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WO2018178777A1 - Procédé de préparation d'une forme cristalline de rifaximine - Google Patents

Procédé de préparation d'une forme cristalline de rifaximine Download PDF

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Publication number
WO2018178777A1
WO2018178777A1 PCT/IB2018/051137 IB2018051137W WO2018178777A1 WO 2018178777 A1 WO2018178777 A1 WO 2018178777A1 IB 2018051137 W IB2018051137 W IB 2018051137W WO 2018178777 A1 WO2018178777 A1 WO 2018178777A1
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WO
WIPO (PCT)
Prior art keywords
rifaximin
hours
crystalline form
suspension
temperature
Prior art date
Application number
PCT/IB2018/051137
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English (en)
Inventor
Prasada Raju VNKV VETUKURI
Ravindra Vedantham
Ambaiah Boini
Goverdhan Gilla
Rama Seshaiah KANUPARTHY
Akshay Kant CHATURVEDI
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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 WO2018178777A1 publication Critical patent/WO2018178777A1/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 G2 of Rifaximin of Formula (I).
  • the invention also relates to crystalline Form G2 of Rifaximin (I) obtained by the process of the present invention, the said Form G2 being substantially pure, stable and characterized by X-ray powder diffraction pattern comprising peaks selected from 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 11.0, 1 1.5, 1 1.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ⁇ 0.2° 2 ⁇ .
  • the invention also relates to crystalline Form Gl of Rifaximin (I) obtained by the process of the present invention, the said Form Gl being substantially pure, stable and characterized by X-ray powder diffraction pattern comprising peaks selected from 5.4, 6.6, 7.4, 7.9, 8.8, 10.5, 1 1.0, 1 1.8, 12.9, 17.6, 18.5, 19.7, 21.0, 21.4, 22.1 ⁇ 0.2° 2 ⁇ .
  • the present invention further relates to process for the preparation of substantially pure Rifaximin comprising recrystallization in alcohol or mixture of water and alcoholic solvents.
  • Rifaximin of formula 1 is chemically known as (2S, 16Z, 18H, 20S, 2 IS, 22R, 23R, 24R, 25S, 26S, 27S, 28E)-5, 6, 21 , 23, 25-pentahydroxy- 27-methoxy-2, 4, 1 1 , 16, 20, 22. 24, 26-octamethyl-2,7-(epoxypentadeca-[l ,1 1 ,13]trienimino)- benzofuro[4, 5-e]- pyrido[l, 2-(alpha)]-benzimidazole-l,15(2H)dione, 25-acetate.
  • Rifaximin was first described and claimed in Italian patent IT 1 154655 and U.S. Pat. No.4,341 ,785. These patents disclose a process for the preparation of Rifaximin and a method for the crystallisation thereof.
  • U.S. Pat. No. 4,179,438 discloses a process for the preparation of 3-bromorifamycin S which comprises reaction of rifamycin S with at least two equivalents of bromine, per one mole of rifamycin S in the presence of at least one mole of pyridine per each equivalent of bromine and in the presence of ethanol, methanol or mixtures thereof with water at a temperature not above the room temperature.
  • the process for the preparation of Rifaximin is as depicted in scheme I given below:
  • 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°; 11 ; 1 1.8°; 12.9°; 17.6°; 18.5°; 19.7°; 21.0°; 21.4°; 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 2 ⁇ 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 2 ⁇ of 5.0°; 7.1 °; and 8.4°.
  • G.C.Viscomi et.al. in US 7,923,553 discloses process for the preparation polymorphous form rifaximin a, rifaximin ⁇ & rifaximin ⁇ .
  • G.C.Viscomi et.al. in US 8, 193, 196 discloses two polymorphic forms of Rifaximin, 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 ⁇ .
  • Vetukuri Vnkv et. al. in the patent application WO/2015/159275 describes crystalline form G of Rifaximin, characterised by powder X- ray diffraction pattern having characteristic peaks at about 5.9, 7.3, 7.9 and 8.6 + 0.2° 2 ⁇ .
  • Vetukuri Vnkv et. al. in the patent application IN 201741007377 describes crystalline form GR of Rifaximin, characterised by powder X- ray diffraction pattern having characteristic peaks at about 5.5, 6.6, 6.8, 7.5, 7.7, 1 1.8, 13.3 and 15.4 ⁇ 0.2° 20.
  • 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 G2 which is stable and thus has easy handling properties.
  • the process of this invention provides the crystalline Form G2 of Rifaximin in substantially pure form.
  • the inventors of this application have also developed a process which provides a stable polymorphic crystalline form of Rifaximin, designated as Form Gl which is stable and thus has easy handling properties.
  • the process of this invention provides the crystalline Form Gl of Rifaximin in substantially pure form.
  • Particular aspects of the present invention relates to a process for the preparation of crystalline Form G2 of Rifaximin (1).
  • Crystalline Form G2 of Rifaximin obtained by the process of the present invention is found to be substantially pure and stable.
  • crystalline Form G2 of Rifaximin (I) characterized by X-ray powder diffraction angle peaks at 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 1 1.0, 1 1.5, 1 1.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ⁇ 0.2° 20 comprising the steps of
  • X-ray powder diffraction angle peaks at 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 11.0, 11.5, 11.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ⁇ 0.2° 20.
  • Fig. 1 is an example of X-ray powder diffraction ("XRPD") pattern of crystalline Form G2 of Rifaximin.
  • Fig. 2 is an example of X-ray powder diffraction ("XRPD") pattern of crystalline crystalline Form Gl of Rifaximin (I).
  • XRPD X-ray powder diffraction
  • Fig. 3 is an example of X-ray powder diffraction ("XRPD") pattern of crystalline Form G of Rifaximin (I).
  • Fig 4 is an example of X-ray powder diffraction ("XRPD") pattern of crystalline
  • Fig 5 is an example of X-ray powder diffraction ("XRPD") pattern of crystalline Amorphous form of Rifaximin (I).
  • XRPD X-ray powder diffraction
  • embodiments of the present invention provide a reproducible and efficient process for the preparation of crystalline Form G2 of Rifaximin (I). Crystalline Form G2. of Rifaximin obtained by the process of the present invention is found to be substantially pure and stable.
  • crystalline Form G2 of Rifaximin (I) characterized by X-ray powder diffraction angle peaks at 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 11.0, 11.5, 1 1.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ⁇ 0.2° 20 comprising the steps of: a. providing a suspension of Rifaximin in water at temperature ranging 20- 100°C;
  • step a of the present invention water is added to Rifaximin at temperature 20-100°C to obtain suspension of Rifaximin.
  • suspension is prepared at temperature 40-45°C.
  • Rifaximin utilized in step a. is in the form of crystalline form or amorphous form.
  • suspension is maintained for a time duration ranging between 1-6 hours at a temperature ranging between 30 - 60°C.
  • suspension is maintained at temperature 40-45°C for 2 hours.
  • suspension is cooled and stirred for a time duration ranging between 1-10 hours at a temperature ranging between 0°C to 40°C.
  • suspension is cooled 25-35°C and stirred for 2 hours.
  • step d of the present invention separating Rifaximin by various conventional methods like distillations, filtering, drying, ccntrifugation etc. followed by drying the separated compound at a temperature 30-80°C to give crystalline Form G2, preferably at temperature until a water content with below 4.0%.
  • crystalline Form G2 of Rifaximin (I) characterized by X-ray powder diffraction angle peaks at 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 11.0, 11.5, 11.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ⁇ 0.2° 20 comprising the steps of:
  • step b maintaining the step a. suspension between 8-12 hours at temperature 25-35°C followed by separating crude Rifaximin;
  • the step of reacting Rifamycin O with 2-amino-4-methylpyridine in a mixture of ethanol and water at a temperature 25-100°C for 8 hours it comprises the source of Rifamycin O that may be obtained according lo any of prior disclosed processes.
  • the solution obtained is maintained for 12 hours at temperature 25-35°C followed by separating crude Rifaximin.
  • Crude Rifaximin obtained is dissolved in mixture of water and ethanol at temperature ranging between 60-80°C.
  • the solution obtained is cooled at temperature 25- 45 °C and followed by seeded with crystalline form of Rifaximin.
  • the solution obtained is cooled at temperature -10 to 10°C and maintained for 12 hours.
  • the solution is cooled at -5 to 5°C for 12 hours.
  • the solid obtained is separated to obtain pure Rifaximin.
  • step f of the present invention can be performed by separating crystalline Rifaximin (I) by various conventional methods like distillations, filtering, drying, centrifugation etc. to obtain Form G2 of Rifaximin (I).
  • step g of the present invention water is added to crystalline Rifaximin at temperature 20-100°C to obtain suspension of Rifaximin.
  • suspension is prepared at temperature 40-45°C.
  • suspension is maintained for a time duration ranging between 1-6 hours at a temperature ranging between 30 - 60°C. Preferably, suspension is maintained at temperature 40-45 °C for 2 hours.
  • suspension is cooled and stirred for a time duration ranging between 1-10 hours at a temperature ranging between 0°C to 40°C. Preferably, suspension is cooled 25-35°C and stirred for a 2 hours.
  • step j of the present invention separating Rifaximin by various conventional methods like distillations, filtering, drying, centrifugation etc. followed by drying the separated compound at a temperature 30-80°C to give crystalline Form G2. Drying the final crystalline form G2 at a temperature until a water content lower than 6.0% wherein the X-ray powder diffraction angle peaks at 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 1 1.0, 11.5, 11.8, 17.2, 17.6, 18.2, 18.5 and 20.9 ⁇ 0.2° 2 ⁇ .
  • rifaximin form G2 depends on drying conditions such that water remaining at the end, lower than 6.0%), and not from the experimental conditions of pressure and temperature at which this critical limit of water percentage is achieved.
  • making solution is in the temperature range of 30 - 100°C.
  • C1-C4 alcoholic solvents are selected from methanol, ethanol, isopropanol, propanol, n-butanol.
  • C1-C4 alcoholic solvents are selected from methanol, ethanol, isopropanol, propanol, n-butanol.
  • process for the preparation of substantially pure Rifaximin comprising recrystallization using alcohol or mixture of water and alcoholic solvent wherein mixture of water and alcoholic solvents is in the ratio of 1 : 10 (v/v).
  • Rifaximin utilized in step a as crystalline form or amorphous form.
  • Crystalline form of Rifaximin is any of the crystalline form known in the prior art.
  • Step b of present embodiment maintaining the solution for a time duration ranging between 1-6 hours at a temperature ranging between 30 - 100°C
  • step b. is maintained for 2 hours at temperature ranging between 75-85°C.
  • Step c of present embodiment cooling the solution and stirring it for a time duration ranging between 5-30 hours at a temperature ranging between 20°C to 40°C.
  • step c maintained for 20 hours at temperature 25-35°C.
  • step d of the present invention can be performed by separating crystalline Rifaximin (I) by various conventional methods like distillations, filtering, drying, eentrifugation etc. to obtain Form Gl of Rifaximin (I). Drying the final crystalline form G2 at a temperature until a water content near 4.0% wherein the X-ray powder diffraction angle peaks at 5.4, 6.6, 7.4, 7.9, 8.8, 10.5, 1 1.0, 1 1.8, 12.9, 17.6, 18.5, 19.7, 21.0, 21.4, 22.1 ⁇ 0.2° 2 ⁇ .
  • crystalline form of Rifaximin is selected from Crystalline Form Gl, Crystalline Form G and Crystalline Form GR.
  • crystalline Form Gl of Rifaximin (I) is characterized by X-ray powder diffraction (XRPD) pattern substantially as depicted in Fig 2.
  • crystalline Form G of Rifaximin (I) is characterized by X-ray powder diffraction (XRPD) pattern substantially as depicted in Fig 3.
  • crystalline Form GR of Rifaximin (I) is characterized by X-ray powder diffraction (XRPD) pattern substantially as depicted in Fig 4.
  • Amorphous Form of Rifaximin (I) is characterized by X-ray powder diffraction (XRPD) pattern substantially as depicted in Fig 5.
  • Substantially pure crystalline Form G2 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 G2 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.
  • compositions of crystalline Form G2 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.
  • Example 1 Process for the preparation of Form G2 of Rifaximin using Rifamycin O:
  • the resultant suspension was stirred at 75-85° C about for about 2 hours and then cooled to 50- 60° C and passed through a micro filter for to make particle free.
  • the solution was further cooled to about 25-35 °C and seeded with rifaximin, stirred for 2-3 hours.
  • the resultant mass was further cooled to 0 ⁇ 5°C and stirred for 10-12 hours.
  • the solid separated was filtered and washed with the chilled mixture (3.5 mL) of ethanol and (1.5 mL) of water.
  • the solid obtained was dried at about 60-65°C for about 6-8 hours to afford 7.5 g of rifaximin as crystalline form.
  • Example 2 Process for the preparation of Form G2 of Rifaximin using Rifamycin S: lOOg of Rifamycin S was charged into toluene (1000 ml) and cooled to -15 to -5°C. To this reaction mixture was added slowly of mixture ethanol (500.0 ml), 40.0 gm of molecular bromine and 40.0 gm of pyridine and maintained the reaction mass for 15-30 minutes at same temperature. Charge 200.0 mL of chilled aqueous HC1 at below 0°C then separate the layers after stirring continued for 10-15 minutes. Isolated the material by using 1580.0 mL of 0.5N HC1 and after 2-3 hours maintenance the resulting of 3-BromoRifamycin S.
  • the solid obtained was dried at about 60-65°C for about 6-8 hours to afford 7.5 g of rifaximin as crystalline form.
  • 7.5 grams of crystalline form of Rifaximin and 30.0 mL of water into a three-necked flask equipped with mechanical stirrer, thermometer and reflux condenser, then the suspension is heated at 40-45° C and kept under stirring for 2 hrs, then cooled the suspension to 25-35°C and stirring continued for another 1 hour.
  • the product was separated by filtration and the solid washed with 5 mL of water and dried at 50-55° C until water content obtained is near 4% to obtain to obtain Rifaximin Form G2.
  • Example-4 Process for the preparation of Rifaximin Form Gl:
  • Example-7 Process for the preparation of Rifaximin Form G2:

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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

La présente invention concerne un procédé amélioré de préparation d'une forme cristalline G2 de rifaximine représentée par la formule (I). L'invention concerne également une forme cristalline G2 de rifaximine (I) obtenue par le procédé selon la présente invention, ladite forme G2 étant sensiblement pure, stable et caractérisée par un diagramme de diffraction des rayons X sur poudre comprenant des pics choisis parmi 5.3, 5.7, 6.4, 6.9, 7.1, 7.7, 8.7, 10.4, 10.5, 11.0, 11.5, 11.8, 17.2, 17.6, 18.2, 18.5 et 20.9 ± 0,2° 2θ. L'invention concerne également une forme cristalline G1 de rifaximine (I) obtenue par le procédé selon la présente invention, ladite forme G1 étant sensiblement pure, stable et caractérisée par un diagramme de diffraction des rayons X sur poudre comprenant comprenant des pics choisis parmi 5.4, 6.6, 7.4, 7.9, 8.8, 10.5, 11.0, 11.8, 12.9, 17.6, 18.5, 19.7, 21.0, 21.4, 22.1 ± 0.2° 2θ. La présente invention concerne en outre un procédé de préparation de rifaximine sensiblement pure comprenant une recristallisation dans de l'alcool ou dans un mélange d'eau et de solvants à base d'alcool.
PCT/IB2018/051137 2017-03-31 2018-02-23 Procédé de préparation d'une forme cristalline de rifaximine WO2018178777A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109400628A (zh) * 2018-12-26 2019-03-01 重庆华邦胜凯制药有限公司 一种利福布汀中间体的制备方法
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
CN118894832A (zh) * 2024-07-18 2024-11-05 中国药科大学 Gl-v9的两种晶型及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120116071A1 (en) * 2006-09-22 2012-05-10 Cipla Limited Rifaximin
WO2017021975A1 (fr) * 2015-08-06 2017-02-09 Msn Laboratories Private Limited Procédé de préparation de formes cristallines de rifaximine

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120116071A1 (en) * 2006-09-22 2012-05-10 Cipla Limited Rifaximin
WO2017021975A1 (fr) * 2015-08-06 2017-02-09 Msn Laboratories Private Limited Procédé de préparation de formes cristallines de rifaximine

Cited By (4)

* 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
CN109400628A (zh) * 2018-12-26 2019-03-01 重庆华邦胜凯制药有限公司 一种利福布汀中间体的制备方法
CN118894832A (zh) * 2024-07-18 2024-11-05 中国药科大学 Gl-v9的两种晶型及其制备方法

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