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

Chitra Telang, Raj Suryanarayanan

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)153-160
Number of pages8
JournalPharmaceutical research
Volume22
Issue number1
DOIs
StatePublished - Jan 2005

Keywords

  • Cephalothin
  • Crystallinity
  • Freeze-drying
  • X-ray diffractometry
  • tert-butyl alcohol

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