WO2007004239A1 - Nouvelle forme polymorphique du tosylate de sultamicilline et procede correspondant - Google Patents

Nouvelle forme polymorphique du tosylate de sultamicilline et procede correspondant Download PDF

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Publication number
WO2007004239A1
WO2007004239A1 PCT/IN2006/000234 IN2006000234W WO2007004239A1 WO 2007004239 A1 WO2007004239 A1 WO 2007004239A1 IN 2006000234 W IN2006000234 W IN 2006000234W WO 2007004239 A1 WO2007004239 A1 WO 2007004239A1
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WO
WIPO (PCT)
Prior art keywords
tosylate
sultamicillin
polymorphic form
sultamicillin tosylate
following
Prior art date
Application number
PCT/IN2006/000234
Other languages
English (en)
Inventor
Sanjay Suri
Tapan Kashyap
Netar Singh
Original Assignee
Morepen 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 Morepen Laboratories Limited filed Critical Morepen Laboratories Limited
Publication of WO2007004239A1 publication Critical patent/WO2007004239A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • This invention specifically relates to a crystalline polymorphic form of sultamicillin tosylate having advantages for use in antibacterial infections.
  • the new form is more stable and has enhanced bioavailability.
  • the chemical name of sultamicillin tosylate is 1 , 1 -dioxopenicillanoyloxymethyl 6-(D- ⁇ -amino- ⁇ -phenylacetamido)penicillanate tosylate (hereinafter "VD 1827 tosylate”) represented by the following formula:
  • the invention also discloses a process for the preparation of new polymorphic form of sultamicillin tosylate.
  • Sultamicllin is a methylenedioxy linked conjugate of penicillanic acid 1,1- dioxide (sulbactam) and ampicillin.
  • US 4,234,579 discloses sulbactam and esters thereof, which are readily hydrolysable in vivo, for enhancing the effectiveness of beta-lactam antibiotics such as ampicillin.
  • US 4,244,951 discloses a novel conjugates of sulbactam and known penicillin antibiotics linked via methylenedioxy group.
  • US 4,432,987 discloses crystalline benzenesulfonate salts of sultamicillin. According to disclosure in column 1, lines 50 to 55, sultamicillin free base has poor handling characteristics and poor stability. Further, the patent teaches that the only salt of sultamicillin disclosed in the prior art is hydrochloride & due to poor solid state stability, it is susceptible to hydrolytic decomposition. It also poses problems particularly in aqueous formulations. Crystalline forms are always preferable due to higher stability. Moreover, the crystalline form with enhanced bioavailability is more desirable.
  • US Patent No. 4,342,772 in general discloses ⁇ -lactam compounds, antibacterial compositions thereof and method of use including sultamicillin for treatment of bacterial infections.
  • the said patent designates 1, 1- dioxopenicillanoyloxymethyl 6-(D- ⁇ -amino- ⁇ -phenyl acetamido)penicillanate as VD 1827 tosylate, which possesses antibacterial property. Further, the advantages of VD 1827 are highlighted by giving comparative account of absorption levels of VD 1827 and existing hydrochloride salt.
  • the patent also discloses method of its preparation and method of treating bacterial infections. Column 17 lines 25 -65 and column 18 lines up to 10 describe the preparation of sultamicillin tosylate. The products so obtained have melting point 141°-148°C & IR-spectrum of the products
  • compositions containing VD 1827 tosylate for administration to mammals in accordance with exacting health registration requirements of the US and international health registration authorities, e.g. the
  • VD 1827 tosylate in as stable a crystalline form as possible, especially a form having good physical and mechanical properties like high melting range and better dissolution profile.
  • One objective of the present invention is to produce a new polymorph of sultamycillin tosylate designated herein after as Form 2.
  • Yet other object is to provide a polymorph with better stability over the existing forms.
  • Another objective of the invention is to produce a new polymorph that should have higher melting range that can withstand the heat generated during formulating the product for finish doses.
  • Still another objective of the invention is to produce a new polymorph that has minimum water content so that the extra weight taken to provide the effective amount of the drug can be minimized.
  • Fig.l Infra red spectrum of crystalline polymorphic form 2 of VD 1827 tosylate
  • Fig.2 X-Ray Diffraction pattern of crystalline polymorphic form 2 of VD 1827 tosylate
  • Fig.3 Differential scanning calorimetric curve of crystalline polymorphic form 2 of VD 1827 tosylate
  • Fig 4 Differential scanning calorimetric curve of crystalline VD 1827 tosylate when prepared by the method disclosed in '772.
  • Fig 5 X-Ray Diffraction pattern of crystalline polymorphic form 1 of VD 1827 tosylate prepared by the method disclosed in'772
  • VD 1827 tosylate can exist in crystalline polymorphic form, that is distinct from the one disclosed in the '772.
  • Form 2 has distinctly different physical properties such as melting point X ray diffraction and IR spectrum. Further, the form 2 of this invention proves to have better stability due to its higher melting point and bioavailability due to its higher dissolution rate as compared to the one described and claimed in '772.
  • the present invention provides a novel polymorph of sultamicillin tosylate having the formula structure.
  • a process for the preparation of novel polymorphic form 2 of Sultamicillin tosylate comprising: a) synthesizing Sultamicillin tosylate pure/recrystallised according to US patent no. 4,342,772 b) dissolving the compound obtained in step (a) in a polar organic solvent c) crystallizing the polymorphic form 2 from the reaction mass followed by filtration and drying.
  • the polar organic solvents used in step (b) may be such as C 1 -C 5 alkanols preferably methanol, ethanol, isopropanol, butanol.
  • the dissolving in step (b) may be carried out at a temperature in the range from 10° to 100 0 C preferably 30° to 8O 0 C, more preferably from 50-60°C.
  • the crystallization temperature may vary from -5°C to +4O 0 C preferably 0° to +30 0 C and more preferably from 0 0 C to 25°C.
  • the sultamicillin base may be prepared by any traditional method using said form 2.
  • Form 2 of this invention is characterized by the following infrared spectrum pattern: 2978, 1793, 1689, 1498, 1459, 1326, 1175, 1126, 1009, 975, 684, 570 ( ⁇ 5 cm-1).
  • the invention is further characterized by the following XRD pattern expressed in terms of "2 Theta” and "d” spacing ( ⁇ 0.5)
  • the invention is still further characterized by the following XRD pattern expressed in terms of "2 Theta” and “d” spacing ( ⁇ 0.5)
  • the invention is additionally characterized by the following DSC pattern: Onset 174.73°C, End set 179.76°C, Peak 177.52°C ( ⁇ 5°C) DETAILED DESCRIPTION OF THE INVENTION:
  • VD 1827 tosylate is distinctly different polymorph from the one VD 1827 tosylate (designated as form 1) as described in US Patent No. '772
  • Form 1 is further characterized by IR cm-1: 2993, 1676, 1521, 1326, 1174, 1121, 1011,
  • Form 2 as claimed in the present invention has the following characteristics: XRD: ( ⁇ 0.5)- Major Signals
  • reaction mixture is seeded with Sultamicillin base (3g) and the resultant reaction mixture is stirred at 0-5 0 C for 30minutes. Then isopropyl alcohol (700ml) is added to it at 0-5 0 C. in order to get complete crystallization of product. The product is filtered followed by washing with isopropyl alcohol (300ml.) and then finally with diisopropyl ether (300ml). The product is dried under vacuum.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une forme 2 polymorphique cristalline de tosylate VD 1827 qui se caractérise par le motif de spectre infrarouge suivant: 2978, 1793, 1689, 1498, 1459, 1326, 1175, 1126, 1009, 975, 684, 570 (± 5 cm-1). Cette invention se caractérise également par le profil XRD suivant exprimé en termes de 'Theta 2' et d'espacement 'd' (± 0,5): 14,78, 15,92, 19,34, 20,70. Cette invention se caractérise en outre par le profil DSC suivant: température de départ: 174,73 °C, température finale: 179,76 °C, crête à 177,52 °C (± 5°C), et gamme de fusion comprise entre 160 et 175 °C. La forme 2 présente le profil de dissolution donné dans le tableau (1). La forme 2 est préparée selon un procédé consistant à synthétiser le tosylate de sultamicilline pur/recristallisé conformément au brevet américain US 4,342,772, à dissoudre le composé obtenu à l'étape (a) dans un solvant organique polaire, à cristalliser la forme 2 à partir de la masse de réaction, après quoi interviennent la filtration et le séchage.
PCT/IN2006/000234 2005-07-06 2006-07-04 Nouvelle forme polymorphique du tosylate de sultamicilline et procede correspondant WO2007004239A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN1755DE2005 2005-07-06
IN1755/DEL/2005 2005-07-06

Publications (1)

Publication Number Publication Date
WO2007004239A1 true WO2007004239A1 (fr) 2007-01-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009527628A (ja) * 2006-02-21 2009-07-30 モメンティブ パフォーマンス マテリアルズ インコーポレイテッド 有機官能性シランおよびそれの混合物を作製するプロセス

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4342772A (en) * 1979-02-13 1982-08-03 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) β-Lactam compounds, antibacterial compositions thereof and method of use
GB2114969A (en) * 1980-10-31 1983-09-01 Leo Pharm Prod Ltd Penicillins
ES2039299A1 (es) * 1991-10-04 1993-09-16 Asturpharma S A Procedimiento de obtencion de esteres de acido 1,1-dioxopenicilanico y sus sales.
ES2161602A1 (es) * 1999-04-08 2001-12-01 Astur Pharma Sa Sintesis de 6-(d-alfa-(bencilidenaminofenilacetamido))penicilinato de 1,1-dioxopenicilanoiloximetilo y analogos. nuevos intermedios para la sintesis de sultamicilina.

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4342772A (en) * 1979-02-13 1982-08-03 Leo Pharmaceutical Products Ltd. A/S (Lovens Kemiske Fabrik Produktionsaktieselskab) β-Lactam compounds, antibacterial compositions thereof and method of use
GB2114969A (en) * 1980-10-31 1983-09-01 Leo Pharm Prod Ltd Penicillins
ES2039299A1 (es) * 1991-10-04 1993-09-16 Asturpharma S A Procedimiento de obtencion de esteres de acido 1,1-dioxopenicilanico y sus sales.
ES2161602A1 (es) * 1999-04-08 2001-12-01 Astur Pharma Sa Sintesis de 6-(d-alfa-(bencilidenaminofenilacetamido))penicilinato de 1,1-dioxopenicilanoiloximetilo y analogos. nuevos intermedios para la sintesis de sultamicilina.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009527628A (ja) * 2006-02-21 2009-07-30 モメンティブ パフォーマンス マテリアルズ インコーポレイテッド 有機官能性シランおよびそれの混合物を作製するプロセス

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