Physicochemical Analyses of Phase Transition and Dehydration Processes of a New Oral 1.BETA.-Methylcarbapenem Antibiotic Agent, CS-834.

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

doi:10.1248/cpb.50.1570

CHEMICAL & PHARMACEUTICAL BULLETIN

2002

DOI: 10.1248/cpb.50.1570

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Physicochemical Analyses of Phase Transition and Dehydration Processes of a New Oral 1.BETA.-Methylcarbapenem Antibiotic Agent, CS-834.

Katsuhiro Kobayashi

Hiroshi Fukuhara²,

Isao Kawamoto³

et al.

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Cited by 2 publications

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“…2. 10) This figure indicates that the B2-form is transformed to the dehydrate form (B0-form) through the B2Ј-, B1-, and B1Ј-forms, where the B1-form was the monohydrate form whereas the B2Ј-and B1Ј-forms were intermediate ones between the B2-and B1-forms, and between the B1-and B0-forms, respectively. The possible crystal transformation of CS-834 is summarized in Fig.…”

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confidence: 97%

In Situ Observation of the Four-step Dehydration Process of the 1.BETA.-Methylcarbapenem Antibiotic CS-834 Crystal by X-Rays

Kobayashi

Fukuhara²,

Hata

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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Bulk drug substances frequently can be obtained as crystalline hydrates rather than as anhydrates, because they can crystallize more easily, 1) or are transformed into hydrates by contact with water molecules from hydrate excipients in the formulation process.2) The hydrate crystals often transform into different solids such as amorphous or dehydrate form in the process of drying or storage under low relative humidity (RH). [3][4][5][6] Generally, the resulting dehydrate crystals can be converted to the different hydrate forms depending on the surrounding RH and temperature. It is also well known that different hydrate drugs show different physicochemical properties, 7,8) such as bioavailability, phase stability, and dissolution rate. For the development of pharmaceuticals using hydrous bulk drug substances, many efforts have been made to investigate the changes in the physicochemical properties in the process of phase transformation to different hydrate states. The prediction of hydration properties has therefore been a long-standing subject of great interest in pharmaceutical science.A compound of pivaloyloxymethyl (1R,5S,6S)-6-[(R)-1-hydroxyethyl]-1-methyl-2-[[(R)-5-oxo-pyrrolidin-3-yl]thio]-1-carbapen-2-em-3-carboxylate, CS-834, was developed as an orally effective 1b-methylcarbapenem antibiotic agent possessing potent and broad-spectrum antibacterial activities and excellent stability against dehydropeptidase-I (Fig. 1). 9)It crystallizes as an anhydrate form (A-form) from anhydrous solutions and as a dihydrate (B2-form) from an aqueous solution. The B2-form undergoes the multistep transformation following the loss of water molecules upon heating, as shown in Fig. 2.10) This figure indicates that the B2-form is transformed to the dehydrate form (B0-form) through the B2Ј-, B1-, and B1Ј-forms, where the B1-form was the monohydrate form whereas the B2Ј-and B1Ј-forms were intermediate ones between the B2-and B1-forms, and between the B1-and B0-forms, respectively. The possible crystal transformation of CS-834 is summarized in Fig. 3.It was reported that the hydrate crystals of disodium adenosine 5Ј-triphophate (Na 2 ATP) and disodium cytidine 5Ј-monophophate (Na 2 CMP) also underwent reversible humidity-dependent structural transformation between the higher hydrate and the lower hydrate forms as observed by X-ray crystal structure analysis.11,12) Here, we report the dehydration process of the hydrous crystal of CS-834, with the change in the RH and the structural changes in the transformation observed by single-crystal X-ray analysis. ExperimentalPreparation of Different Crystal Forms. Materials CS-834 of pharmaceutical grade was synthesized in the Process Development Laboratories of Sankyo Co., Ltd.Preparation of the Dihydrate (B2-Form) The A-form crystals were dissolved in a 3% aqueous ethyl acetate solution at 40°C. The solution was filtrated, evaporated, cooled to about 0°C, and kept at 0°C overnight. The crystals were collected by filtration and washed with 3% aqueous ethyl acetate. The crystals were kept ...

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confidence: 97%

In Situ Observation of the Four-step Dehydration Process of the 1.BETA.-Methylcarbapenem Antibiotic CS-834 Crystal by X-Rays

Kobayashi

Fukuhara²,

Hata

et al. 2003

CHEMICAL & PHARMACEUTICAL BULLETIN

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Analysis of phase transition and dehydration processes of nevirapine

Oliveira

Ferraz

Severino

et al. 2011

J Therm Anal Calorim

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Physicochemical Analyses of Phase Transition and Dehydration Processes of a New Oral 1.BETA.-Methylcarbapenem Antibiotic Agent, CS-834.

Cited by 2 publications

References 18 publications

In Situ Observation of the Four-step Dehydration Process of the 1.BETA.-Methylcarbapenem Antibiotic CS-834 Crystal by X-Rays

In Situ Observation of the Four-step Dehydration Process of the 1.BETA.-Methylcarbapenem Antibiotic CS-834 Crystal by X-Rays

Analysis of phase transition and dehydration processes of nevirapine

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