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Novel crystal form of carbapenem antimicrobial medicament and preparation method of novel crystal form

A technology of antibacterial drugs and carbapenems, applied in the field of new crystal forms of drugs, can solve problems such as difficult industrial production, complicated process, and high cost

Active Publication Date: 2014-03-26
SHANDONG FREDA PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] The purpose of the present invention is to overcome the technical problems of poor stability of the existing crystal form, high cost, complicated process and difficulty in commercial production, without the need for a special intermediate crystal form, and to provide a new type of doripenem crystal with excellent stability. In the X-ray diffraction pattern of crystalline powder, there are characteristic absorption peaks at diffraction angles 2θ=15.20, 16.06, 16.83, 19.40, 21.29, 23.68, 24.08, 24.70, 26.28, 28.43, 29.17, and 34.35

Method used

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  • Novel crystal form of carbapenem antimicrobial medicament and preparation method of novel crystal form
  • Novel crystal form of carbapenem antimicrobial medicament and preparation method of novel crystal form
  • Novel crystal form of carbapenem antimicrobial medicament and preparation method of novel crystal form

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Experimental program
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Effect test

Embodiment 1

[0043]Add 10g of doripenem into 200ml of 80% isopropanol aqueous solution, stir to cool down to 0-5°C, add dropwise 20% NaOH aqueous solution, adjust pH=10, dissolve the solid, filter with suction, and use 10% dilute hydrochloric acid for the filtrate Adjust pH=5, solid precipitates, stir and crystallize at 0~5°C for 3~4h, filter with suction, wash the filter cake with cold 80% isopropanol aqueous solution, dry under reduced pressure (gauge pressure not less than 0.095MPa) at 50°C for 24h , and 8.5 g of the new crystal form of doripenem was obtained.

[0044] The powder X-ray diffraction spectrum of gained crystal sees figure 1 , where there are main peaks at diffraction angles 2θ=15.19, 16.05, 16.84, 19.35, 21.23, 24.08, 26.27, 28.42, 29.14, 34.34.

Embodiment 2

[0046] Add 10g of doripenem into 100ml of 80% ethanol aqueous solution, stir to cool down to 0-5°C, add 20% KOH aqueous solution dropwise, adjust pH to 9, dissolve solid, filter with suction, and adjust pH of filtrate with 10% dilute sulfuric acid = 5, solid precipitated, stirred and crystallized at 0-5°C for 3-4h, filtered with suction, washed the filter cake with cold 80% ethanol aqueous solution, and dried under reduced pressure (gauge pressure not less than 0.095MPa) at 50°C for 24h to obtain new crystals Type doripenem 7.9g.

[0047] The powder X-ray diffraction spectrum of gained crystal sees figure 2 , wherein there are main peaks at diffraction angles 2θ=15.19, 16.05, 16.84, 19.31, 21.26, 24.07, 26.27, 28.42, 29.14, 34.34.

Embodiment 3

[0049] Add 10g of doripenem into 150ml of 80% acetone aqueous solution, stir to cool down to 0-5°C, add 20% sodium carbonate aqueous solution dropwise, adjust the pH to 10, dissolve the solid, filter with suction, and adjust the filtrate with 10% dilute hydrochloric acid. pH = 4.5, solids precipitated, stirred and crystallized at 0-5°C for 3-4 hours, filtered with suction, washed the filter cake with cold 80% acetone aqueous solution, dried under reduced pressure (gauge pressure not less than 0.095MPa) at 50°C for 24 hours, and obtained new Crystal form doripenem 8.2g.

[0050] There are main peaks at diffraction angles 2θ=15.20, 16.05, 16.84, 19.41, 21.30, 23.69, 24.07, 24.69, 26.26, 28.40, 29.21, and 34.38 of the obtained crystals.

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Abstract

The invention provides a novel crystal form of a carbapenem antimicrobial medicament, namely, (+)-(4R,5S,6S)-3-[[(3S,5S)-5-(aminosulfonyl)aminomethyl]-3-pyrrolidine]sulfur]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclic[3,2,0]heptyl-2-ene-2-carboxylic acid-hydrate (doripenem). The X-ray powder diffraction pattern of the crystal powder shows main peaks when 2theta is equal to 15.20 degrees, 16.06 degrees, 16.83 degrees, 19.40 degrees, 21.29 degrees, 23.68 degrees, 24.08 degrees, 24.70 degrees, 26.28 degrees, 28.43 degrees, 29.17 degrees and 34.35 degrees. The novel crystal form has the advantages of easiness in preparation and industrial production, low cost, high solubility and high stability.

Description

technical field [0001] The invention relates to a new crystal form of a drug, in particular to a carbapenem antibacterial drug (+)-(4R, 5S, 6S)-3-[[(3S, 5S)-5-[[(aminosulfonyl)amino ]methyl]-3-pyrrolidine]thio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]heptyl- New crystal forms of 2-ene-2-carboxylic acid monohydrate (doripenem) and methods for their preparation. Background technique [0002] Doripenem (S-4661) is a broad-spectrum carbapenem antibiotic developed by Shionogi Company in Japan. -1 stability and other advantages. Its chemical name is (+)-(4R, 5S, 6S)-3-[[(3S, 5S)-5-[[(aminosulfonyl)amino]methyl]-3-pyrrolidine]sulfur]-6 -[(1R)-1-Hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylic acid monohydrate, the structural formula is as follows Shown in formula (I). [0003] [0004] Chinese patents CN200510021270.1 and CN92111069.3 describe the preparation of its amorphous powder. Due to the relatively poor stability of the amorp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D477/20C07D477/02
CPCC07D477/02C07D477/20
Inventor 郑德强刘文涛毋立华王长斌孙利民索栋李帅任文杰郭新艳张玲凌沛学
Owner SHANDONG FREDA PHARMA GRP CO LTD
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