Freeze-Drying of Cephalothin Sodium: Granularly Agglomerated Crystallization during Freezing. I

Abstract

Optimal conditions for the crystallization and subsequent freeze-drying of an aqueous cephalothin sodium (CET-Na) solution of supersaturated concentrations to obtain granular crystalline CET-Na have been discussed, as have the qualities of the product thus obtained. In general, CET-Na in supersaturated aqueous solution is barely recrystallized, even when in its frozen stage. Our previous report revealed that when the solution is kept at low temperatures for a long duration, the molecules begin to change structurally to as condensed a state as that of liquid crystals, and such change facilitates a spontaneous nucleation and seed-independent crystal growth in the frozen solution. These findings prompted the authors to investigate optimal CET-Na concentrations and thermal histories during the crystallization and subsequent freeze-drying process without seeding. It has subsequently been found out that optimization of the latter conditions gives granular agglomerated crystalline CET-Na contaminated with neither the amorphous nor the quasi-crystalline form. The optimized conditions are: 25—28% CET-Na concentrations; storage before the freezing process at 0°C for 2 h, and subsequent storage at 20—25°C for 1 h; cooling in the freezing process at a rate not faster than 0.5°C/min; warming of the solution for facilitating crystallization prior to vacuum application for drying at -4°C. Under these conditions, the freeze-dried product of CET-Na in granular form has been successfully obtained in a shorter freeze-drying cycle, exhibiting a faster reconstitution time than those of CET-Na prepared according to seeded crystallization followed by a conventional freeze-drying. © 1993, The Pharmaceutical Society of Japan. All rights reserved.