WO2012150561A1 - Solvate de diméthylformamide rifaximine - Google Patents

Solvate de diméthylformamide rifaximine Download PDF

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Publication number
WO2012150561A1
WO2012150561A1 PCT/IB2012/052200 IB2012052200W WO2012150561A1 WO 2012150561 A1 WO2012150561 A1 WO 2012150561A1 IB 2012052200 W IB2012052200 W IB 2012052200W WO 2012150561 A1 WO2012150561 A1 WO 2012150561A1
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WO
WIPO (PCT)
Prior art keywords
rifaximin
solvate
hours
process according
dmf solvate
Prior art date
Application number
PCT/IB2012/052200
Other languages
English (en)
Inventor
Jagdev Singh Jaryal
Munish Kapoor
Swargam Sathyanarayana
Rajesh Kumar Thaper
Mohan Prasad
Sudershan Kumar Arora
Original Assignee
Ranbaxy Laboratories Limited
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 Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Priority to EP12721936.8A priority Critical patent/EP2705042A1/fr
Priority to AU2012251385A priority patent/AU2012251385A1/en
Priority to CA2834829A priority patent/CA2834829A1/fr
Publication of WO2012150561A1 publication Critical patent/WO2012150561A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the present invention provides a new polymorphic form of rifaximin designated as DMF solvate and the process for its preparation. It also provides a pharmaceutical composition comprising the same and its use for the treatment of bowel related disorders.
  • Rifaximin is a semi-synthetic, nonsystemic antibiotic which was disclosed in U.S. Patent No. 4,341,785. It is marketed in the United States under the trade name Xifaxan® for the treatment of Travelers' diarrhea and Hepatic Encephalopathy.
  • Rifaximin is designated as (2S,16Z,18E,20S,21S,22R,23R,24R,25S,26S,27S, 28E)5,6,21,23,25- pentahydroxy-27-methoxy-2,4, 11 , 16,20,22,24,26-octamethyl-2,7(epoxypenta-deca- [ 1 , 11 , 13]trienimino)benzofuro[4,5-e]pyrido[ 1 ,2-a]-benzimidazole-l,15(2H)dione,25- acetate and is represented by the structural formula as shown below:
  • Polymorphism is a property exhibited by several compounds and compound complexes, including pharmaceutical compounds, whether by way of crystal forms or solvates. Different crystalline forms or polymorphs of the same pharmaceutical compounds can have different solubility characteristics, and this, in turn, affects bioavailability.
  • the discovery of new polymorphic forms and solvates of a pharmaceutically useful compound provides opportunities to design the performance characteristics of a pharmaceutical product for formulation according to the need. But there is no real way to predict if a compound actually exhibits polymorphism, and if it did what kind of crystal structures it will exhibit. It requires diligent experimentation and analysis.
  • WO 2009/108730 mentions Form ⁇ -l to be an ethanolate/trihydrate of rifaximin but does not provide any example/experimental evidence to support it.
  • the literature does not provide any specific reference related to the solvated forms of rifaximin.
  • the present invention provides ⁇ , ⁇ -dimethylformamide solvate of rifaximin which is free flowing, stable, easily reproducible and suitable to develop formulations.
  • the present invention provides a new polymorphic form of rifaximin designated as
  • DMF solvate and the process for its preparation. It also provides a pharmaceutical composition comprising the same and its use for the treatment of bowel related disorders.
  • the first aspect of the present invention provides DMF solvate of the rifaximin.
  • the second aspect of the present invention provides DMF solvate of the rifaximin characterized by d-spacing (A) values selected from 17.79, 12.31, 11.82, 10.54, 6.74, 5.91, 4.70, 4.22, 4.16, 4.06, 3.98 or 3.53.
  • A d-spacing
  • the third aspect of the present invention provides a process for the preparation of DMF solvate of the rifaximin, the steps comprising of:
  • the fourth aspect of the present invention provides substantially pure DMF solvate of the rifaximin having a purity greater than 99%, when measured by HPLC area percentage.
  • the present invention provides a pharmaceutical composition comprising DMF solvate of the rifaximin with one or more pharmaceutically acceptable carriers and/or excipients.
  • the present invention provides a method for treating, preventing or alleviating bowel related disorders in humans comprising administering to said patient a therapeutically effective amount of DMF solvate of the rifaximin or a pharmaceutical composition comprising the same.
  • Figure 1 X-Ray Diffraction (XRD) pattern of DMF solvate of rifaximin
  • Ambient temperature refers to temperature ranging from about 15°C to about 30°C.
  • substantially pure refers to the DMF solvate of the rifaximin having purity greater than 99%.
  • DMF solvate of the rifaximin having characteristics d-spacing (A) values selected from 17.79, 12.31, 1 1.82, 10.54, 6.74, 5.91, 4.70, 4.22, 4.16, 4.06, 3.98 or 3.53.
  • DMF solvate of the rifaximin can also be characterized by (i) XRD having substantially the same pattern as depicted in Figure 1, (ii) DSC having substantially the same pattern as depicted in Figure 2, (iii) TGA having substantially the same pattern as depicted in Figure 3.
  • the DSC shows two characteristic endotherm peaks.
  • the first endothermal peak is in the range from about 45.60°C to about 71.59°C and the second endothermal peak is from about 110.15°C to about 1 11.82°C.
  • the DMF solvate of the rifaximin has water content from about 0% to about 5%, when measured by Karl-Fischer analysis. Preferably, water content can be in between 1% to 3%.
  • the mixture of rifaximin in ⁇ , ⁇ -dimethylformamide solvent may be heated at a temperature of about 45°C to about 60°C followed by optional stirring of the mixture, if required for complete dissolution of the mixture.
  • the solid thus formed can be isolated by conventional means known to a person of ordinary skill in the art including, for example, decantation, filtration or centrifugation.
  • the isolated solid, designated as DMF solvate of the rifaximin can be washed with solvent if desired, followed by drying, wherein the drying can be carried out by any drying means known to a person of ordinary skill in the art including, for example, under reduced pressure, vacuum tray drying, air drying and/or combinations thereof.
  • the isolated crystalline solid refers to substantially pure DMF solvate of the rifaximin.
  • DMF solvate of the rifaximin as a medicament for treatment, prevention, alleviating bowel related disorders, preferably Travelers' diarrhea and Hepatic encephalopathy.
  • the packaging of the DMF solvate of the rifaximin can be done in self sealing polybags under vacuum after nitrogen flushing, or under nitrogen atmosphere, optionally including a desiccant to improve stability of the material.
  • preferred embodiments are described by way of examples to illustrate the process. However, these are not intended in any way to limit the scope of the claims. Several variants of these examples would be evident to persons ordinarily skilled in the art.
  • the DMF solvate of the rifaximin obtained by the present invention has an HPLC purity greater than 99.1% as measured by area percentage.
  • HPLC high performance liquid chromatography
  • the XRD pattern was recorded using a PANalytical XPert PRO.
  • the TGA and DSC patterns were recorded using TA instruments-Q500 and Mettler DSC 821 e Perkin Elmer, respectively.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une nouvelle forme polymorphe de rifaximine connue sous le nom de solvate DMF et son procédé de préparation. L'invention concerne également une composition pharmaceutique la comprenant ainsi que son utilisation pour le traitement de troubles intestinaux.
PCT/IB2012/052200 2011-05-02 2012-05-02 Solvate de diméthylformamide rifaximine WO2012150561A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP12721936.8A EP2705042A1 (fr) 2011-05-02 2012-05-02 Solvate de diméthylformamide rifaximine
AU2012251385A AU2012251385A1 (en) 2011-05-02 2012-05-02 Rifaximin dimethylformamide solvate
CA2834829A CA2834829A1 (fr) 2011-05-02 2012-05-02 Solvate de dimethylformamide rifaximine

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1289/DEL/2011 2011-05-02
IN1289DE2011 2011-05-02

Publications (1)

Publication Number Publication Date
WO2012150561A1 true WO2012150561A1 (fr) 2012-11-08

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2012/052200 WO2012150561A1 (fr) 2011-05-02 2012-05-02 Solvate de diméthylformamide rifaximine

Country Status (4)

Country Link
EP (1) EP2705042A1 (fr)
AU (1) AU2012251385A1 (fr)
CA (1) CA2834829A1 (fr)
WO (1) WO2012150561A1 (fr)

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014167533A1 (fr) 2013-04-12 2014-10-16 Alfa Wassermann S.P.A. Administration d'ains, compositions, procédés et systèmes associés
WO2015173697A1 (fr) 2014-05-12 2015-11-19 Alfa Wassermann S.P.A. Nouvelle forme cristalline solvatée de la rifaximine, production, compositions et utilisations associées
US9234872B2 (en) 2009-11-23 2016-01-12 California Institute Of Technology Chemical sensing and/or measuring devices and methods
US9271968B2 (en) 2005-03-03 2016-03-01 Alfa Wassermann S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
US9359374B2 (en) 2012-06-13 2016-06-07 Apotex Pharmachem Inc. Polymorphic forms of rifaximin
US9452157B2 (en) 2012-07-06 2016-09-27 Alfa Wassermann S.P.A Pharmaceutical compositions comprising rifaximin and amino acids, preparation methods and use thereof
US9498442B2 (en) 2010-03-05 2016-11-22 Alfa Wassermann S.P.A. Rifaximin powder, process for preparing the same an controlled release compositions containing said rifaximin useful for obtaining a long-lasting effect
US10556915B2 (en) 2014-03-31 2020-02-11 Euticals Spa Polymorphic mixture of Rifaximin and its use for the preparation of solid formulations

Citations (10)

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US4341785A (en) 1980-05-22 1982-07-27 Alfa Farmaceutici S.P.A. Imidazo-rifamycin derivatives with antibacterial utility
US4557866A (en) 1984-05-15 1985-12-10 Alfa Farmaceutici S.P.A. Process for the synthesis of pyrido-imidazo rifamycins
US7045620B2 (en) 2003-11-07 2006-05-16 Alfa Wassermann, S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in medicinal preparations
WO2006094662A1 (fr) 2005-03-03 2006-09-14 Alfa Wassermann S.P.A. Nouvelles formes polymorphes de rifaximine, leurs procedes de preparation et leur utilisation en medecine
WO2008035109A1 (fr) 2006-09-22 2008-03-27 Cipla Limited Rifaximine
WO2009108730A2 (fr) 2008-02-25 2009-09-03 Salix Pharmaceuticals, Ltd. Formes de rifaximine et utilisations correspondantes
US7612199B2 (en) 2003-11-07 2009-11-03 Alfa Wassermann, S.P.A. Polymorphic forms α, β, and γ of rifaximin
US7709634B2 (en) 2007-09-20 2010-05-04 Apotex Pharmachem Inc. Amorphous form of rifaximin and processes for its preparation
US20100174064A1 (en) * 2008-02-25 2010-07-08 Salix Pharmaceuticals, Ltd. Forms of rifaximin and uses thereof
WO2011153444A1 (fr) * 2010-06-03 2011-12-08 Salix Pharmaceuticals, Ltd Nouvelles formes de la rifaximine et leurs utilisations

Patent Citations (11)

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US4341785A (en) 1980-05-22 1982-07-27 Alfa Farmaceutici S.P.A. Imidazo-rifamycin derivatives with antibacterial utility
US4557866A (en) 1984-05-15 1985-12-10 Alfa Farmaceutici S.P.A. Process for the synthesis of pyrido-imidazo rifamycins
US7045620B2 (en) 2003-11-07 2006-05-16 Alfa Wassermann, S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in medicinal preparations
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WO2006094662A1 (fr) 2005-03-03 2006-09-14 Alfa Wassermann S.P.A. Nouvelles formes polymorphes de rifaximine, leurs procedes de preparation et leur utilisation en medecine
WO2008035109A1 (fr) 2006-09-22 2008-03-27 Cipla Limited Rifaximine
US7709634B2 (en) 2007-09-20 2010-05-04 Apotex Pharmachem Inc. Amorphous form of rifaximin and processes for its preparation
WO2009108730A2 (fr) 2008-02-25 2009-09-03 Salix Pharmaceuticals, Ltd. Formes de rifaximine et utilisations correspondantes
US20100174064A1 (en) * 2008-02-25 2010-07-08 Salix Pharmaceuticals, Ltd. Forms of rifaximin and uses thereof
US20100239664A1 (en) * 2008-02-25 2010-09-23 Salix Pharmaceuticals, Ltd. Forms of rifaximin and uses thereof
WO2011153444A1 (fr) * 2010-06-03 2011-12-08 Salix Pharmaceuticals, Ltd Nouvelles formes de la rifaximine et leurs utilisations

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CAIRA M R: "CRYSTALLINE POLYMORPHISM OF ORGANIC COMPOUNDS", TOPICS IN CURRENT CHEMISTRY, SPRINGER, BERLIN, DE, vol. 198, 1 January 1998 (1998-01-01), pages 163 - 208, XP001156954, ISSN: 0340-1022, ISBN: 978-3-540-36760-4, DOI: 10.1007/3-540-69178-2_5 *

Cited By (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10703763B2 (en) 2005-03-03 2020-07-07 Alfasigma S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
US9271968B2 (en) 2005-03-03 2016-03-01 Alfa Wassermann S.P.A. Polymorphous forms of rifaximin, processes for their production and use thereof in the medicinal preparations
US9234872B2 (en) 2009-11-23 2016-01-12 California Institute Of Technology Chemical sensing and/or measuring devices and methods
US9498442B2 (en) 2010-03-05 2016-11-22 Alfa Wassermann S.P.A. Rifaximin powder, process for preparing the same an controlled release compositions containing said rifaximin useful for obtaining a long-lasting effect
US9359374B2 (en) 2012-06-13 2016-06-07 Apotex Pharmachem Inc. Polymorphic forms of rifaximin
US9452157B2 (en) 2012-07-06 2016-09-27 Alfa Wassermann S.P.A Pharmaceutical compositions comprising rifaximin and amino acids, preparation methods and use thereof
WO2014167533A1 (fr) 2013-04-12 2014-10-16 Alfa Wassermann S.P.A. Administration d'ains, compositions, procédés et systèmes associés
US11739099B2 (en) 2014-03-31 2023-08-29 Curia Ip Holdings, Llc Polymorphic mixture of Rifaximin and its use for the preparation of solid formulations
US10961257B2 (en) 2014-03-31 2021-03-30 Amri Italy S.R.L. Polymorphic mixture of rifaximin and its use for the preparation of solid formulations
US10745415B2 (en) 2014-03-31 2020-08-18 Amri Italy S.R.L. Polymorphic mixture of Rifaximin and its use for the preparation of solid formulations
US10556915B2 (en) 2014-03-31 2020-02-11 Euticals Spa Polymorphic mixture of Rifaximin and its use for the preparation of solid formulations
US10428086B2 (en) 2014-05-12 2019-10-01 Alfasigma S.P.A. Solvated crystal form of rifaximin, production, compositions and uses thereof
AU2015260837B2 (en) * 2014-05-12 2019-02-28 Alfasigma S.P.A. New solvated crystal form of rifaximin, production, compositions and uses thereof
EP3546464A1 (fr) 2014-05-12 2019-10-02 Alfasigma S.p.A. Préparation et utilisation de la forme cristalline tau de rifaximine solvatée par le degme
EA030457B1 (ru) * 2014-05-12 2018-08-31 Альфасигма С.П.А. Новая сольватированная кристаллическая форма рифаксимина, ее получение, композиции и применения
WO2015173697A1 (fr) 2014-05-12 2015-11-19 Alfa Wassermann S.P.A. Nouvelle forme cristalline solvatée de la rifaximine, production, compositions et utilisations associées
US9938298B2 (en) 2014-05-12 2018-04-10 Alfa Wassermann S.P.A. Solvated crystal form of rifaximin, production, compositions and uses thereof
JP2017515821A (ja) * 2014-05-12 2017-06-15 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． リファキシミンの新規溶媒和物結晶形、生成物、組成物及びそれらの使用
KR102362719B1 (ko) 2014-05-12 2022-02-14 알파시그마 에스.피.에이. 리팍시민의 신규한 용매화 결정 형태, 생산물, 조성물 및 이의 용도
KR20170003568A (ko) * 2014-05-12 2017-01-09 알파 와셔만 에스.피.아. 리팍시민의 신규한 용매화 결정 형태, 생산물, 조성물 및 이의 용도

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Publication number Publication date
EP2705042A1 (fr) 2014-03-12
CA2834829A1 (fr) 2012-11-08
AU2012251385A1 (en) 2013-11-21

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