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WO2012066492A1 - Processes for the preparation of carbapenem antibiotic composition - Google Patents

Processes for the preparation of carbapenem antibiotic composition 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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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.)
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PCT/IB2011/055139
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French (fr)
Inventor
Bhaskar Chauhan
Jyoti Srivastava
Vinod Kumar Arora
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Ranbaxy Laboratories Ltd
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Ranbaxy Laboratories Ltd
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Publication of WO2012066492A1 publication Critical patent/WO2012066492A1/en
Anticipated expiration legal-status Critical
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    • 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

The present invention relates to processes for the preparation of carbapenem antibiotic compositions, involving the preparation of the compound of formula II from a compound of formula I and a composition comprising the compound of formula II. (I) (II).

Description

PROCESSES FOR THE PREPARATION OF CARBAPENEM ANTIBIOTIC
COMPOSITION
Field of the Invention
The present invention relates to processes for the preparation of carbapenem antibiotic compositions.
Background of the Invention
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.
Figure imgf000003_0001
FORMULA I
Processes for the preparation of ertapenem sodium are provided in U.S. Patent No. 5,652,233 and J Org. Chem., 70, p. 7479-7487 (2005). 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.
As stated in U.S. Patent No. 5,952,323, when ertapenem or its sodium salts are formulated in a pharmaceutical composition with a suitable amount of sodium carbonate or sodium bicarbonate, the compound of Formula II or sodium salts are formed upon dilution or reconstitution.
Figure imgf000004_0001
FORMULA II
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.
However, 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.
Summary of the Invention
The present inventors have found that 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.
Figure imgf000005_0001
FORMULA Ila
Figure imgf000006_0001
COO
(X+)2
FORMULA lie
Figure imgf000006_0002
FORMULA He
Figure imgf000007_0001
FORMULA Ilf
Figure imgf000007_0002
FORMULA Ilg
wherein X is an alkali metal, for example, sodium or potassium.
Detailed Description of the Invention
The present invention provides a process for the preparation of a composition comprising the compound of Formula II, or its salts;
Figure imgf000007_0003
FORMULA II
wherein the process includes:
a) adding a mixture of ertapenem sodium of Formula I and a carbon dioxide source to water into a compounder or adding water to a mixture of ertapenem sodium of Formula I and a carbon dioxide source into a compounder to obtain a solution;
FORMULA I
b) treating the solution obtained in step a) with a base while maintaining the pH at about 6.5 to about 8.5; and
c) 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). 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 between about 7.4 to about 7.7 during said treatment. The pH may be maintained in said range 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 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. In case of 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. In case of 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.
In case of vial lyophilization, the vials containing the composition so obtained may be completely sealed under a partial vacuum after lyophilization. In case of tray 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;
Figure imgf000010_0001
FORMULA II
wherein the process includes:
a) adding ertapenem sodium of Formula I, a carbon dioxide source, and water simultaneously or in optional order of succession into a compounder to obtain a solution;
adding a solution of ertapenem sodium of Formula I in water and a carbon dioxide source simultaneously or in optional order of succession into a compounder to obtain a solution; or
adding ertapenem sodium of Formula I and a solution of carbon dioxide source in water 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.
Figure imgf000010_0002
FORMULA I b) treating the solution obtained in step a) with a base while maintaining a pH at about 6.5 to about 8.5; and
c) 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). 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. In case of 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. In case of 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. In case of vial lyophilization, the vials containing the composition so obtained may be completely sealed under a partial vacuum after lyophilization. In case of tray 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;
Figure imgf000013_0001
FORMULA II
wherein the process includes:
a) adding ertapenem sodium of Formula I or its solution in water, a carbon dioxide source or its solution in water, and an aqueous base 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;
Figure imgf000013_0002
FORMULA I
b) optionally adjusting the pH of the solution obtained in step a) to about 6.5 to about 8.5; and
c) 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). 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. In the case of 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. In case of 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.
In case of vial lyophilization, the vials containing the composition so obtained may be completely sealed under a partial vacuum after lyophilization. In case of tray lyophilization, the composition so obtained may be packed suitably in containers including, for example, vials.
While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLES
Example 1 : Preparation of a Carbapenem Antibiotic Composition
Water for injection, USP (400 mL) was cooled to 2°C to 8°C in a stainless steel jacketed vessel (2 L) and nitrogen was purged continuously into the vessel. A solid mixture of ertapenem sodium (135.2 g) and sodium bicarbonate (17.5 g) was added into the vessel and stirred until a clear solution was obtained. The pH of the solution was adjusted to 7.5 with sodium hydroxide solution (5.0% w/v, 5 ml). Water for injection, USP (40 mL) was added to the solution to attain a batch volume of 600 mL and filtered through a 0.2 micron membrane filter. The filtered solution (6 mL) was filled into individual glass vials (100 vials of 23 mL capacity). The glass vials were partially sealed with dry stoppers and lyophilized according to the conditions provided below:
Figure imgf000016_0001
The vials were sealed under vacuum (50 mmHg) at a temperature of 25°C.
Moisture content: 1.25% w/w
Assay: 1105.27 mg/vial
Total impurity content: 2.985% w/w
Any individual impurity (highest): 1.794% w/w
Example 2: Preparation of a Carbapenem Antibiotic Composition
Water for injection, USP (400 mL) was cooled to 2°C to 8°C in a stainless steel jacketed vessel (2 L) and nitrogen was purged continuously into the vessel. A solid ertapenem sodium (135.2 g) was added into the vessel and stirred until a clear solution was obtained. Sodium bicarbonate (17.5 g) was added to the vessel and stirred until a clear solution was obtained. The pH of the solution was adjusted to 7.5 with sodium hydroxide solution (5.0% w/v, 5 mL). Water for injection, USP (40 mL) was added to the solution to attain a batch volume of 600 mL and filtered through a 0.2 micron membrane filter. The filtered solution (6 mL) was filled into individual glass vials (100 vials of 23 mL). The glass vials were partially sealed with dry stoppers and lyophilized according to the conditions provided below:
Figure imgf000017_0001
The vials were sealed under vacuum (50 mmHg) at a temperature of 25°C.
Moisture content: 1.28% w/w
Assay: 1151.23 mg/vial
Total impurity content: 3.140%) w/w
Any individual impurity (highest): 1.681% w/w
Example 3: Preparation of a Carbapenem Antibiotic Composition
Water for injection, USP (400 mL) was cooled to 2°C to 8°C in a stainless steel jacketed vessel (2 L) and nitrogen was purged continuously into the vessel. Sodium hydroxide (5.0% w/v) and solid ertapenem sodium (135.2 g) were added into the vessel and stirred until a clear solution was obtained. The sodium bicarbonate (17.5 g) was added to the vessel and stirred until a clear solution was obtained. The pH of the solution was adjusted to 7.5 with sodium hydroxide solution (5.0% w/v). Water for injection, USP (40 mL) was added to the solution to attain a batch volume of 600 mL and filtered through a 0.2 micron membrane filter. The filtered solution (6 mL) was filled into individual glass vials (100 vials of 23 mL). The glass vials were partially sealed with dry stoppers and lyophilized according to the conditions provided below:
Figure imgf000018_0001
The vials were sealed under vacuum (50 mmHg) at a temperature of 25°C.
Moisture content: 1.5% w/w
Assay: 1112.53 mg/vial
Total impurity content: 3.012% w/w
Any individual impurity (highest): 1.756% w/w

Claims

We Claim:
1. A process for the preparation of a composition comprising the compound of
Formula II or its salts;
Figure imgf000019_0001
FORMULA II
wherein the process comprises: a) adding a mixture of ertapenem sodium of Formula I and a carbon dioxide source to water into a compounder or adding water to a mixture of ertapenem sodium of Formula I and a carbon dioxide source into a compounder to obtain a solution;
Figure imgf000019_0002
FORMULA I
b) treating the solution obtained in step a) with a base while maintaining a pH at about 6.5 to about 8.5; and
c) lyophilizing the solution obtained in step b) in a lyophilizer to obtain a
composition comprising the compound of Formula II, or its salts.
2. A process for the preparation of a composition comprising the compound of
Formula II or its salts;
Figure imgf000020_0001
FORMULA II
the process comprises:
a) adding ertapenem sodium of Formula I, a carbon dioxide source, and water simultaneously or in optional order of succession into a compounder to obtain a solution; adding a solution of ertapenem sodium of Formula I in water and a carbon dioxide source simultaneously or in optional order of succession into a compounder to obtain a solution; or adding ertapenem sodium of Formula I and a solution of carbon dioxide source in water 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;
Figure imgf000020_0002
FORMULA I
b) treating the solution obtained in step a) with a base while maintaining a pH at about 6.5 to about 8.5; and c) lyophilizing the solution obtained in step b) in a lyophilizer to obtain a
composition comprising the compound of Formula II, or its salts.
A process for the preparation of a composition comprising the compound of Formula II, or its salts;
Figure imgf000021_0001
FORMULA II
wherein the process comprises:
a) adding ertapenem sodium of Formula I or its solution in water, a carbon dioxide source or its solution in water, and an aqueous base 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;
Figure imgf000021_0002
FORMULA I
b) optionally adjusting the pH of the solution obtained in step a) to about 6.5 to about 8.5; and
c) lyophilizing the solution obtained in step b) in a lyophilizer to obtain a composition comprising the compound of Formula II, or its salts.
4. A process according to claims 1, 2 or 3, wherein step a) is carried out at a
temperature range of about -5°C to about 15°C.
A process according to claims 1, 2 or 3, wherein the carbon dioxide source comprises sodium bicarbonate or sodium carbonate.
6. A process according to claims 1 , 2 or 3, wherein step b) is carried out at a temperature of about -5 °C to about 15°C.
7. A process according to claims 1, 2 or 3, wherein the base comprises sodium hydroxide.
8. The lyophilized composition of claims 1, 2 or 3 has total impurity content less than about 3.5% w/w and any individual impurity content less than about 2% w/w.
PCT/IB2011/055139 2010-11-16 2011-11-16 Processes for the preparation of carbapenem antibiotic composition Ceased WO2012066492A1 (en)

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