US20130338355A1 - Process for preparing amorphous rifaxmin and the amorphous rifaximin thus obtained - Google Patents
Process for preparing amorphous rifaxmin and the amorphous rifaximin thus obtained Download PDFInfo
- Publication number
- US20130338355A1 US20130338355A1 US13/970,576 US201313970576A US2013338355A1 US 20130338355 A1 US20130338355 A1 US 20130338355A1 US 201313970576 A US201313970576 A US 201313970576A US 2013338355 A1 US2013338355 A1 US 2013338355A1
- Authority
- US
- United States
- Prior art keywords
- rifaximin
- amorphous
- absolute ethanol
- dissolved
- stirring
- 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.)
- Abandoned
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Classifications
-
- 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
Definitions
- the present invention relates to the preparation of Rifaximin in amorphous form.
- Rifaximin is a non-systemic antibiotic belonging to the rifaximin-family, applied in the treatment of various pathologies including in particular diarrhoea caused by E. coli or irritable bowel syndrome.
- 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.
- FIG. 1 ( a and b ) and FIG. 2 ( a and b ) show respectively the PXRD and IR spectra of rifaximin obtained according to the process of the present 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 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.
- the PXRD and IR spectra of the obtained product are shown in FIGS. 1 a and 2 a respectively.
- 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.
- the dissolution profile of the substance in amorphous form was also determined, and compared with that of the substance in crystalline form.
- the substance in crystalline form 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.
- the substance in amorphous form has a dissolved percentage which is one order of magnitude greater than that of the substance in crystalline form.
Landscapes
- 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
- The present invention relates to the preparation of Rifaximin in amorphous form.
- As is known Rifaximin is a non-systemic antibiotic belonging to the rifaximin-family, applied in the treatment of various pathologies including in particular diarrhoea 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.
-
FIG. 1 (a and b) andFIG. 2 (a and b) show respectively the PXRD and IR spectra of rifaximin obtained according to the process of the present 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.
- 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. - 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 claims 1 and 2 wherein the crude rifaximin is dissolved in absolute ethanol in the presence of ascorbic acid.
4. Process as claimed in claims 1 to 3 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 claims 1 -6.
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US13/970,576 US20130338355A1 (en) | 2007-06-20 | 2013-08-19 | Process for preparing amorphous rifaxmin and the amorphous rifaximin thus obtained |
US14/261,138 US9273063B2 (en) | 2007-06-20 | 2014-04-24 | Method for preparing a rifaximin product |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI2007A001241 | 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 |
US45215209A | 2009-12-15 | 2009-12-15 | |
US13/970,576 US20130338355A1 (en) | 2007-06-20 | 2013-08-19 | Process for preparing amorphous rifaxmin and the amorphous rifaximin thus obtained |
Related Parent Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/452,152 Continuation US20100137580A1 (en) | 2007-06-20 | 2008-06-18 | Process for preparing amorphous rifaximin and the amorphous rifaximin thus obtained |
PCT/IB2008/052396 Continuation WO2008155728A1 (en) | 2007-06-20 | 2008-06-18 | Process for preparing amorphous rifaximin and the amorphous rifaximin thus obtained |
US45215209A Continuation | 2007-06-20 | 2009-12-15 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US14/261,138 Continuation US9273063B2 (en) | 2007-06-20 | 2014-04-24 | Method for preparing a rifaximin product |
Publications (1)
Publication Number | Publication Date |
---|---|
US20130338355A1 true US20130338355A1 (en) | 2013-12-19 |
Family
ID=39828461
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
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 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US12/452,152 Abandoned US20100137580A1 (en) | 2007-06-20 | 2008-06-18 | Process for preparing amorphous rifaximin and the amorphous rifaximin thus obtained |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
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) |
Families Citing this family (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ITMI20032144A1 (en) | 2003-11-07 | 2005-05-08 | Alfa Wassermann Spa | REFLEXIMINE POLIMORPHIC FORMS, PROCESSES TO OBTAIN THEM AND |
US7906542B2 (en) | 2004-11-04 | 2011-03-15 | Alfa Wassermann, S.P.A. | Pharmaceutical compositions comprising polymorphic forms α, β, and γ of rifaximin |
US7902206B2 (en) | 2003-11-07 | 2011-03-08 | Alfa Wassermann, S.P.A. | Polymorphic forms α, β and γ of rifaximin |
ES2522895T3 (en) | 2005-03-03 | 2014-11-19 | Alfa Wassermann S.P.A. | New polymorphic forms of rifaximin, procedures for their production and use in medicinal preparations |
NZ575550A (en) * | 2006-09-22 | 2011-12-22 | Cipla Ltd | 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 |
MY158257A (en) | 2008-02-25 | 2016-09-30 | Salix Pharmaceuticals Ltd | Forms of rifaximin and uses thereof |
WO2011061748A1 (en) * | 2009-11-19 | 2011-05-26 | Strides Arcolab Limited | Rifaximin premix |
IT1399141B1 (en) * | 2010-04-02 | 2013-04-05 | Secci | METHOD FOR THE PREPARATION OF RIFAXIMINA IN THE AMORPHOUS STATE. |
EP2401282B2 (en) † | 2009-12-28 | 2017-01-04 | Silvio Massimo Lavagna | Method for the production of amorphous rifaximin |
IT1398550B1 (en) * | 2010-03-05 | 2013-03-01 | Alfa Wassermann Spa | RIFAXIMINA COMPREHENSIVE FORMULATIONS USEFUL TO OBTAIN A PROLONGED EFFECT IN TIME |
WO2012035544A2 (en) * | 2010-09-13 | 2012-03-22 | Sequent Scientific Ltd. | A novel polymorphic form of rifaximin and process for its preparation |
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 |
AU2012214239B2 (en) | 2011-02-11 | 2016-06-30 | 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. |
WO2013185211A1 (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. |
US20160038468A1 (en) | 2013-03-15 | 2016-02-11 | Alfa Wassermann S.P.A. | Rifaximin for use in the treating of vaginal infections |
WO2014140995A2 (en) | 2013-03-15 | 2014-09-18 | Alfa Wassermann S.P.A. | Method for diagnosing vaginal infections |
CN105324109A (en) | 2013-04-12 | 2016-02-10 | 意大利阿尔法韦士曼制药公司 | 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 |
ES2810010T3 (en) | 2014-05-12 | 2021-03-08 | Alfasigma Spa | Preparation and use of the tau crystalline form of rifaximin solvated with DEGME |
EP2982764A1 (en) | 2014-08-05 | 2016-02-10 | ALFA WASSERMANN S.p.A. | Identification of vaginal bacteria |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IT1154655B (en) * | 1980-05-22 | 1987-01-21 | Alfa Farmaceutici Spa | IMIDAZO-RIFAMYCIN DERIVATIVES METHODS FOR THEIR PREPARATION AND USE AS AN ANTIBACTERIAL ACTION SUBSTANCE |
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 |
ES2522895T3 (en) * | 2005-03-03 | 2014-11-19 | Alfa Wassermann S.P.A. | New polymorphic forms of rifaximin, procedures for their production and use in medicinal preparations |
NZ575550A (en) * | 2006-09-22 | 2011-12-22 | Cipla Ltd | Rifaximin |
US7709634B2 (en) * | 2007-09-20 | 2010-05-04 | Apotex Pharmachem Inc. | Amorphous form of rifaximin and processes for its preparation |
-
2007
- 2007-06-20 IT IT001241A patent/ITMI20071241A1/en unknown
-
2008
- 2008-06-18 WO PCT/IB2008/052396 patent/WO2008155728A1/en active Application Filing
- 2008-06-18 EP EP08763368.1A patent/EP2170904B1/en active Active
- 2008-06-18 KR KR1020097026690A patent/KR101719366B1/en active IP Right Grant
- 2008-06-18 US US12/452,152 patent/US20100137580A1/en not_active Abandoned
- 2008-06-18 CA CA2691394A patent/CA2691394C/en active Active
- 2008-06-19 AR ARP080102604A patent/AR067055A1/en unknown
- 2008-06-19 CL CL2008001823A patent/CL2008001823A1/en unknown
-
2013
- 2013-08-19 US US13/970,576 patent/US20130338355A1/en not_active Abandoned
-
2014
- 2014-04-24 US US14/261,138 patent/US9273063B2/en active Active
Also Published As
Publication number | Publication date |
---|---|
EP2170904B1 (en) | 2019-09-18 |
EP2170904A1 (en) | 2010-04-07 |
CA2691394A1 (en) | 2008-12-24 |
KR20100038081A (en) | 2010-04-12 |
US20150011750A1 (en) | 2015-01-08 |
AR067055A1 (en) | 2009-09-30 |
CL2008001823A1 (en) | 2009-05-22 |
KR101719366B1 (en) | 2017-03-23 |
US9273063B2 (en) | 2016-03-01 |
CA2691394C (en) | 2016-10-11 |
ITMI20071241A1 (en) | 2008-12-21 |
US20100137580A1 (en) | 2010-06-03 |
WO2008155728A1 (en) | 2008-12-24 |
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Legal Events
Date | Code | Title | Description |
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STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |
|
AS | Assignment |
Owner name: BARCLAYS BANK PLC, AS COLLATERAL AGENT, NEW YORK Free format text: SECURITY AGREEMENT;ASSIGNORS:GLYCYX PHARMACEUTICALS, LTD.;SALIX PHARMACEUTICALS, INC.;SALIX PHARMACEUTICALS, LTD.;AND OTHERS;REEL/FRAME:035364/0396 Effective date: 20150401 |