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LYOPHILIZED PHARMACEUTICAL COMPOSITIONS OF ERTAPENEM

IP.com Disclosure Number: IPCOM000242939D
Publication Date: 2015-Sep-01
Document File: 9 page(s) / 106K

Publishing Venue

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Abstract

The present disclosure relates to lyophilized pharmaceutical compositions of ertapenem comprising: (i) ertapenem sodium having a water content of about 10% to 16% w/w and an organic solvent content of about 1% to 10% w/w; (ii) a carbon dioxide source; and (iii) a pH-adjusting agent. Said lyophilized pharmaceutical compositions have a low level of dimer impurities. It also relates to a process for the preparation of said lyophilized pharmaceutical compositions.

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LYOPHILIZED PHARMACEUTICAL COMPOSITIONS OF ERTAPENEM

Abstract

            The present disclosure relates to lyophilized pharmaceutical compositions of ertapenem comprising: (i) ertapenem sodium having a water content of about 10% to 16% w/w and an organic solvent content of about 1% to 10% w/w; (ii) a carbon dioxide source; and (iii) a pH-adjusting agent.  Said lyophilized pharmaceutical compositions have a low level of dimer impurities.  It also relates to a process for the preparation of said lyophilized pharmaceutical compositions.

            Ertapenem is a carbapenem antibiotic and is widely used for the treatment of moderate to severe infections caused by a broad range of pathogens including multi-drug resistant bacteria.  Ertapenem sodium is chemically described as a monosodium salt of [4R-[3(3S*,5S*),4α,5β,6β(R*)]]-3-[[5-[[(3-carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid represented by Formula I.

Formula I

            Reported in US 5,652,233 is ertapenem sodium of Formula I and processes for its preparation.  

            Reported in US 5,952,323 is ertapenem carbamate, a stabilized form of ertapenem represented by Formula II, and a process for preparation of ertapenem carbamate in a pharmaceutical composition using a suitable amount of a carbon dioxide source and a pH adjusting agent.  

Formula II

            Reported in US 6,548,492 is a detailed process which involves conversion of unstabilized ertapenem sodium to a stabilized ertapenem carbamate in a lyophilized pharmaceutical composition with an acceptable level of degradation impurities. The lyophilized pharmaceutical composition obtained by this process has a purity of only about 95%, and it contains about 1.5%-2.5% w/w of the dimer impurities.

            Further, reported in J. Liq. Chrom. & Rel. Technol., 24(19), 2999-3015 (2001) is the preparation, isolation, and characterization data of the dimer impurities of ertapenem sodium, which are herein represented by Formula III, Formula IV, and Formula V.

Formula III

Formula IV

Formula V

            Provided herein is a lyophilized pharmaceutical composition of ertapenem which comprises:

(i)     ertapenem sodium having a water content of about 10% to 16% w/w and an organic solvent content of about 1% to 10% w/w;

(ii)   a carbon dioxide source; and

(iii)  a pH-adjusting agent;

wherein the lyophilized pharmaceutical composition has a total dimer impurity level of Formula III, Formula IV, and Formula V of not more than about 1.2% w/w.

            The ertapenem sodium having a water content of about 10% to 16% w/w and an organic solvent content of about 1% to 10% w/w is prepared by a process consisting the steps of:

(i)   treating an aqueous solution of ertapenem sodium with an alcohol solvent;

(ii) isolating ertapenem sodium from solution of step (i); and

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