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US20100137580A1 - Process for preparing amorphous rifaximin and the amorphous rifaximin thus obtained - Google Patents

Process for preparing amorphous rifaximin and the amorphous rifaximin thus obtained Download PDF

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Publication number
US20100137580A1
US20100137580A1 US12/452,152 US45215208A US2010137580A1 US 20100137580 A1 US20100137580 A1 US 20100137580A1 US 45215208 A US45215208 A US 45215208A US 2010137580 A1 US2010137580 A1 US 2010137580A1
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Prior art keywords
rifaximin
absolute ethanol
amorphous rifaximin
amorphous
dissolved
Prior art date
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Abandoned
Application number
US12/452,152
Inventor
Emilio Vecchio
Roberta Pizzocaro
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Salix Pharmaceuticals Inc
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Individual
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Application filed by Individual filed Critical Individual
Assigned to SOLMAG S.P.A. reassignment SOLMAG S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: PIZZOCARO, ROBERTA, VECCHIO, EMILIO
Publication of US20100137580A1 publication Critical patent/US20100137580A1/en
Assigned to OLON S.P.A. reassignment OLON S.P.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: FIDIA FARMACEUTICI S.P.A.
Assigned to FIDIA FARMACEUTICI S.P.A. reassignment FIDIA FARMACEUTICI S.P.A. MERGER (SEE DOCUMENT FOR DETAILS). Assignors: SOLMAG S.P.A.
Assigned to SALIX PHARMACEUTICALS, INC. reassignment SALIX PHARMACEUTICALS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: OLON S.P.A.
Assigned to BARCLAYS BANK PLC, AS COLLATERAL AGENT reassignment BARCLAYS BANK PLC, AS COLLATERAL AGENT SECURITY AGREEMENT Assignors: GLYCYX PHARMACEUTICALS, LTD., SALIX PHARMACEUTICALS, INC., SALIX PHARMACEUTICALS, LTD., SANTARUS, INC.
Assigned to BAUSCH HEALTH IRELAND LIMITED (F/K/A/ VALEANT PHARMACEUTICALS IRELAND LIMITED), BAUSCH HEALTH POLAND SPOLKA Z OGRANICZONA ODPOWIEDZIALNOSCIA (F/K/A VALEANT PHARMA POLAND SPOLKA Z OGRANICZONA ODPOWIEDZIALNOSCIA), SOLTA MEDICAL, INC., SANTARUS, INC., BAUSCH HEALTH AMERICAS, INC., SALIX PHARMACEUTICALS, INC., VRX HOLDCO LLC, ORAPHARMA, INC., BAUSCH HEALTH HOLDCO LIMITED, V-BAC HOLDING CORP., BAUSCH HEALTH COMPANIES INC., PRZEDSIEBIORSTWO FARMACEUTYCZNE JELFA SPOLKA AKCYJNA (A/K/A PRZEDSIEBIORSTWO FARMACEUTYCZNE JELFA S.A.), BAUSCH HEALTH, CANADA INC. / SANTE BAUSCH, CANADA INC., 1261229 B.C. LTD., SOLTA MEDICAL IRELAND LIMITED, PRECISION DERMATOLOGY, INC., BAUSCH & LOMB MEXICO, S.A. DE C.V., BAUSCH HEALTH MAGYARORSZAG KFT (A/K/A BAUSCH HEALTH HUNGARY LLC), 1530065 B.C. LTD., ICN POLFA RZESZOW SPOLKA AKCYJNA (A/K/A ICN POLFA RZESZOW S.A.), BAUSCH+LOMB OPS B.V., BAUSCH HEALTH US, LLC, SOLTA MEDICAL DUTCH HOLDINGS B.V., MEDICIS PHARMACEUTICAL CORPORATION, HUMAX PHARMACEUTICAL S.A., Salix Pharmaceuticals, Ltd reassignment BAUSCH HEALTH IRELAND LIMITED (F/K/A/ VALEANT PHARMACEUTICALS IRELAND LIMITED) RELEASE OF SECURITY INTEREST Assignors: BARCLAYS BANK PLC, AS COLLATERAL AGENT
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A process is described which enables Rifaximin in a completely amorphous form to be obtained. Said process comprises the steps of dissolving crude Rifaximin in absolute ethanol while hot and then collecting after precipitation by cooling the title compound under amorphous form.

Description

    FIELD OF THE INVENTION
  • The present invention relates to the preparation of Rifaximin in amorphous form.
    • STATE OF THE ART
  • As is known Rifaximin is a non-systemic antibiotic belonging to the rifaximin-family, applied in the treatment of various pathologies including in particular diarrhea caused by E. coli or irritable bowel syndrome.
  • Various polymorphic forms of the product are known, for which various synthesis and purification processes have been described.
  • The present invention instead relates to the preparation of Rifaximin in amorphous form, by a process that comprises precipitating the desired product in absolute ethanol starting from a solution of crude Rifaximin.
  • Pharmaceutical active principles in amorphous form are in general more soluble than the corresponding crystalline forms, and this can present advantages in terms of improved absorption per os and consequently improved bioavailability.
    • BRIEF DESCRIPTION OF THE FIGURES
  • FIGS. 1 (a and b) and FIGS. 2 (a and b) show respectively the PXRD and IR spectra of rifaximin obtained according to the process of the present invention.
    •  DETAILED DESCRIPTION OF THE INVENTION
  • The process of the invention uses as starting product crude Rifaximin containing water.
  • The starting product is dissolved in absolute ethanol in the presence of ascorbic acid and the solution subjected to mild heating with stirring; the product precipitates by cooling the solution while stirring, and is then collected by filtration, washed with cold absolute ethanol and dried under vacuum.
  • The absence of significant peaks in the PXRD spectra carried out on the product obtained in this manner is evidence of the purity of the amorphous product obtained.
    • EXAMPLE 1
  • 20 g of crude rifaximin (containing an average water quantity of between 4 and 7%) were placed in a reaction flask in which 0.2 g of ascorbic acid and 200 ml of absolute ethanol were added. The suspension was heated to 60° C. with stirring until completely dissolved. The solution was allowed to cool to 25° C., maintaining stirring for a further three hours.
  • After precipitation, the suspension was left for a further 2 hours with stirring at a temperature of 12° C., then filtered.
  • The product on the filter was washed with 20 ml of cold absolute ethanol and the wet solid dried under vacuum at 70° C. for 18 hours until a KF value less than 4% was attained.
  • 15 g of pure amorphous rifaximin were obtained.
  • The PXRD and IR spectra of the obtained product are shown in FIGS. 1 a and 2 a respectively.
    • EXAMPLE 2
  • 20 g of crude rifaximin (containing an average quantity of water of between 4 and 7%) were placed in a reaction flask in which 0.2 g of ascorbic acid and 200 ml of absolute ethanol were added. The suspension was heated to 40° C. with stirring until completely dissolved. The solution was allowed to cool to 18° C., maintaining stirring for a further three hours.
  • After precipitation the suspension was left for a further 2 hours with stirring at a temperature of 8° C., then filtered.
  • The product on the filter was washed with 20 ml of cold absolute ethanol and the wet solid dried under vacuum at 60° C. for 18 hours until a KF value less than 4% was attained.
  • 14 g of pure amorphous rifaximin were obtained.
  • The PXRD and IR spectra of the obtained product are shown in FIGS. 1 b and 2 b respectively.
  • The dissolution profile of the substance in amorphous form was also determined, and compared with that of the substance in crystalline form.
  • It was found that the amorphous form easily dissolves in ethanol even without stirring, while the crystalline form is less wettable.
  • Moreover, with regard to water solubility, after conditioning a dissolution tester (Pharma Test Type PTW S III s/n 5390) using distilled water at a temperature of 37° C.±0.5° C. at a speed of 100 rpm, four dissolutions were carried out, in each of which the first three vessels of the dissolution tester were used for the substance in crystalline form and the last three for the substance in amorphous form.
  • 10 ml of the solute were withdrawn from each vessel after 15 minutes of stirring; the withdrawn samples were filtered with 0.45 μm filters and subjected to spectophotometric analysis, repeating the operation after 30 and 60 minutes.
  • After one hour of dissolution, the substance in crystalline form has a concentration of dissolved substance equal to about 7% of that of the substance in amorphous form.
  • Consequently, the substance in amorphous form has a dissolved percentage which is one order of magnitude greater than that of the substance in crystalline form.

Claims (7)

1. Process for preparing amorphous rifaximin in which crude rifaximin is dissolved in absolute ethanol while hot, then collected after precipitation by cooling of the solution.
2. Process as claimed in claim 1 wherein the crude rifaximin has a water content of between 4 and 7%.
3. Process as claimed in claim 1 wherein the crude rifaximin is dissolved in absolute ethanol in the presence of ascorbic acid.
4. Process as claimed in claim 1 wherein the crude rifaximin is dissolved with stirring at a temperature of 40-60° C. and then re-precipitated by cooling the solution to 8-12° C.
5. Process as claimed in claim 4 wherein the precipitated rifaximin is collected by filtration, washed with absolute ethanol and dried.
6. Process as claimed in claim 5 wherein said drying is conducted under vacuum at 60-70° C.
7. Amorphous rifaximin obtained according to the process of claim 1.
US12/452,152 2007-06-20 2008-06-18 Process for preparing amorphous rifaximin and the amorphous rifaximin thus obtained Abandoned US20100137580A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
ITM12007A001241 2007-06-20
IT001241A ITMI20071241A1 (en) 2007-06-20 2007-06-20 PROCESS FOR THE PREPARATION OF RIFAXIMINA AMORFA AND RIFAXIMINA AMORPHAS SO OBTAINED
PCT/IB2008/052396 WO2008155728A1 (en) 2007-06-20 2008-06-18 Process for preparing amorphous rifaximin and the amorphous rifaximin thus obtained

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2008/052396 A-371-Of-International WO2008155728A1 (en) 2007-06-20 2008-06-18 Process for preparing amorphous rifaximin and the amorphous rifaximin thus obtained

Related Child Applications (1)

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US13/970,576 Continuation US20130338355A1 (en) 2007-06-20 2013-08-19 Process for preparing amorphous rifaxmin and the amorphous rifaximin thus obtained

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US20100137580A1 true US20100137580A1 (en) 2010-06-03

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US12/452,152 Abandoned US20100137580A1 (en) 2007-06-20 2008-06-18 Process for preparing amorphous rifaximin and the amorphous rifaximin thus obtained
US13/970,576 Abandoned US20130338355A1 (en) 2007-06-20 2013-08-19 Process for preparing amorphous rifaxmin and the amorphous rifaximin thus obtained
US14/261,138 Active US9273063B2 (en) 2007-06-20 2014-04-24 Method for preparing a rifaximin product

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Application Number Title Priority Date Filing Date
US13/970,576 Abandoned US20130338355A1 (en) 2007-06-20 2013-08-19 Process for preparing amorphous rifaxmin and the amorphous rifaximin thus obtained
US14/261,138 Active US9273063B2 (en) 2007-06-20 2014-04-24 Method for preparing a rifaximin product

Country Status (8)

Country Link
US (3) US20100137580A1 (en)
EP (1) EP2170904B1 (en)
KR (1) KR101719366B1 (en)
AR (1) AR067055A1 (en)
CA (1) CA2691394C (en)
CL (1) CL2008001823A1 (en)
IT (1) ITMI20071241A1 (en)
WO (1) WO2008155728A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011061748A1 (en) * 2009-11-19 2011-05-26 Strides Arcolab Limited Rifaximin premix
WO2012035544A3 (en) * 2010-09-13 2012-05-18 Sequent Scientific Ltd. A novel polymorphic form of rifaximin and process for its preparation
US8952159B2 (en) 2009-12-28 2015-02-10 Silvio Massimo Lavagna Method for the production of amorphous rifaximin

Families Citing this family (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7902206B2 (en) 2003-11-07 2011-03-08 Alfa Wassermann, S.P.A. Polymorphic forms α, β and γ of rifaximin
US7906542B2 (en) 2004-11-04 2011-03-15 Alfa Wassermann, S.P.A. Pharmaceutical compositions comprising polymorphic forms α, β, and γ of rifaximin
ITMI20032144A1 (en) 2003-11-07 2005-05-08 Alfa Wassermann Spa REFLEXIMINE POLIMORPHIC FORMS, PROCESSES TO OBTAIN THEM AND
PT1698630E (en) 2005-03-03 2014-09-15 Alfa Wassermann Spa New polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
AU2007298733B2 (en) * 2006-09-22 2012-11-08 Cipla Limited Rifaximin
US7709634B2 (en) 2007-09-20 2010-05-04 Apotex Pharmachem Inc. Amorphous form of rifaximin and processes for its preparation
US8486956B2 (en) 2008-02-25 2013-07-16 Salix Pharmaceuticals, Ltd Forms of rifaximin and uses thereof
SG188931A1 (en) 2008-02-25 2013-04-30 Salix Pharmaceuticals Ltd Forms of rifaximin and uses thereof
IT1399141B1 (en) * 2010-04-02 2013-04-05 Secci METHOD FOR THE PREPARATION OF RIFAXIMINA IN THE AMORPHOUS STATE.
IT1398550B1 (en) * 2010-03-05 2013-03-01 Alfa Wassermann Spa RIFAXIMINA COMPREHENSIVE FORMULATIONS USEFUL TO OBTAIN A PROLONGED EFFECT IN TIME
IT1403847B1 (en) 2010-09-22 2013-11-08 Alfa Wassermann Spa PHARMACEUTICAL COMPOSITIONS INCLUDING RIFAXIMINA AND THEIR USE.
WO2012060675A1 (en) * 2010-11-05 2012-05-10 Interquim, S.A. De C.V. Process for the preparation of amorphous rifaximin
PT2672970T (en) 2011-02-11 2018-10-11 Salix Pharmaceuticals Ltd Forms of rifaximin and uses thereof
WO2012155981A1 (en) 2011-05-19 2012-11-22 Friulchem Spa New process for the synthesis of rifaximin and a new pseudo-crystalline form of rifaximin obtained thereby
ITMI20110983A1 (en) * 2011-05-30 2012-12-01 A M S A Anonima Materie Sint & Affini S P A RIFAXIMINA AMORPHOUS AND PROCESS FOR ITS PREPARATION
ITBO20110461A1 (en) 2011-07-29 2013-01-30 Alfa Wassermann Spa PHARMACEUTICAL COMPOSITIONS INCLUDING RIFAXIMINA, PROCESSES FOR THEIR PREPARATION AND THEIR USE IN THE TREATMENT OF VAGINAL INFECTIONS.
CA2876737A1 (en) 2012-06-13 2013-12-19 Apotex Pharmachem Inc. Polymorphic forms of rifaximin
ITBO20120368A1 (en) 2012-07-06 2014-01-07 Alfa Wassermann Spa COMPOSITIONS INCLUDING RIFAXIMINA AND AMINO ACIDS, RIFAXIMINE CRYSTALS DERIVING FROM SUCH COMPOSITIONS AND THEIR USE.
JP2016516988A (en) 2013-03-15 2016-06-09 アルファ ワッセルマン ソシエタ ペル アチオニＡｌｆａ Ｗａｓｓｅｒｍａｎｎ Ｓ．Ｐ．Ａ． Methods for diagnosing vaginal infection
EA201591267A1 (en) 2013-03-15 2016-03-31 Альфа Вассерманн С.П.А. Rifaximine for use in the treatment of vaginal infections
JP6433980B2 (en) 2013-04-12 2018-12-05 アルファシグマ ソシエタ ペル アチオニ NSAID administration and related compositions, methods and systems
EP2927235B1 (en) 2014-03-31 2017-02-08 Euticals S.P.A. Polymorphic mixture of rifaximin and its use for the preparation of solid formulations
ES2742106T3 (en) 2014-05-12 2020-02-13 Alfasigma Spa New form of solvated rifaximin crystal, production, compositions and uses thereof
EP2982764A1 (en) 2014-08-05 2016-02-10 ALFA WASSERMANN S.p.A. Identification of vaginal bacteria

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4341785A (en) * 1980-05-22 1982-07-27 Alfa Farmaceutici S.P.A. Imidazo-rifamycin derivatives with antibacterial utility
US7709634B2 (en) * 2007-09-20 2010-05-04 Apotex Pharmachem Inc. Amorphous form of rifaximin and processes for its preparation

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IT1199374B (en) * 1984-05-15 1988-12-30 Alfa Farmaceutici Spa PROCESS FOR THE PREPARATION OF PIRIDO-IMIDAZO-RIFAMICINE
ITMI20032144A1 (en) * 2003-11-07 2005-05-08 Alfa Wassermann Spa REFLEXIMINE POLIMORPHIC FORMS, PROCESSES TO OBTAIN THEM AND
PT1698630E (en) * 2005-03-03 2014-09-15 Alfa Wassermann Spa New polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
AU2007298733B2 (en) * 2006-09-22 2012-11-08 Cipla Limited Rifaximin

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4341785A (en) * 1980-05-22 1982-07-27 Alfa Farmaceutici S.P.A. Imidazo-rifamycin derivatives with antibacterial utility
US7709634B2 (en) * 2007-09-20 2010-05-04 Apotex Pharmachem Inc. Amorphous form of rifaximin and processes for its preparation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011061748A1 (en) * 2009-11-19 2011-05-26 Strides Arcolab Limited Rifaximin premix
US8952159B2 (en) 2009-12-28 2015-02-10 Silvio Massimo Lavagna Method for the production of amorphous rifaximin
WO2012035544A3 (en) * 2010-09-13 2012-05-18 Sequent Scientific Ltd. A novel polymorphic form of rifaximin and process for its preparation
US8759513B2 (en) 2010-09-13 2014-06-24 Sequent Scientific Limited Polymorphic form of rifaximin and process for its preparation

Also Published As

Publication number Publication date
US9273063B2 (en) 2016-03-01
WO2008155728A1 (en) 2008-12-24
US20130338355A1 (en) 2013-12-19
CA2691394C (en) 2016-10-11
ITMI20071241A1 (en) 2008-12-21
CL2008001823A1 (en) 2009-05-22
EP2170904B1 (en) 2019-09-18
CA2691394A1 (en) 2008-12-24
KR101719366B1 (en) 2017-03-23
EP2170904A1 (en) 2010-04-07
KR20100038081A (en) 2010-04-12
AR067055A1 (en) 2009-09-30
US20150011750A1 (en) 2015-01-08

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