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Process for formulation of antibiotic compounds

A compound and solvate technology, applied in the field of carbapenem antibiotic compositions, can solve the problem of not providing a stable form of carbon dioxide adduct and the like

Inactive Publication Date: 2008-04-30
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Zimmerman et al. (USP 5,952,323) describe a method of stabilizing carbapenem compounds by adding a source of carbon dioxide, but there is also no information on how to obtain a stable form of the carbon dioxide adduct in their final composition

Method used

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  • Process for formulation of antibiotic compounds
  • Process for formulation of antibiotic compounds
  • Process for formulation of antibiotic compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0195] At room temperature and normal pressure, 20 g of sodium hydroxide NF tablets were stirred and dissolved in 250 mL of water for injection (WFI) to prepare a 2N sodium hydroxide solution. The Beckmann pH probes were calibrated with pH 7 and pH 10 buffers. A Kontes 317000-1000, one liter glass mixer / reactor equipped with jacketed cooler and stirrer was charged with 400 mL of WFI (approximately 50% of the total batch volume) pre-cooled to about 5°C. 28.0 g of sodium bicarbonate was then dissolved in the mixer / reactor and the temperature of the mixer / reactor was maintained at a temperature of about 1°C to about 5°C and a pH of about 8.1 to about 8.5.

[0196] About 160 g of free acid with a water content of about 17.0% by weight (calculated from the monosodium salt of carbapenem) was melted from -20°C to room temperature over about 30 minutes. The drug batch was divided into ten equal portions and added gradually to the sodium bicarbonate solution along with the 2N NaOH sol...

Embodiment 3

[0226] Examples 3 and 4 were carried out in essentially the same manner as described below, except for the parameters given in Table 5. The vial used in Example 3 was a common 20mL vial, while the vial used in Example 4 was ADD-Vantage TM 15mL vials.

[0227] Table 5: Reaction Conditions

[0228] parameters

Example 3

Example 4

Drug feeding time (min.)

45

66

Total mixing time (min.)

114

134

pH controller set point during drug dosing

7.6

7.6

pH controller set point during pH adjustment

7.7

7.7

Molar ratio of added NaOH to active drug

0.85

0.87

Filtration time (min.)

30

31

Vial filling time (min.)

203

157

Low temperature freeze dryer cycle time (min.)

65

78

[0229] To prepare a pilot scale batch formulation, a 2N sodium hydroxide solution was prepared by dissolving approximately 250 g of sodium hydroxide...

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Abstract

The present invention involves a process for preparing a stable final formulation product of a compound of formula (I) or its pharmaceutically acceptable salt, hydrate or solvate by incorporating a suitable carbon dioxide source to an unstable monosodium adduct of carbapenem antibiotic compound.

Description

[0001] Related Application Introduction [0002] This application is a continuation-in-part of US Patent Application Serial No. 09 / 698,808, filed October 27,2000. technical field [0003] The present invention relates to methods for the preparation of stable forms of antibiotic compounds, particularly carbapenem antibiotic compositions. Background technique [0004] The β-lactam antibiotics, further defined as carbapenems, are a larger class of antibiotics useful in the treatment of infectious diseases including Gram-positive and negative, aerobic and anaerobic bacteria. Carbapenems were first isolated from fermentation broth in 1974, and they were found to have broad-spectrum antibacterial activity. Since this discovery, extensive research has been conducted to develop new carbapenem derivatives, and hundreds of patents and scientific papers have been published. The carbapenem sold in the market is imipenem (N-iminomethylthiomycin), which has broad-spectrum antibacterial ...

Claims

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Application Information

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IPC IPC(8): C07D477/20A61K31/40A61J3/00A61K9/19A61K31/407A61K47/04A61P31/04C07D477/00C07D477/02
CPCC07D477/02A61K31/407C07D477/20A61K31/40A61P31/04
Inventor A·阿尔-德尼W·A·亨克K·J·伊利A·卡尼克H·帕特尔S·D·雷诺S·C·齐农蒂德斯
Owner SCHERING AG