WO2003018578A1 - Method for producing beta form of crystalline anhydrous aztreonam - Google Patents

Method for producing beta form of crystalline anhydrous aztreonam Download PDF

Info

Publication number
WO2003018578A1
WO2003018578A1 PCT/IN2002/000169 IN0200169W WO03018578A1 WO 2003018578 A1 WO2003018578 A1 WO 2003018578A1 IN 0200169 W IN0200169 W IN 0200169W WO 03018578 A1 WO03018578 A1 WO 03018578A1
Authority
WO
WIPO (PCT)
Prior art keywords
aztreonam
solution
anhydrous
amino
crystalline anhydrous
Prior art date
Application number
PCT/IN2002/000169
Other languages
French (fr)
Inventor
Thakashina Moorthy Chandiran
Satyanarayana Yennam
Dandala Ramesh
Sunderam Sivakumaraa Meenakshi
Original Assignee
Aurobindo Pharma Ltd.
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 Aurobindo Pharma Ltd. filed Critical Aurobindo Pharma Ltd.
Publication of WO2003018578A1 publication Critical patent/WO2003018578A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to a method for producing crystalline anhydrous ⁇ -form of ((Z)-2-[[[(2-amino-4-thiazolyl)[[trans-(2S,3S)-2-methyl-4-oxo-l-sulfo-3-azetidinyl]- carbamoyl]methylene]amino]oxy]-2-methylpropionic acid (also known as Aztreonam)
  • Aztreonam of Formula I is a synthetic monocyclic beta-lactam antimicrobial agent, active against gram-negative organism.
  • Aztreonam such as US Patent 4,775,670 and US Patent 5, 194,604 amongst others.
  • Aztreonam is known to exhibit polymorphism and four distinct crystalline forms designated as ⁇ -, ⁇ -, ⁇ - and ⁇ - forms have been reported in US Patent 4,826,973.
  • the ⁇ -form is in the form of hydrated crystals, it typically contains 7-14% of water and has a poor storage stability. It is desirable to convert it to ⁇ -form that is anhydrous, substantially non-hygroscopic and possesses good flowability, low surface area, enhanced solid state stability and is well suited for use as a pharmaceutical agent.
  • US Patent 4,946,838 describes preparation of ⁇ -form by crystallization of the ⁇ -form from anhydrous alcohol where Aztreonam ⁇ -form is dissolved in absolute methanol or absolute ethanol at 55° to 60°C and under these conditions ⁇ -form dissolves momentarily and then recrystallises spontaneously as the ⁇ -form. This procedure is not suitable for sterile preparation as Aztreonam does not remain in solution long enough to perform aseptic filtration.
  • the instant invention relates to a novel process to produce highly pure sterile crystalline anhydrous Aztreonam ⁇ -form.
  • the present invention enables the preparation of a solution of the ⁇ -form Aztreonam in absolute ethanol without using trialkylamine or silylating agent, and this solution can be sterile filtered to crystallise sterile ⁇ -form.
  • the instant invention involves dissolving the ⁇ -form in absolute ethanol at low temperature.
  • the ⁇ -form of Aztreonam dissolves in absolute ethanol at a temperature varying from -10°C to +15°C and crystallizes out as ⁇ -form on raising the temperature to 50°C to 55°C. Crystallization of Aztreonam does not occur from this solution if maintain at -10°C to +15°C.
  • This unusual solubility characteristic of Aztreonam ⁇ -form has not been reported hitherto in literature.
  • similar solubility behaviour of a different antibiotic namely, cefotaxime sodium has been described in US Patent 4,912,21 1 , example 6.
  • Such a solution of ⁇ -form can be treated with carbon to remove colour and also can be passed through the 0.2 micron sterile filter for aseptic preparation.
  • the ⁇ -form is dissolved in anhydrous alkanol, preferably absolute ethanol, at -10°C to +15°C, most preferably at 5°C to 10°C.
  • This solution maintained at this temperature, is treated with activated carbon and is filtered through clarification filter and a sterile filter to obtain a sterile solution.
  • the anhydrous ⁇ -form of Aztreonam is then crystallised by raising the temperature of the sterile filtrate to 50°C to 55°C.
  • the product is then filtered and dried in vacuum.
  • the ⁇ -form prepared by this process is a suitable pharmaceutical agent for blending with a basic- material, such as L-arginine, for intravenous and intramuscular administration.
  • Preparation of the ⁇ -form from the ⁇ -form can be accomplished by the procedure described in the following preparation.
  • Aztreonam ⁇ -form (40 g) was added to pre-cooled absolute ethanol (2400 ml) at 8-10°C and stirred for 30 minutes to obtain a clear solution. This solution was treated with activated carbon (1 g) for 15 minutes at 8-10°C. The suspension was filtered through celite and the residue was washed with ethanol (50 ml). The filtrate was then warmed to 50-55°C slowly over a period of 2 hours to crystallize ⁇ -form. The hot suspension was cooled to 15-20°C, stirred for 1 hour and filtered. The crystals were dried in vacuo to obtain 33 g of the product which was confirmed to be the ⁇ -form by IR spectrum, powder X-ray diffraction pattern and differential scanning calorimetry.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cephalosporin Compounds (AREA)

Abstract

A process is described for producing anhydrous β-form of ((Z)-2-[[[(2-amino-4-thiazolyl)[[trans-(2S,3S)-2-methyl-4-oxo-1-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2-methylpropionic acid (also known as Aztreonam).

Description

This invention relates to a method for producing crystalline anhydrous β-form of ((Z)-2-[[[(2-amino-4-thiazolyl)[[trans-(2S,3S)-2-methyl-4-oxo-l-sulfo-3-azetidinyl]- carbamoyl]methylene]amino]oxy]-2-methylpropionic acid (also known as Aztreonam)
Aztreonam of Formula I is a synthetic monocyclic beta-lactam antimicrobial agent, active against gram-negative organism.
Formula
Figure imgf000002_0001
A number of references disclose the preparation of Aztreonam such as US Patent 4,775,670 and US Patent 5, 194,604 amongst others. Aztreonam is known to exhibit polymorphism and four distinct crystalline forms designated as α-, β-, γ- and δ- forms have been reported in US Patent 4,826,973. The α-form is in the form of hydrated crystals, it typically contains 7-14% of water and has a poor storage stability. It is desirable to convert it to β-form that is anhydrous, substantially non-hygroscopic and possesses good flowability, low surface area, enhanced solid state stability and is well suited for use as a pharmaceutical agent.
US Patent 4,946,838 describes preparation of β-form by crystallization of the α-form from anhydrous alcohol where Aztreonam α-form is dissolved in absolute methanol or absolute ethanol at 55° to 60°C and under these conditions α-form dissolves momentarily and then recrystallises spontaneously as the β-form. This procedure is not suitable for sterile preparation as Aztreonam does not remain in solution long enough to perform aseptic filtration.
In US Patent 4,946,838, another process to prepare β-form has been disclosed wherein α-form is dissolved as triethylamine salt in an anhydrous ethanol and then β-form is obtained by adding anhydrous hydrogen chloride solution. While this process is suitable for sterile filtration, however the intended product is contaminated with triethylamine hydrochloride.
In yet another procedure described in US Patent 4,946,838, the α-form is treated with silylating agent in an aprotic solvent such as acetonitrile to obtain a solution of Aztreonam as silyl derivative and β-form is then precipitated by addition of ethanol. The yield reported is very low and silylation step is necessary to dissolve α-form. The aim of the present invention is to alleviate these problems. DETAILED DESCRIPTION OF THE INVENTION
The instant invention relates to a novel process to produce highly pure sterile crystalline anhydrous Aztreonam β-form. The present invention enables the preparation of a solution of the α-form Aztreonam in absolute ethanol without using trialkylamine or silylating agent, and this solution can be sterile filtered to crystallise sterile β-form.
Specifically, the instant invention involves dissolving the α-form in absolute ethanol at low temperature. The α-form of Aztreonam dissolves in absolute ethanol at a temperature varying from -10°C to +15°C and crystallizes out as β-form on raising the temperature to 50°C to 55°C. Crystallization of Aztreonam does not occur from this solution if maintain at -10°C to +15°C. This unusual solubility characteristic of Aztreonam α-form has not been reported hitherto in literature. However, similar solubility behaviour of a different antibiotic namely, cefotaxime sodium has been described in US Patent 4,912,21 1 , example 6. Such a solution of α-form can be treated with carbon to remove colour and also can be passed through the 0.2 micron sterile filter for aseptic preparation.
The α-form is dissolved in anhydrous alkanol, preferably absolute ethanol, at -10°C to +15°C, most preferably at 5°C to 10°C. This solution, maintained at this temperature, is treated with activated carbon and is filtered through clarification filter and a sterile filter to obtain a sterile solution. The anhydrous β-form of Aztreonam is then crystallised by raising the temperature of the sterile filtrate to 50°C to 55°C. The product is then filtered and dried in vacuum. The β-form prepared by this process is a suitable pharmaceutical agent for blending with a basic- material, such as L-arginine, for intravenous and intramuscular administration.
Major advantage realised in the present invention compared to the prior art is the process simplicity. Prior art procedure requires an additional step wherein addition of trialkylamine or silylation is necessary to dissolve α-form for sterile filtration; in the present procedure, the α-form is directly dissolved in ethanol at low temperature to obtain a solution which is suitable for sterile β-form preparation.
Preparation of the β-form from the α-form can be accomplished by the procedure described in the following preparation.
Example
Aztreonam α-form (40 g) was added to pre-cooled absolute ethanol (2400 ml) at 8-10°C and stirred for 30 minutes to obtain a clear solution. This solution was treated with activated carbon (1 g) for 15 minutes at 8-10°C. The suspension was filtered through celite and the residue was washed with ethanol (50 ml). The filtrate was then warmed to 50-55°C slowly over a period of 2 hours to crystallize β-form. The hot suspension was cooled to 15-20°C, stirred for 1 hour and filtered. The crystals were dried in vacuo to obtain 33 g of the product which was confirmed to be the β-form by IR spectrum, powder X-ray diffraction pattern and differential scanning calorimetry.

Claims

WE CLAIM:
1 A process for the preparation of the ((Z)-2-[[[(2-amino-4-thiazolyl)[[/n s'-(2S,3S)- 2-methyl-4-oxo-l-sulfo-3-azetidinyl]carbamoyl]methylene]amino]oxy]-2- methylpropionic acid (Aztreonam) which comprises dissolving the α-ibrm of Aztreonam in absolute ethanol at a temperature of -10°C to +15°C and warming the solution to 50-55°C after sterile filtration to crystallise anhydrous β-form.
Dated this the 27th day of August 2001
Aurobindo Pharma Limited / ^ < ibka£f£aX^
Ms. Nanda Bhaskara LEGAL OFFICER FOR THE APPLICANTS
PCT/IN2002/000169 2001-08-27 2002-08-21 Method for producing beta form of crystalline anhydrous aztreonam WO2003018578A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN700/MAS/2001 2001-08-27
IN700CH2001 2001-08-27

Publications (1)

Publication Number Publication Date
WO2003018578A1 true WO2003018578A1 (en) 2003-03-06

Family

ID=11097009

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2002/000169 WO2003018578A1 (en) 2001-08-27 2002-08-21 Method for producing beta form of crystalline anhydrous aztreonam

Country Status (2)

Country Link
CN (1) CN1545514A (en)
WO (1) WO2003018578A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004103999A1 (en) * 2003-05-15 2004-12-02 TEVA Gyógyszergyár Részvénytársaság AZTREONAM β POLYMORPH WITH VERY LOW RESIDUAL SOLVENT CONTENT
US7145017B2 (en) 2002-08-05 2006-12-05 TEVA Gyógyszergyár Zártkörűen Működő Részvénytársaság Preparation of Aztreonam
US7262293B2 (en) 2003-07-02 2007-08-28 Corus Pharma Aztreonam L-lysine and methods for the preparation thereof
US7601832B2 (en) 2005-05-09 2009-10-13 Sicor, Inc. Process for making aztreonam
US7939519B2 (en) 2003-05-19 2011-05-10 Novartis Ag Immunosuppresant compounds and compositions
CN113876722A (en) * 2021-11-04 2022-01-04 海南皇隆制药股份有限公司 Aztreonam for injection and preparation method thereof

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101412715B (en) * 2008-12-16 2010-04-14 海南百那医药发展有限公司 Aztreonam compound and preparation thereof
CN101579336B (en) * 2009-07-07 2010-06-23 重庆市庆余堂制药有限公司 Aztreonam for injection and production method thereof
CN101830895B (en) * 2010-04-16 2012-04-04 海南新中正制药有限公司 Preparation method of aztreonam anhydrous crystal compound
CN102351855A (en) * 2011-08-12 2012-02-15 山西仟源制药股份有限公司 Production method of beta-crystal form aztreonam aseptic raw drug
CN103232449B (en) * 2013-05-08 2014-04-09 四川省惠达药业有限公司 Aztreonam compound, as well as preparation method and pharmaceutical composition thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0070024A1 (en) * 1981-07-13 1983-01-19 E.R. Squibb &amp; Sons, Inc. The crystalline anhydrous form of (3S-(3 alpha(z),4 beta))-3-(((2-amino-4-thiazolyl)(1-carboxy-1-methylethoxy)-imino)-acetyl)-amino)-4-methyl-2-oxo-1-azetidinesulfonic acid, method for its preparation, mixture and pharmaceutical composition containing it
US4826973A (en) * 1984-07-20 1989-05-02 E. R. Squibb & Sons, Inc. Delta form of aztreonam and preparation thereof
US4946838A (en) * 1981-07-13 1990-08-07 E. R. Squibb & Sons, Inc. Crystalline anhydrous aztreonam

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0070024A1 (en) * 1981-07-13 1983-01-19 E.R. Squibb &amp; Sons, Inc. The crystalline anhydrous form of (3S-(3 alpha(z),4 beta))-3-(((2-amino-4-thiazolyl)(1-carboxy-1-methylethoxy)-imino)-acetyl)-amino)-4-methyl-2-oxo-1-azetidinesulfonic acid, method for its preparation, mixture and pharmaceutical composition containing it
US4946838A (en) * 1981-07-13 1990-08-07 E. R. Squibb & Sons, Inc. Crystalline anhydrous aztreonam
US4826973A (en) * 1984-07-20 1989-05-02 E. R. Squibb & Sons, Inc. Delta form of aztreonam and preparation thereof

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7145017B2 (en) 2002-08-05 2006-12-05 TEVA Gyógyszergyár Zártkörűen Működő Részvénytársaság Preparation of Aztreonam
WO2004103999A1 (en) * 2003-05-15 2004-12-02 TEVA Gyógyszergyár Részvénytársaság AZTREONAM β POLYMORPH WITH VERY LOW RESIDUAL SOLVENT CONTENT
US7452991B2 (en) 2003-05-15 2008-11-18 Teva Gyógyszergyár Zártkörüen Müködö Részvénytársaság Aztreonam β polymorph with very low residual solvent content
US7939519B2 (en) 2003-05-19 2011-05-10 Novartis Ag Immunosuppresant compounds and compositions
US7262293B2 (en) 2003-07-02 2007-08-28 Corus Pharma Aztreonam L-lysine and methods for the preparation thereof
US7601832B2 (en) 2005-05-09 2009-10-13 Sicor, Inc. Process for making aztreonam
CN113876722A (en) * 2021-11-04 2022-01-04 海南皇隆制药股份有限公司 Aztreonam for injection and preparation method thereof
CN113876722B (en) * 2021-11-04 2022-12-02 海南皇隆制药股份有限公司 Aztreonam for injection and preparation method thereof

Also Published As

Publication number Publication date
CN1545514A (en) 2004-11-10

Similar Documents

Publication Publication Date Title
CA2418614C (en) Phosphonocephem compound
US20070244315A1 (en) Process for the preparation of cefdinir
US20100099685A1 (en) Crystalline forms of (6r)-l-erythro-tetrahydrobiopterin dihydrochloride
RU2732129C2 (en) Method of producing crystals of a diazabicyclooctane derivative and a stable lyophilized preparation
WO2003018578A1 (en) Method for producing beta form of crystalline anhydrous aztreonam
HU195778B (en) Process for producing stabil modifications of torasemid and pharmaceutical compositions containing them
US20050080255A1 (en) Crystalline cefdinir potassium dihydrate
IE56488B1 (en) Crystalline cephem-acid addition salts and process for their preparation
EP0070024A1 (en) The crystalline anhydrous form of (3S-(3 alpha(z),4 beta))-3-(((2-amino-4-thiazolyl)(1-carboxy-1-methylethoxy)-imino)-acetyl)-amino)-4-methyl-2-oxo-1-azetidinesulfonic acid, method for its preparation, mixture and pharmaceutical composition containing it
US4067867A (en) Process for preparing pyrazine precursor of methotrexate or an N-substituted derivative thereof and/or a di(lower)alkyl ester thereof
EP3947393B1 (en) Process for the preparation of midostaurin with high purity
US20020193587A1 (en) Penicillin crystal and process for producing the same
WO2005090360A1 (en) Novel polymorph of cefdinir
AU2006300882A1 (en) Crystalline sodium salt of cephalosporin antibiotic
CN112469717A (en) Process for purifying isaconazole onium sulphate
JPH11501023A (en) Clavulanate
US6861412B2 (en) Diphosphate salt of A 4″-substituted-9-deoxo-9A-AZA-9A-homoerythromycin derivative and its pharmaceutical composition
IE64076B1 (en) Crystalline cephem acid addition salts and processes for their preparation
US11542279B2 (en) Solid forms of ceftolozane and processes for preparing
EP1828208A2 (en) Crystalline form of cefdinir cesium salt
HU204271B (en) Process for producing cristalline 1-carba-dethia-cepheme-solvates
JP2954956B2 (en) Crystal (5R, 6S) -2-carbamoyloxymethyl-6-[(1R) -hydroxyethyl] -2-penem-carboxylic acid and pharmaceutical formulations thereof
IE49703B1 (en) Oxa-beta-lactam derivative
KR20040069957A (en) Crystalline polymorph of nafamostat mesilate and method for preparing the same
WO2006010978A1 (en) Cefdinir polymorphic forms, and imidazole salt

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EE ES FI GB GD GE GH GM HU ID IL IN IS JP KE KG KP KR KZ LK LR LS LT LU LV MA MD MG MK MW MX MZ NO NZ OM PH PL PT RO SD SE SG SI SK SL TJ TM TN TR TT UA UG US UZ VN YU ZA ZM

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW

WWE Wipo information: entry into national phase

Ref document number: 20028163427

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP