A for Form-V or 5.3 A for hemihydrate, when stored at a temperature of up to about 40°C and a relative humidity of up to about 75% for atleast 6 months.
- the stable crystalline Form-I does not show an X-ray powder diffraction peak at a diffraction angle (2 ⁇ ) of about 8.7 A for Form-IV or 13.7 A for Form-V or 5.3 A for hemihydrate, when stored at a temperature of up to about 25°C and a relative humidity of up to about 60%) for atleast 6 months.
- substantially free herein means, the crystalline Form-I of etoricoxib that contains crystalline Form-V, Form-IV or hemihydrate less than about 1.0%, particularly less than 0.5%, more particularly not in detectable amount when measured by x-ray powder diffraction with respect to its corresponding peaks.
- the term "obtain” or “obtaining” may include decantation or unloading from hydrogenator or pressure reactor.
- the product obtained may be further or additionally dried to achieve the desired moisture values and remove traces of solvents atleast under ICH limits.
- the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
- the present invention can comprise (open ended) or consist essentially of the components of the present invention as well as other ingredients or elements described herein.
- “comprises” means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited.
- the terms “having” and “including” are also to be construed as open ended unless the context suggest otherwise.
- pure When a molecule or other material is identified herein as “pure”, it generally means, unless specified otherwise, that the material is about 99% pure or more. In general, this refers to purity with regard to unwanted residual solvents, reaction byproducts, impurities and unreacted starting materials. In the case substantially pure etoricoxib, “pure” also means about 99% of more of crystalline Form-I free from other known crystalline forms as appropriate or in the case of crystalline solids.
- the inventors have found an improved process for the preparation of etoricoxib of Formula (I) and, in particular, the crystalline Form-I of etoricoxib and amorphous form of etoricoxib.
- the crystalline Form-I of etoricoxib is characterized by its X-ray powder diffraction pattern and differential scanning calorimetry thermogram as shown in Figures 1 and 2, respectively.
- the amorphous form of etoricoxib is characterized by its X-ray powder diffraction pattern as shown in Figure 3.
- the inventors also have developed a process for the preparation of crystalline Form-I of etoricoxib by providing solution of etoricoxib in one or more of suitable solvent and obtaining crystalline Form-I of etoricoxib by removal of solvent.
- the inventors have also developed a process for the preparation of amorphous form of etoricoxib by providing the solution of etoricoxib in one or more of suitable solvent and obtaining amorphous of etoricoxib by addition of one or more of suitable anti- solvent.
- the removal of solvent may be done by a technique which includes, for example, filtration, filtration under vacuum, decantation, centrifugation, distillation and distillation under vacuum.
- the product obtained may be further or additionally dried to achieve the desired moisture values.
- the product may be dried in a hot air oven, tray drier, dried under vacuum and/or in a Fluid Bed Drier.
- a stable etoricoxib crystalline Form-I having particle size distribution dO. l ⁇ 5 ⁇ , d0.5 ⁇ 12 ⁇ and d0.9 ⁇ 50 ⁇ .
- the particle size distribution is dO. l ⁇ 3 ⁇ , d0.5 ⁇ 10 ⁇ and d0.9 ⁇ 35 ⁇ , when measured by Malvern particle size analyzer.
- the particle size distribution may be achieved by the process of the present invention or alternatively by any one of the known methods reported in the art like micronization, milling, grinding and sieving etc. which may reduce the particle.
- the stable crystalline Form-1 of etoricoxib may be characterized by atleast 6 months stability results as outline in Table-1 which is representative for one of the batch.
- the process comprises:
- the etoricoxib hydrochloride may be prepared by the process as disclosed in prior art reference WO 2010/097802 A2 for the preparation of etoricoxib and converting etoricoxib thus obtained to hydrochloride by treating with a hydrochloride source.
- WO 2010/097802 A2 for the preparation of etoricoxib and converting etoricoxib thus obtained to hydrochloride by treating with a hydrochloride source.
- the WO '802 A2 is incorporated herein as reference in its entirety.
- the etoricoxib hydrochloride may be hydrolyzed with suitable base comprises of alkali or alkaline earth metal hydroxide, alkali or alkaline earth metal carbonate or bicarbonates , hydrides, ammonia and the like.
- suitable base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, magnesium hydroxide and the like, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium tert-butoxide, ammonia and the like.
- sodium hydroxide may be used.
- Embodiments of the process include, hydrolysis of etoricoxib hydrochloride in presence of sodium hydroxide in water at about 25°C.
- the reaction proceeds further by extraction of etoricoxib obtain in-situ after hydrolysis in one or more of first solvent.
- the first solvent comprises one or more of toluene, xylene, ethylbenzene, chlorobenzene, n-heptane, n-hexane, ethyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate, methylene dichloride, ethylene dichloride and the like.
- the first solvent may be methylene dichloride.
- the process parameters include washing methylene. dichloride layer with water and separating the layer before removal of methylene dichloride.
- the solvent was distilled below 50°C upto half the volume followed by addition of one or more of second solvent.
- the second solvent comprises one or more of methanol, ethanol, isopropanol, n-butanol, hexanol, heptanol, dodecanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isobutyl acetate, isopropyl acetate, n- butyl acetate, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, sulfolane, acetonitrile, N-methyl pyrrolidone and the like.
- isopropyl acetate was used.
- Embodiments of the process further includes, addition of isopropyl acetate to half volume methylene dichloride containing etoricoxib and heating the reaction mixture at about 40°C to 90°C.
- the reaction mixture was heated from about 45°C to about 55°C to obtain the suspension.
- the reaction mixture may be cooled prior to obtaining of etoricoxib. The cooling may be particularly done to about 0°C to about 10°C to obtain etoricoxib.
- the process may further include drying etoricoxib followed by milling with suitable mesh size to obtain uniform particle size.
- the process comprises:
- the crystallization of etoricoxib may be performed in one or more of second solvent comprises of methanol, ethanol, isopropanol, n-butanol, hexanol, heptanol, dodecanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, sulfolane, acetonitrile, N-methyl pyrrolidone and the like.
- isopropyl acetate was used.
- Embodiments of the process may further include heating the suspension of etoricoxib in isopropyl acetate at about 40°C to about 90°C, particular at about 55°C to obtain crystalline etoricoxib.
- the process parameters may further include drying of crystalline etoricoxib obtained from isopropyl acetate at higher temperature.
- crystalline etoricoxib may be dried at about 70°C to 75°C for 1-10 hours to obtain crystalline Form-I of etoricoxib.
- the process comprises:
- the solution of etoricoxib may be obtained by dissolving etoricoxib in one or more of suitable solvent comprises one or more of toluene, xylene, ethylbenzene, chlorobenzene, n-heptane, n-hexane, ethyl acetate, isopropyl acetate, n- butyl acetate, t-butyl acetate, methylene dichloride, ethylene dichloride.
- the solvent may be methylene dichloride.
- Embodiments of the process may include optionally removing the solvent for obtaining residue of etoricoxib.
- the solvent may be removed for example, one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation, distillation under vacuum and the like.
- the process parameters may include treating the residue with one or more of suitable second solvent to obtain the suspension.
- the second solvent comprise of one or more of methanol, ethanol, isopropanol, n-butanol, hexanol, heptanol, dodecanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, sulfolane, acetonitrile, N-methyl pyrrolidone and the like.
- isopropyl acetate may be used.
- Embodiments of the process may further include heating the suspension of etoricoxib in isopropyl acetate at about 40°C to about 90°C, particular at about 55°C to obtain crystalline etoricoxib.
- the process parameters may further include drying of crystalline etoricoxib obtained from isopropyl acetate at higher temperature.
- crystalline etoricoxib may be dried at about 70°C to 75°C for 1 -10 hours to obtain crystalline Form-I of etoricoxib.
- the crystalline Form-I of etoricoxib may be characterized by its X- ray powder diffraction pattern having characteristic peaks at about 6.9°, 9.5°, 1 1.6°, 12.2°, 12.9°, 15.3°, 16.4°, 17.8°, 19.0°, 19.2°, 20.1°, 21.0°, 21 .7°, 22.6°, 23.1°, 23.5°, 23.9°, 26.2°, 28.3° degrees 2-theta.
- etoricoxib may be characterized by differential scanning calorimetry having endothermic peak at about 139°C.
- the solution of etoricoxib may be obtained by dissolving etoricoxib in one or more of suitable solvent comprises of toluene, xylene, ethylbenzene, chlorobenzene, n-heptane, n-hexane, ethyl acetate, isopropyl acetate, n-butyl acetate, t-butyl acetate, methylene dichloride, chloroform, ethylene dichloride.
- the solvent may be methylene dichloride or chloroform.
- the solution of etoricoxib in one or more of suitable solvent may be treated with one or more of suitable anti-solvent comprises of cyclohexane, n-hexane, n- heptane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-butyl acetate, isopropyl acetate, n-butyl acetate and the like.
- suitable anti-solvent comprises of cyclohexane, n-hexane, n- heptane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-butyl acetate, isopropyl acetate, n-butyl acetate and the like.
- suitable anti-solvent comprises of cyclohexane, n-hexane,
- the solution of etoricoxib may be prepared by dissolving etoricoxib of Formula (I) in one or more of suitable solvent comprises of methanol, ethanol, isopropanol, n-butanol, hexanol, heptanol, dodecanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, sulfolane, acetonitrile, N-methyl pyrrolidone and the like.
- suitable solvent comprises of methanol, ethanol, isopropanol, n-butanol, hexanol, heptanol, dodecanol, acetone, methyl ethyl ketone, methyl is
- the solution of etoricoxib in one or more of suitable solvent may be treated with one or more of suitable anti-solvent comprises of cyclohexane, n-hexane, n- heptane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-butyl acetate, isopropyl acetate, n-butyl acetate and the like.
- suitable anti-solvent comprises of cyclohexane, n-hexane, n- heptane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-butyl acetate, isopropyl acetate, n-butyl acetate and the like.
- suitable anti-solvent comprises of cyclohexane, n-hexane,
- the amorphous form of etoricoxib may be characterized by X-ray powder diffraction pattern as shown in FIG.3.
- etoricoxib can be prepared by the reaction scheme- 1 as shown below, which is also the scope of the present invention.
- etoricoxib can be prepared by the reaction scheme-2 as shown below, which is also the scope of the present invention.
- the process comprises:
- R 2 through R5 are independently Ci -6 alkyl, aryl, aralkyl.
- R 2 and R 3 together as well as R 4 and R5 together represents a cyclic group, optionally containing one or more heteroatom selected from N, O or S,
- the compound of Formula (III-AB) may be selected from and not limited to the compounds of Formula (III-A) or (III-B) as herein below.
- the suitable solvent comprises one or more of hydrocarbons like benzene, toluene, xylene, ethyl benzene and the like, halogenated hydrocarbon like chloroform, methylene dichloride, ethylene dichloride and the like, alcohols like methanol, ethanol, isopropanol, t-butanol and the like, ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like, aprotic polar solvents like dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, dimethylsulfoxide and the like, ethers like diethyl ether, 1 ,4-dioxane, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran and the like, nitriles like acetonitrile and the like or mixture thereof.
- Powder X-ray diffraction of etoricoxib forms can be obtained under following conditions.
- Theta Offset 0.0000
- the crystalline Form-I of Etoricoxib shows DSC peak melting temperature of 139°C and x-ray powder diffraction peaks at about degrees 2-theta and d-spacing : Table-II
- the present invention accordingly provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form-I of etoricoxib and one or more pharmaceutically acceptable carriers, excipients or diluents.
- a pharmaceutical composition comprising a therapeutically effective amount of stable crystalline Form-I of etoricoxib having particle size d0.9 ⁇ 50 ⁇ .
- a pharmaceutical composition comprising a therapeutically effective amount of stable crystalline Form-I of etoricoxib having particle size distribution dO. l ⁇ 5 ⁇ , d0.5 ⁇ 12 ⁇ and d0.9 ⁇ 50 , ⁇ .
- the present invention accordingly provides a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of amorphous form of etoricoxib and one or more pharmaceutically acceptable carriers, excipients or diluents.
- the storage stable crystalline Form-I of etoricoxib does not show any change in the XRD pattern after storage for three months at 40°C and 75% relative humidity or at 25°C and 60% relative humidity. More particularly, the storage . stable crystalline Form-I of etoricoxib has no detectable quantities of polymorphic
- the residue was treated with toluene and water mixture followed by the removal of toluene.
- the residue was crystallized in isopropanol to obtain etoricoxib.
- the etoricoxib thus obtained was converted to its hydrochloride by treating with methanolic HCl.
- the etoricoxib hydrochloride was recrystallized in methanol to obtain pure etoricoxib hydrochloride. HPLC purity > 99.0%.
- the reaction mixture was heated at 60°C for 6 hours and cooled to 40°C.
- Formaldehyde (21.6 g) was added and the reaction mixture was heated at 60°C for 1 hour.
- the separated aqueous layer was treated with tetrahydrofuran (5 mL) and toluene (300 mL) and solvents were removed to obtain a residue.
- the residue was treated with toluene and water mixture followed by the removal of toluene.
- the residue was crystallized in isopropanol to obtain etoricoxib in the presence of seed crystals of Form-I.
- the etoricoxib thus obtained was converted to its hydrochloride by treating with methanolic HCl.
- the etoricoxib hydrochloride was recrystallized in methanol to obtain pure etoricoxib hydrochloride. HPLC purity > 99.0%.
- Etoricoxib 100 g was dissolved in methylene dichloride (500 mL) followed by the addition of sodium chloride solution (45 gm in 300 ml). The reaction mixture was stirred to separate the organic layer. The separated organic layer was dried over anhydrous magnesium sulfate (15 g). The organic layer was filtered through a hyflow bed and methylene dichloride was distilled out to obtain a residue.
- the Form-I of etoricoxib was characterized by XRPD (Fig.l) and DSC (Fig.2).
- Etoricoxib (5 g) was dissolved in chloroform (15 mL) by stirring at 25°C to get a clear solution.
- the clear solution was treated with n-hexane (100 mL) at- 25°C.
- Etoricoxib (5 g) was dissolved in methanol (40 mL) by stirring at 25°C to get a clear solution. The clear solution was treated with n-hexane (200 mL) at 25°C. The reaction mixture was cooled to 5°C and the product obtained was filtered and washed with hexane. The product was dried in hot air oven at 60°C to obtain 3 g amorphous form of etoricoxib characterized by XRPD (Fig.3).
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Abstract
La présente invention concerne un procédé amélioré pour la préparation d'étoricoxibe et de polymorphes de celui-ci. En particulier, l'invention concerne un procédé pour la préparation de la forme cristalline stable I de l'étoricoxibe. La présente invention concerne également un procédé pour la préparation de la forme amorphe de l'étoricoxibe. L'invention concerne également des compositions pharmaceutiques qui contiennent la forme cristalline stable I de l'étoricoxibe.
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EP12839179.4A EP2773618A1 (fr) | 2011-11-03 | 2012-11-02 | Procédé amélioré pour la préparation d'étoricoxibe et de polymorphes de celui-ci |
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IN3101/MUM/2011 | 2011-11-03 | ||
IN3101MU2011 | 2011-11-03 |
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Cited By (9)
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CN106632003A (zh) * | 2015-12-31 | 2017-05-10 | 上海迈柏医药科技有限公司 | 一种依托考昔的制备方法 |
CN107417600A (zh) * | 2017-09-26 | 2017-12-01 | 江苏正大清江制药有限公司 | 一种依托考昔与呋喃甲酸形成盐的新晶型及制备方法 |
CN107556231A (zh) * | 2017-09-23 | 2018-01-09 | 江苏正大清江制药有限公司 | 一种依托考昔与对硝基苯甲酸形成的盐的晶型及制备方法 |
CN107556232A (zh) * | 2017-09-26 | 2018-01-09 | 江苏正大清江制药有限公司 | 一种依托考昔与盐酸形成盐的新晶型及制备方法 |
CN107556233A (zh) * | 2017-09-26 | 2018-01-09 | 江苏正大清江制药有限公司 | 一种依托考昔与噻吩甲酸形成盐的新晶型及制备方法 |
CN107698496A (zh) * | 2017-09-26 | 2018-02-16 | 江苏正大清江制药有限公司 | 一种邻苯二甲酸与依托考昔形成盐的晶型及其制备方法 |
CN108069896A (zh) * | 2016-11-11 | 2018-05-25 | 昆明积大制药股份有限公司 | 一种依托考昔晶型的制备方法 |
EP2888231B1 (fr) * | 2012-08-27 | 2019-01-09 | Glenmark Pharmaceuticals Limited | Procédé de préparation d'étoricoxib cristallin |
CN113264873A (zh) * | 2019-01-18 | 2021-08-17 | 华润双鹤药业股份有限公司 | 一种依托考昔的纯化及制备方法 |
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