1993 年 16 巻 4 号 p. 407-413
The mechanism of granularly agglomerated crystallization during freezing of cephalothin sodium (CET-Na) in aqueous solution has been discussed. Our previous report noted that strict control of the following is important in order to obtain crystalline granular agglomerates of CET-Na : (1) thermal history of the solution before receiving freezing, (2) cooling rate in freezing, and (3) aging temperature level in the crystal growth step. In order to clarify the physico/chemical meanings of the individual controls, further investigations have been made : 1) with varying thermal history, aqueous 30-% CET-Na solutions were prepared for storage, first at 0°C with its supersaturation and secondly at 25°C, in an unsaturated state for observing any structural changes by viscosimetry, refractometry, and surface tensiometry; 2) morphological changes in ice crystals during freezing at varying cooling rates, as well as those during the crystal growth step, were observed by polarized-light cryomicroscopy and scanning electron microscopy; 3) melting, as well as crystal growth, at several aging temperature levels were observed by electrical conductometry and also by the above-mentioned techniques.These investigations have disclosed that the structural properties of both the liquid and frozen solutions should be thermally well-controlled in order to realize each of the following : 1) the condensed structure of CET-Na solute in its liquid solution is just like a cluster level before freezing; 2) ice crystals formed during freezing are less changable morphologically with varying temperatures; 3) CET-Na crystal growth is facilitated by an increased mobility of the solute due to the partial thawing of ice crystals : it therefore is important that the aging temperature is adjusted to a level at which ice crystals show negligible changes in surface area, with the degree of supersaturation in its liquid portion still kept high.Using a freezer-dryer of about 1000 vials of 14-ml size, supersaturated CET-Na solutions have been successfully controlled to achieve the above-described optimal structures in these three steps, the control yielding the freeze-dried product of granular CET-Na crystals almost quantitatively.
