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FK888 (NK1 antagonist) is a candidate drug for migraine and selected as a model of amorphous drug. FK888 was micronized to develop as dry powder inhalers (DPIs) taking into consideration of its water insoluble property. The glass transition temperature (Tg) and fragility (m) were 90 degrees C and 118, respectively, and it was categorized as a fragile glass based on Angell's concept. FK888 was structurally relaxed by aging below Tg, then the effect of aging on their physical and aerosol properties were investigated. The investigation on the moisture sorption-desorption isotherms of FK888 indicated that aged FK888 adsorbed less amount of water than that of unaged FK888. This unique moisture sorption-desorption behavior of the aged sample is explained by structural relaxation accompanying decrease of free volume and/or increase of density. As for the dissolution rate of unaged and aged FK888, they showed the similar value, suggesting that there would be no difference in bioavailability. In relation to the stability, FK888 DPIs prepared by unaged and aged FK888 were stored at 70 degrees C, and the respirable fraction of FK888 DPIs was evaluated by using multistage cascade impactor (USP apparatus 3). As a result, the respirable fraction of FK888 DPIs prepared by unaged sample was significantly decreased compared to the aged sample, suggesting that agglomeration may occur in the unaged sample during the storage. This phenomenon was supported by that the unaged sample showed a significant decrease in the surface area compared to that of the aged sample when stored at various conditions.

Citation

Kazuyuki Tanaka, Satoshi Kitamura, Teruyuki Kitagawa. Effect of structural relaxation on the physical and aerosol properties of amorphous form of FK888 (NK1 antagonist). Chemical & pharmaceutical bulletin. 2005 May;53(5):498-502

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PMID: 15863919

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