Pharmaceutical development of a lyophilised dosage form for the investigational anticancer agent Imexon using dimethyl sulfoxide as solubilising and stabilising agent.

Abstract

Imexon is a member of the class of 2-cyanoaziridine derivatives, which have been of interest as immunomodulators and anticancer agents since the late 1970s. For the scheduled phase I clinical trials a stable, sterile, injectable pharmaceutical dosage form containing 100 mg Imexon was required. Despite adequate solubility, its instability in aqueous media seriously hampered the pharmaceutical development of Imexon. In this study we describe the successful use of the organic solvent dimethyl sulfoxide (DMSO) as a formulation vehicle for Imexon. DMSO is shown to provide the stability required for Imexon during manufacturing and to be a suitable vehicle for lyophilisation, which was employed to gain sufficient shelf-life for the final product. The relatively low vapour pressure of DMSO, which would theoretically result in extremely slow sublimation during lyophilisation, was shown not to limit the successful lyophilisation of Imexon from DMSO at a concentration of 25 mg/mL. The lyophilisation cycle developed for Imexon resulted in residual DMSO contents of 4.6 +/- 0.6% in the lyophilised product, limiting the amount of DMSO administered to the patient to well below the 50 mg/day acceptable in pharmaceutical products as stated in ICH guidelines. Imexon 100 mg/vial lyophilised product was shown stable for at least 12 months of storage at -20 degrees C and +5 +/- 3 degrees C in the dark.