EP2773618A1 - An improved process for the preparation of etoricoxib and polymorphs thereof - Google Patents

An improved process for the preparation of etoricoxib and polymorphs thereof

Info

Publication number
EP2773618A1
EP2773618A1 EP12839179.4A EP12839179A EP2773618A1 EP 2773618 A1 EP2773618 A1 EP 2773618A1 EP 12839179 A EP12839179 A EP 12839179A EP 2773618 A1 EP2773618 A1 EP 2773618A1
Authority
EP
European Patent Office
Prior art keywords
etoricoxib
crystalline form
acetate
solvents
formula
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12839179.4A
Other languages
German (de)
French (fr)
Inventor
Shriprakash Dhar DWIVEDI
Vipul Kantibhai PATEL
Mahesh Shankarbhai PATEL
Niraj Shyamlal Shah
Ashok Prasad
Kuldeep Natwarlal Jain
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zydus Lifesciences Ltd
Original Assignee
Cadila Healthcare Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Cadila Healthcare Ltd filed Critical Cadila Healthcare Ltd
Publication of EP2773618A1 publication Critical patent/EP2773618A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • 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).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to an improved process for the preparation of etoricoxib and polymorphs thereof. In particular, the, invention relates to a process for the preparation of stable crystalline Form-I of etoricoxib. Further, 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.

Description

AN IMPROVED PROCESS FOR THE PREPARATION OF
ETORICOXIB AND POLYMORPHS THEREOF FIELD OF THE INVENTION
The invention relates to an improved process for the preparation of etoricoxib and polymorphs thereof. In particular, the invention relates to a process for the preparation of stable crystalline Form-I of etoricoxib. Further, 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.
BACKGROUND AND THE PRIOR ART
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
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).
(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. Therefore, 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. For a general review of polymorphs and the pharmaceutical applications of polymorphs See G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58, 91 1 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.
International (PCT) Publication No. WO 2001/092230 A l (the WO '230 Al ) discloses different polymorphic forms of etoricoxib, specifically disclosed are Forms I, II, III, IV, V, hemihydrate and sesquihydrate as well as amorphous form characterized by X-ray powder diffraction d-spacings and differential scanning calorimetry (DSC).
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.
International (PCT) Publication No. WO 2005/085199 Al discloses different polymorphic forms of etoricoxib, viz. Forms IX, X, XI, XII, XIII, XIV, XV and XVI.
Organic process research & development 2003, (7) 958-961 discloses preparation of crystalline hemihydrate and anhydrous form of etoricoxib using isopropyl acetate and water combination. The hemihydrate and anhydrous forms of etoricoxib obtained by using isopropyl acetate/water are charaterised by X-ray powder diffraction (Figure. 2).
Journal of Organic Chemistry, 2000, 65(25), 8415-8420 dislcoses the preparation of etoricoxib by condensation of ketosulfone of Formula (IV) and CDPH compound (IIIA) in presence of potassium tert-butoxide as base.
International (PCT) Publication No. WO 2010/097802 discloses the preparation of etoricoxib by condensation of ketosulfone of Formula (IV) and CDPTH compound (III) is presence of potassium tert-butoxide as base.
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.
SUMMARY OF THE INVENTION:
In one general aspect there is provided a stable etoricoxib crystalline Form-I.
In another general aspect there is provided a stable etoricoxib crystalline Form-I having a particle size distribution dO. l < 5 μιη, d0.5 < 12 μιη and d0.9 < 50 μιτι.
In another general aspect there is provided a stable etoricoxib crystalline
Form-I substantially free from Form-V, characterized by having no peak at about 13.7 A by X-ray powder diffraction.
In another general aspect there is provided 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. In another general aspect there is provided 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.
In another general aspect, there is provided an improved process for the preparation of etoricoxib of Formula (I).
the process includes:
(a) providing etoricoxib hydrochloride;
(b) hydrolyzing the etoricoxib hydrochloride with a suitable base;
(c) extracting the etoricoxib with one or more of first solvents;
(d) optionally removing the solvents; and
(e) obtaining the etoricoxib by treating with one or more of second solvents.
In another general aspect there is provided a process for the preparation of crystalline Form-I of etoricoxib of Formula (I).
the process includes:
(a) providing etoricoxib hydrochloride;
(b) hydrolyzing the etoricoxib hydrochloride with a suitable base;
(c) extracting the etoricoxib with one or more of first solvents;
(d) optionally removing the solvents;
(e) crystallizing the etoricoxib with one or more of second solvents; and
(f) obtaining the crystalline Form-I of etoricoxib. In another general aspect there is provide a process for the preparation of crystalline Form-I of etoricoxib of Formula (I).
the process includes:
(a) providing a solution of etoricoxib in one or more of suitable solvents;
(b) optionally removing the solvent to obtain a residue of etoricoxib; and
(c) obtaining the crystalline Form-I of etoricoxib by crystallizing in one or more of second solvents.
In another general aspect there is provide a process for the preparation of crystalline Form-I of etoricoxib of Formula (I).
the process includes:
(a) providing a solution of etoricoxib in one or more suitable solvents; and
(b) obtaining the crystalline Form-I of etoricoxib by addition of one or more suitable anti -sol vents.
; In another general aspect there is provide a process for the preparation of amorphous form of etoricoxib of Formula (I).
the process includes:
(a) providing a solution of etoricoxib in one or more suitable solvents; and
(b) obtaining the amorphous form of etoricoxib by addition of one or more suitable anti-solvents.
In another general aspect there is provided an improved process for the preparation of etoricoxib of Formula (I).
the process includes:
(a) reacting ketosulfone compoun
with a compound of Formula
wherein R2 through R5 are independently C]-6 alkyl, aryl, aralkyl. R2 and R3 together as well as R4 and R5 together represents a cyclic group, optionally containing one or more heteroatom selected from N, O or S,
in the presence of sodium hydride in one or more suitable solvents to obtain etoricoxib; and
(b) obtaining the etoricoxib of Formula (I). In another general aspect there is provided a pharmaceutical composition comprising a therapeutically effective amount of stable crystalline Form-I of etoricoxib having a particle size d0.9 < 50 μπι.
In another general aspect there is provided storage stable crystalline Form-I of etoricoxib.
BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
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.
DETAILED DESCRIPTION OF THE INVENTION
As used herein, the term "stable" refers to crystalline etoricoxib Form-I that includes either of the following:
a) 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
b) 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 (2Θ) 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 (2Θ) 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.
The term "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 other known forms as herein above means, crystalline forms selected from Form-II, Form-Ill, Form-IV, Form-V, hemihydrate or sesquihydrate or amorphous form as characterized in European Patent No. EP 1296951 B l, which is incorporated herein as reference in its entirety.
As used here in 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. For example, the product may be dried in a tray drier, dried under vacuum and/or in a Fluid Bed Drier.
As used here in the term "about" may include the values from ±0.2° in case of 2-theta for diffractogram values. The term "about" may also include the values from ±3°C in case of differential scanning calorimetry.
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. As used 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.
All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "general", "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
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.
In general, 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. For example, the product may be dried in a hot air oven, tray drier, dried under vacuum and/or in a Fluid Bed Drier.
The prior art references like U.S. Patent No. 5,861 ,419 and our own International (PCT) publication WO 2010/097802 A2 are incorporated herein by reference in their entirety wherein the process for the preparation of intermediates and etoricoxib is disclosed.
In one general aspect, there is provided stable etoricoxib crystalline Form-I.
In another general aspect, there is provided a stable etoricoxib crystalline Form-I having particle size distribution dO. l < 5 μηι, d0.5 < 12 μπι and d0.9 < 50 μιη. In particular, the particle size distribution is dO. l < 3 μιη, d0.5 < 10 μιτι and d0.9 < 35 μιη, when measured by Malvern particle size analyzer. In general, 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.
In another general aspect, there is provided a stable etoricoxib crystalline Form-I substantially free from Form-V, characterized by having no peak at about 13.7 A by X-ray powder diffraction.
In another general aspect, there is provided 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.
In another general aspect, there is provided 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.
In another general aspect, 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.
Table !
aNLT = Not less than
bNMT = Not more than
In another general aspect, there is provided an improved process for preparation of etoricoxib of Formula (I),
the process comprises:
(a) providing etoricoxib hydrochloride;
(b) hydrolysing the etoricoxib hydrochloride with suitable base;
(c) extracting etoricoxib with one or more of first solvent;
(d) optionally, removing the solvent; and
(e) obtaining etoricoxib by treating with one or more of second solvent.
In general 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. The WO '802 A2 is incorporated herein as reference in its entirety.
In general, 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. In particular, the 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. In particular, 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. In particular, the first solvent may be methylene dichloride.
In general, 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. In particular, 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. In particular, 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.
In another general aspect, there is provided a process for the preparation of crystalline Form-I of etoricoxib of Formula (I),
the process comprises:
(a) providing etoricoxib hydrochloride;
(b) hydrolysing the etoricoxib hydrochloride with suitable base;
(c) extracting etoricoxib with one or more of first solvent;
(d) optionally, removing the solvent;
(e) crystallizing etoricoxib with one or more of second solvent; and (g) obtaining crystalline Form-I of etoricoxib.
In general, 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. In particular, 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. Particular, crystalline etoricoxib may be dried at about 70°C to 75°C for 1-10 hours to obtain crystalline Form-I of etoricoxib.
In another general aspect, there is provide a process for the preparation of crystalline Form-I of etoricoxib of Formula (I),
the process comprises:
(a) providing the solution of etoricoxib in one or more of suitable solvent;
(b) optionally, removing the solvent to obtain the residue of etoricoxib; and
(c) obtaining crystalline Form-I of etoricoxib by crystallizing the residue in one or more of second solvent.
In general, 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. In particular, 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.
In general, 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. In particular, 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. Particular, crystalline etoricoxib may be dried at about 70°C to 75°C for 1 -10 hours to obtain crystalline Form-I of etoricoxib.
In general, 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. Further, etoricoxib may be characterized by differential scanning calorimetry having endothermic peak at about 139°C.
In another general aspect, there is provide a process for the preparation of crystalline Form-I of etoricoxib of Formula (I),
the process comprising:
(a) providing the solution of etoricoxib in one or more of suitable solvent; and
(b) obtaining crystalline Form-I of etoricoxib by addition of one or more of suitable anti-solvent. In general, 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. In particular, 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. In particular, n-heptane or n- hexane may be used.
In another general aspect, there is provide a process for the preparation of amorphous form of etoricoxib of Formula (I),
the process comprising:
(a) providing the solution of etoricoxib in one or more of suitable solvent; and
(b) obtaining amorphous form of etoricoxib by addition of one or more of suitable anti-solvent.
In general, 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. In .particular, methanol, ethanol, isopropanol, acetone may be used.
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. In particular, n-heptane or n- hexane may be used.
The amorphous form of etoricoxib may be characterized by X-ray powder diffraction pattern as shown in FIG.3.
In another general aspect, etoricoxib can be prepared by the reaction scheme- 1 as shown below, which is also the scope of the present invention.
Scheme-1
In another general aspect, etoricoxib can be prepared by the reaction scheme-2 as shown below, which is also the scope of the present invention.
lll-AB (I)
Scheme-2
In another general aspect, there, is provided an improved process for the preparation of etoricoxib of Formula (I),
the process comprises:
(a) reacting ketosulfone compound of Formula (IV)
)
wherein R2 through R5 are independently Ci-6 alkyl, aryl, aralkyl. R2 and R3 together as well as R4 and R5 together represents a cyclic group, optionally containing one or more heteroatom selected from N, O or S,
in presence of sodium hydride in one or more of suitable solvent to obtain etoricoxib; and
(b) obtaining etoricoxib of Formula (I).
In general, 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.
In general, 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. In particular, the mixture of dimethyl formamide and toluene may be used.
The isolation of etoricoxib may be done with the process disclosed in WO
2010/097802 A2 which is incorporated herein as reference in its entirety.
Powder X-ray diffraction of etoricoxib forms can be obtained under following conditions.
(i) Characterization by Powder X-ray diffraction
The X-ray powder diffraction spectrum was measured under the following experimental conditions:
Instrument : X-Ray Diffractometer, D/Max-2200/PC Make: Rigaku,
Japan.
X- Ray : Cu/40kv/40mA
Diverging : 10
Scattering Slit : 10
Receiving Slit : 0.15 mm
Monochromator RS : 0.8 mm
Counter : Scintillation Counter
Scan Mode : Continuous
Scan Speed : 3.0000 / Min
Sampling Width : 0.020
Scan Axes : Two Theta / Theta
Scan Range : 2.0000 to 40.0000
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
Table-II
In another general aspect, the present invention accordingly provides a pharmaceutical composition comprising a therapeutically effective amount of crystalline Form-I of etoricoxib and one or more pharmaceutically acceptable carriers, excipients or diluents. In another general aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of stable crystalline Form-I of etoricoxib having particle size d0.9 < 50 μιη.
In another general aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of stable crystalline Form-I of etoricoxib having particle size distribution dO. l < 5 μπι, d0.5 < 12 μιη and d0.9 < 50 , μιη.
In another general aspect, the present invention accordingly provides a pharmaceutical composition comprising a therapeutically effective amount of amorphous form of etoricoxib and one or more pharmaceutically acceptable carriers, excipients or diluents.
In another general aspect, there is provided a storage stable crystalline Form-I of etoricoxib.
In particular, 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
Form-IV or Form-V or a hemihydrate after storage for three months at 40°C and 75% relative humidity or at 25°C and 60% relative humidity.
The present invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1: Preparation of etoricoxib hydrochloride:
Potassium tertiary butoxide (0.456 Kg), l-(6-methylpyridin-3-yl)-2[4- (methylsulfonyl)- phenyl]ethanone (1.0 Kg) and 2-chloro-l,3-(bis morpholinyl) trimethinium hexafluoro phosphate of (Formula III) (1.612 Kg) were dissolved in THF (10.0 L) and the solution was heated at 30-55°C for 2-24 hrs. The reaction mixture was treated with acetic acid (1.45 Kg) and basified with ammonia gas (1.2 Kg) followed by the addition of ammonium acetate (0.277 Kg). The solvent was removed by distillation under vacuum 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. 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%.
Example 2; Preparation of etoricoxib hydrochloride:
Sodium hydride (15 g) and l-(6-methylpyridin-3-yl)-2[4-(methylsulfonyl)- phenyl]ethanone (100 g) were taken in dimethylformamide (200 mL) at 10°C. Toluene (500 mL) and compound of (Formula ΠΙ-Α) ( 1 12.32 g) were added to the reaction mixture and stirred for 3 hours at 10°C. The reaction mixture was treated with acetic acid (145.3 g) and basified with ammonia gas (277 g) followed by the addition of ammonium acetate (28.5 g). The solvent was removed by distillation under vacuum to obtain a residue. 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%.
The above example was repeated by replacing compound (III-A) with (III-B) to obtain etoricoxib Form-I or its hydrochloride salt.
Example 3; Preparation of crystalline Form-I etoricoxib:
To a stirred solution of sodium hydroxide (20.20 g) in water (250 mL), etoricoxib hydrochloride (50 g) was added at a temperature of 25°C to 35°C. The reaction mixture was stirred and extracted with methylene dichloride (250 mL). The separated organic layer was filtered through a hyflow bed and distilled out to give a residue. Isopropyl acetate (100 mL) was added to the residue and heated at 50-55°C. The reaction mixture was cooled to 0-10°C and solid was filtered. The solid was dried to obtain the crystalline Form-I of etoricoxib. Example 4: Preparation of crystalline Form-I of etoricoxib:
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. Isopropyl acetate
(200 mL) was added to the residue and heated at 50 C. The reaction mixture was cooled and solid was filtered. The solid was dried to obtain the crystalline Form-I of etoricoxib. The Form-I of etoricoxib was characterized by XRPD (Fig.l) and DSC (Fig.2).
Example 5; Preparation of crystalline Form-I of etoricoxib:
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.
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°-65°C to obtain 4 g crystalline Form-I of etoricoxib characterized by XRPD (Fig. l ) and DSC (Fig.2).
Example 6: Preparation of amorphous form of etoricoxib:
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).
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.

Claims

Claims:
1. A stable etoricoxib crystalline Form-I.
2. A stable etoricoxib crystalline Form-I having a particle size distribution of dO. l < 5 μιη, dO.5 < 12 μιτι, d0.9 < 50 μm, or any combination thereof.
3. A stable etoricoxib crystalline Form-I substantially free from Form-V, characterized by having no peak at about 13.7 A by X-ray powder diffraction.
4. 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.
5. 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.
6. An improved process for the preparation of etoricoxib of Formula (I),
(I)
the process comprising:
(a) providing etoricoxib hydrochloride;
(b) hydrolyzing the etoricoxib hydrochloride with one or more suitable bases;
(c) extracting the etoricoxib with one or more first solvents;
(d) optionally, removing the solvents; and
(e) obtaining the etoricoxib by treating with one or more second solvents.
7. The process as claimed in claim 6, wherein the suitable base comprises one or more of alkali or alkaline earth metal hydroxides, alkali or alkaline earth metal carbonates, or bicarbonates, hydrides, ammonia, and the like.
8. The process as claimed in claim 7, wherein the 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.
9. The process as . claimed in claim 6, wherein 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.
10. The process as claimed in claim 6, wherein 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.
1 1. A process for the preparation of crystalline Form-I of etoricoxib of Formula (I),
the process comprising: ,
(a) providing etoricoxib hydrochloride;
(b) hydrolyzing the etoricoxib hydrochloride with one or more suitable bases;
(c) extracting etoricoxib with one or more of first solvents;
(d) optionally, removing the solvents;
(e) crystallizing the etoricoxib with one or more second solvents; and
(f) obtaining the crystalline Form-I of etoricoxib.
12. The process as claimed in claim 1 1 , wherein the suitable base is sodium hydroxide.
13. The process as claimed in claim 1 1, wherein the first solvent is methylene dichloride.
14. The process as claimed in claim 1 1, wherein the second solvent is isopropyl acetate.
15. A process for the preparation of crystalline Form-I of etoricoxib of Formula (I),
(I)
the process comprising:
(a) providing a solution of etoricoxib in one or more suitable solvents;
(b) optionally, removing the solvents to obtain a residue of etoricoxib; and
(c) obtaining the crystalline Form-I of etoricoxib by crystallizing the residue in one or more second solvents.
16. The process as claimed in claim 15, wherein the 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, and ethylene dichloride.
17. The process as claimed in claim 15, wherein the solvent may be removed by one or more of filtration, filtration under vacuum, decantation, centrifugation, distillation, and distillation under vacuum.
18. The process as claimed in claim 15, wherein 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.
19. The crystalline Form-I of etoricoxib as claimed in any preceding claims is 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. Γ, 23.5°, 23.9°, 26.2°, 28.3° degrees 2-theta.
20. A process for the preparation of crystalline Form-I of etoricoxib of Formula (I), trie process comprising:
(a) providing a solution of etoricoxib in one or more suitable solvents; and
(b) obtaining the crystalline Form-I of etoricoxib by addition of one or more suitable anti-solvents.
21. The process as claimed in claim 20, wherein the 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, chloroform, and ethylene dichloride.
22. The process as claimed in claim 20, wherein the suitable anti-solvent comprises one or more 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.
23. A process for the preparation of amorphous form of etoricoxib of Formula (I),
the process comprising:
(a) providing a solution of etoricoxib in one or more suitable solvents; and
(b) obtaining the amorphous form of etoricoxib by addition of one or more suitable anti-solvents.
24. The process as claimed in claim 23, wherein the suitable 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.
25. The process as claimed in claim 23, wherein the suitable anti-solvent comprises one or more 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.
26. An improved process for the preparation of etoricoxib of Formula (I),
the process comprising:
(a) reacting ketosulfone compound of Formula (IV),
with a compound of Formula
wherein R2 through R5 are independently Ci_6 alkyl, aryl, aralkyl. R2 and R3 together as well as R and R5 together represents a cyclic group, optionally containing one or more heteroatom selected from N, O or S,
in the presence of sodium hydride in one or more suitable solvents to obtain etoricoxib; and
(b) obtaining the etoricoxib of Formula (I).
27. The process as claimed in claim 26, wherein the suitable solvent comprises one or more of hydrocarbons like benzene, toluene, xylene, and ethyl benzene, halogenated hydrocarbons like chloroform, methylene dichloride, and ethylene dichloride, alcohols like methanol, ethanol, isopropanol, and t-butanol, ketones like acetone, methyl ethyl ketone, and methyl isobutyl ketone, aprotic polar solvents like dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone, and dimethylsulfoxide, ethers like diethyl ether, 1,4-dioxane, diisopropyl ether, methyl tert-butyl ether, and tetrahydrofuran, and nitriles like acetonitrile, and the like or mixtures thereof.
28. The process as claimed in claim 27, wherein the suitable solvent comprises a mixture of dimethylformamide and toluene.
29. The process as claimed in claim 26, wherein the compound of Formula (II1-AB) may be selected from the compound of Formula (III-A) or (ΙΠ-Β) as herein below.
30. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline Form-I of etoricoxib and one or more pharmaceutically acceptable carriers, excipients or diluents.
31. A pharmaceutical composition comprising a therapeutically effective amount of a stable crystalline Form-I of etoricoxib having a particle size of d0.9 < 50 μιη.
32. A pharmaceutical composition comprising a therapeutically effective amount of a stable crystalline Form-I of etoricoxib having a particle size distribution of dO. l < 5 μιη, dO.5 < 12 μπι, d0.9 < 50 μιη, or any combination thereof.
33. A pharmaceutical composition comprising a therapeutically effective amount of the amorphous form of etoricoxib and one or more pharmaceutically acceptable carriers, excipients or diluents.
34. Storage stable crystalline Form-I of etoricoxib.
35. The storage stable crystalline Form-I of etoricoxib of claim 34, wherein the 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.
36. The storage stable crystalline Form-I of etoricoxib of claim 34, wherein the etoricoxib has no detectable quantities of polymorphic Form-IV or Form-V or a hemihydrate after storage for three months at 40°C and 75% relative humidity or at 25°C and 60% relative humidity.
EP12839179.4A 2011-11-03 2012-11-02 An improved process for the preparation of etoricoxib and polymorphs thereof Withdrawn EP2773618A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3101MU2011 2011-11-03
PCT/IN2012/000720 WO2013105106A1 (en) 2011-11-03 2012-11-02 An improved process for the preparation of etoricoxib and polymorphs thereof

Publications (1)

Publication Number Publication Date
EP2773618A1 true EP2773618A1 (en) 2014-09-10

Family

ID=48048099

Family Applications (1)

Application Number Title Priority Date Filing Date
EP12839179.4A Withdrawn EP2773618A1 (en) 2011-11-03 2012-11-02 An improved process for the preparation of etoricoxib and polymorphs thereof

Country Status (2)

Country Link
EP (1) EP2773618A1 (en)
WO (1) WO2013105106A1 (en)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2888231B1 (en) * 2012-08-27 2019-01-09 Glenmark Pharmaceuticals Limited Process for preparation of crystalline etoricoxib
CN106632003B (en) * 2015-12-31 2019-02-12 上海博志研新药物技术有限公司 A kind of preparation method of Etoricoxib
CN108069896B (en) * 2016-11-11 2022-08-12 昆明积大制药股份有限公司 Preparation method of etoricoxib crystal form
CN107556231A (en) * 2017-09-23 2018-01-09 江苏正大清江制药有限公司 The crystal formation and preparation method for the salt that a kind of Etoricoxib is formed with paranitrobenzoic acid
CN107698496A (en) * 2017-09-26 2018-02-16 江苏正大清江制药有限公司 A kind of phthalic acid and the crystal formation of Etoricoxib forming salt and preparation method thereof
CN107417600A (en) * 2017-09-26 2017-12-01 江苏正大清江制药有限公司 A kind of Etoricoxib and the novel crystal forms and preparation method of furancarboxylic acid forming salt
CN107556232A (en) * 2017-09-26 2018-01-09 江苏正大清江制药有限公司 A kind of Etoricoxib and the novel crystal forms and preparation method of hydrochloric acid forming salt
CN107556233A (en) * 2017-09-26 2018-01-09 江苏正大清江制药有限公司 A kind of Etoricoxib and the novel crystal forms and preparation method of thiophenic acid forming salt
CN113264873B (en) * 2019-01-18 2022-11-04 华润双鹤药业股份有限公司 Etoricoxib purification and preparation method

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001037833A1 (en) 1999-11-29 2001-05-31 Merck Frosst Canada & Co. Polymorphic, amorphous and hydrated forms of 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl
WO2001092230A1 (en) 2000-05-26 2001-12-06 Merck & Co., Inc. 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl- [2,3']bipyridinyl in pure crystalline form and process for synthesis
WO2002096877A1 (en) 2001-05-25 2002-12-05 Merck & Co., Inc. 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl in pure crystalline form and process for synthesis

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5593994A (en) 1994-09-29 1997-01-14 The Dupont Merck Pharmaceutical Company Prostaglandin synthase inhibitors
US5739166A (en) 1994-11-29 1998-04-14 G.D. Searle & Co. Substituted terphenyl compounds for the treatment of inflammation
US5861419A (en) 1996-07-18 1999-01-19 Merck Frosst Canad, Inc. Substituted pyridines as selective cyclooxygenase-2 inhibitors
WO2005085199A1 (en) 2004-01-14 2005-09-15 Cadila Healthcare Limited Novel polymorphs of etoricoxib
ES2562981T3 (en) 2009-02-27 2016-03-09 Cadila Healthcare Limited A procedure for the preparation of Etoricoxib

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001037833A1 (en) 1999-11-29 2001-05-31 Merck Frosst Canada & Co. Polymorphic, amorphous and hydrated forms of 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl
WO2001092230A1 (en) 2000-05-26 2001-12-06 Merck & Co., Inc. 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl- [2,3']bipyridinyl in pure crystalline form and process for synthesis
WO2002096877A1 (en) 2001-05-25 2002-12-05 Merck & Co., Inc. 5-chloro-3-(4-methanesulfonylphenyl)-6'-methyl-[2,3']bipyridinyl in pure crystalline form and process for synthesis

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
PAWEL GROBELNY ET AL: "POLIMORPHS AND HYDRATES OF ETORICOXIB, A SELECTIVE COX-2 INHIBITOR", CRYSTENGCOMM, vol. 14, no. 18, 8 May 2012 (2012-05-08), pages 5785 - 5794, XP055199324, DOI: 10.1039/C2CE06604A
See also references of WO2013105106A1

Also Published As

Publication number Publication date
WO2013105106A1 (en) 2013-07-18

Similar Documents

Publication Publication Date Title
EP2773618A1 (en) An improved process for the preparation of etoricoxib and polymorphs thereof
EP2718262B1 (en) Apixaban preparation process
EP2951158B1 (en) Process for the preparation of ivacaftor and solvates thereof
EP3401316B1 (en) Chemical process
WO2016092478A1 (en) Process for preparation of luliconazole
WO2016055918A1 (en) Novel stable polymorphs of isavuconazole or its salt thereof
US7989618B2 (en) Linezolid crystalline hydrate form and linezolid salts
EP2451786A2 (en) Improved process for the preparation of ambrisentan and novel intermediates thereof
US20080167477A1 (en) Novel polymorphic forms of carvedilol dihydrogen phosphate and process for preparing the same
WO2013065063A1 (en) Anhydrous form of dasatinib, process for its preparation and its use
HRP20050039A2 (en) Crystal forms of olanzapine and processes for their preparation
WO2014033740A1 (en) Novel polymorphs of azilsartan medoxomil
US9487487B2 (en) Process for preparation of montelukast sodium
US8962833B2 (en) Salts of raltegravir
EP2900662A1 (en) A method of preparing a highly pure potassium salt of azilsartan medoxomil
JP2018528233A (en) Process for producing indoline compounds and novel indoline salts
SI21850A (en) Salts of olanzapin and their transformation into free base of olanzapin
WO2009047797A2 (en) Process for the preparation of perhydroisoindole derivative
EP2480535A1 (en) Polymorphs of sorafenib acid addition salts
CN106146485B (en) Method for preparing tedizolid and tedizolid crystal obtained by method
EP2393786B1 (en) Novel polymorphs of lopinavir
WO2017081014A1 (en) Process for the preparation of eltrombopag olamine
CA2808731A1 (en) Crystalline forms of maraviroc phosphate and process for maraviroc amorphous form
WO2024105519A1 (en) A process for the preparation of levoketoconazole
WO2014009969A2 (en) Novel polymorphs of azilsartan

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20140425

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

17Q First examination report despatched

Effective date: 20150409

TPAC Observations filed by third parties

Free format text: ORIGINAL CODE: EPIDOSNTIPA

TPAC Observations filed by third parties

Free format text: ORIGINAL CODE: EPIDOSNTIPA

TPAC Observations filed by third parties

Free format text: ORIGINAL CODE: EPIDOSNTIPA

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: GRANT OF PATENT IS INTENDED

INTG Intention to grant announced

Effective date: 20161116

TPAC Observations filed by third parties

Free format text: ORIGINAL CODE: EPIDOSNTIPA

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAJ Information related to disapproval of communication of intention to grant by the applicant or resumption of examination proceedings by the epo deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR1

GRAL Information related to payment of fee for publishing/printing deleted

Free format text: ORIGINAL CODE: EPIDOSDIGR3

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

TPAC Observations filed by third parties

Free format text: ORIGINAL CODE: EPIDOSNTIPA

INTC Intention to grant announced (deleted)
TPAA Information related to observations by third parties modified

Free format text: ORIGINAL CODE: EPIDOSCTIPA

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20180824