FREEZE-DRYING OF DRUG-ADDITIVE BINARY-SYSTEMS .3. CRYSTALLIZATION OF ALPHA-CYCLODEXTRIN INCLUSION COMPLEX IN FREEZING PROCESS

The crystallization of α-cyclodextrin (α-CD) inclusion complexes during the process of freeze-drying has been studied. Benzoic acid, salicylic acid, m-hydroxybenzoic acid, p-hydroxybenzoic acid and methyl p-hydroxybenzoate were used as guest molecules. Various amounts of guest compound were dissolved in aqueous α-CD solution. By annealing the binary solutions at -13 to -18°C, the inclusion complex crystallized readily at a molar ratio of 2:1 (α-CD: guest). All inclusion crystals obtained via freeze-drying were of a channel-type structure, while in the coprecipitation method p-hydroxybenzoic acid and methyl p-hydroxybenzoate formed a layer-type inclusion crystal with α-CD. Further, an aqueous binary solution of α-CD and aspirin (2:1 molar ratio) was slowly frozen at -14°C, and then lyophilized. The infrared spectra and the powder X-ray diffractograms indicated that the channel-type inclusion compound of aspirin with α-CD was formed by freeze-drying, although the coprecipitation method did not provide the inclusion compound crystal. It was assumed that the mechanism of solid-phase formation differed between the freezing and coprecipitation processes and that the channel-type structure of α-CD inclusion crystal was preferentially formed during the freezing process. © 1990.