Freeze-drying of cephalothin sodium: granularly agglomerated crystallization during freezing. I.
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 degrees C for 2 h, and subsequent storage at 20-25 degrees C for 1 h; cooling in the freezing process at a rate not faster than 0.5 degrees C/min; warming of the solution for facilitating crystallization prior to vacuum application for drying at -4 degrees 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.
Suzuki
Y
Y
Research Laboratories, Shionogi & Co., Ltd., Hyogo, Japan.
Takeda
T
T
Inazu
K
K
Sakamoto
T
T
D002512:Cephalothin / Q000737:chemistry*; D003460:Crystallization; D004356:Drug Storage; D005612:Freeze Drying; D008855:Microscopy, Electron, Scanning; D011208:Powders; D012995:Solubility; D013696:Temperature; D013818:Thermogravimetry; D014961:X-Ray Diffraction
D011208:Powders; D002512:Cephalothin