Carbapenem compound crystals and injection preparations

Abstract

The present invention provides carbapenem hydrochloride trihydrate crystals, which are chemically stable, easily purified and useful as antimicrobial agents, a process for producing them, and a powdery charged preparation for injection containing them. That is, it provides carbapenem hydrochloride trihydrate crystals having a powdery X-ray diffraction pattern containing lattice distances (d) of 9.0, 4.1 and 2.8 Å, a process for producing them, and a powdery charged preparation for injection containing them.

1 . (+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carboxylic acid monohydrochloride trihydrate crystals having a powdery X-ray diffraction pattern containing lattice distances (d) of 9.0, 4.1 and 2.8 Å, represented by the following formula (1-1):  
     
       
         
         
             
             
         
       
     
   
   
       2 . The crystals according to  claim 1 , which are trihydrate having a powdery X-ray diffraction pattern containing lattice distances (d) of 9.0, 5.4, 5.2, 5.0, 4.1, 4.0, 3.8, 3.6, 3.4, 3.1, 2.8 and 2.6 Å.  
   
   
       3 . A process for producing (+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carboxylic acid monohydrochloride trihydrate crystals, which comprises dissolving (+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carboxylic acid or a salt thereof in a solvent system consisting of water and isopropanol; and then crystallizing from the solution.  
   
   
       4 . The process according to  claim 3 , wherein 50 to 90% (v/v) aqueous isopropanol solution is used as the crystallization solvent.  
   
   
       5 . The process according to  claim 3 , wherein crystallization is conducted at a temperature of 0 to 20° C.  
   
   
       6 . The process according to  claim 5 , wherein crystallization is conducted at a temperature of 10° C.  
   
   
       7 . The process according to  claim 3 , wherein a solution of (+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carboxylic acid at a concentration of 7 to 10% (w/w) in solvent is used in crystallization.  
   
   
       8 . The process for producing according to  claim 3 , wherein the trihydrate crystals are crystals having a powdery X-ray diffraction pattern containing lattice distances (d) of 9.0, 4.1 and 2.8 Å.  
   
   
       9 . The process for producing according to  claim 3 , wherein the trihydrate crystals are crystals having a powdery X-ray diffraction pattern containing lattice distances-(d) of 9.0, 5.4, 5.2, 5.0, 4.1, 4.0, 3.8, 3.6, 3.4, 3.1, 2.8 and 2.6 Å.  
   
   
       10 . A process for producing (+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carboxylic acid monohydrochloride trihydrate crystals, which comprises dissolving (+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2′-[(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thio-1-carbapen-2-em-3-carboxylic acid monohydrochloride monohydrate crystals in 50 to 90% (v/v) aqueous isopropanol solution; and crystallizing at a temperature of 0 to 20° C.  
   
   
       11 . The process according to  claim 10 , wherein the trihydrate crystals are crystals having a powdery X-ray diffraction pattern containing lattice distances (d) of 9.0, 4.1 and 2.8 Å.  
   
   
       12 . The process for producing according to  claim 10 , wherein the trihydrate crystals are crystals having a powdery X-ray diffraction pattern containing lattice distances (d) of 9.0, 5.4, 5.2, 5.0, 4.1, 4.0, 3.8, 3.6, 3.4, 3.1, 2.8 and 2.6 Å.