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.

Description

[0001] This is a continuation of Ser. No. 09 / 979,679, filed Nov. 16, 2001, which was the national stage of International Application No. PCT / JP00 / 03642, filed Jun. 5, 2000, which International Application was not published in English.TECHNICAL FIELD [0002] The present invention relates to a salt of a carbapenem compound or hydrate crystals of the salt, a process for producing it, and a powdery charged preparation for injection. The carbapenem compound is useful as an antimicrobial agent and an antibiotic. PRIOR ART [0003] The carbapenem compound or a salt thereof is known to have a strong and wide antimicrobial spectrum ranging from Gram negative to positive bacteria, but there is a problem with stability thereof in the human body and with safety in the human body owing to its toxicity. [0004] However, JP-A 8-73462 discloses that the carbapenem compound, that is, (+)-(1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-[(3R)-pyrrolidine-3-yl-(R)-hydroxymethyl]pyrrolidine-4-yl]thi...

AI Technical Summary

Benefits of technology

[0120] 250 mg carbapenem hydrochloride was dissolved in 10 mL distilled water for injection to prepare an aqueous injection. The pH value of this aqueous injection was 5.04.

[0121] As the injection to be dissolved just before use, a freeze-dried preparation was prepared in the following manner. 3.5 g carbapenem hydrochloride, 456 mg sodium chloride and 2.815 g lactose were dissolved in 250 mL distilled water for injection. This solution was introduced into 2 mL glass vials (0.25 ml / vial), which were then semi-capped with rubber stoppers and freeze dried for 1 day. After it was confirmed that the samples were dried, the vials were fully capped and bound with aluminum caps.

[0122] As the powdery charged preparation of the amorphous raw medicine, a carbapenem hydrochloride compound prepared in the method described in JP-A 8-73462 was used.

Problems solved by technology

The carbapenem compound or a salt thereof is known to have a strong and wide antimicrobial spectrum ranging from Gram negative to positive bacteria, but there is a problem with stability thereof in the human body and with safety in the human body owing to its toxicity.

However, this carbapenem compound or its hydrochloride is unstable in solution, and the degradation thereof is promoted under heating conditions, so it is hardly formed into a liquid injection.

Further, the carbapenem compound or a salt thereof which was formed by freeze-drying into a powdery charged preparation is amorphous and chemically unstable.

Further, because the carbapenem compound or a salt thereof could not easily be crystallized by techniques at that time, it was finally purified by reverse phase silica gel column chromatography to give an amorphous product.

In such column purification, however, a large amount of solvent is used to increase production costs and to make industrial large-scale treatment difficult, and further there are many problems such as possible pyrolysis in concentration of fractions, residual solvent, waste liquor, and environmental pollution resulting from solvent evaporation.

In addition, this amorphous substance is instable in solution, so the degradation thereof is promoted under heating conditions, thus making pharmaceutical manufacturing problematic.

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