WO2018158646A1 - Forme cristalline de la rifaximine - Google Patents

Forme cristalline de la rifaximine Download PDF

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Publication number
WO2018158646A1
WO2018158646A1 PCT/IB2018/050920 IB2018050920W WO2018158646A1 WO 2018158646 A1 WO2018158646 A1 WO 2018158646A1 IB 2018050920 W IB2018050920 W IB 2018050920W WO 2018158646 A1 WO2018158646 A1 WO 2018158646A1
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WO
WIPO (PCT)
Prior art keywords
rifaximin
crystalline form
mixture
preparation
present
Prior art date
Application number
PCT/IB2018/050920
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English (en)
Inventor
Prasada Raju VNKV VETUKURI
Ravindra Vedantham
Ambaiah Boini
Goverdhan Gilla
Rama Seshaiah KANUPARTHY
Akshay Kant CHATURVEDI
Original Assignee
Granules India 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 Granules India Limited filed Critical Granules India Limited
Publication of WO2018158646A1 publication Critical patent/WO2018158646A1/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

Definitions

  • the present invention relates to an improved process for the preparation Crystalline Form GR of Rifaximin of Formula (I).
  • the present invention further relates to process for the preparation of substantially pure Rifaximin comprising recrystallization using mixture of alcoholic solvents.
  • G.C.Viscomi et.al. in the patent US 7,045,620 discloses that the polymorph called rifaximin form a is characterized by a water content lower than 4.5%, preferably between 2.0% and 3.0% and further by powder X-ray diffractogram which shows peaks at the values of the diffraction angles 2 ⁇ of 6.6°; 7.4°; 7.9°; 8.8°; 10.5°; 1 1; 1 1.8°; 12.9°; 17.6°; 18.5°; 19.7°; 21.0°; 21.1°; 22.1 °.
  • the other polymorph called rifaximin form ⁇ is characterized by a water content higher than 4.5%, preferably between 5,0% and 6.0%, and by a powder X-ray diffractogram which shows peaks at the values of the diffraction angles 20 of 5.4°; 6.4°; 7.0°; 7.8°; 9.0°; 10.4°; 13.1 °; 14.4°; 17.1 °; 17.90°; 18.30°; 20.9°
  • the polymorph called rifaximin ⁇ is characterized by a powder X-ray diffractogram much poorer because of the poor crystallinity; the significant peaks are at the values of the diffraction angles 20 of 5.0°; 7.1 °; and 8.4°.
  • G.C.Viscomi et.al. in US 7,923,553 discloses process for the preparation of polymorphous form rifaximin a, rifaximin ⁇ & rifaximin ⁇ .
  • G.C.Viscomi et.al. in US 8,193,196 discloses two polymorphic forms of Rifaxirain, designated ⁇ characterized by x-ray powder diffraction pattern peaks at about 5.7° ⁇ 0.2, 10.8° ⁇ 0.2, 12.1 ° ⁇ 0.2, and 17.0° ⁇ 0.2, 2 ⁇ and ⁇ respectively.
  • Form ⁇ has water content within the range from 2.5 to 6% by weight (preferably from 3 to 4.5%) and characterized by x-ray powder diffraction pattern peaks at about 8.2° ⁇ 0.2, 12.4° ⁇ 0.2, and 16.3° ⁇ 0.2 2 ⁇ .
  • Form ⁇ exhibits an X-ray powder diffraction pattern having characteristic peaks expressed in 20° (+/-0.20 0 ⁇ ) at 6.1, 7.3, and 7.5° 2- ⁇ ; or 6.1, 7.3, and 7.9° 2- ⁇ ; or 6.1, 7.3, and 8.8° 2- ⁇ ; or 6.1 , 7.3, and 12.7° 2- ⁇ ; or 6.1, 7.5, and 8.8° 2- ⁇ ; or 6.1, 7.5, and 7.9° 2- ⁇ ; or 5.3, 6.1, and 7.3° 2-0; or 5.3, 6.1, and 7.9° 2-0; or 5.3, 6.1, and 12.7° 2-0; or 5.3, 6.1 , and 7.5° 2-0; or 5.3, 6.1, and 7.5° 2-0; or 5.3, 6.1, and 7.5° 2-0; or 5.3, 6.1, and 7.5° 2-0; or 5.3, 6.1, and 7.5° 2-0; or 5.3, 6.1, and 7.5° 2-0; or 5.3, 6.1, and
  • Rifaximin is an important therapeautic agent for the treatment of patients with travelers' diarrhea (TD) and the reduction in risk of overt hepatic encephalopathy (HE) recurrence. Additional and improved ways of preparing new polymorphic forms of Rifaximin may provide an opportunity to improve the drug performance characteristics of such products. Hence, there exists a need for the further development of new stable crystalline form of Rifaximin and commercially viable processes for its preparation, which may be up scalable, safer for handling, less time consuming and with better and consistent quality parameters.
  • the inventors of this application have developed a process which provides a stable polymorphic crystalline form of Rifaximin, designated as Form GR which is stable, non- hygroscopic, and thus has easy handling properties.
  • Form GR which is stable, non- hygroscopic, and thus has easy handling properties.
  • the process of this invention provides the crystalline Form GR of Rifaximin in substantially pure form.
  • Particular aspects of the present invention relates to a process for the preparation of crystalline Form GR of Rifaximin (I). Crystalline Form GR of Rifaximin obtained by the process of the present invention is found to be substantially pure and stable.
  • crystalline Form GR of Rifaximin (I) characterized by X-ray powder diffraction angle peaks at 5.5, 6.6, 6.8, 7.5, 7.7, 1 1.8, 13.3 and 15.4 ⁇ 0.2° 2 ⁇ comprising the steps of- a. providing a solution of Rifaximin in a mixture of alcoholic solvent at room temperature;
  • step b. solution obtained in step a. is maintained for a time duration ranging between 1 -5 hours at a temperature ranging between 5 - 100°C;
  • X-ray powder diffraction pattern comprising of at least five 20° peaks selected from 5.5, 6.6, 6.8, 7.5, 7.7, 1 1.8, 13.3 and 15.4 ⁇ 0.2 20°;
  • TGA weight loss ranging between 1-5% w/w.
  • process for the preparation of substantially pure Rifaximin comprising recrystallization using mixture of alcoholic solvent wherein mixture of alcoholic solvents is in the ratio of 1 : 10 (v/v).
  • Fig. 1 is an example of X-ray powder diffraction "XR rj") pattern of crystalline Form GR of Rifaximin.
  • Fig. 2 is an example of Th ermo gravi metri c analysis ("TGA") curve of Form GR of Rifaximin.
  • TGA Th ermo gravi metri c analysis
  • step of providing a solution according to the present invention comprises the source of Rifaximin that may be obtained according to any of prior disclosed processes.
  • Rifaximin as obtained is dissolved in isopropanol or in a mixture of C1-C4 alcoholic solvent.
  • the mixture of alcoholic solvent is in the ratio of 1 :10 (v/v). Stirring the reaction mass performed for not less than 10 hours at temperature ranging between 20 - 100°C.
  • making solution is in the temperature range of 20 - 100°C.
  • solvents are selected from methanol, ethanol, isopropanol, propanol, n-butanol.
  • reaction is performed at 70-85°C for 1-5 hours.
  • reaction is performed at 70-85°C for 3 hours.
  • reaction is performed at 25-35°C for 3 hours.
  • solution is a mixture of Ethanol & Isopropanol or mixture of Methanol & Isopropanol.
  • Step b of present embodiment maintaining the solution for 5 hours at a temperature ranging between 20 - 100°C.
  • step b is maintained for 2 hours at temperature 70-85°C.
  • stirring plays a very critical role in obtaining the desired characteristics of the end product i.e crystalline Form GR of Rifaximin.
  • solution is stirred at temperature ranging between -10°C to 10°C for 10 hours.
  • stirring is carrying out at RPM ranging from 80 - 150.
  • separating crystalline Rifaximin (I) by performing various conventional methods like distillations, filtering, drying, centrifugation etc. to obtain Form GR of Rifaximin (I).
  • drying wet compound at temperature 55-65°C to get crystalline Form GR of Rifaximin (I). Further, drying conditions may be employed as utilized by person skilled in the art.
  • Process of recovering the desired particle size crystalline Form GR of Rifaximin (I) may further require conventional steps to obtain such desired particle sizes.
  • one embodiment of the present invention provides crystalline Form GR of Rifaximin (I) is characterized by X-ray powder diffraction (XRPD) pattern substantially as depicted in Fig 1.
  • XRPD X-ray powder diffraction
  • Rifaximin (I) which is characterized by TGA weight loss ranging between 1 -5 % w/w.
  • Substantially pure crystalline Form GR of Rifaximin (I) obtained according to the process of the present invention results in the final API purity by HPLC of more than 99% and preferably greater than 99.5%.
  • the purity of the Form GR of Rifaximin (I) samples was measured using Chromatography. Chromatography was performed with Waters Alliance HPLC system (MILD, USA) that consists of quaternary pump equipped with a 2695 separation module with inbuilt auto injector and 2996 photodiode array detector. The output signal was monitored and processed using chromelean software version 6.8.
  • MILD Waters Alliance HPLC system
  • MILD Waters Alliance HPLC system
  • the output signal was monitored and processed using chromelean software version 6.8.
  • In another embodiment of the present invention provides a process for preparation of Form GR of Rifaximin (I) having water content in range of 1 - 6%, preferably between 1 - 5%, as determined by the Karl Fischer method.
  • the crystalline Form GR of Rifaximin (I) obtained by the process of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules.
  • the active product is mixed with one or more pharmaceutically acceptable excipients.
  • the drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.
  • premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with crystalline Form GR of Rifaximin (I), while retaining the amorphous form nature of the premix.
  • compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous sterile solutions.
  • a solvent or vehicle propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed.
  • These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents.
  • the sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
  • compositions of crystalline Form GR of Rifaximin (I) of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
  • Rifaximin (4.0 gr) crude was dissolved in a mixture of IPA (24.0 mL) & Ethanol (12.0 mL) at 70-85°C and the mass was cooled to Room temperature (25-35°C). After 2 hours of maintenance, the mass was further cooled and stirred for 3 hrs at 0-5 °C. Pure Rifaximin was separated by filtration and dried at 55-65°C. Optionally the product is further subjected to the same procedure to improve purity of the product.
  • Rifaximin (4.0 gr) was dissolved in a mixture of IPA (24.0 mL) & Ethanol (12.0 mL) at 25- 35 °C and then heated to 70-85°C. Later, the mass was cooled lo 0-5°C and stirred for 3 hrs at same temperature. The product was separated by filtration and dried at 55-65 "C to yield the crystalline Form GR of Rifaximin.
  • Rifaximin (4.0 gr) was dissolved in isopropyl alcohol (20.0 mL) at 70-85°C and the mass was cooled to Room temperature (25-35°C). After 2 hours of maintenance, the mass was further cooled and stirred for 3 hrs at 0-5°C. Rifaximin was separated by filtration and dried at 55- 65°C to yield the crystalline Form GR of Rifaximin.

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

Abstract

La présente invention concerne un procédé de préparation de la forme cristalline GR de la Rifaximine. L'invention concerne également sur la forme cristalline GR de la Rifaximine obtenue par le procédé selon la présente invention, ladite forme GR étant pratiquement pure, stable et caractérisée par un diagramme de diffraction des rayons X sur poudre comprenant au moins cinq pics de 2θ° choisis parmi 5,5, 6,6, 6,8, 7,5, 7,7, 11,8, 13,3, et 15,4 ± 0,2 2θ°. La présente invention concerne en outre un procédé de préparation de la Rifaximine sensiblement pure comprenant une recristallisation à l'aide d'un mélange de solvants alcooliques.
PCT/IB2018/050920 2017-03-02 2018-02-15 Forme cristalline de la rifaximine WO2018158646A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201741007377 2017-03-02
IN201741007377 2017-03-02

Publications (1)

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WO2018158646A1 true WO2018158646A1 (fr) 2018-09-07

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10428086B2 (en) 2014-05-12 2019-10-01 Alfasigma S.P.A. Solvated crystal form of rifaximin, production, compositions and uses thereof
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

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090082558A1 (en) * 2007-09-20 2009-03-26 Apotex Pharmachem Inc. Amorphous form of rifaximin and processes for its preparation
WO2015159275A2 (fr) * 2014-04-19 2015-10-22 Granules India Limited Procédé amélioré pour la préparation de dérivés de la rifamycine
WO2017021975A1 (fr) * 2015-08-06 2017-02-09 Msn Laboratories Private Limited Procédé de préparation de formes cristallines de rifaximine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090082558A1 (en) * 2007-09-20 2009-03-26 Apotex Pharmachem Inc. Amorphous form of rifaximin and processes for its preparation
WO2015159275A2 (fr) * 2014-04-19 2015-10-22 Granules India Limited Procédé amélioré pour la préparation de dérivés de la rifamycine
WO2017021975A1 (fr) * 2015-08-06 2017-02-09 Msn Laboratories Private Limited Procédé de préparation de formes cristallines de rifaximine

Cited By (2)

* 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
US10428086B2 (en) 2014-05-12 2019-10-01 Alfasigma S.P.A. Solvated crystal form of rifaximin, production, compositions and uses thereof

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