Crystallization of cephalothin sodium during lyophilization from tert-butyl alcohol-water cosolvent system

Purpose. Because cephalothin sodium (I) does not crystallize readily when freeze-dried from aqueous solutions, organic cosolvents were used to increase the crystallinity of lyophilized I. Methods. Compound I was lyophilized from water-organic cosolvent (5% w/w) systems of each ethanol, ispropanol, and tert-butyl alcohol (TBA). Results. When frozen solutions of I (10% w/w) in each of these cosolvent systems was characterized by DSC, the presence of cosolvent in the freeze-concentrate was evident. Moreover, the presence of the cosolvent accelerated the solute crystallization. This observation was based on the XRD of these systems during the various stages of freeze-drying. High initial solute concentration and annealing of frozen solutions facilitated the formation of a highly crystalline lyophile. The accelerated crystallization is attributed to supersaturation in cosolvent systems, facilitating nucleation during freezing with subsequent growth during annealing. Lyophiles obtained from water-isopropanol and water-ethanol systems collapsed, while the use of TBA as a cosolvent yielded a friable and pharmaceutically elegant cake, containing fine needle-shaped crystals of I. Gas chromatography revealed a residual TBA concentration of ∼0.001% w/w in the crystalline lyophiles. In general, residual cosolvent levels were higher in lyophiles with lower crystallinity. Conclusions. TBA-water was found to be a suitable freeze-drying medium to promote crystallization of I and yielded a lyophile with desirable product characteristics.