WO2016142902A1 - Céfixime à aire de surface réduite et haute stabilité - Google Patents

Céfixime à aire de surface réduite et haute stabilité Download PDF

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Publication number
WO2016142902A1
WO2016142902A1 PCT/IB2016/051372 IB2016051372W WO2016142902A1 WO 2016142902 A1 WO2016142902 A1 WO 2016142902A1 IB 2016051372 W IB2016051372 W IB 2016051372W WO 2016142902 A1 WO2016142902 A1 WO 2016142902A1
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WIPO (PCT)
Prior art keywords
less
process according
surface area
cefixime
mixture
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Ceased
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PCT/IB2016/051372
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English (en)
Inventor
Radhakrishna Bhikaji SHIVDAVKAR
Govind Dnyanoba AUSEKAR
Mithun Dasharath SURWASE
Shantanu Gokuldas VARADE
Girij Pal Singh
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Lupin Ltd
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Lupin Ltd
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Publication of WO2016142902A1 publication Critical patent/WO2016142902A1/fr
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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/02—Preparation
    • C07D501/12—Separation; Purification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/22—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with radicals containing only hydrogen and carbon atoms, attached in position 3

Definitions

  • the present invention provides cefixime trihydrate (I) with reduced surface area and high stability. BACKGROUND OF THE INVENTION
  • Cefixime is an orally active third generation broad spectrum cephalosporin antibiotic and is more potent against gram negative bacteria. Cefixime is commonly used to treat various infections caused by susceptible isolates of the designated bacteria. Cefixime and cefixime trihydrate (I) are disclosed in patent US 4,409,214; the patent discloses process for preparation of cefixime and isolation of cefixime trihydrate (I) from a mixture of ethanol and water. Various processes for preparation as well as purification of cefixime and cefixime trihydrate (I) are available in the literature.
  • the present invention provides cefixime trihydrate (I) with reduced surface area and high stability with respect to content of impurity Al.
  • the present invention provides a detailed study of surface area of cefixime trihydrate (I) and the content of impurity Al of cefixime trihydrate (I).
  • the impurity Al is one of the stereoisomer of impurity A which is provided in the British pharmacopeia monograph of cefixime and is as depicted below.
  • Impurity A in the present invention it was surprisingly found that cefixime trihydrate (I) with a surface area of less than 1.2 m /gm is highly stable with respect to impurity Al which is less than 0.5% by area percentage of HPLC.
  • the present invention provides cefixime trihydrate (I) with surface area of less than 1.2 m /gm containing impurity Al less than 0.5% by area percentage of HPLC.
  • the present invention provides cefixime trihydrate (I) with surface area of less than 1.2 m /gm.
  • the surface area is measured by Brunauer-Emmett- Teller (BET) method.
  • BET Brunauer-Emmett- Teller
  • the present invention provides cefixime trihydrate (I) with surface area of less than 1.2 m /gm and the content of impurity Al of less than 0.5% by area percentage of HPLC.
  • the present invention provides process for preparation of cefixime trihydrate (I) with surface area of less than 1.2 m /gm.
  • cefixime trihydrate (I) Various process for purification of cefixime trihydrate (I) were carried out in our endeavor to obtain stable cefixime trihydrate (I). Physical and chemical parameters of the Cefixime trihydrate (I) samples were determined. All the experimental parameters which could alter the physical and chemical properties of cefixime trihydrate (I) were thoroughly studied. After a detailed study it was observed that there was a correlation between experimental parameters and the surface area of cefixime trihydrate (I) obtained and stability of cefixime trihydrate (I).
  • cefixime trihydrate (I) with surface area of less than 1.2 m /gm is stable (entries 2 and 3 of Table 1). As the surface area of cefixime trihydrate (I) increases impurity Al formation also increases (entry 1 of Table 1). The impurity Al appeared at RRT 0.75 in the HPLC chromatogram. Correlation between RPM of the experiment, surface area of cefixime trihydrate (I) and content of impurity Al during stability was studied and the results obtained are depicted below in Table 1. Table 1: Stability study of cefixime trihydrate (I).
  • Table 1 shows that stability of cefixime trihydrate (I) depends on the surface area, which in turn depends on the RPM employed in the purification of cefixime trihydrate (I). Stability of cefixime trihydrate (I) was studied at 40 ⁇ 2°C RH 75 ⁇ 5% RH.
  • the present invention provides process for preparation of cefixime trihydrate (I) with surface area of less than 1.2 m /gm comprising the steps of: i) adjusting pH of cooled aqueous solution of cefixime trihydrate (I) to 5.8-6 using base, ii) optionally treating with EDTA and carbon, iii) stirring the mixture at low RPM, iv) adjusting pH of the mixture to 4.8-5.0 using acid, v) adding ketone solvent, vi) heating the mixture to 34-38°C, vii) adjusting pH to 2.4-2.5 slowly using acid, viii) cooling the mixture, and ix) isolating the solid.
  • Cefixime trihydrate (I) is prepared by methods known in the literature.
  • the process for preparation of cefixime trihydrate (I) is carried out at low RPM.
  • low RPM means RPM less than 400, preferably less than 100, more preferably less than 60.
  • the pH of 5.8 to 6 is achieved by using base selected from alkaline solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate and the like, preferably sodium hydroxide.
  • the pH of 4.8 to 2.4 is achieved by using acid selected from inorganic acids like hydrochloric acid, sulfuric acid and the like, preferably hydrochloric acid.
  • the pH is adjusted to 2.4-2.5 slowly using acid. "Slowly” means over a period of 60-300 minutes.
  • the ketone solvent is selected form acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl isopropyl ketone, acetophenone; preferably acetone.
  • the mixture is cooled to 0-10°C, preferably 0-5°C.
  • UV detector UV detector
  • Instrument Smart Srob 93, based on dynamic BET principal.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

La présente invention concerne du trihydrate de céfixime (I) ayant une aire de surface inférieure à 1,2 m2/gm et dont la teneur en impureté A1 est inférieure à 0,5 % par pourcentage surfacique du HPLC. L'impureté A1 est l'un des stéréoisomères de l'impureté A telle que représentée ci-dessous.
PCT/IB2016/051372 2015-03-11 2016-03-10 Céfixime à aire de surface réduite et haute stabilité Ceased WO2016142902A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN796/MUM/2015 2015-03-11
IN796MU2015 2015-03-11

Publications (1)

Publication Number Publication Date
WO2016142902A1 true WO2016142902A1 (fr) 2016-09-15

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2016/051372 Ceased WO2016142902A1 (fr) 2015-03-11 2016-03-10 Céfixime à aire de surface réduite et haute stabilité

Country Status (1)

Country Link
WO (1) WO2016142902A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109490440A (zh) * 2018-11-21 2019-03-19 成都倍特药业有限公司 一种检测头孢克肟相关杂质的方法
CN111487354A (zh) * 2020-04-27 2020-08-04 广州白云山医药集团股份有限公司白云山制药总厂 一种检测头孢克肟相关杂质的方法
CN111551654A (zh) * 2020-05-07 2020-08-18 广州白云山医药集团股份有限公司白云山制药总厂 检测头孢克肟聚合物杂质的方法
WO2021202481A1 (fr) * 2020-03-30 2021-10-07 Florida State University Research Foundation, Inc. Compositions et procédés pour inhiber la production de collagène de type 1
CN115326950A (zh) * 2022-07-27 2022-11-11 广州白云山医药集团股份有限公司白云山制药总厂 一种检测头孢克肟溶出度的方法

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4409214A (en) 1979-11-19 1983-10-11 Fujisawa Pharmaceutical, Co., Ltd. 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof
WO1995033753A1 (fr) * 1994-06-03 1995-12-14 Marcham Trading & Investment Ltd. Procede pour la preparation du cefixime trihydrate
WO1998006723A1 (fr) * 1996-08-14 1998-02-19 Biochemie Gesellschaft Mbh Sels d'amine
WO1999051607A2 (fr) * 1998-04-02 1999-10-14 Biochemie Gesellschaft Mbh Procede de purification d'un derive de cephalosporine
WO2001070749A1 (fr) * 2000-03-20 2001-09-27 Hanmi Fine Chemicals Co. Ltd. Procede de preparation de derives de cephalosporine utilisant un nouveau compose de thiazole
WO2006067806A1 (fr) * 2004-12-21 2006-06-29 Lupin Limited Procede de preparation du cefixime
WO2006103686A1 (fr) * 2005-03-29 2006-10-05 Hetero Drugs Limited Procede ameliore de preparation de cefixime

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4409214A (en) 1979-11-19 1983-10-11 Fujisawa Pharmaceutical, Co., Ltd. 7-Acylamino-3-vinylcephalosporanic acid derivatives and processes for the preparation thereof
WO1995033753A1 (fr) * 1994-06-03 1995-12-14 Marcham Trading & Investment Ltd. Procede pour la preparation du cefixime trihydrate
WO1998006723A1 (fr) * 1996-08-14 1998-02-19 Biochemie Gesellschaft Mbh Sels d'amine
WO1999051607A2 (fr) * 1998-04-02 1999-10-14 Biochemie Gesellschaft Mbh Procede de purification d'un derive de cephalosporine
WO2001070749A1 (fr) * 2000-03-20 2001-09-27 Hanmi Fine Chemicals Co. Ltd. Procede de preparation de derives de cephalosporine utilisant un nouveau compose de thiazole
WO2006067806A1 (fr) * 2004-12-21 2006-06-29 Lupin Limited Procede de preparation du cefixime
WO2006103686A1 (fr) * 2005-03-29 2006-10-05 Hetero Drugs Limited Procede ameliore de preparation de cefixime

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KITAMURA S ET AL: "Dehydration effect on the stability of cefixime trihydrate", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER BV, NL, vol. 59, no. 3, 30 March 1990 (1990-03-30), pages 217 - 224, XP025554429, ISSN: 0378-5173, [retrieved on 19900330], DOI: 10.1016/0378-5173(90)90112-H *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109490440A (zh) * 2018-11-21 2019-03-19 成都倍特药业有限公司 一种检测头孢克肟相关杂质的方法
CN109490440B (zh) * 2018-11-21 2021-09-07 成都倍特药业股份有限公司 一种检测头孢克肟相关杂质的方法
WO2021202481A1 (fr) * 2020-03-30 2021-10-07 Florida State University Research Foundation, Inc. Compositions et procédés pour inhiber la production de collagène de type 1
US11554121B2 (en) 2020-03-30 2023-01-17 Florida State University Research Foundation, Inc. Compositions and methods for inhibiting type 1 collagen production
US12257256B2 (en) 2020-03-30 2025-03-25 Florida State University Research Foundation, Inc. Compositions and methods for inhibiting type 1 collagen production
CN111487354A (zh) * 2020-04-27 2020-08-04 广州白云山医药集团股份有限公司白云山制药总厂 一种检测头孢克肟相关杂质的方法
CN111551654A (zh) * 2020-05-07 2020-08-18 广州白云山医药集团股份有限公司白云山制药总厂 检测头孢克肟聚合物杂质的方法
CN111551654B (zh) * 2020-05-07 2022-04-22 广州白云山医药集团股份有限公司白云山制药总厂 检测头孢克肟聚合物杂质的方法
CN115326950A (zh) * 2022-07-27 2022-11-11 广州白云山医药集团股份有限公司白云山制药总厂 一种检测头孢克肟溶出度的方法

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