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WO2012066492A1 - Méthodes de préparation d'une composition antibiotique de carbapénème - Google Patents

Méthodes de préparation d'une composition antibiotique de carbapénème Download PDF

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Publication number
WO2012066492A1
WO2012066492A1 PCT/IB2011/055139 IB2011055139W WO2012066492A1 WO 2012066492 A1 WO2012066492 A1 WO 2012066492A1 IB 2011055139 W IB2011055139 W IB 2011055139W WO 2012066492 A1 WO2012066492 A1 WO 2012066492A1
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WO
WIPO (PCT)
Prior art keywords
formula
solution
carbon dioxide
dioxide source
composition
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/IB2011/055139
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English (en)
Inventor
Bhaskar Chauhan
Jyoti Srivastava
Vinod Kumar Arora
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories 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 Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2012066492A1 publication Critical patent/WO2012066492A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D477/00—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring
    • C07D477/02—Preparation
    • C07D477/06—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents

Definitions

  • the present invention relates to processes for the preparation of carbapenem antibiotic compositions.
  • Carbapenem antibiotics are widely used in treating infections caused by a broad range of pathogens includ ing multi-drug-resistant bacteria.
  • Ertapenem sodium is a carbapenem antibiotic, which is chemically 4i--[3(3S*,5S*),4a,5p,6p(i-*)]]-3-[[5-[[(3- carboxyphenyl)amino]carbonyl]-3-pyrrolidinyl]thio]-6-(l-hydroxyethyl)-4-methyl-7-oxo- 1- azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt of Formula I.
  • U.S. Patent No. 7,022,841 provides a process for preparing ertapenem sodium of Formula I as crystalline Form A, Form B and Form C.
  • U.S. Patent No. 7,022,841 also provides a process for reducing residual solvents from Form A, Form B and Form C by sweeping nitrogen through the wet solid at low temperature conditions and by employing agitated filter dryers.
  • U.S. Patent No. 6,548,492 discloses that ertapenem sodium of Formula I is sensitive to temperature and pH fluctuations and remains unstable at temperatures above about -20°C.
  • U.S. Patent No. 6,548,492 further discloses that ertapenem sodium undergoes dimerization and hydrolysis to form undesirable dimers and ring-opened compounds above about -20°C.
  • J Liq. Chrom. & Rel. Technol, 24(19), p. 2999-3015 (2001) provides for the preparation, isolation and associated characterization data of the degradation impurities of ertapenem sodium.
  • U.S. Patent No. 6,548,492 describes a vial lyophilization process for the preparation of a pharmaceutical composition that includes a compound of Formula II or its salts. According to said process, a sterile aqueous solution containing the compound of Formula II or its salts is prepared, filled in vials, lyophilized under specific lyophilization conditions, and the vials are removed as final formulation.
  • the initial sterile aqueous solution containing the compound of Formula II or its salts is prepared by adding an effective amount of a molar ratio of ertapenem sodium of Formula I and a base into a reaction vessel containing the aqueous solution of a carbon dioxide source; maintaining a pH of about 6.0 to about 9.0 and a temperature range of about -3°C to about 15°C.
  • the lyophilized product obtained according to the process described in U.S. Patent No. 6,548,492 has a purity of only about 95% and contains more than 2% of ring opening impurities. Further, dimer impurities are present in the lyophilized product in a range of 1.5% to 1.6% in a lab scale batch and increases to more than 2% at the pilot plant scale batch level.
  • WO 2009/150630 describes a tray lyophilization process of a sterile aqueous solution containing the compound of Formula II, or its salts.
  • the tray lyophilization method described provides a process to obtain the carbapenem antibiotic composition with increased purity levels.
  • the initial sterile aqueous solution containing the compound of Formula II or its salts is prepared by simultaneous addition of ertapenem sodium of Formula I and a base into a reaction vessel containing the aqueous solution of carbon dioxide source.
  • a composition that includes the compound of Formula II or its salts can be prepared with total impurity content less than about 3.5% w/w and any individual impurity content less than about 2% w/w by modifying the sequence of addition of ertapenem sodium of Formula I, the carbon dioxide source and the base while preparing the aqueous solution containing the compound of Formula II or its salts.
  • the present process provides a way to achieve improved purity levels even with vial lyophilization in comparison with the purity levels reported in the prior art for vial lyophilization.
  • the present process is suitable for preparing the composition comprising the compound of Formula II or its salts at industrial scale.
  • the salts of the compound of Formula II for example, alkali metal salts, according to the present invention may exist in various ionization states and their combinations, depending on the carbon dioxide source and the base used for preparing the composition.
  • the compounds of Formula Ha through Ilg are examples of the alkali metal salt forms of the compound of Formula II.
  • X is an alkali metal, for example, sodium or potassium.
  • the present invention provides a process for the preparation of a composition comprising the compound of Formula II, or its salts;
  • step b) treating the solution obtained in step a) with a base while maintaining the pH at about 6.5 to about 8.5;
  • step b) lyophilizing the solution obtained in step b) in a lyophilizer to obtain a
  • composition comprising the compound of Formula II or its salts.
  • the ertapenem sodium of Formula I used as the starting material may be prepared according to the methods provided in WO 2009/150630. A mixture of ertapenem sodium of Formula I and the carbon dioxide source is added to water into a compounder or water is added to a mixture of ertapenem sodium of Formula I and a carbon dioxide source into a compounder to obtain a solution.
  • the compounder may be a vessel, for example, a stainless steel jacketed vessel.
  • the addition may be carried out at a temperature range of about -5°C to about 15°C, for example, about 0°C to about 10°C.
  • the carbon dioxide source may be selected from the group of alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal carbonates and alkaline earth metal bicarbonates.
  • the carbon dioxide source may be, for example, sodium bicarbonate or sodium carbonate.
  • the mixture of ertapenem sodium of Formula I and carbon dioxide source may be a solid or a semisolid mixture.
  • the water may be United States Pharmacopeia (USP).
  • USP United States Pharmacopeia
  • the water may be used in a quantity sufficient to dissolve ertapenem sodium of Formula I and the carbon dioxide source.
  • the dissolution may be facilitated by stirring.
  • the solution so obtained is treated
  • the treatment with base may be carried out at a temperature range of about -5°C to about 15°C, for example, about 0°C to about 10°C.
  • the base may be an inorganic base or an organic base.
  • the base may be selected from a group of alkali hydrides, alkali hydroxides, alkaline hydroxides, alkali carbonates and amines.
  • the base may be, for example, sodium hydroxide.
  • the volume of the solution may optionally be increased to a specified batch size or volume with further addition of water.
  • the solution so obtained is optionally filtered through an about 0.2 micron membrane filter to obtain a sterile solution.
  • the solution is subsequently lyophilized in a lyophilizer.
  • the lyophilization method may be vial lyophilization or tray lyophilization.
  • vial lyophilization a suitable quantity of the solution that includes the compound of Formula II or its salts so obtained is filled in the vials and partially sealed.
  • tray lyophilization the solution that includes the compound of Formula II or its salts is transferred to a lyophilization tray.
  • Conventional lyophilization trays including steel, aluminum, glass, plastic or Lyoguard® trays may be employed. Total mass and tray thickness may be suitably optimized.
  • the lyophilization process may be carried out by freezing the solution that includes the compound of Formula II or its salts at a temperature of about -40°C or below, for example, about -50°C to about -45°C to obtain a frozen composition.
  • the primary drying of the frozen composition may be carried out at a temperature of about -35°C to about 0°C for up to about 60 hours.
  • the secondary drying may be carried out at a temperature of about 10°C to about 65°C.
  • the secondary drying may be carried out for up to about 40 hours.
  • the entire drying process may be carried out under pressure of up to about 150 mTorr, for example, about 75 mTorr to about 150 mTorr.
  • the lyophilized composition that includes the compound of Formula II or its salts so obtained has total impurity content less than about 3.5% w/w and any individual impurity content less than about 2% w/w.
  • the lyophilized composition that includes the compound of Formula II or its salts is unloaded from the lyophilizer.
  • the vials containing the composition so obtained may be completely sealed under a partial vacuum after lyophilization.
  • the composition so obtained may be packed suitably in containers including, for example, vials.
  • the present invention also provides for a process for the preparation of a composition that includes the compound of Formula II, or its salts;
  • step b) lyophilizing the solution obtained in step b) in a lyophilizer to obtain a
  • composition comprising the compound of Formula II or its salts.
  • the ertapenem sodium of Formula I used as the starting material may be prepared according to the methods provided in WO 2009/150630.
  • the ertapenem sodium of Formula I, a carbon dioxide source and water are added simultaneously or in optional order of succession, including simultaneous addition of any two of ertapenem sodium of Formula I, a carbon dioxide source and water, into a compounder to obtain a solution; or a solution of ertapenem sodium of Formula I and a carbon dioxide source are added simultaneously or in optional order of succession into a compounder to obtain a solution; or ertapenem sodium of Formula I and a solution of carbon dioxide source in water are added simultaneously or in optional order of succession into a compounder to obtain a solution; with the proviso that ertapenem sodium of Formula I is not added into a compounder which contains only an aqueous solution of a carbon dioxide source.
  • the compounder may be a vessel, for example, a stainless steel jacketed vessel.
  • the addition may be carried out at a temperature range of about -5°C to about 15°C, for example, about 0°C to about 10°C.
  • the carbon dioxide source may be selected from the group of alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal carbonates and alkaline earth metal bicarbonates.
  • the carbon dioxide source may be, for example, sodium bicarbonate or sodium carbonate.
  • the water may be water for injection, United States Pharmacopeia (USP).
  • USP United States Pharmacopeia
  • the water may be used in a quantity sufficient to dissolve ertapenem sodium of Formula I and the carbon dioxide source.
  • the dissolution may be facilitated by stirring.
  • the solution so obtained is treated with a base while maintaining a pH at about 6.5 to about 8.5.
  • the pH may be maintained, for example, between about 7.4 to about 7.7 during said treatment.
  • the pH may be maintained in said range, for example, by a sequential addition of the base as an aqueous solution.
  • the treatment with base may be carried out at a temperature range of about -5°C to about 15°C, for example, about 0°C to about 10°C.
  • the base may be an inorganic base or an organic base.
  • the base may be selected from the group of alkali hydrides, alkali hydroxides, alkaline hydroxides, alkali carbonates and amines.
  • the base may be, for example, sodium hydroxide.
  • the volume of the solution may optionally be increased to a specified batch size or volume with further addition of water.
  • the solution so obtained is optionally filtered through an about 0.2 micron membrane filter to obtain a sterile solution.
  • the solution is subsequently lyophilized in a lyophilizer.
  • the lyophilization method may be vial lyophilization or tray lyophilization.
  • vial lyophilization a suitable quantity of the solution that includes the compound of Formula II or its salts so obtained is filled in the vials and partially sealed.
  • tray lyophilization the solution that includes the compound of Formula II or its salts is transferred to a
  • lyophilization tray Conventional lyophilization trays including steel, aluminum, glass, plastic or Lyoguard® trays may be employed. Total mass and tray thickness may be suitably optimized.
  • the lyophilization process may be carried out by freezing the solution that includes the compound of Formula II or its salts at a temperature of about -40°C or below, for example, about -50°C to about -45°C to obtain a frozen composition.
  • the primary drying of the frozen composition may be carried out at a temperature of about -35°C to about 0°C for up to about 60 hours.
  • the secondary drying may be carried out at a temperature of about 10°C to about 65°C.
  • the secondary drying may be carried out for up to about 40 hours.
  • the entire drying process may be carried out under pressure of up to about 150 mTorr, for example, about 75 mTorr to about 150 mTorr.
  • the lyophilized composition that includes the compound of Formula II or its salts so obtained has total impurity content less than about 3.5% w/w and any individual impurity content less than about 2% w/w.
  • the lyophilized composition that includes the compound of Formula II or its salts is unloaded from the lyophilizer.
  • vial lyophilization the vials containing the composition so obtained may be completely sealed under a partial vacuum after lyophilization.
  • the composition so obtained may be packed suitably in containers including, for example, vials.
  • the present invention also provides a process for the preparation of a composition comprising the compound of Formula II or its salts;
  • step b) optionally adjusting the pH of the solution obtained in step a) to about 6.5 to about 8.5;
  • step b) lyophilizing the solution obtained in step b) in a lyophilizer to obtain a composition comprising the compound of Formula II, or its salts.
  • the ertapenem sodium of Formula I used as the starting material may be prepared according to the methods provided in WO 2009/150630.
  • the ertapenem sodium of Formula I or its solution in water, a carbon dioxide source or its solution in water and an aqueous base are added simultaneously or in optional order of succession, including simultaneous addition of any two of ertapenem sod ium of Formula I or its solution in water, a carbon dioxide source or its solution in water, and water, into a compounder to obtain a solution with the proviso that ertapenem sodium of Formula I is not added into a compounder which contains only an aqueous solution of a carbon dioxide source.
  • the compounder may be a vessel, for example, a stainless steel jacketed vessel.
  • the addition may be carried out at a temperature range of about -5°C to about 15°C, for example, about 0°C to about 10°C.
  • the carbon dioxide source may be selected from the group of alkali metal carbonates, alkali metal bicarbonates, alkaline earth metal carbonates and alkaline earth metal bicarbonates.
  • the carbon dioxide source may be sodium bicarbonate or sodium carbonate.
  • the base may be an inorganic base or an organic base.
  • the base may be selected from the group of alkali hydrides, alkali hydroxides, alkaline hydroxides, alkali carbonates and amines.
  • the base may be sodium hydroxide.
  • the aqueous solution of the base may be prepared by treating the base with water.
  • the water may be water for injection, United States Pharmacopeia (USP).
  • USP United States Pharmacopeia
  • the water may be used in a quantity sufficient to dissolve ertapenem sodium of Formula I, the carbon dioxide source and the base.
  • the dissolution may be facilitated by stirring.
  • the pH of the solution so obtained may be optionally adjusted to a pH at about 6.5 to about 8.5.
  • the pH may be adjusted, for example, between about 7.4 to about 7.7.
  • the pH may be adjusted to said range, for example, by the addition of a base or an acid depending on the initial pH.
  • the pH adjustment may be carried out at a temperature range of about -5°C to about 15°C, for example, about 0°C to about 10°C.
  • the volume of the solution may optionally be increased to a specified batch size or volume with further addition of water.
  • the solution so obtained is optionally filtered through an about 0.2 micron membrane filter to obtain a sterile solution.
  • the solution is subsequently lyophilized in a lyophilizer.
  • the lyophilization method may be vial lyophilization or tray lyophilization.
  • vial lyophilization a suitable quantity of the solution that includes the compound of Formula II or its salts so obtained is filled in the vials and partially sealed.
  • tray lyophilization the solution that includes the compound of Formula II or its salts is transferred to a
  • lyophilization tray Conventional lyophilization trays including steel, aluminum, glass, plastic or Lyoguard® trays may be employed. Total mass and tray thickness may be suitably optimized.
  • the lyophilization process may be carried out by freezing the solution that includes the compound of Formula II or its salts at a temperature of about -40°C or below, for example, about -50° to about -45°C, to obtain a frozen composition.
  • the primary drying of the frozen composition may be carried out at a temperature of about -35°C to about 0°C for up to about 60 hours.
  • the secondary drying may be carried out at a temperature of about 10°C to about 65°C.
  • the secondary drying may be carried out for up to about 40 hours.
  • the entire drying process may be carried out under pressure of up to about 150 mTorr, for example, about 50 mTorr to about 150 mTorr.
  • the lyophilized composition that includes the compound of Formula II or its salts so obtained has total impurity content less than about 3.5% w/w and any individual impurity content less than about 2% w/w.
  • the lyophilized composition that includes the compound of Formula II or its salts is unloaded from the lyophilizer.
  • the vials containing the composition so obtained may be completely sealed under a partial vacuum after lyophilization.
  • the composition so obtained may be packed suitably in containers including, for example, vials.
  • Example 1 Preparation of a Carbapenem Antibiotic Composition
  • the vials were sealed under vacuum (50 mmHg) at a temperature of 25°C.
  • the vials were sealed under vacuum (50 mmHg) at a temperature of 25°C.
  • the vials were sealed under vacuum (50 mmHg) at a temperature of 25°C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des méthodes de préparation de compositions antibiotiques de carbapénème, qui consistent à préparer le composé de formule II à partir d'un composé de formule I. Elle concerne également une composition comprenant le composé de formule II.
PCT/IB2011/055139 2010-11-16 2011-11-16 Méthodes de préparation d'une composition antibiotique de carbapénème Ceased WO2012066492A1 (fr)

Applications Claiming Priority (2)

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IN2724DE2010 2010-11-16
IN2724/DEL/2010 2010-11-16

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104739780A (zh) * 2013-12-31 2015-07-01 石药集团中奇制药技术（石家庄）有限公司 一种厄他培南钠药物组合物及其制备方法
CN104739828A (zh) * 2013-12-31 2015-07-01 石药集团中奇制药技术（石家庄）有限公司 一种厄他培南钠药物组合物及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5952323A (en) * 1996-05-28 1999-09-14 Merck & Co., Inc. Carbapenem antibiotic
US6548492B1 (en) * 1999-10-29 2003-04-15 Merck & Co., Inc. Process for formulation of carbapenem antibiotic compositions
WO2009150630A2 (fr) * 2008-06-11 2009-12-17 Ranbaxy Laboratories Limited Procédé de préparation d'une composition antibiotique à base de carbapénème

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5952323A (en) * 1996-05-28 1999-09-14 Merck & Co., Inc. Carbapenem antibiotic
US6548492B1 (en) * 1999-10-29 2003-04-15 Merck & Co., Inc. Process for formulation of carbapenem antibiotic compositions
WO2009150630A2 (fr) * 2008-06-11 2009-12-17 Ranbaxy Laboratories Limited Procédé de préparation d'une composition antibiotique à base de carbapénème

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
WILLIAMS J M ET AL: "Practical Synthesis of the New Carbapenem Antibiotic Ertapenem Sodium", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, EASTON.; US, vol. 70, no. 19, 16 September 2005 (2005-09-16), pages 7479 - 7487, XP002591997, ISSN: 0022-3263, [retrieved on 20050813], DOI: 10.1021/JO0501442 *
WILLIAMS J M ET AL: "Supporting Information. Practical Synthesis of the New Carbapenem Antibiotic Ertapenem Sodium", JOURNAL OF ORGANIC CHEMISTRY, AMERICAN CHEMICAL SOCIETY, EASTON.; US, vol. 70, no. 19, 16 September 2005 (2005-09-16), pages S1-S4, ISSN: 0022-3263, [retrieved on 20050813], DOI: 10.1021/JO0501442 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104739780A (zh) * 2013-12-31 2015-07-01 石药集团中奇制药技术（石家庄）有限公司 一种厄他培南钠药物组合物及其制备方法
CN104739828A (zh) * 2013-12-31 2015-07-01 石药集团中奇制药技术（石家庄）有限公司 一种厄他培南钠药物组合物及其制备方法
CN109134469A (zh) * 2013-12-31 2019-01-04 石药集团中奇制药技术（石家庄）有限公司 一种厄他培南钠药物组合物及其制备方法
CN109134469B (zh) * 2013-12-31 2021-10-26 石药集团中奇制药技术（石家庄）有限公司 一种厄他培南钠药物组合物及其制备方法

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