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WO2009034582A2 - Procédé pour la préparation de chlorhydrate de fexofénadine amorphe - Google Patents

Procédé pour la préparation de chlorhydrate de fexofénadine amorphe Download PDF

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Publication number
WO2009034582A2
WO2009034582A2 PCT/IN2008/000581 IN2008000581W WO2009034582A2 WO 2009034582 A2 WO2009034582 A2 WO 2009034582A2 IN 2008000581 W IN2008000581 W IN 2008000581W WO 2009034582 A2 WO2009034582 A2 WO 2009034582A2
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WO
WIPO (PCT)
Prior art keywords
acid
hydrochloride
fexofenadine
process according
mixture
Prior art date
Application number
PCT/IN2008/000581
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English (en)
Other versions
WO2009034582A3 (fr
Inventor
Chidambaram Venkateswaran Srinivasan
Perminder Singh Johar
Lalit Wadhwa
Original Assignee
Ind-Swift Laboratories Limited
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Filing date
Publication date
Application filed by Ind-Swift Laboratories Limited filed Critical Ind-Swift Laboratories Limited
Publication of WO2009034582A2 publication Critical patent/WO2009034582A2/fr
Publication of WO2009034582A3 publication Critical patent/WO2009034582A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms

Definitions

  • the present invention is directed towards process for the preparation of amorphous fexofenadine hydrochloride, a useful antihistamine drug.
  • Fexofenadine hydrochloride having structural formula-I is an Hj receptor antagonist and a useful antihistamine drug and is chemically known as 4-[4-[4-(hydroxydiphenylmethyl)-l- piperidinyl]-l-hydroxybutyl]- ⁇ , ⁇ -dimethylbenzene acetic acid hydrochloride.
  • Fexofenadine and pharmaceutically acceptable salts were first disclosed in US patent no. 4,254,129.
  • fexofenadine can be prepared starting from ethyl, ⁇ , ⁇ - dimethylphenyl acetate and 4-chlorobutyroyl chloride, which are reacted under Friedel-Crafts conditions. Chloride is displaced from the Friedel-Crafts product with ⁇ , ⁇ -diphenyl-4- piperidine-methanol to give 4-[4-[4-(hydroxydiphenylmethyl)-l-piperidinyl]-l-oxobutyl]- ⁇ , ⁇ - dimethyl benzene acetate, which is isolated as its hydrochloride salt. The ketone is then reduced with PtOZH 2 and the ester group is hydrolyzed to yield fexofenadine and converted to its hydrochloride salt.
  • Forms I-IV are hydrates and Forms I and III are anhydrates. Each form is characterized by its melting point, onset of endotherm in the DSC profile, and PXRD.
  • the patent further discusses methods of interconverting Forms I-IV.
  • Aqueous recrystallization of Form I can be used to produce Form II.
  • Water-minimizing recrystallization or azeotropic distillation of either Form II or Form IV can yield Form I.
  • Form III is reported to be accessible by water minimizing recrystallization of Form II. Crystal digestion of Form III can be used to obtain Form I.
  • the above crystalline forms are also disclosed in the PCT publication WO 95/31437.
  • PCT publication WO 2000/71124 Al describes a process for the preparation of amorphous fexofenadine hydrochloride by lyophilizing or spray drying a solution of fexofenadine hydrochloride.
  • US Patent Application 2003/0021849 describes a process for preparing amorphous fexofenadine hydrochloride by preparing a solution of fexofenadine hydrochloride in tetrahydrofuran (THF); removing a portion of THF from the solution; adding a C 5 to C 12 saturated hydrocarbon to THF to form layers; separating and drying the lower layer to obtain amorphous fexofenadine.
  • amorphous fexofenadine hydrochloride can also be prepared by preparing a solution of fexofenadine hydrochloride in an organic solvent and removing the solvent by evaporating under ambient or reduced pressure.
  • US Patent Application 2005/0165056 describes a process for preparing non-hydrated amorphous fexofenadine hydrochloride wherein fexofenadine base in a solvent such as heptane or tert-butyl methyl ether is treated with a solution of hydrogen chloride in isopropyl ether.
  • US Patent Application 2005/0256163 describes a process for preparing amorphous fexofenadine hydrochloride by heating crystalline fexofenadine hydrochloride form XVI at 80-100 °C.
  • the present invention provides a process for the preparation of highly pure amorphous fexofenadine hydrochloride from fexofenadine via its acid addition salts using conditions which are convenient to operate on a commercial scale and are operationally safe.
  • the principal object of the present invention is to provide an industrially advantageous process for the preparation of highly pure fexofenadine hydrochloride in amorphous form that is cost effective, eco-friendly, commercially viable as well as reproducible on industrial scale.
  • One another object of the present invention is to provide a process for the preparation of amorphous fexofenadine hydrochloride from fexofenadine via its acid addition salts.
  • Yet another object of the present invention is to provide a process for the preparation of amorphous fexofenadine hydrochloride from fexofenadine acid addition salts.
  • the present invention encompasses an efficient and industrially advantageous process for the preparation of amorphous fexofenadine hydrochloride of formula I,
  • the present invention provides a process for the preparation of amorphous fexofenadine hydrochloride, comprises the steps of:
  • the present invention provides a process for the preparation of amorphous fexofenadine hydrochloride starting from fexofenadine acid addition salts, which comprises:
  • the present invention also provides novel acid addition salts of fexofenadine.
  • Figure 1 illustrates the powdered X-ray diffraction pattern of fexofenadine formate.
  • Figure 2 illustrates the powdered X-ray diffraction pattern of amorphous fexofenadine hydrochloride.
  • the present invention provides an industrially advantageous process for the preparation of highly pure amorphous fexofenadine hydrochloride.
  • the present invention provides a process for the preparation of amorphous fexofenadine hydrochloride from fexofenadine via its acid addition salts in high yield and purity.
  • fexofenadine is dissolved in a suitable solvent followed by addition of appropriate acid to form fexofenadine acid addition salt.
  • the reaction mass is stirred for few minutes to few hours at ambient temperature to reflux temperature of the solvent.
  • the reaction mixture is stirred at 25-30 0 C for one hour, more preferably reaction mixture is stirred till the completion of the reaction.
  • the solution of fexofenadine in a suitable solvent may optionally be heated.
  • the suitable solvent can be selected from aromatic hydrocarbon; cyclic or acyclic straight chain or branched Ci-Cj 2 ether, preferably Ci-C 6 ether; straight chain or branched saturated or unsaturated Cj-C 6 alcohol; halogenated solvent; dialkoxy ethane; nitriles; ester of general formula RiCOOR wherein R and Ri are individually selected from a straight chain or branched Ci-Ce alkyl group, preferably ester of general formula CH 3 COOR wherein R is as defined above; C 1 -C 8 ketones and the like or mixtures thereof.
  • the solvent can be selected from toluene, xylene, ethylbenzene, tetrahydrofuran, dioxane, methanol, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethoxy ethane, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, ethyl acetate, isopropyl acetate, n-butyl acetate, the like and mixtures thereof.
  • the appropriate acid include weak carboxylic acid such as formic acid; C 2-10 carboxylic acid; substituted or unsubstituted dicarboxylic acid; substituted or unsubstituted tri-carboxylic acid; ascorbic acid; tere-phthalic acid; unsubstituted or substituted benzoic acid (preferably substituted with groups selected from halo, alkoxy, nitro, thioalkoxy, hydroxyl) and the like.
  • weak carboxylic acid such as formic acid; C 2-10 carboxylic acid; substituted or unsubstituted dicarboxylic acid; substituted or unsubstituted tri-carboxylic acid; ascorbic acid; tere-phthalic acid; unsubstituted or substituted benzoic acid (preferably substituted with groups selected from halo, alkoxy, nitro, thioalkoxy, hydroxyl) and the like.
  • the acid is preferably selected from propanoic acid, butanoic acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, lactic acid, succinic acid, fumaric acid, maleic acid, phthalic acid, isophthalic acid, citric acid, ascorbic acid, tere-phthalic acid and the like. Similar organic and inorganic acids well known in art can equally be employed in the reaction and may be obvious to the person skilled in the art.
  • the fexofenadine acid addition salt can optionally be isolated by suitable techniques such as filtration, evaporation, distillation, vacuum drying, centrifugation and the like.
  • Fexofenadine acid addition salt if desired can be treated with a suitable solvent to remove certain unidentified impurities present in the product.
  • the process involves dissolving the fexofenadine acid addition salt in a suitable solvent at a temperature of 25 0 C to reflux temperature of solvent for few minutes to few hours, preferably reaction mixture is heated at the reflux temperature of solvent for a period of 1 to 5 hours. More preferably the mixture is heated for 2 hours.
  • Suitable solvent include C 2 -Ci O ethers, Ci-Cio esters, C 3 -C 10 ketones or mixture thereof, preferably the solvent is tetrahydrofuran.
  • the fexofenadine acid addition salt is then isolated from the reaction mixture by suitable techniques same as described above. The fexofenadine acid addition salt thus isolated is free from certain unidentified impurities. The isolated fexofenadine acid addition salt so obtained is then converted to amorphous fexofenadine hydrochloride.
  • the amorphous fexofenadine hydrochloride can be prepared from fexofenadine directly through in situ fexofenadine acid addition salt formation; that is without the isolation of acid addition salt of fexofenadine.
  • Fexofenadine acid addition salt in a suitable organic solvent or the reaction mixture containing the fexofenadine acid addition salt is treated with a source of hydrogen chloride for a time sufficient to convert it to amorphous fexofenadine hydrochloride, preferably till the pH 1 to 6.5 is attained, more preferably pH of the reaction mixture is 2 to 3.
  • the suitable organic solvent is as described above.
  • the source of hydrogen chloride can be selected from gaseous hydrogen chloride or hydrochloric acid in a mixture with a solvent which includes but not limited to alcoholic hydrochloride preferably methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride; ethereal hydrochloride preferably isopropylether hydrochloride; toluene hydrochloride; ethyl acetate hydrochloride and the like. Ratio of fexofenadine acid' addition salt to solvent is adjusted to about 1 :2-6, preferably 1 :4-5.
  • Amorphous fexofenadine hydrochloride can be isolated from the reaction mixture by suitable techniques such as filtration, centrifugation, decantation, precipitation and the like.
  • amorphous fexofenadine hydrochloride is isolated from the reaction mixture by adding an antisolvent to the solution.
  • the antisolvent can be selected from solvent capable of inducing precipitation of amorphous fexofenadine hydrochloride.
  • Antisolvent include, but not limited to aromatic or aliphatic hydrocarbon; straight chain or branched C 1 -C 6 ether and the like or mixture thereof.
  • the anti solvent can be selected from isopropylether, pentane, hexane, cyclohexane, n-heptane, toluene, xylene, ethyl benzene and the like or mixtures thereof.
  • the reaction can be conducted at a temperature of about -10 0 C to ambient temperature followed by the isolation of amorphous fexofenadine hydrochloride in high yields and purity.
  • the acid addition salts of fexofenadine are preferably isolated as crystalline salts, and further form the inventive part of the invention.
  • Fexofenadine acid addition salt can be characterized by at least one of mass spectra (MS), X-ray diffraction spectroscopy (XRD), infra-red spectroscopy (IR), 1 H or 13 C Nuclear magnetic resonance spectroscopy (NMR) or differential scanning calorimetry (DSC).
  • Formate salt of fexofenadine so obtained by the process of the present invention is characterized by XRD pattern as shown in Figure. 1.
  • X-ray diffraction (XRD) patterns reported as absolute positions in the figures are intended to include the normal amount of positional variation due to experimental error, operator error, differences in equipment, technique, packing, contamination, and the like.
  • this technique particularly in conjugation with other techniques like infra red spectra and endotherm, one of ordinary skill in this art will be able to identify whether or not a compound is fexofenadine acid addition salt in accordance with the present invention.
  • slight variations in the observed 2 ⁇ angles values are expected, based on the specific diffractometer employed, the analyst, and the sample preparation techniques. More variation is expected for the relative peak intensities, which is largely affected by particle size of the sample.
  • identification of exact crystalline form of a compound should be based primarily on observed 2 ⁇ angles with lesser importance attributed to relative peak intensities.
  • the fexofenadine acid addition salt is then converted to amorphous fexofenadine hydrochloride.
  • the present invention provides a process for the preparation of fexofenadine hydrochloride from acid addition salt of fexofenadine.
  • the reaction involves the treatment of fexofenadine acid addition salt in a suitable organic solvent with a source of hydrogen chloride for a time sufficient to convert it to amorphous fexofenadine hydrochloride.
  • a source of hydrogen chloride for a time sufficient to convert it to amorphous fexofenadine hydrochloride.
  • the mixture is treated with a source of hydrogen chloride till the pH of the reaction mixture ranges from 1 to 6.5, more preferably pH of the reaction mixture is 2 to 3.
  • Acid addition salt includes those as defined above.
  • the suitable solvent can be selected from aromatic hydrocarbon; cyclic or acyclic straight chain or branched C 1 -C 12 ether, preferably C 1 -C 6 ether; straight chain or branched saturated or unsaturated C 1 -C 6 alcohol; halogenated solvent; dialkoxy ethane; nitriles; ester of general formula Rj COOR wherein R and Ri are selected independently from straight chain or branched Ci-Ce alkyl group, preferably ester of general formula CH 3 COOR wherein R is as defined above; Ci-C 8 ketones and the like or mixtures thereof.
  • the solvent can be selected from toluene, xylene, ethylbenzene, tetrahydrofuran, dioxane, methanol, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dimethoxy ethane, acetonitrile, propionitrile, butyronitrile, isobutyronitrile, ethyl acetate, isopropyl acetate, n-butyl acetate, the like and mixtures thereof.
  • the source of hydrogen chloride can be selected from dry gaseous hydrogen chloride or hydrochloric acid in a mixture with a solvent.
  • acid addition salt of fexofenadine in a suitable organic solvent is combined with hydrochloric acid in mixture with solvent which includes, but not limited to methanolic hydrochloride, ethanolic hydrochloride, isopropanolic hydrochloride; ethereal hydrochloride preferably isopropylether hydrochloride; toluene hydrochloride; ethyl acetate hydrochloride and the like.
  • Ratio of fexofenadine acid addition salt to solvent is adjusted to about 1:2-6, preferably 1:4-5.
  • the conversion of acid addition salt of fexofenadine to fexofenadine hydrochloride can also be conducted by passing dry hydrogen chloride gas through the reaction mixture till a pH of2-3.
  • Amorphous fexofenadine hydrochloride can be isolated from the reaction mixture by suitable techniques such as filtration, centrifugation, decantation, precipitation and the like.
  • amorphous fexofenadine hydrochloride is isolated from the reaction mixture by adding an antisolvent to the reaction mixture.
  • the antisolvent is same as defined above.
  • the amorphqus fexofenadine hydrochloride so formed by the process of the present invention can be characterized by at least one of mass spectra (MS), X-ray diffraction spectroscopy (XRD), infra-red spectroscopy (IR), 1 H or 13 C Nuclear magnetic resonance spectroscopy (NMR) or differential scanning calorimetry (DSC).
  • MS mass spectra
  • XRD X-ray diffraction spectroscopy
  • IR infra-red spectroscopy
  • NMR Nuclear magnetic resonance spectroscopy
  • DSC differential scanning calorimetry
  • the amorphous fexofenadine hydrochloride is characterized by X-ray diffraction pattern as shown in figure 2.
  • X-ray diffraction is measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities.
  • X-ray diffraction is measured on a PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacings and relative intensities.
  • Melting point is conducted using a Polmon MP Apparatus with a sample weight of about 10 mg.
  • DSC analysis is performed using a Mettler Toledo 823 e .
  • Thermal weight change measurements were made on a Mettler TG5O Thermogravimetric Analyzer.
  • Tetrahydrofuran (4.5 It) was added to compound obtained above and refluxed for 2 hours. Reaction mixture was cooled to 25-30 0 C and filtered. The Resulting product was washed with tetrahydrofuran (900 ml) and dried at 60-65 0 C under vacuum to obtain 415 g of title compound.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne un procédé pour la préparation de chlorhydrate de fexofénadine amorphe à partir de fexofénadine via son sel d'addition avec un acide faible, avec un rendement de production élevé et une pureté élevée. La présente invention concerne en outre un procédé pour la préparation de chlorhydrate de fexofénadine amorphe à partir de sel d'addition avec un acide de la fexofénadine.
PCT/IN2008/000581 2007-09-13 2008-09-11 Procédé pour la préparation de chlorhydrate de fexofénadine amorphe WO2009034582A2 (fr)

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IN1951/DEL/2007 2007-09-13
IN1951DE2007 2007-09-13

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WO2009034582A2 true WO2009034582A2 (fr) 2009-03-19
WO2009034582A3 WO2009034582A3 (fr) 2010-05-06

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2105134A1 (fr) * 2008-03-24 2009-09-30 Ranbaxy Laboratories Limited Hydrochlorure de fexofenadine amorphe stable
WO2011158262A1 (fr) * 2010-06-15 2011-12-22 Chemelectiva S.R.L. Forme polymorphe du chlorhydrate de fexofénadine, intermédiaires et procédé de préparation
WO2012135338A1 (fr) * 2011-03-28 2012-10-04 Ratiopharm Gmbh Procédés pour la préparation de sels de tofacitinib

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005019175A1 (fr) * 2003-08-26 2005-03-03 Cipla Limited Polymorphes de la fexofenadine et leurs procedes de preparation
WO2006037042A1 (fr) * 2004-09-28 2006-04-06 Teva Pharmaceutical Industries Ltd. Forme de cristal de fexofenadine et ses processus de preparation
WO2007007347A1 (fr) * 2005-07-07 2007-01-18 Wockhardt Limited Procédé industriel de préparation du chlorhydrate de fexofénadine avec un minimum de produits secondaires

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005019175A1 (fr) * 2003-08-26 2005-03-03 Cipla Limited Polymorphes de la fexofenadine et leurs procedes de preparation
WO2006037042A1 (fr) * 2004-09-28 2006-04-06 Teva Pharmaceutical Industries Ltd. Forme de cristal de fexofenadine et ses processus de preparation
WO2007007347A1 (fr) * 2005-07-07 2007-01-18 Wockhardt Limited Procédé industriel de préparation du chlorhydrate de fexofénadine avec un minimum de produits secondaires

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2105134A1 (fr) * 2008-03-24 2009-09-30 Ranbaxy Laboratories Limited Hydrochlorure de fexofenadine amorphe stable
WO2011158262A1 (fr) * 2010-06-15 2011-12-22 Chemelectiva S.R.L. Forme polymorphe du chlorhydrate de fexofénadine, intermédiaires et procédé de préparation
ES2403130R1 (es) * 2010-06-15 2013-10-04 Chemelectiva S R L Forma polimorfica de clorhidrato de fexofenadina, compuestos intermedios y procedimiento para su preparacion
US9216955B2 (en) 2010-06-15 2015-12-22 Chemelectiva S.R.L. Polymorphic form of Fexofenadine hydrochloride, intermediates and process for its preparation
WO2012135338A1 (fr) * 2011-03-28 2012-10-04 Ratiopharm Gmbh Procédés pour la préparation de sels de tofacitinib

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