Physicochemical analyses of phase transition and dehydration processes of a new oral 1beta-methylcarbapenem antibiotic agent, CS-834.

Katsuhiro Kobayashi, Hiroshi Fukuhara, Isao Kawamoto, Tadashi Hata, Akiko Sekine, Hidehiro Uekusa, Yuji Ohashi

Process Development Laboratories, Sankyo Co Ltd, Kanagawa, Japan.

Chemical & pharmaceutical bulletin 2002 Dec

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The characterizations of the anhydrate (A-form), monohydrate (B1-form), and dihydrate (B2-form) of CS-834 were investigated by powder X-ray diffraction, differential scanning calorimetry (DSC), thermogravimetry-differential thermal analysis (TG-DTA), infrared spectroscopy, and Karl Fischer moisture titration. The typical DSC curve of the B2-form showed five endothermic peaks at 35.0, 46.4, 56.2, 99.2, and 190.4 degrees C and an exothermic peak at 123.4 degrees C. In TG-DTA analysis, the three peaks at 35.0, 46.4, and 56.2 degrees C had a total weight loss of 7.3%, corresponding to the release of two water molecules. From morphological observation under thermomicroscopy, the endothermic peak at 99.2 degrees C was attributed to the melting of the dehydrous crystals (B0-form) and the exothermic peak at 123.4 degrees C to the recrystallization to the A-form crystals. The endothermic peak at 190.4 degrees C was due to the melting of the A-form crystals. After incubation for 6.0 h at 35, 50, 60, and 80 degrees C, the powder X-ray diffraction patterns of the B2-form indicated that it was converted into the A-form via the B1-form and B0-form. Thus CS-834 exists in homologous hydrous crystal forms in multiple-phase transformations with the dehydration of two water molecules.

Citation

Katsuhiro Kobayashi, Hiroshi Fukuhara, Isao Kawamoto, Tadashi Hata, Akiko Sekine, Hidehiro Uekusa, Yuji Ohashi. Physicochemical analyses of phase transition and dehydration processes of a new oral 1beta-methylcarbapenem antibiotic agent, CS-834. Chemical & pharmaceutical bulletin. 2002 Dec;50(12):1570-3